Publications by authors named "Umberto Gianelli"

107 Publications

Triple-Negative Essential Thrombocythemia: Clinical-Pathological and Molecular Features. A Single-Center Cohort Study.

Front Oncol 2021 12;11:637116. Epub 2021 Mar 12.

Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Lack of demonstrable mutations affecting , or driver genes within the spectrum of -negative myeloproliferative neoplasms (MPNs) is currently referred to as a triple-negative genotype, which is found in about 10% of patients with essential thrombocythemia (ET) and 5-10% of those with primary myelofibrosis (PMF). Very few papers are presently available on triple-negative ET, which is basically described as an indolent disease, differently from triple-negative PMF, which is an aggressive myeloid neoplasm, with a significantly higher risk of leukemic evolution. The aim of the present study was to evaluate the bone marrow morphology and the clinical-laboratory parameters of triple-negative ET patients, as well as to determine their molecular profile using next-generation sequencing (NGS) to identify any potential clonal biomarkers. We evaluated a single-center series of 40 triple-negative ET patients, diagnosed according to the 2017 WHO classification criteria and regularly followed up at the Hematology Unit of our Institution, between January 1983 and January 2019. In all patients, NGS was performed using the Illumina Ampliseq Myeloid Panel; morphological and immunohistochemical features of the bone marrow trephine biopsies were also thoroughly reviewed. Nucleotide variants were detected in 35 out of 40 patients. In detail, 29 subjects harbored one or two variants and six cases showed three or more concomitant nucleotide changes. The most frequent sequence variants involved the gene (55.0%), followed by (27.5%). Histologically, most of the cases displayed a classical ET morphology. Interestingly, prevalent megakaryocytes morphology was more frequently polymorphic with a mixture of giant megakaryocytes with hyperlobulated nuclei, normal and small sized maturing elements, and naked nuclei. Finally, in five cases a mild degree of reticulin fibrosis (MF-1) was evident together with an increase in the micro-vessel density. By means of NGS we were able to identify nucleotide variants in most cases, thus we suggest that a sizeable proportion of triple-negative ET patients do have a clonal disease. In analogy with driver genes-mutated MPNs, these observations may prevent issues arising concerning triple-negative ET treatment, especially when a cytoreductive therapy may be warranted.
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http://dx.doi.org/10.3389/fonc.2021.637116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006378PMC
March 2021

CD34-Positive Blast Count and p53 Expression in Bone Marrow Biopsies of Patients with Low-Risk Myelodysplastic Syndromes: Potential Predictive Tools of Response to Erythropoietin Stimulating Agents.

Pathobiology 2021 15;88(3):242-250. Epub 2021 Feb 15.

Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Introduction: The first-line therapy for patients with low-risk myelodysplastic syndromes (MDSs) commonly consists of erythropoietin stimulating agents (ESAs), with a response rate ranging from 34 to 62%. For nonresponder patients, outside clinical trials, blood transfusions are the most frequent therapeutic option, with detrimental effect on the quality of life and with risks of iron-overload. Since no studies have been yet conducted on this topic, we investigated the potential predictive role of bone marrow (BM) histological evaluation in patients treated with ESAs.

Materials And Methods: We performed a morphological and immunohistochemical retrospective analysis of BM biopsies of 96 patients with low-risk MDSs subsequently treated with ESAs.

Results: In our series, substantial morphological overlap was found between responder and nonresponder patients. On the contrary, patients with a percentage of CD34-positive blasts >3% or with p53 protein expression <1% responded with a significantly higher frequency to ESAs.

Conclusions: Our study reinforces the role of BM biopsy as diagnostic tool in MDSs, being also able to supply information related to response to ESAs and to its loss over time.
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http://dx.doi.org/10.1159/000512700DOI Listing
February 2021

Che-1/AATF-induced transcriptionally active chromatin promotes cell proliferation in multiple myeloma.

Blood Adv 2020 11;4(22):5616-5630

SAFU Laboratory.

Multiple myeloma (MM) is a hematologic malignancy produced by a clonal expansion of plasma cells and characterized by abnormal production and secretion of monoclonal antibodies. This pathology exhibits an enormous heterogeneity resulting not only from genetic alterations but also from several epigenetic dysregulations. Here we provide evidence that Che-1/AATF (Che-1), an interactor of RNA polymerase II, promotes MM proliferation by affecting chromatin structure and sustaining global gene expression. We found that Che-1 depletion leads to a reduction of "active chromatin" by inducing a global decrease of histone acetylation. In this context, Che-1 directly interacts with histones and displaces histone deacetylase class I members from them. Strikingly, transgenic mice expressing human Che-1 in plasma cells develop MM with clinical features resembling those observed in the human disease. Finally, Che-1 downregulation decreases BRD4 chromatin accumulation to further sensitize MM cells to bromodomain and external domain inhibitors. These findings identify Che-1 as a promising target for MM therapy, alone or in combination with bromodomain and external domain inhibitors.
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http://dx.doi.org/10.1182/bloodadvances.2020002566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686885PMC
November 2020

Progression, transformation, and unusual manifestations of myelodysplastic syndromes and myelodysplastic-myeloproliferative neoplasms: lessons learned from the XIV European Bone Marrow Working Group Course 2019.

Ann Hematol 2021 Jan 31;100(1):117-133. Epub 2020 Oct 31.

Institute of Medical Genetics and Pathology, University Hospital of Basel, Schoenbeinstrasse 40, CH-4031, Basel, Switzerland.

Disease progression in myelodysplastic syndromes (MDS) and myelodysplastic-myeloproliferative neoplasms (MDS/MPN) is a major source of mortality. The European Bone Marrow Working Group organized a dedicated workshop to address MDS and MDS/MPN progression, and myeloid neoplasms with histiocytic and lymphoblastic outgrowths in 2019 in Frankfurt, Germany. In this report, we summarize clinical, histopathological, and molecular features of 28 cases. Most cases illustrate that prognostic mutational profiles change during follow-up due to accumulation of high-risk mutations in the trunk clone, and that results from repeated molecular testing can often explain the clinical progression, suggesting that regular genetic testing may predict transformation by early detection of aggressive clones. Importantly, identical mutations can be linked to different clinical behaviors or risks of fibrotic progression and/or transformation in a context-dependent manner, i.e., MDS or MDS/MPN. Moreover, the order of mutational acquisition and the involved cell lineages matter. Several cases exemplify that histiocytic outgrowths in myeloid neoplasms are usually accompanied by a more aggressive clinical course and may be considered harbinger of disease progression. Exceptionally, lymphoblastic transformations can be seen. As best estimable, the histiocytic and lymphoblastic compounds in all occasions were clonally related to the myeloid compound and-where studied-displayed genomic alterations of, e.g., transcription factor genes or genes involved in MAPK signaling that might be mechanistically linked to the respective type of non-myeloid outgrowth.
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http://dx.doi.org/10.1007/s00277-020-04307-9DOI Listing
January 2021

Cytogenetic study in primary myelofibrosis at diagnosis: Clinical and histological association and impact on survival according to WHO 2017 classification in an Italian multicenter series.

Hematol Oncol 2021 Feb 4;39(1):123-128. Epub 2020 Oct 4.

Division of Pathology, Department of Pathophysiology and Transplantation, University of Milan, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

We analyzed cytogenetic data at diagnosis in 395 primary myelofibrosis (PMF) patients to evaluate any possible association between karyotype and WHO 2017 classification and its impact on prognosis. All the cases were diagnosed and followed at five Italian Hematological Centers between November 1983 and December 2016. An abnormal karyotype (AK) was found in 69 patients and clustered differently according to bone marrow fibrosis grade as it was found in 31 (27.0%) cases with overt fibrotic and 38 (13.6%) with pre-fibrotic PMF (p = 0.001). Sex, anemia, thrombocytopenia, circulating blasts ≥1%, higher lactate dehydrogenase, and International Prognostic Scoring System risk classes were all significantly associated with karyotype. At a median follow-up of >6 years, 101 deaths were recorded. Survival was different between AK and normal karyotype (NK) patients with an estimated median overall survival (OS) of 11.6 and 25.7 years, respectively (p = 0.0148). In conclusion, in our cohort around 20% of patients had an AK, more frequently in subjects with an advanced bone marrow fibrosis grade and clinical-laboratory features indicative of a more aggressive disease. This study shows that an AK confers a more severe clinical phenotype and impacts adversely on OS, thus representing an additional parameter to be considered in the evaluation of PMF prognosis.
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http://dx.doi.org/10.1002/hon.2808DOI Listing
February 2021

A woman with refractory edema and pancytopenia.

Intern Emerg Med 2020 May 7. Epub 2020 May 7.

Division of Internal Medicine, IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Via Francesco Sforza 28, 20122, Milan, Italy.

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http://dx.doi.org/10.1007/s11739-020-02333-zDOI Listing
May 2020

The Spectrum of Aggressive Mastocytosis: A Workshop Report and Literature Review.

Pathobiology 2020 4;87(1):2-19. Epub 2019 Dec 4.

Department of Pathology, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA.

Most cases of mastocytosis are indolent, usually cutaneous mastocytosis or indolent systemic mastocytosis (SM). Aggressive mast cell (MC) diseases are very rare and often fatal. They can develop de novo or due to progression of indolent forms and can present in different ways; either as MC sarcoma or as advanced SM which includes aggressive SM, MC leukemia, and SM with an associated hematological neoplasm. This review will describe these different aggressive forms of mastocytosis, illustrated by cases submitted to the workshop of the 18th Meeting of the European Association for Haematopathology, Basel 2016, organized by the European Bone Marrow Working Group. In addition, the diagnostic criteria for identifying myelomastocytic leukemia, an aggressive myeloid neoplasm with partial MC differentiation that falls short of the criteria for SM, and disease progression in patients with established mastocytosis are discussed.
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http://dx.doi.org/10.1159/000504099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158230PMC
October 2020

Defective interaction of mutant calreticulin and SOCE in megakaryocytes from patients with myeloproliferative neoplasms.

Blood 2020 01;135(2):133-144

Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Approximately one-fourth of patients with essential thrombocythemia or primary myelofibrosis carry a somatic mutation of the calreticulin gene (CALR), the gene encoding for calreticulin. A 52-bp deletion (type I mutation) and a 5-bp insertion (type II mutation) are the most frequent genetic lesions. The mechanism(s) by which a CALR mutation leads to a myeloproliferative phenotype has been clarified only in part. We studied the interaction between calreticulin and store-operated calcium (Ca2+) entry (SOCE) machinery in megakaryocytes (Mks) from healthy individuals and from patients with CALR-mutated myeloproliferative neoplasms (MPNs). In Mks from healthy subjects, binding of recombinant human thrombopoietin to c-Mpl induced the activation of signal transducer and activator of transcription 5, AKT, and extracellular signal-regulated kinase 1/2, determining inositol triphosphate-dependent Ca2+ release from the endoplasmic reticulum (ER). This resulted in the dissociation of the ER protein 57 (ERp57)-mediated complex between calreticulin and stromal interaction molecule 1 (STIM1), a protein of the SOCE machinery that leads to Ca2+ mobilization. In Mks from patients with CALR-mutated MPNs, defective interactions between mutant calreticulin, ERp57, and STIM1 activated SOCE and generated spontaneous cytosolic Ca2+ flows. In turn, this resulted in abnormal Mk proliferation that was reverted using a specific SOCE inhibitor. In summary, the abnormal SOCE regulation of Ca2+ flows in Mks contributes to the pathophysiology of CALR-mutated MPNs. In perspective, SOCE may represent a new therapeutic target to counteract Mk proliferation and its clinical consequences in MPNs.
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http://dx.doi.org/10.1182/blood.2019001103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952826PMC
January 2020

Hypereosinophilic syndromes in the precision medicine era: clinical, molecular aspects and therapeutic approaches (targeted therapies).

Expert Rev Hematol 2019 12 15;12(12):1077-1088. Epub 2019 Oct 15.

Division of Pathology, Department of Pathophysiology and Transplantation, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, and University of Milan, Milan, Italy.

: Hypereosinophilic syndromes are a heterogeneous group of disorders that may be associated with life-threatening organ injury as a result of tissues infiltration by eosinophils. The main goal of therapy is to mitigate eosinophil-mediated organ damage. When possible, therapy should be directed at the underlying etiology. However, even in the absence of any known cause, when organ damage is present, hypereosinophilia must be treated promptly and aggressively to reduce potential morbidity and mortality.: Conventional therapies, including corticosteroids, hydroxyurea (hydroxycarbamide) and interferon-alpha, have shown variable efficacy and a non-negligible toxicity emphasizing the need of new therapeutic strategies based on drugs with different mechanisms of action.: Tyrosine kinase inhibitors have a central role among targeted therapies of hypereosinophilic syndromes. Imatinib, initially empirically used based on its activity in chronic myeloid leukemia, achieved preliminary excellent results further confirmed in large series of patients. Third-generation tyrosine kinase inhibitors such as ponatinib, while active in vitro and in vivo in animals, still deserve confirmation in properly designed clinical trials. In addition, clinical investigation on monoclonal antibodies against interleukin-5, interleukin-5Rα, IgE, and CD52 represents a promising area of research.
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http://dx.doi.org/10.1080/17474086.2019.1677461DOI Listing
December 2019

Mitochondrial fission factor is a novel Myc-dependent regulator of mitochondrial permeability in cancer.

EBioMedicine 2019 Oct 18;48:353-363. Epub 2019 Sep 18.

Prostate Cancer Discovery and Development Program, USA; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address:

Background: Mitochondrial functions are exploited in cancer and provide a validated therapeutic target. However, how this process is regulated has remained mostly elusive and the identification of new pathways that control mitochondrial integrity in cancer is an urgent priority.

Methods: We studied clinically-annotated patient series of primary and metastatic prostate cancer, representative cases of multiple myeloma (MM) and publicly available genetic databases. Gene regulation studies involved chromatin immunoprecipitation, PCR amplification and Western blotting of conditional Myc-expressing cell lines. Transient or stable gene silencing was used to quantify mitochondrial functions in bioenergetics, outer membrane permeability, Ca homeostasis, redox balance and cell death. Tumorigenicity was assessed by cell proliferation, colony formation and xenograft tumour growth.

Findings: We identified Mitochondrial Fission Factor (MFF) as a novel transcriptional target of oncogenic Myc overexpressed in primary and metastatic cancer, compared to normal tissues. Biochemically, MFF isoforms, MFF1 and MFF2 associate with the Voltage-Dependent Anion Channel-1 (VDAC1) at the mitochondrial outer membrane, in vivo. Disruption of this complex by MFF silencing induces general collapse of mitochondrial functions with increased outer membrane permeability, loss of inner membrane potential, Ca unbalance, bioenergetics defects and activation of cell death pathways. In turn, this inhibits tumour cell proliferation, suppresses colony formation and reduces xenograft tumour growth in mice.

Interpretation: An MFF-VDAC1 complex is a novel regulator of mitochondrial integrity and actionable therapeutic target in cancer.
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http://dx.doi.org/10.1016/j.ebiom.2019.09.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838406PMC
October 2019

Clinical and molecular characteristics of lymphoplasmacytic lymphoma not associated with an IgM monoclonal protein: A multicentric study of the Rete Ematologica Lombarda (REL) network.

Am J Hematol 2019 11 9;94(11):1193-1199. Epub 2019 Sep 9.

Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Lymphoplasmacytic lymphoma (LPL) is usually associated with a serum IgM paraprotein, corresponding to Waldenström's Macroglobulinemia (WM). Cases presenting with IgG or IgA, or without a monoclonal protein are extremely rare. We analyzed clinical characteristics, frontline treatment, and the outcome of 45 patients with non-IgM LPL, and compared them with a control group of WM patients. The median age was similar, with significantly higher prevalence of females in non-IgM LPL, than in WM patients (60% vs 39%, P = .016). Patients with non-IgM LPL more frequently presented with lymphadenopathies (53% vs 15%, P < .001), splenomegaly (22% vs 8%, P = .015) or extranodal involvement (20% vs 8%, P = .05). In non-IgM LPL a serum monoclonal protein and bone marrow infiltration were less common than in WM patients (69% and 84% of cases respectively, P < .001 for both comparisons). The MYD88 (L265P) mutation was found in 8/19 patients using allele-specific polymerase chain reaction. A CXCR4 mutation was found in 4/17 cases using Sanger. In 16 patients we performed targeted next-generation sequencing of genes MYD88, CXCR4, ARID1-A, KMT2D, NOTCH2, TP53, PRDM1, CD79B, TRAF3, MYBBP1A, TNFAIP3. Seven patients (44%) had a MYD88 mutation (S219C in one), four (25%) a CXCR4 mutation, three (19%) a KMT2D mutation, one (6%) a TP53 mutation and one (6%) a TRAF3 mutation. With a median follow-up of 55.7 months, 36 non-IgM LPL patients (80%) were treated. Non-IgM LPL patients received more frequently anthracycline-containing regimens, as compared with WM patients, who mainly received alkylating-based therapies. Five-year overall survival (OS) was 84%, similar to that of WM patients.
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http://dx.doi.org/10.1002/ajh.25600DOI Listing
November 2019

Integrating clinical, morphological, and molecular data to assess prognosis in patients with primary myelofibrosis at diagnosis: A practical approach.

Hematol Oncol 2019 Oct 22;37(4):424-433. Epub 2019 Aug 22.

Division of Pathology, Department of Pathophysiology and Transplantation, University of Milan, and Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Currently available prognostic scoring systems in primary myelofibrosis (PMF) do not integrate clinical, histological, and molecular data, or they also required information on "other" mutations that are available in the clinical practice only in a very limited number of laboratories. In the present multicenter study, including 401 PMF patients, an integrated International Prognostic Scoring System (I-IPSS) was developed by combining IPSS, grade of bone marrow fibrosis (GBMF), and driver mutations molecular status (MS) to define PMF prognosis at diagnosis. Four prognostic categories were identified: I-IPSS-low risk (113 patients), I-IPSS-intermediate-1 risk (56 patients), I-IPSS-intermediate-2 risk (154 patients), and I-IPSS-high risk (78 patients). Median overall survival was 26.7 years in I-IPSS-intermediate-1, 10.8 in I-IPSS-intermediate-2, and 6.4 in I-IPSS-high-risk patients (log-rank test <0.0001); instead, it was not reached in the I-IPSS-low-risk cohort because of the extremely low number of registered deaths. The addition of GBMF and MS to IPSS improved the efficacy for predicting the risk of death. Indeed, the sensitivity of I-IPSS was significantly higher (P < .05) than that of IPSS, considering both total deaths and 5- and 10-year mortality. This comprehensive approach allows clinicians to evaluate mutual interactions between IPSS, GBMF, and MS and identify high-risk patients with poor prognosis who may benefit from aggressive treatments. More importantly, this integrated score can be easily applicable worldwide as it only required information that represent the good clinical practice in the management of PMF patients.
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http://dx.doi.org/10.1002/hon.2658DOI Listing
October 2019

Blast Transformation in Myeloproliferative Neoplasms: Risk Factors, Biological Findings, and Targeted Therapeutic Options.

Int J Mol Sci 2019 Apr 13;20(8). Epub 2019 Apr 13.

Division of Pathology, Department of Pathophysiology and Transplantation, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, and University of Milan, 20122 Milan, Italy.

Myeloproliferative neoplasms represent a heterogenous group of disorders of the hematopoietic stem cell, with an intrinsic risk of evolution into acute myeloid leukemia. The frequency of leukemic evolution varies according to myeloproliferative neoplasms subtype. It is highest in primary myelofibrosis, where it is estimated to be approximately 10-20% at 10 years, following by polycythemia vera, with a risk of 2.3% at 10 years and 7.9% at 20 years. In essential thrombocythemia, however, transformation to acute myeloid leukemia is considered relatively uncommon. Different factors are associated with leukemic evolution in myeloproliferative neoplasms, but generally include advanced age, leukocytosis, exposure to myelosuppressive therapy, cytogenetic abnormalities, as well as increased number of mutations in genes associated with myeloid neoplasms. The prognosis of these patients is dismal, with a medium overall survival ranging from 2.6-7.0 months. Currently, there is no standard of care for managing the blast phase of these diseases, and no treatment to date has consistently led to prolonged survival and/or hematological remission apart from an allogeneic stem cell transplant. Nevertheless, new targeted agents are currently under development. In this review, we present the current evidence regarding risk factors, molecular characterization, and treatment options for this critical subset of myeloproliferative neoplasms patients.
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http://dx.doi.org/10.3390/ijms20081839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514804PMC
April 2019

Osteolytic Lesions in Primary Myelofibrosis and Effect of Ruxolitinib Therapy: Report of a Case and Literature Review.

Chemotherapy 2018 9;63(6):340-344. Epub 2019 Apr 9.

Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy,

Here, we report the case of a young female affected by primary myelofibrosis (PMF) who developed an osteolytic lesion of the humerus during the follow-up, and the possible efficacy of ruxolitinib in controlling this rare event. After 26 years of follow-up, the patient reported onset of acute pain at the proximal region of the left upper limb. An X-ray revealed an osteolytic bone lesion in the proximal third of the humeral shaft, which was then confirmed by magnetic resonance imaging. A biopsy of the lytic lesion was done, revealing hypercellular bone marrow with hyperplastic granulopoiesis associated with megakaryocytic proliferation and atypia, accompanied by a diffuse and dense increase in reticulin fibrosis with extensive intersections and coarse bundles of thick fibers, consistent with a grade 3 collagen fibrosis. No new therapeutic intervention was initially required; however, 2 years later, the patient reported symptomatic splenomegaly and drenching night sweats, so ruxolitinib therapy was started. By week 8, the patient had near resolution of constitutional symptoms and a reduction of > 50% of the spleen size that normalized by 6 months; in addition, a repeat bone marrow biopsy showed a decrease in reticulin fibrosis grade. Interestingly, after 9 months of ruxolitinib therapy, further magnetic resonance imaging of the left upper limb showed the absence of bone lytic lesions and a substantial normalization of the bone tissue. In conclusion, with the present case report, we confirm ruxolitinib efficacy in reducing bone marrow fibrosis grade and assume its possible role in the resolution of osteolytic lesions in PMF. Obviously, further studies with a greater number of patients are needed to document the exact frequency of these unusual findings and the possible role of ruxolitinib in their treatment.
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http://dx.doi.org/10.1159/000497246DOI Listing
May 2019

A case report of systemic mastocytosis associated with multiple hematologic non-mast cell lineage diseases.

Hematol Oncol 2019 Apr 4;37(2):205-211. Epub 2019 Apr 4.

Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Systemic mastocytosis (SM) is a hematological malignancy characterized by extracutaneous infiltration by atypical mast cells. Together with indolent SM, aggressive SM, and mast cell leukemia, the World Health Organization (WHO) recognizes another major disease subgroup: SM with an associated hematological neoplasm, which is characterized by the presence of a concurrent neoplasm, more commonly, a chronic myelomonocytic leukemia. While KIT D816V is commonly regarded as the driver mutation, the clinical presentation of SM is extremely varied. Treatment of SM might not be simple, but now more specific therapies tailored toward prognostic subgroups of patients have been developed. Here, we report a detailed description of clinical management and biological features of a systemic mastocytocis case associated with multiple hematologic non-mast cell lineage diseases.
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http://dx.doi.org/10.1002/hon.2605DOI Listing
April 2019

EDA fibronectin-TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis.

J Exp Med 2019 03 7;216(3):587-604. Epub 2019 Feb 7.

Department of Molecular Medicine, University of Pavia, Pavia, Italy

The fibronectin EDA isoform (EDA FN) is instrumental in fibrogenesis but, to date, its expression and function in bone marrow (BM) fibrosis have not been explored. We found that mice constitutively expressing the EDA domain (EIIIA), but not EDA knockout mice, are more prone to develop BM fibrosis upon treatment with the thrombopoietin (TPO) mimetic romiplostim (TPO). Mechanistically, EDA FN binds to TLR4 and sustains progenitor cell proliferation and megakaryopoiesis in a TPO-independent fashion, inducing LPS-like responses, such as NF-κB activation and release of profibrotic IL-6. Pharmacological inhibition of TLR4 or TLR4 deletion in TPO mice abrogated Mk hyperplasia, BM fibrosis, IL-6 release, extramedullary hematopoiesis, and splenomegaly. Finally, developing a novel ELISA assay, we analyzed samples from patients affected by primary myelofibrosis (PMF), a well-known pathological situation caused by altered TPO signaling, and found that the EDA FN is increased in plasma and BM biopsies of PMF patients as compared with healthy controls, correlating with fibrotic phase.
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http://dx.doi.org/10.1084/jem.20181074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400533PMC
March 2019

Progressive splenomegaly and mild thrombocytosis in beta-thalassaemia trait and coexisting hereditary hemochromatosis: possible confounders for a subsequent hematological diagnosis.

Intern Emerg Med 2019 08 14;14(5):763-766. Epub 2018 Sep 14.

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, 20122, Italy.

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http://dx.doi.org/10.1007/s11739-018-1947-2DOI Listing
August 2019

Transcriptional analysis distinguishes breast implant-associated anaplastic large cell lymphoma from other peripheral T-cell lymphomas.

Mod Pathol 2019 02 11;32(2):216-230. Epub 2018 Sep 11.

Department of Pathology and Cell Biology, Columbia University Medical Center, New York Presbyterian Hospital, New York, NY, USA.

Breast implant-associated anaplastic large cell lymphoma is a new provisional entity in the revised World Health Organization classification of lymphoid malignancies, the pathogenesis and cell of origin of which are still unknown. We performed gene expression profiling of microdissected breast implant-associated anaplastic large cell lymphoma samples and compared their transcriptional profiles with those previously obtained from normal T-cells and other peripheral T-cell lymphomas and validated expression of selected markers by immunohistochemistry. Our results indicate that most breast implant-associated anaplastic large cell lymphomas exhibit an activated CD4+ memory T-cell phenotype, which is associated with CD25 and FoxP3 expression. Gene ontology analyses revealed upregulation of genes involved in cell motility programs (e.g., CCR6, MET, HGF, CXCL14) in breast implant-associated anaplastic large cell lymphomas compared to normal CD4+ T-cells and upregulation of genes involved in myeloid cell differentiation (e.g., PPARg, JAK2, SPI-1, GAB2) and viral gene transcription (e.g., RPS10, RPL17, RPS29, RPL18A) compared to other types of peripheral T-cell lymphomas. Gene set enrichment analyses also revealed shared features between the molecular profiles of breast implant-associated anaplastic large cell lymphomas and other types of anaplastic large cell lymphomas, including downregulation of T-cell receptor signaling and STAT3 activation. Our findings provide novel insights into the biology of this rare disease and further evidence that breast implant-associated anaplastic large cell lymphoma represents a distinct peripheral T-cell lymphoma entity.
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http://dx.doi.org/10.1038/s41379-018-0130-7DOI Listing
February 2019

Lymphocytic variant hypereosinophilia: a challenging diagnosis of a rare disease with pleomorphic clinical picture.

Eur J Intern Med 2018 11 9;57:e22-e24. Epub 2018 Aug 9.

Hematology Division, Foundation IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.ejim.2018.08.004DOI Listing
November 2018

Histiocytic cell neoplasms involving the bone marrow: summary of the workshop cases submitted to the 18th Meeting of the European Association for Haematopathology (EAHP) organized by the European Bone Marrow Working Group, Basel 2016.

Ann Hematol 2018 Nov 6;97(11):2117-2128. Epub 2018 Aug 6.

Department of Pathology 824, Radboud University Medical Center, POB 9101, 6500 HB, Nijmegen, The Netherlands.

The bone marrow is a preferential site for both reactive and neoplastic histiocytic proliferations. The differential diagnosis ranges from reactive histiocyte hyperplasia in systemic infections, vaccinations, storage diseases, post myeloablative therapy, due to increased cell turnover, and in hemophagocytic lymphohistiocytosis, through extranodal Rosai-Dorfman disease to neoplasms derived from histiocytes, including histiocytic sarcomas (HS), Langerhans cell histiocytoses (LCH), Erdheim-Chester disease (ECD), and disseminated juvenile xanthogranuloma (JXG). One of the most important recent developments in understanding the biology of histiocytic neoplasms and in contributing to diagnosis was the detection of recurrent mutations of genes of the Ras/Raf/MEK/ERK signaling pathway, in particular the BRAF mutation, in LCH and ECD. Here, we summarize clinical and pathological findings of 17 histiocytic neoplasms that were presented during the bone marrow symposium and workshop of the 18th European Association for Haematopathology (EAHP) meeting held in Basel, Switzerland, in 2016. A substantial proportion of these histiocytic neoplasms was combined with clonally related lymphoid (n = 2) or myeloid diseases (n = 5, all ECD). Based on the latter observation, we suggest excluding co-existent myeloid neoplasms at initial staging of elderly ECD patients. The recurrent nature of Ras/Raf/MEK/ERK signaling pathway mutations in histiocytic neoplasms was confirmed in 6 of the 17 workshop cases, illustrating their diagnostic significance and suggesting apotential target for tailored treatments.
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http://dx.doi.org/10.1007/s00277-018-3436-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182749PMC
November 2018

Heterogeneity among splanchnic vein thrombosis associated with myeloproliferative neoplasms.

Eur J Intern Med 2018 06 20;52:e25-e26. Epub 2018 Mar 20.

Hematology Division, IRCCS Ca' Granda - Maggiore Policlinico Hospital Foundation, University of Milan, Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.ejim.2018.03.009DOI Listing
June 2018

Prognostic impact of bone marrow fibrosis and dyserythropoiesis in autoimmune hemolytic anemia.

Am J Hematol 2018 08 10;93(4):E88-E91. Epub 2018 Jan 10.

Hematology Unit, IRCCS Ca' Granda Ospedale Maggiore Policlinico of Milan, Milan, Italy.

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http://dx.doi.org/10.1002/ajh.25020DOI Listing
August 2018

Reactive follicular hyperplasia on dasatinib treatment for chronic myeloid leukemia.

Ann Hematol 2017 Nov 19;96(11):1953-1954. Epub 2017 Aug 19.

Hematology Division, IRCCS Ca' Granda-Maggiore Policlinico Hospital Foundation, Via Francesco Sforza 35, 20122, Milan, Italy.

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http://dx.doi.org/10.1007/s00277-017-3105-8DOI Listing
November 2017

An unusual type of myeloid sarcoma localization following myelofibrosis: A case report and literature review.

Leuk Res Rep 2017 27;8:7-10. Epub 2017 Jul 27.

Hematology Division, IRCCS Ca' Granda - Maggiore Policlinico Hospital Foundation, Milan, Italy.

Myeloid Sarcoma (MS) is a rare malignancy that can present as an isolated disease or more frequently in association with or following acute myeloid leukemia or other myeloid neoplasms and rarely following myelofibrosis. Since molecular pathogenesis and prognostic factors of MS are not well understood, its prognosis remains poor even in the era of novel agents and target therapies. We report the case of a patient with MS following myelofibrosis with multiple subcutaneous, cutaneous and muscle localizations; the latter has been reported in the literature as anecdotal. In this way we aimed to enhance the understanding of this disease.
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http://dx.doi.org/10.1016/j.lrr.2017.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536879PMC
July 2017

Prognostic significance of a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in primary myelofibrosis patients.

Histopathology 2017 Dec 28;71(6):897-908. Epub 2017 Sep 28.

Hematology Division, IRCCS Ca' Granda, Maggiore Policlinico Hospital Foundation, Milan, Italy.

Aims: To evaluate whether a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in bone marrow trephine biopsies (BMBs) of primary myelofibrosis (PMF) patients may have prognostic implications.

Methods And Results: Reticulin fibrosis, collagen deposition and osteosclerosis were graded from 0 to 3 in a series of 122 baseline BMBs. Then, we assigned to each case a comprehensive score [reticulin, collagen, osteosclerosis (RCO) score, ranging from 0 to 9] that allowed us to distinguish two groups of patients, with low-grade (RCO score 0-4) and high-grade (RCO score 5-9) stromal changes. Of 122 patients, 88 displayed a low-grade and 34 a high-grade RCO score. The latter was associated more frequently with anaemia, thrombocytopenia, peripheral blood blasts and increased lactate dehydrogenase levels. The RCO score was correlated strictly with overall mortality (P = 0.013) and International Prognostic Scoring System (IPSS) risk categories, and was able to discriminate the overall survival of both low- and high-grade patients (log-rank test: P < 0.001). Moreover, it proved to be more accurate than the European Consensus on Grading of Bone Marrow Fibrosis (ECGMF grade) in identifying high-risk patients with poor prognosis. Finally, a combined analysis of RCO scores and IPSS risk categories in an integrated clinical-pathological evaluation was able to increase the positive predictive value (PPV) for mortality in high-risk patients.

Conclusion: The comprehensive RCO score, obtained by histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis was prognostically significant and more accurate than ECGMF grade in identifying high-risk patients and improved PPV when applied in addition to IPSS.
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http://dx.doi.org/10.1111/his.13309DOI Listing
December 2017

European LeukemiaNet study on the reproducibility of bone marrow features in masked polycythemia vera and differentiation from essential thrombocythemia.

Am J Hematol 2017 Oct 29;92(10):1062-1067. Epub 2017 Jul 29.

Division of Hematology and Research Foundation, Ospedale Papa Giovanni XXIII, Bergamo, Italy.

The purpose of the study was to assess consensus and interobserver agreement among an international panel of six hematopathologists regarding characterization and reproducibility of bone marrow (BM) histologic features used to diagnose early stage myeloproliferative neoplasms, in particular differentiation of so-called masked/prodromal polycythemia vera (mPV) from JAK2-mutated essential thrombocythemia (ET). The six members of the hematopathology panel evaluated 98 BM specimens independently and in a blinded fashion without knowledge of clinical data. The specimens included 48 cases of mPV according to the originally published hemoglobin threshold values for this entity (male: 16.0-18.4 g/dL, female: 15.0-16.4 g/dL), 31 cases with overt PV according to the updated 2016 WHO criteria, and 19 control cases. The latter group included cases of JAK2-mutated ET, primary myelofibrosis, myelodysplastic syndrome, and various reactive conditions. Inter-rater agreement between the panelists was very high (overall agreement 92.6%, kappa 0.812), particularly with respect to separating mPV from ET. Virtually all cases of mPV were correctly classified as PV according to their BM morphology. In conclusion, a central blinded review of histology slides by six hematopathologists demonstrated that highly reproducible specific histological pattern characterize PV and confirmed the notion that there are no significant differences between mPV and overt PV in relation to BM morphology.
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http://dx.doi.org/10.1002/ajh.24837DOI Listing
October 2017