Publications by authors named "Emanuela Boveri"

69 Publications

Cutaneous lymphocytic vasculitis after administration of COVID-19 mRNA vaccine.

Dermatol Ther 2021 Sep 10;34(5):e15076. Epub 2021 Aug 10.

Unit of Nephrology, Dialysis and Transplantation, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

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http://dx.doi.org/10.1111/dth.15076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420357PMC
September 2021

Relationship between clone metrics and clinical outcome in clonal cytopenia.

Blood 2021 Sep;138(11):965-976

Department of Hematology Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Policlinico San Matteo, Pavia, Italy.

Clonal cytopenia of undetermined significance (CCUS) is associated with an increased risk of developing a myeloid neoplasm with myelodysplasia (MN). To identify the features of the mutant clone(s) that is associated with clinical phenotype and progression, we studied the following cohorts of individuals: 311 patients with idiopathic cytopenia of undetermined significance (ICUS), 532 community-dwelling individuals without hematologic phenotype (n = 355) or with unexplained anemia (n = 177), and 592 patients with overt MN. Ninety-two of 311 (30%) patients with ICUS carried a somatic genetic lesion that signaled CCUS. Clonal hematopoiesis (CH) was detected in 19.7% and 27.7% of nonanemic and anemic community-dwelling individuals, respectively. Different mutation patterns and variant allele frequencies (VAFs) (clone metrics parameters) were observed in the conditions studied. Recurrent mutation patterns exhibited different VAFs associated with marrow dysplasia (0.17-0.48), indicating variable clinical expressivity of mutant clones. Unsupervised clustering analysis based on mutation profiles identified 2 major clusters, characterized by isolated DNMT3A mutations (CH-like cluster) or combinatorial mutation patterns (MN-like cluster), and showing different overall survival (HR, 1.8). In patients with CCUS, the 2 clusters had different risk of progression to MN (HR, 2.7). Within the MN-like cluster, distinct subsets with different risk of progression to MN were identified based on clone metrics. These findings unveil marked variability in the clinical expressivity of myeloid driver genes and underline the limitations of morphologic dysplasia for clinical staging of mutant hematopoietic clones. Clone metrics appears to be critical for informing clinical decision-making in patients with clonal cytopenia.
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http://dx.doi.org/10.1182/blood.2021011323DOI Listing
September 2021

Acute megakaryoblastic leukemia with a novel GATA1 mutation in a second trimester stillborn fetus with trisomy 21.

Leuk Lymphoma 2021 09 30;62(9):2276-2279. Epub 2021 Mar 30.

Unit of Anatomic Pathology, Department of Molecular Medicine, IRCCS San Matteo Foundation, University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.1080/10428194.2021.1907377DOI Listing
September 2021

Systemic mastocytosis and lymphoplasmacytic lymphoma: an unusual and intriguing form of SM-AHN.

Leuk Lymphoma 2021 07 14;62(7):1782-1785. Epub 2021 Feb 14.

Unit of Anatomic Pathology, Department of Molecular Medicine, IRCCS San Matteo Foundation, University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.1080/10428194.2021.1885661DOI Listing
July 2021

Depletion of circulating IgM memory B cells predicts unfavourable outcome in COVID-19.

Sci Rep 2020 11 30;10(1):20836. Epub 2020 Nov 30.

Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy.

Impaired immune responses have been hypothesised to be a possible trigger of unfavourable outcomes in coronavirus disease 2019 (COVID-19). We aimed to characterise IgM memory B cells in patients with COVID-19 admitted to an internal medicine ward in Northern Italy. Overall, 66 COVID-19 patients (mean age 74 ± 16.6 years; 29 females) were enrolled. Three patients (4.5%; 1 female) had been splenectomised and were excluded from further analyses. Fifty-five patients (87.3%) had IgM memory B cell depletion, and 18 (28.6%) died during hospitalisation (cumulative incidence rate 9.26/100 person-week; 5.8-14.7 95% CI). All patients who died had IgM memory B cell depletion. A superimposed infection was found in 6 patients (9.5%), all of them having IgM memory B cell depletion (cumulative incidence rate 3.08/100 person-week; 1.3-6.8 95% CI). At bivariable analyses, older age, sex, number of comorbidities, and peripheral blood lymphocyte count < 1500/µl were not correlated with IgM memory B cell depletion. A discrete-to-marked reduction of the B-cell compartment was also noticed in autoptic spleen specimens of two COVID-19 patients. We conclude that IgM memory B cells are commonly depleted in COVID-19 patients and this correlates with increased mortality and superimposed infections.
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http://dx.doi.org/10.1038/s41598-020-77945-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705651PMC
November 2020

Positive predictive value for malignancy of uncertain malignant potential (B3) breast lesions diagnosed on vacuum-assisted biopsy (VAB): is surgical excision still recommended?

Eur Radiol 2021 Feb 20;31(2):920-927. Epub 2020 Aug 20.

Breast Imaging Department, University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Purpose: Breast lesions classified as of "uncertain malignant potential" represent a heterogeneous group of abnormalities with an increased risk of associated malignancy. Clinical management of B3 lesions diagnosed on vacuum-assisted breast biopsy (VABB) is still challenging: surgical excision is no longer the only available treatment and VABB may be sufficient for therapeutic excision. The aim of the present study is to evaluate the positive predictive value (PPV) for malignancy in B3 lesions that underwent surgical excision, identifying possible upgrading predictive factors and characterizing the malignant lesions eventually diagnosed. These results are compared with a subset of patients with B3 lesions who underwent follow-up.

Methods: A total of 1250 VABBs were performed between January 2006 and December 2017 at our center. In total, 150 B3 cases were diagnosed and 68 of them underwent surgical excision. VABB findings were correlated with excision histology. A PPV for malignancy for each B3 subtype was derived.

Results: The overall PPV rate was 28%, with the highest upgrade rate for atypical ductal hyperplasia (41%), followed by classical lobular neoplasia (29%) and flat epithelial atypia (11%). Only two cases of carcinoma were detected in the follow-up cohort, both associated with atypical ductal hyperplasia at VABB.

Conclusion: Open surgery is recommended in case of atypical ductal hyperplasia while, for other B3 lesions, excision with VABB only may be an acceptable alternative if radio-pathological correlation is assessed, if all microcalcifications have been removed by VABB, and if the lesion lacks high-risk cytological features.

Key Points: • Surgical treatment is strongly recommended in case of ADH, while the upgrade rate in case of pure FEA, especially following complete microcalcification removal by VABB, may be sufficiently low to advice surveillance as a management strategy. • The use of 11-G- or 8-G-needle VABB, resulting in possible complete diagnostic excision of the lesion, can be an acceptable alternative in case of RS, considering open surgery only for selected high-risk patients. • LN management is more controversial: surgical excision may be recommended following classical LN diagnosis on breast biopsy if an additional B3 lesion is concurrently detected while in the presence of isolated LN with adequate radiological-pathological correlation follow-up alone could be an acceptable option.
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http://dx.doi.org/10.1007/s00330-020-07161-5DOI Listing
February 2021

Targeted next-generation sequencing reveals molecular heterogeneity in non-chronic lymphocytic leukemia clonal B-cell lymphocytosis.

Hematol Oncol 2020 Dec 19;38(5):689-697. Epub 2020 Aug 19.

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

Non-chronic lymphocytic leukemia (non-CLL) clonal B-cell lymphocytosis (CBL) encompasses a heterogeneous group of hematologic disorders that are still poorly understood. To shed light on their biological aspects, we retrospectively analyzed a highly selected series of 28 patients, who had a clonal B-cell population in the peripheral blood and in the bone marrow, without evidence of lymphoma. Extended targeted next-generation sequencing revealed wide molecular heterogeneity with MYD88 (14%), PDE4DIP (14%), BIRC3 (11%), CCND3 (11%), NOTCH1 (11%), and TNFAIP3 (11%) as the most mutated genes. Mutations of MYD88 were "nonclassic" in most cases. Although some genetic lesions were overlapping with indolent lymphomas, mainly splenic B-cell lymphomas of marginal zone origin and splenic diffuse red pulp small B-cell lymphoma, the genetic profile of our non-CLL CBL series seemed to suggest that various pathways could be involved in the pathogenesis of these disorders, not mirroring any specific lymphoma entity. These data better enlighten the molecular characteristics of non-CLL CBL; however, more efforts are needed in order to improve the diagnostic process, prognostication, and clinical management.
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http://dx.doi.org/10.1002/hon.2784DOI Listing
December 2020

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

A risk-stratification model based on the initial concentration of the serum monoclonal protein and MYD88 mutation status identifies a subset of patients with IgM monoclonal gammopathy of undetermined significance at high risk of progression to Waldenström macroglobulinaemia or other lymphoproliferative disorders.

Br J Haematol 2019 11 5;187(4):441-446. Epub 2019 Jul 5.

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

IgM monoclonal gammopathies of undetermined significance (IgM MGUS) are associated with a risk of progression to Waldenström macroglobulinaemia (WM) or other lymphoproliferative disorders (LPD) of 1-2% per year. We analysed 176 consecutive patients with IgM MGUS to evaluate risk factors for progression. With a median follow-up of 83 months (1214 person-years), 15 patients (8·5%) progressed to WM (n = 14) or marginal zone lymphoma (n = 1). The rate of progression was 1·32% per year (95% confidence interval [CI] 0·80-2·20). The serum monoclonal protein concentration and the MYD88 mutation were independent risk factors for progression (Hazard ratio [HR] 23·3, 95% CI 2·0-273·3, P = 0·012 and HR 24·4, 95% CI 2·2-275·3, P = 0·010, respectively). The cumulative incidence of progression, while considering death as a competing event, was 11·6% at 5 years and 38·0% at 10 years in MYD88-mutated patients with a serum monoclonal protein of 10 g/l or higher, as compared with 0% at 5 years and 1·1% at 10 years for patients with none or one risk factor. This risk-stratification model is able to identify a subset of patients with IgM MGUS at high risk of progression to WM or LPD who deserve a lifelong follow-up.
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http://dx.doi.org/10.1111/bjh.16086DOI Listing
November 2019

Telangiectasia macularis eruptiva perstans: a neglected type of mastocytosis with exclusively cutaneous involvement? A case series.

Eur J Dermatol 2019 Apr;29(2):174-178

Institute of Dermatology Department of Clinical-Surgical, Diagnostic and Paediatric Sciences, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.

Telangiectasia macularis eruptiva perstans (TMEP) is a rare form of cutaneous mastocytosis (CM). Although TMEP has been traditionally thought to be restricted to the skin, a recent retrospective multicentric study established a diagnosis with systemic involvement of mastocytosis in 47% patients affected by TMEP and aggressive systemic mastocytosis in 9%. To evaluate systemic involvement in patients affected by TMEP. We conducted a retrospective monocentric study among patients affected by TMEP visited in our dermatology clinic. Data regarding gender, age at diagnosis, duration of the disease before diagnosis, topography, clinical features, presence of extra-cutaneous symptoms, serum tryptase levels, and histopathological and bone marrow biopsy features were analysed. Among 119 patients classified with mastocytosis, eight patients (six males, two females) with TMEP and one female patient affected by mastocytosis in the skin, a TMEP variant, were retrospectively studied. The mean diagnostic delay was two years (range: 8-26 months). In two patients (25%), bone marrow involvement was identified and osteoporosis and hepatosplenomegaly were also found. The two patients with systemic involvement exhibited a statistically significant increase in serum tryptase levels (p < 0.05). The detection of KIT gene mutation in skin specimens revealed a somatic mutation, KITD816 V, only in these two patients. TMEP is a rare form of CM, often neglected. A correct and early diagnosis of TMEP is important to rule out systemic involvement of the disease. Detection of serum tryptase levels may be a useful, rapid, and non-invasive marker of systemic involvement.
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http://dx.doi.org/10.1684/ejd.2019.3532DOI Listing
April 2019

Clinical, histopathological and molecular characterization of hypoplastic myelodysplastic syndrome.

Leukemia 2019 10 2;33(10):2495-2505. Epub 2019 Apr 2.

Department of Haematological Medicine, King's College Hospital, London, UK.

Diagnostic criteria for hypoplastic myelodysplasic syndrome (h-MDS) have not been clearly established, making the differential diagnosis from other bone marrow failure syndromes (BMF) challenging. In this study, we aimed to delineate clinical, histopathological, and molecular features of h-MDS, based on a large and well-annotated cohort of patients with bone marrow (BM) hypocellularity. The study included 534 consecutive adult patients with hypocellular BM (278 h-MDS and 136 aplastic anemia), and 727 with normo- or hypercellular MDS (n-MDS). Comparison of clinical features of patients with h-MDS as defined by BM cellularity ≤25% (n = 204) or reduced age-adjusted cellularity (n = 74) did not reveal significant differences. We developed a diagnostic score to discriminate h-MDS from non-malignant BMF based on histological and cytological variables with the highest specificity for MDS (h-score). The information from chromosomal abnormalities and somatic mutation patterns was then integrated into a cyto-histological/genetic score (hg-score). This score was able to segregate two groups of h-MDS with a significantly different risk of blast progression (P < 0.001). The integration of cyto-histological and genetic features in adult patients with hypocellular BM facilitated segregation into two distinct groups, one with clinical and genetic features highly consistent with myeloid neoplasm, and one with features more consistent with non-malignant BMF.
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http://dx.doi.org/10.1038/s41375-019-0457-1DOI Listing
October 2019

The Italian Mastocytosis Registry: 6-year experience from a hospital-based registry.

Future Oncol 2018 11 12;14(26):2713-2723. Epub 2018 Sep 12.

Immunology & Allergology, University of Salerno, Salerno, Italy.

Aim: We collected 'real-life' data on the management of patients with mastocytosis in the Italian Mastocytosis Registry.

Methods: Six hundred patients diagnosed with mastocytosis between 1974 and 2014 were included from 19 centers.

Results: Among adults (n = 401); 156 (38.9%) patients were diagnosed with systemic mastocytosis. In 212 adults, no bone marrow studies were performed resulting in a provisional diagnosis of mastocytosis of the skin. This diagnosis was most frequently established in nonhematologic centers. In total, 182/184 pediatric patients had cutaneous mastocytosis. We confirmed that in the most patients with systemic mastocytosis, serum tryptase levels were >20 ng/ml and KIT D816V was detectable.

Conclusion: The Italian Mastocytosis Registry revealed some center-specific approaches for diagnosis and therapy. Epidemiological evidence on this condition is provided.
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http://dx.doi.org/10.2217/fon-2018-0291DOI Listing
November 2018

Diagnosis and management of prefibrotic myelofibrosis.

Expert Rev Hematol 2018 07 22;11(7):537-545. Epub 2018 Jun 22.

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

Introduction: The 2016 WHO classification comprises two stages of primary myelofibrosis (PMF): early/prefibrotic primary myelofibrosis (pre-PMF) and overt fibrotic PMF (overt PMF). Diagnostic criteria rely on bone marrow morphology, fibrosis grade (0-1 in pre-PMF, 2-3 in overt PMF), and clinical features (leukoerythroblastosis, anemia, leucocytosis, increased lactate dehydrogenase, and palpable splenomegaly). An accurate differentiation from essential thrombocythemia (ET) is pivotal because the two entities show different clinical presentation and outcome, in terms of survival, leukemic evolution, and rates of progression to overt myelofibrosis. Areas covered: The current review provides an overview on how to diagnose and stratify patients with pre-PMF, taking into account their definite and peculiar risk of vascular event, which is often neglected, and their milder disease course, compared with overt PMF, with the aim of improving and individualizing their counseling and management. Expert commentary: Pre-PMF is a new entity characterized by a unique combination of both a thrombo-hemorrhagic risk (that brings it closer to PV and ET) and a definite risk of disease evolution (that places pre-PMF somewhat closer to the overt PMF variant).
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http://dx.doi.org/10.1080/17474086.2018.1484280DOI Listing
July 2018

Clinical course and outcome of essential thrombocythemia and prefibrotic myelofibrosis according to the revised WHO 2016 diagnostic criteria.

Oncotarget 2017 Nov 6;8(60):101735-101744. Epub 2017 Oct 6.

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

The recently revised World Health Organization (WHO) classification of myeloid neoplasms recognizes prefibrotic myelofibrosis (prePMF) as a distinct entity, characterized by well-defined histopathologic features together with minor clinical criteria (leukocytes, anemia, increased LDH, splenomegaly). The aim of the study was to examine the clinical relevance of distinguishing prePMF from essential thrombocythemia (ET). We identified in our database all patients affected with ET, prePMF and primary myelofibrosis (PMF) diagnosed according to 2008 WHO criteria with a bone marrow fibrosis grade 0-1 at diagnosis and one DNA sample to define the mutational status. The bone marrow morphology of all 404 identified patients was reviewed by an expert pathologist and patients were reclassified according to the 2016 WHO criteria. After reclassification, our cohort included 269 ET, 109 prePMF, and 26 myeloproliferative neoplasm unclassificable. In comparison with ET, patients with prePMF had higher leukocyte count, lower hemoglobin level, higher platelet count, higher LDH values, and higher number of circulating CD34-positive cells; they showed more frequently splenomegaly (all values < ·001). mutations were more frequent in prePMF than in ET (35·8% vs 17·8%, < ·001). PrePMF patients had shorter overall survival ( < ·001) and a trend to a higher incidence of leukemic evolution ( ·067) compared to ET patients, while they did not differ in terms of thrombotic and bleeding complications. In conclusion, ET and prePMF diagnosed according to 2016 WHO criteria are two entities with a different clinical phenotype at diagnosis and a different clinical outcome.
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http://dx.doi.org/10.18632/oncotarget.21594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731910PMC
November 2017

Pattern of somatic mutations in patients with Waldenström macroglobulinemia or IgM monoclonal gammopathy of undetermined significance.

Haematologica 2017 12 5;102(12):2077-2085. Epub 2017 Oct 5.

Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

We analyzed and CXCR4 mutation status of 260 patients with Waldenström macroglobulinemia or IgM monoclonal gammopathy of undetermined significance using allele-specific real time quantitative polymerase chain reaction and Sanger sequencing, respectively. A subgroup of 119 patients was further studied with next-generation sequencing of 11 target genes (, , , , , , , , , , and ). (L265P) was found at diagnosis in 91% of patients with Waldenström macroglobulinemia and in 60% of patients with IgM monoclonal gammopathy of undetermined significance using allele-specific polymerase chain reaction analysis. mutations other than the classical L265P (V217F, S219C and M232T) were found in four cases by next-generation sequencing. Waldenström macroglobulinemia patients with wild-type had a distinct clinical phenotype characterized by less bone marrow infiltration (=0.01) and more frequent extramedullary involvement (=0.001) compared to patients with mutated Patients with wild-type did not show additional mutations in the other target genes. mutations were found by Sanger sequencing in 22% of patients with Waldenström macroglobulinemia. With next-generation sequencing, a mutation was detected in 23% of patients with Waldenström macroglobulinemia and 9% of those with IgM monoclonal gammopathy of undetermined significance. Asymptomatic Waldenström macroglobulinemia patients harboring a mutation had a shorter treatment-free survival (51 months) than that of patients with wild-type (median not reached) (=0.007). Analysis of variant allele frequencies indicated that mutations were present in the dominant clone in the majority of cases. Recurrent somatic mutations of were found in 24% of patients with Waldenström macroglobulinemia and 5% of patients with IgM monoclonal gammopathy of undetermined significance and were primarily subclonal.
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http://dx.doi.org/10.3324/haematol.2017.172718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709107PMC
December 2017

Massive mediastinal enlargement due to extramedullary haematopoiesis in a patient with MYH9-related thrombocytopenia.

Br J Haematol 2017 07 17;178(1):10. Epub 2017 May 17.

Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.1111/bjh.14676DOI Listing
July 2017

Clinical significance of somatic mutation in unexplained blood cytopenia.

Blood 2017 06 19;129(25):3371-3378. Epub 2017 Apr 19.

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

Unexplained blood cytopenias, in particular anemia, are often found in older persons. The relationship between these cytopenias and myeloid neoplasms like myelodysplastic syndromes is currently poorly defined. We studied a prospective cohort of patients with unexplained cytopenia with the aim to estimate the predictive value of somatic mutations for identifying subjects with, or at risk of, developing a myeloid neoplasm. The study included a learning cohort of 683 consecutive patients investigated for unexplained cytopenia, and a validation cohort of 190 patients referred for suspected myeloid neoplasm. Using granulocyte DNA, we looked for somatic mutations in 40 genes that are recurrently mutated in myeloid malignancies. Overall, 435/683 patients carried a somatic mutation in at least 1 of these genes. Carrying a somatic mutation with a variant allele frequency ≥0.10, or carrying 2 or more mutations, had a positive predictive value for diagnosis of myeloid neoplasm equal to 0.86 and 0.88, respectively. Spliceosome gene mutations and comutation patterns involving , , or had positive predictive values for myeloid neoplasm ranging from 0.86 to 1.0. Within subjects with inconclusive diagnostic findings, carrying 1 or more somatic mutations was associated with a high probability of developing a myeloid neoplasm during follow-up (hazard ratio = 13.9, < .001). The predictive values of mutation analysis were confirmed in the independent validation cohort. The findings of this study indicate that mutation analysis on peripheral blood granulocytes may significantly improve the current diagnostic approach to unexplained cytopenia and more generally the diagnostic accuracy of myeloid neoplasms.
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http://dx.doi.org/10.1182/blood-2017-01-763425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542849PMC
June 2017

Vascular endothelial growth factor overexpression in myelodysplastic syndrome bone marrow cells: biological and clinical implications.

Leuk Lymphoma 2017 07 29;58(7):1711-1720. Epub 2016 Nov 29.

b Department of Hematology Oncology , IRCCS Policlinico San Matteo Foundation, University of Pavia , Pavia , Italy.

In myelodysplastic syndrome (MDS), vascular endothelial growth factor (VEGF) may have regulatory effects on the hematopoietic system and contribute to disease progression. We analyzed by immunocytochemistry VEGF expression in bone marrow (BM) cells from 188 patients with MDS and 96 non-hemopathic subjects. We also measured VEGF BM plasma levels and in vitro VEGF release. Our aims were to evaluate whether VEGF expression abnormalities were associated with relevant laboratory or clinical findings and their possible prognostic value. In MDS, VEGF expression was higher than in controls (p < .0001) and VEGF release was significantly higher in the low-risk cases. A trend to a positive correlation between VEGF myeloid expression and apoptotic rate was observed. High myeloid VEGF levels were independently associated with longer overall survival (p < .0001) and progression-free survival (p = .0002). Our findings suggest that, in MDS, VEGF production and release may contribute to ineffective hematopoiesis, with a potential prognostic role.
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http://dx.doi.org/10.1080/10428194.2016.1262030DOI Listing
July 2017

c.428T > C (p.V143A) homozygous mutation in TP53 gene as a possible mechanism of resistance to trastuzumab therapy in gastric cancer.

Acta Oncol 2016 Nov 31;55(11):1373-1375. Epub 2016 Aug 31.

e Molecular Pathology Unit, Department of Laboratory Medicine , Niguarda Cancer Center, ASST- Grande Ospedale Metropolitano Niguarda , Milan , Italy.

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http://dx.doi.org/10.1080/0284186X.2016.1196828DOI Listing
November 2016

Parental origin of the deletion del(20q) in Shwachman-Diamond patients and loss of the paternally derived allele of the imprinted L3MBTL1 gene.

Genes Chromosomes Cancer 2017 01 21;56(1):51-58. Epub 2016 Sep 21.

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

Shwachman-Diamond syndrome (SDS) (OMIM 260400) is a rare autosomal recessive disease characterized by exocrine pancreatic insufficiency, skeletal, and hematological abnormalities and bone marrow (BM) dysfunction. Mutations in the SBDS gene cause SDS. Clonal chromosome anomalies are often present in BM, i(7)(q10) and del(20q) being the most frequent ones. We collected 6 SDS cases with del(20q): a cluster of imprinted genes, including L3MBTL1 and SGK2 is present in the deleted region. Only the paternal allele is expressed for these genes. Based on these data, we made the hypothesis that the loss of this region, in relation to parental origin of deletion, may be of relevance for the hematological phenotype. By comparing hematological data of our 6 cases with a group of 20 SDS patients without evidence of del(20q) in BM, we observed a significant difference for Hb levels (P < 0.012), and a difference slightly above the significance level for RBC counts (P < 0.053): in both cases the values were higher in patients with del(20q). We also report preliminary evidence for an increased number of BFU-E colonies in cases with paternal deletion, data on the presence of the deletion in colonies and in mature circulating lymphocytes. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/gcc.22401DOI Listing
January 2017

Particulate cytoplasmic structures with high concentration of ubiquitin-proteasome accumulate in myeloid neoplasms.

J Hematol Oncol 2015 Jun 18;8:71. Epub 2015 Jun 18.

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

Background: Increased plasma levels of proteasome have been associated with various neoplasms, especially myeloid malignancies. Little is known of the cellular origin and release mechanisms of such proteasome. We recently identified and characterized a novel particulate cytoplasmic structure (PaCS) showing selective accumulation of ubiquitin-proteasome system (UPS) components. PaCSs have been reported in some epithelial neoplasms and in two genetic disorders characterized by hematopoietic cell dysplasia and increased risk of leukemia. However, no information is available about PaCSs in hematopoietic neoplasms.

Methods: PaCSs were investigated by ultrastructural, immunogold, and immunofluorescence analysis of bone marrow (BM) biopsies and peripheral blood (PB) cell preparations of 33 consecutive, untreated, or relapsed patients affected by different hematopoietic neoplasms. BM and PB samples from individuals with non-neoplastic BM or healthy donors were studied as controls. Granulocytes and platelet proteasome content was measured by immunoblotting and plasma proteasome levels by ELISA.

Results: PaCSs with typical, selective immunoreactivity for polyubiquitinated proteins and proteasome were widespread in granulocytic cells, megakaryocytes, and platelets of patients with myeloproliferative neoplasms (MPN). In acute myeloid leukemia and myelodysplastic syndromes (MDS), PaCSs were only occasionally detected in blast cells and were found consistently in cells showing granulocytic and megakaryocytic maturation. Conversely, PaCSs were poorly represented or absent in non-neoplastic hematopoietic tissue or lymphoid neoplasms. In MPN granulocytes and platelets, the presence of PaCSs was associated with increased amounts of proteasome in cell lysates. PaCSs were often localized in cytoplasmic blebs generating PaCSs-filled plasma membrane vesicles observable in the BM intercellular space. In MPN and MDS, accumulation of PaCSs was associated with significant increase in plasma proteasome. Immunogold analysis showed that PaCSs of myeloid neoplasia selectively concentrated the chaperone proteins Hsp40, Hsp70, and Hsp90.

Conclusions: PaCSs accumulate in cells of myeloid neoplasms in a lineage- and maturation-restricted manner; in particular, they are widespread in granulocytic and megakaryocytic lineages of MPN patients. PaCSs development was associated with excess accumulation of polyubiquitinated proteins, proteasome, and chaperone molecules, indicating impairment of the UPS-dependent protein homeostasis and a possible link with Hsp90-related leukemogenesis. A mechanism of PaCSs discharge by leukemic cells could contribute to increased plasma proteasome of MPN and MDS.
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http://dx.doi.org/10.1186/s13045-015-0169-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4473848PMC
June 2015

SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts.

Blood 2015 Jul 8;126(2):233-41. Epub 2015 May 8.

Center for Hematology and Regenerative Medicine, Karolinska University Hospital, Stockholm, Sweden;

Refractory anemia with ring sideroblasts (RARS) is a myelodysplastic syndrome (MDS) characterized by isolated erythroid dysplasia and 15% or more bone marrow ring sideroblasts. Ring sideroblasts are found also in other MDS subtypes, such as refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS). A high prevalence of somatic mutations of SF3B1 was reported in these conditions. To identify mutation patterns that affect disease phenotype and clinical outcome, we performed a comprehensive mutation analysis in 293 patients with myeloid neoplasm and 1% or more ring sideroblasts. SF3B1 mutations were detected in 129 of 159 cases (81%) of RARS or RCMD-RS. Among other patients with ring sideroblasts, lower prevalence of SF3B1 mutations and higher prevalence of mutations in other splicing factor genes were observed (P < .001). In multivariable analyses, patients with SF3B1 mutations showed significantly better overall survival (hazard ratio [HR], .37; P = .003) and lower cumulative incidence of disease progression (HR = 0.31; P = .018) compared with SF3B1-unmutated cases. The independent prognostic value of SF3B1 mutation was retained in MDS without excess blasts, as well as in sideroblastic categories (RARS and RCMD-RS). Among SF3B1-mutated patients, coexisting mutations in DNA methylation genes were associated with multilineage dysplasia (P = .015) but had no effect on clinical outcome. TP53 mutations were frequently detected in patients without SF3B1 mutation, and were associated with poor outcome. Thus, SF3B1 mutation identifies a distinct MDS subtype that is unlikely to develop detrimental subclonal mutations and is characterized by indolent clinical course and favorable outcome.
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http://dx.doi.org/10.1182/blood-2015-03-633537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4528082PMC
July 2015

Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis.

Blood 2014 Aug 1;124(7):1062-9. Epub 2014 Jul 1.

Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico [IRCCS] Policlinico San Matteo, and Department of Molecular Medicine, University of Pavia, Pavia, Italy;

We studied the impact of driver mutations of JAK2, CALR, (calreticulin gene) or MPL on clinical course, leukemic transformation, and survival of patients with primary myelofibrosis (PMF). Of the 617 subjects studied, 399 (64.7%) carried JAK2 (V617F), 140 (22.7%) had a CALR exon 9 indel, 25 (4.0%) carried an MPL (W515) mutation, and 53 (8.6%) had nonmutated JAK2, CALR, and MPL (so-called triple-negative PMF). Patients with CALR mutation had a lower risk of developing anemia, thrombocytopenia, and marked leukocytosis compared with other subtypes. They also had a lower risk of thrombosis compared with patients carrying JAK2 (V617F). At the opposite, triple-negative patients had higher incidence of leukemic transformation compared with either CALR-mutant or JAK2-mutant patients. Median overall survival was 17.7 years in CALR-mutant, 9.2 years in JAK2-mutant, 9.1 years in MPL-mutant, and 3.2 years in triple-negative patients. In multivariate analysis corrected for age, CALR-mutant patients had better overall survival than either JAK2-mutant or triple-negative patients. The impact of genetic lesions on survival was independent of current prognostic scoring systems. These observations indicate that driver mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials.
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http://dx.doi.org/10.1182/blood-2014-05-578435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133481PMC
August 2014

Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia.

Blood 2014 Aug 26;124(9):1513-21. Epub 2014 Jun 26.

Department of Molecular Medicine, University of Pavia, Pavia, Italy; Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy;

Our knowledge of the genetic basis of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) has considerably improved. To define genotype/phenotype relationships of clinical relevance, we studied 308 patients with MDS, MDS/MPN, or acute myeloid leukemia evolving from MDS. Unsupervised statistical analysis, including the World Health Organization classification criteria and somatic mutations, showed that MDS associated with SF3B1-mutation (51 of 245 patients, 20.8%) is a distinct nosologic entity irrespective of current morphologic classification criteria. Conversely, MDS with ring sideroblasts with nonmutated SF3B1 segregated in different clusters with other MDS subtypes. Mutations of genes involved in DNA methylation, splicing factors other than SF3B1, and genes of the RAS pathway and cohesin complex were independently associated with multilineage dysplasia and identified a distinct subset (51 of 245 patients, 20.8%). No recurrent mutation pattern correlated with unilineage dysplasia without ring sideroblasts. Irrespective of driver somatic mutations, a threshold of 5% bone marrow blasts retained a significant discriminant value for identifying cases with clonal evolution. Comutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to, chronic myelomonocytic leukemia. These results serve as a proof of concept that a molecular classification of myeloid neoplasms is feasible.
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http://dx.doi.org/10.1182/blood-2014-03-560227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148773PMC
August 2014

CALR exon 9 mutations are somatically acquired events in familial cases of essential thrombocythemia or primary myelofibrosis.

Blood 2014 Apr 19;123(15):2416-9. Epub 2014 Feb 19.

Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy;

Somatic mutations in the calreticulin (CALR) gene were recently discovered in patients with sporadic essential thrombocythemia (ET) and primary myelofibrosis (PMF) lacking JAK2 and MPL mutations. We studied CALR mutation status in familial cases of myeloproliferative neoplasm. In a cohort of 127 patients, CALR indels were identified in 6 of 55 (11%) subjects with ET and in 6 of 20 (30%) with PMF, whereas 52 cases of polycythemia vera had nonmutated CALR. All CALR mutations were somatic, found in granulocytes but not in T lymphocytes. Patients with CALR-mutated ET showed a higher platelet count (P = .017) and a lower cumulative incidence of thrombosis (P = .036) and of disease progression (P = .047) compared with those with JAK2 (V617F). In conclusion, a significant proportion of familial ET and PMF nonmutated for JAK2 carry a somatic mutation of CALR.
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http://dx.doi.org/10.1182/blood-2014-01-550434DOI Listing
April 2014

Bone marrow stroma CD40 expression correlates with inflammatory mast cell infiltration and disease progression in splenic marginal zone lymphoma.

Blood 2014 Mar 22;123(12):1836-49. Epub 2014 Jan 22.

Hematology Unit with Bone Marrow Transplantation and.

Splenic marginal zone lymphoma (SMZL) is a mature B-cell neoplasm characterized by rather indolent clinical course. However, nearly one third of patients experience a rapidly progressive disease with a dismal outcome. Despite the characterization of clone genetics and the recognition of deregulated immunologic stimulation in the pathogenesis of SMZL, little is known about microenvironment dynamics and their potential biological influence on disease outcome. Here we investigate the effect of stroma-intrinsic features on SMZL disease progression by focusing on the microenvironment of the bone marrow (BM), which represents an elective disease localization endorsing diagnostic and prognostic relevance. We show that the quality of the BM stromal meshwork of SMZL infiltrates correlates with time to progression. In particular, we describe the unfavorable prognostic influence of dense CD40 expression by BM stromal cells, which involves the contribution of CD40 ligand (CD40L)-expressing bystander mast cells infiltrating SMZL BM aggregates. The CD40/CD40L-assisted crosstalk between mesenchymal stromal cells and mast cells populating the SMZL microenvironment finds correlation in p53(-/-) mice developing SMZL and contributes to the engendering of detrimental proinflammatory conditions. Our study highlights a dynamic interaction, playing between nonneoplastic elements within the SMZL niche, toward disease progression.
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http://dx.doi.org/10.1182/blood-2013-04-497271DOI Listing
March 2014

JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes.

Blood 2014 Mar 23;123(10):1544-51. Epub 2013 Dec 23.

Department of Hematology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy;

Patients with essential thrombocythemia may carry JAK2 (V617F), an MPL substitution, or a calreticulin gene (CALR) mutation. We studied biologic and clinical features of essential thrombocythemia according to JAK2 or CALR mutation status and in relation to those of polycythemia vera. The mutant allele burden was lower in JAK2-mutated than in CALR-mutated essential thrombocythemia. Patients with JAK2 (V617F) were older, had a higher hemoglobin level and white blood cell count, and lower platelet count and serum erythropoietin than those with CALR mutation. Hematologic parameters of patients with JAK2-mutated essential thrombocythemia or polycythemia vera were related to the mutant allele burden. While no polycythemic transformation was observed in CALR-mutated patients, the cumulative risk was 29% at 15 years in those with JAK2-mutated essential thrombocythemia. There was no significant difference in myelofibrotic transformation between the 2 subtypes of essential thrombocythemia. Patients with JAK2-mutated essential thrombocythemia and those with polycythemia vera had a similar risk of thrombosis, which was twice that of patients with the CALR mutation. These observations are consistent with the notion that JAK2-mutated essential thrombocythemia and polycythemia vera represent different phenotypes of a single myeloproliferative neoplasm, whereas CALR-mutated essential thrombocythemia is a distinct disease entity.
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http://dx.doi.org/10.1182/blood-2013-11-539098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3945864PMC
March 2014

Reproducibility of the WHO histological criteria for the diagnosis of Philadelphia chromosome-negative myeloproliferative neoplasms.

Mod Pathol 2014 Jun 8;27(6):814-22. Epub 2013 Nov 8.

Dipartimento di Scienze per la Promozione della Salute e Materno-Infantile 'G. D'Alessandro', Sezione di Anatomia Patologica, Università degli Studi di Palermo, Palermo, Italy.

This study, performed on behalf of the Italian Registry of Thrombocythaemias (Registro Italiano Trombocitemie), aimed to test the inter-observer reproducibility of the histological parameters proposed by the WHO classification for the diagnosis of the Philadelphia chromosome-negative myeloproliferative neoplasms. A series of 103 bone marrow biopsy samples of Philadelphia chromosome-negative myeloproliferative neoplasms consecutively collected in 2004 were classified according to the WHO criteria as follows: essential thrombocythaemia (n=34), primary myelofibrosis (n=44) and polycythaemia vera (n=25). Two independent groups of pathologists reviewed the bone marrow biopsies. The first group was asked to reach a collegial 'consensus' diagnosis. The second group reviewed individually all the cases to recognize the main morphological parameters indicated by the WHO classification and report their results in a database. They were subsequently instructed to individually build a 'personal' diagnosis of myeloproliferative neoplasms subtype just assembling the parameters collected in the database. Our results indicate that high levels of agreement (≥70%) have been reached for about all of the morphological features. Moreover, among the 18 evaluated histological features, 11 resulted statistically more useful for the differential diagnosis among the different Philadelphia chromosome-negative myeloproliferative neoplasms. Finally, we found a high percentage of agreement (76%) between the 'personal' and 'consensus' diagnosis (Cohen's kappa statistic >0.40). In conclusion, our results support the use of the histological criteria proposed by the WHO classification for the Philadelphia chromosome-negative myeloproliferative neoplasms to ensure a more precise and early diagnosis for these patients.
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http://dx.doi.org/10.1038/modpathol.2013.196DOI Listing
June 2014
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