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  • 1
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 927-927
    Abstract: The purpose of this study was to evaluate the clinical outcome, prognostic factors and the rate of CNS recurrence in PHNBCL patients. From December 1990 to June 2004, 401 patients, with a median age of 60 years (range, 19–85), were diagnosed as having PHNBCL in 9 IELSG centers. The tumor site was: Waldeyer’s ring (69%), followed by parotid and salivary glands (12%), nasal cavity and paranasal sinuses (8%), thyroid (6%) and palate and oral cavity (5%). Regarding histology 77% of cases had DLBCL,18% indolent lymphomas (MALT=42; FL=29), while only 5% had Burkitt lymphoma or MCL. DLBCL and indolent lymphomas (IL) were selected for the present analysis. Stage II was slightly higher in DLBCL (67% vs 54%; P=0.03), while the rate of other adverse features such as advanced age ( & gt;60 yrs), bulky disease ( & gt;10 cm), B symptoms, ECOG-PS & gt;1, No of extranodal sites & gt;1, elevated LDH, beta 2-microglobulin or ESR, reduced albumin and & gt;1 MIPI risk factors (RF) (50 vs 40%) was not statistically different into 2 groups. One hundred ninety four patients (51%) were treated with single therapy, mostly consinsting in anthracyclin containing chemotherapy (CHT), while 183 patients (49%) were given 3–4 courses of CHT, followed by IF RT. Only 26/250 DLBCL (10%) and 2/35 IL (6%) patients received CNS prophylaxis (Methotrexate 12 mg i.t.; median of cycles 3, range1–6). Two hundred sixty two DLBCL (85%) and 63 IL patients (91%) achieved a complete remission. Sixty DLBCL and 25 IL remitters, eventually relapsed (23 vs 40 %; P=0.007), 40 and 35% in the same site, 53 and 60% in other sites (1/234 patients with DLBCL of Waildeyer’s ring or paranasal sinuses, in CNS, 0.4%) and 7 and 5 in both. After a median follow-up of 42 and 35 months the DFS varied according to histology (DLBCL, 73% vs IL 52%; P=0.005), while OS and EFS were comparable into two groups (OS, 72% vs 74%; EFS, 56% vs 45%). In DLBL patients, the 5-year EFS varied according to MIPI (0–1 RF, 44% vs & gt;1 RF, 69%; P=0.0001), and treatment (CHT, 42% vs CHT+IFRT, 60%; P=0.0001), while in IL patients MIPI and treatment did not influence EFS. Cox multivariate analysis showed that MIPI and treatment were independent prognostic factors for OS in DLBCL. Also in IL patients the MIPI score maitained its independent value for OS. In conclusion, this retrospective analysis shows that MIPI, histology and a combined treatment influence the outcome of patients with PHNBCL. Moreover, in the present series a very low rate of CNS recurrence occurred in high risk patients, who did not receive adequate prophylaxis, suggesting that CNS prophylaxis could not be mandatory in PHNBCL patients. This should be confirmed by prospective studies of clinical outcome.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 2
    In: Blood Advances, American Society of Hematology, Vol. 6, No. 15 ( 2022-08-09), p. 4471-4484
    Abstract: Store-operated Ca2+-entry is a cellular mechanism that governs the replenishment of intracellular stores of Ca2+ upon depletion caused by the opening of intracellular Ca2+-channels. Gain-of-function mutations of the 2 key proteins of store-operated Ca2+-entry, STIM1 and ORAI1, are associated with several ultra-rare diseases clustered as tubular aggregate myopathies. Our group has previously demonstrated that a mouse model bearing the STIM1 p.I115F mutation recapitulates the main features of the STIM1 gain-of-function disorders: muscle weakness and thrombocytopenia. Similar findings have been found in other mice bearing different mutations on STIM1. At present, no valid treatment is available for these patients. In the present contribution, we report that CIC-39Na, a store-operated Ca2+-entry inhibitor, restores platelet number and counteracts the abnormal bleeding that characterizes these mice. Subtle differences in thrombopoiesis were observed in STIM1 p.I115F mice, but the main difference between wild-type and STIM1 p.I115F mice was in platelet clearance and in the levels of platelet cytosolic basal Ca2+. Both were restored on treatment of animals with CIC-39Na. This finding paves the way to a pharmacological treatment strategy for thrombocytopenia in tubular aggregate myopathy patients.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 2876449-3
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  • 3
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2651-2651
    Abstract: Abstract 2651 Background and objectives [18F]fluorodeoxyglucose - Positron Emission Tomography (FDG-PET) is confirmed as a useful functional imaging tool for staging and response assessment in Hodgkin lymphoma and Diffuse Large B-Cell Lymphoma. Despite FL is accounted among FDG-avid lymphomas few studies have been performed to investigate how FDG-PET can be used in initial staging of FL patients. We conducted a retrospective analysis to investigate the role of FDG-PET in the initial staging of FL. Patients and methods The study was designed as a retrospective unplanned analysis of patients with newly diagnosed FL enrolled in the FOLL05 phase III trial (NCT00774826) and randomized to one of the three study arms (R-CVP. R-CHOP, R-FM). To be included in the study patients should have confirmed eligibility for the FOLL05 trial, have available data on clinical presentation, treatment details and results, and on follow-up. Baseline staging had to be performed with contrast-enhanced Computed Tomography (CT), with CT-PET, and with Bone Marrow (BM) biopsy. For study purposes disease extension at baseline was defined independently for both CT and PET using on local report and interpretation; only for difficult cases images were centralized and reviewed. For each exam nodal sites (NS) were counted according to the FLIPI schema. NS were considered as positive if greater than 1.5 cm in their maximum transverse diameter at CT or, using PET, if FDG avid or if they had disappeared at the end of treatment. Extranodal sites (ENS) were counted on an organ basis and were considered positive at CT in case of nodular involvement or in case of organ enlargement not otherwise justified. Extranodal involvement at PET was considered for sites showing avidity for FDG not justified by conditions other than FL. Conventional Ann Arbor (AA) staging was based on CT scan assessment only. PET and CT scan results were compared using the kappa-statistic measure of interrater agreement (IR), and the level of agreement was defined by the Koch Landis scale. Results Among 534 patients enrolled in the FOLL05 trial, 122 cases fulfilled eligibility criteria for this study. All but 2 cases were confirmed as FDG avid at PET scan; these two cases were not used for staging comparison. Median age of patients was 57 years (range 33–74), 33% were older than 60 years, 48% were males. Bone marrow biopsy was positive in 52%. Using CT, AA stage was III-IV in 77% of cases. Fifty-two percent, 36%, and 12% of cases had less 0–4, 5–8, and 〉 8 NS, at CT, respectively. Overall CT scan allowed the identification of 48 ENS in 36 patients (30%); 2 or more ENS were described in 8 patients (6%); most frequent ENS were spleen (52%), liver (10%), skin/soft tissue (8%) and GI tract (6%). Using PET 38%, 37%, and 25% of cases had 0–4, 5–8, 〉 8 NS, respectively. PET allowed the identification of 88 ENS in 55 patients (46%) and 2 or more ENS were found in 17 patients (14%). Most frequent ENS at PET were bone (35%), spleen (30%), GI tract (10%), and skin/soft tissue (7%). Classifying patients according to the number of NS (0–4, 5–8, 〉 8) agreement between CT and PET was fair (IR= 61%, Kappa=0.39). Agreement between CT and PET for ENS (grouped as 0, 1, and 〉 1) was also fair (IR= 63%, Kappa=0.31) and improved to moderate when also details on BM histology were considered (IR 82% K=0.4). When PET was used independently of CT to define AA stage a moderate agreement was achieved with CT (IR=76%, kappa= 0.58): in particular 22 cases (18%) were upstaged with PET while only 6 (5%) were downstaged; seventeen out of 25 (68%) patients were reclassified by PET as stage III-IV from a previous localized stage. Looking at FLIPI, 22%, 41%, and 37% were classified by CT as having score of 0–1, 2, and 3–5, respectively. The use of PET modified CT based FLIPI index in 26% of cases, with a substantial agreement between PET and CT (IR=74%, kappa=0.61). FLIPI2 index is not affected by the use of PET. Conclusions The results of this study confirm FL as a FDG-avid disease. The use of PET for the initial staging of patients with FL seems to provide a more accurate definition of disease extent compared with CT. The clinical usefulness of adding PET to the initial staging of FL needs to be further investigated. Disclosures: Di Raimondo: Celgene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
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  • 4
    Online Resource
    Online Resource
    American Society of Hematology ; 2013
    In:  Blood Vol. 121, No. 21 ( 2013-05-23), p. e129-e137
    In: Blood, American Society of Hematology, Vol. 121, No. 21 ( 2013-05-23), p. e129-e137
    Abstract: Human arterial ring assay is an innovative system for the three-dimensional study of tumor angiogenesis. This assay can be exploited for antiangiogenic drug screening and gene function analysis on human vessels.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
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  • 5
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 3432-3432
    Abstract: We compared clinical characteristics, prognostic factors and treatment outcome of primary thyroid DLBCL (PTL) with those of other locations of primary extranodal head and neck lymphomas (PEHNL) and we further analyzed somatic hypermutation in pts with PTL. From December 1990 to June 2004, 48 PTL out of 478 PEHNL patients (pts) (10%) were enrolled in this study, including 10 males and 38 females, with a median age of 73 years (range, 34–90 years). In comparison with other locations PTL cases had more frequently advanced age ( 〉 60 yrs), female sex, bulky disease, poor ECOG-PS, elevated LDH and 〉 1 adverse factors according to stage-modified IPI (MIPI). The commonest treatment was a short course of anthracycline-based chemotherapy (CHT) ± involved field radiotherapy (IFRT). Forty-two percent of PTL pts also underwent surgery. Clonal IGHVDJ rearrangements were analyzed in 17/48 cases. The CR rate of PTL pts (85%) was comparable to those of other locations. After a median follow-up of 41 months (range 1–154.months), 5-yr OS, EFS and DFS were 51%, 46% and 86%, respectively. The OS compared unfavourably with other locations (75%), while the disease-specific survival rate was similar in both groups (80%). Moreover, MIPI was not predictive of survival, probably due to a high mortality unrelated to disease (19% Vs 7%). Regarding treatment PTL pts seem to benefit more from surgery in combination with chemotherapy and/or IFRT than from other treatments not including partial or complete thyroid resection (p=0.04). Somatic hypermutation of IGHV genes was observed in the majority of PTL cases, suggesting that they derive from germinal center experienced B-cell, while the unmutated status in a fraction of pts indicates a different histogenetic and pathogenetic pathway. The significant clustering of S and R mutations in CDRs and FRs in a fraction of cases with high homologous CDR3 suggests that antigen stimulation may have an important role in the pathogenesis of these lymphomas. In conclusion, in spite of more adverse features at presentation PTL pts showed a favorable disease-specific survival, comparable to that of other PEHN. Biological study in PTL pts suggests different histogenetic and pathogenetic pathway. The comparison of thyroid biological profile with that of other PEHNL could help to clarify the different clinical behaviour of this uncommon malignancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
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  • 6
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 6581-6583
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 1468538-3
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  • 7
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1567-1567
    Abstract: BACKGROUND Pediatric aggressive large B-cell lymphomas (LBCL) share morphological and phenotypic features with adult types but seem to have better prognosis. Additionally, a specific subtype carrying IRF4 translocations (LBCL-IRF4) has been recently identified in this age group. In adults, the cell-of-origin (COO) distinction of diffuse large B-cell lymphoma (DLBCL) based on gene expression signatures (germinal center B-cell like, GCB and activated B-cell like, ABC) and more recently clusters of genetic alterations have identified molecularly distinct DLBCL subsets that may benefit from novel therapeutic targets. The integration of pediatric population in these clinically relevant molecular subgroups and its clinical importance is not well known. The aim of this study was to characterize the molecular heterogeneity of LBCL in pediatric and young adult patients and evaluate their potential clinical impact. DESIGN Sixty-one LBCL diagnosed in patients ≤25 years-old (median age 14 years old, male/female 38/23) were included in the study. Molecular analyses included fluorescence in situ hybridization for MYC, BCL2, IRF4 and BCL6, copy number (CN) analysis (Oncoscan, Affymetrix), COO Lymph2Cx assay (NanoString) and targeted next generation sequencing of 96 B-cell lymphoma driver genes (SureSelect XT, Agilent Technologies). CNA and mutational profiles were compared to those previously published in adult DLBCL. Correlation of molecular features and event free survival (EFS) was performed using Kaplan-Meier curves. RESULTS Histologically, 33 were DLBCL, 20 LBCL-IRF4 and 8 high grade B-cell lymphomas, not otherwise specified (HGBCL). Nodal disease was present in 57%, mainly in the cervical region. COO distribution was: 68% GCB, 18% ABC and 13% unclassified. Most of LBCL-IRF4 cases were GCB-COO (73%). The IRF4 translocation was demonstrated in 16 out of 19 cases diagnosed as LBCL-IRF4 and an IGH rearrangement was seen in the other 3. Five cases carried MYC-breaks (3 DLBCL and 2 HGBCL) and two cases carried BCL6-breaks (1DLBCL and 1HGBCL). BCL2 rearrangements were absent. CN analysis detected alterations in 46/51 cases with recurrent gains ( 〉 15%) of 1q, 2p16, 11q, trisomies 7 and 12, and recurrent losses ( 〉 10%) of 1p36, 6q21-q22, 15q24, 17p13 and 19p13. Recurrent homozygous deletions were observed at 19p13/CD70 (6 cases), 9p13/CDKN2A (3 cases) and 13q14/RB1 (2 cases). Alteration patterns suggestive of chromothripsis were found in 10% (5/51) of the cases. No ABC-DLBCL related alterations such as 3p21-p14, 6q21-q25, 9p21.3 and 17p13 losses were seen. Targeted sequencing detected a total of 434 variants in 44 of 47 cases (mean 9.2 mutations/case). A pipeline for selection of driver mutations revealed a total of 270 mutations (62%) with potential functional effect. Recurrent mutations found in 〉 15% of the cases affected IRF4, SOCS1, PIM1, CARD11, ACTB and CCND3 genes. In comparison to adult DLBCL, pediatric and young adult cases had significantly lower incidence of MYD88 (5 cases), CREBBP,TP53 (3 cases each) and TNFRSF14 (2 cases) mutations which are strongly associated with the definition of established mutational clusters in adult DLBCL. In our cohort, the morphological subtypes displayed different molecular profiles. IRF4 variants (some cases with 〉 7 variants) and mutations in NF-kB pathway (CARD11, CD79B and MYD88-non L265P) were found specifically in the LBCL-IRF4 subgroup, whereas mutations in GCB related genes such as SOCS1 and EZH2 were particularly seen in cases with DLBCL diagnosis. All 49 patients with available follow-up received chemotherapy as first line treatment (41% containing Rituximab). Variables significantly associated with poor EFS in univariate analysis were age 〉 18 years, ABC-COO, Stage IV, high genetic complexity (chromothripsis and/or 〉 10 CN alterations), 2p16/REL gain/amplification, 9p21.3/CDKN2A homozygous deletions, MYC rearrangements and mutations in MYC, TP53 and DDX3X genes. CONCLUSION Despite pediatric/young-adult LBCL having overlapping features with adult disease our findings suggest that LBCL in young age have specific molecular mechanisms and highlight potential key drivers of these lymphomas in this age group. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3707-3707
    Abstract: Abstract 3707 Poster Board III-643 Introduction response to salvage chemotherapy prior to high–dose therapy (HDT) is of major prognostic concern in relapsed/refractory HL. FDG-PET is able to distinguish between persistent disease and fibrosis/necrosis and has thus become the mainstay to define clinical response in this setting (Cheson et al, JCO 2007). The value of FDG-PET in this subset of patient is less well established. IGEV chemotherapy has shown very encouraging results as induction therapy in refractory/relapsed HL (Santoro et al, Haematologica 2007). Aims to retrospectively evaluate the predictive value of PET in pts with relapsed/refractory HL receiving IGEV and HDT. Methods seventy-two multicentric cases with refractory/relapsed HL who had completed IGEV x 4 courses and HDT between 01/98 and 05/07 were reviewed. FDG-PET evaluation was performed before HDT and, according to revised Cheson criteria, complete remission (CR) was defined as negative FDG-PET, independently from the presence of residual masses at CT scan. Univariate analysis was performed considering FDG-PET as well as other usually evaluated prognostic factors. Results patient characteristics: M/F 30/42, median age 33 (range 16-71), Nodular sclerosis 61 (85%), refractory 28 (39%), relapsed 44 (61%), one previous regimen 60 (83%), B symptoms 18 (25%), bulky disease 7 (10%), extranodal disease 32 (44%), previous radiotherapy 39 (54%). After induction, 36 pts (50%) received single (with BEAM as conditioning regimen ), and 36 (50%) tandem HDT (with melphalan as first and BEAM as second conditioning). After IGEV, on the basis of PET 47 pts (65%) were classified as complete remission (CR), 21 (29%) as partial remission (PR) and 4 (6%) did not respond. Ten of the 47 PET negative pts, and 18 of the 25 PET positive pts relapsed. With a median follow up 48 months, the 3-year PFS was 80% vs 25% for patient with negative vs positive PET respectively (HR 5.7 no CR vs CR - CI 95%: 2.6-12.4). The 3-year overall survival (OS) was 91% vs 56 % for patient with negative vs positive PET respectively (HR 7.8 no CR vs CR CI 95%: 2.6-23.7). In univariate analysis, factors influencing the probability of achieving CR to IGEV were disease status (refractory vs relapse) (p.096) and bulky disease at IGEV (p .088). Factor significantly associated with PFS and OS are reported in table. In multivariate analysis only response to therapy, as defined by pre-transplant PET result, maintained significance as prognostic indicator for both PFS (HR 5.7) and OS (HR 7.8). Conclusions these data in homogeneously treated pts with refractory/relapsed HL underline the crucial prognostic relevance of pre-transplant FDG-PET, even overwhelming the impact of disease status at progression. FDG-PET driven trials are highly recommended in this subset of patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
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  • 9
    In: Blood, American Society of Hematology, Vol. 135, No. 4 ( 2020-01-23), p. 274-286
    Abstract: Pediatric large B-cell lymphomas (LBCLs) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse LBCLs (DLBCLs), not otherwise specified (NOS); 20 LBCL-IRF4 cases; and 12 cases of high-grade B-cell lymphoma (HGBCL), NOS in patients ≤25 years using an integrated approach, including targeted gene sequencing, copy-number arrays, and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B, and MYD88), losses of 17p13 and gains of chromosome 7, 11q12.3-q25, whereas DLBCL, NOS was predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (eg, SOCS1 and KMT2D), gains of 2p16/REL, and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma–related genes such as MYC, ID3, and DDX3X and homozygous deletions of 9p21/CDKN2A, whereas other cases were genetically closer to GCB DLBCL. Factors related to unfavorable outcome were age & gt;18 years; activated B-cell (ABC) DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric and young adult LBCL, improve the classification of this group of tumors, and provide new parameters for risk stratification.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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