39 results on '"Forconi, Francesco"'
Search Results
2. PB2296: ROBUST BRUTON’S TYROSINE KINASE (BTK) DEGRADATION WITH NX‐5948, AN ORAL BTK DEGRADER, IN A FIRST‐IN‐HUMAN PHASE 1A TRIAL IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY B CELL MALIGNANCIES.
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Linton, Kim, Forconi, Francesco, Lewis, David, Riches, John, El‐Sharkawi, Dima, Gleeson, Mary, Injac, Sarah G, Nandakumar, Srinand, Tan, May, Cherala, Ganesh, and Collins, Graham P
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- 2023
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3. Guideline for diagnosis and management of hairy cell leukaemia (HCL) and hairy cell variant (HCL‐V).
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Parry‐Jones, Nilima, Joshi, Anurag, Forconi, Francesco, and Dearden, Claire
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PANCYTOPENIA ,LEUKEMIA ,T-cell lymphoma ,KIDNEY physiology ,HEMOLYTIC-uremic syndrome ,BURKITT'S lymphoma - Abstract
Keywords: Differential diagnosis; BRAF V600E mutation; hairy Cell Leukaemia; Hairy cell variant; therapy EN Differential diagnosis BRAF V600E mutation hairy Cell Leukaemia Hairy cell variant therapy 730 737 8 12/07/20 20201201 NES 201201 Methodology This guideline was compiled according to the BSH process (https://b-s-h.org.uk/guidelines). Cytoplasm is abundant and pale blue, with circumferential "hairy" projections.9 Discrete cytoplasmic vacuoles or rod-shaped inclusions (ribosome lamellar complexes) may be seen.3 Bone marrow aspirate and trephine biopsy Bone marrow aspiration is frequently unsuccessful, reflecting fibrosis induced by the hairy cell infiltrate. In a single-centre follow-up study of 242 patients,41 18 patients treated with cladribine (12 as first-line and six as second-line therapy) who remained in PR after bone marrow reassessment received a repeat treatment with cladribine 4-7 months after initial treatment, leading to CR in 14 patients, of whom all but one remained in CR at a median follow-up of 6 years. Treatment of relapsed or refractory classical HCL Despite the durable remissions achieved with front-line therapy, approximately 50% of patients will relapse. [Extracted from the article]
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- 2020
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4. The efficacy and safety of venetoclax therapy in elderly patients with relapsed, refractory chronic lymphocytic leukaemia.
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Eyre, Toby A., Roeker, Lindsey E., Fox, Christopher P., Gohill, Satyen H., Walewska, Renata, Walter, Harriet S., Forconi, Francesco, Broom, Angus, Arumainathan, Arvind, Brander, Danielle M., Allan, John N., Schuster, Stephen J., Hill, Brian T., Lansigan, Frederick, Cheson, Bruce D., Lamanna, Nicole, Coombs, Catherine C., Barr, Paul M., Skarbnik, Alan P., and Shadman, Mazyar
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OLDER patients ,LEUKEMIA ,PROTEIN-tyrosine kinases ,SAFETY ,KINASE inhibitors - Abstract
Summary: Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B‐cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non‐trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib‐exposed and therefore may otherwise have few clear therapeutic options. [ABSTRACT FROM AUTHOR]
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- 2020
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5. Efficacy of venetoclax monotherapy in patients with relapsed chronic lymphocytic leukaemia in the post‐BCR inhibitor setting: a UK wide analysis.
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Eyre, Toby A., Kirkwood, Amy A., Gohill, Sat, Follows, George, Walewska, Renata, Walter, Harriet, Cross, Matthew, Forconi, Francesco, Shah, Nimish, Chasty, Richard, Hart, Alistair, Broom, Angus, Marr, Helen, Patten, Piers E. M., Dann, Andy, Arumainathan, Arvind, Munir, Tal, Shankara, Paneesha, Bloor, Adrian, and Johnston, Rosalynd
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B cell receptors ,PROTEIN-tyrosine kinases ,PROGRESSION-free survival - Abstract
Summary: Venetoclax is a BCL2 inhibitor with activity in relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). We conducted a multi‐centre retrospective analysis of 105 R/R CLL patients who received venetoclax pre‐National Health Service commissioning. The median age was 67 years and median prior lines was 3 (range: 1–15). 48% had TP53 disruption. At ≥2 lines, 60% received a Bruton Tyrosine Kinase inhibitor (BTKi) and no prior phosphoinositide 3‐kinase inhibitor (Pi3Ki), 25% received a Pi3Ki and no prior BTKi, and 10% received both. Patients discontinued B cell receptor inhibitor (BCRi) because of toxicity in 44% and progression in 54%. Tumour lysis syndrome risk was low, intermediate or high in 27%, 25%, and 48% respectively. Overall response was 88% (30% complete response [CR]). The overall response rate was 85% (CR 23%) in BTKi‐exposed patients, 92% (CR 38%) in Pi3Ki‐exposed patients and 80% (CR 20%) in both (P = 0·59). With a median follow‐up of 15·6 months, 1‐year progression‐free survival was 65·0% and 1‐year overall survival was 75·1%. Dose reduction or temporary interruption did not result in an inferior progression‐free or discontinuation‐free survival. Risk of progression or death after stopping a prior BCRi for progression was double compared to those stopping for other reasons (predominantly toxicity) (Hazard Ratio 2·01 P = 0·05). Venetoclax is active and well tolerated in R/R CLL post ≥1 BCRi. Reason(s) for stopping BCRi influences venetoclax outcomes. [ABSTRACT FROM AUTHOR]
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- 2019
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6. The outcome of Chronic lymphocytic leukaemia patients with 97% IGHV gene identity to germline is distinct from cases with <97% identity and similar to those with 98% identity.
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Davis, Zadie, Forconi, Francesco, Parker, Anton, Gardiner, Anne, Thomas, Peter, Catovsky, Daniel, Rose‐Zerilli, Matthew, Strefford, Jonathan C, and Oscier, David
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LYMPHOCYTIC leukemia , *IMMUNOGLOBULIN heavy chains , *DISEASE progression , *REGRESSION analysis , *PROGNOSIS , *GENETICS - Abstract
IGHV gene mutational status has prognostic significance in chronic lymphocytic leukaemia ( CLL) but the percentage of mutations that correlates best with clinical outcome remains controversial. We initially studied 558 patients from diagnosis and found significant differences in median time to first treatment ( TTFT) among Stage A patients and in overall survival ( OS) for the whole cohort, between cases with <97% and 97-98·99% identity and between cases with 97-98·99% and ≥99% identity, when cases from the IGHV3-21 Stereotype Subset #2 were excluded. A significant difference in progression-free survival (PFS) and OS between those with <97% and 97-98·99% identity, but not between those with 97-98·99% and ≥99% identity was also observed in a validation cohort comprising 460 patients in the UK CLL4 trial. Cox Regression analyses in the Stage A cohort revealed that a model which incorporated <97%, 97-98·99% and ≥99% identity as subgroups, was a better predictor of TTFT in CLL than using the 98% cut-off. Multivariate analysis selected the three mutational subgroups as independent predictors of TTFT in Stage A patients, and of OS in the diagnostic cohort. This study highlights that cases with 97% identity should not be considered to have the same prognosis as other cases with mutated IGHV genes defined as <98% identity to germline. [ABSTRACT FROM AUTHOR]
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- 2016
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7. Promoter methylation patterns in Richter syndrome affect stem-cell maintenance and cell cycle regulation and differ from de novo diffuse large B-cell lymphoma.
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Rinaldi, Andrea, Mensah, Afua Adjeiwaa, Kwee, Ivo, Forconi, Francesco, Orlandi, Ester M., Lucioni, Marco, Gattei, Valter, Marasca, Roberto, Berger, Françoise, Cogliatti, Sergio, Cavalli, Franco, Zucca, Emanuele, Gaidano, Gianluca, Rossi, Davide, and Bertoni, Francesco
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METHYLATION ,RICHTER syndrome ,B cell lymphoma ,STEM cells ,CELL cycle - Abstract
In a fraction of patients, chronic lymphocytic leukaemia ( CLL) can transform to Richter syndrome ( RS), usually a diffuse large B-cell lymphoma ( DLBCL). We studied genome-wide promoter DNA methylation in RS and clonally related CLL-phases of transformed patients, alongside de novo DLBCL (of non-germinal centre B type), untransformed- CLL and normal B-cells. The greatest differences in global DNA methylation levels were observed between RS and DLBCL, indicating that these two diseases, although histologically similar, are epigenetically distinct. RS was more highly methylated for genes involved in cell cycle regulation. When RS was compared to the preceding CLL-phase and with untransformed- CLL, RS presented a higher degree of methylation for genes possessing the H3 K27me3 mark and PRC2 targets, as well as for gene targets of TP53 and RB1. Comparison of the methylation levels of individual genes revealed that OSM, a stem cell regulatory gene, exhibited significantly higher methylation levels in RS compared to CLL-phases. Its transcriptional repression by DNA methylation was confirmed by 5-aza-2′deoxycytidine treatment of DLBCL cells, determining an increased OSM expression. Our results showed that methylation patterns in RS are largely different from de novo DLBCL. Stem cell-related genes and cell cycle regulation genes are targets of DNA methylation in RS. [ABSTRACT FROM AUTHOR]
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- 2013
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8. Clinical heterogeneity of de novo 11q deletion chronic lymphocytic leukaemia: prognostic relevance of extent of 11q deleted nuclei inside leukemic clone.
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Marasca, Roberto, Maffei, Rossana, Martinelli, Silvia, Fiorcari, Stefania, Bulgarelli, Jenny, Debbia, Giulia, Rossi, Davide, Rossi, Francesca Maria, Rigolin, Gian Matteo, Martinelli, Sara, Gattei, Valter, Del Poeta, Giovanni, Laurenti, Luca, Forconi, Francesco, Montillo, Marco, Gaidano, Gianluca, and Luppi, Mario
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Deletion on the long arm of chromosome 11 occurs in 5-20% of chronic lymphocytic leukaemia (CLL) patients. We analysed clinical-biological characteristics of 131 CLL patients carrying 11q deletion documented before therapy ( de novo 11q deleted CLL). De novo 11q deleted CLL were characterized by high frequencies of unmutated immunoglobulin variable heavy genes, multiple fluorescence in situ hybridization aberrations and lymph node involvement. Factors significantly associated with shorter time to first treatment (TTFT) were advanced Binet stages, high white blood cell count, increased β
2 -microglobulin levels, 17p in addition, splenomegaly and more extensive lymphadenopathy. We found that patients with <25% 11q deleted nuclei ( n = 22) experienced longer TTFT compared with patients with ≥25% 11q deleted nuclei ( n = 87; median TTFT, 40 vs. 14 months, p = 0.011) and also showed better response to treatments (complete response, 50% vs. 21%, p = 0.016). The variables identified by multivariate analysis as independently associated with reduced TTFT were advanced Binet stages [hazard ratio (HR) 4.69; p < 0.001] and ≥25% 11q deleted nuclei (HR 4.73; p = 0.004). De novo 11q deleted CLLs exhibit variable clinical outcome. The percentage of deleted nuclei inside leukemic clone should be included in the prognostic definition of therapy-naïve 11q deleted CLL patients. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]- Published
- 2013
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9. Different impact of NOTCH1 and SF3B1 mutations on the risk of chronic lymphocytic leukemia transformation to Richter syndrome.
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Rossi, Davide, Rasi, Silvia, Spina, Valeria, Fangazio, Marco, Monti, Sara, Greco, Mariangela, Ciardullo, Carmela, Famà, Rosella, Cresta, Stefania, Bruscaggin, Alessio, Laurenti, Luca, Martini, Maurizio, Musto, Pellegrino, Forconi, Francesco, Marasca, Roberto, Larocca, Luigi M., Foà, Robin, and Gaidano, Gianluca
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CHRONIC lymphocytic leukemia ,NOTCH genes ,LYMPHOMAS ,MULTIVARIATE analysis ,GENETIC mutation - Abstract
The article presents a study on 605 patients with chronic lymphocytic leukemia (CLL) focusing on the impact of NOTCH1 and SFB3 mutations on the risk of transformation of CLL to Richter syndrome (RS). Techniques like Sanger sequencing, flow cytometry and multivariate analysis were used during the study. The SFB3 mutations showed no impact on RS development and were absent in all the CLL patients. 40 to 50 percent of NOTCH1 mutated patients developed RS.
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- 2012
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10. Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis.
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Rossi, Davide, Spina, Valeria, Forconi, Francesco, Capello, Daniela, Fangazio, Marco, Rasi, Silvia, Martini, Maurizio, Gattei, Valter, Ramponi, Antonio, Larocca, Luigi M., Bertoni, Francesco, and Gaidano, Gianluca
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Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia to aggressive lymphoma. We explored intraclonal diversification (ID) of immunoglobulin genes in order to ( i) follow the evolutionary history of the RS clone ( ii) compare the role of ID in clonally related RS vs. clonally unrelated cases. Most (10/11, 90.9%) clonally related RS stem from the predominant clone observed at CLL diagnosis. One single RS had a transformation pattern compatible with sequential evolution from a secondary CLL subclone. Once RS transformation had occurred, all secondary CLL subclones disappeared and were substituted by the dominant RS clone with its own descendants. These observations suggest that genetic lesions associated with RS transformation are acquired by a cell belonging to the original CLL clone, rather than being progressively accumulated by later CLL subclones. Accordingly, most (9/11, 81.1%) clonally related RS harbored a genetic lesion disrupting TP53 that was already present, though at subclonal levels, in 5/11 (45.5%) samples of the paired CLL phase. A fraction of clonally related RS switched off ID (4/11, 36.4%) or reduced the levels of ID (5/11, 45.4%) at transformation. Conversely, all clonally unrelated RS harbored ID and were characterized by a significantly higher mutation frequency compared to clonally related RS (median: 1.18 × 10
−3 vs. 0.13 × 10-3 ; p =0.002). These data indicate that ( i) clonally related RS stems from a cell that is already present within the initial CLL clone and ( ii) clonally unrelated and clonally related RS are biologically distinct disorders also in terms of antigen affinity maturation. [ABSTRACT FROM AUTHOR]- Published
- 2012
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11. Del(13q14.3) length matters: an integrated analysis of genomic, fluorescence in situ hybridization and clinical data in 169 chronic lymphocytic leukaemia patients with 13q deletion alone or a normal karyotype.
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Mian, Michael, Rinaldi, Andrea, Mensah, Afua Adjeiwaa, Rossi, Davide, Ladetto, Marco, Forconi, Francesco, Marasca, Roberto, Gattei, Valter, Zucca, Emanuele, Cavalli, Franco, Gaidano, Gianluca, Kwee, Ivo, and Bertoni, Francesco
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- 2012
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12. Integrated DNA copy number and methylation profiling of lymphoid neoplasms using a single array.
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Kwee, Ivo, Rinaldi, Andrea, Rancoita, Paola, Rossi, Davide, Capello, Daniela, Forconi, Francesco, Giuliani, Nicola, Piva, Roberto, Inghirami, Giorgio, Gaidano, Gianluca, Zucca, Emanuele, and Bertoni, Francesco
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DNA ,DNA methylation ,LYMPHOMAS ,METHYLATION ,CANCER ,TUMORS - Abstract
Summary Changes in DNA copy number (CN) and DNA methylation represent important aberrations for lymphomas and other cancers. Here, for the first time, we show that the Illumina Infinium Methylation (IIM) assay, although not originally designed for CN profiling, is able to estimate CN changes. We compared the IIM CN profiles to those obtained with a standard technique in a series of diffuse large B-cell lymphomas: the profiles showed a high degree of consensus. The demonstration of CN profiling as an additional function of the IIM assay may impact the choice of platform for methylation profiling of haematological and solid tumours. [ABSTRACT FROM AUTHOR]
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- 2012
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13. The coexistence of chronic lymphocytic leukemia and myeloproliperative neoplasms: A retrospective multicentric GIMEMA experience.
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Laurenti, Luca, Tarnani, Michela, Nichele, Ilaria, Ciolli, Stefania, Cortelezzi, Agostino, Forconi, Francesco, Rossi, Davide, Mauro, Francesca Romana, D'Arena, Giovanni, Del Poeta, Giovanni, Montanaro, Marco, Morabito, Fortunato, Musolino, Caterina, Callea, Vincenzo, Falchi, Lorenzo, Tedeschi, Alessandra, Ambrosetti, Achille, Gaidano, Gianluca, Leone, Giuseppe, and Foà, Robin
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- 2011
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14. Genome-wide DNA profiling better defines the prognosis of chronic lymphocytic leukaemia.
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Rinaldi, Andrea, Mian, Michael, Kwee, Ivo, Rossi, Davide, Deambrogi, Clara, Mensah, Afua A., Forconi, Francesco, Spina, Valeria, Cencini, Emanuele, Drandi, Daniela, Ladetto, Marco, Santachiara, Rita, Marasca, Roberto, Gattei, Valter, Cavalli, Franco, Zucca, Emanuele, Gaidano, Gianluca, and Bertoni, Francesco
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CHRONIC lymphocytic leukemia ,LYMPHOPROLIFERATIVE disorders ,MULTIVARIATE analysis ,DNA fingerprinting ,FLUORESCENCE in situ hybridization ,CHRONIC diseases ,LYMPHOCYTIC leukemia - Abstract
Summary The integration of molecular and clinical information to tailor treatments remains an important research challenge in chronic lymphocytic leukaemia (CLL). This study aimed to identify genomic lesions associated with a poor outcome and a higher risk of histological transformation. A mono-institutional cohort of 147 cases was used as the test series, and a multi-institutional cohort of 176 cases as a validation series. Genomic profiles were obtained using Affymetrix SNP 6.0. The impact of the recurrent minimal common regions (MCRs) on overall survival was evaluated by univariate analysis followed by multiple-test correction. The independent prognostic significance was assessed by multivariate analysis. Eight MCRs showed a prognostic impact: gains at 2p25.3-p22.3 ( MYCN), 2p22.3, 2p16.2-p14 ( REL), 8q23.3-q24.3 ( MYC), losses at 8p23.1-p21.2, 8p21.2, and of the TP53 locus. Gains at 2p and 8q and TP53 inactivation maintained prognostic significance in multivariate analysis and a hierarchical model confirmed their relevance. Gains at 2p also determined a higher risk of Richter syndrome transformation. The prediction of outcome for CLL patients might be improved by evaluating the presence of gains at 2p and 8q as novel genomic regions besides those included in the 'standard' fluorescence in situ hybridization panel. [ABSTRACT FROM AUTHOR]
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- 2011
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15. A pilot monocentric analysis of efficacy and safety of Fludarabine-Campath combination (Flucam) as first line treatment in elderly patients with chronic lymphocytic leukaemia and Tp53 disfunction.
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Cencini, Emanuele, Sozzi, Elisa, Sicuranza, Anna, Fabbri, Alberto, Raspadori, Donatella, Lauria, Francesco, and Forconi, Francesco
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CHARTS, diagrams, etc. ,CHRONIC lymphocytic leukemia ,PATIENTS ,LYMPHOPROLIFERATIVE disorders ,LEUKEMIA - Abstract
Several appendixes are presented depicting clinical and biological characteristics of patients with chronic lymphocytic leukaemia and Tp53 disfunction.
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- 2011
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16. Multicentre validation of a prognostic index for overall survival in chronic lymphocytic leukaemia.
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Bulian, Pietro, Tarnani, Michela, Rossi, Davide, Forconi, Francesco, Del Poeta, Giovanni, Bertoni, Francesco, Zucca, Emanuele, Montillo, Marco, Pozzato, Gabriele, Deaglio, Silvia, D'Arena, Giovanni, Efremov, Dimitar, Marasca, Roberto, Lauria, Francesco, Gattei, Valter, Gaidano, Gianluca, and Laurenti, Luca
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We wish to validate in a multicentric CLL population a nomogram and a risk score recently developed to predict overall survival (OS). Complete records from 1037 CLL patients were retrospectively collected to estimate OS and time to treatment (TTT). Cox models were used to test the independence of age, β-2-microglobulin, absolute lymphocyte count (ALC), sex, Rai stage and number of involved lymph node regions (LNR). Accuracy of prognostic models was tested with the concordance index (c-index). Median follow-up was 5.5 years, with 151 deaths and 475 treated patients. Median OS was not reached (65% survival rate at 13.9 years), median TTT was 6 years. We confirmed the ability of the prognostic score to predict OS and TTT in three risk groups, with results comparable with those reported in the original report. However, ALC and Rai stage were not independent predictors, whereas the Binet staging system, which incorporates LNR variable, showed independent predictive power; furthermore, both 5- and 10-year OS estimates from nomogram were lower compared to real data. When separately analysed, the impact of therapy on OS was not selected as independent predictor of OS in our series. According to these results, we proposed a simpler four-variable model (age, sex, Binet staging, β-2-microglobulin) and a new nomogram. This model had a c-index of 0.78 versus 0.76 of the six-variable model ( p = 0.043), showing better predictive accuracy. External validation and refinement are needed on independent data sets, possibly from cancer registry patients' series. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
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- 2011
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17. Hairy cell leukaemia: biological and clinical overview from immunogenetic insights.
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Forconi, Francesco
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Hairy cell Leukaemia (HCL) is a rare neoplasm of peripheral B cells which represents a paradox in oncology. Despite its largely unknown origin and behaviour, HCL is one of the few example of dramatic success in the treatment of a malignancy. The recent steps forward to understanding the biology of HCL from immunogenetic and genomic studies have recently provided new insight into diagnosis and prognosis. Several data from immunoglobulin gene (IG) analysis have provided hints regarding the cell of origin and the ongoing selective interactions of the tumour BCR with environmental stimuli. It has also recently emerged that an unmutated status of the HCL IG can be associated with failure to respond to cladribine, genetic abnormalities indicative of poor outcome and aggressive disease. These observations suggest a central role of the tumour B-cell receptor in defining the outcome of HCL and that that IG gene analysis may have biological and prognostic relevance. Hopefully, IG analysis will help tailor treatment strategies for the most aggressive cases. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
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- 2011
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18. B-cell receptor, clinical course and prognosis in chronic lymphocytic leukaemia: the growing saga of the IGHV3 subgroup gene usage.
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Dal-Bo, Michele, Del Giudice, Ilaria, Bomben, Riccardo, Capello, Daniela, Bertoni, Francesco, Forconi, Francesco, Laurenti, Luca, Rossi, Davide, Zucchetto, Antonella, Pozzato, Gabriele, Marasca, Roberto, Efremov, Dimitar G., Guarini, Anna, Del Poeta, Giovanni, Foà, Robin, Gaidano, Gianluca, and Gattei, Valter
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B cells ,CELL receptors ,IMMUNOGLOBULINS ,GENES ,CHRONIC lymphocytic leukemia ,PROGNOSIS - Abstract
The immunoglobulin heavy chain variable gene ( IGHV) mutational status has been recognized as an important predictor of prognosis in chronic lymphocytic leukaemia (CLL) since 1999. More recently, other features of the B-cell receptor, such as stereotypy, have been identified as capable of refining the prognostic potential of IGHV status in the clinical assessment of CLL patients. In this context, different genes belonging to the IGHV3 subgroup, the most frequently used subgroup in CLL, have been shown to denote disease subsets that either display a bad prognosis (i.e. IGHV3-21, IGHV3-23) or are associated with particularly good clinical outcomes, including a highly stable/indolent clinical course, even prone to spontaneous regression (i.e. IGHV3-72, IGHV3-30). The present review focuses on the molecular and biological features of CLL-expressing specific genes belonging to the IGHV3 subgroup that are known to mark disease subsets with completely different clinical courses, and may be possibly related to CLL pathogenesis via antigen and/or superantigen involvement. [ABSTRACT FROM AUTHOR]
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- 2011
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19. Lack of allelic exclusion by secondary rearrangements of tumour B-cell receptor light chains in hairy cell leukaemia.
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Sozzi, Elisa, Amato, Teresa, Sahota, Surinder S., Nuti, Sandra, Raspadori, Donatella, Sicuranza, Anna, Cencini, Emanuele, Tosi, Piero, Lauria, Francesco, and Forconi, Francesco
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- 2011
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20. A variant of the LRP4 gene affects the risk of chronic lymphocytic leukaemia transformation to Richter syndrome.
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Rasi, Silvia, Spina, Valeria, Bruscaggin, Alessio, Vaisitti, Tiziana, Tripodo, Claudio, Forconi, Francesco, De Paoli, Lorenzo, Fangazio, Marco, Sozzi, Elisa, Cencini, Emanuele, Laurenti, Luca, Marasca, Roberto, Visco, Carlo, Xu-Monette, Zijun Y., Gattei, Valter, Young, Ken H., Malavasi, Fabio, Deaglio, Silvia, Gaidano, Gianluca, and Rossi, Davide
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LYMPHOCYTIC leukemia ,LYMPHOMAS ,NUCLEOTIDES ,B cells ,BIOINFORMATICS ,PROGNOSIS ,CANCER risk factors - Abstract
Richter syndrome (RS) represents the transformation of chronic lymphocytic leukaemia (CLL) to aggressive lymphoma. Risk factors of CLL transformation to RS are only partly known. We explored the role of the host genetic background as a risk factor for RS occurrence. Forty-five single nucleotide polimorphisms (SNPs) known to be relevant for CLL prognosis were genotyped in a consecutive cohort of 331 CLL, of which 21 had transformed to RS. After correcting for multiple testing and adjusting for previously reported RS risk factors, the LRP4 rs2306029 TT variant genotype was the sole SNP independently associated with a higher risk of RS transformation (Hazard Ratio: 4·17; P = 0·001; q = 0·047). The enrichment of LRP4 TT genotype in RS was confirmed in an independent series ( n = 44) used for validation purposes. The LRP4 protein was expressed in CLL ( n = 66). Bioinformatic analysis scored LRP4 rs2306029 as a variant with possible deleterious and damaging variant of LRP4. LRP4 genotyping may help the recognition of patients with increased risk of RS at the time of CLL diagnosis. [ABSTRACT FROM AUTHOR]
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- 2011
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21. Immunogenetics features and genomic lesions in splenic marginal zone lymphoma.
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Rinaldi, Andrea, Forconi, Francesco, Arcaini, Luca, Mian, Michael, Sozzi, Elena, Zibellini, Silvia, Baldini, Luca, Franceschetti, Silvia, Gaidano, Gianluca, Marasca, Roberto, Mollejo, Manuela, Piris, Miguel A., Tucci, Alessandra, Facchetti, Fabio, Bhagat, Govind, Favera, Riccardo D., Rancoita, Paola M. V., Zucca, Emanuele, Kwee, Ivo, and Bertoni, Francesco
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IMMUNOGLOBULIN genes , *LYMPHOMAS , *IMMUNOGENETICS , *NUCLEOTIDES , *SPLEEN , *DNA microarrays , *GENETICS - Abstract
Splenic marginal zone lymphomas (MZL) express mutated (M−) or unmutated (U−) immunoglobulin heavy chain (IGHV) genes. To investigate the IGHV mutational status impact on genetic lesions, this study combined single nucleotide polymorphism-arrays and IGHV sequencing in 83 cases. Clinical features and outcome were similar between U- and M- IGHV cases. Recurrent lesions frequency was higher in U- IGHV cases, including poor prognosticators. Frequencies differed among cases bearing individual IGHV genes or lambda light chains. In conclusion, SMZL comprises subgroups based on genetic abnormalities and immunogenetic status. Genomic lesion frequency differed and was higher in U-IGHV cases, possibly affecting the outcome. [ABSTRACT FROM AUTHOR]
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- 2010
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22. Genomic profiling of Richter's syndrome: recurrent lesions and differences with de novo diffuse large B-cell lymphomas.
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Scandurra, Marta, Rossi, Davide, Deambrogi, Clara, Rancoita, Paola MV, Chigrinova, Ekaterina, Mian, Michael, Cerri, Michaela, Rasi, Silvia, Sozzi, Elisa, Forconi, Francesco, Ponzoni, Maurilio, Moreno, Santiago M, Piris, Miguel A, Inghirami, Giorgio, Zucca, Emanuele, Gattei, Valter, Rinaldi, Andrea, Kwee, Ivo, Gaidano, Gianluca, and Bertoni, Francesco
- Abstract
Richter's syndrome (RS) represents the transformation of chronic lymphocytic leukaemia (CLL) to aggressive lymphoma and is mostly represented by diffuse large B-cell lymphoma (DLBCL), with a post-germinal centre (GC) phenotype, clonally related to the pre-existing CLL. RS has a very poor prognosis and its pathogenetic mechanisms are poorly understood. In order to gain additional hints in RS pathogenesis, we performed a genome-wide DNA profiling study of 13 RS phases and eight matched CLL phases using the Affymetrix Human Mapping 250K NspI SNP arrays. Individual genomic profiles were heterogeneous, with no individual lesions occurring in more than half of the cases. However, several observations suggest that MYC pathway might be involved in RS. The 13q13.3-qter region containing MIRHG1 (MIR-17-92), a cluster of microRNA interacting with c-MYC, was acquired at the time of transformation. The 13q gain was coupled with the gain of c-MYC and loss of TP53. Translocation of c-MYC was acquired at transformation in a fraction of cases and this event appeared mutually exclusive with gain of MIRHG1. MYCN, a c-MYC homologue, was also recurrently gained. By comparing RS with 48 de novo DLBCL, RS presented a significantly lower prevalence of deletions affecting the PRDM1 and TNFAIP3, genes on 6q, known to be associated with a post-GC phenotype. In conclusion, the genomic profile of RS seems to differ from what observed in de novo DLBCL and in other transformed DLBCL. Genomic lesions occurring in RS are heterogeneous suggesting the existence of different RS subsets, possibly due to different transforming mechanisms. A deregulation of MYC pathway might represent one of the main transformation events in the pathogenesis of a subset of RS clonally related to the previous CLL. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
23. IGHD3-3 fails to behave as unfavourable prognostic marker in chronic lymphocytic leukaemia.
- Author
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Bomben, Riccardo, Dal Bo, Michele, Capello, Daniela, Forconi, Francesco, Bertoni, Francesco, Maffei, Rossana, Laurenti, Luca, Rossi, Davide, Zucca, Emanuele, Degan, Massimo, Marasca, Roberto, Efremov, Dimitar G., Del Poeta, Giovanni, Gaidano, Gianluca, and Gattei, Valter
- Subjects
LETTERS to the editor ,CHRONIC lymphocytic leukemia - Abstract
A letter to the editor discussing prognostic marker in chronic lymphocytic leukaemia is presented.
- Published
- 2010
- Full Text
- View/download PDF
24. The prognosis of clinical monoclonal B cell lymphocytosis differs from prognosis of Rai 0 chronic lymphocytic leukaemia and is recapitulated by biological risk factors.
- Author
-
Rossi, Davide, Sozzi, Elisa, Puma, Alessia, De Paoli, Lorenzo, Rasi, Silvia, Spina, Valeria, Gozzetti, Alessandro, Tassi, Maristella, Cencini, Emanuele, Raspadori, Donatella, Pinto, Valeria, Bertoni, Francesco, Gattei, Valter, Lauria, Francesco, Gaidano, Gianluca, and Forconi, Francesco
- Subjects
LYMPHOCYTIC leukemia ,B cells ,LYMPHOPROLIFERATIVE disorders ,CHRONIC lymphocytic leukemia ,GENOTYPE-environment interaction ,IN situ hybridization - Abstract
Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic monoclonal expansion of <5·0 × 10
9 /l circulating CLL-phenotype B-cells. The relationship between MBL and Rai 0 CLL, as well as the impact of biological risk factors on MBL prognosis, are unknown. Out of 460 B-cell expansions with CLL-phenotype, 123 clinical MBL (cMBL) were compared to 154 Rai 0 CLL according to clinical and biological profile and outcome. cMBL had better humoral immune capacity and lower infection risk, lower prevalence of del11q22-q23/del17p13 and TP53 mutations, slower lymphocyte doubling time, and longer treatment-free survival. Also, cMBL diagnosis was a protective factor for treatment risk. Despite these favourable features, all cMBL were projected to progress, and lymphocytes <1·2 × 109 /l and >3·7 × 109 /l were the best thresholds predicting the lowest and highest risk of progression to CLL. Although IGHV status, CD38 and CD49d expression, and fluorescence in situ hybridization (FISH) karyotype individually predicted treatment-free survival, multivariate analysis identified the presence of +12 or del17p13 as the sole independent predictor of treatment requirement in cMBL (Hazard ratio: 5·39, 95% confidence interval 1·98–14·44, P = 0·001). Overall, these data showed that cMBL has a more favourable clinical course than Rai 0 CLL. Given that the biological profile can predict treatment requirement, stratification based on biological prognosticators may be helpful for cMBL management. [ABSTRACT FROM AUTHOR]- Published
- 2009
- Full Text
- View/download PDF
25. Long-term follow-up of 233 patients with hairy cell leukaemia, treated initially with pentostatin or cladribine, at a median of 16 years from diagnosis.
- Author
-
Else, Monica, Dearden, Claire E., Matutes, Estella, Garcia-Talavera, Juan, Rohatiner, Ama Z. S., Johnson, Steve A. N., O'Connor, Nigel T. J., Haynes, Andy, Osuji, Nnenna, Forconi, Francesco, Lauria, Francesco, and Catovsky, Daniel
- Subjects
HAIRY cell leukemia ,CANCER relapse ,HEMOGLOBINS ,MONOCLONAL antibodies ,RITUXIMAB - Abstract
Hairy cell leukaemia (HCL) was first described 50 years ago. Median survival was then 4 years. The purine analogues, introduced in the 1980s, transformed this prognosis. We reviewed data retrospectively from 233 patients, treated with pentostatin ( n = 188) or cladribine ( n = 45), to investigate the current long-term outlook. Median follow-up was 16 years. There were no significant differences in outcome between the two agents. Overall, the complete response (CR) rate was 80% and median relapse-free survival was 16 years. After relapse ( n = 79) or non-response ( n = 5), 26 patients received pentostatin and 58 cladribine; 69% achieved CR and median relapse-free survival was 11 years. After third-line therapy ( n = 23), 50% achieved CR and median relapse-free survival was 6·5 years. However, CRs were equally durable, whether after first, second or third-line therapy. Complete responders and those with both haemoglobin >100 g/l and platelet count >100 × 10
9 /l before treatment had the longest relapse-free survival ( P < 0·0001). Patients still in CR at 5 years had only a 25% risk of relapse by 15 years. Outcomes for patients with recurrent disease improved with the monoclonal antibody rituximab, combined with either purine analogue. Overall only eight patients died of HCL-related causes. Patients achieving a CR can expect a normal lifespan. [ABSTRACT FROM AUTHOR]- Published
- 2009
- Full Text
- View/download PDF
26. Molecular and clinical features of chronic lymphocytic leukaemia with stereotyped B cell receptors: results from an Italian multicentre study.
- Author
-
Bomben, Riccardo, Dal Bo, Michele, Capello, Daniela, Forconi, Francesco, Maffei, Rossana, Laurenti, Luca, Rossi, Davide, Del Principe, Maria Ilaria, Zucchetto, Antonella, Bertoni, Francesco, Rossi, Francesca Maria, Bulian, Pietro, Cattarossi, Ilaria, Ilariucci, Fiorella, Sozzi, Elisa, Spina, Valeria, Zucca, Emanuele, Degan, Massimo, Lauria, Francesco, and Del Poeta, Giovanni
- Subjects
CHRONIC lymphocytic leukemia ,B cells ,IMMUNOGLOBULINS ,MOLECULAR genetics ,CHRONIC diseases - Abstract
A fraction of chronic lymphocytic leukaemia (CLL) cases carry highly homologous B-cell receptors (BCR), i.e. characterized by non-random combinations of immunoglobulin heavy-chain variable ( IGHV) genes and heavy-chain complementarity determining region-3 (HCDR3), often associated with a restricted selection of IGVK/L light chains. Such ‘stereotyped’ BCR occur more frequently in CLL with unmutated (UM) than mutated (M) IGHV genes. We analysed 1426 IG rearrangements (from 1398 CLL cases) by a clustering driven by HCDR3 similarities. Molecular findings were correlated to time-to-treatment (TTT) and presence of known prognosticators. Sixty-nine clusters (319 IG-rearrangements, 22·4%) with stereotyped BCR were identified. Among 30 confirmed clusters (≥3 IG-rearrangements/cluster), we found 14 novel clusters, of which 11 had M IG rearrangements (M clusters) and predominantly (8/11) used IGHV3 subgroup genes. Recurrent cluster-biased amino acid changes were found throughout IGHV sequences of these ‘M clusters’. Regarding clinical outcome: (i) UM CLL from the IGHV1-2/1-3/1-18/1-46/7-4-1/IGKV1-39 cluster had poorer prognosis than UM/M cases, or UM cases using the same IGHV genes but not in clusters; (ii) M CLL from the IGHV3-21/IGLV3-21 cluster had TTT similar to UM CLL, and shorter than M CLL expressing IGHV3-21 but not in cluster. Altogether, our analysis identified additional molecular and clinical features for CLL expressing stereotyped BCR. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
27. Low-dose oral fludarabine plus cyclophosphamide in elderly patients with untreated and relapsed or refractory chronic lymphocytic Leukaemia.
- Author
-
Forconi, Francesco, Fabbri, Alberto, Lenoci, Mariapia, Sozzi, Elisa, Gozzetti, Alessandro, Tassi, Maristella, Raspadori, Donatella, and Lauria, Francesco
- Abstract
Fludarabine plus cyclophosphamide (FC) at conventional doses is an effective treatment for chronic lymphocytic leukaemia (CLL). However, FC at standard doses may give hematological and non-hematological toxicity, predominantly in the elderly. Intravenous or oral low-dose FC regimens remain highly effective in elderly patients with Low-Grade Lymphomas other than CLL and are well tolerated. We tested efficacy and toxicity of oral FC at reduced doses in 26 elderly patients (median 71 years) with previously untreated (UT-CLL, n = 14) or relapsed/refractory CLL (R-CLL, n = 12), unfit for conventional treatments. Twentyfour-of-26 (92%) patients (14/14, 100% UT-CLL; 10/12, 83.5% R-CLL) obtained a response, with 12/26 (46%) complete responses (9/14, 64.2% in UT-CLL; 3/12, 25% in R-CLL). Non-hematological toxicity was mild and myelosuppression was documented in 8/26 (31%) patients (4/14, 28% UT-CLL; 4/12, 33% R-CLL). With a median follow-up of 24 months, median event-free survival was 48 months with no differences between UT-CLL and R-CLL and all responders were alive. Low-dose oral FC treatment showed good efficacy in both untreated and refractory/relapsed CLL. The treatment is useful in elderly patients who cannot benefit of more aggressive schedules and is easy to administer on an outpatient basis. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
28. Genome-wide DNA analysis identifies recurrent imbalances predicting outcome in chronic lymphocytic leukaemia with 17p deletion.
- Author
-
Forconi, Francesco, Rinaldi, Andrea, Kwee, Ivo, Sozzi, Elisa, Raspadori, Donatella, Rancoita, Paola M. V., Scandurra, Marta, Rossi, Davide, Deambrogi, Clara, Capello, Daniela, Zucca, Emanuele, Marconi, Daniela, Bomben, Riccardo, Gattei, Valter, Lauria, Francesco, Gaidano, Gianluca, and Bertoni, Francesco
- Subjects
- *
CHRONIC lymphocytic leukemia , *DNA , *LYMPHOCYTIC leukemia , *TUMORS , *DNA fingerprinting - Abstract
Deletion of 17p ( TP53) identifies a rare subset of chronic lymphocytic leukaemia (17p- CLL) with aggressive behaviour. Genome-wide DNA-profiling was performed to investigate 18 patients with 17p- CLL. All cases had multiple copy-number (CN) changes. Among the several recurrent CN changes identified, 8q24.13-q24.1-gain ( MYC), 8p-loss ( TNFRSF10A/B, also known as TRAIL1/2) and 2p16.1-p14-gain ( REL/BCL11A) appeared frequently represented. 8p-loss and 2p16.1-p14-gain also appeared clinically relevant and predicted significant shorter time from diagnosis to treatment (8p-loss) and overall survival (8p-loss and 2p16.1-p14-gain, P < 0·05). These observations document a highly unstable genome in 17p- CLL and suggest that additional genes outside the TP53 locus may be important for tumour behaviour. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
29. Chromosome 14q32 translocations involving the immunoglobulin heavy chain locus in chronic lymphocytic leukaemia identify a disease subset with poor prognosis.
- Author
-
Cavazzini, Francesco, Hernandez, Jose Angel, Gozzetti, Alessandro, Russo Rossi, Antonella, De Angeli, Cristiano, Tiseo, Ruana, Bardi, Antonella, Tammiso, Elisa, Crupi, Rosaria, Lenoci, Maria Pia, Forconi, Francesco, Lauria, Francesco, Marasca, Roberto, Maffei, Rossana, Torelli, Giuseppe, Gonzalez, Marcos, Martin-Jimenez, Patricia, Maria Hernandez, Jesus, Rigolin, Gian Matteo, and Cuneo, Antonio
- Subjects
IMMUNOPHENOTYPING ,FLUORESCENCE in situ hybridization ,CHROMOSOMES ,CYTOGENETICS ,IMMUNOGLOBULIN genes ,CHRONIC lymphocytic leukemia ,MEDICAL research - Abstract
Immunophenotypic studies, fluorescence in situ hybridization (FISH) and conventional karyotyping were used to define the clinicobiological significance of 14q32 translocations involving the immunoglobulin gene locus (14q32/ IGH) in 252 chronic lymphocytic leukaemia (CLL) patients. The following regions were studied: 13q14, centromere 12, 6q21; 11q22/ ATM; 17p13/ TP53, 14q32/ IGH. Patients were classified as group 1 (favourable, i.e. 13q-single or normal), group 2 (intermediate risk, i.e. +12, 6q-, 1–2 anomalies), group 3 (unfavourable, i.e. 17p-, 11q-, complex karyotype), or group 4 (14q32/ IGH translocation). Endpoints were treatment-free survival (TFS) and overall survival (OS). One hundred and ten patients were included in group 1, 99 in group 2, 25 in group 3 and 18 in group 4. 14q32/ IGH translocation partners were identified in eight cases ( BCL2 in five cases, BCL11A, CCND3 and CDK6 in one case each). group 4 showed shorter TFS versus groups 2 and 1 (25% patients treated at 2 months vs. 12 ( P = 0·02) and 20 months ( P = 0·002), respectively) and shorter OS (25% patients dead at 18 months versus 50 ( P = 0·0003) and >60 months ( P < 0·0001) respectively. The 14q32/ IGH translocation maintained prognostic significance at multivariate analysis on TFS ( P = 0·025) and OS ( P < 0·001), along with advanced stage and CD38
+ . These findings show that the 14q32/ IGH translocation predicts for an unfavourable outcome in CLL and that this cytogenetic subset might be included as a separate entity in a hierarchical cytogenetic classification of CLL. [ABSTRACT FROM AUTHOR]- Published
- 2008
- Full Text
- View/download PDF
30. High density genome-wide DNA profiling reveals a remarkably stable profile in hairy cell leukaemia.
- Author
-
Forconi, Francesco, Poretti, Giulia, Kwee, Ivo, Sozzi, Elisa, Rossi, Davide, Rancoita, Paola M. V., Capello, Daniela, Rinaldi, Andrea, Zucca, Emanuele, Raspadori, Donatella, Spina, Valeria, Lauria, Francesco, Gaidano, Gianluca, and Bertoni, Francesco
- Subjects
- *
LEUKEMIA , *HAIRY cell leukemia , *GENOMES , *GENE mapping , *DNA fingerprinting - Abstract
Hairy cell leukaemia (HCL) is a rare B-cell neoplasm for which the molecular mechanisms are largely unknown. High-density genome-wide DNA profiling was performed with Affymetrix 250K arrays to analyse copy number (CN) changes and loss of heterozygosity (LOH) in 16 cases of HCL. Four of 16 cases (25%) demonstrated gross non-recurrent CN deletions. Within the affected regions, we identified genes involved in bone marrow fibrosis ( FGF12) and response to treatment ( TP53) in individual cases. Large regions (>5 Mb) of LOH without any concomitant DNA CN changes were identified in 5/16 (31%) HCL and were indicative of uniparental disomy UD. The germline origin of UD was demonstrated in one case for which a matched normal sample was available. Overall analysis of LOH showed that identical loci were recurrently targeted in chromosomes 1, 2 and 6. As a whole, however, HCL showed a remarkably stable genome. This finding adds to several other features that are unique to HCL among mature B-cell tumours. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
31. The Role of Rituximab in Combination With Pentostatin or Cladribine for the Treatment of Recurrent/Refractory Hairy Cell Leukemia.
- Author
-
Else, Monica, Osuji, Nnenna, Forconi, Francesco, Dearden, Claire, Del Giudice, Ilaria, Matutes, Estella, Wotherspoon, Andrew, Lauria, Francesco, and Catovsky, Daniel
- Subjects
RITUXIMAB ,HAIRY cell leukemia ,THERAPEUTICS ,PATIENTS ,LYMPHOPROLIFERATIVE disorders - Abstract
The article presents a study which investigated the role of rituximab in combination with pentostatin or cladribine for the treatment of recurrent/refractory hairy cell leukemia (HCL). The authors reviewed the cases of 8 patients who received pentostatin or cladribine combined concurrently or sequentially with rituximab at second-line therapy and at subsequent lines of therapy. They found that the combination of purine analogs with rituximab was safe and effective for patients with recurrent and/or refractory HCL.
- Published
- 2007
- Full Text
- View/download PDF
32. research paper Incidence of novel N-glycosylation sites in the B-cell receptor of lymphomas associated with immunodeficiency.
- Author
-
Forconi, Francesco, Capello, Daniela, Berra, Eva, Rossi, Davide, Gloghini, Annunziata, Cerri, Michaela, Muti, Giuliana, Morra, Enrica, Paulli, Marco, Magrini, Umberto, Lucioni, Marco, Rambaldi, Alessandro, Lauria, Francesco, Carbone, Antonio, Stevenson, Freda K., and Gaidano, Gianluca
- Subjects
- *
GLYCOSYLATION , *B cells , *LYMPHOMAS , *IMMUNODEFICIENCY , *ANTIBODY diversity , *HEMATOLOGY - Abstract
Novel N-glycosylation sites are introduced by somatic mutation into the V genes of the majority of follicular lymphomas. Sites are positively selected and rare in normal memory B cells, indicating a potential role in tumour survival in the germinal centre (GC). The incidence of c. 40% in diffuse large B-cell lymphomas (DLBCL) parallels the known heterogenity of the disease. Immunodeficiency-related non-Hodgkin's lymphomas (NHL) include post-transplant lymphoproliferative disorders (PTLD) and acquired immunodeficiency syndrome-related NHL (AIDS-NHL). Most PTLD derive from B cells that carry mutated VH genes and that have completed the GC reaction. All AIDS-NHL carry mutated VH genes and variable features of GC or post-GC cells. To determine if N-glycosylation is a feature of immunodeficiency-related lymphomas, we analysed the VH genes of 19 PTLD and 36 AIDS-NHL. Novel sites were rare in PTLD (4/19), similar to memory B cells ( P = 0·15). AIDS-NHL, including DLBCL and Burkitt's lymphomas (BL), showed heterogeneity with 16 of 36 (44%) having novel sites. The findings indicate no selection of N-glycosylation sites in PTLD, consistent with post-GC features. The variable incidence of N-glycosylation sites in AIDS-NHL mirrors that in DLBCL and sporadic BL of immunocompetent hosts, supporting the known heterogeneity of these disorders, and possibly pointing to distinct routes of tumour development. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
33. Insight into the potential for DNA idiotypic fusion vaccines designed for patients by analysing xenogeneic anti-idiotypic antibody responses.
- Author
-
Forconi, Francesco, King, Catherine A., Sahota, Surinder S., Kennaway, Christopher K., Russell, Nigel H., and Stevenson, Freda K.
- Subjects
- *
DNA vaccines , *CANCER vaccines , *B cell lymphoma - Abstract
Summary DNA vaccines induce immune responses against encoded proteins, and have clear potential for cancer vaccines. For B-cell tumours, idiotypic (Id) immunoglobulin encoded by the variable region genes provides a target antigen. When assembled as single chain Fv (scFv), and fused to an immunoenhancing sequence from tetanus toxin (TT), DNA fusion vaccines induce anti-Id antibodies. In lymphoma models, these antibodies have a critical role in mediating protection. For application to patients with lymphoma, two questions arise: first, whether pre-existing antibody against TT affects induction of anti-scFv antibodies; second, whether individual human scFv fusion sequences are able to fold consistently to generate antibodies able to recognize private conformational Id determinants expressed by tumour cells. Using xenogeneic vaccination with scFv sequences from four patients, we have shown that pre-existing anti-TT immunity slows, but does not prevent, anti-Id antibody responses. To determine folding, we have monitored the ability of nine DNAscFv–FrC patients' vaccines to induce xenogeneic anti-Id antibodies. Antibodies were induced in all cases, and were strikingly specific for each patient's immunoglobulin with little cross-reactivity between patients, even when similar VH or VL genes were involved. Blocking experiments with human serum confirmed reactivity against private determinants in 26–97% of total antibody. Both immunoglobulin G1 (IgG1) and IgG2a subclasses were present at 1·3 : 1–15 : 1 consistent with a T helper 2-dominated response. Xenogeneic vaccination provides a simple route for testing individual patients' DNAscFv–FrC fusion vaccines, and offers a strategy for production of anti-Id antibodies. The findings underpin the approach of DNA idiotypic fusion vaccination for patients with B-cell tumours. [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
- View/download PDF
34. Mutation of BAX occurs infrequently in acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas.
- Author
-
Gaidano, Gianluca, Vivenza, Daniela, Forconi, Francesco, Capello, Daniela, Gloghini, Annunziata, Bhatia, Kishor, Gutierrez, Marina, Gallicchio, Margherita, Avanzi, Gian Carlo, Fassone, Lucia, Ariatti, Cristiano, Buonaiuto, Daniela, Cingolani, Antonella, Saglio, Giuseppe, Tirelli, Umberto, Larocca, Luigi M., Dalla-Favera, Riccardo, and Carbone, Antonino
- Published
- 2000
- Full Text
- View/download PDF
35. Genome-wide high resolution DNA profiling of hairy cell leukaemia.
- Author
-
Rinaldi, Andrea, Kwee, Ivo, Young, Ken H., Zucca, Emanuele, Gaidano, Gianluca, Forconi, Francesco, and Bertoni, Francesco
- Subjects
B cell lymphoma ,HAIRY cell leukemia ,SINGLE nucleotide polymorphisms ,DNA fingerprinting ,GENETIC mutation - Abstract
The article focuses on high resolution DNA profiling of hairy cell leukemia (HCL). It mentions that HCL is a kind of B-cell tumor which is characterized by the presence of leukemic hairy cells. It reports on data obtained with a high-resolution single nucleotide polymorphism (SNP) array in gene BRAF V600E-mutated HCL cases. It mentions that genome-wide DNA profiles were obtained from high molecular weight genomic DNA using the Genome-Wide Human SNP Array 6.0 from Affymetrix Inc.
- Published
- 2013
- Full Text
- View/download PDF
36. MDM4 (MDMX) is overexpressed in chronic lymphocytic leukaemia (CLL) and marks a subset of p53wild-type CLL with a poor cytotoxic response to Nutlin-3.
- Author
-
Bo, Michele Dal, Secchiero, Paola, Degan, Massimo, Marconi, Daniela, Bomben, Riccardo, Pozzato, Gabriele, Gaidano, Gianluca, Del Poeta, Giovanni, Forconi, Francesco, Zauli, Giorgio, and Gattei, Valter
- Subjects
CHRONIC lymphocytic leukemia ,B cells ,MONOCLONAL antibodies ,ALKYLATING agents ,GENES - Abstract
The article offers information about a study conducted to identify the suitable genes associated with resistance of p53
wt chronic lymphocytic leukemia (CLL) cells to the in-vitro Nutlin-3 effects. It mentions that no treatment is required for patients with B-cell (CLL) but in other cases the disease requires treatment by alkylating agents, purine analogs, monoclonal antibodies. The result of the study led to the identification of murine double minute 2 (MDM2) protein as a gene.- Published
- 2010
- Full Text
- View/download PDF
37. Long-term benefit of IGHV mutated patients in a real-life multicenter cohort of FCR-treated chronic lymphocytic leukemia.
- Author
-
Moia R, Dondolin R, De Propris MS, Talotta D, Mouhssine S, Perutelli F, Reda G, Mattiello V, Rigolin GM, Motta M, Olivieri J, Fanin R, Perbellini O, Ferrarini I, Mauro FR, Del Giudice I, Laurenti L, Tomasso A, Gentile M, Frustaci AM, Tedeschi A, Gozzetti A, Stelitano C, Visco C, Moreno C, Forconi F, Marasca R, Coscia M, Rossi D, Foà R, and Gaidano G
- Subjects
- Humans, Cyclophosphamide, Treatment Outcome, Mutation, Prognosis, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Published
- 2023
- Full Text
- View/download PDF
38. MDM4 (MDMX) is overexpressed in chronic lymphocytic leukaemia (CLL) and marks a subset of p53wild-type CLL with a poor cytotoxic response to Nutlin-3.
- Author
-
Bo MD, Secchiero P, Degan M, Marconi D, Bomben R, Pozzato G, Gaidano G, Del Poeta G, Forconi F, Zauli G, and Gattei V
- Subjects
- Cell Cycle Proteins, Gene Expression Regulation, Neoplastic drug effects, Humans, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Biomarkers, Tumor metabolism, Imidazoles pharmacology, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Nuclear Proteins metabolism, Piperazines pharmacology, Proto-Oncogene Proteins metabolism
- Published
- 2010
- Full Text
- View/download PDF
39. Incidence of novel N-glycosylation sites in the B-cell receptor of lymphomas associated with immunodeficiency.
- Author
-
Forconi F, Capello D, Berra E, Rossi D, Gloghini A, Cerri M, Muti G, Morra E, Paulli M, Magrini U, Lucioni M, Rambaldi A, Lauria F, Carbone A, Stevenson FK, and Gaidano G
- Subjects
- Glycosylation, Humans, Lymphoma, AIDS-Related genetics, Lymphoma, B-Cell genetics, Transplantation Immunology genetics, Gene Rearrangement, B-Lymphocyte genetics, Genes, Immunoglobulin genetics, Lymphoproliferative Disorders genetics, Receptors, Antigen, B-Cell genetics
- Abstract
Novel N-glycosylation sites are introduced by somatic mutation into the V genes of the majority of follicular lymphomas. Sites are positively selected and rare in normal memory B cells, indicating a potential role in tumour survival in the germinal centre (GC). The incidence of c. 40% in diffuse large B-cell lymphomas (DLBCL) parallels the known heterogeneity of the disease. Immunodeficiency-related non-Hodgkin's lymphomas (NHL) include post-transplant lymphoproliferative disorders (PTLD) and acquired immunodeficiency syndrome-related NHL (AIDS-NHL). Most PTLD derive from B cells that carry mutated VH genes and that have completed the GC reaction. All AIDS-NHL carry mutated VH genes and variable features of GC or post-GC cells. To determine if N-glycosylation is a feature of immunodeficiency-related lymphomas, we analysed the VH genes of 19 PTLD and 36 AIDS-NHL. Novel sites were rare in PTLD (4/19), similar to memory B cells (P = 0.15). AIDS-NHL, including DLBCL and Burkitt's lymphomas (BL), showed heterogeneity with 16 of 36 (44%) having novel sites. The findings indicate no selection of N-glycosylation sites in PTLD, consistent with post-GC features. The variable incidence of N-glycosylation sites in AIDS-NHL mirrors that in DLBCL and sporadic BL of immunocompetent hosts, supporting the known heterogeneity of these disorders, and possibly pointing to distinct routes of tumour development.
- Published
- 2004
- Full Text
- View/download PDF
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