11 results on '"Caterina Cecchetti"'
Search Results
2. Gamma/delta T‐cell lymphoma with mycosis fungoides‐like clinical course transforming to 'T‐cell‐receptor‐silent' aggressive lymphoma: Description of one case
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Annamaria Hotz, Fabrizio Ciambelli, Stefania Cione, Giorgio Alberto Croci, Caterina Cecchetti, Filippo Crivelli, and Dario Tomasini
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Pathology ,medicine.medical_specialty ,Mycosis fungoides ,Histology ,biology ,business.industry ,Cutaneous T-cell lymphoma ,T-cell receptor ,Aggressive lymphoma ,Dermatology ,medicine.disease ,Blastoid ,biology.organism_classification ,Pathology and Forensic Medicine ,Lymphoma ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Immunophenotyping ,030220 oncology & carcinogenesis ,medicine ,Gamma delta T cell ,business - Abstract
Primary cutaneous γδ T-cell lymphomas (PCGDTLs) are a heterogeneous group of lymphomas representing about 1% of primary cutaneous T-cell lymphomas (CTCLs) and mostly regarded as clinically aggressive. Current WHO-EORTC classification recognizes different clinic-pathologic subsets of PCGDTL, but it suggests that cases showing a mycosis fungoides (MF)-like clinical presentation and histopathology should be classified as MF irrespective of phenotype for their indolent course. Herein, we describe a case of γδ-MF, featuring at onset a granulomatous pattern, with subsequent clinical worsening signaled by the development of an ulcero-necrotic lesion and systemic dissemination, leading to death in 5 months. Clinical progression was sustained by a shift to mature T-cell lymphoma composed of medium to large-sized blastoid T-cells featuring a T-cell receptor (TCR) silent immunophenotype.
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- 2021
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3. Author response for 'LONG-LASTING EFFICACY AND SAFETY OF LENALIDOMIDE MAINTENANCE IN PATIENTS WITH RELAPSED DIFFUSE LARGE B-CELL LYMPHOMA WHO ARE NOT ELIGIBLE FOR OR FAILED AUTOLOGOUS TRANSPLANTATION'
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Michele Spina, Renato Zambello, Piera Angelillo, C. Rusconi, Alberto Fabbri, Eloise Scarano, Sara Steffanoni, Caterina Cecchetti, Fabio Ciceri, Marianna Sassone, Stefano Volpetti, T. Calimeri, Maurizio Frezzato, Maurilio Ponzoni, Alice Di Rocco, Vittoria Tarantino, Annalisa Arcari, A. J. M. Ferreri, Giovanni Bertoldero, Salvatore Perrone, Daniela De Lorenzo, Francesco Zaja, Alessandro Re, Marco Foppoli, Caterina Stelitano, and Alessandro Nonis
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Long lasting ,Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Autologous transplantation ,In patient ,medicine.disease ,business ,Diffuse large B-cell lymphoma ,Lenalidomide ,medicine.drug - Published
- 2020
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4. Multicenter Phase II Trial Addressing Lenalidomide Maintenance in Patients with Relapsed Diffuse Large B-Cell Lymphoma (rDLBCL) Who Are Not Eligible for Autologous Stem Cell Transplantation (ASCT): Efficacy and Safety Results after a Median Follow-up of Five Years
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Stefano Volpetti, Marianna Sassone, Francesco Zaja, Fabio Ciceri, Piera Angelillo, Giovanni Bertoldero, Alice Di Rocco, Andrés J.M. Ferreri, Annalisa Arcari, Maurizio Frezzato, Alberto Fabbri, Daniela De Lorenzo, Salvatore Perrone, Teresa Calimeri, Eloise Scarano, Maurilio Ponzoni, Caterina Cecchetti, Michele Spina, Renato Zambello, Chiara Rusconi, Alessandro Re, and Caterina Stelitano
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Salvage therapy ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Tolerability ,Median follow-up ,Internal medicine ,Clinical endpoint ,Medicine ,business ,Diffuse large B-cell lymphoma ,Progressive disease ,Lenalidomide ,medicine.drug - Abstract
Background: Lenalidomide (LENA) maintenance is associated with significantly improved outcome in patients (pts) with chemosensitive relapse of DLBCL not eligible for ASCT or experiencing relapse after ASCT. Preliminary results of a multicentre phase II trial (NCT00799513), reported after a median follow-up of 25 months, showed a 1-yr PFS of 70 ± 7% and a 1-yr OS of 81 ± 6%, with good tolerability (Ferreri AJM, et al. Lancet Haematol 2017). However, LENA was ongoing in 41% of pts at time of analysis, and late side effects and events after maintenance completion remained to be defined. Herein, we report efficacy and safety results of the trial after a median follow-up of 56 (range 27-100) months. Methods: HIV-neg pts (age ≥18 ys) with de novo or transformed DLBCL and relapsed disease responsive to conventional rituximab-containing salvage therapy were registered and treated with LENA 25 mg/day for 21 days out of 28, until lymphoma progression or unacceptable toxicity. A protocol amendment in 2015 allowed physicians to interrupt maintenance after a minimum duration of two years. Primary endpoint was 1-year PFS. Simon's two-stage optimal design was used. To demonstrate a 1-yr PFS improvement from 30% (P0) to 50% (P1), 47 pts (one-sided; α 5%; β 80%) were needed. Maintenance would be considered effective if ≥19 pts were progression-free survivors at 1 yr. Cell of origin was assessed by NanoString Technology (n=23) and Hans algorithm (n=39). Results: Between 3/2009 and 12/2015, we recruited 48 pts; 46 of them were assessable (median age 72 ys; range 34-86); 36 pts had de novo DLBCL, 10 had transformed DLBCL. All pts were previously treated with anthracycline- and rituximab-based combination, plus ASCT in 6 pts. Thirty-three pts were enrolled at 1st relapse; salvage therapy contained high doses of cytarabine or ifosfamide in two-thirds of cases, and response was complete in 26 pts and partial in 20. Most pts had unfavourable features: IPI ≥2 in 38 (83%) pts, advanced stage in 35 (76%), extranodal disease in 29 (63%), high LDH level in 21 (46%); 28 (61%) pts were older than 70 ys. Sixteen pts received ≥2 years of LENA (5 received >2 ys), 30 pts interrupted treatment due to progressive disease (PD; n= 17), toxicity (9) or pt refusal (4) (Table). LENA was well tolerated after an average of 18 courses/pt (range 3-82). With the exception of neutropenia, grade-4 toxicities occurred in At one year from trial registration, 31 pts were still progression free, which was significantly higher than the pre-determined efficacy threshold (n≥19). During the whole observation period, there were 24 events: progressive disease in 21 pts and death of toxicity in 3, with a 1-yr (primary endpoint) and 5-yr PFS of 67 ± 7% and 50 ± 7%, respectively. The duration of response to LENA was longer than response duration after the prior treatment line in 28 (61%) pts, and was twice as long in 21 (46%) of them. Twenty-six pts were disease-free at the last LENA course (Table), 22 of them remain relapse free after a median observation period from maintenance completion of 26 (8-92) months; 3 of the 4 relapses occurred in pts who received The benefit of LENA was observed both in pts with de novo or transformed DLBCL. According to the Hans' algorithm, the 4-yr PFS was 50 ± 11% for GCB-DLBCL and 42 ± 11% for nonGCB-DLBCL (p= 0.58). Results using the Nanostring technique were consistent with the Hans' algorithm. Overall, 28 (61%) pts are alive, with a 1- and 5-yr OS of 80 ± 6% and 60 ± 8%, respectively. Conclusions: Long-term results of this trial soundly promotes the use of LENA maintenance in pts with chemosensitive relapse of DLBCL not eligible for ASCT or experiencing relapse after ASCT. LENA was well tolerated in this elderly population, without higher toxicity rates in pts treated for ≥2 years, and with enhanced survival figures. These results warrant further investigation of immunomodulatory drugs as maintenance in these high-risk pts. Table. Table. Disclosures Ferreri: Celgene: Research Funding. Zaja:Abbvie: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria; Janssen: Honoraria; Sandoz: Honoraria. Di Rocco:Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Rusconi:Celgene: Research Funding.
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- 2018
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5. R-CHOP Preceded By Engineered Tumor Necrosis Factor (TNF) in Patients with Relapsed or Refractory (r/r) Primary CNS Lymphoma (PCNSL): Results of Antitumor Activity, Safety and Blood-Brain Barrier (BBB) Permeabilization in the 'Ingrid' Phase II Trial
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Paolo Lopedote, Fiorella Ilariucci, Guido Gini, Fabio Ciceri, Dario Marino, Salvatore Perrone, Gian Marco Conte, Carlo Visco, Teresa Calimeri, Alberto Fabbri, Emanuele Angelucci, Marianna Sassone, Maurilio Ponzoni, Francesco Pisani, Roberta Rudà, Andrés J.M. Ferreri, Angelo Corti, Luigi Petrucci, Nicoletta Anzalone, Marco Bregni, Eloise Scarano, Caterina Cecchetti, Federico Fallanca, and Dario Cattaneo
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medicine.medical_specialty ,Cyclophosphamide ,business.industry ,Immunology ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Gastroenterology ,Pharmacokinetics ,Refractory ,Internal medicine ,Toxicity ,medicine ,Clinical endpoint ,Methotrexate ,Rituximab ,business ,medicine.drug - Abstract
Background: Almost all PCNSL belong to the category of DLBCL. However, affected pts are treated with high-dose methotrexate-based combinations that are not currently used in other DLBCL and require hospitalization and extensive expertise to manage toxicity. The use of R-CHOP could overcome these difficulties, but CNS availability of related drugs is poor. TNF induces BBB permeabilization and enhances CNS access of anticancer drugs. Coupling TNF with NGR, a peptide that targets CD13+ tumor vessels, improves its biological effects and therapeutic index. Thus, we tested the hypothesis that this conjugate (called NGR-hTNF) can break the BBB, thereby improving CNS access and activity of R-CHOP in pts with r/rPCNSL enrolled in a phase II trial (NCT03536039). Herein, we report results of activity, safety and BBB permeabilization. Methods: HIV-neg adults with PCNSL failed after methotrexate-based chemo and measurable disease were enrolled and treated with 1 course of R-CHOP, followed by 5 courses of R-CHOP21 preceded by NGR-hTNF (0.8 μg/m², 1-h inf). Overall response rate (ORR) was the primary endpoint. The two-stage Simon Minimax design was used; sample size estimated to demonstrate an improvement from 30% ORR (P0) to 50% (P1) (one-sided test; α 10%; β 90%) was 28 pts. NGR-hTNF/RCHOP would be declared active if ≥12 responses were recorded. As secondary endpoints, changes in vessel permeability, CD13 expression and anticancer drugs pharmacokinetics were assessed in the first 10 pts. Changes in BBB permeability were assessed by Dynamic Contrast Enhanced MRI (DCE-MRI) and 99mTc-DTPA-SPECT in tumor lesions, perilesional areas and normal appearing brain. DCE-MRI findings recorded before/after the 1st course (RCHOP alone - baseline) and before/after the 2nd and 6th courses (NGR-hTNF/RCHOP) were compared to establish the effect of TNF, and results were expressed as Ktrans values normalized using contralateral white matter. SPECT was performed before and after the 3rd course, and results were expressed as changes in the volume of ≥30% 99mTc-DTPA uptake (cm3). CD13 expression was assessed by immunohistochemistry on diagnostic tissue samples. Rituximab, cyclophosphamide and doxorubicin concentrations on matched CSF/plasma samples collected before/after the 1st, 2nd and 6th courses were tested to exclude a non-specific effect of NGR-hTNF on pharmacokinetics. Results: 22 pts (median age: 58 yo, range 26-78; 11 males) were enrolled; 18 pts had intermediate-high IELSG score. Pts were heavily pretreated: 13 had received ASCT, WBRT or both; 13 had refractory disease. Twenty pts were evaluable for the primary endpoint. NGR-hTNF/RCHOP combination was active: the predetermined activity threshold (≥12 responses) was achieved, with confirmed tumor response in 13 pts (65%; 95%CI= 45-85%), which was complete in 9. At a median follow-up of 8 months (2-26), 9 pts remain relapse free and 12 pts are alive. Treatment was well tolerated; toxicities were quickly solved without dose reductions or interruptions. G4 toxicities were neutropenia (49% of courses) and thrombocytopenia (15%), anemia (1%), and FN (1%). Ten SAEs were recorded in 8 pts: g2 seizures (n= 2), g2 DVT (2), g3 infections (2), g3 syncope (2), g4 FN and g2 LVEF reduction. There were 3 cases of g1-2 TNF infusion reaction. DCE-MRI studies showed an increase of vascular permeability after NGR-hTNF infusion as median (range) Ktrans of tumor and perilesional areas raised from baseline values of 23.5 (6.8-98.8) and 2.5 (0.4-3.9) to 35.3 (23.9-887.7; p= 0.39) and 4.7 (2.2-37.7; p= 0.01), respectively. Likewise, SPECT studies showed a significant enlargement of the volume ≥30% 99mTc-DTPA uptake, with median (range) values before and after NGR-hTNF infusion of 26 cm3 (5 - 67) and 40 cm3 (10 - 92), respectively (p= 0.02), with a median volume increase of 45% (14-87%). As important features supporting the specificity of the effect of NGR-hTNF, CD13 was expressed in all diagnostic samples, and drug levels in CSF/plasma samples were not influenced by NGR-hTNF. Conclusions: NGR-hTNF/RCHOP is active and safe in pts with r/rPCNSL. NGR-hTNF enhances vascular permeability specifically in tumor lesions and perilesional areas, which was consistently demonstrated by DCE-MRI, SPECT and plasma/CSF pharmacokinetics studies and was in line with CD13 expression. Accrual completion is warranted. This innovative approach deserves to be addressed as first-line treatment in PCNSL pts. Disclosures Angelucci: Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Roche Italy: Other: Local (national) advisory board; Celgene: Honoraria, Other: Chair DMC.
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- 2018
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6. R-CHOP preceded by blood-brain barrier permeabilization (BBBp) by NGR-tumor necrosis factor (NGR-hTNF) in patients with relapsed or refractory primary CNS lymphoma (rrPCNSL): First results of the 'INGRID' phase II trial
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Nicoletta Anzalone, Andrés J.M. Ferreri, Federico Fallanca, Giovanni Citterio, Dario Cattaneo, Gian Marco Conte, Salvatore Perrone, Marco Foppoli, Alessandro Nonis, Fabio Ciceri, Marianna Sassone, Stefania Girlanda, Caterina Cecchetti, Letterio S. Politi, Maurilio Ponzoni, Angelo Corti, Teresa Calimeri, Paolo Lopedote, and Claudio Bordignon
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Cancer Research ,business.industry ,Blood–brain barrier ,medicine.anatomical_structure ,Oncology ,NGR-hTNF ,Refractory ,Primary CNS Lymphoma ,Toxicity ,Cancer research ,Medicine ,In patient ,Tumor necrosis factor alpha ,business - Abstract
7575Background: PCNSL pts are treated with HDMTX-based chemo, which requires hospitalization and extensive expertise to manage toxicity. R-CHOP could overcome these troubles, but CNS access of rela...
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- 2018
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7. Neurological symptoms in essential thrombocythemia: impact of JAK2V617F mutation and response to therapy
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Elena Maria Elli, Andrea Aroldi, Leonardo Cattaneo, Pietro Pioltelli, Caterina Cecchetti, Enrico Maria Pogliani, Arianna Colombo, Aroldi, A, Cecchetti, C, Colombo, A, Cattaneo, L, Pioltelli, P, Pogliani, E, and Elli, E
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Male ,Response to therapy ,Myeloproliferative neoplasm ,Essential thrombocythemia ,Gastroenterology ,0302 clinical medicine ,Cephalalgia ,Risk Factors ,Nervous System Disease ,book.periodical ,Univariate analysis ,Platelet ,Neurological symptom ,Hematology ,General Medicine ,Middle Aged ,Prognosis ,Combined Modality Therapy ,JAK2V617F mutation ,Treatment Outcome ,030220 oncology & carcinogenesis ,Platelet aggregation inhibitor ,Female ,medicine.symptom ,Human ,Thrombocythemia, Essential ,Adult ,medicine.medical_specialty ,Prognosi ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Jak2v617f mutation ,Codon ,book ,Aged ,business.industry ,Platelet Aggregation Inhibitor ,Risk Factor ,Janus Kinase 2 ,medicine.disease ,Surgery ,Mutation ,Nervous System Diseases ,business ,Tinnitus ,Platelet Aggregation Inhibitors ,030215 immunology - Abstract
Patients with essential thrombocythemia (ET) often suffer from neurological symptoms (NS) not ever resulting from previous thrombotic cerebral events (TCE). We reported NS occurred in 282 patients, in order to identify the factors influencing ET-related NS in the absence of TCE, and the response to therapy. Overall, 116 of 282 patients (41%) presented NS; 101 of them (87%) reported subjective transient and fluctuating NS, without concurrent TCE, which we defined as ET-related NS, by frequency: cephalalgia, chronic paresthesias, dizziness or hypotension, visual disturbances, and tinnitus. In univariate analysis, ET-related NS resulted more frequently in young people (P=0.017) and in females (P=0.025). We found a higher prevalence of JAK2V617F mutation in ET-related NS patients (P=0.021). In multivariate analysis, gender (P=0.024) and JAK2V617F mutation (P=0.041) remained significantly associated with the development of ET-related NS, with a risk of about four times higher for JAK2V617F-mutated patients (OR=3.75). Ninety-seven of 101 patients with ET-related NS received an antiplatelet (AP) agent at the time of NS, whereas only selected high-risk ET-related NS patients were treated with a cytoreductive drug, according to the published guidelines and similarly to patients without NS. We observed that only 32 of 97 (33%) patients with ET-related NS achieved a complete response after AP treatment. Among the 65 non-responder patients, 36 (55.4%) improved NS after the introduction of cytoreductive therapy; therefore, the addition of cytoreductive treatment should be considered in this setting.
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- 2015
8. RNA-seq is a valuable complement of conventional diagnostic tools in newly diagnosed AML patients
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Vera Magistroni, Rocco Piazza, Benedetta Bianchi, Carlo Gambacorti-Passerini, Diletta Fontana, Caterina Cecchetti, Lorenza Borin, Caterina Mezzatesta, Alessandra Pirola, Monica Fumagalli, and Carla Donandoni
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Genetics ,Point mutation ,RNA ,RNA-Seq ,Hematology ,Newly diagnosed ,Biology ,Diagnostic tools ,Complement (complexity) - Published
- 2015
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9. A case of atypical prolonged hematologic toxicity with azacitidine in Chronic Myelomonocytic Leukemia (CMML), review of literature and a proposal of management
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Angelo Belotti, Lorenza Borin, Caterina Cecchetti, Elena Maria Elli, Enrico Maria Pogliani, Elli, E, Cecchetti, C, Belotti, A, Borin, L, and Pogliani, E
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Oncology ,medicine.medical_specialty ,azacitidine ,Azacitidine ,Chronic myelomonocytic leukemia ,Hematologic toxicity ,Internal medicine ,hemic and lymphatic diseases ,Medicine ,Adverse effect ,business.industry ,lcsh:RC633-647.5 ,Myelodysplastic syndromes ,Hematology ,lcsh:Diseases of the blood and blood-forming organs ,medicine.disease ,myelodysplastic syndromes ,Transplantation ,toxicity, azacitidine, Cmml, chronic myelomonocytic leukemia, Hypomethylating drugs, haematopoietic stem cell transplantation, hypomethylating agent, marrow blasts ,Haematopoiesis ,Infectious Diseases ,Hypomethylating agent ,Immunology ,business ,medicine.drug - Abstract
Hypomethylating drugs are useful and have been approved for the treatment of myelodysplastic syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML). However, phase 2 and 3 studies that assessed these agents in MDS, have included only a small number of patients with CMML, and there are just a few specific reports on CMML patients. The Azacitidine is actually authorised for the treatment of CMML patients with 10–29% marrow blasts without myeloproliferative disorder, who are not eligible for haematopoietic stem cell transplantation. This hypomethylating agent in MDS is known for causing transient cytopenias, most often occurring during the first 2 cycles. Here we report a case of an atypical delayed and prolonged hematologic toxicity during Azacitidine treatment in a CMML patient; furthermore we also reviewed the literature regarding the efficacy of the drug and the management of hematologic adverse effects, in term of dose adjustments or alternative schedule of administration, in specific CMML setting.
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- 2012
10. A Pathologic Abdominal Ultrasonography At Diagnosis Of CLL Significantly Reduces The Time To Progression In Patients With Rai 0 Or Rai 1 Disease
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Caterina Cecchetti, Silvia Bolis, Sofia Bozzani, Fausto Rossini, Chiara Scollo, Angelo Belotti, Alessandra Perego, Enrico Pogliani, Sara Pezzatti, Francesca Farina, and Marianna Sassone
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medicine.medical_specialty ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Immunology ,Population ,Cell Biology ,Hematology ,Biochemistry ,Gastroenterology ,Group B ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Abdominal ultrasonography ,Internal medicine ,Absolute neutrophil count ,medicine ,Abdomen ,Lymph ,Stage (cooking) ,Nuclear medicine ,business ,education ,Fluorescence in situ hybridization - Abstract
The most common staging systems for CLL were developed many years ago and are based on blood cell count and the presence of enlarged lymph nodes by physical exam. Many studies have tried to identify prognostic factors in early stage patients. A recent paper (Muntanola et al: Abdominal Computed Tomography Predicts Progression in Patients With Rai Stage 0 CLL. J Clin Oncol. 25:1576-1580) showed that patients with Rai 0 disease and a pathologic abdominal CT scan had a reduced time to progression (TTP), more similar to Rai stage I disease; however CT cannot be used routinely, especially in patients with early stage CLL, whose life expectancy may be very long. When compared to CT, ultrasonography (US) can be used at diagnosis and in follow-up, when it can show progression of abdominal lymph nodes. Patients and Methods The aims of the study were to investigate: 1) if a pathologic ultrasonography (PU) showing the presence of abdominal lymphadenopathy at diagnosis could allow identifying patients with different risk of evolution. 2) if there is a correlation between PU and different prognostic factors, such as mutational state, absolute lymphocyte count, CD38 positivity, age 3) if patients with Rai 0 disease and with PU are prognostically similar to Rai 1. Between 1999 and 2011, 189 patients with Rai 0 or Rai 1 CLL had a ultrasonography (US) performed at diagnosis. Lymph nodes more than 10 mm in diameter were considered abnormal. In 137 of them mutational status had been determined. Fluorescence in situ hybridization (FISH) analysis for 11,12, 13 17 was not generally performed at diagnosis but only before the beginning of treatment. The Fisher’s exact or t tests were used to analyze the association between the presence of an abnormal US and the clinical characteristics. Survival time and time to progression (TTP) were analyzed using the Kaplan-Meier method and curves were compared by means of the log-rank test. Results Mean age was 63.2 years (range 41-85). Patients had Rai stage 0 (n=130) disease or Rai stage 1 (n=59). Median absolute lymphocyte count was 12.2 x 10^9/L. Overall, PU were present in 40/189 (21.2%) patients, with dimensions of lymph nodes up to 120 mm. PU were significantly more frequent in patients with Rai 1 disease (23/59 – 39%) than in Rai 0 (17/130 – 13.1%) disease (p 20 x 10^9/L (15/47 – 31.9%) than in patients with absolute lymphocyte count at diagnosis < 20 x 10^9/L (25/142 – 17.6%) (p=0.03). No significant differences were present in age, hemoglobin concentration, absolute neutrophil count, platelet count or CD38 positivity. When all patients are considered, patients with PU had a shorter time to progression when compared to patients without PU (median 56 months vs not reached - p The presence of PU has a significant prognostic significance for TTP in patients with unmutated disease with median TTP of 68 vs. 25 months (p=0.007). Among patients with mutated disease, median TTP were 112 for patients with PU and not reached for patients without PU (p=n.s.). No differences in overall survival could be shown. Conclusions The presence of PU at diagnosis can identify a subgroup of Rai 0 CLL with shorter TTP; this confirms results reported with computed tomography. Patients with Rai 0 disease and PU had an intermediate but significantly different TTP between Rai 0 without PU and Rai 1. PU retains its importance also when only unmutated patients are considered; among mutated patients, a statistically significant difference could not be shown , also due to the low number of events in these patients. An ultrasonography performed at diagnosis appears to be useful in low-risk CLL patients: it is a non-toxic imaging technique that can identify subgroups of low-risk patients; in patients with PU at diagnosis, it can be repeated in follow-up to evidence progressive abdominal disease. Disclosures: No relevant conflicts of interest to declare.
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- 2013
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11. Whole-Exome Sequencing of 8 Atypical Chronic Myeloid Leukaemia Patients
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Simona Valletta, Rocco Piazza, Nicholas C.P. Cross, Caterina Cecchetti, Carlo Gambacorti-Passerini, Hima Raman, Roberta Spinelli, Alessandra Pirola, Zaira Sortino, Piazza, R, Valletta, S, Pirola, A, Raman, H, Spinelli, R, Cross, N, Cecchetti, C, Sortino, Z, and GAMBACORTI PASSERINI, C
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Genetics ,Mutation ,Myeloid ,Immunology ,Chromosome ,Context (language use) ,Cell Biology ,Hematology ,Biology ,medicine.disease ,medicine.disease_cause ,Biochemistry ,Somatic evolution in cancer ,Whole-exome sequencing, Atypical Chronic Myeloid Leukemia, Somatic mutations ,medicine.anatomical_structure ,MED/15 - MALATTIE DEL SANGUE ,Atypical chronic myeloid leukemia ,medicine ,Exome ,Exome sequencing - Abstract
Abstract 3853 INTRODUCTION According to the WHO-2008 classification, atypical chronic myeloid leukemia (aCML) is a myelodysplastic/myeloproliferative disorder clinically resembling the Philadelphia positive CML but lacking the BCR-ABL fusion. In aCML, the molecular lesions underlying the onset of the disease are unknown. To investigate the somatic events occurring in the genome of the aCML leukemic cells, we carried out whole-exome high-throughput sequencing analyses of 8 aCML patients. The results are described here. METHODS Peripheral blood (PB) or bone marrow cells were obtained after informed consent at diagnosis, before any therapy. Myeloid cells, evaluated by FACS, constituted more than 80% of total cells. Lymphocytes were obtained from PB samples, after culture with PHA/IL2 for 2–3 weeks. The exon-capture protocol was performed on myeloid leukemic cells and normal lymphocytes from the same patients using the Illumina TruSeq Exome Enrichment Kit. The enriched DNA was sequenced with a Genome Analyzer IIx (Illumina), using a 60 bases paired-end protocol and the TruSeq chemistry. On average, 10.5 Gigabases per exome were generated. The bioinformatic analysis was performed using the Galaxy framework (http://main.g2.bx.psu.edu/); the cross-match between leukemic and normal exomes was performed with dedicated in-house C# software. RESULTS The percentage of reads matching the reference human genome was over 90%, with a mean exon coverage of >70-fold and a percentage of exons with a mean coverage ≥ 20x of > 90% for both the leukemic sample and the control. The percentage of nucleotides targeting exonic regions or exonic regions plus 100bp was 48% and 68%, respectively, with an overall 28-fold enrichment for exonic vs. non-exonic regions. The comparison between the leukemic and the control datasets led to the identification of 63 single nucleotide somatic mutations with a relative mutation coverage of > 35%, corresponding to their heterozygous presence in >88% of cells. In total, 46 mutations were transitions and 17 transversions (transition/transversion ratio of 2.7), with the C:G->T:A event occurring at highest frequency (35/63; 55.6%). In 19/35 (54.3%) of the cases, the C:G->T:A transition occurred in the context of a CpG site. Among the 63 variants, 32.8% ranked more than 1.0 and 21.3% more than 2.0 in the GeneRanker cancer scoring system (http://cbio.mskcc.org/tcga-generanker/). Characterization of the top scoring biological functions (Ingenuity Pathway Analysis software) revealed a strong association with the core functional concepts of ‘Cancer/Leukaemia' (p = 3.74 * 10−6) and ‘Myeloproliferative disorder' (p = 9.91 * 10−6), with a total of 23 genes in the Cancer and 18 in the Leukaemia functional annotation. The top scoring cellular functions were connected with the core concepts of ‘Cellular growth and proliferation' (p = 1.03 * 10−3; 17 genes) and ‘DNA replication, recombination and repair' (5 genes). The latter comprised the functional annotations: ‘Chromatin formation', ‘Chromatin remodelling' and ‘Formation of chromosome components' (p = 6.76 * 10−3, 1.96 * 10−2 and 7.76 * 10−4, respectively). A Markov Cluster Algorithm analysis (String, http://string-db.org), confirmed the presence of the same two main mutational clusters (Fig. 1a,b). The individual mutations identified will be presented at the meeting, including two recurrent mutations. Taken globally, these data suggest that somatic mutations targeting a specific cellular proliferation pathway and a chromatin remodelling protein network (Fig. 1a,b) may play a critical role in the onset/clonal evolution of aCML. This information may prove useful in the next future in order to develop evidence-based aCML treatment protocols. Disclosures: No relevant conflicts of interest to declare.
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- 2011
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