Publications by authors named "Gabriele Buda"

87 Publications

Phase II Trial of Maintenance Treatment With IL2 and Zoledronate in Multiple Myeloma After Bone Marrow Transplantation: Biological and Clinical Results.

Front Immunol 2020 3;11:573156. Epub 2021 Feb 3.

Hematology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Background: Maintenance treatment after autologous bone marrow transplantation in multiple myeloma improves the outcome of patients. We designed a phase II clinical trial to evaluate the treatment with IL2 and zoledronate after autologous bone marrow transplantation in myeloma patients.

Methods: Patients with a histologically proven diagnosis of multiple myeloma become eligible if achieved a very good partial remission in bone marrow samples after 3 months from autologous bone marrow transplantation. IL2 was administered from day 1 to 7. In the first cycle, the daily dose was 2 × 10 IU, whereas, in subsequent ones the IL2 dose was progressively escalated, with +25% increases at each cycle, until evidence of toxicity or up to 8 × 10 IU. Four mg of zoledronic acid were infused on day 2. Flow cytometry analysis of γδ-lymphocytes was performed at days 1 and 8 of treatment cycles.

Results: Forty-four patients have been enrolled between 2013 and 2016. The median time to progression was 22.5 months (95% CI 9.7-35.2). A complete remission with a negative immunofixation was obtained in 18% of patients and correlated with a significantly longer time to progression (p = 0.015). Treatment was well tolerated without G3 or 4 toxicities. After a week of treatment with IL2 and zoledronate, γδ lymphocytes, Vγ9δ2, CD57+, effector, late effector, and memory γδ increased but in subsequent cycles, there was a progressive reduction of this expansion.

Conclusions: The maintenance treatment with IL2 and Zoledronate has a modest activity in myeloma patients after autologous bone marrow transplantation.

Eudract Number: 2013-001188-22.
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http://dx.doi.org/10.3389/fimmu.2020.573156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890401PMC
February 2021

A real-world efficacy and safety analysis of combined carfilzomib, lenalidomide, and dexamethasone (KRd) in relapsed/refractory multiple myeloma.

Hematol Oncol 2021 Feb 1;39(1):41-50. Epub 2020 Nov 1.

Azienda Ospedaliero-Universitaria di Bologna, Italia - Istituto di Ematologia "Seràgnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale - Università degli Studi, Bologna, Italy.

Carfilzomib-lenalidomide-dexamethasone (KRd) has been approved for the treatment of relapsed/refractory multiple myeloma (RRMM). We conducted a retrospective analysis of 197 RRMM patients (pts) between January 2016 and March 2018 in six Italian hematologic centers, with the aim to evaluate efficacy and safety of KRd in real-life. At KRd initiation 27% carried high risk cytogenetic abnormalities (HRCA) [del17p and/or t(4;14) and/or t(14;16)], median number of prior lines of therapy was 2 (1-8), nearly all pts (96%) received prior bortezomib (18% refractory) while 45% were exposed to lenalidomide (R; 22% refractory). At the median of 12.5 months, 52% of the pts had discontinued treatment, mainly (66%) for progression. Main grade 3-4 adverse events were neutropenia (21%), infections (11%), and hypertension (6%). Overall, the response rate was 88%. The median progression-free survival (PFS) was 19.8 months and 1-year overall survival (OS) rate was 80.6%. By subgroup analysis, extended PFS and OS were observed for pts who received ≤2 prior lines of therapy (HR = 0.42, p < 0.001 and HR = 0.35, p = 0.001, respectively), not refractory to prior R (HR = 0.37, p < 0.001, and HR = 0.47, p = 0.024), without HRCA (HR = 0.33, p = 0.005 and HR = 0.26, p = 0.016) and achieving ≥ very good partial response (VGPR; HR = 0.17, p < 0.001 and HR = 0.18, p < 0.001). In conclusion, KRd demonstrated to be effective in RRMM pts treated in real-world setting, without new safety concerns. Better survival outcomes emerged for pts with ≤2 prior lines of therapy, achieving at least a VGPR, and without HRCA.
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http://dx.doi.org/10.1002/hon.2820DOI Listing
February 2021

[18F]-Florbetaben PET/CT for Differential Diagnosis Among Cardiac Immunoglobulin Light Chain, Transthyretin Amyloidosis, and Mimicking Conditions.

JACC Cardiovasc Imaging 2021 Jan 5;14(1):246-255. Epub 2020 Aug 5.

Division of Cardiology and Cardiovascular Medicine, Fondazione Toscana Gabriele Monasterio, Pisa, Italy; Institute of Life Science, Scuola Sant'Anna Pisa, Pisa, Italy. Electronic address:

Objectives: This study aimed to test the diagnostic value of [18F]-florbetaben positron emission tomography (PET) in patients with suspicion of CA.

Background: Diagnosis of cardiac involvement in immunoglobulin light-chain-derived amyloidosis (AL) and transthyretin-related amyloidosis (ATTR), which holds major importance in risk stratification and decision making, is frequently delayed. Furthermore, although diphosphonate radiotracers allow a noninvasive diagnosis of ATTR, demonstration of cardiac amyloidosis (CA) in AL may require endomyocardial biopsy.

Methods: Forty patients with biopsy-proven diagnoses of CA (20 ALs, 20 ATTRs) and 20 patients referred with the initial clinical suspicion and later diagnosed with non-CA pathology underwent a cardiac PET/computed tomography scan with a 60-min dynamic [18F]-florbetaben PET acquisition, and 4 10-min static scans at 5, 30, 50, and 110 min after radiotracer injection.

Results: Visual qualitative assessment showed intense early cardiac uptake in all subsets. Patients with AL displayed a high, persistent cardiac uptake in all the static scans, whereas patients with ATTR and those with non-CA showed an uptake decrease soon after the early scan. Semiquantitative assessment demonstrated higher mean standardized uptake value (SUV) in patients with AL, sustained over the whole acquisition period (early SUV: 5.55; interquartile range [IQR]: 4.00 to 7.43; vs. delayed SUV: 3.50; IQR: 2.32 to 6.10; p = NS) compared with in patients with ATTR (early SUV: 2.55; IQR: 1.80 to 2.97; vs. delayed SUV: 1.25; IQR: 0.90 to 1.60; p < 0.001) and in patients with non-CA (early SUV: 3.50; IQR: 1.60 to 3.37; vs. delayed SUV: 1.40; IQR: 1.20 to 1.60; p < 0.001). Similar results were found comparing heart-to-background ratio and molecular volume.

Conclusions: Delayed [18F]-florbetaben cardiac uptake may discriminate CA due to AL from either ATTR or other mimicking conditions. [18F]-florbetaben PET/computed tomography may represent a promising noninvasive tool for the diagnosis of AL amyloidosis, which is still often challenging and delayed. (A Prospective Triple-Arm, Monocentric, Phase-II Explorative Study on Evaluation of Diagnostic Efficacy of the PET Tracer [18F]-Florbetaben [Neuraceq] in Patients With Cardiac Amyloidosis [FLORAMICAR2]; EudraCT number: 2017-001660-38).
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http://dx.doi.org/10.1016/j.jcmg.2020.05.031DOI Listing
January 2021

Organ Stiffness in the Work-Up of Myelofibrosis and Philadelphia-Negative Chronic Myeloproliferative Neoplasms.

J Clin Med 2020 Jul 8;9(7). Epub 2020 Jul 8.

Department of Clinical and Experimental Medicine, UO Haematology, Azienda Ospedaliero-Universitaria Pisana, 56127 Pisa, Italy.

To define the role of spleen stiffness (SS) and liver stiffness (LS) in myelofibrosis and other Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs), we studied, by ultrasonography (US) and elastography (ES), 70 consecutive patients with myelofibrosis (MF) (no.43), essential thrombocythemia (ET) (no.10), and polycythemia vera (PV) (no.17). Overall, the median SS was not different between patients with MF and PV ( = 0.9); however, both MF and PV groups had significantly higher SS than the ET group ( = 0.011 and = 0.035, respectively) and healthy controls ( < 0.0001 and = 0.002, respectively). In patients with MF, SS values above 40 kPa were significantly associated with worse progression-free survival (PFS) ( = 0.012; HR = 3.2). SS also correlated with the extension of bone marrow fibrosis (BMF) ( < 0.0001). SS was higher in advanced fibrotic stages MF-2, MF-3 (W.H.O. criteria) than in pre-fibrotic/early fibrotic stages (MF-0, MF-1) ( < 0.0001) and PFS was significantly different in the two cohorts, with values of 63% and 85%, respectively ( = 0.038; HR = 2.61). LS significantly differed between the patient cohort with MF and healthy controls ( = 0.001), but not between the patient cohorts with ET and PV and healthy controls ( = 0.999 and = 0.101, respectively). We can conclude that organ stiffness adds valuable information to the clinical work-up of MPNs and could be employed to define patients at a higher risk of progression.
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http://dx.doi.org/10.3390/jcm9072149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408647PMC
July 2020

The CoV-2 outbreak: how hematologists could help to fight Covid-19.

Pharmacol Res 2020 07 6;157:104866. Epub 2020 May 6.

Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

COVID-19 is a medical emergency, with 20 % of patients presenting with severe clinical manifestations. From the pathogenetic point of view, COVID-19 mimics two other well-known diseases characterized by cytokine storm and hyper-activation of the immune response, with consequent organ damage: acute graft-versus-host disease (aGVHD) and macrophage activation syndrome (MAS). Hematologists are confident with these situations requiring a prompt therapeutic approach for switching off the uncontrolled cytokine release; here, we discuss pros and cons of drugs that are already employed in hematology in the light of their possible application in COVID-19. The most promising drugs might be: Ruxolitinib, a JAK1/2 inhibitor, with a rapid and powerful anti-cytokine effect, tyrosine kinase inhibitors (TKIs), with their good anti-inflammatory properties, and perhaps the anti-Cd26 antibody Begelomab. We also present immunological data from gene expression experiments where TKIs resulted effective anti-inflammatory and pro-immune drugs. A possible combined treatment algorithm for COVID-19 is here proposed.
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http://dx.doi.org/10.1016/j.phrs.2020.104866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202852PMC
July 2020

Rituximab as a novel treatment for heart failure: evidence from a case series.

Eur Heart J Case Rep 2019 Dec 17;3(4):1-2. Epub 2019 Dec 17.

Institute of Life Sciences, Scuola Superiore Sant'Anna, Piazza Martiri della Libertà 33, Pisa, Italy.

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http://dx.doi.org/10.1093/ehjcr/ytz227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939812PMC
December 2019

Different types of amyloid concomitantly present in the same patients.

Hematol Rep 2019 Nov 4;11(4):7996. Epub 2019 Dec 4.

Department of Clinical and Experimental Medicine, U.O. Hematology, University of Pisa, Italy.

Different types of amyloid concomitantly present in the same patient is believed to be improbable. We reported four cases of patients with plasma cell disorders who were found to have biopsy proven concomitant different types of amyloid fibrils deposition. We characterized amyloid fibrils using immunogold electron microscopy. There is lack of experience in the treatment of these frail and elderly patients, who are on the threshold between necessity of chemotherapy for AL amyloidosis and necessity to avoid harmful treatment related toxicity. All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure. Stem cell transplant (SCT) is preferred, but only 20% of patients are eligible Requirements for safe SCT include systolic blood pressure >90 mm Hg, troponin T <0.06 ng/mL, age <70 years, and serum creatinine ≤1.7 mg/dL Nontransplant candidates can be offered melphalandexamethasone or cyclophosphamide-bortezomibdexamethasone.
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http://dx.doi.org/10.4081/hr.2019.7996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902272PMC
November 2019

Mesangiogenic progenitor cells are forced toward the angiogenic fate, in multiple myeloma.

Oncotarget 2019 Nov 26;10(63):6781-6790. Epub 2019 Nov 26.

Department of Clinical and Experimental Medicine, Hematology Division, University of Pisa, Pisa, Italy.

Multiple myeloma (MM) progresses mainly in the bone marrow where the involvement of a specific microenvironment plays a critical role in maintaining plasma cell growth, spread, and survival. In active disease, the switch from a pre-vascular/non-active phase to a vascular phase is coupled with the impairment of bone turnover. Previously, we have isolated (MPCs), a bone marrow population that showed mesengenic and angiogenic potential, both and . MPC differentiation into musculoskeletal tissue and their ability of sprouting angiogenesis are mutually exclusive, suggesting a role in the imbalancing of the microenvironment in multiple myeloma. MPCs from 32 bone marrow samples of multiple myeloma and 23 non-hematological patients were compared in terms of frequency, phenotype, mesengenic/angiogenic potential, and gene expression profile. Defective osteogenesis was recorded for MM-derived MPCs that showed longer angiogenic sprouting distances respect to non-hematological MPCs, retaining this capability after mesengenic induction. This altered MPCs differentiation potential was not detected in asymptomatic myelomatous disease. These experiments are suggestive of a forced angiogenic fate in MPCs isolated from MM patients, which also showed increased sprouting activity. Taking together our results suggest a possible role of these cells in the "angiogenic switch" in the MM micro-environment.
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http://dx.doi.org/10.18632/oncotarget.27285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887577PMC
November 2019

Autologous stem cell transplantation is safe in selected elderly multiple myeloma patients.

Eur J Haematol 2020 Feb 12;104(2):138-144. Epub 2019 Dec 12.

Cellular Therapy and Transfusion Medicine Unit, Careggi University Hospital, Florence, Italy.

Objectives: ASCT is currently the "gold standard" first-line treatment for multiple myeloma patients younger than 65 years old, and limited data on efficacy and safety in older patients are available.

Methods: We retrospectively analyzed a cohort of 83 newly diagnosed multiple myeloma patients aged 65 or older. All patients were evaluated for fitness at diagnosis and after bortezomib-based induction treatment.

Results And Conclusions: All patients collected an adequate PBSC graft, mainly after G-CSF plus cyclophosphamide; a median of 6.47 × 10 /kg CD34 + cells was collected. The conditioning regimen consisted of melphalan 100, 140 and 200 mg/m in 40, 15 and 28 patients, respectively. Median time to neutrophils' and platelets' recovery was 11 and 12 days, respectively. Adverse events of any grade were referred by 40% of patients. The overall response rate was 93%, CR/sCR were 39%. Median PFS was 35 months; median OS was not reached. In our study cohort, the achievement of at least VGPR after induction therapy and the obtainment of CR/sCR after ASCT are the only parameters that were associated with an improved PFS. ASCT is an effective and safe first-line treatment approach, a careful patients selection reduce the toxicity of the procedure.
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http://dx.doi.org/10.1111/ejh.13357DOI Listing
February 2020

Keys to early diagnosis of cardiac amyloidosis: red flags from clinical, laboratory and imaging findings.

Eur J Prev Cardiol 2020 Nov 4;27(17):1806-1815. Epub 2019 Oct 4.

Institute of Life Sciences, Scuola Superiore Sant'Anna, Italy.

Cardiac involvement in systemic amyloidosis, due either to immunoglobulin light-chain or transthyretin amyloidosis, influences clinical presentation and is a strong predictor of unfavourable outcome. Until recently considered as a rare, incurable disease, cardiac amyloidosis, is still mis/underdiagnosed, although treatments effective in improving patient survival are now available for both subtypes, including chemotherapy regimens for immunoglobulin light-chain amyloidosis and tetramer stabiliser for transthyretin amyloidosis. Achieving a timely diagnosis allows initiating life-saving therapies and requires the early recognition of clinical, laboratory and imaging signs of cardiac involvement, some of them may be apparent well before the disease becomes clinically manifest. Given the systemic nature of amyloidosis, a close interaction among experts in multiple specialties is also required, including cardiologists, nephrologists, haematologists, neurologists, radiologists, nuclear medicine specialists and internists. As an increased awareness about disease presentation is required to ameliorate diagnostic performance, we aim to provide the clinician with a guide to the screening and early diagnosis of cardiac amyloidosis, and to review the clinical, biohumoral and instrumental 'red flags' that should raise the suspicion of cardiac amyloidosis.
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http://dx.doi.org/10.1177/2047487319877708DOI Listing
November 2020

Tumor dormancy as an alternative step in the development of chemoresistance and metastasis - clinical implications.

Cell Oncol (Dordr) 2020 Apr 7;43(2):155-176. Epub 2019 Aug 7.

Hematology Unit, Azienda Ospedaliera Universitaria Pisana, 56126, Pisa, Italy.

Background: The ability of a tumor to become dormant in response to suboptimal conditions has recently been recognized as a key step in tumor progression. Tumor dormancy has been found to be implicated in several tumor types as the culprit of therapy resistance and metastasis development, the deadliest features of a cancer. Several lines of evidence indicate that the development of these traits may rely on the de-differentiation of committed tumor cells that regain stem-like properties during a dormant state. Presently, dormancy is classified into cell- and population-level, according to the preponderance of cellular mechanisms that keep tumor cells quiescent or to a balance between overall cell division and death, respectively. Cellular dormancy is characterized by autophagy, stress-tolerance signaling, microenvironmental cues and, of prime relevance, epigenetic modifications. It has been found that the epigenome alters during cellular quiescence, thus representing the driving force for short-term cancer progression. Population-level dormancy is characterized by processes that counteract proliferation, such as inappropriate blood supply and intense immune responses. The latter two mechanisms are not mutually exclusive and may affect tumor masses both simultaneously and subsequently.

Conclusions: Overall, tumor dormancy may represent an additional step in the acquisition of cancer characteristics, and its comprehension may clarify both theoretical and practical aspects of cancer development. Clinically, only a deep understanding of dormancy may explain the course of tumor development in different patients, thus representing a process that may be targeted to prevent and/or treat advanced-stage cancers. That is especially the case for breast cancer, against which the mTOR inhibitor everolimus displays potent antitumor activity in patients with metastatic disease by impeding autophagy and tumor dormancy onset. Here we will also discuss other targeted therapies directed towards tumor dormancy onset, e.g. specific inhibitors of SFK and MEK, or aimed at keeping tumor cells dormant, e.g. prosaposin derivatives, that may shortly enter clinical assessment in breast, and possibly other cancer types.
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http://dx.doi.org/10.1007/s13402-019-00467-7DOI Listing
April 2020

The WNT Pathway Is Relevant for the BCR-ABL1-Independent Resistance in Chronic Myeloid Leukemia.

Front Oncol 2019 24;9:532. Epub 2019 Jun 24.

Hematology Division, University of Pisa, Pisa, Italy.

Notwithstanding the introduction of Tyrosine Kinase Inhibitors (TKIs) revolutionized the outcome of Chronic Myeloid Leukemia (CML), one third of patients still suspends treatment for failure response. Recent research demonstrated that several BCR/ABL1-independent mechanisms can sustain resistance, but the relationship between these mechanisms and the outcome has not yet been fully understood. This study was designed to evaluate in a "real-life" setting if a change of expression of several genes involved in the WNT/BETA-CATENIN, JAK-STAT, and POLYCOMB pathways might condition the outcome of CML patients receiving TKIs. Thus, the expression of 255 genes, related to the aforementioned pathways, was measured by quantitative PCR after 6 months of therapy and compared with levels observed at diagnosis in 11 CML patients, in order to find possible correlations with quality of response to treatment and event-free-survival (EFS). These results were then re-analyzed by the principal component method (PCA) for tempting to better cluster resistant cases. After 12 months of therapy, 6 patients achieved an optimal response and 5 were "resistant;" after application of both statistical methods, it was evident that in all pathways a significant overall up-regulation occurred, and that WNT was the pathway mostly responsible for the TKIs resistance. Indeed, 100% of patients with a "low" up-regulation of this pathway achieved an optimal response vs. 33% of those who showed a "high" gene over-expression ( = 0.016). Analogously, the 24-months EFS resulted significantly influenced by the degree of up-regulation of the WNT signaling: all patients with a "low" up-regulation were event-free vs. 33% of those who presented a "high" gene expression ( = 0.05). In particular, the PCA analysis confirmed the role of WNT pathway and showed that the most significantly up-regulated genes with negative prognostic value were DKK, WNT6, WISP1, and FZD8. In conclusion, our results sustain the need of a wide and multitasking approach in order to understand the resistance mechanisms in CML.
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http://dx.doi.org/10.3389/fonc.2019.00532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601352PMC
June 2019

Interference of Monoclonal Gammopathy with Fibrinogen Assay Producing Spurious Dysfibrinogenemia.

TH Open 2019 Jan 19;3(1):e64-e66. Epub 2019 Mar 19.

Department of Clinical and Experimental Medicine, U.O. Hematology, University of Pisa, Pisa, Italy.

Abnormal coagulation properties indicative of a dysfibrinogenemia were found in the plasma of an asymptomatic 65-year-old male. An immunoglobulin k light chain was found to interfere with Fg functional assay and coagulation tests (activated partial thromboplastin time, prothrombin time, and thrombin time). Steroid therapy reduced the inhibitory effect (after dexamethasone treatment coagulation test and functional Fg value normalized). Spurious dysfibrinogenemia associated with light chain monoclonal gammopathy of undetermined significance was diagnosed.
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http://dx.doi.org/10.1055/s-0039-1683969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524915PMC
January 2019

The assessment of minimal residual disease versus that of somatic mutations for predicting the outcome of acute myeloid leukemia patients.

Cancer Cell Int 2019 4;19:83. Epub 2019 Apr 4.

1Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy.

Background: In addition to morphological and cytogenetic features, acute myeloid leukemias are characterized by mutations that can be used for target-therapy; also the minimal/measurable residual disease (MRD) could be an important prognostic factor. The purpose of this retrospective study was to investigate if somatic mutations could represent an additional prognostic value in respect of MRD alone.

Method: At baseline, 98 patients were tested for , , and for expression; 31 for , , , , -, , -, , and . The same genes have been also tested after induction and consolidation.

Results: Overall, 60.2% of our patients resulted mutated: 24.5% carried mutations of -, 38.7% of , 48.4% of -, 25.8% of - and 19.3% of . The probability of achieving a complete response (CR) was higher for younger patients, with low ELN risk score, -mutated, with low levels, and without . The presence of additional mutations represented a poor predictive factor: only 19% of these cases achieved CR in comparison to 43% of subjects without any of it. Concerning survival, it was conditioned by a lower ELN risk score, younger age, reduction > 1 log of the mutational burden, disappearance of mutations and lower expression. Regarding the role of the additional mutations, they impaired the outcome of 20% of the already MRD-negative patients. Concerning the possibility of predicting relapse, we observed an increase of the mutational burden at the time-point immediately preceding the relapse (about 2 months earlier) in 50% of subjects. Similarly concerning , an increase of its expression anticipated disease recurrence in 64% of cases.

Conclusions: We demonstrated that additional somatic mutations are able to impair outcome of the already MRD-negative subjects. About MRD, we suggest a prognostic role also for the expression. Finally, we considered as relevant the assessment of quantity clearance instead of the presence/absence of mutations alone. Still remains in doubt the utility in terms of long-term prognosis of a baseline more complex mutational screening; we could hypothesize that it would be useful for those patients where other markers are not available or who reached the MRD negativity.
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http://dx.doi.org/10.1186/s12935-019-0807-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449954PMC
April 2019

Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma.

Leukemia 2019 09 9;33(9):2324-2330. Epub 2019 Apr 9.

ProfilExpert, Lyon, France.

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http://dx.doi.org/10.1038/s41375-019-0452-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756025PMC
September 2019

Genetic polymorphisms in genes of class switch recombination and multiple myeloma risk and survival: an IMMEnSE study.

Leuk Lymphoma 2019 07 11;60(7):1803-1811. Epub 2019 Jan 11.

b Genomic Epidemiology Group, German Cancer Research Center (DKFZ) , Heidelberg , Germany.

Genetic variants in genes acting during the maturation process of immature B-cell to differentiated plasma cell could influence the risk of developing multiple myeloma (MM). During B-cell maturation, several programmed genetic rearrangements occur to increase the variation of the immunoglobulin chains. Class switch recombination (CSR) is one of the most important among these mechanisms. Germline polymorphisms altering even subtly this process could play a role in the etiology and outcome of MM. We performed an association study of 30 genetic variants in the key CSR genes, using 2632 MM patients and 2848 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the Heidelberg MM Group and the ESTHER cohort. We found an association between -rs1555902 and decreased MM risk, which approached statistical significance, as well as significant associations between rs3794318 and better outcome. Our results add to our knowledge on the genetic component of MM risk and survival.
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http://dx.doi.org/10.1080/10428194.2018.1551536DOI Listing
July 2019

The Polycomb BMI1 Protein Is Co-expressed With CD26+ in Leukemic Stem Cells of Chronic Myeloid Leukemia.

Front Oncol 2018 6;8:555. Epub 2018 Dec 6.

Section of Histology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

The Polycomb gene expression exerts a negative predictive impact on several hematological malignancies, such as acute and chronic myeloid leukemia (CML), myelofibrosis, and follicular lymphoma. As already demonstrated in CML, is responsible for the resistance to the tyrosine kinase inhibitors (TKIs) in a -independent way. Even if, it is unknown where in CML is expressed (in progenitors or more mature cells). We decided, therefore, to evaluate if and where the BMI1 protein is located, focusing mainly on the CD34+/CD38-/CD26+ CML progenitors. To begin we measured, by flow cytometry, the proportion of CD34+/CD26+ cells in 31 bone marrow samples from 20 CML patients, at diagnosis and during treatment with imatinib. After that the bone marrow blood smears were stained with antibodies anti-CD26, BCR-ABL1, and BMI1. These smears were observed by a confocal laser microscope and a 3D reconstruction was then performed. At diagnosis, CD34+/CD26+ cells median value/μL was 0.48; this number increased from diagnosis to the third month of therapy and then reduced during treatment with imatinib. The number and behavior of the CD26+ progenitors were independent from the expression, but they summed up what previously observed about the expression modulation. In this work we demonstrate for the first time that in CML the BMI1 protein is co-expressed with BCR-ABL1 only in the cytoplasm of the CD26+ precursors; on the contrary, in other hematological malignancies where BMI1 is commonly expressed (follicular lymphoma, essential thrombocytemia, acute myeloid leukemia), it was not co-localized with CD26 or, obviously, with BCR-ABL1. Once translated into the clinical context, if BMI1 is a marker of stemness, our results would suggest the combination of the BMI1 inhibitors with TKIs as an interesting object of research, and, probably, as a promising way to overcome resistance in CML patients.
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http://dx.doi.org/10.3389/fonc.2018.00555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291509PMC
December 2018

The Onset of Monoclonal and Oligoclonal Gammopathies Is a Good Prognostic Factor after Allogeneic Stem Cell Transplantation.

Acta Haematol 2019 15;141(1):7-11. Epub 2018 Nov 15.

Hematology Division, Pisa University Hospital, Pisa, Italy.

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http://dx.doi.org/10.1159/000493416DOI Listing
September 2019

Therapies for cardiac light chain amyloidosis: An update.

Int J Cardiol 2018 Nov;271:152-160

Amyloidosis Research and Treatment Centre, IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, University of Pavia, Italy.

Light-chain (AL) amyloidosis is the most common type of systemic amyloidosis, affecting around 10 people per million per year. This serious disorder is characterized by the presence of a clone of bone marrow plasma cells that produces monoclonal light chains (LCs) of the κ or predominantly λ type. These amyloidogenic LCs undergo extracellular misfolding and aggregation into proteotoxic soluble oligomers and amyloid fibrils that deposit within tissues. The lethal consequences of AL amyloidosis are due to the toxic products (the LCs) and not to the malignant behaviour of the plasma cell clone. Almost 80% of patients with AL amyloidosis have some degree of cardiac involvement, manifesting as heart failure (HF), and carrying a particularly poor prognosis. The past decade has seen major advances in the treatment of AL amyloidosis, and a rapidly fatal disease has become a treatable and possibly curable condition. The number of therapeutic options is rapidly expanding, offering hope to address currently unmet needs (most notably, the treatment of frail patients). The treatment of AL amyloidosis consists in a combination of agents targeting multiple steps of the amyloid cascade, associated with effective HF management, and there is ground for hope for dramatically improving the outcome in the near future. In the present review we will summarize our current knowledge on therapy for cardiac AL amyloidosis, targeting clinical cardiologists involved in the care of this serious disorder.
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http://dx.doi.org/10.1016/j.ijcard.2018.05.018DOI Listing
November 2018

Inherited variation in the xenobiotic transporter pathway and survival of multiple myeloma patients.

Br J Haematol 2018 11 6;183(3):375-384. Epub 2018 Aug 6.

Department of Biology, University of Pisa, Pisa, Italy.

Over the past four decades, remarkable progress has been made in the treatment and prognosis of multiple myeloma (MM), although it remains an incurable disease. Chemotherapy resistance is a major hurdle for treatment efficacy. Drug resistance can be innate and so driven by genes involved in the drug metabolism pathways. We performed an association study of 71 germline variants within the major genes in those pathways (ABCB1, ABCC2, ABCG2, and their regulators NR1I2/PXR and NR1I3/CAR) in the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries. Two of the SNPs showed a significant association with the survival of MM patients, namely rs2235013, located in ABCB1 [Hazard ratio (HR) = 1·52, 95% confidence interval (CI) = 1·18-1·95, P = 0·00087], and rs4148388, located in ABCC2 (HR = 2·15, 95% CI = 1·44-3·22, P = 0·0001). ABCC2 plays an essential role in transporting various anticancer drugs, including several used against MM, out of the cell. In silico analyses predict that the variant alleles of four SNPs in linkage disequilibrium with ABCC2-rs4148388 are associated with increased gene expression. Overexpression of ABCC2 increases drug clearance and therefore may induce drug resistance mechanisms. In conclusion, we found a promising association between ABCC2-rs4148388 and MM outcome that is supported by a plausible biological explanation.
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http://dx.doi.org/10.1111/bjh.15521DOI Listing
November 2018

High-dose zinc oral supplementation after stem cell transplantation causes an increase of TRECs and CD4+ naïve lymphocytes and prevents TTV reactivation.

Leuk Res 2018 07 2;70:20-24. Epub 2018 May 2.

Hematology Division, Pisa University Hospital, Pisa, Italy.

Introduction: Zinc plays an important role in thymic function and immune homeostasis. We performed a prospective clinical trial using a high-dose zinc oral supplementation to improve the immune reconstitution after hematopoietic stem cell transplant (HSCT).

Patients And Methods: We enrolled 18 patients undergoing autologous HSCT for multiple myeloma. Nine patients were randomized to receive only a standard antimicrobial prophylaxis; whereas, nine patients received in addition 150 mg/day of zinc from day +5 to day +100 after transplant.

Results: CD4+ naïve lymphocytes and TRECs showed a significant increase from day +30 until day +100 only in the zinc-treated group. Moreover, the load of Torquetenovirus, a harmless virus that replicates in course of immunedepression, increased at day +100 only in the control group. No severe adverse events were reported during the zinc consumption.

Conclusion: First data from the ZENITH trial suggest that high-dose zinc supplementation is safe and may enhance the thymic reconstitution after HSCT. Registered: http://Clinicaltrials.gov (NCT03159845); and EUDRACT: 2014-28 004499-47.
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http://dx.doi.org/10.1016/j.leukres.2018.04.016DOI Listing
July 2018

PRDI-BF1 and PRDI-BF1P isoform expressions correlate with disease status in multiple myeloma patients.

Hematol Rep 2017 Dec 22;9(4):7201. Epub 2017 Dec 22.

Department of Clinical and Experimental Medicine, U.O. Hematology, University of Pisa, Italy.

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http://dx.doi.org/10.4081/hr.2017.7201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757414PMC
December 2017

Cardiac light-chain deposition disease relapsing in the transplanted heart.

Amyloid 2017 06 31;24(2):135-137. Epub 2017 May 31.

a Scuola Superiore Sant'Anna , Pisa , Italy.

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http://dx.doi.org/10.1080/13506129.2017.1334196DOI Listing
June 2017

A Multicenter Phase II Study of Twice-Weekly Bortezomib plus Rituximab in Patients with Relapsed Follicular Lymphoma: Long-Term Follow-Up.

Acta Haematol 2017 4;137(1):7-14. Epub 2016 Nov 4.

Program of Innovative Therapy in Oncology and Hematology, Department of Diagnostic, Clinical Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy.

Single-agent bortezomib (B) has shown activity in heavily pretreated patients with relapsed/refractory indolent lymphoma. On the basis of these findings, we performed a phase II study of B combined with rituximab (R) in patients with relapsed follicular lymphoma (FL). Forty-five patients with fairly good prognostic profiles were enrolled from 2007 to 2011 and received a total of 6 cycles of the B+R combination. The endpoints were the overall response rate (ORR), progression-free survival (PFS), duration of remission (DoR), overall survival (OS), and toxicity evaluation. When considering all the enrolled patients the ORR was 64%. At 5 years, the estimated PFS, DoR, and OS were 34, 49, and 70%, respectively. After excluding the 7 R-naïve patients, the ORR was 58%, with a PFS of 19 months. The most common grade >2 toxicities were thrombocytopenia (18%), peripheral neuropathy (13%), and neutropenia (2%). Our study shows the feasibility, long-term efficacy, and excellent tolerability of the B+R combination. We are aware that our study has specific limitations, such as the small sample size consisting of patients with a relatively good prognostic profile. However, because FL patients will be treated with subsequent chemotherapy regimens, a well-tolerated and effective chemotherapy-free therapy could be considered an additional tool for long-term disease control.
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http://dx.doi.org/10.1159/000449052DOI Listing
February 2017

How to facilitate early diagnosis of CNS involvement in malignant lymphoma.

Expert Rev Hematol 2016 Nov 21;9(11):1081-1091. Epub 2016 Oct 21.

k Penn State College of Medicine , Hershey , PA , USA.

Introduction: Making the diagnosis of secondary CNS involvement in lymphoma can be difficult due to unspecific signs and symptoms, limited accessibility of brain/myelon parenchyma and low sensitivity and/or specifity of imaging and cerebrospinal fluid (CSF) examination currently available. Areas covered: MRI of the total neuroaxis followed by CSF cytomorphology and flow cytometry are methods of choice when CNS lymphoma (CNSL) is suspected. To reduce the numerous pitfalls of these examinations several aspects should be considered. New CSF biomarkers might be of potential diagnostic value. Attempts to standardize response criteria are presented. Expert commentary: Diagnosing CNSL remains challenging. Until diagnostic methods combining high sensitivity with high specifity are routinely introduced, high level of awareness and optimal utilization of examinations currently available are needed to early diagnose this potentially devastating disease.
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http://dx.doi.org/10.1080/17474086.2016.1242405DOI Listing
November 2016

Identification of miRSNPs associated with the risk of multiple myeloma.

Int J Cancer 2017 Feb 9;140(3):526-534. Epub 2016 Nov 9.

Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Multiple myeloma (MM) is a malignancy of plasma cells usually infiltrating the bone marrow, associated with the production of a monoclonal immunoglobulin (M protein) which can be detected in the blood and/or urine. Multiple lines of evidence suggest that genetic factors are involved in MM pathogenesis, and several studies have identified single nucleotide polymorphisms (SNPs) associated with the susceptibility to the disease. SNPs within miRNA-binding sites in target genes (miRSNPs) may alter the strength of miRNA-mRNA interactions, thus deregulating protein expression. MiRSNPs are known to be associated with risk of various types of cancer, but they have never been investigated in MM. We performed an in silico genome-wide search for miRSNPs predicted to alter binding of miRNAs to their target sequences. We selected 12 miRSNPs and tested their association with MM risk. Our study population consisted of 1,832 controls and 2,894 MM cases recruited from seven European countries and Israel in the context of the IMMEnSE (International Multiple Myeloma rESEarch) consortium. In this population two SNPs showed an association with p < 0.05: rs286595 (located in gene MRLP22) and rs14191881 (located in gene TCF19). Results from IMMEnSE were meta-analyzed with data from a previously published genome-wide association study (GWAS). The SNPs rs13409 (located in the 3'UTR of the POU5F1 gene), rs1419881 (TCF19), rs1049633, rs1049623 (both in DDR1) showed significant associations with MM risk. In conclusion, we sought to identify genetic polymorphisms associated with MM risk starting from genome-wide prediction of miRSNPs. For some mirSNPs, we have shown promising associations with MM risk.
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http://dx.doi.org/10.1002/ijc.30465DOI Listing
February 2017

A common variant within the HNF1B gene is associated with overall survival of multiple myeloma patients: results from the IMMEnSE consortium and meta-analysis.

Oncotarget 2016 09;7(37):59029-59048

Genomic Oncology Area, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (GENYO), Granada, Spain.

Diabetogenic single nucleotide polymorphisms (SNPs) have recently been associated with multiple myeloma (MM) risk but their impact on overall survival (OS) of MM patients has not been analysed yet. In order to investigate the impact of 58 GWAS-identified variants for type 2 diabetes (T2D) on OS of patients with MM, we analysed genotyping data of 936 MM patients collected by the International Multiple Myeloma rESEarch (IMMENSE) consortium and an independent set of 700 MM patients recruited by the University Clinic of Heidelberg. A meta-analysis of the cox regression results of the two sets showed that rs7501939 located in the HNF1B gene negatively impacted OS (HRRec= 1.44, 95% CI = 1.18-1.76, P = 0.0001). The meta-analysis also showed a noteworthy gender-specific association of the SLC30A8rs13266634 SNP with OS. The presence of each additional copy of the minor allele at rs13266634 was associated with poor OS in men whereas no association was seen in women (HRMen-Add = 1.32, 95% CI 1.13-1.54, P = 0.0003). In conclusion, these data suggest that the HNF1Brs7501939 SNP confers poor OS in patients with MM and that a SNP in SLC30A8 affect OS in men.
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http://dx.doi.org/10.18632/oncotarget.10665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312293PMC
September 2016