Publications by authors named "Mario Luppi"

235 Publications

Genomic and clinical findings in myeloid neoplasms with PDGFRB rearrangement.

Ann Hematol 2021 Dec 2. Epub 2021 Dec 2.

Department of Medicine and Surgery, Center for Hemato-Oncology Research (C.R.E.O.), University of Perugia, Perugia, Italy.

Platelet-derived growth factor receptor B (PDGFRB) gene rearrangements define a unique subgroup of myeloid and lymphoid neoplasms frequently associated with eosinophilia and characterized by high sensitivity to tyrosine kinase inhibition. To date, various PDGFRB/5q32 rearrangements, involving at least 40 fusion partners, have been reported. However, information on genomic and clinical features accompanying rearrangements of PDGFRB is still scarce. Here, we characterized a series of 14 cases with a myeloid neoplasm using cytogenetic, single nucleotide polymorphism array, and next-generation sequencing. We identified nine PDGFRB translocation partners, including the KAZN gene at 1p36.21 as a novel partner in a previously undescribed t(1;5)(p36;q33) chromosome change. In all cases, the PDGFRB recombination was the sole cytogenetic abnormality underlying the phenotype. Acquired somatic variants were mainly found in clinically aggressive diseases and involved epigenetic genes (TET2, DNMT3A, ASXL1), transcription factors (RUNX1 and CEBPA), and signaling modulators (HRAS). By using both cytogenetic and nested PCR monitoring to evaluate response to imatinib, we found that, in non-AML cases, a low dosage (100-200 mg) is sufficient to induce and maintain longstanding hematological, cytogenetic, and molecular remissions.
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http://dx.doi.org/10.1007/s00277-021-04712-8DOI Listing
December 2021

GITMO REGISTRY STUDY ON ALLOGENEIC TRANSPLANTATION IN PATIENTS AGED OVER 60 FROM 2000 TO 2017. IMPROVEMENTS AND CRITICISMS.

Transplant Cell Ther 2021 Nov 21. Epub 2021 Nov 21.

Unit of Haematology and Stem Cell Transplant Centre, "San Camillo" Hospital, Rome, Italy.

Background: Nowadays, allogeneic stem cell transplantation (Allo-SCT) can be offered to patients up to the age of 70-72 years and represents one of the most effective curative treatments for many hematological malignancies.

Objectives: The primary objective of the study is to collect data from the allo-SCTs performed in Italy from 2000 to 2017 in patients over 60 years of age to evaluate the changes in safety and efficacy outcomes as well as their distribution and characteristics over time.

Study Design: The GITMO AlloEld study (ClinicalTrials.gov: NCT04469985) is a retrospective, analysis of the allo-SCTs performed 30 Italian transplant Centers on older patients (≥ 60 years) from 2000 to 2017 (n=1,996).

Results: For the purpose of analysis, patients were grouped into three time periods: time A: 2000-2005, n=256 (12%); time B: 2006-2011, n=584 (29%); and time C: 2012-2017, n=1156 (59%). After a median follow-up of 5.6 years, the 5-year Non Relapse Mortality (NRM) remained stable (time A: 32.8%; time B: 36.2%; and time C: 35.0%, p = 0.5); the Overall Survival (OS) improved (time A: 28.4%; time B: 31.8%; and time C: 37.3%, p = 0.012); and the Cumulative Incidence of Relapse (CIR) reduced (time A: 45.3%; time B: 38.2%; time C: 30.0%, p < 0.0001). The 2-year incidence of extensive cGVHD reduced significantly (time A: 17.2%; time B: 15.8%; and time C: 12.2%, p = 0.004). Considering times A and B together (2000-2011), the 2-year NRM was positively correlated to the HCT-CI score; patients with HCT-CI of 0, 1 or 2, or ≥3 had rates of NRM of 25.2%, 33.9%, and 36.1%, respectively, (p < 0.001). Meanwhile, after 2012, the HCT-CI score was not significantlly predictive of NRM.

Conclusions: The study shows that the transplant procedure in elderly patients became more effective over time. Relapse incidence remains the major problem and strategies to prevent it are under investigation (e.g. post-transplant maintenance). Today, the selection of patients aged over 60 could be improved by combining HCT-CI and frailty assessments to better predict NRM.
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http://dx.doi.org/10.1016/j.jtct.2021.11.006DOI Listing
November 2021

Early palliative/supportive care in acute myeloid leukaemia allows low aggression end-of-life interventions: observational outpatient study.

BMJ Support Palliat Care 2021 Nov 8. Epub 2021 Nov 8.

Oncology and Palliative Care Units, Civil Hospital Carpi, USL, Carpi, Italy.

Objectives: Early palliative supportive care has been associated with many advantages in patients with advanced cancer. However, this model is underutilised in patients with haematological malignancies. We investigated the presence and described the frequency of quality indicators for palliative care and end-of-life care in a cohort of patients with acute myeloid leukaemia receiving early palliative supportive care.

Methods: This is an observational, retrospective study based on 215 patients consecutively enrolled at a haematology early palliative supportive care clinic in Modena, Italy. Comprehensive hospital chart reviews were performed to abstract the presence of well-established quality indicators for palliative care and for aggressiveness of care near the end of life.

Results: 131 patients received a full early palliative supportive care intervention. All patients had at least one and 67 (51%) patients had four or more quality indicators for palliative care. Only 2.7% of them received chemotherapy in the last 14 days of life. None underwent intubation or cardiopulmonary resuscitation and was admitted to intensive care unit during the last month of life. Only 4% had either multiple hospitalisations or two or more emergency department access. Approximately half of them died at home or in a hospice. More than 40% did not receive transfusions within 7 days of death. The remaining 84 patients, considered late referrals to palliative care, demonstrated sensibly lower frequencies of the same indicators.

Conclusions: Patients with acute myeloid leukaemia receiving early palliative supportive care demonstrated high frequency of quality indicators for palliative care and low rates of treatment aggressiveness at the end of life.
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http://dx.doi.org/10.1136/bmjspcare-2021-002898DOI Listing
November 2021

ELN2017 risk stratification improves outcome prediction when applied to the prospective GIMEMA AML1310 protocol.

Blood Adv 2021 Nov 3. Epub 2021 Nov 3.

Fondazione Policlinico Tor Vergata, Rome, Italy.

The 2017 version of the ELN recommendations, by integrating cytogenetics and mutational status of specific genes, sort out patients with Acute Myeloid Leukemia into 3 prognostically distinct risk categories: favorable (ELN2017-FR), intermediate (ELN2017-IR) and adverse (ELN2017-AR). We performed a post-hoc analysis of the GIMEMA AML1310 trial to investigate the applicability of the ELN2017 risk stratification to our study population. In this trial, after induction and consolidation, patients in complete remission were to receive autologous stem cell transplant (AuSCT) if categorized as favorable-risk or allogeneic stem cell transplant (ASCT) if adverse-risk. Intermediate-risk pts were to receive AuSCT or ASCT based on the post-consolidation levels of Measurable Residual Disease as measured by flow-cytometry. Risk categorization was originally conducted according to NCCN2009 recommendations. Among 500 patients, 445 (89%) were re-classified according to the ELN2017 criteria: ELN2017-FR (186/455; 41.8%), ELN2017-IR (179/445 40.2%) and ELN2017-AR (80/455; 18%); in 55 patients (11%) ELN2017 was not applicable (ELN2017-NC). Two-year overall survival (OS) was 68.8%, 51.3%, 45.8% and 42.8% for ELN2017-FR, ELN2017-IR, ELN2017-NC, and ELN2017-AR group, respectively (p<0.001). When comparing the two different transplant strategies in each ELN2017 risk category, a significant benefit of AuSCT over ASCT was observed among ELN2017-FR patients (2-years OS of 83.3% vs. 66.7%; p=0.0421). The two transplant procedures performed almost equally in the ELN2017-IR group (2-years OS of 73.9% vs. 70.8%; p=0.5552). This post-hoc analysis of the GIMEMA AML1310 trial, confirms that the ELN2017 classification is able to accurately discriminate patients with different outcomes and who may benefit from different transplant strategies.
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http://dx.doi.org/10.1182/bloodadvances.2021005717DOI Listing
November 2021

Brentuximab vedotin consolidation after autologous stem cell transplantation for Hodgkin lymphoma: A Fondazione Italiana Linfomi real-life experience.

Hematol Oncol 2021 Oct 25. Epub 2021 Oct 25.

Hematology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

The standard management for relapsed or refractory classical Hodgkin lymphoma (cHL) is salvage therapy followed by autologous stem cell transplantation (ASCT). This strategy allows almost 50% of patients to be cured. Post-ASCT maintenance treatment with brentuximab vedotin (BV) confers improved progression-free survival (PFS) to cHL patients at high risk of relapse. We investigated the outcome of 105 cHL patients receiving post-ASCT BV maintenance in the real-life setting of 23 Italian hematology centers. This population included naïve patients and those previously exposed to BV. Median follow-up was 20 months. Patients presented a median of two lines of treatment pre-ASCT, with 51% receiving BV. Twenty-nine percent of patients had at least two high-risk factors (refractory disease, complete response [CR] less than 12 months, extranodal disease at relapse), while 16% presented none. At PET-CT, a Deauville score (DS) of 1-3 was reported in 75% and 78% of pre- and post-ASCT evaluations, respectively. Grade 3-4 adverse events (AEs), mainly peripheral neuropathy, were observed in 16% of patients. Three-year PFS and overall survival (OS) were 62% and 86%, respectively. According to BV exposure, 3-year PFS and OS were 54% and 71%, respectively, for naïve and 77% and 96%, respectively, for previously exposed patients. Refractory disease (hazard ratio [HR] 4.46; p = 0.003) and post-ASCT DS 4-5 (HR 3.14; p = 0.005) were the only two factors significantly associated with PFS reduction in multivariable analysis. Post-ASCT BV maintenance is an effective, safe treatment option for cHL naïve patients and those previously exposed to BV.
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http://dx.doi.org/10.1002/hon.2939DOI Listing
October 2021

Increased Plasma Levels of lncRNAs , and Correlate with Negative Prognostic Factors in Myelofibrosis.

Cancers (Basel) 2021 Sep 22;13(19). Epub 2021 Sep 22.

Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Policlinico, 41124 Modena, Italy.

Long non-coding RNAs (lncRNAs) have been recently described as key mediators in the development of hematological malignancies. In the last years, circulating lncRNAs have been proposed as a new class of non-invasive biomarkers for cancer diagnosis and prognosis and to predict treatment response. The present study is aimed to investigate the potential of circulating lncRNAs as non-invasive prognostic biomarkers in myelofibrosis (MF), the most severe among Philadelphia-negative myeloproliferative neoplasms. We detected increased levels of seven circulating lncRNAs in plasma samples of MF patients ( = 143), compared to healthy controls ( = 65). Among these, high levels of , or correlate with detrimental clinical variables, such as high count of leukocytes and CD34+ cells, severe grade of bone marrow fibrosis and presence of splenomegaly. Strikingly, high plasma levels of = 0.0018) ( = 0.0008) or ( = 0.0348) are also associated with a poor overall-survival while high levels of correlate with a shorter leukemia-free-survival. Finally, multivariate analysis demonstrated that the plasma level of is an independent prognostic variable, suggesting that, if confirmed in future in an independent patients' cohort, it could be used for further studies to design an updated classification model for MF patients.
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http://dx.doi.org/10.3390/cancers13194744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507546PMC
September 2021

Herpes Simplex Virus Re-Activation in Patients with SARS-CoV-2 Pneumonia: A Prospective, Observational Study.

Microorganisms 2021 Sep 7;9(9). Epub 2021 Sep 7.

Radboud Center for Infectious Diseases, Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.

Background: Herpes simplex 1 co-infections in patients with COVID-19 are considered relatively uncommon; some reports on re-activations in patients in intensive-care units were published. The aim of the study was to analyze herpetic re-activations and their clinical manifestations in hospitalized COVID-19 patients, performing HSV-1 PCR on plasma twice a week.

Methods: we conducted a prospective, observational, single-center study involving 70 consecutive patients with severe/critical SARS-CoV-2 pneumonia tested for HSV-1 hospitalized at Azienda Ospedaliero-Universitaria of Modena.

Results: of these 70 patients, 21 (30.0%) showed detectable viremia and 13 (62%) had clinically relevant manifestations of HSV-1 infection corresponding to 15 events (4 pneumonia, 5 herpes labialis, 3 gingivostomatitis, one encephalitis and two hepatitis). HSV-1 positive patients were more frequently treated with steroids than HSV-1 negative patients (76.2% vs. 49.0%, = 0.036) and more often underwent mechanical ventilation (IMV) (57.1% vs. 22.4%, = 0.005). In the unadjusted logistic regression analysis, steroid treatment, IMV, and higher LDH were significantly associated with an increased risk of HSV1 re-activation (odds ratio 3.33, 4.61, and 16.9, respectively). The association with the use of steroids was even stronger after controlling for previous use of both tocilizumab and IMV (OR = 5.13, 95% CI:1.36-19.32, = 0.016). The effect size was larger when restricting to participants who were treated with high doses of steroids while there was no evidence to support an association with the use of tocilizumab Conclusions: our study shows a high incidence of HSV-1 re-activation both virologically and clinically in patients with SARS-CoV-2 severe pneumonia, especially in those treated with steroids.
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http://dx.doi.org/10.3390/microorganisms9091896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465957PMC
September 2021

Multiparametric Flow Cytometry for MRD Monitoring in Hematologic Malignancies: Clinical Applications and New Challenges.

Cancers (Basel) 2021 Sep 12;13(18). Epub 2021 Sep 12.

Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Modena, 41124 Modena, Italy.

Along with the evolution of immunophenotypic and molecular diagnostics, the assessment of Minimal Residual Disease (MRD) has progressively become a keystone in the clinical management of hematologic malignancies, enabling valuable post-therapy risk stratifications and guiding risk-adapted therapeutic approaches. However, specific prognostic values of MRD in different hematological settings, as well as its appropriate clinical uses (basically, when to measure it and how to deal with different MRD levels), still need further investigations, aiming to improve standardization and harmonization of MRD monitoring protocols and MRD-driven therapeutic strategies. Currently, MRD measurement in hematological neoplasms with bone marrow involvement is based on advanced highly sensitive methods, able to detect either specific genetic abnormalities (by PCR-based techniques and next-generation sequencing) or tumor-associated immunophenotypic profiles (by multiparametric flow cytometry, MFC). In this review, we focus on the growing clinical role for MFC-MRD diagnostics in hematological malignancies-from acute myeloid and lymphoblastic leukemias (AML, B-ALL and T-ALL) to chronic lymphocytic leukemia (CLL) and multiple myeloma (MM)-providing a comparative overview on technical aspects, clinical implications, advantages and pitfalls of MFC-MRD monitoring in different clinical settings.
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http://dx.doi.org/10.3390/cancers13184582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470441PMC
September 2021

Changes in Cancer Patients' and Caregivers' Disease Perceptions While Receiving Early Palliative Care: A Qualitative and Quantitative Analysis.

Oncologist 2021 Sep 12. Epub 2021 Sep 12.

Oncology and Palliative Care Units, Civil Hospital Carpi, USL, Carpi, Italy.

Background: Little is known about the underlying mechanisms through which early palliative care (EPC) improves multiple outcomes in patients with cancer and their caregivers. The aim of this study was to qualitatively and quantitatively analyze patients' and caregivers' thoughts and emotional and cognitive perceptions about the disease prior to and during the EPC intervention, and in the end of life, following the exposure to EPC.

Materials And Methods: Seventy-seven patients with advanced cancer and 48 caregivers from two cancer centers participated in semistructured interviews. Their reports were qualitatively and quantitatively analyzed by the means of the grounded theory and a text-analysis program.

Results: Participants reported their past as overwhelmed by unmanaged symptoms, with detrimental physical and psychosocial consequences. The EPC intervention allowed a prompt resolution of symptoms and of their consequences and empowerment, an appreciation of its multidimensional approach, its focus on the person and its environment, and the need for EPC for oncologic populations. Patients reported that conversations with the EPC team increased their acceptance of end of life and their expectation of a painless future. Quantitative analysis revealed higher use of Negative Affects (p < .001) and Biological Processes words (p < .001) when discussing the past; Agency words when discussing the present (p < .001); Positive Affects (p < .001), Optimism (p = .002), and Insight Thinking words (p < .001) when discussing the present and the future; and Anxiety (p = .002) and Sadness words (p = .003) when discussing the future.

Conclusion: Overall, participants perceived EPC to be beneficial. Our findings suggest that emotional and cognitive processes centered on communication underlie the benefits experienced by participants on EPC.

Implications For Practice: By qualitative and quantitative analyses of the emotional and cognitive perceptions of cancer patients and their caregivers about their experiences before and during EPC interventions, this study may help physicians/nurses to focus on the disease perception by patients/caregivers and the benefits of EPC, as a standard practice. The analysis of words used by patients/caregivers provides a proxy for their psychological condition and support in tailoring an EPC intervention, based on individual needs. This study highlights that the relationship of the triad EPC team/patients/caregivers may rise as a therapeutic tool, allowing increasing awareness and progressive acceptance of the idea of death.
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http://dx.doi.org/10.1002/onco.13974DOI Listing
September 2021

Neoantigen-Specific T-Cell Immune Responses: The Paradigm of NPM1-Mutated Acute Myeloid Leukemia.

Int J Mol Sci 2021 Aug 25;22(17). Epub 2021 Aug 25.

Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria di Modena, Policlinico, 41124 Modena, Italy.

The C-terminal aminoacidic sequence from NPM1-mutated protein, absent in normal human tissues, may serve as a leukemia-specific antigen and can be considered an ideal target for -mutated acute myeloid leukemia (AML) immunotherapy. Different in silico instruments and in vitro/ex vivo immunological platforms have identified the most immunogenic epitopes from NPM1-mutated protein. Spontaneous development of endogenous NPM1-mutated-specific cytotoxic T cells has been observed in patients, potentially contributing to remission maintenance and prolonged survival. Genetically engineered T cells, namely CAR-T or TCR-transduced T cells, directed against NPM1-mutated peptides bound to HLA could prospectively represent a promising therapeutic approach. Although either adoptive or vaccine-based immunotherapies are unlikely to be highly effective in patients with full-blown leukemia, these strategies, potentially in combination with immune-checkpoint inhibitors, could be promising in maintaining remission or preemptively eradicating persistent measurable residual disease, mainly in patients ineligible for allogeneic hematopoietic stem cell transplant (HSCT). Alternatively, neoantigen-specific donor lymphocyte infusion derived from healthy donors and targeting NPM1-mutated protein to selectively elicit graft-versus-leukemia effect may represent an attractive option in subjects experiencing post-HSCT relapse. Future studies are warranted to further investigate dynamics of NPM1-mutated-specific immunity and explore whether novel individualized immunotherapies may have potential clinical utility in -mutated AML patients.
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http://dx.doi.org/10.3390/ijms22179159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431540PMC
August 2021

How to Improve Prognostication in Acute Myeloid Leukemia with Fusion Transcript: Focus on the Role of Molecular Measurable Residual Disease (MRD) Monitoring.

Biomedicines 2021 Aug 3;9(8). Epub 2021 Aug 3.

Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria di Modena, 41124 Modena, Italy.

Acute myeloid leukemia (AML) carrying inv(16)/t(16;16), resulting in fusion transcript , belongs to the favorable-risk category. However, even if most patients obtain morphological complete remission after induction, approximately 30% of cases eventually relapse. While well-established clinical features and concomitant cytogenetic/molecular lesions have been recognized to be relevant to predict prognosis at disease onset, the independent prognostic impact of measurable residual disease (MRD) monitoring by quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR), mainly in predicting relapse, actually supersedes other prognostic factors. Although the ELN Working Party recently indicated that patients affected with AML should have MRD assessment at informative clinical timepoints, at least after two cycles of intensive chemotherapy and after the end of treatment, several controversies could be raised, especially on the frequency of subsequent serial monitoring, the most significant MRD thresholds (most commonly 0.1%) and on the best source to be analyzed, namely, bone marrow or peripheral blood samples. Moreover, persisting low-level MRD positivity at the end of treatment is relatively common and not predictive of relapse, provided that transcript levels remain stably below specific thresholds. Rising MRD levels suggestive of molecular relapse/progression should thus be confirmed in subsequent samples. Further prospective studies would be required to optimize post-remission monitoring and to define effective MRD-based therapeutic strategies.
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http://dx.doi.org/10.3390/biomedicines9080953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391269PMC
August 2021

Chromosome 16 changes do not always come for good.

Int J Lab Hematol 2021 Aug 1. Epub 2021 Aug 1.

Section of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, AOU Policlinico, Modena, Italy.

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http://dx.doi.org/10.1111/ijlh.13676DOI Listing
August 2021

COVID-19 elicits an impaired antibody response against SARS-CoV-2 in patients with haematological malignancies.

Br J Haematol 2021 11 16;195(3):371-377. Epub 2021 Jul 16.

Università di Torino, Azienda Ospedaliera Città della Salute e della Scienza, Alessandria, Italy.

COVID-19 is associated with high mortality in patients with haematological malignancies (HM) and rate of seroconversion is unknown. The ITA-HEMA-COV project (NCT04352556) investigated patterns of seroconversion for SARS-CoV-2 IgG in patients with HMs. A total of 237 patients, SARS-CoV-2 PCR-positive with at least one SARS-CoV-2 IgG test performed during their care, entered the analysis. Among these, 62 (26·2%) had myeloid, 121 (51·1%) lymphoid and 54 (22·8%) plasma cell neoplasms. Overall, 69% of patients (164 of 237) had detectable IgG SARS-CoV-2 serum antibodies. Serologically negative patients (31%, 73 of 237) were evenly distributed across patients with myeloid, lymphoid and plasma cell neoplasms. In the multivariable logistic regression, chemoimmunotherapy [odds ratio (OR), 3·42; 95% confidence interval (CI), 1·04-11·21; P = 0·04] was associated with a lower rate of seroconversion. This effect did not decline after 180 days from treatment withdrawal (OR, 0·35; 95% CI: 0·11-1·13; P = 0·08). This study demonstrates a low rate of seroconversion in HM patients and indicates that treatment-mediated immune dysfunction is the main driver. As a consequence, we expect a low rate of seroconversion after vaccination and thus we suggest testing the efficacy of seroconversion in HM patients.
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http://dx.doi.org/10.1111/bjh.17704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444788PMC
November 2021

Automated capture-based NGS workflow: one thousand patients experience in a clinical routine framework.

Diagnosis (Berl) 2021 Jun 16. Epub 2021 Jun 16.

Department of Laboratory Medicine and Pathology, Diagnostic Hematology and Clinical Genomics Unit, Modena University Hospital, Modena, Italy.

Objectives: The Next Generation Sequencing (NGS) based mutational study of hereditary cancer genes is crucial to design tailored prevention strategies in subjects with different hereditary cancer risk. The ease of amplicon-based NGS library construction protocols contrasts with the greater uniformity of enrichment provided by capture-based protocols and so with greater chances for detecting larger genomic rearrangements and copy-number variations. Capture-based protocols, however, are characterized by a higher level of complexity of sample handling, extremely susceptible to human bias. Robotics platforms may definitely help dealing with these limits, reducing hands-on time, limiting random errors and guaranteeing process standardization.

Methods: We implemented the automation of the CE-IVD SOPHiA Hereditary Cancer Solution™ (HCS) libraries preparation workflow by SOPHiA GENETICS on the Hamilton's STARlet platform. We present the comparison of results between this automated approach, used for more than 1,000 DNA patients' samples, and the performances of the manual protocol evaluated by SOPHiA GENETICS onto 240 samples summarized in their HCS evaluation study.

Results: We demonstrate that this automated workflow achieved the same expected goals of manual setup in terms of coverages and reads uniformity, with extremely lower standard deviations among samples considering the sequencing reads mapped onto the regions of interest.

Conclusions: This automated solution offers same reliable and affordable NGS data, but with the essential advantages of a flexible, automated and integrated framework, minimizing possible human errors and depicting a laboratory's walk-away scenario.
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http://dx.doi.org/10.1515/dx-2021-0051DOI Listing
June 2021

Monocyte Distribution Width (MDW) as novel inflammatory marker with prognostic significance in COVID-19 patients.

Sci Rep 2021 06 16;11(1):12716. Epub 2021 Jun 16.

Diagnostic Hematology and Clinical Genomics Laboratory, Department of Laboratory Medicine and Pathology, AUSL/AOU Policlinico, Via del Pozzo 71, 41124, Modena, Italy.

Monocyte Distribution Width (MDW), a new cytometric parameter correlating with cytomorphologic changes occurring upon massive monocyte activation, has recently emerged as promising early biomarker of sepsis. Similar to sepsis, monocyte/macrophage subsets are considered key mediators of the life-threatening hyper-inflammatory disorder characterizing severe COVID-19. In this study, we longitudinally analyzed MDW values in a cohort of 87 COVID-19 patients consecutively admitted to our hospital, showing significant correlations between MDW and common inflammatory markers, namely CRP (p < 0.001), fibrinogen (p < 0.001) and ferritin (p < 0.01). Moreover, high MDW values resulted to be prognostically associated with fatal outcome in COVID-19 patients (AUC = 0.76, 95% CI: 0.66-0.87, sensitivity 0.75, specificity 0.70, MDW threshold 26.4; RR = 4.91, 95% CI: 1.73-13.96; OR = 7.14, 95% CI: 2.06-24.71). This pilot study shows that MDW can be useful in the monitoring of COVID-19 patients, as this innovative hematologic biomarker is: (1) easy to obtain, (2) directly related to the activation state of a fundamental inflammatory cell subset (i.e. monocytes, pivotal in both cytokine storm and sepsis immunopathogenesis), (3) well correlated with clinical severity of COVID-19-associated inflammatory disorder, and, in turn, (4) endowed with relevant prognostic significance. Additional studies are needed to define further the clinical impact of MDW testing in the management of COVID-19 patients.
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http://dx.doi.org/10.1038/s41598-021-92236-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209163PMC
June 2021

Allelic HLA Matching and Pair Origin Are Favorable Prognostic Factors for Unrelated Hematopoietic Stem Cell Transplantation in Neoplastic Hematologic Diseases: An Italian Analysis by the Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti.

Transplant Cell Ther 2021 05 16;27(5):406.e1-406.e11. Epub 2021 Feb 16.

Stem Cell Transplant and Cellular Therapies Unit, Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy.

HLA molecules are important for immunoreactivity in allogeneic hematopoietic stem cell transplantation (HSCT). The Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari, Italian Bone Marrow Donor Registry, and Associazione Italiana di Immunogenetica e Biologia dei Trapianti promoted a retrospective observational study to evaluate HLA matching and the impact of allelic HLA mismatching and non-HLA factors on unrelated Italian HSCT outcomes. From 2012 to 2015, 1788 patients were enrolled in the study. The average donor age was 29 years and the average recipient age was 49 years. As a conditioning regimen, 71% of the patients received myeloablative conditioning. For GVHD prophylaxis, 76% received either antithymocyte or anti-T lymphocyte globulin, cyclosporine A, and methotrexate. Peripheral blood was the stem cell source in 80%. The median duration of follow-up was 53 months. Regarding HLA matching, 50% of donor-recipient pairs were 10/10 matched, 38% had 1 mismatch, and 12% had 2 or more mismatches. A total of 302 pairs shared Italian origin. Four-year overall survival (OS), progression-free survival, GVHD-free relapse-free survival, and relapse rates were 49%, 40%, 22%, and 34%, respectively. The 4-year NRM was 27%, and the 100-day cumulative incidence of grade ≥II acute GVHD (aGVHD) was 26%. In multivariate analysis, 9/10 and ≤8/10 HLA allele-matched pairs were associated with worse OS (P = .04 and .007, respectively), NRM (P = .007 and P < .0001, respectively), and grade III-IV aGVHD (P = .0001 and .01, respectively). Moreover, the incidences of grade II-IV aGVHD (P = .001) and chronic GVHD (P = .002) were significantly lower in Italian pairs. In conclusion, 10/10 HLA matching is a favorable prognostic factor for unrelated HSCT outcome in the Italian population. Moreover, the presence of 2 HLA-mismatched loci was associated with a higher NRM (P < .0001) and grade II-IV aGVHD (P = .006) and a poorer OS (P = .001) compared with 1 HLA-mismatched locus in early or intermediate disease phases. Finally, we found that Italian donor and recipient origin is a favorable prognostic factor for GVHD occurrence.
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http://dx.doi.org/10.1016/j.jtct.2020.11.021DOI Listing
May 2021

Fatigue in newly diagnosed acute myeloid leukaemia: general population comparison and predictive factors.

BMJ Support Palliat Care 2021 May 3. Epub 2021 May 3.

Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

Objectives: This study compared the burden of fatigue between treatment-naïve patients with newly diagnosed acute myeloid leukaemia (AML) and the general population and investigated patient factors associated with fatigue severity.

Methods: Pretreatment patient-reported fatigue was assessed with the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire in a sample of 463 newly diagnosed patients with AML who were enrolled in a clinical trial. Multivariable linear regression models were used to estimate the adjusted mean differences in fatigue between patients with AML and adults from the general population (n=847) by AML disease risk categories. A clinically meaningful difference in fatigue was defined as ≥3 points. Univariable and multivariable linear regression models were used to identify sociodemographic, clinical and molecular correlates of worse fatigue in patients with AML.

Results: Patients with AML reported adjusted mean fatigue scores that were 7.5 points worse than the general population (95% CI -8.6 to -6.4, p<0.001). Across AML disease risk categories, adjusted mean differences in fatigue compared with the general population ranged from 6.7 points worse (patients with favourable risk: 95% CI -8.6 to -4.8, p<0.001) to 8.9 points worse (patients with poor risk, 95% CI -10.5 to -7.2, p<0.001). Overall, 91% of patients with AML reported fatigue that was equal to or worse than the general population's median fatigue score. Higher pretreatment fatigue was independently associated with female sex, WHO performance status ≥1 and lower platelet levels.

Conclusions: Patients with newly diagnosed AML reported worse fatigue than the general population, and mean differences exceeded twice the threshold for clinical significance. Our findings may help to identify patients with AML most likely to benefit from supportive care interventions to reduce fatigue.
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http://dx.doi.org/10.1136/bmjspcare-2020-002312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8563490PMC
May 2021

Education of early palliative care specialists among hematologists and oncologists to address patients' rather than physicians' rights.

Ann Hematol 2021 Nov 10;100(11):2857-2858. Epub 2021 Apr 10.

Oncology and Palliative Care Units, Civil Hospital Carpi, USL, Carpi, Italy.

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http://dx.doi.org/10.1007/s00277-021-04512-0DOI Listing
November 2021

iVar, an Interpretation-Oriented Tool to Manage the Update and Revision of Variant Annotation and Classification.

Genes (Basel) 2021 03 8;12(3). Epub 2021 Mar 8.

Center for Genome Research, University of Modena and Reggio Emilia, 41125 Modena, Italy.

The rapid evolution of Next Generation Sequencing in clinical settings, and the resulting challenge of variant reinterpretation given the constantly updated information, require robust data management systems and organized approaches. In this paper, we present iVar: a freely available and highly customizable tool with a user-friendly web interface. It represents a platform for the unified management of variants identified by different sequencing technologies. iVar accepts variant call format (VCF) files and text annotation files and elaborates them, optimizing data organization and avoiding redundancies. Updated annotations can be periodically re-uploaded and associated with variants as historically tracked attributes, i.e., modifications can be recorded whenever an updated value is imported, thus keeping track of all changes. Data can be visualized through variant-centered and sample-centered interfaces. A customizable search function can be exploited to periodically check if pathogenicity-related data of a variant has changed over time. Patient recontacting ensuing from variant reinterpretation is made easier by iVar through the effective identification of all patients present in the database carrying a specific variant. We tested iVar by uploading 4171 VCF files and 1463 annotation files, obtaining a database of 4166 samples and 22,569 unique variants. iVar has proven to be a useful tool with good performance in terms of collecting and managing data from a medium-throughput laboratory.
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http://dx.doi.org/10.3390/genes12030384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001268PMC
March 2021

Different semantic and affective meaning of the words associated to physical and social pain in cancer patients on early palliative/supportive care and in healthy, pain-free individuals.

PLoS One 2021 31;16(3):e0248755. Epub 2021 Mar 31.

Oncology and Palliative Care Units, Civil Hospital Carpi, USL, Carpi, Italy.

Early palliative/supportive care (ePSC) is a medical intervention focused on patient's needs, that integrates standard oncological treatment, shortly after a diagnosis of advanced/metastatic cancer. ePSC improves the appropriate management of cancer pain. Understanding the semantic and emotional impact of the words used by patients to describe their pain may further improve its assessment in the ePSC setting. Psycholinguistics assumes that the semantic and affective properties of words affect the ease by which they are processed and comprehended. Therefore, in this cross-sectional survey study we collected normative data about the semantic and affective properties of words associated to physical and social pain, in order to investigate how patients with cancer pain on ePSC process them compared to healthy, pain-free individuals. One hundred ninety patients and 124 matched controls rated the Familiarity, Valence, Arousal, Pain-relatedness, Intensity, and Unpleasantness of 94 words expressing physical and social pain. Descriptive and inferential statistics were performed on ratings in order to unveil patients' semantic and affective representation of pain and compare it with those from controls. Possible effects of variables associated to the illness experience were also tested. Both groups perceived the words conveying social pain as more negative and pain-related than those expressing physical pain, confirming previous evidence of social pain described as worse than physical pain. Patients rated pain words as less negative, less pain-related, and conveying a lower intense and unpleasant pain than controls, suggesting either an adaptation to the pain experience or the role played by ePSC in improving patients' ability to cope with it. This exploratory study suggests that a chronic pain experience as the one experienced by cancer patients on ePSC affects the semantic and affective representation of pain words.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248755PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011738PMC
October 2021

Ibrutinib interferes with innate immunity in chronic lymphocytic leukemia patients during COVID-19 infection.

Haematologica 2021 08 1;106(8):2265-2268. Epub 2021 Aug 1.

Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Modena, Italy; Hematology Unit, Department of Oncology and Hematology, A.O.U of Modena, Policlinico, Modena, Italy.

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http://dx.doi.org/10.3324/haematol.2020.277392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327720PMC
August 2021

Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies.

Int J Mol Sci 2021 Feb 14;22(4). Epub 2021 Feb 14.

Department of Laboratory Medicine and Pathology, Diagnostic Hematology and Clinical Genomics, AUSL/AOU Policlinico, 41124 Modena, Italy.

The Philadelphia-negative myeloproliferative neoplasms (MPNs) are malignancies of the hematopoietic stem cell (HSC) arising as a consequence of clonal proliferation driven by somatically acquired driver mutations in discrete genes (JAK2, CALR, MPL). In recent years, along with the advances in molecular characterization, the role of immune dysregulation has been achieving increasing relevance in the pathogenesis and evolution of MPNs. In particular, a growing number of studies have shown that MPNs are often associated with detrimental cytokine milieu, expansion of the monocyte/macrophage compartment and myeloid-derived suppressor cells, as well as altered functions of T cells, dendritic cells and NK cells. Moreover, akin to solid tumors and other hematological malignancies, MPNs are able to evade T cell immune surveillance by engaging the PD-1/PD-L1 axis, whose pharmacological blockade with checkpoint inhibitors can successfully restore effective antitumor responses. A further interesting cue is provided by the recent discovery of the high immunogenic potential of JAK2V617F and CALR exon 9 mutations, that could be harnessed as intriguing targets for innovative adoptive immunotherapies. This review focuses on the recent insights in the immunological dysfunctions contributing to the pathogenesis of MPNs and outlines the potential impact of related immunotherapeutic approaches.
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http://dx.doi.org/10.3390/ijms22041906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918142PMC
February 2021

IRF4 modulates the response to BCR activation in chronic lymphocytic leukemia regulating IKAROS and SYK.

Leukemia 2021 05 23;35(5):1330-1343. Epub 2021 Feb 23.

Hematology Unit, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Interferon regulatory factor 4 (IRF4) is a transcriptional regulator of immune system development and function. Here, we investigated the role of IRF4 in controlling responsiveness to B-cell receptor (BCR) stimulation in chronic lymphocytic leukemia (CLL). We modulated IRF4 levels by transfecting CLL cells with an IRF4 vector or by silencing using small-interfering RNAs. Higher IRF4 levels attenuated BCR signaling by reducing AKT and ERK phosphorylation and calcium release. Conversely, IRF4 reduction improved the strength of the intracellular cascade activated by BCR engagement. Our results also indicated that IRF4 negatively regulates the expression of the spleen tyrosine kinase SYK, a crucial protein for propagation of BCR signaling, and the zinc finger DNA-binding protein IKAROS. We modulated IKAROS protein levels both by genetic manipulation and pharmacologically by treating CLL cells with lenalidomide and avadomide (IMIDs). IKAROS promoted BCR signaling by reducing the expression of inositol 5-phosphatase SHIP1. Lastly, IMIDs induced IRF4 expression, while down-regulating IKAROS and interfered with survival advantage mediated by BCR triggering, also in combination with ibrutinib. Overall, our findings elucidate the mechanism by which IRF4 tunes BCR signaling in CLL cells. Low IRF4 levels allow an efficient transmission of BCR signal throughout the accumulation of SYK and IKAROS.
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http://dx.doi.org/10.1038/s41375-021-01178-5DOI Listing
May 2021

Cytomegalovirus reactivation after hematopoietic stem cell transplant with CMV-IG prophylaxis: A monocentric retrospective analysis.

J Med Virol 2021 11 19;93(11):6292-6300. Epub 2021 Feb 19.

Section of Hematology, Department of Medical and Surgical Sciences, Azienda Ospedaliero-Universitaria di Modena, University of Modena and Reggio Emilia, Modena, Italy.

Human cytomegalovirus (CMV) represents the most common viral infection after hematopoietic stem cell transplant (HSCT), mainly occurring as reactivation from latency in seropositive patients, with a different prevalence based on the extent and timing of seroconversion in a specific population. Here, we retrospectively analyzed a cohort of patients who underwent HSCT at our Institution between 2013 and 2018, all of whom were prophylactically treated with CMV-IG (Megalotect Biotest®), to define the incidence and clinical outcomes of CMV reactivation and clinically significant infection. CMV infection occurred in 69% of our patient series, mainly resulting from reactivation, and CMV clinically significant infection (CS-CMVi) occurred in 48% of prophylactically treated patients. CMV infection and CS-CMVi impacted neither on relapse incidence nor on overall survival nor on relapse-free survival. Moreover, a very low incidence of CMV end-organ disease was documented. CMV-IG used alone as prophylactic therapy after HSCT does not effectively prevent CMV reactivation.
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http://dx.doi.org/10.1002/jmv.26861DOI Listing
November 2021

MATRix-RICE therapy and autologous haematopoietic stem-cell transplantation in diffuse large B-cell lymphoma with secondary CNS involvement (MARIETTA): an international, single-arm, phase 2 trial.

Lancet Haematol 2021 Feb;8(2):e110-e121

Università Degli Studi di Perugia-AO Santa Maria, Terni, Italy.

Background: Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma.

Methods: This international, single-arm, phase 2 trial was done in 24 hospitals in Italy, the UK, the Netherlands, and Switzerland. Adults (aged 18-70 years) with histologically diagnosed diffuse large B-cell lymphoma and CNS involvement at the time of primary diagnosis or at relapse and Eastern Cooperative Oncology Group Performance Status of 3 or less were enrolled and received three courses of MATRix (rituximab 375 mg/m, intravenous infusion, day 0; methotrexate 3·5 g/m, the first 0·5 g/m in 15 min followed by 3 g/m in a 3 h intravenous infusion, day 1; cytarabine 2 g/m every 12 h, in 1 h intravenous infusions, days 2 and 3; thiotepa 30 mg/m, 30 min intravenous infusion, day 4) followed by three courses of RICE (rituximab 375 mg/m, day 1; etoposide 100 mg/m per day in 500-1000 mL over a 60 min intravenous infusion, days 1, 2, and 3; ifosfamide 5 g/m in 1000 mL in a 24 h intravenous infusion with mesna support, day 2; carboplatin area under the curve of 5 in 500 mL in a 1 h intravenous infusion, day 2) and carmustine-thiotepa and autologous HSCT (carmustine 400 mg/m in 500 mL glucose 5% solution in a 1-2 h infusion, day -6; thiotepa 5 mg/kg in saline solution in a 2 h infusion every 12 h, days -5 and -4). The primary endpoint was progression-free survival at 1 year. Overall and complete response rates before autologous HSCT, duration of response, overall survival, and safety were the secondary endpoints. Analyses were in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02329080. The trial ended after accrual completion; the database lock was Dec 31, 2019.

Findings: Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. 75 patients were assessable. 319 (71%) of the 450 planned courses were delivered. At 1 year from enrolment the primary endpoint was met, 42 patients were progression free (progression-free survival 58%; 95% CI 55-61). 49 patients (65%; 95% CI 54-76) had an objective response after MATRix-RICE, 29 (39%) of whom had a complete response. 37 patients who responded had autologous HSCT. At the end of the programme, 46 patients (61%; 95% CI 51-71) had an objective response, with a median duration of objective response of 26 months (IQR 16-37). At a median follow-up of 29 months (IQR 20-40), 35 patients were progression-free and 33 were alive, with a 2-year overall survival of 46% (95% CI 39-53). Grade 3-4 toxicity was most commonly haematological: neutropenia in 46 (61%) of 75 patients, thrombocytopenia in 45 (60%), and anaemia in 26 (35%). 79 serious adverse events were recorded in 42 (56%) patients; four (5%) of those 79 were lethal due to sepsis caused by Gram-negative bacteria (treatment-related mortality 5%; 95% CI 0·07-9·93).

Interpretation: MATRix-RICE plus autologous HSCT was active in this population of patients with very poor prognosis, and had an acceptable toxicity profile.

Funding: Stand Up To Cancer Campaign for Cancer Research UK, the Swiss Cancer Research foundation, and the Swiss Cancer League.
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http://dx.doi.org/10.1016/S2352-3026(20)30366-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844712PMC
February 2021

Nurse-Like Cells and Chronic Lymphocytic Leukemia B Cells: A Mutualistic Crosstalk inside Tissue Microenvironments.

Cells 2021 01 22;10(2). Epub 2021 Jan 22.

Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, 41124 Modena, Italy.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries and is an example of hematological disease where cooperation between genetic defects and tumor microenvironmental interaction is involved in pathogenesis. CLL is a disease that is considered as "addicted to the host"; indeed, the crosstalk between leukemic cells and the tumor microenvironment is essential for leukemic clone maintenance supporting CLL cells' survival, proliferation, and protection from drug-induced apoptosis. CLL cells are not innocent bystanders but actively model and manipulate the surrounding microenvironment to their own advantage. Besides the different players involved in this crosstalk, nurse-like cells (NLC) resemble features related to leukemia-associated macrophages with an important function in preserving CLL cell survival and supporting an immunosuppressive microenvironment. This review provides a comprehensive overview of the role played by NLC in creating a nurturing and permissive milieu for CLL cells, illustrating the therapeutic possibilities in order to specifically target and re-educate them.
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http://dx.doi.org/10.3390/cells10020217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911538PMC
January 2021
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