Publications by authors named "A Alberto Bosi"

360 Publications

Acute severe asthma: management and treatment.

Minerva Med 2021 Feb 26. Epub 2021 Feb 26.

Respiratory Diseases Unit, University Hospital of Modena, Modena, Italy -

Patients with acute asthma attack usually access the emergency room with severe functional impairment, despite low perception of symptoms. In this scenario, early functional assessment is essential focusing on vital parameters and respiratory function, alongside perceived dyspnea. Impairment of ventilatory mechanics due to progressive dynamic pulmonary hyperinflation should be promptly treated with medical inhalation and/or intravenous therapy, reserving intensive treatment in case of non-response and/or worsening of the clinical conditions. Therapeutic planning at patient's discharge is no less important than treatment management during emergency room access as educating the patient about therapeutic adherence significantly impact long-term outcomes of asthma. With this review we aim at exploring current evidence on acute asthma attack management, focusing of pharmacological and ventilatory strategies of care and highlighting the importance of patient education once clinical stability allows discharge from the emergency department.
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http://dx.doi.org/10.23736/S0026-4806.21.07372-9DOI Listing
February 2021

Prostate Cancer Peripheral Blood NK Cells Show Enhanced CD9, CD49a, CXCR4, CXCL8, MMP-9 Production and Secrete Monocyte-Recruiting and Polarizing Factors.

Front Immunol 2020 25;11:586126. Epub 2021 Jan 25.

Unit of Immunology, IRCCS MultiMedica, Milan, Italy.

Natural killer (NK) cells, effector lymphocytes of the innate immunity, have been shown to be altered in several cancers, both at tissue and peripheral levels. We have shown that in Non-Small Cell Lung Cancer (NSCLC) and colon cancer, tumour associated circulating NK (TA-NK) and tumour infiltrating NK (TI-NK) exhibit pro-angiogenic phenotype/functions. However, there is still a lack of knowledge concerning the phenotype of peripheral blood (PB) NK (pNK) cells in prostate cancer (PCa). Here, we phenotypically and functionally characterized pNK from PCa patients (PCa TA-NKs) and investigated their interactions with endothelial cells and monocytes/macrophages. NK cell subset distribution in PB of PCa patients was investigated, by multicolor flow cytometry, for surface antigens expression. Protein arrays were performed to characterize the secretome on FACS-sorted pNK cells. Conditioned media (CM) from FACS-sorted PCa pTA-NKs were used to determine their ability to induce pro-inflammatory/pro-angiogenic phenotype/functions in endothelial cells, monocytes, and macrophages. CM from three different PCa (PC-3, DU-145, LNCaP) cell lines, were used to assess their effects on human NK cell polarization , by multicolor flow cytometry. We found that PCa pTA-NKs acquire the CD56CD9CD49aCXCR4 phenotype, increased the expression of markers of exhaustion (PD-1, TIM-3) and are impaired in their degranulation capabilities. Similar effects were observed on healthy donor-derived pNK cells, exposed to conditioned media of three different PCa cell lines, together with increased production of pro-inflammatory chemokines/chemokine receptors CXCR4, CXCL8, CXCL12, reduced production of TNFα, IFNγ and Granzyme-B. PCa TA-NKs released factors able to support inflammatory angiogenesis in an model and increased the expression of CXCL8, ICAM-1, and VCAM-1 mRNA in endothelial cells. Secretome analysis revealed the ability of PCa TA-NKs to release pro-inflammatory cytokines/chemokines involved in monocyte recruitment and M2-like polarization. Finally, CMs from PCa pTA-NKs recruit THP-1 and peripheral blood CD14 monocyte and polarize THP-1 and peripheral blood CD14 monocyte-derived macrophage towards M2-like/TAM macrophages. Our results show that PCa pTA-NKs acquire properties related to the pro-inflammatory angiogenesis in endothelial cells, recruit monocytes and polarize macrophage to an M2-like type phenotype. Our data provides a rationale for a potential use of pNK profiling in PCa patients.
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http://dx.doi.org/10.3389/fimmu.2020.586126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868409PMC
January 2021

Impact of Microbial Metabolites on Microbiota-Gut-Brain Axis in Inflammatory Bowel Disease.

Int J Mol Sci 2021 Feb 5;22(4). Epub 2021 Feb 5.

Department of Medicine and Surgery, University of Insubria, via H Dunant 5, 21100 Varese, Italy.

The complex bidirectional communication system existing between the gastrointestinal tract and the brain initially termed the "gut-brain axis" and renamed the "microbiota-gut-brain axis", considering the pivotal role of gut microbiota in sustaining local and systemic homeostasis, has a fundamental role in the pathogenesis of Inflammatory Bowel Disease (IBD). The integration of signals deriving from the host neuronal, immune, and endocrine systems with signals deriving from the microbiota may influence the development of the local inflammatory injury and impacts also more distal brain regions, underlying the psychophysiological vulnerability of IBD patients. Mood disorders and increased response to stress are frequently associated with IBD and may affect the disease recurrence and severity, thus requiring an appropriate therapeutic approach in addition to conventional anti-inflammatory treatments. This review highlights the more recent evidence suggesting that alterations of the microbiota-gut-brain bidirectional communication axis may concur to IBD pathogenesis and sustain the development of both local and CNS symptoms. The participation of the main microbial-derived metabolites, also defined as "postbiotics", such as bile acids, short-chain fatty acids, and tryptophan metabolites in the development of IBD-associated gut and brain dysfunction will be discussed. The last section covers a critical evaluation of the main clinical evidence pointing to the microbiome-based therapeutic approaches for the treatment of IBD-related gastrointestinal and neuropsychiatric symptoms.
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http://dx.doi.org/10.3390/ijms22041623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915037PMC
February 2021

One-year outcomes from a phase 3 randomized trial of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria who received prior eculizumab.

Eur J Haematol 2021 Mar 3;106(3):389-397. Epub 2021 Jan 3.

Bone Marrow Transplantation Unit, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.

Ravulizumab every 8 weeks showed non-inferiority to eculizumab every 2 weeks in a 26-week, phase 3, randomized controlled trial in adults with paroxysmal nocturnal hemoglobinuria (PNH) who were clinically stable on eculizumab (NCT03056040). We report results from the first 26 weeks of the extension period in which patients continued ravulizumab (n = 96) or switched from eculizumab to ravulizumab (n = 95). At week 52, mean (SD) lactate dehydrogenase levels increased 8.8% (29%) with ravulizumab-ravulizumab and 5.8% (27%) with eculizumab-ravulizumab from primary evaluation period baseline. During the extension period, four patients (ravulizumab-ravulizumab, n = 3; eculizumab-ravulizumab, n = 1) experienced breakthrough hemolysis, but none associated with serum free C5 ≥ 0.5 μg/mL. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores remained stable through week 52. During the extension period, proportions of patients avoiding transfusion remained stable (ravulizumab-ravulizumab, 86.5%; eculizumab-ravulizumab, 83.2%); 81.2% and 81.1%, respectively, had stabilized hemoglobin. All patients maintained serum free C5 levels < 0.5 μg/mL. Adverse events were generally similar between groups, and rates were lower in the extension period. Adults with PNH on stable eculizumab therapy who received ravulizumab over 52 weeks experienced durable efficacy, with consistent efficacy in patients who received eculizumab during the primary evaluation period and then switched to ravulizumab. Ravulizumab was well tolerated.
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http://dx.doi.org/10.1111/ejh.13564DOI Listing
March 2021

Multilineage Dysplasia as Assessed by Immunophenotype in Acute Myeloid Leukemia: A Prognostic Tool in a Genetically Undefined Category.

Cancers (Basel) 2020 Oct 30;12(11). Epub 2020 Oct 30.

Struttura Operativa Dipartimentale Ematologia, Azienda Ospedaliero-Universitaria Careggi, 50134 Firenze, Italy.

Acute myeloid leukemia (AML) "with myelodysplasia-related changes (MRC)" is considered a separate entity by the World Health Organization (WHO) classification of myeloid neoplasms. While anamnestic and cytogenetic criteria provide objective attribution to this subset, with clear unfavorable prognostic significance, the actual role of multi-lineage dysplasia (MLD) as assessed by morphology is debated. The aim of our work was to study MLD by a technique alternative to morphology, which is multiparameter flow cytometry (MFC), in a large series of 302 AML patients intensively treated at our Center. The correlation with morphology we observed in the unselected analysis reiterated the capability of the MFC-based approach at highlighting dysplasia. MLD data, estimated through an immune-phenotypic score (IPS), provided no insight into prognosis when considered overall nor within well-defined genetic categories. Of interest, IPS-related dysplasia conveyed significant prognostic information when we focused on genetically undefined patients, triple-negative for , and (TN-AML). In this context, the lack of dysplastic features (IPS_0) correlated with a significantly higher CR rate and longer survival compared to patients showing dysplasia in one or both (neutrophil and erythroid) cell lineages. The impact of IPS category maintained its validity after censoring at allogeneic HSCT and in a multivariate analysis including baseline and treatment-related covariates. In a subgroup featured by the lack of genetic determinants, our data could help address the relative unmet needs in terms of risk assessment and treatment strategy, and provide insight into prediction of response in the rapidly evolving therapeutic scenario of AML.
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http://dx.doi.org/10.3390/cancers12113196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693580PMC
October 2020

Innate Immunity Effector Cells as Inflammatory Drivers of Cardiac Fibrosis.

Int J Mol Sci 2020 Sep 28;21(19). Epub 2020 Sep 28.

Unit of Immunology, IRCCS MultiMedica, 20138 Milan, Italy.

Despite relevant advances made in therapies for cardiovascular diseases (CVDs), they still represent the first cause of death worldwide. Cardiac fibrosis and excessive extracellular matrix (ECM) remodeling are common end-organ features in diseased hearts, leading to tissue stiffness, impaired myocardial functional, and progression to heart failure. Although fibrosis has been largely recognized to accompany and complicate various CVDs, events and mechanisms driving and governing fibrosis are still not entirely elucidated, and clinical interventions targeting cardiac fibrosis are not yet available. Immune cell types, both from innate and adaptive immunity, are involved not just in the classical response to pathogens, but they take an active part in "sterile" inflammation, in response to ischemia and other forms of injury. In this context, different cell types infiltrate the injured heart and release distinct pro-inflammatory cytokines that initiate the fibrotic response by triggering myofibroblast activation. The complex interplay between immune cells, fibroblasts, and other non-immune/host-derived cells is now considered as the major driving force of cardiac fibrosis. Here, we review and discuss the contribution of inflammatory cells of innate immunity, including neutrophils, macrophages, natural killer cells, eosinophils and mast cells, in modulating the myocardial microenvironment, by orchestrating the fibrogenic process in response to tissue injury. A better understanding of the time frame, sequences of events during immune cells infiltration, and their action in the injured inflammatory heart environment, may provide a rationale to design new and more efficacious therapeutic interventions to reduce cardiac fibrosis.
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http://dx.doi.org/10.3390/ijms21197165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583949PMC
September 2020

Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk.

J Hematol Oncol 2020 08 20;13(1):115. Epub 2020 Aug 20.

University Hospital of Salamanca/IBSAL/Cancer Research Center-IBMCC (USAL-CSIC), Salamanca, Spain.

Background: Multiple myeloma (MM) patients with high cytogenetic risk have poor outcomes. In CASTOR, daratumumab plus bortezomib/dexamethasone (D-Vd) prolonged progression-free survival (PFS) versus bortezomib/dexamethasone (Vd) alone and exhibited tolerability in patients with relapsed or refractory MM (RRMM).

Methods: This subgroup analysis evaluated D-Vd versus Vd in CASTOR based on cytogenetic risk, determined using fluorescence in situ hybridization and/or karyotype testing performed locally. High-risk patients had t(4;14), t(14;16), and/or del17p abnormalities. Minimal residual disease (MRD; 10 sensitivity threshold) was assessed via the clonoSEQ® assay V2.0. Of the 498 patients randomized, 40 (16%) in the D-Vd group and 35 (14%) in the Vd group were categorized as high risk.

Results: After a median follow-up of 40.0 months, D-Vd prolonged median PFS versus Vd in patients with standard (16.6 vs 6.6 months; HR, 0.26; 95% CI, 0.19-0.37; P < 0.0001) and high (12.6 vs 6.2 months; HR, 0.41; 95% CI, 0.21-0.83; P = 0.0106) cytogenetic risk. D-Vd achieved deep responses, including higher rates of MRD negativity and sustained MRD negativity versus Vd, regardless of cytogenetic risk. The safety profile was consistent with the overall population of CASTOR.

Conclusion: These updated data reinforce the effectiveness and tolerability of daratumumab-based regimens for RRMM, regardless of cytogenetic risk status.

Trial Registration: ClinicalTrials.gov, NCT02136134 . Registered 12 May 2014.
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http://dx.doi.org/10.1186/s13045-020-00948-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439722PMC
August 2020

Treatment and prognosis of primary pulmonary lymphoma: A long-term follow-up study.

Eur J Haematol 2021 Jan 2;106(1):49-57. Epub 2020 Nov 2.

Haematology and Haematopoietic Stem Cells Transplant Unit, AO San Camillo-Forlanini, Rome, Italy.

Primary pulmonary lymphoma (PPL) is a rare disease with not well-defined optimal treatment. Outcomes and follow-up are variable in published data.

Objectives: To define the outcome and optimal treatment strategies in PPL.

Methods: We reviewed the medical records of 49 patients with PPL treated in three Italian Hematological Institutions between 2002 and 2018.

Results: Thirty-eight (77.5%) cases were indolent PPL, and 11 (22.5%) cases were aggressive PPL. The majority of patients were asymptomatic at diagnosis, early stages (stages IE-IIE), normal serum LDH, no bone marrow involvement, and low or low-intermediate risks of IPI. Local therapy ± immunotherapy or immuno-chemotherapy was possible in 18/49 (37%) patients. Twenty-eight (57%) patients were treated with immuno-chemotherapy after biopsy. Waiting and watching were reported in 3 (6%) patients. Overall, the CR and ORR were 83.7% and 95.9%. With a median follow-up of 62.5 months (range 0.8-199 months), the estimated 5- and 10-year OS rates were 85% and 72.3% for all patients, 89.2% and 80.3% for indolent PPL, and 70.7% and 47.1% for aggressive PPL. Aggressive PPL tended to have a high risk of progression in the first months (P = .056). No advantages were found for indolent PPL who received immuno-chemotherapy or more conservative approaches.

Conclusion: Our studies confirm the epidemiological and favorable survival of patients with PPL, suggesting a very conservative approach, particularly in indolent subtypes.
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http://dx.doi.org/10.1111/ejh.13507DOI Listing
January 2021

Early peripheral blast cell clearance predicts minimal residual disease status and refines disease prognosis in acute myeloid leukemia.

Am J Hematol 2020 11 19;95(11):1304-1313. Epub 2020 Aug 19.

SOD Ematologia, Università di Firenze, AOU Careggi, Florence, Italy.

Minimal residual disease (MRD) assessment in acute myeloid leukemia (AML) is increasingly used in risk stratification. However, several issues around this use are unresolved, including, among others, the most suitable time-point(s) for its application. Overall, late assessments appear more effective at distinguishing outcome but, in some studies, the early evaluations were already highly informative, anticipating the value of later ones. Our work integrated MRD with peripheral blast clearance (PBC), a treatment-related biomarker previously demonstrated to be a powerful predictor of response. From 2007 to 2014, we have studied 120 patients treated according to the NILG 02-06 trial and who achieved CR after induction. Patients in PBC-defined categories (separated by a 1.5-log threshold) showed significantly different probabilities of attaining MRD negativity, after either induction (MRD1) or consolidation (MRD2). Peripheral blast clearance combined with MRD1 largely anticipated MRD2-related information: when both biomarkers predicted chemosensitive disease (PBC /MRD1 ), the rate of MRD2-negativity was 90%, and DFS and OS estimates were 68% and 76% at 3 years, respectively. When both markers were unfavorable (PBC /MRD1 ), rates of MRD2 negativity, DFS, and OS were 20%, 34%, and 24%, respectively, at 3 years. In fact, MRD2 added prognostic value only in cases with discordant PBC/MRD1 data. Our data support a reasoned timing for MRD-based therapeutic decisions, modulated on individual chemosensitivity, an approach we have implemented in a forthcoming prospective multi-center trial by Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA).
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http://dx.doi.org/10.1002/ajh.25942DOI Listing
November 2020

Involvement of hyaluronan in the adaptive changes of the rat small intestine neuromuscular function after ischemia/reperfusion injury.

Sci Rep 2020 07 13;10(1):11521. Epub 2020 Jul 13.

Department of Medicine and Surgery, University of Insubria, via H. Dunant 5, Varese, Italy.

Intestinal ischemia/reperfusion (I/R) injury has severe consequences on myenteric neurons, which can be irreversibly compromised resulting in slowing of transit and hindered food digestion. Myenteric neurons synthesize hyaluronan (HA) to form a well-structured perineuronal net, which undergoes derangement when myenteric ganglia homeostasis is perturbed, i.e. during inflammation. In this study we evaluated HA involvement in rat small intestine myenteric plexus after in vivo I/R injury induced by clamping a branch of the superior mesenteric artery for 60 min, followed by 24 h of reperfusion. In some experiments, 4-methylumbelliferone (4-MU, 25 mg/kg), a HA synthesis inhibitor, was intraperitoneally administered to normal (CTR), sham-operated (SH) and I/R animals for 24 h. In longitudinal muscle myenteric plexus (LMMP) whole-mount preparations, HA binding protein staining as well as HA levels were significantly higher in the I/R group, and were reduced after 4-MU treatment. HA synthase 1 and 2 (HAS1 and HAS2) labelled myenteric neurons and mRNA levels in LMMPs increased in the I/R group with respect to CTR, and were reduced by 4-MU. The efficiency of the gastrointestinal transit was significantly reduced in I/R and 4-MU-treated I/R groups with respect to CTR and SH groups. In the 4-MU-treated I/R group gastric emptying was reduced with respect to the CTR, SH and I/R groups. Carbachol (CCh) and electrical field (EFS, 0.1-40 Hz) stimulated contractions and EFS-induced (10 Hz) NANC relaxations were reduced in the I/R group with respect to both CTR and SH groups. After I/R, 4-MU treatment increased EFS contractions towards control values, but did not affect CCh-induced contractions. NANC on-relaxations after I/R were not influenced by 4-MU treatment. Main alterations in the neurochemical coding of both excitatory (tachykinergic) and inhibitory pathways (iNOS, VIPergic) were also observed after I/R, and were influenced by 4-MU administration. Overall, our data suggest that, after an intestinal I/R damage, changes of HA homeostasis in specific myenteric neuron populations may influence the efficiency of the gastrointestinal transit. We cannot exclude that modulation of HA synthesis in these conditions may ameliorate derangement of the enteric motor function preventing, at least in part, the development of dysmotility.
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http://dx.doi.org/10.1038/s41598-020-67876-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359366PMC
July 2020

Tryptophan Metabolites Along the Microbiota-Gut-Brain Axis: An Interkingdom Communication System Influencing the Gut in Health and Disease.

Int J Tryptophan Res 2020 11;13:1178646920928984. Epub 2020 Jun 11.

Department of Medicine and Surgery, University of Insubria, Varese, Italy.

The 'microbiota-gut-brain axis' plays a fundamental role in maintaining host homeostasis, and different immune, hormonal, and neuronal signals participate to this interkingdom communication system between eukaryota and prokaryota. The essential aminoacid tryptophan, as a precursor of several molecules acting at the interface between the host and the microbiota, is fundamental in the modulation of this bidirectional communication axis. In the gut, tryptophan undergoes 3 major metabolic pathways, the 5-HT, kynurenine, and AhR ligand pathways, which may be directly or indirectly controlled by the saprophytic flora. The importance of tryptophan metabolites in the modulation of the gastrointestinal tract is suggested by several preclinical and clinical studies; however, a thorough revision of the available literature has not been accomplished yet. Thus, this review attempts to cover the major aspects on the role of tryptophan metabolites in host-microbiota cross-talk underlaying regulation of gut functions in health conditions and during disease states, with particular attention to 2 major gastrointestinal diseases, such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), both characterized by psychiatric disorders. Research in this area opens the possibility to target tryptophan metabolism to ameliorate the knowledge on the pathogenesis of both diseases, as well as to discover new therapeutic strategies based either on conventional pharmacological approaches or on the use of pre- and probiotics to manipulate the microbial flora.
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http://dx.doi.org/10.1177/1178646920928984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290275PMC
June 2020

Aggressive Disease Course of Multiple Myeloma with Concomitant ALK-Negative Anaplastic Large Cell Lymphoma: A Case Report with an Unusual Presentation.

Case Rep Hematol 2020 16;2020:6309736. Epub 2020 Jan 16.

Haematology Unit, Careggi University Hospital, Florence, Italy.

ALK-negative anaplastic large cell lymphoma is a rare T-cell neoplasm with an aggressive course requiring prompt diagnostic work-up and treatment. Few cases of concomitant multiple myeloma and T-cell neoplasm are described in the literature, mainly regarding primary cutaneous anaplastic large cell lymphoma. We present the case of a 65-year-old man, simultaneously diagnosed with ALK-negative anaplastic large cell lymphoma with extranodal localization in the gastrocnemius muscle (stage 1AE) and IgG lambda multiple myeloma (ISS 2, Durie-Salmon stage 3A). Both diseases required therapeutic intervention due to the high proliferative index of lymphoma and the presence of bone lesions attributable to myeloma. The therapeutic program initially included chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone; CHOEP), radiotherapy on the leg, bortezomib, and then consolidation with autologous hematopoietic stem cell transplantation. Despite being on bortezomib treatment and waiting for transplantation, the patient experienced an early myeloma progression that turned out to be refractory to second-line lenalidomide-based treatment. To our knowledge, this is the first case of concurrent diagnosis of extranodal ALK-negative anaplastic large cell lymphoma of the muscle and multiple myeloma. Simultaneous onset can be challenging for clinicians as both diseases may have an aggressive course requiring multiple treatments with increased risk of toxicity and complicated management.
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http://dx.doi.org/10.1155/2020/6309736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201522PMC
January 2020

The Ovarian Cancer Tumor Immune Microenvironment (TIME) as Target for Therapy: A Focus on Innate Immunity Cells as Therapeutic Effectors.

Int J Mol Sci 2020 Apr 28;21(9). Epub 2020 Apr 28.

Immunology and General Pathology Laboratory, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy.

Ovarian cancer (OvCA) accounts for one of the leading causes of death from gynecologic malignancy. Despite progress in therapy improvements in OvCA, most patients develop a recurrence after first-line treatments, dependent on the tumor and non-tumor complexity/heterogeneity of the neoplasm and its surrounding tumor microenvironment (TME). The TME has gained greater attention in the design of specific therapies within the new era of immunotherapy. It is now clear that the immune contexture in OvCA, here referred as tumor immune microenvironment (TIME), acts as a crucial orchestrator of OvCA progression, thus representing a necessary target for combined therapies. Currently, several advancements of antitumor immune responses in OvCA are based on the characterization of tumor-infiltrating lymphocytes, which have been shown to correlate with a significantly improved clinical outcome. Here, we reviewed the literature on selected TIME components of OvCA, such as macrophages, neutrophils, γδ T lymphocytes, and natural killer (NK) cells; these cells can have a role in either supporting or limiting OvCA, depending on the TIME stimuli. We also reviewed and discussed the major (immune)-therapeutic approaches currently employed to target and/or potentiate macrophages, neutrophils, γδ T lymphocytes, and NK cells in the OvCA context.
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http://dx.doi.org/10.3390/ijms21093125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247443PMC
April 2020

Homeoprotein OTX1 and OTX2 involvement in rat myenteric neuron adaptation after DNBS-induced colitis.

PeerJ 2020 13;8:e8442. Epub 2020 Feb 13.

Department of Medicine and Surgery, University of Insubria, Varese, Italy.

Background: Inflammatory bowel diseases are associated with remodeling of neuronal circuitries within the enteric nervous system, occurring also at sites distant from the acute site of inflammation and underlying disturbed intestinal functions. Homeoproteins orthodenticle OTX1 and OTX2 are neuronal transcription factors participating to adaptation during inflammation and underlying tumor growth both in the central nervous system and in the periphery. In this study, we evaluated OTX1 and OTX2 expression in the rat small intestine and distal colon myenteric plexus after intrarectal dinitro-benzene sulfonic (DNBS) acid-induced colitis.

Methods: OTX1 and OTX2 distribution was immunohistochemically investigated in longitudinal muscle myenteric plexus (LMMP)-whole mount preparations. mRNAs and protein levels of both OTX1 and OTX2 were evaluated by qRT-PCR and Western blotting in LMMPs.

Results: DNBS-treatment induced major gross morphology and histological alterations in the distal colon, while the number of myenteric neurons was significantly reduced both in the small intestine and colon. mRNA levels of the inflammatory markers, TNFα, pro-IL1β, IL6, HIF1α and VEGFα and myeloperoxidase activity raised in both regions. In both small intestine and colon, an anti-OTX1 antibody labeled a small percentage of myenteric neurons, and prevalently enteric glial cells, as evidenced by co-staining with the glial marker S100β. OTX2 immunoreactivity was present only in myenteric neurons and was highly co-localized with neuronal nitric oxide synthase. Both in the small intestine and distal colon, the number of OTX1- and OTX2-immunoreactive myenteric neurons significantly increased after DNBS treatment. In these conditions, OTX1 immunostaining was highly superimposable with inducible nitric oxide synthase in both regions. OTX1 and OTX2 mRNA and protein levels significantly enhanced in LMMP preparations of both regions after DNBS treatment.

Conclusions: These data suggest that colitis up-regulates OTX1 and OTX2 in myenteric plexus both on site and distantly from the injury, potentially participating to inflammatory-related myenteric ganglia remodeling processes involving nitrergic transmission.
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http://dx.doi.org/10.7717/peerj.8442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024580PMC
February 2020

Extramedullary blastic transformation of primary myelofibrosis in the form of disseminated myeloid sarcoma: a case report and review of the literature.

Clin Exp Med 2020 May 17;20(2):313-320. Epub 2020 Feb 17.

CRIMM, Center of Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliero-Universitaria Careggi, 50134, Florence, Italy.

Splenomegaly is a key clinical manifestation of myelofibrosis, and splenectomy is currently indicated in patients with drug refractory, symptomatic splenomegaly or with the aim of improving refractory cytopenias. Transformation to acute myeloid leukemia occurs in up to 20% of patients with myelofibrosis, while cases of myeloid sarcoma have been reported very unfrequently. In this manuscript, we report the case of a 60-year-old man with a history of primary myelofibrosis who underwent splenectomy because of drug-refractory massive splenomegaly, systemic symptoms and anemia. At the opening of the peritoneal cavity, the spleen resulted massively enlarged and tenaciously entrapped by a pervasive neoplastic-like tissue. The extensive involvement of the abdomen fatally complicated the surgical procedure. At postmortem examination, the spleen showed a diffuse infiltration of immature cells that were also found in the peritoneum, bowel, liver, lungs and myocardium. After immunohistochemical, cytogenetic, flow cytometric and molecular characterization of neoplastic population, a diagnosis of disseminated myeloid sarcoma of the spleen was made. This case report highlights a very unusual case of myeloid sarcoma originating from the spleen in a patient with myelofibrosis who had no evidence of bone marrow or peripheral blood involvement by leukemic cells. Molecular characterization showed that leukemic cells originated from the founding clone of the chronic phase. The sarcoma could not be suspected based on clinical findings and was diagnosed only at the time of surgical procedure and autopsy. This case suggests that leukemic transformation of myelofibrosis can originate outside the bone marrow and, presumably rarely, present as a granulocytic sarcoma.
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http://dx.doi.org/10.1007/s10238-020-00616-5DOI Listing
May 2020

Early peripheral clearance of leukemia-associated immunophenotypes in AML: centralized analysis of a randomized trial.

Blood Adv 2020 01;4(2):301-311

Unità Operativa di Ematologia, Ospedale dell'Angelo, Mestre-Venezia, Italy.

Although genetics is a relevant risk factor in acute myeloid leukemia (AML), it can be minimally informative and/or not readily available for the early identification of patients at risk for treatment failure. In a randomized trial comparing standard vs high-dose induction (ClinicalTrials.gov #NCT00495287), we studied early peripheral blast cell clearance (PBC) as a rapid predictive assay of chemotherapy response to determine whether it correlates with the achievement of complete remission (CR), as well as postremission outcome, according to induction intensity. Individual leukemia-associated immunophenotypes (LAIPs) identified pretherapy by flow cytometry were validated and quantified centrally after 3 days of treatment, expressing PBC on a logarithmic scale as the ratio of absolute LAIP+ cells on day 1 and day 4. Of 178 patients, 151 (84.8%) were evaluable. Patients in CR exhibited significantly higher median PBC (2.3 log) compared with chemoresistant patients (1.0 log; P < .0001). PBC < 1.0 predicted the worst outcome (CR, 28%). With 1.5 log established as the most accurate cutoff predicting CR, 87.5% of patients with PBC >1.5 (PBChigh, n = 96) and 43.6% of patients with PBC ≤1.5 (PBClow, n = 55) achieved CR after single-course induction (P < .0001). CR and PBChigh rates were increased in patients randomized to the high-dose induction arm (P = .04) and correlated strongly with genetic/cytogenetic risk. In multivariate analysis, PBC retained significant predictive power for CR, relapse risk, and survival. Thus, PBC analysis can provide a very early prediction of outcome, correlates with treatment intensity and disease subset, and may support studies of customized AML therapy.
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http://dx.doi.org/10.1182/bloodadvances.2019000406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988394PMC
January 2020

The microbiota-gut-brain axis: Focus on the fundamental communication pathways.

Prog Mol Biol Transl Sci 2020 24;176:43-110. Epub 2020 Sep 24.

Department of Medicine and Surgery, University of Insubria, Varese, Italy.

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http://dx.doi.org/10.1016/bs.pmbts.2020.08.012DOI Listing
September 2020

Clinical, molecular, and prognostic correlates of number, type, and functional localization of TET2 mutations in chronic myelomonocytic leukemia (CMML)-a study of 1084 patients.

Leukemia 2020 05 13;34(5):1407-1421. Epub 2019 Dec 13.

Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.

Loss-of-function TET2 mutations (TET2) are frequent early clonal events in myeloid neoplasms and are thought to confer a fitness advantage to hematopoietic precursors. This large, multi-institutional study (n = 1084), investigated the TET2 mutational landscape and prognostic implications of the number, type, and location of TET2 and the epistatic relationship with other somatic events in chronic myelomonocytic leukemia (CMML). Nine hundred and forty-two TET2 were identified in 604 (56%) patients, of which 710 (75%) were predicted to be truncating (involving the catalytic domain). Three hundred and sixteen (29%) patients had ≥1 TET2, with 28%, 1%, and 0.2% harboring 2, 3, and 5 mutations, respectively. In comparison to TET2, TET2 patients were older in age, more likely to have dysplastic CMML, a higher number of co-occurring mutations, and lower-risk stratification. Importantly, TET2 were associated with a survival advantage (49 vs. 30 months, p < 0.0001), especially in the context of multiple TET2 (≥2; 57 months, p < 0.001), and truncating TET2 (51 months, p < 0.001). In addition, the adverse prognostic impact of ASXL1 was partially mitigated by concurrent TET2, with the ASXL1/TET2 genotype having better outcomes and resulting in further risk stratification of ASXL1 inclusive CMML prognostic models, in comparison to ASXL1 alone.
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http://dx.doi.org/10.1038/s41375-019-0690-7DOI Listing
May 2020

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

A refinement approach in a mouse model of rehabilitation research. Analgesia strategy, reduction approach and infrared thermography in spinal cord injury.

PLoS One 2019 30;14(10):e0224337. Epub 2019 Oct 30.

Department of Cardiovascular, Neural and Metabolic Sciences, S.Luca Hospital, Istituto Auxologico Italiano IRCCS, Milan, Italy.

The principles of Refinement, Replacement and Reduction (3R's) should be taken into account when animals must be used for scientific purpose. Here, a Reduction / Refinement approach was applied to the procedure of spinal cord injury (SCI), an animal model used in rehabilitation medicine research, in order to improve the quality of experiments, avoiding unnecessary suffering. The aims of this investigation were 1- to assess acute surgical pain in mice subjected to SCI, 2- to compare the efficacy of commonly used analgesia (three buprenorphine subcutaneous injection in 48 hours, 0,15 mg/kg each) with a combination of opioid and NSAID (one subcutaneous injection of 5 mg/kg carprofen before surgery followed by three buprenorphine subcutaneous injection in 48 hours, 0,15 mg/kg each) and 3- to test if Infrared Thermography (IRT) could be a potential new Refinement method to easily assess thermoregulation, an important metabolic parameter. Finally, we aimed to achieve these goals without recruiting animals on purpose, but using mice already scheduled for studies on SCI. By using behaviours analysis, we found that, despite being commonly used, buprenorphine does not completely relieve acute surgical pain, whereas the combination of buprenorphine and carprofen significantly decreases pain signs by 80%. IRT technology turned out to be a very useful Refinement tool being a non invasive methods to measure animal temperature, particularly useful when rectal probe cannot be used, as in the case of SCI. We could find that temperatures constantly and significantly increased until 7 days after surgery and then slowly decreased and, finally, we could observe that in the buprenorphine and carprofen treated group, temperatures were statistically lower than in the buprenorphine-alone treated mice. To our knowledge this is the first work providing an analgesic Refinement and a description of thermoregulatory response using the IRT technology, in mice subjected to SCI.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224337PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821094PMC
March 2020

Street art graffiti: Discovering their composition and alteration by FTIR and micro-Raman spectroscopy.

Spectrochim Acta A Mol Biomol Spectrosc 2020 Jan 19;225:117474. Epub 2019 Aug 19.

Dipartimento di Chimica, Università di Roma "La Sapienza", P. le Aldo Moro 5, Rome, Italy.

Paints used in street art are modern materials subjected to degradation processes, which are very complex and difficult to predict without taking into account of several factors. This study investigates three outdoor murals in Lazio, - namely "graffiti", a word now used to indicate a spontaneous street art tendency consisting in images and writings realized by spray paints in public spaces to provoke passersby -with the aim to discover materials application techniques and chemical composition and figure out whether alteration phenomena occurred. Twenty-two samples were collected, and their stratigraphy was studied by optical microscopy. Fourier Transformed Infrared spectroscopy was used to identify binders and their degradation products in paints and preparatory layers, while for characterization of organic pigments used in all different stratigraphy layers of samples micro-Raman spectroscopy analyses was carried out. Furthermore, micro-Raman spectroscopy allowed to study an unusual patina formed on the surface of a pink paint. This information is useful for artists as well as for conservators, who must face numerous issues related to the preservation of this modern and labile kind of artistic expression, very fashionable nowadays but often created without care for materials duration. Conservation issues were also deepened by interviews with several contemporary mural authors. Artists underlined how contemporary murals are a very heterogeneous means of expression. Different cultural tendencies coexisting result in different attitude towards conservation.
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http://dx.doi.org/10.1016/j.saa.2019.117474DOI Listing
January 2020

Chemotherapy-related nail toxicity.

Int J Hematol 2019 Nov 10;110(5):519-520. Epub 2019 Aug 10.

Haematology Unit, Careggi Hospital-University of Florence, Largo Brambilla 3, 50134, Florence, Italy.

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http://dx.doi.org/10.1007/s12185-019-02724-9DOI Listing
November 2019

Marine Toxins and Nociception: Potential Therapeutic Use in the Treatment of Visceral Pain Associated with Gastrointestinal Disorders.

Toxins (Basel) 2019 07 31;11(8). Epub 2019 Jul 31.

Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy.

Visceral pain, of which the pathogenic basis is currently largely unknown, is a hallmark symptom of both functional disorders, such as irritable bowel syndrome, and inflammatory bowel disease. Intrinsic sensory neurons in the enteric nervous system and afferent sensory neurons of the dorsal root ganglia, connecting with the central nervous system, represent the primary neuronal pathways transducing gut visceral pain. Current pharmacological therapies have several limitations, owing to their partial efficacy and the generation of severe adverse effects. Numerous cellular targets of visceral nociception have been recognized, including, among others, channels (i.e., voltage-gated sodium channels, VGSCs, voltage-gated calcium channels, VGCCs, Transient Receptor Potential, TRP, and Acid-sensing ion channels, ASICs) and neurotransmitter pathways (i.e., GABAergic pathways), which represent attractive targets for the discovery of novel drugs. Natural biologically active compounds, such as marine toxins, able to bind with high affinity and selectivity to different visceral pain molecular mediators, may represent a useful tool (1) to improve our knowledge of the physiological and pathological relevance of each nociceptive target, and (2) to discover therapeutically valuable molecules. In this review we report the most recent literature describing the effects of marine toxin on gastrointestinal visceral pain pathways and the possible clinical implications in the treatment of chronic pain associated with gut diseases.
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http://dx.doi.org/10.3390/toxins11080449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723473PMC
July 2019

Treatment Patterns in Patients with Chronic-Phase Chronic Myeloid Leukaemia in Routine Clinical Practice: the SIMPLICITY Italian Population.

Mediterr J Hematol Infect Dis 2019 1;11(1):e2019025. Epub 2019 May 1.

Azienda Ospedaliera San Gerardo, University of Milano Bicocca, Monza, Italy.

Background And Objectives: While tyrosine kinase inhibitors (TKIs) have transformed CP-CML management, limited data exist on their use in clinical practice.

Methods: SIMPLICITY (NCT01244750) is an observational study in CP-CML patients, exploring first-line (1L) TKI use and management patterns in the US and Europe. Over half of the patients recruited in Europe are from Italy (n=266). This is an analysis of the Italian cohort and a comparison with the rest of the European SIMPLICITY population. Baseline demographic, factors influencing the choice of first-line TKI, response monitoring patterns and predictors of monitoring, and treatment interruptions, discontinuations and switching by index TKIs are presented for the Italian cohort in the first year of treatment and compared with that for the overall European SIMPLICITY cohort.

Results: Italian patients received 1L imatinib (IM; retrospective [(n=31]; prospective [n=106]), dasatinib (DAS; n=56) or nilotinib (NIL; n=73). Documented cytogenetic response monitoring by 12 months was lower than expected, but almost all patients had documented molecular response monitoring. Fewer patients discontinued first-line TKI by 12 months in Italy compared with the rest of the European SIMPLICITY population (p=0.003). Of those with ≥12 months follow-up since the start of 1L TKI, only 7.1% (n=19) of Italian patients switched to a second-line TKI, a third less than in the rest of the European SIMPLICITY population. Of interest, intolerance as opposed to resistance, was the main reason for switching.

Conclusions: This analysis provides valuable insights into management and treatment patterns in Italian patients with CML within routine clinical practice.
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http://dx.doi.org/10.4084/MJHID.2019.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548212PMC
May 2019

Umbilical cord blood versus unrelated donor transplantation in adults with primary refractory or relapsed acute myeloid leukemia: a report from Eurocord, the Acute Leukemia Working Party and the Cord Blood Committee of the Cellular Therapy and Immunobiology Working Party of the EBMT.

Blood Cancer J 2019 04 12;9(4):46. Epub 2019 Apr 12.

EBMT Paris Study Office/CEREST-TC, Paris, France.

The role of umbilical cord blood transplantation (CBT) in acute myeloid leukemia (AML) patients with active disease at allogeneic hematopoietic cell transplantation (allo-HCT) remains poorly investigated. In this study, we compared transplantation outcomes of 2963 patients with primary refractory or relapsed AML given CBT, 10/10 HLA-matched UD, or 9/10 HLA-matched UD allo-HCT from 2004 to 2015 at EBMT-affiliated centers. Neutrophil engraftment and complete remission rates in CBT, UD 10/10, and UD 9/10 recipients were 75 and 48%, 93 and 69%, and 93 and 70%, respectively. In multivariate Cox analyses, in comparison with CBT (n = 285), UD 10/10 recipients (n = 2001) had a lower incidence of relapse (HR = 0.7, P = 0.001), a lower incidence of non relapse mortality (HR = 0.6, P < 0.001), better GVHD-free and leukemia-free survival (GRFS, HR = 0.8, P < 0.001) and better survival (HR = 0.6, P < 0.001). Further, in comparison with CBT, 9/10 UD recipients (n = 677) also had a lower incidence of relapse (HR = 0.8, P = 0.02), a lower incidence of nonrelapse mortality (HR = 0.7, P = 0.008), better GRFS (HR = 0.8, P = 0.01) and better survival (HR = 0.7, P < 0.001). In summary, these data suggest that in AML patients with active disease at transplantation, allo-HCT with UD results in better transplantation outcomes than CBT.
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http://dx.doi.org/10.1038/s41408-019-0204-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461673PMC
April 2019

Randomized trial comparing standard vs sequential high-dose chemotherapy for inducing early CR in adult AML.

Blood Adv 2019 04;3(7):1103-1117

Azienda Socio-Sanitaria Territoriale (ASST) Ospedale Papa Giovanni XXIII, Bergamo, Italy.

Here we evaluated whether sequential high-dose chemotherapy (sHD) increased the early complete remission (CR) rate in acute myelogenous leukemia (AML) compared with standard-intensity idarubicin-cytarabine-etoposide (ICE) chemotherapy. This study enrolled 574 patients (age, 16-73 years; median, 52 years) who were randomly assigned to ICE (n = 286 evaluable) or sHD (2 weekly 3-day blocks with cytarabine 2 g/m twice a day for 2 days plus idarubicin; n = 286 evaluable). Responsive patients were risk-stratified for a second randomization. Standard-risk patients received autograft or repetitive blood stem cell-supported high-dose courses. High-risk patients (and standard-risk patients not mobilizing stem cells) underwent allotransplantation. CR rates after 2 induction courses were comparable between ICE (80.8%) and sHD (83.6%; 38). sHD yielded a higher single-induction CR rate (69.2% vs 81.5%; 0007) with lower resistance risk ( < .0001), comparable mortality (39), and improved 5-year overall survival (39% vs 49%; 045) and relapse-free survival (36% vs 48%; 028), despite greater hematotoxicity delaying or reducing consolidation blocks. sHD improved the early CR rate in high-risk AML (odds ratio, 0.48; 95% confidence interval [CI], 0.31-0.74; 0008) and in patients aged 60 years and less with de novo AML (odds ratio, 0.46; 95% CI, 0.27-0.78; 003), and also improved overall/relapse-free survival in the latter group (hazard ratio, 0.70; 95% CI, 0.52-0.94; 01), in standard-risk AML, and postallograft (hazard ratio, 0.61; 95% CI, 0.39-0.96; 03). sHD was feasible, effectively achieved rapid CR, and improved outcomes in AML subsets. This study is registered at www.clinicaltrials.gov as #NCT00495287.
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http://dx.doi.org/10.1182/bloodadvances.2018026625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457212PMC
April 2019