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1.  Circulating Calreticulin Is Increased in Myelofibrosis: Correlation with Interleukin-6 Plasma Levels, Bone Marrow Fibrosis, and Splenomegaly 
Mediators of Inflammation  2016;2016:5860657.
Myelofibrosis (MF) is a clonal neoplasia of the hemopoietic stem/progenitor cells associated with genetic mutations in the Janus kinase 2 (JAK2), myeloproliferative leukemia virus oncogene (MPL), and calreticulin (CALR) genes. MF is also characterized by a state of chronic inflammation. Calreticulin (CRT), as a multifunctional protein, is involved in a spectrum of cellular processes including inflammation, autoimmunity, and cancer initiation/progression. Based on this background, we hypothesised that in MF circulating CRT might reflect the inflammatory process. In the present study we show that circulating CRT is increased in MF patients compared to healthy controls. Also, in MF, CRT levels highly correlate with bone marrow fibrosis, splenomegaly, and Interleukin-6 (IL-6) plasma levels. In turn, higher IL-6 levels also correlated with disease severity in terms of increased spleen size, bone marrow fibrosis, number of circulating CD34+ cells, and lower hemoglobin values. These results demonstrate that the circulating CRT takes part in the inflammatory network of MF and correlates with aggressiveness of the disease.
PMCID: PMC5031875  PMID: 27672242
2.  Crucial factors of the inflammatory microenvironment (IL-1β/TNF-α/TIMP-1) promote the maintenance of the malignant hemopoietic clone of myelofibrosis: an in vitro study 
Oncotarget  2016;7(28):43974-43988.
Along with molecular abnormalities (mutations in JAK2, Calreticulin (CALR) and MPL genes), chronic inflammation is the major hallmark of Myelofibrosis (MF). Here, we investigated the in vitro effects of crucial factors of the inflammatory microenvironment (Interleukin (IL)-1β, Tumor Necrosis Factor (TNF)-α, Tissue Inhibitor of Metalloproteinases (TIMP)-1 and ATP) on the functional behaviour of MF-derived circulating CD34+ cells.
We found that, regardless mutation status, IL-1β or TNF-α increases the survival of MF-derived CD34+ cells. In addition, along with stimulation of cell cycle progression to the S-phase, IL-1β or TNF-α ± TIMP-1 significantly stimulate(s) the in vitro clonogenic ability of CD34+ cells from JAK2V617 mutated patients. Whereas in the JAK2V617F mutated group, the addition of IL-1β or TNF-α + TIMP-1 decreased the erythroid compartment of the CALR mutated patients. Megakaryocyte progenitors were stimulated by IL-1β (JAK2V617F mutated patients only) and inhibited by TNF-α. IL-1β + TNF-α + C-X-C motif chemokine 12 (CXCL12) ± TIMP-1 highly stimulates the in vitro migration of MF-derived CD34+ cells. Interestingly, after migration toward IL-1β + TNF-α + CXCL12 ± TIMP-1, CD34+ cells from JAK2V617F mutated patients show increased clonogenic ability.
Here we demonstrate that the interplay of these inflammatory factors promotes and selects the circulating MF-derived CD34+ cells with higher proliferative activity, clonogenic potential and migration ability. Targeting these micro-environmental interactions may be a clinically relevant approach.
PMCID: PMC5190072  PMID: 27304059
circulating CD34+ cells; myelofibrosis; inflammatory microenvironment; migration; survival
3.  A Risk Prediction Score for Invasive Mold Disease in Patients with Hematological Malignancies 
PLoS ONE  2013;8(9):e75531.
A risk score for invasive mold disease (IMD) in patients with hematological malignancies could facilitate patient screening and improve the targeted use of antifungal prophylaxis.
We retrospectively analyzed 1,709 hospital admissions of 840 patients with hematological malignancies (2005-2008) to collect data on 17 epidemiological and treatment-related risk factors for IMD. Multivariate regression was used to develop a weighted risk score based on independent risk factors associated with proven or probable IMD, which was prospectively validated during 1,746 hospital admissions of 855 patients from 2009-2012.
Of the 17 candidate variables analyzed, 11 correlated with IMD by univariate analysis, but only 4 risk factors (neutropenia, lymphocytopenia or lymphocyte dysfunction in allogeneic hematopoietic stem cell transplant recipients, malignancy status, and prior IMD) were retained in the final multivariate model, resulting in a weighted risk score 0-13. A risk score of < 6 discriminated patients with low (< 1%) versus higher incidence rates (> 5%) of IMD, with a negative predictive value (NPV) of 0.99, (95% CI 0.98-0.99). During 2009-2012, patients with a calculated risk score at admission of < 6 had significantly lower 90-day incidence rates of IMD compared to patients with scores > 6 (0.9% vs. 10.6%, P <0.001).
An objective, weighted risk score for IMD can accurately discriminate patients with hematological malignancies at low risk for developing mold disease, and could possibly facilitate “screening-out” of low risk patients less likely to benefit from intensive diagnostic monitoring or mold-directed antifungal prophylaxis.
PMCID: PMC3784450  PMID: 24086555
4.  Derivation and Validation of a Scoring System to Identify Patients with Bacteremia and Hematological Malignancies at Higher Risk for Mortality 
PLoS ONE  2012;7(12):e51612.
The aim of this study was to develop and validate a reliable clinical prediction rule that could be employed to identify patients at higher likelihood of mortality among those with hematological malignancies (HMs) and bacterial bloodstream infections (BBSIs).
Methods and Findings
We conducted a retrospective cohort study in nine Italian hematological units. The derivation cohort consisted of adult patients with BBSI and HMs admitted to the Catholic University Hospital (Rome) between January 2002 and December 2008. Survivors and nonsurvivors were compared to identify predictors of 30-day mortality. The validation cohort consisted of patients hospitalized with BBSI and HMs who were admitted in 8 other Italian hematological units between January 2009 and December 2010. The inclusion and exclusion criteria were identical for both cohorts, with type and stage of HMs used as matching criteria. In the derivation set (247 episodes), the multivariate analysis yielded the following significant mortality-related risk factors acute renal failure (Odds Ratio [OR] 6.44, Confidential Interval [CI], 2.36–17.57, P<0.001); severe neutropenia (absolute neutrophil count <100/mm3) (OR 4.38, CI, 2.04–9.43, P<0.001); nosocomial infection (OR, 3.73, CI, 1.36–10.22, P = 0.01); age ≥65 years (OR, 3.42, CI, 1.49–7.80, P = 0.003); and Charlson Comorbidity Index ≥4 (OR, 3.01, CI 1.36–6.65, P = 0.006). The variables unable to be evaluated at that time (for example, prolonged neutropenia) were not included in the final logistic model. The equal-weight risk score model, which assigned 1 point to each risk factor, yielded good-excellent discrimination in both cohorts, with areas under the receiver operating curve of 0.83 versus 0.93 (derivation versus validation) and good calibration (Hosmer-Lemshow P = 0.16 versus 0.75).
The risk index accurately identifies patients with HMs and BBSIs at high risk for mortality; a better initial predictive approach may yield better therapeutic decisions for these patients, with an eventual reduction in mortality.
PMCID: PMC3522733  PMID: 23272123
5.  Romiplostim as early treatment of immune thrombocytopenia with severe immunodeficiency 
Hematology Reports  2012;4(2):e10.
Immunosuppressive agents are the standard therapeutic approach for immune thrombocy-topenia (ITP). Their prolonged use may increase the risk of infectious complications, particularly when the patient is already at higher infectious risk. In this setting, the use of drugs with a mechanism of action alternative to immunosuppression, like thrombopoietin receptor agonists (TRAs), may find particular indication. We report the unique case of a patient with severe immunodeficiency and ITP, who experienced a serious infectious complication while on steroids treatment, and who was successfully treated with Romiplostim second-line. The present experience supports the effectiveness and safety of TRAs as early treatment of ITP patients with drug-induced immunodeficiency or with active infections.
PMCID: PMC3401131  PMID: 22826792
immune thrombocytopenia; romi-plostim; TPO receptor agonist; immunodeficiency.
6.  Sinonasal risk factors for the development of invasive fungal sinusitis in hematological patients: Are they important? 
Allergy & Rhinology  2011;2(1):6-11.
Invasive fungal sinusitis (IFS) is a highly aggressive infection that can affect hematologic patients. The classically described general risk factors, however, do not fully explain the development of IFS in a small percentage of cases. This study examined the impact of anatomic sinonasal factors and environmental factors on the development of IFS in high-risk patients. Medical records and computed tomography (CT) scans of patients admitted to our institution who were at high risk of developing IFS were retrospectively reviewed. Twenty-seven patients of 797 fulfilled the inclusion criteria. Patients affected by IFS were compared with patients not affected to identify possible sinonasal and environmental risk factors of IFS. Seven patients were excluded because of the lack of adequate radiological images. Six of the 20 eligible patients were assigned to the study group of patients affected by IFS and the remaining 14 patients were assigned to the control group. All but one case developed the infection during the summer with a significantly higher mean environmental temperature (p = 0.002). Anatomic nasal alterations were found in all patients affected by IFS and were significantly more frequent than in the control group (p = 0.014). It would be advisable to have patients with hematologic risk factors of IFS, especially during the summer period, undergo endoscopic nasal assessment. Furthermore, a CT finding of anatomic nasal alterations, such as anterior nasal septum deviation causing nasal obstruction, should increase the suspicion of IFS in case of the occurrence of nasal symptoms.
PMCID: PMC3390131  PMID: 22852108
fungal infection; hematologic malignancy; invasive fungal sinusitis; nasal endoscopy; sinonasal risk factors; sinus endoscopic surgery
7.  Update on the treatment of disseminated fusariosis: Focus on voriconazole 
Invasive fungal infections are a major cause of morbidity and mortality in immunocompromised patients, such as subjects with hematological malignancies and patients who underwent to hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT). Fusarium spp. cause a broad spectrum of infections in humans. Immunologically competent hosts show mainly localized skin infections, whereas disseminated fusariosis occurs almost exclusively in immunocompromised patients. Fusarium spp. are resistant to many antifungal agents with equivocal in vitro and in vivo susceptibility to amphotericin B. Voriconazole (VRC) is a triazole shown to be safe, well tolerated, and in vitro efficacious against Fusarium spp. Although clinical experience is limited, many case reports have shown the efficacy of VRC in the treatment of fusariosis.
PMCID: PMC2387295  PMID: 18516266
fusariosis; voriconazole; immunocompromised patient; cancer; fungal infections; aspergillus

Results 1-7 (7)