[Show abstract][Hide abstract] ABSTRACT: In the spectrum of diffuse large B-cell lymphomas (DLBCL), both T-cell/histiocyte-rich large B-cell lymphoma (TCHRBCL) and most lymphomatoid granulomatosis (LG) cases are characterized by the relative rarity of the neoplastic B-cell population, with respect to the overwhelming non-neoplastic counterpart of T cells or histiocytes. Here we report a case of aggressive B-cell lymphoma with unusual clinicopathological features partially overlapping these two entities.The patient was a previously healthy 55-year-old male, presenting with a computed tomography finding of a pelvic mass, inguinal lymphadenopathies, and pulmonary nodules. Two excisional lymph node biopsies resulted inconclusive for lymphoproliferative disease. Because of a colonic perforation, the patient underwent an urgent laparotomy, which disclosed a large pelvic abscess. The pathological examination of the surgical specimen could not discriminate between a primary aggressive B-cell lymphoproliferative disorder and an abnormal inflammatory hyper-reaction. The patient developed a septic state, not resolving until death, which occurred because of an abdominal hemorrhage. A second perimortem surgical specimen consisting of a nodal mass revealed a diagnosis of an Epstein-Barr virus-negative high-grade large B-cell lymphoma with massive necrosis, angiocentric pattern of growth, and prominent T-cell infiltrate.The unique clinicopathological features did not allow to classify this tumor within any of the recognized WHO entities, potentially representing a new clinicopathological variant of DLBCL in-between TCHRBCL and LG.
[Show abstract][Hide abstract] ABSTRACT: We prospectively evaluated two post-consolidation strategies, administered according to the mobilization outcome, in 72 AML fit elderly patients, achieving CR after the 1st high-dose Cytarabine-based induction. Autologous Stem Cell Transplantation (ASCT) was performed in patients collecting ≥3x10(6) CD34+/kg and low-dose Gemtuzumab-Ozogamicin (GO) in poor mobilizers (collecting<3x10(6) CD34+/kg). Fifty-five patients (76,3%) undergo PBSC mobilization, after 1rst consolidation and 24/55 (44%) collected >3x10(6) CD34+ cells/kg; among the 55 patients eligible for PBSC mobilization, 7 did not receive the planned treatment, 23 were allocated for ASCT and 25 for GO on an ITT basis. With a median follow-up of 70 months (range: 24-124), 20/55 patients are alive, 18 of them in CCR. The 8 years OS and DFS are respectively 35.9% (24%-49.8%) and 31.2% (21%-43.8%), median OS and DFS: 22 and 16 months respectively. At multivariate analysis post-consolidation treatment and hyperleukocytosis (WBC>50,000/μl) significantly predicted OS and DFS, while secondary AML was significantly associated with a higher relapse rate (83.4% vs 54% of de novo AML). Patients with hyperleukocytosis had 0% 3 years OS vs the 46% (at 8 years) in patients without hyperleukocytosis (p=0.01); 57% of patients in the GO arm are alive at 8 years, compared to 25.4% of patients in the ASCT arm who had an overall RR to die of 2.6 (95% CI: 1.2-5.8; p=0.02). DFS at 8 years was 45.3% in patients receiving GO, compared to 26% observed in ASCT arm (RR: 2.1; 95% CI: 1-4.3, p= 0.05). Our study outlines low feasibility and efficacy of ASCT in elderly AML patients, while post-consolidation with GO appears safe and effective in this unfavorable setting. The study was registered at Umin Clinical Trial Registry (www.umin.ac.jp/ctr), number R000014052.
No preview · Article · May 2014 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Telomere dysfunction might generate genomic instability leading to the progression of myelodysplastic syndromes (MDS) into acute myeloid leukemia (AML). We investigated telomere length (TL), telomerase activity (TA) and hTERT, c-myc, mad1, and p53 expression in the bone marrow of patients with MDS (n=109), AML (n=47) and in controls (n=24). TL was lower in MDS patients than in controls (p<0.001) and higher in L-MDS (low, intermediate-1 IPSS, p<0.01) respect H-MDS (high, intermediate-2 IPSS, p<0.01) patients. Mad-1 expression was higher in MDS patients than in controls (p<0.01), c-myc expression was highest in AML and in H-MDS patients. Our results show that the telomere dynamics might be useful for stratifying patients according to a risk scoring system.
No preview · Article · Oct 2013 · Leukemia research
[Show abstract][Hide abstract] ABSTRACT: Aberrant DNA methylation at CpG islands within promoters is increasingly recognised as a common event in human cancers and has been associated with the silencing of important tumour suppressor genes. Epigenetic therapy using hypomethylating agents has demonstrated clinical effectiveness; the drugs azacitidine and decitabine have been approved for the treatment of MDS.
We investigated the association between global DNA methylation and clinical outcome in MDS. We evaluated 134 MDS bone marrow trephine biopsies (BMTB) by immunohistochemistry and compared the results with those from an age-matched group of normal BMTB. Immunohistochemistry was performed on paraffin-embedded sections using the anti-5-methylcytosine (5mc) antibody.
Our results showed that the 5mc immunostaining score (M-score) of patients with MDS was higher than those of normal controls and that overall survival significantly correlated with global DNA methylation, age and IPSS score. Therefore, we found that patients with high levels of methylation had a shorter median overall survival (OS) compared with patients with lower levels. These immunohistochemistry results were confirmed by analysing global DNA methylation on LINE-1 sequences using the COBRA method and pyrosequencing.
This study reports that global DNA methylation detected by immunohistochemistry predicts OS in MDS.
Full-text · Article · May 2013 · European Journal Of Haematology
[Show abstract][Hide abstract] ABSTRACT: To detect factors associated with quality of life (QOL) of patients with myelodysplastic syndrome (MDS) and to compare the MDS patients' self-assessed QOL with that perceived by their physicians. In an observational, non-interventional, prospective, multicentre study, QOL was evaluated in 148 patients with newly diagnosed low- and intermediate-risk IPSS MDS. QOL measures (QOL-E v.2, LASA and EQ-5D) and patient-related candidate determinants of QOL were assessed for up to 18 months. Patients' QOL scores were compared with those obtained by appointed hematologists' assessment and with ECOG performance status (PS). Fatigue was not prevalent at diagnosis, though physical QOL and energy levels were low. Transfusion-dependent patients had worse QOL scores. In multivariate analysis, Hb levels and comorbidities were a major determinant of QOL. Physicians' perception of patients' well-being correlated with patients' QOL. Physicians underestimated the impact of disturbances on patients' QOL, mainly in the MDS-specific components. ECOG PS did not discriminate patients according to QOL status. In conclusion, the association of anemia with QOL is confirmed, while co-morbidities emerge as an independent predictor of QOL in MDS. Fatigue is not a major concern. ECOG PS is not a valuable surrogate of patient's QOL, thus highlighting that physician's judgment of patient's well-being must not substitute patient-reported outcomes. Appropriate questionnaires should be used to assess MDS patients' QOL in order to improve communication and therapeutic choice.
Full-text · Article · Jul 2012 · American Journal of Blood Research
[Show abstract][Hide abstract] ABSTRACT: Elderly patients with diffuse large B-cell lymphoma (DLBCL) are a heterogeneous population; clinical trials have evaluated a minority of these patients.
Ninety-one elderly patients with DLBCL received tailored treatment based on a comprehensive geriatric assessment (CGA). Three groups were identified: I, fit patients; II, patients with comorbidities; III, frail patients. Group I received 21-day cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-21), group II received R-CHOP-21 with liposomal doxorubicin, and group III received 21-day cycles of reduced-dose CHOP. Fifty-four patients (59%) were allocated to group I, 22 (25%) were allocated to group II, and 15 (16%) were allocated to group III.
The complete response (CR) rates were 81.5% in group I, 64% in group II, and 60% in group III. With a median follow-up of 57 months, 42 patients are alive, with 41 in continuous CR: 31 patients (57%) in group I, seven patients (32%) in group II, and four patients (20%) in group III. The 5-year overall survival, event-free survival, and disease-free survival rates in all patients were 46%, 31%, and 41%, respectively. Multivariate analysis selected group I assignment as the main significant prognostic factor for outcome.
This approach in an unselected population of elderly DLBCL patients shows that treatment tailored according to a CGA allows the evaluation of elderly patients who are currently excluded from clinical trials.
[Show abstract][Hide abstract] ABSTRACT: There are no reliable markers useful to predict the onset or the evolution of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT), although several candidate biomarkers have been identified from limited hypothesis-driven studies. In this study we evaluated 14 patients who received a reduced intensity conditioning HSCT. Seven patients had cGVHD, whereas 7 never developed cGVHD during the period of observation. The expression of 114 cytokines in immunoselected cell populations was explored by microarray analysis and 11 cytokines were selected for further evaluation by real-time PCR. Differential gene expression measurements showed a significant up-regulation for INFγ (interferon, gamma) in CD8+ and for TNFSF3 (tumor necrosis factor superfamily, member 3) and for TNFSF10 (tumor necrosis factor superfamily, member 10) in CD14+ cell population when comparing cGVHD with control samples. The expression levels were significantly decreased for TNFSF10 in CD8+ cell population and for TNFSF12 (tumor necrosis factor superfamily, member 12) and for PDGFβ (platelet-derived growth factor, beta) in CD4+. Our data seem to suggest that different immune populations can play a role in cGVHD pathogenesis and the early detection of gene expression profile in these patients could be useful in the monitoring of GVHD. We hypothesized that PDGFβ down-regulation could represent a negative feedback to compensate for enhanced expression of its receptor recently reported.
[Show abstract][Hide abstract] ABSTRACT: Testing for viral BKV-DNA in urine is a non-invasive early detection and monitoring tool in the diagnostic of BKV-related pathologies: quantitative analysis by Real-Time PCR can provide useful information in addition to cytologic analysis, although our study suggests that high BKV viruria is not necessarily associated with kidney or bladder damage.
Full-text · Article · Aug 2007 · The New Microbiologica: official journal of the Italian Society for Medical Virology (SIVIM)
[Show abstract][Hide abstract] ABSTRACT: Extensive chronic graft-versus-host disease (ecGVHD) is characterized by fibrosis similar to that of patients with systemic sclerosis (scleroderma). Since stimulatory autoantibodies against the platelet-derived growth factor (PDGF) receptor (PDGFR) have been found in patients with scleroderma and are responsible for the activation of skin fibroblasts, we tested the hypothesis that these autoantibodies are also present in patients affected by ecGVHD. Serum from 39 patients subjected to allogeneic stem cell transplantation for hematologic malignancies (22 with ecGVHD and 17 without cGVHD) and 20 healthy controls was assayed for the presence of stimulatory autoantibodies to the PDGFR by incubating purified IgG with mouse-embryo fibroblasts lacking PDGFR alpha or beta chains or with the same cells expressing PDGFR alpha. Stimulatory antibodies to the PDGFR were found selectively in all patients with ecGVHD but in none of the patients without cGVHD. Higher levels were detected in patients with generalized skin involvement and/or lung fibrosis. Antibodies recognized native PDGFR, induced tyrosine phosphorylation, accumulation of reactive oxygen species (ROS), and stimulated type 1 collagen gene expression through the Ha-Ras-ERK1/2-ROS signaling pathway. The biologic activity of these autoantibodies suggests a role in the development of fibrosis and argues for a common pathogenetic trait in ecGVDH and scleroderma phenotypes.