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Objective: We performed an external and multicentric validation of the predictive value of abdominal computed tomography (aCT) on time tofirst treatment (TTFT) in early stage chronic lymphocytic leukemia (CLL) patients. Methods: aCT was performed at diagnosis in 181 Rai 0 patients enrolled in the O-CLL1- GISL trial (clinicaltrial.gov ID:NCT00917549). Results: Fifty-five patients showed an abnormal aCT. Patients with an abnormal aCT showed a significantly shorter TTFT than those with normal aCT (P < 0.0001). At multivariate analysis, aCT (P = 0.011), β-2 microglobulin (P = 0.019), and CD38 expression (P = 0.047) correlated with TTFT. Following IWCLL 2008 criteria, 112 (61.9%) cases remained at Rai 0, while 69 (38.1%) satisfied the criteria of clinical monoclonal B-cell lymphocytosis (cMBL). Reclassified Rai 0 patients with an abnormal aCT showed a significantly shorter TTFT than those with a normal aCT (P < 0.0001). At multivariate analysis, only aCT (P = 0.011) correlated with TTFT. Eleven cMBL cases (15.9%) showed an abnormal aCT and were reclassified as small lymphocytic lymphomas (SLL); nonetheless, TTFT was similar for cMBLs and SLLs. Conclusion: Our results confirm the ability of the abnormal aCT to predict progression in early stage cases. [ABSTRACT FROM AUTHOR]

Background The role of oxidative stress in the initiation and progression of endothelial damage in thrombotic thrombocytopenic purpura ( TTP) syndrome has been the subject of much speculation in the recent past. Objectives The aim of this study was to measure the concentration of plasma advanced oxidation protein products ( AOPPs), advanced glycation end products ( AGEs), and carbonyl groups ( CG) as markers of oxidative stress in plasma of a patient with TTP during the course of the disease until recovery and to evaluate the effect of plasmapheresis ( PE) on these biomarkers. Materials and methods The study consisted of plasma analysis of the patient, and 23 healthy subjects served as controls. In the patient with TTP, AOPP, AGE, and CG analysis was performed before and after each PE at the days +1 ( Tα), +2, +4, +6, +10, +9, and +17 after the last plasmapheresis ( Tω). Results Plasma concentrations of AOPPs were increased in the acute phase of TTP, and at Tα, the patient had AOPPs levels higher than 99°‰ of controls. AOPPs decreased in the recovery phase, and at Tω, their values were between 84° and 85°‰ of controls. No significant difference was found in AOPP levels before and after each PE. No significant differences for AGEs or CG concentrations were found at Tα with respect to the control group, while only a trend was observed for reduction of plasma AGEs after each plasmapheresis. Conclusion Our data seem to confirm the hypothesis that oxidative stress is a critical component of the pathogenesis of TTP. [ABSTRACT FROM AUTHOR]

The article presents a multicentre observational study conducted to establish association of ZAP70 protein-coding gene with early stage chronic lymphocytic leukaemia. It mentions the unstability of ZAP70 protein-coding gene and states that re assessment of ZAP70 gene in lymphocytic leukaemia patients after 3 years suggested that 30.3 percent became positive, while 35.7 percent positive cases became negative. It states that ZAP70 gene expression in time to first treatment (TTFT).

MicroRNAs (miRNAs) are short non-coding RNAs involved in the regulation of gene expression. Selected groups of miRNAs are differentially expressed in various types of cancers. Alterations in miRNAs gene expression have been shown in cells from the B-cell malignancy, multiple myeloma (MM). However, although MM is a disease of plasma cells, abnormalities have been detected in the peripheral blood of the patients. The goal of our study was to analyse the entire miRNome in peripheral lymphocytes of MM patients using reverse transcription quantitative polymerase chain reaction. Using in silica analysis, we also evaluated some of the most interesting and significant pathways. Analysis revealed that MM samples had a distinct miRNA profile compared to the controls. This resulted in the identification of 203 miRNAs, 85 of which were over-expressed and 118 under-expressed. Of these, 184 possessed validated or highly predicted mRNA targets. We identified 12 354 mRNA targets of the transcriptome: 36·4% of the related proteins are involved in death processes while the 21% are required for growth and cell proliferation. We have demonstrated that miRNAs are differentially expressed in the peripheral blood of MM patients compared to controls, affecting some pathways involved in the anti-apoptotic process, cell proliferation and maybe anti-angiogenesis. [ABSTRACT FROM AUTHOR]

NOTCH1 mutations have recently emerged as new genetic lesions significantly correlated with survival in chronic lymphocytic leukaemia ( CLL). We performed deep next generation sequencing of the NOTCH1 mutation hotspot in 384 cases at diagnosis, including 100 monoclonal B cell lymphocytosis ( MBL) and 284 Binet stage A CLL cases, enrolled in the Gruppo Italiano Studio Linfomi O- CLL1 multicentre trial. The NOTCH1 c.7541_7542del CT dinucleotide deletion was detected and confirmed by an extremely sensitive polymerase chain reaction-based approach in 11% of MBL and 13·4% of CLL patients. Remarkably, the NOTCH1 mutation was often observed at low clonal level, mainly in MBL patients. Sequential analyses in a fraction of cases showed that the NOTCH1 mutation generally does not occur during the disease course and that the mutational load in positive cases tends to be stable over time. NOTCH1-mutated cases, even at low clonal level, displayed a significant reduction in median progression-free survival, although NOTCH1 mutation lost its prognostic impact in a multivariate analysis including 11q and/or 17p deletion, IGHV mutational status, and MBL or CLL status. Our data highlight the importance of using highly sensitive methods to measure NOTCH1 mutations, in order to improve prognostic stratification and obtain useful information for potential therapeutic approaches. [ABSTRACT FROM AUTHOR]

Givinostat, a histone-deacetylase inhibitor ( HDACi), inhibits proliferation of cells bearing the JAK2 V617F mutation and has shown significant activity with good tolerability in patients with chronic myeloproliferative neoplasms ( MPN). In this multicentre, open-label, phase II study, 44 patients with polycythaemia vera ( PV), unresponsive to the maximum tolerated doses ( MTD) of hydroxycarbamide ( HC), were treated with Givinostat (50 or 100 mg/d) in combination with MTD of HC. The European LeukaemiaNet response criteria were used to assess the primary endpoint after 12 weeks of treatment. Complete or partial response was observed in 55% and 50% of patients receiving 50 or 100 mg of Givinostat, respectively. Control of pruritus was observed in 64% and 67% of patients in the 50 and 100 mg groups, respectively. The combination of Givinostat and HC was well tolerated: eight patients (18%) discontinued, four in each treatment arm; grade 3 adverse events were reported in one patient (4·5%) in each treatment arm. The combined use of Givinostat and HC was safe and clinically effective in HC-unresponsive PV patients. [ABSTRACT FROM AUTHOR]

Despite recent treatments, such as bortezomib, thalidomide, and lenalidomide, therapy of multiple myeloma ( MM) is limited, and MM remains an incurable disease associated with high mortality. The outcome of patients treated with cytotoxic therapy has not been satisfactory. Therefore, new therapies are needed for relapsed MM. A new anticancer strategy is the use of monoclonal antibodies ( Mo Abs) that represent the best available combination of tumor cytotoxicity, environmental signal privation, and immune system redirection. Clinical results in patients with relapsed/refractory MM suggest that Mo Abs are likely to operate synergistically with traditional therapies (dexamethasone), immune modulators (thalidomide, lenalidomide), and other novel therapies (bortezomib); in addition, Mo Abs have shown the ability to overcome resistance to these therapies. It remains to be defined how Mo Ab therapy can most fruitfully be incorporated into the current therapeutic paradigms that have achieved significant survival earnings in patients with MM. This will require careful consideration of the optimal sequence of treatments and their clinical position as either short-term induction therapy, frontline therapy in patients ineligible for ASCT, or long-term maintenance treatment. [ABSTRACT FROM AUTHOR]

Stevens- Johnson syndrome (SJS) is a severe and life-threatening condition. Although allopurinol, an antihyperuricemia drug, is the drug most commonly associated with SJS, more than 100 different causative drugs have been reported. Among hematologic drugs recently introduced into the market, drugs such as rituximab, imatinib, and bortezomib are reported. Here, we describe a patient with SJS while receiving lenalidomide in combination with prednisolone for treatment-naïve multiple myeloma. Although SJS has been reported rarely as an adverse reaction to Lenalidomide, this drug should be considered in the etiology of SJS, and the increased number of prescriptions of Lenalidomide for the therapy of multiple myeloma has to stress the awareness of its potentially serious side-effects. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Despite advances in understanding the molecular pathogenesis of multiple myeloma and promising new therapies, almost all patients eventually relapse with resistant disease. There is therefore a strong rationale for combining novel therapies that target intrinsic molecular pathways mediating multiple myeloma cell resistance. One such protein family is the heat shock proteins (HSP), especially the HSP90 family. Heat shock protein inhibitors have been identified as promising cancer treatments as, while they only inhibit a single biologic function, the chaperone-protein association, their effect is widespread as it results in the destruction of numerous client proteins. This article reviews the preclinical and clinical data, which support the testing of HSP90 inhibitors as cancer drugs and update the reader on the current status of the ongoing clinical trials of HSP90 inhibitors in multiple myeloma. [ABSTRACT FROM AUTHOR]

The wide spectrum of clonal hematopoietic disorders that fall under the broad diagnostic category of myelodysplastic syndromes (MDS) consist of a family of bone marrow malignancies – with ineffective, inadequate, and dysplastic hematopoiesis, and with an increased risk of life-threatening infections, bleeding, and progression to acute myeloid leukemia (AML) – that are characterized by a deep heterogeneity on the clinical, biologic and prognostic level. The intrinsic complexity of this group of disorders and the frequent association with one or more comorbidities have limited for many years the number of effective treatment options available: most patients are, indeed, still managed by supportive care measures, with just a minority of them being eligible for allogeneic stem cell transplantation, which is still the only potentially curative modality. In the last two decades, the progressively better understanding of MDS biology has shown how an abnormal epigenetic modulation might play a crucial part in the pathogenesis and in the process of biologic evolution of these disorders. Moreover, pharmacological agents that target the so-called epigenome have shown a significant clinical activity for diverse hematologic malignancies, including MDS. The aim of this review is to highlight recent developments within the context of current knowledge of MDS and its altered epigenetic regulation and to recall the experimental steps that have brought to the clinical development and application of epigenetic modifiers, such as azacytidine and decitabine, trying to explain the biologic rationale for their use in this setting. [ABSTRACT FROM AUTHOR]

Musolino C, Alonci A, Bellomo G, Loteta B, Quartarone E, Gangemi D, Massara E, Calabro L. Levels of soluble angiogenin in chronic myeloid malignancies: clinical implications. Eur J Haematol 2004: 72: 416–419. © Blackwell Munksgaard 2004. Angiogenesis is critical for the clinical progression of haematopoietic malignancies and depends on angiogenic factors. Angiogenin is a powerful factor produced by neoplastic cells and host microenvironment. High levels of soluble angiogenin (sAng) correlate with a poor prognosis in patients affected by acute myeloid leukaemia and myelodisplastic syndromes, but no data are available on sAng in chronic myeloproliferative disorders (CMD). Therefore, in this study we investigated the clinical significance of the angiogenin in sera of patients with chronic myeloid leukaemia (CML) ( n = 14) or essential thrombocythaemia (ET) ( n = 20), and correlated them with those of soluble transforming growth factor-beta1 (sTGF β1). Enzyme-linked immunosorbent assay detected ( P < 0.05) higher levels of sAng in CMD compared with healthy subjects (1026.74 ± 464.60 pg/mL and 196.00 ± 39.90 pg/mL, respectively). The highest levels of sAng were detected in CML patients (1349.23 ± 549.55 pg/mL). Interestingly, CML patients who achieved haematological remission after interferon therapy showed circulating levels of angiogenin significantly ( P < 0.05) decreased when compared with those at diagnosis. In ET patients, levels of angiogenin (889.34 ± 267.66 pg/mL) and sTGF β1 (76.69 ±6.08 pg/mL) were higher ( P < 0.05) compared with healthy controls (57.93 ± 19.39 pg/mL). No correlation was found between levels of sAng and levels of sTGF β1 or platelet count among ET patients. Our results show for the first time that elevated blood levels of angiogenin feature chronic myeloid malignancies, suggesting a role of angiogenin in the pathogenesis of these diseases. [ABSTRACT FROM AUTHOR]

The article presents the case study of a 79 year old woman with subcutaneous nodules and skin lesions located in the abdomen, arms, and thighs. The article discusses multiple myeloma disease that involved the skin in multiple nodules and showed high serum levels of Interleukin-16. It states that IL-16 could modify the immune response status, thus clearly discussing the natural history of the disease, the onset of infectious complications, and the poor response to drugs.

The article presents a study that determines the plasma levels of IL-33 among patients with multiple myeloma (MM). The study is conducted under the principles of the Declaration of Helsinki wherein patients were informed and written consent was derived from the patients. The study also uses the Durie-Salmon staging system and the utilization of immunoglopbulin G as paraprotein. The results of the study show that the deficiency in cytokine secretion worsens during disease progression.

The recent development of reduced intensity conditioning and allotransplantation (RICT) has opened a new way to assure engraftment of donor cells while reducing early transplant-related mortality. We evaluated the combination of high-dose therapy and autologous peripheral blood stem cells transplantation (APBSCT) followed by RICT to extend the benefit of allografting procedures in de novo multiple myeloma (MM) patients. Fifteen subjects with stage III MM (median age 51 years, range 40-57) received high dose melphalan (200 mg/m(2)) followed by APBSCT previously collected after cyclophosphamide (4 g/m(2)) and granulocyte colony-stimulating factor (G-CSF). After 3-4 months from APBSCT, the patients underwent RICT, consisting of fludarabine 30 mg/m(2) + cyclophosphamide 300 mg/m(2) on days -4, -3, and -2. Acute graft-versus-host disease (GVHD) occurred in 2 patients; 6 patients developed chronic GVHD; 4 patients developed CMV antigenemia and were treated pre-emptively with ganciclovir. No transplant related mortality was shown. Response was simultaneously measured by both electrophoresis (EP) and immunofixation (IF); when IF was negative, patients were classified in complete remission (CR) and when it remained positive, near CR (nCR). After a median follow up of 44 months post APBSCT, 100 and 43% of patients are still alive and progression-free, respectively. Overall, the CR + nCR rate after dose-reduced allograft was enhanced from 26.7 to 73.3%. A correlation not statistically significant between GVHD and remission was found. In conclusion, an up-front tandem strategy with a very low reduced intensity-conditioning regimen for allografting following autografting is feasible and induces high CR/nCR rate in MM.