The importance of early therapy intensification in B-cell CLL (B-CLL) patients remains to be defined. Even though several studies have been published, no randomized trials comparing directly ...autologous stem cell transplant (ASCT) and the accepted conventional therapy (that is, rituximab, fludarabine and CY; R-FC) have been reported so far. To assess the benefit of a first-line aggressive therapy, we designed a multicenter, randomized, phase 3 trial comparing R-FC and high-dose chemotherapy supported by ASCT in patients under 65 years of age, with stage B(II) or C B-CLL. Primary end point was CR: 96 patients were enrolled (48 in each arm). On an intent-to-treat basis, the CR rates in the ASCT and R-FC arms were 62.5% and 58%, respectively. After 5 years of follow-up, PFS was 60.4% in the ASCT arm and 65.1% in the R-FC arm, time to progression 65.8 and 70.5%, and overall survival 88% vs 88.1%, respectively. Our trial demonstrates, for the first time in a randomized manner, that frontline ASCT does not translate into a survival advantage when compared with benchmark chemoimmunotherapy in B-CLL patients; the possibility of its clinical benefit in certain subgroups remains uncertain.
Purpose of Review
A working group of six expert physicians convened to assess the spectrum of multiple myeloma relapse presentations, discussed the features that can define the disease as aggressive ...and not aggressive, and established whether this information could help in selecting treatment together with the characteristics of disease and of patients and type of prior therapy.
Recent Findings
The working group agreed that relapse should be distinguished between biochemical and clinical according to IMWG. Moreover, the expert panel defined “aggressive disease” as a clinical condition that requires therapy able to induce a rapid and as deep as possible response to release symptoms and to avoid impending danger of new events. According to this definition, relapse was considered aggressive if it presents with at least one of the following features: doubling of M protein rate over 2 months, renal insufficiency, hypercalcemia, extramedullary disease, elevated LDH, high plasma cell proliferative index, presence of plasma cells in peripheral blood, or skeletal-related complications. Moreover, the panel agreed that this classification can be useful to choose therapy in first relapse together with other patient, disease, and prior therapy characteristics. So, this item was included in a new therapeutic algorithm.
Summary
The treatment choice in MM at relapse is wider than in the past with the availability of many new therapeutic regimens leading to increased diversity of approaches and relevant risk of inappropriate treatment decisions. A practical classification of relapses into aggressive or non-aggressive, included in a decisional algorithm on MM management at first relapse, could help to make the appropriate treatment decisions.
Long non-coding RNAs (lncRNAs) represent a novel class of functional RNA molecules with an important emerging role in cancer. To elucidate their potential pathogenetic role in chronic lymphocytic ...leukemia (CLL), a biologically and clinically heterogeneous neoplasia, we investigated lncRNAs expression in a prospective series of 217 early-stage Binet A CLL patients and 26 different subpopulations of normal B-cells, through a custom annotation pipeline of microarray data. Our study identified a 24-lncRNA-signature specifically deregulated in CLL compared with the normal B-cell counterpart. Importantly, this classifier was validated on an independent data set of CLL samples. Belonging to the lncRNA signature characterizing distinct molecular CLL subgroups, we identified lncRNAs recurrently associated with adverse prognostic markers, such as unmutated IGHV status, CD38 expression, 11q and 17p deletions, and NOTCH1 mutations. In addition, correlation analyses predicted a putative lncRNAs interplay with genes and miRNAs expression. Finally, we generated a 2-lncRNA independent risk model, based on lnc-IRF2-3 and lnc-KIAA1755-4 expression, able to distinguish three different prognostic groups in our series of early-stage patients. Overall, our study provides an important resource for future studies on the functions of lncRNAs in CLL, and contributes to the discovery of novel molecular markers with clinical relevance associated with the disease.
1 Department of Morphology and Embryology, Section of Histology, University of Ferrara
2 Department of Hematology Oncology, University of Pavia Medical School and Fondazione IRCCS Policlinico San ...Matteo, Pavia, Italy
3 Department of Biomedical Sciences and Advanced Therapies, Section of Hematology, University of Ferrara
4 Department of Biomedical Sciences, Section of Hematology, University of Catania
5 Department of Biomedical Sciences and Advanced Therapies, Section of Haematology, Center for the Study of Hemostasis and Thrombosis, University of Ferrara, Italy
Correspondence: Monica De Mattei/Alessia Ongaro, Department of Morphology and Embryology, Section of Histology, University of Ferrara, Via Fossato di Mortara 64/B, 44100 Ferrara, Italy. E-mail: dmm{at}unife.it
Background: The antifolate agent methotrexate is an important component of maintenance therapy in acute lymphoblastic leukemia, although methotrexate-related toxicity is often a reason for interruption of chemotherapy. Prediction of toxicity is difficult because of inter-individual variability susceptibility to antileukemic agents. Methotrexate interferes with folate metabolism leading to depletion of reduced folates.
Design and Methods: The aim of this study was to investigate the influence of polymorphisms for folate metabolizing enzymes with respect to toxicity and survival in adult patients with acute lymphoblastic leukemia treated with methotrexate maintenance therapy. To this purpose, we evaluated possible associations between genotype and hematologic and non-hematologic toxicity and effects on survival at 2 years of follow-up in patients with acute lymphoblastic leukemia.
Results: Polymorphisms in the genes encoding for methylenetetrahydrofolate reductase ( MTHFR 677C>T) and in dihydrofolate reductase ( DHFR 19 bp deletion) significantly increased the risk of hepatotoxicity in single (odds ratio 5.23, 95% confidence interval 1.13–21.95 and odds ratio 4.57, 95% confidence interval 1.01–20.77, respectively) and in combined analysis (odds ratio 6.82, 95% confidence interval 1.38–33.59). MTHFR 677C>T also increased the risk of leukopenia and gastrointestinal toxicity, whilst thymidylate synthase 28 bp repeat polymorphism increased the risk of anemia (odds ratio 8.48, 95% confidence interval 2.00–36.09). Finally, patients with MTHFR 677TT had a decreased overall survival rate (hazard ratio 2.37, 95% confidence interval 1.46–8.45).
Conclusions: Genotyping of folate polymorphisms might be useful in adult acute lymphoblastic leukemia to optimize methotrexate therapy, reducing the associated toxicity with possible effects on survival.
Key words: gene polymorphisms, adult acute lymphoblastic leukemia, methotrexate-related toxicity, folate.
We studied the consequences of freezing/thawing processes on mRNA contents in MII oocytes after slow-freezing/rapid thawing (SF/RT) and vitrification/warming (V/W) protocols, and compared the results ...to fresh MII oocytes. We quantified the nuclear transcript mRNA responsible for the translation of proteins belonging either to trans-regulatory protein family or to functional structural proteins such as proteins involved in DNA structural organization (NAP1L1, TOP1, H1F0H1), chromosomal structure maintenance (SMC, SCC3, RAD21, SMC1A, SMC1B, STAG3, REC8), mitochondrial energetic pathways (ATP5GJ, SDHC), cell cycle regulation and processes (CLTA, MAPK6, CKS2) and staminal cell potency-development competence stage (DPPA3, OCT4, FOXJ2).
Surplus MII oocytes were donated from patients in IVF cycles and divided in three groups of 15 oocytes. Group 1 was comprised of non-cryopreserved oocytes and Groups 2 and 3 underwent SF/RT and V/W procedures, respectively.
There was an overall decrease of mRNA extracted from cryopreserved oocytes compared to control group. Only 39.4% of mRNA content were preserved after SF/RT while 63.3% of mRNA content were maintained after V/W.
Oocyte cryopreservation is associated with molecular injury associated with the decrease of stored mRNA. However the V/W protocol is more conservative than SF/RT resulting in a level of mRNA sufficient to maintain biologic functions in the subsequent fertilized oocyte.
Hieracium pallidum subsp . aetnense Gottschl., Raimondo & Di Grist. is described and illustrated. H. pallidum is considered as an intermediate species between H. schmidtii and H. racemosum (“ ...schmidtii > racemosum ”) and is placed in H. sect. Grovesiana . By consequence, H. lanudae Gottschl. is transferred to H. pallidum as H. pallidum subsp. lanudae (Gottschl.) Gottschl., Raimondo & Di Grist. A key for the three recognised subspecies of H. pallidum is provided.
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