1,721,083 research outputs found
Morphological, immunophenotypic, and genetic features of chronic lymphocytic leukemia with trisomy 12: a comprehensive review
Full text linkChronic lymphocytic leukemia is an extremely heterogeneous disease and prognostic factors such as chromosomal abnormalities are important predictors of time to first treatment and survival. Trisomy 12 is the second most frequent aberration detected by fluorescence in situ hybridization at the time of diagnosis (10–25%), and it confers an intermediate prognostic risk, with a median time to first treatment of 33 months and a median overall survival of 114 months. Here, we review the unique morphological, immunophenotypic, and genetic characteristics of patients with chronic lymphocytic leukemia and trisomy 12. These patients carry a significantly higher expression of CD19, CD22, CD20, CD79b, CD24, CD27, CD38, CD49d, sIgM, sIgk, and sIgλ and lower expression of CD43 compared with patients with normal karyotype. Circulating cells show increased expression of the integrins CD11b, CD18, CD29, and ITGB7, and of the adhesion molecule CD323. Patients with chronic lymphocytic leukemia and trisomy 12 frequently have unmutated IGHV, ZAP-70 positivity, and closely homologous stereotyped B-cell receptors. They rarely show TP53 mutations but frequently have NOTCH1 mutations, which can be identified in up to 40% of those with a rapidly progressive clinical course
Measurable residual disease in chronic lymphocytic leukemia
Full text linkMeasurable residual disease (MRD) is defined as the presence of residual cancer cells after treatment in patients with clinically undetectable disease, who would otherwise be considered in complete remission. It is a highly sensitive parameter which indicates the disease burden and predicts survival in this setting of patients. In recent years, MRD has gained a role in many hematological malignancies as a surrogate endpoint for clinical trials: undetectable MRD has been correlated to longer progression free survival (PFS) and overall survival (OS). New drugs and combinations have been developed with the aim to achieve MRD negativity, which would indicate favorable prognosis. Different methods to measure MRD have also been devised, which include flow cytometry, polymerase chain reaction (PCR) and next generation sequencing (NGS), with different sensitivity and accuracy in evaluating deep remission after treatment. In this review, we will analyze the current recommendations for the detection of MRD, with particular focus on its role in Chronic Lymphocytic Leukemia (CLL), as well as the different detection methods. Moreover, we will discuss the results of clinical trials and the role of MRD in new therapeutic schemes with inhibitors and monoclonal antibodies. MRD is not currently used in the clinical practice to evaluate response to treatment, due to technical and economical limitations, but it’s gaining more and more interest in trials settings, especially since the introduction of venetoclax. The use of MRD in trials will likely be followed by a broader practical application in the future. The aim of this work is to provide a reader-friendly summary of the state of art in the field, as MRD will soon become an accessible tool to evaluate our patients, predict their survival and guide physician’s therapeutic choices and preferences
Allele-specific loss and transcription of the miR-15a/16-1 cluster in chronic lymphocytic leukemia
Full text linkDeregulation of the miR-15a/16-1 cluster has a key role in the pathogenesis of chronic lymphocytic leukemia (CLL), a clinically heterogeneous disease with indolent and aggressive forms. The miR-15a/16-1 locus is located at 13q14, the most frequently deleted region in CLL. Starting from functional investigations of a rare SNP upstream the miR cluster, we identified a novel allele-specific mechanism that exploits a cryptic activator region to recruit the RNA polymerase III for miR-15a/16-1 transcription. This regulation of the miR-15a/16-locus is independent of the DLEU2 host gene, which is often transcribed monoallellically by RPII. We found that normally one allele of miR-15a/16-1 is transcribed by RNAPII, the other one by RNAPIII. In our subset of CLL patients harboring 13q14 deletions, exclusive RNA polymerase III (RPIII)-driven transcription of the miR-15a/16-1 was the consequence of loss of the RPII-regulated allele and correlated with high expression of the poor prognostic marker ZAP70 (P=0.019). Thus, our findings point to a novel biological process, characterized by double allele-specific transcriptional regulation of the miR-15a/16-1 locus by alternative mechanisms. Differential usage of these mechanisms may distinguish at onset aggressive from indolent forms of CLL. This provides a basis for the clinical heterogeneity of the CLL patients carrying 13q14 deletions. © 2015 Macmillan Publishers Limited
New developments in the management of chronic lymphocytic leukemia: role of ofatumumab
Full text linkOfatumumab is one of the three anti-CD20 monoclonal antibodies currently available for the treatment of chronic lymphocytic leukemia (CLL). The US Food and Drug Administration (FDA) approved the use of ofatumumab in patients with CLL refractory to fludarabine and alemtuzumab in 2009, and the European Medicines Agency (EMA) granted approval for the same indication in 2010. Subsequent positive results of ofatumumab in combination with chlorambucil in treatment-naïve patients led the FDA in April 2014 to approve the use of this combination for first-line treatment of patients with CLL for whom fludarabine-based therapy is considered inappropriate. Later that year, the EMA approved the use of ofatumumab in combination with chlorambucil or bendamustine for the same indication. Ofatumumab has also shown potential as maintenance therapy for patients with relapsed CLL; an application to broaden the label for ofatumumab as maintenance therapy was submitted earlier this year to the EMA and FDA. Finally, ofatumumab has shown promising activity in combination with ibrutinib or idelalisib in relapsed/refractory CLL patients; combinations of ofatumumab with B-cell-receptor pathway inhibitors could represent another potential use of this antibody in the near future
Treatment approach for elderly and unfit patients with chronic lymphocytic leukemia
No full textIntroduction: Elderly patients with chronic lymphocytic leukemia (CLL) or patients with comorbidities are often treated with chlorambucil (Chl) as front-line therapy despite relatively low response rates. The addition of a monoclonal anti-CD20 antibody to Chl substantially increases response rates and prolongs progression-free survival (PFS) in these patients, without increasing toxicity. As a result, the ESMO guidelines recommend that previously untreated CLL patients with relevant co-morbidity, but without TP53 deletion/mutation, should be treated with the combination of Chl plus an anti-CD20 antibody (rituximab, ofatumumab or obinutuzumab). Areas covered: This review focuses on the treatment approach of elderly and unfit patients with untreated chronic lymphocytic leukemia. Expert commentary: The addition of a monoclonal anti-CD20 antibody to Chl is currently the suggested treatment in this subset of CLL patients. The choice of the anti-CD20 antibody remains an open question, although obinutuzumab was found to be superior to rituximab, in a head-to-head comparison of Chl-based combinations, in untreated CLL patients with comorbidities, with higher progression free survival, complete remission rates and minimal residual disease-negative remissions. Because patients with a TP53 deletion/mutation are resistant to chemo-immunotherapy, treatment with the BTK inhibitor ibrutinib is recommended in this setting
Chronic Lymphocitic Leukaemia: Census of Patients Treated in Italian Haematology Units
No full textThis study was conducted by contacting the population of the Italian haematology units and collecting from 68% of them data concerning the number of patients with chronic lymphocytic leukaemia visited over the previous 12 months, with the aim of obtaining an overview of the treatment of this disease and comparing the results with the prevalence estimates found in literature. The projection obtained (about 17,000 patients visited in the previous 12 months) is probably overestimated because of double-counting of patients who may have been treated at two different facilities during the year, although it is also underestimated since the internal medicine units were not involved. The balance of these two opposite factors is not known. It is important to bear in mind the approximation with which the count was performed in facilities for which no official data were available. Albeit with these limits, the results obtained are in line with some existing prevalence data and make it possible to determine the portion of patients at different Binet stages and in the various age ranges, identifying the corresponding therapeutic treatments. Use of the CIRS scale to classify patients as FIT and UNFIT was seen to be still somewhat limited
'Secondary chronic myeloid leukemia': comparison between patients previously exposed or not to chemo- and/or radiotherapy
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Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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