Background: Different prognostic scores have been proposed to predict the outcome of follicular lymphoma (FL) patients at diagnosis. A new prognostic index specifically addressing FL patients, the ...Follicular Lymphoma International Prognostic Index (FLIPI), has recently been developed, which might also be useful in patients with progression. Patients and methods: One hundred and three patients (55 male, 48 female; median age 59 years) with FL in first relapse/progression after an initial response to therapy (50 complete responders/ 53 partial responders) were included in the study. Results: Five-year survival from progression (SFP) was 55% (95% confidence interval 44%–66%). The distribution according to the FLIPI at relapse was 39% good prognosis, 24% intermediate prognosis and 37% poor prognosis. Five-year SFP for these groups were 85%, 79% and 28%, respectively (P < 0.0001). Other variables at relapse with prognostic significance for SFP were age, presence of B symptoms, performance status, bulky disease, number of involved nodal sites, lactate dehydrogenase level, hemoglobin level, histological transformation, the Italian Lymphoma Intergroup prognostic index for FL and the International Prognostic Index for aggressive lymphomas. In the multivariate analysis bulky disease (P=0.01), presence of B symptoms (P=0.03) and FLIPI at relapse (P=0.0003) were the most important variables for predicting SFP. Conclusions: In patients with FL at first relapse/progression, the FLIPI, along with the presence of bulky disease and B symptoms, are features that predict SFP and thus could be useful to select candidates for experimental treatments.
Chromosomal imbalances were examined by comparative genomic hybridization in 30 cases of B-cell chronic lymphocytic leukemia (CLL) at diagnosis, in sequential samples from 17 of these patients, and ...in 6 large B-cell lymphomas transformed from CLL Richter's syndrome (RS) with no available previous sample. The most common imbalances in CLL at diagnosis were gains in chromosome 12 (30%), and losses in chromosomes 13 (17%), 17p (17%), 8p (7%), 11q (7%), and 14q (7%). The analysis of sequential samples showed an increased number of chromosomal imbalances in 6 of 10 (60%) patients with clinical progression and in 2 patients with stable stage C disease. No karyotypic evolution was observed in four cases with stable stage A disease and in one RS clonally unrelated to the previous CLL. Gains of 2pter, and 7pter, and losses of 8p, 11q, and 17p were recurrent alterations associated with karyotype progression. RS showed a higher number of gains, losses, total alterations, and losses of 8p and chromosome 9 than CLL at diagnosis. 17p losses were associated with p53 gene mutations and with a significantly higher number of chromosomal imbalances than tumors with normal chromosome 17 profile. However, no relationship was observed between 9p deletions and p16
INK4a gene alterations. Losses of 17p and an increased number of losses at diagnosis were significantly associated with a shorter survival. These findings indicate that CLL has frequent chromosomal imbalances, which may increase during the progression of the disease and transformation into large cell lymphoma. Genetic alterations detected by comparative genomic hybridization may also be of prognostic significance.
In this study, we determined the presence of virulence factors in nonoutbreak, high-risk clones and other isolates belonging to less common sequence types associated with the spread of ...OXA-48-producing Klebsiella pneumoniae clinical isolates from The Netherlands (
= 61) and Spain (
= 53). Most isolates shared a chromosomally encoded core of virulence factors, including the enterobactin gene cluster, fimbrial
and
gene clusters, and urea metabolism genes (
). We observed a high diversity of K-Locus and K/O loci combinations, KL17 and KL24 (both 16%), and the O1/O2v1 locus (51%) being the most prevalent in our study. The most prevalent accessory virulence factor was the yersiniabactin gene cluster (66.7%). We found seven yersiniabactin lineages-
9,
10,
13,
14,
16,
17, and
27-which were chromosomally embedded in seven integrative conjugative elements (ICE
): ICE
, ICE
, ICE
, ICE
, ICE
, ICE
, and ICE
, respectively. Multidrug-resistant lineages-ST11, ST101, and ST405-were associated with
10/ICE
,
9/ICE
, and
27/ICE
, respectively. The fimbrial adhesin
operon (
) was predominant among ST14, ST15, and ST405 isolates, as well as the ferric uptake system
, which was also predominant among ST101 isolates. No convergence of hypervirulence and resistance was observed in this collection of OXA-48-producing K. pneumoniae clinical isolates. Nevertheless, two isolates, ST133 and ST792, were positive for the genotoxin colibactin gene cluster (ICE
). In this study, the integrative conjugative element, ICE
, was the major vehicle for yersiniabactin and colibactin gene clusters spreading.
Convergence of multidrug resistance and hypervirulence in Klebsiella pneumoniae isolates has been reported mostly related to sporadic cases or small outbreaks. Nevertheless, little is known about the real prevalence of carbapenem-resistant hypervirulent K. pneumoniae since these two phenomena are often separately studied. In this study, we gathered information on the virulent content of nonoutbreak, high-risk clones (i.e., ST11, ST15, and ST405) and other less common STs associated with the spread of OXA-48-producing K. pneumoniae clinical isolates. The study of virulence content in nonoutbreak isolates can help us to expand information on the genomic landscape of virulence factors in K. pneumoniae population by identifying virulence markers and their mechanisms of spread. Surveillance should focus not only on antimicrobial resistance but also on virulence characteristics to avoid the spread of multidrug and (hyper)virulent K. pneumoniae that may cause untreatable and more severe infections.
: Background and objectives: Patients with follicular lymphoma (FL) in advanced stages are currently deemed incurable with standard treatments. However, FL is considered to be eradicable in the ...small group of patients presenting with localized disease. The objective of this study was to analyze the clinical features and the outcome of a series of patients with FL in early stages with a long follow‐up.Patients and methods: A total of 48 patients (25m/23f; median age: 50 yr) diagnosed consecutively with FL in Ann Arbor stage I (25 cases) or II (23) at a single institution with a median follow‐up of 9.5 yr were included in the study. Main biological and clinical characteristics at diagnosis, including Follicular Lymphoma International Prognostic Index (FLIPI) were analyzed; treatment and response were assessed and analyzed for prognosis.Results: The histologic subtypes were: FL type I, 20 cases (42%); type II, 24 (50%); type III, three (6%); and unclassifiable, one (2%). Distribution according to FLIPI was: low risk (36 cases) and intermediate risk (five cases). Treatment mainly consisted of combination chemotherapy (CHOP in 34 cases) plus involved‐field radiotherapy in 26 cases. Forty patients (89%) achieved a complete response (CR), three (7%) a partial response, and two (4%) were non‐responders; the remaining three patients did not receive therapy. No initial variable predicted CR achievement. About 57% of the patients in CR eventually relapsed with a relapse risk of 46% at 10 yr. Intermediate‐risk FLIPI predicted failure‐free survival. Histologic transformation was observed in six patients with a 10‐yr risk of transformation of 13%. Twelve patients died during follow‐up, in two cases as a result of unrelated causes. Overall survival (OS) at 10 yr was 79%. The FLIPI was the sole variable predicting OS.Conclusions: Although the majority of patients with localized FL achieve CR, the risk of relapse is high. The FLIPI is of prognostic value in these patients.
Abstract
Introduction: Clonal evolution drives cancer development due to the emergence and/or selection of proliferatively advantageous subclones. Its understanding may facilitate the design of ...anticipation-based management strategies. Richter transformation (RT) is a paradigmatic tumor evolution in which chronic lymphocytic leukemia (CLL), an indolent neoplasia of mature B-cells, transforms into a high-grade lymphoma, usually diffuse large B-cell lymphoma (DLBCL), conferring a dismal prognosis. The evolutionary trajectories of RT and its driving (epi)genomic mechanisms remain largely unknown.
Aims: To reconstruct the evolutionary history of RT and to reveal the molecular processes underlying this transformation.
Methods: We characterized the whole genome (WGS), epigenome (DNA methylation, H3K27ac, ATAC-seq), and transcriptome (RNA-seq), combined with single-cell DNA and RNA sequencing analyses, of 19 CLL patients developing RT before (n=3) or after treatment with chemoimmunotherapy (n=6) and targeted therapies (BCR or BCL2 inhibitors, n=10). We analyzed 54 longitudinal samples covering up to 19 years of disease course.
Results: Our WGS analyses uncovered that RT is characterized by a remarkable structural complexity. We also identified a novel treatment-independent RT-specific mutational process, which we named SBS-RT. The genetic driver landscape of RT is a compendium of alterations in genes involved in cell cycle, MYC, and NF-κB pathways, frequently targeted in single catastrophic events including chromothripsis and chromoplexy. The WGS-based phylogenic reconstruction and single-cell DNA/RNA-seq analyses identified a very early diversification of CLL leading to emergence of RT-cells carrying specific genetic drivers and transcriptomic profiles of RT already at CLL diagnosis. These small subclones were dormant for 6-19 years until rapid expansion associated with the clinical transformation. While the DNA methylome kept track of the cell of origin and proliferative history of RT cells, their chromatin configuration and transcriptional program converged into the overexpression of cell cycle regulators, Toll-like receptors, MYC, MTORC1, and OXPHOS related transcripts, as well as downregulation of BCR pathway. This phenotypic shift was related to de novo activation of key transcription factors. In vitro experiments confirmed that RT cells have a 4-fold higher oxygen consumption at routine respiration and electron transfer system capacity compared to CLL. The resistance of RT to BCR inhibition is consistent with its high OXPHOS and low BCR signaling, which mimics de novo DLBCL-OXPHOS insensitive to BCR inhibition. This OXPHOShigh-BCRlow transcriptional axis of RT can be exploited therapeutically.
Conclusions: These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover therapeutic targets for the, once expanded, lethal Richter transformation.
Citation Format: Ferran Nadeu, Romina Royo, Ramon Massoni-Badosa, Beatriz Garcia-Torre, Martí Duran-Ferrer, Kevin J. Dawson, Marta Kulis, Ander Diaz-Navarro, Neus Villamor, Juan L. Melero, Vicente Chapaprieta, Ana Dueso-Barroso, Julio Delgado, Riccardo Moia, Sara Ruiz-Gil, Domenica Marchese, Núria Verdaguer-Dot, Mónica Romo, Maria Rozman, Gerard Frigola, Alfredo Rivas-Delgado, Tycho Baumann, Miguel Alcoceba, Marcos González, Fina Climent, Pau Abrisqueta, Josep Castellví, Francesc Bosch, Marta Aymerich, Anna Enjuanes, Sílvia Ruiz-Gaspà, Armando López-Guillermo, Pedro Jares, Sílvia Beà, Dolors Colomer, Núria López-Bigas, Josep LlGelpí, David Torrents, Peter J. Campbell, Ivo Gut, Pablo M. Garcia-Roves, Davide Rossi, Gianluca Gaidano, Xose S. Puente, Holger Heyn, Francesco Maura, José I. Martín-Subero, Elías Campo. Early seeding of Richter transformation in chronic lymphocytic leukemia abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3795.
Background & Aims: The association of prazosin to propranolol enhances the decrease in portal pressure but may cause hypotension and sodium retention. The aim of this study was to compare the portal ...pressure reduction and safety of the combination of propranolol plus prazosin with that of propranolol plus isosorbide-5-mononitrate (ISMN).
Methods: Fifty-six portal-hypertensive cirrhotics received randomly propranolol plus prazosin (n = 28) or propranolol plus ISMN (n = 28) orally for 3 months. Hemodynamics and liver and renal function were assessed at baseline and after 3 months.
Results: Propranolol plus prazosin caused a greater reduction in hepatic venous pressure gradient (HVPG) than propranolol plus ISMN (−24.2% ± 11% vs. −16.1% ± 11%;
P < 0.01). A reduction in HVPG of >20% was significantly more frequent in the propranolol plus prazosin group than in the propranolol plus ISMN group (85% vs. 53%;
P < 0.05). Neither treatment modified hepatic blood flow, quantitative liver function test results, glomerular filtration rate, plasma renin activity, or plasma aldosterone level. Side effects occurred in 13 patients receiving propranolol plus prazosin compared with 7 receiving propranolol plus ISMN (
P = 0.16).
Conclusions: Propranolol plus prazosin has a greater portal pressure–lowering effect than propranolol plus ISMN. Both therapies were safe for liver and renal function. However, the combination of propranolol plus prazosin caused a greater decrease in arterial pressure and was less well tolerated than propranolol plus ISMN.
GASTROENTEROLOGY 1998;115:116-123
To investigate the role of the cell cycle regulators p21(Waf1), p27(Kip1), retinoblastoma (Rb), and cyclin D1 in Richter's transformation of chronic lymphocytic leukemia (CLL), we analyzed 19 CLL and ...eight Richter's syndrome (RS) tumors, previously characterized for p53 and ARF/INK4a abnormalities. p21(Waf1)immunohistochemical expression was negative in 12 of 15 CLL (80%), whereas it was moderate or strong in three of seven RS (43%). p21(Waf1) gene was in germline configuration in all the tumors analyzed. Four immunohistochemical patterns of p53 and p21(Waf1) expression were observed: (1) p53-/p21- in 10 of 15 CLL (67%), but only in two of six RS (33%); (2) p53+/p21+ in three CLL (20%) and two RS (33%); (3) p53-/p21+ in one RS; and (4) p53++/p21- in two CLL and one RS. Two p53+/p21+ CLL evolved into RS. p53 mutations clustered around the p53++/p21- (two CLL and one RS) and p53-/p21- (one CLL and one RS) tumors. While the majority of CLL displayed strong p27 immunoreactivity, RS tumors were constantly p27-negative. p27(Kip1) gene was in germline configuration in all the tumors analyzed. Most CLL cases were negative for Rb expression. In contrast, all RS exhibited strong Rb expression. Cyclin D1 overexpression was only detected in one CLL evolving into RS and one RS. In conclusion, a p53+/p21- immunohistochemical pattern is shown exclusively by p53-mutated CLL/RS. Additionally, our results suggest a possible implication of moderate/strong p21(Waf1) expression, loss of p27 expression, and cyclin D1 overexpression in the Richter's transformation of CLL.
Department of Hematology, Hospital Clinic, Universitat de Barcelona, Villarroel 170, 08036 Barcelona, Spain.
BACKGROUND AND OBJECTIVES: Microsatellite instability (MSI) is characterized by ...tumor-associated alterations in the germline size of microsatellite repeats caused by a reduced efficacy of the DNA mismatch repair machinery. The aim of this study was to investigate the presence of MSI in a number of cases of indolent and aggressive mantle cell lymphoma (MCL) and B-cell chronic lymphocytic leukemia (B-CLL) to determine its possible role in the initial development and progression of these disorders. DESIGN AND METHODS: We examined the presence of MSI in 28 B-CLL, 24 typical and 4 transformed B-CLL (Richter's syndrome) and 29 MCL, 19 typical and 10 blastoid variants by using a panel of 10 microsatellite markers and analyzed them using an AbiPrism 310 DNA sequencer. Fisher's exact test was used to compare categorical variables and Mann-Whitney's U-test for continuous variables. RESULTS: MSI alterations were not observed in any case of MCL or Richter's syndrome and in only three (13%) patients with typical B-CLL. Two of these patients also had loss of heterozygosity in one of the 10 sites examined. These patients presented with a more advanced stage, diffuse bone marrow involvement, and poorer performance status than patients without these alterations. INTERPRETATION AND CONCLUSIONS: These findings indicate that MSI is not involved in the pathogenesis or progression of B-CLL and MCL but may appear in a small subset of patients with advanced B-CLL.
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