Diffuse large B-cell lymphoma (DLBCL) patients with relapsed or refractory (RR) disease have poor outcomes with current salvage regimens. We conducted a phase 2 trial to analyse the safety and ...efficacy of adding lenalidomide to R-ESHAP (LR-ESHAP) in patients with RR DLBCL. Subjects received 3 cycles of lenalidomide 10 mg/day on days 1-14 of every 21-day cycle, in combination with R-ESHAP at standard doses. Responding patients underwent autologous stem-cell transplantation (ASCT). The primary endpoint was the overall response rate (ORR) after 3 cycles. Centralized cell-of-origin (COO) classification was performed. Forty-six patients were included. The ORR after LR-ESHAP was 67% (35% of patients achieved complete remission). Patients with primary refractory disease (n = 26) had significantly worse ORR than patients with non-refractory disease (54% vs. 85%, p = 0.031). No differences in response rates according to the COO were observed. Twenty-eight patients (61%) underwent ASCT. At a median follow-up of 41 months, the estimated 3-year PFS and OS were 42% and 48%, respectively. The most common grade ≥3 adverse events were thrombocytopenia (70% of patients), neutropenia (67%) and anaemia (35%). There were no treatment-related deaths during LR-ESHAP cycles. In conclusion, LR-ESHAP is a feasible salvage regimen with promising efficacy results for patients with RR DLBCL.
Mantle cell lymphoma (MCL) is a B-cell malignancy characterized by a poor response to treatment and prognosis. Constitutive activation of different signaling pathways in subsets of MCLs, through ...genetic and/or nongenetic alterations, endows tumor cells with enhanced proliferation and reduced apoptosis. The canonical Wnt pathway (β-catenin/TCF-LEF), implicated in the pathogenesis of numerous cancers, is constitutively active in half of MCLs. Here, we show that ZEB1, a transcription factor better known for promoting metastasis in carcinomas, is expressed in primary MCLs with active Wnt signaling. ZEB1 expression in MCL cells depends on Wnt, being downregulated by β-catenin knockdown or blocking of Wnt signaling by salinomycin. Knockdown of ZEB1 reduces in vitro cell viability and proliferation in MCL cells, and, importantly, tumor growth in mouse xenograft models. ZEB1 activates proliferation-associated (HMGB2, UHRF1, CENPF, MYC, MKI67, and CCND1) and anti-apoptotic (MCL1, BCL2, and BIRC5) genes and inhibits pro-apoptotic ones (TP53, BBC3, PMAIP1, and BAX). We show that ZEB1 expression in MCL cells determines differential resistance to chemotherapy drugs and regulates transporters involved in drug influx/efflux. Downregulation of ZEB1 by salinomycin increases the sensitivity of MCL cells to the cytotoxic effect of doxorubicin, cytarabine and gemcitabine. Lastly, salinomycin and doxorubicin display a synergistic effect in established and primary MCL cells. These results identify ZEB1 in MCL where it promotes cell proliferation, enhanced tumor growth and a differential response to chemotherapy drugs. ZEB1 could thus potentially become a predictive biomarker and therapeutic target in this lymphoma.
PCR-based immunoglobulin (Ig)/T-cell receptor (TCR) clonality testing in suspected lymphoproliferations has largely been standardized and has consequently become technically feasible in a routine ...diagnostic setting. Standardization of the pre-analytical and post-analytical phases is now essential to prevent misinterpretation and incorrect conclusions derived from clonality data. As clonality testing is not a quantitative assay, but rather concerns recognition of molecular patterns, guidelines for reliable interpretation and reporting are mandatory. Here, the EuroClonality (BIOMED-2) consortium summarizes important pre- and post-analytical aspects of clonality testing, provides guidelines for interpretation of clonality testing results, and presents a uniform way to report the results of the Ig/TCR assays. Starting from an immunobiological concept, two levels to report Ig/TCR profiles are discerned: the technical description of individual (multiplex) PCR reactions and the overall molecular conclusion for B and T cells. Collectively, the EuroClonality (BIOMED-2) guidelines and consensus reporting system should help to improve the general performance level of clonality assessment and interpretation, which will directly impact on routine clinical management (standardized best-practice) in patients with suspected lymphoproliferations.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a very rare disease that currently lacks genomic and genetic biomarkers to assist in its clinical management. We performed whole-exome ...sequencing (WES) of three BPDCN cases. Based on these data, we designed a resequencing approach to identify mutations in 38 selected genes in 25 BPDCN samples. WES revealed 37-99 deleterious gene mutations per exome with no common affected genes between patients, but with clear overlap in terms of molecular and disease pathways (hematological and dermatological disease). We identified for the first time deleterious mutations in IKZF3, HOXB9, UBE2G2 and ZEB2 in human leukemia. Target sequencing identified 29 recurring genes, ranging in prevalence from 36% for previously known genes, such as TET2, to 12-16% for newly identified genes, such as IKZF3 or ZEB2. Half of the tumors had mutations affecting either the DNA methylation or chromatin remodeling pathways. The clinical analysis revealed that patients with mutations in DNA methylation pathway had a significantly reduced overall survival (P=0.047). We provide the first mutational profiling of BPDCN. The data support the current WHO classification of the disease as a myeloid disorder and provide a biological rationale for the incorporation of epigenetic therapies for its treatment.
Abstract
Background
Nonalcoholic fatty liver disease (NAFLD) is a major nonacquired immune deficiency syndrome-defining condition for persons with human immunodeficiency virus (PWH). We aimed to ...validate noninvasive tests for the diagnosis of NAFLD in PWH.
Methods
This is a cross-sectional study of PWH on stable antiretroviral therapy with persistently elevated transaminases and no known liver disease. The area under the receiver operating characteristic curve (AUROC) was calculated to compare the diagnostic accuracy of liver biopsy with abdominal ultrasound, transient elastography (TE) (including controlled attenuation parameter CAP), and noninvasive markers of steatosis (triglyceride and glucose index TyG, hepatic steatosis index HSI, fatty liver index FLI) and fibrosis (FIB-4, aminotransferase-to-platelet ratio index APRI, NAFLD fibrosis score). We developed a diagnostic algorithm with serial combinations of markers.
Results
Of 146 patients with increased transaminase levels, 69 underwent liver biopsy (90% steatosis, 61% steatohepatitis, and 4% F ≥3). The AUROC for steatosis was as follows: ultrasound, 0.90 (0.75–1); CAP, 0.94 (0.88–1); FLI, 0.81 (0.58–1); HSI, 0.74 (0.62–0.87); and TyG, 0.75 (0.49–1). For liver fibrosis ≥F3, the AUROC for TE, APRI, FIB-4, and NAFLD fibrosis score was 0.92 (0.82–1), 0.96 (0.90–1), 0.97 (0.93–1), and 0.85 (0.68–1). Optimal diagnostic performance for liver steatosis was for 2 noninvasive combined models of tests with TyG and FLI/HSI as the first tests and ultrasound or CAP as the second tests: AUROC = 0.99 (0.97–1, P < .001) and 0.92 (0.77–1, P < .001).
Conclusions
Ultrasound and CAP performed best in diagnosing liver steatosis, and FLI, TyG, and HSI performed well. We propose an easy-to-implement algorithm with TyG or FLI as the first test and ultrasound or CAP as the second test to accurately diagnose or exclude NAFLD.
An easy-to-implement algorithm diminishes diagnostic uncertainty and the likelihood of diagnostic errors, thus eventually reducing the need for liver biopsy. Ultrasound and controlled attenuation parameter perform very well in diagnosing liver steatosis in persons with HIV.
The purpose of this study was to determine the maximum amount of lead that can be electrodeposited on a graphite cathode during the application of the electro-remediation technique. The lead comes ...from the reduction of soil contaminated with galena. The project was divided into three sections: the first was an electrochemical study at the microelectrolysis level carried out to evaluate the behavior of galena (lead sulfide, PbS) in the cathodic zone using different electrolytes where the reduction potentials of galena were determined; the second stage consisted of laboratory experiments on the leaching of PbS in mining tailings; finally, the maximum electrodeposition of lead on graphite electrodes was evaluated. Different electrolytes at different concentrations were studied as variables. The microelectrolysis level results show that ferric chloride (FeCl
3
) is a faster leaching agent than hydrochloric acid (HCl) or sodium chloride. However, in the case of the electrodeposition of lead, the HCl electrolytic medium was the best of the tested solutions.
Follicular lymphoma (FL) is characterized besides the t(14;18)(q32;q21), by recurrent chromosomal alterations and somatic mutations. In this study, we analyzed cases of FL in situ (FLIS) without ...manifest FL (mFL), partial involvement by FL (PFL) and paired cases of FLIS and mFL to detect possible early chromosomal imbalances, mutations, as well as DNA-methylation patterns of genomic regions of selected genes. We demonstrate that all paired FLIS and mFL cases were clonally related, based on IGH rearrangement patterns and BCL2 breakpoint sequences. FLIS and PFL had no or few secondary chromosomal imbalances detectable by array comparative genomic hybridization (FLIS 0.8 copy number alterations (CNA)/case; PFL 2.0 CNA/case; mFL 6.3 CNA/case) and a lower level of DNA methylation of genes recurrently de novo methylated in lymphomas, as compared with mFL. EZH2 Tyr641 mutations were detected in a subset of both FLIS (2/9) and PFL (1/3) cases. In conclusion, these findings provide evidence that FLIS represents a FL precursor lesion of long-lived clonal B cells carrying the t(14;18) with no or few secondary genetic changes. Our data suggest that there may be more than one distinct lesion driving the progression from FLIS to manifest lymphoma.
In the present paper we investigated the effects of sub-lethal concentrations of Cu
2+ in the growth and metabolism of
Scenedesmus incrassatulus. We found that the effect of Cu
2+ on growth, ...photosynthetic pigments (chlorophylls and carotenoids) and metabolism do not follow the same pattern. Photosynthesis was more sensitive than respiration. The analysis of chlorophyll
a fluorescence transient shows that the effect of sub-lethal Cu
2+ concentration
in vivo, causes a reduction of the active PSII reaction centers and the primary charge separation, decreasing the quantum yield of PSII, the electron transport rate and the photosynthetic O
2 evolution. The order of sensitivity found was: Growth
>
photosynthetic pigments content
=
photosynthetic O
2 evolution
>
photosynthetic electron transport
>
respiration. The uncoupled relationship between growth and metabolism is discussed.
Gene expression profiling (GEP) has stratified diffuse large B-cell lymphoma (DLBCL) into molecular subgroups that correspond to different stages of lymphocyte development-namely germinal center ...B-cell like and activated B-cell like. This classification has prognostic significance, but GEP is expensive and not readily applicable into daily practice, which has lead to immunohistochemical algorithms proposed as a surrogate for GEP analysis. We assembled tissue microarrays from 475 de novo DLBCL patients who were treated with rituximab-CHOP chemotherapy. All cases were successfully profiled by GEP on formalin-fixed, paraffin-embedded tissue samples. Sections were stained with antibodies reactive with CD10, GCET1, FOXP1, MUM1 and BCL6 and cases were classified following a rationale of sequential steps of differentiation of B cells. Cutoffs for each marker were obtained using receiver-operating characteristic curves, obviating the need for any arbitrary method. An algorithm based on the expression of CD10, FOXP1 and BCL6 was developed that had a simpler structure than other recently proposed algorithms and 92.6% concordance with GEP. In multivariate analysis, both the International Prognostic Index and our proposed algorithm were significant independent predictors of progression-free and overall survival. In conclusion, this algorithm effectively predicts prognosis of DLBCL patients matching GEP subgroups in the era of rituximab therapy.
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