Mitochondrial Lipids: From Membrane Organization to Apoptotic Facilitation.

Mitochondria are the most complex intracellular organelles, their function combining energy production for survival and apoptosis facilitation for death. Such a multivariate physiology is structurally and functionally reflected upon their membrane configuration and lipid composition. Mitochondrial double membrane lipids, with cardiolipin as the protagonist, show an impressive level of complexity that is mandatory for maintenance of mitochondrial health and protection from apoptosis. Given that lipidomics is an emerging field in cancer research and that mitochondria are the organelles with the most important role in malignant maintenance knowledge of the mitochondrial membrane, lipid physiology in health is mandatory. In this review, we will thus describe the delicate nature of the healthy mitochondrial double membrane and its role in apoptosis. Emphasis will be given on mitochondrial membrane lipids and the changes that they undergo during apoptosis induction and progression.

Real-life experience with the combination of polatuzumab vedotin, rituximab, and bendamustine in aggressive B-cell lymphomas.

Transplant-ineligible relapsed/refractory (rr) diffuse large B-cell lymphoma (DLBCL) patients represent an unmet medical need. Polatuzumab vedotin (Pola), an anti-CD79b antibody-drug-conjugate (ADG), with bendamustine- rituximab(BR) has recently gained approval for these patients, both in the USA and Europe, based on the GO29365 phase IIb trial. Real-life data with Pola are extremely limited. We report the outcomes of 61 Greek patients, who received Pola-(B)R mainly within a compassionate use program. Treatment was given for up to six 21-day cycles. Bendamustine was omitted in three cases due to previous short-lived responses. Fourty-nine rrDLBCL(efficacy cohort-EC) and 58 rr aggressive B-NHL (safety cohort-SC) patients received at least 1 Pola-BR cycle. Twenty-one (43%) patients of the EC responded with 12/49 (25%) CR and 9/49 (18%) PR as best response. Median progression-free survival, overall survival and duration of response were 4.0, 8.5, and 8.5 months respectively, while 55% of patients experienced a grade ≥3 adverse event, mainly hematologic. Treatment discontinuations and death during treatment were mainly due to disease progression. Twenty-two (41%) patients received further treatment; 11/22 are still alive, including one after CAR-T cells, and two after stem cell transplantation. Our data confirm that Pola-BR is a promising treatment for rrDLBCL patients, inducing an adequate response rate with acceptable toxicity. Pola-BR could be used as bridging therapy before further consolidative treatments.

Metabolic Swifts Govern Normal and Malignant B Cell Lymphopoiesis.

B lymphocytes are an indispensable part of the human immune system. They are the effective mediators of adaptive immunity and memory. To accomplish specificity against an antigen, and to establish the related immunologic memory, B cells differentiate through a complicated and strenuous training program that is characterized by multiple drastic genomic modifications. In order to avoid malignant transformation, these events are tightly regulated by multiple checkpoints, the vast majority of them involving bioenergetic alterations. Despite this stringent control program, B cell malignancies are amongst the top ten most common worldwide. In an effort to better understand malignant pathobiology, in this review, we summarize the metabolic swifts that govern normal B cell lymphopoiesis. We also review the existent knowledge regarding malignant metabolism as a means to unravel new research goals and/or therapeutic targets.

From the (Epi)Genome to Metabolism and Vice Versa; Examples from Hematologic Malignancy.

Hematologic malignancies comprise a heterogeneous group of neoplasms arising from hematopoietic cells or their precursors and most commonly presenting as leukemias, lymphomas, and myelomas. Genetic analyses have uncovered recurrent mutations which initiate or accumulate in the course of malignant transformation, as they provide selective growth advantage to the cell. These include mutations in genes encoding transcription factors and epigenetic regulators of metabolic genes, as well as genes encoding key metabolic enzymes. The resulting alterations contribute to the extensive metabolic reprogramming characterizing the transformed cell, supporting its increased biosynthetic needs and allowing it to withstand the metabolic stress that arises as a consequence of increased metabolic rates and changes in its microenvironment. Interestingly, this cross-talk is bidirectional, as metabolites also signal back to the nucleus and, via their widespread effects on modulating epigenetic modifications, shape the chromatin landscape and the transcriptional programs of the cell. In this article, we provide an overview of the main metabolic changes and relevant genetic alterations that characterize malignant hematopoiesis and discuss how, in turn, metabolites regulate epigenetic events during this process. The aim is to illustrate the intricate interrelationship between the genome (and epigenome) and metabolism and its relevance to hematologic malignancy.

Akt Signaling Pathway Is Activated in the Minor Salivary Glands of Patients with Primary Sjögren's Syndrome.

Primary Sjögren's syndrome (pSS) is an autoimmune exocrinopathy of mainly the salivary and lacrimal glands associated with high prevalence of lymphoma. Akt is a phosphoinositide-dependent serine/threonine kinase, controlling numerous pathological processes, including oncogenesis and autoimmunity. Herein, we sought to examine its implication in pSS pathogenesis and related lymphomagenesis. The expression of the entire and activated forms of Akt (partially and fully activated: phosphorylated at threonine-308 (T308) and serine-473 (S473), respectively), and two of its substrates, the proline-rich Akt-substrate of 40 kDa (PRAS40) and FoxO1 transcription factor has been immunohistochemically examined in minor salivary glands (MSG) of pSS patients (n = 29; including 9 with pSS-associated lymphoma) and sicca-complaining controls (sicca-controls; n = 10). The entire and phosphorylated Akt, PRAS40, and FoxO1 molecules were strongly, uniformly expressed in the MSG epithelia and infiltrating mononuclear cells of pSS patients, but not sicca-controls. Morphometric analysis revealed that the staining intensity of the fully activated phospho-Akt-S473 in pSS patients (with or without lymphoma) was significantly higher than sicca-controls. Akt pathway activation was independent from the extent or proximity of infiltrates, as well as other disease features, including lymphoma. Our findings support that the Akt pathway is specifically activated in MSGs of pSS patients, revealing novel therapeutic targets.

Exploiting the Role of Hypoxia-Inducible Factor 1 and Pseudohypoxia in the Myelodysplastic Syndrome Pathophysiology.

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem (HSCs) and/or progenitor cells disorders. The established dependence of MDS progenitors on the hypoxic bone marrow (BM) microenvironment turned scientific interests to the transcription factor hypoxia-inducible factor 1 (HIF-1). HIF-1 facilitates quiescence maintenance and regulates differentiation by manipulating HSCs metabolism, being thus an appealing research target. Therefore, we examine the aberrant HIF-1 stabilization in BMs from MDS patients and controls (CTRLs). Using a nitroimidazole-indocyanine conjugate, we show that HIF-1 aberrant expression and transcription activity is oxygen independent, establishing the phenomenon of pseudohypoxia in MDS BM. Next, we examine mitochondrial quality and quantity along with levels of autophagy in the differentiating myeloid lineage isolated from fresh BM MDS and CTRL aspirates given that both phenomena are HIF-1 dependent. We show that the mitophagy of abnormal mitochondria and autophagic death are prominently featured in the MDS myeloid lineage, their severity increasing with intra-BM blast counts. Finally, we use in vitro cultured CD34+ HSCs isolated from fresh human BM aspirates to manipulate HIF-1 expression and examine its potential as a therapeutic target. We find that despite being cultured under 21% FiO2, HIF-1 remained aberrantly stable in all MDS cultures. Inhibition of the HIF-1α subunit had a variable beneficial effect in all <5%-intra-BM blasts-MDS, while it had no effect in CTRLs or in ≥5%-intra-BM blasts-MDS that uniformly died within 3 days of culture. We conclude that HIF-1 and pseudohypoxia are prominently featured in MDS pathobiology, and their manipulation has some potential in the therapeutics of benign MDS.

Transcriptome reprogramming and myeloid skewing in haematopoietic stem and progenitor cells in systemic lupus erythematosus.

OBJECTIVES: Haematopoietic stem and progenitor cells (HSPCs) are multipotent cells giving rise to both myeloid and lymphoid cell lineages. We reasoned that the aberrancies of immune cells in systemic lupus erythematosus (SLE) could be traced back to HSPCs. METHODS: A global gene expression map of bone marrow (BM)-derived HSPCs was completed by RNA sequencing followed by pathway and enrichment analysis. The cell cycle status and apoptosis status of HSPCs were assessed by flow cytometry, while DNA damage was assessed via immunofluorescence. RESULTS: Transcriptomic analysis of Lin-Sca-1+c-Kit+ haematopoietic progenitors from diseased lupus mice demonstrated a strong myeloid signature with expanded frequencies of common myeloid progenitors (CMPs)-but not of common lymphoid progenitors-reminiscent of a 'trained immunity' signature. CMP profiling revealed an intense transcriptome reprogramming with suppression of granulocytic regulators indicative of a differentiation arrest with downregulation trend of major regulators such as Cebpe, Cebpd and Csf3r, and disturbed myelopoiesis. Despite the differentiation arrest, frequencies of BM neutrophils were markedly increased in diseased mice, suggesting an alternative granulopoiesis pathway. In patients with SLE with severe disease, haematopoietic progenitor cells (CD34+) demonstrated enhanced proliferation, cell differentiation and transcriptional activation of cytokines and chemokines that drive differentiation towards myelopoiesis, thus mirroring the murine data. CONCLUSIONS: Aberrancies of immune cells in SLE can be traced back to the BM HSPCs. Priming of HSPCs and aberrant regulation of myelopoiesis may contribute to inflammation and risk of flare. TRIAL REGISTRATION NUMBER: 4948/19-07-2016.

Clinical and prognostic significance of serum levels of von Willebrand factor and ADAMTS-13 antigens in AL amyloidosis.

Cardiac dysfunction determines prognosis in amyloid light-chain (AL) amyloidosis. The heart is the central organ of the vascular system in which endothelium function is critical for the circulatory homeostasis, but there are limited data on endothelial function in AL amyloidosis. von Willebrand factor (VWF) has been considered as a marker of endothelial activation and dysfunction, whereas a disintegrin and metalloproteinase with thrombospondin type-1 repeats 13 (ADAMTS-13) cleaves VWF multimers, but both have been associated with prognosis in cardiovascular disease. We measured the serum levels of VWF (VWF:Ag) and ADAMTS-13 antigens in 111 newly diagnosed patients with AL amyloidosis. The levels of VWF:Ag were significantly higher than in healthy controls; 76% of patients with AL had VWF:Ag levels higher than the upper levels of controls. There was no significant association of VWF:Ag levels with patterns of organ involvement, free light-chain levels, the levels of cardiac biomarkers, or renal dysfunction but correlated with low systolic blood pressure. VWF:Ag levels ≥230.0 U/dL were associated with higher probability of early death and poor survival independently of cardiac biomarkers and low systolic blood pressure (SBP). Moreover, among patients with Mayo stage III or stage IIIB (that is stage III with N-terminal pro-brain natriuretic peptide [NTproBNP] >8500 pg/mL) disease, VWF:Ag identified subgroups of patients with very poor outcome. Low ADAMTS-13 levels correlated with high levels of NTproBNP but had no independent prognostic significance. In conclusion, high VWF:Ag levels, probably representing endothelial dysfunction, are associated with prognosis in patients with AL amyloidosis, independently of other features of the disease or cardiac biomarkers.

Evaluation of the Revised International Staging System in an independent cohort of unselected patients with multiple myeloma.

The Revised International Staging System (R-ISS) was recently introduced in order to improve risk stratification over that provided by the widely used standard International Staging System. In addition to the parameters of the standard system, the R-ISS incorporates the presence of chromosomal abnormalities detected by interphase fluorescence in situ hybridization [t(4;14), t(14;16) and del17p] and elevated serum lactate dehydrogenase. The R-ISS was formulated on the basis of a large dataset of selected patients who had participated in clinical trials and has not been validated in an independent cohort of unselected patients. Thus, we evaluated the R-ISS in 475 consecutive, unselected patients, treated in a single center. Our patients were older and more often had severe renal dysfunction than those in the original publication on the R-ISS. As regards distribution by group, 18% had R-ISS-1, 64.5% R-ISS-2 and 18% R-ISS-3. According to R-ISS group, the 5-year survival rate was 77%, 53% and 19% for R-ISS-1, -2 and -3, respectively (P<0.001). The R-ISS could identify three groups with distinct outcomes among patients treated with or without autologous stem cell transplantation, among those treated with either bortezomib-based or immunomodulatory drug-based primary therapy and in patients ≤65, 66-75 or >75 years. However, in patients with severe renal dysfunction the distinction between groups was less clear. In conclusion, our data in consecutive, unselected patients, with differences in the characteristics and treatment approaches compared to the original International Myeloma Working Group cohort, verified that R-ISS is a robust tool for risk stratification of newly diagnosed patients with symptomatic myeloma.

Hypercalcemia remains an adverse prognostic factor for newly diagnosed multiple myeloma patients in the era of novel antimyeloma therapies.

OBJECTIVES: To evaluate the prognostic impact of hypercalcemia in newly diagnosed patients with symptomatic multiple myeloma (MM), especially after the incorporation of new agents. METHODS: we analyzed the outcomes of newly diagnosed patients with symptomatic myeloma included in the database of the Greek Myeloma Study Group for the prognostic effect of the presence of hypercalcemia (defined as corrected serum calcium ≥11 mg/dL) at diagnosis. RESULTS: Among 2129 consecutive patients with symptomatic MM, 19.5% presented with hypercalcemia at the time of diagnosis. The presence of hypercalcemia was associated with anemia, thrombocytopenia, lower estimated glomerular filtration rate (eGFR), advanced ISS stage, and presence of lytic lesions. Hypercalcemia was more common in patients with high-risk cytogenetics and was associated with inferior survival across different time periods, age groups, and primary treatments. Hypercalcemia was also associated with a twofold increase in the risk of early death. In patients without available FISH, hypercalcemia could substitute for the presence of high-risk cytogenetics and identify patients with worse prognosis along with ISS stage and elevated serum LDH. CONCLUSION: Hypercalcemia remains a poor prognostic feature in the era of novel agents despite the improvement in the outcomes of patients who present with elevated calcium.

Renal outcomes in patients with AL amyloidosis: Prognostic factors, renal response and the impact of therapy.

A staging system for patients with renal AL amyloidosis, based on eGFR (<50 ml/min/1.73 m2 ) and proteinuria (≥5 g/day) at diagnosis, as well as criteria for renal progression (≥25% eGFR reduction) and response (≥30% reduction of proteinuria without renal progression) were recently proposed. We validated these criteria in a cohort of 125 patients with renal AL amyloidosis, mostly treated with bortezomib or lenalidomide. We confirmed the prognostic value of the renal staging system but also identified the limitations of renal progression criteria which are based only on eGFR reduction. We identified the ratio of 24h proteinuria to eGFR as a sensitive marker of renal risk which also accounts for changes in both proteinuria and eGFR: 24h proteinuria/eGFR ratio <30 (in mg/ml/min/1.73 m2 ) was associated with a 2-year progression to dialysis rate of 0% compared to 9% for a ratio of 31-99 and 35% for a ratio ≥100 (P < .001). In landmark analysis, patients who achieved a reduction of this ratio by at least 25% or ≤100 (if initially >100) at 3 months had a 2-year progression to dialysis of 0% vs 24% for patients who either did not reduce to or still had a ratio >100 (P = .001); similar results were obtained by applying the same criteria at 6 months; thus, the evaluation of treatment effect on renal function may be identified early. Furthermore, primary bortezomib-based therapy was more effective than lenalidomide-based therapy, in terms of renal outcomes, especially in patients at intermediate renal risk, but without affecting overall survival.

A combination of clot formation abnormalities in thromboelastometry has a high prognostic value in patients with acute-on-chronic liver failure.

BACKGROUND: Global coagulation tests offer a better tool to assess procoagulant and anticoagulant pathways, fibrinolysis and clot firmness and evaluate more accurately coagulation defects compared to conventional coagulation tests. Their prognostic role in acute-on-chronic liver disease (ACLF) or acute decompensation (AD) has not been well established. AIMS: To assess the properties and prognostic value of the coagulation profile measured by rotational thromboelastometry (ROTEM) in ACLF and AD. METHODS: 84 consecutive patients (35 ACLF and 49 AD) were prospectively studied. Twenty healthy persons matched for age and gender were used as controls. 'Hypocoagulable' or 'hypercoagulable' profiles on admission were assessed based on nine ROTEM parameters and mortality was recorded at 30 and 90 days. RESULTS: Individual ROTEM parameters denoted significantly more hypocoagulability in patients compared to controls. 'Hypocoagulable' profile (defined as a composite of 4 or more ROTEM parameters outside the range) was associated with more severe liver disease assessed either as MELD or Child-Pugh scores ( P  < 0.001 for both) and higher 30-day mortality (Log-rank P  = 0.012). 'Hypocoagulable' profile (HR 3.160, 95% CI 1.003-9.957, P  = 0.049) and ACLF status (HR 23.786, 95% CI 3.115-181.614, P  = 0.002) were independent predictors of 30-day mortality, in multivariate model. A higher early mortality rate was shown in ACLF patients with 'hypocoagulable' phenotype compared to those without (Log-rank P  = 0.017). 'Hypocoagulable' profile was not associated with mortality in AD. CONCLUSION: 'Hypocoagulable' profile was associated with more advanced liver disease and higher short-term mortality in patients with ACLF.

Serial rotational thromboelastometry measurements show worsening hypocoagulability in acute-on-chronic liver failure and are associated with the severity of liver disease.

Background: Viscoelastic tests are used to better understand the complex picture of hemostasis in cirrhosis. Limited data exist regarding the clinical relevance of rotational thromboelastometry (ROTEM) in acute-on-chronic liver failure (ACLF) or acute decompensation (AD). We examined the pattern and role of sequential observations of 9 ROTEM components in both ACLF and AD groups. Method: ROTEM measurements were compared within and between groups at 3 time points: on admission (T1), at 24 h (T2) and 48 h post-admission (T3). Results: Forty-two consecutive patients (22 ACLF, 20 AD) were included. ROTEM determinants exhibited significant hypocoagulable deterioration in ACLF but not in AD over the 3 time points in clot formation time (CFT)EXTEM (P=0.01), maximum clot firmnessEXTEM (P=0.014), CFTINTEM (P<0.001), and alphaINTEM (P=0.028). The sum of hypocoagulable determinants increased from T1 to T3 in ACLF (P=0.029), but remained stable in AD. Five ROTEM variables showed significant differences towards hypocoagulability in ACLF compared to AD at T3. A "hypocoagulable" profile was associated with more severe liver disease (P<0.001 for model for end-stage liver disease [MELD] or Child-Pugh scores) and higher 30- and 90-day mortality (log-rank P=0.001 and P=0.013, respectively) but no more bleeding episodes or transfusions. Two ROTEM variables displayed strong correlations with MELD at T1 and 7 at T3 (|r coefficient|>0.5). Conclusions: ROTEM measurements indicated worsening hypocoagulability shortly post-admission compared to baseline in ACLF, but remained stable in AD. The hypocoagulable derangement was mostly correlated with the severity of liver disease and higher short-term mortality, but not more bleeding episodes.

Single-cell transcriptomic analysis of hematopoietic progenitor cells from patients with systemic lupus erythematosus reveals interferon-inducible reprogramming in early progenitors.

Introduction: Immune cells that contribute to the pathogenesis of systemic lupus erythematosus (SLE) derive from adult hematopoietic stem and progenitor cells (HSPCs) within the bone marrow (BM). For this reason, we reasoned that fundamental abnormalities in SLE can be traced to a BM-derived HSPC inflammatory signature. Methods: BM samples from four SLE patients, six healthy controls, and two umbilical cord blood (CB) samples were used. CD34+ cells were isolated from BM and CB samples, and single-cell RNA-sequencing was performed. Results: A total of 426 cells and 24,473 genes were used in the analysis. Clustering analysis resulted in seven distinct clusters of cell types. Mutually exclusive markers, which were characteristic of each cell type, were identified. We identified three HSPC subpopulations, one of which consisted of proliferating cells (MKI67 expressing cells), one T-like, one B-like, and two myeloid-like progenitor subpopulations. Differential expression analysis revealed i) cell cycle-associated signatures, in healthy BM of HSPC clusters 3 and 4 when compared with CB, and ii) interferon (IFN) signatures in SLE BM of HSPC clusters 3 and 4 and myeloid-like progenitor cluster 5 when compared with healthy controls. The IFN signature in SLE appeared to be deregulated following TF regulatory network analysis and differential alternative splicing analysis between SLE and healthy controls in HSPC subpopulations. Discussion: This study revealed both quantitative-as evidenced by decreased numbers of non-proliferating early progenitors-and qualitative differences-characterized by an IFN signature in SLE, which is known to drive loss of function and depletion of HSPCs. Chronic IFN exposure affects early hematopoietic progenitors in SLE, which may account for the immune aberrancies and the cytopenias in SLE.

Effects of Chemotherapy on Aortic 18-Fluorodeoxyglucose Uptake in Patients With Hodgkin and Non-Hodgkin Lymphoma.

Background: Despite advances in the treatment of oncology patients, therapy-related side effects may lead to premature morbidity. Inflammatory activation that has been linked to cardiovascular disease is crucial for the pathogenesis of both Hodgkin (HL) and non-Hodgkin lymphoma (NHL). Objectives: The purpose of this study was to assess the vascular effects of chemotherapy in patients with HL and NHL by positron emission tomography/computed tomography with 18-fluorodeoxyglucose (18-FDG PET/CT) and to investigate interactions with systemic inflammation as assessed by circulating inflammatory markers. Methods: Between July 2015 and July 2019, 65 consecutive patients (mean age 56 ± 17.78 years) with confirmed diagnosis of either HL (n = 33) or NHL (n = 32) were prospectively studied. PET/CT imaging was performed at baseline, at an interim phase, and after first-line treatment. Aortic FDG uptake was assessed by measuring global aortic target-to-background ratio (GLA-TBR). Serum biomarkers interleukin (IL)-6 and IL-1b were measured at each phase. Results: Patients with HL demonstrated significant reduction in aortic TBR after first-line treatment (median GLA-TBR baseline: 1.98, median GLA-TBR third scan: 1.75, median difference = -0.20, 95% CI: -0.07 to -0.33, P = 0.006), which remained significant after adjustment for confounders (adj. R2 of model = 0.53). In contrast, patients with NHL did not demonstrate a significant aortic inflammation response (P = 0.306). Furthermore, patients with HL demonstrated a significant reduction in IL-6 (P = 0.048) and IL-1b (P = 0.045), whereas patients with NHL did not demonstrate significant reduction in IL-6 (P = 0.085) and IL-1b levels (P = 0.476). Conclusions: Aortic inflammation, as assessed by 18-FDG PET/CT, is reduced in HL patients after first-line treatment but not in NHL patients. These findings imply that different pathophysiological pathways and different therapies might affect the arterial bed in different ways for patients with lymphoma.

Myelodysplasia and autoimmunity.

PURPOSE OF REVIEW: Primary myelodysplastic syndromes (MDS) are heterogeneous clonal haemopoietic stem-cell disorders clinically presented with a varying degree of peripheral cytopenias and an increased probability of leukemic evolution. The natural history of MDS ranges from more indolent forms of disease spanning years to those rapidly progressing to overt leukemia. A distinct subset of MDS patients manifest overt autoimmune manifestations (AIMs), the pathogenesis and prognostic significance of which remain controversial. This review will briefly highlight aspects of immune-mediated myelosuppression and cytokine-induced cytopenias in MDS and further analyze MDS-associated AIMs clinically and pathogenetically. RECENT FINDINGS: Facts provided by advanced studies suggest that an immune reaction against the evolving clone, operated by macrophages, T, natural killer and other effectors contribute to ineffective and dysplastic MDS hemopoiesis. Despite the fact that several immunologic abnormalities have been described in MDS, the precise pathophysiologic mechanism underlying AIMs remains unclear. SUMMARY: The encouraging biological insights into the autoimmune component of MDS pathophysiology can lead to the development of novel forms of treatment for controlling MDS process. MDS with AIMs constitute an ideal model in the investigation of disordered immune function in preleukemic states.

Biomarkers of lymphoma in Sjögren's syndrome: what's the latest?

INTRODUCTION: Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease standing in the crossroads of autoimmunity and lymphomagenesis, characterized by chronic B-cell hyperactivity and ectopic lymphoid tissue neoformation, potentially driving lymphoid malignant transformation. Lymphoma development is considered the most serious complication of pSS. AREAS COVERED: 'Old-classical' biomarkers (clinical, serological, hematological, and histological) validated in the past are analyzed under the perspective of recently published research. Biomarkers that have emerged during the last decade are subdivided to 'old-new' and 'newly proposed-novel' ones, including biomarkers pathophysiologically related to B-cell differentiation, lymphoid organization, and immune responses, identified in serum and tissue, both at genetic and protein level. Upcoming new imaging biomarkers, promising for further patient stratification, are also analyzed. EXPERT OPINION: Salivary gland enlargement and cryoglobulinemia still remain the best validated 'classical-old' biomarkers for lymphoma development. Though new biomarkers still need to be validated, some can be used for the identification of high-risk patients long before lymphoma diagnosis, and some might be more relevant in distinct age subgroups, while others have an added value in the assessment of lymphoma remission or relapse. Future development of composite indices, integrating old and recently proposed biomarkers, could contribute to a more precise lymphoma prediction model.

GSTT1 and GSTM1 polymorphisms and myelodysplastic syndrome risk: a systematic review and meta-analysis.

Glutathione-S-transferace polymorphisms may make hematopoietic lineage cells susceptible to genotoxicity following exposure to heavy metals or benzene. We conducted a systematic review and meta-analysis to define the effect of GSTM1 and GSTT1 null polymorphisms on MDS risk. We searched the PubMed and SCOPUS databases to identify peer-reviewed published case-control studies investigating the association between GSTT1 and/or GSTM1 null genotypes and development of MDS. Between-study heterogeneity was assessed using Cochran's Q statistic and the I(2) statistic. Odds ratios from individual studies were pooled using fixed and random effects models. Thirteen studies were considered eligible for the GSTT1 meta-analysis (1471 cases, 1907 controls) and 10 were considered eligible for the GSTM1 meta-analysis (1161 cases, 1668 controls). For the GSTT1 polymorphism, there was moderate between study heterogeneity (p(Q) = 0.01; I(2) = 52.3%) and the null genotype was significantly associated with increased risk of MDS development, random effects OR = 1.43 (95% CI, 1.09-1.89); p = 0.01. For the GSTM1 polymorphisms there was moderate between-study heterogeneity (p = 0.07; I(2) = 43.1%) and the random effects OR = 1.02 (95% CI, 0.82-1.28) was non-significant (p = 0.85). The GSTT1 null genotype is a significant risk factor for MDS development. Gene-environment interactions need to be further explored.

Bioenergetic Profiling of the Differentiating Human MDS Myeloid Lineage with Low and High Bone Marrow Blast Counts.

Myelodysplastic syndromes (MDS) encompass a very heterogeneous group of clonal hematopoietic stem cell differentiation disorders with malignant potential and an elusive pathobiology. Given the central role of metabolism in effective differentiation, we performed an untargeted metabolomic analysis of differentiating myeloid lineage cells from MDS bone marrow aspirates that exhibited <5% (G1) or ≥5% (G2) blasts, in order to delineate its role in MDS severity and malignant potential. Bone marrow aspirates were collected from 14 previously untreated MDS patients (G1, n = 10 and G2, n = 4) and age matched controls (n = 5). Following myeloid lineage cell isolation, untargeted mass spectrometry-based metabolomics analysis was performed. Data were processed and analyzed using Metabokit. Enrichment analysis was performed using Metaboanalyst v4 employing pathway-associated metabolite sets. We established a bioenergetic profile coordinated by the Warburg phenomenon in both groups, but with a massively different outcome that mainly depended upon its group mitochondrial function and redox state. G1 cells are overwhelmed by glycolytic intermediate accumulation due to failing mitochondria, while the functional electron transport chain and improved redox in G2 compensate for Warburg disruption. Both metabolomes reveal the production and abundance of epigenetic modifiers. G1 and G2 metabolomes differ and eventually determine the MDS clinical phenotype, as well as the potential for malignant transformation.

Carfilzomib-associated renal toxicity is common and unpredictable: a comprehensive analysis of 114 multiple myeloma patients.

Carfilzomib (CFZ) is a non-reversible proteasome inhibitor approved for the treatment of patients with relapsed and refractory myeloma (RRMM). Its use has been associated with cardiovascular toxicity but although recently a signal of clinically significant renal complications has also been identified, it is less extensively investigated. We analyzed data of 114 consecutive patients with RRMM who received CFZ-based regimens. Renal complications not related to MM progression were observed in 19 (17%) patients; thrombotic microangiopathy (TMA) was seen in 6 (5%) patients, albuminuria >1 gr/day in 7 patients (6%) and at least grade 3 acute kidney injury (AKI) which could not be otherwise explained in 6 patients (5%). A total of 15 patients discontinued CFZ and dosing was reinitiated at a lower level in one patient with AKI. Albuminuria was associated with focal segmental glomerulosclerosis in the renal biopsy (performed in a total of 6 patients). Renal complications during CFZ therapy are common, occur mostly early and are unpredictable. A potential effect of CFZ on the renal endothelium could be implicated in the pathogenesis of these complications and may also share common pathophysiology with cardiovascular effects of CFZ.