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Beside their role in the control of water and electrolyte homeostasis, recent data clearly indicate that aldosterone and the mineralocorticoid receptor (MR) are involved in adipocyte biology. It has been recently shown that aldosterone promotes white and brown adipocyte differentiation in vitro through specific activation of the MR. In addition, a non-epithelial pro-inflammatory role for MR activation has been recently inferred from studies on mineralocorticoid/salt administration in experimental animal models and from clinical studies. The mineralocorticoid system could hence represent a potential target for new therapeutic strategies in obesity and the metabolic syndrome. Progesterone has high affinity for the MR and is a natural antagonist of aldosterone. Differently from classic synthetic progestins, which are devoid of antimineralocorticoid properties, progesterone and new progestogens show remarkable antimineralocorticoid effects. Here, we discuss the potential role of the antimineralocorticoid properties of progestogens in the control of body weight, adipose tissue proliferation and salt sensitivity; their therapeutic use in postmenopausal women, as well as in women affected by polycystic ovary syndrome, may open new and unexpected possibilities in the treatment of related metabolic disorders. [ABSTRACT FROM AUTHOR]

In order to attain a finer reconstruction of the peopling of southern and central-eastern Europe from the Levant, we determined the frequencies of eight lineages internal to the Y chromosomal haplogroup J, defined by biallelic markers, in 22 population samples obtained with a fine-grained sampling scheme. Our results partially resolve a major multifurcation of lineages within the haplogroup. Analyses of molecular variance show that the area covered by haplogroup J dispersal is characterized by a significant degree of molecular radiation for unique event polymorphisms within the haplogroup, with a higher incidence of the most derived sub-haplogroups on the northern Mediterranean coast, from Turkey westward; here, J diversity is not simply a subset of that present in the area in which this haplogroup first originated. Dating estimates, based on simple tandem repeat loci (STR) diversity within each lineage, confirmed the presence of a major population structuring at the time of spread of haplogroup J in Europe and a punctuation in the peopling of this continent in the post-Neolithic, compatible with the expansion of the Greek world. We also present here, for the first time, a novel method for comparative dating of lineages, free of assumptions of STR mutation rates. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic inflammatory disorder of the large arteries and represents the primary cause of heart disease and stroke. The exact cause of atherosclerosis is not known. A variety of studies show that autophagy deficiency may be pro-atherogenic and the role of autophagy in smooth muscle cells, macrophages and endothelial cells has been investigated [1]. However, to date no studies addressed the effect of autophagy on leukocyte subsets playing a role in plaque formation and development. The presentproject aims to better clarify the role played by autophagy in lymphocyte homeostasis in human atherosclerotic plaques and in APOE-KO, a mouse model of atherogenesis [2]. In particular, we will investigate cell-autonomous autophagy in mouse Tconv/Tregfunctions, evaluate autophagy-driven T cell polarization in stabilizing atherosclerotic plaques in a mouse model mouse of atherosclerosis. The comprehension of the role of autophagy as a further mechanism underlying Treg induction and stability may open new therapeutic avenues for atherosclerosis. [ABSTRACT FROM AUTHOR]

Ischemic stroke is a complex multifactorial disease and approximately 30%, especially in the young, are cryptogenic. In some of the patients with cryptogenic ischemic stroke the underlying risk factor may be a prothrombotic state. We studied 101 patients with ischemic stroke under 55 years of age. All the patients underwent an extensive diagnostic evaluation to determine the cause of stroke. Common variations in the genes encoding factor V, prothrombin, 5,10-methylenetetrahydrofolate reductase, plasminogen activator inhibitor-1, and human platelet alloantigens-1 were evaluated. Of the 101 patients with ischemic stroke, 28 patients had cryptogenic ischemic stroke. At least one of the different genetic polymorphisms investigated was present in 44% patients in the total group and in 48% of patients with cryptogenic ischemic stroke. In this study population under 55 years of age there was no significant difference in the prevalence of various genetic polymorphisms, factor V, prothrombin, 5,10-methylenetetrahydrofolate reductase, plasminogen activator inhibitor-1, and human platelet alloantigens) in patients with cryptogenic ischemic stroke and in patients with ischemic stroke of determined cause. [ABSTRACT FROM AUTHOR]

An abstract of the article "Effect of Nebivolol and Carvedilol on insulin resistance in Chronic Heart Failure patients," by G. Marazzi and colleagues is presented.

Objectives: This study investigated the effect of a 12-week long-acting testosterone administration on maximal exercise capacity, ventilatory efficiency, muscle strength, insulin resistance, and baroreflex sensitivity (BRS) in elderly patients with chronic heart failure (CHF). Background: CHF is characterized by a metabolic shift favoring catabolism and impairment in skeletal muscle bulk and function that could be involved in the pathophysiology of heart failure. Methods: Seventy elderly patients with stable CHF-median age 70 years, ejection fraction 31.8 +/- 7%-were randomly assigned to receive testosterone (n = 35, intramuscular injection every 6 weeks) or placebo (n = 35), both on top of optimal medical therapy. At baseline and at the end of the study, all patients underwent echocardiogram, cardiopulmonary exercise test, 6-min walk test (6MWT), quadriceps maximal voluntary contraction (MVC), and isokinetic strength (peak torque) and BRS assessment (sequences technique). Results: Baseline peak oxygen consumption (VO(2)) and quadriceps isometric strength showed a direct relation with serum testosterone concentration. Peak VO(2) significantly improved in testosterone but was unchanged in placebo. Insulin sensitivity was significantly improved in testosterone. The MVC and peak torque significantly increased in testosterone but not in placebo. The BRS significantly improved in testosterone but not in placebo. Increase in testosterone levels was significantly related to improvement in peak VO(2) and MVC. There were no significant changes in left ventricular function either in testosterone or placebo. Conclusions: These results suggest that long-acting testosterone therapy improves exercise capacity, muscle strength, glucose metabolism, and BRS in men with moderately severe CHF. Testosterone benefits seem to be mediated by metabolic and peripheral effects. [ABSTRACT FROM AUTHOR]

Background: Migraine is the second world's cause of disability. Among non-pharmacological treatments, nutritional intervention, particularly ketogenic diet, represents one of the most promising approaches., Methods: This a prospective, single center, randomized, controlled study aimed at evaluating the efficacy of a very low-calorie ketogenic diet (VLCKD) compared to a hypocaloric balanced diet (HBD) in migraine prophylaxis in patients affected by high-frequency episodic migraine (HFEM) with a Body Mass Index (BMI) > 27 kg/m 2 . Fifty-seven patients were randomly assigned to a VLCKD (group 1) or HBD (group 2). Group 1 patients followed a VLCKD for 8 weeks, followed by a low calorie diet (LCD, weeks 9-12), and a HBD (weeks 13-24), whereas group 2 patients followed a HBD from week 0 to 24. Anthropometric indexes, urine and blood chemistry were assessed at enrollment, baseline, weeks 4, 8, 12, and 24. Migraine characteristics were evaluated at baseline, weeks 8, 12 and 24. Change in monthly migraine days (MMDs) at weeks 5-8 compared to baseline was the primary endpoint. Secondary endpoints encompassed changes in visual analogue scale (VAS), Headache Impact Test-6 (HIT-6) and Short Form Health Survey-36 (SF-36) scores. We also studied effects on circulating lymphocytes and markers of inflammation, changes in plasma aldosterone and renin levels before and after VLCKD or HBD treatment., Results: Reduction from baseline in MMDs was greater in VLCKD compared to HBD group at week 8 (p = 0.008), at week 12 (p = 0.007), when ketosis had been interrupted by carbohydrates reintroduction, and at week 24 (p = 0.042), when all patients were following the same dietary regimen. Quality of life scores (SF-36) were improved in VLCKD group at week 8 and 12, and were also improved in HBD group, but only at week 12. Weight-loss was significantly higher in VLCKD group at week 8 (p = 0.002) and week 12 (p = 0.020). At the end of the study weight loss was maintained in VLCKD group whereas a slight weight regain was observed in HBD group. Inflammatory indexes, namely C reactive protein (CRP), neutrophil to lymphocyte ratio (NLR) and total white blood cell count (WBC) were significantly reduced (p < 0.05) in VLCKD group at week 12. Aldosterone plasma level were significantly increased in both groups at week 8, particularly in VLCKD group. However, electrolytes and renin plasma levels were never altered throughout the study in both groups., Conclusions: VLCKD is more effective than HBD in reducing MMD in patients with HFEM and represents an effective prophylaxis in patients with overweight/obesity. Trial registration ClinicalTrials.gov identifier: NCT04360148., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the most commonly used regimen for the upfront treatment of diffuse large B-cell lymphoma (DLBCL). However, it is associated with cardiotoxicity, especially in older patients. Substituting doxorubicin with non-PEGylated liposomal doxorubicin (R-COMP) may reduce the risk of cardiac events, but its efficacy has never been demonstrated in prospective trials. We describe the characteristics and outcome of patients with DLBCL aged ≥65 years prospectively enrolled in the Elderly Project by the Fondazione Italiana Linfomi and treated with full doses of R-CHOP or R-COMP per local practice. Starting from 1163 patients, 383 (55%) were treated with R-CHOP and 308 (45%) with R-COMP. Patients treated with R-COMP were older (median age, 76 vs 71 years), less frequently fit at simplified geriatric assessment (61% vs 88%; P < .001), and had a more frequent baseline cardiac disorders (grade >1, 32% vs 8%; P < .001). Three-year progression-free survival (PFS) was similar between R-CHOP and R-COMP (70% and 64%); 3-year overall survival was 77%, and 71% respectively. R-CHOP was associated with better PFS vs R-COMP only in the Elderly Prognostic Index (EPI) low-risk group. The two groups had similar rates of treatment interruptions due to toxicities or of cardiac events (P = 1.00). We suggest R-COMP is a potentially curative treatment for older patients with intermediate- or high-risk EPI, even in the presence of a baseline cardiopathy. R-CHOP is confirmed as the standard therapy for low risk patients., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Deleterious variants in collagen genes are the most common cause of hereditary connective tissue disorders (HCTD). Adaptations of the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria are still lacking. A multidisciplinary team was set up for developing specifications of the ACMG/AMP criteria for COL1A1, COL1A2, COL2A1, COL3A1, COL5A1, COL5A2, COL11A1, COL11A2 and COL12A1, associated with various forms of HCTD featuring joint hypermobility, which is becoming one of the most common reasons of referral for molecular testing in this field. Such specifications were validated against 209 variants, and resulted effective for classifying as pathogenic and likely pathogenic null alleles without downgrading of the PVS1 level of strength and recurrent Glycine substitutions. Adaptations of selected criteria reduced uncertainties on private Glycine substitutions, intronic variants predicted to affect the splicing, and null alleles with a downgraded PVS1 level of strength. Segregation and multigene panel sequencing data mitigated uncertainties on non-Glycine substitutions by the attribution of one or more benignity criteria. These specifications may improve the clinical utility of molecular testing in HCTD by reducing the number of variants with neutral/conflicting interpretations. Close interactions between laboratory and clinicians are crucial to estimate the a priori utility of molecular test and to improve medical reports., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Gain of function pathogenic variants in MRAS have been found in a small subset of pediatric subjects presenting with Noonan syndrome (NS) associated with hypertrophic cardiomyopathy (HCM) and moderate to severe intellectual disability. These variants are considered to confer a high-risk for the development of severe HCM with poor prognosis and fatal outcome. We report on the natural history of the first adult subject with NS carrying the recurrent pathogenic p.Thr68Ile amino acid substitution. Different from what had previously been observed, he presented with a mild, late-onset left ventricular hypertrophy, and a constellation of additional symptoms rarely seen in NS. The present case provides evidence that HCM does not represent an obligatory, early-onset and severe complication in subjects with MRAS variants. It also adds new data about late-onset features suggesting that other unexpected complications might be observed in adult subjects providing anticipatory guidance for individuals of all age., (© 2023 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)

The mineralocorticoid receptor (MR) is able to regulate the transcription of a number of genes in the myotube, although its roles in skeletal muscle (SM) metabolism still await demonstration. SM represents a major site for glucose uptake, and its metabolic derangements play a pivotal role in the development of insulin resistance (IR). The aim of this study was to investigate the contribution of SM MR in mediating derangements of glucose metabolism in a mouse model of diet-induced obesity. We observed that mice fed a high-fat diet (HFD mice) showed impaired glucose tolerance compared to mice fed a normal diet (ND mice). Mice fed a 60% HFD treated with the MR antagonist Spironolactone (HFD + Spiro) for 12 weeks revealed an improvement in glucose tolerance, as measured with an intraperitoneal glucose tolerance test, compared with HFD mice. To investigate if blockade of SM MR could contribute to the favorable metabolic effects observed with pharmacological MR antagonism, we analyzed MR expression in the gastrocnemius, showing that SM MR protein abundance is downregulated by HFD compared to ND mice and that pharmacological treatment with Spiro was able to partially revert this effect in HFD + Spiro mice. Differently from what we have observed in adipose tissue, where HDF increased adipocyte MR expression, SM MR protein was down-regulated in our experimental model, suggesting a completely different role of SM MR in the regulation of glucose metabolism. To confirm this hypothesis, we investigated the effects of MR blockade on insulin signaling in a cellular model of IRin C2C12 myocytes, which were treated with or without Spiro. We confirmed MR protein downregulation in insulin-resistant myotubes. We also analyzed Akt phosphorylation upon insulin stimulation, and we did not observe any difference between palmitate- and palmitate + Spiro-treated cells. These results were confirmed by in vitro glucose uptake analysis. Taken together, our data indicate that reduced activity of SM MR does not improve insulin signaling in mouse skeletal myocytes and does not contribute to the favorable metabolic effects on glucose tolerance and IR induced by systemic pharmacological MR blockade.

Octogenarian patients with diffuse large B-cell lymphoma are managed mainly with palliation, but recent improvement in their overall condition makes potentially curative treatment a possibility. Studies have shown that half of selected octogenarians may be cured using reduced-dose anthracycline chemoimmunotherapy. However, patients aged >85 (late octogenarians [LO]) were underrepresented, and selection criteria were poorly defined. We analyzed the clinical characteristics and outcomes of LO enrolled in the FIL Elderly Project in terms of the treatment received (palliative vs. curative) and of their simplified geriatric assessment (sGA), then compared them with early octogenarians (EO) aged 80- 84 and with those aged 65-79 classified as UNFIT or FRAIL according to sGA enrolled in the same study. Of the 1,163 patients, 370 were >80 and 129 LO. Clinical characteristics were similar between LO and EO, but LO more frequently received palliation (50% vs. 23%; P=0.001) and had worse 2-year overall survival (OS) (48% vs. 63%; P=0.001) and 2-year progression-free survival (PFS) (43% vs. 56%; P=0.01). Patients receiving anthracycline did better than patients receiving palliation (P<0.001), without any difference between full or reduced doses. Rituximab within palliation improved outcome (2-yr OS with or without rituximab 42% vs. 22%; P=0.008). Elderly Prognostic Index (EPI) performed better than sGA in identifying different risk categories, and high-risk EPI retained an independent unfavorable effect on OS and PFS, together with treatment without anthracycline. In conclusion, late octogenarians can benefit from a curative approach with reduced-dose anthracycline and from rituximab within palliation. EPI may help in patient selection more than sGA can.

Background : Obesity is a pandemic disease characterized by excessive severe body comorbidities. Reduction in fat accumulation represents a mechanism of prevention, and the replacement of white adipose tissue (WAT) with brown adipose tissue (BAT) has been proposed as one promising strategy against obesity. In the present study, we sought to investigate the ability of a natural mixture of polyphenols and micronutrients (A5 + ) to counteract white adipogenesis by promoting WAT browning. Methods : For this study, we employed a murine 3T3-L1 fibroblast cell line treated with A5 + , or DMSO as control, during the differentiation in mature adipocytes for 10 days. Cell cycle analysis was performed using propidium iodide staining and cytofluorimetric analysis. Intracellular lipid contents were detected by Oil Red O staining. Inflammation Array, along with qRT-PCR and Western Blot analyses, served to measure the expression of the analyzed markers, such as pro-inflammatory cytokines. Results : A5 + administration significantly reduced lipids' accumulation in adipocytes when compared to control cells ( p < 0.005). Similarly, A5 + inhibited cellular proliferation during the mitotic clonal expansion (MCE), the most relevant stage in adipocytes differentiation ( p < 0.0001). We also found that A5 + significantly reduced the release of pro-inflammatory cytokines, such as IL-6 and Leptin ( p < 0.005), and promoted fat browning and fatty acid oxidation through increasing expression levels of genes related to BAT, such as UCP1 ( p < 0.05). This thermogenic process is mediated via AMPK-ATGL pathway activation. Conclusion : Overall, these results demonstrated that the synergistic effect of compounds contained in A5 + may be able to counteract adipogenesis and then obesity by inducing fat browning.

The Elderly Prognostic Index (EPI) is based on the integration of a simplified geriatric assessment, hemoglobin levels and International Prognostic Index and has been validated to predict overall survival in older patients with diffuse large B-cell lymphoma (DLBCL). In this study, we evaluated the ability of EPI to predict the risk of early mortality. This study included all patients registered in the Elderly Project for whom treatment details and a minimum follow-up of 3 months were available. Three main treatment groups were identified based on the anthracycline amount administered: cases receiving >70% of the theoretical anthracyclines dose (Full Dose [FD] group), ≤70% (Reduced Dose [RD]) and palliative therapy (PT; no anthracyclines). The primary endpoint was early mortality rate, defined as death for any cause occurring within 90 days from diagnosis. We identified 1150 patients with a median age of 76 years (range 65-94). Overall, 69 early deaths were observed, accounting for 19% of all reported deaths. The cumulative rate of early mortality at 90 days was 6.0%. Comparing early with delayed deaths, we observed a lower frequency of deaths due to lymphoma progression (42% vs. 75%; p < 0.001) and a higher frequency due to toxicity and infections (22% vs. 4%, p < 0.001, and 22% vs. 3%, p < 0.001, respectively) for early events. A multivariable logistic analysis on 931 patients (excluding PT) confirmed an independent association of high-risk EPI (odds ratio [OR] 3.60; 95% confidence interval [CI] 1.15-11.2) and bulky disease (OR 2.08; 95% CI 1.09-3.97) with the risk of early mortality. The cumulative incidence of early mortality for older patients with DLBCL is not negligible and is mainly associated with non-lymphoma related events. For patients receiving anthracyclines, high-risk EPI and bulky disease are associated with a higher probability of early mortality., (© 2022 John Wiley & Sons Ltd.)

Purpose: To prospectively validate the use of a simplified geriatric assessment (sGA) at diagnosis and to integrate it into a prognostic score for older patients with diffuse large B-cell lymphoma (DLBCL)., Methods: We conducted the prospective Elderly Project study on patients with DLBCL older than 64 years who underwent our Fondazione Italiana Linfomi original geriatric assessment (oGA) (age, Cumulative Illness Rating Scale for Geriatrics, activities of daily living, and instrumental activities of daily living) before treatment. Treatment choice was left to the physician's discretion. The primary end point was overall survival (OS) (ClinicalTrials.gov identifier: NCT02364050)., Results: We analyzed 1,163 patients (median age 76 years), with a 3-year OS of 65% (95% CI, 62 to 68). Because at multivariate analysis on oGA, age > 80 years retained an independent correlation with OS, we also developed a new, simplified version of the GA (sGA) that classifies patients as fit (55%), unfit (28%), and frail (18%) with significantly different 3-year OS of 75%, 58%, and 43%, respectively. The sGA groups, International Prognostic Index, and hemoglobin levels were independent predictors of OS and were used to build the Elderly Prognostic Index (EPI). Three risk groups were identified: low (23%), intermediate (48%), and high (29%), with an estimated 3-year OS of 87% (95% CI, 81 to 91), 69% (95% CI, 63 to 73), and 42% (95% CI, 36 to 49), respectively. The EPI was validated using an independent external series of 328 cases., Conclusion: The Elderly Project validates sGA as an objective tool to assess fitness status and defines the new EPI to predict OS of older patients with DLBCL., Competing Interests: Francesco MerliConsulting or Advisory Role: Janssen, Gilead Sciences, MSD, Takeda, RocheTravel, Accommodations, Expenses: Janssen, Gilead Sciences, EUSA Pharma, Celgene, Roche, Takeda Stefano LuminariConsulting or Advisory Role: Roche, Gilead Sciences, CelgeneTravel, Accommodations, Expenses: Janssen, Celgene Alessandra TucciConsulting or Advisory Role: Janssen, TakedaTravel, Accommodations, Expenses: Sandoz Annalisa ArcariConsulting or Advisory Role: Janssen-CilagTravel, Accommodations, Expenses: Janssen-Cilag, Takeda Luigi RigacciConsulting or Advisory Role: Roche, Gilead Sciences, Takeda, Janssen-Cilag, AbbVie, Celgene/Bristol-Myers Squibb, Merck, MenariniSpeakers' Bureau: Roche, Gilead Sciences, CelgeneTravel, Accommodations, Expenses: Takeda Eliza HawkesConsulting or Advisory Role: Merck Sharpe & Dohme, Roche/Genentech, AstraZeneca, Gilead SciencesSpeakers' Bureau: Roche/GenentechResearch Funding: AstraZeneca, Celgene, Merck KGaA, Janssen-Cilag, Gilead Sciences, Mundipharma, Bristol-Myers SquibbTravel, Accommodations, Expenses: Roche/Genentech Carlos S. ChiattoneConsulting or Advisory Role: Roche, Takeda, Janssen Federica CavalloHonoraria: Takeda, Janssen-Cilag, Gilead SciencesConsulting or Advisory Role: Janssen-Cilag, Gilead SciencesTravel, Accommodations, Expenses: Celgene Alberto FabbriHonoraria: Takeda, Servier/PfizerTravel, Accommodations, Expenses: Takeda Allison BarracloughTravel, Accommodations, Expenses: Roche Simone FerreroConsulting or Advisory Role: Janssen-Cilag, EUSA Pharma, Clinigen GroupSpeakers' Bureau: Janssen-Cilag, Servier, EUSA Pharma, Gilead SciencesTravel, Accommodations, Expenses: Roche, Servier, Sanofi, Janssen-Cilag, EUSA Pharma, Gentili Alice Di RoccoSpeakers' Bureau: Roche/GenentechTravel, Accommodations, Expenses: Roche, Novartis Stefan HohausConsulting or Advisory Role: MSD, EusaPharma, Servier, GentiliniTravel, Accommodations, Expenses: Roche Luca NassiEmployment: SanofiStock and Other Ownership Interests: Sanofi, MolMedConsulting or Advisory Role: Takeda Gerardo MusuracaConsulting or Advisory Role: Janssen Oncology, Servier Leonardo FlenghiTravel, Accommodations, Expenses: Roche, Janssen Michele SpinaEmployment: Bristol-Myers Squibb/Medarex, SanofiConsulting or Advisory Role: Gilead Sciences, IncyteNo other potential conflicts of interest were reported.

Tyrosol (TR), a major polyphenol found in extra virgin olive oil (EVOO), exerts several antioxidant effects. However, only scarce evidences are present regarding its activity on adipocytes and obesity. This study evaluated the role of TR in adipogenesis. Murine 3T3-L1 preadipocytes were incubated with TR (300 and 500  μ M), and TR administration inhibited adipogenesis by downregulation of several adipogenic factors (leptin and aP2) and transcription factors (C/EBP α , PPAR γ , SREBP1c, and Glut4) and by modulation of the histone deacetylase sirtuin 1. After complete differentiation, adipocytes treated with 300 and 500  μ M TR showed a reduction of 20% and 30% in lipid droplets, respectively. Intracellular triglycerides were significantly reduced after TR treatment ( p < 0.05). Mature adipocytes treated with TR at 300 and 500  μ M showed a marked decrease in the inflammatory state and oxidative stress as shown by the modulation of specific biomarkers (TNF, IL6, ROS, and SOD2). TR treatment also acted on the early stage of differentiation by reducing cell proliferation (~40%) and inducing cell cycle arrest during Mitotic Expansion Clonal (first 48 h of differentiation), as shown by the increase in both S1 phase and p21 protein expression. We also showed that TR induced lipolysis by activating the AMPK-ATGL-HSL pathway. In conclusion, we provided evidence that TR reduces 3T3-L1 differentiation through downregulation of adipogenic proteins, inflammation, and oxidative stress. Moreover, TR may trigger adipose tissue browning throughout the induction of the AMPK-ATGL-UCP1 pathway and, subsequently, may have promise as a potential therapeutic agent for the treatment and prevention of obesity., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this article., (Copyright © 2020 Francesca Pacifici et al.)

Mineralocorticoid receptor antagonists (MRAs) are recommended for the treatment of heart failure and hypertension, mainly due to their natriuretic and anti-fibrotic mode of action. Rodent studies have shown that MRAs can prevent adverse metabolic consequences of obesity but an elucidation of underlying molecular mechanisms is missing. Here, we investigated metabolic effects of the novel non-steroidal MRA finerenone (FIN) in a mouse model of high-fat diet (HFD)-induced obesity and the signaling pathways activated by MR antagonism at level of interscapular brown adipose tissue (iBAT). C57BL/6J male mice were fed a normal diet or a HFD (with60% kcal from fat) containing or not FIN for 3 months. Metabolic parameters, adipose tissue morphology, gene and protein expression analysis were assessed. We also used brown adipocyte cultures (T37i cells) to investigate the effects of FIN-mediated MR antagonism upon lipid and mitochondrial metabolism. HFD + FIN-treated mice showed improved glucose tolerance together with increased multilocularity and higher expression of thermogenic markers at the level of iBAT, without differences in white adipose depots, suggesting an iBAT-specific effect of FIN. Mechanistically, FIN increased activation of AMP-activated protein kinase which, in turn, stimulated adipose triglyceride lipase activation, with subsequent increased expression of uncoupling protein-1 in brown adipocytes., (© 2020 Federation of American Societies for Experimental Biology.)

Atherosclerosis is a progressive vascular disease representing the primary cause of morbidity and mortality in developed countries. Formerly, atherosclerosis was considered as a mere passive accumulation of lipids in blood vessels. However, it is now clear that atherosclerosis is a complex and multifactorial disease, in which the involvement of immune cells and inflammation play a key role. A variety of studies have shown that autophagy-a cellular catalytic mechanism able to remove injured cytoplasmic components in response to cellular stress-may be proatherogenic. So far, in this context, its role has been investigated in smooth muscle cells, macrophages, and endothelial cells, while the function of this catabolic protective process in lymphocyte functionality has been overlooked. The few studies carried out so far, however, suggested that autophagy modulation in lymphocyte subsets may be functionally related to plaque formation and development. Therefore, in this research, we aimed at better clarifying the role of lymphocyte subsets, mainly regulatory T cells (Tregs), in human atherosclerotic plaques and in animal models of atherosclerosis investigating the contribution of autophagy on immune cell homeostasis. Here, we investigate basal autophagy in a mouse model of atherosclerosis, apolipoprotein E (ApoE)-knockout (KO) mice, and we analyze the role of autophagy in driving Tregs polarization. We observed defective maturation of Tregs from ApoE-KO mice in response to tumor growth factor-β (TGFβ). TGFβ is a well-known autophagy inducer, and Tregs maturation defects in ApoE-KO mice seem to be related to autophagy impairment. In this work, we propose that autophagy underlies Tregs maturation, advocating that the study of this process in atherosclerosis may open new therapeutic strategies., (Copyright © 2020 Mandatori, Pacella, Marzolla, Mammi, Starace, Padula, Vitiello, Armani, Savoia, Taurino, De Zio, Giampietri, Piconese, Cecconi, Caprio and Filippini.)

Objective: To evaluate activity and safety of obinutuzumab-miniCHOP (Ga101-miniCHOP) combination in older patients with Diffuse Large B-Cell Lymphoma (DLBCL) unfit to receive full dose immunochemotherapy., Materials and Methods: We conducted a Simon's two-stage phase II multicenter trial to investigate response rate (primary endpoint) and safety of six courses of Ga101-miniCHOP in older patients with DLBCL (≥65 years), prospectively defined as unfit according to a simplified Comprehensive Geriatric Assessment (sCGA)., Results: Overall, 34 patients were enrolled (median age 82 years; range 68-89), with 27 out of the 33 eligible patients completing all six planned courses. Complete Remission (CR) rate was reported in fourteen patients (42%). After a median follow-up of sixteen months, the two-year Progression Free and Overall Survival (PFS and OS) were 49% (95% Confidence Interval (CI), 28 to 67) and 68% (95% CI, 49 to 81), respectively. The most frequent grade 3-4 adverse event was neutropenia in thirteen patients (26%)., Conclusions: Based on the observed CR rate, study accrual was interrupted due to the very low probability of demonstrating the initial study hypothesis that Ga101-miniCHOP could improve results of historical data obtained with R-miniCHOP in this group of patients. Nonetheless, results achieved with the 33 treated patients confirm activity and good tolerability of the Ga101-miniCHOP regimen for older unfit adult patients with DLBCL., (Copyright © 2019. Published by Elsevier Ltd.)

The mineralocorticoid receptor (MR) was originally identified as a regulator of blood pressure, able to modulate renal sodium handling in response to its principal ligand aldosterone. MR is expressed in several extra-renal tissues, including the heart, vasculature, and adipose tissue. More recent studies have shown that extra-renal MR plays a relevant role in the control of cardiovascular and metabolic functions and has recently been implicated in the pathophysiology of aging. MR activation promotes vasoconstriction and acts as a potent pro-fibrotic agent in cardiovascular remodeling. Aging is associated with increased arterial stiffness and vascular tone, and modifications of arterial structure and function are responsible for these alterations. MR activation contributes to increase blood pressure with aging by regulating myogenic tone, vasoconstriction, and vascular oxidative stress. Importantly, aging represents an important contributor to the increased prevalence of cardiometabolic syndrome. In the elderly, dysregulation of MR signaling is associated with hypertension, obesity, and diabetes, representing an important cause of increased cardiovascular risk. Clinical use of MR antagonists is limited by the adverse effects induced by MR blockade in the kidney, raising the risk of hyperkalaemia in older patients with reduced renal function. Therefore, there is an unmet need for the enhanced understanding of the role of MR in aging and for development of novel specific MR antagonists in the context of cardiovascular rehabilitation in the elderly, in order to reduce relevant side effects.

Atherosclerosis is due to a chronic inflammatory response affecting vascular endothelium and is promoted by several factors such as hypertension, dyslipidemia, and diabetes. To date, there is evidence to support a role for circulating aldosterone as a risk factor for the development of cardiovascular disease. Transgenic mouse models have been generated to study cellular and molecular processes leading to atherosclerosis. In this manuscript, we describe a protocol that takes advantage of continuous infusion of aldosterone in ApoE -/- mice and generates atherosclerotic plaques in the aortic root after 4 weeks of treatment. We, therefore, illustrate a method for quantification and characterization of atherosclerotic lesions at the aortic root level. The added value of aldosterone infusion is represented by the generation of atherosclerotic lesions rich in lipid and inflammatory cells after 4 weeks of treatment. We describe in detail the staining procedures to quantify lipid and macrophage content within the plaque. Notably, in this protocol, we perform heart tissue-embedding in OCT in order to preserve the antigenicity of cardiac tissue and facilitate detectability of antigens of interest. Analysis of the plaque phenotype represents a valid approach to study the pathophysiology of atherosclerosis development and to identify novel pharmacological targets for the development of anti-atherogenic drugs.

The mineralocorticoid receptor (MR) was first identified as a blood pressure regulator, modulating renal sodium handling in response to its principal ligand aldosterone. The mineralocorticoid receptor is also expressed in many tissues other than the kidney, such as adipose tissue, heart and vasculature. Recent studies have shown that MR plays a relevant role in the control of cardiovascular and metabolic function, as well as in adipogenesis. Dysregulation of aldosterone/MR signaling represents an important cause of disease as high plasma levels of aldosterone are associated with hypertension, obesity and increased cardiovascular risk. Aldosterone displays powerful vascular effects and acts as a potent pro-fibrotic agent in cardiovascular remodeling. Mineralocorticoid receptor activation regulates genes involved in vascular and cardiac fibrosis, calcification and inflammation. This review focuses on the role of novel potential biomarkers related to aldosterone/MR system that could help identify cardiovascular and metabolic detrimental conditions, as a result of altered MR activation. Specifically, we discuss: (1) how MR signaling regulates the number and function of different subpopulations of circulating and intra-tissue immune cells; (2) the role of aldosterone/MR system in mediating cardiometabolic diseases induced by obesity; and (3) the role of several MR downstream molecules as novel potential biomarkers of cardiometabolic diseases, end-organ damage and rehabilitation outcome.

Corticosteroids are secreted by the adrenal glands and control the functions of adipose tissue via the activation of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). In turn, adipocytes release a large variety of adipokines into the bloodstream, regulating the function of several organs and tissues, including the adrenal glands, hereby controlling corticosteroid production. In adipose tissue, the activation of the MR by glucocorticoids (GC) and aldosterone affects important processes such as adipocyte differentiation, oxidative stress, autophagic flux, adipokine expression as well as local production of GC through upregulation of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Notably, the proinflammatory responses induced by the MR are counteracted by activation of the GR, whose activity inhibits the expression of inflammatory adipokines. Both GR and MR are deeply involved in adipogenesis and adipose expansion; hence pharmacological blockade of these two receptors has proven effective against adipose tissue dysfunction in experimental models of obesity and metabolic syndrome (MetS), suggesting a potential use for MR and GR antagonists in these clinical settings. Importantly, obesity and Cushing's syndrome (CS) share metabolic similarities and are characterized by high levels of circulating corticosteroids, which in turn are able to deeply affect adipose tissue. In addition, pharmacological approaches aimed at reducing aldosterone and GC levels, by means of the inhibition of CYP11B2 (aldosterone synthase) or 11β-HSD1, represent alternative strategies to counter the detrimental effects of excessive levels of corticosteroids, which are often observed in obesity and, more general, in MetS. © 2017 American Physiological Society. Compr Physiol 7:1425-1447, 2017., (Copyright © 2017 John Wiley & Sons, Inc.)

Objective: Elevated aldosterone is associated with increased risk of atherosclerosis complications, whereas treatment with mineralocorticoid receptor (MR) antagonists decreases the rate of cardiovascular events. Here we test the hypothesis that aldosterone promotes early atherosclerosis by modulating intercellular adhesion molecule-1 (ICAM-1) expression and investigate the molecular mechanisms by which aldosterone regulates ICAM-1 expression., Methods and Results: Apolipoprotein-E (ApoE) -/- mice fed an atherogenic diet and treated with aldosterone for 4weeks showed increased vascular expression of ICAM-1, paralleled by enhanced atherosclerotic plaque size in the aortic root. Moreover, aldosterone treatment resulted in increased plaque lipid and inflammatory cell content, consistent with an unstable plaque phenotype. ApoE/ICAM-1 double knockout (ApoE -/- /ICAM-1 -/- ) littermates were protected from the aldosterone-induced increase in plaque size, lipid content and macrophage infiltration. Since aldosterone is known to regulate ICAM-1 transcription via MR in human endothelial cells, we explored MR regulation of the ICAM-1 promoter. Luciferase reporter assays performed in HUVECs using deletion constructs of the human ICAM-1 gene promoter showed that a region containing a predicted MR-responsive element (MRE) is required for MR-dependent transcriptional regulation of ICAM-1., Conclusions: Pro-atherogenic effects of aldosterone are mediated by increased ICAM-1 expression, through transcriptional regulation by endothelial MR. These data enhance our understanding of the molecular mechanism by which MR activation promotes atherosclerosis complications., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Vitamin D is a fat-soluble vitamin and a steroid hormone that plays a central role in maintaining calcium-phosphorus and bone homeostasis in close interaction with parathyroid hormone, acting on its classical target tissues, namely, bone, kidney, intestine, and parathyroid glands. However, vitamin D endocrine system regulates several genes (about 3 % of the human genome) involved in cell differentiation, cell-cycle control, and cell function and exerts noncalcemic/pleiotropic effects on extraskeletal target tissues, such as immune and cardiovascular system, pancreatic endocrine cells, muscle, and adipose tissue. Several studies have demonstrated the role of vitamin D supplementation in the prevention/treatment of various autoimmune diseases and improvement of glucose metabolism, muscle, and adipose tissue function. Hence, this review aims to elucidate the effects of vitamin D on extraskeletal target tissues and to investigate the potential therapeutic benefit of vitamin D supplementation among a broad group of pathological conditions, especially with regard to metabolic and autoimmune diseases. In addition, we focused on the best daily intakes and serum levels of vitamin D required for extraskeletal benefits which, even if still controversial, appear to be higher than those widely accepted for skeletal effects.

Drospirenone (DRSP) is an antialdosterone agent with progestogenic and antiandrogenic effects. This compound, has been recently used in combination with 17β-estradiol (E2) as hormonal therapy in postmenopausal women and has been shown to exert a significant antihypertensive effect in hypertensive post-menopausal women. Aim of the present study was to compare the effect of DRSP/E2 with those of Tibolone (T) on endothelial function, arterial stiffness, and lipid profile of early postmenopausal women naïve on post-menopausal hormonal therapy. Twenty-four women met the inclusion criteria and entered the study. Women were randomized to receive either DRSP/E2 or T for 6months. Blood pressure and heart rate were similar in both groups at baseline and at the end of the study. Compared to baseline, endothelial function assessed by Reactive Hyperemia (RH) significantly improved in women receiving E2/DRSP, whereas no significant differences between baseline and follow up were detected in women receiving Tibolone. Women receiving E2/DRSP showed a significant decrease in pulse wave velocity and Augmentation Index compared to baseline while no changes were observed in women receiving Tibolone. The capacity of sera to trigger endothelial cells apoptosis in vitro measured by cell death assay was significantly reduced by E/DRSP but not by T (HFA-E 70±5,6% vs HFD-E 41±4,5%, p<0,001). In conclusion, the present study shows that the association of Estradiol and Drospirenone as hormonal replacement therapy significantly improves vascular parameters and the composition of sera relevant for vascular protection in early post-menopausal normotensive women. These effects are not shared by Tibolone., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The randomized HD2000 trial compared six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), four escalated plus two standard cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), and six cycles of COPP-EBV-CAD (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxorubicin, vincristine, procarbazine, vinblastine, and bleomycin; CEC) in patients with advanced-stage Hodgkin lymphoma. After a median follow-up of 42 months, patients who received BEACOPP were reported to have experienced better progression-free survival (PFS) but not better overall survival (OS) results than those receiving ABVD. We here report a post hoc analysis of this trial after a median follow-up of 10 years., Patients and Methods: Three hundred seven patients were enrolled, 295 of whom were evaluable. At the time of our analysis, the median follow-up for the entire group was 120 months (range, 4 to 169 months)., Results: The 10-year PFS results for the ABVD, BEACOPP, and CEC arms were 69%, 75%, and 76%, respectively; corresponding OS results were 85%, 84%, and 86%. Overall, 13 second malignancies were reported: one in the ABVD arm and six each in the BEACOPP and CEC arms. The cumulative risk of developing second malignancies at 10 years was 0.9%, 6.6%, and 6% with ABVD, BEACOPP, and CEC, respectively; the risk with either BEACOPP or CEC was significantly higher than that reported with ABVD (P = .027 and .02, respectively)., Conclusion: With these mature results, we confirm that patients with advanced Hodgkin lymphoma have similar OS results when treated with ABVD, BEACOPP, or CEC. However, with longer follow-up, we were not able to confirm the superiority of BEACOPP over ABVD in terms of PFS, mainly because of higher mortality rates resulting from second malignancies observed after treatment with BEACOPP and CEC., (© 2015 by American Society of Clinical Oncology.)

Ceramide regulates several different cellular responses including mechanisms leading to apoptosis. Serum- and glucocorticoid-inducible protein kinase (SGK)-1 is a serine threonine kinase, which activates survival pathways in response to stress stimuli. Recently, we demonstrated an anti-apoptotic role of SGK-1 in human umbilical endothelial cells treated with high glucose. In the present study, since ceramide induces apoptosis by multiple mechanisms in diabetes and its complication such as nephropathy, we aimed to investigate whether SGK-1 may protect even against apoptosis induced by ceramide in kidney cells. Human embryonic kidney (HEK)-293 cells stable transfected with SGK-1 wild type (SGK-1wt) and its dominant negative gene (SGK-1dn) have been used in this study. Apoptotic stimuli were induced by C2-ceramide and TNF-α to increase endogenous synthesis of ceramide. Upon activation with these stimuli, SGK-1wt transfected cells have a statistically significant reduction of apoptosis compared with SGK-1dn cells (P<0.001). This protection was dependent on activation of caspase-3 and Poly-ADP-ribose-polymerase-1 (PARP-1) cleavage. SGK-1 and AKT-1 two highly homologous kinases differently reacted to ceramide treatment, since SGK-1 increases in response to apoptotic stimulus while AKT-1 decreases. This enhancement of SGK-1 was dependent on p38-mitogen-activated-protein kinases (p38MAPK), cyclic-adenosine-monophosphate/protein kinase A (cAMP/PKA) and phosphoinositide-3-kinase (PI3K) pathways. Especially, by using selective LY294002 inhibitor, we demonstrated that the most involved pathway in the SGK-1 mediated process of protection was PI3K. Treatment with inhibitor of SGK-1 (GSK650394) significantly enhanced TNF-α-dependent apoptosis in HEK-293 cells overexpressing SGK-1wt. Caspase-3, -8 and -9 selective inhibitors confirmed that SGK-1 reduced the activation of caspase-dependent apoptosis, probably by both intrinsic and extrinsic pathways. In conclusion, we demonstrated that in kidney cells, overexpression of SGK-1 is protective against ceramide-induced apoptosis and the role of SGK-1 can be potentially explored as a therapeutic target in conditions like diabetes, where ceramide levels are increased.

Although the achievement of deep and long lasting remissions is a realistic goal of therapy in the fit patient with chronic lymphocytic leukemia (CLL), this disease typically affects elderly patients who also show one or more concomitant pathological conditions or functional limitations that have an additive effects on the reduction of patient's life expectancy and represent major limitations in the adoption of standard therapies. In these unfit but typical patients with CLL, the goals of treatment may vary from achieving good remissions without severe toxicity to simple palliation. Differently from the past when the definition of patient medical status was mainly based on age and was left to the subjective assessment of the physician, today there are several tools to define in a standardized, reproducible, and multidimensional way the initial patient assessment and to plan treatment goals in an objective way. In this review, an overview of the current approaches to the definition of the medical fitness of the patient is provided along with some practical suggestions to integrate these tools in the clinical approach to elderly patients with CLL.

Geldanamycin derivatives are benzoquinone ansamycin antibiotics that bind to Hsp90 and alter its function. The alteration of Hsp90 activity limits some cellular hormonal responses by inhibiting nuclear receptors activation. The nuclear receptors activity, such as PPARγ, the mineralocorticoid and glucocorticoid receptors (MR and GR) play a critical role in the conversion of preadipocytes to mature adipocytes. Given the importance of these nuclear receptors for adipogenesis, we investigated the effects of geldanamycin analogues (GA) on adipocyte differentiation and function. We found that early exposure of preadipocyte cells to GA inhibited their conversion into mature adipocytes by inhibiting the adipogenic transcriptional program and lipid droplets accumulation. Furthermore, GA altered the adipokines secretion profile of mature adipocyte. The anti-adipogenic effect of GA was also confirmed in mice fed a high fat diet. Biochemical analysis revealed that anti-adipogenic effects of geldanamycin analogues may result from the simultaneous inhibition of MR, GR and PPARγ activity. Taken together, our observations lead us to propose Hsp90 as a potent target for drug development in the control of obesity and its related metabolic complications.

In 2003 the Fondazione Italiana Linfomi (FIL) started a clinical research program for investigating initial treatment of frail elderly patients with diffuse large B-cell lymphoma (DLBCL) identified by Comprehensive Geriatric Assessment (CGA). From 2003 to 2006, 334 elderly patients underwent CGA assessment, and 99 patients were classified as frail. Frail patients had a median age of 78 years, stage III-IV disease in 62% and age-adjusted International Prognostic Index (aaIPI) of 2-3 in 53%. Treatment consisted of several different regimens according to physician discretion. After a median follow-up of 36 months, 5-year overall survival (OS) was 28%. In multivariate analysis, aaIPI 2-3 (p = 0.005) and the presence of respiratory comorbidity (p = 0.044) were the only factors that showed independent correlation with OS. Frail patients had a poorer outcome compared with fit patients also if they were treated with rituximab-containing combination chemotherapy (hazard ratio 2.37, 95% confidence interval 1.48-3.78; p < 0.001). CGA is a valid tool to prospectively identify frail subjects among elderly patients with DLBCL.

The mineralocorticoid receptor (MR) classically mediates aldosterone effects on salt homeostasis and blood pressure regulation in epithelial target tissues. In recent years, functional MRs have been identified in non classical targets of aldosterone actions, in particular in adipose tissue, where they mediate the effects of aldosterone and glucocorticoids in the control of adipogenesis, adipose expansion and its pro-inflammatory capacity. In this context, inappropriate MR activation has been demonstrated to be a causal factor in several pathologic conditions such as vascular inflammation, endothelial dysfunction, insulin resistance and obesity. The aim of this review is to summarize the latest developments in this rapidly developing field, and will focus on the role of MR and renin-angiotensin-aldosterone system (RAAS) as potential leading characters in the early steps of adipocyte dysfunction and obesity. Indeed modulation of MR activity in adipose tissue has promise as a novel therapeutic approach to treat obesity and its related metabolic complications. This article is part of a Special Issue entitled 'CSR 2013'., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

We conducted a prospective study to compare epirubicin, cyclophosphamide, vinblastine, prednisone and rituximab (R-miniCEOP) with cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab (R-CHOP) for the treatment of "fit" elderly patients with diffuse large B-cell lymphoma (DLBCL). Patients over the age of 65 with stage II-IV DLBCL were screened with a comprehensive geriatric assessment. Patients were randomized to receive six courses of R-miniCEOP (n = 114) or R-CHOP (n = 110). Overall, the rate of complete remission was 70% (p = 0.466). After a median follow-up of 42 months, 5-year event-free survival (EFS) rates were 46% and 48% for R-miniCEOP and R-CHOP, respectively (p = 0.538). Patients older than 72 years and with low-risk disease had a better outcome when treated with R-miniCEOP (p = 0.011). Overall R-CHOP and R-miniCEOP are similarly effective for elderly "fit" patients with DLBCL. The less intense R-miniCEOP may be an acceptable option for the treatment of relatively older patients with low-risk disease.

Aldosterone controls blood pressure by binding to the mineralocorticoid receptor (MR), a ligand-activated transcription factor which regulates critical genes controlling salt and water homeostasis in the kidney. In recent years, inappropriate MR activation has been shown to trigger deleterious responses in various tissues, including vessels, heart and brain, hence promoting vascular inflammation, cardiovascular remodeling, endothelial dysfunction, and oxidative stress. Moreover, epidemiological studies have shown a clear association between aldosterone levels and the incidence of metabolic syndrome. In particular, recent work has revealed functional MRs in adipose tissue, where they mediate the effects of aldosterone and glucocorticoids, displaying important and specific functions involving adipose differentiation, expansion and proinflammatory capacity. This recent evidence finally moved MR out of the shadow of the glucocorticoid receptor (GR), which had previously been considered the only player mediating corticosteroid action in adipose tissue. This has opened a new era of research focusing on the complexity and selectivity of MR function in adipocyte biology. The aim of this review is to summarize the latest concepts on the role of MR in white and brown adipocytes, and to discuss the potential benefits of tissue-selective MR blockade in the treatment of obesity and metabolic syndrome., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Polymorphisms of the Glutathione-S Transferase (GST) family may influence the prognosis in lymphoma patients. We aimed to validate the impact of GSTT1 and GSTM1 deletions and of the GSTP1Ile105Val polymorphism on outcome and toxicity in 140 patients with advanced Hodgkin's lymphoma enrolled in the prospective multicenter HD2000-GISL trial, comparing ABVD, BEACOPP and CEC regimens. Carriers of the GSTP1Ile105Val polymorphism had a higher rate of grade 3-4 anemia following treatment. Overall, our study failed to validate GST genotyping as prognostic factor for progression-free survival (PFS). Only the small cohort of patients with an international prognostic score (IPS) >3 and undeleted GSTT1 and/or GSTM1, treated with ABVD had worse progression-free survival (PFS) (GSTT1 + vs GSTT1-: HR 5.02, 95% C.I., 1.16-21.8, p = 0.031, GSTM1 + /GSTT1 + vs GSTM1-and/or GSTT1-: HR 4.61, 95% C.I. 1.28- 16.6, p = 0.019, respectively). No differences were observed for patients treated with intensified regimens, as BEACOPP and CEC. In conclusion, the prognostic role of GST polymorphism, if at all, is limited to a small subgroup of patients treated with standard ABVD regimen.