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Background: The Molecular International Prognostic Scoring System (IPSS-M) has improved the prediction of clinical outcomes for myelodysplastic syndromes (MDS). The Artificial Intelligence Prognostic Scoring System for MDS (AIPSS-MDS), based on classical clinical parameters, has outperformed the IPSS, revised version (IPSS-R). For the first time, we validated the IPSS-M and other molecular prognostic models and compared them with the established IPSS-R and AIPSS-MDS models using data from South American patients., Methods: Molecular and clinical data from 145 patients with MDS and 37 patients with MDS/myeloproliferative neoplasms were retrospectively analyzed., Results: Prognostic power evaluation revealed that the IPSS-M (Harrell's concordance [C]-index: 0.75, area under the receiver operating characteristic curve [AUC]: 0.68) predicted overall survival better than the European MDS (EuroMDS; C-index: 0.72, AUC: 0.68) and Munich Leukemia Laboratory (MLL) (C-index: 0.70, AUC: 0.64) models. The IPSS-M prognostic discrimination was similar to that of the AIPSS-MDS model (C-index: 0.74, AUC: 0.66) and outperformed the IPSS-R model (C-index: 0.70, AUC: 0.61). Considering simplified low- and high-risk groups for clinical management, after restratifying from IPSS-R (57% and 32%, respectively, hazard ratio [HR]: 2.8; P =0.002) to IPSS-M, 12.6% of patients were upstaged, and 5% were downstaged (HR: 2.9; P =0.001). The AIPSS-MDS recategorized 51% of the low-risk cohort as high-risk, with no patients being downstaged (HR: 5.6; P <0.001), consistent with most patients requiring disease-modifying therapy., Conclusions: The IPSS-M and AIPSS-MDS models provide more accurate survival prognoses than the IPSS-R, EuroMDS, and MLL models. The AIPSS-MDS model is a valid option for assessing risks for all patients with MDS, especially in resource-limited centers where molecular testing is not currently a standard clinical practice.

Introduction: The treatment of elderly multiple myeloma (MM) patients with autologous stem cell transplantation (ASCT) is a controversial procedure. Most clinical trials evaluating the safety and efficacy of ASCT have primarily included patients younger than 65 years., Design and Methods: This was a retrospective analysis of patients with MM who underwent ASCT between 2008 and 2018. Patients at or over 65 years were compared with patients under 65 years. We analyzed treatment-related mortality (TRM), response rate, progression-free survival (PFS) and overall survival (OS)., Results: Two hundred and twenty-one patients were included: 50 patients at or over 65 years, (median age 68 years), including 7 patients over 70 years and 151 patients under 65 years, (median age 57 years). No differences were found in the neutrophil and platelet engraftment, median days of hospitalization and life support requirement during the hospitalization period for the ASCT. No statistically significant differences were found in the incidence of TRM between both groups at 100 days post-transplant (2% vs. 2.9%, p = 0.322). The ASCT improved complete response and stringent complete response rates (44% vs. 37%, p < 0.001). Survival was not modified by age: after a median follow-up of 53 months, the estimated PFS rates at three years were 63% and 60% (p = 0.88) and the OS rates at five years were 75% and 74% (p = 0.72), respectively., Conclusions: Our data suggest that the ASCT is feasible in selected elderly patients with MM over 65 years of age, achieving response and survival rates similar to those of younger patients., Competing Interests: Conflicts of interest The authors declare no potential conflicts of interest, either financial or other., (Copyright © 2023 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier España, S.L.U. All rights reserved.)

Background and Objectives: Allogeneic stem cell transplantation (Allo-SCT) in elderly patients is a growing practice. We aimed to determine the graft-versus-host disease (GVHD) relapse-free survival (GRFS) in patients ≥65 years who underwent Allo-SCT in two countries from Latin America., Patients and Methods: We performed a retrospective analysis of patients ≥65 years who underwent Allo-SCT in Argentina and Brazil from 2007 to 2019., Results: Ninety-eight patients were evaluated, with primary diagnoses of acute myeloid leukemia and myelodysplastic syndrome; 30% of patients had a hematopoietic cell transplant-comorbidity index (HCT-CI) score ≥3 and 49% were in complete remission. Donor types included matched sibling (n = 41), matched unrelated (n = 31), and haploidentical (HID; n = 26) donors. The conditioning regimen was myeloablative in 28 patients (14 busulfan pharmacokinetically [PK]-guided) and reduced-intensity in 70 patients. The two-year non-relapse mortality (NRM) was 29%, with a higher NRM in melphalan-based compared to other conditionings (51% vs. 33%, p = 0.02). The two-year relapse rate was 24%, with a reduction in PK-guided busulfan (0% vs. 28%, p = 0.03). The two-year overall survival (OS) and GRFS was 52% and 38%, respectively, with a significant reduction in GRFS in HCT-CI ≥3 (27% vs. others 42%, p = 0.02) and donors ≥40 years (29% vs. <40 years 55%, p = 0.02). These variables remained significantly associated with GRFS after multivariate analysis., Conclusion: In this cohort of elderly patients from Argentina and Brazil undergoing Allo-SCT, donor age and comorbidities significantly influenced GRFS. The role of the conditioning regimen in this population deserves further investigation.

Knowledge on chronic myelomonocytic leukemia (CMML) patients from Argentina and Brazil is limited. Our series of 280 patients depicted an older age at diagnosis (median 72 years old), 26% of aberrant karyotypes, and a prevalence of myelodysplastic (60%) and CMML-0 subtypes (56%). The median overall survival (OS) was 48.2 months for patients in CMML-0 (Ref.), 24.7 months for those in CMML-1 (HR = 2.0, p = 0.001), and 8.8 months for patients in CMML-2 (HR = 4.6, p < 0.001). In the CMML-0 category, median OS were different between myelodysplastic and myeloproliferative subtypes (63.7 vs 21.2 months, p < 0.001); however, no differences were observed within CMML-1 and CMML-2 subtypes (24.7 vs 23.7 months, p = 0.540, and 9.1 vs 8.2 months, p = 0.160). The prognostic impact of 24 variables and 7 prognostic systems was adjusted to the WHO 2016 after validating their usefulness. Multivariate analysis were performed, and the final model revealed Hb ≥ 8 -< 10g/dL (HR 1.7), Hb < 8g/dL (HR 2.8), poor karyotypes (HR 2.1), WHO 2016-CMML-1 (HR 2.1), and CMML-2 (HR 3.5) as independent adverse clinical parameters in our cohort with a borderline influence of platelets count < 50 × 10 9 /L (HR 1.4). We could validate several scoring systems, the WHO 2016 proposal and its prognostic capability, along with accessible covariates, on predicting the outcome in our series of CMML patients from Latin America.

Introduction: Factor XIII (FXIII) deficiency may cause bleeding under certain clinical circumstances. Therapeutic plasma exchange (TPE) may lead to a transient deficiency., Objectives: To describe the clinical evolution of patients with acquired FXIII deficiency secondary to TPE., Methods: We respectively studied a cohort of consecutive patients from 2014 to 2019 who were treated with TPE with FXIII levels <50%. The FXIII was measured after the start of the TPE course, on days between the TPE sessions, due to suspected acquired deficiency. All TPE were performed using continuous flow cell separator. In all cases, the initial replacement fluid applied was albumin. Apheresis procedures were held at 24to 48 hours intervals., Results: Eighteen patients were included, 13 of them were recipients of kidney transplants. The main TPE prescription was humoral rejection. Median FXIII at diagnosis (measured on days between sessions of the TPE course) was 19%(IQR17-25). The median of apheresis procedures before measurement of FXIII was 3(IQR2-4). Among the total cohort, 10 patients suffered hemorrhages. None of the patients without history of kidney transplants had bleeding (n = 5), however, 10/13 with kidney transplants did. Five kidney transplant patients received therapy with FXIII concentrate because of life-threatening bleeding. In all cases, the bleeding stopped within the first 24 hours. All patients had their FXIII levels measured again after finishing the TPE course, with normal results., Conclusions: TPE is an under-diagnosed cause of acquired FXIII deficiency since routine coagulation tests remain unaltered. It might cause major bleeding, particularly in patients with a recent history of surgery like kidney transplants., (© 2020 Wiley Periodicals LLC.)

Adult T-cell lymphoma is an aggressive and poor prognosis HTLV1-associated lymphoma. There is no standard treatment, but it is known that intensive chemotherapy regimens are necessary, with or without concomitant antiretroviral therapy, plus consolidation with allogeneic stem cell transplantation. Our case report shows a favorable outcome after 2 cycles of chemotherapy and allogeneic stem cell transplantation without antiretroviral agents, achieving complete remission, and a negative proviral load., (© 2020 Wiley Periodicals LLC.)

There have been several efforts to predict mortality after autologous stem cell transplantation (ASCT), such as the hematopoietic cell transplant-comorbidity index (HCT-CI), described for allogeneic stem cell transplantation and validated for ASCT, but there is no composite score in the setting of ASCT combining comorbidities with other clinical characteristics. Our aim is to describe a comprehensive score combining comorbidities with other clinical factors and to analyze the impact of this score on nonrelapse mortality (NRM), overall survival (OS), and early morbidity endpoints (mechanical ventilation, shock or dialysis) after ASCT. For the training cohort, we retrospectively reviewed data of 2068 adult patients who received an ASCT in Argentina (October 2002 to June 2017) for multiple myeloma or lymphoma. For the validation cohort, we analyzed 2168 ASCTs performed in the Medical College of Wisconsin and Spanish stem cell transplant group (Grupo Español de Trasplante Hematopoyético (GETH)) (January 2012 to December 2018). We first performed a multivariate analysis for NRM in order to select and assign weight to the risk factors included in the score (male patients, aged 55 to 64 and ≥65 years, HCT-CI ≥3, Hodgkin lymphoma and non-Hodgkin lymphoma). The hazard ratio for NRM increased proportionally with the score. Patients were grouped as low risk (LR) with a score of 0 to 1 (686, 33%), intermediate risk (IR) with a score of 2 to 3 (1109, 53%), high risk (HR) with a score of 4 (198, 10%), and very high risk (VHR) with a score of ≥5 (75, 4%). The score was associated with a progressive increase in all the early morbidity endpoints. Moreover, the score was significantly associated with early NRM (day 100: 1.5% versus 2.4% versus 7.6% versus 17.6%) as well as long term (1 to 3 years; 1.8% to 2.3% versus 3.8% to 4.9% versus 11.7% to 14.5% versus 25.0% to 27.4%, respectively; P< .0001) and OS (1 to 5 years; 94% to 73% versus 89% to 75% versus 76% to 47% versus 65% to 52% respectively; P < .0001). The score was validated in an independent cohort (N = 2168) and was significantly associated with early and late events. In conclusion, we developed and validated a novel score predicting NRM and OS in 2 large cohorts of more than 2000 autologous transplant patients. This tool can be useful for tailoring conditioning regimens or defining risk for transplant program decision making., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. All rights reserved.)

Argentina is a country characterized by a heterogeneous distribution of its population, its economic resources and, consequently, access to health services, which could affect the diagnosis and treatment of patients with myelodysplastic syndromes. Based on the increasing complexity to arrive at the diagnosis, estimate the risk and indicate an adequate treatment, we have conducted a survey of twenty-three questions to evaluate patterns of clinical practice. The questionnaire was distributed among 850 hematologists registered at the XXII Argentine Congress of Hematology, and 195 (22.9%) were answered; 40.0% report that < 75% of their patients access the karyotype, bone marrow histology and flow cytometry. This access decreases significantly due to low health coverage (OR 6.3), in the adult population (OR 3.8), when the cytogenetic study is derived (OR 3.2) and outside the metropolitan area of Buenos Aires (OR 2.4). The respondents avoid oncological terminologies (77.0%) when introducing the diagnosis and use the international prediction system or its review (74.2%) to stage risk. However, they prioritize age when selecting treatment and pediatricians preferentially recommend the transplantation of hematopoietic precursors. Most of the haematologists have prescribed the recommended treatments, whose suspensions were related to lack of response (62.7%), with reduced participation in clinical trials (8.9%). Therefore, they report heterogeneity in the access to complementary diagnostic tools with differences at the time of indicating a treatment, depending on the age of their patients without apparent limitations in their prescription.

: Coumadin oral anticoagulants are widely used in multiple clinical scenarios. Their narrow therapeutic range and a dosing strategy based on 'a posteriori' algorithms, pose them as an interesting group for prediction modelling research. Extensive literature explaining the association between clinical and genetic variables with the dose of warfarin have been published. Limited information exists regarding these factors and acenocoumarol dosing. The aim of the study is to explain through clinical/genetic variables, the weekly dose of acenocoumarol necessary for achieving stable anticoagulation status. We performed a cross-sectional study enrolling adults under treatment with acenocoumarol with at least three consecutive INRs between 2 and 3. To explain the association between demographic, clinical and genotype data (VKORC1, CYP2C9 and CYP4F2) and the mean weekly dose of acenocoumarol, we performed a multiple linear regression model. In our cohort, a higher age, the presence of atrial fibrillation, chronic renal failure and VKORC1 haplotype A were associated with a lower mean weekly dose of acenocoumarol. On the other side, a higher weight was associated with a higher weekly dose. Amongst anticoagulated adult patients, VKORC1 genotype and baseline clinical factors can explain acenocoumarol dosing, and therefore, help clinicians while deciding the initial anticoagulant dose.

Monoclonal gammopathy of renal significance (MGRS) is a new nosological group of entities (meta-entity) defined in 2012, whose pathogenesis depends on monoclonal immunoglobulins (Ig) secreted by low-grade lymphoproliferative disorders, which belong to M-protein-related diseases. Renal damage is the result of monoclonal Ig deposit or its activity as autoantibodies, which can compromise any nephronal area. MGRS does not include kidney diseases produced by high-grade lymphoproliferative disorders as well as those whose pathogenesis are independent of monoclonal Ig (such as drug toxicity or metabolic disorders). The importance of this hemato-nephrological meta-entity is based on two aspects: First, it is associated with increased morbidity and mortality, including recurrence in post-renal transplant or its appearance as "de novo" after it; and second, it usually improves after treating the plasmocyte or lymphocyte clone responsible, leading to the elimination of M-protein. Between low-grade lymphoproliferative disorders, monoclonal gammopathy of undetermined significance (MGUS) requires special consideration for two reasons: First, it is the disorder most related to MGRS; second, when MGUS progresses to MGRS, effective treatment against toxic underline clone should be performed taking into account the nephrological perspective.

Background: A large group of patients with myelodysplastic syndromes (MDS) will die of causes intrinsic to bone marrow failure. One third of patients will develop acute myeloid leukemia (AML), which is associated with an extremely poor outcome and a short survival. Our objectives were to analyze the prognostic variables and scoring systems in the attempt to determine the influence of progression on the overall survival of MDS patients., Patients and Methods: We performed a retrospective analysis of 831 MDS patients, including those from the Argentine Registry., Results: Of the 831 MDS patients, 158 (19.0%) experienced transformation, with a median overall survival of 17.9 months from diagnosis and 3.5 months after progression. The survival of patients with adverse karyotypes or greater risk, according to the International Prognostic Scoring System-revised (IPSS-R) or World Health Organization-based Prognostic Scoring System (WPSS) was not affected when stratified by patients with and without evolution to AML (P > .05). In contrast, the survival of lower risk patients was significantly reduced for those patients with progression to AML (P < .001) and those younger (P = .024) than those who died of non-AML-related causes. The intermediate-risk patients were heterogeneously distributed; however, an upgrade from a lower IPSS-R to a higher WPSS-hemoglobin risk category was associated with a worse outcome, not affected by progression (P = .420), with a median event-free survival of 16 months., Conclusion: The use of the IPSS-R and WPSS systems simultaneously might help in identifying those patients who require more aggressive treatment. Nevertheless, more efforts are needed to improve the identification of those lower risk patients whose survival is significantly reduced by progression to AML., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematologic disorders characterized by cytopenia(s) and predisposition to leukemic progression. An immune dysregulation and an aberrant bone marrow microenvironment seem to be key elements in the physiopathological process of MDS. In order to evaluate a possible association between susceptibility and clinic-pathologic features, we genotyped 153 MDS patients for functional cytokine polymorphisms: TNF (-308 G/A), IFNG (+874 A/T and +875 CAn), IL6 (-174 G/C), and TGFB1 (+869 C/T and +915 G/C). The frequency of TNF and IL6 polymorphisms was different between patients and healthy controls (n = 131), suggesting a relatedness to MDS susceptibility in our population. Furthermore, the presence of each or both high-producing genotypes [TNF: p = 0.048, odds ratio (OR): 3.979; IL6: p = 0.001, OR: 6.835; both: p = 0.010, OR: 6.068] and thrombocytopenia at platelet counts of <50,000/μL (p = 0.004, OR: 4.857) were independently associated with an increased risk of manifesting a hemoglobin level of <8 g/dL at diagnosis. In particular, a severe bicytopenia was more frequently observed in patients with the TNF (high)&#95;IL6 (high) combined genotype (p = 0.004, OR: 8.357), who consistently became transfusion dependent earlier (2.9 vs. 34.6 months; p = 0.001); and this likelihood was more evident in patients with lower bone marrow blast counts. The contribution of the remaining functional polymorphisms to the disease phenotype was less relevant. Our results demonstrate that TNF and IL6 gene polymorphisms, as underlying host features, are likely to play a key role in influencing the severity of the cytopenias in MDS and they may be instrumental for tailoring cytokine-target therapies.

Background and Aims: Iron deficiency anemia (IDA) affects around 20-30% of adults worldwide. An association between IDA and cardiovascular disease (CVD) has been reported. Oxidative stress, inflammation and low concentration of high-density lipoproteins (HDL) were implicated on endothelial dysfunction and CVD in IDA. We studied the effects of iron deficiency and of an intravenous iron administration on oxidative stress and HDL characteristics in IDA women., Methods: Two studies in IDA women are presented: a case-control study, including 18 patients and 18 age-matched healthy women, and a follow-up study 72hr after the administration of intravenous iron (n = 16). Lipids, malondialdehyde, cholesteryl ester transfer protein (CETP), paraoxonase-1 (PON-1) and HDL chemical composition and functionality (cholesterol efflux and antioxidative activity) were measured. Cell cholesterol efflux from iron-deficient macrophages to a reference HDL was also evaluated., Results: IDA patients showed higher triglycerides and CETP activity and lower HDL-C than controls (all p < 0.001). HDL particles from IDA patients showed higher triglyceride content (+30%,p < 0.05) and lower antioxidative capacity (-23%,p < 0.05). Although HDL-mediated cholesterol efflux was similar between the patients and controls, iron deficiency provoked a significant reduction in macrophage cholesterol efflux (-25%,p < 0.05). Arylesterase activity of PON-1 was significantly lower in IDA patients than controls (-16%,p < 0.05). The intravenous administration of iron was associated with a decrease in malondialdehyde levels and an increase in arylesterase activity of PON-1 (-22% and +18%, respectively, p < 0.05)., Conclusion: IDA is associated with oxidative stress and functionally deficient HDL particles. It remains to be determined if such alterations suffice to impair endothelial function in IDA., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Introduction: Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative approach for patients with myelodysplastic syndrome (MDS)., Methods: In this multicenter retrospective study, we analyzed the outcome of adult patients with MDS who underwent AHSCT in Argentina and evaluated the prognostic factors associated with progression-free survival (PFS), overall survival (OS), cumulative incidence (CI) of relapse, and non-relapse mortality (NRM)., Results: We analyzed data from 87 adults (median age: 43 years, range 18-66) who underwent SCT after myeloablative (n = 60) or non-myeloablative conditioning (n = 27), and from related (n = 62) or unrelated (n = 25) donors. For all patients, unadjusted 4-year PFS and OS were 37% and 38%, respectively; no significant differences were found between recipients of related or unrelated donors. One-year CI of relapse and NRM were 21% and 20%, respectively. In the multivariate analysis, intermediate disease risk index (DRI) and acute graft versus host disease AGVHD of all grades (I-IV) were independent variables associated with better PFS and lower relapse CI; only intermediate DRI was associated with better OS., Conclusions: AHSCT is a feasible procedure in Argentina, with more than 30% of the patients achieving long-term survival. Recipients with unrelated donors had at least similar outcome than those with related donors. DRI may be useful to identify patients at higher risk of relapse after transplantation.

The core complex of telomere-associated proteins, named the shelterin complex, plays a critical role in telomere protection and telomere length (TL) homeostasis. In this study, we have explored changes in the expression of telomere-associated genes POT1, TIN2, RAP1 and TPP1, in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). A total of 154 patients: 70 with MGUS and 84 with MM were studied. Real-time quantitative PCR was used to quantify gene expression. TL was evaluated by Terminal Restriction Fragments. Our data showed increased expression of POT1, TPP1, TIN2 and RAP1 in MM with respect to MGUS patients, with significant differences for POT1 gene (p=0.002). In MM, the correlation of gene expression profiles with clinical characteristics highlighted POT1 for its significant association with advanced clinical stages, high calcium and β2-microglobulin levels (p=0.02) and bone lesions (p=0.009). In multivariate analysis, POT1 expression (p=0.04) was a significant independent prognostic factor for overall survival as well as the staging system (ISS) (p<0.02). Our findings suggest for the first time the participation of POT1 in the transformation process from MGUS to MM, and provide evidence of this gene as a useful prognostic factor in MM as well as a possible molecular target to design new therapeutic strategies., (© 2013.)

Myelodysplastic syndromes (MDS) include a group of heterogeneous hematological disorders with a variable risk of leukemic evolution and short survival. Around 40-50% of patients show abnormal karyotypes that are mostly characterized by monosomies or deletions. Cytogenetic findings are an independent prognostic factor and the International prognostic scoring system (IPSS) differentiates three cytogenetic categories, despite the Intermediate one being heterogeneous. The aim of this study, including 421 Argentinean patients with primary MDS, is to characterize the cytogenetic profile, to test its prognostic value and to compare partial and monosomal karyotypes against other cytogenetic findings. An abnormal karyotype (median survival: 26 months) was observed in 176 patients. The presence of complex karyotypes, number of alterations, and the IPSS cytogenetic groups showed significant differences for predicting outcome. Behavior of patients with isolated deletions (median survival: 49 months) did not differ from those with normal karyotype (56 months, P = 0.654) or Good prognostic findings (43 months, P = 0.371). However, a worse prognosis was observed when another alteration was added (31 months, P = 0.043). Karyotypes with autosomal monosomies (median survival: 16 months) had a prognostic impact similar to other Poor cytogenetic findings (17 months, P = 0.626). In our population classified according to French-American-British (FAB) or World Health Organization (WHO), this new categorization of cytogenetic abnormalities, recognizing three different risk groups, showed an independent prognostic impact and a better discriminating power than the IPSS categories. It can be concluded that all isolate deletions (excluding 7q-) are good prognostic findings and all monosomies (excluding Y chromosome loss) are bad indicators., (Copyright © 2011 Wiley-Liss, Inc.)

Introduction: Iron overload (IO) is defined as an increase in storage iron, regardless of the presence or absence of tissue damage. Whether increased iron stores are involved in the pathogenesis of cardiovascular disease remains controversial., Objectives:  To study insulin resistance markers, lipoprotein profile, activities of anti and prooxidant enzymes and cholesteryl ester transfer protein (CETP) in patients with IO., Methods: Twenty male patients with IO were compared with 20 sex- and age-matched controls. General biochemical parameters, lipoprotein profile, and activities of paraoxonase 1, employing two substrates, paraoxon (PON) and phenylacetate (ARE), lipoprotein-associated phospholipase A(2) (Lp-PLA(2) ) and CETP were determined., Results: IO patients showed higher levels of HOMA-IR and triglycerides [median (Q1-Q3)] [128 (93-193) vs. 79(51-91) mg dL(-1) , P < 0·0005] while lower high-density lipoprotein (HDL) cholesterol (mean ± SD) (41 ± 9 vs. 52 ± 10 mg dL(-1) , P < 0·0005) in comparison with controls. Moreover, the triglycerides/HDL-cholesterol [3·2 (2·0-5·1) vs. 1·5 (1·0-1·9), P < 0·0005] ratio and oxidized low-density lipoprotein levels [94 (64-103) vs. 68 (59-70) IU L(-1) , P < 0·05] were increased in the patient group. Although no difference was observed in ARE activity, PON activity was decreased in IO patients [246 (127-410) vs. 428 (263-516) nmol mL(-1) min(-1) , P < 0·05]. In addition, CETP and Lp-PLA(2) activities were also increased in the patients (189 ± 31 vs. 155 ± 36% ml(-1)  h(-1) , P < 0·005; and 10·1 ± 2·9 vs. 8·2 ± 2·4 μmol mL(-1) h(-1) , P < 0·05, respectively). Associations between ferritin concentration and the alterations in lipid metabolism were also found. Multiple regression analyses identified HOMA-IR as independent predictor of CETP activity (B = 65·9, P < 0·0001, r(2) = 0·35), as well as ferritin concentration of Lp-PLA(2) activity (B = 3·7, P < 0·0001, r(2) = 0·40) after adjusting for confounding variables., Conclusions:   IO patients presented not only insulin resistance but also metabolic alterations that were related to elevated iron stores and are associated with high risk of cardiovascular disease., (© 2010 The Authors. European Journal of Clinical Investigation © 2010 Stichting European Society for Clinical Investigation Journal Foundation.)

In this study, we explored changes in the expression of the telomere maintenance genes, TRF1, TRF2 and TANK1 in patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Results were correlated with human telomerase reverse transcriptase (hTERT ) expression, telomere length (TL) and clinicopathological characteristics. Bone marrow (BM) samples from 132 patients, 64 with MGUS and 68 with MM, were studied. Real-time quantitative reverse transcription-polymerase chain reaction was used to quantify gene expression. TL was evaluated by terminal restriction fragment length analysis. MGUS patients showed increased TRF1 levels (P = 0.006) and lower expression of TRF2 (P = 0.005) and TANK1 (P = 0.003) compared with MM patients. For hTERT analysis, patients were divided into three groups by use of receiver operating characteristics: low (group I [GI]), intermediate (group II [GII]) and high (group III [GIII]) expression. We observed increasing expression of TRF2 and TANK1 from GI to GIII in MGUS and MM, with differences for both genes in MM (P < 0.01) and for TRF2 in MGUS (P < 0.01). GIII patients with the highest telomerase expression had the shortest TL. In both entities, a positive association between TRF2-TANK1, TRF2-hTERT and TANK1-hTERT (P ≤ 0.01) was observed. In MM, the percentage of BM infiltration and Ki-67 index were positively associated with TRF2, TANK1 and hTERT expression (P ≤ 0.03) and negatively with TL (P = 0.02), whereas lactate dehydrogenase was significantly correlated with TRF2 mRNA (P = 0.008). Our findings provide the first evidence of a modification in the expression of telomeric proteins in plasma cell disorders, and suggest that mechanisms other than telomerase activation are involved in TL maintenance in these pathologies.

Aberrant DNA methylation is considered an important epigenetic mechanism for gene inactivation. Monoclonal gammopathy of undetermined significance (MGUS) is believed to be a precursor of multiple myeloma (MM). We have analyzed methylation status of p15 INK4B , p16 INK4A , ARF, SOCS-1, p27 KIP1 , RASSF1A, and TP73 genes in bone marrow DNA samples from 21 MGUS and 44 MM patients, in order to determine the role of aberrant promoter methylation as one of the steps involved in the progression of MGUS to MM. Methylation specific polymerase chain reaction assay followed by DNA sequencing of the resulting product was performed. SOCS-1 gene methylation was significantly more frequent in MM (52%) than in MGUS (14%; p=0,006). Methylation frequencies of TP73, ARF, p15 INK4B , p16 INK4A , and RASSF1A were comparable in MGUS: 33%, 29%, 29%, 5%, and 0%, to that observed in MM: 45%, 29%, 32%, 7%, and 2%. All patients lacked methylation at p27 KIP1 gene. In both entities, a concurrent methylation of p15 INK4B and TP73 was observed. The mean methylation index of MGUS was lower (0.16) than that of MM (0.24; p<0.05). Correlations with clinicopathologic characteristics showed a higher mean age in MGUS patients with SOCS-1 methylated (p<0.001); meanwhile in MM, methylation of p15 INK4B was more frequent in males (p=0.009) and IgG isotype (p=0.038). Our findings suggest methylation of TP73, ARF, p15 INK4B , and p16 INK4A as early events in the pathogenesis and development of plasma cell disorders; meanwhile, SOCS-1 methylation would be an important step in the clonal evolution from MGUS to MM.