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The comorbidity burden is an important risk factor for overall survival (OS) in several hematological malignancies. This observational prospective study was conducted to evaluate the impact of individual comorbidities on survival in a multicenter series of 668 patients with primary myelofibrosis (PMF) or MF secondary to polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). Hypertension (hazard ratio (HR) = 4.96, p < 0.001), smoking (HR = 5.08, p < 0.001), dyslipidemia (HR = 4.65, p < 0.001) and hepatitis C virus (HCV) (HR = 4.26, p = 0.015) were most adversely associated with OS. Diabetes (HR = 3.01, p < 0.001), pulmonary disease (HR = 3.13, p < 0.001) and renal dysfunction (HR = 1.82, p = 0.037) were also associated with an increased risk of death. Multivariate analysis showed that pulmonary disease (HR = 2.69, p = 0.001), smoking (HR = 3.34, p < 0.001), renal dysfunction (HR = 2.08, p = 0.043) and HCV (HR = 11.49, p = 0.001) had a negative impact on OS. When ruxolitinib exposure was included in the model, the effect of each comorbidity on survival was modified. Therefore, individual comorbidities should be taken into account in determining the survival prognosis for patients with MF.

OBJECTIVE: To provide practical recommendations for the evaluation and management of hypoglycemia in patients with diabetes mellitus. PARTICIPANTS: Members of the Diabetes Mellitus Working Group of the Spanish Society of Endocrinology and Nutrition (SEEN). METHODS: The recommendations were made based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system to establish both the strength of the recommendations and the level of evidence. A systematic search was made in MEDLINE (PubMed) for the available evidence on each subject, and articles written in English and Spanish with an inclusion date up to 30 November 2019 were reviewed. This executive summary takes account of the evidence incorporated since 2013. CONCLUSIONS: The document establishes practical evidence-based recommendations regarding the evaluation and management of hypoglycemia in patients with diabetes mellitus.

OBJECTIVE: To provide practical recommendations for the evaluation and management of hypoglycemia in patients with diabetes mellitus. PARTICIPANTS: Members of the Diabetes Mellitus Working Group of the Spanish Society of Endocrinology and Nutrition (SEEN). METHODS: The recommendations were made based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system to establish both the strength of the recommendations and the level of evidence. A systematic search was made in MEDLINE (PubMed) for the available evidence on each subject, and articles written in English and Spanish with an inclusion date up to 30 November 2019 were reviewed. This executive summary takes account of the evidence incorporated since 2013. CONCLUSIONS: The document establishes practical evidence-based recommendations regarding the evaluation and management of hypoglycemia in patients with diabetes mellitus.

The present study assessed the criteria for initiating cytoreduction and response to conventional therapies in 1446 patients with essential thrombocythemia (ET), 267 (17%) of which wereCALR-mutated. In low risk patients, time from diagnosis to cytoreduction was shorter inCALR-positive than in the other genotypes (2 center dot 8, 3 center dot 2, 7 center dot 4 and 12 center dot 5 years forCALR,MPL,JAK2V617F and TN, respectively,P < 0 center dot 0001). A total of 1104 (76%) patients received cytoreductive treatment with hydroxycarbamide (HC) (n = 977), anagrelide (n = 113), or others (n = 14). The estimated cumulative rates of complete haematological response (CR) at 12 months were 40 % and 67% inCALRandJAK2V617F genotypes, respectively. Median time to CR was 192 days forJAK2V617F, 343 for TN, 433 forMPL, and 705 forCALRgenotypes (P < 0 center dot 0001). Duration of CR was shorter inCALR-mutated ET than in the remaining patients (P = 0 center dot 003). InCALR-positive patients, HC and anagrelide had similar efficacy in terms of response rates and duration.CALR-mutated patients developed resistance/intolerance to HC more frequently (5%, 23%, 27% and 15% forJAK2V617F,CALR,MPLand TN, respectively;P < 0 center dot 0001). In conclusion, conventional cytoreductive agents are less effective inCALR-mutated ET, highlighting the need for new treatment modalities and redefinition of haematologic targets for patients with this genotype.

Molecular monitoring of BCR-ABL1 transcripts is a critical prognostic indicator of treatment response in chronic myeloid leukemia (CML). Quantification of BCR-ABL1 transcripts using ABL1 or GUSB as control genes on the early molecular response (MR) to frontline nilotinib was studied using data from 60 patients with chronic-phase CML from the Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) substudy. Effects of BCR-ABL1/ABL1 and BCR-ABL1/GUSB ratios at early time points as independent variables on subsequent MR were determined by logistic regression analyses and predictive cut-off values determined by receiver operating curve analyses. From day 45, concordance was found for both control genes' early transcript kinetics and ability to predict subsequent deep MR at 18 months. From baseline to 3 months, transcripts descended linearly with both control genes. Use of ABL1 allowed for an earlier prediction (2 months) of subsequent MR than with GUSB (3 months), with cut-off values of 1.5% and 0.19%, respectively. The dynamic determination of BCR-ABL1 transcripts using either internal control gene is valid and predictive of subsequent MR. The use of GUSB to predict an earlier and more accurate response than ABL1 is not supported in the results. Accurate early indicators of MR are essential to identify patients likely to have inferior outcomes who may benefit from treatment with an alternative tyrosine kinase inhibitor.

Myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PV) and essential thrombocythemia (ET), and remarkably shortens survival. Although JAK2V617F and CALR allele burden are the main transformation risk factors, inflammation plays a critical role by driving clonal expansion toward end-stage disease. NF-kappa B is a key mediator of inflammation-induced carcinogenesis. Here, we explored the involvement of miR-146a, a brake in NF-kappa B signaling, in MPN susceptibility and progression. rs2910164 and rs2431697, that affect miR-146a expression, were analyzed in 967 MPN (320 PV/333 ET/314 MF) patients and 600 controls. We found that rs2431697 TT genotype was associated with MF, particularly with post-PV/ET MF (HR = 1.5; p < 0.05). Among 232 PV/ET patients (follow-up time=8.5 years), 18 (7.8%) progressed to MF, being MF-free-survival shorter for rs2431697 TT than CC + CT patients (p = 0.01). Multivariate analysis identified TT genotype as independent predictor of MF progression. In addition, TT (vs. CC + CT) patients showed increased plasma inflammatory cytokines. Finally, miR-146a(-/-) mice showed significantly higher Stat3 activity with aging, parallel to the development of the MF-like phenotype. In conclusion, we demonstrated that rs2431697 TT genotype is an early predictor of MF progression independent of the JAK2V617F allele burden. Low levels of miR-146a contribute to the MF phenotype by increasing Stat3 signaling.

4 páginas. Funded by CEU Universidad Cardenal Herrera (IDOC-1610). Analyses were performed with a slide scanner purchased with European Union funds (FEDER Programme: PO FEDER 2007-2013).

Background: Hypoglycemia is a limiting factor to achieving optimal glycemic control in patients with type-2 diabetes mellitus (T2DM), increasing risk of death and complications, reducing health-related quality of life (HRQoL) and work productivity and increasing healthcare costs. The study's primary objective was to develop and validate a specific questionnaire to assess the impact of hypoglycemia on the HRQoL of T2DM patients (QoLHYPO (c) questionnaire). Methods: A two-phase multicenter prospective, longitudinal, observational, epidemiologic study of consecutively enrolled patients, not involving any drug, was conducted: In phase 1 (questionnaire development), patients who had given their written informed consent, who were at least 30 years of age, had been diagnosed with T2DM at least 5 years prior, had an HbA1c test in the previous 3 months, and a hypoglycemic episode in the previous 6 months were included. To validate the questionnaire and assess reliability and responsiveness, phase 2 included two cohorts of patients. Patients in the reliability cohort would likely have stable clinical course during the 3 weeks following inclusion in the study and patients in the responsiveness cohort would likely experience changes in their clinical course in the 3 months after enrollment. Results: Phase 1 included 168 patients: 10 attended semi-structured interviews, 18 for face validity, and 140 for the pilot test (Rasch analysis). Phase 2 included 227 patients: 142 in the reliability cohort and 85 in the responsiveness cohort. Of the 37 items initially included in Phase 1, 11 (floor/ceiling effect analysis) and 13 (Rasch analysis) were discarded. The final version of the questionnaire consisted of 13 items. Phase 2 results showed the questionnaire was unidimensional and able to accurately assess HRQoL. Intra-observer reproducibility (ICC = 0.920) and internal consistency (Cronbach's alpha: visit 1 = 0.912; visit 2 = 0.901) were high, showing high reliability. Internal responsiveness was moderate (standardized effect size 0.5-0.8) and external responsiveness was lower (AUC > 0.5; not statistically significant). Minimal clinically important difference (MCID) was estimated to be 3.2 points. Conclusions: The QoLHYPO (c) questionnaire is a tool that can be used in routine clinical practice to assess the impact of hypoglycemia on the HRQoL of T2DM patients.

OBJECTIVE: To study the factors associated with choice of therapy and prognosis in octogenarians with severe symptomatic aortic stenosis (AS). STUDY DESIGN: Prospective, observational, multicenter registry. Centralized follow-up included survival status and, if possible, mode of death and Katz index. SETTING: Transnational registry in Spain. SUBJECTS: We included 928 patients aged ≥80 years with severe symptomatic AS. INTERVENTIONS: Aortic-valve replacement (AVR), transcatheter aortic-valve implantation (TAVI) or conservative therapy. MAIN OUTCOME MEASURES: All-cause death. RESULTS: Mean age was 84.2 ± 3.5 years, and only 49.0% were independent (Katz index A). The most frequent planned management was conservative therapy in 423 (46%) patients, followed by TAVI in 261 (28%) and AVR in 244 (26%). The main reason against recommending AVR in 684 patients was high surgical risk [322 (47.1%)], other medical motives [193 (28.2%)], patient refusal [134 (19.6%)] and family refusal in the case of incompetent patients [35 (5.1%)]. The mean time from treatment decision to AVR was 4.8 ± 4.6 months and to TAVI 2.1 ± 3.2 months, P < 0.001. During follow-up (11.2-38.9 months), 357 patients (38.5%) died. Survival rates at 6, 12, 18 and 24 months were 81.8%, 72.6%, 64.1% and 57.3%, respectively. Planned intervention, adjusted for multiple propensity score, was associated with lower mortality when compared with planned conservative treatment: TAVI Hazard ratio (HR) 0.68 (95% confidence interval [CI] 0.49-0.93; P = 0.016) and AVR HR 0.56 (95% CI 0.39-0.8; P = 0.002). CONCLUSION: Octogenarians with symptomatic severe AS are frequently managed conservatively. Planned conservative management is associated with a poor prognosis.

OBJECTIVE: To provide practical recommendations for evaluation and management of hypoglycemia in patients with diabetes mellitus. PARTICIPANTS: Members of the Diabetes Mellitus Working Group of the Spanish Society of Endocrinology and Nutrition. METHODS: Recommendations were formulated according to the Grading of Recommendations, Assessment, Development, and Evaluation system to describe both the strength of recommendations and the quality of evidence. A systematic search was made in MEDLINE (PubMed). Papers in English and Spanish with publication date before 15 February 2013 were included. For recommendations about drugs only those approved by the European Medicines Agency were included. After formulation of recommendations, they were discussed by the Working Group. CONCLUSIONS: The document provides evidence-based practical recommendations for evaluation and management of hypoglycemia in patients with diabetes mellitus.

Trabajo presentado al "22th Biennial Congress of the European Association for Cancer Research" celebrado en Barcelona del 7 al 10 de julio de 2012.-- et al., [Background]: Chronic Iymphocytic leukemia (CLL) is the most common leukemia in the western world. CLL is characterized by the accumulation of CD5+ 8 Iymphocytes. However, clinical outcome of CLL may be different. Some patients have an indolent leukemia with long survival while others experience an aggressive disease. Contrary to other human malignancies, the cyclin-dependent kinase inhibitor p27kip1 (p27) has been described to be overexpressed in CLL cells. On the other hand, Myc is an oncogenic transcription factor overexpressed in many human tumours. In recent years, work in several cellular models have demonstrated that Myc, through different mechanisms, antagonize p27 express ion and its anti-proliferatice activity. Thus we set out to study the interaction functional between p27 and Myc in 8-CLL and whether changes in p27/Myc ratio correlated with the clinic features of the disease. [Material and Methods]: Protein and mRNA levels of Myc and p27 in CLL patients and Mec1 cells were analyzed by Western 810t and real time RTPCR. We studied p27 and Myc localization by immunofluorescence. Annexin assay was performed to study the fludarabine resistance. SPSS and GraphPad Prism were used for statistical studies. [Results]: We studied expression levels of p27 and Myc in more than 100 CLL patients using peripheral blood, tonsil and CD19+ Iymphocytes as control. p27 and Myc levels were inversely correlated. Thus, the ratio between p27 (overexpressed) and Myc (downregulated) appears inverted in CLL with respect to the other tumours so far known. Moreover, low p27 and high Myc express ion correlated with the expression of Skp2, a subunit of ubiquitin protein ligase complex SCF which is the main responsible for p27 degradation. Skp2 is a Myc target gene and promotes the degradation of p27, suggesting a pathway Myo-Skp2-p27 in CLL. To investigate why p27 is expressed in CLL we overexpressed in a CLL-derived cellline (Mec1) and observed that high levels of p27 provide resistance to fludarabine treatment. In fact, p27 expression was strongly correlated with Bcl2 levels, an antiapoptotic protein, in CLL samples. [Conclusions]: Our data provide new insights into the p27/Myc balance in CLL cells. The high percentage of p27 overexpressed patients suggests an important function in CLL. causing low levels of Myc and increasing resistan ce to apoptosis, likely through collaboration with 8c12. These resu lts suggest a functional explanation so as why p27 is overexpressed in CLL.

Erceg, Henderson and Levin (2000, Journal of Monetary Economics) introduce sticky wages in a New-Keynesian general-equilibrium model. Alternatively, it is shown here how wage stickiness may bring unemployment fluctuations into a New-Keynesian model. Using Bayesian econometric techniques, both models are estimated with U.S. quarterly data of the Great Moderation. Estimation results are similar and provide a good empirical fit with the crucial difference that our proposal delivers unemployment fluctuations. Thus, second-moment statistics of U.S. unemployment are replicated reasonably well in our proposed New-Keynesian model with sticky wages. In the welfare analysis, the cost of cyclical fluctuations during the Great Moderation is estimated at 0.60% of steady-state consumption. The first and third authors would like to acknowledge financial support from the Spanish government (research projects ECO2008-02641 and SEJ2007-66592C03-01/ECON from Ministerio de Ciencia e Innovación, respectively). The first author also thanks Fundación Ramón Areces (VII Concurso Investigación en Economía) for financial support.

Fundamento y objetivo: El hiperparatiroidismo primario (HPTP) en la mayoría de los casos es asintomático. Hoy día, se discute la necesidad de someter a estos enfermos a paratiroidectomía. En el presente estudio, pretendemos describir las características clínicas y bioquímicas de nuestra serie de HPTP, además, de describir las técnicas utilizadas en el diagnóstico y los resultados obtenidos tras la intervención quirúrgica. Material y métodos: Hemos revisado las historias clínicas de 47 pacientes diagnosticados y operados de HPTP en nuestro centro en los últimos cinco años. Primero, recogimos las manifestaciones clínicas; segundo, los resultados bioquímicos anteriores y posteriores a la intervención quirúrgica; tercero, los datos de la ecografía paratiroidea, tomografía computerizada (TC) cervico-torácica, gammagrafía paratiroidea con 99Tc-Sestamibi y densitometría dual de rayos X ( DEXA); y por último, los resultados derivados de la intervención quirúrgica. Resultados: Fueron intervenidos 47 pacientes de HPTP, 89,4% mujeres, con edad media 61,4 ±12,8 años. La gran mayoría se encontraban asintomáticos (45,7%). En cuanto a las técnicas de localización, la gammagrafía con 99mTc-sestamibi fue la que tuvo mayor sensibilidad y especificidad 75 y 100%, respectivamente. Ninguno de los pacientes presentó osteoporosis mediante densitometría ósea. El principal diagnóstico fue el de adenoma 85,1%. Todos los pacientes curaron tras la intervención, con la excepción de un solo caso. Conclusión: El HPTP presenta escasos síntomas. Principalmente se trata de adenomas. La técnica de localización preoperatoria más útil es la gammagrafía. El tratamiento definitivo es la extirpación.

Imatinib (Glivec, Gleevec, STI571), a Bcr-Abl kinase inhibitor, is the most used drug in chronic myeloid leukemia. Imatinib induces apoptosis in a number of CML-derived cell lines, including K562. However, in order to achieve hematological remissions it is required chronic treatment with the drug, a fact inconsistent with a cytotoxic mechanism of imatinib in vivo. In this work we have analysed the effects of imatinib on the proliferation and apoptosis of K562-derived cell lines with constitutive expression of the anti-apoptotic genes Bcl2 and BclX. We found that imatinib-mediated apoptosis was completely abrogated in both Bcl2- and BclX-cell lines. However, imatinib inhibited proliferation, although growth rate was higher than in parental K562. We conclude that, besides its apoptotic effect, imatinib acts through an apoptosis-independent mechanism to arrest cell growth., The work was supported by grant PM98-0109 and SAF2002-04193 from Spanish Ministry of Science and Technology to J.L.