Deliberative processes in health technology assessment of medicines: the case of Spain.

OBJECTIVES: Spain incorporated in 2020 changes in its health technology assessment (HTA), pricing, and reimbursement system for medicines including publishing reports, development of networks of experts, or consultation with stakeholders. Despite these changes, it is unclear how deliberative frameworks are applied and the process has been criticized for not being sufficiently transparent. This study analyses the level of implementation of deliberative processes in HTA for medicines in Spain. METHODS: We review the grey literature and summarize the Spanish HTA, pricing, and reimbursement process of medicines. We apply the deliberative processes for HTA checklist, developed to assess the overall context of the deliberative process, and identify the stakeholders involved and type of involvement following the framework for evidence-informed deliberative processes, a framework for benefit package design that aims to optimize the legitimacy of decision making. RESULTS: In the Spanish HTA, pricing, and reimbursement process deliberation takes place in order to exchange viewpoints and reach common ground, mainly during the prioritization, assessment, and appraisal steps. It is closed to the public, not clearly summarized in published documents and limited to the Ministry of Health, the regulatory agency, other Ministries, and experts with mostly clinical and/or pharmaceutical background. The views of stakeholders are only represented through consultation. Communication is the most commonly used form of stakeholder engagement. CONCLUSIONS: Despite improvements in transparency of the Spanish HTA process for evaluating medicines, aspects related to stakeholder involvement and implementation of deliberative frameworks need further attention in order to achieve further legitimacy of the process.

Impact of Systemic Lupus Erythematosus on Pregnancy: Analysis of a Large 10-Year Longitudinal Mexican Cohort.

BACKGROUND: Pregnancy in patients with systemic lupus erythematosus is considered a high risk one since it is associated with a higher rate of maternal-fetal complications compared with the pregnancies in healthy women. OBJECTIVES: The aim of this study was to describe the maternal-fetal outcomes in a cohort of Mexican patients with systemic lupus erythematosus and to identify risk factors associated with adverse maternal and fetal outcomes. PATIENTS AND METHODS: A cohort of pregnant lupus patients was analyzed. Maternal-fetal complications were described, and clinical, biochemical, and immunological variables associated with obstetric adverse outcomes were studied. Descriptive statistics, comparison of variables using appropriate tests, and finally logistic regression analysis were performed to identify potential risk factors for adverse maternal and fetal outcomes. RESULTS: A total of 351 pregnancies were included in a 10-year period. The most frequently observed maternal adverse outcomes were lupus flare (35%) and preeclampsia (14.5%). Active lupus before pregnancy (hazards ratio [HR], 3.7; 95% confidence interval [CI], 1.1-12.5; p = 0.003) was a predictor for these complications, whereas the use of antimalarial drugs (HR, 0.4; 95% CI, 0.2-0.7; p = 0.007) was a protective factor. The most frequent fetal adverse outcomes were preterm birth (38.1%), miscarriages (10%), and low birth weight babies (28%), and very low birth weight newborns (11%). Proteinuria in early pregnancy (HR, 7.1; 95% CI, 1.01-50.3; p = 0.04) and preeclampsia (HR, 9.3; 95% CI, 1.7-49.7; p = 0.009) were risk factors associated with these complications. CONCLUSIONS: Variables related to systemic lupus erythematosus activity predict an adverse maternal outcome, whereas proteinuria in early pregnancy and preeclampsia are associated with an adverse fetal outcome.

Extracellular vesicles in DLBCL provide abundant clues to aberrant transcriptional programming and genomic alterations.

The biological role of extracellular vesicles (EVs) in diffuse large B-cell lymphoma (DLBCL) initiation and progression remains largely unknown. We characterized EVs secreted by 5 DLBCL cell lines, a primary DLBCL tumor, and a normal control B-cell sample, optimized their purification, and analyzed their content. We found that DLBCLs secreted large quantities of CD63, Alix, TSG101, and CD81 EVs, which can be extracted using an ultracentrifugation-based method and traced by their cell of origin surface markers. We also showed that tumor-derived EVs can be exchanged between lymphoma cells, normal tonsillar cells, and HK stromal cells. We then examined the content of EVs, focusing on isolation of high-quality total RNA. We sequenced the total RNA and analyzed the nature of RNA species, including coding and noncoding RNAs. We compared whole-cell and EV-derived RNA composition in benign and malignant B cells and discovered that transcripts from EVs were involved in many critical cellular functions. Finally, we performed mutational analysis and found that mutations detected in EVs exquisitely represented mutations in the cell of origin. These results enhance our understanding and enable future studies of the role that EVs may play in the pathogenesis of DLBCL, particularly with regards to the exchange of genomic information. Current findings open a new strategy for liquid biopsy approaches in disease monitoring.

NICE's evaluations of medicines authorized by EMA with conditional marketing authorization or under exceptional circumstances.

OBJECTIVES: To investigate the impact of the uncertainty stemming from products with European conditional marketing authorization (CMA) or authorization in exceptional circumstances (AEC) on the National Institute for Health and Care Excellence's (NICE) recommendations. METHODS: Products which received CMA/AEC by European Medicines Agency (EMA) up to 1 December 2016 were identified and matched with corresponding NICE decisions issued by August 2017, the status of which was then traced to August 2019. We assessed whether the conversion of CMA to full marketing authorization triggered a review of a NICE decision. The odds of a recommendation carrying a commercial arrangement for products with and without CMA/AEC were calculated. RESULTS: Fifty-four products were granted CMA/AEC by EMA. NICE conducted thirty evaluations of products with CMA/AEC. Twelve products were recommended by NICE by August 2017 and fourteen by August 2019. All recommendations had an associated commercial arrangement. The odds of carrying a commercial arrangement were higher for products with CMA/AEC compared to those with full authorization. Conversions from conditional to full authorization among products not recommended by NICE did not trigger an appraisal review. CONCLUSIONS: Uncertainty, stemming from the lack of robust clinical data of products authorized with CMA/AEC, has a substantial impact on HTA recommendations, frequently requiring risk mitigation mechanisms such as commercial and data collection arrangements. Further analyses should be conducted to assess whether the benefits of early access strategies outweigh the risks for patients and the healthcare system.

[Analysis of the situation, evaluation and improvement proposals of the Preventive Activities and Health Promotion Program (PAPPS)]. / Análisis de la situación, evaluación y propuestas de mejora del Programa de Actividades Preventivas y de Promoción de la Salud (PAPPS).

OBJECTIVE: To analyze the situation, evaluation and proposals for improvement of the Preventive Activities and Health Promotion Program (PAPPS). MATERIAL AND METHODS: A qualitative study of situation analysis was carried out for the evaluation of the PAPPS in 2 phases: 1) Generation of ideas and collection of information through a DAFO matrix, using 2 types of criteria: internal (strengths and weaknesses), and external (threats and opportunities); 2) Prioritization of the improvement proposals collected. Selection of participants: Key informants were identified taking into account their relationship and knowledge of the PAPPS program. All members of the PAPPS, expert groups and members with past participation were included, as well as the coordinators, including the autonomous leaders of the PAPPS. Two invitations to participate in the study were sent: the first from December 29, 2017 to February 11, 2018, and the second from January 10 to 23, 2019. The information was obtained from a questionnaire designed to be self-completed. RESULTS AND CONCLUSIONS: A total of 73 subjects answered the questionnaire. 35% of the participants were members of the PAPPS working groups, followed by family doctors from other areas, with 20.5%. The order of prioritization of the improvement proposals was as follows: 1) Unify recommendations with other semFYC working groups; 2) Prepare lists with "Recommendations not to do" from the point of view of prevention; 3) Incorporate PAPPS in the political agenda; 4) Greater coordination and interaction between groups with common competences; 5) Teaching in undergraduate and teaching units; 6) Review, update and dissemination of the program in Primary Care.

Portal Angiogenesis in Chronic Liver Disease Patients Correlates with Portal Pressure and Collateral Formation.

BACKGROUND/AIMS: One hallmark of chronic liver disease in patients with portal hypertension is the formation of portal-systemic collaterals in which angiogenesis has a fundamental role. We studied patients with chronic liver disease undergoing liver transplantation to correlate levels of circulating angiogenic factors in portal and peripheral circulation with portal pressure and portal-systemic collaterals. METHODS: Sixteen patients who underwent liver transplantation were enrolled. During transplant surgery, we determined portal venous pressure and portal-systemic collateral formation. We determined angiogenics mediator levels in systemic and portal plasma. Peripheral plasma from healthy donors was measured as controls. RESULTS: Vascular endothelial growth factor (VEGF)-R1 and 2, Ang-1 and 2, Tie2, FGF- 1 and 2, CD163, PDGFR-ß, PDGFsRα, PDGF-AB and BB, CD163, TGF-ß VASH-1 levels were significantly different in the controls in comparison to cases. Significantly decreased portal venous levels of Ang-1, FGF-1, PDGF-AB/BB, and CC were observed in patients with higher portal pressure. Peripheral VEGF, Ang-1, pPDGF-AB, BB, and CC were significantly decreased in patients with more severe collateral formation. While peripheral VEGF-R1 was higher in patients with severe collateral formation. For portal circulation, VEGF, Ang-1, -pPDGF-AB, BB, and CC were significantly decreased in patients with more severe collateral formation Conclusions: Angiogenesis factors correlated with portal pressure and collateral formation and different patterns of circulating angiogenesis mediators were found in peripheral and portal blood of patients with chronic liver disease. These results support the importance of angiogenic pathways in cirrhosis and portal hypertension and highlight areas for further study to identify clinically useful noninvasive markers of portal pressure and collateral formation.

The new frontier of epigenetic heterogeneity in B-cell neoplasms.

PURPOSE OF REVIEW: There is mounting evidence that heterogeneity of the epigenome is a feature of many cancers, including B-cell lymphomas, and presents important clinical implications. The purpose of this review is to explain the biological and clinical relevance of this epigenetic phenomenon in B-cell neoplasms. RECENT FINDINGS: Here, we summarize new findings demonstrating that B-cell lymphomas display increased DNA methylation heterogeneity compared to their normal counterparts. This plasticity of cytosine methylation manifests both as intertumor and intratumor heterogeneity and is associated with worse prognosis and poor clinical outcome in lymphoma patients. Recent studies of different subtypes of B-cell lymphomas have revealed that epigenetic aberrations and heterogeneous cytosine methylation patterning are common features of all neoplasms derived from B-lymphocytes, irrespective of maturation stage. With regard to mechanisms driving this process, recent reports suggest that cytosine methylation heterogeneity arises through passive and active processes. One factor implicated in active generation of cytosine methylation heterogeneity is activation-induced cytidine deaminase, which mediates DNA methylation changes and introduces epigenetic heterogeneity in normal germinal center B cells, the cells of origin of mature B-cell neoplasms such as diffuse large B-cell lymphoma and follicular lymphoma. SUMMARY: Understanding the scope and mechanism of epigenetic heterogeneity in cancer is of paramount importance to our understanding of clonal plasticity and treatment responses in B-cell lymphomas.

Integrating health technology assessment requirements in the clinical development of medicines: the experience from NICE scientific advice.

PURPOSE: The primary objective of the study was to analyse the proposed clinical development and economic evaluation plans for investigational medicinal products for which pharmaceutical companies have sought health technology assessment (HTA) scientific advice (SA). METHODS: We have selected and analysed all the scientific advice procedures undertaken by National Institute for Health and Care Excellence (NICE) SA between 1 January 2009 and 3 December 2015 for investigational medicinal products. We have mapped the questions asked by the companies and the areas of advice highlighted in the advice reports to the sections of the NICE methods guide to the technology appraisals (2013). RESULTS: An overwhelming proportion of SA procedures have addressed questions related to the clinical development and specifically the main pivotal efficacy studies. Approximately a quarter of the questions relate to the approaches to economic evaluation. Questions raised in European Medicines Agency-HTA procedures generally focus on clinical efficacy issues whereas cost-effectiveness ones tend to dominate in NICE-only procedures. Our analysis shows that the issues mostly discussed in the HTA SA are the choice of comparator, the generalisability of the clinical trial evidence to the NHS practice and the impact of the clinical trial outcomes on quality of life and survival. Less disagreement with the developers' plans was seen in the choice of clinical endpoints, population definition, position of the technology in the treatment pathway and study design. CONCLUSIONS: Scientific advice is designed to improve the quality of evidence and approaches to evidence generation for future regulatory approval and HTA evaluation. Our experience to date suggests that payer requirements are inconsistently integrated in the clinical development programmes. More efforts should be dedicated to demonstrating the clinical value of new medicinal products to patients and key decision-makers.

The many layers of epigenetic dysfunction in B-cell lymphomas.

PURPOSE OF REVIEW: Perturbation of the epigenome is emerging as a central driving force in the pathogenesis of diffuse large B-cell lymphomas (DLBCL) and follicular lymphoma. The purpose of this review is to explain how alteration of different layers of the epigenome contributes to the biology and clinical features of these tumors. RECENT FINDINGS: Key new findings implicate DNA methylation heterogeneity as a core feature of DLBCL. Epigenetic diversity is linked to unfavorable clinical outcomes, clonal selection at relapse, and is driven at least in part because of the actions of activation-induced cytosine deaminase, which is a unique feature of B-cell lymphomas. Somatic mutations in histone modifier genes drive lymphomagenesis through the establishment of aberrant gene-specific histone modification signatures. For example, EZH2 somatic mutations drive silencing of bivalent gene promoters through histone 3 lysine 27 trimethylation, whereas KMT2D (MLL2) mutations disrupt specific sets of enhancers through depletion of histone 3 lysine 4 mono and dimethylation (H3K4me1/me2). SUMMARY: Appreciation of the epigenome in determining lymphoma clonal heterogeneity and in driving lymphoma phenotypes through altered promoter and enhancer histone modification profiles is leading to a paradigm shift in how we understand and design therapies for DLBCL and follicular lymphoma.

A team-based multidisciplinary approach to managing peripherally inserted central catheter complications in high-risk haematological patients: a prospective study.

PURPOSE: Use of peripherally inserted central catheters (PICCs) has markedly increased during the last decade. However, there are few studies on use of PICCs in patients with haematological malignancies (HM) receiving intensive chemotherapy. Preliminary data suggest a higher rate of PICC-related complications in these high-risk patients. This prospective observational single-centre study aimed to investigate PICC-related complications after implementation of a multidisciplinary approach to PICC care and compared it with previous literature. METHODS: A total of 44 PICCs were inserted in 36 patients (27.3%, thrombocytopenia <50 × 10(9)/L at insertion) over 5045 PICC days (median duration, 114.5 days). RESULTS: No major insertion-related complications were observed. Major late complications were obstruction in 13.6% (1.19/1000 PICC days) of patients, catheter-related bloodstream infection in 6.8% (0.59/1000 PICC days), and catheter-related thrombosis in 4.5% (0.39/1000 PICC days). Premature PICC removal occurred in 34% (2.97/1000 PICC days) of patients. The overall rate of potentially major dangerous complications was particularly low (11.36%, 0.99/1000 PICC days) compared with previous studies. CONCLUSIONS: This study highlights the utility of a multidisciplinary approach for PICC care in adults with HM receiving intensive chemotherapy. We provide further data to support use of PICCs in such patient populations.

Pregnancy outcomes in women with childhood-onset and adult-onset systemic lupus erythematosus: a comparative study.

To compare the maternal and fetal outcomes between childhood-onset and adult-onset systemic lupus erythematosus (SLE), we reviewed the medical records of SLE pregnant women treated from January 2005 to August 2013. For comparison, patients were allocated to one of the two groups, those pregnant patients with SLE onset before 18 years of age (childhood-onset) and ≥18 years (adult-onset). The patients were evaluated at least once in each trimester and postpartum. Relevant maternal and fetal outcomes were extracted, such as lupus flare, preeclampsia/eclampsia, rate of liveborns, fetal loss (spontaneous abortion and stillbirth), term delivery, preterm birth, neonatal death, low birth weight, low birth weight at term, and congenital malformations. We studied 186 pregnancies (in 180 women), 58 of them had childhood-onset SLE, and the remaining 128 had adult-onset SLE. The rate of maternal and fetal complications was similar in both groups. Multivariate analysis showed that active SLE before pregnancy, primigravida, renal flare, preeclampsia, lupus flare, anticardiolipin antibodies, and low serum complement were associated with an increased risk of poor maternal and fetal outcomes. The diagnosis of childhood-onset had no impact on maternal-fetal outcome. The maternal and fetal outcome in women with childhood-onset SLE is similar to that reported in women with adult-onset SLE. Pregnancy in women with childhood-onset SLE should not be contraindicated if the disease is well controlled.

[AN EDUCATIONAL EXPERIENCE BASED ON CLICKERS]. / Una experiencia educativa basada en los clickers.

Active learning or self-learning increases the student's participation and commitment to his studies; these conditions are necessary to improve academic performance. An intervention has been designed based on the experience in the use of clickers in other universities, but without the actual technology. This work has been performed in the School of Nursing affiliated to the University of Malaga (UMA) on students enrolled in their second year of Degree in Adult Nursing Course I. Three sessions of multiple-choice questions were scheduled on the subject "distance learning" in which master classes were not taught. The answers were collected on paper templates. We wanted to determine the degree of relationship between the attendance of sessions and the results obtained by students in the final examination of the subject, as well as, the questions dedicated to assess the "distance learning" matter. The results support a significant statistical difference in the correct answers by students according to the number of sessions attended. These differences are highest among students who did not attend any session and those who attended the three planned sessions.

IL-4 blocks TH1-polarizing/inflammatory cytokine gene expression during monocyte-derived dendritic cell differentiation through histone hypoacetylation.

BACKGROUND: Whereas recent research has characterized the mechanism by which dendritic cells (DCs) induce T(H)1/T(H)17 responses, the functional specialization enabling DCs to polarize T(H)2 responses remains undefined. Because IL-4 is essential during T(H)2 responses not only by acting on CD4(+) T cells through the activation of GATA-3 but also by regulating IgE class-switching, epithelial cell permeability, and muscle contractility, we hypothesized that IL-4 could also have a role in the conditioning of DCs during T(H)2 responses. OBJECTIVE: We sought to analyze whether IL-4 exerts an immunomodulatory function on DCs during their differentiation, leading to their functional specialization for the induction of T(H)2 responses. METHODS: Monocyte-derived DCs (moDCs) conditioned by IL-4 during their differentiation (IL-4-conditioned moDCs [IL-4-moDCs]) were analyzed for T(H)1-polarizing/inflammatory cytokine production in response to Toll-like receptor stimulation. The acetylation level of the promoters of the genes encoding these cytokines was analyzed by using chromatin immunoprecipitation. Gene expression profiling of IL-4-moDCs was defined by using mouse genome microarrays. IL-4-moDCs were tested for their capacity to induce house dust mite-mediated allergic reactions. RESULTS: Our data suggest that IL-4 inhibits T(H)1-polarizing/inflammatory cytokine gene expression on IL-4-moDCs through the deacetylation of the promoters of these genes, leading to their transcriptional repression. Microarray analyses confirmed that IL-4 upregulated T(H)2-related genes as eosinophil-associated ribonucleases, eosinophil/basophil chemokines, and M2 genes. IL-4 licensed moDCs for the induction of T(H)2 responses, causing house dust mite-mediated allergic airway inflammation. CONCLUSION: This study describes a new role for IL-4 by demonstrating that moDCs are conditioned by IL-4 for the induction of T(H)2 responses by blocking T(H)1-polarizing/inflammatory cytokine production through histone hypoacetylation and upregulating T(H)2-related genes.

[Outcomes using two preservation solutions (UW/HTK) in liver transplantation from brain death donors]. / ¿Influye el medio de preservación del injerto en los resultados y costos del trasplante hepático de donante fallecido?: Comparación de dos soluciones de preservación.

BACKGROUND: Preservation solutions are critical for organ transplantation. In liver transplant (LT), the solution developed by the University Of Wisconsin (UW) is the gold-standard to perfuse deceased brain death donor (DBD) grafts. Histidine-Tryptophan-Ketoglutarate (HTK), formerly a cardioplegic infusion, has been also used in solid organ transplantation. AIM: To compare the outcomes of LT in our center using either HTK or UW solution. PATIENTS AND METHODS: Retrospective study including 93 LT DBD liver grafts in 89 patients transplanted between March 1994 and July 2010. Forty-eight grafts were preserved with UW and 45 with HTK. Donor and recipient demographics, total infused volume, cold ischemia time, post-reperfusion biopsy, liver function tests, incidence of biliary complications, acute rejection and 12-month graft and patient survival were assessed. Preservation solution costs per liver graft were also recorded. RESULTS: Donor and recipient demographics were similar. When comparing UW and HTK, no differences were observed in cold ischemia time (9.6 ± 3 and 8.7 ± 2 h respectively, p = 0.23), biliary complications, the incidence of acute rejection, primary or delayed graft dysfunction. Histology on post-reperfusion biopsies revealed no differences between groups. The infused volume was significantly higher with HTK than with UW (9 (5-16) and 6 (3-11) l, p < 0.001). The cost per procurement was remarkably lower using HTK. CONCLUSIONS: Perfusion of DBD liver grafts with HTK is clinically equivalent to UW, with a significant cost reduction.

Differentiation and function of mouse monocyte-derived dendritic cells in steady state and inflammation.

Although monocytes were originally described as precursors to all the different subpopulations of macrophages found in the steady state and formed under inflammatory and infectious conditions, recent data have demonstrated conclusively that monocytes can also differentiate into dendritic cells (DCs). Monocytes are the precursors to different subsets of DCs, such as Langerhans cells and DCs found in the lamina propria of the gastrointestinal, respiratory, and urogenital tracts. In addition, monocyte-derived DCs (moDCs), newly formed during inflammatory reactions, appear to fulfill an essential role in defense mechanisms against pathogens by participating in the induction of both adaptive and innate immune responses. In this regard, moDCs have the capacity to activate antigen-specific CD4(+) T-cell responses and to cross-prime CD8(+) T cells, during viral, bacterial, and parasitic infections. In addition, monocytes have been recently described as the precursors to a subset of DCs specialized in innate immunity against pathogens, named TipDCs [for TNF-alpha (tumor necrosis factor-alpha)-iNOS (inducible nitric oxide synthase)-producing DCs] that display a remarkable microbicidal activity and also provide iNOS-dependent help for antibody production by B cells. Importantly, in contrast to DCs developing in the steady state, moDCs formed during inflammatory and infectious processes are subjected to diverse soluble mediators that determine the multiple functional specificities displayed by moDCs, as a result of the remarkable developmental plasticity of monocytes. In this review, we discuss recent findings dealing with the differentiation and functional relevance of moDCs that have widened the frontiers of DC immunobiology in relation to innate and adaptive immunity and the etiology of chronic inflammatory diseases.

Percutaneous Gastrostomies: Associated Complications in PUSH vs. PULL Techniques over 12 Years in a Referral Centre.

Objectives: To compare complications associated with percutaneous gastrostomies performed using PUSH and PULL techniques, whether endoscopic (PEG) or radiological (PRG), in a tertiary-level hospital. Methods: This was a prospective observational study. Adult patients who underwent percutaneous PULL or PUSH gastrostomy using PEG or PRG techniques at the Virgen del Rocio University Hospital and subsequently followed up in the Nutrition Unit between 2009-2020 were included. X2 tests or Fisher's test were used for the comparison of proportions when necessary. Univariate analysis was conducted to study risk factors for PRG-associated complications. Results: n = 423 (PULL = 181; PUSH = 242). The PULL technique was associated with a higher percentage of total complications (37.6% vs. 23.8%; p = 0.005), exudate (18.2% vs. 11.2%; p = 0.039), and irritation (3.3% vs. 0%; p = 0.006). In the total sample, there were 5 (1.1%) cases of peritonitis, 3 (0.7%) gastrocolic fistulas, and 1 (0.2%) death due to complications associated with gastrostomy. Gender, age, and different indications were not risk factors for a higher number of complications. The most common indications were neurological diseases (35.9%), head and neck cancer (29%), and amyotrophic lateral sclerosis (17.2%). Conclusions: The PULL technique was associated with more total complications than the PUSH technique, but both were shown to be safe techniques, as the majority of complications were minor.

Gastrostomies: experience and complications with three modalities in a tertiary centre over a 26-year period.

Objectives: To describe the complications associated with the different gastrostomy techniques [endoscopic (PEG), radiologic (PRG), and surgical (SG)] performed in the last 26 years in a terciary hospital. Methods: Retrospective observational study. Patients who underwent gastrostomy at the Virgen del Rocío University Hospital between 1995 and 2021 were included. For PEG, the PULL technique was performed until 2018 and subsequently the PUSH technique predominantly. For PRG, a pigtail catheter was used until 2003, a balloon catheter between 2003 and 2009, and a balloon catheter with gastropexy between 2015 and 2021. For SG, the conventional technique (CSG) was performed until 2009 and since then the laparoscopic assisted percutaneous gastrostomy (PLAG) technique. Descriptive analysis was performed obtaining the median and quartiles of the quantitative variables [P50 (P25-P75)] and the frequency for the qualitative variables [n (%)].The comparison of complications between patients who underwent different techniques was performed with Fisher's test. Results: n = 1,070 (PEG = 608, PRG = 344, SG = 118). The three most frequent indications were head and neck tumors, neurological diseases and gastroesophageal tumors. The percentage of patients who had any complication was 48.9% (PEG-PULL), 23.7% (PEG-PUSH), 38.5% (pigtail PRG), 39.2% (balloon PRG), 29.7% (balloon with gastropexy PRG), 87.3% (CSG), and 41.26% (PLAG). 2 (0.18%) patients died from gastrostomy-related complications. 18(1.68%) presented with peritonitis and 5 (0.4%) presented with gastrocolic fistula. The rest of the complications were minor. Conclusion: Gastrostomy in any of its modalities is currently a safe procedure with a low rate of complications, most of which are minor.

Statins inhibit iNOS-mediated microbicidal potential of activated monocyte-derived dendritic cells by an IFN-ß-dependent mechanism.

Statins are prescribed to 25 million people worldwide for treating hypercholesterolemia and reducing the risk of cardiovascular diseases. However, the side effects of statins on immunity, and particularly on DC immunobiology, have not been analyzed in-depth. Here, we have investigated the impact of lovastatin treatment during monocyte differentiation into DCs on the responsiveness of the resulting monocyte-derived DCs (moDCs) to TLR-mediated activation. Lovastatin positively regulated TLR4 signaling in LPS-stimulated moDCs, leading to strong activation of p38 MAP-kinase paralleled by increased proinflammatory cytokine and IFN-ß production. In contrast, lovastatin promoted negative regulation of IFN-ß-mediated autocrine signaling through the IFN-αß receptor, paralleled by low expression of the transcription factor IRF-1, leading to the inhibition of the enzymes iNOS and HO-1. Defective activation of iNOS/HO-1 resulted in limited cytoprotective capacity against ROS and reduced microbicidal potential. These data were validated using an in vivo model of Listeria monocytogenes infection, which revealed that iNOS activation by splenic inflammatory moDCs, specialized in NO and TNF-α production, was strongly reduced in lovastatin-treated, Listeria-infected mice. Statin treatment could have severe implications in immunity against pathogens due to defective iNOS/HO-1 metabolism activation in inflammatory moDCs that might lead to immune failure.

Steatotic livers. Can we use them in OLTX? Outcome data from a prospective baseline liver biopsy study.

INTRODUCTION: Steatotic livers have been associated with greater risk of allograft dysfunction in liver transplantation. Our aim was to determinate the prevalence of steatosis in grafts from deceased donors in Chile and to assess the utility of a protocol-bench biopsy as an outcome predictor of steatotic grafts in our transplant program. MATERIAL AND METHODS: We prospectively performed protocol-bench graft biopsies from March 2004 to January 2009. Biopsies were analyzed and classified by two independent pathologists. Steatosis severity was graded as normal from absent to < 6%; grade 1: 6-33%; grade 2: > 33-66% and grade 3: > 66%. RESULTS: We analyzed 58 liver grafts from deceased donors. Twenty-nine grafts (50%) were steatotic; 9 of them (16%) with grade 3. Donor age (p < 0.001) and BMI over 25 kg/m 2 (p = 0.012) were significantly associated with the presence of steatosis. There were two primary non-functions (PNF); both in a grade 3 steatotic graft. The 3-year overall survival was lower among recipients with macrovesicular steatotic graft (57%) than recipients with microvesicular (85%) or non-steatotic grafts (95%) (p = 0.026). CONCLUSION: Macrovesicular steatosis was associated with a poor outcome in this series. A protocol bench-biopsy would be useful to identify these grafts.

[Treatment of the patient with castration-resistant biochemical progression of prostate cancer]. / Tratamiento del paciente con carcinoma de próstata en progresión bioquímica resistente a castración.

Castration resistant prostatic carcinoma (CRPC) is defined as tumor progression despite an effective castration (serum testosterone levels < 50 ng/dL). Biochemical progression requires at least two successive increases from the previous lowest value of serum prostate-specific antigen (PSA) spaced at least a week, and with a minimum value of 2 ng/mL. In patients receiving complete androgen blockade, antiandrogen should be discontinued prior to diagnosis of CRPC. CPRC is a heterogeneous entity. Baseline PSA and PSA velocity seem to be the most important prognostic factors in patients with biochemical relapse as the only manifestation of CRPC. Some of these patients can be followed without treatment until disease progression. Because of a large proportion of tumors progressing under androgen deprivation therapy remain hormone-dependent, the use of other hormonal therapies has been the preferred treatment for the majority of these patients. Besides inhibitors of adrenal steroidogenesis, other novel hormonal approaches are currently under investigation to avoid the effect of the activated androgenic receptor on the tumor cell. In recent years there has been an important development of immunotherapy, which has demonstrated to increase survival in CRPC oligosymptomatic patients. First and second line chemotherapy in CRPC are associated with an increase in overall survival, but they are usually recommended for patients with metastases. Until the results of ongoing trials are available, the type and timing of the treatment for patients with CRPC and biochemical recurrence should be individualized.