Autologous stem cell transplantation (ASCT) in patients with mantle cell lymphoma: a retrospective study of the Spanish lymphoma group (GELTAMO).

Guidelines recommend autologous stem cell transplantation (ASCT) consolidation in first complete or partial response after regimens including rituximab (R) and high-dose AraC (HDAC), but its use beyond that response is questioned. We present a retrospective analysis of 268 patients with MCL who received ASCT. With a median follow-up for survival patients of 54 months, progression-free survival and overall survival for the whole series were 38 and 74 months, respectively, and for patients transplanted in first CR 49 and 97 months, respectively. Patients without CR before transplant were analyzed separately, those who achieved CR after transplantation had better PFS (48 vs 0.03 months, p < 0.001) and OS (92 vs 16 months, p < 0.001) than the remaining. In univariate analysis, first CR at transplant (p = 0.01) and prior rituximab (p = 0.02) were the variables associated with PFS. For OS, the same variables resulted significant (p = 0.03 and p < 0.001, respectively). In multivariate analysis, only the status at transplant (first CR) remained significant. This retrospective study concludes that ASCT consolidation in first CR induces high survival rates. In other stages of disease, the need of ASCT as consolidation may be questioned.

Increased expression of microRNA-155 in peripheral blood mononuclear cells from psoriasis patients is related to disease activity.

BACKGROUND: MicroRNAs (miRNAs) gene expression regulators are altered in psoriasis suggesting their role in the pathogenesis. OBJECTIVE: To study expression changes of inflammation and toll-like receptor (TLR)-related miRNAs, miRNA-155, let-7i, miRNA-21, miRNA-146a and miRNA-223 in peripheral mononuclear cells (PBMCs) and miRNA-21, miRNA-146a and miRNA-223 in plasma, from chronic plaque-type psoriasis patients who were treatment-naive or had undergone a washout period (n = 11). MiRNAs were evaluated at baseline and after 11 (9-12) months [median (25th-75th percentile range)] of methotrexate (MTX) or topical (betamethasone plus calcipotriene) treatment. METHODS: MiRNA expression was analysed with quantitative real-time reverse transcription-polymerase chain reaction. Matched controls were studied. RESULTS: Psoriasis patients presented, at baseline, increased expression of miRNA-155, let-7i, miRNA-146a, miRNA-21 and miRNA-223 in PBMCs, plus miRNA-21, miRNA-146a and miRNA-223 in plasma. Receiver-operator characteristic (ROC) curve analysis and area under the curve (AUC) showed that expression of these miRNAs have the potential to distinguish between psoriasis and controls. At baseline, miRNA-155 expression in PBMCs correlated with Psoriasis Area Severity Index (PASI) [12 (8-14)] (Spearman r: 0.7140, P < 0.05) suggesting a role in psoriasis. After MTX or topical treatment, reduction in PASI was observed [87.5% (75-100)]; miRNA-155 expression in PBMCs decreased; plasma miRNA-21, miRNA-146a and miRNA-223 were down-regulated. ROC analysis showed that miRNA-155 expression in PBMCs from psoriasis patients have the potential to distinguish between patients' samples at baseline and after treatment (AUC: 0.942, sensitivity: 0.91; specificity: 0.91 values; maximum likelihood ratio =10). After treatment, miRNA-146a expression in PBMCs increased; miRNA-155/miRNA-146a ratio decreased, suggestive of a regulatory feedback; let-7i expression decreased; miRNA-21 and miRNA-223 remained elevated. CONCLUSION: In this exploratory study, psoriasis patients presented increased expression of miRNA-155 in PBMCs that correlated with PASI and decreased with disease remission. MiRNA-21, miRNA-146a and miRNA-223 in PBMCs and plasma were increased at baseline and differentially modulated, underscoring different roles of TLR-related miRNAs in psoriasis.

Antidiabetic and antioxidant activity of Stevia rebaudiana extracts (Var. Morita) and their incorporation into a potential functional bread.

In this study a new wheat bread was designed whose sugars were replaced with S. rebaudiana Bertoni aqueous extract. The impact of the S. rebaudiana Bertoni aqueous extract on nutritional and sensory quality, its ability to reduce sugar intake and its antioxidant properties were investigated. Functional bread with 50 % of sugars replaced with S. rebaudiana extract was compared with traditional wheat bread. The extract demonstrated alpha amylase (IC50 = 198.40 µg/mL) glucosidase (596.77 µg/mL) inhibition. The radical scavenging activity exhibited an IC50 value of 335.94 mg/mL. In comparison with the control, the bread with stevia extract was softer and had lower microbial growth during the shelf-life study. The sensory test showed that the substitution of 50 % stevia extract was more acceptable when comparing with all quality characteristics. Regarding the nutritional contribution, the content of dietary fiber and digestible carbohydrates in the bread with stevia extract was higher and lower respectively, so caloric intake was significantly reduced. The results showed that the biological properties of S. rebaudiana extract were retained after the bread making process and that the proposed bread is suitable as functional food in human nutrition.

Increased gene expression of Toll-like receptor 4 on peripheral blood mononuclear cells in patients with psoriasis.

BACKGROUND: A role for the innate immune system in driving the autoimmune T cell cascade in psoriasis has been proposed. Toll-like receptors-(TLR)-2 and -4 play a role in inflammation, atherosclerosis, and their specific role in psoriasis remains unclear. OBJECTIVE: To evaluate TLR2 and TLR4 gene expression levels in peripheral blood mononuclear cells from psoriatic patients. METHODS: Changes in TLR2 / 4 gene expressions were evaluated using quantitative real-time reverse transcription polymerase chain reaction in peripheral blood mononuclear cells, from twenty-one patients with severe psoriasis, and analysed whether there was any correlation with cytokine plasma levels (T-helper 0-, T-helper 1-, T-helper 2- or regulatory T cells-type), or Calprotectin and with S100A8 and S100A9 gene expression levels. Eleven non-psoriatic healthy controls were analysed. RESULTS: A clear increase in TLR4 gene expression was observed (3.84 ± 0.93, n = 21) together with a moderate increase in TLR2 expression (1.522 ± 0.31, n = 21). Both TLR4 and TLR2 gene expressions were significantly augmented in psoriatic patients compared with controls (all P < 0.001). Correlations between TLR2 and S100A9 gene expressions (r = 0.5145, P = 0.0170, n = 21); and between TLR2 expression and plasma interleukin-2 (r = 0.5667, P = 0.0074); interleukin-4 (r = 0.4766, P = 0.0289), interleukin-10 (r = 0.4355, P = 0.0484) and interleukin-13 (r = 0.4603, P = 0.0358), were found. When patients with atheroma plaque were considered (n = 7), both TLR4 (3.47 ± 0.99, P = 0.0156) and TLR2 (1.63 ± 0.31, P = 0.0156) expressions were significantly increased vs. controls and correlated with plasma TNF-a (r = 0.8929, P = 0.0123, in both cases). CONCLUSION: Differential TLR4 / 2 gene expressions on psoriatic peripheral blood mononuclear cells and correlations with regulatory and / or proinflammatory cytokines and / or damage-associated molecular pattern molecule S100A9 emphasize innate immune response role in psoriasis.

[The 2013 Seville Consensus Document on alternatives to allogenic blood transfusion. An update on the Seville Document]. / 2013. Documento Sevilla de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica. Actualización del Documento Sevilla.

Since allogeneic blood transfusion (ABT) is not harmless, multiple alternatives to ABT (AABT) have emerged, though there is great variability in their indications and appropriate use. This variability results from the interaction of a number of factors, including the specialty of the physician, knowledge and preferences, the degree of anemia, transfusion policy, and AABT availability. Since AABTs are not harmless and may not meet cost-effectiveness criteria, such variability is unacceptable. The Spanish Societies of Anesthesiology (SEDAR), Hematology and Hemotherapy (SEHH), Hospital Pharmacy (SEFH), Critical Care Medicine (SEMICYUC), Thrombosis and Hemostasis (SETH) and Blood Transfusion (SETS) have developed a Consensus Document for the proper use of AABTs. A panel of experts convened by these 6 Societies have conducted a systematic review of the medical literature and have developed the 2013 Seville Consensus Document on Alternatives to Allogeneic Blood Transfusion, which only considers those AABT aimed at decreasing the transfusion of packed red cells. AABTs are defined as any pharmacological or non-pharmacological measure aimed at decreasing the transfusion of red blood cell concentrates, while preserving patient safety. For each AABT, the main question formulated, positively or negatively, is: « Does this particular AABT reduce the transfusion rate or not?¼ All the recommendations on the use of AABTs were formulated according to the Grades of Recommendation Assessment, Development and Evaluation (GRADE) methodology.

Decreased plasma levels of clusterin in patients with psoriasis.

INTRODUCTION AND OBJECTIVES: Psoriasis is a chronic inflammatory disease that has been linked to increased cardiovascular risk. The glycoprotein clusterin (apolipoprotein J) is a component of high-density lipoproteins and has a protective role in atherosclerosis. The aim of the present study was to evaluate the plasma levels of clusterin and the proinflammatory cytokine macrophage migration inhibitory factor (MIF) in patients with severe psoriasis, comparing groups of patients with different risks of cardiovascular disease. MATERIAL AND METHODS: Twenty-one patients with severe psoriasis (psoriasis area severity index and body surface area>10) and 11 healthy controls with no dermatologic disease were studied. Cardiovascular risk factors were assessed according to the Adult Treatment Panel (ATP) III criteria. Subclinical carotid atheromatosis was assessed by Doppler ultrasonography of the carotid arteries. Plasma clusterin and MIF levels were measured by enzyme-linked immunosorbent assay. RESULTS: ATP-III criteria for metabolic syndrome were met by 47% of the patients, and 33% had carotid atheromatous plaque. Mean (SD) clusterin plasma levels were significantly lower in patients with psoriasis compared with controls (81.39 [27.30] µg/mL for the 21 patients vs 117 [21.6] µg/mL for the 11 controls; P=.0017). MIF plasma levels (ng/ml) were significantly higher in patients with atheromatous plaque compared with controls (53.22 [29.02] for the 6 patients with plaque vs 34.21 [9.65] for the 11 controls; P=.0394). CONCLUSIONS: The decreased plasma levels of clusterin in psoriatic patients suggested an association with the disease and might be an indicator of systemic inflammatory activity. Increased levels of MIF appear to be associated with cardiovascular risk factors and carotid atheromatous plaque.

Prediction of delayed graft function by means of a novel web-based calculator: a single-center experience.

Renal failure persisting after renal transplant is known as delayed graft function (DGF). DGF predisposes the graft to acute rejection and increases the risk of graft loss. In 2010, Irish et al. developed a new model designed to predict DGF risk. This model was used to program a web-based DGF risk calculator, which can be accessed via http://www.transplantcalculator.com . The predictive performance of this score has not been tested in a different population. We analyzed 342 deceased-donor adult renal transplants performed in our hospital. Individual and population DGF risk was assessed using the web-based calculator. The area under the ROC curve to predict DGF was 0.710 (95% CI 0.653-0.767, p < 0.001). The "goodness-of-fit" test demonstrates that the DGF risk was well calibrated (p = 0.309). Graft survival was significantly better for patients with a lower DGF risk (5-year survival 71.1% vs. 60.1%, log rank p = 0.036). The model performed well with good discrimination ability and good calibration to predict DGF in a single transplant center. Using the web-based DGF calculator, we can predict the risk of developing DGF with a moderate to high degree of certainty only by using information available at the time of transplantation.

Treatment of cutaneous lymphomas: an update.

Primary cutaneous lymphomas (PCLs) are a heterogeneous group of lymphoid tumors that originate primarily in the skin. Most PCLs (75%) are T-cell lymphomas and only 20% to 25% involve B cells. It is important to differentiate between cutaneous lymphomas and lymph node tumors given the differences in their molecular biology and clinical, histopathologic, and immunophenotypic features. Moreover, PCLs generally follow a more indolent course and require different treatments. Many treatment options are available for managing PLC's. The choice should be based primarily on the clinical stage of disease but must also take into consideration other factors, such as the patient's age and general health, the availability and accessibility of the treatment, and the cost-benefit ratio. It will be important to use a multidisciplinary approach, involving a team of expert dermatologists, hematologist-oncologists, and radiotherapists who are familiar with this rare disease. Recent years have seen the emergence of many new therapies, particularly for advanced stages of the disease and for patients whose tumors have proven refractory to treatment. The objective of this article is to review all the treatment options available to us.

Efficacy and safety of conversion from twice-daily to once-daily tacrolimus in a large cohort of stable kidney transplant recipients.

Prolonged-release tacrolimus was developed to provide a more convenient once-daily dosing that could improve patient adherence. We conducted a multicenter, prospective, observational, 12-month study to describe the efficacy, safety and patient preference of conversion from tacrolimus twice-daily to once-daily formulation in stable kidney transplant recipients in routine clinical practice. Conversion was made on a 1 mg: 1 mg basis (1 mg: 1.1 mg in patients with trough levels <6 ng/mL). The study included 1832 patients (mean age (± SD): 50.0 ± 13.4 years; 62.7% male). After conversion, a modest reduction in tacrolimus trough levels, necessitating an increase in daily dose, was observed (mean changes at 12 months of -9.1% and +1.24%, respectively; p < 0.0001). Mean glomerular filtration rate did not change significantly (56.5 ± 19.7 mL/min at conversion vs. 55.7 ± 20.6 mL/min at 12 months). Proteinuria, blood pressure, lipid, hepatic and glucose parameters remained stable. Eight patients (0.4%) had acute rejection and 34 patients (1.85%) discontinued treatment. Almost all patients (99.4%) preferred the once-daily formulation, because of less frequent dosing (66%) and improved adherence (34%). In conclusion, at similar doses to twice-daily tacrolimus, once-daily formulation provided stable renal function, a low acute rejection rate, and good tolerability in stable kidney transplant recipients in the routine clinical practice setting.

Temporomandibular joint injections in dogs with temporomandibular joint pain: 11 cases (2015-2019).

OBJECTIVES: To describe and evaluate the clinical application of temporomandibular joint injections using betamethasone and ropivacaine in German Shepherd dogs suffering from non-odontogenic orofacial pain due to temporomandibular dysplasia and/or osteoarthritis. MATERIALS AND METHODS: Outcomes in dogs presented with clinical signs of non-odontogenic orofacial pain associated to temporomandibular joint dysplasia and/or arthritis and treated with a temporomandibular joint injection were retrospectively-prospectively evaluated. RESULTS: The overall clinical signs free period ranged between 25 to 1579 days, with an average of 461 days. The clinical signs free period for temporomandibular joint osteoarthritis scores 1, 2 and 3 were on average 659 days (180-1579 days), 134 days (42-355 days) and 723 days (25-1377 days), respectively. Similarly the temporomandibular dysplasia scores 1, 2 and 3 were on average 306 days (26-1579 days), 1377 days and 669 days (25-1429 days) respectively. Those dogs in which only one side was injected the clinical signs free period average was 639 days (25-1578 days), compared with dogs in which both temporomandibular joints were injected showing a clinical signs free period average of 378 days (42-1377 days). CLINICAL SIGNIFICANCE: The temporomandibular joint injection technique proved to be feasible with a decent outcome in dogs suffering from non-odontogenic orofacial pain associated with temporomandibular joint osteoarthritis and/or dysplasia. Further randomised studies are required to confirm the effectiveness of this intervention.

Determinants of resistive index shortly after transplantation: independent relationship with delayed graft function.

Measurement of the vascular resistive index (RI) by Doppler ultrasonography has been proposed as a non-invasive method to evaluate renal allograft dysfunction, but there are conflicting reports about its clinical utility. The aim of our study was to analyse the donor and recipient characteristics related to RI measured at days 2 and 3 after renal transplantation and the relationship between RI and allograft outcome. RI was measured by Doppler ultrasonography in 333 patients at days 2 or 3 post-transplantation. Donor and recipient variables and allograft outcome were collected from a prospectively maintained institutional database. In patients with RI higher than 0.7, donor age, recipient age, duration of renal replacement therapy, incidence of diabetes, hypertension and atherosclerosis in the recipient, pulse pressure, initial creatinine and the incidence of delayed graft function (DGF) were higher. After multivariate analysis, the only variables that remained significant for an increased risk of higher RI were recipient age over 55 years, presence of diabetes in the recipient and DGF. Recipient age, previous diabetes mellitus and DGF are the most important determinants of transplant kidney RI in the first days after transplantation. So both the graft recipient and the graft itself, but not the donor, determine intra-renal Doppler indices.

100% peer review in radiation oncology: is it feasible?

PURPOSE: Peer review has been proposed as a strategy to ensure patient safety and plan quality in radiation oncology. Despite its potential benefits, barriers commonly exist to its optimal implementation in daily clinical routine. Our purpose is to analyze peer-review process at our institution. METHODS AND MATERIALS: Based on our group peer-review process, we quantified the rate of plan changes, time and resources needed for this process. Prospectively, data on cases presented at our institutional peer-review conference attended by physicians, resident physicians and physicists were collected. Items such as time to present per case, type of patient (adult or pediatric), treatment intent, dose, aimed technique, disease location and receipt of previous radiation were gathered. Cases were then analyzed to determine the rate of major change, minor change and plan rejection after presentation as well as the median time per session. RESULTS: Over a period of 4 weeks, 148 cases were reviewed. Median of attendants was six physicians, three in-training-physicians and one physicist. Median time per session was 38 (4-72) minutes. 59.5% of cases presented in 1-4 min, 32.4% in 5-9 min and 8.1% in ≥ 10 min. 79.1% of cases were accepted without changes, 11.5% with minor changes, 6% with major changes and 3.4% were rejected with indication of new presentation. Most frequent reason of change was contouring corrections (53.8%) followed by dose or fractionation (26.9%). CONCLUSION: Everyday group consensus peer review is an efficient manner to recollect clinical and technical data of cases presented to ensure quality radiation care before initiation of treatment as well as ensuring department quality in a feedback team environment. This model is feasible within the normal operation of every radiation oncology Department.

Lung cavitation due to Mycobacterium xenopi in a renal transplant recipient.

Mycobacterium xenopi is an unusual pathogen and few such cases have been reported in the literature. We report the case of a patient with a sirolimus-based immunosuppressive regimen, who developed lung cavitation. M. xenopi was isolated from the sputum. The patient was treated initially with rifampicin, isoniazid, and pyrazinamide; levofloxacin was added to the treatment regimen after M. xenopi was demonstrated. A possible relationship between sirolimus and M. xenopi infection has been postulated, probably due to the combination of pulmonary toxicity and cellular immunosuppression of rapamycin.

The phenomenon of hemoglobin variability with erythropoiesis stimulating agents in renal transplant patients.

Treatment with erythropoiesis-stimulating agents (ESA) is often associated with fluctuation in hemoglobin (Hb) levels that has been considered a factor that influences morbidity/mortality in hemodialysis patients. Our aim was to describe the hemoglobin variability during ESA treatment and to study associated factors in kidney transplants. Hb variability (defined as fluctuations of Hb +/- 1.5 g/dl) was assessed in 85 renal transplant patients treated with ESA for at least 3 months and with a minimum of 6 Hb measurements along 1 year. 58% of patients experienced Hb variability during follow-up. Although 71.3% of patients maintained Hb levels greater than 11 g/dl along the whole follow-up, only 3% of patients maintained stable Hb levels within the target range all the time (11 - 13 g/dl). By multivariate analysis, clinical factors associated with variability were changes in ESA dose (RR 2.92, p = 0.04), infectious events with hospitalization (RR 1.95, p = 0.03) and the use of sirolimus (RR 1.1, p < 0.05). Excluding dose changes and hospitalization in the analysis variability was an independent predictor of graft function deterioration. In conclusion, Hb variability is common in renal transplants treated with ESA. Only few patients maintained Hb levels in the therapeutic range (11 - 13 g/dl). Dose changes, inflammatory status and graft function deterioration are the determining factors.

Biogeographical origin and timing of the founder ichthyosis TGM1 c.1187G > A mutation in an isolated Ecuadorian population.

An unusually high frequency of the lamellar ichthyosis TGM1 mutation, c.1187G > A, has been observed in the Ecuadorian province of Manabí. Recently, the same mutation has been detected in a Galician patient (Northwest of Spain). By analyzing patterns of genetic variation around this mutation in Ecuadorian patients and population matched controls, we were able to estimate the age of c.1187G > A and the time to their most recent common ancestor (TMRCA) of c.1187G > A Ecuadorian carriers. While the estimated mutation age is 41 generations ago (~1,025 years ago [ya]), the TMRCA of Ecuadorian c.1187G > A carrier haplotypes dates to just 17 generations (~425 ya). Probabilistic-based inferences of local ancestry allowed us to infer a most likely European origin of a few (16% to 30%) Ecuadorian haplotypes carrying this mutation. In addition, inferences on demographic historical changes based on c.1187G > A Ecuadorian carrier haplotypes estimated an exponential population growth starting ~20 generations, compatible with a recent founder effect occurring in Manabí. Two main hypotheses can be considered for the origin of c.1187G > A: (i) the mutation could have arisen in Spain >1,000 ya (being Galicia the possible homeland) and then carried to Ecuador by Spaniards in colonial times ~400 ya, and (ii) two independent mutational events originated this mutation in Ecuador and Galicia. The geographic and cultural characteristics of Manabí could have favored a founder effect that explains the high prevalence of TGM1 c.1187G > A in this region.

Identification of putative miRNA biomarkers in early rheumatoid arthritis by genome-wide microarray profiling: A pilot study.

Despite the existing research, the etiology of rheumatoid arthritis (RA), an autoimmune disease remains poorly understood with early and accurate diagnosis difficult to achieve. MicroRNAs (miRNAs) play an important role in biological processes as modulators of transcription and translation. Previous studies have demonstrated a downregulation of several genes in early RA stages and in addition, miRNAs may serve as early biomarkers of subclinical changes in early RA. When comparing the four groups (ANOVA P < 0.01, fold change > 4), we found 253 differentially expressed miRNAs. Of these, 97 miRNAs were identified as overexpressed in early rheumatoid arthritis. The validation of miRNA microarray expression was performed in a set by RT-qPCR and showed strong agreement with microarray expression data. The putative targets of overexpressed microRNAs in early RA were significantly enriched in apoptosis, tolerance loss and Wnt pathways. Moreover, ROC analysis showed values of AUC 0.76 and P < 0.05 for miR 361-5p, identifying this miRNA as a potential biomarker of disease. We identified specific microRNAs associated with early rheumatoid arthritis and proposed them as early biomarkers of disease. Our results provide novel insight into immune disease physiopathology and describe unreported microRNAs in RA with potential for clinical use.

Survival after dialysis initiation: a comparison of transplant patients after graft loss versus nontransplant patients.

BACKGROUND: A substantial number of patients return to dialysis therapy after a renal transplant fails. It is not clear whether mortality increases among patients with graft failure relative to those who initiate dialysis but who have not yet received a kidney transplant. PATIENTS AND METHODS: We compared the outcomes of an incident cohort of patients (n = 194) with a cohort of renal transplant patients who returned to dialysis after graft loss (n = 74). We analyzed the morbidity and mortality after dialysis initiation and the parameters during the year beforehand. RESULTS: Mortality among post-graft loss dialysis patients was higher than transplant-naive patients (relative risk [RR]: 2.05; 95% confidence interval [CI]: 1.26-3.35). Additionally, complications, such as the number of hospitalizations during the first year after dialysis initiation, were higher (29% vs 57%; P > .001). At dialysis initiation no differences were found in glomerular filtration rate, although hemoglobin and albumin levels were lower and C-reactive protein was higher in post-graft loss dialysis patients. CONCLUSIONS: Mortality among patients on dialysis therapy after graft loss increased significantly compared with mortality among patients who initiated dialysis for the first time, despite specialty physicians being aware of them. Additional studies are urgently needed to define the mechanisms of the increased risk and strategies to decrease mortality.