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Introduction: The present study evaluates CD30 expression by immunohistochemistry (IHQ) in 216 patients with de novo DLBCL.Methods: CD30 expression was assessed retrospectively in all cases by IHQ....

The discriminative power of International Prognostic Index (IPI) in diffuse large B-cell lymphoma (DLBCL) decreased with the addition of rituximab to chemotherapy. The National Comprehensive Cancer Network (NCCN)-IPI and the Grupo Español de Linfomas y Trasplante Autólogo de Médula Ósea (GELTAMO)-IPI were developed to improve the risk prediction for DLBCL patients. We aim to validate the NCCN-IPI and GELTAMO-IPI in a large and homogeneous cohort of 337 DLBCL patients treated with curative intent with R-CHOP/R-CHOP-like immunochemotherapy. The IPI stratifies patients in two independent risk groups and the estimated 5-year overall survival (OS) of the high-risk (HR) group was 43%. NCCN-IPI discriminated four risk groups and GELTAMO-IPI three risk groups of patients. The predicted 5-year OS of the HR group was 38% and 29%, respectively. NCCN-IPI and GELTAMO-IPI are more accurate prognostic indices than IPI in DBLCL patients treated with immunochemotherapy. GELTAMO-IPI demonstrated enhanced discrimination than NCCN-IPI for the higher-risk population.

Introduction Besides the main treatment for their disease, hospital patients receive multiple care measures which include venous lines (VL), urinary catheters (UC), dietary restrictions (DR), mandatory bed rest (BR), deep venous thrombosis prophylaxis (VTP), stress ulcer prophylaxis (SUP) and anticoagulation bridge therapy for atrial fibrillation (BAF). In many cases these practices are of low value. Methods We analysed patients admitted to Internal Medicine wards throughout 2018 (2714 inpatients). We used different methodologies to identify low-value clinical practices. Results BR or DR at admission were recommended in 37% (32–44) and 24% (19–30) of the patients respectively. In 81% (71–87) and 33% (21–45) of the cases this restriction was deemed unnecessary. Ninety-six percent (92–98) had VL and 25% (19–32) UC. VL were not used in 10% (6–12), UC had no indications for insertion in 21% (11–35) and for maintenance in 31% (12–46) patients. Fifty-seven percent (49–64) of the patients were administered VTP and 69% (62–76) were prescribed SUP. Twenty-two percent (15–31) of patients with VTP and 52% (43–60) with SUP had no indication. Chronic anticoagulation for AF was interrupted in 65% (53–75) with BAF was prescribed in 38% (25–52) of them. An intervention to reduce low-value care supporting clinical practices addressed only to the Internal Medicine Wards showed very poor results. Conclusion These results demonstrate that there is ample room for reduction of low-value care. Interventions to implement clinical guidelines at admissions should be addressed to cover the entire admission process, from the emergency room to the ward. Partial approaches are discouraged.

Positive implications of schizotypal personality have been discussed in the literature in the last few years, higher creativity being one of them. Specifically, positive and negative schizotypy dimensions have been respectively related to higher and lower creativity levels. However, a considerable amount of null associations between these two constructs have also been reported. This heterogeneity could be due to the multidimensionality of both constructs. The aim of this study is to go deeper into the general relationship between creativity and schizotypy, disentangling the associations between specific dimensions of these two constructs. We assessed schizotypy in a sample of 154 volunteers. They also filled out creative personality and creative products questionnaires. Regression analyses showed no effect of scores in the positive dimension of schizotypy over either of the two creativity measures. Interestingly, lower scores in the negative dimension were associated with more creative products, whereas lower scores in the disorganized dimension were associated with a more creative personality. Our results point toward the need to use assessment tools tapping into the different aspects of creativity and to take into account the multidimensional nature of schizotypal personality in order to clarify the relationship between these two complex constructs.

© 2021 by the authors., B-cell regeneration during therapy has been considered as a strong prognostic factor in multiple myeloma (MM). However, the effects of therapy and hemodilution in bone marrow (BM) B-cell recovery have not been systematically evaluated during follow-up. MM (n = 177) and adult (≥50y) healthy donor (HD; n = 14) BM samples were studied by next-generation flow (NGF) to simultaneously assess measurable residual disease (MRD) and residual normal B-cell populations. BM hemodilution was detected in 41 out of 177 (23%) patient samples, leading to lower total B-cell, B-cell precursor (BCP) and normal plasma cell (nPC) counts. Among MM BM, decreased percentages (vs. HD) of BCP, transitional/naïve B-cell (TBC/NBC) and nPC populations were observed at diagnosis. BM BCP increased after induction therapy, whereas TBC/NBC counts remained abnormally low. At day+100 postautologous stem cell transplantation, a greater increase in BCP with recovered TBC/NBC cell numbers but persistently low memory B-cell and nPC counts were found. At the end of therapy, complete response (CR) BM samples showed higher CD19− nPC counts vs. non-CR specimens. MRD positivity was associated with higher BCP and nPC percentages. Hemodilution showed a negative impact on BM B-cell distribution. Different BM B-cell regeneration profiles are present in MM at diagnosis and after therapy with no significant association with patient outcome., This work has been supported by the International Myeloma Foundation-Black Swan Research Initiative, the EuroFlow Consortium (grant LSHB-CT-2006-018708); Centro de Investigación Biomédica en Red de Cáncer (CIBER-ONC; Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Madrid, Spain and FONDOS FEDER), numbers: CB16/12/00400, CB16/12/00233, CB16/12/00369, CB16/12/00489 and CB16/12/00480; grant from Bilateral Cooperation Program between Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-CAPES (Brasília/Brazil) and Dirección General de Políticas Universitárias (DGPU)-Ministério de Educación, Cultura y Deportes (Madrid/Spain) number DGPU 311/15; Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro of Brazil (FAPERJ) numbers: E26/110.105/2014 and E26/102.191/2013; grant from Conselho Nacional de Desenvolvimento Científico e Tecnológico of Brazil (CNPQ), number: 400194/2014-7. R.M.d.P. was supported by a grant from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/DGPU), number: 000281/2016-06 and CAPES/PROEX 641/2018, Brazil; Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro of Brazil (FAPERJ) number: E01/200/537/2018.

Objectives To clarify the impact of histological grades in follicular lymphoma. Methods We retrospectively analysed 250 patients diagnosed with FL treated with chemoimmunotherapy: 188 patients were grades 1-2 and 62 grade 3A. Results In our series, grade 3A FL patients were older, higher proportion of localised disease and lower bone marrow infiltration at diagnosis comparing grades 1-2 FL patients. Estimated six-year progression-free survival and time to progression showed no differences between both groups [grade 3A: 56% (95%CI: 39%-73%) and 51% (95%CI: 41%-61%) vs grades 1-2:55% (95%CI: 46%-63%) and 57% (95%CI: 49%-65%), P = .782 and P = .521, respectively]. Estimated six-year overall survival was lower, 76% (95%CI: 64%-88%) for the grade 3A group than grades 1-2 83% (95%CI: 77%-89%); P = .044. In addition to that, cumulative incidence curves of death not related to lymphoma at 10 years between groups were as follows: [0.26 (95%CI: 0.25-0.27) and 0.05 (95%CI: 0.04-0.06) for G3AFL and G1-2FL, respectively], P = .010. Grade 3A FL showed in PFS curve no relapses after 6 years. These results were absolutely reproduced in 199 patients receiving R-CHOP regimen as induction. Conclusions Our results indicate similar long-term outcomes in terms of progression-free survival and time to progression in grades 1-2 and 3A. No relapses were observed in G3AFL group after 6 years.

HbA1c is the gold standard test for monitoring medium/long term glycemia conditions in diabetes care, which is a critical factor in reducing the risk of chronic diabetes complications. Current technologies for measuring HbA1c concentration are invasive and adequate assays are still limited to laboratory-based methods that are not widely available worldwide. The development of a non-invasive diagnostic tool for HbA1c concentration can lead to the decrease of the rate of undiagnosed cases and facilitate early detection in diabetes care. We present a preliminary validation diagnostic study of W-band spectroscopy for detection and monitoring of sustained hyperglycemia, using the HbA1c concentration as reference. A group of 20 patients with type 1 diabetes mellitus and 10 healthy subjects were non-invasively assessed at three different visits over a period of 7 months by a millimeter-wave spectrometer (transmission mode) operating across the full W-band. The relationship between the W-band spectral profile and the HbA1c concentration is studied using longitudinal and non-longitudinal functional data analysis methods. A potential blind discrimination between patients with or without diabetes is obtained, and more importantly, an excellent relation (R-squared = 0.97) between the non-invasive assessment and the HbA1c measure is achieved. Such results support that W-band spectroscopy has great potential for developing a non-invasive diagnostic tool for in-vivo HbA1c concentration monitoring in humans.

Semantic disturbances have been proposed as a possible cause of formal thought disorder in schizophrenia. Fluency tasks, in which volunteers are asked to produce as many exemplars as they can for a given category during one minute, are usually applied to the assessment of semantic processing. However, studies associating fluency and proneness to psychosis have provided conflicting results so it is not clear whether these disturbances can be identified at subclinical stages. We conducted two experiments. In the first one, 71 volunteers completed written category fluency tasks with four semantic categories (animals, fruits, clothing and vehicles). In the second experiment, 77 new participants completed oral category and phonological fluency tasks (words starting with f, t, p and c). In both experiments, we assessed schizotypal personality and vocabulary size. Schizotypal traits were not reliably associated with either productivity or originality of the responses in any experiment. In contrast, vocabulary size significantly predicted the participants’ scores in all the tasks. Along with results of other recent studies, our data cast doubt on the reliability of previous observations pointing out an association between schizotypy and lexical-semantic disturbances, at least in relation to productivity and originality in fluency tests.

Diabetes is a very complex condition a ecting millions of people around the world. Its occurrence, always accompanied by sustained hyperglycemia, leads to many medical complications that can be greatly mitigated when the disease is treated in its earliest stage. In this paper, a novel sensing approach for the early non-invasive detection and monitoring of sustained hyperglycemia is presented. The sensing principle is based on millimeter-wave transmission spectroscopy through the skin and subsequent statistical analysis of the amplitude data. A classifier based on functional principal components for sustained hyperglycemia prediction was validated on a sample of twelve mice, correctly classifying the condition in diabetic mice. Using the same classifier, sixteen mice with drug-induced diabetes were studied for two weeks. The proposed sensing approach was capable of assessing the glycemic states at different stages of induced diabetes, providing a clear transition from normoglycemia to hyperglycemia typically associated with diabetes. This is believed to be the first presentation of such evolution studies using non-invasive sensing. The results obtained indicate that gradual glycemic changes associated with diabetes can be accurately detected by non-invasively sensing the metabolism using a millimeter-wave spectral sensor, with an observed temporal resolution of around four days. This unprecedented detection speed and its non-invasive character could open new opportunities for the continuous control and monitoring of diabetics and the evaluation of response to treatments (including new therapies), enabling a much more appropriate control of the condition. Thanks to the Consejo Nacional de Ciencia y Tecnología de México (CONACYT) for financially supporting the doctoral education of Aldo M-O (PhD. Grant). Viktor Krozer is thankful for partial financial support in the frame of the Chairs of Excellence program of the Universidad Carlos III, Madrid, Spain. This research was partially supported by Project MTM2017-88708-P from Ministerio de Economía y Competitividad, FEDER funds, Project IJCI-2017-34038 from Agencia Estatal de Investigación, Ministerio de Ciencia, Innovación y Universidades and the Spanish Ministry of Economy and Competitiveness MTM2014-52184-P.

INTRODUCTION The t (11; 14) by fluorescent in situ hybridization (FISH) is found in 15-20% of patients with multiple myeloma (MM) . Although it was classically considered a standard risk translocation or even a good prognosis, recent studies conducted in the era of new drugs show contradictory results and it is not well established if they have to be considered intermediate or standard risk. The possibility of using targeted therapy with venetoclax for patients harboring t(11;14) makes the investigation of the outcome of newly diagnosed multiple myeloma (NDMM) with t(11;14) as relevant. METHODS We analyzed the baseline characteristics and outcome of patients with t(11;14)and receiving HDT-ASCT within the series of 647 patients with NDMM between 1988 and 2018 according to the current criteria at each moment at two academic hospitals in Spain (University Hospital of Salamanca and Hospital of Leon) . The FISH was performed on selected cells according to international regulations and centralized at the University Hospital of Salamanca. For this purpose, a descriptive cross-sectional study was first conducted comparing the characteristics of patients with t (11; 14) versus the rest. The final objective wasto evaluate the role of HDT-ASCT in NDMM with t(11;14). RESULTS The baseline characteristics of the whole series were: a median age of 71years (yrs) (range:30-96). 217 patients (33,5%) were under 65 years. 352 (56.2%) were IgG; 161 (25.7%) IgA; 87 (13.9%) Bence Jones; 19 (3%) non-secretors, and 5 and 2 cases were IgD and IgM, respectively. 320 (53.2%) received novel agents as part of the first line of therapy. Overall, 153 (27.8%) achieved complete response (CR) after first line, and 403 (73.1%) at least a partial response. After a median follow-up for living patients of 4.26 yrs (range: 0,1-27.3), the OS of the entire series was 2.74 years. T(11;14) was performed in 440 NDMM patients and was positive in 80 (18.2%). Only in 5 patients other high-risk alterations (t (14:16), t (4:14) or del17p (p53)) were detected. The baseline characteristics of patients with and without t (11:14) did not show significant differences, except for the heavy chain pattern(p Of note, most patients with non-secretory MM (10 out of 16, 62,5%) had the t(11;14) whilst in the conventional secretory MM patients, t(11;14) was observed in 68out of 415(16,4%). In addition, the plasma cell bone marrow infiltration was significantly higher in patients with t(11;14)(> 60% Plasma Cells) 32.8% vs 13.3%(p HDT-ASCT was performed in 162 patients (25%)and 22 of them (13,5%) were positive for the t(11:14) and only in 2 patients, other high-risk alterations were detected.The induction therapy received in both treatments arms was homogeneous basically consisted on combinations of proteasome inhibitors plus immunomodulatory drugs. The median OS for NDMM patients undergoing ASCT was 4,33 years. (range: 0,47-26,85) and the median PFS for this patients was 2,25 yrs (range: 0,1-27,25) The median PFS for patients with t (11/14) undergoing ASCT trended to be higher than that observed in patients without t(11;14) who received also HDT-ASCT (99.1 vs 54.9 months), without obtaining significant results, (p 0.205) maybe due to the small number of patients (Figure 1).The median OS in the group of patients with and without t(11:14) undergoing ASCT was 120,8 vs 140 months (p= 0,829). In the cohort of non eligible ASCT patients both median PFS and OS for patients with t(11:14) was similar than that observed in patients without t(11:14)(median PFS of 19,9 vs 19,4 months) (p 0,438) and (median OS of 31,5 vs 44 months) (p 0,424), respectively. CONCLUSION T(11;14) seems to be a cytogenetic abnormality more frequently observed in patients with NDMM and non secretory phenotype what requires further investigation. Patients with t(11;14) benefit the most if they received HDT-ASCT and it would represent a therapeutic strategy of choice if the patient is transplant-eligible. Figure 1 Disclosures Puig: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; The Binding Site: Honoraria; Takeda, Amgen: Consultancy, Honoraria. Mateos:Abbvie: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria; EDO: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Immunoparesis or suppression of polyclonal immunoglobulins is a very common condition in newly diagnosed myeloma patients. However, the recovery of polyclonal immunoglobulins in the setting of immune reconstitution after autologous stem cell transplantation and its effect on outcome has not yet been explored. We conducted this study in a cohort of 295 patients who had undergone autologous transplantation. In order to explore the potential role of immunoglubulin recovery as a dynamic predictor of progression or survival after transplantation, conditional probabilities of progression-free survival and overall survival were estimated according to immunoglobulin recovery at different time points using a landmark approach. One year after transplant, when B-cell reconstitution is expected to be completed, among 169 patients alive and progression free, 88 patients (52%) showed immunoglobulin recovery and 81 (48%) did not. Interestingly, the group with immunoglobulin recovery had a significantly longer median progression-free survival than the group with persistent immunoparesis (median 60.4 vs. 27.9 months, respectively; Hazard Ratio: 0.45, 95%Confidence Interval: 0.31-0.66; P

Objective To analyze the effect of the structure of mood over the following assessment tools for rheumatoid arthritis: visual analog scale (VAS) for pain, HAQ and DAS28. Patients and methods We studied 86 patients with recent onset rheumatoid arthritis, of which 75.7% were female, with a mean age at disease onset of 55 years. All patients were administered the Spanish version of the PANAS questionnaire that evaluates the components of positive (PA) and negative mood (AN). Patients belonged to the registry of new-onset arthritis in our center, so clinical information was available for 282 patients visits. To determine the effect of PA and AN on each of the dependent variables we performed three multivariate linear regression models using generalized linear models through the Stata glm command 10.1. Results The mean score for PA and AN in our patients was similar to that described for the healthy Spanish population. The high scores on the subscale of AN were associated with worse scores in both the VAS for pain and the HAQ. By contrast, high scores on PA were associated with better outcomes of disease activity measured by DAS28. Conclusion The structure of mood may influence the tools we use for evaluating patients with rheumatoid arthritis, so it might be advisable to include the PANAS questionnaire as part of that assessment.

Myxomas are uncommon soft-tissue neoplasms, which are extremely rare in the kidney, with only five cases documented in the intraparenchymal location. However, renal capsular myxoma has not yet been reported. We describe a unique case of a clinically detected renal myxoma arising in the capsule. A 37-year-old man receiving treatment for epididymitis sought medical assistance for infertility. A radiological examination incidentally discovered a right renal tumor. The mass intruded into the perirenal tissue and measured 6 cm in major diameter. The resected kidney contained a well-circumscribed gelatinous capsular tumor. It was composed of sparse, bland, slender, spindle-shaped cells scattered in large amounts of basophilic interstitial mucoid material. The tumor cells showed diffuse immunoreactivity for vimentin. Occasional cells stained for alpha-smooth muscle actin and calponin. Reactivity was negative for S100 protein, epithelial membrane antigen, pancytokeratin, neurofilament protein, and h-caldesmon antibodies. Ultrastructural examination revealed fibroblast-like cells with long thin cytoplasmic processes, prominent rough endoplasmic reticulum, a well-developed Golgi complex, and secretory vesicles. No basal lamina was identified around the tumor cells. The differential diagnosis includes many other benign and malignant soft-tissue lesions exhibiting prominent secondary myxoid features. It is important to consider a renal capsular myxoma when examining lesions at this anatomic site to avoid misdiagnoses and to ensure that the patient receives appropriate treatment and prognostic information.

We have read with great interest the editorial by Beattie and Johnson,1 discussing the role of subcutaneous furosemide (SCF) as an off-label palliative symptomatic treatment feasible for patients with decompensated advanced heart failure (DAHF), whose preferences led to being attended to in their homes, thus avoiding inappropriate hospitalisations, as demonstrated by Zacharias and Johnson in their recently published study.2 In this sense, we have performed an observational retrospective study with the aims to determine the effects of SCF dose amount on hospital length of stay, and time to symptom improvement, among patients with DAHF. We also compared the results with a cohort of patients treated with intravenous furosemide on wards. Between January 2008 and January 2012, all episodes of DAHF consecutively attended to at home were recruited. Inclusion criteria were: older than 18 years, heart failure, New York Heart Association (NYHA) class III or IV symptoms, treated at home with SCF by a Southern Spanish university hospital at-home unit. Analysed variables were: number of hospital admissions before …

Background: DLBCL is a heterogeneous disease with 30% of patients presenting as refractory/relapsing disease following R-CHOP treatment. Therefore, new prognostic factors to identify the poor-risk population and alternative therapies for them are needed. CD30 is a member of the tumour necrosis factor receptor (TNFR) super family and is expressed by several types of T- and B-cell non-Hodgkin lymphomas. Brentuximab vedotin, an anti CD30 antibody, is used in clinical practice for Hodgkin lymphoma and systemic anaplastic large cell lymphoma. The significance of CD30 expression in DLBCL remains unknown. We aimed to study the expression of CD30 in a large cohort of the novo DLBCL patients homogeneously treated with R-CHOP or R-CHOP-like protocols to evaluate its correlation with clinical and biological characteristics at diagnosis and its impact in clinical outcome. Methods: we prospectively registered 155 patients diagnosed of DLBCL between January 2012 to December 2015 in our center. Twenty-one patients with primary central nervous system DLBCL, transformed lymphoma or post-transplant DLBCL were excluded from the study. Anatomopathology review was performed in all cases, and 14 cases with not enough histological tissue to perform additional staining were also excluded. Immunohistochemistry was performed in 120 cases on 4 microns' paraffin sections using routine protocols,CD30 expression was analyzed using the antibodyCD30 clone BerH2, dilution 1:30; Dako; staining in more than 10% of the malignant cells was considered positive. Samples were classified as germinal center B-cell-like (GCB) vs. non-GCB subtypes by immunohistochemistry according to Hans algorithm. Univariate analyses were assessed by Chi square test. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate analyses for progression-free survival (PFS) were assessed Cox proportional hazard regression model. Results: among the 120 cases analyzed, CD30 was expressed in 40 (33.3%). Clinical and biological characteristics at disease presentation are shown in Table 1. The expression of CD30 was significantly higher in the non-GCB subtype cases (p=0.0001). One hundred and six patients were homogeneously treated with R-CHOP (100 patients) or R-CHOP-like (1 R-COMP, 2 Burkitt scheme, 1 GA101-CHOP and 2 R-Bortezomib-CAP), and were included in the outcome analyses. Response rates and survival of this subgroup of patients are shown in Table 2. With a median follow-up of 16.4 months, no differences were found neither in PFS or OS between CD30 positive and CD30 negative patients (Table 2). In the multivariate analyses including the following independent variables: gender, B-symptoms, Bulky mass (>5cm), cell of origin (GCB vs non-GCB), International Prognostic Index (IPI) and CD30 expression, IPI 3-5 was de only factor significantly related with poor PFS (HR 2.92, 95% CI:1.18-7.24, p=0.02). Conclusion: CD30 is expressed in one third of DLBCL patients, in whom an anti-CD30 therapy could be used. CD30 expression is significantly higher in patients with non-CGB DLBCL, however and in our experience, its expression does not influence either response to R-CHOP or R-CHOP- like therapy or survival. Disclosures Gonzalez Barca: Gilead: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Speakers Bureau.

OBJETIVOS Resaltar la diferencia entre Enfermedad de Mondor y Linfangitis Esclerosante del Pene mediante el analisis de tres casos clinicos y la revision de la literatura existente. METODOS Describimos dos casos clinicos compatibles con el diagnostico de enfermedad de Mondor y otro compatible con Linfangitis. RESULTADOS La buena y muchas veces espontanea resolucion de estas dos patologias dificulta el diagnostico y seguimiento de estos pacientes. CONCLUSIONES La abstinencia sexual es una de las medidas mas efectiva para la pronta resolucion de ambos procesos. Para el diagnostico diferencial entre ambas entidades es de gran utilidad el eco-doppler peneano. El tratamiento farmacologico principal se basa en antiinflamatorios.

The evaluation of bone disease in multiple myeloma (MM) by conventional radiology has low reproducibility. In the last decade, several serum and urine biochemical parameters, for evaluation of bone turnover, have become available. The present study was designed to explore the value of six bone remodelation markers. It was studied in a series of 176 newly diagnosed patients with monoclonal gammopathies (107 MM and 69 monoclonal gammopathies of unknown significance (MGUS)). As control groups we used 25 patients with benign osteoporosis (BO) and 32 healthy individuals (HI). The bone markers analyzed included: bone resorption markers (BRM) (total pyridinoline, total deoxypyridinoline, free deoxypyridinoline and C-terminal telopeptide of collagen I) and bone formation markers (BFM) (bone alkaline phosphatase (bAP) and osteocalcin (OC)). Serum or urinary levels of BRM were significantly higher in MM patients than in MGUS patients, BO patients or HI (P < 0.001, respectively). BRM were higher in MM patients with lytic lesions. However, only C-terminal telopeptide discriminated MM patients without bone lesions from MGUS patients. BFM did not show significant differences in the aforementioned comparisons, although a trend toward higher values of OC and lower values of bAP in patients with early bone affectation was observed. Ratios BRM/BFM that contained bAP exhibited differences that were most significant between the MM group and other entities, as well as between the different MM subgroups. In fact, the ratios BRM/bAP provided discrimination between the MM subgroup without lyses and MGUS group (P < 0.01). BRM and BFM, especially the ratios, are useful in the evaluation of bone lesions in patients with monoclonal gammopathies.

Introduction The inherited platelet disorders (IPD) are a heterogeneous group of rare diseases including quantitative and/or qualitative platelet defects. Classically, patients with IPD are first functionally tested to know the possible defect before sequencing a single or a few genes. Phenotipyc diagnostic of IPD often requires light transmission aggregometry, quantitative analysis of receptors by flow cytometry and fluorescence and electron microscopy. This diagnostic strategy is complex, poorly standardised and time consuming. In addition, the phenotype can seldom guide the singles candidates genes for conventional Sanger squencing. Therefore, many patients remain without a accurate diagnosis of their IPD. Next generation sequencing (NGS) enables the simultaneous analysis of large groups of candidate genes in IPD and may be useful for rapid genetic diagnosis. The aim of this study was to design and validate a NGS panel for IPD. Patients & Methods We describe a strategy for rapid genetic diagnosis of IPD with Illumina sequencing of 60 candidates genes previously associated with IPD (table1). The baits were designed to tile 400 kb of gDNA sequence corresponding to the exons and splice sites in all known transcripts of the candidate genes identified. The bait library was tested by enriching the candidate IPD genes from 50 ng DNA obtained and sequencing by Nextera Rapid Custom Enrichment system. Results were analysed by Variant Studio system and Sequencing Analysis Viewer. A total of 21 patients were studied. For the validation process, DNA samples of 9 unrelated patients with IPD and their mutation known were used: two patients with Glanzmann Thrombasthenia (ITGA2B, p.Ala989Thr, p.Val982Met and p.Glu538Stop; ITGB3, p.Leu222Pro and p.Tyr216Cys), one Hermansky-Pudlak Sd. (HPS1, p.Glu204 Stop), another with Bernard-Soulier Sd. (GPIX, p.Phe71Stop), a case of Congenital Amegakaryocytic Thrombocytopenia (MPL, p.Arg102Cys), and 2 patients with Chediak Higashi Sd. (LYST, p.Gly3725Arg and p.Cys258Arg). Once validated, the NGS panel was used for genetic diagnostic of 8 patients with suspected IPD. Results Eleven mutations, previously identified in another center by conventional sequencing, were detected by our panel NGS (100% success in the validation process). We then tested this strategy for patients with suspected of IPD without diagnosis: I. a 13 years old girl with agenesis of the corpus callosum, facial dysmorphia, renal agenesis and thrombocytopenia was diagnosed of Thrombocytopenia FLNA-related and Periventricular Nodular Heterotopia (PNHV)[mutation in the FLNA was detected (p.Thr1232Ile)]. II. A two years old patient with severe thrombocytopenia and recurrent infections was diagnosed of Wiskott-Aldrich Sd (WAS, p.Arg268Gly fs Stop40). III. A patient with deafness, macrothrombocytopenia, and Döhle bodies was diagnosed by MYH9 deletion (MYH9; p.Asp1925Thr fs Stop23). IV. Six members of a family (2 of them with symptoms of mucocutaneous bleeding, and macrothrombocytopenia), in which an insertion in NBAL2 (p.Gly1142Arg fs Stop49) gene was found. Therefore, Gray Platelet Sd was diagnosed. Moreover, one patient with “aspirin-like syndrome” showed a P2RY12 mutation (p.Val279Met). Finally, mother and son with mild Hemophilia A (F8; p.Gln2208Arg) were detected. Conclusions This NGS panel enables a rapid genetic diagnostic of IPD. The use of NGS-based strategy is a feasible tool for the diagnosis of IPD that could be added to the screening of these disorders. Five mutations have not previously been described in the literature. Table 1: Sixty candidates' genes previously associated with IPD: Inherited Platelet Disorders Genes = 60 Cytoskeletal Assembly and Structural Proteins GP1BA, GP1BB, GP5, A2M, GP9, VWF, ITGA2, ITGA2B, ITGB3, ABCA1, ANO6,FERMT3, ACTN1, MASTL Disorders of agonist platelet receptors P2RX1, P2RY1, P2RY12, TBXA2R, TBXAS1, ADRA2A, GP6, CD36 o GP4, DTNBP1 Disorders signal transduction GNAI3, GNAQ, GNAS, PLA2G7, PLCB2PTS, GGCX, DPAGT1, DHCR24 Disorders of platelet granules NBEAL2, GFI1B, PLAU, HPS1, HPS3, HPS4, HPS5, HPS6, LYST, MLPH, BLOC1S3, BLOC1S6, AP3B1, VIPAS39, VPS33B, RAB27A, MYO5A, USF1 Thrombocytopenias and syndromes WAS, MYH9, FLNA, FLI1, STIM1, HOXA11, ANKRD26, MPL, RBM8A RUNX1, GATA1 Disclosures No relevant conflicts of interest to declare.

BACKGROUND Smoldering multiple myeloma (SMM) is a plasma cell proliferative disorder with no related organ or tissue impairment. It is associated with a risk of progression to symptomatic multiple myeloma (MM) of approximately 10% per year. Several prognostic factors for the progression to active disease have been identified, such as those defined by the Mayo Clinic including the proportion of bone marrow plasma cells, the serum monoclonal protein level at diagnosis and the serum immunoglobulin free light chain ratio (FLC); or those defined by the Spanish Group including the proportion of bone marrow aberrant plasma cells assessed by flow cytometry plus immunoparesis. The presence of Bence Jones (BJ) proteinuria is a myeloma feature associated with renal function and tumor burden as well. There is lack of evidence about the role of BJ proteinuria in SMM as predictor marker of progression to symptomatic disease. AIMS The goal of the present study was to investigate the role of the presence of Bence Jones proteinuria at diagnosis in SMM as predictor of progression to symptomatic disease. METHODS We reviewed 147 medical records of SMM patients from area of Castilla y León (Spain), diagnosed between 1983 and 2013, according to the criteria of the International Myeloma Working Group. The primary endpoint was time to progression to active multiple myeloma (hypercalcemia, renal insufficiency, anemia or bone lesions). RESULTS 147 patients with SMM were included in the analysis. The median age at diagnosis was 69 years-old (range: 34-90).The serum M-protein at diagnosis ranged from 1 to 26 g/l (median,25). 70% of SMM were Ig G subtype. The proportion of bone marrow plasma cells ranged from 1% to 55% (median, 14). In 64 % of SMM, the percentage of aberrant plasma cells assessed by flow cytometry was superior to 95% and 51% had immunoparesis. Bence Jones proteinuria was detected at diagnosis in 40 patients (27%) and the average amount of urinary monoclonal light chain was 236 mg per 24h. Of those patients, 58% had a monoclonal kappa light chain. The FLC ratio was assessed in 18 patients and it was abnormal (1.65) in 83% of them. The median level of involved Immunoglobulin was 88.5 mg/l (range, 13-1200) and the median ratio of involved to uninvolved was 10.8 (range, 2.2-3360). In 4 patients, FLC ratio was greater than 100. At a median follow-up of 54 months, progression to active disease occurred in 49%. Anemia was the most common CRAB feature at the time of progression. Median time to progression (TTP) to symptomatic disease in the whole series was 63 months. SMM with BJ proteinuria had a significantly shorter median TTP to active disease as compared with patients without BJ proteinuria (21.7 months vs 82.9 months ;HR: 2.44, IC 95%: 1.48-4.02; p Multivariate analysis selected BJ proteinuria at diagnosis as an independent variable for progression to symptomatic MM (HR: 2.47, IC 95%: 1.32-4.63; P=0.005). Using this independent variable, we identified 4 risk categories according to amount of urinary monoclonal light chain: 0 mg per 24h; 1-250 mg/24h; 251-500 mg/24h ; or more than 500 mg/24h, with a median TTP of 83, 37, 16 and 7 months, respectively; p CONCLUSIONS The presence of Bence Jones proteinuria at diagnosis in SMM patients is associated with significantly higher risk of progression to active MM (53% risk of progression at 2 years). Moreover, the presence of more than 500 mg of BJ proteinuria can be considered as a marker for the identification of ultra high risk SMM. Disclosures No relevant conflicts of interest to declare.

Abstract 4566 Cytogenetic abnormalities are present in virtually all cases of Waldenström's macroglobulinemia (WM). Among them, deletion of the long arm of chromosome 6 (6q-) is the most frequently reported in the literature, but the potential impact on disease evolution has not been completely elucidated. In this study we have analyzed the prevalence of this aberration in 203 patients with B-cell lymphoproliferative disorders (B-LPD) producing a monoclonal IgM component. Detection was evaluated by In Situ Fluorescence Hybridization in CD19+ separated cells and results were correlated with disease characteristics. The frequency of 6q21 deletion varied according to the type of B-LPD: 1/42 (2%) in IgM-MGUS, 5/69 (7%) in asymptomatic WM (aWM), 25/83 (30%) in symptomatic WM (sWM) and 0/9 in other IgM B-LPD. Within MGUS and aWM, patients with deletion of 6q displayed a high frequency of adverse prognostic features and required treatment earlier than patients with normal 6q (37 mo vs. +120 mo, p Disclosures: Ocio: PharmaMar: Patents & Royalties, Research Funding. San Miguel:Celgene: Honoraria; Millenium: Honoraria; Janssen: Honoraria.

Introduction: Waldenström’s Macroglobulinemia (WM) is an uncommon lymphoproliferative disorder characterized by bone marrow infiltration of the lymphoplasmocytic cells and IgM monoclonal gammopathy. The normal counterpart of the WM malignant cell is believed to be a post germinal-center B cell. However, the low frequency of WM has hampered investigation into Immunoglobulin Heavy Chain (IgH) rearrangements in large series of patients and whether preferential use of specific genetic segments or non-functional rearrangements exits. Aim: Molecular characterization in a large cohort of WM patients analyzing their functional, complete VDJH, and non-functional, incomplete DJH, IgH rearrangements, the pattern of somatic hypermutation (SHM) and gene segment usage. Patients and methods: 47 patients with unequivocal diagnosis of WM were included in the study. Bone Marrow samples (always with more than 10% of tumor cell) were used for amplification of clonal rearrangements employing the Biomed-2 strategy (Leukemia2003; 17; 2257), followed by direct automated sequencing in ABI 377 DNA sequencer using Big-Dye terminators (Applied Biosystems, Foster City, CA). Results: All patients showed a monoclonal amplification of at least one VDJH or DJH rearrangement. VDJH monoclonal rearrangements were detected in 42/47 (89.3%) patients while DJH were observed in 20 (42.5%) patients. VH, DH and JH gene segment usage: VH3 gene segment was the most commonly represented family (76,2%) while the other gene segments were scarcely detectable, and VH5 was totally absent. In the complete VDJH rearrangements, DH6 was the family most commonly represented while DH2 (45%) and DH4 (30%) were the most common in the incomplete DJH rearrangement. Regarding JH elements, JH4 (38%) was the most represented in the complete rearrangements and JH5 (46%) in the incomplete rearrangements. Somatic hypermutation: SHM were observed in all except two of the cases (94%, 34 of 36 cases), in which the study could be performed. (median 9,38; range2.9–16.6). In the remaining clonal cases (6 cases, 14.3%) no amplification of FR1 region was obtained, also suggesting the presence of SHM. Conclusions: In this series of patients, we observed the presence of incomplete rearrangements with an incidence similar (44%) to that described in multiple myeloma. The preferential usage for determined families of genetic segments, in VDJH and in DJH, suggests the presence of positive and negative selection processes. Finally, the majority, (94 %) of the cases, presented SHM, although the presence of two patients lacking in SHM suggests a pre-follicular origin for some WM cases.

Fluorescence in situ hybridization (FISH) is an effective alternative for the analysis of cytogenetic abnormalities of low proliferative entities such as Waldenström macroglobulinemia (WM) but, to date, no studies have been carried out to explore the potential impact of molecular cytogenetics on disease evolution. Deletion of the long arm of chromosome 6 (6q-) is the most frequent cytogenetic abnormality in WM. In this study we have analyzed the incidence of this aberration (using both conventional cytogenetics and FISH analysis) in 102 WM patients, and we have correlated it with disease characteristics. Deletion of 6q21 was detected in 6% of patients by conventional cytogenetics, while FISH studies increased this incidence up to 39%. Moreover, in those patients analyzed by cIgM-FISH, the incidence of 6q- was higher (54%). Interestingly, 6q- patients displayed features associated with adverse prognosis (higher levels of ESR, CRP and beta-2 microglobulin), and a greater tendency to display anemia and hypoalbuminemia. Other differentiating variables without reaching statistical significance were a tendency of displaying a higher bone marrow lymphoplasmacytoid infiltration and the amount of monoclonal component in 6q- patients (table). In addition, patients with 6q- displayed shorter survival from time of diagnose (log-rank; p=0.09). In summary, our results show that 6q deletion in WM patients is currently the most frequently found cytogenetic abnormality. Patients with this deletion also shows a trend towards an aggressive disease and poorer outcome in WM. Further studies should focus on possible tumor suppressor genes in the minimal area of deletion at 6q and to determine their role in disease progression. table del6q present del6q absent p-value n 40 (39%) 62 (61%) β2M ≥4mg/dL 48% 16% 0.005 CRP ≥3.5 mg/dL 47% 11% 0.006 Albumin 20 g/L 86% 73% 0.10 BM infiltration >40% 44% 31% 0.20

Introduction Graft versus host disease (GVHD) is the main cause of morbi-mortality after allogeneic stem cell transplantation (allo-SCT). Despite considerable advances in our understanding of the pathophysiology, nowdays anticipation of GVHD is an unresolved matter. Several single-nucleotide polymorphisms (SNPs) in cytokine genes have shown to be associated with donor-recipient alloreactivity and, ultimately, with SCT outcome. In the present study, we propose a novel predictive model based on both clinical and genetic (SNP) variables applying an innovative estimation linear regression model, the least absolute shrinkage and selection operator (LASSO), in a large cohort of HLA-identical sibling donor allo-SCT. Patients and Methods The study evaluated 25 SNPs in 12 genes (Table 1) in genomic DNA obtained from PB samples from 273 patients with available acute GVHD (aGVHD) data and 213 patients with chronic GVHD (cGVHD) data included in the DNA Bank of the Spanish Group for Hematopoietic Stem Cell Transplantation (GETH) and their HLA-identical sibling donors. Each SNP was assessed for different models of transmission (recessive, dominant, co-dominant and additive), producing 25 SNPs x 4 models = 100 variables. Clinical variables known to influence the development of GVHD were also considered (Table 1). Univariate regression analysis was performed using Cox regression (data not shown). Multivariant analysis was made with LASSO, an innovative estimation method for linear regression models which is able to select a set of optimal predictors from a large set of potential predictor variables and was considered as a variables selection method under the estimation of a Logit regression model. In this model, the strength of the penalty term is controlled by a smoothing parameter (λ), which is chosen by maximizing the area under ROC curve (AUC) and the correct classification rate (CCR). The statistical model was fitted (goodness-of-fit assessment) by randomly selecting the 85% of the data (the so-called "training set"), and the predictive ability was computed with the remaining 15% (the so-called "testing set"). In order to evaluate the performance and the prediction ability of each model, training and testing samples were randomly selected a total of 100 times. The distribution of the CCR and the AUC over the 100 samplings, were shown by means of box plots and statistical summary in the results data. Finally, for prediction purposes, we considered a cut-off value according to the proportion of Y=1 in the sample (0.28 for grades II-IV aGVHD, 0.11 for grades III-IV aGVHD and 0.30 for extensive cGVHD). Results The best model to predict aGVHD II-IV included 11 genetic variables and no clinical variables with a CCR for patients who developed (CCR1) aGVHD II-IV of 63.6% (Figure 2). The best model to predict aGVHD III-IV included 20 genetic and 7 clinical variables with a CCR1 for aGVHD III-IV of 100%. The best model to predict extensive chronic GVHD included 10 genetic and 3 clinical variables with a CCR1 for extensive cGVHD of 80%. On the other hand, predictive models with only clinical variables showed a poorer CCR1 for patients who developed aGVHD II-IV, aGVHD III-IV and extensive cGVHD (55.6%, 50% and 66.7% respectively; Figure 1). Based on the results from LASSO multivariate analyses, a risk score was calculated for grades II-IV and III-IV aGVHD as well as for cGVHD and extensive cGVHD. Patients were categorized into two groups: low risk (below the cut-off value) and high risk (above the cut-off). Such risk model was able to stratify patients who develop grades II-IV aGVHD (p Conclusions Identification of biomarkers useful for the estimation of the risk of GVHD constitutes an unmet need in the clinical management of GVHD. The novel predictive model proposed here, based on clinical and genetic factors, allows significantly improved anticipation of aGVHD III-IV (100% accuracy) and extensive cGVHD (80%) after HLA-identical sibling donor allo-SCT. This approach would allow a personalized risk-adapted clinical management of patients after transplantation. Disclosures No relevant conflicts of interest to declare.