Spanish Registry Research Articles

Simplified risk stratification based on cardiopulmonary exercise test: A Spanish two-center experience.

A simplified 4-strata risk stratification approach based on three variables is widespread in pulmonary arterial hypertension (PAH)at follow-up. This study aimed to assess the impact of replacing the 6-min walk test (6MWT)with the peak 02 uptake evaluated by the cardiopulmonary exercise test (CPET)on risk stratification by this scale. We included 180 prevalent patients with PAH from two reference hospitals in Spain, followed up between 2006 and 2022. Patients were included if all the variables of interest were available within a 3-month period on the Spanish Registry of Pulmonary Arterial Hypertension (REHAP):functional class (FC);NT-proBNP;6MWT; and CPET. The original 4-strata model (NT-proBNP,6MWT, FC) identified most patients at low or intermediate-low risk (36.7% and 51.1%, respectively). Notably, the modified scale (NT-proBNP,CPET, FC) improved the identification of patients at intermediate-high risk up to 18.9%, and at high risk up to 1.1% in comparison with the previous 12.2% and 0.0% in the original scale. This new model increased the number of patients correctly classified into higher-risk strata (positive NRI of 0.06), as well as classified more patients without events in lower-risk strata (negative NRI of 0.04). The proposed score showed a slightly superior prognostic capacity compared with the original model (Harrel's C-index 0.717 vs. 0.709). Using O2 uptake instead of distance walked in the 6MWT improves the identification of high-risk patients using the 4-strata scale. This change could have relevant prognostic implications and lead to changes in the specific treatment of PAH.

Generation of a bank of clinical-grade, HLA-homozygous iPSC lines with high coverage of the Spanish population

BackgroundInduced pluripotent stem cell (iPSC)-derived cell therapies are an interesting new area in the field of regenerative medicine. One of the approaches to decrease the costs of iPSC-derived therapies is the use of allogenic homozygous human leukocyte antigen (HLA)-matched donors to generate iPSC lines and to build a clinical-grade iPSC bank covering a high percentage of the Spanish population.MethodsThe Spanish Stem Cell Transplantation Registry was screened for cord blood units (CBUs) homozygous for the most common HLA-A, HLA-B and HLA-DRB1 haplotypes. Seven donors were selected with haplotypes covering 21.37% of the haplotypes of the Spanish population. CD34-positive hematopoietic progenitors were isolated from the mononuclear cell fraction of frozen cord blood units from each donor by density gradient centrifugation and further by immune magnetic labeling and separation using purification columns. Purified CD34 + cells were reprogrammed to iPSCs by transduction with the CTS CytoTune-iPS 2.1 Sendai Reprogramming Kit.ResultsThe iPSCs generated from the 7 donors were expanded, characterized, banked and registered. Master cell banks (MCBs) and working cell banks (WCBs) from the iPSCs of each donor were produced under GMP conditions in qualified clean rooms.ConclusionsHere, we present the first clinical-grade, iPSC haplobank in Spain made from CD34 + cells from seven cord blood units homozygous for the most common HLA-A, HLA-B and HLA-DRB1 haplotypes within the Spanish population. We describe their generation by transduction with Sendai viral vectors and their GMP-compliant expansion and banking. These haplolines will constitute starting materials for advanced therapy medicinal product development (ATMP).

Prior drug allergies are associated with worse outcome in patients with idiosyncratic drug-induced liver injury: A machine learning approach for risk stratification

The impact of prior drug allergies (PDA) on the clinical features and outcomes of patients who develop idiosyncratic drug-induced liver injury (DILI) is largely unknown. We aimed to assess the clinical presentation and outcomes of DILI patients based on the presence or absence of PDA and explore the association between culprit drugs responsible for DILI and allergy. We analysed a well-vetted cohort of DILI cases enrolled from the Spanish DILI Registry. Bootstrap-enhanced least absolute shrinkage operator procedure was used in variable selection, and a multivariable logistic model was fitted to predict poor outcomes in DILI. Of 912 cases with a first episode of DILI, 61 (6.7%) had documented PDA. Patients with PDA were older (p = 0.009), had higher aspartate aminotransferase (AST) levels (p = 0.047), lower platelet count (p = 0.011) and higher liver-related mortality than those without a history of drug allergies (11% vs. 1.6%, p < 0.001). Penicillin was the most common drug associated with PDA in DILI patients (32%). A model including PDA, nR-based type of liver injury, female sex, AST, total bilirubin, and platelet count showed an excellent performance in predicting poor outcome in patients from the Spanish DILI Registry (area under the ROC curve [AUC] 0.887; 95% confidence interval [CI] 0.794 – 0.981) and the LATINDILI Network (AUC 0.932; 95% CI 0.884 – 0.981). Patients with suspected DILI should be screened for PDA as they would require a close monitoring for early detection of worsening clinical course.

Renal Function Impairment in Children With Congenital Cytomegalovirus Infection: A Cross-sectional Study.

We aimed to determine the prevalence and severity of glomerular and tubular renal dysfunction by means of urinalysis in infants and toddlers with congenital cytomegalovirus infection (cCMV) and their association with cCMV disease, viruria and antiviral treatment. This cross-sectional study was done using the Spanish Registry of Congenital Cytomegalovirus Infection. First-morning urine samples were collected from January 2016 to December 2018 from patients <5 years old enrolled in Spanish Registry of Congenital Cytomegalovirus Infection. Samples were excluded in case of fever or other signs or symptoms consistent with acute infection, bacteriuria or bacterial growth in urine culture. Urinary protein/creatinine and albumin/creatinine ratios, urinary beta-2-microglobulin levels, hematuria and CMV viruria were determined. A 0.4 cutoff in the urinary albumin/protein ratio was used to define tubular (<0.4) or glomerular (>0.4) proteinuria. Signs and symptoms of cCMV at birth, the use of antivirals and cCMV-associated sequelae at last available follow-up were obtained from Spanish Registry of Congenital Cytomegalovirus Infection. Seventy-seven patients (37 females, 48.1%; median [interquartile range] age: 14.0 [4.4-36.2] months) were included. Symptom-free elevated urinary protein/creatinine and albumin/creatinine ratios were observed in 37.5% and 41.9% of patients, respectively, with tubular proteinuria prevailing (88.3%) over glomerular proteinuria (11.6%). Proteinuria in the nephrotic range was not observed in any patients. In multivariate analysis, female gender was the only risk factor for tubular proteinuria (adjusted odds ratio = 3.339, 95% confidence interval: 1.086-10.268; P = 0.035). cCMV disease at birth, long-term sequelae, viruria or the use of antivirals were not associated with urinalysis findings. Mild nonsymptomatic tubular proteinuria affects approximately 40% of infants and toddlers with mostly symptomatic cCMV in the first 5 years of life.

Characterization of drug-induced liver injury associated with drug reaction with eosinophilia and systemic symptoms in two prospective DILI registries.

Idiosyncratic drug-induced liver injury (DILI) associated with drug reactions with eosinophilia and systemic symptoms (DRESS) is poorly characterized among patients of Western countries. We aimed to comprehensively assess the clinical characteristics, outcomes, and causative agents in a prospective, well-vetted cohort of DILI patients with DRESS (DILI-DRESS). We identified 53 DILI-DRESS cases from the Spanish DILI Registry and the Latin American DILI Network. For comparison purposes, we defined a group of DILI patients (n = 881). DILI-DRESS cases were younger (47 vs. 53years, respectively; p = 0.042) and presented more frequently with cholestatic/mixed damage (p = 0.018). Most DILI-DRESS patients showed moderate liver injury, 13% developed severe damage, and only one patient (with hepatocellular injury due to anti-tuberculosis drugs) progressed to acute liver failure and died. DILI-DRESS cases showed a distinctive causative drug pattern compared to DILI cases. The most frequent drugs were carbamazepine (13%), anti-tuberculosis drugs (13%), amoxicillin-clavulanate (11%), and allopurinol and lamotrigine (7.6% each). Among all cases of DILI due to allopurinol and lamotrigine, 67% presented with a DILI-DRESS phenotype, respectively. Higher total bilirubin (TBL) levels at DILI recognition (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.04-1.45) and absence of eosinophilia (OR 8.77; 95% CI 1.11-69.20) increased the risk for developing a severe-fatal injury in DILI-DRESS patients. DILI-DRESS patients have a more frequent cholestasis/mixed pattern of injury at presentation, with antiepileptics as distinctive causative drug class. Most of the lamotrigine and allopurinol cases present with this phenotype. Higher TBL levels and absence of eosinophilia at DILI recognition are markers of poor outcomes.

Vigilancia epidemiológica en los últimos 4 años del Registro Español de Investigación en Dermatitis de Contacto y Alergia Cutánea: situación actual y tendencias

BackgroundThe epidemiological surveillance of contact dermatitis is one of the objectives of the Spanish Registry of Research in Contact Dermatitis and Cutaneous Allergy. Knowing whether the prevalence of positive tests to the different allergens changes over time is important for this monitoring process. ObjectivesTo describe the various temporary trends in allergen positivity in the GEIDAC standard series from 2018 through December 31, 2022. MethodsThis was a multicenter, observational trial of consecutive patients analyzed via patch tests as part of the study of possible allergic contact dermatitises collected prospectively within the Spanish Registry of Research in Contact Dermatitis and Cutaneous Allergy. The data was analyzed using 2 statistical tests: one homogeneity test (to describe the changes seen over time) and one trend test (to see whether the changes described followed a linear trend). ResultsA total of 11327 patients were included in the study. Overall, the allergens associated with a highest sensitization were nickel sulfate, methylisothiazolinone, cobalt chloride, methylchloroisothiazolinone/methylisothiazolinone, and fragrance mix i. A statistically significant decrease was found in the percentage of methylisothiazolinone positive tests across the study years with an orderly trend. ConclusionsAlthough various changes were seen in the sensitizations trends to several allergens of the standard testing, it became obvious that a high sensitization to nickel, methylchloroisothiazolinone/methylisothiazolinone and fragrances mix i remained. Only a significant downward trend was seen for methylisothiazolinone.

Effect of Caplacizumab in the Recovery of ADAMTS13 Level in Patients with Autoimmune Thrombotic Thrombocytopenic Purpura. Analysis from the Spanish Registry (REPTT)

INTRODUCTION Treatment of immune thrombotic thrombocytopenic purpura (iTTP) includes plasma exchanges (PEX) and immunosuppressive treatment with steroids with or without rituximab (RTX). Actually, caplacizumab (CPZ) has been included in this scheme of treatment, because of its effect in decreasing clinical response time, exacerbations and refractoriness. A longer time to recovery of ADAMTS13 levels has recently been described in a group of patients from United Kingdom in subjects treated with caplacizumab. We analysed the behaviour of ADAMTS13 recovery in patients from the Spanish TTP registry (REPTT). METHODS Retrospective, multicentre, non-interventional study. Data collected by the Spanish PTT Registry (REPTT) from September-2018 to February-23. The objective is to describe the efficacy of standard therapy with and without CPZ with regard to recovery of ADAMTS13 levels higher than 20%. Episodes evaluable for ADAMTS13 &amp;gt;20% recovery were those with data available 48 hours or more after last PEX. Data about clinical response, clinical remission, exacerbations and relapses will be described. Qualitative variables described in percentages, quantitative in median and interquartile range (IQR). RESULTS We included 178 patients from REPTT, but only 164 were analysed. Reasons for exclusion were 5 were congenital TTP, 3 patients were younger than 16 years-old, and 6 patients because of lack of data. The 164 patients presented 172 episodes whose characteristics are described in Table 1. Clinical remission rate did not differ between groups, 95% CPZ vs 97% no CPZ, with a median time of 41 days (36-50) vs 43 days (38-50), respectively. A median of 11 PEX (IQR:6-20) were required to get clinical remission, lower in CPZ group (CPZ 10 PEX, IQR:5-18 vs no CPZ 12 PEX, IQR: 7-23, p=0.044). In 49 of the 103 CPZ episodes, CPZ was introduce in the 3 first days from diagnosis (CPZ3). In this group, number of PEX was critically reduced (CPZ 6 PEX, IQR: 4-9 vs no CPZ 12 PEX, IQR: 7-23; p&amp;lt;0.001). Exacerbation rate was lower CPZ group (12.5% vs 23.2%, p. 0.033), as refractoriness rate(4.1% vs 8.7%, p = 0.038). With a median follow-up of 188.5 days (110.5-354.5), relapse rate was 10.5%, lower in subjects treated with CPZ (4% vs 25.5%, p &amp;lt; 0.001). Mortality before reaching clinical remission was 1.9% in the CPZ group and 4.3% in the non-CPZ group (p. 0.177). Adverse events (AEs) rate was 10.5% in the non-CPZ group, most related to plasma infusion, all mild. Incidence of AEs related to CPZ was 24.5%, with 12 bleeding events: 11 WHO grade 1 (3 metrorrhagia, 2 pericatheter bleeds, 6 mucosal bleeds) and one grade 2 (1 gastrointestinal in a patient with intestinal polyposis). Regarding patients reaching ADAMTS13 &amp;gt;20%, we found no differences with regard to CPZ use (Fig 1). There were 114 evaluable episodes (66% of serie): 39 No-CPZ (56.5% of No CPZ group) and 75 CPZ group (72.8% CPZ group). The 93% achieved ADAMTS13 levels &amp;gt;20%, with no difference between groups(CPZ 93.3% vs No CPZ 94.9%, p. 0.082). In the 107 episodes who reached ADAMTS13 &amp;gt;20%, time from start of PEX to ADAMTS13 &amp;gt; 20% was 27 days (IQR:17-51),(CPZ 26.5 days, IQR:17.75-39, vs no CPZ 22 days, IQR:14.75-33.5, p.0.077). ADAMTS13 levels at that time were 51% (IQR: 36-80%),(CPZ 50%, IQR: 33-71% vs No CPZ 59%, IQR: 37-89%, p. 0.437). Time from last PEX to ADAMTS13 levels &amp;gt;20% was similar in both groups (CPZ 15.5 days, IQR: 7.75-29.25 vs No CPZ 13 days, IQR: 8-22 days, p. 0.063). In patients treated with CPZ in the 3 first days from diagnosis, there is no difference in time from start PEX and ADMATS13 &amp;gt;20%, but we found longer time from last PEX to ADAMTS13 &amp;gt;20% (CPZ3 18 days, IQR: 12-43 days vs No CPZ 13 days, IQR: 8-22 days, p. 0.026). The 81.3% of the episodes who reached ADAMTS13 levels &amp;gt;20% received RTX and 71.4% (2/7) of the non-responders (p. 0.385). We found no differences in time to ADAMTS13 &amp;gt; 20% in none of both groups with regard of RTX used. CONCLUSIONS CPZ is safe and effective in the treatment of iTTP. Its use in the first 3 days of diagnosis shortens clinical response times. Exacerbation and refractoriness are lower in patients treated with CPZ. In our series, the use of CPZ did not extend time to ADAMTS13 levels greater than 20%, neither from the start of PEX nor from PEX stop evaluation. Only in the group of patients treated with CPZ in the first 3 days of diagnosis, time from last PEX to ADAMTS13 &amp;gt;20% is longer, probably because they need less PEX, but time from PEX start to ADAMTS13 &amp;gt;20% is the same than in the rest of patients.

Clinical Characteristics, Treatment Approach and Long-Term Outcomes of 678 Patients with Symptomatic Waldenstrom's Macroglobulinemia: Comprehensive Insights from a Spanish Registry of IgM Gammapathies

Introduction The pathogenesis of Waldenstrom's macroglobulinemia (WM) involves the clonal expansion of lymphoplasmacytic B cells in bone marrow, producing monoclonal immunoglobulin M (IgM). The heterogeneity of clinical manifestations in this uncommon disease represents the treatment approach more challenging. Multicenter registries may help in improving health care and scientific research. PRAME is a Spanish national registry of WM and IgM-related disorders with comprehensive data collection, providing insights for a better understanding of WM. Methods This is a retrospective, multicenter study that included newly diagnosed symptomatic WM (SWM) patients, evaluated at (24) Spanish hospitals between 1990 and 2023. All patients had confirmed diagnoses of SWM according to the International Workshop Consensus. Data collection on patients' demographics and disease epidemiology, clinical characteristics, diagnosis, treatment approaches and outcomes were performed from patients' local medical files. Results From 1796 total patients included in the Spanish registry for IgM gammopathies, a total of 678 newly SWM patients were identified. The median age was 71(range 35-94) years, 37% of patients had aged ≥ 75 years and 63% were male. The most common symptom at diagnosis was anemia (43%), followed by B symptoms (30%). Fifteen percent had peripheral neuropathy (PN) as the first WM symptom (39% with sensitive motor PN). Hyperviscosity was only observed in 15%. The free light chain isotypes were mostly kappa (75.4%). Less than 5% of the total cohort, had an ECOG ≥3, at diagnosis. Among 403 patients, who had samples available for assessing MYD88L265P by quantitative allele-specific PCR, 75% were positive for the mutation. However, out of the 199 patients assessed for CXCR4(S388X) mutation, only 12% were positive. The first line of therapy was started in 98% of patients. Plasmapheresis was indicated in 10%, with a median number of 2 sessions. The most frequent indications for initiating the treatment were anemia (48%), B symptoms (13%), and neuropathy (9%). Symptoms related to IgM monoclonal and extramedullary involvement were seen in 15% (56% associated with hyperviscosity) and 11.3%, respectively. The main first-line treatment regimens received were: chlorambucil (37%), dexamethasone, rituximab and cyclophosphamide (DRC)(21%), rituximab monotherapy (13%), bendamustine/rituximab (BR) (9.1%), Bruton tyrosine kinase (BTK) inhibitors (7%), and bortezomib, dexamethasone and rituximab (BDR) (5.5%). The overall and major response rates (ORR and MRR) were 67% and 58%, respectively. (Table 1). The MRR was higher among patients who received BR as the first line of therapy (88%), with a 26% of complete response (CR) and 21% of very good partial responses (VGPR). The CR+VGPR rates with other common regimens were 17% for DRC, 9% for BDR and 21% for BTK inhibitors, respectively. With a median follow-up of 96 months (IQR, 43 to 192), the median overall survival (OS) was 8.7 years (95% confidence interval [CI]:7.3-10.1) and the median progression-free survival (PFS) was 6.8 years (95% CI:6.2-7.5) with no relevant improvement over the last years. (Figure 1) Conclusion In the current registry, we observed a high proportion of younger patients with good performance status at diagnosis. Among newly diagnosed SWM patients, BR demonstrated ongoing superiority as a front line of therapy, leading to deeper responses compared to other therapeutic schemes. There were no significant differences in OS between different times of diagnosis. This Spanish registry for SWM contributes to advancing knowledge and the continual enhancement of treatment strategies for WM.

Splanchnic Vein Thrombosis in Inflammatory Bowel Disease: An Observational Study from the ENEIDA Registry and Systematic Review

Background: Thromboembolic events are frequent among patients with inflammatory bowel disease (IBD). However, there is little information on the prevalence, features and outcomes of splanchnic vein thrombosis (SVT) in patients with IBD. Aims: To describe the clinical features and outcomes of SVT in patients with IBD and to perform a systematic review of these data with published cases and series. Methods: A retrospective observational study from the Spanish nationwide ENEIDA registry was performed. A systematic search of the literature was performed to identify studies with at least one case of SVT in IBD patients. Results: A new cohort of 49 episodes of SVT from the Eneida registry and 318 IBD patients with IBD identified from the literature review (sixty studies: two multicentre, six single-centre and fifty-two case reports or case series) were analysed. There was a mild predominance of Crohn’s disease and the most frequent clinical presentation was abdominal pain with or without fever followed by the incidental finding in cross-sectional imaging techniques. The most frequent SVT location was the main portal trunk in two-thirds of the cases, followed by the superior mesenteric vein. Anticoagulation therapy was prescribed in almost 90% of the cases, with a high rate of radiologic resolution of SVT. Thrombophilic conditions other than IBD itself were found in at least one-fifth of patients. Conclusions: SVT seems to be a rare (or underdiagnosed) complication in IBD patients. SVT is mostly associated with disease activity and evolves suitably when anticoagulation therapy is started.

Clinical and Molecular Characterization of Triple-Negative Essential Thrombocythemia: Data from the Prospective Spanish Registry of Essential Thrombocythemia

Introduction Triple-negative Essential Thrombocythemia (TN-ET) accounts for up to 10-20% of patients with a histological diagnosis of ET. Despite being considered an indolent disease, it remains a diagnostic and therapeutic challenge as it can be confused with non-clonal thrombocytosis and its prognostic factors and management are not standardized. Objectives The aim of this study was to evaluate the utility of a Next Generation Sequencing (NGS) panel targeting recurrently mutated genes in myeloid pathology for detecting genetic variants in patients diagnosed with TN-ET and to assess the significance of these variants in the risk of thrombosis and hemorrhage, progression to Acute Leukemia (AL) or Myelofibrosis (MF), and overall survival. Materials and Methods Data from 151 TN-ET patients with confirmed biopsy and NGS sequencing from the Spanish Registry of Essential Thrombocythemia of the Spanish Group of Philadelphia-Negative Myeloproliferative Neoplasms was obtained. This registry includes information on diagnosis, molecular biology, clinical characteristics, and molecular biology. In addition, 39 patients whose molecular diagnosis was performed at the Molecular Biology Laboratory of the Hematology Department at Hospital Universitario 12 de Octubre, Madrid, Spain were included. This last panel included the genes: ANKRD26, ASXL1, ATG2B, BCOR, BCORL1, CALR, CBL, CEBPA, CSF3R, CUX1, DDX41, DNMT3A, EGLN1, EPAS1, EPOR, ETNK1, ETV6, EZH2, FLT3, GATA2, GNAS, GNB1, GSKIP, IDH1, IDH2, JAK2, KDM6A, KIT, KMT2A, KRAS, MBD4, MPL, NF1, NFE2, NPM1, NRAS, PHF6, PPM1D, PRPF8, PTPN11, RAD21, RIT1, RRAS, RUNX1, SAMD9, SAMD9L, SETBP1, SF3A1, SF3B1, SH2B3, SMC1A, SMC3, SRSF2, STAG2, TERC, TERT, TET2, THPO, TP53, U2AF1, VHL, WT1, ZRSR2. Statistical analyses were performed using SPSS v.29.0. Results A canonical mutation was detected in 20 out of the 190 studied patients, ( JAK2 V617F n=13, CALR n=3 and MPL n=4) being discarded from subsequent studies. Among the other 170 samples, 206 genetic variants were detected in a total of 86 patients (median 2, range 1-9). A total of 39 pathogenic (P) or probably pathogenic (PP) variants were found in 28 patients, whereas 59 uncertain significance (US) and 108 benign (B) variants were found in 44 and 54 patients, respectively. The distribution of genes in which P/PP/US variants were detected is shown in Figure 1. Patients with P /PP mutations had a statistically higher age compared to the remaining (50 vs. 64.8 years; p&amp;lt;0.001). The prevalence of males was higher in the group where P/PP mutations were detected (57.14% vs. 28.87%; p=0.004). No differences were found regarding cardiovascular comorbidity or symptomatology at diagnosis, but the P/PP group presented a higher frequency of thrombosis prior to diagnosis (28.57% vs. 5.64%; p=0.001). There were no differences in hemoglobin, leukocyte, or platelet counts at diagnosis according to the presence of P/PP variants. The presence of P/PP mutations was associated with a higher risk of progression to AL and a lower overall survival. A higher risk of thrombosis or progression to MF was not found (Figure 2). No differences were found in the risk of thrombosis, transformation, or overall survival between patients with or without the presence of US, PB or B variants. Conclusions The use of NGS technology is useful for the diagnosis and prognostication of TN-ET. The detection of P/PP mutations in patients diagnosed with TN-ET is associated with a higher risk of transformation to AL and lower overall survival, but not with higher risk of thrombosis or progression to MF. It is necessary to evaluate the individual risk of each of these mutations and the potential prognostic role of variants of US.

Cosmetovigilance for infrequent allergens in Spain using a national online registry: The example of allergic contact dermatitis caused by phenylethyl resorcinol.

Monitoring of adverse events induced by cosmetics performed by health authorities, known as cosmetovigilance, has been relied on the collection of case notifications. We aimed to show how a contact dermatitis registry can contribute to the cosmetovigilance of emerging allergens. We used the example of phenylethyl resorcinol, an infrequent allergen with only 6 previous cases reported in Europe and Japan since 2013. A systematic search in the Spanish Registry of Contact Dermatitis and Cutaneous Allergy (REIDAC) database was performed to identify patients with positive patch test to phenylethyl resorcinol or cosmetics that contains it between June 2018 and January 2023. We collected the main clinical features of these patients and compared them with those of patients recorded in the registry with similar epidemiological features. Thirteen patients with positive patch test to phenylethyl resorcinol were identified. All the patients were women with a mean age of 42 years (range 32-59) and their lesions were mainly in the face. Assessing the importance of infrequent allergens based solely on a case series is difficult. Multicentre registries facilitate the collection of cases and provide appropriate background information for new allergens.

Efficacy and safety of chemotherapy in young patients with advanced gastroesophageal adenocarcinoma: data from the Spanish AGAMENON-SEOM registry.

Gastroesophageal adenocarcinoma in young adults (GCYA) counts for 10-15% of diagnoses. Previous studies have mainly focused on surgical outcomes in patients with resectable tumors; however, systemic therapy for advanced GCYA remains under-evaluated. This study aims to assess the efficacy-related outcomes and safety of first-line chemotherapy (CT) in younger versus older patients with advanced gastroesophageal adenocarcinoma. Patients with advanced gastroesophageal adenocarcinoma from the AGAMENON-SEOM registry treated with first-line polychemotherapy between January 2008 and October 2022 were included. We compared clinicopathological features, therapies received, efficacy-related outcomes, and toxicity between individuals aged < and ≥ 45years. Out of 3386 patients, 263 (7.8%) were < 45years. Young patients exhibited a higher proportion of females affected, lower ECOG-PS ≥ 2, fewer comorbidities, and more aggressive disease-related features, such as higher proportion of diffuse subtype, signet-ring cells, plastic linitis, grade 3, peritoneal metastases and metastatic disease at diagnosis. They received more triple-agent combinations and underwent more surgeries in metastatic setting. No significant differences were observed between groups in overall response rate (53.1% vs. 52.3% in < and ≥ 45years, respectively, p = 0.579), progression-free survival (6.1 vs. 6.83months, p = 0.158) and overall survival (11.07 vs. 10.81months, p = 0.82), even after adjusting for potential confounding factors. Grade 3-4 adverse events were comparable in both groups, although toxicity leading to treatment discontinuation was more frequent in older patients. In the AGAMENON-SEOM registry, younger patients with GCYA exhibited more aggressive clinicopathological features, and despite receiving more aggressive treatments, similar efficacy outcomes and toxicity profiles were achieved compared to their older counterparts. In the AGAMENON-SEOM registry, GEAC in < 45years showed more aggressive clinicopathological features and, although treated with more intense first-line CT regimens, similar efficacy outcomes and toxicity were achieved compared to older patients.

Increase in Incidence Rates and Risk Factors for Multidrug Resistant Bacteria in Septic Children: A Nationwide Spanish Cohort Study (2013-2019).

The emergence of multidrug-resistant (MDR) bacteria in children is a growing concern, particularly among septic patients, given the need for first-right dosing. Our aim was to determine the incidence rates and factors associated with MDR-sepsis in the pediatric intensive care unit (PICU), using data from the Spanish ENVIN-HELICS PICU registry between 2013 and 2019. The rate of MDR bacteria among septic children ranged between 5.8 and 16.2% throughout this study period, with a significant increase since 2015 (p = 0.013). MDR-gram-negative bacteria (92%), particularly EBL-Enterobacterales (63.7%), were the most frequent causative microorganisms of MDR-sepsis. During this study period, sixteen MDR-sepsis (32.6%) corresponded to intrahospital infections, and 33 (67.4%) had community-onset sepsis, accounting for 10.5% of the overall community-onset sepsis. Independent risk factors associated with MDR-sepsis were antibiotics 48 h prior to PICU admission (OR 2.38) and PICU onset of sepsis (OR 2.58) in >1 year-old children, and previous malnourishment (OR 4.99) in <1 year-old children. Conclusions: There was an alarming increase in MDR among septic children in Spain, mainly by gram-negative (ESBL-Enterobacterales), mostly coming from the community setting. Malnourished infants and children on antibiotics 48 h prior to PICU are at increased risk and therefore require closer surveillance.

Description of clinical and genetic features of 122 patients included in the Spanish Pompe registry

Pompe disease is a rare genetic disorder with an estimated prevalence of 1:60.000. The two main phenotypes are Infantile Onset Pompe Disease (IOPD) and Late Onset Pompe Disease (LOPD). There is no published data from Spain regarding the existing number of cases, regional distribution, clinical features or, access and response to the treatment. We created a registry to collect all these data from patients with Pompe in Spain. Here, we report the data of the 122 patients registered including nine IOPD and 113 LOPD patients. There was a high variability in how the diagnosis was obtained and how the follow-up was performed among different centres. Seven IOPD patients were still alive being all treated with enzymatic replacement therapy (ERT) at last visit. Ninety four of the 113 LOPD patients had muscle weakness of which 81 were receiving ERT. We observed a progressive decline in the results of muscle function tests during follow-up. Overall, the Spanish Pompe Registry is a valuable resource for understanding the demographics, patient's journey and clinical characteristics of patients in Spain. Our data supports the development of agreed guidelines to ensure that the care provided to the patients is standardized across the country.

Veno-arterial extracorporeal membrane oxygenation as direct bridge to heart transplantation in a low and middle income country

Abstract Introduction The use of veno-arterial extracorporeal membrane oxygenation (VA ECMO) as a direct bridge to heart transplantation (BTT) is not common in adults worldwide. BTT with ECMO is associated with increased early/mid-term mortality compared with other interventions. In low- and middle-income countries (LMIC), where no other type of short-term mechanical circulatory support is available, its use is widespread and increasingly used as rescue therapy in patients with cardiogenic shock (CS) as a direct bridge to heart transplantation (HT). Objective To assess the outcomes of adult patients using VA ECMO as a direct bridge to heart transplantation in a LMIC and compare them with international registries. Methods We conducted a single-center study analyzing consecutive adult patients requiring VA-ECMO as BTT due to refractory CS or cardiac arrest (CA) in a cardiovascular center in Argentina between January 2014 and December 2022. Survival and adverse clinical events after VA-ECMO implantation were evaluated. Results Of 86 VA-ECMO, 22 (25.5%) were implanted as initial BTT strategy and 52.1% finally underwent HT. Mean age was 46 years (SD 12); 59% were male. ECMO was indicated in all cases for CS and the most common underlying condition was coronary artery disease (30%), followed by idiopathic dilated cardiomyopathy (15%). Patient outcomes are described in Figure 1. Overall in-hospital mortality for VA ECMO as BTT was 50%. Survival to discharge was 83% in those who achieved HT and 10% in those who did not, p&amp;lt;0.001. In those who did not achieve HT, the main cause of death was haemorrhagic complications (44%), followed by thrombotic complications (33%). The median duration of VA ECMO was 6 days (IQR 3-16). There were no differences in the number of days on ECMO between those who received a transplant and those who did not. In the Spanish registry (Barge Caballero et al 2018), in-hospital survival after HT was 66.7%, the United Network of Organ Sharing registry (Fukuhara et al 2018) estimated post-transplant survival at 73.1% ± 4.4%, and in the French national registry (Jasserson et al 2016), 1-year post-transplant survival was 70% in the VA ECMO group. Conclusions In adult patients with cardiogenic shock, VA-ECMO as a direct BTT allowed successful HT in half of the patients. HT provided a survival benefit in listed patients on VA-ECMO. VA-ECMO can be used to bridge critically ill candidates directly to HT in a setting where no other circulatory support is available, as a salvage strategy with acceptable mortality in a high-volume specialized center. We present a single center experience with results comparable to registries in Spain, France and the United States.

Applicability of the 3-Strata ESC/ERS risk model at baseline in pulmonary veno-occlusive disease

Abstract Introduction The risk of death or lung transplantation in Pulmonary Arterial Hypertension (PAH) is influenced by many factors. The recently published European Society of Cardiology/ European Respiratory Society (ESC/ERC) Guidelines for the study and management of PAH recommend the use of a multiparametric 3-strata model for risk stratification at diagnosis [1]. Heritable pulmonary veno-occlusive disease (PVOD) is an especially infrequent form of PAH caused by homozygous variants in the gene encoding the Eukaryotic Translation Initiation Factor 2 Alpha Kinase 4 (EIF2AK4). PVOD has a dramatically low long-term survival. There is no evidence confirming the applicability of the risk scores in PVOD. Our aim was to evaluate the usefulness of the 3-strata ESC/ERC score at diagnosis in patients with heritable PVOD. Methods We considered patients with the diagnosis of heritable PVOD included in the Spanish registry of PAH (REHAP) between 2011 and 2022. The diagnosis required a homozygous variant in EIF2AK4, and a diagnostic right heart catheterization (RHC). The other group was composed of patients with PAH and pathogenic or likely pathogenic variants in the gene BMPR2. The prognostic evaluation was done when these patients were included in the registry. All participants signed informed consent. Results In the 2011-2022 period up to 32 cases of PVOD in 23 unrelated families and 28 cases in 23 families were collected. 10 patients were excluded due to incomplete RHC at diagnosis. The baseline characteristics of the population can be seen in the Table. After a median follow-up of 16.9 months, up to 15 patients with PVOD needed lung transplantation (46.9%), and 6 patients died (18.7%). On the contrary, only 4 patients needed lung transplantation and one died in the BMPR2 group after a median follow-up of 97.1 months. Most of the included PVOD patients had an intermediate risk of mortality after the application of the 3-strata European model (62.5%), and only one case (3.1%) was categorized as high-risk. There was a non-significant tendency for patients with BMPR2 variants to have lower risk levels. The application of the 3-strata model at diagnosis in patients with PVOD demonstrated a good global prognostic capacity (C Index of 0.707). In our PVOD population, those patients at intermediate risk had a hazard ratio of 9.53 (2.15-42.17, p=0.003) when compared with patients at low risk. Similarly, those patients at high risk at diagnosis had a hazard ratio of 9.49 (0.86-104.69, p=0.066) when compared with patients at intermediate risk (Figure). Conclusions The application of the ESC/ERC three-strata risk tool in patients with PVOD demonstrates a good global prognostic capacity. Nevertheless, the risk of death or lung transplantation can be higher than predicted in this population, enhancing the need for an early evaluation for lung transplantation.Figure

Pulmonary arterial hypertension associated to toxic-oil syndrome. A long story short

Abstract Introduction Pulmonary arterial hypertension (PAH) is occasionally related to previous use of drugs or toxins. The toxic oil syndrome (TOS) is a model of drug-induced PAH caused by the prior use of denatured rapeseed oil. This rare condition caused an acute epidemic disease in Spain, including the development of pulmonary arterial hypertension, with a mortality rate of 82% from 1981 to 1987. Several cases have been discovered in the successive years until 2018. The clinical profile and outcome of those patients with PAH-TOS diagnosed since 1988 are unknown. Methods Historical cases of PAH-TOS since 1988 were collected. We analysed baseline characteristics, genetic testing, and the rates of lung transplantation or mortality in PAH-TOS, comparing these outcomes with incident idiopathic and heritable PAH cases (i/hPAH) from the Spanish Registry of Pulmonary Hypertension (REHAP). Results Thirty-nine patients with PAH-TOS between 1988 and 2018 were selected for this study. The median time between the toxic intake and the disease onset was 20.3 years (Interquartile range: 14.3 – 25.6). At least one patient per year was identified in that period, with a mean incidence of 1.63 cases/per year. Genetic testing was done in 21 patients, using a 37-gene Next Generation Sequencing panel, not finding any pathogenic or likely pathogenic variant. Importantly, in 3 out of 39 cases, the disease resolved (7.7%), while 4 cases needed lung transplantation. The 10-year mortality was 35.9%. Cases of PAH-TOS were compared with 200 incident patients with i/hPAH collected from 2003 onwards. PAH-TOS patients were significantly younger when compared with i/hPAH patients (p&amp;lt;0.0035). At baseline, patients with PAH-TOS had higher haemodynamically severity when compared with i/hPAH (mean pulmonary artery pressure of 65.0 mmHg Vs 53.5 mmHg, and pulmonary vascular resistance of 15.1 Vs 12.1 Wood Units, respectively; p=0.003, and p=0.02). In PAH-TOS the 5- and 10-year survival free of lung transplantation was 81.3%, and 52.7%, similar to the rates in the i/hPAH group (76.6%, and 59.2%, respectively; Log-rank test p=0.881. Figure). Conclusions The toxic oil syndrome is a unique model of drug-induced PAH, with new cases diagnosed several years after the toxic exposure. We did not find genetic variants in PAH-SOT patients. As described in other drug-induced cases of PAH, some patients experience a resolution of the disease over time. The very long-term survival of these patients is similar to that of patients with idiopathic or heritable pulmonary arterial hypertension.Figure

Caplacizumab Treatment in Elderly Patients with iTTP: Updated Experience from the Spanish TTP Registry

Introduction Immune thrombotic thrombocytopenic purpura (iTPP) is a rare microangiopathic thrombotic disorder with severely reduced levels of ADAMTS13 due to the presence of autoantibodies. It has classically been treated with plasma exchange (PEx) therapy and steroids, with the introduction of novel therapies in recent years such as rituximab and caplacizumab. Data concerning caplacizumabs' efficacy and safety profile in elderly patients is scarce, as iTTP is rarely presented in this population. We aimed to compare response to treatment with caplacizumab as well as safety, and tolerability in patients ≥60 years compared to those aged &amp;lt;60. Mat&amp;Met Data were obtained from the Spanish TTP Registry. Patients were eligible if the diagnosis of iTTP was confirmed by ADAMTS13 activity &amp;lt;20%, presence of anti-ADAMTS13 autoantibodies, and had received caplacizumab at any time during the acute episode. Response criteria were defined following the revised criteria published by the International Working Group (Cucker et al. 2021). Statistical analysis was performed using EzR software, based on R commander (R Commander Version 2.6-1). Results A total of 104 patients from 39 centers, diagnosed from November 2018 to April 2023 were included (93 first episodes and 11 relapses). Twenty-nine patients (28%) were ≥60 years (Group 1) and 75 were &amp;lt;60 years (Group 2). Main characteristics of these patients are detailed in Table 1. Front-line treatment consisted of PEx and steroids in every patient, while rituximab was administered in 84% of patients. Caplacizumab was administered at a median (range) of 3 days (0-26) after diagnosis in patients &amp;lt;60 years and 5 days (0-23) in patients ≥60 years ( P= n.s.). Caplacizumab was administered as front-line therapy (n=21), after an exacerbation (n=5) or due to refractoriness (n=3) in the cohort of patients ≥60 years, and this occurred in a similar proportion in patients &amp;lt;60 years (58, 12 and 5, respectively; P= n.s.). The duration of treatment with caplacizumab was 34 (range, 1-77) and 35 days (range, 1-188) in patients ≥60 and &amp;lt;60 years, respectively ( P= n.s.). Final outcomes are detailed in Table 2. One patient ≥60 years died due to refractory disease despite starting caplacizumab during the first 24h after diagnosis Three of the 21 patients receiving caplacizumab as front-line treatment in Group 2 suffered an exacerbation (two due to treatment discontinuation and one while receiving caplacizumab). In 5/29 patients in Group 2, therapy with caplacizumab was delayed due to initial hemorrhagic symptoms (n=3) or ongoing anticoagulation or antiaggregation (one each). Bleeding motivating transient caplacizumab discontinuation occurred in five patients (17%) (subarachnoideal hemorrhage [one patient], hematuria, and pericatheter hemorrhage [one patient], abdominal hematoma, gastrointestinal, and gingival hemorrhage [one each]), and this was more frequent than in younger patients (one case of rectal bleeding [1.3%], P= .006). No other side-effects were reported. Conclusion Association of caplacizumab to PEx and immunosuppressive therapy improves outcomes in elderly patients with iTTP, although relevant bleeding complications might be higher than in younger patients.

Impact of Patient Selection and Management over Different Time Periods on the Outcome of Patients with Large B-Cell Lymphoma Receiving Chimeric Antigen Receptor T-Cell Therapy

Introduction. Autologous chimeric antigen receptor (CAR) T-cell therapy targeting CD19 is an effective treatment for relapsed or refractory large B-cell lymphoma (LBCL). Real-world studies have reported improved outcomes in terms of safety and efficacy in comparison with pivotal trials. These differences have been associated to a learning curve in patient selection and adverse event control, but this hypothesis has not been proven. The aim of this study was to analyze patient selection and CAR T-cell management across different time periods and assess its impact on treatment outcomes Methods. This retrospective analysis included all consecutive LBCL patients receiving CAR-T cell therapy (axicabtagene-ciloleucel [axi-cel] and tisagenlecleucel) in the third line setting from approval in 2019 to 2023 and reported in the Spanish Registry. Patients were categorized in 3 consecutive time periods of 18 months each according to infusion date. Baseline characteristics, manufacturing times and production failures as well as efficacy and safety outcomes were compared across periods. An additional safety and efficacy analysis was conducted in patients receiving axi-cel. Results. The study included 458 patients: 117 (26%), 194 (42%) and 147 (32%) in the early (EP) (January 2019-June 2020), intermediate (IP) (July 2020-December 2021) and recent period (RP) (January 2022-June 2023), respectively. In terms of patient profile, baseline characteristics evolved overtime as patients in the RP had received less number of prior therapies, had less primary refractory disease, less bulky disease and had lower LDH at lymphodepletion. On the contrary, the RP had more patients with ECOG performance status ³2 and higher comorbidity burden. Regarding the product, the use of axi-cel increased overtime, from 45% in the EP to 83% in the RP (Table). The time from apheresis to infusion improved overtime, moving from 48 days in the EP to 38 days in the RP. Manufacturing failures (5%) and use of bridging therapy (81%) remained stable overtime. Regarding efficacy, overall (complete) response rates improved overtime (from 66% [25%] in the EP to 78% [52%] in the RP [p&amp;lt;0.001], respectively). Median PFS and OS for the whole cohort were 3.9 months (95% CI 3.23-5.83) and 18.5 months (95% CI 13.53 - 27.67) without differences across periods. In terms of toxicity, patients in the RP had more grade &amp;gt; or = 3 CRS and ICANS, received more tocilizumab and corticosteroids and required more ICU admission compared with the EP. These results were driven by the higher use of axi-cel in the RP. When focusing exclusively on axi-cel patients (n=301), the CR rate also improved overtime (32% in the EP; 37% in the IP and 55% in the RP, p=0.016) (Figure) while median PFS (6.63 months, 95%CI 3.90 - 11.43) and OS (25.73 months, 95%CI 18.57 - NA) remained stable. In the multivariable analysis, ECOG PS &amp;gt; 1 (HR 2.68, 95% CI 1.35-5.09, p=0.005) and LDH ³ 500 UI/L (HR 1.54, 95% CI 1.02-2.31, p=0.04) but not treatment period were associated with a shorter PFS. In terms of toxicity, the time to CRS onset (median of 3 vs. 1 days, p=0.001) and ICANS (median of 8 vs. 6 days, p=0.06) was later in the EP compared with the RP. The incidence of grade &amp;gt; or = 3 CRS and ICANS (ranging from 10% to 7% and 36% to 41%, respectively), the use of tocilizumab, corticosteroids, and anakinra as well as ICU admission rate and 12-month non-relapse mortality (2% vs 5%) remained stable across periods. Conclusion. The criteria for selecting patients for CAR T-cell therapy have evolved overtime towards a less aggressive disease profile and allowing less fit patients for therapy in recent times. Patients treated in the RP were more likely to respond to these therapies but this did not translate into prolonged survival or an improved safety profile.

Spanish pacemaker registry. 20th official report of the Heart Rhythm Association of the Spanish Society of Cardiology (2022)

Introduction and objectivesThis article reports the cardiac pacing activity performed in 2022, including the total number of implants, adherence to remote monitoring, demographic and clinical factors, and the characteristics of the implanted devices. MethodsThe information sources were the CardioDispositivos online platform, the European pacemaker patient identification card, and data provided by the manufacturers. ResultsThe rates of conventional pacemakers and low-energy resynchronizers were 866 and 34 units per million population, respectively. A total of 815 leadless pacemakers were implanted. In all, 16426 procedures performed in 82 hospitals were reported (9407 through CardioDispositivos), representing 40% of the activity. The mean age was 78.6 years, with a predominance of men (60.3%). The most frequent disorder was atrioventricular block, and 14.5% of the patients had atrial fibrillation. There was a predominance of the DDD/R pacing mode (55.6%), and pacing mode was influenced by age, such that more than one-third of patients older than 80 years in sinus rhythm received single-chamber ventricular pacing. The remote monitoring program included 35% of conventional pacemakers and 55% of low-energy resynchronization pacemakers. ConclusionsThe number of conventional pacemakers increased by 5.6%, low-energy resynchronizers by 16%, and leadless pacemakers by 25%. Adherence to remote monitoring was stable. The number of procedures included in CardioDispositivos increased by 11%, although the sample volume decreased. In the coming years, the widespread use of the platform will likely lead to a high-quality registry.