Linfoma de Hodgkin

Thomas Hodgkin described Hodgkin�s lymphoma in the first half of the XIX century. The disease was still invariably lethal more than a century after his original description. Remarkable progress in the understanding of the pathophysiology of Hodgkin�s lymphoma and dramatic therapeutic developments occurred over the past fifty years. Nowadays between 85 and 95% of patients can be cured. There are four major landmarks on this successful path. First, the understanding of Reed-Stenberg�s cell biology. During the 1960s the true neoplastic character of this cell was established. During the 1990s it was confirmed that Reed-Stenberg cell originated from the Blymphocites of the germinal center. Secondly, the advent of accurate staging methods and the development of prognostic factors. From the 1970 the advent of computed tomography replaces laparotomy and lympography for staging, resulting in simpler yet more accurate staging. Recently, positron emission tomograpghy allows further refinement in staging. In 1971 the Ann Arbor staging system was developed and is still in use today. The International Progonostic Index developed in 1998 allowed further delineation of therapeutic subgroups. Thirdly, improvements in radiotherapy. The advent of mega-voltage devices and broad-field techniques designed by Kaplan open up the road to cure. And finally, multicenter cooperative randomized trials effectively favor application of polychemotherapy and combined treatment to patients with Hodgkin�s lymphoma. During the most recent years, studies aiming at improved cure rates and disease control together with diminished side effects are under way. New drugs such as Brentuximab Vedotin are promising.En la primera mitad del siglo XIX Thomas Hodgkin describe el linfoma de Hodgkin. Sin embargo, más de un siglo después la enfermedad seguía siendo indefectiblemente mortal. En los últimos 50 años hemos asistido a avances espectaculares en la comprensión de la patogenia de la enfermedad y a logros terapéuticos extraordinarios.Actualmente entre un 85 y 95% de los pacientes pueden obtener la curación. En este exitoso camino pueden destacarse cuatro hitos: Primero, el conocimiento de la biología de la célula de Reed-Stenberg. Tras varias teorías sobre la etiopatogenia de la enfermedad, en los años 60 se establece definitivamente el carácter neoplásico de esta célula y en la última decáda del siglo XX se confirma su origen en linfocitos B del centro germinal. Segundo, el desarrollo de métodos adecuados para el estadiaje y el establecimiento de factores pronósticos. A partir de los años 70 el desarrollo de la tomografía axial computarizada permite perfeccionar y simplificar el estadiaje de los enfermos, dejando obsoletas la laparotomía exploradora y la linfografía. En los últimos años la PET está refinando dicho estadiaje. En 1971 se establece asimismo la clasificación por estadios de Ann Arbor que continúa hoy vigente y en 1998 se publica el Índice pronóstico internacional, separándose así claros grupos terapéuticos.Tercero, el perfeccionamiento de las técnicas de radioterapia. La aparición de los dispositivos de megavoltaje y las técnicas de campo extenso diseñadas por Kaplan inician el camino de la curación. Cuarto, el desarrollo de los ensayos clínicos de los grupos cooperativos consigue trasladar los logros de la poliquimioterapia y del tratamiento combinado a los pacientes con linfoma de Hodgkin. En los últimos años se trabaja en mejorar los porcentajes de curación y de control de la enfermedad conjugándolo con una disminución de los efectos secundarios. Nuevos fármacos como Brentuximab Vedotin prometen un final feliz

Survival of wild adults of Ceratitis capitata (Wiedemann) under natural winter conditions in north east Spain

The overwintering of the Mediterranean fruit fly (medfly), Ceratitis capitata (Wiedemann) at the northern limits of its geographic distribution is not yet well known. With the aim of estimating the survival rate of medfly adults in northeast Spain under natural winter conditions, a two-winter-season trial was carried out. A control was carried out in a climatic chamber at 25°C. The results showed that medfly adults were unable to survive the entire winter season in the Girona area. Climatic conditions, including the daily minimum temperature, daily maximum temperature and the high rainfall, appeared to be involved in adult mortality in winter

ADHD Symptomatology, Executive Function and Cognitive Performance Differences between Family Foster Care and Control Group in ADHD-Diagnosed Children

Children in foster care have a high prevalence of attention deficit and hyperactivity disorder (ADHD) diagnosis, together with other difficulties in inattentive/hyperactive behaviors, executive and cognitive processes. Early exposure to adversity is a risk factor for developing ADHD via neurodevelopmental pathways. The goal of this research is (a) to study the cognitive and executive performance and inattentive/hyperactive behavior of ADHD-diagnosed children living in foster families in Spain, and (b) to analyze the role of placement variables in their performance. The sample was composed of 102 ADHD-diagnosed children aged 6- to 12-years-old, divided into two groups: 59 children living with non-relative foster families and 43 children not involved with protection services. Children’s executive function–inhibition, working memory, flexibility, attention, intellectual capacity, verbal comprehension, perceptive reasoning, working memory and processing speed were assessed using objective testing measures. At the same time, parents and teachers reported on children’s inattentive, hyperactive and impulsive behaviors. Children in foster care obtained lower scores in the general ability index than the control group after controlling the age at assessment. However, no differences were found in executive processes. Regarding placement factors, children with shorter exposure to adversities in their birth families and more time in foster care showed better executive performance. Professionals should consider the placement history of children in foster care and its influence on their symptomatology and cognitive capacities

Polymorphisms in receptors involved in opsonic and nonopsonic phagocytosis, and correlation with risk of infection in oncohematology patients

Producción CientíficaHigh-risk hematological malignancies are a privileged setting for infection by opportunistic microbes, with invasive mycosis being one of the most serious complications. Recently, genetic background has emerged as an unanticipated risk factor. For this reason, polymorphisms for genes encoding archetypal receptors involved in the opsonic and nonopsonic clearance of microbes, pentraxin-3 (PTX3) and Dectin-1, respectively, were studied and correlated with the risk of infection. Fungal, bacterial, and viral infections were registered for a group of 198 patients with highrisk hematological malignancies. Polymorphisms for the pentraxin-3 gene (PTX3) showed a significant association with the risk of fungal infection by Candida spp. and, especially, by Aspergillus spp. This link remained even for patients undergoing antifungal prophylaxis, thus demonstrating the clinical relevance of PTX3 in the defense against fungi. CLEC7A polymorphisms did not show any definite correlation with the risk of invasive mycosis, nor did they influence the expression of Dectin-1 isoforms generated by alternative splicing. The PTX3 mRNA expression level was significantly lower in samples from healthy volunteers who showed these polymorphisms, although no differences were observed in the extents of induction elicited by bacterial lipopolysaccharide and heat-killed Candida albicans, thus suggesting that the expression of PTX3 at the start of infection may influence the clinical outcome. PTX3 mRNA expression can be a good biomarker to establish proper antifungal prophylaxis in immunodepressed patients

Evaluation of cytokines as robust diagnostic biomarkers for COVID-19 detection

Producción CientíficaAntigen tests or polymerase chain reaction (PCR) amplification are currently COVID-19 diagnostic tools. However, developing complementary diagnosis tools is mandatory. Thus, we performed a plasma cytokine array in COVID-19 patients to identify novel diagnostic biomarkers. A discovery–validation study in two independent prospective cohorts was performed. The discovery cohort included 136 COVID-19 and non-COVID-19 patients recruited consecutively from 24 March to 11 April 2020. Forty-five cytokines’ quantification by the MAGPIX system (Luminex Corp., Austin, TX, USA) was performed in plasma samples. The validation cohort included 117 patients recruited consecutively from 15 to 25 April 2020 for validating results by ELISA. COVID-19 patients showed different levels of multiple cytokines compared to non-COVID-19 patients. A single chemokine, IP-10, accurately identified COVID-19 patients who required hospital admission (AUC: 0.962; 95%CI (0.933–0.992); p < 0.001)). The results were validated in an independent cohort by multivariable analysis (OR: 25.573; 95%CI (8.127–80.469); p < 0.001) and AUROC (AUC: 0.900; 95%CI (0.846–0.954); p < 0.001). Moreover, showing IP-10 plasma levels over 173.35 pg/mL identified COVID-19 with higher sensitivity (86.20%) than the first SARS-CoV-2 PCR. Our discover–validation study identified IP-10 as a robust biomarker in clinical practice for COVID-19 diagnosis at hospital. Therefore, IP-10 could be used as a complementary tool in clinical practice, especially in emergency departments.Instituto de Salud Carlos III (grant COV20/00491)Consejo Superior de Investigaciones científicas (grant CSIC-COV19-016/202020E155)Junta de Castilla y León (project COVID 07.04.467B04.74011.0)IBGM excellence programme (grant CLU-2029-02

Predictive modeling of poor outcome in severe COVID-19: A single-center observational study based on clinical, cytokine and laboratory profiles

Producción CientíficaPneumonia is the main cause of hospital admission in COVID-19 patients. We aimed to perform an extensive characterization of clinical, laboratory, and cytokine profiles in order to identify poor outcomes in COVID-19 patients. Methods: A prospective and consecutive study involving 108 COVID-19 patients was conducted between March and April 2020 at Hospital Clínico Universitario de Valladolid (Spain). Plasma samples from each patient were collected after emergency room admission. Forty-five serum cytokines were measured in duplicate, and clinical data were analyzed using SPPS version 25.0. Results: A multivariate predictive model showed high hepatocyte growth factor (HGF) plasma levels as the only cytokine related to intubation or death risk at hospital admission (OR = 7.38, 95%CI—(1.28–42.4), p = 0.025). There were no comorbidities included in the model except for the ABO blood group, in which the O blood group was associated with a 14-fold lower risk of a poor outcome. Other clinical variables were also included in the predictive model. The predictive model was internally validated by the receiver operating characteristic (ROC) curve with an area under the curve (AUC) of 0.94, a sensitivity of 91.7% and a specificity of 95%. The use of a bootstrapping method confirmed these results. Conclusions: A simple, robust, and quick predictive model, based on the ABO blood group, four common laboratory values, and one specific cytokine (HGF), could be used in order to predict poor outcomes in COVID-19 patients.Instituto de Salud Carlos III - ( Proyecto COV20/00491)Consejeria de Educación de Castilla y León - (Proyecto VA256P20)Junta de Castilla y León y Fondo Europeo de Desarrollo Regional (FEDER) - (Proyecto EDU/1100/2017

Can the Cytokine Profile According to ABO Blood Groups Be Related to Worse Outcome in COVID-19 Patients? Yes, They Can

Producción CientíficaSevere status of coronavirus disease 2019 (COVID-19) is extremely associated to cytokine release. Moreover, it has been suggested that blood group is also associated with the prevalence and severity of this disease. However, the relationship between the cytokine profile and blood group remains unclear in COVID-19 patients. In this sense, we prospectively recruited 108 COVID-19 patients between March and April 2020 and divided according to ABO blood group. For the analysis of 45 cytokines, plasma samples were collected in the time of admission to hospital ward or intensive care unit and at the sixth day after hospital admission. The results show that there was a risk of more than two times lower of mechanical ventilation or death in patients with blood group O (log rank: p = 0.042). At first time, all statistically significant cytokine levels, except from hepatocyte growth factor, were higher in O blood group patients meanwhile the second time showed a significant drop, between 20% and 40%. In contrast, A/B/AB group presented a maintenance of cytokine levels during time. Hepatocyte growth factor showed a significant association with intubation or mortality risk in non-O blood group patients (OR: 4.229, 95% CI (2.064–8.665), p < 0.001) and also was the only one bad prognosis biomarker in O blood group patients (OR: 8.852, 95% CI (1.540–50.878), p = 0.015). Therefore, higher cytokine levels in O blood group are associated with a better outcome than A/B/AB group in COVID-19 patients.Instituto de Salud Carlos III (grant COV20/00491)Junta de Castilla y León (grant 18IGOF

Results of an early access treatment protocol of daratumumab monotherapy in spanish patients with relapsed or refractory multiple myeloma

Daratumumab is a human CD38-targeted monoclonal antibody approved as monotherapy for heavily pretreated relapsed and refractory multiple myeloma. We report findings for the Spanish cohort of an open-label treatment protocol that provided early access to daratumumab monotherapy and collected safety and patient-reported outcomes data for patients with relapsed or refractory multiple myeloma. At 15 centers across Spain, intravenous daratumumab (16mg/kg) was administered to 73 patients who had ≥3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who were double refractory to both. The median duration of daratumumab treatment was 3.3 (range: 0.03–13.17) months, with a median number of 12 (range: 1–25) infusions. Grade 3/4 treatment-emergent adverse events were reported in 74% of patients and included lymphopenia (28.8%), thrombocytopenia (27.4%), neutropenia (21.9%), leukopenia (19.2%), and anemia (15.1%). Common (>5%) serious treatmentemergent adverse events included respiratory tract infection (9.6%), general physical health deterioration (6.8%), and back pain (5.5%). Infusion-related reactions occurred in 45% of patients. The median change from baseline in all domains of the EQ-5D-5L and EORTC QLQ-C30 was mostly 0. A total of 18 (24.7%) patients achieved a partial response or better, with 10 (13.7%) patients achieving a very good partial response or better. Median progression-free survival was 3.98 months. The results of this early access treatment protocol are consistent with previously reported trials of daratumumab monotherapy and confirm its safety and antitumoral efficacy in Spanish patients with heavily treated relapsed or refractory multiple myeloma

Use of eltrombopag for patients 65 years old or older with immune thrombocytopenia

Background Eltrombopag is useful for immune thrombocytopenia (ITP). However, results of clinical trials may not accurately mirror clinical practice reality. Here we evaluated eltrombopag for primary and secondary ITP in our ≥65‐year‐old population. Methods A total of 106 primary ITP patients (16 with newly diagnosed ITP, 16 with persistent ITP, and 74 with chronic ITP) and 39 secondary ITP patients (20 with ITP secondary to immune disorders, 7 with ITP secondary to infectious diseases, and 12 with ITP secondary to lymphoproliferative disorders [LPD]) were retrospectively evaluated. Results Median age of our cohort was 76 (interquartile range, IQR, 70‐81) years. 75.9% of patients yielded a platelet response including 66.2% complete responders. Median time to platelet response was 14 (IQR, 8‐21) days. Median time on response was 320 (IQR, 147‐526) days. Sixty‐three adverse events (AEs), mainly grade 1‐2, occurred. The most common were hepatobiliary laboratory abnormalities (HBLAs) and headaches. One transient ischemic attack in a newly diagnosed ITP and two self‐limited pulmonary embolisms in secondary ITP were the only thrombotic events observed. Conclusion Eltrombopag showed efficacy and safety in ITP patients aged ≥65 years with primary and secondary ITP. However, efficacy results in LPD‐ITP were poor. A relatively high number of deaths were observed

Chemotherapy or allogeneic transplantation in high-risk Philadelphia chromosome–negative adult lymphoblastic leukemia

The need for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome–negative (Ph−) acute lymphoblastic leukemia (ALL) with high-risk (HR) features and adequate measurable residual disease (MRD) clearance remains unclear. The aim of the ALL-HR-11 trial was to evaluate the outcomes of HR Ph− adult ALL patients following chemotherapy or allo-HSCT administered based on end-induction and consolidation MRD levels. Patients aged 15 to 60 years with HR-ALL in complete response (CR) and MRD levels (centrally assessed by 8-color flow cytometry) <0.1% after induction and <0.01% after early consolidation were assigned to receive delayed consolidation and maintenance therapy up to 2 years in CR. The remaining patients were allocated to allo-HSCT. CR was attained in 315/348 patients (91%), with MRD <0.1% after induction in 220/289 patients (76%). By intention-to-treat, 218 patients were assigned to chemotherapy and 106 to allo-HSCT. The 5-year (±95% confidence interval) cumulative incidence of relapse (CIR), overall survival (OS), and event-free survival probabilities for the whole series were 43% ± 7%, 49% ± 7%, and 40% ± 6%, respectively, with CIR and OS rates of 45% ± 8% and 59% ± 9% for patients assigned to chemotherapy and of 40% ± 12% and 38% ± 11% for those assigned to allo-HSCT, respectively. Our results show that avoiding allo-HSCT does not hamper the outcomes of HR Ph− adult ALL patients up to 60 years with adequate MRD response after induction and consolidation. Better postremission alternative therapies are especially needed for patients with poor MRD clearance