Expert-based collaborative analysis of the situation and prospects of biomarker test implementation in oncology in Spain / Análisis colaborativo de expertos de la situación y perspectivas de la implementación de pruebas de biomarcadores en oncología en España

Purpose: Biomarkers as screening for precision medicine is a fundamental step. The purpose of this article is twofold. First, to highlight the existing barriers in the implementation of Precision Medicine in Spain, with a special emphasis on barriers in access to the determination of biomarkers. Second, to provide a Roadmap that can help implement Precision Medicine equitably at the national level and optimize the use of biomarkers. Methods: A systematic review of literature (SRL) and a focus group (FG) with multidisciplinary experts has been carried out in 2023. Participants were contacted individually, and discourse analysis was processed anonymously. Results: We carried out a quantitative (SRL) and a qualitative approach (FG). The discourse analysis and roadmap were sent individually to each expert for approval. Conclusions: The potential of Precision Medicine has not been fulfilled in Spain. While several regional initiatives are in place, a national plan or strategy around Precision Medicine and use of biomarkers is lacking. In a general context of rapid progress at a global and European level, including the 2021 Europe’s Beating Cancer Plan, it is time to define and implement a National Plan to make the promise come true. While some comparable countries within Europe – such as the UK or France – are mature enough to adopt such strategies, in Spain there is still a long way to go. We consider that the different strands of work outlined in the Roadmap can be used as basis for such purpose.(AU)

Expert-based collaborative analysis of the situation and prospects of biomarker test implementation in oncology in Spain.

PURPOSE: Biomarkers as screening for precision medicine is a fundamental step. The purpose of this article is twofold. First, to highlight the existing barriers in the implementation of Precision Medicine in Spain, with a special emphasis on barriers in access to the determination of biomarkers. Second, to provide a Roadmap that can help implement Precision Medicine equitably at the national level and optimize the use of biomarkers. METHODS: A systematic review of literature (SRL) and a focus group (FG) with multidisciplinary experts has been carried out in 2023. Participants were contacted individually, and discourse analysis was processed anonymously. RESULTS: We carried out a quantitative (SRL) and a qualitative approach (FG). The discourse analysis and roadmap were sent individually to each expert for approval. CONCLUSIONS: The potential of Precision Medicine has not been fulfilled in Spain. While several regional initiatives are in place, a national plan or strategy around Precision Medicine and use of biomarkers is lacking. In a general context of rapid progress at a global and European level, including the 2021 Europe's Beating Cancer Plan, it is time to define and implement a National Plan to make the promise come true. While some comparable countries within Europe - such as the UK or France - are mature enough to adopt such strategies, in Spain there is still a long way to go. We consider that the different strands of work outlined in the Roadmap can be used as basis for such purpose.

Evaluation of antibody-based preventive alternatives for respiratory syncytial virus: a novel multi-criteria decision analysis framework and assessment of nirsevimab in Spain.

BACKGROUND: Respiratory syncytial virus (RSV) is a highly infectious disease that poses a significant clinical and medical burden, as well as social disruption and economic costs, recognized by the World Health Organization as a public health issue. After several failed attempts to find preventive candidates (compounds, products, including vaccines), new alternatives might be available, one being nirsevimab, the first and only option approved for RSV prevention in neonates and infants during their first RSV season. The objective of this study was to develop a novel multi-criteria decision analysis (MCDA) framework for RSV antibody-based preventive alternatives and to use it to assess the value of nirsevimab vs. placebo as a systematic immunization approach to prevent RSV in neonates and infants during their first RSV season in Spain. METHODS: Based on a pre-established model called Vaccinex, an ad-hoc MCDA framework was created to reflect relevant attributes for the assessment of current and future antibody-based preventive measures for RSV. The estimated value of nirsevimab was obtained by means of an additive linear model combining weights and scores assigned by a multidisciplinary committee of 9 experts. A retest and three sensitivity analyses were conducted. RESULTS: Nirsevimab was evaluated through a novel framework with 26 criteria by the committee as a measure that adds value (positive final estimated value: 0.56 ± 0.11) to the current RSV scenario in Spain, by providing a high efficacy for prevention of neonates and infants. In addition, its implementation might generate cost savings in hospitalizations and to the healthcare system and increase the level of public health awareness among the general population, while reducing health inequities. CONCLUSIONS: Under a methodology with increasing use in the health field, nirsevimab has been evaluated as a measure which adds value for RSV prevention in neonates and infants during their first RSV season in Spain.

A strategic reflection for the management and implementation of CAR-T therapy in Spain: an expert consensus paper

CAR-T cell therapy represents a therapeutic revolution in the prognosis and treatment of patients with certain types of hematological cancer. However, they also pose new challenges in the healthcare, regulatory and financial fields. The aim of the RET-A project was to undertake a strategic reflection on the management of CAR-T therapies within the Spanish National Health System, to agree on recommendations that will help to better deal with the new context introduced by these cell therapies in the present and in the future. This think tank involved 40 key agents and opinion leaders. The experts identified three great challenges for implementing advanced therapies in Spain: therapeutic individualisation, with a multidisciplinary approach; acceleration of access times, by minimizing bureaucracy; and increase in the number of centers qualified to manage the CAR-T therapies in the NHS. The experts agreed on the ideal criteria for designating those qualified centers. They also agreed on a comprehensive CAR-T care pathway with the timings and roles which would ideally be involved in each part of the process.

Use of Patent Information to Characterize Trends in the Therapeutic Applications of Extracellular Vesicles Derived from Mesenchymal Stem Cells (MSC-EVs).

Extracellular vesicles derived from mesenchymal stromal cells (MSC-EVs) are gaining interest for medical purposes. The promising therapeutic effects exhibited in both preclinical and clinical studies have suggested that they may become an alternative for certain applications to cell-based therapies, which are subjected to stricter regulations. The commercial exploitation of these candidates requires a proper patent strategy from both the industry and public research organizations. Here, we performed a global patent literature analysis to identify key players and therapeutic applications in the field. Our results showed an increasing rate of patent publications since 2009, with Asia (specifically China) leading the patenting activity. The therapeutic use of MSC-EVs within patent literature covers a wide range of diseases, in which "Dermal and Wounds," "Neurology" and "Cardiovascular" are the main therapeutic areas. Moreover, most of these patents include "productby- process" claims, since the therapeutic effects of MSC-EVs could be influenced by their manufacturing process. Our results followed scientific and clinical literature trends.

Cost of illness of invasive meningococcal disease caused by serogroup B Neisseria meningitidis in Spain.

INTRODUCTION: Invasive meningococcal disease (IMD) is a severe infectious disease, mainly affecting children under 5 years, associated with long-term physical, neurological and psychological sequelae. In Spain, most IMD cases are caused by meningococcal serogroup B (MenB). This study estimates its economic burden from a societal perspective in Spain. METHODS: A previously published bottom-up, model-based incidence costing approach by Scholz et al. (2019) to estimate the economic burden of MenB in Germany was adapted to the Spanish setting. Diagnosis and age-related costs for a hypothetical Spanish cohort were calculated over a lifetime horizon. Official Spanish databases, literature and expert opinion were used as data sources. The costs were updated to 2019 prices, and a 3% discount rate was applied. Direct costs related to the acute IMD phase, long-term sequelae, rehabilitation and public health response were considered. Indirect costs included productivity losses and premature mortality and were calculated using the human-capital approach (HCA) and friction-cost approach (FCA). Deterministic and probabilistic sensitivity analyses were also performed. RESULT: At base-case, the total cost for a cohort of 142 patients (2017-2018 period) was €4.74 million (€33,484/case) using the FCA and €13.14 million (€92,768/case) using the HCA. Direct costs amounted to €4.65 million (€32,765/case). Sequelae costs represented 62.46% of the total cost using the FCA and 77.63% using the HCA. Deterministic sensitivity analysis showed that variation of ± 20% in the input parameter values (population, epidemiology, productivity, costs) had the greatest influence on the base-case results, and the probabilistic sensitivity analysis showed the probability of fitting base-case estimates was > 99%, both for FCA and HCA. DISCUSSION: MenB IMD is an uncommon but severe disease, with a high economic burden for Spanish society. The elevated costs per IMD case reflect its severity in each patient suffering this disease, especially due to the development of sequelae.

Strontium-Modified Scaffolds Based on Mesoporous Bioactive Glasses/Polyvinyl Alcohol Composites for Bone Regeneration.

In the search of a new biomaterial for the treatment of bone defects resulting from traumatic events, an osteoporosis scenario with bone fractures, tumor removal, congenital pathologies or implant revisions for infection, we developed 3D scaffolds based on mesoporous bioactive glasses (MBGs) (85-x)SiO2-5P2O5-10CaO-xSrO (x = 0, 2.5 and 5 mol.%). The scaffolds with meso-macroporosity were fabricated by pouring a suspension of MBG powders in polyvinyl alcohol (PVA) into a negative template of polylactic acid (PLA), followed by removal of the template by extraction at low temperature. SrO-containing MBGs exhibited excellent properties for bone substitution including ordered mesoporous structure, high textural properties, quick in vitro bioactive response in simulated body fluid (SBF) and the ability of releasing concentrations of strontium ions able to stimulate expression of early markers of osteoblastic differentiation. Moreover, the direct contact of MC3T3-E1 pre-osteoblastic cells with the scaffolds confirmed the cytocompatibility of the three compositions investigated. Nevertheless, the scaffold containing 2.5% of SrO induced the best cellular proliferation showing the potential of this scaffold as a candidate to be further investigated in vitro and in vivo, aiming to be clinically used for bone regeneration applications in non-load bearing sites.

Diseño y validación de la escala pronóstica cubana PREDICMED para estratificar el riesgo de mediastinitis postoperatoria / Design and validation of the Cuban prognostic scale PREDICMED to stratify the risk of postoperative mediastinitis

RESUMEN Introducción: La predicción de fenómenos en las ciencias médicas mediante escalas pronósticas constituye una herramienta valiosa en la actualidad y deben incluirse en el proceso de toma de decisiones. Pronosticar la mediastinitis postoperatoria permite disponer de recursos para su prevención. Objetivo: Construir una escala pronóstica para estratificar el riesgo de padecer mediastinitis postoperatoria. Método: Se realizó un estudio de casos y controles para los factores de riesgo de mediastinitis postoperatoria en el Cardiocentro Ernesto Guevara de Santa Clara, Cuba. Luego de la regresión logística se obtuvo el modelo y, a partir de este, se incluyeron y ponderaron los predictores para obtener la escala cubana pronóstica de mediastinitis postoperatoria: PREDICMED, que se validó por diversos métodos. Resultados: Esta escala se obtuvo con seis predictores y dos estratos de riesgo. Se analizó su rendimiento mediante ajuste, calibración y determinación de su poder discriminante, con buenos resultados. Se realizó validación interna por el método de división de datos y se comparó su capacidad en ambos subconjuntos (desarrollo y validación) sin diferencias. Se probó su buena validez de constructo, al no existir diferencias entre las probabilidades predichas y las observadas. También se analizó su validez de contenido mediante expertos. Por último, se determinó su validez de criterio al comparar con otra escala similar (MEDSCORE). PREDICMED presentó muy buena capacidad discriminatoria (área bajo la curva 0,962) y elevados valores de sensibilidad (84,62%) y especificidad (92,31%). Conclusiones: La escala pronóstica cubana PREDICMED, para estratificar el riesgo de mediastinitis postoperatoria, mostró buenos parámetros de validación y logró estratificar el riesgo en no alto y alto.

ABSTRACT Introduction: Phenomena prediction through prognostic scales is a valuable tool in medical sciences nowadays and it should be included in the decision-making process. Predicting postoperative mediastinitis allows to count on resources for its prevention. Objective: To build a prognostic scale to stratify the risk of suffering from postoperative mediastinitis. Method: A case-control study for the risk factors of postoperative mediastinitis was carried out at the Cardiocentro Ernesto Guevara from Santa Clara, Cuba. After the logistic regression, the model was obtained and from it, the predictors to obtain the Cuban prognostic scale of postoperative mediastinitis PREDICMED were included and weighted, which was validated through several methods. Results: This scale was obtained, counting on six predictors and two risk strata. Its performance was analyzed through adjustment, calibration and determination of its discriminating capacity, showing good results. Internal validation was carried out through the data division method and its capacity was compared in both subsets (development and validation) showing no differences. Its good construct validity was demonstrated, since there were no differences between the predicted and the observed probabilities. Its contents validity was also analyzed by experts. Finally, its criteria validity was determined when compared with another similar scale (Medscore). PREDICMED showed a very good discriminatory capacity (area under the curve 0.962) as well as high values of sensitivity (84.62%) and specificity (92.31%). Conclusions: The Cuban prognostic scale PREDICMED, to stratify the risk of postoperative mediastinitis showed good validation parameters and it was able to stratify the risk in not high and high.

A cost-effectiveness analysis of robotic versus laparoscopic distal pancreatectomy.

AIM: There is no study in the literature that evaluates the cost-effectiveness of robotic distal pancreatectomy (RDP) over laparoscopic distal pancreatectomy (LDP). We performed a comparative study of RDP and LDP with the aim of evaluating clinical and cost-effective outcomes. MATERIAL AND METHODS: This is an observational, comparative prospective nonrandomized study. The primary end point was to compare the cost-effectiveness differences between both groups. A willingness to pay of €20 000 and €30 000 per quality-adjusted life year (QALY) was used as a threshold to recognize which treatment was most cost-effective. RESULTS: A total of 31 RDP and 28 LDP have been included. The overall mean total cost was similar in both groups (RDP: €9712.15 versus LDP: €9424.68; P > .5). Mean QALYs for RDP (0.652) was higher than that associated with LDP (0.59) (P > .5). CONCLUSION: This study seems to provide data of cost-effectiveness between RDP and LDP approaches, showing some benefits for RDP.

Quality of life in patients with hepatitis C. Importance of treatment. / Calidad de vida en los pacientes con hepatitis C. Importancia del tratamiento.

Chronic hepatitis C virus infection is a systemic disease that impairs the quality of life of affected individuals. The impairment is not only due to physiological factors, such as the non-hepatic manifestations of the disease or certain symptoms such as fatigue, weakness and nausea, but is also due to the substantial psychological impact of the infection. Treatment with direct-acting antivirals (DAA) has been demonstrated to substantially improve patient's quality of life, starting in the initial phases. Supplement information: This article is part of a supplement entitled "The value of simplicity in hepatitis C treatment", which is sponsored by Gilead. © 2019 Elsevier España, S.L.U. All rights reserved.

Efectividad de las alternativas terapéuticas para la solución quirúrgica de las mediastinitis después de una cirugía cardíaca / Effectiveness of therapeutic alternatives for the surgical solution of mediastinitis after a cardiac surgery

Introducción: La esternotomía mediana longitudinal es una incisión ampliamente empleada en la cirugía cardiovascular. Las infecciones de la herida quirúrgica constituyen un serio problema de salud; pero en este tipo de cirugía, la infección profunda, la mediastinitis posoperatoria, presenta elevadas morbilidad y mortalidad, y constituye un desafío diagnóstico y terapéutico. Inicialmente los protocolos de tratamiento quirúrgico eran abiertos, pero su evolución ha estimulado que aparezcan los métodos cerrados. Objetivo: Evaluar la efectividad de las alternativas terapéuticas para la solución quirúrgica de las mediastinitis después de una cirugía cardíaca. Método: Se realizó un estudio de evaluación de tecnología sanitaria en fase de aplicación, de corte transversal, con la información contenida entre los años 2000 y 2016, con la previa determinación de los indicadores para ello y sus puntos de corte. Resultados: La incidencia de mediastinitis posoperatoria fue de 1,54 por ciento. El 59,1 por ciento de los pacientes fue tratado con métodos cerrados, mediante el empleo de irrigación al mediastino con yodo povidona diluida. La aplicación del método abierto tuvo una efectividad de 57,1 por ciento, evaluada mediante 7 indicadores previamente determinados, y el método cerrado presentó una efectividad total (100 por ciento), tras la evaluación de 9 indicadores. Conclusiones: La mediastinitis posoperatoria tiene una incidencia similar a otros centros, y ha sido tratada con métodos abiertos y cerrados. La técnica cerrada fue la más utilizada y alcanzó una excelente efectividad terapéutica, superior a la abierta(AU)

Immunogenicity and protective efficacy of a single-dose live non-pathogenic Escherichia coli oral vaccine against F4-positive enterotoxigenic Escherichia coli challenge in pigs.

Enterotoxigenic Escherichia coli strains expressing F4 (K88) fimbriae (F4-ETEC) are one of the most important causes of post-weaning diarrhea (PWD) in pigs. F4, a major antigen, plays an important role in the early steps of the infection. Herein, the efficacy of a live oral vaccine consisting of a non-pathogenic E. coli strain expressing F4 for protection of pigs against PWD was evaluated. Three blinded, placebo-controlled, block design, parallel-group confirmatory experiments were conducted, using an F4-ETEC PWD challenge model, each with a different vaccination-challenge interval (3, 7, and 21days). The pigs were vaccinated via the drinking water with a single dose of the Coliprotec® F4 vaccine one day post-weaning. Efficacy was assessed by evaluating diarrhea, clinical observations, intestinal fluid accumulation, weight gain, intestinal colonization and fecal shedding of F4-ETEC. The immune response was evaluated by measuring serum and intestinal F4-specific antibodies. The administration of the vaccine resulted in a significant reduction of the incidence of moderate to severe diarrhea, ileal colonization by F4-ETEC, and fecal shedding of F4-ETEC after the heterologous challenge at 7 and 21days post-vaccination. The 7-day onset of protection was associated with an increase of serum anti-F4 IgM whereas the 21-day duration of protection was associated with an increase of both serum anti-F4 IgM and IgA. Significant correlations between levels of serum and intestinal secretory anti-F4 antibodies were detected. Maternally derived F4-specific serum antibodies did not interfere with the vaccine efficacy. The evaluation of protection following a challenge three days after vaccination showed a reduction of the severity and the duration of diarrhea and of fecal shedding of F4-ETEC. The 7-day onset and the 21-day duration of protection induced by Coliprotec® F4 vaccine administered once in drinking water to pigs of at least 18days of age were confirmed by protection against F4-ETEC and induction of F4-specific protective immunity.

Coste-efectividad de una unidad monográfica de asma / Cost Effectiveness of Outpatient Asthma Clinics

INTRODUCCIÓN: Las unidades monográficas de asma (UMA) son consultas hospitalarias implementadas para lograr una mejoría clínica de los pacientes. Este estudio analiza su impacto sobre el control del asma y su coste-efectividad en comparación con las consultas ordinarias. MÉTODOS: Estudio de casos cruzados que incluyó a todos los pacientes que fueron atendidos por primera vez en la UMA de Lugo durante 2012. Se definió el «periodo-caso» como los 365días que siguieron a la primera visita en la UMA, y el «periodo-control» como los 365días que la antecedieron. Se calcularon los cambios en indicadores clínicos relevantes para el control del asma y se estimó la relación de coste-efectividad incremental (RCEI) por cada paciente adicional que fue controlado y por cada año de vida ajustado por calidad (AVAC). RESULTADOS: El porcentaje de pacientes (n = 83, edad media 49 ± 15,2 años; 60,2% mujeres) controlados aumentó del 41 al 86%. El resultado del test de control del asma mejoró desde 18,7 ± 4,6 hasta 22,6 ± 2,3 (p < 0,05) y el FEV1 se elevó desde 81,4% ± 17,5 hasta 84,4% ± 16,6 (p < 0,05). Las exacerbaciones, hospitalizaciones y visitas a urgencias disminuyeron un 75, un 78 y un 75%, respectivamente. La utilización de combinaciones CI/LABA decreció del 79,5% al 41%. El uso de otros fármacos aumentó: anticolinérgicos del 3,6 al 16,9%, CI en monoterapia del 3,6 al 45,8%, y omalizumab del 0 al 6%. Las RCEI por paciente controlado y por AVAC ganado fueron de 1.399 y 6.876 €, respectivamente (perspectiva social). CONCLUSIONES: La atención en una UMA es coste-efectiva y tiene un impacto beneficioso sobre el control del asma

INTRODUCTION: Asthma clinics (AC) are hospital outpatient services specialising in the management of asthma. In this study, we analysed the impact of these clinics on asthma management and their cost effectiveness in comparison with standard outpatient services. METHODS: A case cross-over study in which all new patients seen in the AC of Lugo in 2012 were included. The case period was defined as one year following the first visit to the AC; the control period was defined as the preceding year. We calculated changes in clinical quality indicators for asthma management, and estimated the incremental cost-effectiveness ratio (ICER) for each additional patient treated and for each quality-adjusted life year (QALY) RESULTS: The number of patients (n = 83, mean age 49 ± 15.2 years; 60.2% women) managed in the AC increased from 41% to 86%. The Asthma Control Test score increased from 18.7 ± 4.6 to 22.6 ± 2.3 (p < 0.05) and FEV1 increased from 81.4% ± 17.5 to 84.4% ± 16.6 (p < 0.05). The number of exacerbations, hospitalisations and visits to accident and emergency fell by 75%. The number of patients given combination LABA + ICS therapy fell from 79.5% to 41%. The use of other drug therapy increased: anticholinergics, from 3.6% to 16.9%; ICS in monotherapy, from 3.6% to 45.8%; and omalizumab, from 0% to 6%. ICERs per patient managed and per QALY gained were €1,399 and €6,876, respectively (social perspective). CONCLUSIONS: Treatment in ACs is cost-effective and beneficial in asthma management

Cost Effectiveness of Outpatient Asthma Clinics.

INTRODUCTION: Asthma clinics (AC) are hospital outpatient services specialising in the management of asthma. In this study, we analysed the impact of these clinics on asthma management and their cost effectiveness in comparison with standard outpatient services. METHODS: A case cross-over study in which all new patients seen in the AC of Lugo in 2012 were included. The case period was defined as one year following the first visit to the AC; the control period was defined as the preceding year. We calculated changes in clinical quality indicators for asthma management, and estimated the incremental cost-effectiveness ratio (ICER) for each additional patient treated and for each quality-adjusted life year (QALY) RESULTS: The number of patients (n=83, mean age 49 ± 15.2 years; 60.2% women) managed in the AC increased from 41% to 86%. The Asthma Control Test score increased from 18.7 ± 4.6 to 22.6 ± 2.3 (p<0.05) and FEV1 increased from 81.4% ± 17.5 to 84.4% ± 16.6 (p<0.05). The number of exacerbations, hospitalisations and visits to accident and emergency fell by 75%. The number of patients given combination LABA+ICS therapy fell from 79.5% to 41%. The use of other drug therapy increased: anticholinergics, from 3.6% to 16.9%; ICS in monotherapy, from 3.6% to 45.8%; and omalizumab, from 0% to 6%. ICERs per patient managed and per QALY gained were €1,399 and €6,876, respectively (social perspective). CONCLUSIONS: Treatment in ACs is cost-effective and beneficial in asthma management.

Prevalence of virulence factors in enterotoxigenic Escherichia coli isolated from pigs with post-weaning diarrhoea in Europe.

BACKGROUND: Post-weaning diarrhoea (PWD), due to Escherichia coli, is an important cause of economic losses to the pig industry primarily as a result of mortality and worsened productive performance. In spite of its relevance, recent data about the prevalence of virulence genes and pathotypes among E. coli isolates recovered from cases of PWD in Europe are scarce. RESULTS: This study investigates the prevalence of fimbrial and toxin genes of E. coli by PCR among 280 farms with PWD across Europe. A total of 873 samples collected within the first 48 h after the onset of PWD (occurring 7-21 days post weaning) were submitted to the laboratory for diagnostic purposes. Isolation and identification of E. coli were performed following standard bacteriological methods and PCR assays for the detection of genes encoding for fimbriae (F4, F5, F6, F18 and F41) and toxins (LT, STa, STb and Stx2e). The prevalence of fimbriae and toxins among E. coli isolates from cases of PWD was: F4 (45.1 %), F18 (33.9 %), F5 (0.6 %), F6 (0.6 %), F41 (0.3 %), STb (59.1 %), STa (38.1 %), LT (31.9 %) and Stx2e (9.7 %). E. coli isolates carrying both fimbrial and toxin genes were detected in 52.5 % of the cases (178 out of 339 isolates), with 94.9 % of them being classified as enterotoxigenic E. coli (ETEC). The most common virotype detected was F4, STb, LT. CONCLUSIONS: This study confirms that ETEC is frequently isolated in pig farms with PWD across Europe, with F4- and F18-ETEC variants involved in 36.1 % and 18.2 % of the outbreaks, respectively.