BACKGROUND:The evaluation of innovative oncology medicines presents significant challenges related to the selection of appropriate clinical endpoints and the sufficiency of evidence, particularly in therapeutic areas, such as immunotherapies, targeted treatments, single-arm trials, and tumor-agnostic therapies. In these contexts, the added value of new treatments is often not adequately captured by traditional clinical trial endpoints, such as overall survival (OS), which remains the gold standard in oncology assessment. This article aims to analyze the main sources of uncertainty in the value assessment of oncology therapies in Spain, with a focus on the limitations of current endpoints and evidence-generation processes, and to provide recommendations for enhancing the recognition and assessment of additional clinical benefit. METHODS:A multidisciplinary expert panel composed of twelve professionals, including medical oncologists, hospital pharmacists, health economists, and patient representatives, was convened to identify and discuss key sources of uncertainty in the value assessment of oncology treatments, particularly those related to clinical endpoint selection and evidence generation. The panel participated in three structured plenary sessions. Additional external experts were engaged to provide complementary input in areas, such as tumor-specific characteristics and statistical methodology. Consensus statements were developed through an iterative process of discussion, critical appraisal, and refinement across and between sessions. RESULTS:The expert panel issued twelve recommendations to improve value assessment in oncology. These include tailoring clinical endpoints to treatment type, tumor characteristics, and stage; complementing overall survival with milestone analysis and quality-of-life measures; and standardizing real-world evidence collection across the healthcare system. The panel advocated for a national portfolio of prioritized endpoints, appropriate statistical methods by context, and the conditional use of early-phase data for decision-making. Additional recommendations addressed the use of synthetic control arms, flexible reimbursement models, advanced analytics (e.g., AI and Big Data), evaluator expertise, and the promotion of stakeholder training and transparency. CONCLUSIONS:Addressing the challenges of clinical endpoint selection and evidence generation is essential to reduce uncertainty in the value assessment of innovative oncology treatments. The twelve expert recommendations outlined in this study provide a structured roadmap to improve methodological consistency, enhance the relevance and robustness of clinical and real-world data, and promote a more adaptive and transparent evaluation framework. These proposals aim to support more evidence-based, equitable, and sustainable decision-making within the Spanish healthcare system, while aligning with broader European initiatives in oncology drug assessment.
This update and revision of the international guideline for urticaria was developed in accordance with the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. It is an initiative of the Global Allergy and Asthma Excellence Network (GA(2)LEN) and its Urticaria and Angioedema Centers of Reference and Excellence (UCAREs and ACAREs), with the participation of 210 delegates from 107 national and international societies, from 59 countries. The consensus conference was held on December 6th, 2024. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, defined by a rapid appearance of wheals, angioedema, or both. The lifetime prevalence of acute urticaria is estimated to be approximately 20%. Chronic urticaria, categorized as either chronic spontaneous urticaria or chronic inducible urticaria, is disabling, impairs quality of life, and affects performance at work and school, however, novel therapies are available. This updated version of the international guideline for urticaria covers the definition and classification of urticaria and outlines expert-guided and evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.
Abstract Introduction: In RRMM, increasing rates of pt attrition and decreasing durability of responses with each line of therapy (LOT) necessitate early treatment (tx) with the most effective therapies. Immunotherapies that are widely accessible across different MM tx settings have the potential to change the trajectory of RRMM. Teclistamab (Tec), the first approved BCMA×CD3 bispecific antibody (BsAb) for heavily pretreated RRMM, provided deep, durable responses in MajesTEC-1, with improved efficacy and safety in earlier LOTs. Daratumumab (Dara), a standard-of-care (SoC) foundational CD38 targeted therapy with direct on-tumor activity, has been shown to deplete immunosuppressive T-cells and expand cytotoxic T-cells, creating an immune-permissive microenvironment for synergistic Tec-mediated killing of MM cells. MajesTEC-3 (NCT05083169) evaluates Tec-Dara vs SoC DPd/DVd in RRMM. We report initial results for this first phase 3 study of BsAb therapy in MM. Methods: Eligible pts had 1-3 prior LOTs including a PI and lenalidomide (Len; pts with 1 prior LOT must have been Len-refractory) with progressive disease (PD) on or after the last LOT. Pts with prior BCMA-directed therapy or refractory to anti-CD38 were excluded; prior anti-CD38 exposure was permitted. Pts were randomized 1:1 to Tec-Dara or DPd/DVd. The Tec-Dara group received 28-day cycles (C) of Tec (1.5 mg/kg QW in C1-2 [C1 preceded by the approved step-up dose schedule]; 3 mg/kg Q2W in C3-6; and 3 mg/kg Q4W in C7+) with Dara; steroids were not required after C1 Day 8. Tec and Dara dosing were aligned with the approved Dara schedule. DPd/DVd were administered per approved schedules. Progression-free survival (PFS) by IRC was the primary endpoint; secondary endpoints included complete response or better (≥CR), overall response, minimal residual disease (MRD) negativity (10–5; next-generation sequencing), overall survival (OS), time to worsening of symptoms (MySIm-Q), and safety. Results: 587 pts were randomized (Tec-Dara, n=291; DPd/DVd, n=296). Median (range) age was 64 (25-88) yrs, median number of prior LOTs was 2 (1-3). With 34.5-mo median follow-up, Tec-Dara significantly improved PFS vs DPd/DVd (HR, 0.17; 95% CI, 0.12-0.23; P<0.0001); mPFS was NR and 18.1 mo, and 36-mo PFS rate was 83.4% and 29.7%, respectively. PFS benefit was consistent across all prespecified and clinically relevant pt subgroups, including age ≥75 yrs, Len-refractory, high-risk cytogenetics, ≥60% bone marrow plasma cells, soft-tissue plasmacytomas, and anti-CD38 exposed. Significantly higher rates of ≥CR (81.8% vs 32.1%; OR, 9.56; 95% CI, 6.47-14.14), overall response (89.0% vs 75.3%; OR, 2.65; 95% CI, 1.68-4.18), and MRD-negativity (58.4% vs 17.1%; OR, 6.78; 95% CI, 4.53-10.15) were observed with Tec-Dara (P<0.0001). There were 45 deaths with Tec-Dara and 96 with DPd/DVd, primarily due to PD (4.6%; 20.3%). OS significantly favored Tec-Dara (HR, 0.46; 95% CI, 0.32-0.65; P<0.0001), including across all prespecified subgroups. The 36-mo OS rates were 83.3% and 65.0%, respectively and >90% of Tec-Dara pts alive at 6 mo were also alive at 30 mo. Median time to worsening of MM symptoms was NR with Tec-Dara vs 39.9 mo with DPd/DVd (HR, 0.50; 95% CI, 0.34-0.72; P=0.0002). At data cutoff, 49.4% of pts remained on study tx (Tec-Dara, 71.0%; DPd/DVd, 28.3%). Median tx duration was twice as long with Tec-Dara vs DPd/DVd (32.4 vs 16.1 mo). Frequency of grade 3/4 (Tec-Dara, 95.1%; DPd/DVd, 96.6%) and grade 5 (7.8%; 6.2%) treatment-emergent adverse events (TEAEs), were comparable (safety set: Tec-Dara, n=283; DPd/DVd, n=290). Serious TEAEs occurred in 70.7% Tec-Dara and 62.4% DPd/DVd pts; tx discontinuations due to TEAEs were low (4.6% vs 5.5%). Any grade infections occurred in 96.5% and 84.1% of Tec-Dara and DPd/DVd pts, respectively; grade 3/4 infections occurred in 54.1% and 43.4%. New onset grade ≥3 infections decreased over time, coinciding with transition to Q4W dosing and supported by antimicrobial and Ig prophylaxis guidance. CRS rate was 60.1% (grade 1/2: 44.2%/15.9%) and ICANS was 1.1% with Tec-Dara. Conclusion: We demonstrate the clinically remarkable and statistically significant PFS and OS benefits of Tec-Dara vs SoC triplets in RRMM, with 83.4% of Tec-Dara pts alive and progression-free at 3 yrs. Infections with Tec-Dara were well managed with established protocols. This highly effective, off-the-shelf, immunotherapy combination represents a new SoC for RRMM as early as first relapse.
Introduction:Bilateral vestibulopathy (BVP) is a chronic, disabling disorder characterized by bilateral loss of vestibular function, leading to imbalance, oscillopsia, and falls. Despite established diagnostic criteria, clinical expression and rehabilitation potential vary widely across etiologies. Understanding these functional signatures is crucial for tailoring future neurostimulation strategies. The main objective of this study is to decode the etiological and functional heterogeneity of BVP and define clinical-functional profiles guiding vestibular or cochleo-vestibular implant candidacy. Methods:A multicenter retrospective study included 119 adults fulfilling Bárány Society criteria for definite BVP (>1 year). Comprehensive audiovestibular testing comprised pure-tone audiometry (PTA), video head impulse test (vHIT), vestibular evoked myogenic potentials (VEMPs), and dynamic posturography (SOT, LOS). Group comparisons used Kruskal-Wallis and Dunn-Bonferroni tests; oscillopsia predictors were analyzed by binary logistic regression. Results:Etiologies included idiopathic (29.41%), Ménière's disease (26.89%), iatrogenic (18.49%), post-infectious (14.29%), cerebellar ataxia/CANVAS (6.72%), and post-traumatic (4.20%). Oscillopsia was reported by 48.74% and falls by 22.69%. Significant inter-etiological differences were found for semicircular canal gains (p < 0.001), with idiopathic and Ménière phenotypes showing higher vHIT gains and CANVAS/vestibulotoxic forms the lowest. IAAR-VEMP amplitudes were higher in idiopathic and Ménière groups than in CANVAS and vestibulotoxic etiologies (p < 0.01). Posturography differed across groups (SOT p = 0.007; LOS p = 0.010), CANVAS showing the poorest stability. Logistic regression identified reduced VOR gain in both the lateral and posterior semicircular canals as significant predictors of oscillopsia (LSC: right OR 0.185, p = 0.036; left OR 0.149, p = 0.035; PSC: right OR 0.167, p = 0.043; left OR 0.182, p = 0.047), together with an increased right PR index (OR 1.045, p = 0.010). Fourteen patients (11.76%) were qualified for cochleo-vestibular and the same amount for vestibular implant candidacy. Conclusion:BVP comprises etiology-specific phenotypes. Oscillopsia is driven mainly by VOR performance and PR index in LSC. Integrating auditory status, canal-otolith function, and compensation quality supports precision selection for vestibular versus cochleo-vestibular implantation.
BACKGROUND:Systemic inflammation is a central feature of advanced chronic liver disease (AdvCLD). However, the relationship between inflammatory status, as reflected by the systemic immune-inflammation index (SII), and frailty in this population remains undefined. METHODS:We performed a retrolective analysis of a prospective cohort of 291 patients with AdvCLD evaluated for liver transplantation (LT). Frailty was assessed using the Liver Frailty Index (LFI), gait speed test (GST) and the 6-minute walk test (6MWT). The SII, calculated as (platelets x neutrophils) / lymphocytes. Patients were categorized into low and high SII groups. Associations between SII and frailty were examined using multivariable logistic and linear regression. The prognostic value of SII for one-year all-cause mortality was evaluated using a competing-risk model with LT as the competing event. RESULTS:Among 291 patients, 46 (16%) met criteria for LFI ≥ 4.5, and 56 (19%) had a 6MWT <250 m. High SII (≥3.52) was associated with higher MELD 3.0 scores, greater LFI ≥ 4.5 prevalence (23% vs. 9%), slower GS (0.8 m/s vs 1.0 m/s) and a higher proportion walking <250 m (27% vs 12%). Median SII increased progressively across LFI categories and was significantly higher in individuals walking <250 m. High SII remained independently associated with frailty (LFI ≥ 4.5), 6MWT <250 m and GST in multivariable models. After MELD 3.0 adjustment, high SII was associated with increased mortality (aSHR 2.74; 95% CI 1.18-6.33). CONCLUSION:SII reflects systemic inflammation, and higher SII values are associated with increased frailty and higher mortality in AdvCLD.
