Instituto de Investigación Sanitaria del Principado de Asturias

Alba E., García-Mesa Y., Cobo R., Cuendias P., Martín-Cruces J., Suazo I., Martínez-Barbero G., Vega J.A., García-Suárez O., Cobo T.

The carotid sinus and the carotid body are major peripheral chemo- and baro(mechano)receptors that sense changes in arterial wall pressure and in oxygen, carbon dioxide, and pH in arterial blood. Recently, it was demonstrated that the PIEZO1 and PIEZO2 mechanoreceptor/mechanotransducers are responsible for the baroreflex in the murine aortic arch (aortic sinus). Furthermore, some experimental evidence suggests that the carotid body could participate in mechanosensing. In this study, we used immunohistochemistry and immunofluorescence in conjunction with laser confocal microscopy to study the distribution of PIEZO1 and PIEZO2 in the human carotid sinus and carotid body as well as in the petrosal ganglion of the glossopharyngeal nerve and the superior cervical sympathetic ganglion. PIEZO1 and PIEZO2 were detected in different morphotypes of sensory nerve formations in the walls of the carotid sinus and carotid artery walls. In the carotid body, PIEZO1 was present in a small population of type I glomus cells and absent in nerves, whereas PIEZO2 was present in both clusters of type I glomus cells and nerves. The most prominent expression of PIEZO1 and PIEZO2 in the carotid body was found in type II glomus cells. On the other hand, in the petrosal ganglion, around 25% of neurons were PIEZO1-positive, and around 85% were PIEZO2-positive; regarding the superior cervical sympathetic ganglion, around 71% and 86% displayed PIEZO1 and PIEZO2, respectively. The results of this study suggest that PIEZO1 and PIEZO2 could be involved in the detection and/or mechanotransduction of the human carotid sinus, whereas the role of the carotid body is more doubtful since PIEZO1 and PIEZO2 were only detected in some nerves and PIEZO2 was present in a small population of type I glomus cells, with PIEZO1 being absent in these cells. However, since immunoreactivity for PIEZO2 was detected in type II glomus cells, researchers should investigate whether these cells play a role in the detection of mechanical stimuli and/or participate in mechanotransduction.

Bermúdez-Egidos M., Pérez-Llanes R., Ucero-Lozano R., Cuesta-Barriuso R.

Background/Objectives: Hemophilic arthropathy causes functional impairment, disability, and chronic pain. Conditioned pain modulation describes the effect of endogenous pathways that potentiate or diminish the effects of noxious afferent stimuli. The objective was to identify conditioned pain modulation in patients with bilateral hemophilic ankle and knee arthropathy, and the best predictive model thereof. Methods: Cross-sectional cohort study. Forty-nine adult patients with hemophilic arthropathy were recruited. The dependent variable was the Conditioned Pain Modulation Index (CPMI). Age was the predictor variable. Secondary variables, estimated as modifying or confounding variables, were kinesiophobia (Tampa Scale for Kinesiophobia), catastrophizing (Pain Catastrophizing Scale), anxiety (State-Trait Anxiety Inventory), and clinical, anthropometric, and sociodemographic variables. Results: Conditioned pain modulation in patients with hemophilic arthropathy presents values close to zero (mean = 0.004: 95%CI: −0.05; 0.06). Anxiety, pain intensity, and pressure pain threshold explained the variability in the conditioned modulation of ankle pain (R2adj = 0.24). Variables explaining 23.05% of variability of conditioned modulation of knee pain were age, inhibitor development, anxiety, and pressure pain threshold (R2adj = 0.23). Conclusions: Patients with hemophilia presented a modulation close to zero, representing a balance between the ability to inhibit and facilitate painful stimuli. The predictive model of conditioned modulation of ankle pain includes anxiety, and pain intensity and threshold. Age, inhibitory development, anxiety, and pain threshold predict knee pain modulation.

Martín-Vírgala J., Martín-Carro B., Fernández-Villabrille S., Fernández-Mariño B., Astudillo-Cortés E., Rodríguez-García M., Díaz-Corte C., Fernández-Martín J.L., Gómez-Alonso C., Dusso A.S., Alonso-Montes C., Naves-Díaz M., Panizo S., Carrillo-López N.

Background/Objectives: Cardiovascular disease is the main cause of morbidity and mortality in Chronic Kidney Disease (CKD), so it is of great importance to find simple and non-invasive tools to detect vascular damage in pre-dialysis CKD patients. This study aimed to assess the applicability of non-invasive techniques to evaluate vascular damage in stages CKD-2 to CKD-5 and its progression after an 18-month follow-up using (A) carotid–femoral pulse wave velocity (PWV) to assess aortic stiffness and (B) Superb Microvascular Imaging (SMI) ultrasound to assess adventitial neovascularization compared with other traditional techniques to evaluate vascular damage, such as carotid intima–media thickness and Kauppila index. Methods: The study involved 43 CKD patients in stages CKD-2 to CKD-5 and a group of 38 sex- and age-matched controls, studied at baseline and at an 18-month follow-up. Age, sex, body mass index, arterial pressure, pharmacological treatments, and blood and urinary parameters were collected. Aortic stiffness was determined by carotid–femoral PWV and abdominal aortic calcification was assessed in lateral lumbar X-rays and quantified by the Kauppila index. Carotid intima–media thickness (cIMT), the number of carotid plaques, and adventitial neovascularization were evaluated by SMI. Results: Vascular impairment was mostly detected in CKD-4 and CKD-5 stages, with increased aortic stiffness measured by PWV and increased carotid plaques and adventitial neovascularization measured by SMI ultrasound. Furthermore, CKD-5 patients showed greater abdominal aortic calcification. Interestingly, CKD patients displayed a negative correlation between serum soluble Klotho (sKlotho) and cIMT. Finally, CKD patients showed no progression of vascular impairment after the 18-month follow-up, with the exception of carotid plaques. Conclusions: Performing non-invasive PWV and SMI ultrasound might be useful to evaluate vascular damage in CKD before entering dialysis, possibly helping to prevent cardiovascular events, although future studies should clarify the use of these techniques in clinical practice.

Boluda B., Rodriguez-Veiga R., Sargas C., Ayala R., Larráyoz M.J., Chillón M.C., Soria-Saldise E., Bilbao C., Prados de la Torre E.P., Navarro I., Martinez-Cuadron D., Gil C., Bernal T., Bergua J., Algarra L., et. al.

Background/Objectives: This PETHEMA PCR-LMA study aimed to evaluate whether mutations detected by NGS (VAF cut-off of ≥5%) correlate with NPM1, FLT3-ITD, FLT3-TKD, IDH1, and IDH2 mutations detected using conventional PCR (analytical sensitivity 3%) in a nationwide network of seven reference laboratories. Methods: Between 2019 and 2021, 1685 adult AML patients with at least one centralized sample (NGS or PCR) at primary diagnosis or relapse/refractory episode were included. Results: During this period, 1288 paired NGS/PCR samples (1094 at diagnosis, 103 at relapse and 88 at refractoriness) were analyzed. Considering PCR the gold-standard, for NPM1 NGS sensitivity was 98.5% and specificity 98.9%, for FLT3-ITD 73.8% and 99.6%, for FLT3-TKD 84.5% and 99.3%, for IDH1 98.7% and 98.7%, and for IDH2 99.1% and 97.7%, respectively. Overall concordance rate of positive results between NGS (and PCR was 95% (262/276) for NPM1, 72% (149/206) for FLT3-ITD, 74% (49/66) for FLT3-TKD, 87% (77/89) for IDH1 and 84% (107/127) for IDH2. Overall, median days from sample reception until report were 7 for PCR and 28 for NGS. Conclusions: This study shows high concordance between NPM1 and IDH results using PCR and NGS. However, sensible important discrepancies are observed for FLT3 mutations. In our context, rapid screening for these druggable mutations should be performed by conventional PCR.

Alperi A., Antuna P., Almendárez M., Álvarez R., del Valle R., Pascual I., Hernández-Vaquero D., Avanzas P.

Coronary artery disease is a highly prevalent disease that constitutes the leading cause of mortality worldwide. Acute coronary syndromes are the most devastating form of presentation of coronary disease, involving the acute formation of a thrombus within the coronary vessel lumen, further leading to flow limitation and diminished myocardial perfusion. Vulnerable plaques, which are characterized by thin-cap fibroatheroma, a large lipid pool, and macrophage infiltration and spotty calcification of the cap, pose a higher risk of coronary events despite not being flow-limiting. Iterations in intravascular imaging and coronary computed tomography have largely increased the ability to detect and define vulnerable plaques, and its clinical impact in early- and mid-term outcomes has been confirmed in several studies. In this review, we aimed to revise the current concept of vulnerable coronary plaque and its repercussion, to summarize the main pharmacological approaches for its management, and to provide an updated overview of the available evidence on preventive percutaneous interventional strategies in this clinical setting.

García Moreira V., Cepeda Piorno J., Sanders Vegara J., Eyo González A., Alberdi García del Castillo C., González García C., Vaktangova N., García Castañón S., Al Kassam Martínez D., Chávez Collazos P., González García E.

Background/Objectives: Bence Jones proteins (BJPs) are monoclonal immunoglobulin free light chains (FLCs) that appear in the urine of patients with plasma cell disorders, including multiple myeloma (MM), Waldenström’s macroglobulinemia (WM), or light chain amyloidosis (AL). Their presence can provide valuable information about disease progression and treatment efficacy. These proteins are typically detected through a 24-h urine collection, as recommended by clinical guidelines. However, this method can be inconvenient for both patients and laboratory personnel due to its time-consuming nature and the potential for collection errors. We propose an algorithm based on serum FLC (sFLC) to rule out the presence of BJPs and diminish the need for urine testing. Methods: A retrospective data analysis of 268 serum and urine samples from 44 patients with MM was performed, and cutoffs were established to predict BJP absence: total urine protein (0.115 g/L), sFLC κ/λ ratio (>0.82 λ monoclonality and <1.99 κ monoclonality), and difference of involved–uninvolved FLC (dFLC; <11.93 mg/L). A subsequent algorithm validation was performed in 716 samples from patients who underwent the same testing in routine 2023 other laboratory activity. Results: The validation of these cutoffs to rule out the presence of BJP showed that, if the protocol based on the sFLC κ/λ ratio and dFLC had been applied, 42% of the urine studies would have been avoided, achieving a sensitivity of 93.9% and a false negative rate of 6.11%. Conclusions: We propose a laboratory work protocol that would allow for the avoidance of almost half of the 24-h urine studies based on sFLC measurement, a faster and more objective alternative to urine analysis for screening out the presence of BJP, with a good sensitivity and a low false negative rate.

Álvarez Marcos F., Reyes Valdivia A., De Blas Bravo M., Alonso Pérez M.

Introduction and objectives: Complex abdominal aortic aneurysm (AAA) repair often requires the use of fenestrated and branched endografts, which can be influenced by factors such as device availability, cost, and operator expertise. This study aims to evaluate the preliminary results with physician-modified endografts (PMEGs) utilizing the Medtronic Endurant platform. Methods: Retrospective analysis of consecutive patients unsuitable for other techniques or custom-made devices, in which a PMEG Endurant was used for repair between 2021 and 2024. Bidimensional templates of the Endurant endograft were developed to ensure precise fenestration placement, which was confirmed intraoperatively with a 3D-printed aortic template. Endpoints were technical success, mortality, reinterventions, and target vessel patency. Results: Thirty-seven target vessels in 18 patients (mean age 79.4 ± 9 years, 94% male) were treated with Endurant main bodies (n=10, 55.6%), abdominal tubes (n=4, 22.2%), or aortic extensions (n=4, 22.2%). Mean aneurysm diameter was 70.0 ± 23 mm. Mean number of fenestrations was 2.1 ± 1 (33.3% 3-FEN or 4-FEN). The most frequent bridging stents were iCover (n=15, 40.5%), BeGraft (n=10, 27.0%), and VBX (n=9, 24.3%). Mean implantation time was 198.9 ± 90 minutes. Technical success was achieved in all but one case (n=17, 94%), with no 30 day mortality, no reinterventions, and 100% target vessel patency at a median follow-up of 10 months. Three patients (16.7%) died of non aortic-related causes. One residual type IA endoleak was adverted in computed tomography scan controls and was left untreated according to patient’s decision. Conclusion: PMEG utilizing the Medtronic Endurant endograft, supported by bidimensional templates and 3D-printed confirmation models, provided safe and effective short-term outcomes for complex, non-deferrable AAA repair. Long-term data and a prospective study on PMEG with a standardized protocol would allow for evidence to arise on this technique, facilitating adequate comparisons with custom-made and off-the-shelf devices. Clinical Impact This short series highlights the initial outcomes of physician-modified endografts (PMEG) using the Medtronic Endurant platform. Dedicated 2D templates for all Endurant sizes are provided as supplementary material, offering valuable assistance to practitioners in the vascular community. A standardized modification protocol, based on these templates along with the double-check of a sterile 3D-printed model, has allowed to achieve satisfactory short term outcomes. These outcomes are comparable to those of custom-made devices, even in scenarios requiring non-deferrable repairs and involving challenging anatomic constraints, such as type 1A endoleaks.

Moledo-Nodar L., Celemín-Capaldi V., Ugalde A.P., Freije J.M.

Cell reprogramming consists in the reverse process to cell differentiation, making cells lose their identity and age-related characteristics and granting an increased potential for proliferation and redifferentiation on different lineages. This process holds immense potential for the treatment of several pathologies, including progeroid syndromes, diseases that recapitulate the symptoms seen in physiological aging in an accelerated manner. Among the recent advances on the use of cell reprogramming in the context of progeroid syndromes, the interventions based on partial reprogramming, consisting on the dedifferentiation of cells only up to a point in which they lose age related characteristics but keep their identity, stand out. This partial reprogramming can be achieved both using the forced expression of transcription factors or cocktails of small molecules that regulate different biological processes. While all these advances are promising, the use of cell reprogramming in the treatment of progeroid syndromes still faces several challenges, such as the development of methods that allow for an efficient delivery of cell reprogramming factors in vivo and fine tuning of the dose used. Furthermore, these approaches should be accompanied by treatments targeting the original cause of the disease or they could be proven futile in the long term.

Llana T., Perpetuini D., Zorzo C., Mendez M.

Visuospatial memory plays a crucial role in everyday functioning. However, its assessment was less explored compared to other memory systems. Immersive virtual reality (iVR) devices can add valuable information about visuospatial memory providing more realistic and ecological environments and allowing for the recording of brain activity in real time. This present systematic review summarizes the current knowledge of brain dynamics during the execution of iVR-based visuospatial memory tasks. Nine articles were reviewed, employing visuospatial working memory, visuospatial memory recognition, and spatial memory tasks through commercial iVR devices such as HTC Vive or Oculus. Most studies measured brain activity using electroencephalography. The findings highlight different key aspects, such as the sensitivity of the prefrontal cortex under stressful conditions, the relationship between memory load and brain activity, the involvement of medial temporal lobe regions on spatial memory and its improvement using memory reactivation paradigms, the importance of some environmental characteristics (i.e., the space where the task is carried out), and the implication of the parietal cortex in processing allocentric information. These results enhance our understanding of brain activity during iVR-based visuospatial tasks and highlight iVR technologies as promising tools in cognitive neuroscience.

Alonso S., Alvarez P., Calleja N., Queiro R.

The applicability of the new Assessment of Spondyloarthritis International Society (ASAS) consensus definition of early axial spondyloarthritis (axSpA) has barely been tested in clinical settings. We aimed to check the applicability of this new definition in a real clinical context. Single-center cross-sectional study involving 330 consecutive patients fulfilling axSpA criteria. Similarities and differences between patients with early (according to the new ad hoc definition) and established disease were analyzed. Logistic regression models adjusted for sex and exposure to biologic therapies were constructed to analyze the different disease outcomes between both subpopulations. Of 299 patients for whom information on defining characteristics of early axSpA could be reliably collated, 45 (15%) met the ASAS definition of early axSpA, median disease duration of 1.0 year [IQR, 1.0–2.0]. Compared to established disease, these patients were younger (p = 0.001), with a similar male-to-female ratio, and a higher exposure to NSAIDs (p = 0.015) but lower to biologics (p = 0.005). Uveitis prevalence was similar between both groups (early, 15.6% and established, 16.1%). Regardless of sex and biologic therapy, inflammatory burden, disease activity and the impact on quality of life were similar in both groups. As expected, structural damage was higher among established cases. Also, regardless of disease duration and exposure to biologic therapies, men had better disease outcomes than women. Patients with early axSpA present similarities and differences with respect to established cases. The new ASAS definition of early disease may be applicable in real-world clinical settings. • Patients with early axial spondyloarthritis show similarities and differences with respect to established cases. • The overall burden of disease is similar in both subgroups of patients with axial SpA. • In both study groups, men showed better disease outcomes than women. • The new ASAS definition of early axial spondyloarthritis is applicable in real-life clinical settings.

Santamarina-Ojeda P., Fernández A.F., Fraga M.F.

Epitranscriptomics, the study of chemical modifications in RNA, has emerged as a crucial field in cellular regulation, adding another layer to the established landscape of DNA- and histone-based epigenetics. A wide range of RNA modifications, including N6-methyladenosine, pseudouridine, and inosine, have been identified across nearly all RNA species, influencing essential processes such as transcription, splicing, RNA stability, and translation. In the context of brain tumors, particularly gliomas, specific epitranscriptomic signatures have been reported to play a role in tumorigenesis. Despite growing evidence, the biological implications of various RNA modifications remain poorly understood. This review offers an examination of the main RNA modifications, the interplay between modified and unmodified molecules, how they could contribute to glioma-like phenotypes, and the therapeutic impact of targeting these mechanisms.

Cardoner N., Gutiérrez-Rojas L., Saiz P., Lahera G., Álvarez-Mon M.Á., Alonso Ortega P., Pérez-Páramo M.

IntroductionGeneralized Anxiety Disorder (GAD) is a mental health condition with a recent increase in prevalence. GAD is often underdiagnosed, leading to negative consequences for individuals, healthcare systems, and society. The economic burden and impaired quality of life associated with GAD underscores the need for effective treatment. Pregabalin has shown promise in reducing anxiety symptoms; however, further research is needed to evaluate its efficacy and compare it with other treatment options. This study aimed to assess the efficacy, safety, and optimal pregabalin dosage for the treatment of GAD.MethodsThis meta-analysis followed PRISMA guidelines. Pregabalin-treated patients comprised the intervention group, whereas the comparator group received benzodiazepines, SSRIs, SNRIs, or placebo. Efficacy and safety were evaluated using various scales and adverse events (AEs). Randomized clinical trials were included in the study. Four major databases were used for this study. Outcome measures included the Hamilton Anxiety Rating Scale (HAM-A), Clinical Global Impression Improvement Scale (CGI-I), discontinuation rates, costs, and quality-adjusted life-years (QALYs). Meta-analyses were conducted using Review Manager 5.4 software, employing odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (CIs). Subgroup and sensitivity analyses were performed based on follow-up and dosage.ResultsFourteen studies involving 4,822 patients were analyzed. Pregabalin demonstrated superior efficacy in reducing HAM-A global scores at 2 weeks (MD −1.23, 95% CI −1.79 to −0.66), 4 weeks (MD −1.12, 95% CI −1.60 to −0.63), 8 weeks (MD −2.50, 95% CI −4.21 to −0.79), 12 weeks (MD 0.99, 95% CI 0.35–1.63), and 6 months to 1 year (MD −3.31, 95% CI −4.30 to −2.31). Pregabalin also showed a higher response rate to HAM-A (OR 1.51, 95% CI 1.31 1.75). CGI-I scores favored pregabalin (MD −0.25, 95% CI −0.38 to −0.12), with a higher response rate (OR 1.33, 95% CI 1.15–1.55). The discontinuation rates were lower with pregabalin (OR 0.80, 95% CI 0.70, 0.91). Adverse events favored pregabalin over SSRIs/SNRIs and benzodiazepines at different doses. Pregabalin was associated with higher cost-effectiveness (MD 0.02, 95% CI 0.01, 0.03).ConclusionPregabalin is an effective and well-tolerated treatment for generalized anxiety disorder, showing superior efficacy and safety compared with first-line medications.Systematic Review RegistrationPROSPERO CRD42024556152.

Truque‐Díaz C., Meroño‐Gallut J., Cuesta‐Barriuso R., Pérez‐Llanes R.

ABSTRACTBackgroundHaemophilic ankle arthropathy is characterized by chronic pain, loss of strength and proprioception, decreased range of motion (ROM) and impaired functionality.ObjectiveTo evaluate the safety and efficacy of a manual therapy protocol based on joint and myofascial techniques in patients with haemophilic ankle arthropathy.MethodsA randomized, single‐blind pilot study. Twenty‐four patients with haemophilia were randomized to the experimental (manual therapy) and control (no intervention) groups. The intervention lasted for 3 weeks, with one 50‐min weekly session. Techniques used: active‐passive joint mobilization, articulatory technique, joint decompression and high‐speed and short‐stroke manipulation, and sustained myofascial induction techniques. The study variables were safety of the intervention (number of hemarthroses), joint pain intensity (visual analogue scale), pressure pain threshold (pressure algometer), range of ankle motion (Leg Motion) and joint condition (Haemophilia Joint Health Score).ResultsNone of the patients developed ankle hemarthrosis during the intervention. After the intervention there were intergroup differences in the variables pain intensity (MD = −0.45; p < 0.001), ROM (MD = 0.19; p = 0.003), joint condition (MD = 0.04; p = 0.03) and pressure pain threshold in the internal malleolus (MD = 1.36; p = 0.01). For the interaction time*group after the follow‐up period, there were statistically significant differences in pain intensity (F = 6.94; p = 0.01) and dorsal flexion (F = 3.36; p = 0.04) of the ankle.ConclusionsManual therapy based on joint and myofascial techniques is safe in haemophilia patients. A protocol implementing joint and myofascial techniques having the dosage and safety parameters established in this study can improve the intensity of pain and dorsal flexion of the ankle in these patients.Trial RegistrationClinicalTrials.gov identifier: NCT05549843

Yoon H.H., Xu J., Kato K., Pan Y., Park S.R., Shen L., Van Cutsem E., Jimenez-Fonseca P., Barnes F., Sun T., Barnes G., Victor T.

366 Background: While improved survival has been previously demonstrated, the impact of immunotherapy on HRQoL in ESCC has not been well examined. Traditional PRO-based analyses in oncology trials, such as time to deterioration (TTD) and mixed models for repeated measures (MMRMs), are limited by discounting recurrent PRO events. Thus, we applied a 3-component joint model (JM) framework to define more clinically interpretable associations between patient-reported symptoms, treatment effects, and OS among subgroups of patients with ESCC from RATIONALE-306, which met its primary endpoint, with PD-L1 expression of ≥1%, ≥5%, and ≥10%. Methods: The final analytic sample included 226 patients in the tislelizumab + chemotherapy arm (T+C), 242 in the placebo + chemotherapy arm (P+C) for PD-L1 ≥1%, 113 in the T+C arm and 103 in the P+C arm for PD-L1 ≥5%, and 168 in the T+C arm and 178 in the P+C arm for PD-L1 ≥10%.From EORTC QLQ-C30 and OES18, 7 keysymptom domains were modeled (GHS, physical functioning, fatigue, dysphagia, pain, reflux, dietary restrictions). PRO data were collected at baseline and at every treatment cycle (up to 6 cycles), then every other cycle, and at safety follow-up, and change from baseline (CFBL) was analyzed. The joint model comprised three components: 1) linear mixed model predicting CFBL symptom scores; 2) Cox proportional hazard model (CPH) for time to OS; and 3) frailty (random effects for recurrent deterioration events [RDEs]) CPH model for time to PRO-based RDEs. Osoba (1998) 10-point threshold was used to define RDEs. Results: Adjusted completion rates were >90% in the ITT population for both arms. Significant T+C treatment effects wereobserved for physical functioning in PD-L1 ≥5% ( P =0.0476), and pain in PD-L1 ≥1% ( P =0.0028) and PD-L1 ≥5% ( P =0.0149) subgroups, but not in PD-L1 ≥10%. For other 5 symptoms (ie, GHS, fatigue, reflux, dysphagia, dietary restrictions), there were no statistically significant differences between treatment arms. However, T+C was associated with significant reductions in the risk of death across all 7 key symptoms and PD-L1 subgroups. As one example, with respect to interaction between pain and OS, T+C was associated with a 22% (HR, 0.78 [95% CI, 0.652-0.931]), 33% (HR, 0.67 [95% CI, 0.515-0.860]), and 47% (HR, 0.50 [95% CI, 0.344-0.720]) reduction in the risk of death in PD-L1 ≥1%, ≥5%, and ≥10%, respectively compared with P+C. Conclusions: In this analysis, the addition of tislelizumab to chemotherapy was associated with significantly less deterioration in multiple PRO symptoms including physical functioning and pain, alongside a lower risk of death, after adjusting for recurring deterioration events using a frailty model across multiple PD-L1 expression subgroups.

Martín-Vicente P., López-Martínez C., López-Alonso I., Exojo-Ramírez S.M., Duarte-Herrera I.D., Amado-Rodríguez L., Ordoñez I., Cuesta-Llavona E., Gómez J., Campo N., O'Kane C.M., McAuley D.F., Huidobro C., Albaiceta G.M.