Scientia, Dipòsit d’Informació Digital del Departament de Salut
Not a member yet
12576 research outputs found
Sort by
Convergent Genetic Adaptation in Human Tumors Developed Under Systemic Hypoxia and in Populations Living at High Altitudes
Get PDFGenetic; Human tumors; Systemic hypoxiaGenètica; Tumors humans; Hipòxia sistèmicaGenética; Tumores humanos; Hipoxia sistémicaThis study explores parallels between systemic hypoxia adaptation in high-altitude populations and tumorigenesis. We identified EPAS1, a gene critical for hypoxia adaptation in populations such as Tibetans and Sherpas, as playing a similar adaptive role in tumors arising under hypoxic conditions. Tumors from patients with chronic hypoxia displayed impaired DNA repair and frequent emergence of EPAS1 variants, with frequencies reaching up to 90%, echoing the positive selection seen in high-altitude dwellers. Mechanistically, EPAS1 gain-of-function mutations promote COX4I2 expression, reducing cellular oxygen consumption and supporting tumor proliferation in hypoxia. Analysis of clinical data from patients with hypoxia revealed tissue-specific and time-sensitive tumorigenic effects, particularly impacting oxygen-sensitive cells in the postnatal period. Our findings suggest that EPAS1-driven adaptation mechanisms in high-altitude populations provide a model for understanding tumor evolution under hypoxic stress, highlighting how genetic adaptations to diverse stressors in natural populations may yield insights into tumorigenesis and cancer progression.
Significance:
This study reveals a broad convergence in genetic adaptation to hypoxia between natural populations and tumors, suggesting that insights from natural populations could enhance our understanding of cancer biology and identify novel therapeutic targets.The authors would like to thank especially patients and their families for their participation and contribution to this research study. We acknowledge IdiPAZ Biobank for the assistance in some tumor samples collection; VHIO’s Oncology Data Science (ODysSey) for carrying out some statistical analyses; European Network for the Study of Adrenal Tumors (ENS@T) and COST Action CA20122 Harmonisation for supportive networking; FERO Foundation for providing a startup grant for VHIO’s Biomarkers and Clonal Dynamics Laboratory led by R.A. Toledo; and Editage for its editing services. VHIO would like to acknowledge: the State Agency for Research (Agencia Estatal de Investigación) for the financial support as a Center of Excellence Severo Ochoa (CEX2020-001024-S/AEI/10.13039/501100011033), the Cellex Foundation for providing research facilities and equipment, the CERCA Programme from the Generalitat de Catalunya for their support on this research, and the Banco Bilbao Vizcaya Argentaria (BBVA) Foundation for supporting the Comprehensive Program of Cancer Immunotherapy and Immunology (CAIMI-I and CAIMI-II, grant no. 53/2021). In memory of Dr. José María Oliver, who played a pivotal role in the development of the field of Adult Congenital Heart Diseases in Spain and his early assessment of CCHD and PPGL association. The sponsors of this study listed below supported the costs related to the research experiments and salary of the investigators. Paradifference Foundation supported this PPGL research and provided funding support to J. Favier, M. Robledo, I. Adameyko, P.L.M. Dahia, and R.A. Toledo. The Pheipas Patient Association provided a research grant to R.A. Toledo for the study of PPGL tumors (grant #914300). C. Arenillas was supported by a CIBERONC predoctoral fellowship. R.A. Toledo holds a Miguel Servet-I research contract and a Plan Nacional grant by the Institute of Health Carlos III (ISCIII) of the Ministry of Economy and Competitiveness from the Spanish government (grants #CP17/00199 and #PID2021-126297OA-I00). P.L.M. Dahia received grants from the NIH/NIGMS (#GM114102), NIH/NCI (#CA264248), Neuroendocrine Tumor Research Foundation (NETRF), VHL Alliance, Paradifference Foundation and is the holder of the Robert Tucker Hayes Distinguished Chair in Oncology. M.-D. Chiara received grants from the Institute of Health Carlos III (ISCIII) of the Ministry of Economy and Competitiveness from the Spanish government (grants #PI20/01754 and #PID2023-151388OB-I00). J. Capdevila was partially supported by the Institute of Health Carlos III (ISCIII; #PI20/00895) and co-funded by the European Union (ERDF/ESF)—A way to build Europe and the Enric Masip Foundation. C. Arenillas, B. Calsina, T. Cubiella, J. Favier, M. Robledo, M.-D. Chiara, and R.A. Toledo were awarded with travel grants by European Cooperation in Science and Technology (COST) Action CA20122 Harmonisation
Safety of tarlatamab with 6-8-h outpatient versus 48-h inpatient monitoring during cycle 1: DeLLphi-300 phase 1 substudy
Get PDFPatient monitoring; Safety; Small-cell lung cancerMonitoreo de pacientes; Seguridad; Cáncer de pulmón de células pequeñasMonitorització de pacients; Seguretat; Càncer de pulmó de cèl·lules petitesBackground
Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3, has demonstrated promising survival outcomes in small-cell lung cancer (SCLC). Given the risk of cytokine release syndrome (CRS), initial clinical trials incorporated 48-72-h inpatient monitoring in cycle 1.
Methods
Patients with previously treated SCLC were enrolled into DeLLphi-300 part F, which evaluated the safety of tarlatamab 10 mg every 2 weeks (Q2W) with 6-8-h outpatient monitoring following cycle 1 doses. The primary endpoint, safety, was compared with patients from DeLLphi-300 part A receiving tarlatamab 10 mg Q2W with 48-h inpatient monitoring for cycle 1 doses.
Results
In cycle 1, the rates of treatment-related adverse events and hospitalizations, including emergency room visits, were similar between outpatient (n = 30) and inpatient (n = 58) groups (93% versus 100% and 27% versus 34%, respectively). The incidence of all grade and serious CRS during cycle 1 was similar between outpatient and inpatient groups (any grade: 60% versus 62%; serious: 17% versus 22%). The median time to CRS resolution was 3 days for both groups.
Conclusions
Safety outcomes, including hospitalization rates, were similar in this first-in-human study following tarlatamab 10 mg Q2W administration with 6-8-h outpatient versus 48-h inpatient monitoring in cycle 1.This work was funded by Amgen Inc.; DeLLphi-300 ClinicalTrials.gov number NCT03319940 (no grant number)
Respiratory dysbiosis as prognostic biomarker of disease severity for adults with community-acquired pneumonia requiring mechanical ventilation
Get PDFBiomarkers; Lung microbiome; Severe community-acquired pneumoniaBiomarcadores; Microbioma pulmonar; Neumonía grave adquirida en la comunidadBiomarcadors; Microbioma pulmonar; Pneumònia greu adquirida a la comunitatObjetives
To ascertain the role of the lung microbiome in the development of severe pneumonia and its potential as a biomarker for disease progression.
Methods
BAL samples from 34 adults with severe community-acquired pneumonia (CAP) (17 viral, 8 viral coinfected with bacteria and 9 bacterial) admitted to the ICU for acute respiratory failure between 2019 and 2021 were collected within the first 48 h of admission to the ICU. The microbiome was characterized via the Ion 16S Metagenomics Kit and the Ion Torrent sequencing platform. Clinical factors, including survival, mechanical ventilation duration, blood biomarkers and organ failure in terms of acute respiratory distress syndrome (ARDS), shock or acute renal failure, were correlated with microbiome characteristics.
Results
The microbiome diversity in patients with viral pneumonia was significantly greater than that in patients with bacterial or coinfected pneumonia: the Shannon diversity index was 3.75 (Q1–Q3: 2.5–4.1) versus 0.4 (Q1–Q3: 0.2–1.3) and 0.48 (Q1–Q3: 0.3–1.1), respectively (p < 0.05). The microbiome diversity index was associated with severity-of-illness (APACHE II), independent of the etiology of pneumonia (B coefficient -1.845; p < 0.01). Patients with severe viral CAP who developed ARDS had a lower presence of Proteobacteria, and those who were complicated with ventilator-associated pneumonia had a higher prevalence of Acinetobacter at admission. The mortality of patients with bacterial or coinfected pneumonia was 35%. In coinfected patients, the diversity index was associated with the development of shock.
Conclusion
Patients with severe CAP have low respiratory microbiome diversity, indicating that respiratory microbiome diversity is a potential biomarker of disease severity.This study was supported by a grant from the Spanish Ministry of Health, Instituto de Salud Carlos III, FIS17/01463
Adverse events and impact on quality of life of antibody-drug conjugates in the treatment of metastatic breast cancer: A systematic review and meta-analysis
Get PDFAntibody‐drug conjugate; Breast cancer; Quality of lifeConjugat d'anticossos i fàrmacs; Càncer de mama; Qualitat de vidaConjugado anticuerpo-fármaco; Cáncer de mama; Calidad de vidaBackground
Antibody-drug conjugates are novel effective therapies for metastatic breast cancer. Nevertheless, their toxicity profile can significantly affect patients' quality of life over time.
Methods
This is a systematic review and meta-analysis of randomized controlled trials of antibody-drug conjugates currently approved for the treatment of metastatic breast cancer [trastuzumab-emtansine (T-DM1), trastuzumab deruxtecan (T-DXd) and sacituzumab-govitecan (SG)] versus standard therapy to evaluate the risk of adverse events, discontinuation rate due to toxicity, impact on quality of life according to EORTC QLQ-C30 scale and subdomains. Relative risks (RR) and hazard ratios (HR) with 95% CIs were calculated using random effects models.
Results
Nine trials with a total of 5753 patients were included. The most common adverse events of any grade for T-DM1 included thrombocytopenia (RR 7.14, 95% CI 4.13–12.36) and increased alanine-transaminase (ALT) (RR 2.04, 95% CI 1.43–2.91), for T-DXd were nausea (RR 2.39, 95% CI 1.90–3.00) and anemia (RR 1.55, 95% CI 1.27–1.90), while for SG were neutropenia (RR 1.30, 95% CI 1.14–1.49), diarrhea (RR 3.62, 95% CI 2.97–4.42) and nausea (RR1.90, 95% CI 1.65–2.19). Severe adverse events such as interstitial lung disease and left ventricular dysfunction were peculiar of T-DXd. Antibody-drug conjugates significantly delayed clinical deterioration of global health status by EORTC QLQ-C30 (HR .71, 95% CI .59–.86), physical, emotional and social functioning, pain and fatigue symptoms.
Conclusions
This meta-analysis offers consolidated data on adverse events associated with antibody-drug conjugates and their effects on patients' quality of life, emphasizing differences based on the specific agent. These findings underscore the critical need for effective strategies to prevent, diagnose and manage these toxicities
HEBE: A novel chimeric chronokine for ameliorating memory deficits in Alzheimer's disease
Get PDFAlzheimer’s disease; Chimeric protein; Memory impairmentEnfermedad de Alzheimer; Proteína quimérica; Deterioro de memoriaMalaltia d'Alzheimer; Proteïna quimèrica; Deteriorament de la memòriaAlzheimer’s disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-β and Tau protein depositions, with treatments focusing on single proteins have shown limited success due to the complexity of pathways involved. This study explored the potential of chronokines —proteins that modulate aging-related processes— as an alternative therapeutic approach. Specifically, we focused on a novel pleiotropic chimeric protein named HEBE, combining s-KL, sTREM2 and TIMP2, guided by bioinformatic analyses to ensure the preservation of each protein’s conformation, crucial for their functions. In vitro studies confirmed HEBE’s stability and enzymatic activities, even suggesting it has different activities compared to the individual chronokines. In vivo experiments on APP/Tau mice revealed improved learning and memory functions with HEBE treatment, along with decreased levels of phosphorylated Tau and minor effects on amyloid-β levels. These findings suggest that HEBE is as a promising therapeutic candidate for ameliorating memory deficits and reducing pTau in an AD mouse model.This work was funded by MICINN/AEI/10.13039/501100011033 (PID2022–142624OB-I00 and PID2019–104034RB-I00 to MC); (PID2022-137668OB-I00) to CS; and (PID2023–148834OB-I00) to AB; by Instituto de Salud Carlos III and NexGenerationEU (RICORS, RD21/0017/0008) to MC and AB; and Generalitat de Catalunya (2021SGR-00529) to AB and MC, and (2021SGR-00142) to CS. JE was a recipient of a fellowship by the Generalitat de Catalunya (2020FI-SDUR0037). DRG was a recipient of a VHIR Fellowship. RB was a recipient of a fellowship by the Gobierno de España (FPU16/03137). MDCL was a recipient of a fellowship by the Ministerio de Ciencia e Innovación (BES-2017-082072)
Circular (purse-string) vs primary skin closure following stoma closure: an up-to-date systematic review and meta-analysis
Get PDFOstomy closure; Postoperative complications; Surgical wound infectionCierre de ostomía; Complicaciones postoperatorias; Infección de herida quirúrgicaTancament d'ostomia; Complicacions postoperatòries; Infecció de la ferida quirúrgicaBackground
Surgical site infections (SSI) are the most common complication after stoma closure. Circular skin closure (CSC) has been proposed to reduce SSI with comparable or even better outcomes than conventional primary sutures (PS). The aim of this meta-analysis is to compare circular with primary skin closure in stoma closure.
Method
A systematic review of the literature was performed for articles published between January 2010 and June 2023, including all randomized control trials (RCT) on wound infection of adult patients following stoma reversal. The primary outcome was 30-day SSI; secondary outcomes were operative time, length of stay, and incisional hernia.
Results
Eight RCTs were identified that included a total of 606 patients undergoing stoma closure surgery. Four percent of patients in the CSC group developed SSI, compared to 27% of patients undergoing PS. The 30-day SSI rate was lower after the circular skin closure (OR 0.11, 95% CI 0.06–0.21; p < 0.00001, I2 = 0%). There was no difference in the operative time (99.2 vs 103.5 min; MD − 0.17, 95% CI − 0.37, 0.03; p = 0.10), length of stay (7.1 vs 7.7 days; MD − 0.34, 95% CI − 0.55, − 0.12; p = 0.002), and incisional hernia rate (2% vs 4%; OR 0.61, 95% CI 0.23, 1.60; p = 0.31).
Conclusion
CSC is associated with lower SSI rate and should be preferred to linear skin closure technique after stoma closure surgery
Impact of the restrictive technique on outcomes in Baerveldt-350 implant surgery
Get PDFGlaucoma; Presión intraocular; Tratamiento quirúrgicoGlaucoma; Pressió intraocular; Tractament quirúrgicGlaucoma; Intraocular pressure; Treatment surgeryBackground Different aqueous restrictive manoeuvres in non-valved devices affect intraocular pressure (IOP) levels in the first postoperative month. This study compares tube ligature (TL) alone to TL plus rip cord stent (TLS) on the efficacy of the Baerveldt 350.
Methods We conducted a retrospective consecutive case-series observational study to assess efficacy by measuring IOP, success rates and the reduction of antiglaucoma medication usage over 3 years.
Results The study included 43 eyes in the TL group and 29 in the TLS group. Initial IOPs were 26.67 mm Hg for TL and 28.21 mm Hg for TLS. After 1 year, IOP decreased to 13.03 mm Hg and 12.11 mm Hg, respectively. Over 3 years, TLS consistently achieved greater reductions in IOP compared with TL, with significant differences of 3.56 mm Hg in the second year (p=0.01) and 3.34 mm Hg in the third year (p=0.01). Mean antiglaucoma medication use decreased from 3.03 (SD 1.29) to 0.72 (SD 0.47) over 3 years, representing a 76.24% reduction, with no differences between the TL and TLS groups. Failure rate at 1 year was significantly lower for TLS under the success criteria of IOP=(6–18) mm Hg (TL: 33.33%, TLS: 7.14%, p=0.02). Rates of transient hypotension and hypertensive phase were higher in the TL group: 93.02% vs 34.48% (p<0.001) and 58.14% vs 32.14% (χ²=4.59, p=0.03), respectively.
Conclusion Adding the rip cord stent to the Baerveldt implant significantly enhances long-term IOP control and reduces failure rates compared with TL alone. The lower incidence of hypertensive phases could be due to sequential tube opening. Small sample size, lack of randomisation and follow-up discrepancies may introduce bias and limit statistical power, highlighting the need for further research to confirm these conclusions
Nutritional status and quality of life of patients with advanced gastroenteropancreatic neuroendocrine neoplasms in Spain: the NUTRIGETNE (GETNE-S2109) study
Get PDFMalnutrition; Neuroendocrine neoplasms; SarcopeniaMalnutrició; Neoplàsies neuroendocrines; SarcopèniaMalnutrición; Neoplasias neuroendocrinas; SarcopeniaPatients with advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have impaired nutritional and physical performance due to the cancer pathophysiology and its treatment. The NUTRIGETNE study sought to characterize the nutritional status of patients with advanced GEP-NENs in Spain. This is a cross-sectional study that included patients with advanced GEP-NENs receiving active oncological treatment. Patients had a complete physical examination, anthropometry, bioelectrical impedance, dynamometry, laboratory analysis, and a comprehensive nutritional risk assessment. Malnutrition was defined according to Global Leadership Initiative on Malnutrition (GLIM) criteria. The study included 399 patients out of the 400 planned (Pearson's χ2; α 0.05). Median age was 62 years (22-83). Tumors most commonly originated in the small intestine (43.9%) and the pancreas (41.6%), 94.7% were metastatic, and 36.7%, 49.4%, and 12.5% were G1, G2, and G3, respectively. Malnutrition prevalence was 61.9% (25.8% moderate; 36.1% severe), mainly due to low muscle mass (50.9%), which was the most prevalent GLIM phenotypic criteria. Moreover, malnutrition showed a correlation with decreased hand grip strength (mean 23 vs 31.9 kg; P <.001) and phase angle (median 5o vs 5.6o; P <.001). The prevalence of sarcopenia was 15%. Malnutrition was more frequent in patients with diabetes (74.4% vs 56.7%; P <.001), NECs (82.1% vs 60.3%; P =.062), and in those treated with chemotherapy (71.2% vs 59.7%; P =.058), whereas it did not correlate with tumor origin (P =.507), histological grade (P =.781), or functionality (P =.465). Malnutrition was correlated to body mass index (BMI) (P =.015), although it was also diagnosed in a high proportion of patients with no weight loss (63%, 54.1%, and 65.1% of patients with normal BMI, overweight, and obesity, respectively). Cachexia was present in 109 (27.3%) patients. Malnutrition is very prevalent and commonly underdiagnosed in patients with GEP-NENs. It is associated with sarcopenia and a worse QoL, requiring a multifactorial nutritional assessment. Certain factors such as the presence of diabetes may require closer monitoring due to a higher risk of malnutrition.This study was funded by GETNE with the collaboration of Ipsen and Vegenat. The funders had no role in the design and conduct of the study
Safety, immunogenicity and effect on viral rebound of HTI vaccines combined with a TLR7 agonist in early-treated HIV-1 infection: a randomized, placebo-controlled phase 2a trial
Get PDFImmunogenicity; HIV-1 infectionInmunogenicidad; Infección por VIH-1Immunogenicitat; Infecció per VIH-1Building on results from the AELIX-002 trial with HIVACAT T-cell immunogen (HTI)-based vaccines, the AELIX-003 (NCT04364035) trial tested the safety of the combination of ChAdOx1.HTI (C) and MVA.HTI (M), with the TLR7 agonist vesatolimod (VES), in a double-blind, placebo-controlled, randomized clinical trial in 50 virally suppressed early-treated men with HIV-1 infection. Secondary objectives included immunogenicity and effects on viral rebound kinetics during a 24-week antiretroviral treatment interruption (ATI). The most common treatment-related adverse events were mild-to-moderate injection-site pain, influenza-like illness, headache, and fatigue. Strong, broad, and HTI-focused T-cell responses were induced by vaccination. All participants experienced viral rebound in ATI; 33.3% and 23.5% (P = 0.4494) of CCMM + VES and placebo recipients, respectively, remained off antiretroviral therapy for 24 weeks. Post hoc analysis confirmed a correlation between levels of HTI-specific T cells and prolonged time off antiretroviral therapy. The combination of HTI vaccines and VES was safe and elicited robust T-cell responses.Special thanks to all the volunteers participating in this study, all the site investigators for their perseverance and dedication to the study, and Gilead study team members (Mary Wire, Cori Calabi, Donovan Verrill, Jamil Hussain, Felicity Blackburn, Andrea Knapp, and Gordon Strachan) for their support of the VES pharmacokinetic/pharmacodynamic analysis and the manuscript development. We thank Marie Pierre Malice of StatAdvice (Brussels) for statistical support. Editing and production assistance for the manuscript were provided by Parexel and funded by Gilead Sciences, Inc. This study was funded by AELIX Therapeutics and Gilead Sciences, Inc. J.M.M. received a personal 80:20 research grant from Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, during 2017-2024. L.B. was supported by a PhD grant from the ISCIII Rio Hortega program (CM20/00097) during 2021–2023. The sponsors of the study, AELIX Therapeutics and Gilead Sciences, Inc., contributed to the study design, provided the treatments used in the study, oversaw all safety monitoring activities, data analysis, and interpretation, and provided a review of the manuscript
The efficacy and safety of mirvetuximab soravtansine in FRα-positive, third-line and later, recurrent platinum-sensitive ovarian cancer: the single-arm phase II PICCOLO trial
Get PDFAntibody–drug conjugate; Folate receptor alpha; Platinum-sensitive ovarian cancerConjugado anticuerpo-fármaco; Receptor de folato alfa; Cáncer de ovario sensible al platinoConjugat anticòs-fàrmac; Receptor de folat alfa; Càncer d'ovari sensible al platíBackground
Mirvetuximab soravtansine-gynx (MIRV) is a first-in-class, folate receptor alpha (FRα)-targeting antibody–drug conjugate with United States Food and Drug Administration approval for FRα-positive platinum-resistant ovarian cancer. PICCOLO is a phase II, global, open-label, single-arm trial of MIRV as third-line or greater (≥3L) treatment in patients with FRα-positive (≥75% of cells with ≥2+ staining intensity) recurrent platinum-sensitive ovarian cancer (PSOC).
Patients and methods
Participants received MIRV (6 mg/kg adjusted ideal body weight every 3 weeks) until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. Primary endpoint was investigator-assessed objective response rate (ORR). Key secondary endpoint was investigator-assessed duration of response (DOR). Additional endpoints included investigator-assessed progression-free survival (PFS), overall survival (OS), and safety. Analyses of subgroups by disease characteristics (e.g. platinum-free interval) and treatment history [e.g. prior bevacizumab and poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitor (PARPi) treatment] were exploratory.
Results
Seventy-nine participants were enrolled and efficacy assessable. The primary endpoint was met; ORR was 51.9% [95% confidence interval (CI) 40.4% to 63.3%]. Median DOR was 8.25 months (95% CI 5.55-10.78 months) and median PFS was 6.93 months (95% CI 5.85-9.59 months). OS was not mature at data cut-off. ORR was 45.8% (95% CI 32.7% to 59.2%) in participants with PD while on/within 30 days of prior PARPi (n = 59) and 60.0% (95% CI 14.7% to 94.7%) in those without PD with prior PARPi (n = 5). No new safety signals occurred; most common treatment-emergent adverse events (TEAEs) were gastrointestinal, neurosensory, and resolvable ocular events. TEAEs led to discontinuation in 13 participants (16%) and death in 2 participants (3%).
Conclusions
MIRV as ≥3L treatment in heavily pretreated recurrent FRα-positive PSOC demonstrated notable efficacy and tolerable safety, including among those with prior PD on or within 30 days of PARPi (NCT05041257).This work was supported by ImmunoGen, Inc. (no grant number). The sponsor designed, collected, analyzed, and interpreted the trial data in collaboration with the authors