To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial ...growth factor-A bispecific antibody.
YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study ETDRS letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593).
3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters 97·52% CI 9·4 to 12·0 vs 10·9 ETDRS letters 9·6 to 12·2, difference −0·2 ETDRS letters −2·0 to 1·6; RHINE 11·8 ETDRS letters 10·6 to 13·0 vs 10·3 ETDRS letters 9·1 to 11·4 letters, difference 1·5 ETDRS letters −0·1 to 3·2) and faricimab PTI (YOSEMITE 11·6 ETDRS letters 10·3 to 12·9, difference 0·7 ETDRS letters −1·1 to 2·5; RHINE 10·8 ETDRS letters 9·6 to 11·9, difference 0·5 ETDRS letters −1·1 to 2·1). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 31%, RHINE n=137 43%), faricimab PTI (n=106 34%, n=119 37%), and aflibercept every 8 weeks (n=102 33%, n=113 36%).
Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema.
F Hoffmann-La Roche.
Intravesical Bacillus Calmette Guerin (BCG) is the gold standard therapy for intermediate/high-risk non-muscle invasive bladder cancer (NMIBC). However, the response rate is ~60%, and 50% of ...non-responders will progress to muscle-invasive disease. BCG induces massive local infiltration of inflammatory cells (Th1) and ultimately cytotoxic tumor elimination. We searched for predictive biomarker of BCG response by analyzing tumor-infiltrating lymphocyte (TIL) polarization in the tumor microenvironment (TME) in pre-treatment biopsies. Pre-treatment biopsies from patients with NMIBC who received adequate intravesical instillation of BCG (n = 32) were evaluated retrospectively by immunohistochemistry. TME polarization was assessed by quantifying the T-Bet+ (Th1) and GATA-3+ (Th2) lymphocyte ratio (G/T), and the density and degranulation of EPX+ eosinophils. In addition, PD-1/PD-L1 staining was quantified. The results correlated with BCG response. In most non-responders, Th1/Th2 markers were compared in pre-and post-BCG biopsies. ORR was 65.6% in the study population. BCG responders had a higher G/T ratio and a greater number of degranulated EPX+ cells. Variables combined into a Th2-score showed a significant association with higher scores in responders (
= 0.027). A Th2-score cut-off value >48.1 allowed discrimination of responders with 91% sensitivity but lower specificity. Relapse-free survival was significantly associated with the Th2-score (
= 0.007). In post-BCG biopsies from recurring patients, TILs increased Th2-polarization, probably reflecting BCG failure to induce a pro-inflammatory status and, thus, a lack of response. PD-L1/PD-1 expression was not associated with the response to BCG. Our results support the hypothesis that a pre-existing Th2-polarized TME predicts a better response to BCG, assuming a reversion to Th1 polarization and antitumor activity.
Cysts of the brine shrimp Artemia franciscana are harvested from the Great Salt Lake (GSL) and San Francisco Bay (SFB) saltworks in the USA, and marketed worldwide to provide live food for ...aquaculture. This species has become invasive across several countries. We investigated (1) if the introduced populations in the Mediterranean region could have originated from these USA populations, (2) how the genetic diversity of Mediterranean compares to that at GSL and SFB, and (3) if genetic patterns in the Mediterranean can shed light on colonization routes. We sequenced a fragment of the cytochrome c oxidase subunit I and screened microsatellites loci from Mediterranean populations and the two putative USA sources. Haplotypes from Mediterranean populations were identical or closely related to those from SFB and GSL, and not related to other available American populations. Microsatellite analyses showed a reduced population diversity for most Mediterranean populations suggesting bottleneck effects, but few populations were showing similar or higher genetic diversity than native ones, which are likely to be admixed from both GSL and SFB because of multiple introductions. Results suggest natural dispersal, potentially via flamingos, between two Spanish populations. Our analyses show that all invaded populations could have originated from those commercialized USA populations.
Abstract Eslicarbazepine acetate (ESL, Aptiom™) is a once-daily anticonvulsant, approved as adjunctive treatment of partial-onset seizures (POS). Historical-controlled trials investigating the use of ...ESL as monotherapy have demonstrated a favorable efficacy and tolerability profile in patients with POS. This prospective, non-interventional study recruited POS patients in 17 hospitals in Spain. After a 3-month baseline period, ESL therapy was initiated as 400 mg QD and up-titrated to an optimal maintenance dose based on clinical response and tolerance. The incidence of seizures was assessed via seizure calendars and the nature and severity of adverse events (AEs) were also recorded. A total of 117 patients (aged 9–87 years) enrolled in the study and were treated with ESL at either 400 mg/day (3.4% patients), 800 mg/day (61% patients), 1200 mg/day (27.1% patients) or 1600 mg/day (8.5% patients). At 3 months, 82.0% (n = 72) of patients achieved a ≥ 50% reduction in seizure frequency, compared to 79.7% (n = 67) of patients at 6 months and 83.0% (n = 49) at 12 months. Patients who suffered secondary generalized tonic-clonic (SGTC) seizures had seizure-free rates of 71% (n = 27), 69.6% (n = 29), and 72.7% (n = 16) at 3, 6, and 12 months, respectively. Overall, 18 patients (15.3%) reported AEs of instability and dizziness (n = 9), somnolence (n = 3), mild hyponatremia (n = 3), headache (n = 1), hypertriglyceridemia (n = 1), and allergic reaction (n = 1), which caused ESL discontinuation of ESL treatment. ESL is effective and well tolerated as monotherapy for patients with POS, which supports previous findings. Early use is supported by its frequent use as monotherapy in this study and lack of severe side effects.
Despite the efforts made to improve the care of cardiogenic shock (CS) patients, including the development of mechanical circulatory support (MCS), the prognosis of these patients continues to be ...poor. In this context, CS code initiatives arise, based on providing adequate, rapid, and quality care to these patients. In this multidisciplinary document we try to justify the need to implement the SC code, defining its structure/organization, activation criteria, patient flow according to care level, and quality indicators. Our specific purposes are: a) to present the peculiarities of this condition and the lessons of infarction code and previous experiences in CS; b) to detail the structure of the teams, their logistics and the bases for the management of these patients, the choice of the type of MCS, and the moment of its implantation, and c) to address challenges to SC code implementation, including the uniqueness of the pediatric SC code. There is an urgent need to develop protocolized, multidisciplinary, and centralized care in hospitals with a large volume and experience that will minimize inequity in access to the MCS and improve the survival of these patients. Only institutional and structural support from the different administrations will allow optimizing care for CS.
Pese a los esfuerzos realizados para mejorar la atención al shock cardiogénico (SC), incluyendo el desarrollo de dispositivos de asistencia circulatoria mecánica (ACM), su pronóstico continúa siendo desfavorable. En este contexto surgen iniciativas de código SC, basadas en proporcionar una asistencia rápida y de calidad a estos pacientes. Este documento multidisciplinario trata de justificar la necesidad de implantar el código SC, definiendo su estructura/organización, criterios de activación, flujo de pacientes según nivel asistencial e indicadores de calidad. Sus propósitos concretos son: a) presentar las peculiaridades de esta enfermedad y el aprendizaje del código infarto y de experiencias previas en SC; b) detallar las bases para el abordaje de estos pacientes, la estructura de los equipos, su logística, la elección del tipo de ACM y el momento de su implante, y c) abordar los desafíos para la implantación del código SC, como la singularidad del código SC pediátrico. Urge desarrollar una asistencia protocolizada, multidisciplinaria y centralizada en hospitales con gran volumen y experiencia que permita minimizar la inequidad en el acceso a la ACM y mejorar la supervivencia de estos enfermos. Solo el apoyo institucional y estructural de las distintas administraciones permitirá optimizar la atención al SC.
•There is a significant overlap between the clinical characteristics and molecular profiles of CNL and aCML.•CNL and aCML can be classified as a single entity.
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Chronic neutrophilic ...leukemia (CNL) and atypical chronic myeloid leukemia (aCML) are rare myeloid disorders that are challenging with regard to diagnosis and clinical management. To study the similarities and differences between these disorders, we undertook a multicenter international study of one of the largest case series (CNL, n = 24; aCML, n = 37 cases, respectively), focusing on the clinical and mutational profiles (n = 53 with molecular data) of these diseases. We found no differences in clinical presentations or outcomes of both entities. As previously described, both CNL and aCML share a complex mutational profile with mutations in genes involved in epigenetic regulation, splicing, and signaling pathways. Apart from CSF3R, only EZH2 and TET2 were differentially mutated between them. The molecular profiles support the notion of CNL and aCML being a continuum of the same disease that may fit best within the myelodysplastic/myeloproliferative neoplasms. We identified 4 high-risk mutated genes, specifically CEBPA (β = 2.26, hazard ratio HR = 9.54, P = .003), EZH2 (β = 1.12, HR = 3.062, P = .009), NRAS (β = 1.29, HR = 3.63, P = .048), and U2AF1 (β = 1.75, HR = 5.74, P = .013) using multivariate analysis. Our findings underscore the relevance of molecular-risk classification in CNL/aCML as well as the importance of CSF3R mutations in these diseases.
ABSTRACT Introduction and objectives: This is the 2021 annual activity report from the Interventional Cardiology Association of the Spanish Society of Cardiology (ACI-SEC), and the Interventional ...Working Group of the Spanish Society of Pediatric Cardiology (GTH-SECPCC). Methods: All Spanish centers with cath lab capabilities and interventional activity in congenital heart diseases were invited to participate. Data were collected online, analyzed by an external company, and ACI-SEC and GTH-SECPCC members. Results: A total of 16 centers participated—15 public and 1 private—including 34 cath labs with experience in congenital heart diseases, 7 of them (20.5%) exclusively dedicated to pediatric patients. A total of 1094 diagnostic studies (4.5% more than 2020) and 1553 interventional catheterizations (5.8% more than 2020) were registered. The most common procedures were atrial septal defect closure (336 cases), pulmonary branch artery angioplasty (231 cases), and percutaneous closure of the patent ductus arteriosus (228 cases). Interventional procedures were considered successful in 95% of the cases with rates of major procedural complication and in-hospital mortality of 2.7% and 0.2%, respectively. Conclusions: This is the second Spanish Cardiac Catheterization in Congenital Heart Diseases Registry report. A significant increase of diagnostic and interventional procedures was reported with a special increase of percutaneous valve implantation, ductus arteriosus closure, and aortic angioplasty. Most interventional techniques continue to demonstrate excellent safety and efficacy outcomes.
Checkpoint with forkhead-associated and ring finger domains (
CHFR
) has been proposed as a predictive and prognosis biomarker for different tumor types, but its role in pancreatic ductal ...adenocarcinoma (PDAC) remains unknown. The aim of this study was two-pronged: to review the role of
CHFR
in PDAC and evaluating
CHFR
as a potential predictive biomarker in this disease. For this purpose, we first explored the CHFR messenger (m)RNA expression and promoter methylation through the TCGA database. Secondly, the CHFR expression and promoter methylation were prospectively evaluated in a cohort of patients diagnosed with borderline (
n
= 19) or resectable (
n
= 16) PDAC by immunohistochemistry (IHC), methylation specific-PCR (MSP), and pyrosequencing. The results from the TCGA database showed significant differences in terms of progression-free survival (PFS) and overall survival (OS) based on the CHFR mRNA expression, which was likely independent from the promoter methylation. Importantly, our results showed that in primarily resected patients and also the entire cohort, a higher CHFR expression as indicated by the higher IHC staining intensity might identify patients with longer disease-free survival (DFS) and OS, respectively. Similarly, in the same cohorts, patients with lower methylation levels by pyrosequencing showed significantly longer OS than patients without this pattern. Both, the CHFR expression intensity and its promoter methylation were established as independent prognostic factors for PFS and OS in the entire cohort. In contrast, no significant differences were found between different methylation patterns for
CHFR
and the response to taxane-based neoadjuvant treatment. These results suggest the potential role of the higher expression of CHFR and the methylation pattern of its promoter as potential prognostic biomarkers in PDAC, thus warranting further comprehensive studies to extend and confirm our preliminary findings.
Advance in the knowledge of molecular biology has thrown light on many aspects of apoptosis regulation mechanisms. This has allowed a change in anti-cancer therapy trends, from classic cytotoxic ...strategies to the development of new non-harmful therapies which target the apoptosis response selectively only in tumour cells. We have selected an anthranilic alcohol-derived acyclic 5-fluorouracil O,N-acetal (5) to carry out the anti-cancer studies. This compound shows activity as a potent growth inhibitor of the tumour cell line MCF-7 at a very low concentration. Moreover, when this compound was administered to the non-neoplastic cell line, MCF-10A displayed less toxicity resulting in lower rates of apoptosis. Further studies by microarray hybridization, real-time PCR and western blot showed that when administered to human breast cancer cells, MCF-7, 5 had no activity against classic pro-apoptotic genes such as p53, and even induced the down-regulation of anti-apoptotic genes such as Bcl-2. In contrast, several pro-apoptotic genes related with the endoplasmic reticulum (ER)-stress-induced apoptosis, such as BBC3 and Noxa, appeared up-regulated. These results seem to show that the mechanism of action and selectivity of 5 was via the activation of the ER stress-induced apoptosis. The selective activity of this compound against tumour cells via the ER stress-induced apoptosis supposes a great advantage for future therapeutic use.
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► An alcohol-derived acyclic 5-FU O,N-acetal has been studied for anti-cancer activity. ► It shows potent growth inhibition of the cell line MCF-7 at a very low concentration. ► ER stress-induced apoptosis is the mechanism of action against MCF-7. ► When it is administered to the non-neoplastic cell line MCF-10A displayed less toxicity. ► It has no activity against p53 and induces down-regulation of Bcl-2.
Pese a los esfuerzos realizados para mejorar la atención al shock cardiogénico (SC), incluyendo el desarrollo de dispositivos de asistencia circulatoria mecánica (ACM), su pronóstico continúa siendo ...desfavorable. En este contexto surgen iniciativas de código SC, basadas en proporcionar una asistencia rápida y de calidad a estos pacientes. Este documento multidisciplinario trata de justificar la necesidad de implantar el código SC, definiendo su estructura/organización, criterios de activación, flujo de pacientes según nivel asistencial e indicadores de calidad. Sus propósitos concretos son: a) presentar las peculiaridades de esta enfermedad y el aprendizaje del código infarto y de experiencias previas en SC; b) detallar las bases para el abordaje de estos pacientes, la estructura de los equipos, su logística, la elección del tipo de ACM y el momento de su implante, y c) abordar los desafíos para la implantación del código SC, como la singularidad del código SC pediátrico. Urge desarrollar una asistencia protocolizada, multidisciplinaria y centralizada en hospitales con gran volumen y experiencia que permita minimizar la inequidad en el acceso a la ACM y mejorar la supervivencia de estos enfermos. Solo el apoyo institucional y estructural de las distintas administraciones permitirá optimizar la atención al SC.
Despite the efforts made to improve the care of cardiogenic shock (CS) patients, including the development of mechanical circulatory support (MCS), the prognosis of these patients continues to be poor. In this context, CS code initiatives arise, based on providing adequate, rapid, and quality care to these patients. In this multidisciplinary document we try to justify the need to implement the SC code, defining its structure/organization, activation criteria, patient flow according to care level, and quality indicators. Our specific purposes are: a) to present the peculiarities of this condition and the lessons of infarction code and previous experiences in CS; b) to detail the structure of the teams, their logistics and the bases for the management of these patients, the choice of the type of MCS, and the moment of its implantation, and c) to address challenges to SC code implementation, including the uniqueness of the pediatric SC code. There is an urgent need to develop protocolized, multidisciplinary, and centralized care in hospitals with a large volume and experience that will minimize inequity in access to the MCS and improve the survival of these patients. Only institutional and structural support from the different administrations will allow optimizing care for CS.
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