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Drug-drug interactions between palbociclib and proton pump inhibitors in early breast cancer: an exploratory analysis of PALLAS (ABCSG-42/AFT-05/BIG-14-13/PrE0109)
Get PDFBreast cancer; Palbociclib; Proton pump inhibitorsCáncer de mama; Palbociclib; Inhibidores de la bomba de protonesCàncer de mama; Palbociclib; Inhibidors de la bomba de protonsBackground
Concomitant intake of proton pump inhibitors (PPIs) may create drug–drug interactions, potentially impacting efficacy of anticancer agents. In the phase III PALLAS trial, the addition of palbociclib capsules to standard adjuvant endocrine therapy in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer did not improve invasive disease-free survival (iDFS). We explored whether concomitant use of PPIs affected survival outcomes in patients treated with palbociclib in PALLAS.
Methods
This is an exploratory analysis of PALLAS including patients who received at least one dose of palbociclib capsules. We aimed to determine the association of concomitant PPI use with iDFS, distant relapse-free survival and overall survival. Uni- and multivariable Cox models with time-dependent PPI were used. The association between PPI use and neutropenia was also investigated.
Results
Of 2840 patients treated with palbociclib + endocrine therapy, 525 (18.5%) had concomitant PPI and palbociclib intake. PPI intake was significantly associated with older age, post-menopausal status, use of aromatase inhibitors, higher body mass index, and worse Eastern Cooperative Oncology Group status (all P < 0.001). Concomitant PPI intake was not significantly associated with survival outcomes (iDFS, distant relapse-free survival, overall survival). All-grade neutropenia rates were numerically lower in patients who initiated a PPI before study start compared with patients never initiating PPIs (adjusted odds ratio 0.81, 95% confidence interval 0.60-1.09).
Conclusions
Our exploratory analysis did not demonstrate worse survival outcomes in patients receiving concomitant palbociclib and PPIs in PALLAS. Nonetheless, careful consideration of possible drug–drug interactions is important, especially when studying novel agents in the early breast cancer setting
Subchondroplasty® (SCP) Provides Resolution of Symptoms and Functional Improvements in Mild-to-Moderate Knee Osteoarthritis with Persistent Bone Marrow Lesions: 12-Month Follow-Up Results from a Multicentric Open-Label Prospective Clinical Trial
Get PDFBone marrow lesions; Osteoarthritis; SubchondroplastyLesions de medul·la òssia; Osteoartritis; SubcondroplàstiaLesiones de médula ósea; Osteoartritis; SubcondroplastiaIntroduction. Bone marrow lesions (BMLs) are MRI-visible subchondral bone alterations, highly correlated with symptoms in the knee. Subchondroplasty (SCP) is able to fill the subchondral defects associated with BMLs using an injectable bone substitute material. The aim of the present study is to evaluate the 12-month outcomes of the SCP in the treatment of symptoms of mild-to-moderate knee osteoarthritis (OA) patients with persistent BMLs of the knee. Materials and Methods. Subjects affected by BMLs of the femoral condyle or tibial plateau that were present for >3 months and not responsive to conservative treatments were enrolled in this prospective multicenter trial. All the patients underwent SCP. Follow-up was conducted at 1, 3, 6 and 12 months. All subjects completed Numerical Rating Scale (NRS) for pain, Knee Injury and Osteoarthritis Outcome (KOOS) score, Euro Quality of life-5 dimensions (EQ-5D) score, and a subject global satisfaction scale. Demographic information of the patients was also collected. Results. A total of 79 patients completed the 12-month follow-up. Statistically significant improvements on all clinical scales were registered from baseline to the 12-month follow-up. No severe adverse events were reported. Four patients were considered failed. A 12-month subgroup analysis was performed to evaluate the possible correlation between all the KOOS subscales and age, gender, number of BMLs, location of BMLs, and Kellgren-Lawrence grade: no statistically significant associations were observed. Conclusion. SCP is a safe and effective procedure for the treatment of symptoms related to persisting BMLs in mild-to-moderate osteoarthritic knees, with a low failure rate up to 12 months’ evaluation.The presented study was fully sponsored by Zimmer Biomet
Myo-Guide: A Machine Learning-Based Web Application for Neuromuscular Disease Diagnosis With MRI
Get PDFMRI; Artificial intelligence; Neuromuscular diseasesImagen por resonancia magnética; Inteligencia artificial; Enfermedades neuromuscularesImatges per ressonància magnètica; Intel·ligència artificial; Malalties neuromuscularsBackground
Neuromuscular diseases (NMDs) are rare disorders characterized by progressive muscle fibre loss, leading to replacement by fibrotic and fatty tissue, muscle weakness and disability. Early diagnosis is critical for therapeutic decisions, care planning and genetic counselling. Muscle magnetic resonance imaging (MRI) has emerged as a valuable diagnostic tool by identifying characteristic patterns of muscle involvement. However, the increasing complexity of these patterns complicates their interpretation, limiting their clinical utility. Additionally, multi-study data aggregation introduces heterogeneity challenges. This study presents a novel multi-study harmonization pipeline for muscle MRI and an AI-driven diagnostic tool to assist clinicians in identifying disease-specific muscle involvement patterns.
Methods
We developed a preprocessing pipeline to standardize MRI fat content across datasets, minimizing source bias. An ensemble of XGBoost models was trained to classify patients based on intramuscular fat replacement, age at MRI and sex. The SHapley Additive exPlanations (SHAP) framework was adapted to analyse model predictions and identify disease-specific muscle involvement patterns. To address class imbalance, training and evaluation were conducted using class-balanced metrics. The model's performance was compared against four expert clinicians using 14 previously unseen MRI scans.
Results
Using our harmonization approach, we curated a dataset of 2961 MRI samples from genetically confirmed cases of 20 paediatric and adult NMDs. The model achieved a balanced accuracy of 64.8% ± 3.4%, with a weighted top-3 accuracy of 84.7% ± 1.8% and top-5 accuracy of 90.2% ± 2.4%. It also identified key features relevant for differential diagnosis, aiding clinical decision-making. Compared to four expert clinicians, the model obtained the highest top-3 accuracy (75.0% ± 4.8%). The diagnostic tool has been implemented as a free web platform, providing global access to the medical community.
Conclusions
The application of AI in muscle MRI for NMD diagnosis remains underexplored due to data scarcity. This study introduces a framework for dataset harmonization, enabling advanced computational techniques. Our findings demonstrate the potential of AI-based approaches to enhance differential diagnosis by identifying disease-specific muscle involvement patterns. The developed tool surpasses expert performance in diagnostic ranking and is accessible to clinicians worldwide via the Myo-Guide online platform.Jose Verdu-Diaz, Carla Bolano-Díaz, Alejandro Gonzalez-Chamorro, Sam Fitzsimmons, Jaume Bacardit and Jordi Díaz-Manera disclose support for the research of this work from Muscular Dystrophy UK (grant number: 22GRO-PG24-0575 and 24GRO-PG24-0736-1) and AFM-Telethon (grant number: 23444). Jose Verdu-Diaz is also supported by the NHIR Newcastle Biomedical Research Centre (BRC) (grant number: NIHR203309). The NHIR Newcastle BRC is a partnership between Newcastle Hospitals NHS Foundation Trust and Newcastle University, funded by the National Institute for Health and Care Research (NIHR). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care
Late arrhythmic burden in patients with left bundle branch block after TAVR with the Evolut valve
Get PDFConduction disturbances; Pacemaker implantation; Transcatheter aortic valve replacementTrastornos de la conducción; Implante de marcapasos; Reemplazo de válvula aórtica transcatéterTrastorns de la conducció; Implant de marcapassos; Substitució de la vàlvula aòrtica transcatèterAims
Arrhythmic burden after discharge in patients with new-onset persistent left bundle branch block (NOP-LBBB) following transcatheter aortic valve replacement (TAVR) with Evolut devices remains largely unknown. The aim of this study is to assess the incidence and type of arrhythmias at 2-year follow-up in patients with NOP-LBBB post-TAVR.
Methods and results
This is a prospective multicentre study including 88 patients with LBBB persisting for ≥3 days post-implantation. Before discharge, an implantable loop recorder (REVEAL XT/LINQ) was implanted; patients had continuous monitoring for 2 years. Arrhythmic events were adjudicated in a central core lab. Of the arrhythmic events, 411 were detected in 58 patients [65.9%; 2 (1–4) events per patient]. Symptoms were reported in 12/58 (20.7%), and therapy was changed in 25/58 (43.1%). There were 101 bradyarrhythmic events in 33 patients [35 high-grade atrioventricular block (HAVB) and 66 severe bradycardia]. The HAVB incidence was higher in the early (4-week) phase and remained stable over time, whereas severe bradycardia increased after 1 year. Permanent pacemaker was required in 11 (12.5%) patients (6.8% and 5.7% in the first and second year, respectively). There were 310 tachyarrhythmic events in 29 patients (120 AF/AFL, 111 AT, 72 SVT, 6 NSVT, and 1 VT); its incidence decreased throughout the 2 years. New AF/AFL episodes occurred in 20/69 patients [29%; symptomatic in 2/20 (10%)].
Conclusion
Patients with NOP-LBBB post-TAVR with Evolut devices exhibited a high burden of late arrhythmias, with events occurring in two-thirds of patients and leading to treatment changes in about half of them. These data should inform future studies on cardiac monitoring devices for follow-up and treatment optimization in this challenging population.S.M.-P. has received a research grant from the ‘Fundación Alfonso Martín Escudero’ (Madrid, Spain). J.R.-C. holds the Research Chair in ‘Fondation Famille Jaques Larivière’ for the Development of Structural Heart Interventions
MIA40 circumvents the folding constraints imposed by TRIAP1 function
Get PDFFolding intermediates; Molten globule; Oxidative foldingIntermediarios de plegamiento; Glóbulo fundido; Plegamiento oxidativoIntermedis de plegament; Glòbul fos; Plegament oxidatiuThe MIA40 relay system mediates the import of small cysteine-rich proteins into the intermembrane mitochondrial space (IMS). MIA40 substrates are synthesized in the cytosol and assumed to be disordered in their reduced state in this compartment. As they cross the outer mitochondrial membrane, MIA40 promotes the oxidation of critical native disulfides to facilitate folding, trapping functional species in the IMS. Here, we study the redox-controled folding of TRIAP1, a small cysteine-rich protein with moonlighting function: regulating phospholipid trafficking between mitochondrial membranes in the IMS and preventing apoptosis in the cytosol. TRIAP1 dysregulation is connected to oncogenesis. Although TRIAP1 contains a canonical twin CX9C motif, its sequence characteristics and folding pathway deviate from typical MIA40 substrates. In its reduced state, TRIAP1 rapidly populates a hydrophobic collapsed, alpha-helical, and marginally stable molten globule. This intermediate biases oxidative folding towards a non-native Cys37-Cys47 kinetic trap, slowing the reaction. MIA40 accelerates TRIAP1 folding rate by 30-fold, bypassing the formation of this folding trap. MIA40 drives the oxidation of the inner disulfide bond Cys18-Cys37, and subsequently, it can catalyze the formation of the outer disulfide bond Cys8-Cys47 to attain the native two-disulfide-bridged structure. We demonstrate that, unlike most MIA40 substrates, TRIAP1's folding pathway is strongly constrained by the structural requirements for its function in phospholipid traffic at the IMS. The obligatory population of a reduced, alpha-helical, metastable molten globule in the cytoplasm may explain TRIAP1's connection to the p53-dependent cell survival pathway, constituting a remarkable example of a functional molten globule state.This work was funded by the Spanish Ministry of Science and Innovation (MICINN, Spain) (PID2022-137963OB-I00), by ICREA (ICREA-Academia 2020, Spain), and by CERCA Programme (Generalitat de Catalunya) to S. V. J. P., M. G.-G., and M. F.-S. were supported by the Spanish Ministry of Science and Innovation via a doctoral grant (FPU14/07161, FPU16/02465, and FPU20/02897), respectively
Medical Nutrition Therapy and Physical Exercise for Acute and Chronic Hyperglycemic Patients with Sarcopenia
Get PDFHyperglycemia; Nutritional formulae; Physical exerciseHiperglucemia; Fórmulas nutricionales; Ejercicio físicoHiperglucèmia; Fórmules nutricionals; Exercici físicA wide range of factors contribute to the overlap of hyperglycemia—acute or chronic—and sarcopenia, as well as their associated adverse consequences, which can lead to impaired physical function, reduced quality of life, and increased mortality risk. These factors include malnutrition (both overnutrition and undernutrition) and low levels of physical activity. Hyperglycemia and sarcopenia are interconnected through a vicious cycle of events that mutually reinforce and worsen each other. To explore this association, our review compiles evidence on: (i) the impact of hyperglycemia on motor and muscle function, with a focus on the mechanisms underlying biochemical changes in the muscles of individuals with or at risk of diabetes and sarcopenia; (ii) the importance of the clinical assessment and control of sarcopenia under hyperglycemic conditions; and (iii) the potential benefits of medical nutrition therapy and increased physical activity as muscle-targeted treatments for this population. Based on the reviewed evidence, we conclude that a regular intake of key functional nutrients, together with structured and supervised resistance and/or aerobic physical activity, can help maintain euglycemia and improve muscle status in all patients with hyperglycemia and sarcopenia.Medical writing services were sponsored by Fresenius Kabi. Nevertheless, Fresenius Kabi was not involved in the literature review or the selection of content for the publication, which was carried out exclusively at the discretion of the author
Spanish consensus on the diagnosis and management of adrenocortical carcinoma
Get PDFAdrenalectomy; Adrenocortical carcinoma; MitotaneAdrenalectomia; Carcinoma adrenocortical; MitotàAdrenalectomía; Carcinoma adrenocortical; MitotanoAdrenocortical carcinoma (ACC) is a rare endocrine malignancy with an estimated incidence of 0.7-2 cases per million/year. The rarity of this disease, coupled with limited preclinical models and clinical trials, has hindered progress, resulting in poor outcomes, with a 5-year survival rate of approximately 35%. Currently, the only available curative treatment is complete surgical resection of the adrenal tumor. For unresectable or metastatic ACC, the current standard therapeutic modalities are mitotane, chemotherapy, radiotherapy and locoregional treatments; however, these are noncurative. Mitotane has an adrenolytic and anti-steroidogenic effect, and it is used in the adjuvant setting for high-risk patients, as systemic therapy for metastatic disease, and/or to control hormonal secretion. While key pathways in ACC pathogenesis have been identified as potential therapeutic targets, results with targeted therapies remain modest, showing that there is a clinical unmet need for novel treatments or new combinations of exiting drugs. Effective management requires a multidisciplinary team of experts to optimize outcomes for patients. This article presents a multidisciplinary consensus on the diagnosis, management, prognosis and follow-up of patients with ACC, and the approach to two special contexts, ACC in pregnant women and hormone-producing ACC. The consensus was coordinated by the Spanish Society of Endocrinology and Nutrition (SEEN) and the Spanish Group of Neuroendocrine and Endocrine Tumors (GETNE), with contribution from experts from related societies including the Spanish Association of Surgeons (AEC), Spanish Society of Urology (AEU), Anatomic-Pathology (SEAP), Nuclear Medicine (SEMNIM), Medical Oncology (SEOM) and Radiotherapeutic Oncology (SEOR).This work was funded by Sociedad Española de Endocrinología y Nutrición (SEEN) and the Spanish Group of Neuroendocrine and Endocrine Tumors (GETNE)
Comparison of clinical measures of motor function with a Holter monitor in Parkinson’s disease
Get PDFAutomatic ambulatory monitoring; Motor fluctuations; Parkinson’s diseaseMonitorització ambulatòria automàtica; Fluctuacions motores; Malaltia de ParkinsonMonitoreo ambulatorio automático; Fluctuaciones motoras; Enfermedad de ParkinsonBackground
Parkinson’s disease (PD) is a significant global health challenge, affecting millions worldwide. This sub-study aims to explore the potential of ambulatory monitoring devices in identifying disease severity and progression in patients. As part of the MOMOPA-EC clinical trial, 156 patients with moderate to severe PD underwent 435 assessments using clinical scales and ambulatory monitoring devices (Parkinson’s Holter). This sub-study seeks to establish relations between parameters derived from Holter monitors and clinical severity measures to enhance personalized disease management strategies. Methods: In the MOMOPA-EC trial, 435 patient monitoring sessions were conducted, during which patients wore Parkinson’s Holter monitors for a week before completing clinical assessments, including the Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Questionnaire (PDQ-39), and Freezing of Gait Questionnaire (FoG-Q). Results: The reports obtained during the monitoring of the patients were classified into three groups based on the greater or lesser gait fluidity (according to the measurements from the Parkinson’s Holter). All clinical scales were significantly different in each of these groups, indicating that patients with lower stride fluidity had poorer outcomes across the different clinical scales. Conclusions: The findings of this study underscore the potential of Parkinson’s Holters in providing objective data for personalized disease management in PD patients. Integrating such technologies into routine clinical practice could enhance patient care and treatment strategies by offering clinicians objective insights into both disease progression and therapeutic response.This work is supported by the Instituto de Salud Carlos III [DTS17/ 00195], the “A way to make Europe” European Fund for Regional Development, and AbbVie S.L.U
I have tested positive for human papillomavirus. Should i take any oral or vaginal treatment?
Get PDFVirus de papil·loma humà (VPH); Infeccions de transmissió sexual (ITS); TractamentVirus de papiloma humano (VPH); Infecciones de transmisión sexual (ITS); TratamientoHuman papillomavirus (HPV); Sexually transmitted infections (STIs); TreatmentRecomanació Essencial sobre la infecció pel virus de papil·loma humà i tractament segons la qual "en les persones amb un resultat positiu a la prova de detecció del virus de papil·loma humà (VPH), no existeix evidència suficient per recomanar la prescripció de prebiòtics, probiòtics o altres suplements, ni orals ni tòpics per a la prevenció del càncer ginecològic". Essencial és un projecte de l'Agència de Qualitat i Avaluació Sanitàries de Catalunya del Departament de Salut per reduir o evitar les pràctiques clíniques de poc valor.Recomendación Esssencial sobre la infección por el virus del papiloma humano y tratamiento según la cual "en las personas con un resultado positivo en la prueba de detección del virus del papiloma humano (VPH), no existe evidencia suficiente para recomendar la prescripción de prebióticos, probióticos u otros suplementos, ya sean orales o tópicos, para la prevención del cáncer ginecológico". Essencial es un proyecto de la Agencia de Calidad y Evaluación Sanitarias de Cataluña del Departamento de Salud para reducir o evitar las prácticas clínicas de poco valor.Essential Recommendation on human papillomavirus (HPV) infection and treatment stating that "in individuals with a positive result on the human papillomavirus (HPV) screening test, there is insufficient evidence to recommend the use of prebiotics, probiotics, or other supplements, whether oral or topical, for the prevention of gynecological cancer." Essencial is a project of the Catalan Agency for Health Quality and Assessment under the Department of Health aimed at reducing or avoiding low-value clinical practices
In Situ Detection of Programmed Cell Death Protein 1 and Programmed Death Ligand 1 Interactions as a Functional Predictor for Response to Immune Checkpoint Inhibition in NSCLC
Get PDFImmune checkpoint inhibitor; Programmed cell death protein 1; Non-small cell lung cancerInhibidor del punto de control inmunitario; Proteína de muerte celular programada 1; Cáncer de pulmón de células no pequeñasInhibidor del punt de control immunitari; Proteïna de mort cel·lular programada 1; Càncer de pulmó de cèl·lules no petitesIntroduction
Immune checkpoint inhibitors (ICIs) have transformed lung cancer treatment, yet their effectiveness seem restricted to certain patient subsets. Current clinical stratification on the basis of programmed death ligand 1 (PD-L1) expression offers limited predictive value. Given the mechanism of action, directly detecting spatial programmed cell death protein 1 (PD1)–PD-L1 interactions might yield more precise insights into immune responses and treatment outcomes.
Methods
We applied a second-generation in situ proximity ligation assay to detect PD1–PD-L1 interactions in diagnostic tissue samples from 16 different cancer types, a tissue microarray with surgically resected early-stage NSCLC, and finally diagnostic biopsies from 140 patients with advanced NSCLC with and without ICI treatment. RNA sequencing analysis was used to identify potential resistance mechanisms.
Results
In the early-stage NSCLC, only approximately half of the cases with detectable PD-L1 and PD1 expression exhibited PD1–PD-L1 interactions, with significantly lower levels in EGFR-mutated tumors. Interaction levels varied across cancer types, aligning with reported ICI response rates. In ICI-treated patients with NSCLC, higher PD1–PD-L1 interactions were linked to complete responses and longer survival, outperforming standard PD-L1 expression assays. Patients who did not respond to ICIs despite high PD1–PD-L1 interactions exhibited additional expression of stromal immune mediators (EOMES, HAVCR1/TIM-1, JAML, FCRL1).
Conclusion
Our study proposes a diagnostic shift from static biomarker quantification to assessing active immune pathways, providing more precise ICI treatment. This functional concept applies to tiny lung biopsies and can be extended to further immune checkpoints. Accordingly, our results indicate concerted ICI resistance mechanisms, highlighting the need for combination diagnostics and therapies.This study received funding through the following authors: Dr. Strell from the Norwegian Cancer Society (#255690), the Swedish Cancer Society (21149PJ), The Swedish Research Council (2022-01151), and a starting grant from the Trond Mohn Foundation (TMS2022STG01); Dr. Micke from the Sjöberg Foundation, The Swedish Cancer Society (211790PJ), The Swedish Research Council (2021-02693), and The Lions Cancer Foundation Uppsala; Dr. Isaksson from the Gävle Cancer Society; Dr. Kärre from the Sjöberg Foundation and the Swedish Cancer Society (201368Pj); and Ms. Lindberg from the Dr. Margaretha Nilsson Stiftelse for Medicinsk Forskning (travel grant). The authors also thank the Research, Development, and Teaching Unit at the Department of Clinical Pathology of Uppsala University Hospital, Uppsala, Sweden, for practical support