Policlínica Gipuzkoa

Cancer dormancy refers to an asymptomatic stage in cancer progression that contains residual disease. Cancer cells can disseminate from early tumors even before they are detectable, from advanced tumors, and from other metastases. Thus, cancer dormancy is a collective phenomenon, composed of single dormant cells that stopped dividing, tumor mass dormancy where cell proliferation is balanced by cell death, and active micrometastases. Dormancy evolves with complex spatiotemporal dynamics across length scales (from cell-intrinsic to cell-extrinsic interactions and microenvironmental regulation up to the body-wide systemic level) and across timescales (from single dormant cells to dormant tumor masses and active micrometastases), each responding differently to fluctuating microenvironments. Here we review biological in vivo and clinical observations of breast cancer dormancy across scales in length and time. Next, we outline 3D bioengineered models in which these different spatial and temporal scales are considered. Finally, we discuss challenges and opportunities of incorporating patient-derived cells. Collective cell behavior is an important aspect in cancer progression and, as such, modeling dormancy across scales in length and time could open new avenues to help us understand and predict the transition to active metastatic growth.

Polyphenols represent the largest and most diverse class of dietary antioxidants. Epidemiological evidence linking specific (poly)phenol classes, such as flavonoids and lignans, to breast cancer (BC) risk remains limited and largely inconclusive in prospective studies. The aim of this study is to examine the association between the intake of total (poly)phenols-and its classes and subclasses-and BC risk-overall and by subtypes (estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2))-in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The EPIC cohort includes 257,960 adult women from seven European countries. During a mean follow-up of 14 years, there were 10,722 incident overall BC cases. Associations were computed using Cox regression models adjusted for potential confounders. No significant associations were found between total (poly)phenol intake and overall BC risk (HRQ5 vs. Q1 = 1.02; 95% CI: 0.95-1.11). In addition, null associations were mostly found between classes and subclasses of (poly)phenols and BC subtypes. After stratifying by menopausal status, no significant associations were observed. In conclusion, this study found no evidence of associations between the intake of any class or subclass of (poly)phenols and BC risk in the European population.

Este trabajo presenta un modelo computacional simplificado o modelo de juguete de una unidad funcional espinal (FSU) lumbar, centrado en el segmento L4-L5, con el objetivo de explorar parámetros relevantes para la planificación de cirugías mínimamente invasivas, como la discoplastía percutánea ósea. Al mismo tiempo la utilización de un "modelo de juguete"sirve para poder parametrizar la FSU. Utilizando herramientas de software libre, Gmsh, Dolfinx y Paraview, se creó un modelo simplificado por elementos finitos que permite simular condiciones fisiológicas y patológicas del disco intervertebral (DIV). En particular, se analiza cómo cambios en la altura del disco, el volumen del núcleo pulposo y la cantidad de cemento óseo inyectado afectan el comportamiento de la FSU. Este trabajo busca sentar las bases para, en el futuro, determinar de forma más precisa parámetros quirúrgicos como el volumen óptimo de cemento a utilizar en casos específicos.

Background:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a largely unknown duration and pathophysiology of the pre-diagnostic phase, especially for the common non-monogenic form.Methods:We leveraged the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with up to 30 years of follow-up to identify incident ALS cases across five European countries. Pre-diagnostic plasma samples from initially healthy participants underwent high-throughput proteomic profiling (7,285 protein markers, SomaScan). Cox proportional hazards models based on 4,567 participants (including 172 incident ALS cases) were used to identify protein biomarkers associated with future ALS diagnosis. Top results were indirectly validated in two independent case-control studies of prevalent ALS (n=417 ALS, 852 controls). Functional annotation included cross-disease comparisons, gene set and tissue enrichment testing, organ-specific proteomic clocks, and the application of large-language models (LLM).Findings:Five proteins (SECTM1, CA3, THAP4, KLHL41, SLC26A7) were identified as significant pre-diagnostic ALS biomarkers (FDR=0.05), detectable approximately two decades before diagnosis. Of these, all except SECTM1 were indirectly validated in independent cohorts of prevalent ALS cases, supporting their clinical significance. Additionally, 22 nominally significant (p<0.05) pre-diagnostic biomarkers were FDR-significant in prevalent ALS with consistent effect directions. Cross-disease comparisons with pre-diagnostic Parkinson’s and Alzheimer’s disease suggested a largely specific pre-diagnostic ALS biomarker signature. Gene ontology and tissue enrichment highlighted early involvement of immune, muscle, metabolic, and digestive processes. Furthermore, analyses of proteomic clocks revealed accelerated aging in brain-cognition, immune, and muscle tissues before clinical diagnosis. Druggability and LLM analyses revealed possible therapeutic targets and novel strategies, emphasizing translational relevance.Interpretation:Our study provides first evidence of ultra-early molecular changes in common ALS up to two decades prior to clinical onset, mainly affecting immune, muscle, metabolic, digestive, and cognitive systems. Our study nominates several compelling candidates for risk stratification studies and novel therapeutic targets for early intervention.Funding:Clinical Research in ALS and Related Disorders for Therapeutic Development (CreATe) Consortium, Cure Alzheimer’s Fund, Michael J Fox Foundation, Interdisciplinary Centre for Clinical Research, University Münster

When listening to speech, intelligibility (measured as percent words or phonemes correct) is increased for familiar talkers, both for talkers who are naturally familiar with the listener and for talkers who become familiar through lab-based training. These findings are robust and have been shown for individual words and sentences and for younger and older listeners. In the current study, we test the extent to which talker familiarity affects speech processing time. Listeners are familiarized with three talkers in a talker identification task. To test differences in processing speech, listeners then complete a lexical decision task with both familiarized and unfamiliar speakers. We predict that listeners will be faster at making lexical decisions for familiar speakers compared to unfamiliar speakers. Data collection is ongoing and results of this study will inform how talker familiarity impacts processing more broadly speaking.

Abstract Digital health interventions and gamification hold promise for managing chronic diseases, but evidence comparing their efficacy to usual care is limited. This two-arm parallel randomized controlled trial with embedded N-of-1 analyses assessed whether a digital intervention integrating gamification and telecoaching (Kiplin) outperform a supervised face-to-face adapted physical activity (PA) program (usual care) in obesity management. Patients with obesity and/or T2D (N = 50, Mage = 46.7 years, 74% female) were randomized to either the Kiplin digital intervention or usual care group, and completed a 3-month program with a 6-month follow-up. The primary outcome was the change in daily step count between baseline and the intervention’s end. Secondary outcomes assessed changes in daily steps, PA, quality of life, body composition, and physical capacities over nine months. Mixed-effects models and generative additive models were conducted to analyze both between- and within-person evolutions in PA. A cost-utility analysis was computed to compare the cost-effectiveness of the programs. Compared to usual care, Kiplin participants showed significant increases in daily steps during the intervention and follow-up periods, with sustained effect sizes. Idiographic analyses revealed variable individual responses, highlighting the need for tailored approaches. No significant differences were observed in secondary clinical outcomes or the cost-utility analysis. This study demonstrates the potential of digital interventions to sustain PA improvements that could offer an alternative to face-to-face programs, but the clinical and economic impacts need to be further evaluated.

173 Background: Microsatellite instability (MSI) localized colorectal cancer (CRC) constitutes a subgroup of patients (pts) with different clinical and molecular characteristics and prognosis compared to microsatellite stable (MSS) disease. Here, we present our real world data regarding the management and clinical outcomes of a cohort of MSI-h localized CRC patients included in the Spanish Group of Treatment of Digestive Tumors (TTD) Registry (RETUD). Methods: RETUD is a national, multicenter registry for gastrointestinal tumors from the Spanish TTD Group. In this cross-sectional analysis we evaluated a real-world cohort of MSI-h localized CRC pts diagnosed from 1 st January 2017 to 29 th April 2024. Baseline characteristics and neo/adjuvant treatments are descriptively presented. Disease-free survival (DFS) and overall survival (OS) analyzed by Kaplan-Meier method are presented along with 95% confidence intervals (CI). Results: Five hundred and sixty-one (561) evaluable pts out of 679 MSI-CRC included in RETUD had a localized disease as initial diagnosis. Pts had a median age of 73.1 years and were predominantly Caucasian (97.7%) and female (52.6%). Fifty (12.4%) pts had Lynch Syndrome. Main tumor baseline characteristics are described (Table). Local-locoregional therapeutic procedures were: primary tumor resection in 531 (99.1%) pts and radiotherapy in 18 (3.2%) pts. A total of 198 (35.3%) pts received systemic therapy, mostly chemotherapy (n=165 83.3%) but 18 (9.1%) were treated with pembrolizumab due to unresectable disease. At database cut-off, 123 (21.9%) patients died, mostly due to not related intercurrent illness, and 96 (17.1%) pts developed metastasis. After a median follow up period of 28.5 months, the median (95% CI) OS was not reached and DFS was 78.2 (55.4-NA) months. The impact of adjuvant systemic therapy (chemotherapy vs. non-chemotherapy) for both stage II and stage III pts is under evaluation. Conclusions: Our work provides valuable real-world data from a cohort of MSI-h localized CRC pts treated under clinical practice conditions in Spain, reiterating the good disease prognosis exhibited by this subset of pts in contrast to MSS pts. Main tumor characteristics. Stage at initial diagnosis, n (%) I/II n (%) 55 (9.8) / 258 (46.0) III, n (%) 248 (44.2) Location of primary tumor a , n (%) right colon /left colon /rectum 447 (78.4) / 82 (14.4) / 41 (7.2) Type histological b , n (%) Intestinal 271 (48.9) Mucinous (colloid) adenocarcinoma (&gt;50% mucinous) 115 (20.8) Signet ring cell carcinoma (&gt;50% signet ring) 14 (2.5) Medullary carcinoma 18 (3.2) a Pts with more than 1 primary tumor; the percentage may be over 100%. b Unknown histology in 132 (23.8%) pts and missing data in 7 pts.

Suicide remains a frequent cause of death in adults, often overlooked despite known risk factors like mental disorders, older age, and chronic illness. Emergency department visits offer critical opportunities to identify suicidal ideation and provide preventive care. This study reviewed deaths within 30 days of discharge from the emergency department of a major public hospital in Alicante, Spain, focusing on deaths by suicide. Over five years, 529,312 emergency visits were recorded, with 453,599 patients (85.7%) discharged home. Of the 356 patients (0.078%) who died within 30 days post-discharge, 7 (1.97%) died by suicide. Among these, four had a psychiatric history, and one had a history of substance abuse, both established risk factors. The overall suicide rate among adults discharged from the emergency department was 1.54 per 100,000. Compared with those who died from other causes within 30 days of discharge, patients who died by suicide were younger (median age 72 vs. 83 years; p = 0.037, adjusted OR: 0.59, 95% CI: 0.34–1.03; p = 0.06), had a lower Charlson Comorbidity Index (median 3 vs. 6; p = 0.003), and were more often male (6/7 vs. 50.1%; p = 0.1). The presence of psychiatric history was the most significant risk factor for suicide within 30 days of discharge from the emergency department among patients aged 15 and older. Men were more likely than women to die by suicide, with the majority between the ages of 65 and 79. Notably, only one individual had a prior suicide attempt.