Estudio de las vías de señalización celular en cáncer de ovario y de endometrio : implicaciones en el pronóstico

Los carcinomas de ovario y de endometrio son los tumores malignos ginecológicos más frecuentes en nuestro entorno. Se han descrito alteraciones genéticas recurrentes que son características de algunos tipos histológicos y que han permitido definir vías patogenéticas distintas tanto para ovario como para endometrio. Entre estas alteraciones, algunas afectan directamente las vías de señalización celular que regulan el crecimiento y proliferación de la célula. Estas vías representan una de las alteraciones clave implicadas en el desarrollo del cáncer y que han adquirido una trascendencia importante, desde la aplicación en la práctica clínica, de tratamientos dirigidos contra algunas de estas moléculas. Sin embargo, la comprensión de estas vías se complica por la presencia de múltiples interacciones entre ellas, así como redundancias que hacen que el bloqueo de las mismas no siempre produzca los efectos esperados. Dada la complejidad y redundancia de vías que transmiten la señal proliferativa desde la membrana hacia al núcleo, deben existir factores que centralicen la acción oncogénica, de forma que sobre ellas converjan diversas vías y sean representativos del grado de activación de los mismos y por tanto de interés pronóstico y terapéutico. Se seleccionaron 129 neoplasias de ovario que incluyeron 27 tumores benignos, 27 tumores borderline y 75 carcinomas de ovario, y 138 muestras de endometrio que incluyeron 120 carcinomas, 15 endometrios funcionales y atróficos y 3 hiperplasias endometriales. Se construyeron matrices de tejidos (tissue microarrays) a partir de 3 muestras de cada caso y se realizó estudio inmunohistoquímico con los anticuerpos para HER2, EGFR y las formas fosforiladas de AKT, ERK, 4E-BP1, p70S6K y S6. Los resultados se analizaron estadísticamente para valorar de forma descriptiva la expresión de estos marcadores, su relación con las variables clínico-patológicas, la relación entre ellos y con la supervivencia global y libre de enfermedad. De los parámetros estudiados, el estadio según los criterios de la FIGO y el grado de diferenciación fueron las únicas variables clínico-patológicas de valor pronóstico tanto en cáncer de ovario como de endometrio. De los marcadores, HER2 se asoció a peor pronóstico en cáncer de endometrio pero no de ovario, EGFR a mejor pronóstico en cáncer de endometrio. La sobreexpresión de p-4E-BP1 identifica carcinomas de ovario y de endometrio de peor pronóstico y su expresión se relaciona tanto con la activación de AKT como de ERK por lo que apoya su importancia como proteína centralizadora de la señal oncogénica procedente de cualquiera de las 2 vías, representando una buena diana para el tratamiento de estas pacientes.Ovarian and endometrial carcinomas are the most frequent gynecological malignant tumors in our area. Recurrent genetic alterations that are characteristic of some histological types have been described and have allowed the identification of pathogenetic pathways, in both endometrial and ovarian cancers. Among these alterations, some affect cell signaling pathways that regulate cell growth and cell proliferation. These pathways represent one of the hallmarks of cancer, and have become especially important since the appearance of new drugs that target specific molecules involved in their regulation. However, our understanding of these signaling pathways is complicated by the presence of multiple cross-talks between them, as well as multiple redundancies of molecules, both of with are probably responsible for some of the unexplained results that occur when one of the molecules involved is blocked by a drug. Due to the complexity and redundancy of cell signaling pathways that transmit the proliferative signal from the cellular membrane to the nucleus, there should be some factors that centralize the oncogenic action in a way that several stimuli could converge on them. These factors should be representative of the activation level of the oncogenic process, and therefore, should be of prognostic and therapeutic interest. 129 ovarian neoplasms were selected, including 27 benign tumors, 27 borderline tumors, and 75 ovarian carcinomas. Additionally, 138 endometrial samples were selected including 15 atrophic and functional endometria, 3 hyperplastic endometria and 120 endometrial carcinomas. Tissue microarrays were constructed using 3 samples from each case, and an immunohistochemical study with HER2, EGFR, and the phosphorylated forms of AKT, ERK, 4E-BP1, p70S6K and ribosomal protein S6 was performed. The results obtained were statistically analyzed to evaluate the correlation of these markers with clinicopathological features, the relationship between them, and their impact on overall survival and progression-free survival. Surgical stage defined by FIGO, and differentiation grade were the only clinicopathologic variants with prognostic significance in ovarian and endometrial cancer. Among the cell signaling markers evaluated, HER2 was associated with prognosis in endometrial cancer but not in ovarian cancer and EGFR with better survival in endometrial cancer. P-4E-BP1 overexpression identifies a subset of ovarian and endometrial cancers with worse prognosis, and its expression is related to the activation of AKT and ERK pathways, suggesting that it has a central role in cell signal transduction by both pathways, and therefore could be a therapeutic target in these patients

Beyond molecular tumor heterogeneity : protein synthesis takes control

Altres ajuts: 245 SRYC acknowledges support from Fondo de Investigaciones Sanitarias (P1170185 and PI 14/01320), Redes Temáticas de Investigación Cooperativa en Salud (RTICC, RD 12/0036/0057), and CIBERONC 2017.One of the daunting challenges facing modern medicine lies in the understanding and treatment of tumor heterogeneity. Most tumors show intra-tumor heterogeneity at both genomic and proteomic levels, with marked impacts on the responses of therapeutic targets. Therapeutic target-related gene expression pathways are affected by hypoxia and cellular stress. However, the finding that targets such as eukaryotic initiation factor (eIF) 4E (and its phosphorylated form, p-eIF4E) are generally homogenously expressed throughout tumors, regardless of the presence of hypoxia or other cellular stress conditions, opens the exciting possibility that malignancies could be treated with therapies that combine targeting of eIF4E phosphorylation with immune checkpoint inhibitors or chemotherapy

Concordance in the estimation of tumor percentage in non-small cell lung cancer using digital pathology

Non-small cell lung cancer; Digital pathologyCáncer de pulmón de células no pequeñas; Patología digitalCàncer de pulmó de cèl·lules no petites; Patologia digitalThe incorporation of digital pathology in clinical practice will require the training of pathologists in digital skills. Our study aimed to assess the reliability among pathologists in determining tumor percentage in whole slide images (WSI) of non-small cell lung cancer (NSCLC) using digital image analysis, and study how the results correlate with the molecular findings. Pathologists from nine centers were trained to quantify epithelial tumor cells, tumor-associated stromal cells, and non-neoplastic cells from NSCLC WSI using QuPath. Then, we conducted two consecutive ring trials. In the first trial, analyzing four WSI, reliability between pathologists in the assessment of tumor cell percentage was poor (intraclass correlation coefficient (ICC) 0.09). After performing the first ring trial pathologists received feedback. The second trial, comprising 10 WSI with paired next-generation sequencing results, also showed poor reliability (ICC 0.24). Cases near the recommended 20% visual threshold for molecular techniques exhibited higher values with digital analysis. In the second ring trial reliability slightly improved and human errors were reduced from 5.6% to 1.25%. Most discrepancies arose from subjective tasks, such as the annotation process, suggesting potential improvement with future artificial intelligence solutions.This work has been supported by CIBERONC (grant CB16/12/00316), by Instituto de Salud Carlos III (ISCIII) through the project “PI22/01892”, by the European Union. Developed with the financial support of Immune4ALL Project (PMP22/00054), with European funds of the Recovery, Transformation and Resilence Plan; and by the Spanish Ministry of Science, Innovation and Universities under grants PID2022-141493OB-I00 and PDC2022-133865-I00 (https://doi.org/10.13039/501100011033/MCIN/AEI/ERDF, UE) - NextGenerationEU. FLR also acknowledges the support of Fundacion Mutua Madrileña (AP18051-2022), Instituto de Salud Carlos III (ISCIII) (PI22-01700, co-funded by the European Union) and the Comunidad de Madrid iLUNG Program (P2022/BMD-7437). CÓDIGO DE PROYECTO: PMP21/00107 - TÍTULO: “INtegrative GENomic, digital Imaging and clinical information towards Precision Oncology Optimization – INGENIO” - IP: LUIS PAZ-ARES RODRIGUEZ “ENTIDAD FINANCIADORA: INSTITUTO DE SALUD CARLOS III (ISCIII). PROYECTO “FINANCIADO CON CARGO A FONDOS NEXTGENERATIONEU, QUE FINANCIAN LAS ACTUACIONES DEL MRR”

Peripheral T-cell lymphoma with a T follicular-helper phenotype: a different entity? Results of the Spanish Real-T study

Peripheral T-cell lymphomaLimfoma perifèric de cèl·lules TLinfoma periférico de células TNodal peripheral T-cell lymphoma (PTCL) with a T follicular helper phenotype (PTCL-TFH) is a new type of PTCL. We aimed to define its clinical characteristics and prognosis compared to PTCL not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL). This retrospective observational study included 175 patients diagnosed with PTCL between 2008 and 2013 in 13 Spanish sites. Patient diagnosis was centrally reviewed, and patients were reclassified according to the World Health Organization (WHO) 2016 criteria: 21 patients as PTCL-NOS, 55 as AITL and 23 as PTCL-TFH. Median follow-up was 56.07 months (95% CI 38.7–73.4). Progression-free survival (PFS) and overall survival (OS) were significantly higher in patients with PTCL-TFH than in those with PTCL-NOS and AITL (PFS, 24.6 months vs. 4.6 and 7.8 months, respectively, p = 0.002; OS, 52.6 months vs. 10.0 and 19.3 months, respectively, p < 0.001). Histological diagnosis maintained an independent influence on both PFS (hazard ratio [HR] 4.1 vs. PTCL-NOS, p = 0.008; HR 2.6 vs. AITL, p = 0.047) and OS (HR 5.7 vs. PTCL-NOS, p = 0.004; HR 2.6 vs. AITL, p = 0.096), regardless of the International Prognostic Index. These results suggest that PTCL-TFH could have more favourable features and prognosis than the other PTCL subtypes, although larger series are needed to corroborate these findings.This work was supported by Takeda Farmacéutica España, S.A. The authors received no compensation for writing the manuscript

Le Perthus – Panissars

Date de l'opération : 1985 - 1993 (FP) ; 1984 (SD) Inventeur(s) : Castellvi Georges ; Nolla Josep Maria ; Rodà Isabel Localisation Les ruines superposées des édifices sont situées au col de Panissars (335 m), partie en France (pour les 2/3), partie en Espagne (pour 1/3) [ (Fig. n°1 : Plan des ruines du trophée de Pompée et du prieuré médiéval Sainte-Marie) et (Fig. n°2 : Ruines du prieuré médiéval et du trphée républicain de Panissars)]. Depuis plus de deux mille ans, ce col et son voisin, l..

Clinical implications of intratumor heterogeneity : challenges and opportunities

In this review, we highlight the role of intratumoral heterogeneity, focusing on the clinical and biological ramifications this phenomenon poses. Intratumoral heterogeneity arises through complex genetic, epigenetic, and protein modifications that drive phenotypic selection in response to environmental pressures. Functionally, heterogeneity provides tumors with significant adaptability. This ranges from mutual beneficial cooperation between cells, which nurture features such as growth and metastasis, to the narrow escape and survival of clonal cell populations that have adapted to thrive under specific conditions such as hypoxia or chemotherapy. These dynamic intercellular interplays are guided by a Darwinian selection landscape between clonal tumor cell populations and the tumor microenvironment. Understanding the involved drivers and functional consequences of such tumor heterogeneity is challenging but also promises to provide novel insight needed to confront the problem of therapeutic resistance in tumors

A combination of molecular and clinical parameters provides a new strategy for high-grade serous ovarian cancer patient management

High-grade serous carcinoma (HGSC) is the most common and deadly subtype of ovarian cancer. Although most patients will initially respond to first-line treatment with a combination of surgery and platinum-based chemotherapy, up to a quarter will be resistant to treatment. We aimed to identify a new strategy to improve HGSC patient management at the time of cancer diagnosis (HGSC-1LTR). A total of 109 ready-available formalin-fixed paraffin-embedded HGSC tissues obtained at the time of HGSC diagnosis were selected for proteomic analysis. Clinical data, treatment approach and outcomes were collected for all patients. An initial discovery cohort (n = 21) were divided into chemoresistant and chemosensitive groups and evaluated using discovery mass-spectrometry (MS)-based proteomics. Proteins showing differential abundance between groups were verified in a verification cohort (n = 88) using targeted MS-based proteomics. A logistic regression model was used to select those proteins able to correctly classify patients into chemoresistant and chemosensitive. The classification performance of the protein and clinical data combinations were assessed through the generation of receiver operating characteristic (ROC) curves. Using the HGSC-1LTR strategy we have identified a molecular signature (TKT, LAMC1 and FUCO) that combined with ready available clinical data (patients' age, menopausal status, serum CA125 levels, and treatment approach) is able to predict patient response to first-line treatment with an AUC: 0.82 (95% CI 0.72-0.92). We have established a new strategy that combines molecular and clinical parameters to predict the response to first-line treatment in HGSC patients (HGSC-1LTR). This strategy can allow the identification of chemoresistance at the time of diagnosis providing the optimization of therapeutic decision making and the evaluation of alternative treatment strategies. Thus, advancing towards the improvement of patient outcome and the individualization of HGSC patients' care. The online version contains supplementary material available at 10.1186/s12967-022-03816-7

Lgr5 Does Not Vary Throughout the Menstrual Cycle in Endometriotic Human Eutopic Endometrium

Endometriosis is characterized by the abnormal presence of endometrium outside of the uterus, resulting in pelvic pain and infertility. The leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) has been postulated to be a marker of stem cells in the endometrium. However, LGR5 + cells have a macrophage-like phenotype in this tissue, so it is unclear what role LGR5 + cells actually play in the endometrium. Macrophages serve an important function in the endometrium to maintain fertility, while LGR5 + cells generally have a role in tumor progression and are involved in invasion in some cancers. We sought to determine whether LGR5 + cells vary across the menstrual cycle in women with endometriosis and whether there are implications for LGR5 in the aggressiveness of endometriosis and reproductive outcomes. We performed immunofluorescence, flow cytometry, and primary culture in vitro experiments on eutopic and ectopic endometrium from healthy and endometriosis patients and observed that neither LGR5 + cells nor LGR5 expression varied throughout the cycle. Interestingly, we observed that LGR5 + cell percentage overexpressing CD163 (anti-inflammatory marker) was higher in healthy endometrium, suggesting that in endometriosis, endometrium presents a more pro-inflammatory phenotype that likely leads to poor obstetric outcomes. We also observed higher levels of LGR5 + cells in ectopic lesions compared to eutopic endometrium and specifically in deep infiltrating endometriosis, indicating that LGR5 could be involved in progression and aggressiveness of the disease

TSPAN1 : a Novel Protein Involved in Head and Neck Squamous Cell Carcinoma Chemoresistance

Altres ajuts: This work was supported by grants from the Instituto de Salud Carlos III, Ayudas a Grupos PCTI Principado de Asturias (IDI2018/155 to J.P.R.), co-financed by the European Regional Fund (ERDF) and AECC (Spanish Association of Cancer Research) Founding Ref. GC16173720CARR (M.E.L.). Y.G.-M. and C.M. were granted by the VHIR and iP-FIS (ISCIII) fellowships respectively.Sensitization of resistant cells and cancer stem cells (CSCs) represents a major challenge in cancer therapy. A proteomic study revealed tetraspanin-1 (TSPAN1) as a protein involved in acquisition of cisplatin (CDDP) resistance (Data are available via ProteomeXchange with identifier PXD020159). TSPAN1 was found to increase in CDDP-resistant cells, CSCs and biopsies from head and neck squamous cell carcinoma (HNSCC) patients. TSPAN1 depletion in parental and CDDP-resistant HNSCC cells reduced cell proliferation, induced apoptosis, decreased autophagy, sensitized to chemotherapeutic agents and inhibited several signaling cascades, with phospho-SRC inhibition being a major common target. Moreover, TSPAN1 depletion in vivo decreased the size and proliferation of parental and CDDP-resistant tumors and reduced metastatic spreading. Notably, CDDP-resistant tumors showed epithelial-mesenchymal transition (EMT) features that disappeared upon TSPAN1 inhibition, suggesting a link of TSPAN1 with EMT and metastasis. Immunohistochemical analysis of HNSCC specimens further revealed that TSPAN1 expression was correlated with phospho-SRC (pSRC), and inversely with E-cadherin, thus reinforcing TSPAN1 association with EMT. Overall, TSPAN1 emerges as a novel oncogenic protein and a promising target for HNSCC therapy

Voies romaines du Rhône à l’Èbre : via Domitia et via Augusta

Issu d’un colloque organisé à Perpignan par l’Association archéologique des Pyrénées-Orientales, ce volume rassemble les contributions de 42 chercheurs du Languedoc, du Roussillon, de Catalogne espagnole et de l’Aragon. On y traite successivement de la via Domitia et de la via Augusta, deux des plus prestigieuses voies romaines, chaque partie étant précédée d’une cartographie raisonnée et d’une notice pour toutes les stations routières traversées. La troisième partie étudie la structure des voies et leur impact dans l’organisation du paysage et amorce une réflexion sur l’aménagement et la mise en valeur des tronçons conservés. Une bibliographie générale, puis thématique, ainsi qu’un rappel des données des itinéraires routiers achèvent de faire de ce volume, qui fait le point sur les recherches récentes, un ouvrage de référence essentiel.Produced following a colloquium held in Perpignan by the Association archéologique des Pyrénées-Orientales, this volume assembles the contributions of 42 researchers of the Languedoc-Roussillon region and adjoining Spanish Catalonia and Aragon. The via Domitia and the via Augusta, two of the most famous roman roads, are treated successively, each section being preceeded by explanatory maps and notices for each of the road stations traversed. The third part examins the structure of these roads and their impact on the organisation of the landscape and discusses the organisation and presentation of conserved sections. A bibliography, general and thematic, as well as a listing comprising the data concerning road itineries concludes this volume, which reviews recent research, an essential work of reference