RESUMEN
OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies. DESIGN: We used the KPC mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) and primary tumour cell lines to investigate putative CSC populations. Transcriptomic analyses were conducted to pinpoint new genes involved in immune evasion. Overexpressing and knockout cell lines were established with lentiviral vectors. Subsequent in vitro coculture assays, in vivo mouse and zebrafish tumorigenesis studies, and in silico database approaches were performed. RESULTS: Using the KPC mouse model, we functionally confirmed a population of cells marked by EpCAM, Sca-1 and CD133 as authentic CSCs and investigated their transcriptional profile. Immune evasion signatures/genes, notably the gene peptidoglycan recognition protein 1 (PGLYRP1), were significantly overexpressed in these CSCs. Modulating PGLYRP1 impacted CSC immune evasion, affecting their resistance to macrophage-mediated and T-cell-mediated killing and their tumourigenesis in immunocompetent mice. Mechanistically, tumour necrosis factor alpha (TNFα)-regulated PGLYRP1 expression interferes with the immune tumour microenvironment (TME) landscape, promoting myeloid cell-derived immunosuppression and activated T-cell death. Importantly, these findings were not only replicated in human models, but clinically, secreted PGLYRP1 levels were significantly elevated in patients with PDAC. CONCLUSIONS: This study establishes PGLYRP1 as a novel CSC-associated marker crucial for immune evasion, particularly against macrophage phagocytosis and T-cell killing, presenting it as a promising target for PDAC immunotherapy.
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Carcinoma Ductal Pancreático , Células Madre Neoplásicas , Neoplasias Pancreáticas , Animales , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Ratones , Células Madre Neoplásicas/inmunología , Células Madre Neoplásicas/metabolismo , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Humanos , Línea Celular Tumoral , Escape del Tumor/inmunología , Modelos Animales de Enfermedad , Evasión Inmune , Microambiente Tumoral/inmunologíaRESUMEN
OBJECTIVE: The lysyl oxidase-like protein 2 (LOXL2) contributes to tumour progression and metastasis in different tumour entities, but its role in pancreatic ductal adenocarcinoma (PDAC) has not been evaluated in immunocompetent in vivo PDAC models. DESIGN: Towards this end, we used PDAC patient data sets, patient-derived xenograft in vivo and in vitro models, and four conditional genetically-engineered mouse models (GEMMS) to dissect the role of LOXL2 in PDAC. For GEMM-based studies, K-Ras +/LSL-G12D;Trp53 LSL-R172H;Pdx1-Cre mice (KPC) and the K-Ras +/LSL-G12D;Pdx1-Cre mice (KC) were crossed with Loxl2 allele floxed mice (Loxl2Exon2 fl/fl) or conditional Loxl2 overexpressing mice (R26Loxl2 KI/KI) to generate KPCL2KO or KCL2KO and KPCL2KI or KCL2KI mice, which were used to study overall survival; tumour incidence, burden and differentiation; metastases; epithelial to mesenchymal transition (EMT); stemness and extracellular collagen matrix (ECM) organisation. RESULTS: Using these PDAC mouse models, we show that while Loxl2 ablation had little effect on primary tumour development and growth, its loss significantly decreased metastasis and increased overall survival. We attribute this effect to non-cell autonomous factors, primarily ECM remodelling. Loxl2 overexpression, on the other hand, promoted primary and metastatic tumour growth and decreased overall survival, which could be linked to increased EMT and stemness. We also identified tumour-associated macrophage-secreted oncostatin M (OSM) as an inducer of LOXL2 expression, and show that targeting macrophages in vivo affects Osm and Loxl2 expression and collagen fibre alignment. CONCLUSION: Taken together, our findings establish novel pathophysiological roles and functions for LOXL2 in PDAC, which could be potentially exploited to treat metastatic disease.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Ratones , Animales , Transición Epitelial-Mesenquimal/genética , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/patología , Modelos Animales de Enfermedad , Macrófagos/metabolismo , Aminoácido Oxidorreductasas/genética , Neoplasias PancreáticasRESUMEN
BACKGROUND & AIMS: To successfully implement imaging-based pancreatic cancer (PC) surveillance, understanding the timeline and morphologic features of neoplastic progression is key. We aimed to investigate the progression to neoplasia from serial prediagnostic pancreatic imaging tests in high-risk individuals and identify factors associated with successful early detection. METHODS: We retrospectively examined the development of pancreatic abnormalities in high-risk individuals who were diagnosed with PC or underwent pancreatic surgery, or both, in 16 international surveillance programs. RESULTS: Of 2552 high-risk individuals under surveillance, 28 (1%) developed neoplastic progression to PC or high-grade dysplasia during a median follow-up of 29 months after baseline (interquartile range [IQR], 40 months). Of these, 13 of 28 (46%) presented with a new lesion (median size, 15 mm; range 7-57 mm), a median of 11 months (IQR, 8; range 3-17 months) after a prior examination, by which time 10 of 13 (77%) had progressed beyond the pancreas. The remaining 15 of 28 (54%) had neoplastic progression in a previously detected lesion (12 originally cystic, 2 indeterminate, 1 solid), and 11 (73%) had PC progressed beyond the pancreas. The 12 patients with cysts had been monitored for 21 months (IQR, 15 months) and had a median growth of 5 mm/y (IQR, 8 mm/y). Successful early detection (as high-grade dysplasia or PC confined to the pancreas) was associated with resection of cystic lesions (vs solid or indeterminate lesions (odds ratio, 5.388; 95% confidence interval, 1.525-19.029) and small lesions (odds ratio, 0.890/mm; 95% confidence interval 0.812-0.976/mm). CONCLUSIONS: In nearly half of high-risk individuals developing high-grade dysplasia or PC, no prior lesions are detected by imaging, yet they present at an advanced stage. Progression can occur before the next scheduled annual examination. More sensitive diagnostic tools or a different management strategy for rapidly growing cysts are needed.
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Detección Precoz del Cáncer , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/patología , Lesiones Precancerosas/diagnóstico por imagen , Lesiones Precancerosas/patología , Espera Vigilante , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Endosonografía , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Páncreas/patología , Quiste Pancreático/diagnóstico por imagen , Quiste Pancreático/patología , Neoplasias Pancreáticas/cirugía , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Tomografía Computarizada por Rayos X , Carga TumoralRESUMEN
BACKGROUND: Recent evidence suggests a role for the microbiome in pancreatic ductal adenocarcinoma (PDAC) aetiology and progression. OBJECTIVE: To explore the faecal and salivary microbiota as potential diagnostic biomarkers. METHODS: We applied shotgun metagenomic and 16S rRNA amplicon sequencing to samples from a Spanish case-control study (n=136), including 57 cases, 50 controls, and 29 patients with chronic pancreatitis in the discovery phase, and from a German case-control study (n=76), in the validation phase. RESULTS: Faecal metagenomic classifiers performed much better than saliva-based classifiers and identified patients with PDAC with an accuracy of up to 0.84 area under the receiver operating characteristic curve (AUROC) based on a set of 27 microbial species, with consistent accuracy across early and late disease stages. Performance further improved to up to 0.94 AUROC when we combined our microbiome-based predictions with serum levels of carbohydrate antigen (CA) 19-9, the only current non-invasive, Food and Drug Administration approved, low specificity PDAC diagnostic biomarker. Furthermore, a microbiota-based classification model confined to PDAC-enriched species was highly disease-specific when validated against 25 publicly available metagenomic study populations for various health conditions (n=5792). Both microbiome-based models had a high prediction accuracy on a German validation population (n=76). Several faecal PDAC marker species were detectable in pancreatic tumour and non-tumour tissue using 16S rRNA sequencing and fluorescence in situ hybridisation. CONCLUSION: Taken together, our results indicate that non-invasive, robust and specific faecal microbiota-based screening for the early detection of PDAC is feasible.
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Carcinoma Ductal Pancreático , Microbiota , Neoplasias Pancreáticas , Biomarcadores de Tumor , Antígeno CA-19-9 , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Estudios de Casos y Controles , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , ARN Ribosómico 16S/genética , Neoplasias PancreáticasRESUMEN
Nutritional intervention is an essential part of cancer treatments. Research and clinical evidence in cancer have shown that nutritional support can reduce length of hospitalisation, diminish treatment-related toxicity, and improve nutrient intake, quality of life, and physical function. Nutritional intervention can improve outcomes and help patients in the successful completion of oncological treatments by preventing malnutrition. Malnutrition is a very common hallmark in patients with cancers. Almost one-fourth of cancer patients are at risk of dying because of the consequences of malnutrition, rather than cancer itself. Patients with digestive cancers are at higher risk of suffering malnutrition due to the gastrointestinal impairment caused by their disease. They are at high nutritional risk by definition, yet the majority of them have insufficient or null access to nutritional intervention.Inadequate resources are dedicated to implementing nutritional services in Europe. Universal access to nutritional support for digestive cancer patients is not a reality in many European countries. To change this situation, health systems should invest in qualified staff to reinforce or create nutritional teams' experts in digestive cancer treatments. We aim to share the patient community's perspective on the status and the importance of nutritional intervention. This is an advocacy manuscript presenting data on the topic and analysing the current situations and the challenges for nutrition in digestive cancers. It highlights the importance of integrative nutrition in the treatment of digestive cancers and advocates for equitable and universal access to nutritional intervention for all patients.
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Neoplasias Gastrointestinales , Desnutrición , Neoplasias Gastrointestinales/complicaciones , Neoplasias Gastrointestinales/terapia , Humanos , Desnutrición/etiología , Desnutrición/prevención & control , Evaluación Nutricional , Estado Nutricional , Apoyo Nutricional , Calidad de VidaRESUMEN
OBJECTIVES: To characterise the association between type 2 diabetes mellitus (T2DM) subtypes (new-onset T2DM (NODM) or long-standing T2DM (LSDM)) and pancreatic cancer (PC) risk, to explore the direction of causation through Mendelian randomisation (MR) analysis and to assess the mediation role of body mass index (BMI). DESIGN: Information about T2DM and related factors was collected from 2018 PC cases and 1540 controls from the PanGenEU (European Study into Digestive Illnesses and Genetics) study. A subset of PC cases and controls had glycated haemoglobin, C-peptide and genotype data. Multivariate logistic regression models were applied to derive ORs and 95% CIs. T2DM and PC-related single nucleotide polymorphism (SNP) were used as instrumental variables (IVs) in bidirectional MR analysis to test for two-way causal associations between PC, NODM and LSDM. Indirect and direct effects of the BMI-T2DM-PC association were further explored using mediation analysis. RESULTS: T2DM was associated with an increased PC risk when compared with non-T2DM (OR=2.50; 95% CI: 2.05 to 3.05), the risk being greater for NODM (OR=6.39; 95% CI: 4.18 to 9.78) and insulin users (OR=3.69; 95% CI: 2.80 to 4.86). The causal association between T2DM (57-SNP IV) and PC was not statistically significant (ORLSDM=1.08, 95% CI: 0.86 to 1.29, ORNODM=1.06, 95% CI: 0.95 to 1.17). In contrast, there was a causal association between PC (40-SNP IV) and NODM (OR=2.85; 95% CI: 2.04 to 3.98), although genetic pleiotropy was present (MR-Egger: p value=0.03). Potential mediating effects of BMI (125-SNPs as IV), particularly in terms of weight loss, were evidenced on the NODM-PC association (indirect effect for BMI in previous years=0.55). CONCLUSION: Findings of this study do not support a causal effect of LSDM on PC, but suggest that PC causes NODM. The interplay between obesity, PC and T2DM is complex.
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Diabetes Mellitus Tipo 2/complicaciones , Obesidad/complicaciones , Neoplasias Pancreáticas/etiología , Anciano , Índice de Masa Corporal , Péptido C/sangre , Estudios de Casos y Controles , Causalidad , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/genética , Escolaridad , Femenino , Hemoglobina Glucada/análisis , Humanos , Masculino , Análisis de Mediación , Persona de Mediana Edad , Obesidad/genética , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/genética , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Factores Sexuales , Fumar/efectos adversosRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, mainly due to late diagnosis at advanced tumor stages. In this study, we aimed to identify plasma protein biomarkers for early detection of PDAC. Totally, 135 PDAC patients (early PDAC, Stage I/II, n = 71; advanced PDAC, Stage III/IV, n = 64), 13 benign lesions/chronic pancreatitis patients and 72 healthy individuals, with corresponding plasma samples from a case-control study in Sweden were included. A proximity extension assay was used to detect 92 cancer-related proteins, and an enzyme-linked immunosorbent assay/electrochemiluminescence immunoassay was used to detect CA19-9. Predictive features were selected from these 93 candidate proteins and three covariates in the Swedish participants, and then validated in Spanish participants, including 37 early PDAC patients, 38 advanced PDAC patients, 19 chronic pancreatitis patients and 36 healthy controls. A panel of eight proteins discriminating early PDAC from healthy individuals was identified, and the cross-validated area under the curves (AUCs) were 0.85 (95% confidence interval, 95% CI, 0.78-0.91) and 0.81 (95% CI, 0.70-0.92) in the Swedish and Spanish participants, respectively. Another eight-protein panel was predictive for classifying advanced PDAC from healthy controls in two populations, with cross-validated AUCs of 0.89 (95% CI, 0.83-0.95) and 0.90 (95% CI, 0.83-0.98), respectively. In conclusion, eight protein biomarkers were identified and externally validated, potentially allowing early detection of PDAC patients if validated in additional prospective studies.
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Biomarcadores de Tumor/sangre , Proteínas Sanguíneas/análisis , Carcinoma Ductal Pancreático/diagnóstico , Detección Precoz del Cáncer/métodos , Neoplasias Pancreáticas/diagnóstico , Anciano , Antígenos CD/sangre , Antígeno CA-19-9/sangre , Carcinoma Ductal Pancreático/sangre , Estudios de Casos y Controles , Moléculas de Adhesión Celular/sangre , Femenino , Humanos , Cadenas beta de Integrinas/sangre , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/sangre , Curva ROCRESUMEN
Colorectal cancer is a common cancer worldwide. Several risk factors have been described, such as age, lifestyle and family history. Inflammatory bowel diseases (IBD) are a well-recognized risk factor for the development of colorectal cancer. However, the onset of an IBD de novo in the context of the treatment of a colorectal neoplasia has not been reported before, except in the context of the treatment with immunocheckpoint inhibitors. Fifty-nine-years old man diagnosed with a metastatic colorectal cancer who received conventional treatment with chemotherapy and an antiangiogenic inhibitor. The patient had a complete response with the therapy after few cycles. Nevertheless, during the treatment, the patient presented with rectal bleeding, and was diagnosed with ulcerative colitis. Although the treatment was discontinued, tumoral complete remission is maintained. The relevance of this case lies in the concurrence of the onset of an autoimmune disease and a complete response of the malignancy. The concurrence of these events has been described previously only with immunotherapy. There are not cases reported involving chemotherapy and antiangiogenic drugs. Other causes of colitis were ruled out due to the unusual presentation of the case.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Colitis Ulcerosa/complicaciones , Neoplasias del Colon/complicaciones , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la NeoplasiaRESUMEN
Aim: To survey European physicians managing patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and understand differences in baseline characteristics, diagnostic methods, symptoms and co-morbidities. Materials & methods: Patient record inclusion criteria were: ≥18 years old, metastatic PDAC diagnosis and completion of first-line treatment between July 2014 and January 2016. Records were grouped by patient age, gender and primary tumor location. Results: Records (n = 2565) were collected from nine countries. Baseline characteristics varied between subgroups. Computed tomography was the most frequently used diagnostic technique. Symptoms at diagnosis included abdominal and/or mid-back pain (72% of patients) and weight loss (61.5%). Co-morbidities varied with patient age. Conclusion: Greater awareness of symptoms, diagnostic methods and co-morbidities present at PDAC diagnosis may support better patient management decisions.
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Carcinoma Ductal Pancreático/diagnóstico , Competencia Clínica/estadística & datos numéricos , Neoplasias Pancreáticas/diagnóstico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Anciano , Carcinoma Ductal Pancreático/epidemiología , Carcinoma Ductal Pancreático/terapia , Toma de Decisiones Clínicas , Comorbilidad , Europa (Continente)/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/terapia , Estudios Retrospectivos , Encuestas y Cuestionarios/estadística & datos numéricos , Tomografía Computarizada por Rayos X/estadística & datos numéricosRESUMEN
Urothelial carcinoma represents one of the most prevalent types of cancer worldwide, and its incidence is expected to grow. Although the treatment of the advanced disease was based on chemotherapy for decades, the developments of different therapies, such as immune checkpoint inhibitors, antibody drug conjugates and tyrosine kinase inhibitors, are revolutionizing the therapeutic landscape of this tumor. This development coincides with the increasing knowledge of the pathogenesis and genetic alterations in urothelial carcinoma, from the non-muscle invasive setting to the metastatic one. The purpose of this article is to provide a comprehensive review of the different tyrosine kinase targets and their roles in the therapeutic scene of urothelial carcinoma.
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Biomarcadores de Tumor , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/metabolismo , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/etiología , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Ensayos Clínicos como Asunto , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Humanos , Invasividad Neoplásica , Estadificación de Neoplasias , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/etiología , Neoplasias Urológicas/diagnósticoRESUMEN
BACKGROUND AND AIM: The International Cancer of the Pancreas Screening Consortium met in 2018 to update its consensus recommendations for the management of individuals with increased risk of pancreatic cancer based on family history or germline mutation status (high-risk individuals). METHODS: A modified Delphi approach was employed to reach consensus among a multidisciplinary group of experts who voted on consensus statements. Consensus was considered reached if ≥75% agreed or disagreed. RESULTS: Consensus was reached on 55 statements. The main goals of surveillance (to identify high-grade dysplastic precursor lesions and T1N0M0 pancreatic cancer) remained unchanged. Experts agreed that for those with familial risk, surveillance should start no earlier than age 50 or 10 years earlier than the youngest relative with pancreatic cancer, but were split on whether to start at age 50 or 55. Germline ATM mutation carriers with one affected first-degree relative are now considered eligible for surveillance. Experts agreed that preferred surveillance tests are endoscopic ultrasound and MRI/magnetic retrograde cholangiopancreatography, but no consensus was reached on how to alternate these modalities. Annual surveillance is recommended in the absence of concerning lesions. Main areas of disagreement included if and how surveillance should be performed for hereditary pancreatitis, and the management of indeterminate lesions. CONCLUSIONS: Pancreatic surveillance is recommended for selected high-risk individuals to detect early pancreatic cancer and its high-grade precursors, but should be performed in a research setting by multidisciplinary teams in centres with appropriate expertise. Until more evidence supporting these recommendations is available, the benefits, risks and costs of surveillance of pancreatic surveillance need additional evaluation.
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Carcinoma/diagnóstico , Detección Precoz del Cáncer/métodos , Neoplasias Pancreáticas/diagnóstico , Factores de Edad , Investigación Biomédica/métodos , Carcinoma/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Tamizaje Masivo/métodos , Neoplasias Pancreáticas/genética , Vigilancia de la Población/métodos , Factores de RiesgoRESUMEN
The rise of precision oncology has made clinical decision making more complex than ever before. The Oncology Data Network was established to enable the clinical community to efficiently access potentially practicechanging insights from an extended network of cancer centers. This article describes the progress to date and calls for greater collaboration.
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Difusión de la Información/métodos , Medicina de Precisión/métodos , Europa (Continente) , HumanosRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies due to the rapid rate of metastasis and high resistance to currently applied cancer therapies. The complex mechanism underlying the development and progression of PDAC includes interactions between genomic, epigenomic, and signaling pathway alterations. In this review, we summarize the current research findings on the deregulation of epigenetic mechanisms in PDAC and the influence of the epigenome on the dynamics of the gene expression changes underlying epithelial-mesenchymal transition (EMT), which is responsible for the invasive phenotype of cancer cells and, therefore, their metastatic potential. More importantly, we provide an overview of the studies that uncover potentially actionable pathways. These studies provide a scientific basis to test epigenetic drug efficacy in synergy with other anticancer therapies in future clinical trials, in order to reverse acquired therapy resistance. Thus, epigenomics has the potential to generate relevant new knowledge of both a biological and clinical impact. Moreover, the potential, hurdles, and challenges of predictive biomarker discoveries will be discussed, with a special focus on the promise of liquid biopsies.
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Carcinoma Ductal Pancreático/genética , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas/genética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Detección Precoz del Cáncer , Epigenómica/métodos , Transición Epitelial-Mesenquimal/genética , Heterogeneidad Genética , Histonas/metabolismo , Humanos , Biopsia Líquida , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismoRESUMEN
Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.
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Neoplasias/metabolismo , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/metabolismo , Quinasa de Linfoma Anaplásico/metabolismo , Carcinogénesis , Receptores ErbB/metabolismo , Humanos , Inmunoterapia , Ligandos , Neovascularización Patológica , Fosforilación , Medicina de Precisión , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Receptor ErbB-2/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor trkA/metabolismo , Transducción de SeñalRESUMEN
Thyroid cancer represents a heterogenous disease whose incidence has increased in the last decades. Although three main different subtypes have been described, molecular characterization is progressively being included in the diagnostic and therapeutic algorithm of these patients. In fact, thyroid cancer is a landmark in the oncological approach to solid tumors as it harbors key genetic alterations driving tumor progression that have been demonstrated to be potential actionable targets. Within this promising and rapid changing scenario, current efforts are directed to improve tumor characterization for an accurate guidance in the therapeutic management. In this sense, it is strongly recommended to perform tissue genotyping to patients that are going to be considered for systemic therapy in order to select the adequate treatment, according to recent clinical trials data. Overall, the aim of this article is to provide a comprehensive review on the molecular biology of thyroid cancer focusing on the key role of tyrosine kinases. Additionally, from a clinical point of view, we provide a thorough perspective, current and future, in the treatment landscape of this tumor.
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Antineoplásicos/uso terapéutico , Terapia Molecular Dirigida , Proteínas de Neoplasias/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Neoplasias de la Tiroides/terapia , Adenocarcinoma Folicular/enzimología , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/terapia , Adenoma Oxifílico/enzimología , Adenoma Oxifílico/genética , Adenoma Oxifílico/terapia , Antineoplásicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma Medular/enzimología , Carcinoma Medular/genética , Carcinoma Medular/terapia , Carcinoma Papilar/enzimología , Carcinoma Papilar/genética , Carcinoma Papilar/terapia , Ensayos Clínicos como Asunto , Terapia Combinada , Manejo de la Enfermedad , Predicción , Genes Relacionados con las Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoconjugados/uso terapéutico , Inmunoterapia , Radioisótopos de Yodo/uso terapéutico , Estudios Multicéntricos como Asunto , Proteínas de Neoplasias/genética , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/genética , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias de la Tiroides/enzimología , Neoplasias de la Tiroides/genética , Microambiente Tumoral/inmunologíaRESUMEN
OBJECTIVE: Resection can potentially cure resectable pancreatic cancer (PaC) and significantly prolong survival in some patients. This large-scale international study aimed to investigate variations in resection for PaC in Europe and USA and determinants for its utilisation. DESIGN: Data from six European population-based cancer registries and the US Surveillance, Epidemiology, and End Results Program database during 2003-2016 were analysed. Age-standardised resection rates for overall and stage I-II PaCs were computed. Associations between resection and demographic and clinical parameters were assessed using multivariable logistic regression models. RESULTS: A total of 153 698 records were analysed. In population-based registries in 2012-2014, resection rates ranged from 13.2% (Estonia) to 21.2% (Slovenia) overall and from 34.8% (Norway) to 68.7% (Denmark) for stage I-II tumours, with great international variations. During 2003-2014, resection rates only increased in USA, the Netherlands and Denmark. Resection was significantly less frequently performed with more advanced tumour stage (ORs for stage III and IV versus stage I-II tumours: 0.05-0.18 and 0.01-0.06 across countries) and increasing age (ORs for patients 70-79 and ≥80 versus those <60 years: 0.37-0.63 and 0.03-0.16 across countries). Patients with advanced-stage tumours (stage III-IV: 63.8%-81.2%) and at older ages (≥70 years: 52.6%-59.5%) receiving less frequently resection comprised the majority of diagnosed cases. Patient performance status, tumour location and size were also associated with resection application. CONCLUSION: Rates of PaC resection remain low in Europe and USA with great international variations. Further studies are warranted to explore reasons for these variations.
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Neoplasias Pancreáticas/cirugía , Pautas de la Práctica en Medicina/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/patología , Sistema de Registros , Programa de VERF , Análisis de Supervivencia , Estados Unidos/epidemiologíaRESUMEN
Although outdoor air pollution and particulate matter in outdoor air have been consistently linked with increased lung cancer risk, the evidence for associations at other cancer sites is limited. Bladder cancer shares several risk factors with lung cancer and some positive associations of ambient air pollution and bladder cancer risk have been observed. This study examined associations of ambient air pollution and bladder cancer risk in the large-scale Spanish Bladder Cancer Study. Estimates of ambient fine particulate matter (PM2.5 ) and nitrogen dioxide (NO2 ) concentrations were assigned to the geocoded participant residence of 938 incident bladder cancer cases and 973 hospital controls based on European multicity land-use regression models. Adjusted odds ratios (ORs) and 95% confidence intervals (CI) for associations of ambient air pollution and bladder cancer risk were estimated using unconditional logistic regression models. Overall, there was no clear association between either ambient PM2.5 (OR per 5.9 µg/m3 = 1.06, 95% CI 0.71-1.60) or NO2 (OR per 14.2 µg/m3 = 0.97, 95% CI 0.84-1.13) concentrations and incident bladder cancer risk. There was no clear evidence for effect modification according to age group, sex, region, education, cigarette smoking status, or pack-years. Results were also similar among more residentially stable participants and in two-pollutant models. Overall, there was no clear evidence for associations of ambient PM2.5 and NO2 concentrations and incident bladder cancer risk. Further research in other large-scale population studies is needed with detailed information on measured or modeled estimates of ambient air pollution concentrations and individual level risk factors.
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Contaminación del Aire/efectos adversos , Neoplasias de la Vejiga Urinaria/etiología , Adulto , Anciano , Anciano de 80 o más Años , Contaminantes Atmosféricos/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Femenino , Hispánicos o Latinos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Dióxido de Nitrógeno/efectos adversos , Oportunidad Relativa , Material Particulado/efectos adversos , Factores de Riesgo , Adulto JovenRESUMEN
Deciphering the underlying genetic basis behind pancreatic cancer (PC) and its associated multimorbidities will enhance our knowledge toward PC control. The study investigated the common genetic background of PC and different morbidities through a computational approach and further evaluated the less explored association between PC and autoimmune diseases (AIDs) through an epidemiological analysis. Gene-disease associations (GDAs) of 26 morbidities of interest and PC were obtained using the DisGeNET public discovery platform. The association between AIDs and PC pointed by the computational analysis was confirmed through multivariable logistic regression models in the PanGen European case-control study population of 1,705 PC cases and 1,084 controls. Fifteen morbidities shared at least one gene with PC in the DisGeNET database. Based on common genes, several AIDs were genetically associated with PC pointing to a potential link between them. An epidemiologic analysis confirmed that having any of the nine AIDs studied was significantly associated with a reduced risk of PC (Odds Ratio (OR) = 0.74, 95% confidence interval (CI) 0.58-0.93) which decreased in subjects having ≥2 AIDs (OR = 0.39, 95%CI 0.21-0.73). In independent analyses, polymyalgia rheumatica, and rheumatoid arthritis were significantly associated with low PC risk (OR = 0.40, 95%CI 0.19-0.89, and OR = 0.73, 95%CI 0.53-1.00, respectively). Several inflammatory-related morbidities shared a common genetic component with PC based on public databases. These molecular links could shed light into the molecular mechanisms underlying PC development and simultaneously generate novel hypotheses. In our study, we report sound findings pointing to an association between AIDs and a reduced risk of PC.
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Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/genética , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/genética , Estudios de Casos y Controles , Biología Computacional/métodos , Europa (Continente)/epidemiología , Femenino , Ontología de Genes , Predisposición Genética a la Enfermedad , Humanos , Modelos Logísticos , Masculino , Oportunidad Relativa , Factores de RiesgoRESUMEN
BACKGROUND: Targeted agents are standard treatment for RAS wild-type metastatic colorectal cancer in the first- and second-line settings. This phase 2 study determined the benefit of targeting the epidermal growth factor receptor (EGFR) with panitumumab plus irinotecan in irinotecan-refractory patients. METHODS: KRAS exon-2 wild-type patients failing prior irinotecan received panitumumab (6 mg/kg) and irinotecan (180 mg/m²) every 2 weeks. The primary endpoint was the overall response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). KRAS exon-2 status was evaluated centrally, along with NRAS, BRAF mutations, epiregulin, amphiregulin, PTEN and EGFR copy number status, and correlated with efficacy. RESULTS: Sixty-one patients were treated. Among the 46 wild-type RAS patients, the ORR was 15.2% (seven partial responses), with median PFS of 3.8 months (95% CI 2.7-4.3) and median OS of 12.5 months (95% CI 6.7-15.9). Wild-type BRAF patients showed a 13.0% response rate. No significant correlations between response and baseline biomarker expression were identified. Common grade 3-4 adverse events were diarrhoea and rash (18.0% each), hypomagnesaemia and asthenia (8.2% each). CONCLUSIONS: The addition of panitumumab to irinotecan as salvage therapy is feasible but has limited activity in irinotecan-refractory metastatic colorectal cancer. No biomarkers predictive of response were identified.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Peritoneales/tratamiento farmacológico , Terapia Recuperativa , Adenocarcinoma/genética , Adenocarcinoma/secundario , Adulto , Anciano , Anciano de 80 o más Años , Anfirregulina/genética , Astenia/inducido químicamente , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Diarrea/inducido químicamente , Erupciones por Medicamentos , Epirregulina/genética , Receptores ErbB/genética , Femenino , GTP Fosfohidrolasas/genética , Humanos , Irinotecán/administración & dosificación , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Ganglios Linfáticos/patología , Magnesio/sangre , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Fosfohidrolasa PTEN/genética , Panitumumab/administración & dosificación , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/secundario , Supervivencia sin Progresión , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Tasa de Supervivencia , Resultado del Tratamiento , Desequilibrio Hidroelectrolítico/inducido químicamenteRESUMEN
Clear cell renal cell carcinoma (ccRCC) is the seventh most frequently diagnosed tumor in adults in Europe and represents approximately 2.5% of cancer deaths. The molecular biology underlying renal cell carcinoma (RCC) development and progression has been a key milestone in the management of this type of tumor. The discovery of Von Hippel Lindau (VHL) gene alterations that arouse in 50% of ccRCC patients, leads the identification of an intracellular accumulation of HIF and, consequently an increase of VEGFR expression. This change in cell biology represents a new paradigm in the treatment of metastatic renal cancer by targeting angiogenesis. Currently, there are multiple therapeutic drugs available for advanced disease, including therapies against VEGFR with successful results in patients´ survival. Other tyrosine kinases' pathways, including PDGFR, Axl or MET have emerged as key signaling pathways involved in RCC biology. Indeed, promising new drugs targeting those tyrosine kinases have exhibited outstanding efficacy. In this review we aim to present an overview of the central role of these tyrosine kinases' activities in relevant biological processes for kidney cancer and their usefulness in RCC targeted therapy development. In the immunotherapy era, angiogenesis is still an "old guy" that the medical community is trying to fight using "new bullets".