RESUMO
The oncogenic KRAS mutation is associated with increased tissue factor expression and thus hypercoagulability. In this regard, numerous studies published in the last decade have shown that KRAS mutations are an important risk factor for the development of thromboembolic phenomena in neoplasms of the digestive tract, such as colorectal cancer. On the other hand, some recently published studies suggest that KRAS mutations are also associated with an increased risk of developing thromboembolic phenomena in pancreatic cancer. Based on these premises, we have conducted a single-centre retrospective study on a cohort of patients with pancreatic cancer. Our aim is to demonstrate whether there is an association between the presence of KRAS mutations in our cohort of pancreatic cancer patients and an increased risk of developing thromboembolic phenomena.
Assuntos
Neoplasias Colorretais , Neoplasias Pancreáticas , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genética , Estudos Retrospectivos , Neoplasias Pancreáticas/genética , Mutação , Neoplasias Colorretais/genéticaRESUMO
Head and neck squamous cell cancer patients suffer from a high postoperative recurrence rate and poor prognosis. Thus, it is essential to better understand the underlying molecular mechanisms and identify the role of new biomarkers. Recent research has shown that the dysregulation of microRNAs is a potential biomarker as a screening or prognostic tool. Moreover, the literature reveals its promising usefulness to select the best treatment strategy and monitor tumour response. The purpose of this review is to identify and synthesize the available literature on microRNAs as biomarkers that could help manage patients with head and neck squamous cell cancer. A search in scientific databases was completed, including all relevant articles related to circulating microRNAs in head and neck squamous cell cancer published in English or Spanish. We focused on articles whose main findings were related to their usefulness in diagnosis and prognosis. Conclusion: Knowledge of microRNAs opens the possibilities that these molecules offer in terms of monitoring cancer disease in a less-invasive, simple manner, allowing for serial sampling to assess the response to treatment and minimal residual disease. It is yet to be determined whether liquid biopsy will replace the traditional biopsy in the future but it represents a change in the paradigm of management of head and neck squamous cell cancer.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , MicroRNAs , Humanos , MicroRNAs/genética , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/genética , Motivação , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , PrognósticoRESUMO
An intrinsic timing mechanism specifies the positional values of the zeugopod (i.e. radius/ulna) and then autopod (i.e. wrist/digits) segments during limb development. Here, we have addressed whether this timing mechanism ensures that patterning events occur only once by grafting GFP-expressing autopod progenitor cells to the earlier host signalling environment of zeugopod progenitor cells. We show by detecting Hoxa13 expression that early and late autopod progenitors fated for the wrist and phalanges, respectively, both contribute to the entire host autopod, indicating that the autopod positional value is irreversibly determined. We provide evidence that Hoxa13 provides an autopod-specific positional value that correctly allocates cells into the autopod, most likely through the control of cell-surface properties as shown by cell-cell sorting analyses. However, we demonstrate that only the earlier autopod cells can adopt the host proliferation rate to permit normal morphogenesis. Therefore, our findings reveal that the ability of embryonic cells to differentially reset their intrinsic behaviours confers robustness to limb morphogenesis. We speculate that this plasticity could be maintained beyond embryogenesis in limbs with regenerative capacity.
Assuntos
Botões de Extremidades/citologia , Botões de Extremidades/embriologia , Animais , Animais Geneticamente Modificados , Proteínas Aviárias/genética , Proteínas Aviárias/metabolismo , Padronização Corporal , Pontos de Checagem do Ciclo Celular , Linhagem da Célula , Embrião de Galinha , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Células-Tronco Embrionárias/transplante , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Botões de Extremidades/metabolismo , Regeneração , Asas de Animais/citologia , Asas de Animais/embriologia , Asas de Animais/metabolismoRESUMO
PURPOSE: To describe the molecular profile of a real-world cohort of patients with metastatic urothelial carcinoma (mUC) and to evaluate the benefit of next-generation sequencing (NGS) panels in guiding therapy in patients with mUC and the outcomes of DNA-matched treatments recommended by a multidisciplinary molecular tumor board (MMTB). METHODS: This was a single-center analysis of a real-world cohort of adult patients with mUC included in an ongoing trial that aimed to evaluate the clinical utility of NGS for solid tumors. Genomic analysis was performed for each patient, most of them using the Ion Torrent Oncomine Focus Assay. Genomic results were discussed during MMTB meetings. RESULTS: We included 43 patients with mUC treated with platinum-based combinations and immunotherapy. Twenty-five patients (58.1%; 95% CI 43.4-72.9) had at least one tumor pathogenic alteration. The MMTB classified 16 (48.5%) of the 33 tumor pathogenic alterations found in our real-world cohort of mUC patients as ESCAT I, which is the maximum grade of actionability. After excluding patients who were not candidates for targeted therapies, the MMTB provided guidance on matched therapy for seven patients. Among these patients, three achieved a partial response for an overall response rate of 42.9%, a median progression-free survival of 7.3 months (95% CI 6.7-7.9) and a median overall survival of 10.9 months (95% CI 2.4-19.5). CONCLUSIONS: We recommend that all patients with mUC undergo NGS at diagnosis given the high percentage of patients with pathogenic alterations in our real-world cohort and the efficacy data of patients treated with targeted therapies.
RESUMO
CONTEXT.: The neurotrophic tropomyosin receptor kinase (NTRK) family gene rearrangements have been recently incorporated as predictive biomarkers in a "tumor-agnostic" manner. However, the identification of these patients is extremely challenging because the overall frequency of NTRK fusions is below 1%. Academic groups and professional organizations have released recommendations on the algorithms to detect NTRK fusions. The European Society for Medical Oncology proposal encourages the use of next-generation sequencing (NGS) if available, or alternatively immunohistochemistry (IHC) could be used for screening with NGS confirmation of all positive IHC results. Other academic groups have included histologic and genomic information in the testing algorithm. OBJECTIVE.: To apply some of these triaging strategies for a more efficient identification of NTRK fusions within a single institution, so pathologists can gain practical insight on how to start looking for NTRK fusions. DESIGN.: A multiparametric strategy combining histologic (secretory carcinomas of the breast and salivary gland; papillary thyroid carcinomas; infantile fibrosarcoma) and genomic (driver-negative non-small cell lung carcinomas, microsatellite instability-high colorectal adenocarcinomas, and wild-type gastrointestinal stromal tumors) triaging was put forward. RESULTS.: Samples from 323 tumors were stained with the VENTANA pan-TRK EPR17341 Assay as a screening method. All positive IHC cases were simultaneously studied by 2 NGS tests, Oncomine Comprehensive Assay v3 and FoundationOne CDx. With this approach, the detection rate of NTRK fusions was 20 times higher (5.57%) by only screening 323 patients than the largest cohort in the literature (0.30%) comprising several hundred thousand patients. CONCLUSIONS.: Based on our findings, we propose a multiparametric strategy (ie, "supervised tumor-agnostic approach") when pathologists start searching for NTRK fusions.
Assuntos
Neoplasias da Mama , Carcinoma , Neoplasias , Humanos , Feminino , Receptor trkA/genética , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/patologia , Genômica , Proteínas de Fusão Oncogênica/genéticaRESUMO
Complex signalling between the apical ectodermal ridge (AER - a thickening of the distal epithelium) and the mesoderm controls limb patterning along the proximo-distal axis (humerus to digits). However, the essential in vivo requirement for AER-Fgf signalling makes it difficult to understand the exact roles that it fulfils. To overcome this barrier, we developed an amenable ex vivo chick wing tissue explant system that faithfully replicates in vivo parameters. Using inhibition experiments and RNA-sequencing, we identify a transient role for Fgfs in triggering the distal patterning phase. Fgfs are then dispensable for the maintenance of an intrinsic mesodermal transcriptome, which controls proliferation/differentiation timing and the duration of patterning. We also uncover additional roles for Fgf signalling in maintaining AER-related gene expression and in suppressing myogenesis. We describe a simple logic for limb patterning duration, which is potentially applicable to other systems, including the main body axis.
Assuntos
Galinhas , Extremidades , Animais , Epitélio , Fatores de Crescimento de Fibroblastos/genética , MesodermaRESUMO
The longstanding view of how proliferative outgrowth terminates following the patterning phase of limb development involves the breakdown of reciprocal extrinsic signalling between the distal mesenchyme and the overlying epithelium (e-m signalling). However, by grafting distal mesenchyme cells from late stage chick wing buds to the epithelial environment of younger wing buds, we show that this mechanism is not required. RNA sequencing reveals that distal mesenchyme cells complete proliferative outgrowth by an intrinsic cell cycle timer in the presence of e-m signalling. In this process, e-m signalling is required permissively to allow the intrinsic cell cycle timer to run its course. We provide evidence that a temporal switch from BMP antagonism to BMP signalling controls the intrinsic cell cycle timer during limb outgrowth. Our findings have general implications for other patterning systems in which extrinsic signals and intrinsic timers are integrated.
Assuntos
Epitélio/crescimento & desenvolvimento , Botões de Extremidades/crescimento & desenvolvimento , Mesoderma/crescimento & desenvolvimento , Organogênese/genética , Animais , Ciclo Celular/genética , Proliferação de Células/genética , Galinhas , Extremidades/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Botões de Extremidades/metabolismo , Análise de Sequência de RNA , Transdução de Sinais/genéticaRESUMO
How the positional values along the proximo-distal axis (stylopod-zeugopod-autopod) of the limb are specified is intensely debated. Early work suggested that cells intrinsically change their proximo-distal positional values by measuring time. Recently, however, it is suggested that instructive extrinsic signals from the trunk and apical ectodermal ridge specify the stylopod and zeugopod/autopod, respectively. Here, we show that the zeugopod and autopod are specified by an intrinsic timing mechanism. By grafting green fluorescent protein-expressing cells from early to late chick wing buds, we demonstrate that distal mesenchyme cells intrinsically time Hoxa13 expression, cell cycle parameters and the duration of the overlying apical ectodermal ridge. In addition, we reveal that cell affinities intrinsically change in the distal mesenchyme, which we suggest results in a gradient of positional values along the proximo-distal axis. We propose a complete model in which a switch from extrinsic signalling to intrinsic timing patterns the vertebrate limb.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Asas de Animais/embriologia , Animais , Ossos da Extremidade Superior/embriologia , Ossos da Extremidade Superior/metabolismo , Ciclo Celular , Embrião de Galinha , Ectoderma/embriologia , Ectoderma/metabolismo , Extremidades/embriologia , Citometria de Fluxo , Imunofluorescência , Proteínas de Fluorescência Verde , Proteínas de Homeodomínio/metabolismo , Hibridização In Situ , Marcação In Situ das Extremidades Cortadas , Mesoderma/embriologia , Mesoderma/metabolismo , Fatores de Tempo , Asas de Animais/metabolismoRESUMO
The oncogenic KRAS mutation is associated with increased tissue factor expression and thus hypercoagulability. In this regard, numerous studies published in the last decade have shown that KRAS mutations are an important risk factor for the development of thromboembolic phenomena in neoplasms of the digestive tract, such as colorectal cancer. On the other hand, some recently published studies suggest that KRAS mutations are also associated with an increased risk of developing thromboembolic phenomena in pancreatic cancer. Based on these premises, we have conducted a single-centre retrospective study on a cohort of patients with pancreatic cancer. Our aim is to demonstrate whether there is an association between the presence of KRAS mutations in our cohort of pancreatic cancer patients and an increased risk of developing thromboembolic phenomena. (AU)