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Linitis plastica (LP) is a very aggressive and rare carcinoma with a scirrhous stroma that affects the submucosal and muscular layers of the stomach even without mucosal alterations. Lack of timely diagnosis is a crucial problem related to its prognosis and treatment. In this study, we investigated the LP-associated vascular pattern as a possible means to improve the diagnosis of these patients. During standard endoscopy, mucosal architecture, tortuosity and enlargement of vessels, as well as the presence of vascular leakage and efficiency of the blood flow were assessed in six LP patients using probe-based Confocal Laser Endomicroscopy (pCLE). In all LP patients, we detected abnormal changes in vasculature. The aberrant features of the vascular network were common to all LP patients examined and consisted of vessel enlargement, tortuosity, and leakage associated with the affected submucosal layer. This is the first study to highlight the presence of marked vascularization associated with LP, characterized by the presence of abnormal and non-functional vessels, similar to what is observed in neoplastic tissues. Therefore, the analysis of LP by pCLE may provide a new endoscopic approach and strategy to better define these patients.
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Linitis Plástica , Neoplasias Gástricas , Humanos , Linitis Plástica/diagnóstico , Linitis Plástica/complicaciones , Linitis Plástica/patología , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patología , Pronóstico , Endoscopía , Microscopía ConfocalRESUMEN
Until recently, effective therapies for advanced endometrial cancer progressing to a platinum-based combination were lacking. In this setting, immunotherapy with anti PD-1/PDL-1 monoclonal antibodies is rising as a new paradigm in particular for patients with microsatellites instability/mismatch repair deficiency. In this case report, we describe an exceptional and rapid response to dostarlimab in a platinum refractory endometrial cancer patient with high disease burden harboring a mismatch repair deficiency.
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Neoplasias Endometriales , Síndromes Neoplásicos Hereditarios , Anticuerpos Monoclonales Humanizados , Neoplasias Encefálicas , Neoplasias Colorrectales , Reparación de la Incompatibilidad de ADN , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico , Inestabilidad de Microsatélites , Platino (Metal)/uso terapéutico , Receptor de Muerte Celular Programada 1RESUMEN
BACKGROUND: Colorectal cancer is one of the most frequent and deadly tumors. Among the key regulators of CRC growth and progression, the microenvironment has emerged as a crucial player and as a possible route for the development of new therapeutic opportunities. More specifically, the extracellular matrix acts directly on cancer cells and indirectly affecting the behavior of stromal and inflammatory cells, as well as the bioavailability of growth factors. Among the ECM molecules, EMILIN-2 is frequently down-regulated by methylation in CRC and the purpose of this study was to verify the impact of EMILIN-2 loss in CRC development and its possible value as a prognostic biomarker. METHODS: The AOM/DSS CRC protocol was applied to Emilin-2 null and wild type mice. Tumor development was monitored by endoscopy, the molecular analyses performed by IHC, IF and WB and the immune subpopulations characterized by flow cytometry. Ex vivo cultures of monocyte/macrophages from the murine models were used to verify the molecular pathways. Publicly available datasets were exploited to determine the CRC patients' expression profile; Spearman's correlation analyses and Cox regression were applied to evaluate the association with the inflammatory response; the clinical outcome was predicted by Kaplan-Meier survival curves. Pearson correlation analyses were also applied to a cohort of patients enrolled in our Institute. RESULTS: In preclinical settings, loss of EMILIN-2 associated with an increased number of tumor lesions upon AOM/DSS treatment. In addition, in the early stages of the disease, the Emilin-2 knockout mice displayed a myeloid-derived suppressor cells-rich infiltrate. Instead, in the late stages, lack of EMILIN-2 associated with a decreased number of M1 macrophages, resulting in a higher percentage of the tumor-promoting M2 macrophages. Mechanistically, EMILIN-2 triggered the activation of the Toll-like Receptor 4/MyD88/NF-κB pathway, instrumental for the polarization of macrophages towards the M1 phenotype. Accordingly, dataset and immunofluorescence analyses indicated that low EMILIN-2 expression levels correlated with an increased M2/M1 ratio and with poor CRC patients' prognosis. CONCLUSIONS: These novel results indicate that EMILIN-2 is a key regulator of the tumor-associated inflammatory environment and may represent a promising prognostic biomarker for CRC patients.
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Neoplasias Colorrectales/genética , Matriz Extracelular/metabolismo , Macrófagos/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Microambiente TumoralRESUMEN
Endoscopy is widely used to detect and diagnose precancerous lesions and gastric cancer (GC). The probe-based Confocal Laser Endomicroscopy (pCLE) is an endoscopic technique suitable for subcellular resolution and for microvasculature analyses. The aim of this study was to use pCLE to identify specific vascular patterns in high-risk and early stage GC. Mucosal architecture, vessel tortuosity, enlargements and leakage were assessed in patients with autoimmune gastritis and early gastric cancer (EGC). We were able to stratify gastritis patients by identifying distinct vascular profiles: gastritis was usually associated with increased vascularization characterized by a high number of tortuous vessels, which were also found in atrophic autoimmune disease. Leaky and tortuous vessels, distributed in a spatially irregular network, characterized the atrophic metaplastic mucosa. The mucosal vasculature of EGC patients displayed tortuous vessels, but unlike what detected in atrophic gastritis, they appeared patchy, as is in neoplastic gastric tissue. Very importantly, we detected vascular changes even in areas without lesions, supporting the contention that vascular alterations may provide a favorable microenvironment for carcinogenesis. This report confirms that pCLE is a valid endoscopic approach to improve the definition of patients with malignant lesions or at increased risk for GC by assessing vascular changes.
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Endoscopía Gastrointestinal , Gastritis Atrófica/patología , Neovascularización Patológica/patología , Lesiones Precancerosas/patología , Neoplasias Gástricas , Adulto , Anciano , Femenino , Mucosa Gástrica/irrigación sanguínea , Mucosa Gástrica/patología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/irrigación sanguínea , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUNDS: MUTYH-associated polyposis (MAP) is an autosomal recessive disease caused by biallelic pathogenic variants (PV) of the MUTYH gene. The aim of this study was to investigate the genetic causes of unexplained polyposis patients with monoallelic MUTYH PV. The analysis focused on 26 patients with suspected MAP, belonging to 23 families. Ten probands carried also one or more additional MUTYH variants of unknown significance. METHODS: Based on variant type and on the collected clinical and molecular data, these variants were reinterpreted by applying the ACMG/AMP rules. Moreover, supplementary analyses were carried out to investigate the presence of other variants and copy number variations in the coding and promoter regions of MUTYH, as well as other polyposis genes (APC, NTHL1, POLE, POLD1, MSH3, RNF43, and MCM9). RESULTS: We reclassified 4 out of 10 MUTYH variants as pathogenic or likely pathogenic, thus supporting the diagnosis of MAP in only four cases. Two other patients belonging to the same family showed a previously undetected deletion of the APC gene promoter. No PVs were found in the other investigated genes. However, 6 out of the 18 remaining families are still interesting MAP candidates, due to the co-presence of a class 3 MUTYH variant that could be reinterpreted in the next future. CONCLUSION: Several efforts are necessary to fully elucidate the genetic etiology of suspected MAP patients, especially those with the most severe polyposis/tumor phenotype. Clinical data, tumor molecular profile, family history, and polyposis inheritance mode may guide variant interpretation and address supplementary studies.
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Pólipos Adenomatosos/diagnóstico , Pólipos Adenomatosos/etiología , Alelos , ADN Glicosilasas/genética , Variación Genética , Biomarcadores , Biología Computacional/métodos , Femenino , Genes APC , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Genómica/métodos , Genotipo , Humanos , Masculino , Linaje , Regiones Promotoras GenéticasRESUMEN
Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, are characterized by activating mutations in KIT or PDGFRA genes. The vast majority of GISTs are sporadic, but rare hereditary forms have been reported, often featuring multifocality and younger age of onset. We here report the identification of a novel kindred affected by familial GIST caused by a KIT germline mutation in exon 13 (N655K). No family affected by hereditary GIST due to this KIT variant has been reported in literature so far. We were able to track the mutation in three members of the family (proband, mother, and second-degree cousin), all affected by multiple GISTs. Due to its rarity, the N655K variant is poorly characterized. We conducted in vitro drug sensitivity assays that indicated that most tyrosine kinase inhibitors (TKIs) currently included in the therapeutic armamentarium for GISTs have a limited inhibitory activity toward this mutation. However, when compared to a classical imatinib-resistant KIT mutation (T670I), N655K was slightly more sensitive to imatinib, and encouraging responses were observed with last-generation TKIs.
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INTRODUCTION: Chronic atrophic autoimmune gastritis (CAAG) can lead to the development of gastric neuroendocrine tumors (gNETs) and can be accompanied by other autoimmune diseases. This study aimed to determine, in CAAG patients, the association of gNET development, the prevalence of autoimmune diseases other than CAAG, the association of autoimmunity, and gNET development with pepsinogen I, II, gastrin-17, and Helicobacter pylori infection analysis. METHODS: We determined the prevalence of gNETs and other autoimmune diseases and analyzed pepsinogen I and II, gastrin-17 serum levels, and H. pylori infection in all patients diagnosed with CAAG at our hospital between 2013 and 2017. RESULTS: A total of 156 patients were studied and in 15.4% was observed concomitant gNET. Approximately 68.6% had at least 1 other autoimmune disease at diagnosis of CAAG. Approximately 60.9% had autoimmune thyroiditis, followed by diabetes (19.9%) and autoimmune polyendocrine syndrome (12.8%). CAAG patients with and without gNET had similar rates of comorbidity with other autoimmune diseases, but the pepsinogen I/II ratio was lower in patients with gNET (1.6 vs 4.5, P = 0.018). Receiver operating characteristic curve analyses identified a pepsinogen I/II ratio <2.3 and gastrin-17 levels >29.6 pmol/L as cutoffs distinguishing CAAG patients with gNET from those without. The combined use of these cutoff correctly identified 16 of the 18 CAAG patients with gNET (P = 0.007). H. pylori infection was observed in 28.7% of cases tested but did not associate with gNET. DISCUSSION: This study suggests that a low pepsinogen I/II ratio and high gastrin-17 levels characterize patients with CAAG and gNET and confirms the frequent coexistence of CAAG with other autoimmune diseases.
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Enfermedades Autoinmunes/diagnóstico , Gastritis Atrófica/diagnóstico , Infecciones por Helicobacter/diagnóstico , Tumores Neuroendocrinos/diagnóstico , Neoplasias Gástricas/diagnóstico , Adolescente , Adulto , Anciano , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/inmunología , Biomarcadores/sangre , Diagnóstico Diferencial , Femenino , Gastrinas/sangre , Gastritis Atrófica/sangre , Gastritis Atrófica/epidemiología , Gastritis Atrófica/inmunología , Infecciones por Helicobacter/sangre , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/inmunología , Helicobacter pylori/inmunología , Helicobacter pylori/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Tumores Neuroendocrinos/sangre , Tumores Neuroendocrinos/epidemiología , Pepsinógeno A/sangre , Pepsinógeno C/sangre , Prevalencia , Curva ROC , Estudios Retrospectivos , Neoplasias Gástricas/sangre , Neoplasias Gástricas/epidemiología , Adulto JovenRESUMEN
Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome caused by germline pathogenic variant in CDH1, the gene encoding E-cadherin. The germline loss-of-function variants are the only proven cause of the cancer syndrome HDGC, occurring in approximately 10-18% of cases and representing a helpful tool in genetic counseling. The current case reports the family history based on a CDH1 gene variant, c.360delG, p.His121Thr in a suspected family for hereditary gastric cancer form. This frameshift deletion generates a premature stop codon at the amino acid 214, which leads to a truncated E-cadherin protein detecting it as a deleterious variant. The present study expands the mutational spectra of the family with the CDH1 variant. Our results highlight the clinical impact of the reported CDH1 variant running in gastric cancer families.
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Antígenos CD/genética , Cadherinas/genética , Mutación de Línea Germinal , Síndromes Neoplásicos Hereditarios/genética , Neoplasias Gástricas/genética , Secuencia de Aminoácidos , Antígenos CD/química , Antígenos CD/fisiología , Secuencia de Bases , Neoplasias de la Mama/genética , Cadherinas/química , Cadherinas/fisiología , Cromosomas Humanos Par 16/genética , Codón sin Sentido , Femenino , Mutación del Sistema de Lectura , Asesoramiento Genético , Humanos , Masculino , Persona de Mediana Edad , Linaje , Eliminación de SecuenciaRESUMEN
Gastric cancer is a frequent human tumor and often a lethal disease. Targeted therapy for gastric carcinomas is far behind vis-à-vis other solid tumors, primarily because of the paucity of cancer-driving mutations that could be efficiently and specifically targeted by current therapy. Thus, there is a need to discover actionable pathways/proteins and new diagnostic and prognostic biomarkers. In this study, we explored the role of the extracellular matrix glycoprotein EMILIN2, Elastin Microfibril Interfacer 2, in a cohort of gastric cancer patients. We discovered that EMILIN2 expression was consistently suppressed in gastric cancer and high expression levels of this glycoprotein were linked to abnormal vascular density. Furthermore, we found that EMILIN2 had a dual effect on gastric carcinoma cells: on one hand, it decreased tumor cell proliferation by triggering apoptosis, and on the other hand, it evoked the production of a number of cytokines involved in angiogenesis and inflammation, such as IL-8. Collectively, our findings posit EMILIN2 as an important onco-regulator exerting pleiotropic effects on the gastric cancer microenvironment.
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The potential role of the probe-based confocal laser endomicroscopy (pCLE) has been analyzed in different pathologic conditions of the gastrointestinal tract. Here, we analyzed a case of extrapulmonary high grade neuroendocrine rectal carcinoma (HGNEC) using, for the first time, the pCLE system. A 72-year old man was diagnosed with an 8 cm diameter rectal HGNEC by standard colonoscopy integrated with the pCLE system. The diagnosis of neuroendocrine carcinoma was confirmed by immunohistochemical analyses. By using the pCLE system, we well defined and resolved vascular structures and mucosal architecture. An altered mucosal pattern and vascular defects, peculiar for HGNEC, were observed at high magnification, allowing the identification of a pattern which was quite different from that observed in poorly differentiated adenocarcinomas (PDA) where tissues appear darker, very irregular, even if glandular structures can still be recognized. This underlines the usefulness of pCLE in discriminating HGNECs from PDAs. In conclusion, pCLE could represent a valid and helpful method for in vivo HGNEC diagnosis, allowing prompt and careful management of the patient.
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Probe based confocal laser endomicroscopy (pCLE) is an advanced technique which provides imaging of gastrointestinal mucosa at subcellular resolution and, importantly, a valid tool for the evaluation of microvasculature during endoscopic examination. In order to assess intratumoral vascularization and the efficiency of blood flow in locally advanced gastric cancer, we examined 57 patients through pCLE imaging. The vascular alterations in gastric cancer were mainly characterized by leakage and by the presence of tortuous and large size vessels. Defects in blood flow were detected very rarely. No association between the angiogenic score and the gastric tumor site or histological type was observed. Interestingly, no correlation was also found with the tumor grading indicating that the vascular angiogenic anomalies in gastric cancer represent an early pathological event to be observed and detected. The majority of patients displayed unchanged vascular alterations following neoadjuvant chemotherapy and this positively correlated with stable or progressive disease, suggesting that an unaltered angiogenic score could per se be indicative of poor therapeutic efficacy. Different vascular parameters were evaluated by immunofluorescence using bioptic samples and the vessel density did not correlate with clinical staging, site or histologic type. Interestingly, only CD105, Multimerin-2 and GLUT1 were able to discriminate normal from tumoral gastric mucosa. Taken together, these findings indicate that functional and structural angiogenic parameters characteristic of tumor blood network were fully detectable by pCLE. Moreover, the evaluation of tumor vasculature by real-time assessment may provide useful information to achieve tailored therapeutic interventions for gastric cancer patients.
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BACKGROUND: Inherited epimutations of Mismatch Repair (MMR) genes are responsible for Lynch Syndrome (LS) in a small, but well defined, subset of patients. Methylation of the MSH2 promoter consequent to the deletion of the upstream EPCAM gene is found in about 1%-3% of the LS patients and represents a classical secondary, constitutional and tissue-specific epimutation. Several different EPCAM deletions have been reported worldwide, for the most part representing private variants caused by an Alu-mediated recombination. METHODS: 712 patients with suspected LS were tested for MMR mutation in our Institute. EPCAM deletions were detected by multiplex ligation-dependent probe amplification (MLPA) and then defined by Long-Range polymerase chain reaction (PCR)/Sanger sequencing. A comprehensive molecular characterization of colorectal cancer (CRC) tissues was carried out by immunohistochemistry of MMR proteins, Microsatellite Instability (MSI) assay, methylation specific MLPA and transcript analyses. In addition, somatic deletions and/or variants were investigated by MLPA and next generation sequencing (NGS). RESULTS: An EPCAM deletion was found in five unrelated probands in Italy: variants c.556-490_*8438del and c.858+1193_*5826del are novel; c.859-1430_*2033del and c.859-670_*530del were previously reported. All probands were affected by CRC at young age; tumors showed MSI and abnormal MSH2/MSH6 proteins expression. MSH2 promoter methylation, as well as aberrant in-frame or out-of-frame EPCAM/MSH2 fusion transcripts, were detected in CRCs and normal mucosae. CONCLUSION: An EPCAM deletion was the causative variant in about 2% of our institutional series of 224 LS patients, consistent with previously estimated frequencies. Early age and multiple CRCs was the main clinical feature of this subset of patients.
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Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Molécula de Adhesión Celular Epitelial/genética , Eliminación de Gen , Frecuencia de los Genes , Adulto , Metilación de ADN , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , FenotipoRESUMEN
Gastric cancer is a deadly tumor and a relatively common disease worldwide. Surgical resection and chemotherapy are the main clinical options to treat this type of disease, however the median overall survival rate is limited to one year. Thus, the development of new therapies is a highly necessary clinical need. Angiogenesis is a promising target for this tumor type, however clinical trials with the use of anti-angiogenic drugs have so far not met expectations. Therefore, it is important to better characterize the expression of molecules whose expression levels may impact on the efficacy of the treatments. In this study the characteristics of the gastric tumor associated blood vessels were first assessed by endomicroscopy. Next, we analyzed the expression of Multimerin-2, EMILIN-2 and EMILIN-1, three molecules of the EMI Domain ENdowed (EDEN) protein family. These molecules play important functions in the tumor microenvironment, affecting cancer progression both directly and indirectly impinging on angiogenesis and lymphangiogenesis. All the molecules were highly expressed in the normal mucosa whereas in a number of patients their expression was altered. We consider that better characterizing the gastric tumor microenvironment and the quality of the vasculature may achieve effective patient tailored therapies.
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Antígenos de Superficie/metabolismo , Glicoproteínas/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Glicoproteínas de Membrana/metabolismo , Neovascularización Patológica/metabolismo , Neoplasias Gástricas/metabolismo , Antígenos de Superficie/genética , Técnica del Anticuerpo Fluorescente , Glicoproteínas/genética , Humanos , Glicoproteínas de Membrana/genética , Neovascularización Patológica/genética , Neoplasias Gástricas/genéticaRESUMEN
Lynch syndrome (LS) and familial adenomatous polyposis (FAP) are autosomal dominant hereditary diseases caused by germline mutations leading to the development of colorectal cancer. Moreover, these mutations result in the development of a spectrum of different tumors, including gastric cancers (GCs). Since the clinical characteristics of GCs associated with LS and FAP are not well known, we investigated clinical and molecular features of GCs occurring in patients with LS and FAP attending our Institution. The Hereditary Tumor Registry was established in 1994 at the Department of Oncologic Gastroenterology, CRO Aviano National Cancer Institute, Italy. It includes 139 patients with LS and 86 patients with FAP. Patients were recruited locally for prospective surveillance. Out of 139 LS patients, 4 developed GC3 in the presence of helicobacter pylori infection and 1 on the background of autoimmune diseases. All GCs displayed a high microsatellite instability (MSI-H) and loss of related mismatch repair (MMR) protein. One of the FAP patients developed a flat adenoma, displaying low-grade dysplasia at the gastric body, and another poorly differentiated adenocarcinoma with signet ring cells like Krukenberg without HP infection. LS carriers displayed a risk of GC. The recognition of HP infection and autoimmune diseases would indicate those at higher risk for an endoscopic surveillance. Regarding FAP, the data suggested the need of suitable endoscopic surveillance in long survivals with diffuse fundic gland polyps.
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Poliposis Adenomatosa del Colon/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Neoplasias Gástricas/patología , Poliposis Adenomatosa del Colon/genética , Adulto , Anciano , Antígenos CD , Cadherinas/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN , Femenino , Mutación de Línea Germinal , Humanos , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Estudios Prospectivos , Neoplasias Gástricas/genéticaRESUMEN
Probe-based Confocal Laser Endomicroscopy (pCLE) is a powerful imaging technique that allows to perform gastrointestinal endomicroscopy at subcellular resolution. The aim of this study was to assess the use of pCLE to evaluate tumor angiogenesis in rectal and gastric cancers. A total of 35 consecutive patients with gastric and 91 with rectal carcinomas underwent endoscopy and pCLE during the same examination. Vascular assessment was based on vessel shape and size, vessel permeability and blood flow, and allowed the creation of an angiogenic score ranging from 0, for normal vasculature, to 4, for aberrant vasculature. A significant difference for the presence of vessels with large diameter and defective blood flow was found between rectal and gastric cancers. Overall, rectal cancers displayed a higher angiogenic score compared to gastric cancers. Conventional therapy induced a striking reduction in the angiogenic score only in rectal cancer patients. Taken together, our findings suggest that the pCLE technology is suitable for the evaluation of the tumor microvasculature abnormalities. Therefore, the real-time assessment of the vasculature status may represent a promising approach to predict the efficacy of the treatments and improve the clinical management of patients with gastric or rectal carcinomas.
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Endoscopía Gastrointestinal , Imagen Molecular , Neovascularización Patológica/diagnóstico por imagen , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/patología , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/patología , Biomarcadores , Endoscopía Gastrointestinal/métodos , Humanos , Inmunohistoquímica , Imagen Molecular/métodos , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias del Recto/metabolismo , Neoplasias del Recto/terapia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/terapiaRESUMEN
8-Oxoguanine, a common mutagenic DNA lesion, generates G:C>T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC) in MUTYH-Associated Polyposis (MAP) syndrome. Here, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours. The excess G:C>T:A transversion mutations in MAP CRCs exhibits a novel mutational signature, termed Signature 36, with a strong sequence dependence. The MUTYH mutational signature reflecting persistent 8-oxoG:A mismatches occurs frequently in the APC, KRAS, PIK3CA, FAT4, TP53, FAT1, AMER1, KDM6A, SMAD4 and SMAD2 genes that are associated with CRC. The occurrence of Signature 36 in other types of human cancer indicates that DNA 8-oxoguanine-related mutations might contribute to the development of cancer in other organs.
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Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Daño del ADN , ADN Glicosilasas/genética , Guanina/análogos & derivados , Alelos , Neoplasias Colorrectales/patología , ADN Glicosilasas/metabolismo , Análisis Mutacional de ADN , Reparación del ADN , Frecuencia de los Genes , Genes Supresores de Tumor , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Guanina/metabolismo , Humanos , Inestabilidad de Microsatélites , Mutación , Tasa de Mutación , Oncogenes , Secuenciación del ExomaRESUMEN
The CDH1 gene, coding for the E-cadherin protein, is linked to gastric cancer (GC) susceptibility and tumor invasion. The human epidermal growth factor receptor 2 (HER2) is amplified and overexpressed in a portion of GC. HER2 is an established therapeutic target in metastatic GC (mGC). Trastuzumab, in combination with various chemotherapeutic agents, is a standard treatment for these tumors leading to outcome improvement. Unfortunately, the survival benefit is limited to a fraction of patients. The aim of this study was to improve knowledge of the HER2 and the E-cadherin alterations in the context of GC to characterize subtypes of patients that could better benefit from targeted therapy. An association between the P7-CDH1 haplotype, including two polymorphisms (rs16260A-rs1801552T) and a subset of HER2-positive mGC with better prognosis was observed. Results indicated the potential evaluation of CDH1 haplotypes in mGC to stratify patients that will benefit from trastuzumab-based treatments. Moreover, data may have implications to understanding the HER2 and the E-cadherin interactions in vivo and in response to treatments.
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Cadherinas/genética , Haplotipos/genética , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Adulto , Anciano , Antígenos CD , Secuencia de Bases , Femenino , Frecuencia de los Genes/genética , Mutación de Línea Germinal/genética , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Modelos de Riesgos Proporcionales , Análisis de SupervivenciaRESUMEN
OBJECTIVES: The objectives of this study were to investigate the serum pepsinogen test for the prediction of OLGIM (Operative Link on Gastric Intestinal Metaplasia Assessment) stages in first-degree relatives (FDR-GC) of patients with gastric cancer (GC) and autoimmune chronic atrophic gastritis (ACAG). METHODS: In 67 consecutive patients with ACAG, 82 FDR-GC, and 53 controls (CTRL) without gastric disease (confirmed by biopsy), serum levels of pepsinogen 1 (PG1), pepsinogen 2 (PG2), G17, and the PG1/2 ratio were assessed by enzyme-linked immunosorbent assay kit. All ACAG patients had positive antiparietal cell antibody levels, estimated by indirect immunofluorescence. Biopsies taken in duplicate from the antrum, corpus, and fundus were stained with Giemsa for Helicobacter pylori detection. Endoscopic detection of metaplasia was confirmed by histological diagnosis. Histological classification of OLGIM stages was applied by using the criteria of severity and topography of intestinal metaplasia (IM). RESULTS: The highest discrimination capacity for distinguishing ACAG from other groups of patients was the gastrin G17 test. The lowest mean for PG1 and PG2 serum levels was found in ACAG. In multivariate analysis by age, PG1 and PG1/PG2 were independent prognostic factors for metaplasia, and PG2 also for the presence of a histological H. pylori infection. The serum PG1 level was significantly lower in individuals with IM at OLGIM stage >2 than in those with IM at OLGIM stage <2, resulting in a useful method for the prediction of OLGIM stage. With the inclusion of patient age at diagnosis in the prediction of ≥2 vs. 0-1 OLGIM stages, the receiver operating characteristic (ROC) curve at 47.9 ng/ml PG1 level reached a significant area under the curve (AUC) value (0.978, P<0.001). We also observed a slight difference in PG2 serum levels between histological H. pylori-positive and H. pylori-negative subjects (ROC AUC: 0.599). CONCLUSIONS: This study demonstrated an important increase in gastrin G17 serum level in autoimmune gastritis. PG1 serum level corrected by patient age can be used in the management of patients at risk for GC with a high predicted probability of having an OLGIM stage ≥2. Using a cutoff of 47.9 ng/ml, PG1 testing in FDR-GC and ACAG patients had a sensitivity of 95.83% and a specificity of 93.37. Although these results could be validated in a prospective study, the known importance of higher OLGIM stages in increasing the risk of GC development supports the rationale of proposing PG1 algorithm as a diagnostic tool for the selection of high-risk FDR-GC and ACAG patients at high-risk stages for subsequent detailed endoscopic examination to detect dysplasia and asymptomatic GC. In addition, serum PG1 and PG2 levels could stratify patients based on both H. pylori infection and OLGIM risk in consideration of the increased acknowledge regarding the role of H. pylori in the progression of gastritis to GC.
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PURPOSE: The purpose of this study was to evaluate patient-centered outcomes of decompressive percutaneous endoscopic gastrostomy (dPEG) in patients with malignant bowel obstruction due to advanced gynecological and gastroenteric malignancies. METHODS: This is a prospective analysis of 158 consecutive patients with small-bowel obstruction from advanced gynecological and gastroenteric cancer who underwent PEG or percutaneous endoscopic jejunostomy (PEJ) positioning for decompressive purposes from 2002 to 2012. All of them had previous abdominal surgery and were unfit for any other surgical procedures. Symptom relief, procedural complications, and post dPEG palliation were assessed. Global Quality of Life (QoL) was evaluated in the last 2 years (25 consecutive patients) before and 7 days after dPEG placement using the Symptom Distress Scale (SDS). RESULTS: dPEG was successfully performed in 142 out of 158 patients (89.8 %). Failure of tube placement occurred in 16 patients (10.1 %). In 8/142 (5.6 %) patients, dPEG was guided by abdominal ultrasound. In 3/142 patients, dPEG was CT-guided. In 14 (9.8 %) patients, who had previously undergone total or subtotal gastrectomy, decompressive percutaneous endoscopic jejunostomy (dPEJ) was performed. In 1/14 patients, dPEJ was CT-guided. Out of 142 patients, 110 (77.4 %) experienced relief from nausea and vomiting 2 days after PEG. Out of 142 patients, 116 (81.6 %) were discharged. The median postoperative hospital stay was 9 days (range 3-60). Peristomal infection (14 %) and intermittent obstruction (8.4 %) were the most frequent complications associated with PEG. Median survival time was 57 days (range 4-472) after PEG placement. Twenty-five patients had QoL properly evaluated with SDS score before and 7 days after dPEG. Sixteen patients (64 %) out of 25 exhibited an improvement of QoL (p < 0.05), 7 (28 %) patients exhibited a non-significant worsening of QoL (p = 0.18), and in 2 (8 %) patients, it remained unmodified. CONCLUSIONS: dPEG is feasible, effective, relieves nausea and vomiting in patients with unremitting small-bowel obstruction from advanced gynecological and gastroenteric cancer, and improves QoL.
Asunto(s)
Gastrostomía/métodos , Obstrucción Intestinal/complicaciones , Adulto , Anciano , Femenino , Gastrostomía/efectos adversos , Humanos , Obstrucción Intestinal/cirugía , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Calidad de VidaRESUMEN
OBJECTIVE: To evaluate the prevalence of celiac disease in asymptomatic iron-deficient blood donors without anemia. MATERIAL AND METHODS: Between the period February 2004 and January 2006, iron-deficient male donors with serum ferritin less than 30 ng/ml and female donors with serum ferritin less than 10 ng/ml were screened for immunoglobulin A (IgA) and IgG antitissue transglutaminase antibodies and donors with positive antibody titers were referred for endoscopy with multiple biopsies of the second/third part of duodenum. The frequency of celiac disease in iron-deficient blood donors without anemia and the predictive value of ferritin levels were analyzed. RESULTS: Of the 1679 blood donors, 579 (34.4%) were identified as iron deficient and screened for celiac disease. 290 (50%) were men (mean age: 39 years; range: 19-65) and 289 (50%) were women (mean age: 37 years; range: 19-63). Thirteen donors (2.2%) were positive for serum IgA antitissue transglutaminase antibodies, of whom six were men (2.0%) and seven were women (2.4%). 10 donors of 13 (1.7%) at histology presented alterations in the mucosal architecture according to the modified Marsh classification (Marsh I-III). Low ferritin level was not predictive for celiac disease (median serum ferritin level in celiac donors 14.7 ng/ml and in nonceliac donors 15.8 ng/ml, Wilcoxon test: P not significant). The prevalence of celiac disease among iron-deficient blood donors without anemia was 1.7%. CONCLUSION: The prevalence of celiac disease in our population of asymptomatic iron-deficient blood donors without anemia was 1.7%. We suggest screening for celiac disease in iron-deficient individuals without anemia to increase diagnosis of asymptomatic celiac disease.