RESUMO
Tumors of the intestinal tract are among the most common tumor diseases in humans, but, like many other tumor entities, show an unsatisfactory prognosis with a need for effective therapies. To test whether nutritional interventions and a combination with a targeted therapy can effectively cure these cancers, we used the fruit fly Drosophila as a model. In this system, we induced tumors by EGFR overexpression in intestinal stem cells. Limiting the amount of protein in the diet restored life span to that of control animals. In combination with a specific EGFR inhibitor, all major tumor-associated phenotypes could be rescued. This form of treatment was also successful in a real treatment scenario, which means when they started after the full tumor phenotype was expressed. In conclusion, reduced protein administration can be a very promising form of adjuvant cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Dieta com Restrição de Proteínas , Neoplasias Intestinais , Longevidade/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Animais , Restrição Calórica , Proliferação de Células/efeitos dos fármacos , Drosophila melanogaster , Feminino , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/fisiopatologiaRESUMO
Neuroendocrine neoplasms (NENs) are rare neoplasms that occur in various organs and present with diverse clinical manifestations. Pathological classification is important in the diagnosis of NENs. Treatment strategies must be selected according to the status of differentiation and malignancy by accurately determining whether the neoplasm is functioning or nonfunctioning, degree of disease progression, and presence of metastasis. The newly revised Clinical Practice Guidelines for Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) comprises 5 chapters-diagnosis, pathology, surgical treatment, medical and multidisciplinary treatment, and multiple endocrine neoplasia type 1 (MEN1)/von Hippel-Lindau (VHL) disease-and includes 51 clinical questions and 19 columns. These guidelines aim to provide direction and practical clinical content for the management of GEP-NEN preferentially based on clinically useful reports. These revised guidelines also refer to the new concept of "neuroendocrine tumor" (NET) grade 3, which is based on the 2017 and 2019 WHO criteria; this includes health insurance coverage of somatostatin receptor scintigraphy for NEN, everolimus for lung and gastrointestinal NET, and lanreotide for GEP-NET. The guidelines also newly refer to the diagnosis, treatment, and surveillance of NEN associated with VHL disease and MEN1. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the first edition was published.
Assuntos
Guias como Assunto , Neoplasias Intestinais/diagnóstico , Neoplasias Intestinais/terapia , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/terapia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/terapia , Assistência ao Convalescente/métodos , Assistência ao Convalescente/tendências , Humanos , Neoplasias Intestinais/fisiopatologia , Tumores Neuroendócrinos/fisiopatologia , Neoplasias Pancreáticas/fisiopatologia , Neoplasias Gástricas/fisiopatologiaRESUMO
BACKGROUND: The impact of alcohol drinking on gastric precancerous lesions remains unclear. We investigated the relationship of alcohol intake with risk of atrophic gastritis (AG) and intestinal metaplasia (IM). METHODS: This study included 202,675 Korean adults free from AG and IM on their initial endoscopy who were followed with repeated endoscopic examinations. A parametric proportional hazards model was used to estimate the adjusted HR (aHR) with 95% confidence interval (CI) for incident AG and IM based on endoscopic diagnosis. RESULTS: During a mean follow-up of 4.7 years, 64,853 incident AG cases and 4,536 IM cases were identified. Alcohol consumption including drinking frequency, quantity, and binge drinking were consistently associated with increased risk of both AG and IM in a dose-response manner. After adjustment for confounders, the multivariable aHRs (95% CIs) for incident IM comparing average alcohol intake of <10, 10-<20, 20-<40, and ≥40 g/day with lifetime abstainers were 1.27 (1.02-1.56), 1.34 (1.07-1.66), 1.50 (1.20-1.86), and 1.54 (1.23-1.93), respectively. Former drinkers were also at a higher risk for AG and IM compared with lifetime abstainers. These associations were consistently observed in never smokers and in time-dependent analyses. CONCLUSIONS: In a large cohort of Korean individuals, alcohol intake even at low levels was independently associated with increased risk of developing endoscopic AG and IM, supporting a role of alcohol consumption in the pathogenesis of AG and IM, the precursor lesions of stomach cancer. IMPACT: Alcohol consumption from low-level drinking may contribute to gastric carcinogenesis.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Neoplasias Intestinais/etiologia , Metaplasia/etiologia , Adulto , Estudos de Coortes , Feminino , Humanos , Neoplasias Intestinais/fisiopatologia , Masculino , Metaplasia/fisiopatologia , Fatores de RiscoRESUMO
A 38-year-old Japanese man who had been diagnosed with appendiceal carcinoid and undergone ileocecal resection 8 years before presented with duodenal obstruction caused by a submucosal tumor-like appearance. He was diagnosed with long-term recurrence of appendiceal goblet cell carcinoid (GCC) with a multi-morphological pattern based on the histological assessment of a duodenal biopsy and his previously resected appendix. He underwent subtotal stomach-preserving pancreaticoduodenectomy combined with resection of an ileo-colic anastomotic lesion. The GCC recurred at the nearby ileo-colic anastomosis and invaded the duodenum. This late recurrence might have resulted from the unique features of his GCC, which contained cells with different degrees of malignancy.
Assuntos
Neoplasias do Apêndice/cirurgia , Tumor Carcinoide/cirurgia , Cisplatino/uso terapêutico , Obstrução Duodenal/cirurgia , Etoposídeo/uso terapêutico , Neoplasias Intestinais/cirurgia , Recidiva Local de Neoplasia/cirurgia , Adulto , Antineoplásicos/uso terapêutico , Apendicectomia/métodos , Neoplasias do Apêndice/tratamento farmacológico , Tumor Carcinoide/tratamento farmacológico , Tumor Carcinoide/fisiopatologia , Colectomia/métodos , Obstrução Duodenal/etiologia , Humanos , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/fisiopatologia , Japão , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Resultado do TratamentoRESUMO
INTRODUCTION: In recent decades, the number of gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) cases, associated with coexisting metabolic disorders, has been continuously increasing. Patients with progressing neoplastic disease are at a risk of malnutrition. To improve the quality of life of neuroendocrine neoplasms (NEN) patients, the therapeutic approach should be supported by a well-balanced diet. The aim of the study was to analyze the nutritional errors and deficits in a group of GEP-NET patients. MATERIALS AND METHODS: The study group included 26 GEP-NET patients; 13 men and 13 women. The mean age of women was 68.77 ± 8.0, and the mean age of men was 64.69 ± 8.1. Three interviews on consumption in the last 24 h were performed, in order to evaluate the quality and quantity of nutrition. The data was incorporated into a dietetics software, which allows one to calculate the number of over 58 micronutrients and macronutrients with the participation of 52 menus. Subsequently, the mean values were compared with the current nutritional standards. Results: An energy deficit was observed in the group of women-76.9%, and men-100%, as well as high fat consumption in 23.1% in both groups. The proportions of SFA/MUFA/PUFA were very negative, whereas the consumption of saccharose was too high. Vitamin D deficiency was observed in 100% of men and women. Moreover, both men and women experienced the deficiency of vitamin E, folates and niacin. The consumption of sodium and phosphorus was twice as high as recommended, and an insufficient supply of calcium was observed in 80% of women and 90% of men. The insufficient consumption of magnesium, iodine and potassium in a significant part of the studied group was observed. All participants consumed too much cholesterol and insufficient amounts of fiber. The healthy diet indicator (HDI) and diet quality index (DQI) scores were 3.1 ± 1.8 (HDI) and 3.7 ± 1.6 (DQI) for women, and 7.2 ± 2.6 (HDI) and 8.5 ± 2.4 (DQI) for men. CONCLUSIONS: When analyzing the nutrition of GEP-NET patients, we highlight that they do not have a proper diet, despite the fact that they changed the way they eat. Dietetics support and the development of official nutritional standards seem to be a necessary element in the therapy of GEP-NET patients.
Assuntos
Dieta/estatística & dados numéricos , Neoplasias Intestinais/fisiopatologia , Desnutrição/diagnóstico , Tumores Neuroendócrinos/fisiopatologia , Estado Nutricional , Neoplasias Pancreáticas/fisiopatologia , Neoplasias Gástricas/fisiopatologia , Deficiência de Vitamina D/diagnóstico , Idoso , Inquéritos sobre Dietas , Feminino , Humanos , Neoplasias Intestinais/complicações , Masculino , Desnutrição/etiologia , Pessoa de Meia-Idade , Tumores Neuroendócrinos/complicações , Avaliação Nutricional , Neoplasias Pancreáticas/complicações , Qualidade de Vida , Neoplasias Gástricas/complicações , Deficiência de Vitamina D/etiologiaRESUMO
Patients affected by gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) have an increased risk of developing osteopenia and osteoporosis, as several factors impact on bone metabolism in these patients. In fact, besides the direct effect of bone metastasis, bone health can be affected by hormone hypersecretion (including serotonin, cortisol, and parathyroid hormone-related protein), specific microRNAs, nutritional status (which in turn could be affected by medical and surgical treatments), and vitamin D deficiency. In patients with multiple endocrine neoplasia type 1 (MEN1), a hereditary syndrome associated with NET occurrence, bone damage may carry other consequences. Osteoporosis may negatively impact on the quality of life of these patients and can increment the cost of medical care since these patients usually live with their disease for a long time. However, recommendations suggesting screening to assess bone health in GEP-NET patients are missing. The aim of this review is to critically analyze evidence on the mechanisms that could have a potential impact on bone health in patients affected by GEP-NET, focusing on vitamin D and its role in GEP-NET, as well as on factors associated with MEN1 that could have an impact on bone homeostasis.
Assuntos
Osso e Ossos/metabolismo , Neoplasias Intestinais/fisiopatologia , Tumores Neuroendócrinos/fisiopatologia , Estado Nutricional , Neoplasias Pancreáticas/fisiopatologia , Neoplasias Gástricas/fisiopatologia , Vitamina D/sangue , Densidade Óssea , Doenças Ósseas Metabólicas/etiologia , Remodelação Óssea , Humanos , Neoplasias Intestinais/complicações , MicroRNAs/metabolismo , Neoplasia Endócrina Múltipla Tipo 1/complicações , Neoplasia Endócrina Múltipla Tipo 1/fisiopatologia , Tumores Neuroendócrinos/complicações , Osteoporose/etiologia , Neoplasias Pancreáticas/complicações , Qualidade de Vida , Neoplasias Gástricas/complicações , Deficiência de Vitamina D/etiologiaRESUMO
Tool Like Receptors (TLR) are transmembrane proteins that play an important role in immune reactions associated with the recognition of pathogenic factors that cause infection. However, chronic inflammatory conditions associated with the activation of these receptors create favorable conditions for the development of cancerous processes. The relationship between nuclear PPARγ receptors and TLR receptors is also important, whose role and importance in the process of carcinogenesis is the subject of various studies.
Assuntos
Carcinogênese/imunologia , Carcinogênese/patologia , Neoplasias Intestinais/imunologia , Neoplasias Intestinais/fisiopatologia , PPAR gama/imunologia , Transdução de Sinais/imunologia , Proteínas de Transporte Vesicular/imunologia , HumanosRESUMO
RATIONALE: Small intestine stromal tumors (SISTs) are a type of gastrointestinal stromal tumor (GIST) that has an insidious onset. Natural orifice specimen extraction (NOSE) surgery has been gradually developed for the treatment of colorectal, stomach, small intestine, hepatobiliary, and gynecological tumors because of its safety and feasibility. This case study explored the possibility of applying the NOSE method for the treatment of SIST. PATIENT CONCERNS: A 59-year-old male patient was admitted to the hospital after having an irregular abdominal mass for >1 month that was detected by a medical examination. Thoracic and abdominopelvic enhanced computer tomography revealed irregular masses on the left side of the abdominal cavity. DIAGNOSIS: Sist. INTERVENTIONS: Nose (laparoscopic resection of intestinal stromal tumors with transrectal extract specimen and no abdominal auxiliary incision) surgery was performed. OUTCOMES: The patient underwent operation successfully and recuperates well with no complications. LESSONS: Nose surgery is minimally invasive, results in patient recuperation with no complications, and is considered to be feasible for SIST treatment.
Assuntos
Colectomia/métodos , Tumores do Estroma Gastrointestinal , Neoplasias Intestinais , Laparoscopia/métodos , Cirurgia Endoscópica por Orifício Natural/métodos , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/fisiopatologia , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Neoplasias Intestinais/patologia , Neoplasias Intestinais/fisiopatologia , Neoplasias Intestinais/cirurgia , Intestinos/diagnóstico por imagem , Intestinos/patologia , Intestinos/cirurgia , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Tomografia Computadorizada por Raios X/métodos , Resultado do TratamentoRESUMO
Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) arise throughout the gut and feature varying biological behaviour and malignant potential. GEP-NENs include two genetically different entities, well-differentiated neuroendocrine tumours (NETs) and poorly differentiated neuroendocrine carcinomas (NEC). NECs are characterized by a dismal prognosis and by distinctive TP53 and RB1 inactivation which sets them apart from NETs. The latter, conversely, have a wide spectrum of aggressiveness and molecular alterations. Knowledge on their biology has recently expanded thanks to high-throughput studies focused on two important groups of well-differentiated neuroendocrine neoplasms: pancreatic (PanNETs) and small intestinal (SiNETs) tumours. PanNETs have been among the most studied also due to genetic syndromes featuring their onset. Research stemming from this observation has uncovered the inactivation of MEN1, VHL, TSC1/2, and the hyperactivation of the PI3K/mTOR pathway as distinctive biological features of these neoplasms. Next-Generation Sequencing added information on the role of telomere lengthening via ATRX/DAXX inactivation in a fraction of PanNETs, while other display shortened telomeres and recurrent chromosomal alterations. The data so far disclosed a heterogeneous combination of driver events, yet converging into four pathways including DNA damage repair, cell cycle regulation, PI3K/mTOR signalling and telomere maintenance. SiNETs showed a lesser relationship with mutational driver events, even in the case of familial cases. High throughput studies identified putative driver mutations in CDKN1 and APC which, however, were reported in a minor fraction (â¼10%) of cases. Tumorigenesis of SiNETs seems to depend more on chromosomal alterations (loss of chromosome 8, gains at 4, 5 and 20) and epigenetic events, which converge to hyperactivate the PI3K/mTOR, MAPK and Wnt pathways. While calling for further integrative studies, these data lay previous and recent findings in a more defined frame and provide clinical research with several candidate markers for patient stratification and companion diagnostics.
Assuntos
Neoplasias Intestinais/genética , Intestino Delgado , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Epigênese Genética , Amplificação de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Intestinais/fisiopatologia , Proteínas Quinases Ativadas por Mitógeno/genética , Terapia de Alvo Molecular , Mutação , Tumores Neuroendócrinos/fisiopatologia , Neoplasias Pancreáticas/fisiopatologia , Fosfatidilinositol 3-Quinases/genética , Transdução de Sinais , Síndrome , Serina-Treonina Quinases TOR/genética , Via de Sinalização Wnt/genéticaRESUMO
Tgif1 (thymine-guanine-interacting factor 1) and Tgif2 repress gene expression by binding directly to DNA or interacting with transforming growth factor (TGF) ß-responsive SMADs. Tgifs are essential for embryogenesis and may function in tumor progression. By analyzing both gain and loss of Tgif function in a well-established mouse model of intestinal cancer, we show that Tgifs promote adenoma growth in the context of mutant Apc (adenomatous polyposis coli). Despite the tumor-suppressive role of TGFß signaling, transcriptome profiling of colon tumors suggests minimal effect of Tgifs on the TGFß pathway. Instead, it appears that Tgifs, which are up-regulated in Apc mutant colon tumors, contribute to reprogramming metabolic gene expression. Integrating gene expression data from colon tumors with other gene expression and chromatin-binding data identifies a set of direct Tgif target genes encoding proteins involved in acetyl CoA and pyruvate metabolism. Analysis of both tumor and nontumor tissues indicates that these genes are targets of Tgif repression in multiple settings, suggesting that this is a core Tgif function. We propose that Tgifs play an important role in regulating basic energy metabolism in normal cells, and that this function of Tgifs is amplified in some cancers.
Assuntos
Acetilcoenzima A/genética , Adenoma , Regulação Neoplásica da Expressão Gênica/genética , Proteínas de Homeodomínio/metabolismo , Neoplasias Intestinais , Proteínas Repressoras/metabolismo , Adenoma/genética , Adenoma/fisiopatologia , Polipose Adenomatosa do Colo/genética , Animais , Células Cultivadas , Modelos Animais de Doenças , Metabolismo Energético/genética , Células HCT116 , Humanos , Mucosa Intestinal/fisiopatologia , Neoplasias Intestinais/genética , Neoplasias Intestinais/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Sudden massive release of serotonin, histamine, kallikrein, and bradykinin is postulated to cause an intraoperative carcinoid crisis. The exact roles of each of these possible agents, however, remain unknown. Optimal treatment will require an improved understanding of the pathophysiology of the carcinoid crisis. METHODS: Carcinoid patients with liver metastases undergoing elective abdominal operations were studied prospectively, using intraoperative, transesophageal echocardiography, pulmonary artery catheterization, and intraoperative blood collection. Serotonin, histamine, kallikrein, and bradykinin levels were analyzed by enzyme-linked immunosorbent assay. RESULTS: Of 46 patients studied, 16 had intraoperative hypotensive crises. Preincision serotonin levels were greater in patients who had crises (1,064 vs 453 ng/mL, Pâ¯=â¯.0064). Preincision hormone profiles were otherwise diverse. Cardiac function on transesophageal echocardiography during the crisis was normal, but intracardiac hypovolemia was observed consistently. Pulmonary artery pressure decreased during crises (Pâ¯=â¯.025). Linear regression of preincision serotonin levels showed a positive relationship with mid-crisis cardiac index (râ¯=â¯0.73, Pâ¯=â¯.017) and a negative relationship with systemic vascular resistance (r=-0.61, Pâ¯=â¯.015). There were no statistically significant increases of serotonin, histamine, kallikrein, or bradykinin levels during the crises. CONCLUSION: The pathophysiology of carcinoid crisis appears consistent with distributive shock. Hormonal secretion from carcinoid tumors varies widely, but increased preincision serotonin levels correlate with crises and with hemodynamic parameters during the crises. Statistically significant increases of serotonin, histamine, kallikrein, or bradykinin during the crises were not observed.
Assuntos
Hipotensão/fisiopatologia , Hipovolemia/fisiopatologia , Síndrome do Carcinoide Maligno/fisiopatologia , Artéria Pulmonar/fisiopatologia , Serotonina/sangue , Bradicinina/sangue , Tumor Carcinoide/fisiopatologia , Tumor Carcinoide/cirurgia , Ecocardiografia Transesofagiana , Feminino , Histamina/sangue , Humanos , Neoplasias Intestinais/fisiopatologia , Neoplasias Intestinais/cirurgia , Complicações Intraoperatórias , Calicreínas/sangue , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/fisiopatologia , Neoplasias Pulmonares/cirurgia , Masculino , Síndrome do Carcinoide Maligno/sangue , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos ProspectivosRESUMO
trans-Resveratrol has beneficial effects on colorectal cancer, through its antioxidant capacity, and its roles in regulating eicosanoid synthesis. This study determines how changes in resveratrol structure affected its biological activities. Our results showed that trans- and cis-resveratrol and hydroxylated analogs (piceatannol) (10-25 µM) displayed similar antioxidant activities (2-3 fold higher than trolox) and inhibit eicosanoid synthesis and Caco-2 growth (76.5 ± 2.7%, 48.2 ± 3.1% and 41.1 ± 2.3%, p ≤ 0.05). These effects can be related with an increase of the percentage of cells in the S phase (156.3 ± 5.6, 91.2 ± 3.3 and 64.1 ± 2.8, p ≤ 0.05) as a consequence of the impairment of the cells in G0/G1. Furthermore, we observed that these molecules induce apoptosis at 100 µM (48.2 ± 6.6%, p ≤ 0.05; 4.3 ± 2.5% and 21.2 ± 3.3%, p ≤ 0.05). These actions were related with changes of the mitochondrial membrane potential involved in the intrinsic pathway of apoptosis. However, methoxylated (pterostilbene, pinostilbene, trans-trimethoxy-resveratrol, and CAY10616) (0.1-10 µM) and halogenated (PDM11, CAY10464, PDM2, and CAY465) (1-10 µM) stilbenes inhibited Caco-2 cell growth, with a higher potency than resveratrol (50% inhibition at 0.1-1 µM) but without effects on oxidative stress and arachidonic acid cascade. Thus, our results show that the antioxidant effect of hydroxyl stilbenes is related to eicosanoid synthesis regulation and the basic stilbene structure of two benzene rings bonded through a central ethylene, is responsible for its effects on Caco-2 cell growth/DNA synthesis/cell cycle independently of redox state/eicosanoid synthesis modulation.
Assuntos
Antioxidantes/farmacologia , Ácido Araquidônico/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Neoplasias Intestinais/fisiopatologia , Intestinos/citologia , Resveratrol/farmacologia , Antioxidantes/química , Células CACO-2 , Ciclo Celular/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Humanos , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/metabolismo , Intestinos/efeitos dos fármacos , Estresse Oxidativo , Resveratrol/análogos & derivadosRESUMO
The influence of oncogenic phenomena on the ecology and evolution of animal species is becoming an important research topic. Similar to host-pathogen interactions, cancer negatively affects host fitness, which should lead to the selection of host control mechanisms, including behavioral traits that best minimize the proliferation of malignant cells. Social behavior is suggested to influence tumor progression. While the ecological benefits of sociality in gregarious species are widely acknowledged, only limited data are available on the role of the social environment on cancer progression. Here, we exposed adult Drosophila, with colorectal-like tumors, to different social environments. We show how subtle variations in social structure have dramatic effects on the progression of tumor growth. Finally, we reveal that flies can discriminate between individuals at different stages of tumor development and selectively choose their social environment accordingly. Our study demonstrates the reciprocal links between cancer and social interactions and how sociality may impact health and fitness in animals and its potential implications for disease ecology.
Assuntos
Drosophila , Neoplasias Intestinais/fisiopatologia , Meio Social , Animais , Neoplasias Colorretais , Proteínas do Citoesqueleto/genética , Progressão da Doença , Proteínas de Drosophila/genética , Neoplasias Intestinais/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Neoplasms of the small intestine are rare in comparison with colorectal tumors. The most common tumor types arising in the small intestine are adenocarcinomas, well-differentiated neuroendocrine tumors, gastrointestinal stromal tumors, and lymphoma. Primary appendiceal neoplasms are rare and found in less than 2% of appendectomy specimens with an incidence of approximately 1.2 cases per 100,000 people per year in the United States. This article explores molecular diagnostics in the neoplasms of small intestine and appendix.
Assuntos
Neoplasias do Apêndice , Neoplasias Intestinais , Intestino Delgado/fisiopatologia , Neoplasias do Apêndice/diagnóstico , Neoplasias do Apêndice/genética , Neoplasias do Apêndice/fisiopatologia , Humanos , Neoplasias Intestinais/diagnóstico , Neoplasias Intestinais/genética , Neoplasias Intestinais/fisiopatologia , Mutação/genéticaRESUMO
The intestinal epithelium is a multicellular interface in close proximity to a dense microbial milieu that is completely renewed every 3-5 days. Pluripotent stem cells reside at the crypt, giving rise to transient amplifying cells that go through continuous steps of proliferation, differentiation and finally anoikis (a form of programmed cell death) while migrating upwards to the villus tip. During these cellular transitions, intestinal epithelial cells (IECs) possess distinct metabolic identities reflected by changes in mitochondrial activity. Mitochondrial function emerges as a key player in cell fate decisions and in coordinating cellular metabolism, immunity, stress responses and apoptosis. Mediators of mitochondrial signalling include molecules such as ATP and reactive oxygen species and interrelate with pathways such as the mitochondrial unfolded protein response (MT-UPR) and AMP kinase signalling, in turn affecting cell cycle progression and stemness. Alterations in mitochondrial function and MT-UPR activation are integral aspects of pathologies, including IBD and cancer. Mitochondrial signalling and concomitant changes in metabolism contribute to intestinal homeostasis and regulate IEC dedifferentiation-differentiation programmes in the context of diseases, suggesting that mitochondrial function as a cellular checkpoint critically contributes to disease outcome. This Review highlights mitochondrial function and MT-UPR signalling in epithelial cell stemness, differentiation and lineage commitment and illustrates mitochondrial function in intestinal diseases.
Assuntos
Células Epiteliais/fisiologia , Homeostase/fisiologia , Mucosa Intestinal/fisiologia , Mitocôndrias/fisiologia , Ácidos e Sais Biliares/fisiologia , Proliferação de Células/fisiologia , Ácidos Graxos Voláteis/fisiologia , Humanos , Mucosa Intestinal/citologia , Neoplasias Intestinais/etiologia , Neoplasias Intestinais/fisiopatologia , Síndrome do Intestino Irritável/etiologia , Síndrome do Intestino Irritável/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Reconhecimento de Padrão/fisiologia , Transdução de Sinais/fisiologia , Células-Tronco/fisiologia , Resposta a Proteínas não Dobradas/fisiologiaAssuntos
Neoplasias Intestinais/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral , Animais , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Humanos , Neoplasias Intestinais/genética , Neoplasias Intestinais/fisiopatologia , Camundongos , Mutação , Células Mieloides/enzimologia , Células Mieloides/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Peptide receptor radionuclide therapy (PRRT) may induce long-term toxicity to the bone marrow (BM). The aim of this study was to analyze persistent hematologic dysfunction (PHD) after PRRT with 177Lu-DOTATATE in patients with gastroenteropancreatic neuroendocrine tumors (GEP NETs). Methods: The incidence and course of PHD were analyzed in 274 GEP NET patients from a group of 367 patients with somatostatin receptor-positive tumors. PHD was defined as diagnosis of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), myeloproliferative neoplasm (MPN), MDS/MPN, or otherwise unexplained cytopenia (for >6 mo). Using data from The Netherlands Cancer Registry, the expected number of hematopoietic neoplasms (MDS, AML, MPN, and MDS/MPN) was calculated and adjusted for sex, age, and follow-up period. The following risk factors were assessed: sex, age over 70 y, bone metastasis, prior chemotherapy, prior external-beam radiotherapy, uptake on the [111In-DTPA0]octreotide scan, tumor load, grade 3-4 hematologic toxicity during treatment, estimated absorbed BM dose, elevated plasma chromogranin A level, baseline blood counts, and renal function. Results: Eleven (4%) of the 274 patients had PHD after treatment with 177Lu-DOTATATE: 8 patients (2.9%) developed a hematopoietic neoplasm (4 MDS, 1 AML, 1 MPN, and 2 MDS/MPN) and 3 patients (1.1%) developed BM failure characterized by cytopenia and BM aplasia. The median latency period at diagnosis (or first suspicion of a PHD) was 41 mo (range, 15-84 mo). The expected number of hematopoietic neoplasms based on The Netherlands Cancer Registry data was 3.0, resulting in a relative risk of 2.7 (95% confidence interval, 0.7-10.0). No risk factors for PHD could be identified for the GEP NET patients, not even bone metastasis or estimated BM dose. Seven patients with PHD developed anemia in combination with a rise in mean corpuscular volume. Conclusion: The prevalence of PHD after PRRT with 177Lu-DOTATATE was 4% in our patient population. The median time at which PHD developed was 41 mo after the first PRRT cycle. The relative risk for developing a hematopoietic neoplasm was 2.7. No risk factors were found for the development of PHD in GEP NET patients.
Assuntos
Neoplasias Intestinais/fisiopatologia , Neoplasias Intestinais/radioterapia , Tumores Neuroendócrinos/fisiopatologia , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Compostos Organometálicos/uso terapêutico , Neoplasias Pancreáticas/fisiopatologia , Neoplasias Pancreáticas/radioterapia , Receptores de Peptídeos/metabolismo , Neoplasias Gástricas/fisiopatologia , Neoplasias Gástricas/radioterapia , Idoso , Feminino , Hematologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Octreotida/uso terapêuticoRESUMO
To date, because of their rarity, the clinicopathological features and surgical outcomes of small bowel adenocarcinomas (SBAs) have been insufficiently explored. We evaluated the clinicopathological features and long-term outcomes of patients who underwent surgery for SBA.This retrospective study (from 1999 to 2016) examined patients with SBA treated surgically at the China National Cancer Center/Cancer Hospital. Clinicopathological features, preoperative evaluation, surgical treatment, and outcome parameters were reviewed and analyzed.Among the 241 patients studied, pancreaticoduodenectomies were performed in 51.0%, partial resection in 24.5%, palliative bypass surgery in 23.7%, and abdominal exploration in 0.8% of the patients. Majority of the patients were diagnosed at an advanced disease stage, and the duodenum was the most common tumor site. Postoperative complications occurred in 44.4% of the patients. Median overall and progression-free survival rates were 22.0 and 13.0 months, respectively. The 5-year overall and progression-free survival rates for patients with duodenal adenocarcinoma were 30.2% and 21.7%, respectively. Duodenal adenocarcinomas, lymph node metastases, distant metastases, poor differentiation, and lymphovascular invasion were associated with poor overall survival outcomes. The 3 factors associated with progression-free survival were the degree of differentiation, lymph node metastases, and distant metastases.Surgery remains the mainstay of treatment for SBA. A poor prognosis could be owing to the site, metastasis, differentiation, and lymphovascular invasion; however, the prognosis may improve through early diagnosis and operation.
Assuntos
Adenocarcinoma/fisiopatologia , Adenocarcinoma/cirurgia , Neoplasias Intestinais/fisiopatologia , Neoplasias Intestinais/cirurgia , Adenocarcinoma/diagnóstico , Adulto , Idoso , Procedimentos Cirúrgicos do Sistema Digestório , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Intestinais/diagnóstico , Intestino Delgado , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
The development of sustainable intestinal organoid cell culture has emerged as a new modality for the study of intestinal function and cellular processes. Organoid culture is providing a new testbed for therapeutic research and development. Intestinal organoids, self-renewing 3-dimensional structures comprised intestinal stem cells and their differentiated epithelial progeny allow for more facile and robust exploration of cellular activity, cell organization and structure, genetic manipulation, and vastly more physiologic modeling of intestinal response to stimuli as compared to traditional 2-dimensional cell line cultures. Intestinal organoids are affecting a wide variety of research into gastrointestinal pathology. The purpose of this review is to discuss the current state-of-the-art and future effect of research using enteroids and colonoids (organoids grown from the small and large intestines, respectively).
Assuntos
Pesquisa Biomédica/métodos , Enteropatias , Organoides , Animais , Fibrose Cística/genética , Fibrose Cística/microbiologia , Fibrose Cística/fisiopatologia , Fibrose Cística/terapia , Humanos , Infecções/genética , Infecções/microbiologia , Infecções/fisiopatologia , Infecções/terapia , Enteropatias/genética , Enteropatias/microbiologia , Enteropatias/fisiopatologia , Enteropatias/terapia , Neoplasias Intestinais/genética , Neoplasias Intestinais/microbiologia , Neoplasias Intestinais/fisiopatologia , Neoplasias Intestinais/terapia , Modelos Biológicos , Organoides/microbiologia , Organoides/fisiologia , Organoides/fisiopatologia , Medicina de Precisão/métodos , Engenharia Tecidual/métodosRESUMO
OBJECTIVE: To judge whether algesia sensitization of some acupoints is existed and whether the acupoint algesia sensitization area is expanded in the patients of intestinal cancer. METHODS: Totally, 30 patients of intestinal cancer and 30 healthy subjects were included. The electronic Von Fray was used to determine the pressure-pain thresholds at 13 acupoints relevant with gastrointestinal disorders and the reference points at the sites 1 cun and 2 cun lateral to those points as well as the sites at the corresponding nerve segments. Compared with the pressure-pain thresholds at the reference points of the different segments, the relative value was calculated. The changes were analyzed in the pressure-pain thresholds at the relevant acupoints on the body surface in the patients of intestinal cancer as compared with the relative pressure-pain thresholds in the healthy volunteers. RESULTS: The pressure-pain thresholds at Zusanli (ST 36), Shangjuxu (ST 37), Xiajuxu (ST 39), Quchi (LI 11) and Dachangshu (BL 25) in the patients of intestinal cancer were all significantly reduced as compared with those of the healthy subjects (P<0.05, P<0.01, P<0.001). At the non-acupoint sites 1 cun and 2 cun lateral to those acupoints as well as at the sites of the same segments, the pressure-pain thresholds were reduced significantly as compared with the control group (P<0.05, P<0.01, P<0.001). Particularly, the sensitization zone of Yinlingquan (SP 9) focused on the acupoint, the site 1 cun lateral to it as well as the non-acupoint sites of the same segments (P<0.01, P<0.001). CONCLUSION: The acupoint sensitization is displayed at Zusanli (ST 36), Shangjuxu (ST 37), Xiajuxu (ST 39), Quchi (LI 11), Dachangshu (BL 25) and Yinlingquan (SP 9) and the sensitization area is expended in the patients of intestinal cancer.