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1.
Medicine (Baltimore) ; 99(9): e19275, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32118738

RESUMO

The advent of imatinib mesylate (IM) has dramatically revolutionized the prognosis of advanced and metastatic/recurrent gastrointestinal stromal tumors (GISTs). The objective of this retrospective study is to investigate the safety and efficacy of combination of surgery following IM treatment in the management of advanced and metastatic/recurrent GISTs. We further explore the long-term clinical outcomes in these who underwent therapy of preoperative IM.Eligible patients with GISTs before the onset of the IM therapy and were periodically followed up in the outpatient clinic were included in this study. Detailed clinical and pathologic characteristics were obtained from the medical records of our institution. Univariate and multivariate regression analyses were performed to use for the evaluation of potential prognostic factors.A total of 51 patients were included in the study, of these patients, 36 patients underwent surgery and median duration of preoperative IM is 8.2months (range 3.5-85 months). Significant median tumor shrinkage rate was 29.27% (95% confidence interval 21.00%-34.00%) observed in these patients who responded to IM, and partial response and stable disease were achieved in 24 patients (47.06%) and 23 patients (45.10%), respectively, in light of the RECIST guideline (version 1.1). After the median follow-up of 43.70 months (range 14.2-131.1 months), 1- and 3-year overall survival (OS) were estimated to be 96.1% and 94.0%, respectively, and there was a significant improvement in OS for patients who received surgical intervention versus those who did not.Our study consolidates that patients were received preoperative IM therapy could shrink the size of tumors and facilitate organ-function preservation. The long-term analysis on this study supports that surgical intervention following IM therapy benefits for patients with primary advanced and recurrent or metastatic GISTs on long-term prognosis.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Gastrointestinais/terapia , Tumores do Estroma Gastrointestinal/terapia , Mesilato de Imatinib/uso terapêutico , Recidiva Local de Neoplasia/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , China , Feminino , Neoplasias Gastrointestinais/diagnóstico por imagem , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/diagnóstico por imagem , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib/administração & dosagem , Masculino , Registros Médicos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Metástase Neoplásica , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
2.
Anticancer Res ; 40(2): 865-871, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32014930

RESUMO

BACKGROUND/AIM: Oxaliplatin-induced neurotoxicity (OIN) can be severe and dose-limiting with clinically significant symptoms that persist for years. Few published reports have described postoperative exacerbation of OIN and more longitudinal data are needed to better characterize the phenomenon. PATIENTS AND METHODS: We identified 13 patients diagnosed with colon (n=7), rectal (n=4) or pancreatic (n=2) cancer who experienced postoperative OIN exacerbation at our medical center. Charts were reviewed for demographic and clinical data regarding OIN. RESULTS: OIN exacerbation was documented 0.5-7.0 months after the first surgery following oxaliplatin exposure, with a median duration of 10.6 months (range=1.4-86.1 months). OIN exacerbation persisted in 3/13 patients at last follow-up, and improved to pre-operative levels in 6/13 patients (with complete resolution in 4/13) within a median of 3.6 months from initial exacerbation. CONCLUSION: Given the widespread use of oxaliplatin in neoadjuvant and first-line treatment for gastrointestinal cancers, further study is warranted to prospectively and systematically define risks for postoperative OIN exacerbation.


Assuntos
Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Oxaliplatina/uso terapêutico , Adulto , Feminino , Neoplasias Gastrointestinais/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina/farmacologia , Período Pós-Operatório
3.
Crit Rev Oncol Hematol ; 146: 102840, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31918344

RESUMO

Neuroendocrine neoplasms (NENs) are a group of tumors originating from the neuroendocrine system. They mainly occur in the digestive system and the respiratory tract. It is well-know a strict interaction between neuroendocrine system and inflammation, which can play an important role in NEN carcinogenesis. Inflammatory mediators, which are produced by the tumor microenvironment, can favor cancer induction and progression, and can promote immune editing. On the other hand, a balanced immune system represents a relevant step in cancer prevention through the elimination of dysplastic and cancer cells. Therefore, an inflammatory response may be both pro- and anti-tumorigenic. In this review, we provide an overview concerning the complex interplay between inflammation and gastroenteropancreatic NENs, focusing on the tumorigenesis and clinical implications in these tumors.


Assuntos
Neoplasias Gastrointestinais/imunologia , Mediadores da Inflamação/imunologia , Inflamação/imunologia , Neoplasias Intestinais/imunologia , Tumores Neuroendócrinos/imunologia , Neoplasias Pancreáticas/imunologia , Neoplasias Gástricas/imunologia , Citocinas/metabolismo , Neoplasias Gastrointestinais/patologia , Humanos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Neoplasias Intestinais/patologia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Neoplasias Gástricas/patologia , Microambiente Tumoral
4.
J Surg Res ; 246: 52-61, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31561178

RESUMO

BACKGROUND: Low-density neutrophils (LDN) have been shown to be increased in peripheral blood in patients with various diseases and closely related to immune-mediated pathology. However, the frequency and function of LDN in circulating blood of the patients following abdominal surgery have not been well understood. METHODS: LDN were determined by CD66b(+) cells, which were copurified with mononuclear cells by density gradient preparations of peripheral blood of surgical patients. The effects of the purified LDN on T cell proliferation and tumor cell lysis were examined in vitro. Neutrophil extracellular traps (NETs) production was examined by extracellular nuclear staining. RESULTS: The number of LDN with an immature phenotype is markedly increased in peripheral blood samples in patients after abdominal surgery. The frequency of LDN correlated positively with operative time and intraoperative blood loss. The purified LDN significantly suppressed the proliferation of autologous T cells stimulated with anti-CD3 mAb coated on plate and partially inhibited the cytotoxicity of lymphocytes activated with recombinant interleukin-2 against a human gastric cancer cell, OCUM-1. The LDN also produced NETs after short-term culture in vitro, which efficiently trap many OCUM-1. These results suggest that surgical stress recruits immunosuppressive LDN in the circulation in the early postoperative period. CONCLUSIONS: The LDN may support the lodging of circulating tumor cells via NETs formation and inhibit T cell-mediated antitumor response in target organs, which may promote postoperative cancer metastases. Functional blockade of LDN might be an effective strategy to reduce tumor recurrence after abdominal surgery.


Assuntos
Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Neoplasias Gastrointestinais/cirurgia , Recidiva Local de Neoplasia/imunologia , Neutrófilos/imunologia , Estresse Fisiológico/imunologia , Antígenos CD/imunologia , Antígenos CD/metabolismo , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Moléculas de Adesão Celular/imunologia , Moléculas de Adesão Celular/metabolismo , Comunicação Celular/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Técnicas de Cocultura , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/patologia , Humanos , Contagem de Leucócitos , Recidiva Local de Neoplasia/epidemiologia , Células Neoplásicas Circulantes/imunologia , Neutrófilos/metabolismo , Duração da Cirurgia , Linfócitos T/imunologia
5.
Cancer Treat Rev ; 82: 101933, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31785412

RESUMO

This systematic review aims to summarize epigenome-wide studies on aberrant DNA methylation and its association with survival in patients with gastrointestinal adenocarcinoma. The 15 studies identified showed a large variety of methodological approaches for the identification of prognostic epigenetic markers from genome-wide methylation analyses. None of the findings were reported by more than one study in this systematic review. Further validation studies, a better reporting of methods and results are needed, as well as a clearer definition of investigated outcomes. At present, no conclusions can be drawn on the clinical relevance of the reported epigenetic markers.


Assuntos
Adenocarcinoma , Metilação de DNA/fisiologia , Neoplasias Gastrointestinais , Adenocarcinoma/genética , Adenocarcinoma/patologia , Biomarcadores Tumorais , Epigênese Genética , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Estudo de Associação Genômica Ampla , Humanos , Prognóstico
7.
Crit Rev Oncol Hematol ; 145: 102854, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31877535

RESUMO

Both environmental and genetic factors are involved in the initiation and development of gastrointestinal cancer. Covalent closed circular RNAs (circRNAs) are produced by a mechanism called "back-splicing" from mRNAs. They are highly stable and show cell and tissue specific expression patterns. Although some functions such as "microRNA sponge" and "RNA binding protein sponge" have been reported for a small number of circRNAs, the function of thousands of other circRNAs is still unknown. Dysregulation of circRNAs has been reported in many GI cancers and are involved in metastasis and invasion. CircRNAs have been reported to be useful as prognostic markers and targets for developing new treatments. We first describe the properties and biogenesis of circRNAs. We then summarize recent reports about circRNA functions, expression status, and their potential to be used as biomarkers in GI cancers including, gastric cancer, colorectal cancer, esophageal cancer, hepatocellular carcinoma, gallbladder cancer and pancreatic cancer.


Assuntos
Neoplasias Gastrointestinais , MicroRNAs , Processamento de RNA , Biomarcadores , Epigênese Genética , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Humanos , MicroRNAs/genética , Prognóstico
8.
J Surg Oncol ; 121(3): 474-479, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31846095

RESUMO

BACKGROUND: Patients with ruptured, perforated or fistulized (RPF) sarcomas commonly have issues such as sepsis and malnutrition and are usually unsuitable for oncologic resection in the emergency setting. We present our approach for managing a series of patients and the outcomes which were achieved with multidisciplinary care. METHODS: We reviewed records of patients referred to the section of sarcoma surgical oncology. Clinicopathologic factors, preoperative and operative interventions as well as short-term oncologic outcomes were assessed. RESULTS: Sixteen patients were identified between 1 January 1998 to 31 December 2018. Median age was 42.8 years. Histologies were; Gastrointestinal stromal tumors (7), desmoid (4), spindle cell tumor (2), dedifferentiated liposarcoma (2), and nonseminomatous germ cell tumor (1). Five patients had preoperative sepsis, 8 received antimicrobials, and 50% required hospitalization with a median stay of 21 days. Total parenteral nutrition was administered to 5 (31.3%) patients. Median tumor size and estimated blood loss were 13.1 cm and 350 mL respectively. No perioperative mortality occurred. Two patients have expired at a median follow-up of 16.1 months. CONCLUSION: Preoperative optimization, including the use of percutaneous drains, and antibiotics to control sepsis, where necessary, can lead to eventual oncologic resection with acceptable morbidity and no short-term mortality for patients with RPF sarcomas.


Assuntos
Neoplasias Gastrointestinais/cirurgia , Tumores do Estroma Gastrointestinal/cirurgia , Sarcoma/cirurgia , Adulto , Idoso , Feminino , Fibromatose Agressiva/patologia , Fibromatose Agressiva/cirurgia , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/patologia , Humanos , Lipossarcoma/patologia , Lipossarcoma/cirurgia , Masculino , Mesoderma/fisiologia , Pessoa de Meia-Idade , Ruptura Espontânea , Sarcoma/patologia , Adulto Jovem
9.
Z Gastroenterol ; 57(12): 1493-1513, 2019 Dec.
Artigo em Alemão | MEDLINE | ID: mdl-31826281

RESUMO

Neuroendocrine tumors of the gastrointestinal tract (GI-NET) are rare tumors. Functional tumors with hormonal syndromes (e. g., insulinoma, gastrinoma) are less common than non-functional tumors, which usually have an indolent course. Therapy for GI-NET is multimodal, including endoscopic or surgical procedures aiming at complete removal of tumor tissue. Patients in later stages may benefit from interventional radiology or medical therapy. This article gives an overview regarding the key aspects of GI-NET therapy in daily gastroenterology practice with emphasis on endoscopic diagnosis and therapy.


Assuntos
Gastroenterologia , Neoplasias Gastrointestinais/cirurgia , Tumores Neuroendócrinos/cirurgia , Guias de Prática Clínica como Assunto , Endoscopia Gastrointestinal/efeitos adversos , Gastrinoma , Neoplasias Gastrointestinais/patologia , Humanos , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas , Resultado do Tratamento
10.
Int J Nanomedicine ; 14: 9469-9482, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819444

RESUMO

Premalignant lesions arise from cells that abnormally proliferate and have a tendency to become cancerous. Developing methods to specifically target and remove these premalignant lesions is imperative to the prevention of malignant progression into gastrointestinal (GI) tumors. However, accurate detection and diagnosis of GI precancerous lesions is challenging, as these lesions show little or no structural change. Thus, this prevents early intervention and reduces the success rate of therapy. In this review, we performed a systematic analysis of the technological advancements in the combined application of nanovesicles (NVs) and the human interstitial fluid (HIF) to specifically target GI premalignant lesions. NVs, which include quantum dots (QDs), are small membranous vehicles of a nanometer diameter that are widely used as drug delivery vectors, therapeutic effectors and diagnostic sensors. HIF is the fluid that is present in human interstitial tissues (HITs) in which signaling molecules and agents travel and can be found throughout the body. HIF is exploited by tumor cells for their invasion, migration and spread. Because the HITs span the entire submucosa of the gastrointestinal tract, they have been increasingly targeted in GI tumor therapy. The challenges involved in the combined application of NVs and HIF in the detection, diagnosis, prognosis and therapy of GI premalignant lesions are also discussed.


Assuntos
Líquido Extracelular/metabolismo , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/terapia , Nanopartículas/química , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/terapia , Neoplasias Gastrointestinais/patologia , Humanos , Lesões Pré-Cancerosas/patologia , Prognóstico
11.
Anticancer Res ; 39(11): 6413-6416, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704875

RESUMO

BACKGROUND/AIM: The aim of this study was to present the clinical characteristics, natural history and survival outcomes of primary gastrointestinal non-Hodgkin lymphomas (PGINHL) in the pediatric population. PATIENTS AND METHODS: Surveillance, Epidemiology, and End Results (SEER) database was queried for patients aged 0 to 19 years with PGINHL between 1973 and 2014. RESULTS: A total of 452 cases were identified [mean age 11.0 (±5.1)] years, whites 84.1%, males (76.5%). The majority of tumors were noted in the small bowel (SB) (47.6%), followed by large bowel (LB) (28.5%) and the stomach (10.0%). Overall, the most common histological subtype was Burkitt lymphoma (51.8%), followed by diffuse large B-cell lymphoma (DLBCL) (26.1%). Mean overall survival (OS) of the entire cohort was 33,33 years with a 5-yr, 10-yr and 30-yr survival rate of 86%, 86% and 79%, respectively. Large bowel tumors had the best long-term survival rates whereas; gastric tumors had the worst with 30-yr survival rate 84% and 74%, respectively. Overall, 328 (72.6%) patients received surgery. No significant survival difference was noted between patients who underwent surgery and those who did not. CONCLUSION: This study presents the largest dataset of pediatric PGINHL and describes the clinical features and outcomes of these patients in addition to summarizing the literature.


Assuntos
Neoplasias Gastrointestinais , Linfoma não Hodgkin , Adolescente , Linfoma de Burkitt/mortalidade , Linfoma de Burkitt/patologia , Linfoma de Burkitt/cirurgia , Neoplasias do Ceco/mortalidade , Neoplasias do Ceco/patologia , Neoplasias do Ceco/cirurgia , Criança , Pré-Escolar , Feminino , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/cirurgia , Humanos , Neoplasias do Íleo/mortalidade , Neoplasias do Íleo/patologia , Neoplasias do Íleo/cirurgia , Lactente , Recém-Nascido , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/cirurgia , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/cirurgia , Masculino , Programa de SEER , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida , Adulto Jovem
12.
World J Gastroenterol ; 25(38): 5732-5772, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31636470

RESUMO

In their seminal papers Hanahan and Weinberg described oncogenic processes a normal cell undergoes to be transformed into a cancer cell. The functions of ion channels in the gastrointestinal (GI) tract influence a variety of cellular processes, many of which overlap with these hallmarks of cancer. In this review we focus on the roles of the calcium (Ca2+), sodium (Na+), potassium (K+), chloride (Cl-) and zinc (Zn2+) transporters in GI cancer, with a special emphasis on the roles of the KCNQ1 K+ channel and CFTR Cl- channel in colorectal cancer (CRC). Ca2+ is a ubiquitous second messenger, serving as a signaling molecule for a variety of cellular processes such as control of the cell cycle, apoptosis, and migration. Various members of the TRP superfamily, including TRPM8, TRPM7, TRPM6 and TRPM2, have been implicated in GI cancers, especially through overexpression in pancreatic adenocarcinomas and down-regulation in colon cancer. Voltage-gated sodium channels (VGSCs) are classically associated with the initiation and conduction of action potentials in electrically excitable cells such as neurons and muscle cells. The VGSC NaV1.5 is abundantly expressed in human colorectal CRC cell lines as well as being highly expressed in primary CRC samples. Studies have demonstrated that conductance through NaV1.5 contributes significantly to CRC cell invasiveness and cancer progression. Zn2+ transporters of the ZIP/SLC39A and ZnT/SLC30A families are dysregulated in all major GI organ cancers, in particular, ZIP4 up-regulation in pancreatic cancer (PC). More than 70 K+ channel genes, clustered in four families, are found expressed in the GI tract, where they regulate a range of cellular processes, including gastrin secretion in the stomach and anion secretion and fluid balance in the intestinal tract. Several distinct types of K+ channels are found dysregulated in the GI tract. Notable are hERG1 upregulation in PC, gastric cancer (GC) and CRC, leading to enhanced cancer angiogenesis and invasion, and KCNQ1 down-regulation in CRC, where KCNQ1 expression is associated with enhanced disease-free survival in stage II, III, and IV disease. Cl- channels are critical for a range of cellular and tissue processes in the GI tract, especially fluid balance in the colon. Most notable is CFTR, whose deficiency leads to mucus blockage, microbial dysbiosis and inflammation in the intestinal tract. CFTR is a tumor suppressor in several GI cancers. Cystic fibrosis patients are at a significant risk for CRC and low levels of CFTR expression are associated with poor overall disease-free survival in sporadic CRC. Two other classes of chloride channels that are dysregulated in GI cancers are the chloride intracellular channels (CLIC1, 3 & 4) and the chloride channel accessory proteins (CLCA1,2,4). CLIC1 & 4 are upregulated in PC, GC, gallbladder cancer, and CRC, while the CLCA proteins have been reported to be down-regulated in CRC. In summary, it is clear, from the diverse influences of ion channels, that their aberrant expression and/or activity can contribute to malignant transformation and tumor progression. Further, because ion channels are often localized to the plasma membrane and subject to multiple layers of regulation, they represent promising clinical targets for therapeutic intervention including the repurposing of current drugs.


Assuntos
Antineoplásicos/farmacologia , Carcinogênese/patologia , Neoplasias Gastrointestinais/tratamento farmacológico , Canais Iônicos/metabolismo , Animais , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Intervalo Livre de Doença , Regulação para Baixo , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/patologia , Humanos , Canais Iônicos/antagonistas & inibidores , Regulação para Cima
13.
Acta Gastroenterol Belg ; 82(3): 359-362, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31566322

RESUMO

AIM: Evaluate the diagnostic yield of biopsies obtained by EUS guidance in patients with gastric wall thickening and prior negative endoscopic biopsies. MATERIAL AND METHODS: Data collected from October 2008 to January 2016 were analyzed in a retrospective manner. All included patients had undergone at least one endoscopy with a negative biopsy and showed evidence of gastric wall thickening by tomography, confirmed by endoscopy. All patients gave their written informed consent before the procedure. Demographics and baseline characteristics, including age, sex, number of previous endoscopies, and histopathological diagnosis were recorded. Follow-up data were obtained from a review of the electronic medical records. RESULT: In total, 22 patients with previous negative endoscopic biopsies and gastric wall thickening were included. Using EUSFNA/FNB, the diagnosis was made in the first procedure in 19/22 (86.30%) cases, while in 1/22 (4.5%) patients the diagnosis was made in the second EUS-FNA. A total of 18 (81.82%) patients with EUS-FNA were assessed using a standard Echo-tip, while the remaining four (18.18%) patients underwent EUS-FNB and using a ProCore needle. All patients with a final diagnosis of malignancy had a thickened gastric wall with impaired gastric distension and a loss of wall structure determined by EUS. Of patients with a benign final diagnosis, all (n=8) showed a thickened gastric wall by EUS but with preservation of the deep layers. CONCLUSION: EUS-FNA/FNB is necessary in patients with a thickened gastric wall and prior negative biopsy on endoscopy. The procedure is safe and has a good diagnostic.


Assuntos
Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Neoplasias Gastrointestinais/diagnóstico por imagem , Endoscopia , Neoplasias Gastrointestinais/patologia , Humanos , Estudos Retrospectivos
14.
Molecules ; 24(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614517

RESUMO

Human A3 adenosine receptor hA3AR has been implicated in gastrointestinal cancer, where its cellular expression has been found increased, thus suggesting its potential as a molecular target for novel anticancer compounds. Observation made in our previous work indicated the importance of the carbonyl group of amide in the indolylpyrimidylpiperazine (IPP) for its human A2A adenosine receptor (hA2AAR) subtype binding selectivity over the other AR subtypes. Taking this observation into account, we structurally modified an indolylpyrimidylpiperazine (IPP) scaffold, 1 (a non-selective adenosine receptors' ligand) into a modified IPP (mIPP) scaffold by switching the position of the carbonyl group, resulting in the formation of both ketone and tertiary amine groups in the new scaffold. Results showed that such modification diminished the A2A activity and instead conferred hA3AR agonistic activity. Among the new mIPP derivatives (3-6), compound 4 showed potential as a hA3AR partial agonist, with an Emax of 30% and EC50 of 2.89 ± 0.55 µM. In the cytotoxicity assays, compound 4 also exhibited higher cytotoxicity against both colorectal and liver cancer cells as compared to normal cells. Overall, this new series of compounds provide a promising starting point for further development of potent and selective hA3AR partial agonists for the treatment of gastrointestinal cancers.


Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Pirimidinonas/química , Receptor A2A de Adenosina/genética , Receptor A3 de Adenosina/genética , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Células CHO , Proliferação de Células/efeitos dos fármacos , Cricetinae , Cricetulus , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Modelos Moleculares , Piperazina/síntese química , Piperazina/química , Piperazina/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Receptor A2A de Adenosina/química , Relação Estrutura-Atividade
16.
Nat Med ; 25(9): 1415-1421, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501609

RESUMO

During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient1-3. Previous case reports and small case series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance4-8. However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger-scale prospective cohorts of patients following progression on targeted therapy. Here, in a prospective cohort of 42 patients with molecularly defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of postprogression cfDNA versus tumor biopsy revealed that cfDNA more frequently identified clinically relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not found in the matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cfDNA, tumor biopsies and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity, and that the emergence of multiple resistance alterations in an individual patient may represent the 'rule' rather than the 'exception'. These findings have profound therapeutic implications and highlight the potential advantages of cfDNA over tissue biopsy in the setting of acquired resistance.


Assuntos
Ácidos Nucleicos Livres/sangue , DNA de Neoplasias/sangue , Neoplasias Gastrointestinais/sangue , Biópsia Líquida , Autopsia , Ácidos Nucleicos Livres/genética , Estudos de Coortes , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Heterogeneidade Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Sequenciamento Completo do Exoma
17.
Chem Biol Interact ; 314: 108839, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31563593

RESUMO

Here, we show that incubation of three human gastrointestinal cancer cell lines (HCT15, LoVo and MKN45) with doxorubicin (DOX) provokes autophagy through facilitating production of reactive oxygen species (ROS). HCT15 cell treatment with DOX resulted in up-regulation of Beclin1, down-regulation of Bcl2, activation of AMPK and JNK, and Akt inactivation, all of which were restored by pretreating with an antioxidant N-acetyl-l-cysteine. These data suggest that all the autophagy-related alterations evoked by DOX result from the ROS production. In the DOX-resistant cancer cells, degree of autophagy elicited by DOX was milder than the parental cells, and DOX treatment hardly activated the ROS-dependent apoptotic signals [formation of 4-hydroxy-2-nonenal (HNE), cytochrome-c release into cytosol, and activation of JNK and caspase-3], inferring an inverse correlation between cellular antioxidant capacity and autophagy induction by DOX. Monitoring of expression levels of aldo-keto reductases (AKRs) in the parental and DOX-resistant cells revealed an up-regulation of AKR1B10 and/or AKR1C3 with acquiring the DOX resistance. Knockdown and inhibition of AKR1B10 or AKR1C3 in these cells enhanced DOX-elicited autophagy. Measurement of DOX-reductase activity and HNE-sensitivity assay also suggested that both AKR1B10 (via high HNE-reductase activity) and AKR1C3 (via low HNE-reductase and DOX-reductase activities) are involved in the development of DOX resistance. Combination of inhibitors of autophagy and the two AKRs overcame DOX resistance and cross-resistance of gastrointestinal cancer cells with resistance development to DOX or cis-diamminedichloroplatinum. Therefore, concomitant treatment with the inhibitors may be effective as an adjuvant therapy for elevating DOX sensitivity of gastrointestinal cancer cells.


Assuntos
Aldo-Ceto Redutases/metabolismo , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Aldeído Redutase/metabolismo , Membro C3 da Família 1 de alfa-Ceto Redutase/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Regulação para Cima/efeitos dos fármacos
18.
BMC Res Notes ; 12(1): 571, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511043

RESUMO

OBJECTIVE: Gastrointestinal tract lymphomas are currently detected more frequently due to advances in endoscopic technology. The aim of this study was to assess the feasibility of flow cytometric analysis of restricted light chain in endoscopic biopsy specimens for the diagnosis of gastrointestinal tract B-cell lymphoma. We prepared viable cell suspensions from unfixed specimens obtained from 10 consecutive patients who had a previous histological diagnosis of gastrointestinal tract B-cell lymphoma. We performed immunophenotypic studies with multi-color flow cytometry and assessed clonality through examination of immunoglobulin light chain expression exclusively in a population identified by anti-CD45 or CD20 antibodies. RESULTS: We could perform light chain expression analysis with 2 endoscopic biopsy specimens from all 10 patients with gastrointestinal tract B-cell lymphoma. We conclude that flow cytometric analysis of endoscopic biopsy specimens is feasible and thus likely useful for the diagnosis of gastrointestinal tract B-cell lymphoma in clinical settings. Trial registration UMIN Clinical Trials Registry, UMIN000027730. Registered 12 June 2017.


Assuntos
Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Citometria de Fluxo/métodos , Neoplasias Gastrointestinais/imunologia , Cadeias Leves de Imunoglobulina/análise , Linfoma de Células B/imunologia , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Estudos de Viabilidade , Feminino , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Humanos , Cadeias Leves de Imunoglobulina/imunologia , Imunofenotipagem , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto
19.
BMC Cancer ; 19(1): 893, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492157

RESUMO

AIMS: To evaluate the short- and long-term outcomes of 3 different endoscopic dissection techniques for upper gastrointestinal (GI) submucosal tumours (SMTs). METHODS: Data for 135 patients withGI SMTs who underwent multiband mucosectomy (MBM), endoscopic submucosal dissection (ESD), or endoscopic submucosal excavation (ESE) were retrospectively assessed. The en bloc resection rate, endoscopic complete resection rate, operation time, potential complications and local recurrence rate were compared. RESULTS: No significant differences were observed in the rate of endoscopic complete resections and pathologic complete resections among the three groups. For SMTs > 15 mm in width, the lowest en bloc resection rate was found for MBM (P = 0.000). MBM was also associated with the shortest procedure time, lowest perforation rate and lowest rate of major bleeding. ESE was the most effective procedure for muscularis propria (MP) lesions but was associated with the longest operation time (P < 0.01). The ESD and ESE groups had similar perforation rates (P > 0.05). No differences were observed in 4-year local recurrence rates among the groups (P = 0.945). CONCLUSIONS: MBM is a simple and effective method for the treatment of small SMTs and achieves clinical success rates similar to those of ESD and ESE. However, ESD and ESE are preferable for larger and deep lesions and are associated with a longer operation time. Nonetheless, all 3 techniques resulted in a low 4-year local recurrence rate. Large-scale randomized clinical trials are needed to further investigate these results.


Assuntos
Ressecção Endoscópica de Mucosa/métodos , Neoplasias Gastrointestinais/cirurgia , Ressecção Endoscópica de Mucosa/efeitos adversos , Mucosa Esofágica/patologia , Mucosa Esofágica/cirurgia , Feminino , Seguimentos , Mucosa Gástrica/patologia , Mucosa Gástrica/cirurgia , Neoplasias Gastrointestinais/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Duração da Cirurgia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Resultado do Tratamento
20.
World J Surg Oncol ; 17(1): 156, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484583

RESUMO

BACKGROUND: Liver resection is a treatment of choice for colorectal and neuroendocrine liver metastases, and laparoscopy is an accepted approach for surgical treatment of these patients. The role of liver resection for patients with non-colorectal non-neuroendocrine liver metastases (NCNNLM), however, is still disputable. Outcomes of laparoscopic liver resection for this group of patients have not been analyzed. MATERIAL AND METHODS: In this retrospective study, patients who underwent laparoscopic liver resection for NCNNLM at Oslo University Hospital between April 2000 and January 2018 were analyzed. Perioperative and oncologic data of these patients were examined. Postoperative morbidity was classified using the Accordion classification. Kaplan-Meier method was used for survival analysis. Median follow-up was 26 (IQR, 12-41) months. RESULTS: Fifty-one patients were identified from a prospectively collected database. The histology of primary tumors was classified as adenocarcinoma (n = 16), sarcoma (n = 4), squamous cell carcinoma (n = 4), melanoma (n = 16), gastrointestinal stromal tumor (n = 9), and adrenocortical carcinoma (n = 2). The median operative time was 147 (IQR, 95-225) min, while the median blood loss was 200 (IQR, 50-500) ml. Nine (18%) patients experienced postoperative complications. There was no 90-day mortality in this study. Thirty-five (68%) patients developed disease recurrence or progression. Seven (14%) patients underwent repeat surgical procedure for recurrent liver metastases. One-, three-, and five-year overall survival rates were 85%, 52%, and 38%, respectively. The median overall survival was 37 (95%CI, 25 to 49) months. CONCLUSION: Laparoscopic liver resection for NCNNLM results in good outcomes and should be considered in patients selected for surgical treatment.


Assuntos
Adenocarcinoma/mortalidade , Carcinoma Adrenocortical/mortalidade , Tumores do Estroma Gastrointestinal/mortalidade , Hepatectomia/mortalidade , Laparoscopia/mortalidade , Neoplasias Hepáticas/mortalidade , Melanoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Neoplasias do Córtex Suprarrenal/mortalidade , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/cirurgia , Carcinoma Adrenocortical/patologia , Carcinoma Adrenocortical/cirurgia , Idoso , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Feminino , Seguimentos , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/cirurgia , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Masculino , Melanoma/patologia , Melanoma/cirurgia , Pessoa de Meia-Idade , Assistência Perioperatória , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Sarcoma/mortalidade , Sarcoma/patologia , Sarcoma/cirurgia , Taxa de Sobrevida
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