RESUMO
Atomically precise graphene nanoribbons (GNRs) have a wide range of electronic properties that depend sensitively on their chemical structure. Several types of GNRs have been synthesized on metal surfaces through selective surface-catalyzed reactions. The resulting GNRs are adsorbed on the metal surface, which may lead to hybridization between the GNR orbitals and those of the substrate. This makes investigation of the intrinsic electronic properties of GNRs more difficult and also rules out capacitive gating. Here, we demonstrate the formation of a dielectric gold chloride adlayer that can intercalate underneath GNRs on the Au(111) surface. The intercalated gold chloride adlayer electronically decouples the GNRs from the metal and leads to a substantial hole-doping of the GNRs. Our results introduce an easily accessible tool in the in situ characterization of GNRs grown on Au(111) that allows for exploration of their electronic properties in a heavily hole-doped regime.
RESUMO
Achieving fundamental understanding of enantioselective heterogeneous synthesis is marred by the permanent presence of multitudinous arrangements of catalytically active sites in real catalysts. In this study, we address this issue by using structurally comparatively simple, well-defined, and chiral intermetallic PdGa{111} surfaces as catalytic substrates. We demonstrate the impact of chirality transfer and ensemble effect for the thermally activated azide-alkyne Huisgen cycloaddition between 3-(4-azidophenyl)propionic acid and 9-ethynylphenanthrene on these threefold symmetric intermetallic surfaces under ultrahigh vacuum conditions. Specifically, we encounter a dominating ensemble effect for this reaction as on the Pd3-terminated PdGa{111} surfaces no stable heterocoupled structures are created, while on the Pd1-terminated PdGa{111} surfaces, the cycloaddition proceeds regioselectively. Moreover, we observe chirality transfer from the substrate to the reaction products, as they are formed enantioselectively on the Pd1-terminated PdGa{111} surfaces. Our results evidence a determinant ensemble effect and the immense potential of PdGa as asymmetric heterogeneous catalyst.
RESUMO
Graphdiyne, atomically thin two-dimensional (2D) carbon nanostructure based on sp-sp2 hybridization is an appealing system potentially showing outstanding mechanical and optoelectronic properties. Surface-catalyzed coupling of halogenated sp-carbon-based molecular precursors represents a promising bottom-up strategy to fabricate extended 2D carbon systems with engineered structure on metallic substrates. Here, we investigate the atomic-scale structure and electronic and vibrational properties of an extended graphdiyne-like sp-sp2 carbon nanonetwork grown on Au(111) by means of the on-surface synthesis. The formation of such a 2D nanonetwork at its different stages as a function of the annealing temperature after the deposition is monitored by scanning tunneling microscopy (STM), Raman spectroscopy, and combined with density functional theory (DFT) calculations. High-resolution STM imaging and the high sensitivity of Raman spectroscopy to the bond nature provide a unique strategy to unravel the atomic-scale properties of sp-sp2 carbon nanostructures. We show that hybridization between the 2D carbon nanonetwork and the underlying substrate states strongly affects its electronic and vibrational properties, modifying substantially the density of states and the Raman spectrum compared to the free standing system. This opens the way to the modulation of the electronic properties with significant prospects in future applications as active nanomaterials for catalysis, photoconversion, and carbon-based nanoelectronics.
RESUMO
BACKGROUND: Interferon gamma (IFNγ) and tumor necrosis factor-related weak inducer of apoptosis (TWEAK) molecules seem to have a potential effect on angiogenic factors such as vascular endothelial growth factor (VEGF). The aim of this study was to assess a possible interplay between IFNγ and TWEAK cytokines and VEGF machinery in the different steps of colorectal carcinogenesis. METHODS: A total of 92 subjects with colonic adenoma or cancer who underwent screening colonoscopy or surgery were prospectively enrolled. Polypoid lesion tissue samples were collected and frozen. Real-time reverse transcription polymerase chain reaction for IFNγ, TWEAK, and VEGF-A mRNA expression was performed. Immunoassays for VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, and VEGFR-3 were also performed. Nonparametric statistics, receiver operating characteristic curve analysis, and logistic multiple regression analysis were used. RESULTS: IFNγ and TWEAK mRNA expression was higher in patients with T2 or more advanced colorectal cancer than in those with adenomas or T1 cancer (p < 0.001 and p = 0.01, respectively). IFNγ and TWEAK mRNA expression levels directly correlated with VEGF-A mRNA expression levels (rho = 0.44, p < 0.001 and rho = 0.29, p = 0.004, respectively). On the contrary, IFNγ and TWEAK mRNA expression levels inversely correlated with VEGF-C protein levels (rho = -0.29, p = 0.04 and rho = -0.31, p = 0.03, respectively). Similarly, IFNγ and TWEAK mRNA expression levels inversely correlated with VEGFR2 protein levels (rho = -0.38, p = 0.033 and rho = -0.40, p = 0.025, respectively). CONCLUSION: This study showed that in colorectal polypoid lesions, IFNγ and TWEAK expressions are directly correlated to VEGF-A expression but inversely correlated with VEGFR2 levels, suggesting a possible feedback mechanism in the regulation of VEGF-A expression.
Assuntos
Neoplasias Colorretais/irrigação sanguínea , Citocina TWEAK/genética , Interferon gama/genética , Neovascularização Patológica/etiologia , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/etiologia , Citocina TWEAK/análise , Feminino , Humanos , Interferon gama/análise , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Mensageiro/análise , Fator A de Crescimento do Endotélio Vascular/análise , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/análiseRESUMO
AIM: Several studies demonstrated the prognostic value of the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and platelet-to-white blood cells ratio (PWR) in different types of tumors. However, there is no information about a possible role of NLR, PLR and PWR as predictor of presence of metastasis or multifocal disease in patients undergoing surgery with curative intent for midgut NET. The aim of our study was to test the role of preoperative NLR, PLR and PWR as predictors of patients undergoing surgery with curative intent for midgut NET. METHODS: We retrospectively enrolled seven foregut, 35 midgut and six hindgut NET patients with gastrointestinal neuroendocrine tumors operated in our Units from January 2005 to June 2016. Details about preoperative laboratory data, surgical operation, histology and follow-up were retrieved. Non-parametric statistics, ROC curve analysis and survival analysis were used. RESULTS: NLR was significantly higher in patients with distant metastasis (p = 0.04). The ROC curve analysis indicated that a threshold value of NLR of 2.6 predicted the presence of peritoneal metastasis with a specificity of 100% and a sensitivity of 71% and an overall accuracy of AUC = 0.81 (95%CI: 0.59-0.94), p = 0.05. PLR and PWR was not be associated to metastasis but tended to be associated to multifocal disease. CONCLUSION: In patients with midgut NET, an impaired adaptive immune response, as suggested by a high NLR ratio, was associated to the presence of distant metastasis and in particular of peritoneal metastasis. This information may be helpful when planning the treatment of a patient with a midgut NET.
Assuntos
Plaquetas/patologia , Procedimentos Cirúrgicos do Sistema Digestório , Neoplasias Intestinais/sangue , Neoplasias Intestinais/cirurgia , Linfócitos/patologia , Tumores Neuroendócrinos/sangue , Tumores Neuroendócrinos/cirurgia , Neutrófilos/patologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Curva ROCRESUMO
BACKGROUND: Younger patients with colorectal cancer (CRC) generally have better survival in spite of worse clinical and pathological features. METHODS: Twenty-six patients under 50 years operated for primary CRC were enrolled and matched 1:2:2 according to stage, tumor site and gender with 52 patients from 50 to 70 years and 52 patients over 70 years old. RESULTS: Patients under 50 years had a significantly longer overall, cancer specific and disease free survival (p = .001, p = .007 and p = .05, respectively). However, they had more frequently lymphovascular invasion (p = .006) and they more frequently developed metachronous CRC at follow-up (p = .03). Nevertheless, preoperative lymphocytes blood count/white blood count (LBC/WBC) ratio inversely correlated with age at operation (rho = -.21, p = .04) and it predicted CRC recurrence with an accuracy of 70%, p < .001 (threshold value LBC/WBC = 0.21%) and better overall, cancer specific and disease free survival (p < .0001 for all). At multivariate analysis, stage and LBC/WBC ratio resulted independent predictors of disease free survival (p = .0001 and p = .01, respectively). CONCLUSIONS: Patients under 50 years had a significantly longer survival with a higher LBC/WBC ratio. These results could suggest a possible role of immunosurveillance in neoplastic control.
Assuntos
Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/mortalidade , Imunocompetência/fisiologia , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Fatores Etários , Idoso , Estudos de Coortes , Colectomia/métodos , Colectomia/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Testes Imunológicos/métodos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Estudos Retrospectivos , Medição de Risco , Taxa de Sobrevida , Resultado do TratamentoRESUMO
The aim of the present study was to evaluate the risk factors for postoperative complications following liver resection for colorectal cancer liver metastases. Patients who underwent hepatic resection for colorectal cancer liver metastases were stratified according to chemotherapy administration and body mass index (BMI) to eliminate potential confounding factors. A univariate analysis was conducted to identify potential risk factors for postoperative complications following liver resection. Variables that exhibited a potential association were evaluated by multivariable logistic regression analysis to identify those independently associated with postoperative morbidity. Between January 2012 and March 2012, 100 patients underwent hepatic resection for liver metastases from colorectal carcinoma at the Treviso Regional Hospital (Treviso, Italy) and at the Regina Elena National Cancer Institute (Rome, Italy). Of the 100 patients, 61 received preoperative oxaliplatin- or irinotecan-based chemotherapy. A total of 25 the patients had a BMI of ≥28 kg/m2. On univariate analysis, BMI ≥28 kg/m2 was found to be positively correlated with the presence of steatosis (P<0.01) and steatohepatitis (P<0.01). The administration of preoperative chemotherapy was correlated with the development of steatosis (P<0.01), steatohepatitis (P=0.02) and postoperative complications (P=0.03). Even following stratification for the use of preoperative chemotherapy, BMI ≥28 kg/m2 maintained its positive association with steatohepatitis. On multivariate analysis, steatohepatitis (P=0.005, HR=0.118, 95% CI: 0.027-0.518) and blood transfusions (P=0.001, HR=0.131, 95% CI: 0.038-0.452) were independently associated with postoperative complications. BMI ≥28 kg/m2 (P=0.004, HR=8.30, 95% CI: 2.39-28.7) and irinotecan treatment (P=0.016, HR=0.16, 95% CI: 0.037-0.711) were independent risk factors for steatohepatitis. In conclusion, steatohepatitis and perioperative blood transfusions were found to be the main determinant of postoperative complications following liver resection for colorectal liver metastases. Overweight patients may be more prone to the cytotoxic effects of irinotecan, harboring a higher risk of developing steatohepatitis.
RESUMO
Colorectal cancer incidence in patients undergoing screening protocols is decreasing because of the higher rate of discovered preneoplastic colonic lesions; however, adenomatous polyps may not always be removable endoscopically and surgery may still be necessary. The aim of this study was to assess the vascular endothelial growth factor expression in the different steps of colorectal carcinogenesis to explore its potential role as a marker of malignancy in polypoid lesions. A total of 92 subjects with colonic adenoma or cancer who underwent screening colonoscopy or surgery were prospectively enrolled. Real-time reverse transcription polymerase chain reaction for VEGF-A messenger RNA expression and immunohistochemistry for VEGF-A were performed. Immunoassays for VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, and VEGFR-3 were also performed. Non-parametric statistics, receiver operating characteristic curve analysis, and logistic multiple regression analysis were used. VEGF-A messenger RNA expression was higher in patients with high-grade dysplasia or colorectal cancer than in those with low-grade dysplasia adenomas (p = 0.01). At immunohistochemistry, VEGF-A expression was significantly higher in colorectal cancer patients compared to dysplastic adenomas (p < 0.001), and the accuracy of VEGF-A expression for prediction of malignancy was 91.7 (95% confidence interval = 78.7-97.9). VEGF-C protein expression was lower in colorectal cancer patients than in simple adenomas (p = 0.02). VEGF-A levels were directly correlated to polyp size (rho = 0.73, p = 0.0062). Multivariate analysis demonstrated that malignancy and polyp size were independent predictors of VEGF-A mucosal levels. This study demonstrated that the VEGF-A expression changes along the colorectal carcinogenesis pathway showing a neat step up at the passage from high-grade dysplasia to invasive cancer. This feature might potentially be useful to stratify colorectal polyps in different risks of progression classes. Moreover, the high level of VEGF-A expression predicted the presence of lymphovascular invasion with good accuracy.
Assuntos
Neoplasias Colorretais/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Estudos de Casos e Controles , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
Gastrointestinal stromal tumours (GISTs) can arise everywhere along the gastrointestinal (GI) tract. Their presentation in unusual locations should always be taken into account. A 74-year-old man referred to the emergency department for small bowel obstruction caused by an incarcerated inguinal hernia. A CT scan showed a mesenchymal tumour originating from the herniated bowel loop and a mass in the ascending colon. Laparoscopic resection of the mass and laparoscopic right hemicolectomy were performed. The histology showed a ruptured GIST arising from the herniated small bowel and a high-grade dysplasia villous adenoma of the right colon. GISTs can present with symptoms spanning from vague abdominal discomfort to surgical urgencies. Strangulated hernia is an extremely rare presentation, with only two cases described in the literature. A safe surgical approach was obtained with laparoscopy, maintaining surgical radicality. The ileal localisation and the pseudocapsule rupture were the main risk factors on prognostic stratification.
Assuntos
Adenoma Viloso/diagnóstico por imagem , Neoplasias do Colo/diagnóstico por imagem , Tumores do Estroma Gastrointestinal/diagnóstico por imagem , Hérnia Inguinal/diagnóstico por imagem , Neoplasias do Íleo/diagnóstico por imagem , Obstrução Intestinal/diagnóstico por imagem , Neoplasias Primárias Múltiplas/diagnóstico por imagem , Adenoma Viloso/complicações , Adenoma Viloso/patologia , Adenoma Viloso/cirurgia , Idoso , Colectomia , Neoplasias do Colo/complicações , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Tumores do Estroma Gastrointestinal/complicações , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/cirurgia , Hérnia Inguinal/complicações , Humanos , Neoplasias do Íleo/classificação , Neoplasias do Íleo/patologia , Neoplasias do Íleo/cirurgia , Obstrução Intestinal/etiologia , Masculino , Neoplasias Primárias Múltiplas/complicações , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/cirurgia , Tomografia Computadorizada por Raios XRESUMO
Inflammatory bowel diseases are an increasing phenomenon in western countries and in growing populations. The physiopathology of these conditions is linked to intestinal stem cells homeostasis and regenerative potential in a chronic inflammatory microenvironment. Patients with IBD present an increased risk of developing colorectal cancer (CRC), or colitis associated cancer (CAC). Conventional treatment for IBD target the inflammatory process (and include anti-inflammatory and immunosuppressive drugs) with biological agents emerging as a therapeutic approach for non-responders to traditional therapy. Conventional treatment provides scarce results and present severe complications. The intestinal environment may host incoming stem cells, able to engraft in the epithelial damaged sites and differentiate. Therefore, stem cell therapies represent an emerging alternative in inflammatory bowel diseases, with current investigations on the use of haematopoietic and mesenchymal stem cells, in particular adipose stem cells, apparently fundamental as regenerators and as immune-modulators. Here, we discuss stem cells in intestinal homeostasis and as therapeutic agents for the treatment of inflammatory bowel diseases.
Assuntos
Adipócitos/transplante , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/patologia , Adipócitos/patologia , Animais , HumanosRESUMO
BACKGROUND: The principal aim of endoscopic follow-up programs after curative resection of colorectal cancer (CRC) is to improve survival and identify local recurrence and metachronous CRC. The aim of our study was to identify the possible predictors of metachronous colorectal lesions. METHODS: The records of 348 consecutive patients with CRC and who completed at least 1 year of endoscopic follow-up after surgery were analyzed. In this group, 336 patients underwent surgery for primitive CRC and 12 for metachronous cancer. Patients' characteristics, operative details, and endoscopical follow-up findings were retrieved. Multivariate survival analyses were used to identify patient categories at risk of metachronous colonic lesions. RESULTS: 128 patients presented a metachronous lesion: 118 adenomas and 10 adenocarcinomas. At multivariate analysis, active smoke (HR = 1.84, p = 0.03), neoadjuvant therapy (HR = 0.24, p = 0.01), and presence of synchronous polyps (HR = 1.55, p = 0.04) resulted independent predictors of metachronous adenoma after CRC removal while neoadjuvant therapy (HR = 0.25, p = 0.02), active smoke (HR = 1.54, p = 0.04), and presence of synchronous polyps (HR = 1.86, p = 0.02) resulted independent predictors of metachronous lesions after CRC removal. CONCLUSIONS: This study demonstrated a high rate of metachronous lesions in the early follow-up after curative CRC resection. The negative effects of synchronous polyps should be carefully evaluated when planning patients' follow-up.
Assuntos
Adenocarcinoma/cirurgia , Neoplasias Colorretais/cirurgia , Neoplasias Primárias Múltiplas/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Pólipos/patologia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Colectomia/efeitos adversos , Colectomia/métodos , Colonoscopia/métodos , Neoplasias Colorretais/patologia , Bases de Dados Factuais , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Neoplasias Primárias Múltiplas/patologia , Segunda Neoplasia Primária/patologia , Pólipos/mortalidade , Pólipos/cirurgia , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Resultado do TratamentoRESUMO
Nuclear expression of the calcium-binding protein S100A4 is a biomarker of increased invasiveness in cholangiocarcinoma, a primary liver cancer with scarce treatment opportunities and dismal prognosis. In this study, we provide evidence that targeting S100A4 nuclear import by low-dose paclitaxel, a microtubule-stabilizing agent, inhibits cholangiocarcinoma invasiveness and metastatic spread. Administration of low-dose paclitaxel to established (EGI-1) and primary (CCA-TV3) cholangiocarcinoma cell lines expressing nuclear S100A4 triggered a marked reduction in nuclear expression of S100A4 without modifying its cytoplasmic levels, an effect associated with a significant decrease in cell migration and invasiveness. While low-dose paclitaxel did not affect cellular proliferation, apoptosis, or cytoskeletal integrity, it significantly reduced SUMOylation of S100A4, a critical posttranslational modification that directs its trafficking to the nucleus. This effect of low-dose paclitaxel was reproduced by ginkolic acid, a specific SUMOylation inhibitor. Downregulation of nuclear S100A4 by low-dose paclitaxel was associated with a strong reduction in RhoA and Cdc42 GTPase activity, MT1-MMP expression, and MMP-9 secretion. In an SCID mouse xenograft model, low-dose metronomic paclitaxel treatment decreased lung dissemination of EGI-1 cells without significantly affecting their local tumor growth. In the tumor mass, nuclear S100A4 expression by cholangiocarcinoma cells was significantly reduced, whereas rates of proliferation and apoptosis were unchanged. Overall, our findings highlight nuclear S100A4 as a candidate therapeutic target in cholangiocarcinoma and establish a mechanistic rationale for the use of low-dose paclitaxel in blocking metastatic progression of cholangiocarcinoma. Cancer Res; 76(16); 4775-84. ©2016 AACR.
Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Antineoplásicos Fitogênicos/farmacologia , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Paclitaxel/farmacologia , Proteína A4 de Ligação a Cálcio da Família S100/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Camundongos SCID , Invasividade Neoplásica/patologia , Metástase Neoplásica , Sumoilação/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Inflammatory bowel diseases (IBD) are associated with an increased risk of colitis-associated colorectal carcinoma (CAC). CAC is one of the most important causes of morbidity and mortality in patients with Crohn's disease and ulcerative colitis. The aim of the present review was to discuss the most important signaling pathways and genetic alterations involved in carcinogenesis related to IBD, focusing on the molecular aspects of cancer stem cell physiology and the impact of the inflammatory microenvironment. Molecular mechanisms involved in CAC development differ from those in sporadic colorectal cancer, reflecting the prominent role of inflammation-induced carcinogenesis in the development of CAC. The alteration of the physiological microenvironment is thought to be responsible for the initiation of carcinogenesis in IBD. Furthermore, cancer stem cells seem to have a fundamental role in the generation and growth of CAC. We also address prevention and treatment modalities of CAC and its involvement in IBD.
Assuntos
Neoplasias Colorretais/etiologia , Doenças Inflamatórias Intestinais/complicações , Animais , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/prevenção & controle , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologiaRESUMO
BACKGROUND: There is evidence that colorectal cancers (CRC) with DNA mismatch repair deficiency (MMR-D) are associated with a better prognosis than the generality of large bowel malignancies. Since an active immune surveillance process has been demonstrated to influence CRC outcome, we investigated whether MMR-D can enhance the immune response in CRC. PATIENTS AND METHODS: A group of 113 consecutive patients operated for CRC (42 stage I or II and 71 with stage III or IV) was retrospectively analyzed. The expression of MMR genes (MSH2, MLH1, MSH6 and PSM2) and co-stimulatory molecule CD80 was assessed by tissue microarray immunohistochemistry. In addition, tumor infiltrating mononuclear cells (TIMC) and T cell subpopulations (CD4, CD8, T-bet and FoxP-3) were quantified. The effect of specific siRNA (siMSH2, siMLH1, siMSH6 and siPSM2) transfection in HT29 on CD80 expression was quantified by flow cytometry. Non parametric statistics and survival analysis were used. RESULTS: Patients with MMR-D showed a higher T-bet/CD4 ratio (p = 0.02), a higher rate of CD80 expression and CD8 lymphocyte infiltration compared to those with no MMR-D. Moreover, in the MMR-D group, the Treg marker FoxP-3 was not expressed (p = 0.05). MMR-D patients with stage I or II and T-bet expression had a significant better survival (p = 0.009). Silencing of MSH2, MLH1 and MSH6, but not PSM2, significantly increased the rate of CD80+ HT29 cells (p = 0.007, p = 0.023 and p = 0.015, respectively). CONCLUSIONS: CRC with MMR-D showed a higher CD80 expression, and CD8+ and Th1 T-cell infiltration. In vitro silencing of MSH2, MLH1 and MSH6 significantly increased CD80+ cell rate. These results suggest an enhanced immune surveillance mechanism in presence of MMR-D.
Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Reparo de Erro de Pareamento de DNA/genética , Linfócitos do Interstício Tumoral/imunologia , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-1/análise , Antígeno B7-1/biossíntese , Neoplasias Colorretais/mortalidade , Feminino , Citometria de Fluxo , Células HT29 , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Análise Serial de TecidosRESUMO
Most patients with intrahepatic cholangiocarcinoma (IH-CCA) are unresectable and treatment options are limited. This study evaluates the efficacy of hepatic artery infusion (HAI) chemotherapy in patients whose disease is not initially treatable with resection. We selected patients with unresectable IH-CCA treated only with HAI chemotherapy at our centre between January 2008 and December 2012. We compared our outcome, using mRECIST, with published results of patients treated with systemic chemotherapy during the same period. Eleven patients underwent HAI chemotherapy with fluorouracil and oxaliplatin after placement of an HAI pump. A CT scan performed after the sixth cycle of therapy revealed that 5 of them had partial hepatic response (more than 45 %), 2 stable disease and 4 showed clear signs of disease progression. The average survival of the entire group was 17.6 months. Three of the patients with partial hepatic response underwent resection and 2 had more than 70 % tumour necrosis, both of whom are still alive and disease free. The median survival of patients with liver-only disease treated with systemic chemotherapy, who were not submitted for resection, was 15.3 months. HAI chemotherapy enables this small group of patients to have their unresectable IH-CCA disease converted into a resectable one, thus confirming its role in treatment of this disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Fluoruracila/administração & dosagem , Compostos Organoplatínicos/administração & dosagem , Adulto , Idoso , Neoplasias dos Ductos Biliares/mortalidade , Colangiocarcinoma/mortalidade , Intervalo Livre de Doença , Feminino , Artéria Hepática , Humanos , Infusões Intra-Arteriais , Masculino , Pessoa de Meia-Idade , Oxaliplatina , Estudos RetrospectivosRESUMO
Cholangiocarcinoma is an aggressive, strongly chemoresistant liver malignancy. Leukemia inhibitory factor (LIF), an IL-6 family cytokine, promotes progression of various carcinomas. To investigate the role of LIF in cholangiocarcinoma, we evaluated the expression of LIF and its receptor (LIFR) in human samples. LIF secretion and LIFR expression were assessed in established and primary human cholangiocarcinoma cell lines. In cholangiocarcinoma cells, we tested LIF effects on proliferation, invasion, stem cell-like phenotype, chemotherapy-induced apoptosis (gemcitabine+cisplatin), expression levels of pro-apoptotic (Bax) and anti-apoptotic (Mcl-1) proteins, with/without PI3K inhibition, and of pSTAT3, pERK1/2, pAKT. LIF effect on chemotherapy-induced apoptosis was evaluated after LIFR silencing and Mcl-1 inactivation.Results show that LIF and LIFR expression were higher in neoplastic than in control cholangiocytes; LIF was also expressed by tumor stromal cells. LIF had no effects on cholangiocarcinoma cell proliferation, invasion, and stemness signatures, whilst it counteracted drug-induced apoptosis. Upon LIF stimulation, decreased apoptosis was associated with Mcl-1 and pAKT up-regulation and abolished by PI3K inhibition. LIFR silencing and Mcl-1 blockade restored drug-induced apoptosis.In conclusion, autocrine and paracrine LIF signaling promote chemoresistance in cholangiocarcinoma by up-regulating Mcl-1 via a novel STAT3- and MAPK-independent, PI3K/AKT-dependent pathway. Targeting LIF signaling may increase CCA responsiveness to chemotherapy.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Fator Inibidor de Leucemia/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Apoptose/genética , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Western Blotting , Linhagem Celular Tumoral , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Cisplatino/farmacologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Fator Inibidor de Leucemia/genética , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/genética , Subunidade alfa de Receptor de Fator Inibidor de Leucemia/metabolismo , Microscopia de Fluorescência , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , GencitabinaRESUMO
BACKGROUND: Two-stage hepatectomy (TSH) is well established for the treatment of patients who have colorectal cancer liver metastases (CRLM) with a small liver remnant. The technique of associating liver partitioning and portal vein occlusion for staged hepatectomy (ALPPS) has been advocated as a novel tool to increase resectability. Using a case-match design, this study aimed to compare TSH and ALPPS for patients with CRLM. METHODS: All patients undergoing ALPPS for CRLM at three major hepatobiliary centers in Italy (ALPPS group) were compared in a case-match analysis with patients undergoing TSH (TSH group) at a single institution. The groups were matched with a 1:3 ratio using propensity scores based on covariates representing severity of metastatic disease. The main end points of the study were feasibility of complete resection and intra- and postoperative outcomes. RESULTS: The two treatments did not differ significantly in feasibility. Two patients in the TSH group dropped out compared with no patients in the ALPPS group. A comparable volume gain in future liver remnant (FLR) was obtained in the ALPPS and TSH groups (47 vs. 41 %, nonsignificant difference) but during a shorter interval in ALPPS group. The overall and major complication rate was significantly higher after stage 2 in the ALPPS group (Clavien ≥ 3a: 41.7 vs. 17.6 % in TSH group; p = 0.025). CONCLUSION: The feasibility of resection using ALPPS compared with TSH for CRLM was not significantly greater, but perioperative complications were increased. Therefore, ALPPS should be proposed to patients with caution and warnings. Currently, TSH remains the standard approach for performing R0 resection in patients with advanced CRLM and inadequate FLR.
Assuntos
Neoplasias Colorretais/cirurgia , Hepatectomia/mortalidade , Neoplasias Hepáticas/cirurgia , Veia Porta/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Ligadura , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Several studies have demonstrated that obesity is a risk factor for colorectal cancer (CRC), but few data are available regarding its role in multifocal disease and postoperative recurrence. The present study aimed to assess the role of obesity as a risk factor for multifocal disease and postoperative recurrence in patients with CRC. PATIENTS AND METHODS: The records of 940 consecutive patients with CRC admitted to three surgical centres between January 2006 and January 2011 were retrospectively analysed. The 595 individuals whose preoperative body mass index (BMI) values were available were included in the study. Following WHO guidelines, the patients were stratified into four groups depending on their BMI values. Age at disease onset, clinical presentation, tumor invasiveness, the presence of multiple foci, and the colon cancer recurrence rate in the four groups were assessed and compared. RESULTS: At multivariate analysis, diagnosis of familial adenomatous polyposis (FAP) and a BMI>30 were found to be independent predictors of synchronous polyps (Odd Ratio [OR]=10.7, 95% Confidence interval (CI)=2-75, p=0.005; and OR=2.2, 95% CI=1.3-3.9, p=0.003, respectively). The cancer recurrence rate in the patients with stage 2 CRC was significantly higher in the obese with respect to the non-obese (p=0.05). At multivariate analysis, BMI>30, FAP, and positivity by the Bethesda criteria were found to be independent predictors of recurrence after CRC surgery. CONCLUSION: Obese patients diagnosed with CRC require thorough colonic exploration prior to surgery and necessitate more frequent postoperative endoscopic examinations with respect to patients without any risk factors.
Assuntos
Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Obesidade/complicações , Idoso , Índice de Massa Corporal , Estudos de Casos e Controles , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Estudos Retrospectivos , Fatores de RiscoRESUMO
Cholangiocarcinoma (CCA) is a devastating malignancy arising from the bile ducts. Cancer-associated fibroblasts (CAFs) are key players in CCA invasiveness and in the generation of a desmoplastic reaction. The aim of the present study was to develop a novel model by which to study tumor-stroma interactions using primary cultures of human biliary epithelial cells (hBECs) and stromal cells (SCs) in CCA. hBECs and SCs, isolated from surgical resections (n=10), were semi-purified by centrifugation on a Percoll gradient; hBECs were further immunopurified. hBECs and SCs were characterized using epithelial [cytokeratin 7 (CK7) and CK19] and mesenchymal [vimentin (VMN), α-smooth muscle actin (α-SMA), CD68] cell markers. The purity of cultured cells was assessed by fluorescent immunocytochemistry. hBECs were HEA125/CK7/CK19-positive and VMN/α-SMA-negative. SCs were VMN/α-SMA-positive and CK7/CK19-negative. CCA 2-D culture models have been described but they use long-standing CCA cell lines of various biliary tumor cell origins with stromal cells derived from non-cholangiocarcinoma tissues. Recently, a novel 3-D organotypic co-culture model of rat cholangiocarcinoma was described. In the present study, we obtained pure and stable primary cultures of hBECs and SCs from CCA surgical specimens. These cell cultures may provide a useful tool by which to study CCA tumor-stroma interactions.
Assuntos
Neoplasias dos Ductos Biliares/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismo , Biomarcadores Tumorais/metabolismo , Colangiocarcinoma/metabolismo , Transição Epitelial-Mesenquimal , Fibroblastos/metabolismo , Células Estromais/metabolismo , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Comunicação Celular , Colangiocarcinoma/patologia , Técnicas de Cocultura , Fibroblastos/patologia , Citometria de Fluxo , Imunofluorescência , Humanos , Técnicas Imunoenzimáticas , Separação Imunomagnética , Gradação de Tumores , Células Estromais/patologia , Células Tumorais CultivadasRESUMO
UNLABELLED: Cholangiocarcinoma (CCA) is characterized by an abundant stromal reaction. Cancer-associated fibroblasts (CAFs) are pivotal in tumor growth and invasiveness and represent a potential therapeutic target. To understand the mechanisms leading to CAF recruitment in CCA, we studied (1) expression of epithelial-mesenchymal transition (EMT) in surgical CCA specimens and CCA cells, (2) lineage tracking of an enhanced green fluorescent protein (EGFP)-expressing human male CCA cell line (EGI-1) after xenotransplantation into severe-combined-immunodeficient mice, (3) expression of platelet-derived growth factors (PDGFs) and their receptors in vivo and in vitro, (4) secretion of PDGFs by CCA cells, (5) the role of PDGF-D in fibroblast recruitment in vitro, and (6) downstream effectors of PDGF-D signaling. CCA cells expressed several EMT biomarkers, but not alpha smooth muscle actin (α-SMA). Xenotransplanted CCA masses were surrounded and infiltrated by α-SMA-expressing CAFs, which were negative for EGFP and the human Y-probe, but positive for the murine Y-probe. CCA cells were strongly immunoreactive for PDGF-A and -D, whereas CAFs expressed PDGF receptor (PDGFR)ß. PDGF-D, a PDGFRß agonist, was exclusively secreted by cultured CCA cells. Fibroblast migration was potently induced by PDGF-D and CCA conditioned medium and was significantly inhibited by PDGFRß blockade with Imatinib and by silencing PDGF-D expression in CCA cells. In fibroblasts, PDGF-D activated the Rac1 and Cdc42 Rho GTPases and c-Jun N-terminal kinase (JNK). Selective inhibition of Rho GTPases (particularly Rac1) and of JNK strongly reduced PDGF-D-induced fibroblast migration. CONCLUSION: CCA cells express several mesenchymal markers, but do not transdifferentiate into CAFs. Instead, CCA cells recruit CAFs by secreting PDGF-D, which stimulates fibroblast migration through PDGFRß and Rho GTPase and JNK activation. Targeting tumor or stroma interactions with inhibitors of the PDGF-D pathway may offer a novel therapeutic approach.