RESUMO
Colorectal cancer (CRC) is a complex disease with still unsatisfactory prognosis even in western societies, although substantial progress has been made in pre-screening programs, surgical techniques and targeted therapy options. Mediator of motility-1 (Memo-1) was previously recognized as an important effector of cell migration downstream of receptor tyrosine kinase signaling in breast cancer. This study identified Memo-1 as frequently overexpressed in CRC and established a close link between extracellular HER2 activation, AhR/ARNT transcriptional activity and Memo-1 expression. Dissection of the hMemo-1 gene promoter using reporter assays and chromatin IP techniques revealed recruitment of Aryl hydrocarbon receptor (AhR)/Aryl hydrocarbon receptor nuclear-translocator (ARNT) complex, which positively influenced Memo-1 expression in cancer cells. We found that Memo-1 depletion negatively influenced the cellular actin network and that its expression is required for HER2-mediated cell migration and invasion. Moreover, analyses of Memo-1 expression in primary CRC revealed correlation with clinical parameters that point to Memo-1 as a new prognostic factor of aggressive disease in CRC patients. Altogether, these observations demonstrate that Memo-1 is an important downstream regulator of HER2-driven CRC cell migration and invasion through connecting extracellular signals from membrane to the cytoskeletal actin network.
Assuntos
Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Ferroproteínas não Heme/genética , Proteínas/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Invasividade Neoplásica , Regiões Promotoras Genéticas/genética , Transdução de SinaisRESUMO
OBJECTIVE: To retrospectively assess the frequency and indications for emergency pancreatoduodenctomies in a tertiary referral center. METHODS: Pancreatoduodenectomies between January 2005 and January 2014 were retrospectively assessed for emergency indications defined as surgery following unplanned hospital admission in less than 24 h. Data on indications and on the intraoperative as well as the post-operative course were collected. RESULTS: Out of 583 pancreatoduodenectomies during the interval, a total of 10 (1.7 %) were performed as an emergency surgery. Indications included uncontrollable bleeding, duodenal and proximal jejunal perforations, and endoscopic retrograde cholangiopancreatography-related complications. Three of the 10 (30.0 %) patients died during the hospital course. In one patient, an intraoperative mass transfusion was necessary. No intraoperative death occurred. All but one patient were American Society of Anesthesiologists class three or higher. In two cases, the pancreatic remnant was left without anastomosis for second-stage pancreatojejunostomy. Median operation time was 326.5 min (SD 100.3 min). Hospital stay of the surviving patients was prolonged (median 43.0 days; SD 24.0 days). CONCLUSION: Emergency pancreatoduodenectomies are non-frequent, have a diverse range of indications and serve as an ultima ratio to cope with severe injuries and complications around the pancreatic head area.
Assuntos
Emergências , Pancreaticoduodenectomia/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Duodeno/lesões , Duodeno/cirurgia , Feminino , Hemorragia/cirurgia , Humanos , Perfuração Intestinal/cirurgia , Jejuno/lesões , Jejuno/cirurgia , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Estudos RetrospectivosRESUMO
The basal transcription of heme oxygenase-1 (HO-1) regulation is dependent upon a GT repeat germ line polymorphism (GTn) in the promoter of the HO-1 gene. We determined the prognostic value of HO-1 promoter polymorphism on the natural postoperative course of complete resected oesophageal cancer. Genomic DNA from 297 patients was amplified by polymerase chain reaction and sequenced. The results were correlated with clinicopathological parameters, disseminated tumour cells in bone marrow (DTC) and clinical outcome. Depending on short allele with <25 and long allele with ≥25, GTn repeats three genotypes (SS, SL and LL) were defined. A diverse role of GTn was evident in squamous cell carcinoma (SCC) and adenocarcinoma (AC). In SCC, the SS genotype presented less advanced tumours with lower rate DTC in bone marrow and relapse compared with L-allele carriers. In contrast, AC patients with the SS genotype displayed a complete opposing tumour characteristic. The disease-free (DFS) and overall survival (OS) in SCC patients was markedly reduced in LL genotypes (p < 0.001). In AC contrarily the SS genotype patients displayed the worst DFS and OS (p < 0.001). GTn is a strong prognostic factor with diverse prognostic value for recurrence and survival in AC and SCC.
Assuntos
Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Heme Oxigenase-1/genética , Polimorfismo Genético , Regiões Promotoras Genéticas , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Análise Mutacional de DNA , Intervalo Livre de Doença , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Feminino , Heme Oxigenase-1/química , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Sequências Repetitivas de Ácido Nucleico , Resultado do TratamentoRESUMO
OBJECTIVES: To assess pancreatic fistula rate and secondary endpoints after pancreatogastrostomy (PG) versus pancreatojejunostomy (PJ) for reconstruction in pancreatoduodenectomy in the setting of a multicenter randomized controlled trial. BACKGROUND: PJ and PG are established methods for reconstruction in pancreatoduodenectomy. Recent prospective trials suggest superiority of the PG regarding perioperative complications. METHODS: A multicenter prospective randomized controlled trial comparing PG with PJ was conducted involving 14 German high-volume academic centers for pancreatic surgery. The primary endpoint was clinically relevant postoperative pancreatic fistula. Secondary endpoints comprised perioperative outcome and pancreatic function and quality of life measured at 6 and 12 months of follow-up. RESULTS: From May 2011 to December 2012, 440 patients were randomized, and 320 were included in the intention-to-treat analysis. There was no significant difference in the rate of grade B/C fistula after PG versus PJ (20% vs 22%, P = 0.617). The overall incidence of grade B/C fistula was 21%, and the in-hospital mortality was 6%. Multivariate analysis of the primary endpoint disclosed soft pancreatic texture (odds ratio: 2.1, P = 0.016) as the only independent risk factor. Compared with PJ, PG was associated with an increased rate of grade A/B bleeding events, perioperative stroke, less enzyme supplementation at 6 months, and improved results in some quality of life parameters. CONCLUSIONS: The rate of grade B/C fistula after PG versus PJ was not different. There were more postoperative bleeding events with PG. Perioperative morbidity and mortality of pancreatoduodenectomy seem to be underestimated, even in the high-volume center setting.
Assuntos
Pancreatopatias/cirurgia , Pancreaticoduodenectomia , Pancreaticojejunostomia , Complicações Pós-Operatórias/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Alemanha/epidemiologia , Hemorragia/epidemiologia , Mortalidade Hospitalar , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Pancreatopatias/mortalidade , Fístula Pancreática/epidemiologia , Complicações Pós-Operatórias/mortalidade , Estudos Prospectivos , Qualidade de Vida , Fatores de RiscoRESUMO
Cancer cell invasion takes place at the cancer-host interface and is a prerequisite for distant metastasis. The relationships between current biological and clinical concepts such as cell migration modes, tumour budding and epithelial-mesenchymal transition (EMT) remains unclear in several aspects, especially for the 'real' situation in human cancer. We developed a novel method that provides exact three-dimensional (3D) information on both microscopic morphology and gene expression, over a virtually unlimited spatial range, by reconstruction from serial immunostained tissue slices. Quantitative 3D assessment of tumour budding at the cancer-host interface in human pancreatic, colorectal, lung and breast adenocarcinoma suggests collective cell migration as the mechanism of cancer cell invasion, while single cancer cell migration seems to be virtually absent. Budding tumour cells display a shift towards spindle-like as well as a rounded morphology. This is associated with decreased E-cadherin staining intensity and a shift from membranous to cytoplasmic staining, as well as increased nuclear ZEB1 expression.
Assuntos
Adenocarcinoma/patologia , Transição Epitelial-Mesenquimal , Invasividade Neoplásica/patologia , Biomarcadores Tumorais/análise , Humanos , Imageamento Tridimensional , Imuno-HistoquímicaRESUMO
INTRODUCTION: Expression of cancer testis antigens (CTAs) has been associated with prognosis in gastrointestinal stromal tumors (GIST) and other malignancies. CTAs are currently being investigated for cancer immunotherapy. MATERIALS AND METHODS: We analyzed two CTAs, CT10/MAGE-C2 and GAGE, in 51 GIST by immunohistochemistry and correlated it with established histopathological criteria for malignancy. RESULTS: GAGE expression was found in 6/51 (12%) patients, whereas 5/51 (10%) patients expressed CT10/MAGE-C2. 7/51(14%) patients expressed at least one of both CTAs, in 4/51 (8%) patients both CTAs were positive. High-grade GIST are more likely to express GAGE (p = 0.002) and CT10/MAGE-C2 (p = 0.007) compared to less aggressive tumors. All patients with GAGE or CT10/MAGE-C2 expression had moderate- or high-risk of recurrence according to the established risk criteria. The presence of GAGE correlates with mitotic rate (p = 0.001) and tumor size (p = 0.02), but not with tumor location (p = 0.60). CT10/MAGE-C2 also significantly correlates with mitotic rate (p = 0.004) and tumor size (p = 0.002), whereas no correlation could be found with tumor location (p = 0.36). DISCUSSION: CT10/MAGE-C2 and GAGE should be explored together with other previously described CTAs as targets for immunotherapy of GIST in cases, which are refractory to conventional therapy.
Assuntos
Antígenos de Neoplasias/imunologia , Neoplasias Gastrointestinais/imunologia , Tumores do Estroma Gastrointestinal/imunologia , Proteínas de Neoplasias/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Neuroendocrine tumours (NET) are rare and heterogeneous neoplasia. To obtain valid data on epidemiology, diagnostics, therapy, prognosis and risk factors is the aim of the German NET registry. PATIENTS AND METHODS: Data from 2009 histologically proven NET were collected from 35 NET centres between 1999 and 2010. Data collection has been performed prospectively since 2004. Results: Median follow-up was 34.5 months and median age at diagnosis 56.4 years. Primary tumour localisations were pancreas (34.2%), midgut (5.8%), stomach (6.5%), bowel (6.9%), duodenum (4.8%) and neuroendocrine CUP (12.6%). Synchronous metastases were seen in 46% and second malignancies in 12%. From 860 patients, 402 (46.7%) had functional tumours with the following hormone excess syndromes: carcinoid syndrome (19.1%; n = 164), persistent hyperinsulinaemic hypoglycaemia (17.7%; n = 152), Zollinger- Ellison syndrome (7.1%; n = 61), glucagonoma (0.7%; n = 15), Verner-Morrison syndrome (0.4%; n = 8) and somatostatinoma syndrome(0.1%; n = 2). Surgical therapy was performed in 78%, therapy with somatostatin receptor analogues(SSA) in 28%, peptide radioreceptor therapy (PRRT) in 19%, chemotherapy in 18% and interferon therapy in 6.5%. Only surgery was done in 47%, whereas 53% received a second therapy. General mortality rate during follow-up was 14.9%. The tumour-specific survival rates for 2, 5 and 10 years were 94, 85 and 70%. The 5-year survival is dependent on the surgical or non-surgical therapy (82 versus 61%, p < 0.001) and also on the primary tumour site (90/30% for midgut, 85/65% for pancreas, p < 0.001). Grading (G1, G2, G3) based on proliferation index Ki-67 recommended by the ENETS guidelines and WHO classification is highly correlated to the 5-year survival rate (88, 82, 33%, p < 0.001). CONCLUSION: The German NET registry provides valid multicentric data on NET in Germany. Surgical therapy is the most frequent and important therapy with good clinical outcome. In non-resectable, metastatic tumours, systemic therapies are common. Continuation and evaluation of the new WHO and TNM classifications for NET and their therapies will be a future focus of the registry.
Assuntos
Neoplasias do Sistema Digestório/diagnóstico , Neoplasias do Sistema Digestório/cirurgia , Hormônios Ectópicos/sangue , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/cirurgia , Sistema de Registros , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Neoplasias do Sistema Digestório/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Tumores Neuroendócrinos/patologia , Prognóstico , Síndrome , Adulto JovemRESUMO
BACKGROUND: Hypoxic environment of pancreatic cancer (PC) implicates high vascular in-growth, which may be influenced by angiogenesis-related germline polymorphisms. Our purpose was to evaluate polymorphisms of vascular endothelial growth factor receptor 2 (VEGFR-2), CXC chemokine receptor 2 (CXCR-2), proteinase-activated receptor 1 (PAR-1) and endostatin (ES) as prognostic markers for disease-free (DFS) and overall survival (OS) in PC. PATIENTS AND METHODS: Genotyping of 173 patients, surgically treated for PC between 2004 and 2011, was carried out by TaqMan(®) genotyping assays or polymerase chain reaction. Chi-square test, Kaplan-Meier estimator and Cox regression hazard model were used to assess the prognostic value of selected polymorphisms. RESULTS: VEGFR-2 -906 T/T and PAR-1 -506 Del/Del genotypes predicted longer DFS (P = 0.003, P = 0.014) and OS (VEGFR-2 -906, P = 0.011). CXCR-2 +1208 T/T genotype was a negative predictor for DFS (P < 0.0001). Combined analysis for DFS and OS indicated that patients with the fewest number of favorable genotypes simultaneously present (VEGFR-2 -906 T/T, CXCR-2 +1208 C/T or C/C and PAR-1 -506 Del/Del) were at the highest risk for recurrence or death (P < 0.0001). CONCLUSION: VEGFR-2 -906 C>T, CXCR-2 +1208 C>T and PAR-1 -506 Ins/Del polymorphisms are potential predictors for survival in PC.
Assuntos
Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Receptor PAR-1/genética , Receptores de Interleucina-8B/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Intervalo Livre de Doença , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/genética , Neoplasias Pancreáticas/cirurgia , Polimorfismo de Nucleotídeo Único , Sobrevida , Neoplasias PancreáticasRESUMO
BACKGROUND AND STUDY AIMS: Endoscopic ultrasonography (EUS) has been shown to be the most accurate test for locoregional staging of upper gastrointestinal tumors; however, recent studies have questioned its accuracy level in daily clinical application. The present retrospective study analyzes the accuracy of EUS in guiding interdisciplinary treatment decisions. PATIENTS AND METHODS: 123 primarily operated patients (63 % men, mean age 61.4 years) were included; only cases with tumor-free resection margins and without evidence of distant metastases were selected. EUS and histopathological findings were compared. Main outcome parameter was the distinction between tumors to be primarily operated (T1 /2N0) and those to be treated by neoadjuvant or perioperative chemotherapy (T3/4, or any N + ), based on an assumed algorithm for treatment stratification. RESULTS: Overall staging accuracy of EUS was 44.7 % for T and 71.5 % for N status irrespective of tumor location. Overstaging was the main problem (44.9 % for T, 42.9 % for N staging). The overall EUS classification was correct in 79.7 % (accuracy), with a sensitivity 91.9 % and specificity 51.4 %; only 19 out of 37 cases with histopathological T1/2N0 were correctly classified by EUS. Positive and negative predictive values of EUS in diagnosing advanced tumor stage for assignment to neoadjuvant therapy were 81.4 % and 73.1 %, respectively. CONCLUSIONS: Whereas EUS has a high sensitivity in the diagnosis of locally advanced gastric cancer, endosonographic overstaging of T2 cancers appears to be a frequent problem. EUS stratification between local (T1 /2N0) and advanced (T3/4 or any N + ) tumors would thus result in incorrect assignment to neoadjuvant treatment in half of cases.
Assuntos
Carcinoma/diagnóstico por imagem , Carcinoma/patologia , Endossonografia , Excisão de Linfonodo , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Carcinoma/terapia , Quimioterapia Adjuvante , Feminino , Gastrectomia , Humanos , Masculino , Mediastino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Estudos Retrospectivos , Neoplasias Gástricas/terapiaRESUMO
Here we tested the prognostic impact of genomic alterations in operable localized pancreatic ductal adenocarcinoma (PDAC). Fifty-two formalin-fixed and paraffin-embedded primary PDAC were laser micro-dissected and were investigated by comparative genomic hybridization after whole genome amplification using an adapter-linker PCR. Chromosomal gains and losses were correlated to clinico-pathological parameters and clinical follow-up data. The most frequent aberration was loss on chromosome 17p (65%) while the most frequent gains were detected at 2q (41%) and 8q (41%), respectively. The concomitant occurrence of losses at 9p and 17p was found to be statistically significant. Higher rates of chromosomal losses were associated with a more advanced primary tumor stage and losses at 9p and 18q were significantly associated with presence of lymphatic metastasis (chi-square: p = 0.03, p = 0.05, respectively). Deletions on chromosome 4 were of prognostic significance for overall survival and tumor recurrence (Cox-multivariate analysis: p = 0.026 and p = 0.021, respectively). In conclusion our data suggest the common alterations at chromosome 8q, 9p, 17p and 18q as well as the prognostic relevant deletions on chromosome 4q as relevant for PDAC progression. Our comprehensive data from 52 PDAC should provide a basis for future studies with a higher resolution to discover the relevant genes located within the chromosomal aberrations identified.
Assuntos
Carcinoma Ductal Pancreático/genética , Deleção Cromossômica , Cromossomos Humanos Par 4 , Neoplasias Pancreáticas/genética , Adenocarcinoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/patologia , Aberrações Cromossômicas , Cromossomos Humanos Par 17 , Cromossomos Humanos Par 18 , Cromossomos Humanos Par 8 , Cromossomos Humanos Par 9 , Hibridização Genômica Comparativa , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Prognóstico , Análise de SobrevidaRESUMO
BACKGROUND: Gastroesophageal reflux disease (GERD) is among the most common dysfunctions of the upper gastrointestinal tract. It interferes with quality of life and is a risk factor for the development of adenocarcinoma in the lower esophagus. Laparoscopic fundoplication is an effective treatment of GERD, but the physiologic mechanisms of the different available procedures had not been investigated to date. METHODS: In this study, 28 German Landrace pigs underwent baseline manometry and 24-h pH monitoring followed by myotomy to induce reflux esophagitis. After new-onset reflux was proved, the pigs were randomized to groups based on four treatments: total fundoplication, anterior hemifundoplication, posterior hemifundoplication, and control. On days 10 and 60 after the intervention, the effectiveness of the different fundoplication modifications was compared with that of the control subjects by 24-h pH monitoring manometry. Finally, the pigs were killed, after which the minimum volume and pressure required to breach the gastroesophageal junction were recorded. RESULTS: After myotomy, a significant increase in the reflux could be confirmed. The findings after fundoplication showed a significant decrease in the fraction of time that the pH fell below four and an increase in the vector volume compared with the measurement after myotomy. Total fundoplication and posterior hemifundoplication were highly effective, whereas measurements after anterior fundoplication still showed increased fraction times. Pharmacologic stimulation with pentagastrin showed an increase in the vector volume of the esophageal sphincter. CONCLUSIONS: Total fundoplication and posterior hemifundoplication are potent operations for the treatment of GERD. Anterior hemifundoplication reduces the reflux as well, but the effects are significantly less than with total and posterior fundoplication. Pharmacologic stimulation showed excellent results after posterior hemifundoplication, and a tendency to overcorrection was shown after total fundoplication.
Assuntos
Fundoplicatura/métodos , Refluxo Gastroesofágico/cirurgia , Análise de Variância , Animais , Modelos Animais de Doenças , Monitoramento do pH Esofágico , Manometria , Estudos Prospectivos , Distribuição Aleatória , SuínosRESUMO
BACKGROUND: Transcriptional activity of the heme oxygenase-1 gene (HMOX-1) is modulated by a GTn-repeat promoter polymorphism. The long GTn-repeat allele has been previously reported to be associated with increased risk of oral squamous cell carcinoma (OSCC) in male areca chewer and short GTn-repeat allele has been proposed to have protective properties in OSCC patients. The aim of the present study was to correlate the GTn-repeat genotypes with clinicopathological characteristics along with clinical outcome of non-areca chewer OSCC patients. METHODS: DNA of 99 patients that underwent complete surgical resection of OSCC was analyzed for GTn-repeat polymorphism in the HMOX-1 promoter by polymerase chain reaction, capillary electrophoresis and DNA sequencing. RESULTS: Seven SS (7.1%), 51 SL (51.5%) and 41 LL (41.4%) genotypes were found. In a total of 14 (14.1%) patients, tumor recurrence (TR) was observed. There was no TR in the SS allele carriers. In SL carriers three and in LL 11 TR occurred (P = 0.009, chi-squared test). Mean relapse-free survival was 109.2 months in SL allele carriers compared with 72.3 months in LL allele carriers (P = 0.01, log-rank test). Multivariate Cox regression modeling identified GTn-repeat genotype as an independent prognostic factor (P = 0.03; relative risk (RR) 4.1; 95% CI 1.1-14.6). CONCLUSION: Presence of S allele was associated with a lower TR rate and better relapse-free survival in OSCC patients. HMOX-1 promoter polymorphism might be considered as a potential prognostic marker in OSCC patients.