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1.
Crit Rev Oncol Hematol ; 92(1): 25-37, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24935219

RESUMO

Barrett's metaplasia of the esophagus (BE) is the precursor lesion of esophageal adenocarcinoma (EAC), a deadly disease with a 5-year overall survival of less than 20%. The molecular mechanisms of BE development and its transformation to EAC are poorly understood and current surveillance and treatment strategies are of limited efficacy. Increasing evidence suggests that aberrant signaling through pathways active in the embryological development of the esophagus contributes to BE development and progression to EAC. We discuss the role that the Bone morphogenetic protein, Hedgehog, Wingless-Type MMTV Integration Site Family (WNT) and Retinoic acid signaling pathways play during embryological development of the esophagus and their contribution to BE development and malignant transformation. Modulation of these pathways provides new therapeutic opportunities. By integrating findings in developmental biology with those from translational research and clinical trials, this review provides a platform for future studies aimed at improving current management of BE and EAC.


Assuntos
Esôfago de Barrett/etiologia , Esôfago de Barrett/patologia , Transformação Celular Neoplásica , Transdução de Sinais , Adenocarcinoma/etiologia , Adenocarcinoma/terapia , Animais , Esôfago de Barrett/terapia , Progressão da Doença , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/terapia , Humanos , Terapia de Alvo Molecular
2.
Neth J Med ; 72(3): 139-45, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24846927

RESUMO

BACKGROUND: Colorectal adenoma patients are kept under surveillance because of the risk of developing metachronous neoplasia. The aim is to determine predictors of neoplasia development after polypectomy. METHODS: It is an observational cohort study. 433 Patients who had ≥1 adenoma removed between 1988 and 2004 were included, with follow-up until 2010. Multivariate analysis of patient and adenoma characteristics was performed at initial colonoscopy and at consecutive positive examinations. The main outcome measured was the development of metachronous (advanced) adenomas during follow-up. RESULTS: Median follow-up was 85 months. Multivariate analysis identified male sex, ≥3 adenomas, high-grade dysplasia and age ≥55 years as risk factors for metachronous lesions at first surveillance. Analysis using life expectancy as a timescale showed ≥3 adenomas to be the only predictive factor. The time to second or third metachronous adenoma did not depend on the number of adenomas. Patients with ≥3 adenomas were five years older at the time of their first polypectomy compared with those with fewer adenomas, but of the same age at the first recurrence. Prevalence of high-grade dysplasia was associated with age and high-grade dysplasia in the prior adenoma independent of time interval. CONCLUSIONS: Adenoma development after polypectomy occurs in a regular and repetitive way. Our data suggest that only the interval between the initial colonoscopy and the first follow-up colonoscopy should be based on initial findings, i.e. number of adenomas, and that subsequent colonoscopies can be planned at predetermined intervals.


Assuntos
Adenoma/patologia , Pólipos do Colo/cirurgia , Neoplasias Colorretais/patologia , Recidiva Local de Neoplasia/patologia , Segunda Neoplasia Primária/patologia , Adenoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
3.
Carcinogenesis ; 35(5): 1092-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24379239

RESUMO

Tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL) is being investigated as a targeted cancer therapeutic and the expression of its pro-apoptotic receptors, DR4 and DR5, increases during colorectal carcinogenesis. This study investigated the role of ß-catenin in the regulation of these receptors. In human colorectal adenoma and carcinoma cell lines, downregulation of ß-catenin resulted in lower total DR4 and DR5 protein levels. Similarly, cell membrane expression of DR4 and DR5 was reduced after downregulation of ß-catenin in colon carcinoma cells, whereas induction of ß-catenin in HeLa cells led to increased cell membrane expression of DR4 and DR5. Downregulation of ß-catenin decreased the recombinant human TRAIL sensitivity of human colon carcinoma cells. Activation of the transcription factor T-cell factor-4 (TCF-4) is an important function of ß-catenin. Dominant-negative TCF-4 overexpression, however, did not significantly affect TRAIL receptor expression or recombinant human TRAIL sensitivity. Human colorectal adenomas (N = 158) with aberrant (cytoplasmic and nuclear) ß-catenin expression had a higher percentage of immunohistochemical DR4 and DR5 staining per tumour (mean: 73 and 88%, respectively) than those with membranous ß-catenin staining only (mean: 50 and 70%, respectively, P < 0.01 for both). Furthermore, aberrant ß-catenin staining co-localized with DR4 and DR5 expression in 92% of adenomas. In 53 human colorectal carcinomas, aberrant ß-catenin expression was present in most cases and DR4/5 expression was largely homogenous. Similarly, in adenomas from APC(min) mice, cytoplasmic ß-catenin staining co-localized with staining for the murine TRAIL death receptor. In conclusion, the gradual increase in TRAIL receptor expression during colorectal carcinogenesis is at least partially mediated through increased ß-catenin expression, independently of TCF-4-signalling.


Assuntos
Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , beta Catenina/genética , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patologia , Linhagem Celular Tumoral , Criança , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Ligação Proteica , Transporte Proteico , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Carga Tumoral , Adulto Jovem , beta Catenina/metabolismo
4.
Int J Colorectal Dis ; 28(12): 1643-9, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23857598

RESUMO

PURPOSE: Despite colonoscopic surveillance, Lynch syndrome patients develop colorectal cancer (CRC). Identification of modifiable factors has the potential to improve outcome of surveillance. The aims of this study were to determine (1) characteristics of patients with CRC, (2) endoscopic and histological features of these cancers, and (3) quality of the previous colonoscopy. METHODS: Approximately 2,200 medical reports from proven and obligate mutation carriers identified at the Dutch Lynch Syndrome Registry and two large hospitals were retrospectively analyzed for the presence of an interval cancer defined as CRC diagnosed within 24 months of previous colonoscopy. RESULTS: Thirty-one interval cancers were detected in 29 patients (median age of 52 [range 35-73]), after a median time of 17 months. All were MLH1 or MSH2 mutation carriers, and 39 % had a previous CRC. In patients without previous surgery for CRC, 84 % was proximally located. Of all interval cancers, 77 % were at local stage (T1-3N0Mx). In three patients (9 %) with an incomplete previous colonoscopy, CRC was located in the unexamined colon. In six of the nine patients with an adenoma during previous colonoscopy, the cancer was detected in the same colonic segment as the previously removed adenoma. CONCLUSIONS: Interval cancers were detected in MLH1 and MSH2 mutation carriers, especially in those with a history of previous CRC and between 40 and 60 years. Interval cancer could be related to incompleteness of previous endoscopy and possibly residual adenomatous tissue. Further reduction of the interval cancer risk may be achieved by optimizing endoscopy quality and individualization of surveillance guidelines.


Assuntos
Colonoscopia/normas , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Adulto , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco
6.
Aliment Pharmacol Ther ; 36(8): 765-71, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22928581

RESUMO

BACKGROUND: Formation of antibodies to infliximab (ATI) inversely correlates with functional drug levels and clinical outcome. Comparison of drug levels and anti-drug antibody monitoring is hampered by lack of standardisation. AIM: To determine the correlation between three different assays for measuring infliximab and ATI. METHODS: Serum samples and spiked controls (total 62) were evaluated in a blinded way in infliximab and ATI assays developed by Sanquin Amsterdam, Netherlands (A), Laboratory for Pharmaceutical Biology, KU Leuven, Belgium (B) and a commercially available kit from Biomedical Diagnostics (BMD), Paris, France (C) performed by the University Medical Center Groningen (UMCG), Netherlands. RESULTS: All infliximab assays showed a linear quantitative correlation (Pearson r = 0.91 for A vs. B, 0.83 for A vs. C and 0.73 for B vs. C). Assay C detected infliximab in 11 samples (18%) not detected by A and B, including samples containing only ATI. All ATI assays showed a good linear correlation (Pearson r = 0.95 for A vs. B, 0.99 for A vs. C and 0.97 for B vs. C). Assay A detected ATI in five samples with low ATI that were not detected by assays B and C. Assay B did not detect ATI in three patient samples with low ATI according to assays A and C. CONCLUSIONS: There is a good correlation of infliximab and antibodies to infliximab measurements between these assays. Nevertheless, the Biomedical Diagnostics kit detected false positive infliximab levels in 18% of the samples.


Assuntos
Anti-Inflamatórios não Esteroides/sangue , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/imunologia , Anticorpos/sangue , Imunoensaio/métodos , Anti-Inflamatórios não Esteroides/imunologia , Reações Antígeno-Anticorpo , Biomarcadores/sangue , Reações Falso-Positivas , Humanos , Infliximab , Kit de Reagentes para Diagnóstico/normas , Estatística como Assunto
7.
Oncogene ; 30(17): 2026-36, 2011 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-21217777

RESUMO

Comparing normal colorectal mucosa and adenomas focusing on deregulated pathways obtains insight into the biological processes of early colorectal carcinogenesis. Publicly available microarray expression data from 26 normal mucosa and 47 adenoma samples were analyzed. Biological pathways enriched in adenomas were identified with Gene Set Enrichment Analysis (GSEA). The analysis revealed 10, 11 and 16 gene sets distinguishing adenomas from normal mucosa according to Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Map Annotator and Pathway Profiler (GenMAPP) and Biocarta databases, respectively. Biological pathways known to be involved in colon carcinogenesis such as cell cycle (P=0.002) and Wnt signaling (P=0.007) were enriched in adenomas. In addition, we found enrichment of novel pathways such as retinoblastoma (Rb) pathway (P=0.002), Src pathway (P=0.004), folate biosynthesis (P=0.019) and Hedgehog signaling (P=0.037) in adenomas. Microarray results for Rb and Src pathway genes were validated by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) on mRNA isolated from an independent set of adenoma and normal colon samples. A high correlation between microarray data and qRT-PCR expression data was found. The relevance of targeting of identified pathways was shown using the Rb pathway inhibitors roscovitine and PD-0332991 and the Src pathway inhibitor dasatinib. All inhibitors used induced cell growth reduction in adenoma cells. This study shows a bioinformatical and functional approach leading to potentially new options for chemoprevention of colorectal cancer.


Assuntos
Quimioprevenção/métodos , Neoplasias Colorretais/prevenção & controle , Biologia Computacional/métodos , Adenoma/genética , Adenoma/prevenção & controle , Artefatos , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Biologia Computacional/normas , Regulação Neoplásica da Expressão Gênica , Humanos , Mucosa Intestinal/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Controle de Qualidade , Padrões de Referência , Reprodutibilidade dos Testes , Proteína do Retinoblastoma/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
Gut ; 60(1): 73-6, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20833659

RESUMO

BACKGROUND AND AIMS: Subjects with one first-degree relative (FDR) with colorectal cancer (CRC) <50 years old or two FDRs with CRC have an increased risk for CRC (RR 4-6). Current guidelines recommend colonoscopic surveillance of such families. However, information about the yield of surveillance is limited. The aim of the present study was to evaluate the outcome of surveillance and to identify risk factors for the development of adenomas. PATIENTS AND METHODS: Subjects were included if they fulfilled the following criteria: asymptomatic subjects aged between 45 and 65 years, with one FDR with CRC <50 years old (group A) or two FDRs with CRC diagnosed at any age (group B). Subjects with a personal history of inflammatory bowel disease or colorectal surgery were excluded. RESULTS: A total of 551 subjects (242 male) met the selection criteria. Ninety-five subjects with a previous colonoscopy were excluded. Two of 456 remaining subjects (0.4%) were found to have a colorectal tumour (one CRC and one carcinoid). Adenomas were detected in 85 (18.6%) and adenomas with advanced pathology in 37 subjects (8.1%). 30 subjects (6.6%) had multiple (>1) adenomas. Men were more often found to have an adenoma than women (24% vs 14.3%; p=0.01). Adenomas were more frequent in group B compared with group A (22.0% vs 15.6%; p=0.09). CONCLUSION: The yield of colonoscopic surveillance in familial CRC is substantially higher than the yield of screening reported for the general population.


Assuntos
Adenoma/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Adenoma/epidemiologia , Adenoma/genética , Fatores Etários , Idoso , Colonoscopia , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Vigilância da População/métodos , Fatores de Risco , Fatores Sexuais , Fatores de Tempo
9.
Br J Cancer ; 104(1): 37-42, 2011 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-21063417

RESUMO

BACKGROUND: The optimal treatment of desmoid tumours is controversial. We evaluated desmoid management in Dutch familial adenomatous polyposis (FAP) patients. METHODS: Seventy-eight FAP patients with desmoids were identified from the Dutch Polyposis Registry. Data on desmoid morphology, management, and outcome were analysed retrospectively. Progression-free survival (PFS) rates and final outcome were compared for surgical vs non-surgical treatment, for intra-abdominal and extra-abdominal desmoids separately. Also, pharmacological treatment was evaluated for all desmoids. RESULTS: Median follow-up was 8 years. For intra-abdominal desmoids (n=62), PFS rates at 10 years of follow-up were comparable after surgical and non-surgical treatment (33% and 49%, respectively, P=0.163). None of these desmoids could be removed entirely. Eventually, one fifth died from desmoid disease. Most extra-abdominal and abdominal wall desmoids were treated surgically with a PFS rate of 63% and no deaths from desmoid disease. Comparison between NSAID and anti-estrogen treatment showed comparable outcomes. Four of the 10 patients who received chemotherapy had stabilisation of tumour growth, all after doxorubicin combination therapy. CONCLUSION: For intra-abdominal desmoids, a conservative approach and surgery showed comparable outcomes. For extra-abdominal and abdominal wall desmoids, surgery seemed appropriate. Different pharmacological therapies showed comparable outcomes. If chemotherapy was given for progressively growing intra-abdominal desmoids, most favourable outcomes occurred after combinations including doxorubicin.


Assuntos
Polipose Adenomatosa do Colo/terapia , Antineoplásicos/uso terapêutico , Colectomia , Fibromatose Abdominal/terapia , Fibromatose Agressiva/terapia , Polipose Adenomatosa do Colo/complicações , Adolescente , Adulto , Terapia Combinada , Feminino , Fibromatose Abdominal/complicações , Fibromatose Agressiva/complicações , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Países Baixos , Dosagem Radioterapêutica , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
10.
Aliment Pharmacol Ther ; 32(11-12): 1398-404, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21050243

RESUMO

BACKGROUND: Somatostatin analogues are administered to control hormone hypersecretion in acromegaly and carcinoid patients. Somatostatin analogues can increase fat in the stools, which can lead to loss of fat-soluble vitamins. The effect of long-term somatostatin analogue use on vitamin levels remains unknown. AIM: To investigate the prevalence of fat-soluble vitamin deficiencies in long-term somatostatin analogue users. METHODS: All acromegaly and carcinoid patients using somatostatin analogues for ≥ 18 months visiting the University Medical Center Groningen between December 2008 and April 2009 were eligible. Vitamin levels of fat-soluble vitamins in blood, clinical and vitamin-dependent laboratory parameters were collected. RESULTS: In all, 19 acromegaly and 35 carcinoid patients were included. Twelve patients experienced steatorrhoea; two carcinoid patients experienced night blindness. Forty-two (78%) were deficient for one or more vitamins, and 32% (n = 17) had multiple deficiencies. Deficiencies for vitamin A, D, E, K1 and E in erythrocytes occurred in 6%, 28%, 15%, 63% and 58% of the patients. Prevalence of vitamin D, E and K1 deficiencies was similar in both patient groups. Treatment duration did not influence vitamin levels. The length of intestinal resection and age correlated negatively with vitamin A levels. CONCLUSIONS: Fat-soluble vitamin deficiencies are frequent during long-term somatostatin analogue treatment. Therefore, fat-soluble vitamins should be monitored in these patients.


Assuntos
Acromegalia/tratamento farmacológico , Deficiência de Vitaminas/induzido quimicamente , Tumor Carcinoide/tratamento farmacológico , Somatostatina/análogos & derivados , Vitaminas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Somatostatina/efeitos adversos , Fatores de Tempo
11.
Neth J Med ; 67(5): 161-8, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19581664

RESUMO

Survival outcomes after liver transplantation in adult patients have gradually improved with a five-year survival of about 70% and a ten-year survival of about 60%. The present review focuses on relevant patient-reported outcomes such as self-perceived side effects of immunosuppressive drugs, medication nonadherence and long-term health-related quality of life after liver transplantation. These entities are interrelated but have often been studied separately. Self-perceived symptom experience in liver transplant recipients has not been studied extensively. Symptoms that cause distress differ between men and women, e.g. symptoms related to cosmetic side effects of drugs. Medication nonadherence seems to be infrequent, but if present may have serious consequences. Important risk factors were found to be the costs of drugs, age <40 years, psychiatric disorders, side effects of drugs, beliefs that drugs were harmful, and large influence of the liver transplant on the patient's life. Health-related quality of life is satisfactory, but below the level of the general population. Results, however, must be interpreted with caution as quality-of-life improvements may have been overstated due to variables such as selection bias (e.g. exclusion of severely ill and deceased patients), too many short-term studies, and suboptimal methodology. Presently we lack data on the influence of recurrence of disease, 'de novo' diseases and gender differences on health-related quality of life in liver transplanted patients.


Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Transplante de Fígado/psicologia , Aceitação pelo Paciente de Cuidados de Saúde , Cooperação do Paciente/psicologia , Qualidade de Vida , Comorbidade , Feminino , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/psicologia , Nível de Saúde , Humanos , Imunossupressores/efeitos adversos , Masculino , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Fatores de Risco , Resultado do Tratamento
12.
Neth J Med ; 67(2): 41-5, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19299845

RESUMO

Chronic diarrhoea is a frequent complaint in clinical practice. Microscopic colitis is the cause of this symptom in 10% of these cases and the prevalence is rising. To exclude microscopic colitis a colonoscopy with multiple biopsies of different regions of the colon is mandatory. A sigmoidoscopy alone is insufficient. Two histopathological types of microscopic colitis can be distinguished: collagenous colitis and lymphocytic colitis. Nowadays, there is sufficient evidence to recommend budesonide as the first-choice treatment. Bismuth can also be recommended, but this drug is not easily available in the Netherlands. Evidence of efficacy of other drugs is scant.


Assuntos
Antiácidos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Bismuto/uso terapêutico , Budesonida/uso terapêutico , Colite Colagenosa/tratamento farmacológico , Colite Linfocítica/tratamento farmacológico , Adulto , Colite Colagenosa/diagnóstico , Colite Colagenosa/patologia , Colite Linfocítica/diagnóstico , Colite Linfocítica/patologia , Feminino , Humanos , Masculino
13.
Clin Transplant ; 22(6): 700-9, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18673378

RESUMO

Symptom experience (occurrence and perceived distress) associated with side effects of immunosuppressive medications in organ transplant patients may well be associated with poorer quality of life and medication non-compliance. The aims of this study were: first, to assess symptom experience in clinically stable adult patients during long-term follow-up after liver transplantation; and second, to study the relationship between symptom experience and medication non-compliance. This cross-sectional study included 123 liver transplant patients. Symptom experience was assessed using the "Modified Transplant Symptom Occurrence and Symptom Distress Scale" (29-item version) at the annual evaluation. According to the duration of follow-up, patients were divided into a short-term (1-4 yr) and a long-term (5-18 yr) cohort. Medication non-compliance was measured using electronic monitoring. Results showed that increased hair growth was the most frequent symptom in both sexes. Symptom distress was more serious in women than in men. The most distressing symptom in women was excessive and/or painful periods, while in men this was impotence. Clear differences were revealed at item level between symptom occurrence and symptom distress in relationship with the two time cohorts and between sexes. No relationship was found between symptom experience and prednisolone non-compliance.


Assuntos
Terapia de Imunossupressão/efeitos adversos , Imunossupressores/uso terapêutico , Transplante de Fígado , Cooperação do Paciente , Adulto , Idoso , Azatioprina/uso terapêutico , Estudos Transversais , Ciclosporina/uso terapêutico , Feminino , Rejeição de Enxerto/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Qualidade de Vida , Adulto Jovem
14.
Cell Oncol ; 29(5): 409-19, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17726263

RESUMO

BACKGROUND: TNF-Related Apoptosis Inducing Ligand (TRAIL) is a promising agent for the induction of apoptosis in neoplastic tissues. Important determinants of TRAIL sensitivity are two intracellular proteins of the TRAIL pathway, caspase-8 and its anti-apoptotic competitor cellular Flice-Like Inhibitory Protein (cFLIP). METHODS: The aim of this study was to investigate basic expression of caspase-8 and cFLIP in normal colorectal epithelium (n=20), colorectal adenomas (n=66) and colorectal carcinomas (n=44) using immunohistochemistry performed on both sporadic and Hereditary Non-Polyposis Colorectal Cancer (HNPCC or Lynch syndrome)-associated adenomas and carcinomas. RESULTS: Expression of both caspase-8 and cFLIP was similar in cases with sporadic and hereditary origin. Expression of caspase-8 in colorectal adenomas and carcinomas was increased when compared to normal colon tissue (P=0.02). Nuclear, paranuclear as well as cytoplasmic localizations of caspase-8 were detected. Immunohistochemistry revealed an upregulation of cFLIP in colorectal carcinomas in comparison to normal epithelium and colorectal adenomas (P<0.001). A large variation in the caspase-8/cFLIP ratio was observed between the individual adenomas and carcinomas. CONCLUSION: Caspase-8 and cFLIP are upregulated during colorectal carcinogenesis. Upregulation of caspase-8 and/or downregulation of cFLIP may be interesting approaches to maximize TRAIL sensitivity in colorectal neoplasms.


Assuntos
Adenoma/enzimologia , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Caspase 8/biossíntese , Neoplasias Colorretais Hereditárias sem Polipose/enzimologia , Adenoma/patologia , Idoso , Idoso de 80 Anos ou mais , Apoptose , Proliferação de Células , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Indução Enzimática , Epitélio/enzimologia , Epitélio/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Frações Subcelulares/enzimologia
16.
Gut ; 56(9): 1198-201, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17409122

RESUMO

BACKGROUND: Small bowel cancer (SBC) is one of the tumours associated with Lynch syndrome (LS). To advise on screening for this tumour it is paramount to be informed about the lifetime risk. The aim of this study was to calculate the lifetime risk of SBC in LS and to identify possible risk factors. METHODS: Clinical and pathological data were collected on 1496 proven or putative carriers of a mismatch repair gene mutation from 189 families. Kaplan-Meier survival analysis was used to calculate the lifetime risk and to assess potential risk factors. RESULTS: 28 (1.9%) of the 1496 (putative) mutation carriers were identified with SBC. The median age at diagnosis was 52 years (range 23-69 years). The lifetime risk of developing SBC was 4.2%. There was no difference in risk between males and females (log rank: p = 0.2470), or between MLH1 and MSH2 mutation carriers (log rank: p = 0.2754). SBC was not observed in MSH6 mutation carriers (n = 203). The previous occurrence of colorectal cancer and a family history of SBC did not increase the risk significantly. CONCLUSIONS: Approximately, one out of 25 mutation carriers will develop SBC during life. No specific risk factors were identified. The risk appeared to be too low to advise screening by means of an invasive burdensome procedure like double balloon enteroscopy. However, screening by a non-invasive procedure (videocapsule endoscopy) might be considered if future studies will show its cost effectiveness. In patients with unexplained abdominal complaints and/or unexplained iron deficiency anaemia SBC should be considered.


Assuntos
Neoplasias Intestinais/genética , Intestino Delgado/patologia , Neoplasias Primárias Múltiplas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Saúde da Família , Feminino , Mutação em Linhagem Germinativa/genética , Heterozigoto , Humanos , Neoplasias Intestinais/patologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/patologia , Medição de Risco/métodos , Fatores de Risco
17.
Inflamm Bowel Dis ; 13(6): 703-9, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17230494

RESUMO

BACKGROUND: Regulatory T-cells (Treg) are natural suppressors of autoimmunity. Previous studies indicate that immunosuppressive drugs, especially calcineurin-inhibitors, may interfere with Treg homeostasis. Inflammatory bowel disease (IBD) can relapse or develop de novo after liver transplantation. IBD is associated with a relative deficiency of Treg. The aim of this study was to determine the effect of long-term immunosuppression on the presence of Treg in the noninflamed colonic mucosa of liver transplant recipients. METHODS: Colonic biopsies of normal mucosa of 36 liver transplant recipients on different types of immunosuppression and 11 controls were studied. Treg marker Foxp3 and Treg products transforming growth factor-beta (TGF-beta) and interleukin-10 (IL-10) were studied by quantitative polymerase chain reaction (Q-PCR) and immunohistochemistry. TGF-beta-induced Smad-protein 3 and 7 were studied by Q-PCR. RESULTS: No significant differences between controls and patients were observed in IL-10, TGF-beta, and Smad expression. Mucosal Foxp3 mRNA levels and Foxp3+CD3+ cells were significantly reduced in transplant recipients using prednisone/azathioprine/tacrolimus compared with controls but no direct relationship between Foxp3 expression and 1 specific drug was detected. CONCLUSIONS: These results challenge the hypothesis that calcineurin-induced reduction of Treg or TGF-beta expression predisposes nontransplanted tissue to inflammation, but indicate that combined immunosuppression hampers Treg development in the intestine.


Assuntos
Colo/patologia , Rejeição de Enxerto/prevenção & controle , Terapia de Imunossupressão , Imunossupressores/uso terapêutico , Transplante de Fígado , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Autoimunidade/efeitos dos fármacos , Biópsia , Complexo CD3/imunologia , Complexo CD3/metabolismo , Colo/metabolismo , Progressão da Doença , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Expressão Gênica/efeitos dos fármacos , Rejeição de Enxerto/imunologia , Humanos , Imuno-Histoquímica , Interleucina-10/genética , Interleucina-10/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Hepatopatias/cirurgia , Masculino , Pessoa de Meia-Idade , RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Smad3/genética , Proteína Smad7/genética , Linfócitos T Reguladores/efeitos dos fármacos , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
18.
Aliment Pharmacol Ther ; 26 Suppl 2: 57-65, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18081650

RESUMO

INTRODUCTION: Inflammatory bowel disease (IBD) comprising ulcerative colitis (UC) and Crohn's disease (CD) is multigenic disorder. Tremendous progress has been achieved in unravelling the genetic background of IBD. It has led to the discovery of mutations in NOD2 associated with ileal CD and numerous other genes have been found to be associated with IBD susceptibility. METHODS: A review of the literature on the genetic background of IBD was performed. RESULTS: It is only partially understood how mutations in NOD2 lead to CD. Mouse models, in vitro data and studies in humans offer conflicting data as regards whether there is a loss or gain of function of NOD2 in CD. Several additional genes have been identified of which only a few are currently being recognized as potential disease causing or disease modifying genes. Promising candidate genes include TLR4, MDR1, NOD1 (CARD4), DLG5 as well as the IBD5 locus including SLC22A4/5. CONCLUSIONS: Although genetic research has not yet led to a better prediction of the disease course or patient selection for medical therapy, remarkable progress has been made in the understanding of the pathogenesis of IBD. For future genetic research, accurate phenotyping of patients is very important and large population-based cohorts are needed. Eventually, genetic research may be able to classify different disease phenotypes on a more detailed molecular basis and may provide important contributions in the development of new therapeutic approaches.


Assuntos
Predisposição Genética para Doença/genética , Doenças Inflamatórias Intestinais/genética , Proteína Adaptadora de Sinalização NOD1/genética , Proteína Adaptadora de Sinalização NOD2/genética , Receptor 4 Toll-Like/genética , Humanos
19.
Aliment Pharmacol Ther ; 24(9): 1341-8, 2006 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17059515

RESUMO

BACKGROUND: It is controversial whether proton pump inhibitor use leads to fundic gland polyp development. AIM: To determine whether fundic gland polyp development is due to proton pump inhibitor use and to investigate mechanisms involved. METHODS: Proton pump inhibitor use and the presence of fundic gland polyps were assessed in consecutive patients undergoing oesophagogastroduodenoscopy. Biopsies from fundic gland polyps and gastric mucosa were taken. Dysplasia was graded as negative, low or high grade. Prevalence of parietal cell hyperplasia and parietal cell protrusions and the proportional cystic area were assessed. RESULTS: 599 patients participated, 322 used proton pump inhibitors, 107 had fundic gland polyps. Long-term proton pump inhibitor use was associated with an increased risk of fundic gland polyps (1-4.9 years use: OR 2.2, 95% CI: 1.3-3.8; > or =5 years: OR 3.8, 95% CI: 2.2-6.7) while short-term therapy (<1 year) was not (OR 1.0, 95% CI: 0.5-1.8). Low-grade dysplasia was found in one fundic gland polyp. Fundic gland polyps associated with long-term proton pump inhibitor use had a larger proportional cystic area and higher frequency of parietal cell hyperplasia and parietal cell protrusion. CONCLUSIONS: Long-term proton pump inhibitor use is associated with an up to fourfold increase in the risk of fundic gland polyps. Risk of dysplasia is negligible. Aetiologically, these polyps seem to arise because of parietal cell hyperplasia and parietal cell protrusions resulting from acid suppression.


Assuntos
Pólipos/induzido quimicamente , Bombas de Próton/efeitos adversos , Neoplasias Gástricas/induzido quimicamente , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pólipos/patologia , Estudos Prospectivos , Inibidores da Bomba de Prótons , Estudos Retrospectivos , Neoplasias Gástricas/patologia
20.
Scand J Gastroenterol Suppl ; (243): 55-8, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16894670

RESUMO

Treatment strategies for Crohn's disease are targeted toward lifelong management. Optimization of outpatient care is mandatory, because of many clinics facing capacity issues, and, along with routine follow-up of patients with inflammatory bowel disease, is putting increasing pressure on outpatient clinics. Recent studies demonstrate clearly that alternative management strategies are feasible and effective with a high rate of patient satisfaction. It is recommended that future research evaluates the way in which medical care is provided and explores the long-term effects of novel management strategies in IBD. This approach can then be extrapolated to other chronic conditions.


Assuntos
Assistência Ambulatorial , Doenças Inflamatórias Intestinais/terapia , Colite Ulcerativa/terapia , Doença de Crohn/terapia , Humanos , Satisfação do Paciente
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