RESUMO
Functional inactivation of the p16INK4a gene has been reported to be involved in the development of a variety of human malignancies. Recent evidence shows that transcriptional silencing as a consequence of hypermethylation of CpG islands is the predominant mechanism of p16INK4a gene inactivation in sporadic colon cancer. This study sought to identify the significance of p16INK4a methylation in the colonic epithelium of patients with long-standing ulcerative colitis. A total of 89 tissue samples was retrieved from three colectomy specimens. A methylation-specific PCR assay was applied. The methylation status was compared with histological findings and the flow cytometrically determined DNA index. Hypermethylation of the p16INK4a promoter region was detected in 12.7% of samples that were negative for dysplasia. However, 70.0% of samples with dysplasia and all of the samples with carcinomatous lesions revealed hypermethylation. Hypermethylation of the p16INK4a gene promoter was detected already in 40% of specimens with lesions indefinite for dysplasia and in 13.7% of samples with exclusively diploid cell populations. These results suggest that hypermethylation of the p16INK4a promoter region is a frequent and early occurring event during the process of neoplastic progression in ulcerative colitis.
Assuntos
Colite Ulcerativa/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Metilação de DNA , Regiões Promotoras Genéticas , Colectomia , Humanos , PrognósticoRESUMO
Telomerase activity is frequently associated with neoplasia. It is a ribonucleoprotein capable of replacing telomeric DNA sequences that are lost at each cell division. Neoplastic progression in chronic ulcerative colitis is characterized by the development of epithelial dysplasia which is accompanied by genetic alterations. Therefore we tested telomerase activity in 128 biopsy samples of four colectomy specimens with long-standing ulcerative pancolitis by using the Telomerase PCR ELISA System. In three patients with multiple dysplastic or carcinomatous lesions, telomerase activity was detected in 22 samples with a regional association to dysplastic or carcinomatous areas. 15 of the samples with telomerase activity (68%) were found in dysplastic/carcinomatous samples or in the direct vicinity of dysplastic areas, 4 (18%), 2 positions (about 4 cm) and the remaining three (14%) not more than 3 positions away from such areas. In the fourth patient, resected because of clinical deterioration despite medical treatment and who had no dysplastic lesions, no telomerase activity was detected. These results show that telomerase activity might be used as a complementary marker to histology for the identification of patients with ulcerative colitis who are at an increased risk for neoplastic progression.
Assuntos
Biomarcadores Tumorais/análise , Colite Ulcerativa/patologia , Neoplasias do Colo/patologia , Telomerase/análise , Biópsia , Colectomia , Colite Ulcerativa/complicações , Colite Ulcerativa/cirurgia , Colo/patologia , Neoplasias do Colo/enzimologia , Neoplasias do Colo/etiologia , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Humanos , Reação em Cadeia da Polimerase , Proctocolectomia Restauradora , Telomerase/genética , Fatores de TempoRESUMO
The present study retrospectively examined the correlation between the outcome of patients with locally advanced oesophageal squamous cell carcinoma (cT3-4 cN0-1 cM0) after multimodal treatment (radiochemotherapy +/- surgical resection) and the parameters proliferative activity, apoptotic index and expression of the nuclear enzyme topoisomerase II alpha (topo II alpha) in pre-therapeutic tumour biopsies. Fifty-eight patients who took part in a prospective multicentred trial received radiochemotherapy, optionally followed by surgery. Pre-therapeutic biopsies were immunohistochemically investigated for the extent of proliferation (MIB-I index) and expression of the topo II alpha-enzyme. The apoptotic index was determined by the TUNEL-assay. The three parameters were correlated with tumour response to polychemotherapy and with overall survival. Topo II alpha expression was found in all samples with different percentages of positive cells. The proliferation indices ranged between 9% and 97% (median: 43%) while the apoptotic indices ranged between 0.2% and 2.8% (median: 0.5%). Strong expression of topo II alpha (>50% positive tumour cells) was positively-correlated with response to polychemotherapy (p=0.016) whereas proliferative activity or apoptotic index showed no impact. None of the three parameters under investigation was predictive of overall survival. Pre-therapeutic determination of topo II alpha expression may predict chemosensitivity of oesophageal squamous cell carcinomas. However, determination of proliferative activity and apoptotic index has no predictive value.
Assuntos
Apoptose/fisiologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , DNA Topoisomerases Tipo II/biossíntese , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Antígenos de Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/enzimologia , Divisão Celular/efeitos dos fármacos , Divisão Celular/fisiologia , Ensaios Clínicos como Assunto , Terapia Combinada , Proteínas de Ligação a DNA , Neoplasias Esofágicas/enzimologia , Humanos , Estudos Multicêntricos como Assunto , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVE: Patients with ulcerative colitis are at an increased risk for developing colorectal neoplasms. p53 mutations and the occurrence of DNA aneuploidies are common events in the development of sporadic colorectal neoplasias. This study tried to determine the frequency of these events during the development of colitis-associated colorectal neoplasms. DESIGN/METHODS: Four colectomy specimens with a total of 124 biopsies were investigated. DNA content was measured by flow cytometry and p53 protein expression was detected by immunohistochemistry. These results were correlated with histological findings. RESULTS: DNA aneuploidies were found in 58 (46.8%), and p53 protein expression in 30 samples (24.2%). The presence of DNA aneuploidy as well as of p53 protein expression correlated with the histological characteristics of neoplastic transformation. In areas without dysplasias or with indefinite dysplasias, 31.5% of the samples showed DNA aneuploidies and in about 9% of the samples p53 protein expression could be detected; 33.7% of samples without or with indefinite dysplasias showed p53 protein expression and/or DNA aneuploidies. CONCLUSION: These results show that the occurrence of DNA aneuploidies and nuclear p53 protein expression is a common event in the development of colitis-associated colorectal neoplasias. p53 protein expression seems to be an early event in this process. DNA aneuploidies occur even earlier and more frequently in the absence of p53 protein expression. Therefore, other genetic alterations besides p53 gene mutations might be involved in colitis-associated tumour development.
Assuntos
Aneuploidia , Colite Ulcerativa/genética , Colite Ulcerativa/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , DNA/análise , Proteína Supressora de Tumor p53/metabolismo , Adulto , Biópsia , Citometria de Fluxo , Humanos , Imuno-HistoquímicaRESUMO
At the University of Frankfurt a high current proton source has been developed and tested for the FRANZ-Project [U. Ratzinger, L. P. Chau, O. Meusel, A. Schempp, K. Volk, M. Heil, F. Käppeler, and R. Stieglitz, "Intense pulsed neutron source FRANZ in the 1-500 keV range," ICANS-XVIII Proceedings, Dongguan, April 2007, p. 210]. The ion source is a filament driven arc discharge ion source. The new design consists of a plasma generator, equipped with a filter magnet to produce nearly pure proton beams (92 %), and a compact triode extraction system. The beam current density has been enhanced up to 521 mA/cm(2). Using an emission opening radius of 4 mm, a proton beam current of 240 mA at 50 keV beam energy in continuous wave mode (cw) has been extracted. This paper will present the current status of the proton source including experimental results of detailed investigations of the beam composition in dependence of different plasma parameters. Both, cw and pulsed mode were studied. Furthermore, the performance of the ion source was studied with deuterium as working gas.
Assuntos
Neoplasias dos Ductos Biliares/diagnóstico , Ductos Biliares Intra-Hepáticos , Colangiocarcinoma/diagnóstico , Hepatopatias/diagnóstico , Sarcoidose/diagnóstico , Idoso , Colangiopancreatografia Retrógrada Endoscópica , Diagnóstico Diferencial , Humanos , Icterícia Obstrutiva/etiologia , Imageamento por Ressonância Magnética , MasculinoRESUMO
This prospective multicentre phase II study characterises the toxicity and activity of first-line capecitabine and oxaliplatin combination therapy (CAPOX) in advanced biliary system adenocarcinomas. Patients received oxaliplatin (130 mg m(-2), day 1) plus capecitabine (1000 mg m(-2) b.i.d., days 1-14) every 3 weeks. Patients were stratified prospectively into two groups based on location of the primary (gallbladder carcinoma (GBC) or extrahepatic cholangiocarcinoma (ECC) versus intrahepatic mass-forming type cholangiocarcinoma (ICC)). Sixty-five patients were evaluable. The response rate in 47 patients with GBC/ECC was 27% (4% complete responses), and in 23 patients (49%) stable disease (SD) was encountered. In 18 patients with ICC, we observed no objective responses, but 6 patients (33%) had SD. Median survival was 12.8 months (95% CI, 10.0-15.6) for patients with GBC or ECC (GBC: 8.2 months; 95% CI, 4.3-11.7; ECC: 16.8 months; 95% CI, 12.7-20.5), and 5.2 months (95% CI, 0.6-9.8) for ICC patients. In both cohorts, therapy was well tolerated. The most common grade 3-4 toxicity was peripheral sensory neuropathy (11 patients). Our data suggest that the CAPOX regimen is a well-tolerated and active treatment option for advanced ECC and GBC but might produce poorer results for ICC.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Compostos Organoplatínicos/administração & dosagem , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Biliar/mortalidade , Neoplasias do Sistema Biliar/patologia , Capecitabina , Quimioterapia Adjuvante , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Progressão da Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Análise de Sobrevida , Resultado do TratamentoRESUMO
We evaluated the expression patterns of proapoptotic BAX, antiapoptotic Bcl-2 and p53, the proposed upstream effector of these molecules, as potential prognostic markers in UICC stage III colon cancer by immunohistochemical staining. To identify high-frequency microsatellite instability (MSI+) individuals, we performed single-strand conformation polymorphism-based analysis for BAT26. A total of 188 patients who had received 5-fluorouracil (5-FU)-based adjuvant chemotherapy (5-FU/folinic acid or 5-FU/levamisole) were enrolled. Median follow-up was 84.5 months. We found that BAX, Bcl-2 and p53 protein expressions were high or positive in 59, 70 and 50% of 188 cases, respectively. MSI+ tumours were detected in 9% of 174 evaluable patients. BAX or Bcl-2 was correlated with a higher degree of differentiation or left-sided tumours (P=0.01 or P=0.03, respectively); MSI was correlated with right-sided tumours (P<0.0001). In contrast to p53, Bcl-2, or MSI, low BAX, advanced pN category, low grade of differentiation and treatment with 5-FU/levamisole were univariately associated with poorer disease-free survival (DFS) (P=0.0005, P=0.001, P=0.005 and P=0.01, respectively) and poorer overall survival (OS) (P=0.002, P=0.0001, P=0.003 and P=0.02, respectively). Besides pN category and treatment arm, BAX was an independent variable related to both OS and DFS (P=0.003 and P=0.001, respectively). In both univariate and multivariate analysis, the p53-/BAX high in comparison with the p53+/BAX high subset conferred a significantly improved DFS (P=0.03 and P=0.03, respectively) as well as a marginally improved OS (P=0.07 and P=0.08, respectively). BAX protein expression may be of central significance for clinical outcome to 5-FU-based adjuvant chemotherapy in stage III colon cancer, and bivariate analysis of p53/BAX possibly may provide further prognostic evidence.
Assuntos
Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Fluoruracila/uso terapêutico , Instabilidade de Microssatélites , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína Supressora de Tumor p53/genética , Proteína X Associada a bcl-2/genética , Idoso , Apoptose , Quimioterapia Adjuvante , Neoplasias do Colo/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , PrognósticoRESUMO
BACKGROUND: Health-related quality of life (HRQOL) is an important outcome-parameter in health research and care. The aim of the working group Quality of Life in the Competence Network Inflammatory Bowel Disease (IBD; in the original German: "Kompetenznetz chronisch entzündliche Darmerkrankungen") is to generate instruments for assessment of HRQOL and its implementation as standards in clinical trials, health care and research in IBD. METHODS: The Inflammatory Bowel Disease Questionnaire (IBDQ) is an international validated disease specific instrument for HRQOL-assessment. A German version of the IBDQ was elaborated and tested in 415 outpatients with Crohn's disease (CD, n = 306) and ulcerative colitis (UC, n = 109). The aim of the study was to compare the results of HRQOL-assessment (IBDQ-D) with international investigations, to correlate HRQOL results with disease activity and to preform a pretest of psychometric properties. RESULTS: International data suggest that the IBDQ-D is a suitable instrument for HRQOL-assessment in CD and UC. For both disease a statistically significant negative correlation with disease activity was found. Tested psychometric properties do not suggest that a revision of the IBDQ-D is required. The IBDQ-D offers the HRQOL-assessment as an primary or secondary outcome in clinical trials in IBD in Germany.
Assuntos
Coleta de Dados/métodos , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/psicologia , Garantia da Qualidade dos Cuidados de Saúde/métodos , Qualidade de Vida , Adulto , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Projetos Piloto , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
The role of oxaliplatin in the therapy for advanced colorectal carcinoma. Preclinical models and numerous phase I to III trials have demonstrated the efficacy of oxaliplatin (l-OHP) for colorectal carcinoma. In previously untreated patients, response rates with l-OHP plus 5-fluorouracil and leucovorin (5-FU/LV) have been shown to be more than twice as high as compared with 5-FU/LV alone, and progression-free intervals have been significantly increased. Nevertheless, overall-survival was similar in both treatment arms, that was possibly due to the cross-over-design of these studies. Moreover, the combination regimens with l-OHP and 5-FU/LV often have shown activity in 5-FU-resistant or 5-FU- refractory patients. Furthermore, treatment of previously unresectable liver metastases from colorectal carcinoma with l-OHP in combination with 5-FU/LV has provided promising results. Dose-limiting toxicity is a peripheral sensory neuropathy, that was found to be mostly completely reversible within a few months. Gastrointestinal toxicities have been demonstrated to be mild. Compared to other anticancer drugs currently used in the treatment for colorectal carcinoma, l-OHP not only shows a different mechanism of action but displays synergistic anti-tumor activity as well as minimal hematologic toxicity making this agent interesting for combination chemotherapy protocols. In conclusion, the development of l-OHP has essentially increased the therapeutical possibilities of treatment for colorectal carcinoma.
Assuntos
Neoplasias Colorretais/tratamento farmacológico , Compostos Organoplatínicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Humanos , Estadiamento de Neoplasias , Compostos Organoplatínicos/efeitos adversos , Oxaliplatina , Taxa de Sobrevida , Resultado do TratamentoRESUMO
A 55-year-old man with CREST syndrome had marked telangiectasias of the palms, the face and the gastrointestinal tract. The latter caused slow bleeding and anemia. The telangiectasias were definitely associated with the CREST syndrome. Iron substitution was sufficient therapy. If a need for further therapy should arise, endoscopic sclerotherapy could be employed. Gastrointestinal bleeding in the CREST syndrome is rarely described, probably because it is unrecognized or interpreted as hemorrhagic gastritis. The possibility of gastrointestinal telangiectasias and concomitant bleeding should be kept in mind in cases of CREST syndrome.
Assuntos
Síndrome CREST/diagnóstico , Gastroenteropatias/diagnóstico , Hemorragia Gastrointestinal/etiologia , Síndrome CREST/patologia , Colonoscopia , Diagnóstico Diferencial , Mucosa Gástrica/patologia , Gastroenteropatias/patologia , Hemorragia Gastrointestinal/patologia , Gastroscopia , Humanos , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
Encrustations are the most frequent complications occurring with indwelling catheters and urine drainage systems. The conditions for bacterial infections, using synthetic urine and controlled contamination by Proteus vulgaris, were standardised by using an in vitro model. Crystal deposits on catheters were analysed by infra-red spectroscopy and scanning electron microscopy. The main components of deposits in all investigations were struvite (MgNH4PO4.6H2O) 60-70% and carbonate apatite (Ca10(PO4,CO3)6 (OH,CO3)2) 30-40%. Investigations as to the quality and quantity of encrustations confirmed the analysis. Irrigation treatment was carried out with physiological saline solution and citric acid solution (Suby G) to study and quantify the dissolution of crystal deposits. Regular irrigation with citric solution resulted in a 70% dissolution of encrustations and ensured free flow as ascertained by measuring flow rates.
Assuntos
Contaminação de Equipamentos , Compostos de Magnésio , Proteus vulgaris/metabolismo , Cateterismo Urinário/instrumentação , Animais , Apatitas/metabolismo , Cateteres de Demora , Cristalização , Concentração de Íons de Hidrogênio , Magnésio/metabolismo , Modelos Biológicos , Fosfatos/metabolismo , Infecções por Proteus/metabolismo , Proteus vulgaris/crescimento & desenvolvimento , Estruvita , UrinaRESUMO
PURPOSE: To examine the prevalence of DNA aneuploidy as a function of the extent of ulcerative colitis and to study the correlation of aneuploidy with clinical characteristics. Furthermore, the occurrence of aneuploidy and dysplasia during colonoscopic surveillance was studied in a subset of these patients. METHODS: By analyzing 5404 biopsy samples of 368 patients with ulcerative colitis, we have evaluated the importance of DNA ploidy measured by flow cytometry. We have also investigated the influence of extent (219 patients with extensive or total colitis vs. 149 patients with localized colitis) and duration of colitis on the development of dysplasia (patients with biopsy specimens that showed inflammation alone were compared with those with biopsy specimens that were equivocal or positive for dysplasia) and aneuploidy. Included was a subgroup of patients with ulcerative colitis and primary sclerosing cholangitis (n = 16). RESULTS: Aneuploidy was found in 8.7 percent (32/368) of all patients. The prevalence of aneuploidy increased by the extent of ulcerative colitis (2 percent localized, 6.8 percent extensive colitis, 14.9 percent total colitis). The frequency of aneuploidy was higher in patients with disease duration longer than 10 years (P = 0.007). Patients with ulcerative colitis and primary sclerosing cholangitis were more likely to develop aneuploidy (9/16, 56.3 percent vs. 14/120, 11.7 percent; P < 0.001) and dysplasia (4/16, 25 percent vs. 10/120, 8.3 percent; P = 0.06) than patients without primary sclerosing cholangitis. CONCLUSION: Because DNA aneuploidy represents an early alteration during neoplastic transformation in ulcerative colitis, flow cytometry is a valuable tool in the surveillance of those patients. Primary sclerosing cholangitis represents an additional risk factor for the development of DNA aneuploidy and dysplasia.
Assuntos
Colite Ulcerativa/patologia , Lesões Pré-Cancerosas/patologia , Aneuploidia , Biópsia , Ciclo Celular , Colangite Esclerosante/complicações , Estudos de Coortes , Colite Ulcerativa/complicações , Colite Ulcerativa/genética , Colonoscopia , Feminino , Citometria de Fluxo , Humanos , Masculino , Ploidias , Fatores de RiscoRESUMO
We report on the case of a 55-year-old patient suffering from progressive systemic sclerosis (PSS). The patient was sent to our department when clinical symptoms of an acute upper gastrointestinal hemorrhage occurred. Upper endoscopy showed a watermelon stomach and fresh blood in the stomach. The presence of teleangiectasias in the antrum could be proved histologically. Since the teleangiectasias found in the antrum were the only possible source of the hemorrhage three sessions of endoscopic argon plasma coagulation were performed. Macroscopically, a nearly complete disappearance of teleangiectasias could be achieved. After a follow-up of six months, there have been no clinical signs of another hemorrhage episode. This case shows that the existence of gastrointestinal teleangiectasias should be considered when chronic anemia or acute gastrointestinal hemorrhage occur in patients with PSS. Further it is demonstrated that even extended gastrointestinal teleangiectasias can be successfully treated by endoscopically performed argon plasma coagulation.
Assuntos
Síndrome CREST/cirurgia , Eletrocoagulação/instrumentação , Endoscópios , Hemorragia Gastrointestinal/cirurgia , Síndrome CREST/diagnóstico , Síndrome CREST/patologia , Capilares/patologia , Mucosa Gástrica/irrigação sanguínea , Mucosa Gástrica/patologia , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/patologia , Gastroscopia , Humanos , Masculino , Pessoa de Meia-Idade , Antro Pilórico/irrigação sanguínea , Antro Pilórico/patologia , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Inactivation of the CDKN2/p16(INK4A) tumor-suppressor gene is one of the most frequent genetic alterations in human malignancies. In esophageal adenocarcinomas, mutations of the p16 gene or homozygous deletions of the gene locus 9p21 are rare. This study investigated whether p16 promoter hypermethylation is an alternative mechanism for p16 gene inactivation during neoplastic progression in Barrett's esophagus. METHODS: A methylation-specific polymerase chain reaction protocol was applied. A total of 95 specimens from 14 patients with Barrett's esophagus were analyzed longitudinally. The p16 promoter status was compared with histomorphological findings. RESULTS: p16 promoter hypermethylation was detected in 9 of the 10 patients who had displayed dysplasia at some time during surveillance, whereas none of the patients who had not displayed dysplasia during surveillance had p16 promoter hypermethylation. p16 promoter hypermethylation was detected in 3% (2 of 67) of the samples without dysplasia, 60% (3 of 5) of the samples with lesions indefinite for dysplasia, 55.6% (10 of 18) of the specimens with low-grade dysplasia, and 75% (3 of 4) of the specimens with high-grade dysplasia. CONCLUSIONS: These data suggest that p16 promoter hypermethylation is a common mechanism of p16 gene inactivation during neoplastic progression in Barrett's esophagus.
Assuntos
Esôfago de Barrett/genética , Metilação de DNA , Genes p16/genética , Progressão da Doença , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/genéticaRESUMO
In a young female patient originally coming from Albany, immunoproliferative small intestinal disease (IPSID) could be diagnosed as a cause for severe maladsorption. Considering clinical and histological criteria an early disease stage of IPSID could be diagnosed. Under the continuous treatment of doxycycline for more than 3 1/2 years, all disease manifestations like watery diarrhea, vomiting, pain in the upper abdomen and loss of weight disappeared. After discontinuation of the antibiotic therapy the patient reached a sustained response.
Assuntos
Dor Abdominal/etiologia , Gastroenteropatias/diagnóstico , Doença Imunoproliferativa do Intestino Delgado/diagnóstico , Síndromes de Malabsorção/etiologia , Dor Abdominal/patologia , Adulto , Diagnóstico Diferencial , Doxiciclina/administração & dosagem , Endoscopia Gastrointestinal , Feminino , Mucosa Gástrica/patologia , Gastroenteropatias/tratamento farmacológico , Gastroenteropatias/patologia , Humanos , Doença Imunoproliferativa do Intestino Delgado/tratamento farmacológico , Doença Imunoproliferativa do Intestino Delgado/patologia , Mucosa Intestinal/patologia , Assistência de Longa Duração , Síndromes de Malabsorção/diagnóstico , Síndromes de Malabsorção/patologia , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: We evaluate the usefulness of screening for p53 and Ki-ras mutations in comparison with histological and flow cytometric findings. METHODS: We analyzed 1486 biopsy samples from 769 locations of 83 patients with long-standing ulcerative colitis enrolled in a surveillance program by means of histology, flow cytometry and SSCP analysis. As a control we used 66 biopsy samples of 16 patients with irritable bowel disease. RESULTS: With respect to all biopsy samples analyzed, DNA aneuploidy was found in 32.5% (27/83) of patients, dysplasia in 22.9% (15/83), p53 in 21.7% (18/83) and Ki-ras mutations in 18.1% (15/83) of patients. None of these markers was found in our control group. In 7 out of 10 patients who displayed dysplastic findings during endoscopic surveillance p53 and / or Ki-ras mutations were present in at least one colonoscopy. Statistically significant associations were observed between dysplasia and DNA aneuploidy (P < 0.001), between dysplasia and p53 mutations (P = 0.05) and between dysplasia and p53 and/or Ki-ras mutations (P = 0.002). No significant associations were found between dysplasia and Ki-ras mutations alone. The results for the SSCP analysis showed a much broader variation than those for the flow cytometric analysis. CONCLUSIONS: These results show that screening for p53 and Ki-ras mutations can be a useful adjunct in surveillance of patients with long-standing ulcerative colitis.
Assuntos
Colite Ulcerativa/genética , DNA/genética , Genes p53/genética , Genes ras/genética , Mutação , Aneuploidia , Colite Ulcerativa/patologia , Colo/patologia , Análise Mutacional de DNA , Citometria de Fluxo , Humanos , Polimorfismo Conformacional de Fita SimplesRESUMO
Neoplastic progression in patients with chronic ulcerative colitis is characterized by the development of epithelial dysplasia, which is accompanied by genetic alterations. This study determined the time of onset of p53 and Ki-ras mutations as well as DNA aneuploidy during histological progression towards carcinoma. In all, 278 samples of 7 colectomy specimens were analyzed by flow cytometry, histology and single-strand conformation polymorphism analysis. Of the samples, 22% (61/278) were dysplastic and 43% (122/278) aneuploid, while 25% (71/278) showed p53 and 4% (11/278) Ki-ras mutations. The correlation between aneuploid status and p53 mutations varied among the patients. A strong correlation was noticed between histological progression from low-grade dysplasia to carcinoma and p53 mutations as well as DNA aneuploidy. Ki-ras mutations were found in 40% (2/5) of the carcinomatous samples. The correlation between p53 mutations and the histological status of the samples suggest the involvement of this genetic event in the development of colon cancer in patients with ulcerative colitis. In contrast to Ki-ras mutations, the appearance of p53 mutations is an early event. Therefore p53 analysis might be helpful in the classification of indefinite dysplasia and in the identification of patients at risk for cancer development. Further studies are necessary to detect the additional genetic alterations preceding the development of DNA aneuploidy.
Assuntos
Aneuploidia , Colite Ulcerativa/complicações , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Genes p53 , Genes ras , Transformação Celular Neoplásica , Colectomia , DNA de Neoplasias/análise , Progressão da Doença , Humanos , Mutação , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologiaRESUMO
We studied the activity of combined oxaliplatin and fluorouracil-leucovorin in 16 consecutive patients with advanced biliary tract adenocarcinomas. The disease control rate (responses and stable disease) was 56% (95% confidence interval, 29-84%) and the median overall survival time was 9.5 months (range 0.9-26.8+). Therefore, this regimen might be active in biliary adenocarcinomas with further evaluation necessary.