Browsing by Author "Donato, MM"
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- Aberrant crypt foci: endoscopic assessment and cell kinetics characterizationPublication . Figueiredo, P; Donato, MM; Urbano, M; Goulão, H; Gouveia, H; Sofia, C; Leitão, M; Freitas, DBACKGROUND AND AIMS: Aberrant crypt foci (ACF) are preneoplastic lesions in animal models of colorectal cancer. The aim of the study is to investigate if ACF are involved in human colorectal carcinogenic process and if they can be helpful in predicting the presence of a colorectal neoplasia. METHODS: The study included, between 2003 and 2005, 182 patients, 62 with adenoma, 55 with colorectal carcinoma, 53 without colorectal lesions, and 12 with nonneoplastic mucosal polyps. The number of rectal ACF was determined by colonoscopy. Proliferation and apoptosis indexes were evaluated by immunohistochemistry in rectal ACF, in normal rectal mucosa, and in carcinomatous tissue. RESULTS: The mean number of rectal ACF in patients with rectal neoplasia was 12.64, significantly higher than in patients with neoplastic lesions elsewhere in the colon (p=0.01). The apoptosis index in ACF of patients with colorectal carcinoma or adenoma aged 50 years or older was significantly lower than in younger patients (1.3% vs 2.7%, p=0.01) and, in patients with carcinoma, lower than in normal mucosa (1.1% vs 2.1%, p=0.002). The proliferation index was significantly higher in ACF of patients with colorectal neoplasia aged less than 50 years than in normal mucosa (10.9% vs 7.7%, p=0.02). The apoptosis index in ACF foci of patients with carcinoma (1.1%) was significantly lower than in patients without lesions (2.2%) and than in normal mucosa (2%). The mean number of ACF is significantly higher in patients with polyps larger than 1 cm (11.28 vs 6.27, p=0.02). CONCLUSION: Aberrant crypt foci probably precede the appearance of neoplasia and may be helpful in predicting the presence of a colorectal neoplastic lesion.
- Beyond Maastricht IV: are standard empiric triple therapies for Helicobacter pylori still useful in a South-European country?Publication . Almeida, N; Donato, MM; Romãozinho, JM; Luxo, C; Cardoso, O; Cipriano, MA; Marinho, C; Fernandes, A; Calhau, C; Sofia, CBACKGROUND: Empiric triple treatments for Helicobacter pylori (H. pylori) are increasingly unsuccessful. We evaluated factors associated with failure of these treatments in the central region of Portugal. METHODS: This single-center, prospective study included 154 patients with positive (13)C-urea breath test (UBT). Patients with no previous H. pylori treatments (Group A, n = 103) received pantoprazole 40 mg 2×/day, amoxicillin 1000 mg 12/12 h and clarithromycin (CLARI) 500 mg 12/12 h, for 14 days. Patients with previous failed treatments (Group B, n = 51) and no history of levofloxacin (LVX) consumption were prescribed pantoprazole 40 mg 2×/day, amoxicillin 1000 mg 12/12 h and LVX 250 mg 12/12 h, for 10 days. H. pylori eradication was assessed by UBT 6-10 weeks after treatment. Compliance and adverse events were assessed by verbal and written questionnaires. Risk factors for eradication failure were determined by multivariate analysis. RESULTS: Intention-to-treat and per-protocol eradication rates were Group A: 68.9% (95% CI: 59.4-77.1%) and 68.8% (95% CI: 58.9-77.2%); Group B: 52.9% (95% CI: 39.5-66%) and 55.1% (95% CI: 41.3-68.2%), with 43.7% of Group A and 31.4% of Group B reporting adverse events. Main risk factors for failure were H. pylori resistance to CLARI and LVX in Groups A and B, respectively. Another independent risk factor in Group A was history of frequent infections (OR = 4.24; 95% CI 1.04-17.24). For patients with no H. pylori resistance to CLARI, a history of frequent infections (OR = 4.76; 95% CI 1.24-18.27) and active tobacco consumption (OR = 5.25; 95% CI 1.22-22.69) were also associated with eradication failure. CONCLUSIONS: Empiric first and second-line triple treatments have unacceptable eradication rates in the central region of Portugal and cannot be used, according to Maastricht recommendations. Even for cases with no H. pylori resistance to the used antibiotics, results were unacceptable and, at least for CLARI, are influenced by history of frequent infections and tobacco consumption.
- CARD15 mutations and colorectal cancer in a South European countryPublication . Freire, P; Portela, F; Donato, MM; Figueiredo, M; Amaro, P; Sá, A; Andrade, P; Gouveia, H; Sofia, CPURPOSE: CARD15 mutations are associated with higher susceptibility to Crohn's disease (CD) and longstanding colonic CD increases the risk of developing colorectal cancer (CRC). The relation between these mutations and sporadic CRC remains controversial. The aim of this study was to assess whether germline and/or somatic CARD15 mutations are risk factors for sporadic CRC in Portugal and whether there are genotype-phenotype correlations in these patients. METHODS: The three main CARD15 mutations (R702W, G908R and 3020insC) were researched in 112 sporadic CRC patients and 152 healthy subjects. RESULTS: Overall, CARD15 mutations were found in 18 patients (16.1%) and in 15 controls (9.9%; p = 0.132). Individually, the incidence of R702W was significantly higher in patients than in controls (12.5% vs. 5.3%, p = 0.035), whereas the genotype frequencies for G908R (2.7% vs. 3.3%) and 3020insC (0.9% vs. 1.3%) were not statistically different between the two groups. Entire genotypic agreement was found in patients genotyped for blood and neoplastic DNA. A significantly higher incidence of CARD15 mutations was detected in patients with CRC diagnosed under 60 years old (28.6% vs. 10.4%, p = 0.015) and in female patients (24.4% vs. 10.4%, p = 0.048). No associations were found between CARD15 mutations and family history, symptoms or CRC pathologic characteristics. CONCLUSIONS: The CARD15 R702W variant might be a predisposing factor to sporadic CRC in Portugal, particularly in patients under 60-years old and in female patients. This susceptibility appears to be linked with germline CARD15 mutations. Nevertheless, we have found no evidence that CARD15 mutations predict the pathologic characteristics of CRC.
- CARD15 Mutations and Colorectal Cancer in a South European CountryPublication . Freire, P; Portela, F; Donato, MM; Figueiredo, P; Duque, G; Ferreira, M; Amaro, P; Sá, A; Andrade, P; Gouveia, H; Sofia, C
- CARD15 Mutations and Perianal Fistulating Crohn’s Disease: Correlation and Predictive Value of Antibiotic ResponsePublication . Freire, P; Portela, F; Donato, MM; Ferreira, M; Andrade, P; Sofia, CBACKGROUND: CARD15 mutations alter bowel immunity and increase susceptibility to Crohn's disease (CD). However, the relation between these mutations and Crohn's perianal fistulas has not been fully clarified. AIMS: To assess whether CARD15 mutations are associated with risk of developing Crohn's perianal fistulas and whether these mutations are predictors of the response of perianal fistulas to antibiotics. METHODS: CARD15 mutations were investigated in 203 consecutive CD patients. Presence/absence of history of perianal fistula was recorded. Patients with history of perianal fistula were divided into two groups (with/without CARD15 mutations), and response to antibiotics was evaluated in both groups. RESULTS: Of the 203 patients, 60 (29.6%) showed at least one CARD15 mutation and 55 (27.1%) had history of perianal fistula. History of perianal fistula was identified in 13 (21.7%) patients with mutations and in 42 (29.4%) patients without mutations (P = 0.260). Mean age at diagnosis of first perianal fistula was similar in patients with/without CARD15 mutations (28.7 +/- 9.8 versus 29.7 +/- 10.1 years, P = 0.758). Average time between disease onset and diagnosis of first perianal fistula was also similar in the two groups (4.6 +/- 5.1 versus 5.0 +/- 5.9 years, P = 0.816). Response of perianal fistulas to antibiotics (metronidazole alone or combined with ciprofloxacin) was significantly higher in patients without CARD15 mutations (7.7% versus 40.5%, P = 0.041). CONCLUSIONS: In CD, CARD15 mutations are not associated with risk of developing perianal fistulas or with time of their outbreak. Nevertheless, patients with perianal fistulas and CARD15 mutations showed worse response to antibiotics.
- Correlation of Helicobacter pylori genotypes with gastric histopathology in the central region of a South-European countryPublication . Almeida, N; Donato, MM; Romãozinho, JM; Luxo, C; Cardoso, O; Cipriano, MA; Marinho, C; Fernandes, A; Sofia, CBACKGROUND: Outcome of Helicobacter pylori (H. pylori) infection results from interaction of multiple variables including host, environmental and bacterial-associated virulence factors. AIM: This study aimed to investigate the correlation of cagA, cagE, vacA, iceA and babA2 genotypes with gastric histopathology and disease phenotype in the central region of a South-European country. METHODS: This prospective study involved 148 infected patients (110 female; mean age 43.5 ± 13.4 years) submitted to endoscopy with corpus and antrum biopsies. H. pylori was cultured and DNA extracted from the isolates. Genotypes were determined by PCR. Histopathological features were graded according to the updated Sydney system and OLGA/OLGIM classification. Only patients with single H. pylori genotypes and complete histopathological results were included. RESULTS: Antrum samples presented higher degrees of atrophy, intestinal metaplasia, chronic inflammation and neutrophil activity. Genotype distribution was as follows: cagA-31.8 %; cagE-45.9 %; vacA s1a-24.3 %; vacA s1b-19.6 %; vacA s1c-0.7 %; vacA s2-55.4 %; vacA m1-20.9 %; vacA m2-79.1 %; vacA s1m1-18.9 %; vacA s1m2-25.7 %; vacA s2m1-2 %; vacA s2m2-53.4 %; iceA1-33.8 %; iceA2-66.2 %; babA2-12.2 %. CagA genotype was significantly associated with higher degrees of intestinal metaplasia, neutrophil activity, chronic inflammation and OLGIM stages. BabA2 was linked with higher H. pylori density. Strains with vacA s1m1 or vacA s1m1 + cagA positive genotypes had a significant association with peptic ulcer and vacA s2m2 with iron-deficient anemia. CONCLUSIONS: cagA, vacA s1m1 and babA2 genotypes are relatively rare in the central region of Portugal. cagA-positive strains are correlated with more severe histopathological modifications. This gene is commonly associated with vacA s1m1, and such isolates are frequently found in patients with peptic ulcer.
- A coupled convection-diffusion level set model for tracking epithelial cells in colonic cryptsPublication . Figueiredo, IN; Leal, C; Leonori, T; Romanazzi, G; Figueiredo, P; Donato, MMColorectal cancer is initiated in colonic crypts as a consequence of alterations leading to the disruption of the normal colonic cellular process. We propose a model, which couples a convection-diffusion type equation with a level set equation, for tracking the time evolution of an epithelial cell set, inside a colonic crypt, until it reaches the top of the crypt. The convection-diffusion equation describes the evolution of the density of the cells in the epithelial cell set. The parameters of this equation regulate the geometric and temporal cellular mechanism, and different parameter choices lead to distinct cell behavior. The level set equation tracks the location and shape of the epithelial cell set, inside the crypt, as well as its interface, separating the cell set from the others cells, which reside within the crypt. The interfacial velocity of the epithelial cell set is obtained from the convection-diffusion type equation. Some in silico experiments are described. They are performed in a relative small time, with respect to the real biological evolution.
- NOD2 gene mutations in ulcerative colitis: useless or misunderstood?Publication . Freire, P; Cardoso, R; Figueiredo, P; Donato, MM; Ferreira, M; Mendes, S; Ferreira, AM; Vasconcelos, H; Portela, F; Sofia, CPURPOSE: NOD2 mutations have been linked to an increased risk of Crohn's disease and to some of its phenotypes. The association between NOD2 mutations and susceptibility to ulcerative colitis (UC) remains somewhat controversial and potential correlations between these mutations and UC phenotype have not been studied. AIM: To assess whether NOD2 mutations are a risk factor for UC in Portugal and if there are any genotype-phenotype correlations in these patients. METHODS: The three main NOD2 mutations were searched in 200 patients with UC and in 202 healthy controls. RESULTS: NOD2 mutations were present in 28 patients with UC (14.0 %) and in 27 controls (13.4 %) (p = 0.853). Mutation carriers were more likely to receive steroids during the first year of disease than non-carriers (54.2 % vs. 29.6 %, p = 0.018) and among these patients the need for intravenous administration was more frequent in those with the R702W polymorphism (90.0 % vs. 45.5 %, p = 0.014). In patients with severe colitis admitted for intravenous steroids, a greater proportion of mutation carriers was considered intravenous-steroid refractory and required salvage therapy (90.0 % vs. 38.1 %, p = 0.004). Patients with NOD2 mutation were submitted to colectomy more frequently than non-carriers (17.9 % vs. 4.1 %. p = 0.015). No correlation with the need for immunosuppressants/immunomodulators was found. CONCLUSIONS: In the Portuguese population, NOD2 mutations do not increase the risk of UC but are associated with a more aggressive course including greater need of steroids in the first year, increased incidence of intravenous-steroid refractoriness and a higher colectomy rate.
- Triple Therapy with High-Dose Proton-Pump Inhibitor, Amoxicillin, and Doxycycline Is Useless for Helicobacter pylori Eradication: A Proof-of-Concept StudyPublication . Almeida, N; Romãozinho, JM; Donato, MM; Luxo, C; Cardoso, O; Cipriano, MA; Marinho, C; Sofia, CINTRODUCTION: Helicobacter pylori resistance to antibiotics is steadily increasing and multidrug-resistant strains are common and difficult to eliminate, mainly in countries where bismuth, tetracycline, furazolidone, and rifabutin are unavailable. AIM: To evaluate the efficacy and safety of a triple therapy with proton-pump inhibitor (PPI), amoxicillin, and doxycycline in patients with multidrug-resistant H. pylori. PATIENTS AND METHODS: This prospective study involved 16 patients (13 females; mean age - 50 ± 11.3 years) infected by H. pylori with known resistance to clarithromycin, metronidazole, and levofloxacin, but susceptibility to amoxicillin and tetracycline. All patients were previously submitted to upper endoscopy with gastric biopsies for H. pylori culture and susceptibility testing by Etest. Mutations in 23S rRNA and gyrA genes were determined by real-time PCR. A 10-day eradication regimen with PPI (double-standard dose b.i.d.), amoxicillin (1000 mg b.i.d.), and doxycycline (100 mg b.i.d.) was prescribed after pretreatment with PPI during 3 days. Eradication success was assessed by (13) C-urea breath test 6-10 weeks after treatment. Compliance and adverse events were determined through phone contact immediately after treatment and specific written questionnaires. RESULTS: Only one patient did not complete treatment due to adverse events. Another four patients experienced mild side effects not affecting compliance. The control (13) C-urea breath test was positive in all patients. Per-protocol and intention-to-treat eradication rates were 0%. CONCLUSIONS: Although safe, a triple-therapy protocol with high-dose PPI, amoxicillin, and doxycycline is useless for multidrug-resistant H. pylori eradication.