Sediment toxicity tests using two species of marine amphipods: Gammarus aequicauda and Corophium insidiosum.
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Amphipoda↗
Biomedical subjects
A Di Leo
Publications and source records attributed to A Di Leo.
Peritoneal cytology does not increase the prognostic information provided by TNM in gastric cancer.
BACKGROUND: This study aimed at verifying whether peritoneal cytology could improve the prognostic information provided by TNM staging in gastric cancer patients. METHOD: The presence of free peritoneal tumor cells was investigated in 168 patients who underwent curative resection for gastric cancer from January 1992 to July 2002 in Verona, Italy. The influence of peritoneal cytology on survival was evaluated by a Cox regression model, controlling for potential confounders. RESULTS: Twenty-three patients (14%) had positive peritoneal cytology. Patients with positive lavage were more likely to present serosal infiltration (100 vs. 46%) and nodal metastases (91 vs. 67%; P < 0.001). Positive lavage was associated with a very poor prognosis: 3-year survival was only 9% (95% CI 2-27%) when peritoneal cancer cells had been detected, whereas survival reached 50% (95% CI 42-59%) in patients with a negative cytology. In multivariate survival analysis, peritoneal cytology was an independent predictor of mortality when controlling for sex, age, site, histology, and nodal metastases, but not when adjusting also for depth of tumor invasion (RR of positive versus negative = 1.2, 95% CI 0.7-2.0). Similarly, the influence of peritoneal cytology on survival was no longer significant when univariate analysis was restricted to T3/T4 patients (RR = 1.5, 0.9-2.5). CONCLUSIONS: Positive peritoneal cytology was a marker of poor prognosis in gastric cancer patients. Nevertheless, peritoneal lavage did not increase the prognostic information already provided by the TNM staging system in this Italian series.
Aged↗
Estrogen-induced proliferation in cultured hepatocytes involves cyclin D1, p21(Cip1) and p27(Kip1).
The purpose of this study was to establish if estrogen-induced hepatocyte proliferation in vitro involves the cell cycle regulators cyclin D1, p21(Cip1), and p27(Kip1). Male rat hepatocytes were cultured in presence of 17-beta-estradiol (E2) +/- ICI-182780, a pure estrogen antagonist, and [3H]-thymidine, as required. DNA synthesis as well as p21(Cip1), p27(Kip1), and cyclin D1mRNA and protein levels were evaluated at different times (12, 24, 36, and 48 hours) of incubation. E2-increased DNA synthesis was correlated with cyclin D1 and p21(Cip1) (mRNA and protein) variations that were reversed by the addition of ICI-182780. p27(Kip1) protein levels progressively increased regardless of the presence of E2 or ICI-182780. Our data confirm that estrogens' stimulatory effect is related to their ability to increase cyclin D1 levels. The increase of p21(Cip1) is probably related to the reentry of hepatocytes in the quiescent state. p27(Kip1) protein is not able to arrest hepatocyte proliferation.
Animals↗
Colonization of a water system by Legionella organisms and nosocomial legionellosis: a 5-year report from a large Italian hospital.
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Adult↗
Changes in coagulation-fibrinolysis balance in blood mononuclear cells and in gastric mucosa from patients with Helicobacter pylori infection.
INTRODUCTION: Helicobacter pylori and some of its virulence factors stimulate human blood mononuclear cells (MNC) in vitro to produce tissue factor (TF) and plasminogen activator inhibitor-2 (PAI-2). In this study we investigated the procoagulant-fibrinolytic potential of blood MNC in patients with H. pylori infection. In the same patients we also evaluated the coagulation-fibrinolysis profile in gastric tissue and in plasma. METHODS AND RESULTS: The production of TF and PAI-2 was evaluated in 61 patients with dyspepsia, 31 positive and 30 negative for H. pylori infection. TF expressed by MNC and PAI-2 accumulation in cell culture medium after incubation for 20 h at 37 degrees C were significantly higher in H. pylori(+) than in H. pylori(-) patients and were significantly correlated. TF and PAI-2 content in extracts of gastric mucosa was similar in the two groups whereas lower levels of tissue plasminogen activator (t-PA) and thrombomodulin (TM) antigens were found in the antrum of H. pylori(+) patients. No difference between the groups was observed in plasma thrombus precursor protein, prothrombin fragment 1+2, D-dimer, t-PA, PAI-1, TM and thrombin activatable fibrinolysis inhibitor. CONCLUSIONS: H. pylori infection is associated with functional abnormalities of blood MNC resulting in the coordinate expression of TF and antifibrinolytic activity. Changes in cell coagulation-fibrinolysis balance may represent a link between H. pylori infection and ischemic heart disease.
Adult↗
Sequential treatment for Helicobacter pylori does not share the risk factors of triple therapy failure.
BACKGROUND: Predicting factors for the outcome of conventional Helicobacter pylori triple therapy have been identified. Of these, the presence of the CagA gene is a strong predictor of successful treatment. Our preliminary data show that this factor becomes irrelevant when sequential therapy is used. AIM: To identify predicting factors for the outcome of H. pylori eradication using two therapeutic schemes (triple and sequential) of equal duration (10 days). METHODS: Ninety-six patients with H. pylori infection were randomly assigned to receive one of the following therapeutic schemes: group A: rabeprazole (20 mg b.d.) plus amoxicillin (1 g b.d.) for 5 days, followed by rabeprazole (20 mg b.d.) plus tinidazole (500 mg b.d.) and clarithromycin (500 mg b.d.) for a further 5 days; group B: rabeprazole (20 mg b.d.) plus amoxicillin (1 g b.d.) and clarithromycin (500 mg b.d.) for 10 days. Age, sex, smoking, endoscopic and histological findings, and CagA and VacA status were considered as candidates for a model of multivariate analysis which used therapeutic outcome as the dependent variable. CagA and VacA status were assessed by polymerase chain reaction on DNA isolated from gastric antral specimens. RESULTS: The sequential scheme was significantly more effective than prolonged triple therapy (P < 0.05). Smoking (P < 0.001) and the absence of the CagA gene (P < 0.05) were significantly associated with the failure of triple therapy, but the effectiveness of sequential treatment was not predicted by these factors. CONCLUSION: Our data suggest that sequential therapy is not affected by bacterial and host factors which have, until now, predicted the outcome of conventional eradication treatments.
2-Pyridinylmethylsulfinylbenzimidazoles↗
Exquisite antitumour response to trastuzumab in a patient with no evidence of Ras-Raf-MAPK and PI3K-Akt pathways activation.
We report on the case of a patient with a diagnosis of a HER2-overexpressing metastatic breast cancer which was refractory to a combination of a Raf kinase inhibitor and docetaxel, but highly sensitive to trastuzumab, a HER2-targeted monoclonal antibody. Interestingly, there was no evidence of Ras-Raf-MAPK or PI3K-Akt pathways activation.
Antibodies, Monoclonal↗
Rates of topoisomerase II-alpha and HER-2 gene amplification and expression in epithelial ovarian carcinoma.
OBJECTIVES: Topoisomerase II-alpha (T2a) is being actively investigated as a potential predictive marker of response to anthracyclines in breast cancer (BC). Although the role of T2a inhibitors as upfront and salvage treatment for epithelial ovarian carcinoma (EOC) remains unclear, we speculated that a small subgroup of ovarian cancer patients could derive a selective benefit from these agents. In this study, we investigated the actual rates of T2a and HER-2 amplification and overexpression by fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC), respectively. METHODS: Seventy-three samples of chemotherapy-naive patients with EOC were selected from our archives. FIGO stage and histology were available for most patients. RESULTS: Based on arbitrary cut-offs of > or =1.5 and > or =2 (ratio copies/centromere17), amplification rates for HER-2 were 15/64 (23.4%) and 8/64 (12.5%) versus 16/64 (25%) and 5/64 (7.8%) for T2a. We found only 3/72 (4.2%) cases of HER-2 overexpression (3+) versus 15/70 (21.4%) for T2a (staining of >10% of the cells). There was a modest correlation between T2a amplification and overexpression (P=0.01) and a strong correlation between T2a and HER-2 amplification when these markers were analysed as continuous variables (P<0.001). T2a amplification significantly correlated with advanced FIGO stage (P=0.02). CONCLUSION: The assessment of HER-2 and T2a amplification and overexpression by FISH and IHC, respectively, is feasible in EOC. These tests can be used for large-scale evaluation of the potential predictive and prognostic value of these markers in the future. Further studies with a special focus on T2a are needed to determine the best cut-offs for potential clinical use in the future.
Antigens, Neoplasm↗
HER-2/neu as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel.
PURPOSE: To evaluate the predictive value of HER-2 in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin (A) or with single-agent docetaxel (T). EXPERIMENTAL DESIGN: Patients from this study participated in a phase III clinical trial in which doxorubicin or docetaxel was administered for advanced disease. HER-2 was evaluated by IHC. In all positive cases, FISH was used to confirm the HER-2 positive status. The different cohorts of patients identified by HER-2 were examined to assess a possible relationship between HER-2 status and treatment effect. RESULTS: Tumor samples were available for 176 of the 326 patients entered in the clinical trial (54%). HER-2 positivity was observed in 20% of the study population. A statistically significant interaction was found between response rates to the study drugs and HER-2 status, with HER-2 positive patients deriving the highest benefit from the use of T (odds ratio for HER-2 positive patients treated with T = 3.12 (95% CI 1.11-8.80), p = 0.03). The interaction between HER-2 and response rates to A and T was also confirmed by a multivariate analysis. No statistically significant interaction was found between HER-2 and drugs efficacy evaluated in terms of time to progression and overall survival, although in the HER-2 negative cohort A was at least as effective as T in term of overall survival. CONCLUSIONS: These results suggest that in HER-2 positive breast cancer patients docetaxel might be more active than doxorubicin, while in HER-2 negative patients doxorubicin might be at least as effective as docetaxel. Although the present results cannot have an impact on current practice, they allow us to formulate the hypothesis that HER-2 positive breast cancer is a heterogeneous disease with regard to sensitivity to anthracyclines and taxanes, and that this might be dependent upon other molecular markers including the p-53 and topoisomerase II alpha genes. This hypothesis is currently being tested prospectively in two different 'bench to bed-side' clinical trials.
Adolescent↗
Polyamine biosynthesis in relation to K-ras and p-53 mutations in colorectal carcinoma.
BACKGROUND: Polyamines are important polycations found in high concentrations in gastrointestinal neoplasms, and ornithine decarboxylase is the key enzyme in their biosynthesis. Also genes with oncogenic potential (e.g. K-ras and p53) contribute to neoplastic transformation by modifying normal cellular proliferation and differentiation. Our aim was to evaluate the ornithine decarboxylase activity and polyamine levels in samples of colorectal carcinoma and uninvolved surrounding mucosa from 86 patients (52 men and 34 women) showing different patterns of K-ras/p53 mutations. METHODS: Polyamines were evaluated by high performance liquid chromatography. Ornithine decarboxylase activity was determined using the radiometric method. K-ras and p53 mutations were investigated by PCR followed by restriction fragment length polymorphism (PCR-RFLP) and single strand conformational polymorphism (PCR-SSCP), respectively. Multiple linear regression analysis was used to analyse relationships among polyamine biosynthesis, clinical-pathological variables and K-ras/p53 mutations. RESULTS: ODC activity and polyamine levels were significantly higher in neoplastic samples than in normal surrounding mucosa. K-ras codon 12 mutation was found in 25/86 patients (29.1%) and p53 gene mutation in 41/86 (47.7%). Polyamine biosynthesis was significantly higher in cancers showing K-ras mutation, either with or without p53 mutation [K-ras(+)/p53(-) and K-ras(+)/p53(+)], compared to samples with K-ras wild type [K-ras(-)/p53(-) and K-ras(-)/p53(+)]. Multiple linear regression analysis confirmed this finding. CONCLUSIONS: The present study provides evidence of a close relationship between K-ras mutation and polyamine biosynthesis in human colorectal carcinoma in a way that is largely p53 independent. In addition, our data support the hypothesis of different pathways in colorectal tumorigenesis reflecting different combinations of biochemical parameters and genetic alterations.
Adenocarcinoma↗
Lupus nephritis improvement after anti-tumor necrosis factor alpha monoclonal antibody (infliximab) treatment for Crohn's disease: a case report.
Association between Crohn's disease (CD) and lupus nephritis is very rare and, to the best of our knowledge, it has been described only once. We report here a clinical case of CD occurred in a young woman 8 years after a diagnosis of lupus nephritis according to clinical, laboratory and histological criteria. CD was unresponsive to steroids and immunosuppressants and, therefore, the patient was treated with anti-tumour necrosis factor alpha monoclonal antibody (Infliximab). This therapy led to the remission of both CD (50% of Crohn's Disease Activity Index--CDAI--decrease) and lupus nephritis (disappearance of pyuria in absence of infection, significant increase of serum albumin and improvement of renal function tests). The immunological background of both diseases has to be taken into account to explain either the association of the two disorders or the therapeutic response. Moreover, this clinical case confirms and extends the concept that in patients with CD a more accurate detection of autoimmune associated disorders is required.
Adult↗
Is overall survival a realistic primary end point in advanced colorectal cancer studies? A critical assessment based on four clinical trials comparing fluorouracil plus leucovorin with the same treatment combined either with oxaliplatin or with CPT-11.
BACKGROUND: The adequacy of overall survival (OS) as study end point in phase III trials for advanced solid tumors is questionable. The present review highlights the limits of OS as study end point to evaluate the efficacy of new drugs. METHODS: Four phase III clinical trials comparing a fluorouracil-based regimen with the same regimen plus either CPT-11 or oxaliplatin in advanced colorectal cancer patients were reviewed. The primary aim of the critical assessment was to explain the lack of OS advantage observed in two of the four trials, despite the presence of increased response rate (RR) and time to progression (TTP). Four possible reasons for the lack of OS benefit (i.e. statistical power, cross-over, magnitude of the effect on RR and TTP, non-tumor-related deaths) were systematically reviewed in the trials, and the detectable 1-year OS difference, assuming a statistical power of 80%, was calculated for each. RESULTS: None of these reasons for the lack of OS advantage in presence of RR and TTP benefits convincingly explained the results of the evaluated trials. Three of the four trials had roughly the same statistical power to detect 1-year OS differences, while the fourth trial was underpowered to detect realistic OS differences. The lack of OS advantage observed in the two oxaliplatin trials is therefore likely fortuitous, and due to lack of statistical power. CONCLUSIONS: Although increase in OS remains the ultimate goal of many clinical trials, the choice of OS benefit as a mandatory requirement to register new compounds can lead to a serious underestimation of a drug's real efficacy.
Antimetabolites, Antineoplastic↗
Controversies in the adjuvant treatment of breast cancer: the role of taxanes.
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Antineoplastic Agents, Phytogenic↗
Correlation between topoisomerase-IIalpha gene amplification and protein expression in HER-2 amplified breast cancer.
Topoisomerase-IIalpha (topo-II) is a molecular target for topo-II inhibitors, which makes it a potential predictive marker of responsiveness to these agents. We aim to correlate topo-II gene and protein status on 103 HER-2 amplified breast cancer samples. Paraffin-embedded blocks were screened by FISH for topo-II gene amplification (topo-II: CEP17 ratio >/=1.5; triple probe by Vysis inc.) and analyzed by IHC for topo-II protein expression (continuous variable; clone KiS1) and Ki-67 (positive if >25% of stained cells; clone MIB-1). Topo-II gene amplification was observed in 36.9% (38/103) of the HER-2 amplified study population. HER-2 amplification level (e.g. copy number) was not shown to be predictive for topo-II amplification. The median percentage of topo-II positively stained cells by IHC for topo-II non-amplified and amplified cases were 5% and 10%, respectively. A weak but significant correlation was observed between topo-II gene amplification level and percentage of positively stained cells (Spearman's ranks correlation coefficient of 0.23, p=0.02), the observed correlation being higher in patients with positive staining for Ki-67. Contrary to HER-2, where gene amplification is almost always correlated with protein overexpression in breast cancer, topo-II gene amplification apparently does not always lead to protein overexpression, at least when the latter is evaluated by IHC. Other factors, specifically the tumor proliferation status, may interfere with the topo-II protein status. Although the great majority of topo-II gene aberrations occur in HER-2 positive tumors, the level of HER-2 amplification does not predict for topo-II amplification.
Antigens, Neoplasm↗
Correlation between complete response to anthracycline-based chemotherapy and topoisomerase II-alpha gene amplification and protein overexpression in locally advanced/metastatic breast cancer.
UNLABELLED: Anthracycline-based regimens are among the most active but also with greater risk of both acute and long-term side effects, namely cardiotoxicity. Predictive markers of response to anthracyclines are therefore essential. Topoisomerase-IIalpha (topo-II) is the target of anthracyclines and preliminary data suggest its promising role as a predictive marker of sensitivity to these drugs. After screening a population of about 350 patients with locally advanced or metastatic breast cancer, two subgroups were selected for the present analysis: a study group (31 patients), composed of 14 complete responders (CR-a) and 17 true non-responders (PD-a) to anthracycline-based CT, and a control group (28 patients), composed of 7 CR (CR-t) and 21 true non-responders (PD-t) to taxane-based CT. True non-responders were defined as progressive disease (PD) within the first three cycles of CT. Archival tumor samples of these patients were collected, biological markers evaluated and their status correlated with response to therapy. HER-2 and topo-II gene status were evaluated by FISH (Vysis multi-color probe-positivity cut-off: >/=2 ratio for HER-2 and >/=1.5 for topo-II), topo-II protein was evaluated by IHC (positivity cut-off >10%). All cases in which HER-2 gene was non-amplified did not show topo-II gene aberrations. No association was found between HER-2 gene amplification and response to anthracyclines (5/14 (36%) CR and 5/17 (29%) PD to anthracycline-based CT were HER-2+). The topo-II gene was amplified in 3/14 (21%) CR but only in 1/17 (6%) PD to anthracyclines. Amplification of the topo-II gene was seen in 1/7 (14%) CR and in 3/21 (14%) PD to a taxane-based CT. Topo-II protein was overexpressed in 6/11 (55%) CR and in 2/17 (12%) PD to anthracyclines, while in the control group, overexpression was seen in 5/7 (71%) CR and 8/20 (40%) PD. IN CONCLUSION: i) HER-2 gene amplification did not seem to be correlated with response to anthracyclines. ii) Both topo-II gene amplification and protein overexpression seem to correlate with response to anthracyclines, although other factors, such as p53 and cell proliferation, are most likely to be involved. iii) The role of combined evaluation of several relevant markers and of potential 'molecular signatures' are currently being evaluated in prospective randomized clinical trials.
Adult↗
Prospective study of peritoneal recurrence after curative surgery for gastric cancer.
BACKGROUND: Peritoneal carcinomatosis is a common cause of failure after surgery for gastric cancer. The present longitudinal study was designed to evaluate the incidence and potential predictors of peritoneal recurrence after curative resection for gastric cancer. METHODS: Four hundred and forty-one patients who underwent potentially curative resections for gastric cancer in three surgical centres between 1988 and 1996 were evaluated. All patients were followed using a standard protocol following discharge from hospital. The correlation between tumour recurrence and clinicopathological variables was studied by univariate and multivariate analyses. RESULTS: Gastric cancer recurred in 215 (49 per cent) of 441 patients. Peritoneal recurrence was observed in 77 patients (17 per cent), locoregional recurrence in 96 patients and haematogenous recurrence in 75. Multivariate logistic regression analysis of factors associated with peritoneal recurrence identified diffuse-mixed histological type (relative risk (RR) 4.31, P < 0.001), infiltration of the serosa (RR 3.36, P = 0.001), lymph node involvement (RR 2.67, P = 0.023) and tumour size (RR 1.11, P = 0.050) as significant independent variables. In the diffuse-mixed histological subtype, the 5-year cumulative risk of peritoneal recurrence was 12 per cent in the absence of serosal invasion, and 69 per cent in patients with infiltration of the serosa; in the intestinal subtype, the cumulative risk in patients with serosa-negative and -positive tumours was 4 and 21 per cent respectively. CONCLUSION: Radical surgery offers a low probability of cure in patients with diffuse-mixed type of gastric cancer and involvement of the serosa, due to a high risk of peritoneal recurrence. These patients might benefit from adjuvant therapies to prevent peritoneal carcinomatosis.
Adult↗
Helicobacter pylori is associated with modified lipid profile: impact on Lipoprotein(a).
OBJECTIVES: Helicobacter pylori is a controversial risk factor for atherosclerosis. We investigated whether the bacterium persistent inflammation or the expression of the cytotoxin-associated gene A (CagA) may affect serum lipids as well as Lipoprotein(a). DESIGN AND METHODS: Two hundred-eleven healthy volunteers were evaluated for lipids and Lipoprotein(a). Helicobacter pylori was characterized by Urea Breath Test and IgG-anti-CagA. apo(a) Kringle-IV polymorphism was genotyped. RESULTS: Prevalence of the infection was 72%; 43% of subjects expressed CagA reactivity. Infected subjects showed increased levels of cholesterol, LDL-cholesterol, and cholesterol/HDL-cholesterol atherogenic index. Association with the Helicobacter pylori CagA(-) strains persisted after the adjustment for covariates. Significant difference between infected and uninfected subjects was found in Lipoprotein(a) levels. This difference did not arise from the Kringle-IV genotype. CONCLUSIONS: The infection per se significantly modified serum lipid and Lipoprotein(a) concentrations. CagA does not seem to be a reliable marker of pathogenicity for the atherogenic complications of H. pylori infection.
Adult↗
Comparison of topoisomerase-IIalpha gene status between primary breast cancer and corresponding distant metastatic sites.
BACKGROUND: Topoisomerase-IIalpha (topo-IIalpha) is a key enzyme in DNA replication and a molecular target for anticancer drugs called topoisomerase-II inhibitors, such as anthracyclines. Its value as a predictive marker of responsiveness to these cytotoxic drugs is currently being evaluated with promising results. However, even in the metastatic setting, the choice of treatment is based on the biologic characteristics of the primary tumor. Few data are available regarding the expression of biological markers between the primary tumor and the corresponding distant metastases. METHODS: Topo-IIalpha gene status was evaluated in 29 breast cancer patients in which a primary tumor sample and a corresponding metastatic sample were both available. Fluorescent in situ hybridization (FISH) with the Vysis triple probe (Vysis multi-color topo-IIalpha spectrum orange, Her-2 spectrum green and CEP17 spectrum aqua probe) was used, which allowed the concomitant evaluation of HER-2 gene status. RESULTS: As previously reported, topo-IIalpha gene aberrations are always associated with HER-2 gene amplification; indeed no topo-IIalpha gene aberrations have been observed in the HER-2 negative tumors. Conversely, 38.5% (five patients) of the HER-2 positive primary breast tumors (13 patients) were topo-IIalpha amplified, while 61.5% (eight patients) had a normal topo-IIalpha gene. No topo-IIalpha gene deletion was found in our series. Topo-IIalpha gene amplification in the primary tumor was always associated with amplification in the corresponding metastases, and no metastases with topo-IIalpha gene amplification were seen without amplification in the primary tumor. Furthermore, the amplification level of topo-IIalpha (i.e., ratio topo-IIalpha:CEP17) remained unchanged in primary and metastatic sites. CONCLUSION: Despite the low number of patients, our results seem to indicate that topo-IIalpha gene status evaluation in the primary breast tumor accurately reflects its status in the corresponding distant metastases.
Adult↗