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Biomedical subjects

V Fontana

Publications and source records attributed to V Fontana.

At least 19 recordsLinked to original sources
PubMed2002

CD10 is a marker for cycling cells with propensity to apoptosis in childhood ALL.

CD10 constitutes a favourable prognostic marker for childhood acute lymphoblastic leukaemia. Since correlations between CD10, cell cycle and apoptotic abilities were demonstrated in various cell types, we investigated whether differences existed in the cycling/apoptotic abilities of CD10-positive and CD10-negative B acute lymphoblastic leukaemia cells. Twenty-eight cases of childhood acute lymphoblastic leukaemia (mean age of 6.8 years) were subdivided into two groups according to high (17 cases, 93.2+/-4.5%, MRFI 211+/-82 CD10-positive cells) or low (11 cases, 11.5+/-6.2%, MRFI 10+/-7 CD10-negative cells) expression of CD10. CD10-positive acute lymphoblastic leukaemia cells were cycling cells with elevated c-myc levels and propensity to apoptosis, whereas CD10-negative acute lymphoblastic leukaemia cells had lower cycling capacities and c-myc levels, and were resistant to apoptosis in vitro. A close correlation between all these properties was demonstrated by the observations that the few CD10-positive cells found in the CD10-negative acute lymphoblastic leukaemia group displayed elevated c-myc and cycling capacities and were apoptosis prone. Moreover, exposure of CD10-positive acute lymphoblastic leukaemia B cells to a peptide nucleic acid anti-gene specific for the second exon of c-myc caused inhibition of c-myc expression and reduced cell cycling and apoptotic abilities as well as decreased CD10 expression.

Antigens, CD↗
PubMed2001

Study of pretreatment serum levels of HER-2/neu oncoprotein as a prognostic and predictive factor in patients with advanced nonsmall cell lung carcinoma.

BACKGROUND: HER-2/neu tissue overexpression is found in nearly 15% of patients with nonsmall cell lung carcinoma and is reported to affect prognosis adversely in surgical series. However, the prognostic role of serum HER-2/neu oncoprotein, particularly in patients with advanced lung carcinoma, remains unknown. This study was designed to assess the potential value of measuring serum levels of HER-2/neu oncoprotein in predicting response to treatment and survival in patients with locally advanced and metastatic nonsmall cell lung carcinoma. METHODS: Baseline serum HER-2/neu levels (fm/mL) were studied using an enzyme-linked immunosorbent assay method in 84 patients with newly diagnosed, advanced nonsmall cell lung carcinoma who underwent chemotherapy. RESULTS: The patients enrolled in the study included 76 males and 8 females, with a median age of 62 years (range, 36-73 years) and a median performance status of 1. Fifty patients (59.5%) had nonsquamous histology, and 34 patients (40.5%) had squamous cell carcinoma. Thirty-four patients (40.5%) had Stage III disease, and 50 patients (59.5%) had Stage IV disease. The mean baseline value of HER-2/neu in the whole series was 56.1 fm/mL (range, 13.0-103.8 fm/mL). HER2 immunohistochemistry on paraffin embedded tissue was performed in 18 patients. HER-2/neu tissue overexpression was found in only one patient, who also showed high serum levels (102 fm/mL). No correlation was observed between protein serum quantitation and gender, age, histology, stage, performance status, leukocyte count, or smoking. Nonresponding and responding patients exhibited similar oncoprotein levels (median, 57.6 fm/mL vs. 51.9 fm/mL, respectively). The overall survival rate was 42.5% at 1 year and 12% at 2 years, with a median survival duration of 10 months. At univariate analysis, high HER-2/neu serum levels were associated with an unfavorable survival outcome. Using a cut-off point for HER-2/neu of 73.0 fm/mL (corresponding to the 80th percentile of protein concentration), the survival of patients who had higher serum levels of HER-2/neu was significantly worse compared with patients who had lower serum levels (median, 7.1 months vs. 10.9 months; P = 0.004). Multivariate analysis confirmed the independent predictive value of serum HER-2/neu concentration as a negative prognostic factor (P = 0.02). CONCLUSIONS: High pretreatment levels of HER-2/neu oncoprotein are associated with an adverse prognostic impact on survival in patients with locally advanced or metastatic nonsmall cell lung carcinoma.

Adult↗
PubMed2000

Mesothelioma and lung tumors attributable to asbestos among petroleum workers.

BACKGROUND: Asbestos exposure has been definitively found to be associated with both mesothelioma and lung cancer. Nevertheless, in the overall population of oil refinery workers potentially exposed to asbestos, many studies clearly show a definitely increased risk of mesothelioma, but no proven excess of lung cancer after comparison to the general population. Through the presentation of new data and the re-appraisal of two recent and independent epidemiological studies conducted in Liguria, Italy, and Ontario, Canada, we attempt to shed light on this apparently paradoxical finding. METHODS: Lung cancer mortality was studied among maintenance workers exposed to asbestos, and among two other subgroups of refinery employees: blue collar and white collar workers. The comparison with blue collar workers was performed in order to take into account the role of healthy worker effect, smoking habit, and the socioeconomic level. The comparison with white collar workers was performed to control for other occupational lung carcinogens. RESULTS AND CONCLUSIONS: Results reveal a consistency between the two studies and show that 96-100% of the mesotheliomas and 42-49% of the lung tumors arising among maintenance workers were attributable to asbestos exposure. Our new analysis, estimating two cases of asbestos-related lung cancer for each case of mesothelioma, confirms published findings on the magnitude of asbestos-related tumors in oil refineries.

Asbestos↗
PubMed2000

Simian virus-40 sequences are a negative prognostic cofactor in patients with malignant pleural mesothelioma.

Several biochemical and clinical factors have been shown to correlate with survival in human malignant pleural mesothelioma (MM). Nevertheless, average survival of 4 to 10 months from diagnosis is sometimes not sufficient for full expression of these factors. Several studies have reported SV40 sequences in MM, suggesting a possible pathogenic role. We investigated whether the presence of these sequences had any effect on MM patient survival. For this study, we used polymerase chain reaction and Southern blot analysis to search for and identify SV40 DNA in biopsy samples from 83 MM patients. These cases were divided according to histology: 62/83 (74. 7%) had epithelioid morphology (EMM) and 21/83 (25.3%) had either biphasic or sarcomatous morphology (B/SMM). SV40 positivity was significantly associated with B/SMM growth pattern (chi-squared test = 5.03, P = 0.025). Kaplan-Meier univariate analysis confirmed the independent effect of histology on MM survival (log-rank test = 13.9, P < 0.001) and showed a trend for increased survival in SV40-negative patients (log-rank test = 2.83, P = 0.09). Most importantly, Cox's regression model showed that SV40-positive status affected the predictive value of histology on patient survival. In particular, when SV40 expression was added to the B/SMM histotype, Cox's regression model showed a significant increase in hazard ratio (HR) with respect to SV40-negative B/SMM (HR = 4.25, 95% CI = 2.00-9. 00, likelihood ratio test = 14.31, P < 0.001). We conclude that SV40 expression is significantly associated with B/SMM histology and represents an important prognostic cofactor when associated with the tumor subtype in MM patients.

Adult↗
PubMed2000

Prognostic significance of presence and reduplication of basal lamina in malignant pleural mesothelioma.

The prognosis of patients with malignant pleural mesothelioma (MM) is dependent more on tumor extension and differentiation than on therapeutic effects. Reduplication of the basal lamina (RBL) is an ultrastructural feature of some benign and malignant tumors that has been inversely correlated with aggressiveness and was recently described in MM. To investigate whether RBL is important for predicting the survival of patients with MM, transmission electron microscopy was used to identify the presence of basal lamina or RBL in biopsy specimens obtained by thoracoscopy from 35 patients. Cox's regression analysis was used to study the relation of these ultrastructural features to survival. Better outcomes were found for patients whose tumors expressed either basal lamina (HR 0.48; 95% CI, 0.09-2.47) or RBL (HR 0.38; 95% CI 0.12-1.22) compared with the reference category, where basal lamina or RBL was not found. The expression of basal lamina and RBL is an important novel prognostic factors in MM. HUM PATHOL 31:1341-1345.

Aged↗
PubMed1999

Analysis of correlated data in human biomonitoring studies. The case of high sister chromatid exchange frequency cells.

Sister chromatid exchange (SCE) analysis in peripheral blood lymphocytes is a well established technique that aims to evaluate human exposure to toxic agents. The individual mean value of SCE per cell had been the only recommended index to measure the extent of this cytogenetic damage until the early 1980's, when the concept of high frequency cells (HFC) was introduced to increase the sensitivity of the assay. All statistical analyses proposed thus far to handle these data are based on measures which refer to the individual mean values and not to the single cell. Although this approach allows the use of simple statistical methods, part of the information provided by the distribution of SCE per single cell within the individual is lost. Using the appropriate methods developed for the analysis of correlated data, it is possible to exploit all the available information. In particular, the use of random-effects models seems to be very promising for the analysis of clustered binary data such as HFC. Logistic normal random-effects models, which allow modelling of the correlation among cells within individuals, have been applied to data from a large study population to highlight the advantages of using this methodology in human biomonitoring studies. The inclusion of random-effects terms in a regression model could explain a significant amount of variability, and accordingly change point and/or interval estimates of the corresponding coefficients. Examples of coefficients that change across different regression models and their interpretation are discussed in detail. One model that seems particularly appropriate is the random intercepts and random slopes model.

Adult↗
PubMed1999

Assessment of DNA flow cytometry as a surrogate end point biomarker in a bladder cancer chemoprevention trial.

Although conventional cytology represents the most widely performed cytometric analysis of bladder cancer cells, DNA flow cytometry has, over the past decade, been increasingly used to evaluate cell proliferation and DNA ploidy in cells from bladder washings. We have investigated whether DNA flow cytometry and conventional cytology of epithelial cells obtained from bladder washings provide reliable surrogate endpoint biomarkers in clinical chemoprevention trials. We used cytometric and clinical data from a chemoprevention trial of the synthetic retinoid Fenretinide on 99 patients with superficial bladder cancer. A total of 642 bladder washing specimens obtained from the patients at 4 month intervals was analyzed. Intra-individual agreement and correlation of flow cytometric DNA ploidy (diploid vs. aneuploid), DNA Index, Hyper-Diploid-Fraction (proportion of cells with DNA content higher than 2C), and conventional cytologic examination, as assessed by kappa statistics and Spearman's correlation test, were poor from baseline through 24 months. Moreover, no correlation was found between DNA ploidy and cytology at each time point. The same results were obtained when the analyses were stratified by treatment group. In addition, the association between the results of bladder washing (by either DNA flow cytometry or cytology) and concomitant tumor recurrence was significant only for abnormal cytology, while neither biomarker was predictive of tumor recurrence at the subsequent visit. During the time of this study only four patients progressed to muscle-invasive bladder cancer, indicating the "low-risk" features of the patient population. We conclude that DNA flow cytometry and conventional cytology on epithelial cells obtained from bladder washings do not appear to provide suitable surrogate endpoint biomarkers during the early stages of bladder carcinogenesis.

Antineoplastic Agents↗
PubMed1999

Effect of fenretinide on bone mineral density and metabolism in women with early breast cancer.

Prolonged administration of natural or synthetic retinoids has been associated with significant skeletal abnormalities, including osteoporosis. We studied the effects of the synthetic retinoid fenretinide (N-4-hydroxyphenylretinamide, or 4-HPR) administered for a mean of 40 months on bone mineral density and metabolism in 66 consecutive women with early breast cancer belonging to a secondary prevention trial. The mean (+/-SD) bone mineral density at the distal and ultradistal forearm were, respectively, 0.61+/-0.08 and 0.30+/-0.05 g/cm2 in 33 treated women and 0.62+/-0.07 and 0.29+/-0.07 g/cm2 in 33 control women (p = ns for both). Also, no significant difference was observed in markers of bone formation such as bone alkaline phosphatase and osteocalcin, nor in urinary bone resorption markers such as calcium, hydroxyproline, and type I bone collagen cross-linked N-telopeptide (NTx). However, a border-line higher excretion of urinary calcium and NTx was found in the 4-HPR group after adjustment for menopausal status. We conclude that prolonged administration of 4-HPR is not associated with significant alterations of bone mineral density of the forearm. However, a trend towards an increase in bone resorption markers suggests the need for further assessment at different skeletal sites.

Aged↗
PubMed1999

Similar embryotoxic effects of sera from infertile patients and exogenous interferon-gamma on long-term in-vitro development of mouse embryos.

Circulating embryotoxic factors could be responsible for reproductive failures observed in patients suffering from recurrent spontaneous abortions (RSA) and endometriosis. The mouse bioassay has been widely used to detect such factors, since sera from these patients inhibit early embryonic development. This bioassay consists in the in-vitro culture of two-cell mouse embryos in the presence of different sera up to the blastocyst stage (72 h of culture). In the present study experiments were performed over long culture times (3-7 days), from two-cell to spreading stages, to determine the in-vitro effect of sera obtained from RSA or endometriosis patients, as well as the effect of interferon (INF)-gamma on embryo development. An embryotoxicity cut-off value of 45% blastocyst formation was established using control sera. When development to the blastocyst stage was considered only 25% of RSA and 20% of endometriosis sera were embryotoxic. However, all RSA sera significantly inhibited hatching (P < 0.05) and spreading stages (P < 0.01). IFN-gamma (10 micrograms/ml) (P < 0.001) did not impair early embryo development, but significantly inhibited blastocyst spreading. These observations suggest that culture to advanced embryonic stages increases the sensitivity of the bioassay and that IFN-gamma alters in-vitro peri-implantation mouse embryo development.

Abortion, Spontaneous↗
PubMed1998

Effect of fenretinide on plasma IGF-I and IGFBP-3 in early breast cancer patients.

Growing evidence substantiates the role of the insulin-like growth factor I (IGF-1) system in breast tumorigenesis. Retinoids have been shown to affect the IGF system several experimental models. We extended our previous data on plasma IGF-1 modulation by the synthetic retinoid fenretinide (4-HPR) and investigated the effect of the retinoid on plasma IGF binding protein (BP)-3, the major protein binding IGFs. IGF-1 and IGFBP-3 were measured on plasma samples obtained at randomization and after an interval of approximately 1 year, from 39 and 33 stage 1 breast cancer patients assigned to receive 4-HPR, and from 39 and 34 untreated controls, respectively. There was a significant decrease in plasma IGF-1 after 4-HPR administration, whereas no significant change was observed in controls. The effect of 4-HPR on IGF-1 levels was modified by menopausal status, inasmuch as the decrease in IGF-1 was particularly pronounced in pre-menopausal women, whereas the reverse was observed in untreated controls. By contrast, treatment induced an increase of IGFBP-3 with respect to controls. As a result of this dual effect, the bioavailability of IGF-1 for interaction with receptors at target levels further decreased in pre-menopausal 4-HPR treated patients compared with controls, suggesting that retinoid administration may result in lower concentrations of biologically active IGF-1. Our findings may have important implications for the clinical preventive activity of this retinoid.

Adult↗
PubMed1998

Socioeconomic status and survival of gastric cancer patients.

Survival differences in cancer patients according to socioeconomic status (SES) have been reported for several organs, but the relationship with gastric cancer prognosis has not been conclusively defined. The present study analysed the survival of 122 incident, histologically confirmed gastric cancer patients diagnosed between 1985 and 1987 in Genoa, Italy and enrolled in a multicentric case-control study on gastric cancer occurrence and dietary habits. Adjusting for age at diagnosis, tumour stage, histopathological grading and surgery (i.e. curative gastric resection), Cox's proportional hazards regression model showed statistically significant hazard ratio (HR) (relative risk) estimates below unity for education (> 5 versus < or = 5 years of schooling, HR = 0.40, P = 0.003) and occupation (higher versus lower income job, HR = 0.59, P = 0.030). Also, the same final regression model revealed a positive prognostic effect for origin (Southern Italy migrants versus Genoa natives) (HR = 0.56, P = 0.039) and female gender (HR = 0.58, P = 0.020). High SES, origin from lower risk area for gastric cancer occurrence and female gender are positive prognostic categories for gastric cancer patients.

Adult↗
PubMed1998

Correlation between plasma transforming growth factor-beta 1 and second primary breast cancer in a chemoprevention trial.

The relationship between plasma transforming growth factor-beta 1 (TGF-beta 1) and second primary breast cancer was explored in a prevention trial of the synthetic retinoid fenretinide (N-(4-hydroxyphenyl)retinamide; 4-HPR). Plasma concentrations of TGF-beta 1 were measured by radioimmunoassay in plasma obtained at randomisation and after approximately 1 year of intervention in 28 women treated with 4-HPR and 27 untreated controls with stage I breast cancer. Baseline and 1 year growth factor concentrations were not significantly different between treated and control groups. After a median follow-up of 65 months, an increase in TGF-beta 1 over 1 year was the only significant, independent predictor of a shorter survival free from secondary primary breast cancer. Moreover, the change in TGF-beta 1 levels had a tendency to influence the treatment effect on second breast cancer incidence. Our data suggest that the role of plasma TGF-beta 1 as a surrogate endpoint of breast carcinogenesis should be assessed further.

Adult↗
PubMed1998

The insulin-like growth factor axis and plasma lipid levels in the elderly.

The activity of the hypothalamic-GH-insulin-like growth factor (IGF) network declines with age. It has recently been shown that increased cardiovascular mortality occurs in adults with GH deficiency. As hypercholesterolemia is common in GH-deficient adults, and because there is experimental evidence that GH may play a role in regulating plasma cholesterol, we decided to investigate the activity of the GH-IGF axis in an elderly population by measuring serum IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) levels and to study their relationship with blood lipid levels. One hundred and thirty-two elderly subjects, 52 men and 80 women, were studied (age range, 60-91 yr). Men had significantly lower levels of IGFBP-3, high density lipoprotein cholesterol (HDL-C) and apoprotein A1 (ApoA1) compared to the women, whereas IGF-I and IGF-II were only slightly lower. Using linear regression analysis, we observed an inverse relationship of age with IGF-I (r = -0.35; P < 0.001), IGF-II (r = 0.40; P < 0.001), IGFBP-3 (r = 0.52; P < 0.001), body mass index, and lipid levels. Univariate regression analysis showed a strong and positive correlation of both IGF-I and IGFBP-3 with HDL-C and ApoA1. Partial correlation analysis, after adjustment for age and body mass index, showed that IGFBP-3 and IGF-II were still significantly and positively related to HDL-C and ApoA1. Furthermore, a strong association was documented among IGF-I, IGF-II, and IGFBP-3. These data demonstrate that even in an elderly population, further aging is accompanied by a progressive decline in circulating IGF-I, IGF-II, and IGFBP-3, suggesting a continuing diminution of the GH-IGF axis throughout aging. Moreover, the strong correlation between HDL-C and an index of GH secretion, such as IGFBP-3, suggests that GH might play an important role in lipid metabolism in healthy elderly subjects.

Aged↗
PubMed1998

Urinary excretion of 1-hydroxypyrene as a marker for exposure to urban air levels of polycyclic aromatic hydrocarbons.

A cross-sectional study was conducted among 94 traffic police officers from the Municipality Police of Genoa, Italy, exposed to airborne pollutants and 52 referent subjects exposed to indoor air pollution levels to investigate the relationships between exposure to ambient air polycyclic aromatic hydrocarbons (PAHs) and urinary excretion of 1-hydroxypyrene (1-OH-P). The effects of smoking, lifestyle factors such as exposure to ETS, and diet, along with the role played by the cytochrome P4501A1 (CYP1A1), and glutathione S-transferase M1 and theta metabolic susceptibility gene polymorphisms were examined. The geometric mean of benzo(a)pyrene air measurements (an index compound of PAH levels) was 70 times higher in traffic police officers (3.67 ng/m3) than in referents (0.05 ng/m3). The urinary concentration of 1-OH-P was clearly associated with cigarette smoking and, to a lesser extent, with exposure to ETS and particulate PAH pollution. No association was detected between 1-OH-P excretion and diet. Women exhibited a higher excretion level than did men, and an apparent effect of age was due to differences in cigarette smoking habits. Exposure to PAHs resulted in higher levels of 1-OH-P excretion in all groups except heavy smokers. Overall, no significant role of any metabolic polymorphism was detected. However, stratification of study subjects according to their smoking habits revealed higher levels of excretion of 1-OH-P in subjects smoking < or =15 cigarettes/day carrying the CYP1A1 polymorphism. No such effect was seen either with nonsmokers or with people smoking more than 15 cigarettes/day. These findings are suggestive of a gene-environment interaction, in which subjects with the CYP1A1 polymorphism, relative to subjects without it, have higher levels of 1-OH-P in their urine at low doses of exposure to PAHs.

Age Distribution↗
PubMed1997

Sister chromatid exchange induction in peripheral blood lymphocytes of traffic police workers.

Traffic police workers, as a population exposed to urban atmosphere, were compared with a control population exposed to indoor air pollution levels. Sister chromatid exchanges (SCEs) as a biomarker of effect were measured in peripheral blood lymphocytes of 54 exposed subjects and 35 controls, and environmental concentration of polynuclear aromatic hydrocarbon (PAH) tracer compounds was detected by personal air samplers. The mean exposure level to benzo[a]pyrene in our group of traffic policemen (3.4 mg/m3) was in the range that has been estimated in urban areas in Europe during the last 10 years. No difference in SCE levels was found between exposed workers (7.36, SD 1.35) and controls (7.47, SD 1.28). No correlation was observed between SCE/cell and airborne PAH concentration in the traffic worker population. A positive regression of SCE on exposure estimate was found only in the non-smoking group of police workers. Our findings suggest that exposure to urban air pollution does not induce relevant cytogenetic effects.

Adult↗
PubMed1997

Long-term effects of fenretinide on retinal function.

The long-term effects of the synthetic retinoid fenretinide (4-HPR) on retinal function were studied by electroretinogram (ERG) in 24 women treated for a median of 30.5 months and in 18 untreated controls belonging to a phase III intervention trial. The six outcome measures were: a wave implicit time, peak-to-peak amplitude and implicit time of b wave following both cone stimulation and maximal cone-rod stimulation in the dark-adapted eye. Multivariate analysis of covariance was applied to evaluate the joint effect on the whole set of ERG measures taking into account their inter-relationship. Predictive factors with a significant effect on ERG measures were: (1) a qualitative interaction between age and treatment duration and (2) the squared (parabolic) function of plasma retinol. Individually, the b wave implicit time following cone stimulation was the only ERG measure significantly influenced by the predictors, indicating a primary effect of 4-HPR on retinal photoreceptor sensitivity without significant alterations of the inner nuclear layer. Thus, in contrast to previous reports at higher dose, administration of 4-HPR at 200 mg/day seems to exert subtle alterations of retinal function as measured by ERG.

Age Factors↗
PubMed1996

Effect of tamoxifen on endometrial proliferation.

PURPOSE: An increase in the incidence of endometrial cancer and a potential increase in related mortality has been associated with the administration of 20 mg tamoxifen, the dose adopted in breast cancer chemoprevention trials, thus urging studies on intermediate markers of risk. PATIENTS AND METHODS: Thirty-three women who received 20 mg tamoxifen as adjuvant breast cancer treatment underwent endometrial biopsy. Samples were divided for histologic examination, including a quantitative analysis of stromal:epithelial ratio, and an assessment of DNA ploidy and proliferation by flow cytometry. Results were compared with 37 symptomatic subjects. RESULTS: All histograms were DNA diploid. Compared with controls, a significant increase in the risk of proliferation as measured by the hyperdiploid fraction was associated with tamoxifen duration (< or = 36 months: cumulative odds ratio = 16.5, 95% confidence interval, 1.85 to 146.5; > 36 months: cumulative odds ratio = 28.2, 95% confidence interval, 2.56 to 310.6, P for trend < .05). Tamoxifen-induced risk was significantly reduced by the extent of menopausal status. No cases of cancer or epithelial hyperplasia were observed in the tamoxifen group, whereas seven cases of epithelial hyperplasia without atypia were observed in the control group. The effect of tamoxifen on proliferation was associated with an increase in the stromal component. CONCLUSION: Tamoxifen at 20 mg/d exerts a time-dependent proliferative effect on the endometrium, particularly in premenopausal and early postmenopausal women. This effect appears to be mediated by the stromal component, which accounts for the discrepancy between flow cytometry and histology. Our study provides preliminary evidence that the DNA flow cytometric hyperdiploid fraction may be a useful tool for monitoring endometrial cell proliferation in women exposed to tamoxifen.

Adult↗