Biomedical subjects
Publications and source records attributed to C D'Amico.
Femtosecond laser filamentation is studied in a broadband amplifying medium, sapphire doped with electronically excited Ti ions. Evidence for fluence amplification of self-guided pulses, increase of filamentation length, as well as a lowering of the input laser power necessary for filamentation is reported.
The purpose of this study was to determine the maximum-tolerated dose of gemcitabine plus mitoxantrone in women with metastatic breast cancer (MBC) and to evaluate activity and toxicity of this combination in a phase II trial. Sixty-three patients with MBC, previously treated with chemotherapy including anthracycline and/or taxanes, were treated with mitoxantrone 10 or 12 mg m(-2) intravenously on day 1 plus gemcitabine in escalating doses from 600 to 1200 mg m(-2) intravenously on days 1 and 8, every 3 weeks. In phase I, on 23 patients entered on study, dose-limiting toxicity occurred at the dosage of 1200 mg m(-2) gemcitabine and 10 mg m(-2) mitoxantrone, with three out of five patients developing grade 4 neutropenia. In phase II, with gemcitabine administered at 1000 mg m(-2) and mitoxantrone at 10 mg m(-2), 12 (30%) out of 40 assessable patients responded, even if no complete response was obtained. Moreover, stable disease was observed in eight (20%) patients. The median time to treatment failure was 22 weeks (range, 2-33), and median survival was 42 weeks (range, 2-92). Grade 3 and 4 neutropenia were observed in 12 (30%) and one (2.5%) cases respectively; grade 3 thrombocytopenia was observed in two patients (5%), grade 2 mucositis in two patients (5%), grade 3 anaemia in two patients (5%), grade 3 alopecia in one patient (2.5%) and asymptomatic cardiotoxicity in three patients (8%), respectively. In conclusion, the doses of 10 mg m(-2) (day 1) for mitoxantrone and 1000 mg m(-2) for gemcitabine (days 1-8) every 3 weeks resulted active and safe in MBC. Further investigations in less heavily pretreated patients are warranted.
Using a double-labeling immunocytochemical-autoradiographic assay we studied 18 male breast carcinomas to evaluate the cell kinetic and receptor status in neoplastic cells during S-Phase and to detect possible differences with respect to 21 female breast cancers, from a previously, published study. In male breast cancer, the tumor receptor content and ER/PgR expression in neoplastic cells during S-Phase was higher (p = 0.01) than that in corresponding female tumor while tumoral cell proliferation was lower, but not significantly. In the previous reported study on female breast cancer we demonstrated that proliferative activity was higher in receptor negative cell population both for ER and PgR. Conversely, in male tumor, that difference was only present in relation to the expression of PgR: in fact, the proliferative activity was higher in PgR negative than in PgR positive cells (Anova Test: p = 0.04) while no difference was evidenced between ER negative versus ER positive cells. Moreover, the arrest of DNA synthesis, expressed as percentage of cells without 3H-Tdr labeling, was not related to either the ER or PgR expression, while in female breast cancer it was higher in PgR positive than ER positive cell population. Our data confirmed differences between males and females regarding the receptor status and cell cycle S-Phase in breast cancer. The poorer prognosis of the male breast carcinoma might be related to ineffective therapies which do not consider these differences in the biological profile of the male tumor. The Authors indicate that prognostic and predictive tissutal markers, detected by immunocytochemical methods and useful for therapeutic programming in the female breast cancer have a different significance in the male breast cancer and stress the need for different therapeutic strategies specific for male breast cancer.
Microsatellite instability (MSI) occurs frequently in sporadic gastric cancer (GC) and may define a distinctive molecular pathway of carcinogenesis. We evaluated the role of dietary risk factors in GC according to MSI status. A large series of 382 GC cases and 561 controls were originally identified in a population-based case-control study carried out in the high-risk area around Florence, Italy; 126 GC patients were typed for MSI status. A MSI+ phenotype was detected in 43 of 126 cases (34.1%), whereas 83 cases were classified as MSI-. A multinomial logistic regression model was used to compare the two subgroups of GC classified according to MSI status in the same analysis, with all of the available population controls. A case-case approach was also used. The risk of MSI+ tumors was positively associated with high consumption of red meat and meat sauce and negatively associated with consumption of white meat. A positive association was also seen with total protein and nitrite intake, whereas no relation was found with micronutrient intake. Risk was especially high among subjects reporting both a positive GC family history and a high consumption of red meat (odds ratio, 25.7; 95% confidence interval, 6.4-102.8). For MSI- tumors, a significant protective effect was associated with frequent consumption of citrus and other fresh fruit, garlic, legumes, vegetables, and olive oil and with high intake of beta-carotene and other antioxidants and sugar, whereas positive associations were seen with protein and sodium intake. In summary, a specific dietary pattern emerged for MSI+ gastric tumors, suggesting that factors related to red meat consumption are involved in this pathway, particularly among individuals with a positive family history. In contrast, the risk of MSI- tumors was strongly reduced by the frequent consumption of fresh fruit and vegetables.
BACKGROUND: The need for continued surveillance endomyocardial biopsies beyond the first year after cardiac transplantation is controversial. We evaluated the incidence of rejections requiring treatment (International Society Heart and Lung Transplantation grade 3A or greater) in patients 5 years or more after heart transplantation. METHODS: We conducted a retrospective chart review of all patients who underwent at least 1 endomyocardial biopsy at our center 5 years or more after heart transplantation. RESULTS: A total of 461 biopsies were performed in 77 patients 5 or more years after heart transplantation. Nine episodes of grade 3A or greater rejection were identified in 8 of 77 patients (10%). During the first year, 7.6% of biopsies were grade 3A or greater. Grade 3A rejection occurred in approximately 3.5% to 4% of biopsies during years 2 to 7. The overall incidence of procedural related complications at our institution was < 0.5%. CONCLUSION: Endomyocardial biopsies continue to detect clinically significant rejection beyond 5 years after cardiac transplantation. The overall incidence of procedural related complications requiring treatment was low and none was life threatening. The absence of early rejection does not predict freedom from late rejection. Therefore, we continue to recommend surveillance biopsies in cardiac transplant recipients late after transplantation.
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Protein truncation test (PTT) and single-strand conformation polymorphism (SSCP) assay were used to scan the BRCA1 and BRCA2 genes in 136 unrelated Italian breast/ovarian cancer patients. In the sample tested, BRCA1 and BRCA2 equally contributed to site-specific breast cancer patients who reported one to two breast cancer-affected first-/ second-degree relative(s) or who were diagnosed before age 40 years in the absence of a family history of breast/ovarian cancer. BRCA1 and BRCA2 mutations were mostly found in patients with disease diagnosis before and after age 50 years, respectively. Moreover, in cases with familial clustering of site-specific breast cancer, BRCA1 mostly accounted for tumours diagnosed before age 40 years and BRCA2 for tumours diagnosed after age 50 years. The BRCA1 and BRCA2 mutation spectrum was consistent with a lack of significant founder effects in the sample of patients studied.
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We analyzed 7 mono-, 6 di- and 2 trinucleotide repeat loci in a well characterized series of 69 breast cancer cases, treated in the period 1985-1986 and followed for 12 years. Tumor-associated allele contractions or expansions were observed only at di- and trinucleotide repeats, and were detected in 14/69 cases (20%), of which 7 (10%) showed instability at 2 or more loci (10%). No alterations were detected at mononucleotide repeats known to be unstable in gastrointestinal tumors with the microsatellite mutator phenotype. Disease-free survival at 5 years, overall survival at 12 years of follow-up, tumor stage, estrogen/progesteron receptor status, and expression of the Ki-67 proliferation marker were independent of microsatellite status.
SETTING: Between October 1992 and February 1994, 33 cases of multidrug-resistant tuberculosis (MDR-TB) were diagnosed among patients infected by the human immunodeficiency virus (HIV) and hospitalised in an HIV ward in Milan, Italy. This outbreak was part of a much larger outbreak, begun in another hospital and probably transferred through a patient. OBJECTIVE: To evaluate risk factors for transmission and the effectiveness of infection control measures. DESIGN: 1) Active follow-up of exposed patients, 2) cohort study among HIV-infected patients exposed to MDR-TB cases before and after the implementation of control measures, 3) screening of close contacts of MDR-TB cases, and 4) molecular typing by restriction fragment length polymorphism (RFLP) analysis. RESULTS: The risk of MDR-TB was higher in patients with lower CD4+ lymphocyte percentages and longer duration of exposure. No difference in the daily risk was observed for in-patients vs day-hospital patients or by room distance from an infectious case. Of the 90 patients exposed before the implementation of infection control measures (i.e., October 1992-June 1993) 26 (28.9%) developed MDR-TB, whereas none of the 44 patients exclusively exposed after implementation developed MDR-TB, despite the continuing presence of infectious MDR-TB cases in the ward. CONCLUSION: Simple control measures were effective in significantly reducing nosocomial transmission among patients.
BACKGROUND: There are limited data on the use of percutaneous revascularization techniques for transplant coronary artery disease (CAD). METHODS: Medical records and angiographic results for cardiac transplant patients undergoing percutaneous revascularization at Emory University Hospital were reviewed. Procedural results, results of angiography 4Eth 6 months after intervention, and clinical follow-up were recorded. RESULTS: Nineteen patients underwent 51 interventions. Thirty-eight lesions (75%) were de novo and 13 (25%) were restenotic. All patients had hypertension, 37% had diabetes, 79% had elevated lipid levels, and 53% had at least one episode of moderate to severe allograft rejection (grade 3A or greater). The primary procedural success rate was 100% with no major complications. Six-month restenosis rate (defined as > 50%) was 49%. At 23+/-17 months follow-up, 6 patients were dead or retransplanted (31%). Thirteen patients were alive without retransplantation (9 New York Heart Association class I, 3 class II, 1 class III). CONCLUSION: Percutaneous revascularization is safe and has a high initial procedural success rate in patients with transplant CAD. However, the restenosis rate in this population remains higher than reported for atherosclerotic coronary disease and the long-term prognosis remains poor.
We analysed 50 gastric carcinomas (GCs) to verify whether mutations at coding repeats were associated with microsatellite instability (MSI). The tumors included: ten cases with no MSI, 14 cases with MSI = 1 locus, 13 cases with MSI = two loci and 13 cases with MSI > or = 3 loci. We investigated coding repeats within the TGF-beta RII, IGFIIR, BAX, hMSH6, hMSH3 and BRCA2 genes. The TGF-beta RII, IGFIIR, BAX, hMSH6 and hMSH3 repeats were altered in 11 (22%), five (10%), four (8%), 16 (32%) and five (10%) cases respectively. Mutations occurred only in MSI-positive (MSI+) tumors and correlated with increasing MSI levels. No alterations of the BRCA2 repeat were found. Mutations in genes other than hMSH6 were strongly associated to hMSH6 mutations, suggesting a key role of this gene. The non-coding BAT-26 and E-Cadherin 3' UTR poly(A)8/(T)15 repeats were analysed in 44 of the 50 cases. Novel tumor-associated alleles were observed only in MSI-positive GCs and were in most cases associated with mutations at coding repeats. Further investigations with BAT-40 confirmed that four cases manifested mononucleotide repeat alterations restricted to hMSH6 and one case to TGF-beta RII. A subset of tumors with MSI at two or more dinucleotide loci resulted negative for mutations at coding and non-coding mononucleotide repeats.
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We studied the presence of microsatellite instability (MSI) in a series of 108 gastric cancers (GCs) previously identified in an epidemiological study carried out in a high-risk area around Florence. To investigate associations between MSI and GC family history, 34 cases (31.5%) who had a GC-affected first-degree relative were included in the series. A family history positive for colorectal cancer was reported quite rarely (5.6%). The analysis of 6 microsatellite loci in DNA from paired normal tissue and tumor samples microdissected from paraffin-embedded specimens revealed varying degrees of instability: 56 cases (51.8%) did not show instability at any of the 6 loci; 19 (17.6%) showed instability at 1 locus; 16 (14.8%) showed instability at 2 loci; 11 (10.2%) showed instability at 3 loci; 4 (3.7%) showed instability at 4 loci; and 2 (1.9%) showed instability at 5 loci. The replication error-positive (RER+) phenotype, defined as the presence of MSI at 2 or more loci, had a frequency of 30.6% (33 of 108) and tended to be positively associated with female sex, intestinal histological type, advanced tumor stage, vascular invasion, positive GC family history, and blood group of A type. No correlation emerged between age at diagnosis and RER+ phenotype, whereas a significant association with the RER+ phenotype was shown by the antral location. A multivariate analysis adjusting for a selected group of potential confounding factors confirmed the strong association of the RER+ phenotype with the antral location (P = 0.001) and with a positive GC family history (P < 0.05). Survival analyses at 5 and 8 years showed no difference between RER+ and RER- patients, even when corrected for stage distribution. By the microdissection technique, we also used microsatellite allele patterns to investigate intratumoral heterogeneity and genetic relationships between tumors and adjacent dysplasia and/or intestinal metaplasia. Areas of metaplasia and dysplasia demonstrated MSI only in cases with MSI-positive tumors. In MSI-positive tumors, there was consistent evidence of intratumoral microsatellite allele heterogeneity, indicating the presence of genetically divergent tumor cell clones within the same neoplasm.
We analyzed 81 cases of primary breast carcinoma and 7 cases of fibroadenoma for microsatellite instability at eight loci. Twenty-seven cases (33.3%) manifested aberrant microsatellite alleles: 7 (8.6%) at one locus and 20 (24.7%) at two or more loci [tumors with replication error-positive (RER+) phenotype]. No evidence of microsatellite instability was observed in fibroadenomas. We investigated correlations between RER+ phenotype and clinicopathological characteristics of the carcinomas. The RER+ phenotype was statistically associated with large tumor diameter; of 19 RER+ tumors with measured size, 16 were > 2 cm, compared to 28 of 58 tumors with no evidence of microsatellite instability or with shifts in allele sizes limited to one locus (P </= 0.005, chi2 test). Consistently, there was also a strong statistical association between RER+ phenotype and lymph node metastasis; 14 of 19 RER+ tumors with known lymph node status were N+, compared to 15 of 59 tumors with no evidence of microsatellite instability or with allele shifts limited to one locus (P </= 0.0002, chi2 test). Correlations with age of patients, proliferative activity, histotype (ductal versus lobular), and grade of differentiation were not statistically significant, although the RER+ phenotype was more frequent in lobular and high-grade ductal carcinomas, in carcinomas with high proliferative activity, and in carcinomas from patients </=50 years. Data concerning cancer(s) in first and/or second degree relatives were available for 66 cases, including 33 positive and 33 negative for family history of cancer. No correlations were detected between RER+ phenotype and family history of cancer. In conclusion, our results indicate that in breast cancer, microsatellite instability is associated with clinicopathological parameters that are considered predictors of recurrent disease and aggressive behavior.
Inositol levels have been studied in cellular cultures and recently by perfusion of isolated hearts. The study was aimed to assess inositol turnover in rabbit hearts from intact animals. Thirty rabbits were injected i.v. three times (every 12 hr) with 25 microCi/kg of myo-3H-inositol. The rabbits 12 hr after the last injection were killed and the hearts perfused according to Langerdorff technique. Systolic and diastolic ventricular pressures (SVP, DVP), dp/dt, and coronary flow (CFl) were measured. The hearts (n = 14) were perfused under aerobic conditions and 16 hearts under ischemic conditions for 30 min. In addition, 5 hearts were perfused under aerobic conditions for 10 min, and 6 hearts were perfused under ischemic conditions for 10 min. Samples of myocardial tissue were taken from both groups at the end of 10-min and 30-min period of perfusion, and cAMP and inositol phosphates were assayed. The hearts subjected to ischaemia showed changes of cAMP and 3H-inositol. The cAMP was higher in the ischaemic (10 min and 30 min) than the control hearts, 0.22 +/- 0.09 and 0.21 +/- 0.08 versus 0.41 +/- 0.12 and 0.49 +/- 0.11 pmol 10(6) cells, respectively (p < .05, p < .001. The inositol trisphosphate was higher in control than ischemic hearts (10 min, 30 min), 0.42 +/- 0.02 and 0.39 +/- 0.01 versus 0.31 +/- 0.01 and 0.23 +/- 0.02 (percent of radioactivity) respectively, p < .001. Our data suggest that 3H-inositol may be studied by i.v. administration to intact animals. The ischemia was performed to verify the validity of this new technique.
Sumatriptan provokes, in healthy subjects as well as in those who suffer from hemicrania, a slight increase in both systolic and diastolic arterial pressure. It has also been shown to increase the pressure of pulmonary circulation and to reduce the calibre of coronary arteries. The present investigation was undertaken to study the effects of sumatriptan (75 ng/l) on isolated rabbit hearts. Fifteen isolated rabbit hearts, perfused according to Langerdoff's procedure, were divided into two groups: Group I (5 hearts), perfused with Krebs-Henseleit solution, as a control, and Group II (10 hearts), perfused with Krebs-Henseleit mixed with sumatriptan succinate (75 ng/l). After 30 min of perfusion, the basal values of heart rate (HR) dp/dt, systolic ventricular pressure (SVP), diastolic ventricular pressure (DVP) and coronary flow (CF) were measured. The above values in either control or treated hearts were measured 5, 15, 30, 45, 60 min after recording the baseline values. HR, SVP, DVP, dp/dt and CF did not show significant differences in the two groups. The present data suggest that sumatriptan does not exert any action on isolated rabbit hearts.
BACKGROUND: During heart failure, due to increased level of circulating norepinephrine, the number of beta-adrenergic receptors (beta-AR), both at the cardiac and the lymphocytic level, is reduced (down-regulation). Captopril, an ACE-inhibitor containing an SH group appears capable of resetting beta-AR when used in patients with heart failure. Our study was aimed at checking whether captopril exerts a direct effect upon the beta-AR, possibly through its SH group by disulphur binding with cysteine residues located at the binding sites for catecholamines. METHODS: The study was carried out in vitro on human lymphocytes obtained from healthy volunteers: 10 males (mean age, 34 years; range, 25-45) and 10 females (mean age, 34 years; range 26-48). Lymphocytes were randomly divided in two groups of equal size. Group I were controls; in Group II cells were incubated with three different doses of captopril: 1, 10, and 100 microM. Control lymphocytes and those treated with 10 microM of captopril were exposed to 1 microM isoproterenol. The number of total and surface beta-AR, and the sequestration of beta-AR from isoproterenol under normoxic conditions and after 20 h of hypoxia were checked. Furthermore, the content of cAMP was assayed both in basal conditions and after stimulation with 10 microM and 100 microM isoproterenol and forskolin, respectively. RESULTS: Total beta-AR: 1082 +/- 133 (controls) vs. 1174 +/- 94 (treatment with 1 microM captopril), vs. 1237 +/- 88 (10 microM captopril), vs. 1092 +/- 105 (100 microM captopril). Surface beta-AR: 84 +/- 4.41% (controls) vs. 90.5 +/- 2.1% (10 microM captopril). Basal cAMP: 1.21 +/- 0.4 (controls) vs. 1.23 +/- 0.5 pmol/10 cells (1 microM captopril), 1.05 +/- 0.6 pmol/10 cells (10 microM captopril), 1.15 +/- 0.4 pmol/10 cells (100 microM captopril). After 10 microM isoproterenol: controls 4.10 +/- 0.8 vs. 4.30 +/- 0.9 pmol/10 cells (1 microM captopril), 4.15 +/- 0.7 pmol/10 cells (10 microM captopril), 3.50 +/- 1.0 pmol/10 cells (100 microM captopril). After 100 microM forskolin: controls 13.2 +/- 3.1 vs. 11.2 +/- 3.1 pmol/10 cells (1 microM captopril), 13.1 +/- 4.2 pmol/10 cells (10 microM captopril), 12.6 +/- 2.9 pmol/10 cells (100 microM captopril). Neither of these differences were significant. Lymphocytic beta-AR exposed to hypoxia did not show any significant difference. Exposure to captopril did not cause any further alteration on beta-AR sequestration. CONCLUSIONS: Captopril does not seem to exert any direct action upon lymphocyte beta-AR from healthy volunteers. Moreover, captopril does not modify cAMP storage either in basal conditions or after stimulation with isoproterenol or forskolin. Therefore our data suggest that action of captopril on beta-AR is probably due to the inhibition of both systemic and tissue ACE-system.