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Biomedical subjects

G Milano

Publications and source records attributed to G Milano.

230 records · Page 13Linked to original sources
PubMedDate not supplied

Systemic blood levels after intra-arterial administration of microencapsulated mitomycin C in cancer patients.

Systemic delivery of mitomycin C (MMC) was studied in 6 patients administered microencapsulated MMC (MMC-mc) by an intra-arterial route (IA): 3 IA liver infusions, 3 IA pelvic infusions. Pharmacokinetic data revealed a lower blood MMC availability (peak plasma levels, AUC 0-4 hours) for the pelvis than for the liver; this was attributed to differences in the blood flow infusion rates at these two sites of administration. Direct comparison of systemic MMC exposure was possible for one patient, who received both IA liver MMC (10 mg in standard form, which served as the control) and IA liver MMC-mc (20 mg the day after). The 65% reduction in MMC-mc bioavailability observed for this patient indicates a quantitative local improvement in exposure to the drug and correlates well with the low incidence of systemic side effects noted in preliminary clinical studies.

Aged↗
PubMedDate not supplied

Monitoring of the intracellular activation of 5-fluorouracil to deoxyribonucleotides in HT29 human colon cell line: application to modulation of metabolism and cytotoxicity study.

An HPLC method was developed for in vitro detection and monitoring of intracellular metabolites of [3H]-5-fluorouracil (FUra). Results showed a preferential activation of FUra to ribonucleoside and ribonucleotide derivatives (FURd, FUMP, FUDP and FUTP) in the human colorectal HT29 cell line. We screened various agents so as to determine if they could act as modulators of metabolism and/or toxicity of FUra by reversing the activation pathway of FUra from ribo- to deoxyribonucleotides, thus enhancing FdUMP formation. Different drugs (efflux inhibitors, catabolism inhibitors and enzymatic cofactors) were tested for enhancement of cytotoxicity when associated with FUra. The most promising agents were further studied by assessment of their ability to modulate intracellular activation of FUra to enhance thymidylate synthase (TS) inhibition by FUra and to increase the subsequent induction of apoptosis. 2'-Deoxyinosine (d-Ino), a deoxyribose 1-phosphate donor increasing thymidine phosphorylase activity, stood out as the best modulating agent we screened. Results showed an up to 30-fold increase of cytotoxicity along with a stronger inhibition of TS when FUra was associated with d-Ino, while FUra alone exhibited a lesser effect on TS activity. Besides, HPLC analysis revealed a complete reversal of the activation pathway of FUra, thus leading to an intracellular accumulation of deoxyribonucleotides. Assessment of cell cycle distribution showed a marked increase (+480%) of apoptosis in cells exposed to FUra/d-Ino compared to FUra alone. The HPLC method we developed is a convenient tool for assessing to what extent modulators will actually act on the intracellular activation of FUra. This study confirms the potentiality of d-Ino to modulate FUra metabolism in vitro. It proved to be an agent able to orientate the mechanism of action of FUra towards the inhibition of TS in cells where the normal activation pathway of the drug does not result in the intracellular accumulation of the active metabolite FdUMP.

Cell Cycle↗
PubMedDate not supplied

A multivariate analysis for predicting cisplatin-induced delayed emesis.

The present study was designed to address the question of the early identification of patients at risk of developing cisplatin (CP)-related delayed emesis. This study included demographic, clinical, biological and pharmacological data and was conducted on 110 consecutive patients treated by CP-based chemotherapy. A previously validated single-point CP pharmacokinetic evaluation was performed in all patients. A total of 110 cycles was analyzed. Delayed vomiting (i.e., occurring between day 3 and day 7 following CP administration) was observed in 36.4% of cycles. Among the tested variables, the occurrence of delayed emesis was significantly related to elevated ultrafilterable (UF) platinum concentration (measured 16 h after the end of CP administration) and to low plasma magnesium concentration (measured 48 h before CP administration). Risk-thresholds for delayed emesis were established for UF platinum and magnesemia, at 60 ng/ml and 58 mmol/l, respectively. In the sub-group of patients with magnesemia determination, this later parameter was the only significant predictor of delayed emesis. Gender, cycle number, primary cancer location and age were not associated with the risk of developing delayed emesis. The ability to select patients at risk of delayed vomiting may offer a practical means of targeting administration of specific treatments.

Adult↗
PubMedDate not supplied

Prognostic value of S-phase fraction in 920 breast cancer patients: focus on T1N0 status.

The aim of this study was to reexamine the prognostic role of tumor cell kinetics measured by S-phase fraction (SPF) and to establish its clinically relevant threshold values. SPF was determined by flow cytometry in a group of 920 consecutive breast cancer patients, all followed at our institute for 10 years (1988 to 1998). Mean age was 60.5 years (27-89 years). Median follow-up was 63 months (3-150 months). All patients had initial surgical treatment. SPF quartiles were: Q1=3.08%, median value = 5.98%, Q3=10.22%. A significant difference in overall specific survival was obtained between two populations divided by a cutoff at Q1 (p < 0.0001). A multifactorial analysis including SPF and known prognostic factors such as tumor size, node status, histological grade, ER and PR status was performed using the Cox model in a population of 719 patients: univariate analysis showed that each of these factors had significant influence on overall survival. Multivariate analysis selected three of them, ranked by decreasing order of hazard ratio (HR) value: SPF (HR: 3.88, p < 0.001), tumor size (HR: 2.49, p < 0.001) and nodal status (HR: 2.28, p < 0.001). In addition, when tumors were stratified according to SPF quartile values, there were statistically different overall survival curves in patients with small tumors (< 2 cm) and in axillary node-negative patients.

Biomarkers, Tumor↗
PubMedDate not supplied

Chronomedical aspects of oncology and geriatrics.

Extensive laboratory evidence on the merits of cancer chronotherapy is validated by the doubling of 2-year disease-free survival rate obtained by the chronoradiotherapy of patients with very advanced perioral cancers and by the quadrupling of the 5-year survival achieved by the chronochemotherapy of patients with advanced ovarian and bladder cancer. Miniaturized monitors for marker rhythmometry of tumor and core temperature recorded over long spans should facilitate the optimization of treatment by timing, while also serving the purpose of earliest intervention. The likelihood of a cure should be increased by focusing upon the now extensively documented tumor marker rhythms that may show time structure (chronome) alterations before exceeding the physiological range (that is otherwise neglected as one of random variation), and before overt symptoms appear.

Aging↗
PubMedDate not supplied

[Endoscopic retrograde cholangiography and perioperative cholangiography: to use both, one or none?].

ERCP and cholangiography during surgery (SC) are compared in regard to their usefulness in 100 patients in whom cholecystectomy was performed because of gallstones. The biliary tree was visualized in 73% of patients with ERCP and in 85% with SC 20 patients presented stones in the common bile duct (CBD), of these 19 had previous signs or symptoms clinical history, laboratory, ultrasonography) that suggested this diagnosis, of the rest of the patients (80) without CBD stones only 7 had signs or symptoms that suggested this diagnosis, 4 of these patients had normal cholangiograms and 3 had "odditis". So in 73 patients without symptoms suggestive of CBD stones, preoperative or intraoperative cholangiography was probably not necessary. We consider that it is convenient to perform ERCP only in those patients with gallstones who have clinical findings suggestive of CBD or pancreatic problems (history, laboratory, ultrasonography). Cholangiography during cholecystectomy would be indicated in patients with small gallstones, the finding during operation of a dialted CBD or palpation of stones in the CBD and when ERCP fails in a patient with suggestive symptoms or when there is doubts with the ERCP findings.

Adolescent↗
PubMedDate not supplied

Assessment of nutritional proteins during the parenteral nutrition of cancer patients.

Albumin, prealbumin, retinol-binding protein, and transferrin were all measured on the sera of 39 cancer patients before and during parenteral nutrition (PN). At the outset of PN, the concentrations of all of these proteins were low, as compared to reference values, and thus quantitatively reflected the degree of malnutrition. Prealbumin proved to be the most interesting parameter during PN: (1) during an initial period it rapidly reflects the nutritional input, and (2) after two weeks of PN it allows differentiation of patients whose prealbumin level rises regularly during PN and will survive from those patients whose prealbumin level drops after the initial period and will die during or within the month following PN. Prealbumin thus offers a means for biochemical monitoring of PN as well as having a prognostic value.

Adult↗
PubMedDate not supplied

Dihydropyrimidine dehydrogenase (DPD) and clinical pharmacology of 5-fluorouracil (review).

Fluorouracil (FU) is essentially eliminated in the liver through the rate limiting enzyme dihydropyrimidine dehydrogenase (DPD). DPD is also expressed in various other normal as well as in tumor tissues. DPD activity measured in peripheral blood mononuclear cells (PBMC) is correlated to FU systemic clearance, but this correlation is weak, precluding PBMC-DPD to be considered as a reliable predictor of FU clearance. Nevertheless, patients with suspected or proven PBMC-DPD deficiency exhibit severe FU-related toxicities. Population studies performed so far were unable to detect complete DPD deficient patients, suggesting that complete DPD deficiency is a very rare event; however 3% of patients exhibit a partial DPD deficiency indicative of increased risk for developing FU-related toxicity. Although FU resistance is multifactorial, DPD activity in tumor cells (in vitro and clinical studies) is significantly related to FU sensitivity: the lower the DPD activity, the greater the FU efficacy. Further prospective clinical studies will be required in order to confirm the present observations.

Animals↗
PubMedDate not supplied

Clinical randomized study of 5FU monitoring versus standard dose in patients with head and neck cancer: preliminary results.

Prospective studies of dose adaptation of continuous 5FU infusion combined with cisplatin have shown that pharmacologically guided dosing was feasible in the treatment of head and neck carcinomas. Adaptative dosing results in reduced haematological toxicity, but few data are available for clinical response rate. Preliminary results (38 patients) of a randomized trial comparing standard dose of 5FU (20 patients) and monitoring of 5FU based on pharmacokinetic information (half-cycle area under the curve, 18 patients) indicate that haematological tolerance and complete response rate were improved. Severe (GIII-GIV) thrombocytopenia and neutropenia were significantly reduced during cycle 2 (0% versus 11.1% and 5.5% versus 27.7% respectively, p < 0.01) and cycle 3 (0% versus 27.7% and 6.6% versus 33.3% respectively, p < 0.001). The complete response rate was increased in the group with monitoring of 5FU doses (55.5% versus 40.0%, p < 0.001). These interesting results will be confirmed at the end of the trial, which is expected to include 126 patients.

Adult↗
PubMedDate not supplied

Cisplatin nephrotoxicity: a multivariate analysis of potential predisposing factors.

STUDY OBJECTIVE: To evaluate the usefulness of biologic and pharmacologic parameters for early identification of cisplatin-induced renal dysfunction. DESIGN: Prospective evaluation of 62 consecutively admitted patients with cancer. SETTING: Cancer center. PATIENTS: Sixty-two consecutive patients with cancer (52 men, 10 women; mean age 61.9 yrs). INTERVENTIONS: Patients received cisplatin as a single short intravenous infusion every 3 weeks. One hundred twenty-one cycles were analyzed. The dosage in the first cycle ranged between 61 and 105 mg/m2 (mean 84 mg/m2). All patients received a standard hydration protocol. MEASUREMENTS AND MAIN RESULTS: Renal function was evaluated for each cycle before treatment (day 0) and before next cycle (day 21) based on the estimated creatinine clearance (Clcr). For each cycle, the weighted relative decrease (WD) of Clcr was calculated (WDClcr = 100 x [Clcr (day 0) - Clcr (day 21)]/[Clcr (day 0)](2). Total and ultrafilterable (UF) platinum were measured as a single-sample assay taken 16 hours after the end of cisplatin administration. The mean WDClcr was 0.07 min/100 ml (range -1.0 to +1.7 min/100 ml). The intensity of renal dysfunction evaluated by WDClcr was independent of cisplatin dosage, age, sex, body surface area, initial Clcr, and cycle number. Of interest, total and UF platinum concentrations were significantly correlated to WDClcr: the higher the platinum concentration, the greater the intensity of renal dysfunction. In stepwise regression analysis, UF platinum concentration was the only selected factor. The best prediction of UF platinum was obtained by stepwise regression including cisplatin dosage, initial Clcr, and cycle number (r=0.58, p<0.0001). CONCLUSION: We consider our results to be a first step toward a clinical strategy to identify patients at risk for renal dysfunction after cisplatin treatment.

Adult↗