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Biomedical subjects

Vito Lorusso

Publications and source records attributed to Vito Lorusso.

At least 37 records · Page 2Linked to original sources
PubMed2005

Topotecan plus ifosfamide in patients with platinum refractory advanced/metastatic non-small cell lung cancer: a phase II trial.

A number of second line treatments have been proposed in patients with advanced pretreated non-small cell lung cancer (NSCLC). However, either single agents or two or three drug combinations achieved very poor results with no superiority of any combination over monotherapy. We have treated 42 patients (30 males) affected by advanced/metastatic NSCLC progressing during front line cisplatin-based chemotherapy with a combination of topotecan (1.2 mg/m2) plus ifosfamide (1200 mg/m2) for 3 consecutive days every 3 weeks. The median age was 63 years (range 43-76); cell types were: squamous carcinoma (n=17), adenocarcinoma (n=16), large cell carcinoma (n=3), broncho-alveolar carcinoma (n=2) and undifferentiated carcinoma (n=4). All patients were treated with a platinum containing chemotherapy: 39 patients with cisplatin, 2 patients with carboplatin and 1 patient with oxaliplatin, respectively. The ECOG PS was 0 in 8 patients (19%), 1 in 11 patients (26%), and 2 in 23 patients (55%). The median number of courses administered was 3 (range 1-8). Grade 3-4 neutropenia was the dose limiting toxicity, observed in 36% of patients. Moreover, grade 3-4 anemia and thrombocytopenia were observed in 17% and in 12% of patients, respectively. One PS 2 patient died of grade 4 hematological toxicity after the first cycle. No complete response was observed. Six (14.2%) subjects obtained a partial response (PR). In addition, 1 (2.4%) minimal response (MR) plus 14 (34%) stable diseases (SD) and 21 (51%) progressive diseases (PD) were observed. Median time to disease progression and median survival were 9 weeks (range 1-13) and 26 weeks (range 1-91+), respectively. The 1-year survival rate was 14%. Combination of topotecan and ifosfamide demonstrated antitumor activity in patients with relapsing or refractory NCSLC with a modest side effect profile and an overall disease control (PR + MR + SD) of 50.7%. Nevertheless, the still low response rate and the shortness of median survival indicates the need for more effective second line treatments in this disease.

Adult↗
PubMed2005

Clinical Evidence Supporting the Role of Lonidamine for the Treatment of BPH.

Glandular prostate epithelial cells of the peripheral zone are unique among normal cells in their dependence on glycolysis for energy production, due to a zinc-mediated enzymatic block in the citric acid cycle. Lonidamine (LND), a derivative of indazole-3-carboxylic acid, is thought to disrupt energy metabolism by interfering with glycolysis and to cause cell apoptosis. We evaluated the efficacy of oral LND treatment in subjects with symptomatic benign prostatic hyperplasia (BPH). The following reports the findings of an open-label study of orally administered LND. Thirty subjects with symptomatic BPH received oral LND (150 mg/day) once daily for 28 days. Subjects were assessed at baseline, at active-therapy assessment visits (days 14, 28), and 1, 2, 3, and 6 months post-therapy, for prostate volume (PV) by transrectal ultrasound (TRUS), maximum flow rate (Q(max)) on uroflowmetry, postvoid residual urine volume (PVR), International Prostate Symptom Score (IPSS), prostate-specific antigen (PSA) levels, serum chemistry, and adverse events.

Journal Article↗
PubMed2004

Conjugates of gadolinium complexes to bile acids as hepatocyte-directed contrast agents for magnetic resonance imaging.

A series of structurally different Gd(III) conjugates incorporating a bile acid moiety have been prepared. Polyaminopolycarboxylic ligands such as diethylenetriaminepentaacetic acid (DTPA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid (DOTA) have been selected as chelating subunit for the Gd(III) ion. Cholic acid, cholylglycine, and cholyltaurine have been incorporated as the bile acid moieties. In first generation conjugates the Gd(III) complex is linked to the carboxyl group of cholic acid. Second generation conjugates feature the attachment of the Gd(III) complex to the 3 position of the steroidic backbone of the bile acid. Finally, in third generation conjugates the Gd(III) complex is attached to the epsilon nitrogen atom of cholyllysine. The conjugates are eliminated through the biliary route to a various extent (7.5 to 77% in rats) according to their structural features. Among the most promising terms, a second generation conjugate in which the Gd(III) complex is linked to cholic acid through the 3alpha hydroxy group seems to enter hepatocytes using the Na(+)/taurocholate transporter. Noticeably, some of the second generation conjugates are characterized by very high tolerabilities (LD(50) up to 9.5 mmol/kg) after intravenous administration in mice.

Animals↗
PubMed2004

Safety and activity of the combination of pegylated liposomal doxorubicin and weekly docetaxel in advanced breast cancer.

BACKGROUND: The present study was designed with the aim of evaluating the tolerability and activity of pegylated liposomial doxorubicin (PLD) in combination with weekly docetaxel as first line treatment of advanced breast cancer. PATIENTS AND METHODS: Fifty-seven patients entered the study. PLD was administered at escalating doses starting from 30 mg/m2, on day 1; docetaxel was administered at the fixed dose of 35 mg/m2 on days 2 and 9. A cycle of therapy consisted of 21 days. RESULTS: The MTD was achieved at the dose of 40 mg/m2 of PLD, being febrile neutropenia and palmar-plantar-erythrodisesthesia (PPE) the dose-limiting toxicities (DLTs), so that the fixed dose of PLD for the Phase II study was 35 mg/m2. Forty-two consecutive patients received treatment at the established dose for a total of 194 cycles: among these, three patients were withdrawn for severe allergic reaction at the first administration of PLD. Hematological toxicity was moderate, the most common grade 1-3 non-hematological toxicities were stomatitis and PPE, occurring in 20 (47.5%) and 16 (38%) patients, respectively. No cardiac toxicity was recorded. According to the intent to treat analysis a major objective response was observed in 59.5% of patients (95% CI, 43.3-74.4%), with a median time to progression of 9 months and an estimated overall survival at 18 months of 62%. CONCLUSION: The combination of PLD and weekly docetaxel is an effective first-line therapy for patients with advanced breast cancer. PPE and mucositis are the most relevant side effects of such a combination.

Adult↗
PubMed2004

Radiofrequency ablation of 40 lung neoplasms: preliminary results.

OBJECTIVE: Radiofrequency thermal ablation is a minimally invasive treatment widely used for treatment of liver neoplasms and has also been tested on other types of tumor. Few studies have been published regarding the use of radiofrequency thermal ablation in the treatment of lung neoplasms. This study was performed to evaluate the technical feasibility, the safety, and the efficacy of lung radiofrequency thermal ablation. SUBJECTS AND METHODS: Between February 2002 and March 2003, 18 subjects with unresectable lung neoplasms, four of whom had primary neoplasms and 14 of whom had metastatic neoplasms, underwent lung radiofrequency ablation. The technique was performed percutaneously using a monopolar cooled-tip electrode needle under CT guidance with the patient under general anesthesia. Patients had no more than three nodules with a total diameter of 10 cm and no evidence of extrathoracic disease. A total of 40 nodules were treated in 24 therapeutic sessions. After treatment, patients underwent follow-up every 3 months by CT and nuclear MRI with gadolinium for a median time of 8 months (range, 2-14 months). RESULTS: No evidence of local relapse was discovered in 94.4% of subjects. The treatment was safe and well tolerated. Complications encountered included massive pneumothorax, which occurred in one subject, requiring pleural drainage. Other complications were moderate pneumothorax (also requiring pleural drainage), cough, fever, slight dyspnea, and pain, but these complications were short in duration and successfully treated. CONCLUSION: Radiofrequency thermal ablation is a promising technique in the treatment of patients with lung neoplasms and has been found to be both safe and technically feasible.

Adult↗
PubMed2003

Fibrinogen: a novel predictor of responsiveness in metastatic melanoma patients treated with bio-chemotherapy: IMI (italian melanoma inter-group) trial.

PURPOSE: To evaluate a panel of pretreatment clinical and laboratory parameters in metastatic melanoma (MM) in order to verify their impact on response and survival in a single prospective multi-institutional phase III study comparing out-patient chemotherapy (CT) vs bioCT. METHODS: A total of 176 patients were randomised to receive CT (cisplatin, dacarbazine, optional carmustine) or bioCT (the same CT followed by subcutaneous IL-2 plus intramuscular alpha-IFN-2b). Pretreatment total leucocytes, lymphocytes, eosinophyls, C-reactive protein (CRP), lactate dehydrogenase (LDH), erytrosedimentation rate (ESR), and fibrinogen were analyzed. Some clinical parameters (performance status, age, sex, and disease site) were also considered. As we found a positive trend for bio-CT with no statistical significance in OR (25.3% vs 20.2%) and OS (11 Mo vs 9.5 Mo), all analyses are stratified by treatment arm. RESULTS: In univariate analysis, higher value of lymphocytes percentage (P <.0001), lower value of total leucocytes (P=.005), CRP (P=.003), LHD (P <.0001), ESR (P <.027), fibrinogen (P <.0001), and no liver disease were strongly related to a better survival. In a multivariate analysis, using the Cox proportional hazards model, only fibrinogen (P=.004), LDH (P=.009) and liver disease (P=.04) were found to have an independent role on clinical outcome in metastatic melanoma patients. CONCLUSION: Liver disease and higher LDH and fibrinogen levels had an important impact on survival in MM patients. In particular, fibrinogen has been recently reconsidered both for its determinant role in the host hemostatic system, and for its capability to provide protection against NK and LAK-cell-induced lysis. These observations could have some important implications for therapeutic approaches, in particular when immunological strategies are used.

Journal Article↗
PubMed2003

Kinetics of gadobenate dimeglumine in isolated perfused rat liver: MR imaging evaluation.

PURPOSE: To compare in the entire liver, the hepatic kinetics of gadobenate dimeglumine (Gd-BOPTA) and gadopentetate dimeglumine (Gd-DTPA) and to evaluate the hepatic transport of Gd-BOPTA. MATERIALS AND METHODS: The authors studied both contrast agents in isolated perfused rat livers by measuring the magnetic resonance (MR) signal intensity (SI) in 12 rats, as well as the gadolinium concentrations in hepatic tissues in 42 rats. The intrahepatic transport of Gd-BOPTA was investigated with pharmacologic antagonism by using bromosulfophthalein. MR imaging was performed at 1.5 T with a fast gradient-echo T1-weighted MR sequence. RESULTS: The hepatic kinetics based on the MR SI measured over time showed a rapid steady state during Gd-DTPA perfusion, while the SI continuously increased during the 30-minute Gd-BOPTA perfusion period. The pharmacokinetic modeling indicated that the half-lives of Gd-DTPA entry and exit were identical (mean, 1.3 minutes +/- 0.9 [standard error of mean]) and shorter than those observed with Gd-BOPTA (P <.001). The uptake of Gd-BOPTA was faster (mean half-life, 4.8 minutes +/- 0.3) than the washout (mean half-life, 17.5 minutes +/- 2.8) (P =.001). The combined perfusion of bromosulfophthalein and Gd-BOPTA decreased the SI enhancement in comparison with the perfusion of Gd-BOPTA alone (mean, 0.56 +/- 0.03 vs 2.54 +/- 0.39, P <.001). The entry and exit kinetic parameters obtained during the perfusion of Gd-BOPTA plus bromosulfophthalein were identical and comparable to those obtained during Gd-DTPA perfusion (P =.95). Acute bile duct ligation did not interfere with the uptake of Gd-BOPTA in hepatocytes, but it slowed down the excretion by approximately 50%. Measurements of gadolinium concentrations in hepatic tissues confirmed these findings. CONCLUSION: In the liver, the hepatospecific contrast agent Gd-BOPTA enters into hepatocytes likely through the organic anion transporting peptide 1.

Animals↗
PubMed2003

A phase I study of capecitabine in combination with vinorelbine in advanced breast cancer.

A phase I study was conducted in order to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the combination of vinorelbine and capecitabine in patients affected with metastatic breast cancer. Eighteen patients with histologically confirmed advanced breast cancer, who had failed =1 prior chemotherapy regimen, were enrolled. The median age was 56 years (range, 39-70 years). All but 1 had previously received a combination of anthracyclines and taxanes; performance status (Eastern Cooperative Oncology Group) was 0/1 or 2 in 13 and 5 patients, respectively. Vinorelbine was administered at a fixed dosage of 25 mg/m2 on days 1 and 8 every 3 weeks. Capecitabine was administered orally, at an escalated dose ranging from 1400 mg/m2 to 2250 mg/m2 for 14 consecutive days starting on day 1 of the cycle, divided into 2 daily doses delivered half an hour after eating at 12-hour intervals. Three patients were treated at each dose level: if 1 patient developed a DLT, an additional 3 patients were treated at the same dose level. If 2 additional patients experienced DLT, no further escalation was allowed and the previous dose level was declared MTD. Dose-limiting toxicity was reached at 2250 mg/m2 of capecitabine with 3 out of 3 patients experiencing grade 4 neutropenia plus grade 3 diarrhea and grade 3 oral mucositis in 1 patient). Thus, MTD was defined at 2000 mg/m2 capecitabine. Other observed grade 2 side effects were: 1 patient with neutropenia, 1 with hand-foot syndrome, 2 with mucositis, 1 with cutaneous rash, and 1 with thrombocytopenia. With regard to response rate, we observed 1 complete response (5.5%), 6 partial responses (33%), and 4 disease stabilizations (22%). The median time to progression was 12 weeks and the median survival 41 weeks. The MTD of capecitabine in combination with vinorelbine at 25 mg/m2 dosage on days 1 and 8 of a 3-week schedule is 2000 mg/m2/day for 14 consecutive days. Moreover, this regimen showed interesting activity with 61% overall disease control (complete plus partial response plus disease stabilization) in patients pretreated with anthracyclines and taxanes warranting further investigations in a large, multicenter phase II study.

Administration, Oral↗
PubMed2002

Time to progression in metastatic breast cancer patients treated with epirubicin is not improved by the addition of either cisplatin or lonidamine: final results of a phase III study with a factorial design.

PURPOSE: To investigate the value of the addition of either cisplatin (CDDP) or lonidamine (LND) to epirubicin (EPI) in the first-line treatment of advanced breast cancer. PATIENTS AND METHODS: Three hundred seventy-one metastatic breast cancer patients with no prior systemic chemotherapy for advanced disease were randomized to receive either EPI alone (60 mg/m(2) on days 1 and 2 every 21 days), EPI and CDDP (30 mg/m(2) on days 1 and 2 every 21 days), EPI and LND (450 mg orally daily, given continuously), or EPI, CDDP, and LND. Time to progression, response rates, side effects, and survival were compared according to the 2 x 2 factorial design of this study. RESULTS: The groups were well balanced with respect to prognostic factors. Time to progression did not differ in the comparison between CDDP arms and non-CDDP arms (median, 10.9 months v 9.4 months, respectively; P =.10) or between that of LND arms and non-LND arms (median, 10.8 months v 9.9 months, respectively; P =.47), nor did overall survival. The response rate did not significantly differ in the comparison between LND arms and non-LND arms (62.9% v 54.0%, P =.08). No difference in treatment activity was observed between CDDP arms and non-CDDP arms. Toxicity was significantly higher in the CDDP arms, leading to CDDP dose adjustment in 40% of cases. The most frequent side effects were of a hematologic and gastrointestinal nature. The addition of LND produced more myalgias and fatigue. CONCLUSION: Neither CDDP nor LND was able to significantly improve the time to progression obtained by EPI. CDDP, however, significantly worsened the drug's tolerability.

Adult↗
PubMed2002

Recombinant apolipoprotein A-I(Milano) infusion into rabbit carotid artery rapidly removes lipid from fatty streaks.

Apolipoprotein A-I(Milano) (AIM), a natural variant of human apolipoprotein A-I, confers to carriers a significant protection against vascular disease. In previous studies, administration of recombinant AIM-phospholipid (AIM-PL) complexes to hypercholesterolemic rabbits markedly inhibited neointimal formation after arterial injury; moreover, repeated injections of AIM-PL in apoE-deficient mice significantly reduced atherosclerosis progression. The objective of the present study was to determine if a single localized infusion of AIM-PL complexes administered directly to atheromatous lesions could promote plaque regression. Lipid-rich, atheromatous plaques were generated at both common carotid arteries of 25 rabbits by applying a perivascular electric injury, followed by 1.5% cholesterol diet for 90 days. Rabbits were infused with either saline, phospholipid vesicles, or 3 different AIM-PL doses (250, 500, or 1000 mg of protein) delivered through an intravascular ultrasound (IVUS) catheter positioned at the origin of the right carotid. The lesions at the left carotid artery were therefore exposed to the agents systemically. Infusion of AIM-PL at the 2 highest doses caused reduction of right carotid artery plaque area by the end a 90-minute infusion as assessed by IVUS analysis. Plaque area regression was confirmed by histology in carotid arteries receiving direct (500 and 1000 mg doses) and systemic (500 mg dose) delivery, 72 hours after the start of the treatment. Plaque lipid content was associated with significant and similar decreases in Oil Red O staining in both arteries. These results suggest AIM-PL complexes enhanced lipid removal from arteries is the mechanism responsible for the observed plaque changes.

Animals↗
PubMed2002

In vitro and in vivo hepatic transport of the magnetic resonance imaging contrast agent B22956/1: role of MRP proteins.

The molecular mechanisms of the hepatic transport of B22956/1, a new gadolinium complex from the class of intravascular contrast agents for MRI, which undergoes extensive biliary elimination, were studied. Biliary and urinary elimination of B22956/1 were measured in normal and in mutant MRP2 lacking rats (TR(-)); cellular trafficking of the compound was assessed in wild and MRP1 or MRP2 transfected MDCKII cells. Eight hours after IV injection of B22956/1, 90+/-8% of the dose was recovered in the bile of normal rats. By contrast, in TR(-) rats, the biliary excretion was significantly lower (14+/-3%) while 55+/-9% of the compound was found in urine. In vitro, the cellular accumulation of B22956/1 was significantly lower in both MRP1 and MRP2 transfected cells as compared to wild type MDCKII cells, and the cellular efflux was prevented by the MRP inhibitor MK571, indicating the involvement of both MRP2 and MRP1 in the transport of B22956/1. Due to the distinct cellular localization of the proteins, MRP2 accounts for the biliary and urinary excretion of the compound, while MRP1 prevents cellular accumulation of the MRI agent. B22956/1 may be useful in clinical conditions where a defective biliary transport is present.

ATP-Binding Cassette Transporters↗
PubMed2002

Effect of iomeprol on rat hippocampal slice synaptic transmission: comparison with other X-ray contrast agents.

RATIONALE AND OBJECTIVES: All contrast agents should be neurologically safe because although some are not indicated for procedures, such as myelography, just the same they may come in contact with nervous tissue during contrast-enhanced imaging. This is because even when they are intravascularly injected, the presence of undiagnosed blood-brain barrier damage may allow them to penetrate the brain barrier. In the present study, we investigated the neurologic safety of iomeprol by studying in vitro its potential effects on the central nervous system (CNS) synaptic transmission. Other widely used x-ray contrast agents were also assessed for comparative purposes. METHODS: CNS synaptic transmission was evaluated in terms of evoked field potentials recorded from the pyramidal region of rat hippocampal slices. The field potentials were evoked by electrical stimulation of the Schaffer collateral pathway. The effects of the contrast agents were evaluated in terms of number and amplitude of population spikes (PS) and as the maximal slope of the excitatory postsynaptic potentials (EPSP). The contrast agents were tested at final concentrations of 3, 10, and 30 mg(iodine)/mL in iso-osmolal condition with respect to artificial cerebrospinal fluid (CSF). RESULTS: Iomeprol, like ioversol, principally exerted a mild inhibitory effect on CNS synaptic transmission, an effect that was preceded by a weak, transient excitation. Iopentol exerted a rapid and complete inhibition of synaptic transmission without showing any excitatory effects. Iobitridol, though belonging to the nonionic monomeric class, exerted, surprisingly, an epileptogenic action at the highest concentration, whereas its inhibitory action was slow and mild. Diatrizoate, as expected, exerted an epileptogenic activity even at the lowest concentration, followed by a marked inhibitory action. Ioxaglate, as expected because it is an ionic though dimeric contrast agent, exerted an epileptogenic action at the intermediate concentration, whereas it barely demonstrated an inhibitory effect at all. All the contrast agent effects observed in the study reversed or tended to reverse during washout. CONCLUSIONS: Even taking in account the limitation because of the use of an in vitro approach and high contrast agent concentrations, we can conclude that the positive neuro-tolerability of iomeprol is further confirmed by this model as it proved to be devoid of epileptogenic activity and, among the contrast agents exhibiting inhibitory action, it was the contrast agent with the least amount of activity. In addition, contrary to that generally reported in the literature, nonionic, low osmolal contrast agents are not all identical in their neuro-tolerability when assessed in the rat hippocampal slice model.

Animals↗
PubMed2002

Pharmacokinetics and safety of gadobenate dimeglumine (multihance) in subjects with impaired liver function.

RATIONALE AND OBJECTIVES: To characterize the pharmacokinetics of gadolinium and to evaluate the safety of gadobenate dimeglumine (Gd-BOPTA) compared with placebo, in subjects with impaired liver function. METHODS: Volunteer adult subjects with hepatic impairment (Child-Pugh classification B or C) received, randomly and in double-blind fashion, either 0.1 mmol/kg gadobenate dimeglumine (n = 11) or placebo (n = 5) by intravenous injection. Blood and urine gadolinium concentrations were determined by ICP-AES and data were analyzed by compartmental and noncompartmental modeling. A full safety evaluation was performed. No magnetic resonance imaging was performed. RESULTS: A bi-exponential model fit the gadolinium blood concentration-time data for 10 of 11 subjects administered Gd-BOPTA. The mean (CV%) distribution and elimination half-lives for these subjects were 0.18 (71.9) and 2.18 (44.2) hours, respectively. Non-parametric analysis of all 11 subjects revealed a mean (CV%) area under the curve [0-inf] of 138 (41.9) microg(Gd).h/mL. Mean (CV%) values for blood clearance, steady-state volume of distribution, and renal clearance were 172 (36.0) mL/minute, 22.9 (16.7) L, and 142 (49.0) mL/minute, respectively. A mean (CV%) of approximately 80% (24.5) of the administered dose was excreted in urine during 60 to 72 hours. No safety concerns were apparent. CONCLUSION: Hepatic impairment did not modify the pharmacokinetics of gadobenate dimeglumine compared with values reported elsewhere for healthy subjects. The contrast agent was well tolerated and safe with an overall incidence of adverse events comparable to that of placebo.

Adult↗
PubMed2002

Current status and future potential role of exemestane in the treatment of early and advanced breast cancer (Review).

Exemestane is a new oral steroidal aromatase inactivator, active in postmenopausal women with hormonal sensitive breast carcinoma. This drug, at a dosage of 25 mg once daily, was shown to suppress in vivo aromatase activity by 97.9%, with a subsequent reduction superior to 85% of circulating oestrogen level. It exhibits definite antitumor activity at a relatively low daily dose, and is highly potent, highly selective, and well-tolerated. Moreover, for postmenopausal women with metastatic breast cancer, exemestane demonstrated a higher activity and lower toxicity profile when compared to megestrol acetate and tamoxifen in second- and first-line therapy, respectively. New data on exemestane are forthcoming both in the adjuvant and neoadjuvant setting, which could improve the management of early breast cancer in the future.

Androstadienes↗
PubMed2001

The role of letrozole (Femara(R)) in breast cancer therapy: A clinical review.

Letrozole is a third-generation aromatase inhibitor for use in postmenopausal women with hormonal-sensitive breast cancer. This drug was found to reduce or effectively shrink tumors in a significant number of such patients. It exhibits antitumor activity at a relatively low daily dose, and is highly potent and selective and well tolerated. Results from recent phase III clinical studies have confirmed the efficacy and the key role of this drug in the therapy of advanced breast cancer in postmenopausal women. Moreover, letrozole demonstrated higher activity and lower toxicity compared to tamoxifen in the first-line therapy of postmenopausal women affected with advanced breast cancer. However, it also represents a valid option in second-line therapy after tamoxifen failure. New data on this agent in adjuvant or neoadjuvant treatment also suggest efficacy in the treatment of early breast cancer. This article reviews the clinical data on letrozole in all settings and its future potential in chemoprevention. (c) 2001 Prous Science. All rights reserved.

Journal Article↗