Search PubMed⌕ Search

Biomedical subjects

L Ferrari

Publications and source records attributed to L Ferrari.

At least 37 records · Page 2Linked to original sources
PubMed1997

The minimal effective exemestane dose for endocrine activity in advanced breast cancer.

Phase I studies have demonstrated that exemestane, an irreversible oral aromatase inhibitor, is able to suppress circulating oestrogen levels. In our previous experience, doses ranging from 2.5 to 25 mg induced a similar suppression of oestrogens. The aim of this study was to identify the minimum effective exemestane dose on the basis of endocrine activity. 20 evaluable postmenopausal advanced breast cancer patients were randomly given exemestane 0.5, 1, 2.5 or 5 mg, in double-blind conditions. Oestrone (E1), oestradiol (E2), oestrone sulphate (E1S), gonadotrophins, sex-hormone binding globulin and dehydroepiandrosterone sulphate serum levels were evaluated from the first day of treatment to the 7th, 14th, 28th and 56th day. Serum E1, E2 and E1S levels were suppressed by all doses starting from day 7; the degree of inhibition versus baseline was 25 up to 72% for E1, 30 up to 62% for E2 and 16 up to 52% for E1S, with higher doses achieving greater suppression; these changes were maintained over time. A significant increase in FSH and LH levels was observed for all doses. Treatment tolerability was satisfactory. The endocrine effects of exemestane appear to be dose related and 0.5 and 1 mg are ineffective for adequately suppressing circulating oestrogens.

Aged↗
PubMed1997

A multicentre, randomized, pharmacokinetic, endocrine and clinical study to evaluate formestane in breast cancer patients at first relapse: endocrine and clinical results. The Italian Trials in Medical Oncology (I.T.M.O.) group.

BACKGROUND: In postmenopausal breast cancer (BC) patients, tamoxifen (TAM) is frequently used in first-line therapy, and for those relapsing under TAM, aromatase inhibitors would be the drug of choice. Formestane, a new aromatase inhibitor, has been demonstrated to be as effective as TAM in first-line therapy. This trial was carried out to investigate the pharmacokinetics and antitumor activity of two formestane doses in BC patients at first relapse, as well as their effects on estrogen levels, evaluated by means of a new analytical method. PATIENTS AND METHODS: One hundred fifty-two postmenopausal BC patients were randomly given formestane 250 mg or 500 mg intramuscularly every two weeks. The blood samples for estrogen measurements were taken on the first day of therapy, at 4 and 10 weeks, and every 12 weeks thereafter. Tumor response was first evaluated after 2.5 months, and then every three months. RESULTS: Seventy-three patients received formestane 250 mg and 79 received 500 mg. After four weeks, plasma estrone, estradiol and estrone sulphate levels were significantly (P < 0.001) suppressed in both groups. The overall response rates were 30% and 40% on 250 mg and 500 mg, respectively. CONCLUSIONS: Both of the formestane doses are effective in reducing plasma estrogen levels in BC patients at first relapse, and the new analytical method improved the quality of results. The antitumor response was highly satisfactory.

Adult↗
PubMed1997

Flow cytometry measurement of GM-CSF receptors in acute leukemic blasts, and normal hemopoietic cells.

A quantitative analysis of expression levels of GM-CSF receptors was performed by flow cytometry in different disease categories, ie AML (n = 72), ALL (n = 18), and MDS (n = 12), as well as 12 healthy volunteers, using three different unconjugated GM-CSF/R monoclonal antibodies (McAbs) (HGM-CSFR (CD116), M5D12, 4B5F5), and appropriate standards. By using the reference HGM-CSFR McAb, in healthy subjects we found detectable levels of GM-CSF/R on blood monocytes (mean MESF (molecules of equivalent soluble fluorochrome)/cell: 36.1 x 10[3]), neutrophils (mean MESF/cell: 7.4 x 10[3]), bone marrow (BM) myelo-monocytic precursors (MESF range for the myeloid component, ie promyelocytes, myelocytes, metamyelocytes: 11.7-40.5 x 10[3], and for the monocytic lineage: 25.7-69.2 x 10[3]), and in two distinct subsets of BM CD34+ progenitor cells (GM-CSF/R dim: 2.5 x 10[3] MESF/cell, GM-CSF/R bright (10% of the total number of CD34 cells: 22.0 x 10[3] MESF/cell). In these subjects, there was no correlation between the expression levels of GM-CSF/R and CFU (CFU-GM, CFU-GEMM, BFU-E) colony production. Among the AML samples, M5D12 McAb was positive in 33%, 4B5F5 McAb in 90%, and HGM-CSF/R McAb in 78% of the cases examined (range of MESF/cell for the HGM-CSFR McAb: 0.9 x 10[3]-106.7 x 10[3]). The highest MESF values were seen in the M5 FAB subvariety (mean: 39.4 x 10[3]), where all the patients tested (n = 20) showed a strong positivity for the HGM-CSFR McAb. On the contrary, all ALL samples were GM-CSF/R negative except in two patients, who displayed a dim GM-CSF/R positivity (My+ALL: 1.3 x 10[3] MESF/cell; pro-B ALL: 1.0 x 10[3] MESF/cell). In most (>70%) M1 FAB subtypes, GM-CSF/R+ blasts co-expressed CD34low, HLA-DRhigh, CD33, CD38 antigens, and had little or no capacity to form CFU-GM colonies. GM-CSF/R+ blasts from the M5 FAB category were also positive for CD14, CD11c, CD33 and CD87. Furthermore, the number of GM-CSF/R expressed by leukemic cells from five out of 72 (7%) AML patients was above the highest values seen in normal samples (>69.2 x 10[3] MESF/cell), allowing the possibility of using this marker for the monitoring of the minimal residual disease (MRD) in a subset of AML. Cell culture studies aimed at evaluating GM-CSF receptor modulation following AML blast exposure to rhGM-CSF showed two distinct patterns of response; in the first group (6/10 cases) rhGM-CSF down-modulated GM-CSF receptors, whereas in the second group (4/10 cases), rhGM-CSF treatment was associated with either an increase or no change in the number of GM-CSF/R. In conclusion, cellular GM-CSF/R expression was variable and ranged from undetectable (ALL and a minority of AML) to very high intensities in M5 AML, and were also documented in some M0 AML, thus suggesting the concept that GM-CSF/R detection may be of help in lineage assignment of undifferentiated forms. Since the number of GM-CSF/R on AML blasts may be modulated after GM-CSF treatment, it can be postulated that the clinical use of GM-CSF in this disease may be optimized by a dynamic analysis of the number and the affinity status of GM-CSF-R in blasts and normal hemopoietic cells.

Acute Disease↗
PubMed1997

Serum markers of bone metastases in postmenopausal breast cancer patients treated with formestane.

Bone metabolism marker evaluation is expected to play an auxiliary role in the diagnosis and follow-up of bone metastases in patients affected by different types of neoplasms. In this study we have evaluated osteoblastic and osteoclastic markers in 18 patients with bone metastases from breast cancer at diagnosis and for 1 year of follow-up during treatment with the aromatase inhibitor formestane. Osteoblastic markers include the carboxy-terminal propeptide of type I procollagen, the bone-specific alkaline phosphatase and the bone GLA protein. The carboxy-terminal cross-linked telopeptide of type I collagen (ICTP) was evaluated as a marker of osteoclastic activity. The patients were classified into three groups according to clinical response. A good correlation between marker level modifications and clinical evolution of skeletal metastases was observed for all the examined markers. Patients with progressive disease showed increasing levels of all markers, whereas patients in regression showed a reduction compared to the basal levels; patients with stable disease fell in between these two categories. We also found that basal ICTP values have prognostic significance: in the stable and progressive disease group they were higher than in the partial response group.

Alkaline Phosphatase↗
PubMed1996

A dose-finding study of lanreotide (a somatostatin analog) in patients with colorectal carcinoma.

BACKGROUND: Laboratory data suggest that insulin-like growth factor-1 (IGF-1) may stimulate the growth of different human tumors. At least in acromegalic patients, somatostatin (SMS) analogs, such as lanreotide, suppress the serum levels of growth hormone (GH) and IGF-1. METHODS: To evaluate the tolerability and biologic activity of different doses of lanreotide in patients with advanced colorectal carcinoma, consecutive groups of 3 patients each were subcutaneous treated with lanreotide at doses of 1, 2, 3, 4, 5, or 6 mg three times a day for 2 months. In the event of Grade 3 side effects, 3 additional patients were treated with the same dose before the next dose escalation. Serum samples were obtained on Days 0, 15, 30, and 60 for serum GH, IGF-1, and lanreotide assessment. RESULTS: Twenty-four patients were enrolled and all were evaluable. Except for the 3 and 6 mg doses, for which the observation of a Grade 3 side effect required that an additional three patients be treated, it was sufficient to treat 3 patients at each dose. The overall incidence of side effects was as follows: changes in bowel habits, 83%; abdominal cramps, 79%; diarrhea, 17%; vomiting, 17%; nausea, 21%; steatorrhea, 78%; hyperglycemia, 35%; laboratory hypothyroidism, 39%; gallstones, 13%; and weight loss, 17%. No evidence of an increase in the incidence, intensity, or duration of side effects was observed with dose escalation. Serum IGF-1 levels were as follows: Day 15: 63%, 60%, and 67% of the baseline values for the low (1-2 mg), intermediate (3-4 mg), and high (5-6 mg) dose groups, respectively; Day 30: 63%, 59%, and 51%, respectively; and Day 60: 73%, 69%, and 47%, respectively. Serum lanreotide levels declined during treatment in all of the dose groups (90 ng/mL on Day 15, and 35 ng/mL on Day 60 for the 5-6 mg group; 10 ng/mL on Day 15, and 1.5 ng/mL on Day 60 for the 1-2 mg group). No antitumor activity or tumor marker reduction was observed. CONCLUSIONS: No increase in toxicity was observed when subcutaneous lanreotide doses were escalated to 6 mg three times a day for 2 months. The highest doses seemed to maintain reduced serum IGF-1 levels; with the lowest doses, a "rebound" in serum IGF-1 levels was observed during treatment. Nevertheless, intermittent subcutaneous injections do not ensure constant serum drug concentrations over time.

Adult↗
PubMed1996

Vinorelbine: an active, non cross-resistant drug in advanced breast cancer. Results from a phase II study.

PURPOSE: To evaluate efficacy and toxicity of vinorelbine and to investigate its cross-resistance with other current drug treatments for metastatic breast cancer. PATIENTS AND METHODS: From July 1992 to December 1993, 57 histologically proven breast cancer patients entered this Phase II study. Patients were stratified according to their status of previous treatment, namely, no prior chemotherapy or relapse more than 12 months since the end of adjuvant chemotherapy (Group A) and other patients (Group B). RESULTS: Fifty three patients were evaluable for response, 27 in Group A and 26 in Group B. All patients were evaluable for toxicity. Vinorelbine was initially administered at the dose of 30 mg/sqm weekly by i.v. infusion in 100 ml of normal saline over 20 minutes. A frequency analysis of drug administration in the first 20 cases revealed two main treatment periodicities, corresponding to one week and to three weeks. Thereafter the drug was administered at 30 mg/sqm on day 1 and 8, every 3 weeks. With the new drug schedule, the mean dose intensity increased from 19.7 to 21.1 mg/sqm per week. Overall, an objective response rate of 47% (95% C.I. 33%-61%) was documented. Four patients achieved complete response (7%, CI: 2%-18%) and 21 partial response (40%, CI: 26%-54%). Fifty nine percent of patients in Group A and 35% in Group B showed objective tumor response. The analysis of response rate in previously treated patients failed to show evidence of cross-resistance with vinorelbine. Main side effects, i.e. neutropenia, local pain, and gastrointestinal and flu-like symptoms, were moderate and short lasting. CONCLUSION: Vinorelbine has clinically significant activity in metastatic breast cancer, and no cross-resistance with prior anthracyclines and CMF treatments. The drug schedule of 30 mg/sqm iv bolus on day 1 and 8 every 3 weeks was found effective and tolerable.

Adult↗
PubMed1996

The role of somatostatin analogues in the treatment of gastro-enteropancreatic endocrine tumours.

Neuroendocrine (NE) cells are involved in gastro-enteropancreatic (GEP) neoplasms. Biological markers, such as peptides hypersecreted by biologically active NE tumours, aid in the evaluation of response to treatment. For surgically untreatable NE neoplasms, the therapeutic approach remains undefined. Somatostatin analogues, particularly octreotide, can control the clinical effects of hormone overproduction in NE neoplasms and they have revolutionised individualised treatment, particularly for biologically active tumours. So far, like interferon, octreotide used at standard dosages has failed to control neoplastic growth per se. We gave the somatostatin analogue lanreotide to women with advanced breast cancer and to colorectal carcinoma patients. Results confirmed that inhibition of the production of insulin-like growth factor-1, which plays an important role in neoplastic proliferation, could be obtained using the highest doses. Considering these data, we started a clinical trial of 58 patients affected by NE tumours, treated with two sequential doses (500 and 1,000 micrograms subcutaneously t.i.d.) of octreotide. Long-term disease stabilisation (> 6 months) was achieved in 43% of patients but an objective response in only 3%. Good control of clinical symptoms and markers was obtained in 73 and 77% of cases, respectively. Toxicity was negligible. Somatostatin analogues should be carefully evaluated at high doses for possible anti-proliferative effects. Studies are currently investigating their promising association with interferon.

Antineoplastic Agents, Hormonal↗
PubMed1996

Increased plasma level of vascular endothelial glycoprotein thrombomodulin as an early indicator of endothelial damage in bone marrow transplantation.

We investigated the nature of hemostatic alterations occurring after bone marrow transplantation. In 45 patients, we evaluated the coagulation parameters, naturally occurring anticoagulants and thrombomodulin at days +15 and +22 after conditioning therapy. It was observed that endothelial cell damage is a central pathogenetic mechanism in some BMT complications. The increased plasma level of thrombomodulin after conditioning therapy is therefore discussed as a marker of endothelial cell injury. At day +15 a significant increase of fibrinogen from 276.1 mg/dI to 389.1 mg/dI was observed, while the natural anticoagulants all decreased significantly. Eleven patients with clinical complications related to endothelial damage had a significant thrombomodulin increase which, in uncomplicated patients, remained unchanged or resulted in lower than baseline values. Analysis of the data shows a strong correlation between clinical findings, reflecting endothelial cell injury and thrombomodulin increase when the increment is > or = 30%. We found a significant elevation in thrombomodulin in 70% of clinical complications related to endothelial cell damage namely: septicemia, GVHD, VOD. There were four cases (or 9%) of false positive data, and only two (or 4.5%) of false negative results. We therefore propose thrombomodulin assessment as a valid parameter to monitor chemotherapy toxicity-related complications.

Adolescent↗
PubMed1995

Changes in biological markers after primary chemotherapy for breast cancers.

The profiles of functional (proliferative rate and cell distribution in the cell cycle) and phenotypic (nuclear DNA content and hormone receptor status) biological markers and the expression of P53 and Bcl-2 proteins were prospectively evaluated in breast cancers before and after different regimens of primary chemotherapy. Overall, changes induced on the 2 proliferation indices (3H-thymidine labelling index, 3H-dT LI, and flow-cytometric S-phase fraction, FCM-S) mainly consisted of a decrease for rapidly proliferating tumours and an increase or no change for slowly proliferating tumours. However, when considered as a function of treatment type, changes of 3H-dT LI and FCM-S were superimposable in rapidly proliferating tumours, regardless of the type of treatment, and in slowly proliferating tumours only after anthracycline-including regimens. Conversely, following CMF, FCM-S was increased in 90% of the cases and 3H-dT LI in only 50%. Our data imply that the 2 proliferation indices could reflect different phenomena: an actual variation of proliferative activity by 3H-dT LI and an accumulation of cells in the S-phase by FCM-S. In addition, a higher accumulation of cells in G2-M phases could be detected by FCM after anthracycline-including regimens than after CMF. The fraction of P53-positive cells was reduced by primary chemotherapy in about 50% of P53-positive tumours, whereas Bcl-2 expression was only marginally affected. DNA ploidy and hormone receptor status did not change in about 75% of cases, regardless of the chemotherapeutic regimen.

Aneuploidy↗
PubMed1995

Biological and clinical evaluation of lanreotide (BIM 23014), a somatostatin analogue, in the treatment of advanced breast cancer. A pilot study by the I.T.M.O. Group. Italian Trials in Medical Oncology.

Biological data support the development of clinical trials designed to evaluate the activity of somatostatin (SMS) analogues in advanced breast cancer (ABC). Although previous clinical trials have failed to show antitumor activity, various factors may have biased their results. In an attempt to improve our understanding of the role of SMS analogues in ABC, 10 patients with favourable prognostic factors and who had not been heavily pretreated for advanced disease were treated with lanreotide 30 mg i.m. fortnightly (depot formulation). Blood samples were periodically taken to evaluate the effect of the drug on growth hormone (GH) and insulin-like growth factor 1 (IGF-1) and to determine drug serum levels. Although the drug was well tolerated, no clinical activity was observed. Serum GH and IGF-1 levels were not properly suppressed over time and drug serum concentrations fluctuated widely. In conclusion, SMS analogues cannot be recommended even as palliative treatment of ABC. Further studies should be undertaken to investigate the effect of higher drug doses, given subcutaneously or by means of continuous infusion, in suppressing GH and IGF-1 serum levels.

Adult↗
PubMed1995

Human cell lines in pharmacotoxicology. An introduction to a panel discussion.

Various types of cells lines are used in pharmacotoxicology. Established cell lines are easily available, with few ethical restrictions. Some specific properties are preserved, although they have kept the phenotype of the original tissue, which is frequently a tumor phenotype. They are usually more resistant to toxic compounds than freshly isolated cells. Some drug-metabolizing enzymes are expressed and regulated in these cells. Immortalized cell lines are also of interest in toxicology. They are mainly examined for their potential in mutagenicity testing. These cells and numerous others of animal or human origin can be transfected with cDNA coding for human enzymes. They are used for determination of the individual enzyme involved in a particular metabolic pathway, or, when multiple transfections are successfully achieved, for mutagenicity testing. Regulation studies are also possible in such cells after transfection of DNA elements regulating gene transcription.

Cell Line↗