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Biomedical subjects

Luca Gianni

Publications and source records attributed to Luca Gianni.

At least 19 recordsLinked to original sources
PubMed2006

Defective one- or two-electron reduction of the anticancer anthracycline epirubicin in human heart. Relative importance of vesicular sequestration and impaired efficiency of electron addition.

One-electron quinone reduction and two-electron carbonyl reduction convert the anticancer anthracycline doxorubicin to reactive oxygen species (ROS) or a secondary alcohol metabolite that contributes to inducing a severe form of cardiotoxicity. The closely related analogue epirubicin induces less cardiotoxicity, but the determinants of its different behavior have not been elucidated. We developed a translational model of the human heart and characterized whether epirubicin exhibited a defective conversion to ROS and secondary alcohol metabolites. Small myocardial samples from cardiac surgery patients were reconstituted in plasma that contained clinically relevant concentrations of doxorubicin or epirubicin. In this model only doxorubicin formed ROS, as detected by fluorescent probes or aconitase inactivation. Experiments with cell-free systems and confocal laser scanning microscopy studies of H9c2 cardiomyocytes suggested that epirubicin could not form ROS because of its protonation-dependent sequestration in cytoplasmic acidic organelles and the consequent limited localization to mitochondrial one-electron quinone reductases. Accordingly, blocking the protonation-sequestration mechanism with the vacuolar H+-ATPase inhibitor bafilomycin A1 relocalized epirubicin to mitochondria and increased its conversion to ROS in human myocardial samples. Epirubicin also formed approximately 60% less alcohol metabolites than doxorubicin, but this was caused primarily by its higher Km and lower Vmax values for two-electron carbonyl reduction by aldo/keto-reductases of human cardiac cytosol. Thus, vesicular sequestration and impaired efficiency of electron addition have separate roles in determining a defective bioactivation of epirubicin to ROS or secondary alcohol metabolites in the human heart. These results uncover the molecular determinants of the reduced cardiotoxicity of epirubicin and serve mechanism-based guidelines to improving antitumor therapies.

Aconitate Hydratase↗
PubMed2006

Phase I clinical and pharmacological evaluation of the multi-tyrosine kinase inhibitor SU006668 by chronic oral dosing.

SU006668, an oral inhibitor of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR), was administered in fed conditions to 24 patients with advanced solid cancer at 100, 200 and 300 mg/m(2) b.i.d. Dose escalation was discontinued because the maximum tolerated dose was defined at 400 mg/m(2) b.i.d in a concomitant trial. The drug was generally well tolerated although two patients presented possibly drug-related dose-limiting toxicities (pericardial effusion and thrombocytopenia). SU006668 had a non-linear pharmacokinetic profile characterized by AUC and Cmax decreasing from day 1 to day 28 in all patients at all tested doses; a lower apparent bioavailability on day 28 compared to day 1; and a significant concomitant increase of the urinary metabolites. These findings are in agreement with the presence of saturable absorption and metabolic induction. The peculiar pharmacokinetics and >99% protein binding discouraged further clinical development of oral SU006668 in humans.

Administration, Oral↗
PubMed2005

Feasibility and tolerability of sequential doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as preoperative therapy.

PURPOSE: The European Cooperative Trial in Operable breast cancer (ECTO) randomly tested whether efficacy of adjuvant doxorubicin followed by i.v. cyclophosphamide, methotrexate, and fluorouracil (CMF; doxorubicin-->CMF, arm A) could be improved by adding paclitaxel (doxorubicin/paclitaxel-->CMF) as adjuvant (arm B) or primary systemic therapy (PST, arm C). We report here feasibility, tolerability, locoregional antitumor activity, and breast conservation rate. METHODS: A total of 1,355 women entered the study. Feasibility and safety were compared in arm A versus arms B plus C. Surgical findings were compared in arms A plus B versus arm C. RESULTS: Grade 3 or 4 National Cancer Institute toxicities were low (<5%) in all arms. Neuropathy was more frequent in the paclitaxel-containing arms (grade 2, 20.5% versus 5.0%; grade 3, 1.3% versus 0.2%). At 31 months of follow-up, asymptomatic drop of left ventricular ejection fraction was similar in all arms, whereas symptomatic cardiotoxicity was recorded in three patients (0.5%) in A and in three patients (0.3%) in B plus C. PST induced clinical complete plus partial remission in 78%, with an in-breast pathologic complete response rate of 23% and an in-breast plus axilla pathologic complete response rate of 20%. In the multivariate analysis, only estrogen receptor (ER) status was significantly associated with pathologic complete response (odds ratio for ER negative, 5.77; 95% confidence interval, 3.49-9.52; P<0.0001). PTS induced a significant axillary downstaging (P<0.001), and breast sparing surgery was feasible in 65% versus 34% (P<0.001). CONCLUSIONS: Doxorubicin/paclitaxel-->CMF is feasible, safe, and well tolerated. Given as PST, it is markedly active, allowing for breast-sparing surgery in a large fraction of patients.

Aged↗
PubMed2005

Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.

BACKGROUND: Trastuzumab, a recombinant monoclonal antibody against HER2, has clinical activity in advanced breast cancer that overexpresses HER2. We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy. METHODS: This international, multicenter, randomized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy. RESULTS: Data were available for 1694 women randomly assigned to two years of treatment with trastuzumab, 1694 women assigned to one year of trastuzumab, and 1693 women assigned to observation. We report here the results only of treatment with trastuzumab for one year or observation. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P<0.0001 by the log-rank test, crossing the interim analysis boundary), representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation). Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab. CONCLUSIONS: One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer. (ClinicalTrials.gov number, NCT00045032.)

Adult↗
PubMed2005

Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer.

PURPOSE: We sought to identify gene expression markers that predict the likelihood of chemotherapy response. We also tested whether chemotherapy response is correlated with the 21-gene Recurrence Score assay that quantifies recurrence risk. METHODS: Patients with locally advanced breast cancer received neoadjuvant paclitaxel and doxorubicin. RNA was extracted from the pretreatment formalin-fixed paraffin-embedded core biopsies. The expression of 384 genes was quantified using reverse transcriptase polymerase chain reaction and correlated with pathologic complete response (pCR). The performance of genes predicting for pCR was tested in patients from an independent neoadjuvant study where gene expression was obtained using DNA microarrays. RESULTS: Of 89 assessable patients (mean age, 49.9 years; mean tumor size, 6.4 cm), 11 (12%) had a pCR. Eighty-six genes correlated with pCR (unadjusted P < .05); pCR was more likely with higher expression of proliferation-related genes and immune-related genes, and with lower expression of estrogen receptor (ER) -related genes. In 82 independent patients treated with neoadjuvant paclitaxel and doxorubicin, DNA microarray data were available for 79 of the 86 genes. In univariate analysis, 24 genes correlated with pCR with P < .05 (false discovery, four genes) and 32 genes showed correlation with P < .1 (false discovery, eight genes). The Recurrence Score was positively associated with the likelihood of pCR (P = .005), suggesting that the patients who are at greatest recurrence risk are more likely to have chemotherapy benefit. CONCLUSION: Quantitative expression of ER-related genes, proliferation genes, and immune-related genes are strong predictors of pCR in women with locally advanced breast cancer receiving neoadjuvant anthracyclines and paclitaxel.

Adult↗
PubMed2005

Trabectedin for women with ovarian carcinoma after treatment with platinum and taxanes fails.

PURPOSE: To assess the efficacy and toxicity of the marine-derived alkaloid trabectedin (ET-743) in patients with advanced ovarian cancer refractory to or experiencing disease relapse after platinum- and taxane-based chemotherapy. PATIENTS AND METHODS: Fifty-nine patients from four institutions either resistant (n = 30) or sensitive (n = 29) to prior platinum and taxanes were treated with a 3-hour infusion of trabectedin every 3 weeks. Patients were monitored weekly for toxicity and restaged every two cycles for response. Response was assessed according to Response Evaluation Criteria in Solid Tumors Group. RESULTS: The peer-reviewed objective response rate in platinum-sensitive patients was 43% (95% CI, 23% to 65%) with an estimated median time to progression of 7.9 months (95% CI, 7.5 to 14.1 months); in platinum-resistant patients two partial responses were observed. Responses were durable for up to 12.9 months (median, 5 months). The predominant toxicities at the recommended dose of 1,300 microg/m(2) were neutropenia, asthenia, and self-limited increase of aminotransferases never requiring treatment interruption. CONCLUSION: Trabectedin administered as a 3-hour infusion at 1,300 microg/m(2) is a safe new drug with promising activity in relapsed ovarian cancer, showing a 43% objective response rate in patients with platinum-sensitive disease, which favorably compares with other salvage treatments and warrants additional development either alone or in combination.

Adult↗
PubMed2005

30 years' follow up of randomised studies of adjuvant CMF in operable breast cancer: cohort study.

OBJECTIVE: To assess the long term effectiveness of adjuvant treatment with cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with operable breast cancer at risk of relapse, on the basis of three successive randomised trials and one observational study conducted from June 1973 to December 1980. DESIGN: Cohort study. SETTING: Istituto Nazionale Tumori in Milan, Italy. MAIN OUTCOME MEASURES: Relapse free and overall survival, measured by univariate and multivariate analyses. RESULTS: After a median follow up of 28.5 years for the initial study, adjuvant CMF was found to reduce the relative risk of relapse significantly (hazard ratio 0.71, 95% confidence interval 0.56 to 0.91, P = 0.005) and death (0.79, 0.63 to 0.98, P = 0.04). Administration of CMF for 12 cycles does not seem superior to a shorter administration of six cycles. In the node negative and oestrogen receptor negative trial, intravenous CMF significantly reduced the relative risk of relapse of disease (0.65, 0.47 to 0.90, P = 0.009) and death (0.65, 0.47 to 0.92, P = 0.01) at a median follow up of 20 years. CONCLUSIONS: When delivered optimally, CMF benefits patients at risk of relapse of distant disease without evidence of detrimental effects in any of the examined subgroups.

Adult↗
PubMed2005

Symptomatic and neurophysiological responses of paclitaxel- or cisplatin-induced neuropathy to oral acetyl-L-carnitine.

Acetyl-L-carnitine (ALC) improves non-oncological neuropathies. We tested oral ALC (1 g tid) for 8 weeks in 25 patients with neuropathy grade 3 (common toxicity criteria--CTC) during paclitaxel or cisplatin therapy, or grade 2 persisting for at least three months after discontinuing the drugs. An independent neurologist assessed patients before and after ALC. All patients except one reported symptomatic relief, and only two described grade 1 nausea. The sensory neuropathy grade improved in 15 of 25 (60%), and motor neuropathy in 11 of 14 patients (79%). Total neuropathy score (TNS) that included neurophysiological measures improved in 23 (92%). Amelioration of sensory amplitude and conduction velocity (sural and peroneal nerves) was measured in 22 and 21 patients, respectively. Symptomatic improvement persisted in 12 of 13 evaluable patients at median 13 months after ALC. In view of its effect in improving established paclitaxel- and cisplatin-neuropathy, we recommend ALC testing in preventing progression or revert symptoms during neurotoxic chemotherapy.

Acetylcarnitine↗
PubMed2004

The choice of the correct imaging modality in breast cancer management.

This brief overview discusses which of the diagnostic options are more reliable and effective for breast cancer imaging with a view to avoiding the unjustified use of techniques that are suboptimal. The technological development of diagnostic imaging has been very impressive, and both radiological (mammography, ultrasonography, computed tomography, magnetic resonance imaging) and nuclear medicine tools (bone scan, planar and SPECT scintigraphy, sentinel node biopsy, positron emission tomography) have helped to overcome past limitations in the detection of small lesions. Furthermore, new approaches have been developed that permit successful differential diagnosis of doubtful lesions and rapid identification of systemic metastases, and allow non-invasive characterisation of the biology of cancer tissue. There is evidence that these advances may have helped in optimising therapeutic strategies. Importantly, the metabolic information provided by nuclear medicine procedures may be combined with the anatomical data supplied by radiological techniques in order to assist in predicting tumour response, planning radiotherapy and monitoring patient outcome. It is difficult to formulate conclusive diagnostic guidelines for application in the work-up of breast cancer, because while the role of some examinations, such as mammography and ultrasonography, is well established, that of others, such as magnetic resonance imaging and positron emission tomography, is still a matter of debate. There is a need for further prospective evaluations with appropriate clinical trials designed to evaluate the impact of these approaches in improving survival and quality of life.

Biopsy, Needle↗
PubMed2004

Clinical relevance of different sequencing of doxorubicin and cyclophosphamide, methotrexate, and Fluorouracil in operable breast cancer.

PURPOSE: To assess the clinical relevance of different sequences of doxorubicin (DOX) and cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients with operable breast cancer at risk of disease relapse. PATIENTS AND METHODS: Two randomized trials were activated in the early 1980s. The first study, in patients with one to three involved nodes, was intended to assess the effectiveness of intravenous (i.v.) CMF given every 3 weeks for 12 courses versus eight courses of the same CMF regimen followed by four courses of full-dose DOX (CMF-->DOX). The second study, in patients with more than three involved nodes, compared four courses of full-dose DOX sequentially followed by eight courses of i.v. CMF (DOX-->CMF) versus alternating two courses of the same CMF regimen with one course of DOX (CMF/DOX) for a total of 12 courses. RESULTS: After a median observation of 210 months, no statistically significant difference was documented in the first study (relapse-free survival hazard rate [HR], 1.06; total survival HR, 1.03). In contrast, the delivery of DOX first, followed by CMF significantly reduced the risk of disease relapse (HR, 0.68; 95% CI, 0.54 to 0.87; P =.0017) and death (HR, 0.74; 95% CI, 0.57 to 0.95; P =.018) compared with the alternating regimen. CONCLUSION: Anthracycline-containing regimens can further reduce the odds of relapse and death compared with CMF. However, the findings observed in our trials emphasize that the relative merits of anthracycline adjuvant programs also can depend on the modality of administration and must be assessed in properly designed trials in which the magnitude of the benefits can be weighed against potential risks.

Adult↗
PubMed2004

Inhibition of proliferation and induction of apoptosis in breast cancer cells by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 ('Iressa') is independent of EGFR expression level.

High expression of the epidermal growth factor receptor (EGFR) in breast carcinoma confers a growth advantage to the tumor cells. The EGFR tyrosine kinase inhibitor (EGFR-TKI) ZD1839 ('Iressa') has clinical activity in a wide range of tumor types, although the mechanism(s) by which it exerts its antitumor activity effects remain unclear. We analyzed the ability of ZD1839 to induce apoptosis and/or inhibition of proliferation in breast carcinoma cell lines, as well any association between this ability and the downregulation activity of MAPK and Akt, two recently proposed markers of ZD1839 activity. Proliferation, survival, and activation of Akt and MAPK were evaluated in six human breast cancer cell lines expressing various levels of EGFR and HER2 and exposed to ZD1839. EGFR and HER2 expression levels were determined using specific monoclonal antibodies and FACS analysis. The effects of ZD1839 were independent of EGFR expression levels, but were influenced by high HER2 expression. ZD1839 significantly reduced the rate of [3H]-thymidine incorporation in the four sensitive cell lines, while apoptosis was also induced in two of these cell lines. No correlation was found between the cytostatic or cytotoxic effects of ZD1839 and its ability to downregulate MAPK and Akt activity in the tumor cell lines. Our data suggest that the antitumor activity of ZD1839 is due to a cytostatic effect, and involves apoptosis induction in a subset of sensitive cells only, and that neither MAPK nor Akt is a reliable marker of ZD1839 activity.

Apoptosis↗
PubMed2004

Technology insight: Emerging techniques to predict response to preoperative chemotherapy in breast cancer.

During the past decade, several high-throughput analytical methods have been developed, and most of these are being explored as potential diagnostic tools. Gene expression profiling with DNA microarrays or with multiplex polymerase chain reaction are the methods closest to being of clinical use. Prediction of clinically meaningful response to particular chemotherapy regimens or drugs remains a persistent challenge. There are established clinical and histopathologic predictors of prognosis for breast cancer, but there is no test to assist in selecting the optimal chemotherapy regimen for patients. Here we review recent advances in the application of gene expression profiling to chemotherapy response prediction.

Biomarkers, Tumor↗
PubMed2004

Future options with trastuzumab for primary systemic and adjuvant therapy.

HER2 positivity can be detected early in breast cancer development and is associated with a poor outcome. Primary systemic therapy with trastuzumab (Herceptin; F. Hoffmann-La Roche, Basel, Switzerland) in combination with taxanes and other cytotoxic agents has been studied in phase II clinical trials in women with HER2-positive breast cancer. These combinations have achieved pathologic complete response rates of 12% to 42% and clinical complete response rates of 30% to 67%. These results compare favorably with those of primary systemic therapy using standard combinations in patients with unselected (HER2-positive or -negative) breast cancer. Consequently, larger studies are in progress in which trastuzumab is administered before surgery in combination with chemotherapy. Trastuzumab is continued as monotherapy afterward to complete 1 year of treatment or until disease progression. These studies aim to provide further proof of the clinical benefits associated with trastuzumab as primary systemic therapy. They will also investigate the molecular determinants of sensitivity and resistance. In addition, four major randomized trials, in more than 13,500 patients, are investigating the impact of adding trastuzumab to standard adjuvant therapy. Planned interim cardiac safety analyses have been passed without concerns. Recruitment to these studies has either recently been completed or continues as planned. Together, this extensive program, which includes analysis of predictive molecular and pathologic makers, will establish the efficacy, safety, and role of trastuzumab in early breast cancer.

Antibodies, Monoclonal↗
PubMed2004

Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity.

The clinical use of anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-à-vis toxicity in cardiomyocytes) that anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index.

Anthracyclines↗
PubMed2003

Pilot trial of trastuzumab starting with or after the doxorubicin component of a doxorubicin plus paclitaxel regimen for women with HER2-positive advanced breast cancer.

PURPOSE: Combining trastuzumab with doxorubicin and paclitaxel (AT) is attractive because of the activity of AT and survival improvements observed when trastuzumab is added to either agent in HER2-positive metastatic breast cancer. This pilot study evaluates the efficacy and cardiac tolerability of AT followed by paclitaxel with trastuzumab started with AT or paclitaxel alone and investigates pharmacokinetic interactions. EXPERIMENTAL DESIGN: Two cohorts of 16 patients were enrolled. Cohort 1 received three cycles of AT (60/150 mg/m2) plus trastuzumab (4 mg/kg initial dose followed by 2 mg/kg), initiated concomitantly with doxorubicin, followed by nine cycles of paclitaxel (80 mg/m2) plus trastuzumab and then trastuzumab alone. Cohort 2 was treated with the same regimen, but trastuzumab was initiated with paclitaxel after AT. Cardiac function, pharmacokinetic interactions, and efficacy were evaluated. RESULTS: Median baseline left ventricular ejection fraction (LVEF) was 62% (range, 57-74%) and 66% (range, 57-77%) in cohorts 1 and 2, respectively. Most patients had an absolute decrease in LVEF. Congestive heart failure was not observed. LVEF in three patients decreased to <50% but recovered despite continued treatment. Response rates were 87.5% in both cohorts (cohort 1:2 complete response, 12 partial response; cohort 2:3 complete response, 11 partial response). No unexpected side effects were observed. Pharmacokinetics of paclitaxel and its metabolites and of doxorubicin were similar without and with trastuzumab. CONCLUSIONS: Trastuzumab administered with AT followed by weekly paclitaxel alone is highly active whether trastuzumab is initiated with AT or paclitaxel. Congestive heart failure was not observed, and LVEF decreases were reversible. Further studies of this regimen are warranted.

Adult↗
PubMed2003

International expert panel on the use of primary (preoperative) systemic treatment of operable breast cancer: review and recommendations.

Primary systemic therapy (PST) represents the standard of care in patients with locally advanced breast cancer. In addition, there is increasing information on PST in operable breast disease that supports the use of PST in routine practice. However, current regimens and techniques vary. To address this concern, a group of representatives from breast cancer clinical research groups in France, Germany, Italy, the United Kingdom, and the United States reviewed all available data on prospective randomized trials in this setting. Recommendations are made regarding terminology, indications, regimen, diagnosis before treatment, monitoring of efficacy, tumor localization, surgery, pathologic evaluation, and postoperative treatment.

Antineoplastic Combined Chemotherapy Protocols↗