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G Giaccone

Publications and source records attributed to G Giaccone.

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

Immunocytochemical detection of deoxycytidine kinase in haematological malignancies and solid tumours.

BACKGROUND: Deoxycytidine kinase (dCK) is responsible for the activation of several clinically important deoxynucleoside analogues used for the treatment of haematological and solid malignancies. AIM: To measure dCK expression in tumour cells from different origins. METHOD: A rabbit antihuman dCK antibody was used for the immunocytochemical detection of dCK expression in three leukaemic cell lines (HL60, U937, and CCRF-CEM) and 97 patient samples (paediatric acute myeloid leukaemia (AML) and lymphoid leukaemia (ALL), retinoblastoma, paediatric brain tumours, and adult non-small cell lung cancer (NSCLC)). RESULTS: CCRF-CEM, U937, and HL60 cells stained positively for dCK and the degree of expression correlated with dCK activity. dCK expression varied between tumour types and between individual patients within one tumour type. dCK was located predominantly in the cytoplasm. The staining intensity was scored as negative (0), low (1+), intermediate (2+), or high (3+). Expression of dCK was high in AML blasts. In contrast, brain tumour samples expressed low amounts of dCK. dCK staining ranged from low (1+) to high (3+) in ALL blasts, retinoblastoma, and NSCLC tissue samples. Staining was consistent (interobserver variability, 88%; kappa = 0.83) and specific. Western blotting detected the dCK protein appropriately at 30 kDa, without additional bands. CONCLUSIONS: Immunocytochemistry is an effective and reliable method for determining the expression of dCK in patient samples and requires little tumour material. This method enables large scale screening of dCK expression in tumour samples.

Adult↗
PubMed2005

Morbidity and mortality in the surgery arm of EORTC 08941 trial.

Controversial results of surgical treatment after induction chemotherapy, especially in relation to the extent of resection, have previously been reported. Mortality and morbidity were studied in the surgical arm of the European Organisation for Research and Treatment of Cancer (EORTC) 08941 trial. EORTC 08941 is a multicentre, prospective, randomised, phase-III trial of surgical resection versus radiotherapy in patients with proven stage IIIA-N2 nonsmall cell lung cancer after an objective response to platinum-based induction chemotherapy. Operative results in the 167 patients randomised in the surgical arm are presented within this study. Among these patients, one switched to the radiotherapy arm and 17 patients did not get any protocol treatment or information is not yet available. Radical resection with negative surgical margins was obtained in 74 patients (49.7%). In 61 patients (40.9%), a pathological down-staging to N0 or N1 was present. Operative 30-day mortality was 4.0%. Post-operative complications were mainly pneumonia, respiratory insufficiency, arrhythmias, air leak, cardiac decompensation, empyema and bronchopleural fistula. In total, 12 (8.1%) patients underwent re-operation due to positive margins, haemothorax, empyema and bronchopleural fistula. In conclusion, surgical resection after induction chemotherapy in the multicentre European Organisation for Research and Treatment of Cancer trial has yielded acceptable rates of morbidity and mortality.

Adult↗
PubMed2004

A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene.

Three members of an Italian family with autosomal dominant dementia and multiple strokes had the A713T mutation of the APP gene. The neuropathologic examination of the proband disclosed Alzheimer disease (AD) with severe cerebral amyloid angiopathy and multiple infarcts. This indicates that the A713T mutation of the APP gene, lying at the gamma-secretase cleavage site, can be responsible for AD with symptomatic cerebral amyloid angiopathy.

Alzheimer Disease↗
PubMed2004

Overexpression of Bcl2 abrogates chemo- and radiotherapy-induced sensitisation of NCI-H460 non-small-cell lung cancer cells to adenovirus-mediated expression of full-length TRAIL.

TNF-related apoptosis-inducing ligand (TRAIL, also known as Apo-2L) is a promising novel anticancer agent that selectively induces apoptosis in tumour cells and the activity of which can be enhanced by combined treatment with chemo- or radiotherapy. For therapeutic purposes, the use of full-length TRAIL may be favourable to recombinant TRAIL based on its increased tumour cell killing potential, and the delivery of TRAIL at the tumour site by adenovirus vectors may provide an approach to overcome the short half-life of recombinant TRAIL and hepatocyte toxicity in vivo. Here, we constructed an adenoviral vector expressing full-length TRAIL (AdTRAIL) and studied the potential of chemo- and radiotherapy in enhancing AdTRAIL-induced apoptosis in non-small cell lung cancer (NSCLC) H460 cells and normal cells and, in addition, investigated the mechanism of AdTRAIL-induced apoptosis. AdTRAIL effectively killed H460 cells, which we previously showed to have a deficiency in mitochondria-dependent apoptosis by downstream activation of caspase-8 rather than caspase-9. Further analyses revealed that AdTRAIL induces death receptor- and mitochondria-dependent apoptosis that could be partially suppressed by Bcl2 overexpression. Combined treatment with doxorubicin (DOX), cisplatin (CDDP), paclitaxel (PTX) and radiation strongly enhanced AdTRAIL-induced cytotoxicity in a synergistic way. Synergy was accompanied by the cleavage of Bid and an increase in caspase-8 processing that was abolished by Bcl2 overexpression, indicating that the Bid-mitochondrial amplification loop is functional in H460 cells. Moreover, combination treatment did not alter the tumour selectivity of AdTRAIL since normal human fibroblasts (NHFs) remained resistant under these conditions. These findings further indicate that the combined use of chemo/radiotherapy and adenovirus-produced full-length TRAIL may provide a valuable treatment option for NSCLC.

Adenocarcinoma↗
PubMed2004

Glufosfamide administered by 1-hour infusion as a second-line treatment for advanced non-small cell lung cancer; a phase II trial of the EORTC-New Drug Development Group.

The activity of glufosfamide (beta-D-glucosylisophosphoramide mustard) was tested in a multicentre phase II clinical trial in patients with advanced non-small cell lung cancer (NSCLC) who had received one prior line of platinum-based chemotherapy. Patients were treated with 5000 mg/m(2) glufosfamide by a 1-h intravenous (i.v.) infusion every 3 weeks following registration at the European Organisation for Research and Treatment of Cancer (EORTC) Data Center. Patients were randomised between hydration and no hydration to evaluate the nephroprotective effects of forced diuresis. Patients experiencing >/= 35 micromol/l increase of serum creatinine compared with baseline values were taken off the treatment. The Response evaluation criteria in solid tumours (RECIST) criteria were applied for the response assessment. Blood sampling was performed for a pharmacokinetic analysis. 39 patients from seven institutions were registered and a median of three cycles was given (range 0-6) cycles; 20 patients were randomised to the hydration arm. Haematological toxicity was mild, but treatment-related metabolic and electrolytic abnormalities and increases of serum creatinine occurred in several patients. Hydration did not have any significant influence on the plasma pharmacokinetics of glufosfamide and did not show any nephroprotective effect. Only one confirmed partial remission was observed (response rate 3%; 95% (Confidence Interval (CI) 0-14) and 18 cases with stable disease (49%) were recorded as assessed by an independent panel. Median survival of all patients treated was 5.8 months (95% CI 4.2-7.9). In conclusion, glufosfamide administered by a 1-h infusion every 3 weeks has modest activity in advanced NSCLC patients after one prior platinum-based chemotherapy.

Adolescent↗
PubMed2004

Continuous infusion of hepatic arterial irinotecan in pretreated patients with colorectal cancer metastatic to the liver.

BACKGROUND: Irinotecan is an active drug in colorectal cancer. In patients with liver metastases, hepatic arterial infusion of irinotecan could theoretically result in higher exposure to the drug. In order to determine the efficacy of hepatic arterial irinotecan we conducted a phase II study in pretreated patients with liver metastases of colorectal cancer. PATIENTS AND METHODS: Patients with measurable liver metastases of colorectal cancer with World Health Organization performance status (WHO PS) <2 were treated with a 5-day continuous infusion of hepatic arterial irinotecan every 3 weeks at a dose of 20 mg/m(2)/day. RESULTS: Of the 25 patients included, 22 were evaluable for response. Three of 22 patients (13.6%) had a partial response, nine (40.9%) had stable disease and 10 (45.4%) had progressive disease. No complete responses were observed. Median time to progression was 2.8 (range 1.2-23.8) months. Major toxicities were vomiting and diarrhea. There was no major hematological toxicity. CONCLUSIONS: Five-day continuous hepatic arterial infusion of irinotecan 20 mg/m(2)/day has low activity in patients with liver metastases of colorectal cancer previously treated by chemotherapy.

Adult↗
PubMed2004

Phase II study of cisplatin preceding gemcitabine in patients with advanced oesophageal cancer.

BACKGROUND: For oesophageal cancer there is no effective standard therapy. We studied the feasibility and efficacy of the cisplatin-gemcitabine combination chemotherapy in patients with unresectable oesophageal cancer. PATIENTS AND METHODS: Thirty-six chemonaïve patients with unresectable or metastatic oesophageal adenocarcinoma (24) or squamous-cell-carcinoma (12) were treated with cisplatin (50 mg/m2, days 1 and 8), followed by gemcitabine (800 mg/m2, days 2, 9 and 16), every 28 days. Feasibility and efficacy were studied. RESULTS: Toxicity was substantial but manageable. A median number of four therapy cycles was given. The most frequent grade > or = 3 toxicities were leukopenia (75%) and neutropenia (83%). Three patients developed neutropenic fever. Grade 3/4 thrombocytopenia occurred in 24 out of 36 patients (67%), but did not result in serious bleeding disorders. Myelotoxicity was cumulative and required omission of gemcitabine on day 16 in 63% of cycles. Anaemia required treatment with erythropoietin, red blood cells or both in 81% of patients. Non-haematological toxicity consisted mainly of grade 1/2 nausea/vomiting or fatigue. Fourteen out of 34 evaluable patients had a major objective response (41%; two complete and 12 partial responses). The median actuarial survival was 9.8 months. CONCLUSION: This cisplatin-gemcitabine regimen was feasible, with myelosupression being the main toxicity, and had significant activity in patients with advanced oesophageal cancer.

Adenocarcinoma↗
PubMed2004

Phase II trial of cisplatin and gemcitabine in patients with advanced gastric cancer.

BACKGROUND: This phase II study was performed to determine the efficacy and toxicity of cisplatin and gemcitabine in patients with advanced gastric cancer. PATIENTS AND METHODS: Forty chemo-naïve patients with measurable locoregionally advanced or metastatic gastric cancer were included; the median patient age was 53 years (range 35-71). Cisplatin was administered at a dose of 50 mg/m2, given in 1 h intravenously (i.v.) on days 1 and 8, followed after 24 h by gemcitabine at a dose of 800 mg/m2 given in 30 min i.v. on days 2, 9 and 16, every 28 days. RESULTS: A median number of four therapy cycles were given (range 2-8). Myelosuppresion was the most important toxicity. Grade 3-4 thrombopenia was observed in 19 patients (48%) and grade 3-4 leukopenia was observed in 23 (58%). Myelotoxicity was cumulative and caused omission of gemcitabine on day 16 in 55% of cycles. Non-haematological toxicity consisted mainly of grade 1-2 nausea and vomiting. Objective responses were observed in 30% of patients including two complete remissions and 10 partial remissions. Median survival was 11 months (range 3-27+). CONCLUSIONS: This cisplatin-gemcitabine regimen had moderate efficacy in patients with advanced gastric cancer, with manageable toxicity. Further studies with this combination may be warranted.

Adenocarcinoma↗
PubMed2004

Combination therapy with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, gemcitabine and cisplatin in patients with advanced solid tumors.

BACKGROUND: The aim of this study was to investigate the tolerability, pharmacokinetic interaction and antitumor activity of gefitinib ("Iressa", ZD1839), an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor, combined with gemcitabine and cisplatin in chemotherapy-naïve patients with advanced solid tumors. PATIENTS AND METHODS: This was an open-label feasibility trial evaluating two doses of gefitinib (250 and 500 mg/day) in combination with gemcitabine and cisplatin. Gefitinib was administered daily from day 2 onwards. Gemcitabine 1250 mg/m(2) was given on days 1 and 8 and cisplatin 80 mg/m(2) on day 1 for up to six 3-week cycles. Patients could then continue to receive gefitinib monotherapy. RESULTS: Eighteen patients were entered, nine at each gefitinib dose level. Two patients developed dose-limiting toxicity: one grade 3 convulsion (250 mg/day dose group) and one grade 3 rash (500 mg/day dose group). The most frequently occurring adverse events in the combination phase were vomiting (17 patients), asthenia (16), nausea (14), diarrhea (14) and skin rash (13). The most common grade 3/4 adverse events were vomiting (seven patients), asthenia (six), thrombocytopenia (six), diarrhea (five) and anorexia (five). Pharmacokinetic analyses showed no apparent pharmacokinetic interaction between gefitinib and cisplatin or gemcitabine, with the exception of a possible small increase in the geometric mean exposure to gemcitabine seen on day 8 of therapy when given alone with the higher dose of gefitinib. Of 17 evaluable patients, nine had confirmed partial responses, seven had stable disease and one had progressive disease. CONCLUSIONS: Combination therapy of gefitinib with cisplatin and gemcitabine had a manageable and predictable safety profile, no major effect on exposure to any of the three drugs and antitumor activity.

Adult↗
PubMed2004

Nuclear localization of survivin is a positive prognostic factor for survival in advanced non-small-cell lung cancer.

BACKGROUND: Expression of survivin, a member of the inhibitor of apoptosis protein family, is commonly detected in cancers but not in normal differentiated tissues. Survivin is usually localized in the cytoplasm of cancer cells, but nuclear localization has also been described, and we recently reported that survivin is a nuclear-cytoplasmic shuttling protein. PATIENTS AND METHODS: Fifty-three tumor specimens from patients with inoperable non-small-cell lung cancer (NSCLC) (55% stage IIIA, 17% stage IIIB and 28% stage IV) who underwent chemotherapy treatment were evaluated with immunohistochemistry for survivin expression and localization. These two sets of data were processed and tested for correlation with major patient characteristics, response to chemotherapy, and overall and relapse-free survival. RESULTS: Survivin was present only in malignant tissues, and 47/53 (89%) of the specimens were positive. The overall median expression of tumor cells was 40%, and this value was used as a cut-off point for statistical analysis. By dichotomizing the specimens as expressing low or high levels of survivin, a significant association was seen between the expression of survivin and the histology of the tumors (P=0.020), squamous cell carcinoma being the histotype with lower levels of survivin expression. Three patterns of localization were observed: 42% of cases (22/53) showed reactivity confined to the nucleus, 17% (nine of 53) only in the cytoplasm and 30% (16/53) in both the nucleus and the cytoplasm. Interestingly, nuclear survivin levels predicted longer overall and relapse-free survival, in univariate and multivariate analyses. Expression and localization of survivin did not correlate with response to chemotherapy. CONCLUSIONS: Our results indicate that differential localization of survivin may be a prognostic factor for NSCLC. Further studies are warranted.

Adult↗
PubMed2004

Cancer of the esophagus and gastric cardia: recent advances.

Esophageal cancer and cancer of the gastric cardia, in particular adenocarcinomas, have shown a rapid and largely unexplained increase in incidence in many developed countries around the world. These diseases have a poor prognosis and current therapies have a modest impact on survival. This review presents recent advances in the epidemiology, etiology, diagnosis, staging, prevention and treatment of resectable and advanced disease. Although significant progress has been made in these areas of research and patient management over the past years, prognosis for most patients diagnosed with esophageal cancer or cancer of the gastric cardia remains poor. New diagnostic procedures, improved surgical procedures, combined treatment modalities and new treatment modalities are being evaluated and may be expected to contribute to improved patient outcomes and better palliation of symptoms in the future.

Adenocarcinoma↗
PubMed2003

Creutzfeldt-Jakob disease with a novel extra-repeat insertional mutation in the PRNP gene.

The authors investigated two unrelated patients with Creutzfeldt-Jakob disease (CJD) with clinical features of sporadic CJD (sCJD) carrying one extra octapeptide repeat in the prion protein (PrP) gene (PRNP). A synaptic type PrP distribution throughout the cerebral gray matter and plaque-like PrP deposits in the subcortical gray structures were detected immunocytochemically. The different patterns of PrP deposition were associated with distinct types of protease-resistant PrP, similar to type 1 and type 2 of sCJD. The features suggest that this insertion is a pathogenic mutation.

14-3-3 Proteins↗
PubMed2003

Pharmacokinetics of S-1, an oral formulation of ftorafur, oxonic acid and 5-chloro-2,4-dihydroxypyridine (molar ratio 1:0.4:1) in patients with solid tumors.

S-1 is an oral formulation of ftorafur (FT), oxonic acid and 5-chloro-2,4-dihydroxypyridine (CDHP) at a molar ratio of 1:0.4:1. FT is a 5-fluorouracil (5-FU) prodrug, CDHP is a dihydropyrimidine dehydrogenase (DPD) inhibitor and oxonic acid is an inhibitor of 5-FU phosphoribosylation in the gastrointestinal mucosa and was included to prevent gastrointestinal toxicity. We determined the pharmacokinetics of S-1 in 28 patients at doses of 25, 35, 40 and 45 mg/m(2). The plasma C(max) values of FT, 5-FU, oxonic acid and CDHP increased dose-dependently and after 1-2 h were in the ranges 5.8-13 microM, 0.4-2.4 microM, 0.026-1.337 microM, and 1.1-3.6 microM, respectively. Uracil levels, indicative of DPD inhibition, also increased dose-dependently from basal levels of 0.03-0.25 microM to 3.6-9.4 microM after 2-4 h, and 0.09-0.9 microM was still present after 24 h. The pharmacokinetics of CDHP and uracil were linear over the dose range. The areas under the plasma concentration curves (AUC) for CDHP and uracil were in the ranges 418-1735 and 2281-8627 micromol x min/l, respectively. The t(1/2) values were in the ranges 213-692 and 216-354 min, respectively. Cumulative urinary excretion of FT was predominantly as 5-FU and was 2.2-11.9%; the urinary excretion of both fluoro-beta-alanine and uracil was generally maximal between 6 and 18 h. During 28-day courses with twice-daily S-1 administration, 5-FU and uracil generally increased. Before each intake of S-1, 5-FU varied between 0.5 and 1 microM and uracil was in the micromolar range (up to 7 microM), indicating that effective DPD inhibition was maintained during the course. In a biopsy of an esophageal adenocarcinoma metastasis that had regressed, thymidylate synthase, the target of 5-FU, was inhibited 50%, but increased four- to tenfold after relapse in subsequent biopsies. In conclusion, oral S-1 administration resulted in prolonged exposure to micromolar 5-FU concentrations due to DPD inhibition, and the decrease in uracil levels after 6 h followed the pattern of CDHP and indicates reversible DPD inhibition.

Adult↗
PubMed2003

[Novel approaches; improved diagnosis and therapy with DNA microarrays. I. Technology and data analysis].

With DNA microarrays it will be possible to refine diagnostics and treatment with the use of genome wide information on a patient's sample. Microarrays are currently applied to unravel gene functions, pathogenetic mechanisms, metabolic routes and the effects of drugs on these, to refine diagnostic classifications and prognostic indexes, and to find new targets for therapy. With genotyping it will be possible to generate risk profiles for certain diseases and to assess the likelihood of a given drug-related side effect. Furthermore, it may accelerate research of mutations in genes for which the normal DNA sequences are already known. The basic principle of DNA microarrays is that thousands of different DNA sequences, each specific for a given gene, are immobilised on a solid surface (for example a microscope slide), arranged in a known order, and are hybridised with a solution of labelled DNA or RNA molecules. The DNA or RNA molecules under investigation bind to complementary base pairs on the slide, and permit us to measure the amount of labelled DNA or RNA hybridised to each gene sequence. Sophisticated software is used to analyse the large amount of data generated. The ultimate aim is to group genes with similar expression patterns across all samples, and then group samples accordingly. Conventional biological or biochemical techniques are required to validate the data obtained with microarrays, and to verify whether the observed associations among genes are biologically relevant.

Diagnostic Techniques and Procedures↗
PubMed2003

[Novel approaches; improved diagnostics and therapeutics with DNA microarrays. II. Applications].

The most important (future) applications of DNA microarrays in medicine are based on three different molecular analyses: gene expression analysis, genotyping with a specific type of microarray (single nucleotide polymorphism chip (SNP chip)), and DNA sequencing to search for a well-known mutation in a certain gene. With gene expression analysis one can obtain a 'molecular signature' of a tissue by allowing tissue RNA to react with a DNA microarray. This information may help to refine disease classifications, to guide the choice of therapy and to find new therapeutic targets. Genotyping utilizes genomic DNA that, after digestion, reacts with a SNP chip to obtain an individual SNP pattern. An SNP is a change of a single base pair within a gene sequence that can sometimes influence the function of the gene product. SNPs are considered to be variations in the genome and should be distinguished from mutations. These variations can for instance provide information about the probability of a certain disease, or the effectiveness or side effect of a certain drug. Sequencing well characterized genes to search for mutations is used to screen for genetic abnormalities. This process can be accelerated with the aid of oligonucleotide arrays. With this tool an individual's risk of developing certain forms of cancer or monogenetic diseases can be estimated.

Diagnostic Techniques and Procedures↗
PubMed2003

The activity of raltitrexed (Tomudex) in malignant pleural mesothelioma: an EORTC phase II study (08992).

We investigated the activity and toxicity of raltitrexed (Tomudex) as a single agent treatment in patients with Malignant Pleural Mesothelioma (MPM) in a multicentre phase II European Organization for Research and Treatment of Cancer (EORTC) study. This study enrolled chemonaíve patients with histologically-confirmed measurable MPM. Raltitrexed was administered at the dose of 3 mg/m(2) intravenous (i.v.) bolus on an outpatient basis every 3 weeks. A maximum of eight cycles was planned in cases with an absence of progression or unacceptable toxicity. 24 patients received a total of 104 courses. 5 patients (20.8%, 95% confidence interval (CI) 7.1-42.2%) had a partial response (PR), which was confirmed by an independent radiology committee. Toxicity was mild, with diarrhoea, nausea, vomiting, fatigue and neutropenia as the major side-effects, but not exceeding grade 3 toxicity. We conclude that raltitrexed has activity as a single agent in the treatment of MPM, and that further studies with this drug in MPM are warranted.

Adult↗
PubMed2003

Temozolomide in patients with advanced non-small cell lung cancer with and without brain metastases. a phase II study of the EORTC Lung Cancer Group (08965).

This study was performed to evaluate the activity of single-agent temozolomide in two groups of chemotherapy-naïve non-small cell lung cancer (NSCLC) patients, with (12 patients) and without (13 patients) brain metastases (BM). Patients in both groups were treated with temozolomide 200 mg/m(2)/day, administered orally for 5 consecutive days of a 28-day cycle. Treatment was continued for up to six cycles, disease progression or unacceptable toxicity. The median number of received cycles was only one in the group with and two in the group without BM, and early disease progression was the main reason for treatment discontinuation. Toxicity was moderate-in the group of patients with BM, the most frequently observed grade 3 or 4 side-effects included thrombocytopenia (17%), granulocytopenia (17%), lethargy (17%); other neurological (17%) and other genitourinary toxicity (17%). Patients without BM experienced anaemia (15%), thrombocytopenia (23%), nausea (15%) and lethargy (15%). This trial was designed according to Simon one-sample two-stage testing procedure and both groups of patients were assessed separately. No objective response was observed in either group and the study was closed after the first step of accrual with the conclusion of a lack of therapeutic activity of single-agent temozolomide in patients with stage IV NSCLC.

Adult↗