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Biomedical subjects

V Boige

Publications and source records attributed to V Boige.

At least 37 records · Page 2Linked to original sources
PubMed2001

Detection of circulating carcinoma cells by telomerase activity.

Telomerase has been shown to be a marker of epithelial cancer cells. We developed a method that allows the detection of circulating carcinoma cells in the blood of cancer patients. Circulating epithelial cells are harvested from peripheral blood mononuclear cells by immunomagnetic separation using BerEP4-coated beads. A telomeric repeat amplification protocol (TRAP)-ELISA is then used to measure telomerase in harvested epithelial cells. This method is specific and sensitive as demonstrated by experiments using BerEP4-positive and negative cell lines. Whereas we never found telomerase activity in harvested epithelial cells (HEC) samples from 30/30 healthy donors, we have detected telomerase activity in HEC from 11/15 (73%) patients with stage IIIB or IV non-small cell lung cancer (NSCLC) patients and from 8/11 (72%) stage C or D (Dukes classification) colon cancer patients. This non-invasive method could be of great value as a diagnostic or prognostic marker, or for monitoring cancer progression.

Adult↗
PubMed2001

Gastric linitis adenocarcinoma and carcinomatous meningitis: an infrequent but aggressive association--report of four cases.

Carcinomatous meningitis (CM) is a very rare complication of gastrointestinal malignancies and especially gastric adenocarcinoma. Linitis plastica (LP), which is a specific form of gastric neoplasia, locally penetrates through the gastric wall to reach the peritoneum. Lymph node involvement is frequent and metastatic sites are almost exclusively observed in the abdominal cavity. The meningeal localization is extremely rare with only a few cases described in the literature. We report here, over a five-year period, four cases of CM on a total of eighty linitis cases diagnosed and treated in our institution, which represent 5% of a non selected linitis population. The clinical manifestations were clearly poor, and characterized by aspecific neurological signs. The diagnosis was made by the discovery of signet cells in the cerebrospinal fluid. Invasive treatment, consisting of intrathecal infusion of chemotherapy, was undertaken with mixed clinical response and no cytological normalization of the cerebrospinal fluid (CSF). In conclusion, our observation which is based on a large series of successive gastric linitis, demonstrates a 5% frequency of developing CM with a predominance among metastatic patients. Furthermore, the diagnosis of CM must be done as soon as possible because of the clear effectiveness of a therapeutic approach on the improvement of symptoms and quality of life.

Antimetabolites, Antineoplastic↗
PubMed2001

Influence of cirrhosis on lamotrigine pharmacokinetics.

AIMS: Lamotrigine, an antiepileptic drug, is cleared from the systemic circulation mainly by glucuronidation. The possibility of changes in the pharmacokinetics of lamotrigine in plasma owing to hepatic dysfunction has been evaluated. METHODS: Thirty-six subjects, including 24 patients with various degrees of liver cirrhosis and 12 healthy volunteers received a single 100 mg dose of lamotrgine. Blood samples were taken for 7 days in all subjects, except nine with severe cirrhosis, who had a 29 day blood sampling period. RESULTS: The pharmacokinetics of lamotrigine were comparable between the patients with moderate cirrhosis (corresponding to Child-Pugh grade A) and the healthy subjects. Plasma oral clearance mean ratios (90% confidence interval) in patients with severe cirrhosis without or with ascites (corresponding, respectively, to Child-Pugh grade B and C) to healthy subjects were, respectively, 60% (44%, 83%) and 36% (25%, 52%). Plasma half-life mean ratios (90% confidence interval) in these two patient groups to healthy subjects were, respectively, 204% (149%, 278%) and 287% (202%, 408%). CONCLUSIONS: Lamotrigine administered as a single oral dose of 100 mg was well tolerated in all groups. Initial, escalation and maintenance doses should generally be reduced by approximately 50 or 75% in patients with Child-Pugh Grade B or C cirrhosis. Escalation and maintenance doses should be adjusted according to clinical response.

Adult↗
PubMed2001

A phase I and pharmacokinetic study of the novel aza-anthracenedione compound BBR 2778 in patients with advanced solid malignancies.

BBR 2778 is a novel aza-anthracenedione with no cardiotoxicity in preclinical models. This Phase I dose escalation trial of BBR 2778 was conducted to determine the maximum tolerated dose, the dose-limiting toxicity, and the pharmacokinetic profile of BBR 2778 in patients with advanced solid tumors. BBR 2778 was given in three consecutive weekly 30-min i.v. infusions over a 4-week cycle (cy). Thirty patients (pts) were treated with BBR 2778 at doses ranging from 5 to 150 mg/m2/week. The dose levels 5, 10, 16.5, 25, 37.5, 75, 112.5, and 150 mg/m2/week were investigated in 4 pts (9 cy), 3 pts (3 cy), 3 pts (5 cy), 6 pts (9 cy), 1 pt (1 cy), 4 pts (9 cy), 6 pts (18 cy), and 3 pts (4 cy), respectively. The dose-limiting toxicity was neutropenia, typically occurring at day 14. Other toxicities were mild to moderate and were principally thrombocytopenia, lymphopenia, alopecia, nausea, and vomiting and blue coloration of the skin and urine. No significant cardiac toxicity was observed. The plasma dose concentration curve fitted a biexponential profile, with a rapid distribution phase followed by a prolonged elimination phase (mean t1/2,z, 12 h). BBR 2778 displayed a large volume of distribution (range, 9.7-29.7 l/kg) with a high plasma clearance rate (0.75-1.31 l/h/kg). Less than 10% of the dose was recovered in urine as unchanged drug. The maximum tolerated dose was 150 mg/m2/week for 3 weeks, every 4 weeks. On the basis of this study, the recommended dose for Phase II studies is 112.5 mg/m2/week days 1 and 8 with individual optional administration at day 15, every 4 weeks. Antitumor activity was observed in patients with breast, small cell lung carcinoma, and facial cylindroma. This trial showed that BBR 2778 has a manageable toxicity profile on a weekly schedule. This lead compound of the aza-anthracenedione family shows promising antitumor activity and deserves Phase II investigation in patients with high risk of cumulative cardiotoxicity, such as anthracycline-pretreated breast cancer patients.

Adult↗
PubMed2001

[Prevention and treatment of chemotherapy-induced digestive toxicities].

Digestive complications are frequent dose-limiting side-effects of chemotherapy. The incidence and the severity of these toxicities have to be systematically evaluated in order to provide specific curative and preventive treatments. Quick resolution of these complications is important to improve quality of life, and also to prevent hospitalization. Nausea, vomiting, mucositis, and diarrhea are the main digestive toxicities of chemotherapy. This review emphasizes the recent therapeutic approaches which could lead to a decrease of the incidence or the severity of these toxicities. Although marked progress has been accomplished these last years, a substantial degree of further improvement is needed to improve the effectiveness of specific treatments. Furthermore, research might focus on new strategies which may prevent the development of overall toxicity, by increasing the selectivity of chemotherapy on tumor cells.

Antineoplastic Agents↗
PubMed2000

Phase I and pharmacokinetic study of the camptothecin analog DX-8951f administered as a 30-minute infusion every 3 weeks in patients with advanced cancer.

PURPOSE: DX-8951f is a totally synthetic derivative of camptothecin with greater cytotoxicity and more potent topoisomerase I inhibition than SN-38, topotecan, and camptothecin in preclinical studies. This phase I study aimed to describe the toxicity and to determine the maximum-tolerated dose (MTD) and pharmacokinetics of DX-8951f given as a 30-minute intravenous infusion every 3 weeks. PATIENTS AND METHODS: Twelve patients with refractory solid malignancies were treated with DX-8951f at dose levels ranging from 4 to 7.1 mg/m(2). All but one patient had received previous chemotherapy, and eight patients were considered heavily pretreated. Total DX-8951f plasma concentrations were assayed using high-performance liquid chromatography. RESULTS: Thirty-six cycles of DX-8951f were administered. Neutropenia was the dose-limiting toxicity, and it was dose-related, reversible, and noncumulative. Other toxicities included nausea and vomiting, alopecia, asthenia, fever, and anemia. Grade 1 or 2 diarrhea was observed in seven patients but was transient and resolved without requiring treatment. Pharmacokinetic analysis showed that DX-8951f had a half-life of 7.15 hours and a clearance rate of 1.65 L/h.m(2). The DX-8951f area under the plasma-concentration curve increased linearly with the dose. We defined the MTD of DX-8951f administered as a 30-minute intravenous infusion every 3 weeks as 7.1 mg/m(2). CONCLUSION: The dose-limiting toxicity of DX-8951f is neutropenia. The recommended dose for phase II studies is 5.33 mg/m(2) every 3 weeks in patients previously treated with chemotherapy.

Adult↗
PubMed2000

A dose-finding study of gemcitabine and vinorelbine in advanced previously treated malignancies.

PURPOSE: Gemcitabine and vinorelbine are active drugs with broad spectrum of activity and manageable toxicity in clinical trials. The aims of this study were to describe the toxicity, to determine the dose-limiting toxicity, and to define the doses of gemcitabine and vinorelbine to be recommended for phase II studies in patients with advanced cancers. PATIENTS AND METHODS: Drugs were given as 30-min infusions on day 1 and 8 (vinorelbine before gemcitabine) every 3 weeks. Thirty-six patients (male:female ratio 25:11; mean age 54, PS > 60) were treated including 1 retroperitoneal sarcoma, 7 head and neck, 10 lung, 4 thyroid, 6 pancreatic, 1 bladder, 2 ovary, 2 gastric, 1 rectum, 1 unknown primary, and 1 renal cell carcinoma. Doses of gemcitabine/vinorelbine ranged from 800/20 mg/m2 to 1500/30 mg/m2. RESULTS: The dose-limiting toxicity was neutropenia. A transient grade 2-3 elevation of transaminases was frequently observed at several dose-levels, although this toxicity did not appear to be dose dependant and was reversible at day 21 before the next cycle. Other toxicities were mild and easily manageable, consisting of fatigue and flu-like syndromes. Since the MTD was not reach at the higher dose-level, the recommended dose level of the gemcitabine-vinorelbine combination was 1500/30 mg/m2. One toxic death due to hematologic toxicity was reported in a heavily pretreated patient who underwent prior chemotherapy and pelvic radiotherapy. A total of 12 patients were treated at the recommended dose level which was associated with grade 3-4 neutropenia in 3 of 12 patients and in 22.9% of cycles. CONCLUSIONS: This study estimates that the recommended dose for phase II studies of gemcitabine-vinorelbine is 1500/30 mg/m2 at day 1 and 8 every three weeks. A careful monitoring of the hematologic toxicity is recommended in heavily pretreated patients and in patients who received pelvic radiotherapy. Partial responses observed in a patient with an advanced cisplatin-5-fluorouracil-resistant pancreatic adenocarcinoma and in a patient with mesothelioma support further evaluation of this combination in patients with tumors refractory to classical antitumor agents.

Adult↗
PubMed2000

Radiofrequency ablation of 100 hepatic metastases with a mean follow-up of more than 1 year.

OBJECTIVE: The objective of our study was to evaluate the efficacy and safety of radiofrequency ablation of hepatic metastases performed either percutaneously for treatment of hepatic metastases in patients deemed ineligible for surgery or intraoperatively during partial hepatectomy to destroy unresectable metastases. SUBJECTS AND METHODS: Sixty-eight patients with 121 hepatic metastases (<5 metastases per patient) that were mainly colorectal in origin underwent 76 sessions of radiofrequency ablation with cooled-needle electrodes under sonographic guidance. Twenty-one patients with 33 metastases of 5-20 mm in diameter (mean +/- SD,13 +/- 7 mm) underwent intraoperative radiofrequency ablation. Forty-seven patients with 88 metastases of 10 to 42 mm in diameter (mean +/- SD, 26 +/- 9 mm) were treated with percutaneous radiofrequency ablation. Procedure efficacy was evaluated with dynamic enhanced CT and MR imaging performed 2, 4, and 6 months after treatment and then every 3 months. RESULTS: Radiofrequency ablation allowed eradication of 91% of the 100 treated metastases that were followed up for 4-23 months (mean, 13.7 months). Tumor control was equivalent for percutaneous radiofrequency ablation (90%) and for intraoperative radiofrequency ablation (94%). Failure to achieve tumor control occurred mostly with the largest tumor nodules. One bilioperitoneum and two abscesses were the major complications encountered after treatment of 121 metastases with a follow-up of more than 2 months. CONCLUSION: Radiofrequency ablation appears to be a promising therapeutic modality capable of extending the possibilities of partial hepatectomy and of efficiently treating small metastases percutaneously.

Adult↗
PubMed2000

Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans.

7-Ethyl-10[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin (CPT-11), a DNA topoisomerase I inhibitor, undergoes several metabolic pathways to generate conjugated and unconjugated derivatives that could be excreted from the body. The objective of this study was to determine the oxidative metabolites of CPT-11 recovered in human urine samples and to identify cytochrome P450 (CYP) involved in their formation. In addition to the already known metabolites of CPT-11 [SN-38, SN-38-G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC), and 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin (NPC)], we isolated three oxidized metabolites from the urine of two children and two adults given CPT-11. M1 and M2 (molecular weight, 602) were hydroxylated, respectively, on the CPT moiety and on the terminal piperidine ring of CPT-11. M3 had a molecular mass of 602, but its urine concentration in patients was too low to establish its chemical structure by liquid chromatography/mass spectrometry. In vitro incubations with cells expressing CYP2C8, CYP2C9, CYP1A1, CYP1A2, or CYP3A7 did not produce any detectable metabolites. Only CYP3A4 produced both APC and NPC, resulting from the oxidation of the piperidinylpiperidine side chain of CPT-11 along with metabolite M2. The metabolism of CPT-11 by CYP3A5 was markedly different because neither APC or NPC nor M2 was produced, whereas only one new metabolite, M4 (molecular weight, 558), was generated by de-ethylation of the CPT moiety. No previous study has reported the presence of the M4 metabolite. Production of APC, NPC, M2, and M4 was prevented by ketoconazole, a specific CYP3A inhibitor. The parameters of CPT-11 biotransformation into M2 and M4 were examined using cell lines expressing, respectively, with CYP3A4 and CYP3A5, indicating that CPT-11 is preferentially metabolized by CYP3A4. In conclusion, CYP3A plays a major role in the metabolism of CPT-11, with some differences of the metabolic profile exhibited by 3A4 and 3A5.

Adolescent↗
PubMed2000

[Response of metastatic colorectal cancers to treatment with CPT11 (irinotecan): implications of the mismatched base repair system].

AIMS: The aim of our study was to assess the potential relationships between tumor responsiveness to CPT11, an analogue of camptothecin, which selectively inhibits DNA topoisomerase I, and the microsatellite instability, a feature of tumors with DNA mismatch repair defect. METHODS: We designed a retrospective clinical study including 35 patients with metastatic colorectal cancer treated with CPT11, for which we analyzed the expression of hMLH1 and hMSH2 in the tumor and determined microsatellite status of repeated mononucleotide tracts present in the coding region of RII-TGFB, BAX, hMSH3 and hMSH6 genes. RESULTS: A partial or minor response was observed in 9 patients, disease stabilization in 14 patients and progression in 12 patients. Staining of hMLH1 was undetectable in 2 of the 35 tumors, while only 1 tumor lacked hMSH2 expression. Four of the 31 tumors analyzed displayed intragenic microsatellite instability. We found a good correlation between inactivation of TGFB-RII, BAX or hMSH3 genes and tumor response to CPT-11 (P =0.002). CONCLUSION: Our preliminary data suggest that intragenic microsatellite instability may influence tumor response to CPT-11 in patients with colorectal cancer.

Adaptor Proteins, Signal Transducing↗
PubMed1998

[Irinotecan: various administration schedules, study of drug combinations, phase I experience].

Irinotecan (CPT11) is a synthetic camptothecin-derived DNA topoisomerase I inhibitor. Based on phase I clinical trials, several schedules have been recommended for phase I studies including 350 mg/m2 every 3 weeks in Europe, 125 mg/m2 for 4 weeks every 6 weeks in the USA, and 100 mg/m2 weekly or delayed until recovery in case of grade > 2 toxicity in Japan. The principal dose-limiting toxicities in those schedules are neutropenia and delayed diarrhea. Early treatment with high doses of loperamide has made diarrhea a manageable toxicity and allowed dose escalation up to 500 mg/m2. Recently, two very interesting schedules have been investigated allowing to increase dose-intensity: every other week infusion and protracted infusion. With those schedules, it appears that the diarrhea occurred more frequently with the weekly schedule. In addition, authors have observed interpatients variations in terms of toxicity and pharmacokinetics. Those variations may be related to modifications in the hepatic metabolism of the drug that may occur in patients with hepatic dysfunction and/or in patients with concomitant medications. The understanding of the individual metabolism of the drug would help to determine individual dose adaptation. Based on synergistic preclinical interaction with several drugs, combinations of irinotecan with other cytotoxic drugs such as thymidylate synthethase inhibitors and platinum salts are currently investigated in phase I-II studies.

Administration, Oral↗
PubMed1997

Concerted nonsyntenic allelic losses in hyperploid hepatocellular carcinoma as determined by a high-resolution allelotype.

Although the occurrence of loss of genetic material in hepatocellular carcinoma (HCC) has been documented both by cytogenetic analysis and by monitoring of allelic losses, a global overview of the extent and frequency of deletion occurring throughout the genome is not yet available. To contribute to this information, DNAs extracted from flow-sorted aneuploid nuclei from HCC and matched normal DNAs were typed for 275 microsatellite loci that were distributed along the autosomes. An average of 190 (69%) informative loci per case were generated on 48 HCC. Complete loss of heterozygozity in the tumor DNA was observed for 15.6% of the typed loci. The chromosome segments that were most frequently affected by deletion were: 8p (60%), 17p (48%), 1p (44%), 4q (42%), 16p (40%), 16q (39%), 6q (35%), 9p (30%), and 13q (29%). On average, 8 of the 39 chromosome segments studied per tumor carried at least one locus that demonstrated loss of heterozygosity (ie., the fractional allelic loss was 0.21). Groups of concerted nonsyntenic losses were observed for 16p and 1p and for 16p and 4q. The location of putative tumor suppressor genes on the most frequently deleted regions was confirmed and, in some cases, refined.

Adult↗