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Biomedical subjects

F Demard

Publications and source records attributed to F Demard.

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

Tumoral-reduced folates and clinical resistance to fluorouracil-based treatment in head and neck cancer patients.

PURPOSE: To describe the distribution of tumoral-reduced folates in cancer patients and to analyze the link between this parameter and antitumor efficacy of fluorouracil (FU)-based induction chemotherapy. PATIENTS AND METHODS: Ninety-five patients with head and neck squamous cell carcinoma were included in the present study and 41 received induction treatment with FU-based chemotherapy (35 men and six women; mean age, 59 years; range, 40 to 76). Thymidylate synthase (TS) activity was measured according to the tritium-release assay. Reduced folates (5-10 methylenetetrahydrofolate [CH2FH4] plus tetrahydrofolate) were measured according to the entrapment assay. RESULTS: Among the whole group of patients, reduced folates ranged from nondetectable (< 0.3) to 17.7 pmol/mg protein; CH2FH4 ranged from nondetectable (< 0.3) to 8.2 pmol/mg protein. There was no significant link between tumoral levels of reduced folates and the severity of disease stage. Among 41 treated patients, there were 12 (29%) complete responses (CRs), 18 (44%) partial responses (PRs), and 11 patients (27%) with no response (NR). No statistically significant relationship was observable between TS activity and response. The distribution of CH2FH4 in tumors was significantly higher for complete responders in comparison to patients with a PR or NR. CONCLUSION: The present clinical data demonstrate the importance of basal tumoral-reduced folates for the achievement of optimal efficacy of FU-based treatment. They may have implications for the identification of patients resistant to FU chemotherapy and for a better understanding and management of FU modulation by folinic acid (FA).

Adult↗
PubMed1997

[Malignant nasosinusal melanomas. Review of the literature apropos of 12 cases].

Malignant melanoma with primary onset in the nasal cavity and paranasal sinuses remains a scarcely encountered malignancy and we report 12 cases of our own experience from 1991. These mucosal melanomas occur mainly in the elderly and present most commonly as a one sided airway obstructive syndrome with often bleeding in the nasal cavity. No sex or race ratio is found. Histological examination of the surgical specimen has been made easier since the use of immunohistochemical studies. The original site of onset is commonly located at the inferior part of the nasal cavity but in many cases, it is noted several sites of tumor localization. Despite well conducted treatment the prognosis remains quite deceiving and significantly poor. In our study, the 4-year actuarial survival was 26%. The 5-year survival rate ranges in the literature from 10% to 40%. Short and long term follow-up show an important rate of recurrence (local and lymph node metastases as well as distant metastases). The insidious evolution of the malignancy usually happens during the first year. Computed tomography and MRI are essential in the evaluation of tumor extension. The treatment is based on the combination of surgery and radiotherapy: Surgery is practised first and must ensure sufficient excision of the tumor without minimal functional or aesthetic damage in this complex region. This surgery is based on surgical approaches to the midface known as Lateral rhinotomy and midfacial degloving. When there is cervical lymph node involvement at the time of diagnosis it is suitable to treat it, even in case of recurrence. Complementary high dose radiation is required to treat tumors which could not undergo surgery and also as adjuvant therapy after removal of the mass.

Aged↗
PubMed1997

Analysis of retinoic acid receptor beta expression in normal and malignant laryngeal mucosa by a sensitive and routine applicable reverse transcription-polymerase chain reaction enzyme-linked immunosorbent assay method.

Retinoic acid receptor beta (RAR-beta) seems to be a useful intermediate marker in trials of retinoids, and the aim of this work was to describe a fast, sensitive, and routine applicable method to measure RAR-beta expression in tumor biopsies. We developed a new technique combining reverse transcription-PCR with a colorimetric ELISA detection of amplification products. The principle of this nonradioactive method is based on digoxigenin labeling of PCR products during amplification. Amplified DNA is hybridized with a biotinylated capture probe. The generated hybrid is immobilized on a streptavidin-coated microtiter plate, and detection is performed with the use of an antidigoxigenin peroxidase conjugate. We applied this method to quantify the expression of RAR-beta and an internal control (beta2 microglobulin) in laryngeal tumors. We found a detection threshold at 50 pg of PCR products, which represents a 100-fold improvement when compared to the detection limit of ethidium bromide detection. The method was reproducible (intra- and interassay reproducibilities at 7 and 5%, respectively). We used this technique for determining RAR-beta expression in 20 patients with laryngeal carcinoma and in 20 patients without cancer. The data show that the value of the RAR-beta:beta2 microglobulin ratio is decreased in tumoral versus nontumoral specimens (P = 0.0012), which is consistent with previously published results.

Adult↗
PubMed1996

Boron neutron capture irradiation: setting up a clinical programme in Nice.

Neutron capture irradiation aims to selectively destroy tumor cells using 10B(n,alpha)7Li nuclear reactions produced within themselves. Following the capture reaction, an alpha particle and a, 7Li ion are emitted. Carrying an energy of 2.79 MeV, they destroy all molecular structures along their path close to 10 microns. These captures, used exclusively with a 'slow' neutron irradiation, provide a neutron capture therapy (BNCT). If they are used in addition to a fast neutron beam irradiation, they provide a neutron capture potentiation (NCP). The Centre Antoine-Lacassagne in Nice is actively involved in the European Demonstration Project for BNCT of grade IV glioblastomas (GBM) after surgical excision and BSH administration. Taking into account the preliminary results obtained in Japan, work on an 'epithermal' neutron target compatible with various cyclotron beams is in progress to facilitate further developments of this technique. For NCP, thermalized neutron yield has been measured in phantoms irradiated in the fast neutron beam of the biomedical cyclotron in Nice. A thermal peak appears after 5 cm depth in the tissues, delayed after the fast neutron peak at 1.8 cm depth. Thus, a physical overdosage of 10% may be obtained if 100 ppm of 10B are assumed in the tissues. Our results using CAL 58 GBM cell line demonstrate a dose modification factor (DMF) of 1.19 when 100 ppm of boric acid are added to the growth medium. Thus for the particles, issued from neutron capture, a biological efficiency at least twice that of fast neutrons can be derived. These results, compared with historical data on fast neutron irradiation of glioblastoma, suggest that a therapeutic window may be obtained for GBM.

Boron Neutron Capture Therapy↗
PubMed1996

[New strategies in the surgery of primary hyperparathyroidism].

Although a remarkable pathology in terms of morbidity and life expectancy, primary hyperparathyroidism remains nonetheless a poorly recognized state despite highly suggestive clinical polymorphism, reliable biological signs and performing imaging for localisation. Through a retrospective study of a series of 129 patients surgically treated for primary hyperparathyroidism over a period of 12 years, helped by a review of the literature, we are able to propose an adapted surgical strategy for every different clinical aspect of this pathology (adenoma, benign hyperplasia, carcinoma). This strategy is guided by specific pre-operative findings and the Sestamibi scintigraphy.

Adenoma↗
PubMed1995

Phase II trial of cisplatin, fluorouracil, and pure folinic acid for locally advanced head and neck cancer: a pharmacokinetic and clinical survey.

PURPOSE: To analyze clinical and pharmacokinetic data of cisplatin (CP)/fluorouracil (FU)/l folinic acid (l FA) chemotherapy administered as first-line treatment to locally advanced head and neck cancer patients. PATIENTS AND METHODS: Thirty-nine patients (35 men and four women; median age, 60 years; six stage III and 33 stage IV) received CP on day 1 (100 mg/m2) followed by l FA (200 mg/m2/d x 5) plus FU (500 mg/m2/d x 5) administered by continuous venous infusion (three cycles planned). Mean plasma concentrations of FU, l FA, and 5-methyltetrahydrofolate (5MTHF) over the cycle were computed. RESULTS: Clinical response was assessable for 33 patients. Response rates on the primary tumor site (n = 33) were 63.7% complete responses (CRs), 24.2% partial responses (PRs), and 12.1% treatment failures. Response rates on lymph nodes (n = 27) were 40.7% CRs, 37.1% PRs, and 22.2% treatment failures. The most frequent toxicity was mucositis (36.2% of cycles grade 3 to 4). Grade 3 to 4 nausea-vomiting, diarrhea, neutropenia, and thrombocytopenia occurred in 6.7%, 1.9%, 13.3%, and 1% of cycles, respectively. Pharmacokinetic analysis showed a wide interpatient variability for both FU (mean, 1.01 mumol/L; range, 0.16 to 2.09), l FA (mean, 1.89, mumol/L; range, 0.52 to 7.88) and 5MTHF plasma concentrations (mean, 3.85 mumol/L; range, 1.30 to 8.11). A significant correlation was demonstrated between FU concentration and hematologic toxicity grade, mucositis grade, and nausea-vomiting/diarrhea grade. Regarding tumor response, patients who failed to respond significantly exhibited lower FU and total folate concentrations than patients with a CR or PR. CONCLUSION: This study highlights the efficacy of CP/FU/l FA in head and neck carcinoma and establishes the clinical importance of coupled FU/FA pharmacokinetics to predict pharmacodynamic variability.

Adult↗
PubMed1995

Response to fluorouracil therapy in cancer patients: the role of tumoral dihydropyrimidine dehydrogenase activity.

PURPOSE: The aim of the present study was to analyze the role of thymidylate synthase (TS; main cellular target of fluorouracil [FU]) and dihydropyrimidine dehydrogenase (DPD; rate-limiting enzyme of FU catabolism) in tumoral biopsies with respect to FU responsiveness. PATIENTS AND METHODS: This prospective study was conducted on 62 head and neck cancer patients (six stage II, 16 stage III, and 40 stage IV). All received first-line chemotherapy with biomodulated FU (5-day continuous infusion). Before treatment, a tumor biopsy and control biopsy (symmetrical nontumoral area) were obtained. Cytosolic TS and DPD activities were measured using radioenzymatic assays. RESULTS: DPD activity was detectable in all samples, without a significant difference between tumoral (median, 60 pmol/min/mg protein; range, 13 to 193) and nontumoral samples (median, 68 pmol/min/mg protein; range, 12 to 150). Tumoral TS and tumoral DPD were not significantly influenced by tumor localization or tumor staging. Among 52 tumors assessable for clinical response, we observed 46% complete responses (CRs), 33% partial responses (PRs), and 21% no responses (NRs). No relationship was demonstrated between TS activity and response to FU therapy. The comparison of tumoral DPD between complete responders and partial or nonresponders showed a trend toward significance (P = .06). In an attempt to reduce variability, we analyzed the tumoral/nontumoral DPD activity ratio; complete responders exhibited a significantly lower normalized DPD than partial or nonresponding patients (median, 0.86, 1.18, and 1.42 for CR, PR, and NR, respectively; CR v PR plus NR, P = .03). CONCLUSION: Although resistance to FU is multifactorial, the present clinical study suggests that FU catabolism in target cells is probably a determinant factor for FU responsiveness in cancer patients and justifies the clinical use of specific DPD inhibitors as FU biomodulators.

Adult↗
PubMed1995

[Population study of dihydropyrimidine dehydrogenase in cancer patients].

Dihydropyrimidine dehydrogenase (DPD) is the initial enzyme of 5-fluorouracil (5-FU) catabolism. The clinical importance of DPD has recently been demonstrated with the identification of severe and/or lethal 5-FU-related toxicity in patients with suspected or proven DPD deficiency revealed in lymphocytes. We conducted a prospective study on 185 cancer patients in order to evaluate the incidence of complete or partial DPD deficiency. The population comprised 152 men (mean age 62.1) and 33 women (mean age 59.2). Sixty eight were head and neck patients treated by a 5-day continuous infusion of 5-FU (starting dose 1 g/m2/day, with dose adaptation at mid-cycle) for which DPD activity was measured 2-3 days before 5-FU administration (94 cycles analyzed). DPD activity was measured by a radioenzymatic assay using 14C-5-FU. DPD activity showed a unimodal distribution, which globally fits a Gaussian distribution. Mean and median DPD activity were 0.222 and 0.211 nmol/min/mg prot respectively (range 0.065-0.559). No total DPD deficiency was found. Neither liver function nor age influenced DPD activity, but DPD activity was on average 15% lower in women than in men (0.194 and 0.228 nmol/min/mg prot respectively, p = 0.03). In patients treated with 5-FU, the risk of developing side effects was not linked to pretreatment DPD activity. 5-FU-related toxicity was linked to FU systemic exposure. The correlation between DPD activity and FU clearance was weak (n = 90, r = 0.31, p = 0.002). As a corollary, DPD activity in patients requiring a dose reduction was not significantly different from DPD activity in patients who did not require dose modification. From the present study it appears that total DPD deficiency is a very rare event. Although pre-treatment DPD activity cannot be a useful indicator for improving 5-FU dose adaptation strategy, the identification of partial DPD deficiency (< 0.100 nmol/min/mg prot, 3% of the population) could lead to starting the treatment with a markedly reduce 5-FU dose.

Adult↗
PubMed1994

Population study of dihydropyrimidine dehydrogenase in cancer patients.

PURPOSE: We conducted a prospective study on a large set of cancer patients in an attempt to evaluate the incidence of complete or partial dihydropyrimidine dehydrogenase (DPD) deficiency as found in peripheral mononuclear cells (PMNC). PATIENTS AND METHODS: One hundred eighty-five unselected consecutive cancer patients were included. The population consisted of 152 men (mean age, 62.1 years; range, 35 to 90) and 33 women (mean age, 59.2 years; range, 36 to 77). Sixty-eight were head and neck patients treated by a 5-day continuous infusion of fluorouracil (FU; starting dose, 1 g/m2/d, with dose adaptation based on pharmacokinetics) for which DPD activity was measured 2 to 3 days before FU administration (94 cycles analyzed). PMNC-DPD activity was measured by a radio-enzymatic assay using carbon-14-FU. RESULTS: DPD activity in the entire population showed a unimodal distribution, which globally fits a gaussian distribution. Mean and median DPD activity values were 0.222 and 0.211 nmol/min/mg protein, respectively (range, 0.065 to 0.559). No total DPD deficiency was found. Multifactor analysis of variance showed that liver function (biologic evaluation) and age did not influence DPD activity, but that DPD activity was, on average, 15% lower in women (0.194 nmol/min/mg protein) than in men (0.228 nmol/min/mg protein) (P = .03). No difference was demonstrated between premenopausal and postmenopausal women. In patients treated with FU, the risk of developing side effects was not linked to pretreatment DPD activity. FU-related toxicity was linked to FU systemic exposure. The correlation between pretreatment DPD activity and FU systemic clearance (CI) was weak (n = 90, linear regression r = .31, P = .002). Pretreatment DPD activity in patients who required a dose reduction was not significantly different from DPD activity in patients who did not require dose modification. CONCLUSION: From the present study, it appears that total DPD deficiency is a rare event. Although pretreatment DPD activity cannot be a useful indicator for improving FU dose adaptation strategy, the identification of severe DPD deficiency (< 0.100 nmol/min/mg protein) could lead to starting the treatment with a markedly reduced FU dose or even to using an alternative chemotherapy regimen.

Adult↗
PubMed1994

Relationship between fluorouracil systemic exposure and tumor response and patient survival.

PURPOSE: The aim of this study was to analyze the link between fluorouracil (FU) systemic exposure and tumor response and overall survival. PATIENTS AND METHODS: One hundred eighty-six patients (162 men, 24 women) with head and neck cancer were studied. All received cisplatin plus FU for three cycles as first-line chemotherapy. The treatment consisted of cisplatin (100 mg/m2 intravenously [IV]) followed by a 5-day continuous venous infusion of FU (1 g/m2/d). The median follow-up duration for the 104 patients alive was 24 months. For each cycle, we calculated the area under the curve over the duration of pharmacokinetic follow-up (AUC0-105 h) for plasma FU. For each patient, we analyzed the averaged AUC0-105 h and the averaged total dose for the three cycles. RESULTS: The response rate was 30% complete responses (CRs), 22% partial responses (PRs) more than 75%, 25% PRs less than 75%, and 23% no response (NR). Medians for averaged AUC and dose per cycle were 27,906 ng/mL h (first through third quartile, 25,398 to 31,060) and 7,000 mg (first through third quartile, 6,200 to 7,833), respectively. The tumor response was significantly linked to tumor stage (P < .001) and to averaged AUC (P = .05), but not to averaged dose. Analysis of parameters (continuous variable) expressing FU treatment intensity showed that dose did not influence survival contrary to the AUC (P = .001). The AUC remains significant (P = .025) in a multivariate analysis including tumor stage, demonstrating that the greater the FU systemic exposure, the longer the survival. CONCLUSION: These results strengthen the interest of individual FU dose adaptation based on pharmacokinetics.

Adult↗
PubMed1994

[EGF receptor, a prognostic factor in epidermoid cancers of the upper aerodigestive tracts].

EGFR was determined, before treatment; in tumors biopsies obtained from 109 consecutive patients with head and neck cancer (100 men and nine women), using iodine labelled recombinant EGF. The median age of the study population was 60 years. EGFR levels varied from 2 to 2302 fmol/mg membrane protein (median 71). There was a significant difference of distribution for EGFR levels between stages I and II tumors and stages III and IV tumors (P = 0.03). The EGFR cut-off value for overall survival was 120 fmol/mg protein and the median follow-up was 18 months (3-35) EGFR overexpression was associated with shorter relapse-free (P = 0.0125) and overall survival (P = 0.028). By multivariate analysis the only significant variables were EGFR for relapse-free survival and tumor staging and EGFR for overall survival. Analyzed in 60 patients treated by first-line chemotherapy CDDP-5FU, the longest survival was achieved for patients who had a complete response to chemotherapy and the lowest EGFR levels (P = 0.018). EGFR expression in the primary tumor allows survival among first line chemotherapy responder categories to be discriminated.

Adult↗
PubMed1993

Dihydropyrimidine dehydrogenase activity in cancer patients.

Dihydropyrimidine dehydrogenase (DPD) is the major catabolic enzyme of pyrimidines and fluoropyrimidines. The clinical course of 2 patients with suspected DPD deficiency is described. Both patients had significantly delayed clearance of fluorouracil (5-FU), elevated plasma uracil concentrations, and subsequent lethal toxicity. The prevalence of DPD deficiency in the general population is unknown, but given the large number of cancer patients treated with 5-FU, it may be of great clinical significance. Lymphocytes have been previously shown to be a useful marker of systemic DPD activity. Because DPD activity has not been previously reported in a large population of cancer patients using 5-FU as the substrate, we determined DPD activity in lymphocytes from 66 patients with cancer. DPD activity was determined by a sensitive high performance liquid chromatography method. The mean DPD activity (S.D.) in 66 patients with head and neck cancer was 0.189 (0.071) nomol/min/mg protein with wide interpatient variability (range 0.058-0.357). DPD activity was not correlated to age (r = -0.164, P = 0.188). The mean DPD activity in men [0.192 (0.074)] was not significantly different from that in women [0.172 (0.057); t-test P = 0.418]. Likewise, there was no statistical difference in DPD activity in patients who had not received prior chemotherapy [0.195 (0.066)] to patients receiving one or more cycles of chemotherapy [0.186 (0.074); t-test P = 0.638].

Adult↗
PubMed1993

Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer.

PURPOSE: To determine the expression of epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinoma and to evaluate its prognostic value. MATERIALS AND METHODS: EGFR was determined in tumor biopsies obtained from 109 consecutive patients with head and neck cancer (100 men, nine women). Control biopsies were obtained from 94 patients in a symetric nontumoral area of the same anatomic site. EGFR was measured by a binding assay using human recombinant iodine 125-EGF. RESULTS: The presence of detectable EGFR levels was found in all explored tumors with highly marked differences between patients (median, 71 fmol/mg protein; range, 2 to 2,302). In 93 of 94 cases, EGFR levels were higher in tumor samples as compared with healthy control zones. There was no significant difference in EGFR expression according to the various anatomic sites explored or tumoral differentiation status. There was a significant difference of distribution for EGFR levels between stages I and II tumors and stages III and IV tumors. The tumor EGFR levels were not linked to the response to first-line chemotherapy by cisplatin (CDDP) and fluorouracil (5FU). Survival was assessable for 103 patients for overall survival and for 81 patients for recurrence. EGFR overexpression was associated with shorter relapse-free (P = .0125) and overall survival (P = .028) rates. By multivariate analysis, the only significant variable was EGFR for relapse-free survival and tumor staging for overall survival. The association of EGFR to tumor staging markedly improves the significance for overall survival predictability (P = .002). CONCLUSION: EGFR determination deserves particular attention in head and neck cancer, since it independently carries a strong prognostic value.

Adult↗
PubMed1992

Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients.

Dihydropyrimidine dehydrogenase (DPD) is the initial key enzyme in the catabolism of 5-fluorouracil (5-FU). We measured DPD activity in lymphocytes from 57 consecutive head and neck cancer patients while simultaneously monitoring 5-FU pharmacokinetics during 5-day, continuous infusion (1000 mg/m2/day) 5-FU therapy (82 cycles in total). The mean value for DPD activity was 0.186 +/- 0.068 (SD) nmol/min/mg of protein (range, 0.058 to 0.357). The mean value for 5-FU clearance was 2522.6 +/- 684.2 ml/min/m2 (range, 1052 to 4029). A significant linear correlation was observed between DPD activity and 5-FU clearance (r = 0.716, P less than 0.0001). DPD activity was poorly correlated to plasma uracil concentrations (r = -0.260, P = 0.0215). Likewise, plasma uracil concentrations were poorly correlated to 5-FU clearance (r = -0.214, P = 0.0595). In patients evaluated for more than one cycle (n = 18), there was large intrapatient variability in both DPD activity and 5-FU clearance. No significant difference was noted between cycles for DPD activity or 5-FU clearance (Kruskal-Wallis test). Monitoring DPD activity in lymphocytes may be useful in identifying patients at risk for altered 5-FU disposition.

Adult↗