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Biomedical subjects

D Lacombe

Publications and source records attributed to D Lacombe.

At least 37 records · Page 2Linked to original sources
PubMed2004

Phase II study of OSI-211 (liposomal lurtotecan) in patients with metastatic or loco-regional recurrent squamous cell carcinoma of the head and neck. An EORTC New Drug Development Group study.

The purpose of this study was to evaluate the activity and safety of OSI-211, the liposomal form of lurtotecan, in patients ineligible for curative surgery or radiotherapy and with metastatic/locoregional recurrent squamous cell carcinoma of the head and neck (SCCHN) and target lesions either within a previously irradiated field ("within") or outside a previously irradiated field ("outside"). OSI-211 was given intravenously over 30 min on days 1 and 8 at 2.4 mg/m2/day, repeated every 21 days (1 cycle). From July 2001 to March 2002, 32 patients from 14 institutions were enrolled in the "within" arm and 18 in the "outside" arm. In the "within" arm, two patients were ineligible because their tumour site was not allowed in the protocol (nasopharynx, skin) and two other patients never started treatment. Of the 46 eligible patients who started treatment, there was one objective response (response rate: 2.2% (95% Confidence Interval (CI): [0-11.5%]). Twelve patients in the "within" arm and 6 in the "outside" arm had stable disease, with a median duration of 18 weeks, 95% CI (12.7-25.7). The median time to progression was 6 weeks (95%CI: [5.9-12.7] weeks). Haematological toxicity was moderate in both arms. The most common haematological toxicity was grade 1-2 anaemia in 79% of patients. Non-haematological toxicity was mild in both arms. The most common grade 3-4 non-haematological toxicity was infection in 8.5% of patients. OSI-211 administered on d1 and d8, every 3 weeks, is well tolerated, but shows only minimal activity in locally advanced/metastatic SCCHN.

Adult↗
PubMed2004

Phase II study on 9-nitrocamptothecin (RFS 2000) in patients with advanced or metastatic urothelial tract tumors.

OBJECTIVE: To investigate the antitumor activity and the safety of RFS2000, an oral topoisomerase I inhibitor, in patients with advanced or metastatic urothelial tract tumors refractory to one prior chemotherapy regimen. PATIENTS AND METHODS: Eligible patients were to have failed first line treatment for advanced or metastatic disease. Patients received RFS2000 as one daily oral intake at the dose of 1.5 mg/m(2)/day according to a "5 days on/2 days" off schedule continuously. One cycle was arbitrarily defined as a 3 week period. Sufficient oral fluid intake to prevent cystitis previously described in phase I trials with RFS2000 was recommended. Gehan design was used for sample size determination. Anti-tumor activity was evaluated according to the RECIST criteria and toxicity according to CTC version 2. RESULTS: Twenty patients received a total of 57 cycles (range 1-8). Grade 3-4 toxicity was observed in 10 patients requiring dose or schedule modifications. Hematological grade 3-4 toxicity was observed in 16% of the cycles. Only one patient experienced a partial response. CONCLUSIONS: RFS2000 could be administered orally as a "5 days on/2 days off" schedule continuously with a median dose intensity of 90.6% with an acceptable toxicity profile. However, RFS2000 did not exert significant activity in patients with advanced/metastatic urothelial tract tumors failing prior chemotherapy. The results of this study do not suggest further investigation of RFS2000 at the present dose and schedule for the treatment of urothelial tract tumors in this refractory population.

Administration, Oral↗
PubMed2004

Phase I trial of intravenous aviscumine (rViscumin) in patients with solid tumors: a study of the European Organization for Research and Treatment of Cancer New Drug Development Group.

BACKGROUND: Aviscumine is an Escherichia coli-derived recombinant type II ribosome-inactivating protein with potent antitumor activity in vitro and in vivo. It is the recombinant counterpart of natural mistletoe lectin-I. The current study was performed to determine the safety profile, dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the intravenous (i.v.) administration of aviscumine in cancer patients. Translational research included the evaluation of pharmacokinetics and monitoring of plasma cytokine and anti-aviscumine antibody induction after administration of the drug. PATIENTS AND METHODS: Aviscumine was given twice weekly as a 1 h central i.v. infusion in patients with advanced, refractory progressive, solid malignant tumors who had not been previously exposed to natural mistletoe preparations. They had histologically or cytologically verified disease, were > or =18 years old, had an Eastern Cooperative Oncology Group performance status < or =2 and adequate bone marrow, liver and renal function. DLT was defined as any non-hematological grade 3-4 toxicity (National Cancer Institute Common Toxicity Criteria version 2.0), neutrophil count <500/microl for > or =7 days, febrile neutropenia or thrombocytopenia grade 4. The MTD was defined as the dose at which >20% of patients experienced DLT during the first treatment cycle. The Continual Reassessment Method was used to determine the number of patients required per dose level. RESULTS: Forty-one fully eligible patients (19 male, 22 female) with a median age of 56 years (range 37-74) were enrolled. Colorectal, ovarian, renal cell and breast cancer were the most common tumor types. Dose levels of aviscumine ranged from 10 to 6400 ng/kg. The median number of cycles was two (range one to eight). Common clinical toxicities in cycle 1 were fatigue, fever, nausea, vomiting and allergic reactions. Fatigue grade 3 was dose limiting in one of six patients at 4000 ng/kg and reversible grade 3 liver toxicity (elevation in alkaline phosphatase, transaminases and/or gamma-glutamyltransferase) occurred in one of 10 patients at 4800 ng/kg and in two of five patients at 6400 ng/kg. The best response (RECIST criteria) was stable disease in 11 patients, lasting for two to eight cycles. The pharmacokinetic evaluation revealed a short alpha half-life of 13 min and linear kinetics on dose levels > or =1600 ng/kg. Aviscumine stimulated the immune system with a release of cytokines such as interleukin (IL)-1beta, IL-6 and interferon-gamma, and induced immunoglobulin (Ig) G- and/or IgM-anti-aviscumine antibodies of uncertain clinical relevance. CONCLUSIONS: The recommended dose for further clinical trials is 5600 ng/kg twice weekly. Based on the short half-life of the recombinant protein observed in this trial, the exploration of prolonged infusion schedules of aviscumine is warranted.

Adjuvants, Immunologic↗
PubMed2004

Screening of SLC26A4 (PDS) gene in Pendred's syndrome: a large spectrum of mutations in France and phenotypic heterogeneity.

Sensorineural hearing defect and goiter are common features of Pendred's syndrome. The clinical diagnosis of Pendred's syndrome remains difficult because of the lack of sensitivity and specificity of the thyroid signs. The identification of PDS as the causative gene allowed molecular screening and enabled a re-evaluation of the syndrome to identify potential diagnostic characteristics. This report presents the clinical and genotypic findings of 30 French families, for whom a diagnosis of Pendred's syndrome had been made. Twenty-seven families had at least one mutated allele. Twenty-eight different mutations were identified, 11 of which had never been previously reported. The main clinical characteristics were: early hearing loss, fluctuation in terms of during deafness evolution, and the presence of an enlarged vestibular aqueduct.

Adolescent↗
PubMed2004

Current and future trials of the EORTC brain tumor group.

The EORTC Brain Tumor Group (BTG) is dedicated to clinical research of neoplasms of the brain. In the past years the BTG has carried out phase II and phase III trials on glial tumors, brain metastases and primary CNS lymphomas. Future studies will investigate novel drugs in combination with chemo-radiotherapy in glioblastoma multiforme, radiotherapy in meningioma, and chemotherapy in medulloblastoma. The BTG will also start a new phase III trial on newly diagnosed low-grade glioma comparing radiotherapy to temozolomide. In all our trials translational research is getting more and more important, often this is one of the most important ways to get useful conclusions from clinical trials. The wide recognition of the importance of translational research for clinical trials and in particular with targeted therapies implies that this type of research will become a mandatory element in many of our future trials.

Antineoplastic Agents↗
PubMed2004

Trisomy 22 with thyroid isthmus agenesis and absent gall bladder.

This manuscript reports a fetus of 24 weeks gestation, detected on echography to have congenital anomalies: intra-uterine growth retardation, facial dysmorphism, ventricular septal defect with aortic displacement and 8-mm nuchal skinfold thickness. Karyotype was performed. Post termination of pregnancy autopsy showed additionnal internal organ anomalies included: absent gall bladder and thyroid isthmus agenesis. To our knowledge, these anomalies have never been described in trisomic 22 fetuses. This case suggests that chromosome 22 could play a role in thyroid development.

Centromere↗
PubMed2003

Phase II study of XR 5000 (DACA), an inhibitor of topoisomerase I and II, administered as a 120-h infusion in patients with non-small cell lung cancer.

XR5000 is a tricyclic carboxamide-based cytotoxic agent that binds to DNA by intercalation and stimulates DNA cleavage by inhibition of both topoisomerase I and II. The aim of this study was to evaluate the antitumoral activity and safety profile of XR5000 given as second-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Patients received XR5000 at the dose of 3010 mg/m(2) as a 120-h central venous infusion every 3 weeks. The 15 patients (median age 56 years, range 48-71 years) enrolled had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (3 patients), 1 (11 patients) or 2 (1 patient). A total of 32 cycles of XR5000 (median 2, range 1-6) were given to 14 patients. No objective response (assessed according to World Health Organization (WHO) criteria) was documented in the 12 evaluable patients by an external review panel; in 4 out of the 12 patients disease stabilisation was recorded. The following toxicities graded according to the Common Toxicity Criteria (CTC) version 2.0. were observed: one grade 3 and two grade 4 granulocytopenia, one grade 3 and one grade 4 thrombocytopenia, one grade 3 deep venous thrombosis, one grade 3 fatigue, and grade 3 undocumented epileptic seizures which led to death in 2 patients. With only 4 out of 12 patients reaching stable disease when using this dose and regimen, further evaluation of XR5000 in advanced NSCLC is not justified.

Acridines↗
PubMed2003

Glufosfamide administered using a 1-hour infusion given as first-line treatment for advanced pancreatic cancer. A phase II trial of the EORTC-new drug development group.

The activity of glufosfamide (beta-D-glucopyranosyl-N,N'-di-(2-chloroethyl)-phosphoric acid diamide) against pancreatic cancer was investigated in a multicentre, phase II clinical study. Chemotherapy-nai;ve patients with advanced or metastatic disease were treated with glufosfamide (5 g/m(2)) using a 1-h intravenous (i.v.) infusion every 3 weeks. Patients were randomised between active-hydration and normal fluids to evaluate the nephroprotective effect of forced diuresis. Patients experiencing >0.4 mg/dl (>35 micromol/l) increase in serum creatinine compared with their baseline value were taken off treatment for safety reasons. The evaluation of response was according to the Response evaluation criteria in solid tumours (RECIST). Blood sampling was performed for pharmacokinetic analyses. 35 patients from 13 institutions were registered over a 13-month period. A total of 114 treatment cycles (median 3, range 1-8) were administered to 34 patients; 18 patients were allocated to the hydration arm. Overall haematological toxicity was mild. Metabolic acidosis occurred in 2 patients treated in the active-hydration arm, grade 3 hypokalaemia was recorded in 5 patients and grade 3 hypophosphataemia in 4 patients. One patient had a grade 4 increase in serum creatinine level, concomitantly to disease progression. Active-hydration did not show a nephroprotective effect and the plasma pharmacokinetics (Pk) of glufosfamide was not significantly influenced by hydration. Two confirmed partial remissions (PR) were reported (response rate 5.9%, 95% Confidence Interval (CI) 0.7-19.7%) and 11 cases obtained disease stabilisation (32.4%). An extra mural review panel confirmed all of the responses. Median overall survival was 5.3 months (95% CI 3.9-7.1) and time to progression (TTP) was 1.4 months (95% CI 1.3-2.7). In conclusion, glufosfamide administered using a 1-h infusion every 3 weeks has a modest activity in advanced pancreatic adenocarcinoma. Haematological toxicity is particularly mild, but regular monitoring of renal function is recommended.

Adenocarcinoma↗
PubMed2003

Cancer drug development in Europe: a selection of new agents under development at the European Drug Development Network.

From may 99, three european leaders in anti-cancer drug development (EORTC, Cancer Research UK, SENDO) have got together to form a network of collaborating groups: the European Drug Development Network. The member organisations have all agreed to join their efforts in developing new drugs. They have acquired a great and efficient expertise in anticancer drug development covering all aspects from drug screening to refinement of trial methodology and translational research. In this paper, the most interesting drugs under development in each of the three organisations are being described and discussed.

Angiogenesis Inhibitors↗
PubMed2003

European Organization for Research and Treatment of Cancer (EORTC) open label phase II study on glufosfamide administered as a 60-minute infusion every 3 weeks in recurrent glioblastoma multiforme.

BACKGROUND: Glufosfamide is a new alkylating agent in which the active metabolite of isophosphoramide mustard is covalently linked to beta-D-glucose to target the glucose transporter system and increase intracellular uptake in tumor cells. We investigated this drug in a multicenter prospective phase II trial in recurrent glioblastoma multiforme (GBM). PATIENTS AND METHODS: Eligible patients had recurrent GBM following surgery, radiotherapy and no more than one prior line of chemotherapy. Patients were treated with glufosfamide 5000 mg/m(2) administered as a 1-h intravenous infusion. Treatment success was defined as patients with either an objective response according to Macdonald's criteria or 6 months progression-free survival. Toxicity was assessed with the Common Toxicity Criteria (CTC) version 2.0. RESULTS: Thirty-one eligible patients were included. Toxicity was modest, the main clinically relevant toxicities being leukopenia (CTC grade >3 in five patients) and hepatotoxicity (in three patients). No responses were observed; one patient (3%; 95% confidence interval 0 to 17%) was free from progression at 6 months. Pharmacokinetic analysis showed a 15% decrease in area under the curve and glufosfamide clearance in patients treated with enzyme-inducing antiepileptic drugs, but no effect of these drugs on maximum concentration and plasma half-life. CONCLUSION: Glufosfamide did not show significant clinical antitumor activity in patients with recurrent GBM.

Adult↗
PubMed2003

Spectrum of NSD1 mutations in Sotos and Weaver syndromes.

Sotos syndrome is an overgrowth syndrome characterised by pre- and postnatal overgrowth, macrocephaly, advanced bone age, and typical facial features. Weaver syndrome is a closely related condition characterised by a distinctive craniofacial appearance, advanced carpal maturation, widened distal long bones, and camptodactyly. Haploinsufficiency of the NSD1 gene has recently been reported as the major cause of Sotos syndrome while point mutations accounted for a minority of cases. We looked for NSD1 deletions or mutations in 39 patients with childhood overgrowth. The series included typical Sotos patients (23/39), Sotos-like patients (lacking one major criteria, 10/39), and Weaver patients (6/39). We identified NSD1 deletions (6/33) and intragenic mutations (16/33) in Sotos syndrome patients. We also identified NSD1 intragenic mutations in 3/6 Weaver patients. We conclude therefore that NSD1 mutations account for most cases of Sotos syndrome and a significant number of Weaver syndrome cases in our series. Interestingly, mental retardation was consistently more severe in patients with NSD1 deletions. Macrocephaly and facial gestalt but not overgrowth and advanced bone age were consistently observed in Sotos syndrome patients. We suggest therefore considering macrocephaly and facial gestalt as mandatory criteria for the diagnosis of Sotos syndrome and overgrowth and advanced bone age as minor criteria.

Abnormalities, Multiple↗
PubMed2002

Progressive bulbospinal amyotrophy in triple A syndrome with AAAS gene mutation.

Triple A (3A) syndrome, a rare autosomal recessive disorder, is characterized by adrenocorticotropic hormone-resistant adrenal insufficiency, achalasia of the cardia, alacrima, and variable autonomic and neurologic dysfunction. The gene responsible, AAAS, recently has been identified. We describe the neurologic phenotype of the first adult case of 3A syndrome presenting bulbospinal amyotrophy as the prominent sign in association with a homozygous nonsense mutation identified in the AAAS gene.

Adrenal Gland Diseases↗
PubMed2002

Prenatal diagnosis of female monozygotic twins discordant for Turner syndrome: implications for prenatal genetic counselling.

We describe a set of monozygotic (MZ) female twins, one of whom presented with a typical Turner syndrome (TS) phenotype and the other a normal female phenotype. Prenatal fetal ultrasonographic examination showed a monochorial diamniotic pregnancy with a hygroma colli and growth delay in Twin A and no anomalies in Twin B. Karyotypic analysis performed on fetal blood samples demonstrated a 46,XX/45,X (23/2) mosaicism in Twin A and a normal 46,XX chromosome constitution in Twin B. At birth, Twin A presented with a typical TS and Twin B had a normal female phenotype. Postnatal cytogenetic investigation of blood lymphocytes showed the same 46,XX/45,X mosaicism in both twins: 46,XX/45,X (40/7) in Twin A and 46,XX/45,X (40/5) in Twin B. Further investigations at the age of 10 months showed in Twin A a 46,XX/45,X (98/2) mosaicism in lymphocytes and 100% of 45,X (50 analysed cells) in fibroblasts, and in Twin B a normal 46,XX (100 analysed cells) chromosome constitution in lymphocytes but a mild 46,XX/45,X (78/2) mosaicism in fibroblasts. Monozygosity was confirmed by molecular analysis. To our knowledge, this is the first report of prenatal diagnosis of MZ female twins discordant for TS. Review of reported sets of MZ female twins (eight cases) or triplets (one case) discordant for TS shows, as in the present case, that the phenotype correlates better with the chromosomal distribution of mosaicism in fibroblasts than in lymphocytes. In the blood of MZ twins chimerism may modify the initial allocation of the mosaicism. These results suggest that, in cases of prenatal diagnosis of MZ female twins discordant for TS, the phenotype of each twin would be better predicted from karyotype analysis of cells from amniotic fluid than from fetal blood.

Adult↗
PubMed2002

[Familial idiopathic hypertrophic osteoarthropathy and atopic dermatitis (Currarino's disease)].

CASE REPORT: Two brothers with a Currarino's disease are reported. Patients characteristics included a dysmorphic syndrome, cranial suture defects, hypertrophic osteoarthropathy and severe chronic eczema. COMMENTS: Consanguinity of parents suggests an autosomal recessive inheritance. CONCLUSION: Currarino's disease is a rare unknown constitutional syndrome. The age of beginning of the disease, the cranial suture defects and the chronic eczema allow to distinguish it from the others primary hypertrophic osteoarthropathies.

Abnormalities, Multiple↗