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Biomedical subjects

D Lacombe

Publications and source records attributed to D Lacombe.

At least 55 records · Page 3Linked to original sources
PubMed2002

[Costello syndrome: clinical aspects and tumor risk].

Costello syndrome is a sporadic development anomaly suggesting a genetic determinism. Main features include characteristic facial features, mental retardation, growth retardation, cutis laxa, heart malformation, and peri-orificial papillomata. In previous reported cases, the frequency of tumors is 15%, which argues for a screening protocol. The occurrence of a tumor in a child with growth retardation and cutis laxa must be reminiscent of Costello syndrome. The determinism of this syndrome is still unknown, and the hypothesis of an inactivation of a tumor suppressor gene is to be considered.

Abnormalities, Multiple↗
PubMed2002

Phase II study of XR 5000, an inhibitor of topoisomerases I and II, in advanced colorectal cancer.

XR 5000 is one of a series of tricyclic carboxamide-based cytotoxic agents. It binds to DNA by intercalation and stimulates DNA cleavage by inhibition of both topoisomerase I and II, thus possibly overcoming the resistance resulting from downregulation of either enzyme. Twenty patients with advanced or metastatic colorectal cancer, unpretreated for metastatic disease, received XR 5000 at the dose of 3010 mg/m(2) in a 120-h central intravenous (i.v.) infusion every 3 weeks. Response was evaluated every two cycles. No complete (CR) or partial responses (PR) were observed in eligible patients (response rate, 0 of 19, 0%; 95% confidence interval (CI): 0-18%). 5 patients had stable disease, which lasted from 79 to 157 days. Haematological toxicity was low, since only one grade 4 neutropenia and two grade 3 anaemia were observed. Other treatment-related grade 3-4 toxicities were: deep venous thrombosis (2 cases), liver toxicity, diarrhoea, anorexia, dyspnoea, chest pain, infection (1 case each). Despite the good toxicity profile, these results do not support further trials with XR 5000 in metastatic colorectal cancer.

Acridines↗
PubMed2002

Regulatory issues for clinical trials at EORTC: the way forward. European Organisation for Research and Treatment of Cancer.

Since the Declaration of Helsinki, the performance of clinical trials is subject to ethical and gradually also legal requirements. As the EORTC is performing clinical trials in more then 30 countries, it gained expertise in the field of Regulatory Affairs of all those countries. This paper intends to address the general approach with regard to European Regulatory Affairs. Furthermore, it is focusing on the role of the EORTC at the level of the competent regulatory authorities. As recently things are moving and changing on a European level, it describes the perception of the current and future European regulatory framework, and last, but not least, it is explained in what respect the achievements of the EORTC could be of benefit to society when defining their cancer treatment policies.

Antineoplastic Agents↗
PubMed2002

EORTC Brain Tumor Group: achievements and perspectives.

The EORTC Brain Tumor Group has a long standing history of achievements. The activities of the Brain Tumor Group have recently been re-structured in order to face the challenge of large intergroup/intercontinental trials and be a reference address for early drug development needed for gliomas. Constant adaptation to higher quality assurance criteria and implementation of translational research studies are now priorities for the Brain Tumor Group. Due to such activities, the EORTC Brain Group has become a major player in clinical research. The number of centres and patients joining its trials have greatly increased over the past 2 years. Achievements and strategies are detailed in this article.

Achievement↗
PubMed2002

The EORTC and drug development. European Organisation for Research and Treatment of Cancer.

Early drug development at EORTC has always been subject to structural changes to adapt to the rapid changes that occur in oncological drug development. The expertise of early drug developers has always been cross-fertilised with disease-/tumour-oriented groups and also backwards to the laboratory research groups. This results in the establishment of a solid and dedicated network of medical oncologists with focused expertise in cancer drug development. The EORTC Data Center is fully equipped with all expertise to support clinical research activities and includes regulatory, safety, and quality assurance desks. The EORTC New Drug development Programme (NDDP) provides methodological expertise to early clinical trials and coordinates phase I and phase II studies addressing various approaches. Through NDDP, the early clinical groups and the disease-/tumour-oriented groups have created specific networks to address early drug development in specific tumour types. This results in very efficient networks which have the resources and the patients to address and conduct challenging clinical trials in a standardised fashion ensuring the highest standards in cancer treatment.

Antineoplastic Agents↗
PubMed2002

Multicentre phase II and pharmacokinetic study of RFS2000 (9-nitro-camptothecin) administered orally 5 days a week in patients with glioblastoma multiforme.

A phase II trial was instigated to investigate the antitumour activity, the safety and the pharmacokinetic parameters of RFS2000, a recently identified oral topoisomerase I inhibitor, given once daily (1.5 mg/m(2)/day) as first-line chemotherapy treatment for patients with advanced glioblastoma multiforme (GBM). Between 9 March and 15 September 2000, 17 patients were entered onto the trial. 15 patients were considered eligible. A total of 49 cycles (range 1-8) were administered. Grade 3-4 toxicity was observed in 5 patients. Neutropenia and thrombocytopenia were common toxicities. Pharmacokinetic analysis showed that 9-nitro camptothecin (9-NC) could be detected in the plasma and is progressively converted into 9-amino-camptothecin (9-AC). The response rate was poor, with 5 patients experiencing tumour stabilisation and 10 progressing. Thus, the results do not support the further evaluation of RFS2000 as a single agent in patients with recurrent GBM.

Administration, Oral↗
PubMed2002

Successful laparoscopic operation of bilateral pheochromocytoma in a patient with Beckwith-Wiedemann syndrome.

We report the case of a 20-year-old female patient with Beckwith-Wiedemann syndrome presenting with high blood pressure and bilateral adrenal pheochromocytoma successfully removed with laparoscopy in the same time. To our knowledge, the present case is the first observation of a bilateral pheochromocytoma occurring in the Beckwith-Wiedemann syndrome. It provides further support for a genetic anomaly in this condition. Our case also indicates the interest of laparoscopy for the surgical treatment of adrenal pheochromocytoma, even in bilateral tumors.

Adrenal Gland Neoplasms↗
PubMed2002

Phase II study of XR5000 (DACA) administered as a 120-h infusion in patients with recurrent glioblastoma multiforme.

BACKGROUND: XR5000 is a tricyclic carboxamide that intercalates DNA and inhibits both topoisomerase I and II. The aim of this study was to evaluate the efficacy and tolerability of XR5000 in patients with recurrent glioblastoma multiforme previously untreated with chemotherapy at relapse. PATIENTS AND METHODS: Patients received XR5000 at a dose of 3010 mg/m2 as a 120-h central venous infusion every 3 weeks. An independent panel assessed response every two cycles using McDonald's criteria (tumour size, steroid intake and neurological status); toxicity was graded according to the National Cancer Institute-Common Toxicity Criteria, version 2.0. RESULTS: Sixteen patients were enrolled (one ineligible patient was excluded from efficacy evaluation). Performance status was zero (five patients), one (nine patients) or two (one patient). They received 30 cycles of XR5000 (median 2, range 1-5). Haematological toxicity was mild, with only one patient experiencing grade 3 neutropenia. Other related grade 3/4 adverse events included chest pain (one patient), axillary vein thrombosis (one patient) and rigors/fever in the absence of neutropenia (one patient). There were no objective responses, 14 patients progressing on XR5000 and one having stable disease. CONCLUSIONS: Although XR5000 was generally well tolerated, these results do not support further evaluation in patients with glioblastoma multiforme using this dose and schedule.

Acridines↗
PubMed2002

Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy.

Generalised lipodystrophy of the Berardinelli-Seip type (BSCL) is a rare autosomal recessive human disorder with severe adverse metabolic consequences. A gene on chromosome 9 (BSCL1) has recently been identified, predominantly in African-American families. More recently, mutations in a previously undescribed gene of unknown function (BSCL2) on chromosome 11, termed seipin, have been found to be responsible for this disorder in a number of European and Middle Eastern families. We have studied the genotype/phenotype relationships in 70 affected subjects from 44 apparently unrelated pedigrees of diverse ethnic origin. In all subjects, hepatic dysfunction, hyperlipidaemia, diabetes mellitus, and hypertrophic cardiomyopathy were significant contributors to morbidity with no clear differences in their prevalence between subjects with BSCL1 or BSCL2 and those with evidence against cosegregation with either chromosome 9 or 11 (designated BSCLX). BSCL2 appears to be a more severe disorder than BSCL1 with a higher incidence of premature death and a lower prevalence of partial and/or delayed onset of lipodystrophy. Notably, subjects with BSCL2 had a significantly higher prevalence of intellectual impairment than those with BSCL1 or BSCLX (p<0.0001, OR 17.0, CI 3.6 to 79.0). The higher prevalence of intellectual impairment and the increased risk of premature death in BSCL2 compared to BSCL1 emphasise the importance of molecular diagnosis of this syndrome and have clear implications for genetic counselling.

Adolescent↗
PubMed2002

Association of ectrodactyly and distal phocomelia.

Ectrodactyly and phocomelia are well known limbs malformations. They can be a part of various syndromes, and are more often transmitted with dominant autosomal Inheritance with variable expression and Incomplete penetrance. Different loci have been Identified for ectrodactyly (SHFM1 at 7q21.3q22.1, SHFM2 at Xq26, SHFM3 at 10q24q25, SHFM4 at 3q27), and two genes are known (DSS1 for SHFM1, p63 for SHFM4). We report the case of a 33 year-old female affected with the association of ectrodactyly and phocomelia. It could be a "new" association, or a mild or partial expression of the syndrome Including ectrodactyly, phocomelia, deafness and sinusal arythmia.

Abnormalities, Multiple↗
PubMed2001

Large-scale deletions and SMADIP1 truncating mutations in syndromic Hirschsprung disease with involvement of midline structures.

Hirschsprung disease (HSCR) is a common malformation of neural-crest-derived enteric neurons that is frequently associated with other congenital abnormalities. The SMADIP1 gene recently has been recognized as disease causing in some patients with 2q22 chromosomal rearrangement, resulting in syndromic HSCR with mental retardation, with microcephaly, and with facial dysmorphism. We screened 19 patients with HSCR and mental retardation and eventually identified large-scale SMADIP1 deletions or truncating mutations in 8 of 19 patients. These results allow further delineation of the spectrum of malformations ascribed to SMADIP1 haploinsufficiency, which includes frequent features such as hypospadias and agenesis of the corpus callosum. Thus, SMADIP1, which encodes a transcriptional corepressor of Smad target genes, may play a role not only in the patterning of neural-crest-derived cells and of CNS but also in the development of midline structures in humans.

Abnormalities, Multiple↗
PubMed2001

Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.

Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.

Acanthosis Nigricans↗
PubMed2001

Leucodystrophy and oculocutaneous albinism in a child with an 11q14 deletion.

We report a patient with an undetermined leucodystrophy associated with type 1A oculocutaneous albinism (OCA). Type 1 OCA results from recessive mutations in the tyrosinase gene (TYR) located in 11q14.3. The patient was found by FISH to carry a deletion of at least the first exon of the TYR gene on one chromosome and a (TG) deletion at codon 244/245 on the second chromosome. The existence of the microdeletion suggested that a gene responsible for leucodystrophy was located in the vicinity of the TYR gene. A combination of a test of hemizygosity and contig mapping studies allowed us to map the gene within a 0.6 cM region flanked by microsatellite markers D11S1780 and D11S931.

Adolescent↗