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Biomedical subjects

M F Avril

Publications and source records attributed to M F Avril.

At least 19 recordsLinked to original sources
PubMed2006

Imatinib enhances human melanoma cell susceptibility to TRAIL-induced cell death: Relationship to Bcl-2 family and caspase activation.

In order to define genetic determinants of primary and metastatic melanoma cell susceptibility to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), we have applied oligonucleotide microarrays to TRAIL-sensitive primary T1 cells and TRAIL-resistant metastatic G1 cells treated or not with TRAIL. T1 and G1 cells are isogenic melanoma cell subclones. We examined 22 000 spots, 4.2% of which displayed differential expression in G1 and T1 cells. Cell susceptibility to TRAIL-mediated apoptosis was found to be correlated with gene expression signatures in this model. Some of the differentially expressed genes were identified as involved in ATP-binding and signaling pathways, based on previously published data. Further analysis provided evidences that c-kit was overexpressed in G1 cells while it was absent in T1 cells. The c-kit inhibitor, imatinib, did not restore TRAIL sensitivity, excluding a role for c-kit in TRAIL resistance in G1 cells. Surprisingly, imatinib inhibited cell proliferation and TRAIL-mediated apoptosis in melanoma cells. We investigated the possible involvement of several molecules, including c-ABL, platelet-derived growth factor receptor (PDGFR), cellular FADD-like interleukin-1 alpha-converting enzyme-like inhibitory protein (c-FLIP)(L/S), Fas-associated DD kinase, p53, p21(WAF1), proteins of B-cell leukemia/lymphoma 2 (Bcl-2) family and cytochrome c. Imatinib did not modulate the expression or activation of its own targets, such as c-ABL, PDGFRalpha and PDGFRbeta, but it did affect the expression of c-FLIP(L), BCL2-associated X protein (Bax) and Bcl-2. Moreover, c-FLIP(L) knockdown sensitized T1 cells to TRAIL-mediated apoptosis, with a sensitivity similar to that of cells previously treated with imatinib. More notably, we found that the resistance to TRAIL in G1 cells was correlated with constitutive c-FLIP(L) recruitment to the DISC and the inhibition of caspase 8, 3 and 9 processing. Moreover, c-FLIP(L) knockdown partly restored TRAIL sensitivity in G1 cells, indicating that the expression level of c-FLIP(L) and its interaction with TRAIL receptor2 play a crucial role in determining TRAIL resistance in metastatic melanoma cells. Our results also show that imatinib enhances TRAIL-induced cell death independently of BH3-interacting domain death agonist translocation, in a process involving the Bax:Bcl-X(L) ratio, Bax:Bcl-X(L)/Bcl-2 translocation, cytochrome c release and caspase activation. Our data indicate that imatinib sensitizes T1 cells by directly downregulating c-FLIP(L), with the use of an alternative pathway for antitumor activity, because PDGFRalpha is not activated in T1 cells and these cells do not express c-kit, c-ABL or PDGFRbeta. Caspase cascade activation and mitochondria also play a key role in the imatinib-mediated sensitization of melanoma cells to the proapoptotic action of TRAIL.

Antineoplastic Agents↗
PubMed2005

Risk of melanoma following adulthood cancer: a case-control study.

Melanoma is a severe skin cancer related to sun exposure. Whether this malignancy is linked to exposure to ionising radiation during adulthood is still controversial. This case-control study examined the risk of melanoma following treatment for an adulthood first malignant neoplasm (FMN). Cases were patients who presented with cutaneous melanoma after a first cancer in adulthood. Controls (3 per case) were patients free of melanoma, matched for age, duration of follow-up since the FMN, type of FMN, and followed in the same institution. A total of 57 cases and 171 controls were included. In the final multivariate analysis, no risk of melanoma was associated with radiotherapy (odds ratio (OR) for 1 Gy = 1.01, 95% confidence interval (95%CI) 0.96-1.07) nor hormonotherapy, whereas chemotherapy use (OR = 2.3, 95%CI 0.93-5.6) and having a history of familial cancer (OR = 2.8, 95%CI 1.3-5.9) exhibited a nearly significant risk. In conclusion, unlike the evidence for risk of exposure to ionising radiation during childhood, we did not substantiate a risk for association of melanoma with exposure to ionising radiation during adulthood. The risk associated with chemotherapy should justify the implementation of skin surveillance for early detection of melanoma in these patients.

Adolescent↗
PubMed2005

Comprehensive analysis of CDKN2A (p16INK4A/p14ARF) and CDKN2B genes in 53 melanoma index cases considered to be at heightened risk of melanoma.

OBJECTIVE: Comprehensive analysis of the 9p21 locus including the CDKN2A, ARF, and CDKN2B genes in 53 individuals from melanoma index cases considered to be at heightened risk of melanoma. METHODS AND RESULTS: Using a combination of DNA sequencing, gene copy number by real time quantitative PCR, linkage analysis, and transcript analysis in haploid somatic cell hybrids, we found no evidence for germline alteration in either coding or non-coding domains of CDKN2A and CDKN2B. However, we identified a p14ARF exon 1beta missense germline mutation (G16D) in a melanoma-neural system tumour syndrome (CMM+NST) family and a 8474 bp germline deletion from 196 bp upstream of p14ARF exon 1beta initiation codon to 11233 bp upstream of exon 1alpha of p16(INK4A) in a family with five melanoma cases. For three out of 10 families with at least three melanoma cases, the disease gene was unlinked to the 9p21 region, while linkage analysis was not fully conclusive for seven families. CONCLUSIONS: These data reinforce the hypothesis that ARF is a melanoma susceptibility gene and suggest that germline deletions specifically affecting p14ARF may not be solely responsible for NST susceptibility. Predisposition to CMM+NST could either be due to complete disruption of the CDKN2A locus or be the result of more complex genetic inheritance. In addition, the absence of any genetic alteration in 50 melanoma prone families or patients suggests the presence of additional tumour suppressor genes possibly in the 9p21 region, and on other chromosomes.

Cell Line, Tumor↗
PubMed2004

Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study.

PURPOSE: To compare fotemustine and dacarbazine (DTIC) in terms of overall response rate (ORR) as primary end-point and overall survival, duration of responses, time to progression, time to occurrence of brain metastases (BM), and to assess safety and quality of life in patients with disseminated cutaneous melanoma. PATIENTS AND METHODS: Patients received either intravenous fotemustine 100 mg/m2 weekly for 3 weeks or DTIC 250 mg/m2/d for 5 consecutive days every 4 weeks (two cycles). Nonprogressive patients received a maintenance treatment every 4 weeks (fotemustine 100 mg/m2 or DTIC 250 mg/m2 for 5 days). RESULTS: Two hundred twenty-nine patients were randomly assigned to fotemustine or DTIC arms. The best ORR was higher in the fotemustine arm than in the DTIC arm in the intent-to-treat population (n=229; 15.2% v 6.8%; P=.043) and in full analysis set (n=221) (15.5% v 7.2%; P=.053). Similar median durations of responses (5.8 months with fotemustine v 6.9 months with DTIC) and time to progression (1.8 v 1.9 months, respectively) were observed. In patients without BM at inclusion, the median time to BM was 22.7 months with fotemustine versus 7.2 months with DTIC (P=.059). Median survival was 7.3 months with fotemustine versus 5.6 months with DTIC (P=.067). The main toxicity was grade 3 to 4 neutropenia (51% with fotemustine v 5% with DTIC) and thrombocytopenia (43% v 6%, respectively). No significant difference was noted for quality of life between arms. CONCLUSION: ORR was higher in the fotemustine arm compared to the DTIC arm in first-line treatment of disseminated melanoma. A trend in favor of fotemustine in terms of overall survival and time to BM was evidenced.

Adult↗
PubMed2003

Radiation dose as a risk factor for malignant melanoma following childhood cancer.

The aim of this study was to determine therapy-related risk factors for the development of melanoma after childhood cancer. Among 4401 3-year survivors of a childhood cancer in eight French and British centres and 25120 patients younger than 20 years old at first malignant neoplasm (FMN) extracted from the Nordic Cancer Registries, 16 patients developed a melanoma as a second malignant neoplasm (SMN). A cohort study of the French and British cohorts was performed. In a nested case-control study, the 16 patients who developed a melanoma as a SMN (cases) were matched with 3-5 controls in their respective cohort according to gender, age at the first cancer, the calendar year of occurrence of the first cancer and follow-up. Radiotherapy appeared to increase the risk of melanoma for local doses >15 Gy, Odds Ratio (OR)=13 (95% Confidence Interval (CI): 0.94-174). Regarding chemotherapy, we observed an increased OR for both alkylating agents and spindle inhibitors, OR=2.7 (95% CI: 0.5-14). Children treated for a gonadal tumour as a FMN were found to be at a higher risk of melanoma, OR=8.7 (95% CI: 0.9-86). The adjusted OR for the local radiation dose was 1.07 (95% CI: 1.00-1.15). In conclusion, radiotherapy may contribute to an increased risk of melanoma as a SMN, but only at very high doses of low linear energy transfer radiation. Common genetic origins between gonadal tumours and malignant melanomas are likely.

Adolescent↗
PubMed2003

[Treatment of local recurrent melanomas by isolated limb perfusion: value of Doppler ultrasonography].

PURPOSE: To assess the effectiveness of Color Doppler Ultrasound (US) in the follow-up of recurrent melanoma of the limbs treated by isolated limb perfusion (ILP). MATERIALS AND METHODS: A retrospective study was done looking at 18 patients treated by isolated perfusion of the limb. Number, size and vascularity of subcutaneous metastases were examined for all patients. The results of pre and post therapeutic examinations were compared with clinical data and evolution. RESULTS: US was superior to clinical examination in the detection and measurement of subcutaneous metastases. Decrease in tumor size and early disappearance of tumoral vascularity were associated with an effective tumor response to treatment. Early disappearance of vascularity was associated with early complete response. Initial presence or persistence of vascularity before the third month after treatment were not poor prognostic factors. The appearance of vascularity seemed to be an indicator of early failure of the treatment. CONCLUSION: Color Doppler US is highly effective for the follow-up of patients with recurrent melanoma of the limbs. It provides prognostic factors of treatment failure, which may lead to early modification of the treatment strategy.

Adult↗
PubMed2002

[Delayed cerebral radionecrosis following radiation therapy of cutaneous squamous cell carcinomas of the head].

INTRODUCTION: Three cases of cerebral radionecrosis occurring after radiation therapy for squamous cell carcinomas of the scalp are reported. This rare and poorly documented complication of radiotherapy is discussed. CASE REPORTS: Three patients presenting with squamous cell carcinomas of the scalp were treated with surgery and radiotherapy for recurrent or incomplete resection of squamous cell carcinomas of the head. X-ray doses range were 50 to 60 Grays in 22 to 24 fractions. Cerebral radionecrotic lesions were diagnosed 6 months to 14 years after irradiation, and were inconstantly associated with clinical symptoms. The patients were treated with systemic steroids, which were of limited efficacy in one of our patients. DISCUSSION: Little is known of cerebral radionecrosis following radiotherapy. This may be related to their rare occurrence and/or to the difficulties in establishing diagnosis. The delay of occurrence after radiotherapy can vary between a few months and several years, and the lesions are directly correlated with the doses and the fractionning of the X-rays. Intracerebral localization of the tumour is the main differential diagnosis. Localized and cystic forms of cerebral radionecrosis can be treated by surgery. Treatment otherwise relies on systemic steroids.

Aged↗
PubMed2002

[Cutaneous localization of multiple myeloma on the tract of a central venous catheter].

INTRODUCTION: Extramedullary plasmocytoma are plasmocytic tumours developing outside of the bone marrow. Cutaneous localization of extramedullary plasmocytoma are rare and can be primitive or secondary. We report two cases of secondary extramedullary plasmocytoma occurring on central venous catheterization sites. OBSERVATIONS: A 68 year-old woman and a 69 year-old man presented with subcutaneous metastases located along the tracts of central venous catheters or implantable ports, which were either still on site or removed recently. Although the patients initially responded to melphalan therapy, they eventually died of multiple myeloma a few weeks following the diagnosis of the cutaneous localizations. DISCUSSION: Extramedullary plasmocytoma are most commonly found in the upper respiratory tract, the gut and the lymph, but cutaneous localization is rare. We report two cases of cutaneous extramedullary plasmocytoma located on the tract of central intravenous infusion sites. Both patients were treated with melphalan with initial improvement, followed by an early relapse. Two cases of myeloma metastases occurring on the tract of central venous catheters have previously been published. This localization seems to occur late in the course of this disease and to be associated with a poor prognosis.

Aged↗
PubMed2001

Sporadic multiple primary melanoma cases: CDKN2A germline mutations with a founder effect.

Multiple primary cancers are one of the hallmarks of inherited predisposition. Outside the familial context, multiple primary tumors could be related either to germline de novo mutations or to low-penetrance mutations, in predisposing genes. We selected 100 patients who displayed multiple primary melanoma (MPM) without any known melanoma cases recorded within their families and looked for germline mutations in the two melanoma-predisposing genes identified to date, CDKN2A and CDK4 exon 2. Nine patients (9%) had germline mutations in CDKN2A, whereas none carried germline mutations in exon 2 of CDK4. Seven cases displayed a recurrent missense mutation, G101W, already described in more than 20 melanoma-prone families; one case carried a missense mutation never reported to date (P114S), and the last case was a carrier of a 6 bp insertion at nucleotide 57 resulting in a duplication of codons 18 and 19. To ascertain whether the G101W was a mutational hot spot for de novo mutations or a common founder mutation, we genotyped eight microsatellite markers flanking the CDKN2A gene. After allowing for recombination over time, haplotype sharing provided evidence for an original G101W mutation common to 6 out of 7 sporadic MPM cases. Therefore, it can be concluded that de novo germline CDKN2A mutations associated with MPM are rare.

Adult↗
PubMed2001

Prognostic significance of epithelial disorders adjacent to invasive vulvar carcinomas.

OBJECTIVE: Epithelial disorders are found adjacent to vulvar carcinoma in 70-80% of patients. Epithelial disorder may be human papillomavirus related [undifferentiated high-grade vulvar intraepithelial neoplasia (VIN III)] or not [vulvar lichen sclerosus and squamous cell hyperplasia with or without atypia (differentiated VIN III)]. The aim of this study was to evaluate the impact of associated epithelial disorders on the outcome of patients with cancer of the vulva. METHODS: A retrospective study about 108 patients treated for a squamous cell carcinoma of the vulva was performed. Clinical, surgical, histopathologic, and follow-up data were collected and analyzed. RESULTS: Seventy-seven patients had an epithelial alteration adjacent to the invasive squamous carcinoma. Squamous cell hyperplasia and lichen sclerosus were identified in 48% (n = 52) and undifferentiated VIN III in 23% (n = 25). The 5-year disease-free and overall survival rates were 39 and 55%, respectively. In univariate analysis, age <70, a tumor size <2 cm, depth of invasion < or =1 mm, tumor thickness < or =5 mm, negative lymph node pathology, lymph node resection, and undifferentiated VIN III were predictive of survival. Using Cox's proportional hazards method, undifferentiated VIN III (P = 0.02), depth of invasion < or =1 mm (P < 0.01), and a pathological negative node status (P < 0.01) were independent predictors of survival. Patients without associated epithelial alterations had clinical and prognostic features comparable to those of patients with vulvar lichen sclerosus and squamous cell hyperplasia. CONCLUSION: The results of this study support the view that histological evidence of epithelial alterations adjacent to invasive carcinoma can serve to separate patients that differ in terms of prognosis.

Adult↗
PubMed2001

Indium-111 octreotide scintigraphy of Merkel cell carcinomas and their metastases.

BACKGROUND: Somatostatin receptor scintigraphy (SRS) may be of interest for staging Merkel Cell Carcinoma (MCC). This study was undertaken to evaluate the sensitivity and specificity of SRS and to determine its role compared to conventional investigations. PATIENTS AND METHODS: From 1993 to December 2000, 20 patients (10 females and 10 males, aged from 38 to 88, mean 66 years) were included prospectively. At the time of SRS: 12 patients had been diagnosed as having stage I disease, 6 stage II and 4 stage III. Two patients had two SRS studies during the course of their disease. SRS was performed with Indium-111 pentetreotide (Octreoscan), a radiolabelled somatostatin analogue. Patients were treated according to the clinical stage. A regular follow-up was scheduled every three months. RESULTS: SRS depicted stage I and II MCC tumour sites with an overall sensitivity of 78% (95% confidence interval (CI): 40%-97%) and a specificity of 96% (81%-100%). The histopathological diagnosis was used as the gold standard. Sites visualised by SRS were compared to those detected with conventional modalities and to follow-up data for all stages: SRS visualised four out of five primary tumour sites, six out of eight lymph node sites, no skin metastases (14 sites in 2 patients), two out of three thoracic metastases and zero out of two hepatic metastases. SRS did not influence treatment decision-making in any of the cases. CONCLUSIONS: Although SRS seems highly specific in MCC and could be of help in difficult cases, it cannot be recommended for routine evaluation.

Adult↗
PubMed2001

Direct evidence to support the role of antigen-specific CD8(+) T cells in melanoma-associated vitiligo.

Vitiligo is a cutaneous pigmentary disorder characterized by the loss of melanocytes. An autoimmune mechanism is strongly suspected to be involved in this affection given that it is frequently associated with autoimmune hormonal disorders, and because antibodies directed against melanocytic antigens are found in the serum of patients with vitiligo. We examined the role of cellular immunity in melanoma-associated vitiligo by expanding infiltrating lymphocytes from fresh biopsy specimens of vitiligo patches in melanoma patients. The vitiligo-infiltrating lymphocytes were almost exclusively T lymphocytes, and most were CD8(+). Following in vitro expansion, vitiligo-infiltrating lymphocytes remained predominantly CD8(+) and expressed the cutaneous homing receptor CLA. Furthermore, vitiligo-infiltrating lymphocytes had a clonal or oligoclonal T cell receptor profile, possibly reflecting specific antigenic stimulation. Finally, vitiligo- infiltrating lymphocytes specifically recognized differentiation antigens shared by normal melanocytes and melanoma cells. This direct demonstration of CD8(+) T cell involvement in vitiligo suggests that, in melanoma patients, vitiligo may be a visible effect of a spontaneous antitumoral immune response.

Adult↗
PubMed2001

Association between germ cell tumours, large numbers of naevi, atypical naevi and melanoma.

Identifying groups of subjects at high risk for the development of melanoma is crucial for the early diagnosis of curable tumours. In the present study, we performed a skin examination in a group of 63 patients followed up after treatment of germ cell tumours (GCTs) who were referred to the dermatologist for multiple pigmented cutaneous spots. Forty-nine patients bearing a great number of naevi or atypical naevi were included in the study. Two thin cutaneous melanomas were discovered in two patients. In addition, a third patient had had a conjunctival melanoma since treatment of the GCT. Our study confirms the presence of atypical naevi in a subgroup of GCT patients, who are shown to be at high risk of developing melanoma. Patients harbouring multiple pigmented spots should be referred for a skin examination aimed at early detection of curable melanomas, and should be advised to protect themselves from sun exposure.

Adolescent↗
PubMed2001

[Basal cell carcinoma of the vulva: 21 cases].

INTRODUCTION: Basal cell carcinoma (BCC) accounts for 2 to 3 p. 100 of all vulvar malignancies. PATIENTS AND METHODS: We report a retrospective study of 21 cases treated from 1937 to 1999. RESULTS: Vulvar BCC's occurred in elderly patients (average age: 66 years), with mean delay to diagnosis of 5.5 years. Five patients were referred for recurrence. Lesions were located on the external hairy side of the labia majus, except one located on the internal side. In 4 cases a preexisting risk factor was identified: 2 patients had previously received radiation therapy and 2 other patients had multiple disseminated BCC. Mean BCC diameter was 2 cm. Pathological data were similar to skin BCC, with one case of mixed tumor (BCC and squamous cell carcinoma). The treatment was surgical excision for 19 BCCs. Local recurrence risk was high. Only one patient died of visceral dissemination of the disease. DISCUSSION: More than 250 cases of vulvar BCC have been reported in the literature. Clinical, pathological and follow up data are similar to results in the present series. Treatment of choice consists of surgical excision with tumor-free margins. Because of local recurrence risk and possible association with other primary cancers in this age group, long term follow-up is necessary.

Adult↗
PubMed2000

A single genetic origin for the G101W CDKN2A mutation in 20 melanoma-prone families.

Germline mutations within the coding region of CDKN2A have been observed in affected members of melanoma-prone families. G101W is the most common CDKN2A missense mutation identified to date. It has been reported in several families from around the world, with a particularly high occurrence in France and Italy. Given the frequency of this mutation, we were interested in determining whether the mutation resulted from a single origin or represented a mutational hotspot in the CDKN2A gene. In addition, given the geographical distribution of the mutation, we examined the date of origination of the mutation and its migratory spread. We examined 10 families from Italy, 4 families from the United States, and 6 families from France with the G101W mutation. The following eight markers were employed for the haplotype analysis: IFNA, D9S736, D9S1749, D9S942, D9S1748, D9S1604, D9S171, and D9S126. Our findings showed no significant evidence for mutational heterogeneity, suggesting that all studied families derived from a single ancestral haplotype on which the mutation arose. Using maximum-likelihood methods, we estimated the mutation to have arisen 97 generations ago (1-LOD-unit support interval 70-133 generations) providing some explanation for the wide geographical spread of this common mutation, particularly in southwestern Europe. The presence of a founder mutation in a defined geographic area can facilitate carrier detection and genetic counseling and can provide an opportunity to study disease penetrance and the effect of environmental factors on the background of a common genetic susceptibility.

Amino Acid Substitution↗