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Alain Spatz

Publications and source records attributed to Alain Spatz.

At least 19 recordsLinked to original sources
PubMed2006

Analysis of skin cancer risk factors in immunosuppressed renal transplant patients shows high levels of UV-specific tandem CC to TT mutations of the p53 gene.

Immunosuppressed renal transplant recipients (RTRs) are predisposed to non-melanoma skin cancers (NMSCs), predominantly squamous cell carcinomas (SCCs). We have analyzed skin lesions from RTRs with aggressive tumors for p53 gene modifications, the presence of Human Papillomas Virus (HPV) DNA in relation to the p53 codon 72 genotype and polymorphisms of the XPD repair gene. We detected 24 p53 mutations in 15/25 (60%) NMSCs, 1 deletion and 23 base substitutions, the majority (78%) being UV-specific C to T transitions at bipyrimidine sites. Importantly, 35% (6/17) are tandem mutations, including 4 UV signature CC to TT transitions possibly linked to modulated DNA repair caused by the immunosuppressive drug cyclosporin A (CsA). We found 8 p53 mutations in 7/17 (41%) precancerous actinic keratosis (AK), suggesting that p53 mutations are early events in RTR skin carcinogenesis. Immunohistochemical analysis shows a good correlation between p53 accumulation and mutations. HPV DNA was detected in 78% of skin lesions (60% Basal Cell Carcinomas, 82%AK and 79% SCCs). Thus, immunosuppression has increased the risk of infections by HPVs, predominantly epidermodysplasia verruciformis, speculated to play a role in skin cancer development. No association is found between HPV status and p53 mutation. Moreover, p53 codon 72 or frequencies of three XPD genotypes of RTRs are comparable with control populations. The p53 mutation spectrum, presenting a high level of CC to TT mutations, shows that the UV component of sunlight is the major risk factor and modulated DNA repair by immunosuppressive drug treatment may be significant in the skin carcinogenesis of RTRs.

Carcinoma, Squamous Cell↗
PubMed2006

Dendritic cell derived-exosomes: biology and clinical implementations.

Exosomes are nanometer-sized membrane vesicles invaginating from multivesicular bodies and secreted from different cell types. They represent an "in vitro" discovery, but vesicles with the hallmarks of exosomes are present in vivo in germinal centers and biological fluids. Their protein and lipid composition is unique and could account for their expanding functions such as eradication of obsolete proteins, antigen presentation, or "Trojan horses" for viruses or prions. The potential of dendritic cell-derived exosomes (Dex) as cell-free cancer vaccines is addressed in this review. Lessons learned from the pioneering clinical trials allowed reassessment of the priming capacities of Dex in preclinical models, optimizing clinical protocols, and delineating novel, biological features of Dex in cancer patients.

Animals↗
PubMed2006

Expression and possible role of hPTTG1/securin in cutaneous malignant melanoma.

Human pituitary tumour-transforming gene 1 or hPTTG1 is a proto-oncogene that codes for securin, a protein involved in sister chromatid separation. Based on previous microarray data, we studied the expression of hPTTG1/securin in melanocytic lesions. In contrast to nevi and radial growth phase melanomas, securin was expressed by scattered cells in the vertical growth phase, suggesting a role in tumour progression. In a series of 29 nodular and 29 superficial spreading melanomas, matched for all histological prognostic parameters, securin expression was significantly correlated with the nodular subtype (P=0.018) and not related to thickness. In other cancers, hPTTG1 is involved in various oncogenic pathways, including induction of neovascularisation and aneuploidy, and inhibition of p53 activity. We found coexpression of securin with wild-type p53 in the same neoplastic cells in a minority of melanomas. Expression of securin was significantly correlated with the extent of aneuploidy but not with basic fibroblast growth factor immunoreactivity or microvessel density. DNA cytometry revealed that nuclei-overexpressing securin frequently showed tetraploidy or aneuploidy. Our data show that hPTTG1 is frequently overexpressed in nodular melanoma, and suggest that hPTTG1 may act as an oncogene in the vertical growth phase, either by inhibiting anaphase, thereby causing aneuploidy and genomic instability, or by modulating the function of p53, thereby impairing apoptosis.

Adult↗
PubMed2006

Prognostic value of angiogenesis evaluated with high-frequency and colour Doppler sonography for preoperative assessment of primary cutaneous melanomas: correlation with recurrence after a 5 year follow-up period.

OBJECTIVE: To study the value of high-frequency sonography (HFS) and colour Doppler sonography (CDS) in evaluating the 5 year metastatic potential of primary cutaneous melanomas (CM). MATERIALS AND METHODS: 111 CM were studied before surgical resection and 107 were depicted on HFS. The maximal HFS thickness was measured and compared with the Breslow thickness. A CDS study was performed in each tumour. RESULTS: HFS thickness ranged from 0.26 to 8.0 mm and Breslow thickness from 0.15 to 8.0 mm. HFS and Breslow thickness correlated strongly (r > 0.93). Intratumour vessels were depicted in 43 of the 107 CM, of which 40 were thicker than 2 mm. The median follow-up was 61 months and 27 patients developed relapses. In the univariate analyses, neovascularization visualized with CDS, sonographic thickness and the Breslow thickness were significantly linked to relapses (p < 0.0001), as were lymph node status and ulceration (p = 0.007 and 0.004). CONCLUSION: Vascularization was observed mainly in thick primary melanoma. A median follow-up of 5 years showed the prognostic value of angiogenesis evaluated by CDS.

Adult↗
PubMed2006

Gene expression profiling of primary cutaneous melanoma and clinical outcome.

BACKGROUND: Gene expression profiling data for human primary cutaneous melanomas are scarce because of the lack of retrospective collections of frozen tumors. To identify differentially expressed genes that may be involved in melanoma progression and prognosis, we investigated the relationship between gene expression profiles and clinical outcome in a cohort of patients with primary melanoma. METHODS: Labeled complementary RNA (cRNA) from each tissue sample was hybridized to a pangenomic 44K 60-mer oligonucleotide microarray. Class comparison and class prediction analyses were performed to identify genes whose expression in primary melanomas was associated with 4-year distant metastasis-free survival among 58 patients with at least 4 years of follow-up, distant metastasis, or death. Results were validated immunohistochemically at the protein level in 176 independent primary melanomas from patients with a median clinical follow-up of 8.5 years. Survival was analyzed with a Cox multivariable model and stratified log-rank test. All statistical tests were two-sided. RESULTS: We identified 254 genes that were associated with distant metastasis-free survival of patients with primary melanoma. These 254 genes include genes involved in activating DNA replication origins, such as minichromosome maintenance genes and geminin. Twenty-three of these genes were studied at the protein level; expression of five (MCM4, P = .002; MCM3, P = .030; MCM6, P = .004; KPNA2, P = .021; and geminin, P = .004) was statistically significantly associated with overall survival in the validation set. In a multivariable Cox model adjusted for tumor thickness, ulceration, age, and sex, expression of MCM4 (hazard ratio [HR] of death = 4.04, 95% confidence interval [CI] = 1.39 to 11.76; P = .010) and MCM6 (HR of death = 7.42, 95% CI = 1.99 to 27.64; P = .003) proteins was still statistically significantly associated with overall survival. CONCLUSION: We identified 254 genes whose expression was associated with metastatic dissemination of cutaneous melanomas. These genes may shed light on the molecular mechanisms underlying poor prognosis in melanoma patients.

Adolescent↗
PubMed2005

Factors to keep in mind when introducing virtual microscopy.

Digitization of glass slides and delivery of so-called virtual slides (VS) emulating a real microscope over the Internet have become reality due to recent improvements in technology. We have implemented a virtual microscope for instruction of medical students and for continuing medical education. Up to 30,000 images per slide are captured using a microscope with an automated stage. The images are post-processed and then served by a plain hypertext transfer protocol (http)-server. A virtual slide client (vMic) based on Macromedia's Flash MX, a highly accepted technology available on every modern Web browser, has been developed. All necessary virtual slide parameters are stored in an XML file together with the image. Evaluation of the courses by questionnaire indicated that most students and many but not all pathologists regard virtual slides as an adequate replacement for traditional slides. All our virtual slides are publicly accessible over the World Wide Web (WWW) at http://vmic.unibas.ch . Recently, several commercially available virtual slide acquisition systems (VSAS) have been developed that use various technologies to acquire and distribute virtual slides. These systems differ in speed, image quality, compatibility, viewer functionalities and price. This paper gives an overview of the factors to keep in mind when introducing virtual microscopy.

Education, Medical, Continuing↗
PubMed2005

Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial.

BACKGROUND: DC derived-exosomes are nanomeric vesicles harboring functional MHC/peptide complexes capable of promoting T cell immune responses and tumor rejection. Here we report the feasability and safety of the first Phase I clinical trial using autologous exosomes pulsed with MAGE 3 peptides for the immunization of stage III/IV melanoma patients. Secondary endpoints were the monitoring of T cell responses and the clinical outcome. PATIENTS AND METHODS: Exosomes were purified from day 7 autologous monocyte derived-DC cultures. Fifteen patients fullfilling the inclusion criteria (stage IIIB and IV, HLA-A1+, or -B35+ and HLA-DPO4+ leukocyte phenotype, tumor expressing MAGE3 antigen) were enrolled from 2000 to 2002 and received four exosome vaccinations. Two dose levels of either MHC class II molecules (0.13 versus 0.40 x 1014 molecules) or peptides (10 versus 100 mug/ml) were tested. Evaluations were performed before and 2 weeks after immunization. A continuation treatment was performed in 4 cases of non progression. RESULTS: The GMP process allowed to harvest about 5 x 1014 exosomal MHC class II molecules allowing inclusion of all 15 patients. There was no grade II toxicity and the maximal tolerated dose was not achieved. One patient exhibited a partial response according to the RECIST criteria. This HLA-B35+/A2+ patient vaccinated with A1/B35 defined CTL epitopes developed halo of depigmentation around naevi, a MART1-specific HLA-A2 restricted T cell response in the tumor bed associated with progressive loss of HLA-A2 and HLA-BC molecules on tumor cells during therapy with exosomes. In addition, one minor, two stable and one mixed responses were observed in skin and lymph node sites. MAGE3 specific CD4+ and CD8+ T cell responses could not be detected in peripheral blood. CONCLUSION: The first exosome Phase I trial highlighted the feasibility of large scale exosome production and the safety of exosome administration.

Journal Article↗
PubMed2005

Cutaneous side-effects of kinase inhibitors and blocking antibodies.

Although kinase inhibitors raise hope for people with cancer, patients and their clinicians are commonly confronted with the cutaneous side-effects that are associated with the use of these drugs. This review is the result of collaborations between dermatologists, medical oncologists, and pathologists, and discusses the cutaneous side-effects seen after treatment with the inhibitors of epidermal-growth-factor receptor (EGFR), imatinib, sorafenib, and sunitinib. Some of the side-effects caused by these agents are very distressing, partly because they are chronic owing to the long duration of treatment. Therefore, patients need early and appropriate dermatological management. Moreover, several studies have reported a link between the antitumour efficacy of EGFR inhibitors and cutaneous side-effects. Elucidation of this connection could lead to the identification of crucial predictive factors for tumour response.

Antibodies, Blocking↗
PubMed2005

The importance of mitotic rate as a prognostic factor for localized cutaneous melanoma.

BACKGROUND: Tumor ulceration (TU) is considered the second most important prognostic factor after Breslow thickness for localized cutaneous malignant melanoma (CMM). However, many studies have not included mitotic rate (MR) with TU in these analyses. When both TU and MR are included in the same analysis, MR appears to be the more important than TU and TU loses its significance as an independent prognostic factor. METHODS: The relative importance of TU and MR as prognostic factors in localized CMM were compared in a population-based series of 650 consecutive invasive CMM cases ascertained from the Connecticut tumor registry and reviewed by a single dermatopathologist (RLB), during the period between January 15, 1987 and May 15, 1989. Seventeen clinical and histopathological variables including tumor thickness measured in mm, TU recorded as present or absent, and MR recorded as number per mm(2) were included in an unconditional logistic regression model and selected for inclusion using a backward stepwise algorithm with death as an endpoint or at least five-years follow-up. RESULTS: In the multivariate regression, the independent prognostic factors included: 1. tumor thickness in millimeters (OR = 1.5, 95% CI = 1.3-1.9) 2. moderate mitotic index (between 1 and 6): (OR = 8.3, 95% CI 2.4-28.7), 3. mitotic index (>6): (OR = 11.6, 95% CI = 3.0-44.6), 4. solar elastosis: (inversely associated with mortality)(OR = 0.4, 95% CI = 0.2-8). After adjustment for MR, TU lost its significance. When MR was left out of the analysis, ulceration then became an independent prognostic factor. The model with ulceration only (excluding MR) showed a relative risk (RR) of 2.4 (95%CI: 1.1-5.1). In the model with MR only, MR had a RR of 14.5 (95% CI3.9-53.7). Finally, regression analysis including both TU and MR yielded an RR of 11.6 for MR and 1.7 for TU. CONCLUSIONS: Our results suggest that MR as a proxy for tumor proliferation is a more important prognostic factor than TU.

Adolescent↗
PubMed2004

Comparative genomic hybridization analysis of hereditary swine cutaneous melanoma revealed loss of the swine 13q36-49 chromosomal region in the nodular melanoma subtype.

Genetic alterations implicated in malignant melanoma are still poorly understood. Malignant melanomas present highly variable histologic and cytologic patterns. The aim of the present study is to define genomic imbalances associated with the development of 2 histologic types of swine hereditary cutaneous melanoma. We have investigated 11 swine tumors by comparative genomic hybridization (CGH), 4 superficial spreading melanomas (SSMs) and 7 nodular melanomas (NMs). Following laser capture microdissection and degenerate oligonucleotide primed-polymerase chain reaction, we were able to isolate and then amplify DNA from the 2 histologic subtypes. Consensus regions of chromosome gains were identified on both histologic subtypes, on swine chromosomes 3p13-p17 (75% of the SSMs and 71% of the NMs), 12q (100% of the SSMs and 57% of the NMs) and 14q11-q21 (75% of the SSMs and 42% of NMs). Chromosomal loss was restricted to NM lesions and the swine 13q36-49 region was lost in 100% of the NMs. Interphase fluorescence in situ hybridization with a probe mapping to the 13q41-q42 region indicates loss of the corresponding region on NM lesions. Taking into account this CGH analysis and the comparative genomic data between swine and human genomes, we suggest that a role for the human chromosomes 3p11-qter and chromosome 21 losses should be investigated in human nodular melanoma progression.

Animals↗
PubMed2004

Influence of genes, nevi, and sun sensitivity on melanoma risk in a family sample unselected by family history and in melanoma-prone families.

BACKGROUND: Few family studies have investigated the effects of genetic, environmental, and host factors on melanoma risk, and most have been restricted to high-risk families. We assessed the role of these factors on melanoma risk in two types of families: families ascertained through melanoma probands but unselected by family history and melanoma-prone families. METHODS: Data on pigmentary traits, nevus phenotypes, exposure to sun, and reactions to sunlight were collected from 295 families unselected by family history and 53 melanoma-prone families. We modeled melanoma risk using a logistic regressive model incorporating the effect of a melanoma-predisposing gene, familial dependence, and potential risk factors (e.g., pigmentary traits, nevus phenotypes, history of sun exposure, skin reactions to sunlight). Maximum-likelihood estimates of the parameters of the regressive model were used to compute odds ratios associated with each risk factor and age-specific melanoma risk depending on the genotype at the melanoma-predisposing gene and the effects of risk factors. All statistical tests were two-sided. RESULTS: In the families unselected by family history, there was statistically significant evidence (P<.001) for a dominant gene, with melanoma risk reaching 0.49 and 0.67 by age 80 years in male and female gene carriers, respectively. Melanoma risk was statistically significantly influenced by total nevi (odds ratio of hazard function [OR] = 5.81, 95% confidence interval [CI] = 3.47 to 8.99), sun exposure (OR = 5.37, 95% CI = 4.44 to 6.36), and sunburn interacting with the gene (OR = 26.31, 95% CI = 7.56 to 99.22 in gene carriers and OR = 1.67, 95% CI = 1.36 to 2.03 in noncarriers). Twenty of the 53 melanoma-prone families had cosegregating mutations in CDKN2A, a gene known to be associated with melanoma. In these 53 families, three risk factors in addition to CDKN2A mutations increased melanoma risk: dysplastic nevi (OR = 2.32, 95% CI = 2.08 to 2.58), total nevi (OR = 1.99, 95% CI = 1.61 to 2.20) and sunburn (OR = 5.16, 95% CI = 4.82 to 5.52). CONCLUSIONS: Together, a melanoma-predisposing gene (identified as being CDKN2A in melanoma-prone families), number of nevi and/or dysplastic nevi, and sun-related covariates influence melanoma risk in both families unselected by family history and melanoma-prone families.

Adult↗
PubMed2004

Selective accumulation of mature DC-Lamp+ dendritic cells in tumor sites is associated with efficient T-cell-mediated antitumor response and control of metastatic dissemination in melanoma.

The clinical relevance of dendritic cells (DCs) at the tumor site remains a matter of debate concerning their role in the generation of effective antitumor immunity in human cancers. We performed a comprehensive immunohistochemical analysis using a panel of DC-specific antibodies on regressing tumor lesions and sentinel lymph nodes (SLNs) in melanoma patients. Here we show in a case report involving spontaneous regression of metastatic melanoma that the accumulation of DC-Lamp+ DCs, clustered with tumor cells and lymphocytes, is associated with local expansion of antigen-specific memory effector CTLs. These findings were extended in a series of 19 melanoma-positive SLNs and demonstrated a significant correlation between the density of DC-Lamp+ DC infiltrates in SLNs with the absence of metastasis in downstream lymph nodes. This study, albeit performed in a limited series of patients, points to a pivotal role of mature DCs in the local expansion of efficient antitumor T-cell-mediated immune responses at the initial sites of metastasis and may have important implications regarding the prognosis, staging, and immunotherapy of melanoma patients.

Adult↗
PubMed2004

Clinical and histopathological characterization of cutaneous melanomas in the melanoblastoma-bearing Libechov minipig model.

Spontaneous animal tumors appear to be highly suitable models to study human oncology and cancer therapy. The aim of this study was to characterize the clinical and histological features of hereditary melanocytic lesions found in the French herd of melanoblastoma-bearing Libechov minipigs (MeLiM) and their Duroc crossbreeds. Clinically, we discriminated between three types of melanocytic skin lesions, which offer a lesion continuum from lentigo to metastatic melanomas. More than 70% of these lesions appear on piglets before they are 3 months old and preferentially on homogeneous black coat piglets. The incidence of melanoma reaches 50% in MeLiM. Most of the highly invasive melanomas regressed spontaneously in the first year of the piglet's life and the regression was followed by hair, skin and iris depigmentation. A histopathological study was conducted according to the human melanoma classification. Except for lentigo maligna, we observed the three main types of human melanoma in swine [superficial spreading melanoma (SSM), nodular or unclassified melanoma] with an excess of SSM (59-67%). The histological events leading to total spontaneous regression are chronologically described. The genetic predisposition, the high incidence of melanoma, the clinical and histopathological features similar to the human disease and the high rate of spontaneous regression offer an opportunity to use this model for studying genetic events controlling melanoma development and regression and the biological mechanisms involved in oncogenesis and anti-cancerous self-defense.

Animals↗
PubMed2004

Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects.

Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation. DC-mediated NK cell activation was triggered in vitro and in vivo by treatment of DCs with Gleevec as well as by a loss-of-function mutation of KIT. Therefore, tumors that are refractory to the antiproliferative effects of Gleevec in vitro responded to Gleevec in vivo in an NK cell-dependent manner. Longitudinal studies of Gleevec-treated GIST patients revealed a therapy-induced increase in IFN-gamma production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.

Animals↗