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Robin T. Vollmer - One of the best experts on this subject based on the ideXlab platform.
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Patient Age in Spitz Nevus and Malignant Melanoma
American journal of clinical pathology, 2004Co-Authors: Robin T. VollmerAbstract:In the differential diagnosis of Spitz nevus vs malignant Melanoma, Patient age provides a critical piece of clinical information, because Spitz nevi occur mostly in children and Melanomas occur mostly in adults. Nevertheless, there is overlap in the age distributions of Spitz nevus and Melanoma. The issue to consider is how these age distributions and their governing probability densities can impact the a priori probability that a lesion is a Spitz nevus vs a Melanoma. Herein I introduce a quantitative approach that uses Bayes rule together with previous published data on the age distributions in Spitz nevi and Melanoma. The resulting algorithm yields plots and a table of predictive a priori probabilities of Spitz nevus, given Patient age occurring within narrow intervals, and I believe these provide useful guidelines for using age in the differential diagnosis of Spitz nevus and malignant Melanoma.
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Patient age in spitz nevus and malignant Melanoma implication of bayes rule for differential diagnosis
American Journal of Clinical Pathology, 2004Co-Authors: Robin T. VollmerAbstract:In the differential diagnosis of Spitz nevus vs malignant Melanoma, Patient age provides a critical piece of clinical information, because Spitz nevi occur mostly in children and Melanomas occur mostly in adults. Nevertheless, there is overlap in the age distributions of Spitz nevus and Melanoma. The issue to consider is how these age distributions and their governing probability densities can impact the a priori probability that a lesion is a Spitz nevus vs a Melanoma. Herein I introduce a quantitative approach that uses Bayes rule together with previous published data on the age distributions in Spitz nevi and Melanoma. The resulting algorithm yields plots and a table of predictive a priori probabilities of Spitz nevus, given Patient age occurring within narrow intervals, and I believe these provide useful guidelines for using age in the differential diagnosis of Spitz nevus and malignant Melanoma.
Thierry Boon - One of the best experts on this subject based on the ideXlab platform.
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A new tumor-specific antigen encoded by MAGE-C2 and presented to cytolytic T lymphocytes by HLA-B44
Cancer Immunology Immunotherapy, 2007Co-Authors: Danièle Godelaine, Bart Neyns, Kris Thielemans, Javier Carrasco, Francis Brasseur, Thierry BoonAbstract:A panel of cytolytic T lymphocyte (CTL) clones was isolated from metastases and blood samples of a Melanoma Patient vaccinated with MAGE-3.A1-pulsed autologous dendritic cells. We report here the identification of a new antigen encoded by the MAGE-C2 cancer-germline gene. This antigen is recognized by some of these CTL on HLA-B*4403. The sequence of the peptide is SESIKKKVL. It is processed in various Melanoma cell lines expressing MAGE-C2 and HLA-B*4403 . Because of the expression pattern of gene MAGE-C2 , this new antigen is strictly tumor-specific and could therefore be used for peptide-based antitumoral vaccination.
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a human endogenous retroviral sequence encoding an antigen recognized on Melanoma by cytolytic t lymphocytes
Cancer Research, 2002Co-Authors: Francesca Schiavetti, Thierry Boon, Didier Colau, Joelle Thonnard, Pierre CoulieAbstract:We have identified a gene encoding an antigen recognized by cytolytic T lymphocytes on the autologous tumor cells of a Melanoma Patient, AVL3. The gene shows homologies with members of the HERV-K family of human endogenous retroviruses, and it was provisionally named HERV-K-MEL. It contains many mutations that disrupt the open reading frames coding for all of the viral proteins. The HERV-K-MEL gene is not expressed in normal tissues with the exception of testis and some skin samples. It is expressed in most samples of cutaneous and ocular Melanoma. It is also expressed in a majority of naevi and in a minority of carcinomas and sarcomas. The antigenic peptide, presented by HLA-A2 molecules, is encoded by a very short open reading frame present in the env region of a spliced HERV-K-MEL transcript. Anti-HERV.A2 CTLp could not be detected in the blood of three individuals without cancer but were present at a frequency of 3 x 10(-5) among blood CD8 T cells in Patient AVL3 and 6 x 10(-7) in another HLA-A2 Melanoma Patient whose tumor expressed HERV-K-MEL. Anti-HERV.A2 CTL clones derived from each Patient lysed Melanoma cells. Analysis of T-cell receptor beta chain sequences indicated that the anti-HERV.A2 CTL population was oligoclonal in Patient AVL3 and probably monoclonal in the other Patient. These results suggest that HERV-K-MEL is a source of antigens that are targeted by CTLs in Melanoma Patients and could therefore be used for vaccination.
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a monoclonal cytolytic t lymphocyte response observed in a Melanoma Patient vaccinated with a tumor specific antigenic peptide encoded by gene mage 3
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Pierre Coulie, Vaios Karanikas, Didier Colau, Christophe Lurquin, Claire Landry, Marie Marchand, T Dorval, Vincent Brichard, Thierry BoonAbstract:Vaccination of Melanoma Patients with tumor-specific antigens recognized by cytolytic T lymphocytes (CTL) produces significant tumor regressions in a minority of Patients. These regressions appear to occur in the absence of massive CTL responses. To detect low-level responses, we resorted to antigenic stimulation of blood lymphocyte cultures in limiting dilution conditions, followed by tetramer analysis, cloning of the tetramer-positive cells, and T-cell receptor (TCR) sequence analysis of the CTL clones that showed strict specificity for the tumor antigen. A monoclonal CTL response against a MAGE-3 antigen was observed in a Melanoma Patient, who showed partial rejection of a large metastasis after treatment with a vaccine containing only the tumor-specific antigenic peptide. Tetramer analysis after in vitro restimulation indicated that about 1/40,000 postimmunization CD8(+) blood lymphocytes were directed against the antigen. The same TCR was present in all of the positive microcultures. TCR evaluation carried out directly on blood lymphocytes by PCR amplification led to a similar frequency estimate after immunization, whereas the TCR was not found among 2.5 x 10(6) CD8(+) lymphocytes collected before immunization. Our results prove unambiguously that vaccines containing only a tumor-specific antigenic peptide can elicit a CTL response. Even though they provide no information about the effector mechanisms responsible for the observed reduction in tumor mass in this Patient, they would suggest that low-level CTL responses can initiate tumor rejection.
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a peptide recognized by human cytolytic t lymphocytes on hla a2 Melanomas is encoded by an intron sequence of the n acetylglucosaminyltransferase v gene
Journal of Experimental Medicine, 1996Co-Authors: Yannick Guilloux, Vincent Brichard, Francis Brasseur, Sophie Lucas, C Viret, E De Plaen, Bernard Lethe, Francine Jotereau, Thierry BoonAbstract:A cytolytic T lymphocyte (CTL) clone that lyses many HLA-A2 Melanomas was derived from a population of tumor-infiltrating lymphocytes of an HLA-A2 Melanoma Patient. The gene coding for the antigen recognized by this CTL was identified by transfection of a cDNA library. It is the gene which has been reported to code for N-acetylglucosaminyltransferase V (GnT-V). Remarkably, the antigenic peptide recognized by the CTL is encoded by a sequence located in an intron. In contrast to the fully spliced GnT-V mRNA, which was found in a wide range of normal and tumoral tissues, the mRNA containing the intron region coding for the antigen was not found at a significant level in normal tissues. This mRNA was observed to be present in about 50% of Melanomas. Our results suggest that a promoter located near the end of the relevant intron is activated in Melanoma cells, resulting in the production of an mRNA coding for the antigen.
Jonathan M. Irish - One of the best experts on this subject based on the ideXlab platform.
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Myelodysplastic Syndrome Revealed by Systems Immunology in a Melanoma Patient Undergoing Anti-PD-1 Therapy
Cancer Immunology Research, 2016Co-Authors: Allison R. Greenplate, Douglas B. Johnson, Mikael Roussel, Michael R. Savona, Jeffrey A. Sosman, Igor Puzanov, Jr. Ferrell, Jonathan M. IrishAbstract:Antibodies aimed at blocking the interaction between programmed cell death-1 (PD-1) and its ligands have shown impressive efficacy in a variety of malignancies and are generally well tolerated. Research has focused intensely on T cells and their interaction with cells within Melanoma tumors, while relatively little is understood about the systems immunology of the cells in the blood during checkpoint inhibitor therapy. Longitudinal cytomic analysis using mass cytometry can characterize all the cells in a small sample of blood and has the potential to reveal key shifts in the cellular milieu occurring during treatment. We report a case of advanced Melanoma in which mass cytometry detected abnormal myeloid cells resulting from myelodyspla stic syndrome (MDS) in the blood fol-lowing treatment with an anti-PD-1 agent. Myeloid blasts comprised
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Myelodysplastic Syndrome Revealed by Systems Immunology in a Melanoma Patient Undergoing Anti–PD-1 Therapy
Cancer immunology research, 2016Co-Authors: Allison R. Greenplate, Douglas B. Johnson, Mikael Roussel, Michael R. Savona, Jeffrey A. Sosman, Igor Puzanov, P. Brent Ferrell, Jonathan M. IrishAbstract:Antibodies aimed at blocking the interaction between programmed cell death-1 (PD-1) and its ligands have shown impressive efficacy in a variety of malignancies and are generally well tolerated. Research has focused intensely on T cells and their interaction with cells within Melanoma tumors, while relatively little is understood about the systems immunology of the cells in the blood during checkpoint inhibitor therapy. Longitudinal cytomic analysis using mass cytometry can characterize all the cells in a small sample of blood and has the potential to reveal key shifts in the cellular milieu occurring during treatment. We report a case of advanced Melanoma in which mass cytometry detected abnormal myeloid cells resulting from myelodysplastic syndrome (MDS) in the blood following treatment with an anti-PD-1 agent. Myeloid blasts comprised
Kristel Kemper - One of the best experts on this subject based on the ideXlab platform.
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braf v600e kinase domain duplication identified in therapy refractory Melanoma Patient derived xenografts
Cell Reports, 2016Co-Authors: Kristel Kemper, Oscar Krijgsman, Paulien Cornelissensteijger, Aida Shahrabi, Fleur Weeber, Thomas Kuilman, Xiangjun Kong, Daphne L Van Der Velden, Onno B Bleijerveld, Roel J C KluinAbstract:The therapeutic landscape of Melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. There is a need for in vivo systems that allow for mechanistic drug resistance studies and (combinatorial) treatment optimization. Therefore, we established a large collection of Patient-derived xenografts (PDXs), derived from BRAF(V600E), NRAS(Q61), or BRAF(WT)/NRAS(WT) Melanoma metastases prior to treatment with BRAF inhibitor and after resistance had occurred. Taking advantage of PDXs as a limitless source, we screened tumor lysates for resistance mechanisms. We identified a BRAF(V600E) protein harboring a kinase domain duplication (BRAF(V600E/DK)) in ∼10% of the cases, both in PDXs and in an independent Patient cohort. While BRAF(V600E/DK) depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAF(V600E/DK)-expressing cells. These results illustrate the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of Melanoma Patients.
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intra and inter tumor heterogeneity in a vemurafenib resistant Melanoma Patient and derived xenografts
Embo Molecular Medicine, 2015Co-Authors: Kristel Kemper, Oscar Krijgsman, Paulien Cornelissensteijger, Aida Shahrabi, Fleur Weeber, Jiying Song, Thomas Kuilman, Daniel J Vis, Lodewyk F A Wessels, Emile E VoestAbstract:The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of BRAF(V600E) metastatic Melanoma. However, resistance to such compounds represents a formidable problem. Using whole-exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a Melanoma Patient carrying multiple drug-resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAF(V600E), we identified a new activating insertion in MEK1. This MEK1(T55delins) (RT) mutation could be traced back to a fraction of the pre-treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted Melanomas. Analysis of Patient-derived xenografts (PDX) from therapy-refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter- and intra-tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the Patient. In conclusion, vemurafenib resistance in a single Patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the Patient's Melanoma.
Annemarie Larkin - One of the best experts on this subject based on the ideXlab platform.
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An insight into the molecular genetics of a uveal Melanoma Patient cohort
Journal of Cancer Research and Clinical Oncology, 2018Co-Authors: Susan Kennedy, Michael Rice, Sinead Toomey, Noel Horgan, Bryan T. Hennessey, Annemarie LarkinAbstract:Background/aims Uveal Melanoma (UM) is a highly aggressive malignancy and presents a clinically significant unmet need in cancer therapeutics. The aim of this study was to identify previously unreported mutations in UM among an Irish cohort of Patients which may have potential clinical relevance. Methods DNA was extracted from 36 intraocular Melanoma Patient samples and 4 metastatic Melanoma samples among the Patient cohort by microdissection from formalin-fixed paraffin embedded tissue blocks and underwent genotyping to test for known single nucleotide polymorphisms in 42 cancer associated genes. These mutations were analysed using a custom-designed sequenom panel. Results Using high-throughput genotyping, mutually exclusive GNAQ and GNA11 mutations were detected in 31 of 34 UM Patients together with a number of non-synonymous changes in established cancer driver genes, PHLPP2, MET, PIK3R1 and IDH-1, variants which have not been previously associated with UM. Conclusion Given the lack of knowledge regarding the clinical relevance of the variants identified in this UM cohort and their likely pathogenic nature in other cancers, further studies of the functional impact of these variant mutations are warranted to establish possible previously, undescribed roles in UM pathogenesis, which may provide additional targets for future therapies.