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1.
Lung Cancer ; 141: 56-63, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31955001

RESUMO

OBJECTIVES: Detection of activating epidermal growth factor receptor (EGFR) mutation is crucial for individualized treatment of advanced non-small-cell lung cancer (NSCLC). However little is known about how biopsy technique affects the detection rate of EGFR mutations. This retrospective, single center study evaluated the detection rate of EGFR mutations in tissue obtained by bronchoscopic cryobiopsy and compared this to other standard tissue sampling techniques. MATERIALS AND METHODS: We retrospectively analyzed 414 patients with histologically confirmed NSCLC and known EGFR mutation status between 3/2008-7/2014. Tumor specimens obtained by tissue preserving bronchoscopic cryobiopsy were compared to those obtained by other techniques. RESULTS AND CONCLUSION: Analysis of bronchoscopic cryobiopsy tissue detected 29 activating EGFR mutations in 27 (21.6 %) out of 125 patients, while analysis of tissue obtained by non-cryobiopsy techniques (bronchoscopic forceps biopsies, fine needle aspiration, imaging guided transthoracical and surgical procedures) detected 42 EGFR mutations in 40 (13.8 %) out of 298 patients (p < 0.05). Cryobiopsy increased detection rate of EGFR mutations in central tumors compared with forceps biopsy (19.6 % versus 6.5 %, p < 0.05), while an insignificant trend was detected also for peripheral tumors (33.3 % versus 26.9 %). Bronchosopic cryobiopsy increases the detection rate of activating EGFR mutations in NSCLC in comparison to other tissue sampling techniques. This will help to optimize individualized treatment of patients with advanced tumors. Because of the retrospective nature of this analysis, a prospective trial is mandatory for final assessment.

2.
Mod Pathol ; 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31822801

RESUMO

Extranodal NK/T-cell lymphoma (ENKTL) is an Epstein-Barr virus (EBV) associated lymphoma, prevalent in Asia and Latin America. Studies in Asian cohorts have identified some recurrent gene mutations in ENKTL; however, the mutational landscape of ENKTL in Latin America is unknown. In this study, we investigated the mutational profile and EBV strains of 71 ENKTL cases from Latin America (42 from Mexico, 17 from Peru, and 12 from Argentina) and compared it with Asian cohorts. The mutational analysis was performed by next generation sequencing (NGS) using an Ion AmpliSeq™ custom panel covering for the most frequently mutated genes identified in ENKTL. STAT3 was the most frequent mutated gene (16 cases: 23%), followed by MSN (10 cases; 14%), BCOR (9 cases; 13%), DDX3X (6 cases; 8%), TP53 (6 cases; 8%), MGA (3 cases; 4%), JAK3 (2 cases; 3%), and STAT5B (1 case; 1%). Mutations in STAT3, BCOR, and DDX3X were nearly mutually exclusive, suggesting different molecular pathways involved in the pathogenesis of ENKTL; whereas mutations in MGA, MSN, and TP53 were concomitant with other mutations. Most cases (75%) carried Type A EBV without the 30-bp LMP1 gene deletion. The overall survival was significantly associated with serum LDH level, Eastern Cooperative Oncology Group (ECOG) performance status, International Prognostic Index (IPI) score, and therapy (p < 0.05), but not associated with any mutation, EBV strain or deletion in EBV LMP1 gene. In conclusion, mutational analysis of ENKTL from Latin America reveals frequent gene mutations leading to activation of the JAK-STAT pathway (25%), mostly STAT3. Compared to Asian cohorts, BCOR, DDX3X and TP53 mutations were also identified but with different frequencies. None of these mutations were associated with prognosis.

4.
Haematologica ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296581

RESUMO

SOX11 is a valuable marker to identify biologically and clinically relevant groups of mantle cell lymphoma such as cyclin D1 negative and leukemic non-nodal mantle cell lymphoma. We aimed to establish a sensitive in situ hybridization analysis of SOX11 mRNA allowing its quantification within the histopathological context and compare it with immunohistochemistry and RT-qPCR. Furthermore, TP53 status was correlated with SOX11 mRNA levels. Sixty-six cases were investigated; 58 conventional mantle cell lymphomas, including 6 cyclin D1 negative (46 classic, 12 blastoid) and 8 leukemic non-nodal mantle cell lymphomas. RNAscope was used for the in situ hybridization and the results scored as 0 to 4. Mantle cell lymphoma cases with SOX11 positivity by immunohistochemistry were positive by RNAscope but with different scores. RT-qPCR showed a good correlation with the median of the grouped scores but had a wide variation in individual cases. The SOX11 negative leukemic non-nodal mantle cell lymphomas were also negative by RNAscope. TP53 was mutated in 13/63 (21%) cases, including 5/7 (71%) leukemic non-nodal and 8/56 (14%) conventional mantle cell lymphoma. Interestingly, of the TP53 mutated cases, 9 were in the RNAscope negative/low SOX11 group (9/15; 60%) and 4 in the high SOX11 group (4/36; 11%) (p=.0007). In conclusion, RNAscope is a reliable method to evaluate SOX11 mRNA levels. This study demonstrates the broad range of SOX11 mRNA levels in mantle cell lymphoma. An important finding is the significant correlation of TP53 mutations with negative/low SOX11 mRNA level both in leukemic non-nodal and conventional mantle cell lymphoma.

5.
Virchows Arch ; 475(6): 795-798, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31317311

RESUMO

The traditional concept of unidirectional maturation of hematopoietic cells has been called into question due to the recognition of lineage plasticity, which is increasingly found also in the clonal evolution of hematopoietic and lymphoid malignancies. Here we present an unusual case of a patient with TP53-mutated chronic lymphocytic leukemia (CLL) treated with a PI3Kδ inhibitor evolving to clonally related Langerhans cell histiocytosis (LCH) with acquired BRAF V600E and STK11 mutations and loss of expression of PAX-5 and other examined B cell markers. In indolent B cell lymphoma, transformation to a more aggressive high-grade lymphoma occurs frequently during the course of disease and is thought to be caused by clonal evolution. Our case further supports the concept of significant lineage plasticity in lymphomas and raises the question of a potential role of novel pharmacologic agents in clonal evolution.


Assuntos
Evolução Clonal , Histiocitose de Células de Langerhans/patologia , Ilhotas Pancreáticas/patologia , Leucemia Linfocítica Crônica de Células B/patologia , Neoplasias Pancreáticas/patologia , Feminino , Histiocitose de Células de Langerhans/genética , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/patologia , Pessoa de Meia-Idade
7.
Int J Cancer ; 145(11): 2996-3010, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31008532

RESUMO

Next-generation sequencing has become a cornerstone of therapy guidance in cancer precision medicine and an indispensable research tool in translational oncology. Its rapidly increasing use during the last decade has expanded the options for targeted tumor therapies, and molecular tumor boards have grown accordingly. However, with increasing detection of genetic alterations, their interpretation has become more complex and error-prone, potentially introducing biases and reducing benefits in clinical practice. To facilitate interdisciplinary discussions of genetic alterations for treatment stratification between pathologists, oncologists, bioinformaticians, genetic counselors and medical scientists in specialized molecular tumor boards, several systems for the classification of variants detected by large-scale sequencing have been proposed. We review three recent and commonly applied classifications and discuss their individual strengths and weaknesses. Comparison of the classifications underlines the need for a clinically useful and universally applicable variant reporting system, which will be instrumental for efficient decision making based on sequencing analysis in oncology. Integrating these data, we propose a generalizable classification concept featuring a conservative and a more progressive scheme, which can be readily applied in a clinical setting.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias/genética , Humanos , Terapia de Alvo Molecular , Mutação , Neoplasias/tratamento farmacológico , Medicina de Precisão , Análise de Sequência de DNA
8.
Mod Pathol ; 32(8): 1123-1134, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30952970

RESUMO

Angioimmunoblastic T-cell lymphoma is a peripheral T-cell lymphoma derived from follicular T-helper cells. High-throughput genomic sequencing studies have shown that angioimmunoblastic T-cell lymphoma carries frequent mutations in RHOAG17V and IDH2R172 genes. The clinico-pathological features of angioimmunoblastic T-cell lymphoma cases with RHOAG17V mutations have been addressed; however, similar studies for IDH2 mutated cases are lacking. Therefore, the aim of the present study was to evaluate the pathological features of angioimmunoblastic T-cell lymphoma with IDH2 mutations. In order to identify cases with IDH2 mutations, 50 cases previously diagnosed as angioimmunoblastic T-cell lymphoma were subjected to next-generation sequencing analysis using a custom panel covering four genes frequently mutated in angioimmunoblastic T-cell lymphoma including DNMT3A, TET2, IDH2 and RHOA. All cases were analyzed for PD1, ICOS, CXCL13, CD10, BCL6, CD21, CD23 and EBER in situ hybridization. Mutational analysis recognized three groups. Group 1: IDH2R172 mutations were identified in 20 cases (40%). All cases carried RHOAG17V mutations. Group 2: RHOAG17V mutations without IDH2R172 mutation were identified in 16 cases (32%), and Group 3: 14 cases (28%) without RHOAG17V or IDH2R172 mutations. Morphologically, angioimmunoblastic T-cell lymphoma cases with IDH2R172 mutations were characterized by the presence of medium to large clear cells (p = 0.00001), and a follicular T-helper phenotype with the particular feature of strong CD10 (p = 0.0268) and CXCL13 expression (p = 0.0346). Interestingly, TET2 mutations were identified in 32 of 33 (97%) cases with IDH2R172 and/or RHOAG17V mutations whereas only 55% of angioimmunoblastic T-cell lymphoma cases wild-type for these two genes carried TET2 mutations (p = 0.0022). In contrast, DNMT3A mutations were found in 48% of the cases and were equally distributed in the three groups. In conclusion, our results support the results of gene expression profiling studies suggesting that IDH2R172 mutations define a unique subgroup within angioimmunoblastic T-cell lymphoma with strong follicular T-helper-like phenotype and characteristic morphological features.

10.
BMC Med Genet ; 19(1): 144, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30111295

RESUMO

BACKGROUND: The PTEN-hamartoma-tumor-syndrome (PHTS) is caused by germline mutations in Phosphatase and Tensin homolog (PTEN) and predisposes to the development of several typical malignancies. Whereas PTEN mutations have been implicated in the occurrence of malignant mesotheliomas, the genetic landscape of verrucous carcinomas (VC) is largely uncharted. Both VC and malignant peritoneal mesotheliomas (MPM) are exceedingly rare and a potential link between these malignancies and PHTS has never been reported. CASE PRESENTATION: We here describe the clinical course of a PHTS patient who, in addition to a typical thyroid carcinoma at the age of 36 years, developed a highly-differentiated oral VC and an epithelioid MPM six years later. The patient with a history of occupational asbestos exposure underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for MPM. The clinical diagnosis of PHTS was consequently corroborated by a germline PTEN deletion. Sequencing of tumor tissue revealed a second hit in PTEN in the thyroid carcinoma and VC, confirmed by a PTEN loss and activation of the PI3K/AKT pathway in immunohistochemistry. Furthermore, additional somatic mutations in the thyroid carcinoma as well as in the VC were detected, whereas the genetics of MPM remained unrevealing. DISCUSSION AND CONCLUSIONS: We here report the very unusual clinical course of a patient with rare tumors that have a germline mutation first hit in PTEN in common. Since this patient was exposed to asbestos and current evidence suggests molecular mechanisms that might render PHTS patients particularly susceptible to mesothelioma, we strongly recommend PHTS patients to avoid even minimal exposure.


Assuntos
Carcinoma Verrucoso/genética , Mutação em Linhagem Germinativa/genética , Neoplasias Pulmonares/genética , Mesotelioma/genética , Neoplasias Bucais/genética , PTEN Fosfo-Hidrolase/genética , Humanos , Doenças Raras
11.
Cancers (Basel) ; 10(4)2018 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-29617304

RESUMO

Anaplastic large cell lymphoma (ALCL) represents a group of malignant T-cell lymphoproliferations that share morphological and immunophenotypical features, namely strong CD30 expression and variable loss of T-cell markers, but differ in clinical presentation and prognosis. The recognition of anaplastic lymphoma kinase (ALK) fusion proteins as a result of chromosomal translocations or inversions was the starting point for the distinction of different subgroups of ALCL. According to their distinct clinical settings and molecular findings, the 2016 revised World Health Organization (WHO) classification recognizes four different entities: systemic ALK-positive ALCL (ALK+ ALCL), systemic ALK-negative ALCL (ALK− ALCL), primary cutaneous ALCL (pC-ALCL), and breast implant-associated ALCL (BI-ALCL), the latter included as a provisional entity. ALK is rearranged in approximately 80% of systemic ALCL cases with one of its partner genes, most commonly NPM1, and is associated with favorable prognosis, whereas systemic ALK− ALCL shows heterogeneous clinical, phenotypical, and genetic features, underlining the different oncogenesis between these two entities. Recognition of the pathological spectrum of ALCL is crucial to understand its pathogenesis and its boundaries with other entities. In this review, we will focus on the morphological, immunophenotypical, and molecular features of systemic ALK+ and ALK− ALCL. In addition, BI-ALCL will be discussed.

12.
Oncotarget ; 9(14): 11876-11882, 2018 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-29545943

RESUMO

Activating KIT D816V mutations are frequently found in CBF AML, which predicts for an unfavorable outcome. Dasatinib is a potent inhibitor of wildtype and mutant-KIT isoforms - including D816V. We now provide proof of antileukemic efficacy in a patient with relapsing mutant-KIT D816V CBF AML. Importantly, this effect is mediated via overriding the differentiation blockage of the leukemia clone. In addition, we show that dasatinib is capable to induce pulmonary differentiation syndrome - and therefore needs close monitoring of patients under therapy.

13.
PLoS One ; 12(6): e0178503, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28640838

RESUMO

Follicular lymphoma (FL) is characterized genetically by a significant intraclonal diversity of rearranged immunoglobulin heavy chain (IGH) genes and a substantial cell migration activity (follicular trafficking). Recently, in situ follicular neoplasia (ISFN), characterized by accumulations of immunohistochemically strongly BCL2-positive, t(14;18)+ clonal B cells confined to germinal centers in reactive lymph nodes, has been identified as a precursor lesion of FL with low risk of progression to manifest FL. The extent of ongoing somatic hypermutation of rearranged IGH genes and interfollicular trafficking in ISFN is not known. In this study we performed an in depth analysis of clonal evolution and cell migration patterns in a case of pure ISFN involving multiple lymph nodes. Using laser microdissection and next generation sequencing (NGS) we documented significant intraclonal diversity of the rearranged IGH gene and extensive interfollicular migration between germinal centers of the same lymph node as well as between different lymph nodes. Furthermore, we identified N-glycosylation motifs characteristic for FL in the CDR3 region.


Assuntos
Movimento Celular/genética , Análise Mutacional de DNA , Rearranjo Gênico , Sequenciamento de Nucleotídeos em Larga Escala , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma Folicular/genética , Linfoma Folicular/patologia , Idoso , Feminino , Humanos , Masculino
14.
Lab Invest ; 97(9): 1095-1102, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28581487

RESUMO

Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is characterized by expression of oncogenic ALK fusion proteins due to the translocation t(2;5)(p23;q35) or variants. Although genotypically a T-cell lymphoma, ALK+ ALCL cells frequently show loss of T-cell-specific surface antigens and expression of monocytic markers. C/EBPß, a transcription factor constitutively overexpressed in ALK+ ALCL cells, has been shown to play an important role in the activation and differentiation of macrophages and is furthermore capable of transdifferentiating B-cell and T-cell progenitors to macrophages in vitro. To analyze the role of C/EBPß for the unusual phenotype of ALK+ ALCL cells, C/EBPß was knocked down by RNA interference in two ALK+ ALCL cell lines, and surface antigen expression profiles of these cell lines were generated using a Human Cell Surface Marker Screening Panel (BD Biosciences). Interesting candidate antigens were further analyzed by immunohistochemistry in primary ALCL ALK+ and ALK- cases. Antigen expression profiling revealed marked changes in the expression of the activation markers CD25, CD30, CD98, CD147, and CD227 after C/EBPß knockdown. Immunohistochemical analysis confirmed a strong, membranous CD147 (EMMPRIN) expression in ALK+ ALCL cases. In contrast, ALK- ALCL cases showed a weaker CD147 expression. CD274 or PD-L1, an immune inhibitory receptor ligand, was downregulated after C/EBPß knockdown. PD-L1 also showed stronger expression in ALK+ ALCL compared with ALK- ALCL, suggesting an additional role of C/EBPß in ALK+ ALCL in generating an immunosuppressive environment. Finally, no expression changes of T-cell or monocytic markers were detected. In conclusion, surface antigen expression profiling demonstrates that C/EBPß plays a critical role in the activation state of ALK+ ALCL cells and reveals CD147 and PD-L1 as important downstream targets. The multiple roles of CD147 in migration, adhesion, and invasion, as well as T-cell activation and proliferation suggest its involvement in the pathogenesis of ALCL.


Assuntos
Basigina/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/metabolismo , Receptores Proteína Tirosina Quinases/genética , Quinase do Linfoma Anaplásico , Antígenos CD/análise , Antígenos CD/genética , Antígenos CD/metabolismo , Basigina/análise , Basigina/genética , Proteína beta Intensificadora de Ligação a CCAAT/genética , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Linfonodos/química , Linfonodos/metabolismo , Linfoma Anaplásico de Células Grandes/química , Proteínas de Fusão Oncogênica/genética
15.
Blood ; 130(3): 323-327, 2017 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-28533310

RESUMO

Pediatric-type follicular lymphoma (PTFL) is a B-cell lymphoma with distinctive clinicopathological features. Recently, recurrent genetic alterations of potential importance for its pathogenesis that disrupt pathways associated with the germinal center reaction (TNFRSF14, IRF8), immune escape (TNFRSF14), and anti-apoptosis (MAP2K1) have been described. In an attempt to shed more light onto the pathogenesis of PTFL, an integrative analysis of these mutations was undertaken in a large cohort of 43 cases previously characterized by targeted next-generation sequencing and copy number array. Mutations in MAP2K1 were found in 49% (20/41) of the cases, second in frequency to TNFRSF14 alterations (22/41; 54%), and all together were present in 81% of the cases. Immunohistochemical analysis of the MAP2K1 downstream target extracellular signal-regulated kinase demonstrated its phosphorylation in the evaluable cases and revealed a good correlation with the allelic frequency of the MAP2K1 mutation. The IRF8 p.K66R mutation was present in 15% (6/39) of the cases and was concomitant with TNFRSF14 mutations in 4 cases. This hot spot seems to be highly characteristic for PTFL. In conclusion, TNFRSF14 and MAP2K1 mutations are the most frequent genetic alterations found in PTFL and occur independently in most cases, suggesting that both mutations might play an important role in PTFL lymphomagenesis.


Assuntos
Regulação Neoplásica da Expressão Gênica , Fatores Reguladores de Interferon/genética , Linfoma Folicular/genética , MAP Quinase Quinase 1/genética , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Alelos , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Criança , Variações do Número de Cópias de DNA , Feminino , Perfilação da Expressão Gênica , Frequência do Gene , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fatores Reguladores de Interferon/metabolismo , Linfoma Folicular/diagnóstico , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , MAP Quinase Quinase 1/metabolismo , Masculino , Análise em Microsséries , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Mutação , Fosforilação , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo
16.
Hum Pathol ; 64: 198-206, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28442268

RESUMO

Palisaded neutrophilic and granulomatous dermatitis (PNGD) is characterized by erythematous papules or plaques on trunk or limbs and is frequently associated with rheumatologic, autoimmune, or hematologic malignancies. Histopathology shows interstitial granulomas composed of epitheloid histiocytes in the reticular dermis with surrounding foci of collagen degeneration and variable neutrophilic inflammation. We report 3 cases of generalized PNGD associated with chronic myelomonocytic leukemia (CMML), a myelodysplastic/myeloproliferative neoplasm, which may show a variety of cutaneous manifestations. SRSF2 P95 hotspot mutations, found in 40%-50% of CMML cases, were retrospectively detected in skin and bone marrow biopsies of all 3 patients, in 1 of them already 5 years before CMML diagnosis. Generalized PNGD may represent a type of cutaneous manifestation of CMML. Because diagnosis of CMML is frequently difficult in cases with isolated persistent monocytosis and minimal dysplasia in the bone marrow, patients with a generalized PNGD should be evaluated for the presence of hematologic disorders including CMML, ideally supported by mutational analyses.


Assuntos
Dermatite/diagnóstico , Granuloma/diagnóstico , Leucemia Mielomonocítica Crônica/diagnóstico , Neutrófilos/patologia , Pele/patologia , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biópsia , Exame de Medula Óssea , Análise Mutacional de DNA , Dermatite/genética , Dermatite/imunologia , Dermatite/patologia , Feminino , Predisposição Genética para Doença , Granuloma/genética , Granuloma/imunologia , Granuloma/patologia , Humanos , Imuno-Histoquímica , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/imunologia , Leucemia Mielomonocítica Crônica/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Neutrófilos/imunologia , Fenótipo , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Processamento de Serina-Arginina/genética , Pele/imunologia
17.
Oncoimmunology ; 6(3): e1219825, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28405493

RESUMO

Genome sequencing has uncovered an array of recurring somatic mutations in different non-Hodgkin lymphoma (NHL) subtypes. If affecting protein-coding regions, such mutations may yield mutation-derived peptides that may be presented by HLA class I proteins and recognized by cytotoxic T cells. A recurring somatic and oncogenic driver mutation of the Toll-like receptor adaptor protein MYD88, Leu265Pro (L265P) was identified in up to 90% of different NHL subtype patients. We therefore screened the potential of MYD88L265P-derived peptides to elicit cytotoxic T cell responses as tumor-specific neoantigens. Based on in silico predictions, we identified potential MYD88L265P-containing HLA ligands for several HLA class I restrictions. A set of HLA class I MYD88L265P-derived ligands elicited specific cytotoxic T cell responses for HLA-B*07 and -B*15. These data highlight the potential of MYD88L265P mutation-specific peptide-based immunotherapy as a novel personalized treatment approach for patients with MYD88L265P+ NHLs that may complement pharmacological approaches targeting oncogenic MyD88 L265P signaling.

19.
J Hepatol ; 65(4): 849-855, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27397612

RESUMO

BACKGROUND & AIMS: We report a novel experimental immunotherapeutic approach in a patient with metastatic intrahepatic cholangiocarcinoma. In the 5year course of the disease, the initial tumor mass, two local recurrences and a lung metastasis were surgically removed. Lacking alternative treatment options, aiming at the induction of anti-tumor T cells responses, we initiated a personalized multi-peptide vaccination, based on in-depth analysis of tumor antigens (immunopeptidome) and sequencing. METHODS: Tumors were characterized by immunohistochemistry, next-generation sequencing and mass spectrometry of HLA ligands. RESULTS: Although several tumor-specific neo-epitopes were predicted in silico, none could be validated by mass spectrometry. Instead, a personalized multi-peptide vaccine containing non-mutated tumor-associated epitopes was designed and applied. Immunomonitoring showed vaccine-induced T cell responses to three out of seven peptides administered. The pulmonary metastasis resected after start of vaccination showed strong immune cell infiltration and perforin positivity, in contrast to the previous lesions. The patient remains clinically healthy, without any radiologically detectable tumors since March 2013 and the vaccination is continued. CONCLUSIONS: This remarkable clinical course encourages formal clinical studies on adjuvant personalized peptide vaccination in cholangiocarcinoma. LAY SUMMARY: Metastatic cholangiocarcinomas, cancers that originate from the liver bile ducts, have very limited treatment options and a fatal prognosis. We describe a novel therapeutic approach in such a patient using a personalized multi-peptide vaccine. This vaccine, developed based on the characterization of the patient's tumor, evoked detectable anti-tumor immune responses, associating with long-term tumor-free survival.


Assuntos
Colangiocarcinoma , Neoplasias dos Ductos Biliares , Vacinas Anticâncer , Humanos , Recidiva Local de Neoplasia , Vacinas de Subunidades
20.
Acta Neuropathol Commun ; 4(1): 60, 2016 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-27311324

RESUMO

Gliomas are the most frequent intraaxial CNS neoplasms with a heterogeneous molecular background. Recent studies on diffuse gliomas have shown frequent alterations in the genes involved in chromatin remodelling pathways such as α-thalassemia/mental-retardation-syndrome-X-linked gene (ATRX). Yet, the reliability of ATRX in predicting isocitrate dehydrogenase (IDH) and H3 histone, family 3A (H3F3A) mutations in gliomas, is unclear.We analysed the ATRX expression status by immunohistochemistry, in a large series of 1064 gliomas and analysed the results in correlation to IDH, H3F3A and loss of heterozygosity (LOH) 1p/19q status in these tumors. We also investigated the prognostic potential of ATRX concerning the clinical outcome of patients with diffuse gliomas.According to our results, loss of nuclear ATRX expression was accompanied with an astrocytic tumor lineage and a younger age of onset. ATRX loss in astrocytomas was also strongly associated with IDH1/2 and H3F3A mutation (p < 0.0001). Among 196 glial tumors with nuclear ATRX loss, 173 (89 %) had an IDH1 or IDH2 mutation. Among the remaining 23 cases (11 %) with ATRX loss and IDH wild type status, 7 cases had a H3F3A G34R mutation (3 %) and 2 cases had a H3F3A K27M mutation (1 %). ATRX retention in IDH1/2 mutant tumors was strongly associated with LOH 1p/19q and oligodendroglioma histology (p < 0.0001). We also confirmed the significant prognostic role of ATRX. Diffuse gliomas with ATRX loss (n = 137, median 1413 days, 95 % CI: 1065-1860 days) revealed a significantly better clinical outcome compared with tumors with ATRX retention (n = 335, median: 609, 95 % CI: 539-760 days, HR = 1.81, p < 0.0001).In conclusion, ATRX is a potential marker for prediction of IDH/H3F3A mutations and substratification of diffuse gliomas into survival relevant tumor groups. Such classification is of great importance for further clinical decision making especially concerning the therapeutic options available for diffuse gliomas.


Assuntos
Neoplasias Encefálicas/metabolismo , DNA Helicases/metabolismo , Glioma/metabolismo , Histonas/genética , Isocitrato Desidrogenase/genética , Proteínas Nucleares/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/cirurgia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Criança , Pré-Escolar , Feminino , Glioma/genética , Glioma/patologia , Glioma/cirurgia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Proteína Nuclear Ligada ao X , Adulto Jovem
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