Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 289
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Cell ; 187(2): 390-408.e23, 2024 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-38157855

RESUMO

We describe a human lung disease caused by autosomal recessive, complete deficiency of the monocyte chemokine receptor C-C motif chemokine receptor 2 (CCR2). Nine children from five independent kindreds have pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including bacillus Calmette Guérin (BCG) disease. The CCR2 variants are homozygous in six patients and compound heterozygous in three, and all are loss-of-expression and loss-of-function. They abolish CCR2-agonist chemokine C-C motif ligand 2 (CCL-2)-stimulated Ca2+ signaling in and migration of monocytic cells. All patients have high blood CCL-2 levels, providing a diagnostic test for screening children with unexplained lung or mycobacterial disease. Blood myeloid and lymphoid subsets and interferon (IFN)-γ- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated immunity are unaffected. CCR2-deficient monocytes and alveolar macrophage-like cells have normal gene expression profiles and functions. By contrast, alveolar macrophage counts are about half. Human complete CCR2 deficiency is a genetic etiology of PAP, polycystic lung disease, and recurrent infections caused by impaired CCL2-dependent monocyte migration to the lungs and infected tissues.


Assuntos
Proteinose Alveolar Pulmonar , Receptores CCR2 , Criança , Humanos , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Proteinose Alveolar Pulmonar/genética , Proteinose Alveolar Pulmonar/diagnóstico , Receptores CCR2/deficiência , Receptores CCR2/genética , Receptores CCR2/metabolismo , Reinfecção/metabolismo
3.
Int J Cancer ; 154(3): 504-515, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37908048

RESUMO

The management of anal squamous cell carcinoma (ASCC) has yet to experience the transformative impact of precision medicine. Conducting genomic analyses may uncover novel prognostic biomarkers and offer potential directions for the development of targeted therapies. To that end, we assessed the prognostic and theragnostic implications of pathogenic variants identified in 571 cancer-related genes from surgical samples collected from a homogeneous, multicentric French cohort of 158 ASCC patients who underwent abdominoperineal resection treatment. Alterations in PI3K/AKT/mTOR, chromatin remodeling, and Notch pathways were frequent in HPV-positive tumors, while HPV-negative tumors often harbored variants in cell cycle regulation and genome integrity maintenance genes (e.g., frequent TP53 and TERT promoter mutations). In patients with HPV-positive tumors, KMT2C and PIK3CA exon 9/20 pathogenic variants were associated with worse overall survival in multivariate analysis (Hazard ratio (HR)KMT2C = 2.54, 95%CI = [1.25,5.17], P value = .010; HRPIK3CA = 2.43, 95%CI = [1.3,4.56], P value = .006). Alterations with theragnostic value in another cancer type was detected in 43% of patients. These results suggest that PIK3CA and KMT2C pathogenic variants are independent prognostic factors in patients with ASCC with HPV-positive tumors treated by abdominoperineal resection. And, importantly, the high prevalence of alterations bearing potential theragnostic value strongly supports the use of genomic profiling to allow patient enrollment in precision medicine clinical trials.


Assuntos
Neoplasias do Ânus , Carcinoma de Células Escamosas , Protectomia , Humanos , Neoplasias do Ânus/genética , Neoplasias do Ânus/patologia , Neoplasias do Ânus/cirurgia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , Fosfatidilinositol 3-Quinases/genética , Prognóstico
4.
Br J Haematol ; 204(4): 1383-1392, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38442908

RESUMO

Warts, hypogammaglobulinaemia, infections and myelokathexis syndrome (WHIMS) is a rare combined primary immunodeficiency caused by the gain of function of the CXCR4 chemokine receptor. We present the prevalence of cancer in WHIMS patients based on data from the French Severe Chronic Neutropenia Registry and an exhaustive literature review. The median follow-up of the 14 WHIMS 'patients was 28.5 years. A central review and viral evaluation of pathological samples were organized, and we conducted a thorough literature review to identify all reports of WHIMS cases. Six French patients were diagnosed with cancer at a median age of 37.6 years. The 40-year risk of malignancy was 39% (95% confidence interval [CI]: 6%-74%). We observed two human papillomavirus (HPV)-induced vulvar carcinomas, three lymphomas (two Epstein-Barr virus [EBV]-related) and one basal cell carcinoma. Among the 155 WHIMS cases from the literature, 22 cancers were reported in 16 patients, with an overall cancer 40-year risk of 23% (95% CI: 13%-39%). Malignancies included EBV-associated lymphoproliferative disorders and HPV-positive genital and anal cancers as in the French cohort. Worldwide, nine cases of malignancy were associated with HPV and four with EBV. Immunocompromised WHIMS patients appear to be particularly susceptible to developing early malignancy, mainly HPV-induced carcinomas, followed by EBV-related lymphomas.


Assuntos
Agamaglobulinemia , Carcinoma , Infecções por Vírus Epstein-Barr , Linfoma , Infecções por Papillomavirus , Doenças da Imunodeficiência Primária , Verrugas , Humanos , Adulto , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/epidemiologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/epidemiologia , Herpesvirus Humano 4 , Verrugas/complicações , Verrugas/epidemiologia , Verrugas/diagnóstico , Síndrome , Receptores CXCR4
5.
Eur Heart J ; 44(26): 2376-2385, 2023 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-36545799

RESUMO

AIMS: Cardiac involvement of Erdheim-Chester disease (ECD), a rare L group histiocytosis, has been reported to be associated with poor outcomes, but systematic studies are lacking. The present study aimed to investigate the prevalence, clinical features, imaging features, and prognosis of cardiac involvement in ECD in a large series. METHODS AND RESULTS: All patients with ECD who underwent cardiac magnetic resonance (CMR) imaging between 2003 and 2019 at a French tertiary center were retrospectively included. Primary outcome was all-cause mortality. Secondary outcomes were pericarditis, cardiac tamponade, conduction disorders, device implantation and coronary artery disease (CAD). A total of 200 patients were included [63 (54-71) years, 30% female, 58% BRAFV600E mutated]. Median follow-up was 5.5 years (3.3-9 years). On CMR, right atrioventricular sulcus infiltration was observed in 37% of patients, and pericardial effusion was seen in 24% of patients. In total, 8 patients (4%) had pericarditis (7 acute, 1 constrictive), 10 patients (5%) had cardiac tamponade, 5 patients (2.5%) had ECD-related high-degree conduction disorders, and 45 patients (23%) had CAD. Overall, cardiac involvement was present in 96 patients (48%) and was associated with BRAFV600E mutation [Odds ratio (OR) = 7.4, 95% confidence interval (CI) (3.5-16.8), P < 0.001] and ECD-related clinical events [OR = 5, 95%CI (1.5-21.2), P = 0.004] but not with lower survival in multivariate analysis [adjusted hazard ratio (HR) = 1.4, 95% CI (0.8-2.5), P = 0.2]. CONCLUSION: Cardiac involvement is present in nearly half of ECD patients and is associated with BRAFV600E mutation and complications (pericarditis, cardiac tamponade, and conduction disorders) but not with lower survival.


Assuntos
Tamponamento Cardíaco , Doença de Erdheim-Chester , Pericardite , Humanos , Feminino , Masculino , Doença de Erdheim-Chester/complicações , Doença de Erdheim-Chester/epidemiologia , Doença de Erdheim-Chester/genética , Tamponamento Cardíaco/epidemiologia , Tamponamento Cardíaco/etiologia , Estudos Retrospectivos , Prevalência , Imageamento por Ressonância Magnética , Pericardite/epidemiologia , Pericardite/complicações
6.
Ann Pathol ; 44(1): 69-74, 2024 Feb.
Artigo em Francês | MEDLINE | ID: mdl-38216436

RESUMO

Langerhans cell histiocytosis (LCH) is a disease whose physiopathology remains unclear, involving both inflammatory processes and clonal proliferation. It is observable at any given age, although about ten times more frequent in children than adults. Hepatic involvement is not rare, mostly part of a systemic disease, and linked to a poor prognosis. We report here a case of LCH with solitary hepatic involvement in a 74 year-old patient. This case demonstrated molecular anomaly of the MAPK pathway, BRAF N486_P490del. Through this observation, we precise the epidemiological and histological aspects and diagnostic criteria of this rare disease.


Assuntos
Histiocitose de Células de Langerhans , Idoso , Humanos , Histiocitose de Células de Langerhans/diagnóstico , Fígado/patologia , Doenças Raras
7.
Br J Haematol ; 203(2): 194-201, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37394840

RESUMO

To calculate the prevalence of sinonasal and ear involvement in an Erdheim-Chester disease (ECD) population, to describe the different ear, nose and throat (ENT) manifestations and to study the association between ENT involvement, other organ involvement, and BRAF mutations. We led a retrospective monocentric study in the national referral center for ECD. One hundred and sixty-two patients with ECD and ENT data were included between January 1, 1980 and December 31, 2020. Ear and nose clinical and radiological findings were noted. We described and studied the prevalence of ENT involvement in ECD population. The association between sinonasal and ear involvement, other organ involvement, and BRAF mutations was calculated. The prevalence of ENT manifestations is around 45%. No clinical rhinologic or otologic signs were specific to ECD. Sinus imaging was abnormal in 70% of cases. A bilateral maxillary sinus frame osteosclerosis was highly specific of ECD. Associations were found between the sinus MRI imaging type and BRAF status, central nervous system involvement, cerebellum involvement and xanthelasma. Sinonasal or ear involvement is frequent in ECD and has specific imaging features for sinuses. Trial registration: #2011-A00447-34.


Assuntos
Doença de Erdheim-Chester , Humanos , Doença de Erdheim-Chester/complicações , Doença de Erdheim-Chester/diagnóstico por imagem , Estudos Retrospectivos , Proteínas Proto-Oncogênicas B-raf/genética , Mutação
8.
N Engl J Med ; 382(5): 437-445, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-31995689

RESUMO

BACKGROUND: Cytomegalovirus (CMV) can cause severe disease in children and adults with a variety of inherited or acquired T-cell immunodeficiencies, who are prone to multiple infections. It can also rarely cause disease in otherwise healthy persons. The pathogenesis of idiopathic CMV disease is unknown. Inbred mice that lack the gene encoding nitric oxide synthase 2 (Nos2) are susceptible to the related murine CMV infection. METHODS: We studied a previously healthy 51-year-old man from Iran who after acute CMV infection had an onset of progressive CMV disease that led to his death 29 months later. We hypothesized that the patient may have had a novel type of inborn error of immunity. Thus, we performed whole-exome sequencing and tested candidate mutant alleles experimentally. RESULTS: We found a homozygous frameshift mutation in NOS2 encoding a truncated NOS2 protein that did not produce nitric oxide, which determined that the patient had autosomal recessive NOS2 deficiency. Moreover, all NOS2 variants that we found in homozygosity in public databases encoded functional proteins, as did all other variants with an allele frequency greater than 0.001. CONCLUSIONS: These findings suggest that inherited NOS2 deficiency was clinically silent in this patient until lethal infection with CMV. Moreover, NOS2 appeared to be redundant for control of other pathogens in this patient. (Funded by the National Center for Advancing Translational Sciences and others.).


Assuntos
Infecções por Citomegalovirus , Mutação da Fase de Leitura , Óxido Nítrico Sintase Tipo II/deficiência , Evolução Fatal , Feminino , Genótipo , Homozigoto , Humanos , Mutação com Perda de Função , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Linhagem , Sequenciamento do Exoma
9.
Nat Immunol ; 12(3): 213-21, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21278736

RESUMO

Germline mutations in CYBB, the human gene encoding the gp91(phox) subunit of the phagocyte NADPH oxidase, impair the respiratory burst of all types of phagocytes and result in X-linked chronic granulomatous disease (CGD). We report here two kindreds in which otherwise healthy male adults developed X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD) syndromes. These patients had previously unknown mutations in CYBB that resulted in an impaired respiratory burst in monocyte-derived macrophages but not in monocytes or granulocytes. The macrophage-specific functional consequences of the germline mutation resulted from cell-specific impairment in the assembly of the NADPH oxidase. This 'experiment of nature' indicates that CYBB is associated with MSMD and demonstrates that the respiratory burst in human macrophages is a crucial mechanism for protective immunity to tuberculous mycobacteria.


Assuntos
Genes Ligados ao Cromossomo X , Predisposição Genética para Doença , Macrófagos/imunologia , Glicoproteínas de Membrana/genética , NADPH Oxidases/genética , Tuberculose/genética , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Masculino , Mutação , NADPH Oxidase 2 , NADPH Oxidases/imunologia
10.
Blood ; 137(4): 485-492, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33067622

RESUMO

Erdheim-Chester disease (ECD) is a clonal hematopoietic disorder characterized by the accumulation of foamy histiocytes within organs (in particular, frequent retroperitoneal involvement) and a high frequency of BRAFV600E mutations. Although ECD is not commonly recognized to have overt peripheral blood (PB) or bone marrow (BM) disease, we recently identified that ECD patients have a high frequency of a concomitant myeloid malignancy. We thus conducted a systematic clinical and molecular analysis of the BM from 120 ECD patients. Surprisingly, 42.5% of ECD patients (51 of 120) had clonal hematopoiesis whereas 15.8% of patients (19 of 120) developed an overt hematologic malignancy (nearly all of which were a myeloid neoplasm). The most frequently mutated genes in BM were TET2, ASXL1, DNMT3A, and NRAS. ECD patients with clonal hematopoiesis were more likely to be older (P < .0001), have retroperitoneal involvement (P = .02), and harbor a BRAFV600E mutation (P = .049) than those without clonal hematopoiesis. The presence of the TET2 mutation was associated with a BRAFV600E mutation in tissue ECD lesions (P = .0006) and TET2-mutant ECD patients were more likely to have vascular involvement than TET2 wild-type ECD patients. Clonal hematopoiesis mutations in ECD were detected in cells derived from CD34+CD38- BM progenitors and PB monocytes but less frequently present in PB B and T lymphocytes. These data identify a heretofore unrecognized high frequency of clonal hematopoiesis in ECD patients, reaffirm the development of additional high risk of myeloid neoplasms in ECD, and provide evidence of a BM-based precursor cell of origin for many patients with ECD.


Assuntos
Hematopoiese Clonal , Doença de Erdheim-Chester/fisiopatologia , Cariótipo Anormal , Adulto , Fatores Etários , Idoso , Medula Óssea/patologia , Transformação Celular Neoplásica/genética , Hematopoiese Clonal/genética , Proteínas de Ligação a DNA/genética , Dioxigenases , Progressão da Doença , Doença de Erdheim-Chester/genética , Éxons/genética , Feminino , Genes Neoplásicos , Humanos , Leucemia Mieloide/genética , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mutação , Síndromes Mielodisplásicas/genética , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/patologia , Especificidade de Órgãos , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética
11.
Histopathology ; 83(2): 320-325, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37012662

RESUMO

AIMS: The aim was to test the expression of PU.1 on different types of histiocytoses and to test the utility of PU.1 in confirming or excluding a histiocytic origin in tumour samples with suspicion of histiocytosis. METHODS AND RESULTS: We analysed 66 biopsies of nonmalignant histiocytoses represented by Langerhans-cell histiocytosis (n = 13), Erdheim-Chester disease (ECD) (n = 19), Rosai-Dorfman disease (RDD) (n = 14), mixed ECD-RDD (n = 3), ALK-positive histiocytosis (n = 6), and juvenile xanthogranuloma (n = 11). All cases were positive for PU.1 in reactive and neoplastic histiocytes. In addition, 39 cases of tumours with high-grade cytological atypia were referred to our center as suspicion of malignant histiocytosis/histiocytic sarcoma and only 18 were confirmed. Indeed, more than half of these tumours (21/39) were either undifferentiated malignant tumours with a stroma rich in histiocytes, diffuse large B-cell lymphoma, or high-grade dedifferentiated liposarcoma. PU.1 was useful to distinguish between the negativity of large atypical nuclei and the positivity of stromal reactive histiocytes. CONCLUSION: PU.1 is expressed by all types of histiocytosis. It distinguishes histiocytosis from histiocyte-rich tumours with an easy interpretation due to its sharp nuclear staining. Its negativity in lesional/tumour cells in histiocyte-like lesions is useful to eliminate a histiocytosis.


Assuntos
Doença de Erdheim-Chester , Neoplasias Hematológicas , Histiocitose de Células de Langerhans , Histiocitose Sinusal , Histiocitose , Humanos , Histiócitos/patologia , Histiocitose/diagnóstico , Histiocitose/patologia , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/patologia , Histiocitose Sinusal/metabolismo , Histiocitose Sinusal/patologia , Doença de Erdheim-Chester/patologia , Neoplasias Hematológicas/patologia
12.
Haematologica ; 108(2): 513-521, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36005561

RESUMO

Erdheim-Chester disease (ECD) is a rare histiocytosis, considered to be an inflammatory myeloid neoplasm. Tropism for specific involvements of the disease remains unexplained. Vascular endothelial growth factor-A (VEGF) is implicated in cancer pathophysiology and mutations of the RAS oncogene have been shown to induce upregulation of VEGF gene expression. We therefore hypothesized that VEGF might play a particular role in ECD pathophysiology. We conducted a retrospective, single-center study to assess serum VEGF (sVEGF) concentrations and determine whether they were associated with the characteristics of ECD patients, and to determine whether VEGF was expressed by histiocytes. We evaluated 247 ECD patients, 53.4% of whom had sVEGF levels above the normal range (>500 pg/mL). Patients with high sVEGF levels more frequently had cardiac and vascular involvement (58.3% vs. 41.4%, P=0.008 and 70.5% vs. 48.3%, P=0.0004, respectively). In treatment-naïve patients (n=135), the association of C-reactive protein >5 mg/L and sVEGF >500 pg/mL was strongly associated with vascular involvement (odds ratio=5.54 [95% confidence interval: 2.39-13.62], P<0.001), and independently associated with cardiac involvement (odds ratio=3.18 [95% confidence interval: 1.34-7.83], P=0.010) after adjustment for the presence of the BRAF V600E mutation. Changes in sVEGF concentration on treatment were associated with a response of cardiac involvement on consecutive cardiac magnetic resonance images. All histological samples analyzed (n=24) displayed histiocytes with intracytoplasmic expression of VEGF, which was moderate to high in more than 90% of cases. Our study suggests a role for VEGF in cardiac and vascular involvement in ECD.


Assuntos
Doença de Erdheim-Chester , Neoplasias , Humanos , Fator A de Crescimento do Endotélio Vascular/genética , Estudos Retrospectivos , Doença de Erdheim-Chester/diagnóstico , Doença de Erdheim-Chester/tratamento farmacológico , Doença de Erdheim-Chester/genética , Fatores de Crescimento do Endotélio Vascular
13.
Am J Hematol ; 98(7): 1058-1069, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37115038

RESUMO

The spectrum of somatic mutations in pediatric histiocytoses and their clinical implications are not fully characterized, especially for non-Langerhans cell histiocytosis (-LCH) subtypes. A cohort of 415 children with histiocytosis from the French histiocytosis registry was reviewed and analyzed for BRAFV600E . Most BRAFWT samples were analyzed by next-generation sequencing (NGS) with a custom panel of genes for histiocytosis and myeloid neoplasia. Of 415 case samples, there were 366 LCH, 1 Erdheim-Chester disease, 21 Rosai-Dorfman disease (RDD), 21 juvenile xanthogranuloma (JXG, mostly with severe presentation), and 6 malignant histiocytosis (MH). BRAFV600E was the most common mutation found in LCH (50.3%, n = 184). Among 105 non-BRAFV600E -mutated LCH case samples, NGS revealed mutations as follows: MAP2K1 (n = 44), BRAF exon 12 deletions (n = 26), and duplications (n = 8), other BRAF V600 codon mutation (n = 4), and non-MAP-kinase pathway genes (n = 5). Wild-type sequences were identified in 17.1% of samples. BRAFV600E was the only variant significantly correlated with critical presentations: organ-risk involvement and neurodegeneration. MAP-kinase pathway mutations were identified in seven RDD (mostly MAP2K1) and three JXG samples, but most samples were wild-type on NGS. Finally, two MH samples had KRAS mutations, and one had a novel BRAFG469R mutation. Rarely, we identified mutations unrelated to MAP-kinase pathway genes. In conclusion, we characterized the mutational spectrum of childhood LCH and clinical correlations of variants and subtypes. Variants responsible for JXG and RDD were not elucidated in more than half of the cases, calling for other sequencing approaches.


Assuntos
Doença de Erdheim-Chester , Histiocitose de Células de Langerhans , Humanos , Criança , Histiocitose de Células de Langerhans/genética , Proteínas Proto-Oncogênicas B-raf/genética , Doença de Erdheim-Chester/genética , Mutação , Éxons
14.
Lancet ; 398(10295): 157-170, 2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-33901419

RESUMO

Histiocytoses constitute a heterogeneous group of rare disorders, characterised by infiltration of almost any organ by myeloid cells with diverse macrophage or dendritic cell phenotypes. Histiocytoses can start at any age. Diagnosis is based on histology in combination with appropriate clinical and radiological findings. The low incidence and broad spectrum of clinical manifestations often leads to diagnostic delay, especially for adults. In most cases, biopsy specimens infiltrated by histiocytes have somatic mutations in genes activating the MAP kinase cell-signalling pathway. These mutations might also be present in blood cells and haematopoietic progenitors of patients with multisystem disease. A comprehensive range of investigations and molecular typing are essential to accurately predict prognosis, which can vary from spontaneous resolution to life-threatening disseminated disease. Targeted therapies with BRAF or MEK inhibitors have revolutionised salvage treatment. However, the type and duration of treatment are still debated, and the prevention of neurological sequelae remains a crucial issue.


Assuntos
Diagnóstico Tardio , Histiócitos/patologia , Histiocitose de Células de Langerhans/diagnóstico por imagem , Mutação/genética , Adulto , Humanos , MAP Quinase Quinase Quinases , Macrófagos , Doenças Raras
15.
Cancer Immunol Immunother ; 71(11): 2791-2799, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35435450

RESUMO

BACKGROUND: Despite high expression of PD-L1, around half of advanced non-small cell lung cancer (NSCLC) will not experience tumor response with pembrolizumab. There is an need for a better understanding of the resistance mechanisms in this setting. METHODS: This bi-centric retrospective study included all consecutive patients with PDL1 ≥ 50% advanced NSCLC treated with pembrolizumab in first-line treatment between 2016 and 2020. We compared the clinical characteristics of patients with early progression (refractory) vs others. We performed a comprehensive gene expression profile screening by RNAseq capture on tumor samples. RESULTS: We included 46 patients. Twenty-two patients were refractory to pembrolizumab, mainly women, with poor performance status and lower albumin concentration. RNAseq analysis was performed on 19 samples. Hierarchical clustering allowed the identification of 3 clusters with various proportion of refractory tumors: intermediate (C1: 57%), high (C2: 71%) and low proportion (C3: 40%). Comparative analysis between C2 and C3 allowed the identification of overexpressed (n = 137) and underexpressed (n = 40) genes. Among the genes of interest, C2 exhibits higher activation of pathways associated with stemness phenotype (Hedgehog, Notch and Hippo pathways) and pathways associated with loss of PTEN and JAK2. In C2, genes associated with PD-1, toll-like receptor-9 (TLR-9), major histocompatibility complex (MHC) and interferon-γ pathways were underexpressed. CONCLUSION: This study gives an overview of activated and downregulated pathways in high PD-L1 NSCLC refractory to pembrolizumab. These tumors showed activation of pathways associated with cancer stem cells, loss of PTEN and JAK2, and inhibition of both priming and effector phases of the immune response.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Albuminas/uso terapêutico , Anticorpos Monoclonais Humanizados , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Interferon gama/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Receptor de Morte Celular Programada 1 , Estudos Retrospectivos , Receptor Toll-Like 9/metabolismo , Transcriptoma
16.
Histopathology ; 80(1): 196-215, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34958507

RESUMO

Cutaneous histiocytoses constitute a heterogeneous group of diseases characterised by the cutaneous accumulation of cells with the cytological and phenotypic features of macrophages or dendritic cells. The clinical spectrum ranges from self-resolving, skin-limited conditions to severe, multiorgan disease with a high morbidity rate. Until recently, cutaneous histiocytoses were classified according to the immunophenotype of the pathological cells, with differentiation between Langerhans cell histiocytosis (LCH) [CD1a+, CD207 (langerin)+] and non-Langerhans cell histiocytosis (CD68+, CD163+, CD1a-, CD207-). Over the last 12 years, a number of new pathophysiological findings (in particular, molecular pathology results) regarding histiocytoses have contributed to a new classification based on molecular alterations, as well as on clinical and imaging characteristics and the phenotype. The most frequent entities in children are juvenile xanthogranuloma and LCH.


Assuntos
Histiocitose/patologia , Pele/patologia , Criança , Progressão da Doença , Histiocitose de Células de Langerhans/patologia , Humanos , Xantogranuloma Juvenil/patologia
17.
Haematologica ; 107(6): 1347-1357, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34647443

RESUMO

Erdheim-Chester disease (ECD) is a rare, systemic, non-Langerhans cell histiocytosis neoplasm, which is characterized by the infiltration of CD63+ CD1a- histiocytes in multiple tissues. The BRAFV600E mutation is frequently present in individuals with ECD and has been detected in hematopoietic stem cells and immune cells from the myeloid and systemic compartments. Immune cells and pro-inflammatory cytokines are present in lesions, suggesting that ECD involves immune cell recruitment. Although a systemic cytokine T-helper-1-oriented signature has been reported in ECD, the immune cell network orchestrating the immune response in ECD has yet to be described. To address this issue, the phenotypes of circulating leukocytes were investigated in a large, single-center cohort of 78 patients with ECD and compared with those of a group of 21 control individuals. Major perturbations in the abundance of systemic immune cells were detected in patients with ECD, with decreases in circulating plasmacytoid, myeloid 1, and myeloid 2 dendritic cells, mostly in BRAFV600E carriers, in comparison with individuals in the control group. Similarly, marked decreases in blood Thelper, cytotoxic, and B-lymphocyte numbers were observed in patients with ECD, relative to the control group. Measurement of circulating immunoglobulin concentrations revealed an immunoglobulin G switch, from IgG1 to IgG4 subclasses, which are more frequently associated with the BRAF mutation. First-line therapies, including pegylated interferon-a and vemurafenib, were able to correct most of these alterations. This study reveals a profound disturbance in the systemic immune phenotype in patients with ECD, providing important new information, helping to understand the physiopathological mechanisms involved in this rare disease and improving the therapeutic management of patients.


Assuntos
Doença de Erdheim-Chester , Citocinas/genética , Doença de Erdheim-Chester/diagnóstico , Doença de Erdheim-Chester/tratamento farmacológico , Doença de Erdheim-Chester/genética , Humanos , Imunoglobulina G , Fenótipo , Proteínas Proto-Oncogênicas B-raf/genética , Vemurafenib/uso terapêutico
18.
Pediatr Blood Cancer ; 69(11): e29923, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35969146

RESUMO

Neutropenia related to ELANE gene mutations predisposes patients to infection and leukemia/myelodysplasia, but little is known about the predisposition to cancer. Among a cohort of 147 patients, we identified four with malignant solid tumors (papillary thyroid cancer, anal squamous cell cancer, papillary renal cell carcinoma, and adrenocortical carcinoma), all aged 25-50 years. Three occurred with cyclic neutropenia, and one occurred with severe chronic neutropenia. Previous radiotherapy was identified as a risk factor in one patient. No genetic predisposition was identified in the three other patients.


Assuntos
Neoplasias , Neutropenia , Humanos , Elastase de Leucócito/genética , Mutação , Neoplasias/complicações , Neutropenia/genética , Neutropenia/patologia , Sistema de Registros
19.
Eur J Public Health ; 32(6): 852-857, 2022 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-36374643

RESUMO

BACKGROUND: As a system of European Reference Networks (ERNs) emerges, the differences in quality of care for patients with rare cancers may increase at national level. We aimed to elucidate the processes and healthcare planning principles through which the reference centres (RCs) for rare cancers are embedded in national health systems. METHODS: We used a multiple case-study design based on the experiences of Czechia, Finland, France, Italy, Lithuania and Spain. Using sarcoma as an example of rare cancer, 52 semi-structured interviews were conducted during on-site visits, including a multidisciplinary group of professionals, Ministry of Health professionals, patient representatives and European policymakers. RESULTS: The comparative analysis showed substantial heterogeneity in the processes for formalizing RCs' status and in their levels of integration in the different health systems, but two models (centre-based and the network-based) can be envisaged at national level. RCs for rare cancers were legally established only in France and Spain. Expert clinicians cooperate in a structured way, using network mechanisms, in France and Italy, and these countries, plus Finland and Lithuania, had a referral system to facilitate patients' access from non-expert centres to RCs. Seven key healthcare planning principles in instituting RCs at the national level were identified. CONCLUSIONS: The conditions governing patient access to treatment centres-whether RCs or not-are decided at the national level. It is advisable to progressively align the European and national levels so that the RCs that participate in the ERNs also play a significant role at the national level.


Assuntos
Neoplasias , Humanos , Espanha , Itália , Encaminhamento e Consulta , França
20.
Genes Chromosomes Cancer ; 60(11): 723-732, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34245196

RESUMO

Glomus tumors (GTs) are perivascular tumors mostly occurring in the distal extremities. Rare cases arise in the digestive tract and may be misdiagnosed with neuroendocrine or gastrointestinal stromal tumors. We aimed to specify the features of GT of the upper digestive tract. Clinical, histological, phenotypic, and molecular features of 16 digestive GTs were analyzed, of whom two underwent whole exome and RNA sequencing to search for gene alterations. RNA-sequencing disclosed a t(1:5)(p13;q32) translocation, which resulted in the fusion of CARMN and NOTCH2 in two GTs. The fusion gene encoded a protein sequence corresponding to the NOTCH2 intracellular domain that functions as transcription factor. These finding was supported by high expression of genes targeted by NOTCH. The CARMN-NOTCH2 translocation was detected in 14 out of 16 (88%) GTs of the upper digestive tract; but in only in two out of six cutaneous GTs (33%). Most digestive GT arose from the stomach (n = 13), and the others from duodenal (2) or oesophagous (1). Nuclear expression of NOTCH2 was detected in the 14 cases containing the fusion transcripts. The CARMN-NOTCH2 fusion transcript may contribute to activation of the NOTCH2 pathway in GT and drive tumor development. The high frequency of this translocation in GT of the upper digestive track suggest that detection of nuclear NOTCH2 expression may be useful diagnostic biomarker of these tumors.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Gastrointestinais/genética , Fusão Gênica , Tumor Glômico/genética , MicroRNAs/genética , Receptor Notch2/genética , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Tumor Glômico/metabolismo , Tumor Glômico/patologia , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA