RESUMO
Lymphoid tissue inducer (LTi) cells are critical for inducing the differentiation of most secondary lymphoid organs (SLOs) in mice. In humans, JAK3 and γc deficiencies result in severe combined immunodeficiency (SCIDs) characterized by an absence of T cells, natural killer cells, innate lymphoid cells (ILCs), and presumably LTi cells. Some of these patients have undergone allogeneic stem cell transplantation (HSCT) in the absence of myeloablation, which leads to donor T cell engraftment, while other leukocyte subsets are of host origin. By using MRI to look for SLOs in nine of these patients 16 to 44 y after HSCT, we discovered that SLOs were exclusively found in the three areas of the abdomen that drain the intestinal tract. A postmortem examination of a child with γc-SCID who had died 3.5 mo after HSCT showed corticomedullary differentiation in the thymus, T cell zones in the spleen, and the appendix, but in neither lymph nodes nor Peyer patches. Tertiary lymphoid organs were observed in the lung. No RAR-related orphan receptor-positive LTi cells could be detected in the existing lymphoid structures. These results suggest that while LTi cells are required for the genesis of most SLOs in humans, SLO in the appendix and in gut-draining areas, as well as tertiary lymphoid organs, can be generated likely by LTi cell-independent mechanisms.
Assuntos
Tecido Linfoide/crescimento & desenvolvimento , Imunodeficiência Combinada Severa/imunologia , Adolescente , Adulto , Feminino , Humanos , Tecido Linfoide/diagnóstico por imagem , Tecido Linfoide/imunologia , Imageamento por Ressonância Magnética , Masculino , Imunodeficiência Combinada Severa/diagnóstico por imagem , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/terapia , Baço/diagnóstico por imagem , Baço/crescimento & desenvolvimento , Baço/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Timo/diagnóstico por imagem , Timo/crescimento & desenvolvimento , Timo/imunologia , Transplante Homólogo , Adulto JovemRESUMO
Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping â¼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.
Assuntos
Fator 10 de Crescimento de Fibroblastos/genética , Doenças do Recém-Nascido/genética , Doenças do Recém-Nascido/mortalidade , Pneumopatias/genética , Pneumopatias/mortalidade , Transdução de Sinais/genética , Proteínas com Domínio T/genética , Variações do Número de Cópias de DNA/genética , Feminino , Fator 10 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Idade Gestacional , Humanos , Recém-Nascido , Doenças do Recém-Nascido/metabolismo , Doenças do Recém-Nascido/patologia , Pulmão/embriologia , Pulmão/crescimento & desenvolvimento , Pneumopatias/metabolismo , Pneumopatias/patologia , Masculino , Herança Materna , Organogênese , Herança Paterna , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Proteínas com Domínio T/metabolismoRESUMO
The RYTHMIC network, supported by the French National Cancer Institute is dedicated to the management of patients with thymic epithelial tumors through regional and national multidisciplinary tumor boards. Tumor board decisions are based on the initial pathology diagnoses. However, following clinical inclusion in the network, a central pathology review is organized, implicating a panel of pathologists, for histotype and stage classification, which is different from a classical second opinion from pathologist to pathologist for a difficult case. Thanks to the participation of all French pathologists, more than 1000 cases have been reviewed by the panel. The aim of this review is to share with the French pathology community, the experience of the group. It underlines the importance of macroscopy and surgeon-pathologist involvement to allow a good central review, the main histopathological and immunophenotypical patterns of the most frequent thymomas and thymic carcinoma types, the differential diagnoses, as well as the difficulties for the panel to reproducibly assess on slides, stage, for some cases.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Epiteliais e Glandulares , Timoma , Neoplasias do Timo , Carcinoma de Células Escamosas/diagnóstico , Diagnóstico Diferencial , Humanos , Timoma/diagnóstico , Neoplasias do Timo/diagnósticoRESUMO
Diffuse alveolar hemorrhage (DAH) is a life-threatening complication of systemic lupus erythematosus (SLE) and systemic vasculitis. Although initially described to have antibacterial properties, increasing evidence suggests that neutrophil extracellular traps (NETs) have a detrimental role in both autoimmune diseases and acute lung injury. We investigated whether NETs could be detected in a murine model of pristane-induced lupus DAH and contribute to lung injury. Such NETs might constitute a therapeutic target. NETs were characterized by immunofluorescence staining of DNA, neutrophil elastase and citrullinated histones. Evaluation of lung injury was performed by haematoxylin-eosin staining and a quantification program. Clinical status of the mice was assessed by measurement of arterial oxygen saturation and survival curves after recombinant human deoxyribonuclease-1 (Rh-DNase-1) inhalations or polymorphonuclear neutrophil (PMN) depletion. Pristane was found to promote NETs formation in vitro and in vivo. Treatment of mice with Rh-DNase-1 inhalations cleared NETs and reduced lung injury. Clinical status improved significantly, with increased arterial oxygenation and survival. Following PMN depletion, NETs were absent with a subsequent reduction of lung injury and improved arterial oxygenation. These results support a pathogenic role of PMNs and NETs in lung injury during pristane-induced DAH. Targeting NETs with Rh-DNase-1 inhalations could constitute an interesting adjuvant therapy in human DAH.
Assuntos
Lesão Pulmonar Aguda/imunologia , Armadilhas Extracelulares/imunologia , Hemorragia/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Neutrófilos/imunologia , Alvéolos Pulmonares/imunologia , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/patologia , Animais , Desoxirribonuclease I/farmacologia , Hemorragia/tratamento farmacológico , Hemorragia/patologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Neutrófilos/patologia , Alvéolos Pulmonares/patologiaRESUMO
Diffuse esophageal leiomyomatosis is a rare esophageal tumor characterized by circumferential thickening of smooth muscle layers. Diffuse esophageal leiomyomatosis can be associated with Alport's syndrome and therefore diagnosed by skin biopsy. Alport syndrome is a hereditary disease usually defined by the association of glomerular nephropathy and perceptual deafness. Here we describe the management of a young women with a diffuse esophageal leiomyomatosis and a past history of uterine leiomyoma. The surgical treatment depends on the esophageal extent of the disease. Association between diffuse esophageal leiomyomatosis and early uterine leiomyomas could be also observed and leading to Alport's syndrome diagnosis despite the absence of renal abnormalities.
Assuntos
Neoplasias Esofágicas/complicações , Leiomiomatose/complicações , Nefrite Hereditária/complicações , Adulto , Feminino , HumanosRESUMO
BACKGROUND: In lung adenocarcinoma, molecular profiling of actionable genes has become essential to set up targeted therapies. However, the feasibility and the relevance of molecular profiling from the cerebrospinal fluid (CSF) in the context of meningeal metastasis have been poorly assessed. METHODS: We selected patients with stage IV lung adenocarcinoma harbouring metastatic cells in the CSF after cytological analysis. Seven samples from six patients were eligible for molecular testing of epidermal growth factor receptor (EGFR), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS), v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) and human epidermal growth factor receptor 2 (HER2) mutations using quantitative polymerase chain reaction (PCR) high-resolution melting curve analysis and Sanger sequencing after DNA extraction from the cell pellets of the CSF. RESULTS: Five patients showed mutations in one or two actionable genes, two harboured an EGFR mutation (exons 19 and 21), one only a KRAS mutation, one both EGFR and KRAS mutations and one a BRAF mutation. In all cases, the results of mutation testing provided new major information for patient management, leading to therapeutic adaptation. CSF molecular analysis identified mutations not detected in other neoplastic sites for two patients. In one case, the EGFR p.Thr790Met was identified. CSF was also the only sample available for genetic testing for almost all patients at the time of disease progression. CONCLUSIONS: When cancer cells are present in the CSF, the molecular profiling from the cell pellets is relevant, as it can detect supplemental or different mutations compared to a previous analysis of the primitive tumour or plasma cell-free DNA and allows the adaptation of the treatment strategy.
Assuntos
Adenocarcinoma de Pulmão/líquido cefalorraquidiano , Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/líquido cefalorraquidiano , Neoplasias Pulmonares/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma de Pulmão/patologia , Idoso , Receptores ErbB/química , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/química , Proteínas Proto-Oncogênicas p21(ras)/químicaRESUMO
OBJECTIVES: The incidence of pneumothorax is 7 times higher after lung radiofrequency ablation (RFA) than after lung biopsy. The reasons for such a difference have never been objectified. The histopathologic changes in lung tissue are well-studied and established for RF in the ablation zone. However, it has not been previously described what the nature of thermal injury might be along the shaft of the RF electrode as it traverses through normal lung tissue to reach the ablation zone. The purpose of this study was to determine the changes occurring around the RF needle along the pathway between the ablated zone and the pleura. MATERIAL AND METHODS: In 3 anaesthetised and ventilated swine, 6 RFA procedures (right and left lungs) were performed using a 14-gauge unipolar multi-tined retractable 3 cm radiofrequency LeVeen probe with a coaxial introducer positioned under CT fluoroscopic guidance. In compliance with literature guidelines, we implemented a gradually increasing thermo-ablation protocol using a RF generator. Helical CT images were acquired pre- and post-RFA procedure to detect and evaluate pneumothorax. Four percutaneous 19-gauge lung biopsies were also performed on the fourth swine under CT guidance. Swine were sacrificed for lung ex vivo examinations, scanning electron microscopy (SEM) and pathological analysis. RESULTS: Three severe (over 50 ml) pneumothorax were detected after RFA. In each one of them, pathological examination revealed a fistulous tract between ablation zone and pleura. No fistulous tract was observed after biopsies. In the 3 cases of severe pneumothorax, the tract was wide open and clearly visible on post procedure CT images and SEM examinations. The RFA tract differed from the needle biopsy tract. The histological changes that are usually found in the ablated zone were observed in the RFA tract's wall and were related to thermal lesions. These modifications caused the creation of a coagulated pulmonary parenchyma rim between the thermo-ablation zone and the pleural space. The structural properties of the damage can explain why the RFA tract is remains patent after needle withdrawal. CONCLUSION: Our study demonstrates for the first time that the changes around the RF needle are the same as in the ablated zone. The damage could create fistulous tracts along the needle path between thermo-ablation zone and pleural space. These fistulas could certainly be responsible for severe pneumothorax that occurs in many patients treated with lung RFA.
Assuntos
Ablação por Cateter/efeitos adversos , Pulmão/patologia , Agulhas/efeitos adversos , Pneumotórax/etiologia , Fístula do Sistema Respiratório/etiologia , Animais , Pulmão/diagnóstico por imagem , Pneumotórax/diagnóstico por imagem , Pneumotórax/patologia , Fístula do Sistema Respiratório/diagnóstico por imagem , Fístula do Sistema Respiratório/patologia , Suínos , Tomografia Computadorizada por Raios XRESUMO
A major impediment to the effective treatment of patients with pancreatic ductal adenocarcinoma (PDAC) is the molecular heterogeneity of this disease, which is reflected in an equally diverse pattern of clinical outcome and in responses to therapies. We developed an efficient strategy in which PDAC samples from 17 consecutive patients were collected by endoscopic ultrasound-guided fine-needle aspiration or surgery and were preserved as breathing tumors by xenografting and as a primary culture of epithelial cells. Transcriptomic analysis was performed from breathing tumors by an Affymetrix approach. We observed significant heterogeneity in the RNA expression profile of tumors. However, the bioinformatic analysis of these data was able to discriminate between patients with long- and short-term survival corresponding to patients with moderately or poorly differentiated PDAC tumors, respectively. Primary culture of cells allowed us to analyze their relative sensitivity to anticancer drugs in vitro using a chemogram, similar to the antibiogram for microorganisms, establishing an individual profile of drug sensitivity. As expected, the response was patient dependent. We also found that transcriptomic analysis predicts the sensitivity of cells to the five anticancer drugs most frequently used to treat patients with PDAC. In conclusion, using this approach, we found that transcriptomic analysis could predict the sensitivity to anticancer drugs and the clinical outcome of patients with PDAC.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Antineoplásicos/uso terapêutico , Perfilação da Expressão Gênica , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Adenocarcinoma/patologia , Animais , Antineoplásicos/farmacologia , Biópsia por Agulha Fina , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Endoscopia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Neoplasias Pancreáticas/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Coloração e Rotulagem , Análise de Sobrevida , Transcriptoma/genética , Resultado do Tratamento , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias PancreáticasRESUMO
In this article we report the obesogenic role of the acute phase protein PAP/HIP. We found that the transgenic TgPAP/HIP mice develop spontaneous obesity under standard nutritional conditions, with high levels of glucose, leptin, and LDL and low levels of triglycerides and HDL in blood. Accordingly, PAP/HIP-deficient mice are skinny under standard nutritional conditions. We also found that expression of PAP/HIP is induced in intestinal epithelial cells in response to gavage with olive oil and this induction is AG490 sensitive. We demonstrated that incubation of 3T3-L1 preadipocytes with a low concentration as 1 ng/ml of recombinant PAP/HIP results in accelerated BrdU incorporation in vitro. PAP/HIP-dependent adipocytes growth is sensitive to the MEK inhibitor U0126. Finally, patients with severe obesity present higher blood levels of PAP/HIP than non-obese control individuals. Altogether our data suggest that PAP/HIP could be a mediator of fat tissue development, released by the intestine and induced by the presence of food into the gut.
Assuntos
Fatores de Coagulação Sanguínea/metabolismo , Obesidade/metabolismo , Proteínas/metabolismo , Células 3T3-L1 , Tecido Adiposo/metabolismo , Adulto , Animais , Fatores de Coagulação Sanguínea/genética , Butadienos , Feminino , Regulação da Expressão Gênica/fisiologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Pessoa de Meia-Idade , Nitrilas , Obesidade/genética , Proteínas Associadas a Pancreatite , Proteínas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA , Proteínas RibossômicasRESUMO
Epithelial thymic tumours are rare and sometimes difficult to classify. Since 2010, the French National Cancer Institute supports a French national network, called Rythmic, devoted to the treatment of these tumours through regional and national multidisciplinary conferences using the web. All the tumours are secondarily reviewed by a French pathology national network for classification and staging. This review focuses on the presentation of the Rythmic network, and mainly to the Pathology review process.
Assuntos
Sistemas Multi-Institucionais , Patologia Clínica , Neoplasias do Timo/patologia , França , HumanosRESUMO
We hypothesized that inhibiting molecules that mediate the adaptation response to cellular stress can antagonize the resistance of pancreatic cancer cells to chemotherapeutic drugs. Toward this end, here, we investigated how VMP1, a stress-induced autophagy-associated protein, modulate stress responses triggered by chemotherapeutic agents in PDAC. We find that VMP1 is particularly over-expressed in poorly differentiated human pancreatic cancer. Pharmacological studies show that drugs that work, in part, via the endoplasmic reticulum stress response, induce VMP1 expression. Similarly, VMP1 is induced by known endoplasmic reticulum stress activators. Genetic inactivation of VMP1 using RNAi-based antagonize the pancreatic cancer stress response to antitumoral agents. Functionally, we find that VMP1 regulates both autophagy and chemotherapeutic resistance even in the presence of chloroquin, ATG5 or Beclin 1 siRNAs, or a Beclin 1-binding VMP1 mutant. In addition, VMP1 modulates endoplasmic reticulum stress independently of its coupling to the molecular and cellular autophagy machinery. Preclinical studies demonstrate that xenografts expressing an inducible and tractable form of VMP1 show increased resistance to the gemcitabine treatment. These results underscore a novel role for VMP1 as a potential therapeutic target for combinatorial therapies aimed at sensitizing pancreatic cancer cells to chemotherapeutic agents as well as provide novel molecular mechanisms to better understand this phenomenon.
Assuntos
Desoxicitidina/análogos & derivados , Proteínas de Membrana/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Biomarcadores Farmacológicos/metabolismo , Linhagem Celular Tumoral , Desoxicitidina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Camundongos , Neoplasias Pancreáticas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , GencitabinaRESUMO
We recently reported that standardized quantitative immunohistochemical (IHC) assays allowed prediction of an adverse outcome among 572 node negative (N-) patients with breast carcinoma (BrCa). To further validate our prior findings, we repeated the IHC stains including a second series of BrCa diagnosed at Yale University. Tissue microarrays (TMAs) of two cohorts of patients with BrCa (418 Marseille University and 303 Yale University) were respectively investigated for IHC expression of 15 markers (HIF-1α, PI3K, pAKT, pmTOR, moesin, P21, 4(E) BP-1, P27, Ker5-6, pMAPKAPK-2, SHARP2, claudin-1, ALDH, AF6 and CD24). Quantitative measurements of immunoprecipitates densitometry assessed with an image analyzer were correlated with 8-year patients' outcome and compared in the two cohorts. The best predictive signature consisted of a combination of five markers that included HIF-1α, PI3K, claudin-1, AF6 and pAKT in N- BrCa. This combination permitted an accurate prediction of outcome in 92.34% (386/418) of N- patients in the first set (Marseille) and 89.8% (158/176) in the second set (Yale). The close results in both cohorts confirmed the validity of this original IHC signature predictive of prognosis in node negative BrCa. This validation suggests that in clinical practice, it would be possible with standardized kits (i) to identify patients with poor prognosis at diagnosis time, particularly in the N- BrCa subset, who would require more aggressive adjuvant therapy and (ii) to avoid useless expensive therapies and their side effects in N- patients with favorable prognosis.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/mortalidade , Imuno-Histoquímica , Idoso , Neoplasias da Mama/patologia , Claudina-1 , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Cinesinas/análise , Proteínas de Membrana/análise , Pessoa de Meia-Idade , Miosinas/análise , Fosfatidilinositol 3-Quinases/análise , Prognóstico , Análise Serial de Proteínas , Proteínas Proto-Oncogênicas c-akt/análiseRESUMO
LABELLED BACKGROUND: Haemoptysis is a life-threatening complication of cystic fibrosis (CF). One treatment is bronchial artery embolisation (BAE) using embolic-microspheres (EMs). During BAE, pulmonary arteries can be seen on digital subtracted angiography while iodine containing contrast material injection is performed in the bronchial artery. This suggests that EMs could go from bronchial to nontarget pulmonary arteries. The aim was to evaluate if EMs could be found inside pulmonary arteries on lung explants after BAE in transplanted CF patients. METHODS: Retrospective observational study including patients with CF who underwent lung transplantation and had previously needed BAE. Clinical, chest CT angiography, and angiographic data were reviewed from medical records. Pathology examination of lung explants was performed to analyze the EMs anatomical localisation. RESULTS: Eight patients were included between 2013 and 2015, four males with a mean age of 29 (19-45) years. All patients had bronchial artery hypertrophy on CT and bronchial-to-pulmonary artery shunting during BAE. On pathology examination, EM ≤800 µm were found in the pulmonary arteries in all patients and were responsible for distal branch occlusions. Two pulmonary infarcts were observed on CT angiography after BAE and confirmed histopathologically. CONCLUSIONS: EM migration from the bronchial to pulmonary arteries is a common occurrence after BAE in patients with advanced stage CF. Although BAE is a highly effective means of controlling haemoptysis in CF, studies on the optimal particle size are needed to preserve pulmonary artery circulation, because these results suggest that low size EMs could lead to nontarget embolisation.
Assuntos
Fibrose Cística , Embolização Terapêutica , Masculino , Humanos , Adulto , Artérias Brônquicas/diagnóstico por imagem , Hemoptise/diagnóstico , Hemoptise/etiologia , Hemoptise/terapia , Fibrose Cística/complicações , Fibrose Cística/terapia , Embolização Terapêutica/efeitos adversos , Angiografia/efeitos adversos , Estudos Retrospectivos , Resultado do TratamentoAssuntos
Lesão Pulmonar Aguda/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transfusão de Linfócitos/efeitos adversos , Síndrome do Desconforto Respiratório/etiologia , Idoso , Evolução Fatal , Humanos , Linfócitos , Masculino , Alvéolos Pulmonares/patologia , Doadores de Tecidos , Transplante Homólogo/efeitos adversosAssuntos
Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Fibrose Pulmonar Idiopática/complicações , Tromboflebite/complicações , Tromboflebite/tratamento farmacológico , Varfarina/efeitos adversos , Idoso , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Cytoplasmic aminoacyl-tRNA synthetases (ARSs) are emerging as a cause of numerous rare inherited diseases. Recently, biallelic variants in tyrosyl-tRNA synthetase 1 (YARS1) have been described in ten patients of three families with multi-systemic disease (failure to thrive, developmental delay, liver dysfunction, and lung cysts). Here, we report an additional subject with overlapping clinical findings, heterozygous for two novel variants in tyrosyl-tRNA synthetase 1 (NM_003680.3(YARS1):c.176T>C; p.(Ile59Thr) and NM_003680.3(YARS1):c.237C>G; p.(Tyr79*) identified by whole exome sequencing. The p.Ile59Thr variant is located in the highly conserved aminoacylation domain of the protein. Compared to subjects previously described, this patient presents a much more severe condition. Our findings support implication of two novel YARS1 variants in these disorders. Furthermore, we provide evidence for a reduced protein abundance in cells of the patient, in favor of a partial loss-of-function mechanism.
Assuntos
Deficiências do Desenvolvimento/genética , Insuficiência de Crescimento/genética , Hepatopatias/genética , Pneumopatias/genética , Tirosina-tRNA Ligase/genética , Deficiências do Desenvolvimento/patologia , Insuficiência de Crescimento/patologia , Feminino , Humanos , Lactente , Hepatopatias/patologia , Mutação com Perda de Função , Pneumopatias/patologiaRESUMO
BACKGROUND: Classification of thymic epithelial tumours (TETs) is known to be challenging; however, the level of discordances at a nationwide level between initial and expert diagnosis and their clinical consequences are currently unknown. RYTHMIC is a national network dedicated to the management of TET based on initial histological diagnosis, followed by an additional expert review of all cases. Our aim was to evaluate the discordances between initial and expert diagnoses and whether they would have led to different clinical management. PATIENTS AND METHODS: We conducted a retrospective analysis of the cohort of patients discussed at RYTHMIC tumour board from January 2012 to December 2016. Assessment of disagreement was made for histological typing and for staging. The discordances were classified as major or minor based on whether they would have changed or not the proposed therapeutic strategy, respectively. Follow-up of the patients with major discordances was conducted until December 2018. RESULTS: Four hundred sixty-seven patients were reviewed, and 183 (39%) discordances were identified either related to histological subtype (132) and/or stage (72). Major discordances were identified in 27 patients (6%). They included 16 patients with TET for whom treatment recommendation based on the central review would have been post-operative radiotherapy, whereas it had not been the case. However, follow-up did not show any progression among the 15 patients with high-grade histology and/or stage resected thymomas. On the other hand, among the remaining 11 patients including 7 with a diagnosis other than TET, the overall management or follow-up would have been completely different with the expert diagnosis. CONCLUSION: Our real-life cohort reveals a high level of discordances considering TET diagnosis and supports expert review for optimal clinical management.
Assuntos
Neoplasias Epiteliais e Glandulares/diagnóstico , Neoplasias Epiteliais e Glandulares/terapia , Neoplasias do Timo/diagnóstico , Neoplasias do Timo/terapia , Estudos de Coortes , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
Quantitative immunocytochemical assays of 1,200 breast carcinomas were assessed after construction of tissue microarrays. A total of 42 markers were evaluated for prognostic significance by univariate log rank test (mean follow-up, 79 months), using quantitative scoring by an image analysis device and specific software. Complete data were obtained for 924 patients, for whom 27 of the 42 markers proved to be significant prognostic indicators. Analysis of these 27 markers by logistic regression showed that 18 (cMet, CD44v6, FAK, moesin, caveolin, c-Kit, CK14, CD10, P21, P27, pMAPK, pSTAT3, STAT1, SHARP2, FYN, ER, PgR and c-erb B2), and 15 when ER, PgR and c-erb B2 were excluded, were 80.52% and 78.9% predictive of disease outcome, respectively. The immunocytochemical assays on 4 micron thick sections of fixed tissue are easy to handle in current practice and are cost-effective. Quantitative densitometric measurement of immunoprecipitates by computer-assisted devices from digitized microscopic images allows standardized high-throughput "in situ" molecular profiling within tumors. It is concluded that this 15 marker immunohistochemical signature is suitable for current practice, since performed on paraffin sections of fixed tumor samples, and can be used to select patients needing more aggressive therapy, since this signature is about 80% predictive of poor clinical outcome. Also, the markers included in the signature may be indicative of tumor responsiveness to current chemotherapy or suggest new targets for specific therapies.
Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Adenocarcinoma/secundário , Adenocarcinoma/cirurgia , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Feminino , Humanos , Técnicas Imunoenzimáticas , Imunoprecipitação , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Curva ROC , Fatores de Risco , Taxa de SobrevidaRESUMO
We aimed in this study at identifying prognostic immunohistochemical molecular signatures indicative of disease outcome, also relevant for development of new specific therapies, in triple-negative (ER, PR, c-erbB2- negative) breast carcinoma subtypes. We evaluated 42 markers in tissue micro-arrays from a series of 924 breast carcinomas including 184 triple-negative tumors using standardized quantitative immunocytochemical assays and correlated the data with patients' outcome (mean follow-up of 79 months). When 27/42 markers including basal-like markers first found to be individually significant for prognosis in a univariate analysis (log-rank test) in 924 tumors, were secondly evaluated in the triple-negative tumor subtype (184/924), eleven including maspin, P21, P27, PTEN, caveolin, EGFR, FAK, P38, pMAPK, STAT1 and CD10 were 89.2% predictive of disease outcome in logistic regression. When markers reported in the literature as expressed in basal-like subtype were evaluated in the 924 series, only eight (EGFR, CK14, moesin, caveolin, cMet, ckit, CD44v6, C10) were prognosis predictive in univariate analysis (log-rank test) and in logistic regression were predictive of disease outcome in 66.3% independently of ER, PR and c-erbB2 expression and in 72% in triple-negative tumor subset. The results suggest that the category of 'triple-negative' breast carcinomas does not exactly overlap the basal-like subtype, and that immunoprofiling of triple-negative tumors (not similar to that of basal-like tumors) may be helpful to select patients for more aggressive treatment and provides a basis for development of tailored therapy.