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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.
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Fibrosis Quística , Embolización Terapéutica , Masculino , Humanos , Adulto , Arterias Bronquiales/diagnóstico por imagen , Hemoptisis/diagnóstico , Hemoptisis/etiología , Hemoptisis/terapia , Fibrosis Quística/complicaciones , Fibrosis Quística/terapia , Embolización Terapéutica/efectos adversos , Angiografía/efectos adversos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
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.
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Discapacidades del Desarrollo/genética , Insuficiencia de Crecimiento/genética , Hepatopatías/genética , Enfermedades Pulmonares/genética , Tirosina-ARNt Ligasa/genética , Discapacidades del Desarrollo/patología , Insuficiencia de Crecimiento/patología , Femenino , Humanos , Lactante , Hepatopatías/patología , Mutación con Pérdida de Función , Enfermedades Pulmonares/patologíaRESUMEN
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.
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Tejido Linfoide/crecimiento & desarrollo , Inmunodeficiencia Combinada Grave/inmunología , Adolescente , Adulto , Femenino , Humanos , Tejido Linfoide/diagnóstico por imagen , Tejido Linfoide/inmunología , Imagen por Resonancia Magnética , Masculino , Inmunodeficiencia Combinada Grave/diagnóstico por imagen , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/terapia , Bazo/diagnóstico por imagen , Bazo/crecimiento & desarrollo , Bazo/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Timo/diagnóstico por imagen , Timo/crecimiento & desarrollo , Timo/inmunología , Trasplante Homólogo , Adulto JovenRESUMEN
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.
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Neoplasias Glandulares y Epiteliales/diagnóstico , Neoplasias Glandulares y Epiteliales/terapia , Neoplasias del Timo/diagnóstico , Neoplasias del Timo/terapia , Estudios de Cohortes , Femenino , Humanos , Masculino , Estudios RetrospectivosRESUMEN
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.
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Carcinoma de Células Escamosas , Neoplasias Glandulares y Epiteliales , Timoma , Neoplasias del Timo , Carcinoma de Células Escamosas/diagnóstico , Diagnóstico Diferencial , Humanos , Timoma/diagnóstico , Neoplasias del Timo/diagnósticoRESUMEN
BACKGROUND: Immunotherapy is currently under investigation in B3 Thymoma (TB3) and Thymic Carcinoma (TC). PD-L1 expression has been evaluated on a limited number of patients with selected antibodies. We aimed to analyze cohort of TB3 and TC with a panel of antibodies to assess the prevalence of PD-L1 expression, its prognostic value and to set up a reproducible test. METHODS: We retrospectively studied 103 patients samples of FFPE histologically confirmed TB3 (n = 53) and TC (n = 50) by expert pathologists within the RYTHMIC national network. We compared PD-L1, PD1, CD8 and PD-L2 expression and performed correlation with tumor types and patients outcomes. Four PD-L1 antibodies were tested, three of them validated as companion tests in lung cancer, one tested on two automates on whole section of tumors. We evaluated the percentage and intensity of both epithelial and immune stained cells. RESULTS: TB3 epithelial cells had a higher and more diffuse expression of PD-L1 than TC regardless the antibodies tested (p < 0.0001). Three out of four antibodies targeting PD-L1 tested on the DAKO autostainer gave similar staining. Concordance between antibodies was lower for PD-L1 staining on immune cells with no significant difference between TB3 and TC except on E1L3N antibody. PD-L2 antibody stained no tumor epithelial cells. High PD-L1 expression was correlated with a better overall survival for TB3 and was not correlated with tumor staging. CONCLUSION: Frequent PD-L1 expression, particularly in TB3, paves the way for immunotherapy in TET (Thymic Epithelial Tumor). Otherwise, we have set up three reproducible LDT (laboratory-developed test) for four PD-L1 antibodies.
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Childhood pulmonary Langerhans cell histiocytosis (PLCH) is a rare disease. Its pulmonary histopathology, according to comprehensive clinical-radiological findings and BRAFV600E mutation status, has not yet been thoroughly documented. From the 167 childhood PLCH cases entered in the French National Histiocytosis Registry (1983-2016), we retrieved lung biopsies from a consecutive retrospective series of 17 patients, diagnosed when they were 2 weeks to 16 years old (median, 9.4 years), and report the clinical and histopathological findings herein. Histological analyses of biopsies (16 surgical and 1 postmortem) found the following features, alone or associated: Langerhans cell (LC) nodules with cavitation (9/17), cysts (14/17), fibrotic scars (2/17), peribronchiolar topographic distribution of the lesions (10/17), and accessory changes, like stretch emphysema (7/17). Those characteristics closely resemble those describing adult PLCH. However, unusual findings observed were 2 large nodules and a diffuse interstitial LC infiltrate. BRAFV600E mutation was detected in 4 of 12 samples tested, notably in the 3 with unusual features. In conclusion, childhood PLCH mostly shares the common histology features already described in adult PLCH, regardless of age. Because smoking is considered the major trigger in PLCH pathogenesis, the findings based on this series suggest other inducers of bronchiolar LC recruitment, especially in very young patients.
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Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/patología , Enfermedades Pulmonares/genética , Enfermedades Pulmonares/patología , Proteínas Proto-Oncogénicas B-raf/genética , Adolescente , Niño , Preescolar , Estudios de Cohortes , Femenino , Francia , Humanos , Lactante , Recién Nacido , Masculino , Mutación , Estudios RetrospectivosRESUMEN
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.
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Lesión Pulmonar Aguda/inmunología , Trampas Extracelulares/inmunología , Hemorragia/inmunología , Lupus Eritematoso Sistémico/inmunología , Neutrófilos/inmunología , Alveolos Pulmonares/inmunología , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/patología , Animales , Desoxirribonucleasa I/farmacología , Hemorragia/tratamiento farmacológico , Hemorragia/patología , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/patología , Ratones , Neutrófilos/patología , Alveolos Pulmonares/patologíaRESUMEN
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.
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Factor 10 de Crecimiento de Fibroblastos/genética , Enfermedades del Recién Nacido/genética , Enfermedades del Recién Nacido/mortalidad , Enfermedades Pulmonares/genética , Enfermedades Pulmonares/mortalidad , Transducción de Señal/genética , Proteínas de Dominio T Box/genética , Variaciones en el Número de Copia de ADN/genética , Femenino , Factor 10 de Crecimiento de Fibroblastos/metabolismo , Regulación de la Expresión Génica , Edad Gestacional , Humanos , Recién Nacido , Enfermedades del Recién Nacido/metabolismo , Enfermedades del Recién Nacido/patología , Pulmón/embriología , Pulmón/crecimiento & desarrollo , Enfermedades Pulmonares/metabolismo , Enfermedades Pulmonares/patología , Masculino , Herencia Materna , Organogénesis , Herencia Paterna , Linaje , Polimorfismo de Nucleótido Simple/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Proteínas de Dominio T Box/metabolismoRESUMEN
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.
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Neoplasias Esofágicas/complicaciones , Leiomiomatosis/complicaciones , Nefritis Hereditaria/complicaciones , Adulto , Femenino , HumanosRESUMEN
Recent studies have offered ample insight into genome-wide expression patterns to define pancreatic ductal adenocarcinoma (PDAC) subtypes, although there remains a lack of knowledge regarding the underlying epigenomics of PDAC. Here we perform multi-parametric integrative analyses of chromatin immunoprecipitation-sequencing (ChIP-seq) on multiple histone modifications, RNA-sequencing (RNA-seq), and DNA methylation to define epigenomic landscapes for PDAC subtypes, which can predict their relative aggressiveness and survival. Moreover, we describe the state of promoters, enhancers, super-enhancers, euchromatic, and heterochromatic regions for each subtype. Further analyses indicate that the distinct epigenomic landscapes are regulated by different membrane-to-nucleus pathways. Inactivation of a basal-specific super-enhancer associated pathway reveals the existence of plasticity between subtypes. Thus, our study provides new insight into the epigenetic landscapes associated with the heterogeneity of PDAC, thereby increasing our mechanistic understanding of this disease, as well as offering potential new markers and therapeutic targets.
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Biomarcadores de Tumor/genética , Carcinoma Ductal Pancreático/genética , Epigénesis Genética/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas/genética , Anciano , Anciano de 80 o más Años , Animales , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Inmunoprecipitación de Cromatina/métodos , Metilación de ADN/genética , Conjuntos de Datos como Asunto , Femenino , Histonas/genética , Humanos , Masculino , Ratones , Ratones Desnudos , Persona de Mediana Edad , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Secuencias Reguladoras de Ácidos Nucleicos/genética , Análisis de Secuencia de ARN/métodos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
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.
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Adenocarcinoma del Pulmón/líquido cefalorraquídeo , Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/líquido cefalorraquídeo , Neoplasias Pulmonares/genética , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Adenocarcinoma del Pulmón/patología , Anciano , Receptores ErbB/química , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas B-raf/química , Proteínas Proto-Oncogénicas p21(ras)/químicaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive stroma and pathogenic modifications to the peripheral nervous system that elevate metastatic capacity. In this study, we show that the IL6-related stem cell-promoting factor LIF supports PDAC-associated neural remodeling (PANR). LIF was overexpressed in tumor tissue compared with healthy pancreas, but its receptors LIFR and gp130 were expressed only in intratumoral nerves. Cancer cells and stromal cells in PDAC tissues both expressed LIF, but only stromal cells could secrete it. Biological investigations showed that LIF promoted the differentiation of glial nerve sheath Schwann cells and induced their migration by activating JAK/STAT3/AKT signaling. LIF also induced neuronal plasticity in dorsal root ganglia neurons by increasing the number of neurites and the soma area. Notably, injection of LIF-blocking antibody into PDAC-bearing mice reduced intratumoral nerve density, supporting a critical role for LIF function in PANR. In serum from human PDAC patients and mouse models of PDAC, we found that LIF titers positively correlated with intratumoral nerve density. Taken together, our findings suggest LIF as a candidate serum biomarker and diagnostic tool and a possible therapeutic target for limiting the impact of PANR in PDAC pathophysiology and metastatic progression.Significance: This study suggests a target to limit neural remodeling in pancreatic cancer, which contributes to poorer quality of life and heightened metastatic progression in patients. Cancer Res; 78(4); 909-21. ©2017 AACR.
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Carcinoma Ductal Pancreático/metabolismo , Factor Inhibidor de Leucemia/metabolismo , Neuronas/metabolismo , Neoplasias Pancreáticas/metabolismo , Animales , Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Femenino , Xenoinjertos , Humanos , Factor Inhibidor de Leucemia/genética , Masculino , Ratones , Neuronas/patología , Páncreas/inervación , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Fosforilación , Células RAW 264.7 , Transducción de SeñalRESUMEN
Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We obtained 29 pancreatic ductal adenocarcinoma (PDAC) xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively). Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered specific alterations in DNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk. The analysis of these pathways indicates therapeutic opportunities for targeting both compartments and their interactions. In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers. These findings uncover the complex and diverse interplay between PDAC tumors and the stroma and demonstrate the pivotal role of xenografts for drug discovery and relevance to PDAC.
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Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Carcinoma Ductal Pancreático , Transformación Celular Neoplásica/efectos de los fármacos , Conjuntos de Datos como Asunto , Ezetimiba/farmacología , Ezetimiba/uso terapéutico , Humanos , Masculino , Ratones , Neoplasias Pancreáticas/metabolismo , Esferoides Celulares/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Neoplasias PancreáticasRESUMEN
Tissue architecture contributes to pancreatic ductal adenocarcinoma (PDAC) phenotypes. Cancer cells within PDAC form gland-like structures embedded in a collagen-rich meshwork where nutrients and oxygen are scarce. Altered metabolism is needed for tumour cells to survive in this environment, but the metabolic modifications that allow PDAC cells to endure these conditions are incompletely understood. Here we demonstrate that collagen serves as a proline reservoir for PDAC cells to use as a nutrient source when other fuels are limited. We show PDAC cells are able to take up collagen fragments, which can promote PDAC cell survival under nutrient limited conditions, and that collagen-derived proline contributes to PDAC cell metabolism. Finally, we show that proline oxidase (PRODH1) is required for PDAC cell proliferation in vitro and in vivo. Collectively, our results indicate that PDAC extracellular matrix represents a nutrient reservoir for tumour cells highlighting the metabolic flexibility of this cancer.
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Carcinoma Ductal Pancreático/genética , Colágeno/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Pancreáticas/genética , Prolina Oxidasa/genética , Prolina/metabolismo , Animales , Transporte Biológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Colágeno/química , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Humanos , Masculino , Metaloproteinasa 13 de la Matriz/genética , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Transgénicos , Trasplante de Neoplasias , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Procolágeno-Prolina Dioxigenasa/genética , Procolágeno-Prolina Dioxigenasa/metabolismo , Prolina Oxidasa/metabolismo , Transducción de SeñalRESUMEN
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.
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Ablación por Catéter/efectos adversos , Pulmón/patología , Agujas/efectos adversos , Neumotórax/etiología , Fístula del Sistema Respiratorio/etiología , Animales , Pulmón/diagnóstico por imagen , Neumotórax/diagnóstico por imagen , Neumotórax/patología , Fístula del Sistema Respiratorio/diagnóstico por imagen , Fístula del Sistema Respiratorio/patología , Porcinos , Tomografía Computarizada por Rayos XRESUMEN
c-MYC controls more than 15% of genes responsible for proliferation, differentiation, and cellular metabolism in pancreatic as well as other cancers making this transcription factor a prime target for treating patients. The transcriptome of 55 patient-derived xenografts show that 30% of them share an exacerbated expression profile of MYC transcriptional targets (MYC-high). This cohort is characterized by a high level of Ki67 staining, a lower differentiation state, and a shorter survival time compared to the MYC-low subgroup. To define classifier expression signature, we selected a group of 10 MYC target transcripts which expression is increased in the MYC-high group and six transcripts increased in the MYC-low group. We validated the ability of these markers panel to identify MYC-high patient-derived xenografts from both: discovery and validation cohorts as well as primary cell cultures from the same patients. We then showed that cells from MYC-high patients are more sensitive to JQ1 treatment compared to MYC-low cells, in monolayer, 3D cultured spheroids and in vivo xenografted tumors, due to cell cycle arrest followed by apoptosis. Therefore, these results provide new markers and potentially novel therapeutic modalities for distinct subgroups of pancreatic tumors and may find application to the future management of these patients within the setting of individualized medicine clinics.
Asunto(s)
Antineoplásicos/metabolismo , Azepinas/metabolismo , Perfilación de la Expresión Génica , Xenoinjertos , Neoplasias Pancreáticas/patología , Triazoles/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Medicina de Precisión/métodosRESUMEN
RATIONALE: Solid organ transplant recipients, especially after lung transplantation, are at increased risk for Mycobacterium tuberculosis pulmonary tuberculosis due to lifelong immunosuppression. PATIENT CONCERNS: A 41-year-old woman underwent a second bilateral lung transplantation that was complicated by fatal pulmonary tuberculosis. DIAGNOSES: Histological examination of a lung biopsy performed 6 weeks after retransplantation revealed a caseating granuloma and necrosis. Acid-fast bacilli were identified as rifampicin-susceptible M. tuberculosis by real-time polymerase chain reaction (PCR), confirmed by culture 2 weeks later. INTERVENTIONS: Our investigation led us to highly suspect that the transplanted lungs were the source of M. tuberculosis transmission. LESSONS: In order to optimize diagnosis and treatment for lung recipients with latent or active tuberculosis, regular assessment of lower respiratory samples for M. tuberculosis, particularly during the 12-month period posttransplant should be implemented. Regarding donor-derived transmission, screening donor grafts with latent tuberculosis by M. tuberculosis real-time PCR in lymphoid and adipose tissues is an option that should be considered.
Asunto(s)
Trasplante de Pulmón/efectos adversos , Complicaciones Posoperatorias/microbiología , Tuberculosis Pulmonar/etiología , Adulto , Fibrosis Quística/cirugía , Femenino , HumanosRESUMEN
Vγ9Vδ2 T cells are anti-tumor immune effectors of growing interest in cancer including Pancreatic Ductal Adenocarcinoma (PDAC), an especially aggressive cancer characterized by a hypoxic and nutrient-starved immunosuppressive microenvironment. Since Butyrophilin 3 A (BTN3A) isoforms are critical activating molecules of Vγ9Vδ2 T cells, we set out to study BTN3A expression under both basal and stress conditions in PDAC primary tumors, and in novel patient-derived xenograft and PDAC-derived cell lines. BTN3A2 was shown to be the most abundant isoform in PDAC and was stress-regulated. Vγ9Vδ2 T cells cytolytic functions against PDAC required BTN3A and this activity was strongly enhanced by the agonist anti-BTN3A 20.1 mAb even under conditions of hypoxia. In PDAC primary tumors, we established that BTN3A expression and high plasma levels of soluble BTN3A were strongly associated with a decreased survival. These findings may have important implications in the design of new immunotherapeutic strategies that target BTN3A for treating PDAC.