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In a mouse model of influenza pneumonia, we previously documented that proliferating alveolar type II (AT2) cells are the major stem cells involved in early lung recovery. Profiling of microRNAs revealed significant dysregulation of specific ones, including miR-21 and miR-99a. Moreover, miR-145 is known to exhibit antagonism to miR-21. This follow-up study investigated the roles of microRNAs miR-21, miR-99a, and miR-145 in the murine pulmonary regenerative process and inflammation during influenza pneumonia. Inhibition of miR-21 resulted in severe morbidity, and in significantly decreased proliferating AT2 cells due to impaired transition from innate to adaptive immune responses. Knockdown of miR-99a culminated in moderate morbidity, with a significant increase in proliferating AT2 cells that may be linked to PTEN downregulation. In contrast, miR-145 antagonism did not impact morbidity nor the proliferating AT2 cell population, and was associated with downregulation of TNF-alpha, IL1-beta, YM1, and LY6G. Hence, a complex interplay exists between expression of specific miRNAs, lung regeneration, and inflammation during recovery from influenza pneumonia. Inhibition of miR-21 and miR-99a (but not miR-145) can lead to deleterious cellular and molecular effects on pulmonary repair and inflammatory processes during influenza pneumonia.
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Gripe Humana , MicroARNs , Neumonía , Animales , Humanos , Ratones , Estudios de Seguimiento , Inflamación/metabolismo , Gripe Humana/metabolismo , Pulmón/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Neumonía/genética , RegeneraciónRESUMEN
BACKGROUND: The frontal sinus and its drainage pathway are difficult spaces to navigate surgically. The complexity of the frontal recess anatomy as well as inflammatory factors may influence outcomes of endoscopic frontal sinusotomy. It is not clear which factors are more important in determining post-operative frontal ostium patency. OBJECTIVE: The objective is to investigate whether the distribution of fronto-ethmoidal cells, frontal recess dimensions and sinonasal inflammation predict frontal ostium patency at 1- and 2-years after endoscopic frontal sinusotomy. METHODS: A retrospective review of 94 chronic rhinosinusitis patients (185 sides) who had undergone endoscopic frontal sinusotomies between 2015 and 2019 was conducted. Computed tomography was used to evaluate the type of fronto-ethmoidal cells present and determine the dimensions of the frontal recess. The International Classification of the Radiological Complexity of frontal recess and frontal sinus was used to grade the complexity of frontal recess anatomy. Mucosal inflammation was graded according to a structured histopathology report. Frontal ostium patency at 1- and 2-years post-operatively was recorded. RESULTS: The frontal ostium patency rates were 80.9% and 73.4% at 1- and 2-years respectively. Eosinophilic predominance (adjusted OR 3.5, 95% CI 1.6-8.0, p = 0.003) and mucosal ulceration on histology (adjusted OR 4.5, 95% CI 1.1-17.9, p = 0.033) predicted ostial stenosis at 1 year. Smoking (adjusted OR 7.6, 95% CI 2.4-24.7, p = 0.001), aspirin exacerbated respiratory disease (AERD) (adjusted OR 7.6, 95% CI 1.9-30.1, p = 0.004) and histological findings of severe inflammation (adjusted OR 8.9, 95% CI 1.9-41.2, p = 0.005) were independent predictors of ostial stenosis at 2 years. Frontal cell patterns, frontal recess dimensions and frontal recess complexity did not predict frontal ostium stenosis at both 1- and 2-years post-operatively. CONCLUSION: Post-operative control of sinonasal inflammation is important in maintaining frontal ostium patency, regardless of frontal cell patterns or frontal recess dimensions.
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Seno Frontal , Sinusitis , Humanos , Seno Frontal/diagnóstico por imagen , Seno Frontal/cirugía , Seno Frontal/patología , Constricción Patológica/diagnóstico por imagen , Constricción Patológica/etiología , Constricción Patológica/cirugía , Pueblos del Sudeste Asiático , Sinusitis/diagnóstico por imagen , Sinusitis/cirugía , Sinusitis/patología , Endoscopía/métodos , Inflamación/patología , Enfermedad CrónicaRESUMEN
BACKGROUND: Adding intraperitoneal paclitaxel (IP-PTX) to paclitaxel/5-fluoropyrimidine has shown promising results in patients with gastric cancer peritoneal metastases (GCPM) but has not been studied with standard-of-care platinum/fluoropyrimidine combinations. Our goal to was evaluate IP-PTX with capecitabine/oxaliplatin (XELOX) in GCPM. METHODS: Forty-four patients with GCPM received IP PTX (40 mg/m2, Days 1, 8), oral capecitabine (1000 mg/m2 twice daily, Days 1-14) and intravenous oxaliplatin (100 mg/m2, Day 1) in 21-day cycles. Patients with synchronous GCPM underwent conversion surgery if they had good response after chemotherapy, conversion to negative cytology, no extraperitoneal metastasis, and no peritoneal disease during surgery. The primary endpoint was overall survival and secondary endpoints were progression-free survival and safety. Outcomes from the trial were compared against a matched cohort of 39 GCPM patients who received systemic chemotherapy (SC) comprising platinum/fluoropyrimidine. RESULTS: The median OS for the IP and SC groups was 14.6 and 10.6 months (hazard ratio [HR] 0.44; 95% confidence interval [CI], 0.26-0.74; p = 0.002). The median PFS for the IP and SC group was 9.5 and 4.4 months respectively (HR 0.39; 95% CI 0.25-0.66; p < 0.001). Patients in the SC group were younger (IP vs. SC, 61 vs. 56 years, p = 0.021) and had better performance status (ECOG 0, IP vs. SC, 47.7% vs. 76.9%, p = 0.007) compared with the IP cohort. In IP group, conversion surgery was performed in 36.1% (13/36) of patients, with a median OS of 24.2 (95% CI 13.1-35.3) months and 1-year OS of 84.6%. CONCLUSIONS: IP PTX with XELOX is a promising treatment option for GCPM patients. In patients with good response, conversion surgery was feasible with favourable outcomes.
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Neoplasias Peritoneales , Neoplasias Gástricas , Humanos , Capecitabina , Oxaliplatino/uso terapéutico , Neoplasias Gástricas/patología , Paclitaxel , Neoplasias Peritoneales/secundario , Platino (Metal)/uso terapéutico , Fluorouracilo , Desoxicitidina , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMEN
BACKGROUND: Despite advances in our understanding of the mechanisms of influenza A virus (IAV) infection, the crucial virus-host interactions during the viral replication cycle still remain incomplete. Tetraspanin CD151 is highly expressed in the human respiratory tract, but its pathological role in IAV infection is unknown. OBJECTIVES: We sought to characterize the functional role and mechanisms of action of CD151 in IAV infection of the upper and lower respiratory tracts with H1N1 and H3N2 strains. METHODS: We used CD151-null mice in an in vivo model of IAV infection and clinical donor samples of in vitro-differentiated human nasal epithelial cells cultured at air-liquid interface. RESULTS: As compared with wild-type infected mice, CD151-null infected mice exhibited a significant reduction in virus titer and improvement in survival that is associated with pronounced host antiviral response and inflammasome activation together with accelerated lung repair. Interestingly, we show that CD151 complexes newly synthesized viral proteins with host nuclear export proteins and stabilizes microtubule complexes, which are key processes necessary for the polarized trafficking of viral progeny to the host plasma membrane for assembly. CONCLUSIONS: Our results provide new mechanistic insights into our understanding of IAV infection. We show that CD151 is a critical novel host factor of nuclear export signaling whereby the IAV nuclear export uses it to complement its own nuclear export proteins (a site not targeted by current therapy), making this regulation unique, and holds promise for the development of novel alternative/complementary strategies to reduce IAV severity.
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Núcleo Celular/metabolismo , Interacciones Huésped-Patógeno/fisiología , Gripe Humana/metabolismo , Infecciones por Orthomyxoviridae/metabolismo , Transducción de Señal/fisiología , Tetraspanina 24/metabolismo , Animales , Línea Celular , Núcleo Celular/virología , Células Epiteliales/metabolismo , Humanos , Inmunidad Innata/fisiología , Subtipo H1N1 del Virus de la Influenza A/metabolismo , Subtipo H3N2 del Virus de la Influenza A/metabolismo , Ratones , Ratones Endogámicos C57BL , Tetraspaninas/metabolismo , Proteínas Virales/metabolismo , Replicación Viral/fisiologíaAsunto(s)
Carcinoma Adenoide Quístico/secundario , Neoplasias Pulmonares/secundario , Metástasis Linfática , Neoplasias de la Tiroides/secundario , Neoplasias de la Tráquea/patología , Adulto , Broncoscopía , Carcinoma Adenoide Quístico/diagnóstico , Carcinoma Adenoide Quístico/terapia , Terapia Combinada , Diagnóstico Diferencial , Femenino , Humanos , Tomografía Computarizada por Rayos X , Neoplasias de la Tráquea/diagnóstico por imagen , Neoplasias de la Tráquea/terapiaRESUMEN
BACKGROUND: Tissue regeneration in the lungs is gaining increasing interest as a potential influenza management strategy. In this study, we explored the role of microRNAs, short non-coding RNAs involved in post-transcriptional regulation, during pulmonary regeneration after influenza infection. RESULTS: We profiled miRNA and mRNA expression levels following lung injury and tissue regeneration using a murine influenza pneumonia model. BALB/c mice were infected with a sub-lethal dose of influenza A/PR/8(H1N1) virus, and their lungs were harvested at 7 and 15 days post-infection to evaluate the expression of ~300 miRNAs along with ~36,000 genes using microarrays. A global network was constructed between differentially expressed miRNAs and their potential target genes with particular focus on the pulmonary repair and regeneration processes to elucidate the regulatory role of miRNAs in the lung repair pathways. The miRNA arrays revealed a global down-regulation of miRNAs. TargetScan analyses also revealed specific miRNAs highly involved in targeting relevant gene functions in repair such as miR-290 and miR-505 at 7 dpi; and let-7, miR-21 and miR-30 at 15 dpi. CONCLUSION: The significantly differentially regulated miRNAs are implicated in the activation or suppression of cellular proliferation and stem cell maintenance, which are required during the repair of the damaged lungs. These findings provide opportunities in the development of novel repair strategies in influenza-induced pulmonary injury.
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Pulmón/metabolismo , MicroARNs/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Inmunohistoquímica , Subtipo H1N1 del Virus de la Influenza A/patogenicidad , Ratones , Ratones Endogámicos BALB C , MicroARNs/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Neumonía/patología , Neumonía/virología , Regeneración/genética , TranscriptomaRESUMEN
Capturing the full complexity of the diverse hierarchical interactions in the protein interactome is challenging. Here we report a DNA-barcoding method for the multiplexed mapping of pairwise and higher-order protein interactions and their dynamics within cells. The method leverages antibodies conjugated with barcoded DNA strands that can bidirectionally hybridize and covalently link to linearize closely spaced interactions within individual 3D protein complexes, encoding and decoding the protein constituents and the interactions among them. By mapping protein interactions in cancer cells and normal cells, we found that tumour cells exhibit a larger diversity and abundance of protein complexes with higher-order interactions. In biopsies of human breast-cancer tissue, the method accurately identified the cancer subtype and revealed that higher-order protein interactions are associated with cancer aggressiveness.
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Neoplasias de la Mama , Código de Barras del ADN Taxonómico , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Código de Barras del ADN Taxonómico/métodos , Mapeo de Interacción de Proteínas/métodos , Línea Celular Tumoral , ADN/química , ADN/metabolismo , ADN/genética , FemeninoRESUMEN
This study investigates CD151, a protein linked to cancer progression, in non-small cell lung cancer (NSCLC) patients without epidermal growth factor receptor (EGFR) mutations. These patients often have limited treatment options. The study used retrospective analysis to examine 157 adenocarcinoma biopsy specimens and 199 patient cases from The Cancer Genome Atlas, correlating CD151 expression with patient survival. Cellular studies revealed that CD151 interacts with EGFR, influencing epidermal growth factor (EGF)-induced cell proliferation and the effectiveness of the EGFR inhibitor, erlotinib. A strong association was found between CD151 expression and EGFR mutation status. High CD151 expression in the absence of EGFR mutations is correlated with poorer survival outcomes. Biological assays showed that CD151 colocalizes and associates with EGFR, playing a crucial role in regulating EGF-induced cell proliferation via the AKT and ERK1/2 pathways. Importantly, CD151 expression was found to influence the anti-proliferative effects of the EGFR tyrosine kinase inhibitor, erlotinib. High CD151 expression, in the absence of EGFR mutations, was associated with poorer survival outcomes. It could serve as a potential prognostic marker and influence cellular responses to EGFR-targeted treatments. This study highlights CD151 as a potential novel target for therapeutic intervention in NSCLC, especially in populations lacking EGFR mutations.
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Influenza A virus has caused a number of pandemics in past decades, including the recent H1N1-2009 pandemic. Viperin is an interferon (IFN)-inducible protein of innate immunity, and acts as a broad-spectrum antiviral protein. We explored the antiviral activities and mechanisms of viperin during influenza virus (IFV) infection in vitro and in vivo. Wild-type (WT) HeLa and viperin-expressing HeLa cells were infected with influenza A/WSN/33/H1N1 (WSN33) virus, and subjected to virological, light and electron microscopic analyses. Viperin expression reduced virus replication and titres, and restricted viral budding. Young and old viperin-knockout (KO) mice and WT control animals were challenged with influenza WSN33 at lethal doses of 10(3) and 10(4) p.f.u. via the intratracheal route. Lungs were subjected to histopathological, virological and molecular studies. Upon lethal IFV challenge, both WT and KO mice revealed similar trends of infection and recovery with similar mortality rates. Viral quantification assay and histopathological evaluation of lungs from different time points showed no significant difference in viral loads and lung damage scores between the two groups of mice. Although the in vitro studies demonstrated the ability of viperin to restrict influenza H1N1 virus replication, the viperin-deficient mouse model indicated that absence of viperin enhanced neither the viral load nor pulmonary damage in the lungs of infected mice. This may be due to the compensation of IFN-stimulated genes in the lungs and/or the influenza non-structural protein 1-mediated IFN antagonism dampening the IFN response, thereby rendering the loss of viperin insignificant. Nevertheless, further investigations that exploit the antiviral mechanisms of viperin as prophylaxis are still warranted.
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Antivirales/metabolismo , Subtipo H1N1 del Virus de la Influenza A/fisiología , Gripe Humana/metabolismo , Proteínas/metabolismo , Animales , Línea Celular , Femenino , Humanos , Subtipo H1N1 del Virus de la Influenza A/genética , Gripe Humana/genética , Gripe Humana/virología , Pulmón/metabolismo , Pulmón/virología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH , Proteínas/genética , Carga Viral , Replicación ViralRESUMEN
Invasive aspergillosis (IA) is a major opportunistic fungal infection in patients with haematological malignancies. Morbidity and mortality rates are high despite anti-fungal treatment, as the compromised status of immune system prevents the host from responding optimally to conventional therapy. This raises the consideration for immunotherapy as an adjunctive treatment. In this study, we evaluated the utility of expanded human NK cells as treatment against Aspergillus fumigatus infection in vitro and in vivo. The NK cells were expanded and activated by K562 cells genetically modified to express 4-1BB ligand and membrane-bound interleukin-15 (K562-41BBL-mbIL-15) as feeders. The efficacy of these cells was investigated in A. fumigatus killing assays in vitro and as adoptive cellular therapy in vivo. The expanded NK cells possessed potent killing activity at low effector-to-target ratio of 2:1. Fungicidal activity was morphotypal-dependent and most efficacious against A. fumigatus conidia. Fungicidal activity was mediated by dectin-1 receptors on the expanded NK cells leading to augmented release of perforin, resulting in enhanced direct cytolysis. In an immunocompromised mice pulmonary aspergillosis model, we showed that NK cell treatment significantly reduced fungal burden, hence demonstrating the translational potential of expanded NK cells as adjunctive therapy against IA in immunocompromised patients.
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During influenza pneumonia, the alveolar epithelial cells of the lungs are targeted by the influenza virus. The distal airway stem cells (DASCs) and proliferating alveolar type II (AT2) cells are reported to be putative lung repair cells. However, their relative spatial and temporal distribution is still unknown during influenza-induced acute lung injury. Here, we investigated the distribution of these cells, and concurrently performed global proteomic analysis of the infected lungs to elucidate and link the cellular and molecular events during influenza pneumonia recovery. BALB/c mice were infected with a sub-lethal dose of influenza H1N1 virus. From 5 to 25 days post-infection (dpi), mouse lungs were subjected to histopathologic and immunofluorescence analysis to probe for global distribution of lung repair cells (using P63 and KRT5 markers for DASCs; SPC and PCNA markers for AT2 cells). At 7 and 15 dpi, infected mouse lungs were also subjected to protein mass spectrometry for relative protein quantification. DASCs appeared only in the damaged area of the lung from 7 dpi onwards, reaching a peak at 21 dpi, and persisted until 25 dpi. However, no differentiation of DASCs to AT2 cells was observed by 25 dpi. In contrast, AT2 cells began proliferating from 7 dpi to replenish their population, especially within the boundary area between damaged and undamaged areas of the infected lungs. Mass spectrometry and gene ontology analysis revealed prominent innate immune responses at 7 dpi, which shifted towards adaptive immune responses by 15 dpi. Hence, proliferating AT2 cells but not DASCs contribute to AT2 cell regeneration following transition from innate to adaptive immune responses during the early phase of recovery from influenza pneumonia up to 25 dpi.
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Inmunidad Adaptativa , Células Epiteliales Alveolares/citología , Inmunidad Innata , Pulmón/fisiología , Infecciones por Orthomyxoviridae/metabolismo , Neumonía Viral/metabolismo , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/virología , Animales , Proliferación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Subtipo H1N1 del Virus de la Influenza A , Queratina-15/metabolismo , Pulmón/metabolismo , Pulmón/virología , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/virología , Neumonía Viral/virología , Proteómica , Regeneración , Factores de Tiempo , Transactivadores/metabolismoRESUMEN
We describe a case of papillary thyroid carcinoma with fibromatosis/fasciitis-like stroma (PTC-FLS) that contained the rare BRAF c.1799_1801delTGA (p.V600_K601delinsE) mutation, which has not previously been reported in this tumour, as well as the CTNNB1 c.133T>C (p.S45P) mutation. We also report the novel observation that spindle cells of the mesenchymal component exhibit diffuse nuclear but not cytoplasmic expression of SOX11, whereas the malignant epithelial cells did not. This suggests that immunoreactivity for SOX11 can be an alternative diagnostic tool for evaluating cases of PTC-FLS where the nuclear expression of ß-catenin is ambiguous.
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Factores de Transcripción SOXC/biosíntesis , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/patología , Humanos , Masculino , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/metabolismo , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , beta Catenina/genéticaRESUMEN
Massively parallel DNA sequencing is established, yet high-throughput protein profiling remains challenging. Here, we report a barcoding approach that leverages the combinatorial sequence content and the configurational programmability of DNA nanostructures for high-throughput multiplexed profiling of the subcellular expression and distribution of proteins in whole cells. The barcodes are formed by in situ hybridization of tetrahedral DNA nanostructures and short DNA sequences conjugated with protein-targeting antibodies, and by nanostructure-assisted ligation (either enzymatic or chemical) of the nanostructures and exogenous DNA sequences bound to nanoparticles of different sizes (which cause these localization sequences to differentially distribute across subcellular compartments). Compared with linear DNA barcoding, the nanostructured barcodes enhance the signal by more than 100-fold. By implementing the barcoding approach on a microfluidic device for the analysis of rare patient samples, we show that molecular subtypes of breast cancer can be accurately classified and that subcellular spatial markers of disease aggressiveness can be identified.
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Código de Barras del ADN Taxonómico/métodos , ADN/química , ADN/clasificación , Perfilación de la Expresión Génica/métodos , Nanoestructuras , Anticuerpos/inmunología , Anticuerpos/metabolismo , Secuencia de Bases , Línea Celular Tumoral , Código de Barras del ADN Taxonómico/instrumentación , Humanos , Cinética , Dispositivos Laboratorio en un Chip , Proteínas , Coloración y EtiquetadoRESUMEN
Secondary bacterial lung infection by Streptococcus pneumoniae (S. pneumoniae) poses a serious health concern, especially in developing countries. We posit that the emergence of multiantibiotic-resistant strains will jeopardize current treatments in these regions. Deaths arising from secondary infections are more often associated with acute lung injury, a common consequence of hypercytokinemia, than with the infection per se Given that secondary bacterial pneumonia often has a poor prognosis, newer approaches to improve treatment outcomes are urgently needed to reduce the high levels of morbidity and mortality. Using a sequential dual-infection mouse model of secondary bacterial lung infection, we show that host-directed therapy via immunoneutralization of the angiopoietin-like 4 c-isoform (cANGPTL4) reduced pulmonary edema and damage in infected mice. RNA sequencing analysis revealed that anti-cANGPTL4 treatment improved immune and coagulation functions and reduced internal bleeding and edema. Importantly, anti-cANGPTL4 antibody, when used concurrently with either conventional antibiotics or antipneumolysin antibody, prolonged the median survival of mice compared to monotherapy. Anti-cANGPTL4 treatment enhanced immune cell phagocytosis of bacteria while restricting excessive inflammation. This modification of immune responses improved the disease outcomes of secondary pneumococcal pneumonia. Taken together, our study emphasizes that host-directed therapeutic strategies are viable adjuncts to standard antimicrobial treatments.IMPORTANCE Despite extensive global efforts, secondary bacterial pneumonia still represents a major cause of death in developing countries and is an important cause of long-term functional disability arising from lung tissue damage. Newer approaches to improving treatment outcomes are needed to reduce the significant morbidity and mortality caused by infectious diseases. Our study, using an experimental mouse model of secondary S. pneumoniae infection, shows that a multimodal treatment that concurrently targets host and pathogen factors improved lung tissue integrity and extended the median survival time of infected mice. The immunoneutralization of host protein cANGPTL4 reduced the severity of pulmonary edema and damage. We show that host-directed therapeutic strategies as well as neutralizing antibodies against pathogen virulence factors are viable adjuncts to standard antimicrobial treatments such as antibiotics. In view of their different modes of action compared to antibiotics, concurrent immunotherapies using antibodies are potentially efficacious against secondary pneumococcal pneumonia caused by antibiotic-resistant pathogens.
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Proteína 4 Similar a la Angiopoyetina/antagonistas & inhibidores , Anticuerpos/uso terapéutico , Coinfección/terapia , Neumonía Neumocócica/inmunología , Neumonía Neumocócica/terapia , Edema Pulmonar/terapia , Proteína 4 Similar a la Angiopoyetina/inmunología , Animales , Antibacterianos/uso terapéutico , Coinfección/inmunología , Coinfección/microbiología , Modelos Animales de Enfermedad , Femenino , Inflamación , Pulmón/microbiología , Ratones , Ratones Endogámicos BALB C , Neumonía Neumocócica/tratamiento farmacológico , Edema Pulmonar/inmunología , Streptococcus pneumoniae/inmunologíaRESUMEN
Cryptococcal pleural infection is rare with about 50 cases reported. It tends to occur in immunocompromised individuals. We describe a 38-year-old male who presented with a lymphocytic exudative right pleural effusion and a raised pleural fluid adenosine deaminase (ADA) level. He was initially treated for pleural tuberculosis, but presented again with worsening pleural effusion 6 weeks later. A thoracoscopic pleural biopsy revealed chronic nodular granulomatous pleuritis with cryptococcal organisms present. The repeat pleural fluid culture was positive for Cryptococcus neoformans. He was started on intravenous amphotericin B and oral flucytosine for 1 week, and then continued on oral fluconazole. He was subsequently diagnosed to have acute myeloid leukaemia. His peripheral blood film showed presence of blast cells (33%), with flow cytometry showing increased myeloblast population. Lymphocytic exudative pleural effusions with raised ADA levels in an immunocompromised patient can be due to opportunistic fungal infections.
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A 67-year-old retired air force officer presented with a 6-month history of nonproductive cough, progressive exertional dyspnea, and weight loss. He was unable to walk beyond 100 m compared with his baseline of unlimited walking distance. He denied fever, hemoptysis, myalgia, or chest pain. He had a 30-year history of chronic plaque psoriasis with arthritis, which was managed by his dermatologist with emollients and vitamin D analogues. Joint involvement had previously been controlled with methotrexate, which was discontinued 15 years ago after resolution of his symptoms. He developed a polyarthritis flare a year ago, and adalimumab was initiated with good response.
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Adalimumab/efectos adversos , Artritis Psoriásica/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales , Pulmón , Adalimumab/administración & dosificación , Anciano , Antiinflamatorios/administración & dosificación , Antiinflamatorios/efectos adversos , Artritis Psoriásica/diagnóstico , Artritis Psoriásica/fisiopatología , Diagnóstico Diferencial , Disnea/diagnóstico , Disnea/etiología , Humanos , Biopsia Guiada por Imagen/métodos , Pulmón/diagnóstico por imagen , Pulmón/patología , Enfermedades Pulmonares Intersticiales/inducido químicamente , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/fisiopatología , Masculino , Manejo de Atención al Paciente/métodos , Radiografía Torácica/métodos , Toracoscopía/métodos , Tomografía Computarizada por Rayos X/métodos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
Programmed death ligand-1 (PD-L1) expression as determined by immunohistochemistry (IHC) is potentially predictive of clinical outcome. The aim of this study was to assess the concordance of reported PD-L1 IHC assays and investigate factors influencing variability. Consecutive sections from 20 non-small cell lung cancers (NSCLCs) comprising resection, core biopsy, cytology and pleural fluid samples underwent IHC with 5 different antibody/autostainer combinations: 22C3/Link48, 28-8/BOND-MAX, E1L3N/BOND-MAX, SP142/BenchMark and SP263/BenchMark. PD-L1 RNA levels were assessed using RNAscope. The frequency of positive cases using scoring thresholds from clinical trials was 72%, 33%, 61%, 56%, and 33% for the 5 IHC protocols respectively, and 33% for RNAscope. Pairwise agreement on the classification of cases as positive or negative for PD-L1 expression ranged from 61%-94%. On a continuous scale, the lowest correlation was between 28-8/BOND-MAX and SP142/BenchMark (R2=0.25) and highest was between 22C3/Link48 and E1L3N/BOND-MAX (R2=0.71). When cases were ordered according to tumor cell (TC)%, a similar ranking of cases across IHC protocols could be observed, albeit with different quanta and limits of detection. Single-slide OPAL 7-color fluorescence IHC analysis revealed a high degree of co-localization of staining from the 5 PD-L1 antibodies. Using SP142 antibody in a BOND-MAX protocol led to increased TC% quanta, while retaining a similar ranking of samples according to TC%. The results of this study highlight tumor PD-L1 status can vary significantly according to IHC protocol. Protocol-dependent staining intensities and nominated thresholds for positivity contribute to this variability, while the antibody used appears to be less of a factor.