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Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or without immunotherapy. In patients with disease confined to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum-etoposide chemotherapy. Patients with metastatic (extensive-stage) disease are treated with a combination of platinum-etoposide chemotherapy plus immunotherapy with an anti-programmed death-ligand 1 monoclonal antibody. Although SCLC is initially very responsive to platinum-based chemotherapy, these responses are transient because of the development of drug resistance. In recent years, the authors have witnessed an accelerating pace of biologic insights into the disease, leading to the redefinition of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current knowledge of SCLC biology and clinical management may lead to unprecedented advances in SCLC patient care. Here, the authors present an overview of multimodal clinical approaches in SCLC, with a special focus on illuminating how recent advancements in SCLC research could accelerate clinical development.
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Produtos Biológicos , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/terapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Etoposídeo/uso terapêutico , Terapia Combinada , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Produtos Biológicos/uso terapêuticoRESUMO
Rationale: Passenger lymphocyte syndrome (PLS) may complicate minor ABO mismatched lung transplantation (LuTX) via donor-derived red cell antibody-induced hemolysis.Objectives: To ascertain the incidence and specificity of PLS-relevant antibodies among the study population as well as the dynamics of hemolysis parameters and the transfusion requirement of patients with or without PLS.Methods: In this cohort study, 1,011 patients who received LuTX between January 2010 and June 2019 were studied retrospectively. Prospectively, 87 LuTX (July 2019 to June 2021) were analyzed. Postoperative ABO antibody and hemolytic marker determinations, transfusion requirement, and duration of postoperative hospital care were analyzed. Retrospectively, blood group A recipients of O grafts with PLS were compared with those without.Measurements and Main Results: PLS affected 18.18% (retrospective) and 30.77% (prospective) of A recipients receiving O grafts, 5.13% of B recipients of O grafts, and 20% of AB patients receiving O transplants. Anti-A and anti-A1 were the predominant PLS-inducing antibodies, followed by anti-B and anti-A,B. Significantly lower hemoglobin values (median, 7.4 vs. 8.3 g/dl; P = 0.0063) and an approximately twice as high percentage of patients requiring blood transfusions were seen in PLS. No significant differences in other laboratory markers, duration of hospital stay, or other complications after LuTX were registered.Conclusions: Minor ABO incompatible LuTX recipients are at considerable risk of developing clinically significant PLS. Post-transplant monitoring combining red cell serology and hemolysis marker determination appears advisable so as not to overlook hemolytic episodes that necessitate antigen-negative transfusion therapy.
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Hemólise , Transplante de Pulmão , Humanos , Incompatibilidade de Grupos Sanguíneos/complicações , Estudos Retrospectivos , Estudos de Coortes , Estudos Prospectivos , Linfócitos , Transplante de Pulmão/efeitos adversosRESUMO
Pulmonary fibrosis can be a fatal disease characterized by progressive lung scarring. It is still poorly understood how the pulmonary endothelium is involved in the disease pathogenesis. Differences of the pulmonary vasculature between patients and donors were analysed using transmission electron microscopy, immunohistochemistry and single-cell-RNA-sequencing. Vascular barrier resistance, endothelial-immune cell adhesion, and sensitivity to an inflammatory milieu were studied in-vitro. Integrity and activation markers were measured by ELISA in human plasma. Transmission electron microscopy demonstrated abnormally swollen endothelial cells in fibrotic lungs as compared to donors. A more intense CD31 and vWF and patchy VE-Cadherin staining in fibrotic lungs supported the presence of a dysregulated endothelium. Integrity markers CD31, VE-Cadherin, Thrombomodulin and VEGFR-2 and activation marker von-Willebrand-Factor gene expression was increased in different endothelial subpopulations (e.g. arterial, venous, gCap, aCap) in pulmonary fibrosis. This was associated with a heightened sensitivity of fibrotic endothelial cells to TNF-α or IFN-γ and elevated immune cell adhesion. The barrier strength was overall reduced in endothelial cells from fibrotic lungs. vWF and IL-8 were increased in the plasma of patients, while VE-Cadherin, Thrombomodulin and VEGFR-2 were decreased. VE-Cadherin staining was also patchy in biopsy tissue and was decreased in plasma samples of PF patients six months after the initial diagnosis. Our data demonstrate highly abnormal endothelial cells in PF. The vascular compartment is characterized by hyper-activation and increased immune cell adhesion, as well as dysfunctional endothelial barrier function. Re-establishing endothelial cell homeostasis and function might represent a new therapeutic option for fibrotic lung diseases.
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Changes in the extracellular matrix of pulmonary arteries (PAs) are a key aspect of vascular remodeling in pulmonary hypertension (PH). Yet, our understanding of the alterations affecting the proteoglycan (PG) family remains limited. We sought to investigate the expression and spatial distribution of major vascular PGs in PAs from healthy individuals and various PH groups (chronic obstructive pulmonary disease: PH-COPD, pulmonary fibrosis: PH-PF, idiopathic: IPAH). PG regulation, deposition, and synthesis were notably heightened in IPAH, followed by PH-PF, with minor alterations in PH-COPD. Single-cell analysis unveiled cell-type and disease-specific PG regulation. Agrin expression, a basement membrane PG, was increased in IPAH, with PA endothelial cells (PAECs) identified as a major source. PA smooth muscle cells (PASMCs) mainly produced large-PGs, aggrecan and versican, and small-leucine-like proteoglycan (SLRP) biglycan, whereas the major PGs produced by adventitial fibroblasts were SLRP decorin and lumican. In IPAH and PF-PH, the neointima-forming PASMC population increased the expression of all investigated large-PGs and SLRPs, except fibroblast-predominant decorin (DCN). Expression of lumican, versican, and biglycan also positively correlated with collagen 1α1/1α2 expression in PASMCs in patients with IPAH and PH-PF. We demonstrated that transforming growth factor-beta (TGF-ß) regulates versican and biglycan expression, indicating their contribution to vessel fibrosis in IPAH and PF-PH. We furthermore show that certain circulating PG levels display a disease-dependent pattern, with increased decorin and lumican across all patient groups, while versican was elevated in PH-COPD and IPAH and biglycan reduced in IPAH. These findings suggest unique compartment-specific PG regulation in different forms of PH, indicating distinct pathological processes.NEW & NOTEWORTHY Idiopathic pulmonary arterial hypertension (IPAH) pulmonary arteries (PAs) displayed the greatest proteoglycan (PG) changes, with PH associated with pulmonary fibrosis (PH-PF) and PH associated with chronic obstructive pulmonary disease (PH-COPD) following. Agrin, an endothelial cell-specific PG, was solely upregulated in IPAH. Among all cells, neo-intima-forming smooth muscle cells (SMCs) displayed the most significant PG increase. Increased levels of circulating decorin, lumican, and versican, mainly derived from SMCs, and adventitial fibroblasts, may serve as systemic indicators of pulmonary remodeling, reflecting perivascular fibrosis and neointima formation.
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Hipertensão Pulmonar , Miócitos de Músculo Liso , Proteoglicanas , Artéria Pulmonar , Humanos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Proteoglicanas/metabolismo , Masculino , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Feminino , Pessoa de Meia-Idade , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Remodelação Vascular , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Idoso , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Biglicano/metabolismo , Decorina/metabolismo , Adulto , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Lumicana/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/patologiaRESUMO
Donor and recipient human cytomegalovirus (HCMV) seropositive (D+R+) lung transplant recipients (LTRs) often harbor multiple strains of HCMV, likely due to transmitted donor (D) strains and reactivated recipient (R) strains. To date, the extent and timely occurrence of each likely source in shaping the post-transplantation (post-Tx) strain population is unknown. Here, we deciphered the D and R origin of the post-Tx HCMV strain composition in blood, bronchoalveolar lavage (BAL), and CD45+ BAL cell subsets. We investigated either D and/or R formalin-fixed paraffin-embedded blocks or fresh D lung tissue from four D+R+ LTRs obtained before transplantation. HCMV strains were characterized by short amplicon deep sequencing. In two LTRs, we show that the transplanted lung is reseeded by R strains within the first 6 months after transplantation, likely by infiltrating CD14+ CD163+/- alveolar macrophages. In three LTRs, we demonstrate both rapid D-strain dissemination and persistence in the transplanted lung for >1 year post-Tx. Broad inter-host diversity contrasts with intra-host genotype sequence stability upon transmission, during follow-up and across compartments. In D+R+ LTRs, HCMV strains of both, D and R origin can emerge first and dominate long-term in subsequent episodes of infection, indicating replication of both sources despite pre-existing immunity.
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Infecções por Citomegalovirus , Citomegalovirus , Transplante de Pulmão , Doadores de Tecidos , Transplantados , Humanos , Transplante de Pulmão/efeitos adversos , Citomegalovirus/genética , Citomegalovirus/classificação , Infecções por Citomegalovirus/virologia , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Genótipo , Pulmão/virologia , Líquido da Lavagem Broncoalveolar/virologiaRESUMO
BACKGROUND: In older patients, a limited physical reserve is considered a contraindication for lung transplantation (LTx). Herein, we aimed to establish a computed tomography (CT)-based quantification of physical reserve in older patients scheduled for transplantation. METHODS: This retrospective study included patients older than 60 years who received LTx. Semiautomatic measurements of the mediastinal fat area and the dorsal muscle group area in pretransplantation CT scans were performed, and normalized data were correlated with clinical parameters. RESULTS: Patients (n = 108) were assigned into three groups (Musclehighfatlow [n = 25], Musclelowfathigh [n = 24], and other combinations [n = 59]). The Musclelowfathigh group had a significantly increased risk of wound infections (p = 0.002) and tracheostomy (p = 0.001) compared with Musclehighfatlow patients. The median length of intensive care unit stay (25 vs. 3.5 days; p = 0.002) and the median length of hospital stay (44 vs. 22.5 days; p = 0.013) post-LTx were significantly prolonged in the Musclelowfathigh group. Significantly more patients in this group had a prolonged ventilation time (11 vs. 0; p < 0.001). CONCLUSION: Body composition parameters determined in pretransplant chest CT scans in older LTx candidates might aid in identifying high-risk patients with a worse perioperative outcome after LTx.
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BACKGROUND: By being highly involved in the tumor evolution and disease progression of small cell lung cancer (SCLC), Myc family members (C-Myc, L-Myc, and N-Myc) might represent promising targetable molecules. Our aim was to investigate the expression pattern and prognostic relevance of these oncogenic proteins in an international cohort of surgically resected SCLC tumors. METHODS: Clinicopathological data and surgically resected tissue specimens from 104 SCLC patients were collected from two collaborating European institutes. Tissue sections were stained by immunohistochemistry (IHC) for all three Myc family members and the recently introduced SCLC molecular subtype-markers (ASCL1, NEUROD1, POU2F3, and YAP1). RESULTS: IHC analysis showed C-Myc, L-Myc, and N-Myc positivity in 48%, 63%, and 9% of the specimens, respectively. N-Myc positivity significantly correlated with the POU2F3-defined molecular subtype (r = 0.6913, p = 0.0056). SCLC patients with C-Myc positive tumors exhibited significantly worse overall survival (OS) (20 vs. 44 months compared to those with C-Myc negative tumors, p = 0.0176). Ultimately, in a multivariate risk model adjusted for clinicopathological and treatment confounders, positive C-Myc expression was confirmed as an independent prognosticator of impaired OS (HR 1.811, CI 95% 1.054-3.113, p = 0.032). CONCLUSIONS: Our study provides insights into the clinical aspects of Myc family members in surgically resected SCLC tumors. Notably, besides showing that positivity of Myc family members varies across the patients, we also reveal that C-Myc protein expression independently correlates with worse survival outcomes. Further studies are warranted to investigate the role of Myc family members as potential prognostic and predictive markers in this hard-to-treat disease.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/cirurgia , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas c-myc/metabolismo , Prognóstico , Progressão da DoençaRESUMO
BACKGROUND: Mast cells (MC) and basophils are effector cells of allergic reactions and display a number of activation-linked cell surface antigens. Of these antigens, however, only a few are functionally relevant and specifically expressed in these cells. OBJECTIVE: We sought to identify MC- and basophil-specific surface molecules and to study their cellular distribution and regulation during cytokine-induced and IgE-dependent activation. METHODS: Multicolor flow cytometry was performed to recognize surface antigens and to determine changes in antigen expression upon activation. RESULTS: We identified Siglec-6 (CD327) as a differentially regulated surface antigen on human MC and basophils. In the bone marrow, Siglec-6 was expressed abundantly on MC in patients with mastocytosis and in reactive states, but it was not detected on other myeloid cells, with the exception of basophils and monocytes. In healthy individuals, allergic patients, and patients with chronic myeloid leukemia (CML), Siglec-6 was identified on CD203c+ blood basophils, a subset of CD19+ B lymphocytes, and few CD14+ monocytes, but not on other blood leukocytes. CML basophils expressed higher levels of Siglec-6 than normal basophils. IL-3 promoted Siglec-6 expression on normal and CML basophils, and stem cell factor increased the expression of Siglec-6 on tissue MC. Unexpectedly, IgE-dependent activation resulted in downregulation of Siglec-6 in IL-3-primed basophils, whereas in MC, IgE-dependent activation augmented stem cell factor-induced upregulation of Siglec-6. CONCLUSIONS: Siglec-6 is a dynamically regulated marker of MC and basophils. Activated MC and basophils exhibit unique Siglec-6 responses, including cytokine-dependent upregulation and unique, cell-specific, responses to IgE-receptor cross-linking.
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Basófilos , Mastócitos , Humanos , Antígenos CD , Doença Crônica , Imunoglobulina E , Interleucina-3/metabolismo , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico , Fator de Células-Tronco/metabolismoRESUMO
Deposition of basement membrane components, such as collagen IVα5, is associated with altered endothelial cell function in pulmonary hypertension. Collagen IVα5 harbors a functionally active fragment within its C-terminal noncollageneous (NC1) domain, called pentastatin, whose role in pulmonary endothelial cell behavior remains unknown. Here, we demonstrate that pentastatin serves as a mediator of pulmonary endothelial cell dysfunction, contributing to pulmonary hypertension. In vitro, treatment with pentastatin induced transcription of immediate early genes and proinflammatory cytokines and led to a functional loss of endothelial barrier integrity in pulmonary arterial endothelial cells. Mechanistically, pentastatin leads to ß1-integrin subunit clustering and Rho/ROCK activation. Blockage of the ß1-integrin subunit or the Rho/ROCK pathway partially attenuated the pentastatin-induced endothelial barrier disruption. Although pentastatin reduced the viability of endothelial cells, smooth muscle cell proliferation was induced. These effects on the pulmonary vascular cells were recapitulated ex vivo in the isolated-perfused lung model, where treatment with pentastatin-induced swelling of the endothelium accompanied by occasional endothelial cell apoptosis. This was reflected by increased vascular permeability and elevated pulmonary arterial pressure induced by pentastatin. This study identifies pentastatin as a mediator of endothelial cell dysfunction, which thus might contribute to the pathogenesis of pulmonary vascular disorders such as pulmonary hypertension.NEW & NOTEWORTHY This study is the first to show that pentastatin, the matrikine of the basement membrane (BM) collagen IVα5 polypeptide, triggers rapid pulmonary arterial endothelial cell barrier disruption, activation, and apoptosis in vitro and ex vivo. Mechanistically, pentastatin partially acts through binding to the ß1-integrin subunit and the Rho/ROCK pathway. These findings are the first to link pentastatin to pulmonary endothelial dysfunction and, thus, suggest a major role for BM-matrikines in pulmonary vascular diseases such as pulmonary hypertension.
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Hipertensão Pulmonar , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Células Endoteliais/metabolismo , Pulmão/metabolismo , Endotélio/metabolismo , Artéria Pulmonar/metabolismo , Colágeno/metabolismo , Integrinas/metabolismoRESUMO
BACKGROUND: No targeted drugs are currently available against small cell lung cancer (SCLC). BCL-2 family members are involved in apoptosis regulation and represent therapeutic targets in many malignancies. METHODS: Expression of BCL-2 family members in 27 SCLC cell lines representing all known four SCLC molecular subtypes was assessed by qPCR, Western blot and mass spectrometry-based proteomics. BCL-2 and MCL-1 inhibition (venetoclax and S63845, respectively) was assessed by MTT assay and flow cytometry and in mice bearing human SCLC tumours. Drug interactions were calculated using the Combenefit software. Ectopic BAX overexpression was achieved by expression plasmids. RESULTS: The highest BCL-2 expression levels were detected in ASCL1- and POU2F3-driven SCLC cells. Although sensitivity to venetoclax was reflected by BCL-2 levels, not all cell lines responded consistently despite their high BCL-2 expression. MCL-1 overexpression and low BAX levels were both characteristic for venetoclax resistance in SCLC, whereas the expression of other BCL-2 family members did not affect therapeutic efficacy. Combination of venetoclax and S63845 resulted in significant, synergistic in vitro and in vivo anti-tumour activity and apoptosis induction in double-resistant cells; however, this was seen only in a subset with detectable BAX. In non-responding cells, ectopic BAX overexpression sensitised to venetoclax and S63845 and, furthermore, induced synergistic drug interaction. CONCLUSIONS: The current study reveals the subtype specificity of BCL-2 expression and sheds light on the mechanism of venetoclax resistance in SCLC. Additionally, we provide preclinical evidence that combined BCL-2 and MCL-1 targeting is an effective approach to overcome venetoclax resistance in high BCL-2-expressing SCLCs with intact BAX.
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Antineoplásicos , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteínas Proto-Oncogênicas c-bcl-2 , Carcinoma de Pequenas Células do Pulmão , Animais , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/efeitos dos fármacos , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genéticaRESUMO
BACKGROUND: SCLC is an aggressive malignancy where immunotherapies show limited efficacy. We aimed to characterize the SCLC microenvironment according to the expression patterns of SCLC subtype markers and novel immune checkpoints to identify therapeutic vulnerabilities. METHODS: We included SCLC tissue samples from 219 surgically resected, limited-stage patients in this cross-sectional study. We performed immunohistochemistry for STING and MHCII, as well as for the novel subtype markers (ASCL1, NEUROD1, POU2F3, YAP1). Moreover, we assessed CD45 + , CD8 + and CD68 + immune cell infiltration. RESULTS: 36% of SCLC tumors showed significant stromal or intraepithelial CD45 + immune cell infiltration. These patients exhibited significantly increased overall survival (OS) (vs. patients with immune-deserted tumors). High CD8 expression was associated with increased median OS. We found STING expression on cancer-associated fibroblasts in the stroma and on T-cells and macrophages in both tumorous and stromal compartments. STING expression positively correlated with immune cell infiltration. Increased STING-positivity in tumor nests was an independent favorable prognosticator for OS. ASCL1 was the most frequently expressed subtype-specific protein. Concomitant expression of three or four subtype-defining markers was seen in 13.8% of the included samples, whereas 24.1% of the cases were classified as quadruple negative tumors. YAP1 expression was associated with increased immune infiltrates. Tumor cell MHCII expression positively correlated with immune cell infiltration and with STING- and YAP1 expressions. CONCLUSIONS: STING and MHCII are expressed in SCLC. The majority of immune-infiltrated SCLCs exhibit increased STING expression. Immune infiltration and STING expression are prognostic in limited-stage SCLC, making STING a potential therapeutic target.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Estudos Transversais , Prognóstico , Imuno-Histoquímica , Microambiente TumoralRESUMO
AIMS: Pleural mesothelioma (PM) is a highly aggressive thoracic tumour with poor prognosis. Although reduced tissue drug accumulation is one of the key features of platinum (Pt) resistance, little is known about Pt distribution in human PM. METHODS: We assessed Pt levels of blood samples and surgically resected specimens from 25 PM patients who had received neoadjuvant Pt-based chemotherapy (CHT). Pt levels and tissue distributions were measured by laser ablation-inductively coupled plasma-mass spectrometry and correlated with clinicopathological features. RESULTS: In surgically resected PM specimens, mean Pt levels of nontumourous (fibrotic) areas were significantly higher (vs tumourous regions, P = 0.0031). No major heterogeneity of Pt distribution was seen within the tumourous areas. Pt levels correlated neither with the microvessel area nor with apoptosis rate in the tumourous or nontumourous regions. A significant positive correlation was found between serum and both full tissue section and tumourous area mean Pt levels (r = 0.532, P = 0.006, 95% confidence interval [95% CI] 0.161-0.771 and r = 0.415, P = 0.039, 95% CI 0.011-0.702, respectively). Furthermore, a significant negative correlation was detected between serum Pt concentrations and elapsed time from the last cycle of CHT (r = -0.474, P = 0.017, 95% CI -0.738--0.084). Serum Pt levels correlated negatively with overall survival (OS) (P = 0.029). CONCLUSIONS: There are major differences in drug distribution between tumourous and nontumourous areas of PM specimens. Serum Pt levels significantly correlate with full section and tumourous area average Pt levels, elapsed time from the last CHT cycle, and OS. Further studies investigating clinicopathological factors that modulate tissue Pt concentration and distribution are warranted.
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Terapia a Laser , Mesotelioma , Humanos , Mesotelioma/cirurgia , Mesotelioma/tratamento farmacológico , Platina/uso terapêutico , Platina/análise , Espectrometria de Massas/métodosRESUMO
The tissue distribution and prognostic relevance of subtype-specific proteins (ASCL1, NEUROD1, POU2F3, YAP1) present an evolving area of research in small-cell lung cancer (SCLC). The expression of subtype-specific transcription factors and P53 and RB1 proteins were measured by immunohistochemistry (IHC) in 386 surgically resected SCLC samples. Correlations between subtype-specific proteins and in vitro efficacy of various therapeutic agents were investigated by proteomics and cell viability assays in 26 human SCLC cell lines. Besides SCLC-A (ASCL1-dominant), SCLC-AN (combined ASCL1/NEUROD1), SCLC-N (NEUROD1-dominant), and SCLC-P (POU2F3-dominant), IHC and cluster analyses identified a quadruple-negative SCLC subtype (SCLC-QN). No unique YAP1-subtype was found. The highest overall survival rates were associated with non-neuroendocrine subtypes (SCLC-P and SCLC-QN) and the lowest with neuroendocrine subtypes (SCLC-A, SCLC-N, SCLC-AN). In univariate analyses, high ASCL1 expression was associated with poor prognosis and high POU2F3 expression with good prognosis. Notably, high ASCL1 expression influenced survival outcomes independently of other variables in a multivariate model. High POU2F3 and YAP1 protein abundances correlated with sensitivity and resistance to standard-of-care chemotherapeutics, respectively. Specific correlation patterns were also found between the efficacy of targeted agents and subtype-specific protein abundances. In conclusion, we investigated the clinicopathological relevance of SCLC molecular subtypes in a large cohort of surgically resected specimens. Differential IHC expression of ASCL1, NEUROD1, and POU2F3 defines SCLC subtypes. No YAP1-subtype can be distinguished by IHC. High POU2F3 expression is associated with improved survival in a univariate analysis, whereas elevated ASCL1 expression is an independent negative prognosticator. Proteomic and cell viability assays of human SCLC cell lines revealed distinct vulnerability profiles defined by transcription regulators. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/cirurgia , Prognóstico , Proteômica , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/cirurgia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Extracorporeal photopheresis (ECP) is used by few lung transplant centers to treat chronic lung allograft dysfunction (CLAD). Although reported results suggest a beneficial effect on CLAD progression, evidence is limited to single center experiences. The aim of this study is to analyze outcomes of ECP in a large multicenter European cohort. The primary endpoint was patient survival after initiation of ECP. This study included 631 patients, 87% suffered from bronchiolitis obliterans syndrome (BOS), and 13% had restrictive allograft syndrome (RAS). Long-term stabilization was achieved in 42%, improvement in 9%, and no response in 26%. Within the first 12 months of therapy, 23% of patients died. Patients' survival after initiation of ECP at 5 years was 56% in stable, 70% in responders, and 35% in non-responders (p = 0.001). In multivariable Cox regression, both stabilization (HR: 0.48, CI: 0.27-0.86, p = 0.013) and response (HR: 0.11, CI: 0.04-0.35, p < 0.001) to ECP were associated with survival. Absolute FEV1 at baseline was also protective (HR: 0.09, CI: 0.01-0.94, p = 0.046). RAS phenotype was the only risk factor for mortality (HR: 2.11, 1.16-3.83, p = 0.006). This study provides long-term outcomes of ECP use in CLAD patients in the largest published cohort to date. Two-thirds of the cohort had a sustained response to ECP with excellent long-term results.
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Aloenxertos , Transplante de Pulmão , Fotoferese , Humanos , Aloenxertos/fisiopatologia , Transplante de Pulmão/métodos , Fotoferese/métodos , Estudos de CoortesRESUMO
Endoplasmic reticulum (ER) and mitochondria (mito) play a vital role in alveolar type II cell (AEC2) homeostasis and are both stressed in patients with idiopathic pulmonary fibrosis (IPF). Up to now, no data are available with regard to ER-mito cross talk and tethering under conditions of IPF. We here demonstrate that ER-mitochondrial tethering is reduced upon experimental ER stress in vitro and in the IPF AECII ex vivo, and this is-at least in part-due to decreased phosphofurin acidic cluster sorting protein 2 (PACS-2, also called PACS2) protein levels. PACS2 levels are influenced by its interaction with the transient receptor potential cation channel subfamily V member 1 (TRPV1) and can be experimentally modified by the TRPV1-modulating drug capsaicin (CPS). Employing alveolar epithelial cells with overexpression of the terminal ER stress signaling factor Chop or the IPF-associated surfactant protein C mutation (SPCΔexon4) in vitro, we observed a restoration of PACS2 levels upon treatment with CPS. Similarly, treatment of precision cut lung slices from IPF patients with CPS ex vivo forwarded similar effects. Importantly, in all models such kind of intervention also greatly reduced the extent of alveolar epithelial apoptosis. We therefore conclude that therapeutic targeting of the PACS2-TRPV1 axis represents an interesting novel, epithelial-protective approach in IPF.
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Estresse do Retículo Endoplasmático , Retículo Endoplasmático/metabolismo , Mitocôndrias/metabolismo , Canais de Cátion TRPV/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Células Epiteliais Alveolares/citologia , Células Epiteliais Alveolares/metabolismo , Animais , Apoptose/efeitos dos fármacos , Capsaicina/farmacologia , Linhagem Celular , Doxorrubicina/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Pulmão/citologia , Pulmão/metabolismo , Camundongos , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo , Proteínas de Transporte Vesicular/genética , Canal de Ânion 1 Dependente de Voltagem/metabolismoRESUMO
Lung transplantation is the ultimate treatment for end-stage lung disease (ESLD) arising from various etiologies. This manuscript will focus on selected aspects of a theoretical perioperative lung transplantation plan, highlighting data-driven and theoretical techniques the authors would employ if they were the index patient undergoing surgery. Beginning with looking for a transplant center using an Internet search, patient advocacy organizations, and artificial intelligence guidance, the authors lay out a course for multidisciplinary care throughout the entire patient journey, ending with ideal approaches to recovery 6 months posttransplantation. Although the index case will focus on a theoretical patient with pulmonary fibrosis, the general management principles will be applicable across the entire spectrum of patients with ESLD presenting for lung transplantation.
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Pneumopatias , Transplante de Pulmão , Fibrose Pulmonar , Humanos , Inteligência Artificial , Internacionalidade , Pneumopatias/cirurgiaRESUMO
Even in specialised centres, surgical procedures on the airway are only rarely performed in paediatric patients. Moreover, knowledge of various specific anatomical characteristics, diseases and surgical techniques is a prerequisite to treat these patients. Most commonly, sequelae of long-term intubation or tracheostomy in multimorbid patients necessitate surgical repair. Moreover, congenital malformations of the airways might require surgical interventions. However, these are commonly associated with other organ malformations, which adds further complexity to the treatment concept. Thus, cooperation within an interdisciplinary team is absolutely necessary to treat these patients. However, good postoperative outcomes after paediatric airway surgery can be achieved in experienced centres with an appropriate infrastructure. Specifically, this means long-term tracheostomy-free survival with preserved laryngeal functions in most of the patients. This review provides a summary of common indications and surgical techniques in paediatric airway surgery.
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Laringe , Traqueostomia , Humanos , Criança , Traqueostomia/métodos , Laringe/cirurgia , Intubação Intratraqueal/efeitos adversos , Estudos RetrospectivosRESUMO
Acute respiratory distress syndrome (ARDS) is a rapidly progressive lung disease with a high mortality rate. Although lung transplantation (LTx) is a well-established treatment for a variety of chronic pulmonary diseases, LTx for acute lung failure (due to ARDS) remains controversial. We reviewed posttransplant outcome of ARDS patients from three high-volume European transplant centers. Demographics and clinical data were collected and analyzed. Viral infection was the main reason for ARDS (n = 7/13, 53.8%). All patients were admitted to ICU and required mechanical ventilation, 11/13 were supported with ECMO at the time of listing. They were granted a median LAS of 76 (IQR 50-85) and waited for a median of 3 days (IQR 1.5-14). Postoperatively, median length of mechanical ventilation was 33 days (IQR 17-52.5), median length of ICU and hospital stay were 39 days (IQR 19.5-58.5) and 54 days (IQR 43.5-127). Prolongation of peripheral postoperative ECMO was required in 7/13 (53.8%) patients with a median duration of 2 days (IQR 2-7). 30-day mortality was 7.7%, 1 and 5-year survival rates were calculated as 71.6% and 54.2%, respectively. Given the lack of alternative treatment options, the herein presented results support the concept of offering live-saving LTx to carefully selected ARDS patients.
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Transplante de Pulmão , Síndrome do Desconforto Respiratório , Humanos , Tempo de Internação , Pulmão , Respiração ArtificialRESUMO
BACKGROUND: The published experience of lung transplantation in acute respiratory distress syndrome (ARDS) is limited. The aim of this study was to investigate the contemporary results of lung transplantation attempts in ARDS in major European centres. METHODS: We conducted a retrospective multicentre cohort study of all patients listed for lung transplantation between 2011 and 2019. We surveyed 68 centres in 22 European countries. All patients admitted to the waitlist for lung transplantation with a diagnosis of "ARDS/pneumonia" were included. Patients without extracorporeal membrane oxygenation (ECMO) or mechanical ventilation were excluded. Patients were followed until 1 October 2020 or death. Multivariable analysis for 1-year survival after listing and lung transplantation was performed. RESULTS: 55 centres (81%) with a total transplant activity of 12â438 lung transplants during the 9-year period gave feedback. 40 patients with a median age of 35â years were identified. Patients were listed for lung transplantation in 18 different centres in 10 countries. 31 patients underwent lung transplantation (0.25% of all indications) and nine patients died on the waitlist. 90% of transplanted patients were on ECMO in combination with mechanical ventilation before lung transplantation. On multivariable analysis, transplantation during 2015-2019 was independently associated with better 1-year survival after lung transplantation (OR 10.493, 95% CI 1.977-55.705; p=0.006). 16 survivors out of 23 patients with known status (70%) returned to work after lung transplantation. CONCLUSIONS: Lung transplantation in highly selected ARDS patients is feasible and outcome has improved in the modern era. The selection process remains ethically and technically challenging.
Assuntos
Oxigenação por Membrana Extracorpórea , Transplante de Pulmão , Síndrome do Desconforto Respiratório , Adulto , Estudos de Coortes , Oxigenação por Membrana Extracorpórea/métodos , Humanos , Respiração Artificial/métodos , Síndrome do Desconforto Respiratório/terapia , Estudos RetrospectivosRESUMO
RATIONALE: Lung transplantation is the ultimate treatment option for patients with end-stage respiratory diseases but bears the highest mortality rate among all solid organ transplantations due to chronic lung allograft dysfunction (CLAD). The mechanisms leading to CLAD remain elusive due to an insufficient understanding of the complex post-transplant adaptation processes. OBJECTIVES: To better understand these lung adaptation processes after transplantation and to investigate their association with future changes in allograft function. METHODS: We performed an exploratory cohort study of bronchoalveolar lavage samples from 78 lung recipients and donors. We analysed the alveolar microbiome using 16S rRNA sequencing, the cellular composition using flow cytometry, as well as metabolome and lipidome profiling. MEASUREMENTS AND MAIN RESULTS: We established distinct temporal dynamics for each of the analysed data sets. Comparing matched donor and recipient samples, we revealed that recipient-specific as well as environmental factors, rather than the donor microbiome, shape the long-term lung microbiome. We further discovered that the abundance of certain bacterial strains correlated with underlying lung diseases even after transplantation. A decline in forced expiratory volume during the first second (FEV1) is a major characteristic of lung allograft dysfunction in transplant recipients. By using a machine learning approach, we could accurately predict future changes in FEV1 from our multi-omics data, whereby microbial profiles showed a particularly high predictive power. CONCLUSION: Bronchoalveolar microbiome, cellular composition, metabolome and lipidome show specific temporal dynamics after lung transplantation. The lung microbiome can predict future changes in lung function with high precision.