Carbon nanotubes (CNTs) are nanomaterials with broad applications that are produced on a large scale. Animal experiments have shown that exposure to CNTs, especially one type of multi-walled carbon ...nanotube, MWCNT-7, can lead to malignant transformation. CNTs have characteristics similar to asbestos (size, shape, and biopersistence) and use the same molecular mechanisms and signaling pathways as those involved in asbestos tumorigenesis. Here, a comprehensive review of the characteristics of carbon nanotubes is provided, as well as insights that may assist in the design and production of safer nanomaterials to limit the hazards of currently used CNTs.
Pulmonary endarterectomy is the treatment of choice for chronic thromboembolic pulmonary hypertension. This case report outlines the importance of venoarterial extracorporeal membrane oxygenation and ...plasmapheresis as two important options in the management of heparin-induced thrombocytopenia–positive patients requiring urgent pulmonary endarterectomy.
BackgroundMalignant pleural mesothelioma (MPM) is an aggressive cancer with median survival of 18 months. Due to the lack of proper tumour targets, no cellular immunotherapy is currently available ...for MPM. New non-ablative radiation and surgery combination therapy programs for MPM are underway at the Princess Margaret Cancer Centre in Toronto. As part of a comprehensive multiomics study of tumor microenvironment, we implemented a computational method for discovery and prioritization of endogenous retroviral protein (ERV) particles as novel antigen-specific targets in MPM.MethodsWe performed ERV gene-discovery based on identification of protein-coding open-reading frames with viral or bacterial origins.1 An extended human reference genome was constructed with novel open-reading frames and single-cell RNAseq sequencing (10Xgenomics Inc.) reads of tumor samples were aligned and gene-count tables were computed. ERVs with less than ten aligned reads or present in only one patient were removed from the analysis. ERVs with transcripts overlapping GTEx Consortium database (10K samples, 56 tissues) were removed to ensure no remaining ERV was constitutively expressed in normal tissues. The ERVs were further annotated with experimentally validated T and B cell epitopes in the Immune Epitope Database (IEDB).2 BLAST searches performed to identify humongous epitope of ERVs in human pathogen. A select set of identified transcripts were validated with PCR.ResultsSingle-cell RNAseq expression of tumor microenvironment of 19 MPM patients was analyzed. All patients expressed two ERVs annotated in the human reference genome (ERV3–1, ERVK3–1) with another four (ERVFRD-1, ERVH48–1, ERVMER34–1, ERVW-1) expressed in at least 5 patients. We identified 400 ERVs not curated in the human reference genome with lengths of 95–3935 amino acids (1520.9525 +- 1069). From this, 224 contained at least one T-cell epitope (with presentation at MHC class-I and class-II) or B epitope (antibody binding) record in IEDB. 135 ERVs had at least one epitope with 100% homology in human pathogens. We further measured the expression (in terms of TPM) of identified genes in 2708 publicly available cell lines of 14 cancers. All 400 ERVs were shared with at least one and some with all 14 other cancers.ConclusionsWe identified several ERV proteins present in MPM tumors that are prominently encoded in intronic regions of but not curated in the human reference genome. Annotation of these proteins with homologues epitopes of human pathogen and IEDB epitopes provide opportunities for prioritization of these novel targets for T-cell therapies or antibody drugs.ReferencesNakagawa S, Takahashi MU. gEVE: a genome-based endogenous viral element database provides comprehensive viral protein-coding sequences in mammalian genomes. Database, 2016; 2016 :1–8. https://doi.org/10.1093/database/baw087Vita R, Mahajan S, Overton JA, Dhanda SK, Martini S, Cantrell JR, Wheeler DK, Sette A, Peters B. The Immune Epitope Database (IEDB): 2018 update. Nucleic Acids Research, 2019; 47 (D1):D339-D343. https://doi.org/10.1093/nar/gky1006
Tumour thickness was assessed to determine if this parameter could refine patients' selection for multimodality therapy in malignant pleural mesothelioma.We reviewed 65 consecutive treatment-naïve ...malignant pleural mesothelioma patients undergoing surgery for mesothelioma after radiation therapy (SMART). Total tumour thickness was determined by measuring the maximal thickness on nine predefined sectors on the chest wall, mediastinum and diaphragm.After a median follow-up of 19 months, 40 patients (62%) developed recurrence and 36 died (55%). Total tumour thickness, ranging between 2.4 and 21 cm (median 6.9 cm), correlated with tumour volume (p<0.0001, R
=0.29) and maximum standardised uptake value (p=0.006, R
=0.11). Total tumour thickness had a significant impact on overall survival and disease-free survival in univariate analysis. In multivariate analysis, total tumour thickness remained an independent predictor of survival (p=0.02, hazard ratio (HR) 1.12, 95% CI 1.02-1.23) and disease-free survival (p=0.01, HR 1.13, 95% CI 1.03-1.24) along with epithelial histologic subtype (p<0.0001, HR 0.25, 95% CI 0.13-0.50) and pN2 disease (p=0.03, HR 2.15, 95% CI 1.07-4.33). Diaphragmatic tumour thickness correlated best with time to recurrence (p=0.002, R
=0.22) and time to death (p=0.003, R
=0.2).The impact of tumour thickness on survival and disease-free survival independent of histologic subtypes and nodal disease is extremely encouraging. This parameter could potentially be used to refine the clinical staging of malignant pleural mesothelioma and optimise patient selection for radical treatment.
Malignant pleural mesothelioma (MPM) is a rare and aggressive form of cancer commonly associated with asbestos exposure that stems from the thoracic mesothelium with high mortality rate. Currently, ...treatment options for MPM are limited, and new molecular targets for treatments are urgently needed. Using quantitative reverse transcription-polymerase chain reaction (RT-PCR) and an RNA interference-based screening, we screened two kinesin family members as potential therapeutic targets for MPM. Following in vitro investigation of the target silencing effects on MPM cells, a total of 53 MPMs were analyzed immunohistochemically with tissue microarray. KIF11 and KIF23 transcripts were found to be overexpressed in the majority of clinical MPM samples as well as human MPM cell lines as determined by quantitative RT-PCR. Gene knockdown in MPM cell lines identified growth inhibition following knockdown of KIF11 and KIF23. High expression of KIF11 (KIF11-H) and KIF23 (KIF23-H) were found in 43.4 and 50.9% of all the MPM cases, respectively. Patients who received curative resection with tumors displaying KIF23-H showed shorter overall survival (P=0.0194). These results provide that inhibition of KIF11 and KIF23 may hold promise for treatment of MPMs, raising the possibility that kinesin-based drug targets may be developed in the future.
The SPARC gene plays multiple roles in extracellular matrix synthesis and cell shaping, associated with tumor cell migration, invasion, and metastasis. The SPARC gene is also involved in the ...epithelial-mesenchymal transition (EMT) process, which is a critical phenomenon leading to a more aggressive cancer cell phenotype. SPARC gene overexpression has shown to be associated with poor survival in the mesothelioma (MESO) cohort from the TCGA database, indicating that this gene may be a powerful prognostic factor in MESO. Its overexpression is correlated with the immunosuppressive tumor microenvironment. Here, we summarize the omics advances of the SPARC gene, including the summary of SPARC gene expression associated with prognosis in pancancer and MESO, the immunosuppressive microenvironment, and cancer cell stemness. In addition, SPARC might be targeted by microRNAs. Notably, despite the controversial functions on angiogenesis, SPARC may directly or indirectly contribute to tumor angiogenesis in MESO. In conclusion, SPARC is involved in tumor invasion, metastasis, immunosuppression, cancer cell stemness, and tumor angiogenesis, eventually impacting patient survival. Strategies targeting this gene may provide novel therapeutic approaches to the treatment of MESO.
Objectives A minimal-dose computed tomography scan of the thorax (MnDCT) delivers a radiation dose comparable with a chest x-ray (CXR). We hypothesized that in patients with completely resected lung ...cancer, surveillance with MnDCT, when compared with CXR, leads to earlier detection and a higher rate of treatment of new or recurrent lung cancer. Methods After lung cancer resection, patients prospectively were enrolled for surveillance with MnDCT and CXR at 3, 6, 12, 18, 24, 36, 48, and 60 months. Images were interpreted by different blinded radiologists. When new or recurrent cancer was suspected, standard-dose CT and/or a tissue biopsy were performed for confirmation. Results Between 2007 and 2012, 271 patients were included and 1137 pairs of CXR and MnDCT were analyzed. MnDCT was more sensitive (94% vs 21%; P < .0001) and had a higher negative predictive value (99% vs 96%; P = .007) than CXR for the diagnosis of new or recurrent lung cancer. The prevalence of new or recurrent lung cancer was 23.2% (63 of 271), of whom 78% (49 of 63) had asymptomatic disease. The majority of asymptomatic patients (75%; 37 of 49) were treated with curative intent and had a median survival of 69 months. The remainder of patients received palliative treatment (24%; 12 of 49) and had a median survival of 25 months ( P < .0001). Conclusions After curative resection of lung cancer, MnDCT is superior to CXR for the detection of new or recurrent lung cancer. The majority of new or recurrent cancer was detected by MnDCT at an asymptomatic phase, allowing for curative treatment, leading to a long survival.
Abstract Objective To assess the cost-effectiveness of various modes of mediastinal staging in non–small cell lung cancer (NSCLC) in a single-payer health care system. Methods We performed a decision ...analysis to compare the health outcomes and costs of 4 mediastinal staging strategies: no invasive staging, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), mediastinoscopy, and EBUS-TBNA followed by mediastinoscopy if EBUS-TBNA is negative. We determined incremental cost effectiveness ratios (ICER) for all strategies and performed comprehensive deterministic sensitivity analyses using a willingness to pay threshold of $80,000/quality adjusted life year (QALY). Results Under the base-case scenario, the no invasive mediastinal staging strategy was least effective (QALY, 5.80) and least expensive ($11,863), followed by mediastinoscopy, EBUS-TBNA, and EBUS-TBNA followed by mediastinoscopy with 5.86, 5.87, and 5.88 QALYs, respectively. The ICER was ∼$26,000/QALY for EBUS-TBNA staging and ∼$1,400,000/QALY for EBUS-TBNA followed by mediastinoscopy. The mediastinoscopy strategy was dominated. Once pN2 exceeds 2.5%, EBUS-TBNA staging is cost-effective (∼$80,000/QALY). Once the pN2 reaches 57%, EBUS-TBNA followed by mediastinoscopy is cost-effective (ICER ∼$79,000/QALY). Once EBUS-TBNA sensitivity exceeds 25%, EBUS-TBNA staging is cost-effective (ICER ∼$79,000/QALY). Once pN2 exceeds 25%, confirmatory mediastinoscopy should be added, in cases of EBUS-TBNA sensitivity ≤ 60%. Conclusions Invasive mediastinal staging in NSCLC is unlikely to be cost-effective in clinical N0 patients if pN2 <2.5%. In patients with probability of mediastinal metastasis between 2.5% and 57% EBUS-TBNA is cost-effective as the only staging modality. Confirmatory mediastinoscopy should be considered in high-risk patients (pN2 > 57%) in case of negative EBUS-TBNA.
The inhibition of cellular metabolism induced by hypothermia obviates the possibility of substantial reparative processes occurring during organ preservation. The aim of this study was to develop a ...technique of extended (12-hour) ex vivo lung perfusion (EVLP) at normothermia for assessment and protective maintenance of the donor lung.
Six double-lung blocks from 35-kg pigs and 5 single human lungs were subjected to 12 hours of normothermic EVLP using acellular Steen Solution. In the animal studies, the left lung was transplanted into recipients at the end of EVLP and reperfused for 4 hours to evaluate the impact of prolonged EVLP on post-transplant lung function. A protective mode of mechanical ventilation with controlled perfusion flows and pressures in the pulmonary vasculature were employed during EVLP. Lung oxygenation capacity (DeltaPo(2)), pulmonary vascular resistance and airway pressures were evaluated in the system. Red blood cells were added to the perfusate to a hematocrit of 20% at the end of human lung EVLP to study lung functional assessment with and without cells.
Lung function was stable during 12 hours of EVLP. This stability during prolonged normothermic EVLP translated into excellent post-transplant lung function (Pao(2)/Fio(2): 527 +/- 22 mm Hg), low edema formation (wet/dry ratio: 5.24 +/- 0.38) and preserved lung histology after transplantation. The acellular perfusion assessment of lung function accurately correlated with post-transplant graft function.
Twelve hours of EVLP at physiologic temperatures using an acellular perfusate is achievable and maintains the donor lungs without inflicting significant added injury. This system can be used to assess, maintain and treat injured donor lungs.
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