The role of endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of mediastinal lymphadenopathy

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a novel procedure for the diagnosis of mediastinal lymphadenopathy. Its utility in clinical practice for the diagnosis of patients presenting with mediastinal lymphadenopathy is unknown. This thesis describes the learning curve associated with EBUS-TBNA using cumulative sum analysis and then the diagnostic yield of EBUS-TBNA in different clinical scenarios. EBUS-TBNA was combined with standard bronchoscopy in patients with suspected sarcoidosis in a prospective trial. The role of EBUS-TBNA in patients with tuberculous lymphadenopathy and also patients with extra-thoracic malignancy was then clarified in multi-centre studies. A further prospective trial (REMEDY) aimed to ascertain whether mediastinoscopies could be prevented in patients presenting with isolated mediastinal lymphadenopathy. The utility of the specimens from EBUS-TBNA for sub-typing and genotyping of non-small cell lung cancer are also described in a multi-centre study. Finally, the results from a major multi-centre randomised controlled trial (Lung-BOOST) are presented, investigating whether EBUS-TBNA should be implemented as a first test in patients with suspected lung cancer. The data included in this thesis demonstrate that EBUS-TBNA has high diagnostic yield in patients with sarcoidosis, tuberculosis and extra-thoracic malignancy. For the first time, the REMEDY trial demonstrates that EBUS-TBNA can prevent 87% of mediastinoscopies in patients with isolated mediastinal lymphadenopathy. In patients with lung cancer, specimens from EBUS-TBNA are suitable for sub-typing and genotyping of NSCLC and results from the randomised Lung-BOOST trial demonstrate that when EBUS-TBNA is used as an initial investigation in patients with suspected lung cancer the time to treatment decision is significantly reduced

High prevalence of malignancy in HIV-positive patients with mediastinal lymphadenopathy: A study in the era of antiretroviral therapy.

Mediastinal lymphadenopathy (MLN) in human immunodeficiency virus (HIV) infection has a wide spectrum of aetiologies with different prognoses and treatments. The decision to pursue a histopathological diagnosis represents a clinical challenge as patients present with non-specific symptoms. This study aimed to determine the aetiology and predictive factors of MLN in a cohort of HIV-infected patients in the combination antiretroviral therapy (cART) era

Pulmonary nodules and CT screening: the past, present and future

Lung cancer screening has come a long way since the early studies with chest X-ray. Advancing technology and progress in the processing of images have enabled low dose CT to be tried and tested, and evidence suggests its use can result in a significant mortality benefit. There are several issues that need refining in order to successfully implement screening in the UK and elsewhere. Some countries have started patchy implementation of screening and there is increased recognition that the appropriate management of pulmonary nodules is crucial to optimise benefits of early detection, while reducing harm caused by inappropriate medical intervention. This review summarises and differentiates the many recent guidelines on pulmonary nodule management, discusses screening activity in other countries and exposes the present barriers to implementation in the UK

PD-L1 testing for lung cancer in the UK: recognizing the challenges for implementation.

A new approach to the management of non-small-cell lung cancer (NSCLC) has recently emerged that works by manipulating the immune checkpoint controlled by programmed death receptor 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1). Several drugs targeting PD-1 (pembrolizumab and nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved or are in the late stages of development. Inevitably, the introduction of these drugs will put pressure on healthcare systems, and there is a need to stratify patients to identify those who are most likely to benefit from such treatment. There is evidence that responsiveness to PD-1 inhibitors may be predicted by expression of PD-L1 on neoplastic cells. Hence, there is considerable interest in using PD-L1 immunohistochemical staining to guide the use of PD-1-targeted treatments in patients with NSCLC. This article reviews the current knowledge about PD-L1 testing, and identifies current research requirements. Key factors to consider include the source and timing of sample collection, pre-analytical steps (sample tracking, fixation, tissue processing, sectioning, and tissue prioritization), analytical decisions (choice of biomarker assay/kit and automated staining platform, with verification of standardized assays or validation of laboratory-devised techniques, internal and external quality assurance, and audit), and reporting and interpretation of the results. This review addresses the need for integration of PD-L1 immunohistochemistry with other tests as part of locally agreed pathways and protocols. There remain areas of uncertainty, and guidance should be updated regularly as new information becomes available

Transcriptional profiling of endobronchial ultrasound guided lymph node samples aids diagnosis of mediastinal lymphadenopathy

Background: Endobronchial ultrasound (EBUS) guided biopsy is the mainstay for investigation of mediastinal lymphadenopathy for laboratory diagnosis of malignancy, sarcoidosis or tuberculosis. However, improved methods for discriminating between tuberculosis and sarcoidosis and excluding malignancy are still needed. We sought to evaluate the role of genome-wide transcriptional profiling to aid diagnostic processes in this setting. Methods: Mediastinal lymph node samples from 88 individuals were obtained by EBUS guided aspiration for investigation of mediastinal lymphadenopathy and subjected to transcriptional profiling in addition to conventional laboratory assessments. Computational strategies were employed to evaluate the potential for using the transcriptome to distinguish between diagnostic categories. Results: Molecular signatures associated with granulomas or neoplastic and metastatic processes were clearly discernible in granulomatous and malignant lymph node samples respectively. Support vector machine (SVM) learning using differentially expressed genes showed excellent sensitivity and specificity profiles in receiver operating characteristic curve analysis with area under curve values >0.9 for discriminating between granulomatous and non-granulomatous disease, tuberculosis and sarcoidosis, and between cancer and reactive lymphadenopathy. A two-step decision tree using SVM to distinguish granulomatous and non-granulomatous disease, then between tuberculosis and sarcoidosis in granulomatous cases and between cancer and reactive lymphadenopathy in non-granulomatous cases achieved >90% specificity for each diagnosis and afforded greater sensitivity than existing tests to detect tuberculosis and cancer. In some diagnostically ambiguous cases computational classification predicted granulomatous disease or cancer before pathological abnormalities were evident. Conclusions: Machine learning analysis of transcriptional profiling in mediastinal lymphadenopathy may significantly improve the clinical utility of EBUS guided biopsies