Anatomy and Neuroscience - Research Publications
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ItemNo Preview AvailableEarly immune pressure initiated by tissue-resident memory T cells sculpts tumor evolution in non-small cell lung cancer(CELL PRESS, 2023-05-08)Tissue-resident memory T (TRM) cells provide immune defense against local infection and can inhibit cancer progression. However, it is unclear to what extent chronic inflammation impacts TRM activation and whether TRM cells existing in tissues before tumor onset influence cancer evolution in humans. We performed deep profiling of healthy lungs and lung cancers in never-smokers (NSs) and ever-smokers (ESs), finding evidence of enhanced immunosurveillance by cells with a TRM-like phenotype in ES lungs. In preclinical models, tumor-specific or bystander TRM-like cells present prior to tumor onset boosted immune cell recruitment, causing tumor immune evasion through loss of MHC class I protein expression and resistance to immune checkpoint inhibitors. In humans, only tumors arising in ES patients underwent clonal immune evasion, unrelated to tobacco-associated mutagenic signatures or oncogenic drivers. These data demonstrate that enhanced TRM-like activity prior to tumor development shapes the evolution of tumor immunogenicity and can impact immunotherapy outcomes.
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ItemSystematic endoscopic staging of mediastinum to determine impact on radiotherapy for locally advanced lung cancer (SEISMIC): protocol for a prospective single arm multicentre interventional study(BMC, 2022-09-24)BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is established as the preferred method of mediastinal lymph node (LN) staging in non-small cell lung cancer (NSCLC). Selective (targeted) LN sampling is most commonly performed however studies in early stage NSCLC and locally advanced NSCLC confirm systematic EBUS-TBNA evaluation improves accuracy of mediastinal staging. This study aims to establish the rate of detection of positron emission tomography (PET)-occult LN metastases following systematic LN staging by EBUS-TBNA, and to determine the utility of systematic mediastinal staging for accurate delineation of radiation treatment fields in patients with locally advanced NSCLC. METHODS: Consecutive patients undergoing EBUS-TBNA for diagnosis/staging of locally advanced NSCLC will be enrolled in this international multi-centre single arm study. Systematic mediastinal LN evaluation will be performed, with all LN exceeding 6 mm to be sampled by TBNA. Where feasible, endoscopic ultrasound staging (EUS-B) may also be performed. Results of minimally invasive staging will be compared to FDG-PET. The primary end-point is proportion of patients in whom systematic LN staging identified PET-occult NSCLC metastases. Secondary outcome measures include (i) rate of nodal upstaging, (ii) false positive rate of PET for mediastinal LN assessment, (iii) analysis of clinicoradiologic risk factors for presence of PET-occult LN metastases, (iv) impact of systematic LN staging in patients with discrepant findings on PET and EBUS-TBNA on target coverage and dose to organs at risk (OAR) in patients undergoing radiotherapy. DISCUSSION: With specificity of PET of 90%, guidelines recommend tissue confirmation of positive mediastinal LN to ensure potentially early stage patients are not erroneously denied potentially curative resection. However, while confirmation of pathologic LN is routinely sought, the exact extent of mediastinal LN involvement in NSCLC in patient with Stage III NSCLC is rarely established. Studies examining systematic LN staging in early stage NSCLC report a significant discordance between PET and EBUS-TBNA. In patients with locally advanced disease this has significant implications for radiation field planning, with risk of geographic miss in the event of PET-occult mediastinal LN metastases. The SEISMIC study will examine both diagnostic outcomes following systematic LN staging with EBUS-TBNA, and impact on radiation treatment planning. TRIAL REGISTRATION: ACTRN12617000333314, ANZCTR, Registered on 3 March 2017.
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ItemA randomised controlled trial comparing high-flow nasal oxygen with standard management for conscious sedation during bronchoscopy(WILEY, 2018-02)Traditional conscious sedation for endobronchial ultrasound procedures places patients at risk of desaturation, and high-flow nasal oxygen may reduce the risk. We designed a parallel-group randomised controlled trial of high-flow nasal oxygen at a flow rate of 30-70 l.min-1 via nasal cannulae, compared with standard oxygen therapy at 10 l.min-1 via a bite block in adults planned for conscious sedation for endobronchial ultrasound. The primary outcome was the proportion of patients experiencing desaturation (defined as SpO2 < 90%). Secondary outcomes included oxygen saturation after pre-oxygenation, lowest oxygen saturation during procedure, number of hypoxic episodes, duration of hypoxia, end-procedure end-tidal CO2 , satisfaction scores and complications. Thirty participants were allocated to each group. Baseline patient characteristics, procedure time and anaesthetic agents used were similar between the groups. Desaturation occurred in 4 out of 30 patients allocated to the high-flow nasal oxygen group, compared with 10 out of 30 allocated to the standard oxygenation group, a non-significant difference (p = 0.07) with intention to treat analysis. The difference was significant (p = 0.047) when using a per-protocol analysis. Oxygen saturation after pre-oxygenation and the lowest oxygen saturation during procedure were significantly higher in the high-flow nasal oxygen group compared with the standard oxygenation group; median (IQR [range] 100 (99-100 [93-100]) vs. 98 (97-99 [94-100]), p = 0.0001 and 97.5 (94-99 [77-100]) vs. 92 (88-95 [79-98]), p < 0.001, respectively. There were no differences in other secondary outcomes. Although high-flow nasal oxygen may prevent desaturation due to some causes, it does not protect against hypoxaemia in all circumstances.
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ItemCommencement of cardioselective beta-blockers during hospitalisation for acute exacerbations of chronic obstructive pulmonary disease(WILEY, 2017-09)BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD) and co-morbid cardiovascular disease, emerging evidence suggests a benefit in commencing cardioselective beta-blockers. AIM: Our objective was to determine the safety of beta-blocker commencement during hospitalisation for acute exacerbation of COPD. METHODS: A retrospective cohort study of 1071 patients hospitalised for acute exacerbation of COPD was conducted across two tertiary hospitals over a 12-month period. We identified 36 patients in whom beta-blocker therapy was commenced during admission. The primary outcome of the study was to assess cardiovascular and respiratory adverse events related to the commencement of beta-blocker therapy. RESULTS: The most common indications for beta-blockers were atrial fibrillation (53%) and acute coronary syndrome (36%). Metoprolol was the most commonly prescribed beta-blocker (75%). No patients suffered clinically significant declines of respiratory function following the commencement of a beta-blocker, including worsening respiratory symptoms, oxygen, bronchodilator or ventilation requirements. These results were demonstrable in patients with reversible airways disease and advanced COPD. Only one patient (2.8%) experienced symptomatic hypotension after 48 h of therapy. CONCLUSION: The commencement of cardioselective beta-blockers during acute exacerbations of COPD appears to be well-tolerated.
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ItemPulmonologist-performed transoesophageal sampling for lung cancer staging using an endobronchial ultrasound video-bronchoscope: an Australian experience(WILEY, 2017-02)BACKGROUND: Transoesophageal endobronchial ultrasound (EBUS) video-bronchoscope insertion provides pulmonologists access to conduct endoscopic fine-needle aspiration (EUS-B-FNA) of mediastinal lymph node (LN) lesions and also assist in lung cancer staging by sampling left adrenal gland (LAG) lesions. Limited literature has described additional diagnostic value whilst maintaining patient safety. To elicit whether combining endoscopic transoesophageal fine-needle aspiration using convex probe bronchoscope (EUS-B-FNA) and EBUS bronchoscopy enhances the diagnostic yield of mediastinal nodal staging in lung cancer, whilst maintaining safety. METHODS: All eligible patients with paraoesophageal lesions on thoracic computed tomography (CT) underwent pulmonologist-performed EUS-B-FNA at two tertiary centres and were included in this prospective observational cohort study. RESULTS: EUS-B-FNA sampling was performed at 69 mediastinal LN lesion sites, including 17 sites inaccessible to bronchoscopic sampling. Four LAG lesions were sampled via EUS-B-FNA. There were no complications. EBUS-TBNA was augmented by EUS-B-FNA because of accessibility of sampling lesions otherwise unamenable bronchoscopically, thereby increasing diagnostic utility. Diagnostic sensitivity of EUS-B-FNA for malignancy in mediastinal LN lesions was 88% (51 of 58). For mediastinal LN lesions not amenable to EBUS-TBNA, the sensitivity for diagnosis of malignancy via EUS-B-FNA was 88% (15 of 17). Diagnostic sensitivity of EUS-B-FNA for malignancy in LAG lesions was 50% (2 of 4). CONCLUSION: EUS-B-FNA is a precise and safe approach in the evaluation and staging of lung cancer when performed by a pulmonologist. It complements and increases the diagnostic utility of EBUS-TBNA by further coverage of mediastinal LN stations and access to LAG lesions.
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ItemAccuracy and safety of ward based pleural ultrasound in the Australian healthcare system(WILEY, 2017-04)BACKGROUND AND OBJECTIVE: Ultrasound has been shown to improve the accuracy and safety of pleural procedures. Studies to date have been performed in large, specialized units, where pleural procedures are performed by a small number of highly specialized physicians. There are no studies examining the safety and accuracy of ultrasound in the Australian healthcare system where procedures are performed by junior doctors with a high staff turnover. METHODS: We performed a retrospective review of the ultrasound database in the Respiratory Department at the Royal Melbourne Hospital to determine accuracy and complications associated pleural procedures. RESULTS: A total of 357 ultrasounds were performed between October 2010 and June 2013. Accuracy of pleural procedures was 350 of 356 (98.3%). Aspiration of pleural fluid was successful in 121 of 126 (96%) of patients. Two (0.9%) patients required chest tube insertion for management of pneumothorax. There were no recorded pleural infections, haemorrhage or viscera puncture. CONCLUSION: Ward-based ultrasound for pleural procedures is safe and accurate when performed by appropriately trained and supported junior medical officers. Our findings support this model of pleural service care in the Australian healthcare system.
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ItemDiagnostic yield of pleural fluid cytology in malignant effusions: an Australian tertiary centre experience(WILEY, 2018-11)BACKGROUND: Timely diagnosis of malignant pleural effusions is critical to guide prognosis and management decisions. Cytological analysis of pleural fluid has been the first-line diagnostic test for many decades, with highly variable reported sensitivities of 40-90%. Its diagnostic accuracy in modern practice in Australia needs to be understood. AIMS: To determine the diagnostic yield of pleural fluid cytology for the detection of malignant pleural effusions and to determine the aetiologies of pleural effusions at our centre. METHODS: The study involved the retrospective chart review of all pleural fluid samples submitted for cytological analysis at a tertiary referral centre in Melbourne, Australia, over a 12-month period. Aetiology of all effusions was determined, and sensitivity, specificity, negative predictive value and diagnostic accuracy for the detection of malignant pleural effusions were calculated. We also examined diagnostic yield based on tumour cell type. RESULTS: Of the 153 cases analysed, 61 (39.9%) were malignant. Lung cancers accounted for 44.3% of malignant effusions, followed by mesothelioma (18%), ovarian carcinoma (11.5%) and lymphoma (8.2%). The commonest single causes of a benign effusion were cardiac (16.3%) and parapneumonic (13%). Sensitivity for diagnosis of malignant effusions was 67.2% overall, but 87.9% for adenocarcinomas and only 45.5% for mesothelioma. CONCLUSION: Tumour type is an important determinant of pleural fluid cytology diagnostic yield. Cytology has good sensitivity and specificity for the diagnosis of adenocarcinoma, but if another tumour type is suspected, particularly mesothelioma, clinicians should be aware of the limitations.
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ItemLow rates of eligibility for lung cancer screening in patients undergoing computed tomography coronary angiography(WILEY, 2018-10)Incidental findings, including pulmonary nodules, on computed tomography coronary angiography (CTCA) are common. Previous authors have suggested CTCA could allow opportunistic screening for lung cancer, though the lung cancer risk profile of this patient group has not previously been established. Smoking histories of 229 patients undergoing CTCA at two tertiary hospitals were reviewed and only 25% were current or former smokers aged 55-80 years old. Less than half of this group were eligible for screening based on the PLCOm2012 risk model. We conclude that routine screening in the form of full thoracic field imaging, of individuals undergoing CTCA is not appropriate as it would likely result in net harm.
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ItemOutcomes following resection of non-small cell lung cancer in octogenarians(WILEY, 2018-12)BACKGROUND: The treatment of choice for early stage non-small cell lung cancer (NSCLC) is surgical resection. Little is known about the short- and long-term outcomes among very elderly patients. We sought to determine predictors of short- and long-term survival among octogenarians undergoing curative-intent resection for NSCLC in Victoria, Australia. METHODS: We retrospectively reviewed data from all patients aged ≥80 years who underwent curative-intent resection for NSCLC over 12 years (January 2005-December 2016) across five tertiary centres. We examined effect of age, stage of disease, extent of surgery and lung function on short- and long-term survival. RESULTS: Two hundred patients aged ≥80 years underwent curative-intent resections. Mortality at 30 and 120 days was 2.9% and 5.9%, respectively. Increased early mortality was observed among those ≥83 years, at 30 days (6.8% versus 0.8%, P = 0.044) and 120 days (12.2% versus 2.3%, P = 0.0096). Early mortality was highest among patients ≥83 years requiring lobectomy, compared to sub-lobar resection at 120 days (17% versus 3.8%, P = 0.019). Long-term survival was predicted by age and stage of disease. Among patients with Stage I disease aged <83 years, lobectomy was associated with superior 5-year survival, compared to sub-lobar resection (83% versus 61%, P = 0.02). CONCLUSION: In carefully selected elderly patients undergoing curative-intent resection of early stage NSCLC, both short- and long-term outcomes appear consistent with younger historical cohorts. Early mortality was associated with lobectomy in those with advanced age. Older patients undergoing lobectomy appeared to be at highest risk for early mortality, while younger patients with Stage I disease undergoing at least lobectomy appear to have the best long-term survival.
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