Determining sex-specific preoperative haemoglobin levels associated with intraoperative red blood cell transfusion in cardiac surgery: a retrospective cohort study.

BACKGROUND: Anaemic cardiac surgery patients are at greater risk of intraoperative red blood cell transfusion. This study questions the application of the World Health Organization population-based anaemia thresholds (haemoglobin <120 g L-1 in non-pregnant females and <130 g L-1 in males) as appropriate preoperative optimisation targets for cardiac surgery. METHODS: A retrospective cohort study was conducted on adults ≥18 yr old undergoing cardiopulmonary bypass surgery. Logistic regression was applied to define sex-specific preoperative haemoglobin concentrations with reduced probability of intraoperative red blood cell transfusion for cardiac surgery patients. RESULTS: Data on 4384 male and 1676 female patients were analysed. Binarily stratified multivariable logistic regression odds of receiving intraoperative red blood cell transfusion increased in cardiac surgery patients >45 yr old (odds ratio [OR] 1.84; 95% confidence interval [CI] 1.33-2.55), surgery urgency <30 days (OR 2.03; 95% CI 1.66-2.48), combined coronary artery bypass grafting and valve surgery, or other surgery types (OR 2.24; 95% CI 1.87-2.67), and female sex (OR 1.92; 95% CI 1.62-2.28). The odds decreased by 8.4% with each 1 g L-1 increase in preoperative haemoglobin (OR 0.92; 95% CI 0.91-0.92). Logistic regression predicted females required a preoperative haemoglobin concentration of 133 g L-1 and males 127 g L-1 to have a 15% probability of intraoperative transfusion. CONCLUSIONS: The World Health Organization female anaemia threshold of haemoglobin <120 g L-1 disproportionately disadvantages female cardiac surgery patients. A preoperative haemoglobin concentration ≥130 g L-1 in adult cardiac surgery patients would minimise their overall probability of intraoperative red blood cell transfusion to <15%.

Thoracic Surgery and the Elderly; Is Lobectomy Safe in Octogenarians?

PURPOSE: Non-small cell lung cancer is the most common malignancy of the elderly, with 5-year survival estimates of 16.8%. The prognostic benefit of surgical resection for early lung cancer is irrefutable and maintained irrespective of age, even in patients over 75 years. Concerningly, despite the prognostic benefit of surgery there are deviations from standard treatment protocols with increasing age due to concerns of increased morbidity and mortality with surgery, without evidence to support this. METHOD: A state-wide retrospective registry study of Queensland's Cardiac Outcomes Registry's (QCOR) Thoracic Database examining the influence of age on the safety of Lung Resection (1 January 2016-20 April 2022). RESULTS: This included 1,232 patients, mean age at surgery was 66 years (range 14-91 years), with 918 thoracotomies performed. Three deaths occurred within 30-days (0.24%). Octogenarians (n=60) had lower rates of smoking (26% vs 6%), respiratory, cardiovascular, and cerebrovascular disease suggesting this subset of patients is carefully selected. Octogenarian status was not associated with an increased all-cause morbidity (p=0.09) or 30-day mortality (p=0.06). Further to this it was not associated with re-operation (4.4% vs 8.3%, p=0.1), increased postoperative stay (6.66 vs 6.65 days, p=0.99) or myocardial infarction. An independent predictor of morbidity was male sex (OR 1.58, CI 1.2-2.1 p=0.001). CONCLUSION: Age ≥80 years did not increase surgical morbidity or mortality in the appropriately selected patient and should not be a barrier to referral for consideration of surgical resection.

Long Term Survival After Surgery for Ischaemic Mitral Regurgitation: A Single Centre Australian Experience.

BACKGROUND: Ischaemic mitral regurgitation (IMR) is associated with an increase in both mortality and congestive heart failure in patients undergoing coronary artery bypass grafting (CABG). Intervention for moderate to severe IMR involves either valve repair or replacement. The ideal option is yet to be fully defined with relatively poor long-term survival being noted in the literature. METHOD: A retrospective observational study was conducted to review the outcomes of patients undergoing CABG in combination with either mitral valve repair (MVr) or mitral valve replacement (MVR) for concurrent coronary artery disease with moderate to severe IMR at The Prince Charles Hospital in Brisbane between the years 2002 to 2015. RESULTS: One hundred and five (105) patients were included, 81 patients (77%) undergoing CABG and MVr and 24 patients (23%) undergoing CABG and MVR. There was no difference in 30-day mortality between the two groups (1% in MVr and 0% in MVR, p=0.589), however patients in the MVr group were significantly more likely, in univariate and multivariate analysis, to develop at least moderate MR (40% v. 8%, p=0.006). The 5-year survival was 87% and 55% at 10 years. CONCLUSIONS: In patients undergoing CABG and mitral valve intervention for IMR, long-term mortality remains high. There was no difference in short- or long-term mortality between repair and replacement although recurrence of at least moderate mitral regurgitation was significantly higher with mitral valve repair.

Coronary artery bypass grafting is associated with immunoparalysis of monocytes and dendritic cells.

Coronary artery bypass grafting (CABG) triggers a systemic inflammatory response that may contribute to adverse outcomes. Dendritic cells (DC) and monocytes are immunoregulatory cells potentially affected by CABG, contributing to an altered immune state. This study investigated changes in DC and monocyte responses in CABG patients at 5 time-points: admission, peri-operative, ICU, day 3 and day 5. Whole blood from 49 CABG patients was used in an ex vivo whole blood culture model to prospectively assess DC and monocyte responses. Lipopolysaccharide (LPS) was added in parallel to model responses to an infectious complication. Co-stimulatory and adhesion molecule expression and intracellular mediator production was measured by flow cytometry. CABG modulated monocyte and DC responses. In addition, DC and monocytes were immunoparalysed, evidenced by failure of co-stimulatory and adhesion molecules (eg HLA-DR), and intracellular mediators (eg IL-6) to respond to LPS stimulation. DC and monocyte modulation was associated with prolonged ICU length of stay and post-operative atrial fibrillation. DC and monocyte cytokine production did not recover by day 5 post-surgery. This study provides evidence that CABG modulates DC and monocyte responses. Using an ex vivo model to assess immune competency of CABG patients may help identify biomarkers to predict adverse outcomes.

Multivisceral Transplant, The Prince Charles Hospital Experience.

BACKGROUND: Multi-visceral organ transplant is uncommon. As a result of the rarity of these surgeries, there are limited studies, making it difficult to interpret outcomes and identify specific patient complications. We aim to assess the indications for multi-organ transplant, the time on the wait-list and evaluate outcomes including patient survival, graft survival and postoperative complications in an Australian context. METHODS: Patients undergoing multi-organ transplant from 1993 to 2018 at The Prince Charles Hospital, Brisbane, Australia were retrospectively reviewed, looking at baseline characteristics and post-transplant morbidity, mortality and graft survival. RESULTS: A total of 37 patients were included in the study, comprising 22 heart-lung transplants, eight heart-kidney transplants and seven heart-lung-liver transplants. There were six domino heart transplants performed, all in the heart-lung-liver transplant group. The mean age at transplant was 37 years and the mean wait-list time was 10 months. One patient, receiving a heart-lung transplant, required re-transplantation (bilateral lung) at 3 years. One-year (1-year) survival was 91% for heart-lung transplants, 86% for heart-lung-liver transplants and 87.5% for heart-kidney transplants. Five- and ten-year (5- and 10-year) survival was 79% for both in heart-lung transplant, 43% and 29% for heart-lung-liver transplant and 87.5% for both in heart-kidney transplant. CONCLUSION: Patients undergoing multi-organ transplant at our unit had long-term survival and organ function comparable to international data. In addition, waitlist time for multi-organ transplant was not found to be excessive.

Redo Aortic Valve Replacement Following Bio-Bentall's Procedure.

BACKGROUND: Structural valve degeneration is a known sequel of aortic valve replacement with bioprosthetic valves, not infrequently leading to redo valve replacement. Reoperation on the aortic valve is associated with an incumbent increase in perioperative risk, and this risk is further increased when reoperation is performed on an already replaced aortic root. METHODS: We present a technique of opening the aortic graft and explanting the bioprosthesis by dividing the plane between the stent frame and the sewing ring of the bioprosthesis, followed by re-implantation of a bioprosthesis using simple sutures incorporating the remaining valve seat. RESULTS: The patient experienced an uneventful postoperative course and was discharged on the fifth day postoperatively. CONCLUSIONS: The author presents a simple and reproducible technique to replace a degenerated bioprosthetic aortic valve while preserving the previous aortic root replacement.

Catamenial Pneumothorax, a Commonly Misdiagnosed Thoracic Condition: Multicentre Experience and Audit of a Small Case Series With Review of the Literature.

BACKGROUND: Catamenial pneumothorax (CP) is an unusual condition affecting premenopausal women and commonly misdiagnosed as simple pneumothorax. It is characterised by its recurrence between the day before and within 72 hours after the onset of menstruation. It has been associated with thoracic endometriosis but the aetiology is not well understood and there is no unified agreement for its optimal management. The aim of this study is to determine the incidence of CP in surgical patients and the results of their treatment. METHODS: Females between the ages of 30 to 50 years with a diagnosis of pneumothorax, admitted for surgery over a 10-year period in four different hospitals were retrospectively reviewed for evidence of CP. An audit of surgical and medical management of the patients with CP and their short to midterm outcomes was performed in addition to a systemic review of the literature on CP. RESULT: A total of 120 premenopausal female patients with a diagnosis of pneumothorax were admitted for Video Assisted Thoracoscopic (VAT) surgery and five women (4.1%) with a mean age of 42.6 years were diagnosed to have CP through surgical and histological findings. The first case was diagnosed 5 years ago and the last three within recent 12 months after the changes in surgical practices of inspecting diaphragmatic surface in suspected cases of CP. Four patients underwent diaphragmatic plication and one patient had a pleural biopsy. All patients underwent talc pleurodesis and hormone therapy in the postoperative period. Short to midterm (mean follow-up period of 25.2 months) results of the patients with CP were encouraging. CONCLUSIONS: It is possible that many of the cohort of premenopausal female patients presenting with recurrent pneumothorax are misdiagnosed as spontaneous pneumothorax (SP) because routine inspection of the diaphragmatic surface is not often performed. A thorough menstrual history and its temporal relation to pneumothorax onset should be assessed on every woman presenting with recurrent pneumothorax and intraoperative exploration of diaphragmatic surface should be performed in the patients with high suspicion of CP as the patients diagnosed with CP have a good outcome with surgery and hormone therapy.

Long-term outcomes following Medtronic Open Pivot valved conduit.

BACKGROUND AND AIM OF THE STUDY: Aortic root replacement is a complex procedure, though subsequent modifications of the original Bentall procedure have made surgery more reproducible. The study aim was to examine the outcomes of a modified Bentall procedure, using the Medtronic Open PivotTM valved conduit. Whilst short-term data on the conduit and long-term data on the valve itself are available, little is known of the long-term results with the valved conduit. METHODS: Patients undergoing aortic root replacement between February 1999 and February 2010, using the Medtronic Open Pivot valved conduit were identified from the prospectively collected Cardiothoracic Register at The Prince Charles Hospital, Brisbane, Australia. All patients were followed up echocardiographically and clinically. The primary end-point was death, and a Cox proportional model was used to identify factors associated.with survival. Secondary end-points were valve-related morbidity (as defined by STS guidelines) and postoperative morbidity. Predictors of morbidity were identified using logistic regression. RESULTS: A total of 246 patients (mean age 50 years) was included in the study. The overall mortality was 12%, with actuarial 10-year survival 79% and a 10-year estimate of valve-related death of 0.04 (95% CI: 0.004, 0.07). Preoperative myocardial infarction (p = 0.004, HR 4.74), urgency of operation (p = 0.038, HR 2.8) and 10% incremental decreases in ejection fraction (p = 0.046, HR 0.69) were predictive of mortality. Survival was also affected by the valve gradients, with a unit increase in peak gradient reducing mortality (p = 0.021, HR 0.93). Valve-related morbidity occurred in 11 patients. Urgent surgery (p <0.001, OR 4.12), aortic dissection (p = 0.015, OR 3.35), calcific aortic stenosis (p = 0.016, OR 2.35) and Marfan syndrome (p 0.009, OR 3.75) were predictive of postoperative morbidity. The reoperation rate was 1.2%. CONCLUSION: The Medtronic Open Pivot valved conduit is a safe and durable option for aortic root replacement, and is associated with low morbidity and 10-year survival of 79%. However, further studies are required to determine the effect of valve gradient on survival.

Delayed cardiac herniation after left pneumonectomy.

Cardiac herniation is a rare potentially life-threatening complication that can occur after pneumonectomy, involving displacement of the heart through a pericardial defect, which can lead to hemodynamic instability, impaired cardiac function, and in severe cases, death. We describe a case of delayed cardiac herniation 1-month post left pneumonectomy for pulmonary leiomyosarcoma.

Intraoperative cytokine adsorption in cardiothoracic transplant patients: an Australian propensity-score matched pilot study.

BACKGROUND: It is unclear if immunomodulation via cytokine adsorption (CA) to reduce perioperative inflammatory cascade in cardiothoracic transplants is associated with better outcomes. OBJECTIVE: This pilot study aims to assess the clinical outcomes of intraoperative CA in heart/lung transplantation. METHODS: From July to October 2020, intraoperative CA was instituted in 11 patients who underwent heart/lung transplantation. One-to-one propensity score matching without replacement was conducted with historical patients who did not receive CA at the time of surgery. Primary end-points evaluated were vasopressor/ inotropic demands, blood loss and mortality. Secondary end-points measured were operative morbidities. RESULTS: After matching, there were 2 (18.2%) ventricular assist device explant with heart transplantation, 2 (18.2%) heart transplantation and 7 (63.6%) lung transplantation in each group. Mean age in both groups were 53.3 years and 54.9 years respectively. The duration of noradrenaline requirement in the CA group was shorter (median, 1627 versus 3144 min, P = 0.5) and postoperative dopamine demand was significantly higher (median peak dose, 5.0 versus 0 µg/kg/min, P = 1.0; median duration of use, 7729 versus 0 min, P = 0.01). Non-red blood cell transfusion rate was two times higher in CA patients (90.9% versus 45.4%, P = 0.06). Early mortality was higher in the control group (18.2% versus 9.1%, P = 1.0). No differences were observed in the incidences of operative morbidities. CONCLUSION: Intraoperative CA in heart and lung transplantation in our institution was not associated with significant improvement in clinical outcomes, including vasopressor/inotropic demand. Larger studies are required to evaluate the transfusion requirements and mortality risks with CA use in this patient population.

A Pragmatic Informatics Approach to Develop Knowledge Tools for Supporting Cardiac Surgical Patients' Mental Health Needs.

A pragmatic informatics approach was developed to create knowledge tools for co-design of a new model of mental healthcare in cardiac surgery The real-world evidence generation leverages existing technological platforms and routine data collections plus tailored brief tools, surveys and qualitative data.

A rare case of true thymic hyperplasia in an adult.

True thymic hyperplasia (TTH) is a rare cause of a fat-containing mediastinal mass, most commonly found in infants and young children. We report a case of TTH in a 22-year-old adult, successfully managed via minimally invasive video-assisted thoracoscopic surgery.

Comparison of Lung Cancer Surgery Outcomes in Queensland for Indigenous and Nonindigenous Australians.

Introduction: Indigenous Australians (Aboriginal and Torres Strait Islander) have lower overall survival from lung cancer compared with nonindigenous Australians. Indigenous Australians receive higher rates of chemotherapy and/or radiotherapy. The equity of peri-operative care and thoracic surgical outcomes in Australian indigenous populations have not been contemporarily evaluated. Methods: We performed a retrospective registry analysis of the Queensland Cardiac Outcomes Registry Thoracic Database evaluating all adult lung cancer resections across Queensland from January 1, 2016 to April 20, 2022. Evaluating the time from diagnosis to surgery, operative data, and postoperative morbidity and mortality comparing Aboriginal and/or Torres Strait Islander people with nonindigenous Australians. Results: There were 31 patients (2.56%) of 1208 who identified as indigenous. The mean age at surgery was 68.2 years versus 66 years in the indigenous and nonindigenous, respectively (p = 0.23). There was female predominance among indigenous patients (n = 28, 90.32%, p < 0.01) and the average body mass index was lower (22.52 versus 27.09, p < 0.01). There was no variation in the surgical parameters or histopathologic distribution of cancer type between groups. Multivariable logistic regression analysis suggested that indigenous patients were at elevated risk of blood transfusion (relative risk 3.9, p = 0.014, OR = 9.01, 95% confidence interval [CI]: 2.25-36.33, p < 0.01) and had greater transfusion requirements (risk ratio 4.08, p = 0.0116 and OR = 12.67, 95% CI: 2.25-71.49, p < 0.01); however, the influence of low absolute number of transfusions must be acknowledged here. Indigenous status was not associated with increased intensive care unit admission (OR = 1.79, 95% CI: 0.17-18.80, p = 0.62), return to operating theater (OR = 2.1, 95% CI: 0.24-18.15, p = 0.50), new atrial fibrillation (OR = 0.52, 95% CI: 0.07-4.01, p = 0.55), prolonged air leak (OR = 0.29, 95% CI: 0.04- 2.16, p = 0.228), or pneumonia postoperatively (OR = 4.77, 95% CI: 0.55-41.71, p = 0.16). With only three deaths, no meaningful trends were observed. Time from diagnosis to surgery was comparable in the indigenous and nonindigenous groups (88.6 d, 95% CI: 54.26-123.24 versus 86.2 d, 81.40-91.02, p = 0.87). Postoperative length of stay was not numerically or statistically different between groups. (indigenous 7.54 d versus nonindigenous 7.13 d, p = 0.90). Conclusions: Indigenous patients are more likely to receive a blood transfusion than nonindigenous patients during lung resection. Reassuringly, the perioperative care provided to indigenous Australians undergoing lung resection in Queensland seems to be comparable to that of the nonindigenous population.

The influence of the COVID-19 pandemic on lung cancer surgery in Queensland.

BACKGROUND: The coronavirus disease-19 (COVID-19) pandemic poses unprecedented challenges to global healthcare. The contemporary influence of COVID-19 on the delivery of lung cancer surgery has not been examined in Queensland. METHODS: We performed a retrospective registry analysis of the Queensland Cardiac Outcomes Registry (QCOR), thoracic database examining all adult lung cancer resections across Queensland from 1/1/2016 to 30/4/2022. We compared the data prior to, and after, the introduction of COVID-restrictions. RESULTS: There were 1207 patients. Mean age at surgery was 66 years and 1115 (92%) lobectomies were performed. We demonstrated a significant delay from time of diagnosis to surgery from 80 to 96 days (P < 0.0005), after introducing COVID-restrictions. The number of surgeries performed per month decreased after the pandemic and has not recovered (P = 0.012). 2022 saw a sharp reduction in cases with 49 surgeries, compared to 71 in 2019 for the same period. CONCLUSION: Restrictions were associated with a significant increase in pathological upstaging, greatest immediately after the introduction of COVID-restrictions (IRR 1.71, CI 0.93-2.94, P = 0.05). COVID-19 delayed the access to surgery, reduced surgical capacity and consequently resulted in pathological upstaging throughout Queensland.

Pleural fluid cell-free DNA integrity index to identify cytologically negative malignant pleural effusions including mesotheliomas.

BACKGROUND: The diagnosis of malignant pleural effusions (MPE) is often clinically challenging, especially if the cytology is negative for malignancy. DNA integrity index has been reported to be a marker of malignancy. The aim of this study was to evaluate the utility of pleural fluid DNA integrity index in the diagnosis of MPE. METHODS: We studied 75 pleural fluid and matched serum samples from consecutive subjects. Pleural fluid and serum ALU DNA repeats [115bp, 247bp and 247bp/115bp ratio (DNA integrity index)] were assessed by real-time quantitative PCR. Pleural fluid and serum mesothelin levels were quantified using ELISA. RESULTS: Based on clinico-pathological evaluation, 52 subjects had MPE (including 16 mesotheliomas) and 23 had benign effusions. Pleural fluid DNA integrity index was higher in MPE compared with benign effusions (1.2 vs. 0.8; p<0.001). Cytology had a sensitivity of 55% in diagnosing MPE. If cytology and pleural fluid DNA integrity index were considered together, they exhibited 81% sensitivity and 87% specificity in distinguishing benign and malignant effusions. In cytology-negative pleural effusions (35 MPE and 28 benign effusions), elevated pleural fluid DNA integrity index had an 81% positive predictive value in detecting MPEs. In the detection of mesothelioma, at a specificity of 90%, pleural fluid DNA integrity index had similar sensitivity to pleural fluid and serum mesothelin (75% each respectively). CONCLUSION: Pleural fluid DNA integrity index is a promising diagnostic biomarker for identification of MPEs, including mesothelioma. This biomarker may be particularly useful in cases of MPE where pleural aspirate cytology is negative, and could guide the decision to undertake more invasive definitive testing. A prospective validation study is being undertaken to validate our findings and test the clinical utility of this biomarker for altering clinical practice.

Fluid resuscitation after cardiac surgery in the intensive care unit: A bi-national survey of clinician practice. (The FRACS-ICU clinician survey).

Context and Aims: To describe current fluid and vasopressor practices after cardiac surgery in Australia and New Zealand cardiothoracic intensive care units (ICU). Design and Setting: This web-based survey was conducted in cardiothoracic ICUs in Australia and New Zealand. Methods: Intensivists, cardiac surgeons, and anesthetists were contacted to complete the online survey that asked questions regarding first and second choice fluids and vasopressors and the tools and factors that influenced these choices. Results: There were 96 respondents including 51 intensivists, 27 anesthetists, and 18 cardiac surgeons. Balanced crystalloids were the most preferred fluids (70%) followed by 4% albumin (18%) overall and among intensivists and anesthetists; however, cardiac surgeons (41%) preferred 4% albumin as their first choice. The most preferred second choice was 4% albumin (74%). Among vasopressors, noradrenaline was the preferred first choice (93%) and vasopressin the preferred second choice (80%). 53% initiated blood transfusion at a hemoglobin threshold of 70 g/L. Clinical acumen and mean arterial pressure were the most commonly used modalities in determining the need for fluids. Conclusions: There is practice variation in preference for fluids used in cardiac surgical patients in Australia and New Zealand; however, balanced crystalloids and 4% albumin were the most popular choices. In contrast, there is broad agreement with the use of noradrenaline and vasopressin as first and second-line vasopressors. These data will inform the design of future studies that aim to investigate hemodynamic management post cardiac surgery.

Albumin Use After Cardiac Surgery.

OBJECTIVES: To investigate the effect of albumin exposure in ICU after cardiac surgery on hospital mortality, complications, and costs. DESIGN: A retrospective, single-center cohort study with economic evaluation. SETTING: Cardiothoracic ICU in Australia. PATIENTS: Adult patients admitted to the ICU after cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Comparison of outcomes and costs in ICU after cardiac surgery based on 4% human albumin exposure. During the study period, 3,656 patients underwent cardiac surgery. After exclusions, 2,594 patients were suitable for analysis. One-thousand two-hundred sixty-four (48.7%) were exposed to albumin and 19 (1.4%) of those died. The adjusted hospital mortality of albumin exposure compared with no albumin was not significant (odds ratio, 1.24; 95% CI, 0.56-2.79; p = 0.6). More patients exposed to albumin returned to the operating theater for bleeding and/or tamponade (6.1% vs 2.1%; odds ratio, 2.84; 95% CI, 1.81-4.45; p < 0.01) and received packed red cell transfusions (p < 0.001). ICU and hospital lengths of stay were prolonged in those exposed to albumin (mean difference, 18 hr; 95% CI, 10.3-25.6; p < 0.001 and 87.5 hr; 95% CI, 40.5-134.6; p < 0.001). Costs (U.S. dollar) were higher in patients exposed to albumin, compared with those with no albumin exposure (mean difference in ICU costs, $2,728; 95% CI, $1,566-3,890 and mean difference in hospital costs, $5,427; 95% CI, $3,294-7,560). CONCLUSIONS: There is no increased mortality in patients who are exposed to albumin after cardiac surgery. The patients exposed to albumin had higher illness severity, suffered more complications, and incurred higher healthcare costs. A randomized controlled trial is required to determine whether albumin use is effective and safe in this setting.

Validation of the Eighth Edition TNM Lung Cancer Staging System.

INTRODUCTION: We performed a validation study at our institution, the International Union Against Cancer (Union for International Cancer Control latest version of TNM Classification of Malignant Tumors Eighth Edition). METHODS: Data were collected from the Queensland Oncology Online registry of NSCLC or SCLC cases between 2000 and 2015 and validated against the Queensland Integrated Lung Cancer Outcomes Project registry using case identification number, first name, last name, and date of birth. Where data were available, cases were classified according to the Union for International Cancer Control TNM seventh edition stage groupings and then compared with the eighth edition groupings. Kaplan-Meier curves were plotted, and the log-rank test of survival differences was performed with SPSS version 25 (IBM Corp, Armonk, NY). RESULTS: Of the 3636 cases, 3352 and 1031 had complete clinical and pathologic staging, respectively. Median survival time was found to reduce with increasing clinical stage: seventh edition (IA: 88, IB: 44, IIA: 31, IIB: 18, IIIA: 15, IIIB: 8, and IV: 5 mo) versus eighth edition TNM stage (IA1: not reached, IA2: 88, IA3: 53, IB: 56, IIA: 36, IIB: 22, IIIA: 14, IIIB: 9, IIIC: 8, IVA: 6, and IVB: 3 mo). A similar overall pattern was reflected in the pathologic stage: seventh edition (IA: 124, IB: 110, IIA: 48, IIB: 42, IIIA: 26, IIIB: 31, and IV: 27 mo) versus eighth edition (IA1: not reached, IA2: 122, IA3: 125, IB: 144, IIA: 98, IIB: 57, IIIA: 31, IIIB: 24, and IVA: 7 mo). The log-rank test for survival curves was significant at p < 0.001. CONCLUSIONS: Our external validation study confirms the prognostic accuracy of the eighth edition TNM lung cancer classification. Our analyses also indicated that IIIB, IIIC, and IVA stage groups had similar survival outcomes and suggest further research for refinement.

Pharmacodynamics of Pre-Operative PD1 checkpoint blockade and receptor activator of NFkB ligand (RANKL) inhibition in non-small cell lung cancer (NSCLC): study protocol for a multicentre, open-label, phase 1B/2, translational trial (POPCORN).

BACKGROUND: Neoadjuvant immunotherapy targeting immune checkpoint programmed death-1 (PD-1) is under investigation in various tumour settings including non-small-cell lung cancer (NSCLC). Preclinical models demonstrate the superior power of the immunotherapy provided in a neoadjuvant (pre-operative) compared with an adjuvant (post-operative) setting to eradicate metastatic disease and induce long-lasting antigen-specific immunity. Novel effective immunotherapy combinations are widely sought in the oncology field, targeting non-redundant mechanisms of immune evasion. A promising combination partner with anti-PD1 in NSCLC is denosumab, a monoclonal antibody blocking receptor activator of NF-κB ligand (RANKL). In preclinical cancer models and in a large retrospective case series in NSCLC, anti-cancer activity has been reported for the combination of immune checkpoint inhibition (ICI) and denosumab. Furthermore, clinical trials of ICI and denosumab are underway in advanced melanoma and clear-cell renal cell carcinoma. However, the mechanism of action of combination anti-PD1 and anti-RANKL is poorly defined. METHODS: This open-label multicentre trial will randomise by minimisation 30 patients with resectable stage IA (primary > 2 cm) to IIIA NSCLC to a neoadjuvant treatment regime of either two doses of nivolumab (3 mg/kg every 2 weeks) or two doses of nivolumab (same regimen) plus denosumab (120 mg every 2 weeks, following nivolumab). Each treatment arm is of equal size and will be approximately balanced with respect to histology (squamous vs. non-squamous) and clinical stage (I-II vs. IIIA). All patients will receive surgery for their tumour 2 weeks after the final dose of neoadjuvant therapy. The primary outcome will be translational research to define the tumour-immune correlates of combination therapy compared with monotherapy. Key secondary outcomes will include a comparison of rates of the following between each arm: toxicity, response (pathological and radiological), and microscopically complete resection. DISCUSSION: The POPCORN study provides a unique platform for translational research to determine the mechanism of action of a novel proposed combination immunotherapy for cancer. TRIAL REGISTRATION: Prospectively registered on Australian New Zealand Clinical Trials Registry (ACTRN12618001121257) on 06/07/2018.

Study Protocol for a Pilot, Open-Label, Prospective, and Observational Study to Evaluate the Pharmacokinetics of Drugs Administered to Patients during Extracorporeal Circulation; Potential of In Vivo Cytochrome P450 Phenotyping to Optimise Pharmacotherapy.

Pharmacokinetic alterations of medications administered during surgeries involving cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO) have been reported. The impact of CPB on the cytochrome P450 (CYP) enzymes' activity is the key factor. The metabolic rates of caffeine, dextromethorphan, midazolam, omeprazole, and Losartan to the CYP-specific metabolites are validated measures of in vivo CYP 1A2, 2D6, 3A4, 2C19, and 2C9 activities, respectively. The study aim is to assess the activities of major CYPs in patients on extracorporeal circulation (EC). This is a pilot, prospective, open-label, observational study in patients undergoing surgery using EC and patients undergoing laparoscopic cholecystectomy as a control group. CYP activities will be measured on the day, and 1-2 days pre-surgery/3-4 days post-surgery (cardiac surgery and Laparoscopic cholecystectomy) and 1-2 days after starting ECMO, 1-2 weeks after starting ECMO, and 1-2 days after discontinuation from ECMO. Aforementioned CYP substrates will be administered to the patient and blood samples will be collected at 0, 1, 2, 4, and 6 h post-dose. Major CYP enzymes' activities will be compared in each participant on the day, and before/after surgery. The CYP activities will be compared in three study groups to investigate the impact of CYPs on EC.