Recent Submissions

  • Evaluating niraparib versus active symptom control in patients with previously treated mesothelioma (NERO): a study protocol for a multicentre, randomised, two-arm, open-label phase II trial in UK secondary care centres

    Fennell, Dean; Darlison, Liz; Dulloo, Sean; Poile, Charlotte (2023-11-22)
    Background: Malignant mesothelioma is a rapidly lethal cancer that has been increasing at an epidemic rate over the last three decades. Targeted therapies for mesothelioma have been lacking. A previous study called MiST1 (NCT03654833), evaluated the efficacy of Poly (ADP-ribose) polymerase (PARP) inhibition in mesothelioma. This study met its primary endpoint with 15% of patients having durable responses exceeding 1 year. Therefore, there is a need to evaluate PARP inhibitors in relapsed mesothelioma patients, where options are limited. Niraparib is the PARP inhibitor used in NERO. Methods: NERO is a multicentre, two-arm, open-label UK randomised phase II trial designed to evaluate the efficacy of PARP inhibition in relapsed mesothelioma. 84 patients are being recruited. NERO is not restricted by line of therapy; however, eligible participants must have been treated with an approved platinum based systemic therapy. Participants will be randomised 2:1, stratified according to histology and response to prior platinum-based chemotherapy, to receive either active symptom control (ASC) and niraparib or ASC alone, for up to 24 weeks. Participants will be treated until disease progression, withdrawal, death or development of significant treatment limiting toxicity. Participants randomised to niraparib will receive 200 or 300 mg daily in a 3-weekly cycle. The primary endpoint is progression-free survival, where progression is determined by modified Response Evaluation Criteria in Solid Tumors (mRECIST) or RECIST 1.1; investigator reported progression; or death from any cause, whichever comes first. Secondary endpoints include overall survival, best overall response, 12-week and 24 week disease control, duration of response, treatment compliance and safety/tolerability. If NERO shows niraparib to be safe and biologically effective, it may lead to future late phase randomised controlled trials in relapsed mesothelioma. Ethics and dissemination: The study received ethical approval from London-Hampstead Research Ethics Committee on 06-May-2022 (22/LO/0281). Data from all centres will be analysed together and published as soon as possible. Trial registration number: ISCRTN16171129; NCT05455424.
  • Enabling adults with severe asthma to exercise: a qualitative examination of the challenges for patients and health care professionals

    Evans, Rachael A; Bradding, Peter; Green, Ruth H; Murphy, Anna C; Singh, Sally J (2023-11)
    Background: Adults living with severe asthma have lower physical activity levels, particularly high-intensity physical activity, compared with their healthy peers. Physical inactivity is associated with increased morbidity and mortality. Objective: To understand patient and health care professional attitudes toward exercise and physical activity to inform future strategies for the improvement of healthy lifestyle behaviors, including exercise. Methods: Participants recruited from a specialist difficult asthma service were interviewed individually, and health care professionals (HCPs) from primary care, secondary care, and a tertiary center were invited to attend focus groups. Interviews and focus groups were transcribed verbatim. We performed thematic analysis on interviews and focus groups separately, followed by an adapted framework analysis to analyze datasets together. Results: Twenty-nine people with severe asthma participated in a semi-structured interview. A total of 51 HCPs took part in eight focus groups across the East Midlands, United Kingdom. Final analysis resulted in three major themes: barriers to exercise and exercise counseling - in which patients and HCPs identified disease and non-disease factors affecting those living with severe asthma; attitudes toward HCP support for exercise - highlighting education needs for HCPs and preference for supervised exercise programs; and areas for system improvement in supporting patients and HCPs - challenges exist across health sectors that limit patient support are described. Conclusions: Patients identified the important role of HCPs in supporting and advising on lifestyle change. Despite a preference for supervised exercise programs, both patient and HCP barriers existed. To meet patients' varied support needs, improved integration of services is required and HCP skills need extending.
  • Gene fusions during the early evolution of mesothelioma correlate with impaired DNA repair and Hippo pathways

    Nakas, Apostolos; Dawson, Alan; Fennell, Dean (2023-07-08)
    Malignant pleural mesothelioma (MPM), a rare cancer a long latency period (up to 40 years) between asbestos exposure and disease presentation. The mechanisms coupling asbestos to recurrent somatic alterations are poorly defined. Gene fusions arising through genomic instability may create novel drivers during early MPM evolution. We explored the gene fusions that occurred early in the evolutionary history of the tumor. We conducted multiregional whole exome sequencing (WES) of 106 samples from 20 patients undergoing pleurectomy decortication and identified 24 clonal nonrecurrent gene fusions, three of which were novel (FMO9P-OR2W5, GBA3, and SP9). The number of early gene fusion events detected varied from zero to eight per tumor, and presence of gene fusions was associated with clonal losses involving the Hippo pathway genes and homologous recombination DNA repair genes. Fusions involved known tumor suppressors BAP1, MTAP, and LRP1B, and a clonal oncogenic fusion involving CACNA1D-ERC2, PARD3B-NT5DC2, and STAB2-NT5DC2 fusions were also identified as clonal fusions. Gene fusions events occur early during MPM evolution. Individual fusions are rare as no recurrent truncal fusions event were found. This suggests the importance of early disruption of these pathways in generating genomic rearrangements resulting in potentially oncogenic gene fusions.
  • Barriers to research progress for perioperative care practitioners working in cardiothoracic surgery

    Rathinam, Sridhar (2023-06-29)
    Policy and research literature worldwide support the need to build research capacity and capability among non-medical practitioners within healthcare systems. However, there exists a paucity of evidence on whether practitioners in cardiothoracic surgery are attuned to this and on what barriers or enablers exist. A survey was carried out with non-medical practitioners working in cardiothoracic surgery in the United Kingdom to explore attitudes towards health research and audit, and to identify current challenges and barriers to surgical research and audit as perceived by cardiothoracic nurses and allied health professionals. A total of 160 completed questionnaires were returned. 99% of respondents supported the need for research and believed that evidence-based surgical care improves outcomes for patients. Seventy-two percent reported that their employer motivates them to take part in national research or audit but, only 22% were allocated time to do so within their role; 96% reported their interest in being involved in research and audit, yet only 30% believed they had the skills to undertake research, and 96% reported needing additional training. More work is needed to increase awareness, capacity and capability among cardiothoracic surgery care practitioners, and indeed other specialities to achieve research progress.
  • Early video assisted thoracoscopic surgery (VATS) or intrapleural enzyme therapy (IET) in pleural infection - a feasibility randomized controlled trial (the third multicenter intrapleural sepsis trial - MIST-3)

    Panchal, Rakesh; Caruana, Edward (11/10/2023)
    Rationale: Assessing the early use of video-assisted thoracoscopic surgery (VATS) or intrapleural enzyme therapy (IET) in pleural infection requires a phase III randomized controlled trial (RCT). Objectives: To establish the feasibility of randomization in a surgery versus non-surgery trial as well as the key outcome measures which are important to identify relevant patient-centered outcomes in a RCT. Methods: MIST-3 was a prospective multicenter RCT. All-comers with a confirmed diagnosis of pleural infection were enrolled and those with ongoing pleural sepsis after up to 24-hours of standard care were randomized to one of 3 arms; continued standard care, IET, or surgical opinion for VATS. The analysis was by intention to treat, despite some participants in the VATS arm not being fit enough to undergo surgical intervention. Main results: Of 97 eligible patients, 60 (62%) participants were randomized. Despite a difference in time-to-intervention, length of stay was similar in both arms. There were no significant inter-group differences in 2-month readmission and further intervention. Compared to VATS, IET demonstrated a greater improvement in mean EQ-5D-5L health utility index at 2 months from baseline. Conclusion: This is the first multicenter RCT of early IET vs early surgery in pleural infection. Despite logistical challenges posed by the COVID-19 pandemic, the study met its predefined feasibility criteria. Potential shortening of LOS with early surgery, and signals toward earlier resolution of pain and shortened recovery with IET were demonstrated. The study findings suggest that a definitive study is feasible and required to assess optimal initial management. Clinical trial registration available at www.isrctn.com, ID: ISRCTN18192121.
  • The impact of perioperative NSAID use on pleurodesis following thoracic surgery

    Kutywayo, Kudzayi; Habib, Akolade; Caruana, Edward (04/09/2023)
    A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was: in patients who have had {visceral and parietal pleural symphysis}, {do NSAIDs reduce} {the efficacy of pleurodesis}? 16 papers were discovered in the search. Of these, 3 human studies were included in the analysis. None showed a significantly higher rate of pleurodesis failure in patients given perioperative NSAIDs. The results from the largest study met criteria for non-inferiority. Within the constraints of the study the results suggest that systemic administration of non-steroidal anti-inflammatory medication in the peri-operative period does not necessarily attenuate effective pleurodesis. However further study is needed as there is a clear paucity of human based studies.
  • International RELAY®, branched outcomes - designed to respect and repair the thoracic aorta: A comparative analysis between double and triple branched configurations

    Mariscalco, Giovanni (2023-06-04)
    Background: Endovascular aortic arch repair (EAR) has emerged as an alternative to open surgical repair. A growing interest in endovascular repair techniques for aortic arch aneurysms and dissection has been met with a focus on the clinical efficacy of EAR devices. We present multicentre comparative data on the clinical outcomes associated with EAR using the double- and triple-branched configurations of the RELAY™ (Terumo Aortic, Scotland, UK) endograft. Methods: Multicentre data on EAR procedures, carried out from January 2019 to January 2022, using the double- and triple-branched RELAY™ endograft were collected prospectively. Follow-up data were collected at 30 days, 6 months, 12 months, and 24 months postoperative. Retrospective descriptive analysis, logistic regression, and Kaplan-Meier analysis were carried out on procedural and follow-up data. Results: A total of 131 patients were included in the series. In total, 103 and 28 patients were treated with the double-branched and triple-branched RELAY™ endograft, respectively. Over the 24-month follow-up period, zero mortality, cases of stroke, or reinterventions were recorded in the triple-branched group. Four mortalities, 19 disabling strokes, and 50 reinterventions were recorded in the double-branched group within 30 postoperative days. Target vessel patency was maintained in all patients in the triple-branched group, while vessel patency was maintained in 74.0% of patients in the double-branched group. Conclusion: Outcomes associated with the triple-branched group are consistent with those reported in the literature. Our data suggest that EAR with the RELAY™ endograft is associated with favourable clinical outcomes and clinical efficacy. Further comparative research into EAR devices is needed.
  • The evolution of non-small cell lung cancer metastases in TRACERx

    Fennell, Dean (2023-04-12)
    Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse.
  • The evolution of lung cancer and impact of subclonal selection in TRACERx

    Fennell, Dean (2023-04-12)
    Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.
  • Lung volume reduction surgery versus endobronchial valves: a randomised controlled trial

    Greening, Neil; Latimer, Lorna; Rathinam, Sridhar; Steiner, Michael (2023-04-27)
    Background: Lung volume reduction surgery (LVRS) and bronchoscopic lung volume reduction (BLVR) with endobronchial valves can improve outcomes in appropriately selected patients with emphysema. However, no direct comparison data exist to inform clinical decision making in people who appear suitable for both procedures. Our aim was to investigate whether LVRS produces superior health outcomes when compared with BLVR at 12 months. Methods: This multicentre, single-blind, parallel-group trial randomised patients from five UK hospitals, who were suitable for a targeted lung volume reduction procedure, to either LVRS or BLVR and compared outcomes at 1 year using the i-BODE score. This composite disease severity measure includes body mass index, airflow obstruction, dyspnoea and exercise capacity (incremental shuttle walk test). The researchers responsible for collecting outcomes were masked to treatment allocation. All outcomes were assessed in the intention-to-treat population. Results: 88 participants (48% female, mean±sd age 64.6±7.7 years, forced expiratory volume in 1 s percent predicted 31.0±7.9%) were recruited at five specialist centres across the UK and randomised to either LVRS (n=41) or BLVR (n=47). At 12 months follow-up, the complete i-BODE was available in 49 participants (21 LVRS/28 BLVR). Neither improvement in the i-BODE score (LVRS -1.10±1.44 versus BLVR -0.82±1.61; p=0.54) nor in its individual components differed between groups. Both treatments produced similar improvements in gas trapping (residual volume percent predicted: LVRS -36.1% (95% CI -54.6- -10%) versus BLVR -30.1% (95% CI -53.7- -9%); p=0.81). There was one death in each treatment arm. Conclusion: Our findings do not support the hypothesis that LVRS is a substantially superior treatment to BLVR in individuals who are suitable for both treatments.
  • BAP1 loss induces mitotic defects in mesothelioma cells through BRCA1-dependent and independent mechanisms

    Nakas, Apostolos; Dawson, Alan; Fennell, Dean (2022-12-22)
    The tumour suppressor BRCA1-associated protein 1 (BAP1) is the most frequently mutated cancer gene in mesothelioma. Here we report novel functions for BAP1 in mitotic progression highlighting the relationship between BAP1 and control of genome stability in mesothelioma cells with therapeutic implications. Depletion of BAP1 protein induced proteasome-mediated degradation of BRCA1 in mesothelioma cells while loss of BAP1 correlated with BRCA1 loss in mesothelioma patient tumour samples. BAP1 loss also led to mitotic defects that phenocopied the loss of BRCA1 including spindle assembly checkpoint failure, centrosome amplification and chromosome segregation errors. However, loss of BAP1 also led to additional mitotic changes that were not observed upon BRCA1 loss, including an increase in spindle length and enhanced growth of astral microtubules. Intriguingly, these consequences could be explained by loss of expression of the KIF18A and KIF18B kinesin motors that occurred upon depletion of BAP1 but not BRCA1, as spindle and astral microtubule defects were rescued by re-expression of KIF18A and KIF18B, respectively. We therefore propose that BAP1 inactivation causes mitotic defects through BRCA1-dependent and independent mechanisms revealing novel routes by which mesothelioma cells lacking BAP1 may acquire genome instability and exhibit altered responses to microtubule-targeted agents.
  • Extracellular vesicles isolated from malignant mesothelioma cancer-associated fibroblasts induce pro-oncogenic changes in healthy mesothelial cells

    Nakas, Apostolos (2022-10-18)
    Malignant mesothelioma is an aggressive tumour of the pleura (MPM) or peritoneum with a clinical presentation at an advanced stage of the disease. Current therapies only marginally improve survival and there is an urgent need to identify new treatments. Carcinoma-associated fibroblasts (CAFs) represent the main component of a vast stroma within MPM and play an important role in the tumour microenvironment. The influence of CAFs on cancer progression, aggressiveness and metastasis is well understood; however, the role of CAF-derived extracellular vesicles (CAF-EVs) in the promotion of tumour development and invasiveness is underexplored. We purified CAF-EVs from MPM-associated cells and healthy dermal human fibroblasts and examined their effect on cell proliferation and motility. The data show that exposure of healthy mesothelial cells to EVs derived from CAFs, but not from normal dermal human fibroblasts (NDHF) resulted in activating pro-oncogenic signalling pathways and increased proliferation and motility. Consistent with its role in suppressing Yes-Associated Protein (YAP) activation (which in MPM is a result of Hippo pathway inactivation), treatment with Simvastatin ameliorated the pro-oncogenic effects instigated by CAF-EVs by mechanisms involving both a reduction in EV number and changes in EV cargo. Collectively, these data determine the significance of CAF-derived EVs in mesothelioma development and progression and suggest new targets in cancer therapy.
  • ERS international congress 2021: highlights from the thoracic surgery and lung transplantation assembly

    Caruana, Edward
    The thoracic surgery and lung transplantation assembly of the European Respiratory Society (ERS) is delighted to present the highlights from the 2021 ERS International Congress. We have selected four sessions that discussed recent advances across a wide range of topics including: digital health surveillance in thoracic surgery, emerging concepts in pulmonary metastasectomy, advances in mesothelioma care, and novel developments in lung graft allocation and monitoring. The sessions are summarised by early career members in close collaboration with the assembly faculty. We aim to give the reader an update on the highlights of the conference in the fields of thoracic surgery and lung transplantation.
  • Do older surgeons have safer hands? A retrospective cohort study

    Caruana, Edward
    Background: For complex surgical procedures a volume-outcome relationship can often be demonstrated implicating multiple factors at a unit and surgeon specific level. This study aims to investigate this phenomenon in lung transplantation over a 30-year period with particular reference to surgeon age and experience, cumulative unit activity and time/day of transplant. Methods: Prospective databases identified adult patients undergoing isolated lung transplantation at a single UK centre between June 1987 and October 2017. Mortality data was acquired from NHS Spine. Individual surgeon demographics were obtained from the General Medical Council. Student t-test, Pearson's Chi-squared, Logistic Regression, and Kaplan-Meier Survival analyses were performed using Analyse-it package for MicrosoftExcel and STATA/IC. Results: 954 transplants (55.9% male, age 44.4 ± 13.8 years, 67.9% bilateral lung) were performed, with a median survival to follow-up of 4.37 years. There was no difference in survival by recipient gender (p = 0.661), between individual surgeons (p = 0.224), or between weekday/weekend procedures (p = 0.327). Increasing centre experience with lung transplantation (OR1.001, 95%CI: 1.000-1.001, p = 0.03) and successive calendar years (OR1.028, 95%CI: 1.005-1.052, p = 0.017) was associated with improved 5-year survival. Advancing surgeon age at the time of transplant (mean, 48.8 ± 6.6 years) was associated with improved 30-day survival (OR1.062, 95%CI: 1.019 to1.106, p = 0.003), which persisted 5 years post-transplant (OR1.043, 95%CI: 1.014-1.073, p = 0.003). Individual surgeon experience, measured by the number of previous lung transplants performed, showed a trend towards improved outcomes at 30 days (p = 0.0413) with no difference in 5-year survival (p = 0.192). Conclusions: Our study demonstrates a relationship between unit volume, increasing surgeon age and survival after lung transplantation. A transplant volume: outcome relationship was not seen for individual surgeons.
  • Cytoreductive surgery with hyperthermic intrathoracic chemotherapy for malignant pleural mesothelioma: a systematic review

    Dawson, Alan; Kutywayo, Kudzayi; Fennell, Dean; Fakis, Apostolos (2022-04-11)
    Introduction: Cytoreductive surgery has been used a part of multimodality treatment in patients with malignant pleural mesothelioma (MPM). The residual microscopic disease that remains will lead to disease progression in the majority of patients. Delivery of hyperthermic intrathoracic chemotherapy at the time of surgery has been used to address this microscopic disease, however it's effect and place in the multimodality treatment sphere is unknown. The aim of this systematic review was to assess the effect of surgery and hyperthermic intrathoracic chemotherapy in patients with MPM on overall survival and disease-free interval. Methods: Ovid MEDLINE, Embase, Web of Science and the Cochrane Database of Systematic Reviews were searched from database inception through to June 2021. Studies reporting overall survival and/or disease-free interval in patients with MPM undergoing cytoreductive surgery with hyperthermic intrathoracic chemotherapy were considered. Study quality was assessed using the Newcastle-Ottawa Scale. A narrative review was performed. Results: Fifteen studies were eligible for inclusion comprising 598 patients. Surgery with hyperthermic intrathoracic chemotherapy was associated with a median overall survival and disease-free interval ranging from 11 to 75 months and 7.2 to 57 months, respectively. These appeared to be superior to patients not receiving hyperthermic intrathoracic chemotherapy (overall survival: 5-36 months and disease-free interval: 12.1-21 months). A higher dose of hyperthermic intrathoracic chemotherapy was associated with an improvement in overall survival compared with a lower dose: 18-31 months versus 6-18 months, respectively. The most common morbidity was atrial fibrillation followed by renal complications. Conclusion: Surgery with hyperthermic intrathoracic chemotherapy offers a safe and effective therapy with an improvement in disease-free interval and overall survival, particularly when hyperthermic intrathoracic chemotherapy is administered at a higher dose. Prospero registration number: CRD42019129002.
  • Utilization of high-pressure suction for EBUS-TBNA sampling in suspected lung cancer

    Rathinam, Sridhar (2022-04-01)
    Background: Sample adequacy for immediate molecular testing is paramount in lung cancer. To date, several endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) sampling setups have been evaluated, however, the utilization of high-pressure suction (HPS) has not yet been reported.The aim of this study was to evaluate the utilization of HPS onto the needle and its effect on sample volume and adequacy for molecular testing in patients with suspected lung cancer. Methods: We retrospectively analyzed 128 consecutive EBUS-TBNA performed for suspected lung cancer. This was confirmed in 109 patients. Other diagnoses confirmed in 12, and 7 referred for surgery. Sixty-three patients (89 targets) had HPS (May to September 2020), and compared with 46 (72 targets) who had standard vacuum syringe suction (October 2019 to March 2020). Several parameters and outcomes evaluated, such as number of needle passes, needle strokes, needle size, target size, positron emission tomography avidity, procedure time, blood content score, sample volume, adequacy for molecular testing, as well as baseline patient characteristics and complication rate. Results: There was no difference between the 2 groups in all baseline parameters and characteristics. In multivariable analysis, HPS was associated with significantly higher sample volume (11.2 vs. 9.1 mm3, P=0.036) and less additional procedures to achieve full molecular profiling (2/52 vs. 7/40, P=0.042), in necrotic targets of non-small cell lung cancer. Diagnostic yields were comparable. Conclusion: HPS appears to be simple, no-cost, and safe, promising higher sample volume compared with vacuum syringe suction, and also appears to be associated with higher success of full molecular testing with less additional procedures, in non-small cell lung cancer necrotic targets.
  • A systematic review of the quality of abstracts reporting on randomized controlled trials presented at major international cardiothoracic conferences

    Caruana, Edward (2022-03-17)
    Conference proceedings are widely available and may represent the only report of given research. Poor reporting of randomized controlled trials (RCTs) in conference abstracts may impede interpretability. In 2008, the Consolidating Standards of Reporting Trials group published minimum standards for RCT reporting in conference abstracts (CONSORT-A). We sought to evaluate the reporting quality of abstracts presented at major international cardiothoracic conferences. Abstracts were retrieved for the annual meetings of 5 cardiothoracic societies over 3 consecutive years (2016 to 2018). After screening, those reporting on RCTs were scored by 2 independent reviewers against the 17-item CONSORT-A checklist. The primary endpoint was the total number of checklist criteria reported in individual abstracts. Statistical analysis was performed using STATA ICv16. Of 3233 screened abstracts, 100 (3.1%) reported on RCTs. Average checklist adherence was 35% (median 6/17 items, IQR 2-15) across abstracts. Author contact (n = 0), funding disclosures (n = 3, 2.9%) and randomization methodology (n = 5, 4.8%) were the least-frequently reported. There was no statistically-significant difference in terms of reporting quality between conferences (n = 0.07) or years (p = .06). Trial registration, word count (>300), multicentre trial design and mention of CONSORT in the abstract were associated with higher reporting quality. Reporting quality was not associated with successful full-length publication within 2 years (p = .33). The reporting quality of abstracts of RCTs presented at international cardiothoracic conferences is poor when benchmarked against the CONSORT-A standards. This highlights an area for targeted improvement.
  • True thymic hyperplasia causing pure red cell aplasia: a case report

    Mohammad, Adam; Dawson, Alan; Bajaj, Amrita; Rathinam, Sridhar (2021-11-13)
    Pure red cell aplasia caused by true thymic hyperplasia is extremely rare. We report the case of a 25-year-old female diagnosed with pure red cell aplasia. Following a thymectomy confirming true thymic hyperplasia and corticosteroid therapy, complete response was achieved. Patients diagnosed with pure red cell aplasia should be investigated with a computerized tomographic scan to assess for thymic pathology and if present, this should be resected. Follow-up is essential to monitor for recurrence.
  • Revascularization of occluded right coronary artery and outcome after coronary artery bypass grafting

    El-Dean, Zein; Mariscalco, Giovanni
    Objectives: The aim of the present study was to evaluate the results of isolated coronary artery bypass grafting (CABG) with or without revascularization of the occluded right coronary artery (RCA). Methods: Patients undergoing isolated CABG were included in a prospective European multicenter registry. Outcomes were adjusted for imbalance in preoperative variables with propensity score matching analysis. Late outcomes were evaluated with Kaplan-Meier's method and competing risk analysis. Results: Out of 2,948 included in this registry, 724 patients had a total occlusion of the RCA and were the subjects of this analysis. Occluded RCA was not revascularized in 251 (34.7%) patients with significant variability between centers. Among 245 propensity score-matched pairs, patients with and without revascularization of occluded RCA had similar early outcomes. The nonrevascularized RCA group had increased rates of 5-year all-cause mortality (17.7 vs. 11.7%, p = 0.039) compared with patients who had their RCA revascularized. The rates of myocardial infarction and repeat revascularization were only numerically increased but contributed to a significantly higher rate of MACCE (24.7 vs. 15.7%, p = 0.020) at 5 year among patients with nonrevascularized RCA. Conclusions: In this multicenter study, one-third of totally occluded RCAs was not revascularized during isolated CABG for multivessel coronary artery disease. Failure to revascularize an occluded RCA in these patients increased the risk of all-cause mortality and MACCEs at 5 years.
  • Abemaciclib in patients with p16ink4A-deficient mesothelioma (MiST2): a single-arm, open-label, phase 2 trial

    Fennell, Dean; King, Amy; Anthony, Sarah; Poile, Charlotte; Scotland, Molly; Bhundia, Vina; Darlison, Liz; Dawson, Alan; Gaba, Aarti; Hutka, Margaret; et al. (2022)
    Background: Genetically stratified therapy for malignant mesothelioma is unavailable. Mesotheliomas frequently harbour loss of the chromosome 9p21.3 locus (CDKN2A-MTAP), which is associated with shorter overall survival due to loss of the tumour suppressor p16ink4A, an endogenous suppressor of cyclin-dependent kinase (CDK)4 and CDK6. Genetic restoration of p16ink4A suppresses mesothelioma in preclinical models, underpinning the rationale for targeting CDK4 and CDK6 in p16ink4A-negative mesothelioma. We developed a multicentre, stratified, phase 2 trial to test this hypothesis. Methods: The MiST2 study was a single-arm, open-label, phase 2 clinical trial done two UK centres. Patients older than 18 years with any histologically confirmed subtype of mesothelioma (pleural or peritoneal) with radiological progression after at least one course of platinum-based chemotherapy were molecularly screened by immunohistochemistry for p16ink4A. Patients with p16ink4A-negative mesothelioma were eligible for inclusion in the study. Patients were required to have measurable disease by modified Response Evaluation Criteria in Solid Tumours version 1.1 for malignant mesothelioma, a predicted life expectancy of at least 12 weeks, and an Eastern Cooperative Oncology Group performance status score of 0-1. Patients received oral abemaciclib 200 mg twice daily, administered in 28-day cycles for 24 weeks. The primary endpoint was the disease control rate (patients with complete responses, partial responses, or stable disease) at 12 weeks. The null hypothesis could be rejected if at least 11 patients had disease control. The efficacy and safety populations were defined as all patients who received at least one dose of the study drug. The study is registered with ClinicalTrials.gov, NCT03654833, and is ongoing (but MiST2 is now closed). Findings: Between Sept 31, 2019, and March 2, 2020, 27 eligible patients consented to molecular screening. The median follow-up was 18·4 weeks (IQR 6·7-23·9). One patient was excluded before treatment because of a serious adverse event before study drug allocation. 26 (100%) of 26 treated patients were p16ink4A deficient and received at least one dose of abemaciclib. Disease control at 12 weeks was reported in 14 (54%) of 26 patients (95% CI 36-71). Grade 3 or worse treatment-related adverse events (of any cause) occurred in eight (27%) of 26 patients (diarrhoea, dyspnoea, thrombocytopenia, vomiting, urinary tract infection, increased alanine aminotransferase, ascites, chest infection or suspected chest infection, neutropenic sepsis, alopecia, blood clot left calf, fall [broken neck and collar bone], haemoptysis, lower respiratory tract infection, and pulmonary embolism). Grade 3 or worse treatment-related adverse events occurred in three (12%) of 26 patients (diarrhoea, thrombocytopenia, vomiting, increased alanine aminotransferase, and pulmonary embolism). Serious adverse events occurred in six (23%) of 26 patients, leading to treatment discontinuation in one (4%) patient (diarrhoea, urinary tract infection, chest infection, neutropenic sepsis, fall [broken neck and collar bone], haemoptysis, lower respiratory tract infection, and pulmonary embolism). One patient had a serious adverse event related to abemaciclib (diarrhoea). One (4%) of 26 patients died from an adverse event (neutropenic sepsis). Interpretation: This study met its primary endpoint, showing promising clinical activity of abemaciclib in patients with p16ink4A-negative mesothelioma who were previously treated with chemotherapy, and warrants its further investigation in a randomised study as a targeted stratified therapy.

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