Genomic analysis defines distinct pancreatic and neuronal subtypes of lung carcinoid.

Lung carcinoids (L-CDs) are rare, poorly characterised neuroendocrine tumours (NETs). L-CDs are more common in women and are not the consequence of cigarette smoking. They are classified histologically as typical carcinoids (TCs) or atypical carcinoids (ACs). ACs confer a worse survival. Histological classification is imperfect, and there is increasing interest in molecular markers. We therefore investigated global transcriptomic and epigenomic profiles of 15 L-CDs resected with curative intent at Royal Brompton Hospital. We identified underlying mutations and structural abnormalities through whole-exome sequencing (WES) and single nucleotide polymorphism (SNP) genotyping. Transcriptomic clustering algorithms identified two distinct L-CD subtypes. These showed similarities either to pancreatic or neuroendocrine tumours at other sites and so were named respectively L-CD-PanC and L-CD-NeU. L-CD-PanC tumours featured upregulation of pancreatic and metabolic pathway genes matched by promoter hypomethylation of genes for beta cells and insulin secretion (p < 1 × 10-6). These tumours were centrally located and showed mutational signatures of activation-induced deaminase/apolipoprotein B editing complex  activity, together with genome-wide DNA methylation loss enriched in repetitive elements (p = 2.2 × 10-16). By contrast, the L-CD-NeU group exhibited upregulation of neuronal markers (adjusted p < 0.01) and was characterised by focal spindle cell morphology (p = 0.04), peripheral location (p = 0.01), high mutational load (p = 2.17 × 10-4), recurrent copy number alterations, and enrichment for ACs. Mutations affected chromatin remodelling and SWI/SNF complex pathways. L-CD-NeU tumours carried a mutational signature attributable to aflatoxin and aristolochic acid (p = 0.05), suggesting a possible environmental exposure in their pathogenesis. Immunologically, myeloid and T-cell markers were enriched in L-CD-PanC and B-cell markers in L-CD-NeU tumours. The substantial epigenetic and non-coding differences between L-CD-PanC and L-CD-NeU open new possibilities for biomarker selection and targeted treatment of L-CD. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Consumers' Experiences of Comprehensive-Prepared Graduate Nurses and Their Nursing Care in Acute Mental Health Settings.

Pre-registration nursing education has long moved away from preparing nurses with mental health specialisation to nurses with comprehensive knowledge and skills. However, the consumers' experiences of comprehensive-prepared nurses and their nursing care has not been widely explored. This paper reports on a study with consumers to explore their experiences with comprehensive-prepared graduate nurses and the nursing care that they provide in acute mental health settings. An exploratory qualitative study using semi-structured interviews was chosen as the research method. Purposeful sampling recruited 12 consumers and data saturation was achieved. Braun and Clarke's method of thematic analysis was used to analyse the collected data and three themes emerged. The themes are: (i) You got what it takes to be a mental health nurse, (ii) Slow down and spend quality time with us, and (iii) Read in between the lines when we share our negative lived experiences. The findings are useful for identifying strategies to develop evidence-based nursing education for comprehensive-prepared graduate nurses to improve the consumers' experiences of their nursing care.

Longitudinal reduction in fluoroscopy with continued use of 3-dimensional electroanatomic mapping systems in catheter ablation of supraventricular tachycardia - then and now.

BACKGROUND: Catheter ablation is a first-line treatment for symptomatic, recurrent supraventricular tachycardia (SVT). This study aims to demonstrate if 3D-electroanatomic mapping (EAM) during SVT ablation reduces fluoroscopy time (FT) and determine if further reductions in FT are observed longitudinally. METHODS: All cases of SVT ablation between May 2011-May 2022 at a single tertiary centre were prospectively recruited. FT between the cohorts with and without EAM were compared. Within the EAM subset, the trend of FT across the years was analysed. RESULTS: There were 1758 cases included, 563 without EAM, 1195 with EAM. EAM was associated with a longer procedure time (mean + 8.8 min, p = 0.001), but with mean reductions in FT and dose area product (DAP) by 19.6 min and 18 621 mGy*cm2 respectively (p < 0.001). There was comparable efficacy without any increase in complication rates. Over time (2011-2022), further reduction in FT of 0.9 min year on year was observed (p = 0.001). Between 2011 and 2017, there was a significant reduction in FT of 1.1 min year on year (p = 0.019), which was not observed from 2017 onwards (p = 0.061). The greatest reduction in FT was after the first year of adoption. CONCLUSION: EAM in SVT ablation reduces fluoroscopy use. FT was initially observed to reduce further over time before plateauing, likely due to increased operator experience. While there is increased interest in zero fluoroscopy SVT ablation, complementary use of fluoroscopy may still be necessary in complex cases.

Acute aortic syndrome: nationwide study of epidemiology, management, and outcomes.

BACKGROUND: Epidemiological studies on acute aortic syndrome (AAS) have relied largely on unverified administrative coding, leading to wide-ranging estimates of incidence. This study aimed to evaluate the incidence, management, and outcomes of AAS in Aotearoa New Zealand. METHODS: This was a national population-based retrospective study of patients presenting with an index admission of AAS from 2010 to 2020. Cases from the Ministry of Health National Minimum Dataset, National Mortality Collection, and the Australasian Vascular Audit were cross-verified with hospital notes. Poisson regression adjusted for sex and age was used to investigate trends over time. RESULTS: During the study interval, 1295 patients presented to hospital with confirmed AAS, including 790 with type A (61.0 per cent) and 505 with type B (39.0 per cent) AAS. A total of 290 patients died out of hospital between 2010 and 2018. The overall incidence of aortic dissection including out-of-hospital cases was 3.13 (95 per cent c.i. 2.96 to 3.30) per 100 000 person-years, and this increased by an average of 3 (95 per cent c.i. 1 to 6) per cent per year after adjustment for age and sex adjustment on Poisson regression, driven by increasing type A cases. Age-standardized rates of disease were higher in men, and in Maori and Pacific populations. The management strategies used, and 30-day mortality rates among patients with type A (31.9 per cent) and B (9.7 per cent) disease have remained constant over time. CONCLUSION: Mortality after AAS remains high despite advances over the past decade. The disease incidence and burden are likely to continue to increase with an ageing population. There is impetus now for further work on disease prevention and the reduction of ethnic disparities.

Novel modification of a branched arch endograft with a retrograde left common carotid branch for acute pseudoaneurysm post type A repair.

OBJECTIVE: Pseudoaneurysm formation post type A aortic dissection repair is rare. Revision surgical repair is challenging, with a risk of death from haemorrhage. METHODS: We present a 56-year-old man who presented with a rapidly enlarging distal ascending aortic anastomotic pseudoaneurysm following a recent ascending and hemiarch replacement for acute type A aortic dissection. RESULTS: A tight kink in the ascending aortic graft precluded an endovascular repair utilizing two antegrade branches, and so a novel custom-made 3 inner branched aortic endograft was designed, with an antegrade brachiocephalic inner branch and retrograde left common carotid and subclavian artery inner branches. The patient required an angioplasty to dilate the kinked/coarcted surgical graft, but made an uneventful recovery. CONCLUSION: An aortic arch inner branch design with an antegrade brachiocephalic branch but retrograde left common carotid and left subclavian branches was feasible and may prove particularly useful when there is limited space in the ascending aorta.

Mechanical aortic valve may no longer be a contraindication to inner branch aortic arch endografts.

OBJECTIVES: The presence of a mechanical aortic valve has been a contraindication to the use of an arch branch aortic endograft due to the risk of damaging the valve, resulting in acute aortic regurgitation, or a trapped endograft. METHODS: We present a 67-year-old woman, with a background of Marfan's syndrome and a previous Bentall's procedure, who presented with a symptomatic enlarging aortic arch and descending thoracic aortic aneurysm, with a type 1A endoleak. RESULTS: Using an inner branch arch endograft (Cook Medical, Bloomington, Indiana), the nose cone of the delivery system was passed laterally through the semi-circular aperture of the mechanical aortic valve to facilitate deployment just distal to the coronary buttons. CONCLUSIONS: With advancement of endovascular technology, techniques and experience, endovascular aortic arch repair in the presence of a mechanical aortic valve is feasible.

Understanding work experience in epidemic-induced telecommuting: The roles of misfit, reactance, and collaborative technologies.

In the management of the global COVID-19 pandemic, the mandated closure of workplaces and stay-at-home orders have forced workers to adapt to a prolonged period of unplanned telecommuting, which we term epidemic-induced telecommuting. Although epidemic-induced telecommuting has drastically altered how work is conducted, scant attention is being paid to this emerging work arrangement. To this end, we combine psychological reactance theory and person-environment fit theory to advance the concept of misfit between worker and environment as a core determinant of employees' work experience in the epidemic-induced telecommuting. Particularly, we distinguish between supply-value and demand-ability misfits as constraints on workers' freedom at work. Having analyzed data collected through a survey administered on remote workers, we discovered that both misfits positively influenced workers' perceived psychological reactance, which led to work exhaustion and counter-productive behaviors. We also found that the utilization of collaborative technologies moderated the effects of misfit on workers' psychological reactance.

Initial experience of left bundle branch pacing using the Abbott Agilis HisPro Catheter with stylet-driven leads.

AIMS: Conduction system pacing has gained steady interest over recent years. While the majority of tools and delivery techniques were developed for His bundle pacing (HBP), the feasibility and reproducibility of using these similar tools for left bundle branch pacing (LBBP) has yet to be determined. We describe our technique for performing LBBP using the Abbott Agilis HisPro™ Steerable Catheter. METHODS AND RESULTS: A series of 22 patients with a mean age of 71.7 years (16 males, 72.7%), underwent LBBP procedure with this catheter between May and October 2021. Nineteen patients (86%) had successful LBBP lead implantation. There were no major complications or mortality. CONCLUSION: The Agilis HisPro™ catheter along with the stylet driven Tendril STS Model 2088TC lead is a safe and feasible delivery system for LBBP.

An open approach to a ruptured common iliac artery aneurysm with resultant ilio-iliac arteriovenous fistula.

OBJECTIVE: Presentations of a spontaneous ilio-iliac arteriovenous fistula are considered a rare occurrence and warrant urgent intervention. They are usually a result following trauma, previous surgery or uncommonly from a ruptured aneurysm. METHOD: We describe a case of a patient presenting with general malaise who examined to have a pulsatile abdominal mass with an associated bruit. He was found to have an ilio-iliac arteriovenous fistula secondary to a ruptured iliac aneurysm that was treated successfully with open surgical repair. RESULT: The patient was brought forward for open surgical repair due to haemodynamic instability as well as likely predicted difficulties with endovascular repair. Intra-operatively, his sigmoid colon was adherent to the aneurysm prompting the need for a Hartmann's procedure to allow for better visualisation of the aneurysm. A combination of external digital compression and Prolene suture was used to close the arteriovenous fistula. CONCLUSION: Open surgical repair of an ilio-iliac arteriovenous fistula secondary to a ruptured iliac aneurysm appears to be safe and feasible approach. The advancement of medical technology does open up the possibility of an endovascular approach; however, in a small subset of patients, open repair would appear to be better.

Blood-based circulating tumor DNA mutations as a diagnostic and prognostic biomarker for lung cancer.

BACKGROUND: The objectives of the current study were to develop an initial blood-based circulating tumor DNA (ctDNA) gene signature and to validate the clinical test performance in patients with early primary and secondary lung cancer. METHODS: Between January 2009 and October 2014, a total of 211 patients with known or suspected lung cancer donated their blood prior to surgery and were followed up to May 2018. ctDNA was extracted from plasma and from corresponding formalin-fixed, paraffin-embedded tissues. The blood was analyzed in a blinded manner and pathology reports were issued that were blinded to the blood test results. The reference standard was histopathology confirmed cancer in the resected surgical specimens as reported according to World Health Organization criteria and staged using the eighth edition of the TNM Classification of Malignant Tumors criteria. RESULTS: Of 211 consenting patients, 19 (9.0%) were excluded, leaving 192 participants, consisting of 95 men (49%) and with a mean age of 63 years (SD, 15 years). The clinical test performance for the blood-based diagnostic signature demonstrated a sensitivity of 75% (95% CI, 67%-81%), specificity of 89% (95% CI, 70%-98%), positive predictive value of 98% (95% CI, 93%-100%), and negative predictive value of 35% (95% CI, 24%-48%) when compared with conventional clinical histopathology reporting of the resected tissue. CONCLUSIONS: The results of the current study suggested that blood-based ctDNA analysis of cancer mutations is a specific, noninvasive test for the diagnosis of cancer.

Presence of pleomorphic features but not growth patterns improves prognostic stratification of epithelioid malignant pleural mesothelioma by 2-tier nuclear grade.

AIMS: Nuclear grade has been recently validated as a powerful prognostic tool in epithelioid malignant pleural mesothelioma (E-MPM). In other studies histological parameters including pleomorphic features and growth patterns were also shown to exert prognostic impact. The primary aims of our study are (i) externally validate the prognostic role of pleomorphic features in E-MPM and (ii) investigate if evaluating growth pattern in addition to 2-tier nuclear grade improves prognostication. METHODS AND RESULTS: 614 consecutive cases of E-MPM from our institution over a period of 15 years were retrospectively reviewed, of which 51 showed pleomorphic features. E-MPM with pleomorphic features showed significantly worse overall survival compared to those without (5.4 versus 14.7 months). Tumours with predominantly micropapillary pattern showed the worst survival (6.2 months) followed by solid (10.5 months), microcystic (15.3 months), discohesive (16.1 months), trabecular (17.6 months) and tubulo-papillary (18.6 months). Sub-classification of growth patterns into high grade (solid, micropapillary) and low grade (all others) led to good separation of overall survival (10.5 versus 18.0 months) but did not predict survival independent of 2-tier nuclear grade. A composite score comprised of growth pattern and 2-tier nuclear grade did not improve prognostication compared with nuclear grade alone. Intra-tumoural heterogeneity in growth patterns is ubiquitous. CONCLUSIONS: Our findings support the incorporation of E-MPM with pleomorphic features in the epithelioid subtype as a highly aggressive variant distinct from 2-tier nuclear grade. E-MPM demonstrates extensive heterogeneity in growth pattern but its evaluation does not offer additional prognostic utility to 2-tier nuclear grade.

Unmet Medical Needs in Pulmonary Neuroendocrine (Carcinoid) Neoplasms.

Pulmonary carcinoids (PCs) display the common features of all well-differentiated neuroendocrine neoplasms (NEN) and are classified as low- and intermediate-grade malignant tumours (i.e., typical and atypical carcinoid, respectively). There is a paucity of randomised studies dedicated to advanced PCs and management principles are drawn from the larger gastroenteropancreatic NEN experience. There is growing evidence that NEN anatomic subgroups have different biology and different responses to treatment and, therefore, should be investigated as separate entities in clinical trials. In this review, we discuss the existing evidence and limitations of tumour classification, diagnostics and staging, prognostication, and treatment in the setting of PC, with focus on unmet medical needs and directions for the future.

Characterising the difference in electrophysiological substrate and outcomes between heart failure and non-heart failure patients with persistent atrial fibrillation.

Aims: Characterizing the differences in substrate and clinical outcome between heart failure (HF) and non-heart failure (non-HF) patients undergoing persistent atrial fibrillation (AF) ablation. Methods and results: Using complex fractionated electrograms (CFE) as a surrogate marker of substrate complexity, we compared the bi-atrial substrate in patients with persistent AF with and without HF, at baseline and after ablation, to determine its impact on clinical outcome. In this retrospective analysis of two prospective studies, 60 patients underwent de-novo step-wise left atrial (LA) ablation, 30 with normal left ventricular ejection fraction (LVEF) ≥ 50% (non-HF group) and 30 with LVEF ≤ 35% (HF group). Multiple high-density bi-atrial CFE maps were acquired along with AF cycle length (AFCL) at each procedural stage. Change in bi-atrial CFE areas, AFCL and outcome data were then compared. In the non-HF group, higher CFE-areas were found at baseline and at each step of the procedure in the LA. In both LA and the right atrium (RA), baseline and final CFE area were also higher in the non-HF group. Single procedure, arrhythmia-free survival at 1 year was higher in the HF group compared with the non-HF group (72% vs. 43%, log rank P = 0.04). Final total bi-atrial CFE area was an independent predictor of arrhythmia recurrence. Conclusions: CFE represents an important surrogate marker of atrial substrate complexity. The atrial substrate in persistent AF differs between HF and non-HF with the latter representing a more complex 'primary' bi-atrial myopathy. LA focussed ablation results in more extensive substrate modification in HF and better clinical outcomes as compared with non-HF.

Randomized controlled trial of internal and external targeted temperature management methods in post- cardiac arrest patients.

BACKGROUND: Targeted temperature management post-cardiac arrest is currently implemented using various methods, broadly categorized as internal and external. This study aimed to evaluate survival-to-hospital discharge and neurological outcomes (Glasgow-Pittsburgh Score) of post-cardiac arrest patients undergoing internal cooling verses external cooling. METHODOLOGY: A randomized controlled trial of post-resuscitation cardiac arrest patients was conducted from October 2008-September 2014. Patients were randomized to either internal or external cooling methods. Historical controls were selected matched by age and gender. Analysis using SPSS version 21.0 presented descriptive statistics and frequencies while univariate logistic regression was done using R 3.1.3. RESULTS: 23 patients were randomized to internal cooling and 22 patients to external cooling and 42 matched controls were selected. No significant difference was seen between internal and external cooling in terms of survival, neurological outcomes and complications. However in the internal cooling arm, there was lower risk of developing overcooling (p=0.01) and rebound hyperthermia (p=0.02). Compared to normothermia, internal cooling had higher survival (OR=3.36, 95% CI=(1.130, 10.412), and lower risk of developing cardiac arrhythmias (OR=0.18, 95% CI=(0.04, 0.63)). Subgroup analysis showed those with cardiac cause of arrest (OR=4.29, 95% CI=(1.26, 15.80)) and sustained ROSC (OR=5.50, 95% CI=(1.64, 20.39)) had better survival with internal cooling compared to normothermia. Cooling curves showed tighter temperature control for internal compared to external cooling. CONCLUSION: Internal cooling showed tighter temperature control compared to external cooling. Internal cooling can potentially provide better survival-to-hospital discharge outcomes and reduce cardiac arrhythmia complications in carefully selected patients as compared to normothermia.

Cardiac CT assessment of tissue thickness at the ostium of the left atrial appendage predicts acute success of radiofrequency ablation.

BACKGROUND: Tissue thickness at the site of ablation is a determinant of lesion transmurality. We reported the feasibility, safety, and efficacy of longstanding persistent atrial fibrillation ablation, incorporating deliberate left atrial appendage (LAA) isolation and occlusion, and identified systematic differences in ostial LAA tissue thickness in a matched cohort of cadaveric specimens. METHODS: Preprocedural cardiac computed tomography (CCT) scans were acquired from 22 patients undergoing LAA isolation and subsequent occlusion. Using a novel CCT wall thickness algorithm, LAA ostial wall thickness was assessed in vivo, compared with measurements from the cadaveric specimens, and analyzed for differences between regions that demonstrated acute electrical reconnection and those that did not. RESULTS: Mean tissue thickness calculated for each LAA ostial quadrant was 2.1 (±0.6) mm (anterior quadrant), 1.9 (±0.4) mm (superior quadrant), 1.5 (±0.4) mm (posterior quadrant), and 1.8 (±0.7) mm (inferior quadrant). Tissue was significantly thicker in the anterior (P  =  0.004) and superior quadrants (P  =  0.014) than the posterior quadrant. Higher thickness measurements were recorded from quadrants demonstrated to be thicker from histology. Tissue was significantly thicker in regions that demonstrated acute electrical reconnection (1.9 (±0.6) mm) when compared with those that did not (1.6 (±0.5) mm) (P  =  0.008). CONCLUSIONS: CCT imaging may be used to detect differences in wall thickness at different atrial locations and success of LAA ablation may be affected by local tissue thickness. Atrial wall thickness may need to be considered as a metric to guide titration of radiofrequency energy for safe and successful ablation.

Diagnostic procedures for non-small-cell lung cancer (NSCLC): recommendations of the European Expert Group.

BACKGROUND: There is currently no Europe-wide consensus on the appropriate preanalytical measures and workflow to optimise procedures for tissue-based molecular testing of non-small-cell lung cancer (NSCLC). To address this, a group of lung cancer experts (see list of authors) convened to discuss and propose standard operating procedures (SOPs) for NSCLC. METHODS: Based on earlier meetings and scientific expertise on lung cancer, a multidisciplinary group meeting was aligned. The aim was to include all relevant aspects concerning NSCLC diagnosis. After careful consideration, the following topics were selected and each was reviewed by the experts: surgical resection and sampling; biopsy procedures for analysis; preanalytical and other variables affecting quality of tissue; tissue conservation; testing procedures for epidermal growth factor receptor, anaplastic lymphoma kinase and ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) in lung tissue and cytological specimens; as well as standardised reporting and quality control (QC). Finally, an optimal workflow was described. RESULTS: Suggested optimal procedures and workflows are discussed in detail. The broad consensus was that the complex workflow presented can only be executed effectively by an interdisciplinary approach using a well-trained team. CONCLUSIONS: To optimise diagnosis and treatment of patients with NSCLC, it is essential to establish SOPs that are adaptable to the local situation. In addition, a continuous QC system and a local multidisciplinary tumour-type-oriented board are essential.

Management of bronchial carcinoids: international practice survey among the European Society of Thoracic Surgeons.

OBJECTIVE: This study aims to assess the international practice of management of bronchial carcinoids. MATERIALS & METHODS: A survey designed by the Neuroendocrine Tumors of the Lung Working Group, was conducted among the members of the European Society of Thoracic Surgeons. RESULTS: A total of 172 centers worldwide replied to the questionnaire. General agreement was observed concerning the use of anatomic resections and parenchyma-sparing surgery, the importance of lymphadenectomy, the adjuvant regimens in N(+) atypical carcinoids and the role of surgery for local recurrences. Controversies emerged in the use of nuclear medicine imaging and measurement of serum markers and on the timing of follow-up. CONCLUSION: This survey provides the largest international overview of the current practice in the management of bronchial carcinoids and identifies discrepancies that could be the focus of future investigations.