Endobronchially Implanted Real-Time Electromagnetic Transponder Beacon-Guided, Respiratory-Gated SABR for Moving Lung Tumors: A Prospective Phase 1/2 Cohort Study.

Purpose: Endobronchial electromagnetic transponder beacons (EMT) provide real-time, precise positional data of moving lung tumors. We report results of a phase 1/2, prospective, single-arm cohort study evaluating the treatment planning effects of EMT-guided SABR for moving lung tumors. Methods and Materials: Eligible patients were adults, Eastern Cooperative Oncology Group 0 to 2, with T1-T2N0 non-small cell lung cancer or pulmonary metastasis ≤4 cm with motion amplitude ≥5 mm. Three EMTs were endobronchially implanted using navigational bronchoscopy. Four-dimensional free-breathing computed tomography simulation scans were obtained, and end-exhalation phases were used to define the gating window internal target volume. A 3-mm expansion of gating window internal target volume defined the planning target volume (PTV). EMT-guided, respiratory-gated (RG) SABR was delivered (54 Gy/3 fractions or 48 Gy/4 fractions) using volumetric modulated arc therapy. For each RG-SABR plan, a 10-phase image-guided SABR plan was generated for dosimetric comparison. PTV/organ-at-risk (OAR) metrics were tabulated and analyzed using the Wilcoxon signed-rank pair test. Treatment outcomes were evaluated using RECIST (Response Evaluation Criteria in Solid Tumours; version 1.1). Results: Of 41 patients screened, 17 were enrolled and 2 withdrew from the study. Median age was 73 years, with 7 women. Sixty percent had T1/T2 non-small cell lung cancer and 40% had M1 disease. Median tumor diameter was 1.9 cm with 73% of targets located peripherally. Mean respiratory tumor motion was 1.25 cm (range, 0.53-4.04 cm). Thirteen tumors were treated with EMT-guided SABR and 47% of patients received 48 Gy in 4 fractions while 53% received 54 Gy in 3 fractions. RG-SABR yielded an average PTV reduction of 46.9% (P < .005). Lung V5, V10, V20, and mean lung dose had mean relative reductions of 11.3%, 20.3%, 31.1%, and 20.3%, respectively (P < .005). Dose to OARs was significantly reduced (P < .05) except for spinal cord. At 6 months, mean radiographic tumor volume reduction was 53.5% (P < .005). Conclusions: EMT-guided RG-SABR significantly reduced PTVs of moving lung tumors compared with image-guided SABR. EMT-guided RG-SABR should be considered for tumors with large respiratory motion amplitudes or those located in close proximity to OARs.

Variation in Experiences and Attainment in Surgery Between Ethnicities of UK Medical Students and Doctors (ATTAIN): Protocol for a Cross-Sectional Study.

BACKGROUND: The unequal distribution of academic and professional outcomes between different minority groups is a pervasive issue in many fields, including surgery. The implications of differential attainment remain significant, not only for the individuals affected but also for the wider health care system. An inclusive health care system is crucial in meeting the needs of an increasingly diverse patient population, thereby leading to better outcomes. One barrier to diversifying the workforce is the differential attainment in educational outcomes between Black and Minority Ethnic (BME) and White medical students and doctors in the United Kingdom. BME trainees are known to have lower performance rates in medical examinations, including undergraduate and postgraduate exams, Annual Review of Competence Progression, as well as training and consultant job applications. Studies have shown that BME candidates have a higher likelihood of failing both parts of the Membership of the Royal Colleges of Surgeons exams and are 10% less likely to be considered suitable for core surgical training. Several contributing factors have been identified; however, there has been limited evidence investigating surgical training experiences and their relationship to differential attainment. To understand the nature of differential attainment in surgery and to develop effective strategies to address it, it is essential to examine the underlying causes and contributing factors. The Variation in Experiences and Attainment in Surgery Between Ethnicities of UK Medical Students and Doctors (ATTAIN) study aims to describe and compare the factors and outcomes of attainment between different ethnicities of doctors and medical students. OBJECTIVE: The primary aim will be to compare the effect of experiences and perceptions of surgical education of students and doctors of different ethnicities. METHODS: This protocol describes a nationwide cross-sectional study of medical students and nonconsultant grade doctors in the United Kingdom. Participants will complete a web-based questionnaire collecting data on experiences and perceptions of surgical placements as well as self-reported academic attainment data. A comprehensive data collection strategy will be used to collect a representative sample of the population. A set of surrogate markers relevant to surgical training will be used to establish a primary outcome to determine variations in attainment. Regression analyses will be used to identify potential causes for the variation in attainment. RESULTS: Data collected between February 2022 and September 2022 yielded 1603 respondents. Data analysis is yet to be competed. The protocol was approved by the University College London Research Ethics Committee on September 16, 2021 (ethics approval reference 19071/004). The findings will be disseminated through peer-reviewed publications and conference presentations. CONCLUSIONS: Drawing upon the conclusions of this study, we aim to make recommendations on educational policy reforms. Additionally, the creation of a large, comprehensive data set can be used for further research. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/40545.

Temporal and Spatial Patterns of Inflammation and Tissue Injury in Patients with Postoperative Respiratory Failure after Lung Resection Surgery: A Nested Case-Control Study.

Thoracic surgeries involving resection of lung tissue pose a risk of severe postoperative pulmonary complications, including acute respiratory distress syndrome (ARDS) and respiratory failure. Lung resections require one-lung ventilation (OLV) and, thus, are at higher risk of ventilator-induced lung injury (VILI) attributable to barotrauma and volutrauma in the one ventilated lung, as well as hypoxemia and reperfusion injury on the operated lung. Further, we also aimed to assess the differences in localized and systemic markers of tissue injury/inflammation in those who developed respiratory failure after lung surgery versus matched controls who did not develop respiratory failure. We aimed to assess the different inflammatory/injury marker patterns induced in the operated and ventilated lung and how this compared to the systemic circulating inflammatory/injury marker pattern. A case-control study nested within a prospective cohort study was performed. Patients with postoperative respiratory failure after lung surgery (n = 5) were matched with control patients (n = 6) who did not develop postoperative respiratory failure. Biospecimens (arterial plasma, bronchoalveolar lavage separately from ventilated and operated lungs) were obtained from patients undergoing lung surgery at two timepoints: (1) just prior to initiation of OLV and (2) after lung resection was completed and OLV stopped. Multiplex electrochemiluminescent immunoassays were performed for these biospecimen. We quantified 50 protein biomarkers of inflammation and tissue injury and identified significant differences between those who did and did not develop postoperative respiratory failure. The three biospecimen types also display unique biomarker patterns.

Impact of cost-awareness education and surgeon-led positive deviance on intraoperative costs of thoracoscopic lobectomy.

OBJECTIVE: Disposable instrument use during video-assisted thoracoscopic lobectomy is a significant driver of cost. The purpose of the study was to measure the effect of increasing surgeon cost awareness via successive "value improvement initiatives" on instrument costs. METHODS: We prospectively collected disposable instrument use data for all video-assisted thoracoscopic lobectomies performed by 5 Board-certified thoracic surgeons over 4 successive time periods: Period 1: control group of consecutive video-assisted thoracoscopic lobectomies before interventions; Period 2: video-assisted thoracoscopic lobectomies after displaying disposables price list in operating room; Period 3: video-assisted thoracoscopic lobectomies after educational presentation outlining disposable instrument price differences; Period 4: video-assisted thoracoscopic lobectomies after surgeon self-assessment with peer comparison of cost data from Period 3 and positive deviance seminar identifying the lowest-cost surgeon to lead discussion of optimal cost-reduction strategies. Instrument use and costs were compared among the 4 groups using the Kruskal-Wallis test. RESULTS: A total of 373 lobectomy cases were analyzed. Compared with Period 1, median stapler-related and total disposable costs for video-assisted thoracoscopic lobectomy cases decreased after successive value improvement initiatives, with lowest costs in Period 4 (P < .0001). Multiple linear regression analysis demonstrated per lobectomy disposables cost reduction of $397.53 in Period 4, after controlling for surgeon and lobe (P < .0001). Operating room time was reduced after successive value improvement initiatives (P < .0001). CONCLUSIONS: Cost awareness and surgeon engagement activities were associated with sustained cost reduction for video-assisted thoracoscopic lobectomies. Surgeon self-assessment, peer comparison, and positive deviance seminar were associated with the largest cost reduction. Significant hospital cost-savings may be realized with surgeon-led value improvement initiatives.

Identifying biomarkers of ventilator induced lung injury during one-lung ventilation surgery: a scoping review.

Background: Ventilator-induced lung injury (VILI) can occur as a result of mechanical ventilation to two lungs. Thoracic surgery often requires one-lung ventilation (OLV). The potential for VILI is likely higher in OLV. The impact of OLV on development of post-operative pulmonary complications is not well understood. We aimed to perform a scoping review to determine reliable biomarkers of VILI after OLV. Methods: A scoping review was performed using Cochrane Collaboration methodology. We searched Medline, EMBASE and SCOPUS. Gray literature was searched. Studies of adult human or animal models without pre-existing lung damage exposed to OLV, with biomarker responses analyzed were included. Results: After screening 5,613 eligible papers, 89 papers were chosen for full text review, with 29 meeting inclusion. Approximately half (52%, n=15) of studies were conducted in humans in an intra-operative setting. Bronchoalveolar lavage (BAL) & serum analyses with enzyme-linked immunosorbent assay (ELISA)-based assays were most commonly used. The majority of analytes were investigated by a single study. Of the analytes that were investigated by two or more studies (n=31), only 16 were concordant in their findings. Across all sample types and studies 84% (n=66) of the 79 inflammatory markers and 75% (n=6) of the 8 anti-inflammatory markers tested were found to increase. Half (48%) of all studies showed an increase in TNF-α or IL-6. Conclusions: A scoping review of the state of the evidence demonstrated that candidate biomarkers with the most evidence and greatest reliability are general markers of inflammation, such as IL-6 and TNF-α assessed using ELISA assays. Studies were limited in the number of biomarkers measured concurrently, sample size, and studies using human participants. In conclusion these identified markers can potentially serve as outcome measures for studies on OLV.

Data-driven identification of plasma metabolite clusters and metabolites of interest for potential detection of early-stage non-small cell lung cancer cases versus cancer-free controls.

BACKGROUND: Metabolomics is a potential means for biofluid-based lung cancer detection. We conducted a non-targeted, data-driven assessment of plasma from early-stage non-small cell lung cancer (ES-NSCLC) cases versus cancer-free controls (CFC) to explore and identify the classes of metabolites for further targeted metabolomics biomarker development. METHODS: Plasma from 250 ES-NSCLC cases and 250 CFCs underwent ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) in positive and negative electrospray ionization (ESI) modes. Molecular feature extraction, formula generation, and find-by-ion tools annotated metabolic entities. Analysis was restricted to endogenous metabolites present in ≥ 80% of samples. Unsupervised hierarchical cluster analysis identified clusters of metabolites. The metabolites with the strongest correlation with the principal component of each cluster were included in logistic regression modeling to assess discriminatory performance with and without adjustment for clinical covariates. RESULTS: A total of 1900 UHPLC-QTOF-MS assessments identified 1667 and 2032 endogenous metabolites in the ESI-positive and ESI-negative modes, respectively. After data filtration, 676 metabolites remained, and 12 clusters of metabolites were identified from each ESI mode. Multivariable logistic regression using the representative metabolite from each cluster revealed effective classification of cases from controls with overall diagnostic accuracy of 91% (ESI positive) and 94% (ESI negative). Metabolites of interest identified for further targeted analysis include the following: 1b, 3a, 12a-trihydroxy-5b-cholanoic acid, pyridoxamine 5'-phosphate, sphinganine 1-phosphate, gamma-CEHC, 20-carboxy-leukotriene B4, isodesmosine, and 18-hydroxycortisol. CONCLUSIONS: Plasma-based metabolomic detection of early-stage NSCLC appears feasible. Further metabolomics studies targeting phospholipid, steroid, and fatty acid metabolism are warranted to further develop noninvasive metabolomics-based detection of early-stage NSCLC.

Metabolic Alterations in Sputum and Exhaled Breath Condensate of Early Stage Non-Small Cell Lung Cancer Patients After Surgical Resection: A Pilot Study.

Every year, close to two million people world-wide are diagnosed with and die of lung cancer. Most patients present with advanced-stage cancer with limited curative options and poor prognosis. Diagnosis of lung cancer at an early stage provides the best chance for a cure. Low- dose CT screening of the chest in the high-risk population is the current standard of care for early detection of lung cancer. However, CT screening is invasive due to radiation exposure and carries the risk of unnecessary biopsies in non-cancerous tumors. In this pilot study, we present metabolic alterations observed in sputum and breath condensate of the same population of early- stage non-small cell lung cancer (NSCLC) patients cancer before and after surgical resection (SR), which could serve as noninvasive diagnostic tool. Exhaled breath condensate (EBC) (n=35) and sputum (n=15) were collected from early-stage non-small cell lung cancer (NSCLC) patients before and after SR. Median number of days for EBC and sputum collection before and after SR were 7 and 42; and 7 and 36 respectively Nuclear magnetic resonance (NMR) and liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) were used to analyze the metabolic profile of the collected samples. A total of 26 metabolites with significant alteration post SR were identified, of which 14 (54%) were lipids and 12 constituted nine different chemical metabolite classes. Eighteen metabolites (69%) were significantly upregulated and 8 (31%) were downregulated. Median fold change for all the up- and downregulated metabolites (LC-QTOF-MS) were 10 and 8, respectively. Median fold change (MFC) in concentration of all the up- and downregulated metabolites (NMR) were 0.04 and 0.27, respectively. Furthermore, glucose (median fold change, 0.01, p=0.037), adenosine monophosphate (13 log fold, p=0.0037) and N1, N12- diacetylspermine (8 log fold p=0.011) sputum levels were significantly increased post-SR. These identified sputa and EBC indices of altered metabolism could serve as basis for further exploration of biomarkers for early detection of lung cancer, treatment response, and targets for drug discovery. Validation of these promising results by larger clinical studies is warranted.

Metabolic Changes in Early-Stage Non-Small Cell Lung Cancer Patients after Surgical Resection.

Metabolic alterations in malignant cells play a vital role in tumor initiation, proliferation, and metastasis. Biofluids from patients with non-small cell lung cancer (NSCLC) harbor metabolic biomarkers with potential clinical applications. In this study, we assessed the changes in the metabolic profile of patients with early-stage NSCLC using mass spectrometry and nuclear magnetic resonance spectroscopy before and after surgical resection. A single cohort of 35 patients provided a total of 29 and 32 pairs of urine and serum samples, respectively, pre-and post-surgery. We identified a profile of 48 metabolites that were significantly different pre- and post-surgery: 17 in urine and 31 in serum. A higher proportion of metabolites were upregulated than downregulated post-surgery (p < 0.01); however, the median fold change (FC) was higher for downregulated than upregulated metabolites (p < 0.05). Purines/pyrimidines and proteins had a larger dysregulation than other classes of metabolites (p < 0.05 for each class). Several of the dysregulated metabolites have been previously associated with cancer, including leucyl proline, asymmetric dimethylarginine, isopentenyladenine, fumaric acid (all downregulated post-surgery), as well as N6-methyladenosine and several deoxycholic acid moieties, which were upregulated post-surgery. This study establishes metabolomic analysis of biofluids as a path to non-invasive diagnostics, screening, and monitoring in NSCLC.

Lung Resection Without Tissue Diagnosis: A Pragmatic Perspective on the Indeterminate Pulmonary Nodule.

BACKGROUND: The indeterminate pulmonary nodule is a common clinical problem. Preoperative tissue diagnosis is not always possible, despite all attempts. The objectives of this study were to determine the frequency of a malignant diagnosis in this scenario and whether attempted preoperative biopsy impacted estimation of the risk of malignancy. PATIENTS AND METHODS: We reviewed 500 consecutive cases of pulmonary resection without a preoperative tissue diagnosis at a tertiary care center from 2009 to 2013. Age, sex, smoking status, prior malignancy, tumor size, and whether or not tissue diagnosis had been attempted were recorded. Logistic regression models were constructed to determine factors associated with a malignant diagnosis. RESULTS: There were 297 males (59.4%), the mean age was 64.9 years, and 412 had a smoking history (82.4%). Also, 203 patients (40.6%) had a malignancy history, and 36 patients (7.2%) had previous lung cancer. Biopsy was attempted for 102 patients (20.5%). The final diagnosis was lung cancer in 336 patients (67.2%), metastatic cancer in 93 patients (18.6%), and benign tumour in 71 patients (14.2%). Male sex, increasing age, smoking history, and prior lung cancer were positive predictors of lung cancer. Model discrimination was good (c-statistic, 0.83). Attempted biopsy did not alter model discrimination. CONCLUSION: In this cohort, 86% of resected lesions were malignant. The decision to pursue preoperative tissue diagnosis did not change the predictive ability offered by clinical factors. These findings are reassuring in the scenario when a patient is operable but the diagnosis remains unknown.

Found in translation: navigating uncertainty to save a child's heart. Paediatric cardiac surgery in Cape Town, South Africa.

This medical humanities paper describes our qualitative research into pathways to care and informed consent for 10 children who had cardiac surgery in the Red Cross War Memorial Children's Hospital, Cape Town, South Africa. Our multidisciplinary team consists of cardiologists, anthropologists, a social scientist and a general practitioner in two sites, South Africa and Australia. This paper builds on our first publication in a specialist cardiology journal on a 'qualitative snapshot' of these children's life stories from 2011 to 2016 but turns to the medical humanities to explore a concept of 'uncertainty'. Data analysis revealed that for the children's parents and doctors, 'uncertainty' underscored procedures. Indeed, the literature review showed that 'uncertainty' is intrinsic to heart surgery and was integral to Barnard's first heart transplant in Cape Town in 1967. We demonstrate that in meeting the challenges inherent in the 'uncertainty dimension', doctors established greater 'medical certainty'about each operation. This happened as they encountered the difficult clinical and biopsychosocial factors that were fundamental to the diagnosis of children's cardiac defects. It was doctors' translation of these decision-making processes that informed parental decisions and described why, despite feelings of uncertainty, parents signed consent. To visually describe heart surgery in this locality we asked the South African photographer, Guy Neveling to record some children undergoing echocardiograms and surgery. These photographs qualitatively demonstrate what medical certainty entails, and parents' trust in doctors and surgeons, whom they knew had 'reasonable certainty' that their child's 'heart is worth saving'.

One medical school's experience of sustaining general practice teaching in the time of COVID-19.

Challenges have been encountered in maintaining the Western Sydney University general practice program but effective strategies have been adopted to manage the impact of COVID-19.

A Creeping Malaise Leading to Calamity: Herpes Esophagitis Perforation.

Herpes simplex virus is an uncommon cause of esophagitis and particularly so in immunocompetent individuals. Although the common presentation tends to be odynophagia and/or dysphagia, fever, and retrosternal chest pain, there are variations and rarely it can present more ominously as esophageal rupture. We report a rare case of esophageal perforation with penetration into the vertebral space secondary to chronic herpes simplex virus esophagitis in a 71-year-old immunocompetent woman. This is the second known such occurrence. The patient had a long stay in the hospital but recovered from the condition and was followed up for 1 year after initial presentation.

Non-invasive exploration of metabolic profile of lung cancer with Magnetic Resonance Spectroscopy and Mass Spectrometry.

BACKGROUND: Lung cancer is a major cause of global morbidity and mortality. Current low dose CT screening is invasive and its role remains contentious. There are no known biomarkers to monitor treatment response, detect disease recurrence and patient selection for adjuvant treatment after curative surgical resection. Hence there is an urgent need to explore non-conventional and non-invasive tools to develop novel biomarkers to improve the outcome of this lethal cancer. METHODS: This is an ongoing exploratory and translational study involving collection of bio fluids from 50 patients with early stage non-small cell lung cancer before and after surgical resection. The primary objective is to identify cancer specific metabolome in body fluids - sputum, exhaled breath condensate, blood and urine of the patients with early stage non-small cell lung cancer using Magnetic Resonance Spectroscopy and Mass Spectroscopy. CONCLUSION: The trajectory of change in metabolic profile of body fluids before and after surgical resection may have potential clinical applications in lung cancer screening, as biomarkers for disease recurrence and exploration of novel targets for therapeutic intervention.

Determinants of trends in neonatal, post-neonatal, infant, child and under-five mortalities in Tanzania from 2004 to 2016.

BACKGROUND: Under-five mortality is still a major health issue in many developing countries like Tanzania. To achieve the Sustainable Development Goal target of ending preventable child deaths in Tanzania, a detailed understanding of the risk factors for under-five deaths is essential to guide targeted interventions. This study aimed to investigate trends and determinants of neonatal, post-neonatal, infant, child and under-five mortalities in Tanzania from 2004 to 2016. METHODS: The study used combined data from the 2004-2005, 2010 and 2015-2016 Tanzania Demographic and Health Surveys, with a sample of 25,951 singletons live births and 1585 under-five deaths. We calculated age-specific mortality rates, followed by an assessment of trends and determinants (community, socioeconomic, individual and health service) of neonatal, postneonatal, infant, child and under-five mortalities in Cox regression models. The models adjusted for potential confounders, clustering and sampling weights. RESULTS: Between 2004 and 2016, we found that neonatal mortality rate remained unchanged, while postneonatal mortality and child mortality rates have halved in Tanzania. Infant mortality and under-five mortality rates have also declined. Mothers who gave births through caesarean section, younger mothers (< 20 years), mothers who perceived their babies to be small or very small and those with fourth or higher birth rank and a short preceding birth interval (≤2 years) reported higher risk of neonatal, postneonatal and infant mortalities. CONCLUSION: Our study suggests that there was increased survival of children under-5 years in Tanzania driven by significant improvements in postneonatal, infant and child survival rates. However, there remains unfinished work in ending preventable child deaths in Tanzania.

Pathways to diagnosis of non-small cell lung cancer: a descriptive cohort study.

Little has been published on the diagnostic and referral pathway for lung cancer in Australia. This study set out to quantify general practitioner (GP) and lung specialist attendance and diagnostic imaging in the lead-up to a diagnosis of non-small cell lung cancer (NSCLC) and identify common pathways to diagnosis in New South Wales (NSW), Australia. We used linked health data for participants of the 45 and Up Study (a NSW population-based cohort study) diagnosed with NSCLC between 2006 and 2012. Our main outcome measures were GP and specialist attendances, X-rays and computed tomography (CT) scans of the chest and lung cancer-related hospital admissions. Among our study cohort (N = 894), 60% (n = 536) had ≥4 GP attendances in the 3 months prior to diagnosis of NSCLC, 56% (n = 505) had GP-ordered imaging (chest X-ray or CT scan), 39% (N = 349) attended a respiratory physician and 11% (N = 102) attended a cardiothoracic surgeon. The two most common pathways to diagnosis, accounting for one in three people, included GP and lung specialist (respiratory physician or cardiothoracic surgeon) involvement. Overall, 25% of people (n = 223) had an emergency hospital admission. For 14% of people (N = 129), an emergency hospital admission was the only event identified on the pathway to diagnosis. We found little effect of remoteness of residence on access to services. This study identified a substantial proportion of people with NSCLC being diagnosed in an emergency setting. Further research is needed to establish whether there were barriers to the timely diagnosis of these cases.