Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in mycobacterium tuberculosis–infected individuals

Copyright © 2009 by the American Thoracic Society.Rationale: An effective new tuberculosis (TB) vaccine regimen must be safe in individuals with latent TB infection (LTBI) and is a priority for global health care. Objectives: To evaluate the safety and immunogenicity of a leading new TB vaccine, recombinant Modified Vaccinia Ankara expressing Antigen 85A (MVA85A) in individuals with LTBI. Methods: An open-label, phase I trial of MVA85A was performed in 12 subjects with LTBI recruited from TB contact clinics in Oxford and London or by poster advertisements in Oxford hospitals. Patients were assessed clinically and had blood samples drawn for immunological analysis over a 52-week period after vaccination with MVA85A. Thoracic computed tomography scans were performed at baseline and at 10 weeks after vaccination. Safety of MVA85A was assessed by clinical, radiological, and inflammatory markers. The immunogenicity of MVA85A was assessed by IFNγ and IL-2 ELISpot assays and FACS. Measurements and Main Results: MVA85A was safe in subjects with LTBI, with comparable adverse events to previous trials of MVA85A. There were no clinically significant changes in inflammatory markers or thoracic computed tomography scans after vaccination. MVA85A induced a strong antigen-specific IFN-γ and IL-2 response that was durable for 52 weeks. The magnitude of IFN-γ response was comparable to previous trials of MVA85A in bacillus Calmette-Guérin–vaccinated individuals. Antigen 85A–specific polyfunctional CD4+ T cells were detectable prior to vaccination with statistically significant increases in cell numbers after vaccination. Conclusions: MVA85A is safe and highly immunogenic in individuals with LTBI. These results will facilitate further trials in TB-endemic areas.Oxford Biomedical Research Centre, Wellcome Trust, and AFTBVAC

Predicting Pathologic Response of Esophageal Cancer to Neoadjuvant Chemotherapy: The Implications of Metabolic Nodal Response for Personalized Therapy

INTRODUCTION Only a minority of esophageal cancers demonstrates a pathological tumor response (pTR) to neoadjuvant chemotherapy (NAC). 18F-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET-CT) is often used for restaging after NAC and to assess response. Increasingly, it is used during therapy to identify unresponsive tumors and predict pTR , using avidity of the primary tumor alone. However, definitions of such metabolic tumor response (mTR) vary. We aimed to comprehensively re-evaluate metabolic response assessment using accepted parameters, as well as novel concepts of metabolic nodal stage (mN) and nodal response (mNR). PATIENTS AND METHODS This was a single-center retrospective UK cohort study. All patients with esophageal cancer staged before NAC with PET-CT and after with CT or PET-CT and undergoing resection from 2006-2014 were identified. pTR was defined as Mandard tumor regression grade 1-3; imaging parameters included metrics of tumor avidity (standardized uptake value [SUV]max/mean/peak), composites of avidity and volume (including metabolic tumor volume), nodal SUVmax, and our new concepts of mN stage and mNR. RESULTS Eighty-two (27.2%) of 301 patients demonstrated pTR. No pre-NAC PET parameters predicted pTR. In 220 patients re-staged by PET-CT, The optimal tumor ΔSUVmax threshold was a 77.8% reduction. This was as sensitive as the current PET Response Criteria in Solid Tumors (PERCIST) 30% reduction, but more specific with a higher negative predictive value (p<0.001). ΔSUVmax and Δlength independently predicted pTR, and composite avidity/spatial metrics outperformed avidity alone. Whilst both mTR and mNR were associated with pTR, in 82 patients with FDG-avid nodes before NAC we observed mNR in 10 (12.2%) not demonstrating mTR. CONCLUSION Current definitions of metabolic response are suboptimal and too simplistic. Composite avidity/volume measures improve prediction. mNR may further improve response assessment, by specifically assessing metastatic tumor sub-populations, likely responsible for disease relapse, and should be urgently assessed when considering aborting therapy on the basis of mTR alone

Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial

BACKGROUND: Previous preclinical research has shown that extracorporeal devices can be used to enhance the delivery and distribution of systemically administered anticancer drugs, resulting in increased intratumoural concentrations. We aimed to assess the safety and feasibility of targeted release and enhanced delivery of doxorubicin to solid tumours from thermosensitive liposomes triggered by mild hyperthermia, induced non-invasively by focused ultrasound. METHODS: We did an open-label, single-centre, phase 1 trial in a single UK hospital. Adult patients (aged ≥18 years) with unresectable and non-ablatable primary or secondary liver tumours of any histological subtype were considered for the study. Patients received a single intravenous infusion (50 mg/m2) of lyso-thermosensitive liposomal doxorubicin (LTLD), followed by extracorporeal focused ultrasound exposure of a single target liver tumour. The trial had two parts: in part I, patients had a real-time thermometry device implanted intratumourally, whereas patients in part II proceeded without thermometry and we used a patient-specific model to predict optimal exposure parameters. We assessed tumour biopsies obtained before and after focused ultrasound exposure for doxorubicin concentration and distribution. The primary endpoint was at least a doubling of total intratumoural doxorubicin concentration in at least half of the patients treated, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT02181075, and is now closed to recruitment. FINDINGS: Between March 13, 2015, and March 27, 2017, ten patients were enrolled in the study (six patients in part I and four in part II), and received a dose of LTLD followed by focused ultrasound exposure. The treatment resulted in an average increase of 3·7 times in intratumoural biopsy doxorubicin concentrations, from an estimate of 2·34 μg/g (SD 0·93) immediately after drug infusion to 8·56 μg/g (5·69) after focused ultrasound. Increases of two to ten times were observed in seven (70%) of ten patients, satisfying the primary endpoint. Serious adverse events registered were expected grade 4 transient neutropenia in five patients and prolonged hospital stay due to unexpected grade 1 confusion in one patient. Grade 3-4 adverse events recorded were neutropenia (grade 3 in one patient and grade 4 in five patients), and grade 3 anaemia in one patient. No treatment-related deaths occurred. INTERPRETATION: The combined treatment of LTLD and non-invasive focused ultrasound hyperthermia in this study seemed to be clinically feasible, safe, and able to enhance intratumoural drug delivery, providing targeted chemo-ablative response in human liver tumours that were refractory to standard chemotherapy. FUNDING: Oxford Biomedical Research Centre, National Institute for Health Research

Long-term radiological and histological outcomes following selective internal radiation therapy to liver metastases from breast cancer.

Liver metastasis from breast cancer is associated with poor prognosis and is a major cause of early morbidity and mortality. When liver resection is not feasible, minimally invasive directed therapies are considered to attempt to prolong survival. Selective internal radiation therapy (SIRT) with yttrium-90 microspheres is a liver-directed therapy that can improve local control of liver metastases from colorectal cancer. We present a case of a patient with a ductal breast adenocarcinoma, who developed liver and bone metastasis despite extensive treatment with systemic chemotherapies. Following SIRT to the liver, after an initial response, the patient ultimately progressed in the liver after 7 months. Liver tumor histology obtained 20 months after the SIRT intervention demonstrated the presence of the resin microspheres in situ. This case report demonstrates the long-term control that may be achieved with SIRT to treat liver metastases from breast cancer that is refractory to previous chemotherapies, and the presence of microspheres in situ long-term

Accuracy and cost-effectiveness of dynamic contrast-enhanced CT in the characterisation of solitary pulmonary nodules — the SPUtNIk study

$\textbf{Introduction:}$ Solitary pulmonary nodules (SPNs) are common on CT. The most cost-effective investigation algorithm is still to be determined. Dynamic contrastenhanced CT (DCE-CT) is an established diagnostic test not widely available in the UK currently. $\textbf{Methods and analysis:}$ The SPUtNIk study will assess the diagnostic accuracy, clinical utility and cost-effectiveness of DCE-CT, alongside the current CT and 18-flurodeoxyglucose-positron emission tomography) ($^{18}$FDG-PET)-CT nodule characterisation strategies in the National Health Service (NHS). Image acquisition and data analysis for $^{18}$FDG-PET-CT and DCE-CT will follow a standardised protocol with central review of 10% to ensure quality assurance. Decision analytic modelling will assess the likely costs and health outcomes resulting from incorporation of DCE-CT into management strategies for patients with SPNs. $\textbf{Ethics and dissemination:}$ Approval has been granted by the South West Research Ethics Committee. Ethics reference number 12/SW/0206. The results of the trial will be presented at national and international meetings and published in an Health Technology Assessment (HTA) Monograph and in peer-reviewed journals.The trial is funded by the National Institute for Health Research HTA Programme (grant no: 09/22/117) and is being run by Southampton Clinical Trials Unit, directed by Professor Gareth Griffiths and part funded by Cancer Research UK. NRQ and RCR are part funded by the Cambridge Biomedical Research Centre and the Cancer Research Network: Eastern

Understanding the burden of interstitial lung disease post-COVID-19: the UK Interstitial Lung Disease-Long COVID Study (UKILD-Long COVID)

Introduction The COVID-19 pandemic has led to over 100 million cases worldwide. The UK has had over 4 million cases, 400 000 hospital admissions and 100 000 deaths. Many patients with COVID-19 suffer long-term symptoms, predominantly breathlessness and fatigue whether hospitalised or not. Early data suggest potentially severe long-term consequence of COVID-19 is development of long COVID-19-related interstitial lung disease (LC-ILD). Methods and analysis The UK Interstitial Lung Disease Consortium (UKILD) will undertake longitudinal observational studies of patients with suspected ILD following COVID-19. The primary objective is to determine ILD prevalence at 12 months following infection and whether clinically severe infection correlates with severity of ILD. Secondary objectives will determine the clinical, genetic, epigenetic and biochemical factors that determine the trajectory of recovery or progression of ILD. Data will be obtained through linkage to the Post-Hospitalisation COVID platform study and community studies. Additional substudies will conduct deep phenotyping. The Xenon MRI investigation of Alveolar dysfunction Substudy will conduct longitudinal xenon alveolar gas transfer and proton perfusion MRI. The POST COVID-19 interstitial lung DiseasE substudy will conduct clinically indicated bronchoalveolar lavage with matched whole blood sampling. Assessments include exploratory single cell RNA and lung microbiomics analysis, gene expression and epigenetic assessment. Ethics and dissemination All contributing studies have been granted appropriate ethical approvals. Results from this study will be disseminated through peer-reviewed journals. Conclusion This study will ensure the extent and consequences of LC-ILD are established and enable strategies to mitigate progression of LC-ILD

Biomechanics of Running Indicates Endothermy in Bipedal Dinosaurs

One of the great unresolved controversies in paleobiology is whether extinct dinosaurs were endothermic, ectothermic, or some combination thereof, and when endothermy first evolved in the lineage leading to birds. Although it is well established that high, sustained growth rates and, presumably, high activity levels are ancestral for dinosaurs and pterosaurs (clade Ornithodira), other independent lines of evidence for high metabolic rates, locomotor costs, or endothermy are needed. For example, some studies have suggested that, because large dinosaurs may have been homeothermic due to their size alone and could have had heat loss problems, ectothermy would be a more plausible metabolic strategy for such animals.Here we describe two new biomechanical approaches for reconstructing the metabolic rate of 14 extinct bipedal dinosauriforms during walking and running. These methods, well validated for extant animals, indicate that during walking and slow running the metabolic rate of at least the larger extinct dinosaurs exceeded the maximum aerobic capabilities of modern ectotherms, falling instead within the range of modern birds and mammals. Estimated metabolic rates for smaller dinosaurs are more ambiguous, but generally approach or exceed the ectotherm boundary.Our results support the hypothesis that endothermy was widespread in at least larger non-avian dinosaurs. It was plausibly ancestral for all dinosauriforms (perhaps Ornithodira), but this is perhaps more strongly indicated by high growth rates than by locomotor costs. The polarity of the evolution of endothermy indicates that rapid growth, insulation, erect postures, and perhaps aerobic power predated advanced “avian” lung structure and high locomotor costs

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research