The Biomarker Toolkit - an evidence-based guideline to predict cancer biomarker success and guide development.

BACKGROUND: An increased number of resources are allocated on cancer biomarker discovery, but very few of these biomarkers are clinically adopted. To bridge the gap between Biomarker discovery and clinical use, we aim to generate the Biomarker Toolkit, a tool designed to identify clinically promising biomarkers and promote successful biomarker translation. METHODS: All features associated with a clinically useful biomarker were identified using mixed-methodology, including systematic literature search, semi-structured interviews, and an online two-stage Delphi-Survey. Validation of the checklist was achieved by independent systematic literature searches using keywords/subheadings related to clinically and non-clinically utilised breast and colorectal cancer biomarkers. Composite aggregated scores were generated for each selected publication based on the presence/absence of an attribute listed in the Biomarker Toolkit checklist. RESULTS: Systematic literature search identified 129 attributes associated with a clinically useful biomarker. These were grouped in four main categories including: rationale, clinical utility, analytical validity, and clinical validity. This checklist was subsequently developed using semi-structured interviews with biomarker experts (n=34); and 88.23% agreement was achieved regarding the identified attributes, via the Delphi survey (consensus level:75%, n=51). Quantitative validation was completed using clinically and non-clinically implemented breast and colorectal cancer biomarkers. Cox-regression analysis suggested that total score is a significant driver of biomarker success in both cancer types (BC: p>0.0001, 95.0% CI: 0.869-0.935, CRC: p>0.0001, 95.0% CI: 0.918-0.954). CONCLUSIONS: This novel study generated a validated checklist with literature-reported attributes linked with successful biomarker implementation. Ultimately, the application of this toolkit can be used to detect biomarkers with the highest clinical potential and shape how biomarker studies are designed/performed.

The Role of Artificial Intelligence in Prospective Real-Time Histological Prediction of Colorectal Lesions during Colonoscopy: A Systematic Review and Meta-Analysis.

Artificial intelligence (AI) presents a novel platform for improving disease diagnosis. However, the clinical utility of AI remains limited to discovery studies, with poor translation to clinical practice. Current data suggests that 26% of diminutive pre-malignant lesions and 3.5% of colorectal cancers are missed during colonoscopies. The primary aim of this study was to explore the role of artificial intelligence in real-time histological prediction of colorectal lesions during colonoscopy. A systematic search using MeSH headings relating to "AI", "machine learning", "computer-aided", "colonoscopy", and "colon/rectum/colorectal" identified 2290 studies. Thirteen studies reporting real-time analysis were included. A total of 2958 patients with 5908 colorectal lesions were included. A meta-analysis of six studies reporting sensitivities (95% CI) demonstrated that endoscopist diagnosis was superior to a computer-assisted detection platform, although no statistical significance was reached (p = 0.43). AI applications have shown encouraging results in differentiating neoplastic and non-neoplastic lesions using narrow-band imaging, white light imaging, and blue light imaging. Other modalities include autofluorescence imaging and elastic scattering microscopy. The current literature demonstrates that despite the promise of new endoscopic AI models, they remain inferior to expert endoscopist diagnosis. There is a need to focus developments on real-time histological predictions prior to clinical translation to demonstrate improved diagnostic capabilities and time efficiency.

Evaluation of the Oesophagogastric Cancer-Associated Microbiome: A Systematic Review and Quality Assessment.

OBJECTIVE: Oesophagogastric cancer is the fifth most common cancer worldwide, with poor survival outcomes. The role of bacteria in the pathogenesis of oesophagogastric cancer remains poorly understood. DESIGN: A systematic search identified studies assessing the oesophagogastric cancer microbiome. The primary outcome was to identify bacterial enrichment specific to oesophagogastric cancer. Secondary outcomes included appraisal of the methodology, diagnostic performance of cancer bacteria and the relationship between oral and tissue microbiome. RESULTS: A total of 9295 articles were identified, and 87 studies were selected for analysis. Five genera were enriched in gastric cancer: Lactobacillus, Streptococcus, Prevotella, Fusobacterium and Veillonella. No clear trends were observed in oesophageal adenocarcinoma. Streptococcus, Prevotella and Fusobacterium were abundant in oesophageal squamous cell carcinoma. Functional analysis supports the role of immune cells, localised inflammation and cancer-specific pathways mediating carcinogenesis. STORMS reporting assessment identified experimental deficiencies, considering batch effects and sources of contamination prevalent in low-biomass samples. CONCLUSIONS: Functional analysis of cancer pathways can infer tumorigenesis within the cancer-microbe-immune axis. There is evidence that study design, experimental protocols and analytical techniques could be improved to achieve more accurate and representative results. Whole-genome sequencing is recommended to identify key metabolic and functional capabilities of candidate bacteria biomarkers.

Usability challenges in the use of medical devices in the home environment: A systematic review of literature.

BACKGROUND: Home care medical devices are the fastest-growing segment of the medical device industry with associated safety and usability challenges. Human factor studies in the home environment present many difficulties resulting in limited knowledge of device use in this setting. This systematic review aims to identify usability challenges reported directly by end-users in the home environment. METHODS: A systematic review of the literature was conducted concentrating on studies involving end user reporting. Reported challenges were grouped into a) device-user, b) device use environment and c) device-user interface challenges. RESULTS: 3471 studies were screened and 202 underwent full-text review. Only twelve studies had direct involvement of end users. Multiple challenges were identified, with device-user interface problems being the most common. No effective, standardised method was found to collect patient/user feedback on usability challenges in the post-market stage, leading to a knowledge gap. CONCLUSIONS: This study brought together multiple usability challenges reported by individual studies. Involvement of medical device end-users in usability studies is essential and their experiences must be effectively utilised in device design.

Systematic review and validation of clinical models predicting survival after oesophagectomy for adenocarcinoma.

BACKGROUND: Oesophageal adenocarcinoma poses a significant global health burden, yet the staging used to predict survival has limited ability to stratify patients by outcome. This study aimed to identify published clinical models that predict survival in oesophageal adenocarcinoma and to evaluate them using an independent international multicentre dataset. METHODS: A systematic literature search (title and abstract) using the Ovid Embase and MEDLINE databases (from 1947 to 11 July 2020) was performed. Inclusion criteria were studies that developed or validated a clinical prognostication model to predict either overall or disease-specific survival in patients with oesophageal adenocarcinoma undergoing surgical treatment with curative intent. Published models were validated using an independent dataset of 2450 patients who underwent oesophagectomy for oesophageal adenocarcinoma with curative intent. RESULTS: Seventeen articles were eligible for inclusion in the study. Eleven models were suitable for testing in the independent validation dataset and nine of these were able to stratify patients successfully into groups with significantly different survival outcomes. Area under the receiver operating characteristic curves for individual survival prediction models ranged from 0.658 to 0.705, suggesting poor-to-fair accuracy. CONCLUSION: This study highlights the need to concentrate on robust methodologies and improved, independent, validation, to increase the likelihood of clinical adoption of survival predictions models.

Selected ion flow tube mass spectrometry for targeted analysis of volatile organic compounds in human breath.

The analysis of volatile organic compounds (VOCs) within breath for noninvasive disease detection and monitoring is an emergent research field that has the potential to reshape current clinical practice. However, adoption of breath testing has been limited by a lack of standardization. This protocol provides a comprehensive workflow for online and offline breath analysis using selected ion flow tube mass spectrometry (SIFT-MS). Following the suggested protocol, 50 human breath samples can be analyzed and interpreted in <3 h. Key advantages of SIFT-MS are exploited, including the acquisition of real-time results and direct compound quantification without need for calibration curves. The protocol includes details of methods developed for targeted analysis of disease-specific VOCs, specifically short-chain fatty acids, aldehydes, phenols, alcohols and alkanes. A procedure to make custom breath collection bags is also described. This standardized protocol for VOC analysis using SIFT-MS is intended to provide a basis for wider application and the use of breath analysis in clinical studies.

Cross Platform Analysis of Volatile Organic Compounds Using Selected Ion Flow Tube and Proton-Transfer-Reaction Mass Spectrometry.

Volatile breath metabolites serve as potential disease biomarkers. Online mass spectrometry (MS) presents real-time quantification of breath volatile organic compounds (VOCs). The study aims to assess the relationship between two online analytical mass spectrometry techniques in the quantification of target breath metabolites: selected ion flow tube mass spectrometry (SIFT-MS) and proton-transfer-reaction time-of-flight mass spectrometry (PTR-ToF-MS). The two following techniques were employed: (i) direct injection with bag sampling using SIFT-MS and PTR-ToF-MS and (ii) direct injection and thermal desorption (TD) tube comparison using PTR-ToF-MS. The concentration of abundant breath metabolites, acetone and isoprene, demonstrated a strong positive linear correlation between both mass spectrometry techniques (r = 0.97, r = 0.89, respectively; p < 0.001) and between direct injection and TD tube (r = 0.97, r = 0.92, respectively; p < 0.001) breath sampling techniques. This was reflected for the majority of short chain fatty acids and alcohols tested (r > 0.80, p < 0.001). Analyte concentrations were notably higher with the direct injection of a sampling bag compared to the TD method. All metabolites produced a high degree of agreement in the detection range of VOCs between SIFT-MS and PTR-ToF-MS, with the majority of compounds falling within 95% of the limits of agreement with Bland-Altman analysis. The cross platform analysis of exhaled breath demonstrates strong positive correlation coefficients, linear regression, and agreement in target metabolite detection rates between both breath sampling techniques. The study demonstrates the transferability of using data outputs between SIFT-MS and PTR-ToF-MS. It supports the implementation of a TD platform in multi-site studies for breath biomarker research in order to facilitate sample transport between clinics and the laboratory.

Impact on Quality of Life After Parathyroidectomy for Asymptomatic Primary Hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (PHPT) is associated with a poorer quality of life. The role of neuropsychiatric symptoms in asymptomatic patients who do not display classical features of PHPT remains undefined. It is unclear whether parathyroidectomy provides immediate benefit beyond the long-term risk reduction of adverse effects. The aim of the study is to assess the effect on quality of life in patients with asymptomatic PHPT undergoing parathyroidectomy. METHODS: Consecutive patients with PHPT undergoing parathyroidectomy by a single surgeon were recruited from a single center between 2014 and 2019. All patients prospectively completed the validated EQ-5D-3L health status questionnaire preoperatively and postoperatively, comprising two components: (i) five domains including physical and mental health and (ii) visual analog scale (VAS). Biochemical and clinical indices were recorded. RESULTS: Seventy-eight patients were included, 72% female (n = 56), median age 62 y (interquartile range (IQR): 52-70), and 28 (36%) asymptomatic. A global improvement in health-related quality of life was observed with a VAS score increase from 70 (IQR: 50-80) to 80 (IQR: 70-90); P < 0.001. VAS scores also improved significantly in asymptomatic patients increasing from 77 to 85 (P = 0.014), with an overall improvement in all five domains of quality of life. The symptomatic group showed a significant improvement in anxiety/depression levels (P < 0.01), although this was not the primary complaint in any of the cases. CONCLUSIONS: Parathyroidectomy is associated with a significant improvement in the quality of life of patients with asymptomatic PHPT. In symptomatic patients, this includes a reduction in anxiety and depression. Benefits are observed as early as 2 mo postoperatively, and results suggest a potentially important cognitive and social aspect of this disease.

Impact of oral cleansing strategies on exhaled volatile organic compound levels.

RATIONALE: The analysis of volatile organic compounds (VOCs) within exhaled breath potentially offers a non-invasive method for the detection and surveillance of human disease. Oral contamination of exhaled breath may influence the detection of systemic VOCs relevant to human disease. This study aims to assess the impact of oral cleansing strategies on exhaled VOC levels in order to standardise practice for breath sampling. METHODS: Ten healthy volunteers consumed a nutrient challenge followed by four oral cleansing methods: (a) water, (b) saltwater, (c) toothbrushing, and (d) alcohol-free mouthwash. Direct breath sampling was performed using selected ion flow tube mass spectrometry after each intervention. RESULTS: Proposed reactions suggest that volatile fatty acid and alcohol levels (butanoic, pentanoic acid, ethanol) declined with oral cleansing interventions, predominantly after an initial oral rinse with water. Concentrations of aldehydes and phenols (acetaldehyde, menthone, p-cresol) declined with oral water rinse; however, they increased after toothbrushing and mouthwash use, secondary to flavoured ingredients within these products. No significant reductions were observed with sulphur compounds. CONCLUSIONS: Findings suggest that oral rinsing with water prior to breath sampling may reduce oral contamination of VOC levels, and further interventions for oral decontamination with flavoured products may compromise results. This intervention may serve as a simple and inexpensive method of standardisation within breath research.

Adjuvant radiotherapy in oesophageal cancer with positive circumferential resection margins-recurrence and survival outcomes.

BACKGROUND: The role of adjuvant radiotherapy in patients with microscopically positive circumferential resection margins (CRM), R1 specimen, in oesophageal resections for cancer with curative intent remains unclear. However, R1 specimens are associated with poorer survival outcomes. The aim was to assess the benefit of adjuvant radiotherapy on recurrence and survival in these patients. METHODS: Patients were identified in a single centre between July 2000 and December 2016. Patient demographics, tumour characteristics and survival outcomes were assimilated and compared between those who received adjuvant therapy and those who did not. RESULTS: Sixty-eight patients were included in the study; 57 (83.8%) male and 11 (16.2%) female with a median age of 67 years. The adjuvant radiotherapy regimen used was 40-50 Gy in 25 fractions over 5 weeks. Median follow-up was 13 months (interquartile range, 6-27 months). Twenty-five (36.8%) patients received adjuvant radiotherapy. There was no statistically significant correlation between administration of adjuvant radiotherapy and local recurrence (P=0.148), distant metastases (P=0.605), overall disease progression (P=0.561), progression-free survival (P=0.663) and overall survival (P=0.538). CONCLUSIONS: This study detects no benefit to oncological outcomes with the use of adjuvant radiotherapy in patients with microscopically positive CRM. Larger randomized studies are needed to further confirm these results.

Predictors of abnormalities on magnetic resonance cholangiopancreatography: is there a role when the biliary tree is normal on previous imaging?

BACKGROUND: There is limited evidence supporting the use of magnetic resonance cholangiopancreatography (MRCP) if the biliary tree is within normal limits on ultrasound scan (US) or computed tomography (CT). The aim of this study was to assess the role of MRCP in the absence of a dilated biliary system on index imaging. METHODS: A retrospective observational study of consecutive MRCP investigations (n=427) was performed between October 2010 and June 2013 at a single district general hospital. Data collected included patient demographics, clinical presentation, liver function tests (LFTs) and radiological presence of stones. Binary logistic regression and chi-square test were performed using SPSS v23. RESULTS: We included 358 cases, 65% female (n=231) and 35% male (n=127), with a mean age of 60 years. Of these, 63% presented with abdominal pain (n=225), with 20% having concurrent deranged LFTs (n=44) and 8% jaundice (n=18). Index imaging demonstrated a dilated biliary system >6 mm in 68% (n=245). Alkaline phosphatase (ALP) elevation was an independent positive predictor for an abnormal MRCP (P=0.003). Abnormal index imaging, ALP and clinical jaundice were all significantly associated with a positive MRCP (P<0.001, P=0.028, P=0.018). CONCLUSIONS: It is efficacious to proceed to MRCP with abnormal findings on index imaging, clinical jaundice or elevated ALP. An MRCP scan should be strongly considered in the context of elevated ALP and normal US/CT biliary system.

Computed tomography colonography: a retrospective analysis of outcomes of 2 years experience in a district general hospital.

BACKGROUND: Colonoscopy is the gold-standard investigation for direct luminal visualization of the large bowel. Studies have shown the efficacy of computed tomography colonography (CTC) is equivalent to colonoscopy in both cancer and polyp detection. METHODS: A retrospective review of patients undergoing CTC from January 2013 to October 2014 was performed. Patient demographics, indication for investigation, computed tomography findings, optical colonoscopy findings and histology results were recorded. RESULTS: Seven hundred and fifty-eight CTC were performed. Three hundred and seventeen patients were male (42%) and 441 (58%) were female. Endoscopy was advised in 209 cases. One hundred and twenty (16%) were deemed suspicious for cancer of whom 96 (80%) had optical colonoscopy. A total of 12 colorectal cancers were detected. Potential polyps were noted in 58 cases (8%). Forty-four patients underwent endoscopy (75%) and 17 polyps confirmed (38%). Two patients had foci of invasive cancer histologically. Significant extracolonic findings were identified in 60%, including five cases of gastric carcinomas. The most common other findings were gallstones and hernias. CONCLUSION: The rate of colorectal cancer detection in this study was 2%. The rate of biopsy proven cancer was 10% following a suspicious colonogram. Endoscopic correlation was not obtained in 20% of cases of radiological suspicion. CTC is as efficacious as optical colonoscopy for colorectal cancer and polyp detection.

Early astrocytic atrophy in the entorhinal cortex of a triple transgenic animal model of Alzheimer's disease.

The EC (entorhinal cortex) is fundamental for cognitive and mnesic functions. Thus damage to this area appears as a key element in the progression of AD (Alzheimer's disease), resulting in memory deficits arising from neuronal and synaptic alterations as well as glial malfunction. In this paper, we have performed an in-depth analysis of astroglial morphology in the EC by measuring the surface and volume of the GFAP (glial fibrillary acidic protein) profiles in a triple transgenic mouse model of AD [3xTg-AD (triple transgenic mice of AD)]. We found significant reduction in both the surface and volume of GFAP-labelled profiles in 3xTg-AD animals from very early ages (1 month) when compared with non-Tg (non-transgenic) controls (48 and 54%, reduction respectively), which was sustained for up to 12 months (33 and 45% reduction respectively). The appearance of Aß (amyloid ß-peptide) depositions at 12 months of age did not trigger astroglial hypertrophy; nor did it result in the close association of astrocytes with senile plaques. Our results suggest that the AD progressive cognitive deterioration can be associated with an early reduction of astrocytic arborization and shrinkage of the astroglial domain, which may affect synaptic connectivity within the EC and between the EC and other brain regions. In addition, the EC seems to be particularly vulnerable to AD pathology because of the absence of evident astrogliosis in response to Aß accumulation. Thus we can consider that targeting astroglial atrophy may represent a therapeutic strategy which might slow down the progression of AD.

"Blowing up the barriers" in surgical training: exploring and validating the concept of distributed simulation.

OBJECTIVES: To explore face, content and construct validity of Distributed Simulation (DS), an innovative approach to low-cost, high-fidelity surgical simulation and compare technical performance in the DS with that on a standard surgical box trainer. BACKGROUND: Immersive simulation is widely accepted as an important modality for surgical education. However, access and cost limit the uptake of full-scale simulation training. DS is a portable, simulated clinical environment aiming at widening access to immersive simulation. METHODS: Ten novice and 10 expert surgeons performed a laparoscopic cholecystectomy on a porcine model in the DS and on a box trainer. Face and content validity were measured using 6-point Likert-type questionnaires. Construct validity was rated using the Objective Structured Assessment of Technical Skills (OSATS). Comparison of technical performance between DS and box trainer was measured using the Wilcoxon test. RESULTS: Face validity was rated as 5.1 (SD = 0.54) by novices and 4.8 (SD = 0.64) by experts.Content validity was rated as 5.2 (SD = 0.40) by novices and 5.1 (SD = 0.56) by experts. Experts performed significantly better than novices in the DS (16.3 vs. 27.3, P < 0.001) demonstrating construct validity. Experts' technical performance did not differ between DS and box trainer (26.5 vs. 27.3, P > 0.84) whereas novices performed better on the box trainer (19.8 vs. 16.3, P < 0.01). Qualitative data analysis demonstrated that surgeons felt able to behave as if in a real operating room (OR). CONCLUSION: DS offers a valid, low-cost, accessible environment for training and assessing surgeons. This approach has major implications for surgical education and for the widespread implementation of immersive simulation at a time of increasing financial austerity.