17 results found
Savva K-V, Das B, Antonowicz S, et al., 2022, Progress with metabolomic blood tests for gastrointestinal cancer diagnosis-an assessment of biomarker translation, Cancer Epidemiology, Biomarkers and Prevention, Vol: 31, Pages: 2095-2105, ISSN: 1055-9965
There is an urgent need for cost-effective, non-invasive tools to detect early stages of gastrointestinal cancer (colorectal, gastric, and esophageal cancers). Despite many publications suggesting circulating metabolites acting as accurate cancer biomarkers, few have reached the clinic. In upper gastrointestinal cancer this is critically important, as there is no test to complement gold-standard endoscopic evaluation in patients with mild symptoms that do not meet referral criteria. Therefore, this study aimed to describe and solve this translational gap. Studies reporting diagnostic accuracy of metabolomic blood-based gastrointestinal cancer biomarkers from 2007 to 2020 were systematically reviewed and progress of each biomarker along the discovery–validation–adoption pathway was mapped. Successful biomarker translation was defined as a composite endpoint, including patent protection/FDA approval/recommendation in national guidelines. The review found 77 biomarker panels of gastrointestinal cancer, including 25 with an AUROC >0.9. All but one was stalled at the discovery phase, 9.09% were patented and none were clinically approved, confirming the extent of biomarker translational gap. In addition, there were numerous “re-discoveries,” including histidine, discovered in 7 colorectal studies. Finally, this study quantitatively supports the presence of a translational gap between discovery and clinical adoption, despite clear evidence of highly performing biomarkers with significant potential clinical value.
Das B, Leung KHP, Antonowicz S, et al., 2022, A novel prognostic hypoxia gene signature identifies de novo nucleotide synthesis as a metabolic vulnerability in gastric cancer, European Journal of Surgical Oncology
Markar SR, Zaninotto G, Castoro C, et al., 2022, Lasting Symptoms After Esophageal Resection (LASER) European Multicenter Cross-sectional Study, ANNALS OF SURGERY, Vol: 275, Pages: E392-E400, ISSN: 0003-4932
- Author Web Link
- Citations: 16
Markar SR, Sounderajah V, Johar A, et al., 2021, Patient-reported outcomes after oesophagectomy in the multicentre LASER study, BRITISH JOURNAL OF SURGERY, Vol: 108, Pages: 1090-1096, ISSN: 0007-1323
Antonowicz S, Bodai Z, Wiggins T, et al., 2021, Endogenous aldehyde accumulation generates genotoxicity and exhaled biomarkers in esophageal adenocarcinoma, Nature Communications, Vol: 12, ISSN: 2041-1723
Volatile aldehydes are enriched in esophageal adenocarcinoma (EAC) patients’ breath and could improve early diagnosis, however the mechanisms of their production are unknown. Here, we show that weak aldehyde detoxification characterizes EAC, which is sufficient to cause endogenous aldehyde accumulation in vitro. Two aldehyde groups are significantly enriched in EAC biopsies and adjacent tissue: (i) short-chain alkanals, and (ii) medium-chain alkanals, including decanal. The short-chain alkanals form DNA-adducts, which demonstrates genotoxicity and confirms inadequate detoxification. Metformin, a putative aldehyde scavenger, reduces this toxicity. Tissue and breath concentrations of the medium-chain alkanal decanal are correlated, and increased decanal is linked to reduced ALDH3A2 expression, TP53 deletion, and adverse clinical features. Thus, we present a model for increased exhaled aldehydes based on endogenous accumulation from reduced detoxification, which also causes therapeutically actionable genotoxicity. These results support EAC early diagnosis trials using exhaled aldehyde analysis.
Abbassi-Ghadi N, Antonowicz S, McKenzie J, et al., 2020, De novo lipogenesis alters the phospholipidome of esophageal adenocarcinoma, Cancer Research, Vol: 80, Pages: 2764-2774, ISSN: 0008-5472
The incidence of esophageal adenocarcinoma is rising, survival remains poor, and new tools to improve early diagnosis and precise treatment are needed. Cancer phospholipidomes quantified with mass spectrometry imaging can support objective diagnosis in minutes using a routine frozen tissue section. However, whether mass spectrometry imaging can objectively identify primary esophageal adenocarcinoma is currently unknown and represents a significant challenge, as this microenvironment is complex with phenotypically similar tissue-types. Here we used desorption electrospray ionisation mass spectrometry imaging (DESI-MSI) and bespoke chemometrics to assess the phospholipidomes of esophageal adenocarcinoma and relevant control tissues. Multivariable models derived from phospholipid profiles of 117 patients were highly discriminant for esophageal adenocarcinoma both in discovery (area-under-curve = 0.97) and validation cohorts (AUC = 1). Among many other changes, esophageal adenocarcinoma samples were markedly enriched for polyunsaturated phosphatidylglycerols with longer acyl chains, with stepwise enrichment in pre-malignant tissues. Expression of fatty acid and glycerophospholipid synthesis genes was significantly upregulated, and characteristics of fatty acid acyls matched glycerophospholipid acyls. Mechanistically, silencing the carbon switch ACLY in esophageal adenocarcinoma cells shortened GPL chains, linking de novo lipogenesis to the phospholipidome. Thus, DESI-MSI can objectively identify invasive esophageal adenocarcinoma from a number of pre-malignant tissues and unveils mechanisms of phospholipidomic reprogramming. These results call for accelerated diagnosis studies using DESI-MSI in the upper gastrointestinal endoscopy suite as well as functional studies to determine how polyunsaturated phosphatidylglycerols contribute to esophageal carcinogenesis.
Goh YM, Antonowicz S, Boshier P, et al., 2020, Metabolic biomarkers of squamous cell carcinoma of the aerodigestive tract: a systematic review and quality assessment, Oxidative Medicine and Cellular Longevity, Vol: 2020, Pages: 1-13, ISSN: 1942-0900
Introduction. Aerodigestive squamous cell carcinomas (ASCC) constitute a major source of global cancer deaths. Patients typically present with advanced, incurable disease, so new means of detecting early disease are a research priority. Metabolite quantitation is amenable to point-of-care analysis and can be performed in ASCC surrogates such as breath and saliva. The purpose of this systematic review is to summarise progress of ASCC metabolomic studies, with an emphasis on the critical appraisal of methodological quality and reporting. Method. A systematic online literature search was performed to identify studies reporting metabolic biomarkers of ASCC. This review was conducted in accordance with the recommendations of the Cochrane Library and MOOSE guidelines. Results. Thirty studies comprising 2117 patients were included in the review. All publications represented phase-I biomarker discovery studies, and none validated their findings in an independent cohort. There was heterogeneity in study design and methodological and reporting quality. Sensitivities and specificities were higher in oesophageal and head and neck squamous cell carcinomas compared to those in lung squamous cell carcinoma. The metabolic phenotypes of these cancers were similar, as was the kinetics of metabolite groups when comparing blood, tissue, and breath/saliva concentrations. Deregulation of amino acid metabolism was the most frequently reported theme. Conclusion. Metabolite analysis has shown promising diagnostic performance, especially for oesophageal and head and neck ASCC subtypes, which are phenotypically similar. However, shortcomings in study design have led to inconsistencies between studies. To support future studies and ultimately clinical adoption, these limitations are discussed.
Markar SR, Chin S-T, Romano A, et al., 2019, Breath Volatile Organic Compound Profiling of Colorectal Cancer Using Selected Ion Flow-Tube Mass Spectrometry., Annals of Surgery, Vol: 269, Pages: 903-910, ISSN: 0003-4932
OBJECTIVE: BACKGROUND:: Breath VOCs have the potential to noninvasively diagnose cancer. METHODS: Exhaled breath samples were collected using 2-L double-layered Nalophan bags, and were analyzed using selected-ion-flow-tube mass-spectrometry. Gold-standard test for comparison was endoscopy for luminal inspection and computed tomography (CT) to confirm cancer recurrence. Three studies were conducted: RESULTS:: CONCLUSION:: This study suggests the association of a single breath biomarker with the primary presence and recurrence of CRCa. Further multicenter validation studies are required to validate these findings.
Wiggins T, Antonowicz SS, Markar SR, 2018, Cancer Risk Following Bariatric Surgery-Systematic Review and Meta-analysis of National Population-Based Cohort Studies., Obes Surg
This study has analyzed results from registry-based population studies to assess the effect of bariatric surgery upon cancer incidence at a population level. Relevant studies were identified and meta-analysis was used to calculate pooled odds ratios (POR) for the incidence of cancer after bariatric surgery compared to controls. Eight population-based studies were included with 635,642 total patients. Bariatric surgery was associated with a significant reduction in overall cancer incidence (POR = 0.72; 95% CI 0.59 to 0.87; p = 0.0007) and incidence of obesity-related cancer (POR = 0.55; 95% CI 0.31 to 0.96; p = 0.04). Bariatric surgery was also protective for breast cancer development (POR = 0.50; 95% CI 0.25 to 0.99; p = 0.045). Bariatric surgery appears to be associated with a reduction in cancer incidence at a population-based level.
Antonowicz S, Hanna GB, Takats Z, et al., 2018, Pragmatic and rapid analysis of carbonyl, oxidation and chlorination nucleoside-adducts in murine tissue by UPLC-ESI-MS/MS, Talanta, Vol: 190, Pages: 436-442, ISSN: 0039-9140
Nucleoside-adduct analysis by liquid chromatography mass spectrometry is a powerful tool in genotoxicity studies. Efforts to date have quantified an impressive array of DNA damage products, although methodological diversity suggests quantification is still a challenging task. For example, inadequate co-examination of normal nucleosides, cumbersome sample preparation and large DNA requirements were identified to be recurring issues. A six-minute ultra-performance liquid chromatography method is presented which adequately separates seven candidate nucleoside-adducts from the four unmodified nucleosides. The method was sensitive to 1 adduct per 108 normal bases with 20 µg DNA input for most targets. The method was shown to be accurate (81–119% across quintuplets of six tissue types) and precise (relative standard deviation 4–13%). The fast method time facilitated a second quantitation for normal nucleosides at an appropriate dilution, allowing DNA damage concentrations to be contextualised accurately sample-to-sample. From DNA samples, the analytical processing time was < 8 h, and 96 samples can easily be prepared in a day. The method was used to quantify carbonyl, chloro- and oxo- adducts in murine tissue samples.
Markar S, Wiggins T, Antonowicz S, et al., 2018, Assessment of a noninvasive exhaled breath test for the diagnosis of oesophagogastric cancer, JAMA Oncology, Vol: 4, Pages: 970-976, ISSN: 2374-2445
Importance Early esophagogastric cancer (OGC) stage presents with nonspecific symptoms.Objective The aim of this study was to determine the accuracy of a breath test for the diagnosis of OGC in a multicenter validation study.Design, Setting, and Participants Patient recruitment for this diagnostic validation study was conducted at 3 London hospital sites, with breath samples returned to a central laboratory for selected ion flow tube mass spectrometry (SIFT-MS) analysis. Based on a 1:1 cancer:control ratio, and maintaining a sensitivity and specificity of 80%, the sample size required was 325 patients. All patients with cancer were on a curative treatment pathway, and patients were recruited consecutively. Among the 335 patients included; 172 were in the control group and 163 had OGC.Interventions Breath samples were collected using secure 500-mL steel breath bags and analyzed by SIFT-MS. Quality assurance measures included sampling room air, training all researchers in breath sampling, regular instrument calibration, and unambiguous volatile organic compounds (VOCs) identification by gas chromatography mass spectrometry.Main Outcomes and Measures The risk of cancer was identified based on a previously generated 5-VOCs model and compared with histopathology-proven diagnosis.Results Patients in the OGC group were older (median [IQR] age 68 [60-75] vs 55 [41-69] years) and had a greater proportion of men (134 [82.2%]) vs women (81 [47.4%]) compared with the control group. Of the 163 patients with OGC, 123 (69%) had tumor stage T3/4, and 106 (65%) had nodal metastasis on clinical staging. The predictive probabilities generated by this 5-VOCs diagnostic model were used to generate a receiver operator characteristic curve, with good diagnostic accuracy, area under the curve of 0.85. This translated to a sensitivity of 80% and specificity of 81% for the diagnosis of OGC.Conclusions and Relevance This study shows the potential of breath analysis in noninvasive diagn
Antonowicz SS, Cavallaro D, Jacques N, et al., 2018, Remote ischemic preconditioning for cardioprotection in elective inpatient abdominal surgery - a randomized controlled trial, BMC Anesthesiology, Vol: 18, ISSN: 1471-2253
BACKGROUND: Perioperative myocardial injury (PMI) is common in elective inpatient abdominal surgery and correlates with mortality risk. Simple measures for reducing PMI in this cohort are needed. This study evaluated whether remote ischemic preconditioning (RIPC) could reduce PMI in elective inpatient abdominal surgery. METHODS: This was a double-blind, sham-controlled trial with 1:1 parallel randomization. PMI was defined as any post-operative serum troponin T (hs-TNT) > 14 ng/L. Eighty-four participants were randomized to receiving RIPC (5 min of upper arm ischemia followed by 5 min reperfusion, for three cycles) or a sham-treatment immediately prior to surgery. The primary outcome was mean peak post-operative troponin in patients with PMI, and secondary outcomes included mean hs-TnT at individual timepoints, post-operative hs-TnT area under the curve (AUC), cardiovascular events and mortality. Predictors of PMI were also collected. Follow up was to 1 year. RESULTS: PMI was observed in 21% of participants. RIPC did not significantly influence the mean peak post-operative hs-TnT concentration in these patients (RIPC 25.65 ng/L [SD 9.33], sham-RIPC 23.91 [SD 13.2], mean difference 1.73 ng/L, 95% confidence interval - 9.7 to 13.1 ng/L, P = 0.753). The treatment did not influence any secondary outcome with the pre-determined definition of PMI. Redefining PMI as > 5 ng/L in line with recent data revealed a non-significant lower incidence in the RIPC cohort (68% vs 81%, P = 0.211), and significantly lower early hs-TnT release (12 h time-point, RIPC 5.5 ng/L [SD 5.5] vs sham 9.1 ng/L [SD 8.2], P = 0.03). CONCLUSIONS: RIPC did not at reduce the incidence or severity of PMI in these general surgical patients using pre-determined definitions. PMI is nonetheless common and effective cardioprotective strategies are required. TRIAL REGISTRATION: This tr
Abbassi-Ghadi N, Golf O, Kumar S, et al., 2016, Imaging of esophageal lymph node metastases by desorption electrospray ionization mass spectrometry, Cancer Research, Vol: 76, Pages: 5647-5656, ISSN: 1538-7445
Histopathological assessment of lymph node metastases (LNM) depends on subjective analysis of cellular morphology with inter-/intra-observer variability. In this study, LNM from esophageal adenocarcinoma was objectively detected using desorption electrospray ionization-mass spectrometry imaging (DESI-MSI). Ninety lymph nodes and their primary tumor biopsies from 11 esophago-gastrectomy specimens were examined and analyzed by DESI-MSI. Images from mass spectrometry and corresponding histology were co-registered and analyzed using multivariate statistical tools. The MSIs revealed consistent lipidomic profiles of individual tissue types found within lymph nodes. Spatial mapping of the profiles showed identical distribution patterns as per the tissue types in matched immunohistochemistry images. Lipidomic profile comparisons of LNM versus the primary tumor revealed a close association in contrast to benign lymph node tissue types. This similarity was used for the objective prediction of LNM in mass spectrometry images utilizing the average lipidomic profile of esophageal adenocarcinoma. The multivariate statistical algorithm developed for LNM identification demonstrated a sensitivity, specificity, positive predictive value and negative predictive value of 89.5, 100, 100 and 97.2 per-cent, respectively, when compared to gold-standard immunohistochemistry. DESI-MSI has the potential to be a diagnostic tool for peri-operative identification of LNM and compares favorably with techniques currently used by histopathology experts.
Antonowicz S, Kumar S, Wiggins T, et al., 2015, Diagnostic metabolomic blood tests for endoluminal gastrointestinal cancer - a systematic review and assessment of quality, Cancer Epidemiology Biomarkers & Prevention, Vol: 25, Pages: 6-15, ISSN: 1538-7755
Advances in analytics have resulted in metabolomic blood tests being developed for the detection of cancer. This systematic review aims to assess the diagnostic accuracy of blood-based metabolomic biomarkers for endoluminal gastrointestinal (GI) cancer. Using endoscopic diagnosis as a reference standard, methodologic and reporting quality was assessed using validated tools, in addition to pathway-based informatics to biologically contextualize discriminant features. Twenty-nine studies (15 colorectal, 9 esophageal, 3 gastric, and 2 mixed) with data from 10,835 participants were included. All reported significant differences in hematologic metabolites. In pooled analysis, 246 metabolites were found to be significantly different after multiplicity correction. Incremental metabolic flux with disease progression was frequently reported. Two promising candidates have been validated in independent populations (both colorectal biomarkers), and one has been approved for clinical use. Networks analysis suggested modulation of elements of up to half of Edinburgh Human Metabolic Network subdivisions, and that the poor clinical applicability of commonly modulated metabolites could be due to extensive molecular interconnectivity. Methodologic and reporting quality was assessed as moderate-to-poor. Serum metabolomics holds promise for GI cancer diagnostics; however, future efforts must adhere to consensus standardization initiatives, utilize high-resolution discovery analytics, and compare candidate biomarkers with peer nonendoscopic alternatives.
Markar SR, Wiggins T, Antonowicz S, et al., 2015, Minimally invasive esophagectomy: Lateral decubitus vs. prone positioning; systematic review and pooled analysis, SURGICAL ONCOLOGY-OXFORD, Vol: 24, Pages: 212-219, ISSN: 0960-7404
- Author Web Link
- Citations: 41
Wiggins T, Kumar S, Markar SR, et al., 2015, Tyrosine, Phenylalanine, and Tryptophan in Gastroesophageal Malignancy: A Systematic Review, CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, Vol: 24, Pages: 32-38, ISSN: 1055-9965
- Author Web Link
- Citations: 59
Haddow JB, Adwan H, Clark SE, et al., 2014, Use of the surgical Apgar score to guide postoperative care, ANNALS OF THE ROYAL COLLEGE OF SURGEONS OF ENGLAND, Vol: 96, Pages: 352-358, ISSN: 0035-8843
- Author Web Link
- Citations: 19
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