Nima Abbassi-Ghadi

Tracking the genomic evolution of esophageal adenocarcinoma through neoadjuvant chemotherapy

UNLABELLED Esophageal adenocarcinomas are associated with a dismal prognosis. Deciphering the evolutionary history of this disease may shed light on therapeutically tractable targets and reveal dynamic mutational processes during the disease course and following neoadjuvant chemotherapy (NAC). We exome sequenced 40 tumor regions from 8 patients with operable esophageal adenocarcinomas, before and after platinum-containing NAC. This revealed the evolutionary genomic landscape of esophageal adenocarcinomas with the presence of heterogeneous driver mutations, parallel evolution, early genome-doubling events, and an association between high intratumor heterogeneity and poor response to NAC. Multiregion sequencing demonstrated a significant reduction in thymine to guanine mutations within a CpTpT context when comparing early and late mutational processes and the presence of a platinum signature with enrichment of cytosine to adenine mutations within a CpC context following NAC. Esophageal adenocarcinomas are characterized by early chromosomal instability leading to amplifications containing targetable oncogenes persisting through chemotherapy, providing a rationale for future therapeutic approaches. SIGNIFICANCE This work illustrates dynamic mutational processes occurring during esophageal adenocarcinoma evolution and following selective pressures of platinum exposure, emphasizing the iatrogenic impact of therapy on cancer evolution. Identification of amplifications encoding targetable oncogenes maintained through NAC suggests the presence of stable vulnerabilities, unimpeded by cytotoxics, suitable for therapeutic intervention.

Selected Ion Flow Tube Mass Spectrometry Analysis of Exhaled Breath for Volatile Organic Compound Profiling of Esophago-Gastric Cancer

Exhaled breath analysis of volatile organic compounds (VOCs) has great potential in terms of disease diagnosis and measuring physiological response to treatment. In this study, selected ion flow tube mass spectrometry (SIFT-MS) has been applied for the quantification of VOCs in the exhaled breath from 3 groups of patients, viz., those with esophago-gastric cancer, noncancer diseases of the upper gastro-intestinal tract, and a healthy upper gastrointestinal tract cohort. A total of 17 VOCs have been investigated in this study. The concentrations of 4 VOCs, hexanoic acid, phenol, methyl phenol, and ethyl phenol, were found to be significantly different between cancer and positive control groups using the Mann-Whitney U test. Receiver operating characteristics (ROC) analysis was applied for a combination of 4 VOCs (hexanoic acid, phenol, methyl phenol, and ethyl phenol) to discriminate the esophago-gastric cancer cohort from positive controls. The integrated area under the ROC curve (AUC) is 0.91. The results highlight the potential of VOC profiling as a noninvasive test to identify those with esophago-gastric cancer.

Selected ion flow tube mass spectrometry analysis of volatile metabolites in urine headspace for the profiling of gastro-esophageal cancer.

Urine is considered an ideal biofluid for clinical investigation because it is obtained noninvasively and relatively large volumes are easily acquired. In this study, selected ion flow tube mass spectrometry (SIFT-MS) has been applied for the quantification of volatile organic compounds (VOCs) in the headspace vapor of urine samples, which were retrieved from three groups of patients with gastro-esophageal cancer, noncancer diseases of the upper gastro-intestinal tract, and a healthy cohort. Eleven VOCs have been investigated in this study. The concentrations of seven VOCs-acetaldehyde, acetone, acetic acid, hexanoic acid, hydrogen sulfide, methanol, and phenol-were found to be significantly different between cancer, positive control, and healthy groups using the Kruskal-Wallis test. The concentrations of acetaldehyde, acetone, acetic acid, hexanoic acid, hydrogen sulfide, and methanol were increased in the cancer cohort compared with healthy controls while the concentration of phenol decreased. The differences in the concentrations of ethanol, propanol, methyl phenol, and ethyl phenol were not significant between cancer and control groups. Receiver operating characteristics (ROC) analysis was applied for a combination of six VOCs (acetaldehyde, acetone, acetic acid, hexanoic acid, hydrogen sulfide, and methanol) to discriminate cancer patients from noncancer controls. The integrated area under ROC curve is 0.904. This result indicates that VOC profiling may be suitable in identifying those at high risk of gastro-esophageal cancer. Therefore, further investigations should be undertaken to assess the potential for VOC profiling as a new screening test in gastro-esophageal cancer.

Mass Spectrometric Analysis of Exhaled Breath for the Identification of Volatile Organic Compound Biomarkers in Esophageal and Gastric Adenocarcinoma

Objective: The present study assessed whether exhaled breath analysis using Selected Ion Flow Tube Mass Spectrometry could distinguish esophageal and gastric adenocarcinoma from noncancer controls. Background: The majority of patients with upper gastrointestinal cancer present with advanced disease, resulting in poor long-term survival rates. Novel methods are needed to diagnose potentially curable upper gastrointestinal malignancies. Methods: A Profile-3 Selected Ion Flow Tube Mass Spectrometry instrument was used for analysis of volatile organic compounds (VOCs) within exhaled breath samples. All study participants had undergone upper gastrointestinal endoscopy on the day of breath sampling. Receiver operating characteristic analysis and a diagnostic risk prediction model were used to assess the discriminatory accuracy of the identified VOCs. Results: Exhaled breath samples were analyzed from 81 patients with esophageal (N = 48) or gastric adenocarcinoma (N = 33) and 129 controls including Barretts metaplasia (N = 16), benign upper gastrointestinal diseases (N = 62), or a normal upper gastrointestinal tract (N = 51). Twelve VOCs—pentanoic acid, hexanoic acid, phenol, methyl phenol, ethyl phenol, butanal, pentanal, hexanal, heptanal, octanal, nonanal, and decanal—were present at significantly higher concentrations (P < 0.05) in the cancer groups than in the noncancer controls. The area under the ROC curve using these significant VOCs to discriminate esophageal and gastric adenocarcinoma from those with normal upper gastrointestinal tracts was 0.97 and 0.98, respectively. The area under the ROC curve for the model and validation subsets of the diagnostic prediction model was 0.92 ± 0.01 and 0.87 ± 0.03, respectively. Conclusions: Distinct exhaled breath VOC profiles can distinguish patients with esophageal and gastric adenocarcinoma from noncancer controls.

In Vivo Endoscopic Tissue Identification by Rapid Evaporative Ionization Mass Spectrometry (REIMS)

Gastrointestinal cancers are a leading cause of mortality, accounting for 23 % of cancer-related deaths worldwide. In order to improve outcomes from these cancers, novel tissue characterization methods are needed to facilitate accurate diagnosis. Rapid evaporative ionization mass spectrometry (REIMS) is a technique developed for the in vivo classification of human tissue through mass spectrometric analysis of aerosols released during electrosurgical dissection. This ionization technique was further developed by utilizing surface induced dissociation and was integrated with an endoscopic polypectomy snare to allow in vivo analysis of the gastrointestinal tract. We tested the classification performance of this novel endoscopic REIMS method in vivo. It was shown to be capable of differentiating between healthy layers of the intestinal wall, cancer, and adenomatous polyps based on the REIMS fingerprint of each tissue type in vivo.

Rapid Evaporative Ionization Mass Spectrometry Imaging Platform for Direct Mapping from Bulk Tissue and Bacterial Growth Media

Rapid evaporative ionization mass spectrometry (REIMS) technology allows real time intraoperative tissue classification and the characterization and identification of microorganisms. In order to create spectral libraries for training the classification models, reference data need to be acquired in large quantities as classification accuracy generally improves as a function of number of training samples. In this study, we present an automated high-throughput method for collecting REIMS data from heterogeneous organic tissue. The underlying instrumentation consists of a 2D stage with an additional high-precision z-axis actuator that is equipped with an electrosurgical diathermy-based sampling probe. The approach was validated using samples of human liver with metastases and bacterial strains, cultured on solid medium, belonging to the species P. aeruginosa, B. subtilis, and S. aureus. For both sample types, spatially resolved spectral information was obtained that resulted in clearly distinguishable multivariate clustering between the healthy/cancerous liver tissues and between the bacterial species.

Metabolomic profiling of oesophago-gastric cancer: A systematic review

AIMS This review aims to identify metabolomic biomarkers of oesophago-gastric (OG) cancer in human biological samples, and to discuss the dominant metabolic pathways associated with the observed changes. METHODS A systematic review of the literature, up to and including 9th November 2012, was conducted for experimental studies investigating the metabolomic profile of human biological samples from patients with OG cancer compared to a control group. Inclusion criteria for analytical platforms were mass spectrometry or nuclear magnetic resonance spectroscopy. The QUADAS-2 tool was used to assess the quality of the included studies. RESULTS Twenty studies met the inclusion criteria and samples utilised for metabolomic analysis included tissue (n = 11), serum (n = 8), urine (n = 1) and gastric content (n = 1). Several metabolites of glycolysis, the tricarboxylic acid cycle, anaerobic respiration and protein/lipid metabolism were found to be significantly different between cancer and control samples. Lactate and fumurate were the most commonly recognised biomarkers of OG cancer related to cellular respiration. Valine, glutamine and glutamate were the most commonly identified amino acid biomarkers. Products of lipid metabolism including saturated and un-saturated free fatty acids, ketones and aldehydes and triacylglycerides were also identified as biomarkers of OG cancer. Unclear risk of bias for patient selection was reported for the majority of studies due to the lack of clarity regarding patient recruitment. CONCLUSION The application of metabolomics for biomarker detection in OG cancer presents new opportunities for the purposes of screening and therapeutic monitoring. Future studies should provide clear details of patient selection and develop metabolite assays suitable for progress beyond phase 1 pre-clinical exploratory studies.

Anti-reflux surgery for lung transplant recipients in the presence of impedance-detected duodenogastroesophageal reflux and bronchiolitis obliterans syndrome: A study of efficacy and safety

BACKGROUND The aim of this study was to determine the safety of anti-reflux surgery for lung transplant recipients and assess its effect on lung function. METHODS We retrospectively collected and analyzed data from all lung transplant recipients who underwent anti-reflux surgery at St Marys Hospital London from July 2005 to May 2012. The indications for surgery were histologic evidence of gastroesophageal reflux aspiration on bronchoscopy biopsy specimens or a positive impedance study with symptomatic reflux or a consistent decline/fluctuating forced expiratory volume in 1 second (FEV(1)). We studied the difference in mean FEV(1) and rate of change of FEV(1), before and after fundoplication. The safety of anti-reflux surgery was determined by post-operative morbidity and mortality and compared with predicted figures, using a risk prediction model based on the P-POSSUM (Portsmouth Modification of the Physiological and Operative Severity Score for Enumeration of Mortality and Morbidity) assessment. RESULTS Forty patients underwent laparoscopic Nissen fundoplication. Overall, mean FEV(1) declined from 2119 ± 890 to 1967 ± 1027 ml (p = 0.027), and mean rate of change in FEV(1) improved from -2.42 ± 4.40 to -0.41 ± 1.77 ml/day (p = 0.007). Patients referred for fundoplication based on histologic evidence of reflux (n = 9) showed an improvement in rate of change of FEV(1) from -3.39 ± 6.00 to -0.17 ± 1.50 ml/day (p = 0.057), and those with positive impedance study and consistent decline in FEV(1) (n = 13) showed a significant improvement from -3.62 ± 3.35 to -0.74 ± 2.33 ml (p = 0.021). Actual and predicted morbidity was 2.5% and 31%, respectively. Actual and predicted 30-day mortality was 0% and 1.9%, respectively. CONCLUSIONS Anti-reflux surgery is safe for lung transplant recipients and results in an improvement in the rate of change in FEV(1) despite a decline in mean FEV(1) post-operatively.

Repeatability and reproducibility of desorption electrospray ionization-mass spectrometry (DESI-MS) for the imaging analysis of human cancer tissue: a gateway for clinical applications

In this study, we aim to demonstrate the repeatability and reproducibility of DESI-MS for the imaging analysis of human cancer tissue using a set of optimal geometric and electrospray solvent parameters. Oesophageal cancer tissue was retrieved from four quadrants of a freshly removed tumor specimen, snap frozen, cryo-sectioned and mounted on glass slides for DESI-MS image acquisition. Prior to assessing precision, optimal geometric and electrospray solvent parameters were determined to maximize the number of detected lipid species and associated Total Ion Count (TIC). The same settings were utilized for all subsequent experiments. Repeatability measurements were performed using the same instrument, by the same operator on a total of 16 tissue sections (four from each quadrant of the tumor). Reproducibility measurements were determined in a different laboratory, on a separate DESI-MS platform and by an independent operator on 4 sections of one quadrant and compared to the corresponding measurements made for the repeatability experiments. The mean ± SD CV of lipid ion intensities was found to be 22 ± 7% and 18 ± 8% as measures of repeatability and reproducibility, respectively. In conclusion, DESI-MS has acceptable levels of reproducibility for the analysis of lipids in human cancer tissue and is suitable for the purposes of clinical research and diagnostics.

Mapping Local Cytosolic Enzymatic Activity in Human Esophageal Mucosa with Porous Silicon Nanoneedles

Porous silicon nanoneedles can map Cathepsin B activity across normal and tumor human esophageal mucosa. Assembling a peptide‐based Cathepsin B cleavable sensor over a large array of nanoneedles allows the discrimination of cancer cells from healthy ones in mixed culture. The same sensor applied to tissue can map Cathepsin B activity with high resolution across the tumor margin area of esophageal adenocarcinoma.