Digestive System Diseases

Symptoms and General Pathology

All Conditions

Neoplasms

Liver Cirrhosis

Carcinoma

Carcinoma, Hepatocellular

Liver Diseases

Fibrosis

Liver Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Hematinics

All Drugs and Chemicals

Liver Extracts

Healthy Controls with or without risk factors for Chronic Liver Disease (i.e. patients referred due to concerns re: liver disease but found to have no evidence of chronic liver disease following assessment)

Patients with evidence of Liver Fibrosis on the basis of current diagnostic techniques / expert opinion.

Patients with evidence of Compensated Cirrhosis on the basis of current diagnostic techniques / expert opinion.

Patients with evidence of Decompensated Cirrhosis on the basis of current diagnostic techniques / expert opinion.

Patients with evidence of Hepatocellular Carcinoma on the basis of current diagnostic techniques / expert opinion.

Participants will be asked to provide 500mls of exhaled breath which will be loaded on to thermal desorption tubes and analysed via Mass Spectrometry.

Breath Analysis

Michael J Hewitt, MBBS BSc

Michael J Hewitt, MBBS

George B Hanna, FRCS

This study aims to determine whether a breath test could be used for early detection of hepatic fibrosis, cirrhosis or hepatocellular carcinoma.

Patients who are attending for a planned liver outpatient services or investigations will be approached to provide a breath sample.

Multi platform mass spectrometry analysis will be performed to establish volatile biomarkers that can discriminate between fibrosis, cirrhosis and hepatocellular carcinoma.

Volatile organic compound (VOCs) emitted from the human body have been of interest to researchers for several decades. In 1971, Pauling et al reported that breath and urine contained approximately 250 and 280 VOCs respectively in normal human subjects. VOCs are traditionally measured in food industry and counter-terrorism. Routine clinical applications include the alcohol breathalyser, 13-C urea breath test for H. pylori, nitric oxide in asthma, and hydrogen/methane test for bacteria overgrowth.

Preliminary work has suggested that there is alteration in the VOC profile of patients with liver disease. It is suggested that as fibrosis increases, liver function is impaired, resulting in increased levels of certain compounds. These compounds are then present at higher levels within the blood stream and when they reach the lungs, they are exhaled. There has also been work demonstrating a change in the profile of VOCs within cancers, demonstrating specific "breath signatures" in patients with oesophageal cancer. At Imperial College London, Marker et al have developed a breath test as screening test for oesophageal cancer with comparable sensitivity and specificity to other screening methods (e.g. faecal occult blood testing). The investigators would aim to achieve similar with hepatobiliary disease via a prospective cross-sectional study aimed at determining the diagnostic accuracy of exhaled breath volatile organic compounds (VOC) for the detection of liver disease.

Patients will be recruited from outpatient clinics and hospital wards based across Imperial College Healthcare Trust. They may also be recruited from the radiology department when attending for liver biopsies or hepatocellular carcinoma surveillance ultrasound scans. When attending for their appointment, a member of the research team will discuss the research project with the patient, explain that is requires the patient to provide a breath +/- urine sample. Patients will be provided with a patient information leaflet. If the patient is to agree to this, they will be asked to sign a written consent form. If a recent PHES test has not been performed, one will be conducted otherwise no additional investigations, invasive or otherwise will be required of the patients.

For patients under regular follow up within the trust, they may be asked to consent to further breath samples being taken at future appointments to facilitate longitudinal follow up. Patients will be entitled to withdraw at any point.

Patients attending for endoscopy, fibroscan or liver biopsy will have been nil by mouth for 4-6 hours prior to the procedure as per local guidelines. For those attending outpatient appointments, if identified prior to their appointment by their clinical team, the investigators will aim to contact the patients and request that they fast. Should they not be fasted, they may be asked to perform basic oral hygiene techniques (e.g. rinsing mouth with water), prior to the breath sample being taken. A food diary of the preceding 24 hours will be taken as part of the pre-sampling questionnaire.

As part of the consent process, patients will also be asked permission to access their hospital records for the purpose of the research study only, including their blood tests, radiology and pathology results. All data will be anonymised and all hospital records shall be handled with strict confidentiality in accordance with the Data Protection Act 1998 and the General Data Protection Regulation (GDPR).

Patients will be asked to give a number of exhalations into a breath sampling device until a defined volume of breath has been sampled. This may be done via one of several techniques. The investigators preferred option is that they breathe into a custom designed nalophan bag which is attached to thermal desorption tubes and a breath sampling device. Alternatively, patient may be asked to perform normal tidal breathing whilst wearing a face mask, which takes around 2 minutes on average. Patients located at St Mary's Hospital may also be asked to breathe directly into a mass spectrometer machine (SYFT Voice200Ultra). This mass spectrometer instrument is a self-contained mobile device which can be moved between clinical areas within St Mary's Hospital. Sampling by this method will involve a single deep nasal inhalation followed by complete exhalation via their mouth into a plastic cylinder connected to a tube leading to the mass spectrometer itself. This is repeated three times within a 60 second window. The investigators expect the breath sampling process to take no longer than 5-10 minutes in total. Patients will be requested to pass urine into a standardised 60ml urine specimen vial, which will be immediately sealed. 20ml of urine will be aliquoted into a standard 60ml specimen vial.

The VOCs from the breath will be trapped onto adsorbent tubes inserted into the breath taking device. After sampling the adsorbent tube is removed from the device, capped and transported back to the laboratory at St Mary's Hospital London for analysis. Samples will be transported by courier or by a member of the research team. The sample(s) shall undergo analysis via mass spectrometry instruments, at St Mary's Hospital London.

Breath VOCs sampled on adsorbent tubes will be analysed within 48 hours of collection. The sample constituents are destroyed within the mass spectrometer for detection meaning that no clinical material will remain after analysis by the mass spectrometry instruments. Urine samples will be stored within a registered tissue bank in accordance with the Human Tissue Act and disposed of following analysis.

As part of the study, the investigators will aim to follow patients up longitudinally to ascertain if a participant's VOC profile changes with progression or regression of liver disease. At each appointment, before sample is taken, the participant's consent will be reviewed and if the participant is still willing to continue in the study, further breath and urine samples will then be collected. This would be for a maximum of 24 months.

Breath VOCs sampled on adsorbent tubes will be analysed within 48 hours of collection. The sample constituents are destroyed within the mass spectrometer for detection meaning that no clinical material will remain after analysis by the mass spectrometry instruments. Urine samples will be stored within a registered tissue bank (REC Ref no. 04/Q0403/119, custodian Prof G Hanna) in accordance with the Human Tissue Act and disposed of following analysis.

Volatile Organic Compounds for the Assessment of Liver Disease

Volatile Organic Compounds for the Assessment of Liver Disease: Assessment of Hepatobiliary Disease Through Non-Invasive Detection of Exhaled Volatile Organic Compounds

Diagnostic accuracy will be measured by calculating the sensitivity and specificity of the test for detection of fibrosis / cirrhosis / hepatocellular carcinoma. Sensitivity and specificity values are represented by a number between 0 to 1 indicating the test's ability to pick up true positive results and true negative results respectively, where a number closer to one indicates a greater detection ability.

Imperial College London

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

These are the participants with identified stage 1 lung cancer.

These are participants who have similar clinical characteristics as our cases, but do not have any history of cancer.

These are housemates of the participants with stage 1 lung cancer (cases).

Breath will be analyzed in all three groups using gas chromatography mass spectrometry.

Lonny Yarmus, DO

This study will evaluate exhaled volatile organic compounds (VOC's) in the breath of participants with stage 1 lung cancer, their house-mates, and matched controls. The goal of the study is to identify VOC fingerprints that are only detectable in those with stage 1 lung cancer.

Lung cancer is by far the leading cause of cancer death in the United States. More people die annually of lung cancer than of colon, breast, and prostate cancers combined. Worldwide it is already the leading cause of cancer death among males, and with smoking rates substantially higher in developing countries relative to the United States the worldwide burden of lung cancer is projected to increase considerably in the future.

For lung cancer, as for many cancers, early diagnosis allowing for full resection offers the greatest chance for long-term survival, but unfortunately these individuals currently constitute only a minority of the lung-cancer population. Screening technologies that allow for the earliest detection of lung cancer would therefore have tremendous potential to substantially improve outcomes. Recently, and for the first time, a screening test for lung cancer of high risk individuals has been recommended by the US Preventive Services Task Force, as well as others, for the reduction of lung cancer mortality. This recommendation was based primarily on the results of the National Lung Screening Trial (NLST) that randomized over 53,000 individuals considered at high risk for lung cancer to 3 annual screenings with either low-dose CT (LDCT) or a chest x-ray and then followed for a median of 6.5 years. In this study LDCT scanning was associated with a statistically significant 20% relative decrease in lung cancer mortality, and a smaller, but still significant 6.7% decrease in overall mortality. Despite these encouraging results of LDCT, as a screening tool it has substantial limitations. Beyond the costs, inconvenience and radiation exposure associated with LDCT, its performance characteristics are far from optimal. For example, nearly a quarter of the LDCT population had a positive screening test, with the vast majority - 96.4% - proving to be false-positive. With a positive predictive value of \<4% LDCT screening will lead to a great number of unnecessary diagnostic procedures as well as substantial anxiety in the screened population and their family.

Breath analytics is a new and very promising tool for diagnosing lung cancer, as well as multiple other conditions. Previous studies identified that dog's heightened olfactory senses were able to detect cancer in an individual's breath with an accuracy of nearly 100%. Since then attempts have been made to mimic canine capabilities with "electronic noses" to detect and quantitate the nearly 3000 compounds, many in the parts per billion or even parts per trillion ranges, in exhaled breath. Early studies of these technologies support great potential as a diagnostic and screening tool. As a screening tool it could be ideal as it is noninvasive, painless and free of any undesirable side effects. In addition, new advances in nanotechnology have allowed these extremely sensitive detection technologies to be miniaturized to the point that they can be linked to a smartphone, providing future possibilities to almost continuously surveil individuals for the development of lung cancer and other life-threatening conditions. This study is concerned with comparing the concentrations of volatile organic compounds (VOCs) in the breath of lung cancer patients (cases) and lung-cancer-free individuals (controls).

NanoSpectrometer Biomarker Discovery and Confirmation Study

Volatile organic compounds will be measured between the cases and both types of controls. We will report the different volatile organic compound fingerprints that are present in cases and not in controls.

Nanobeak Inc.

Johns Hopkins University

Carcinoma, Non-Small-Cell Lung

Multiple Pulmonary Nodules

Patients with pulmonary nodule diagnosed as malignant cancer by pathological examinations after surgical resection.

Patients with pulmonary nodule diagnosed as benign disease by pathological examinations after surgical resection.

Pathological diagnosis, as the golden standard for diagnosing pulmonary nodules, is achieved by two experienced pathologists and validated by the third senior pathologist.

Pathological examinations as the golden diagnosis criteria

Exhaled breath of each participant will be collected with Tedlar bags. The volatile organic compounds will be detected by a high-resolution high-pressure photon ionization time-of-ﬂight mass spectrometry (HPPI-TOFMS).

The Imaging markers of pulmonary nodules, including the size, three-dimensional shape, and appearance characteristics, are derived from the chest computed tomography within 2 weeks before surgery resection.

Breath test combined with computed tomography

Mantang Qiu, PhD

Peiyu Wang, MM

Pulmonary nodules diagnosis using breath test of volatile organic compound (VOC) is in its infancy. The accuracy of VOC analysis in diagnosing malignant pulmonary nodules varies cross the published studies. The diagnosis accuracy of VOC alone is generally poor. We speculate that the accuracy of diagnosing malignant pulmonary nodules will be improved by combining breath test with chest computed tomography (CT). This study aims to establish a predictive model of malignant pulmonary nodule using bio-markers from exhaled breath and image-markers from chest CT with retrospective data from multi centers. The sensitivity, specificity and accuracy of the model will be validated prospectively.

Endogenous volatile organic compounds (VOCs) can be derived from many different metabolic pathways. VOCs can be transported to the alveoli through the blood circulation and expelled by exhalation. Changes in VOCs production, clearance, and alterations in lung air-blood exchange functions can lead to aberrant VOCs profiles in the exhaled breath. Testing exhaled breath has the advantages of being completely non-invasive and easy to collect, and has been considered as a perfect approach for disease diagnoses and therapeutic monitoring. Many clinical studies have found that VOCs in exhaled breath are closely related to disease status. Specific VOCs alterations have been identified in many tumors, especially lung cancer. Pulmonary nodules diagnosis using breath test of volatile organic compound (VOC) is in its infancy. The accuracy of VOC analysis in diagnosing malignant pulmonary nodules varies cross the published studies. The diagnosis accuracy of VOC alone is generally poor. We speculate that the accuracy of diagnosing malignant pulmonary nodules will be improved by combining VOC analysis with chest computed tomography.

In this study, we use a highly sensitive mass spectrometry to detect exhaled VOCs of patients with pulmonary nodules. The chest CT will be used for detecting the imaging characteristics of pulmonary nodules. The pathological diagnosis of pulmonary nodules after surgical resections is selected as golden standard.

This study aims to establish a predictive model of malignant pulmonary nodule using bio-markers from breath test and image-markers from chest CT with retrospective data from multi centers. The sensitivity, specificity and accuracy of the model will be varied prospectively.

Volatile organic compound (VOC) in exhalation collected with air bags.

Breath Combined With CT for Diagnoses of Pulmonary Nodules

Assessment of the Efficacy of Breath Test Combined With Computed Tomography for Diagnoses of Pulmonary Nodules.

Using pathological diagnosis of pulmonary nodule as gold standard, diagnostic specificity of breath test combined with computed tomography will be calculated

Using pathological diagnosis of pulmonary nodule as gold standard, diagnostic accuracy of breath test combined with computed tomography will be calculated

Using pathological diagnosis of pulmonary nodule as gold standard, positive predictive value of breath test combined with computed tomography will be calculated

Using pathological diagnosis of pulmonary nodule as gold standard, negative predictive value of breath test combined with computed tomography will be calculated

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Volatile Organic Compounds for the Assessment of Liver Disease	NCT04620538	Cirrhosis Cirrhosis, Live... Fibrosis, Liver Hepatocellular ... Hepatocellular ...	Breath Analysis	18 Years - 90 Years	Imperial College London
Volatile Organic Compounds for the Assessment of Liver Disease	NCT04620538	Cirrhosis Cirrhosis, Live... Fibrosis, Liver Hepatocellular ... Hepatocellular ...	Breath Analysis	18 Years - 90 Years	Imperial College London
NanoSpectrometer Biomarker Discovery and Confirmation Study	NCT03275688	Lung Cancer	Breath Analysis	18 Years -	Johns Hopkins University
Breath Combined With CT for Diagnoses of Pulmonary Nodules	NCT04948047	Non-small Cell ... Pulmonary Nodul...	Pathological ex... Breath test com...	18 Years -	Peking University People's Hospital

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