Neoplasms

Gland and Hormone Related Diseases

All Conditions

Thyroid Neoplasms

Thyroid Diseases

Thyroid Nodule

Endocrine System Diseases

Endocrine Gland Neoplasms

Head and Neck Neoplasms

A disease group including patients older than 18 years old with any kind of histopathologically proven malignancy of the thyroid gland (including Papillary thyroid cancer (PTC), Follicular thyroid cancer (FTC), Medullary thyroid cancer (MTC), and Anaplastic thyroid cancer);

A control group including patients older than 18 years old with any kind of histopathologically proven benign thyroid gland disease (including adenoma, hyperplasia).

All participants breathed through the Aeonose for five minutes. This device contains metal-oxide sensors that change in conductivity upon reaction with VOCs in exhaled breath. These conductivity changes are input data for machine-learning and used for pattern recognition. A nose clip was placed on the nose of each participant to avoid entry of non-filtered air in the device. Before measuring, the Aeonose was flushed with room air, guided through a carbon filter as well. Failed breath tests were excluded from analysis; the reason for failure was documented.

Electronic Nose

Nicole Bouvy, Prof, MD, PhD

Zaid Al-Difaie, Dr.

Nicole Bouvy, Prof,MD,PhD

Patients with a suspected thyroid nodule face an invasive and patient unfriendly diagnostic work-up to determine the risk of malignancy. Typically, patients undergo ultrasound of the thyroid gland followed by fine-needle aspiration cytology (FNAC). FNAC has been considered as a gold standard diagnostic procedure in suspected thyroid nodules. Unfortunately, both the negative- and positive predictive value of FNAC is poor, often resulting in the need for a diagnostic hemithyroidectomy for definite diagnosis . Approximately 40-94% of the suspected thyroid nodules appear to be benign after resection and thus exposes patients to unnecessary surgery with unnecessary risks. Therefore, a quick, non-invasive assessment of the risk of malignancy of thyroid nodules is of paramount importance. Such a novel test could fasten the diagnostic process for patients with malignancies and reduce the amount of 'unnecessary' surgeries for benign conditions.

A promising development in cancer detection is based on volatile organic compounds (VOCs), gaseous degradation products of biochemical processes detectable in exhaled breath. During pathophysiological processes related to tumor growth, alterations in cell metabolism lead to a shift in the production of VOCs. The VOCs' patterns can be detected by the Aeonose™ through their reaction with the metal-oxide sensors in this device. A pilot study conducted at the Maastricht University Medical Center demonstrated that, by creating an artificial neural network (ANN) from the VOC patterns of numerous patients and their specific histopathological diagnosis, the Aeonose™ has a high diagnostic accuracy to discriminate benign from malignant thyroid nodules.

The purpose of this study is to validate the accuracy of the Aeonose™, to prevent unnecessary surgery and to investigate the use of the Aeonose™ as a surveillance tool in the postoperative follow-up of differentiated thyroid cancer.

We hypothesize that the high negative predictive value of the pilot study will be confirmed in the validation study and expect that implementation of the Aeonose™ in clinical practice will subsequently reduce the number of unnecessary surgeries below 10% for patients with Bethesda ≥ III nodules and may provide an important role in non-invasive detection of recurrent disease.

Thyroid cancer is the most common endocrine cancer worldwide. In most developed countries, the incidence of thyroid cancer has rapidly increased in the last three decades In the Netherlands, 700 patients are diagnosed with thyroid cancer each year. The most common histological forms are the well-differentiated papillary and follicular cancer, comprising of 80-85% of all thyroid cancers

Patients often present themselves with a thyroid nodule, which can be benign or malignant. Current diagnostic work-up includes ultrasound of the neck, resulting in the Thyroid Imaging Reporting And Data System (TI-RADS). This risk-stratification system for thyroid nodules is based on ultrasound features. When indicated, fine-needle aspiration cytology (FNAC) is performed, resulting in the Bethesda classification to report the risk of malignancy. The FNAC has been considered as gold standard diagnostic procedure in suspected thyroid nodules . Unfortunately, both negative- and positive predictive value of FNAC is poor, often resulting in the need for a diagnostic hemithyroidectomy for definite diagnosis. 40-94% of the suspected thyroid nodules appear to be benign after resection. After surgical removal, patients with differentiated thyroid cancer sometimes receive adjuvant treatment with radioactive-iodine. Thereafter, patients face a long-term follow-up since recurrence of the disease may occur years after removal of the primary tumor. Based on risk stratification, serum thyroglobulin (Tg) levels are determined once or twice per year with or without additional imaging (e.g. thyroid ultrasound or total body scintigraphy). So, both diagnosis and follow-up of thyroid cancer are associated with invasive and unpleasant procedures for the patient.

After surgical removal, patients with differentiated thyroid cancer sometimes receive adjuvant treatment with radioactive-iodine. Thereafter, patients will be subjected to a long-term follow- up since recurrence of the disease may occur years after removal of the primary tumor. Based on risk stratification, serum thyroglobulin (Tg) levels are determined once or twice per year with or without additional imaging (e.g. thyroid ultrasound or total body scintigraphy). So, both diagnosis and follow-up of thyroid cancer are associated with invasive and unpleasant procedures for the patient.

A promising development in cancer detection is based on volatile organic compounds (VOCs), gaseous degradation products of biochemical processes detectable in exhaled breath. During pathophysiological processes related to tumor growth, alterations in cell metabolism lead to a shift in the production of VOCs. The VOCs' patterns can be detected by the Aeonose™ through their reaction to the metal-oxide sensors in this device. A pilot study conducted at the Maastricht University Medical Center+ demonstrated that, by creating an artificial neural network (ANN) from the VOC patterns of numerous patients and their specific histopathological diagnosis, the Aeonose™ has a high diagnostic accuracy to discriminate benign from malignant thyroid nodules.

The purpose of this study is to validate the accuracy of the Aeonose™, to prevent unnecessary surgery and to investigate the use of the Aeonose™ as a surveillance tool in the postoperative follow-up of differentiated thyroid cancer.

Aim

This study consists of three aims:

1. Confirm the results of the pilot study on the use of the Aeonose™ to distinguish benign from malignant thyroid nodules in a multicenter validation study.
2. Implement the use of the Aeonose™ in clinical practice, aiming to reduce unnecessary surgeries to \<10%.
3. Investigate the use of the Aeonose™ to detect recurrent thyroid cancer in a patient friendly, non-invasive way compared to regular follow-up in a pilot study.

We plan to conduct an international prospective, observational multicenter study in twelve hospitals in the Netherlands, Belgium and Germany to validate the diagnostic performance of the Aeonose™ and to investigate its efficacy in the follow-up of differentiated thyroid cancer. First, a database of breathing patterns will be built to develop an ANN. An external validation study will be conducted using exhaled breath patterns of a total of 500 patients to address the first aim. Data from the validation study together with clinical parameters will be used to determine the necessity for a diagnostic hemithyroidectomy. The number of unnecessary surgeries will be evaluated. To address the third aim, a pilot study will be conducted. Patients with histologically proven differentiated thyroid cancer are asked to breathe in the Aeonose™ parallel to every regular follow-up moment. The Aeonose™ will be trained by the input of data of patients developing a recurrence or not to develop an ANN that can be used as a surveillance tool to detect recurrence non-invasively.

Before starting the validation study, the artificial neural network (ANN) that has been built in the pilot study will be expanded in the training study. The more patients included with a variety in breathing patterns (as a result of e.g. gender, age, smoking-status, food intake, medication use), the more stable and robust the model becomes. For this training study, a total of 200 patients with histopathological proven differentiated thyroid cancer is needed. Assuming that the prevalence of thyroid cancer among suspected thyroid nodules is 20%, a total of 1000 patients would be required for the training study. Data of patients who participated in the pilot study will be used in the training study. The training study will be carried out in all 12 hospitals.

Validation study Directly after finishing the training study, the validation study will be started in 'new' patients that have not participated in the training study.

Every patient with a suspected thyroid nodule, indicated for additional diagnostic procedures including an ultrasound of the thyroid gland (resulting in the TIRADS classification) followed by a fine-needle aspiration for cytology (resulting in the Bethesda classification), will be asked to participate. We will provide information about the study and obtain a signed informed consent. We expect that in particular, the FNAC might influence the patterns of the VOCs in the exhaled breath, measured by the Aeonose™. For this reason, we will include patients in this study before FNAC will take place.

Patients in the validation study will be asked to participate only once by breathing in the Aeonose™ for five minutes, followed by completing a short questionnaire of known factors that can influence the breathing patterns.

A minimum of 500 patients will be necessary to validate the sensitivity of the pilot study.

This study has no specific benefits for the participating patients. The risks of using the Aeonose are very small. Possible side effects during measurements are dizziness and nausea, usually due to hyperventilation. Other side effects are hypo- or hyper salivation during measurements. Blood will be collected during regular pre-operative blood collection, resulting in no extra skin puncture. Furthermore two quick to answer questionnaires as well as a short case report form (CRF) will be filled in by the participating patients. Using the Aeonose as a non-invasive, rapid and inexpensive diagnostic tool could be a major benefit for patients with thyroid nodules due to the faster and less invasive diagnostic process. Benefits for patients with benign thyroid diseases include the possibility to resign from unnecessary invasive treatments such as (diagnostic) surgery.

We hypothesize that the high negative predictive value of the pilot study will be confirmed in the validation study and expect that implementation of the Aeonose™ in clinical practice will subsequently reduce the number of unnecessary surgeries below 10% for patients with Bethesda ≥ III nodules. For the pilot study on the follow-up, we hypothesize that the Aeonose™ can play an important role in non-invasive detection of recurrent disease. Within several years, analysis of exhaled breath using the Aeonose™ will play an important role in the detection of thyroid cancer and/or its recurrence and will, therefore, have a position in regular clinical decision making

Blood, Histology and Post-operative thyroid specimen

Validation of the Diagnostic Accuracy of the Electronic Nose in the Detection of Thyroid Cancer

We plan to make the following end products available for further research and verification:

* Raw data
* (Several versions of) processed data
* Data documentation
* Documentation of the research process, including documentation of all participants
* Syntaxes

All data and samples will be stored for 15 years in order to be used for further research in the field of thyroid cancer.

olecular diagnostics on the cytology of thyroid punctures, blood after regular blood sampling, and histology will be evaluated.

Maastricht University Medical Center

Symptoms and General Pathology

Digestive System Diseases

Infections

Respiratory Tract (Lung and Bronchial) Diseases

Rare Diseases

Ulcer

Liver Cirrhosis

Stomach Neoplasms

Tuberculosis

Pancreatic Neoplasms

Influenza, Human

Atrophy

Adenoma

Communicable Diseases

Liver Neoplasms

Inflammatory Bowel Diseases

Intestinal Diseases

Pancreatitis

Pancreatitis, Chronic

Polyps

Peptic Ulcer

Gastritis, Atrophic

Metaplasia

Gastritis

Gastrointestinal Diseases

Pancreatic Diseases

Stomach Diseases

Fibrosis

Mycobacterium Infections

Bacterial Infections

Gram-Positive Bacterial Infections

Mycoses

Bacterial Infections and Mycoses

Gastroenteritis

Liver Diseases

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Disease Attributes

Duodenal Diseases

Chronic Disease

Respiratory Tract Infections

Orthomyxoviridae Infections

Virus Diseases

RNA Virus Infections

Respiratory Tract Diseases

Chronic Graft Versus Host Disease

Stomach Cancer

Pancreatic Cancer

Hematinics

All Drugs and Chemicals

Liver Extracts

Participants with Active Tuberculosis Disease Intervention: Diagnostic Test: VOC detection in breath and in skin headspace Procedure/Surgery: Whole blood/ Plasma / serum sampling Intervention: Diagnostic Test: Breath sampling Intervention: Headspace analysis for biological material

Participants Without Active Tuberculosis Disease Intervention: Diagnostic Test: VOC detection in breath and in skin headspace Procedure/Surgery: Whole blood/ Plasma / serum sampling Intervention: Diagnostic Test: Breath sampling Intervention: Headspace analysis for biological material

Patients with histologically confirmed gastric cancer Intervention: Diagnostic Test: Breath sampling Intervention: Procedure/Surgery: Upper endoscopy with biopsies Intervention: Procedure/Surgery: Whole blood/ Plasma / serum sampling Intervention: Diagnostic Test: Feacal sampling Intervention: Headspace analysis for biological material Intervention: Procedure/Surgery: Histological examination of surgical speciment

Patients without gastric adenocarcinoma but with histologically confirmed dysplasia (either high- or low-grade) of the stomach Intervention: Diagnostic Test: Breath sampling Intervention: Procedure/Surgery: Upper endoscopy with biopsies Intervention: Procedure/Surgery: Whole blood/ Plasma / serum sampling Intervention: Headspace analysis for biological material Intervention: Diagnostic Test: Fecal sampling Intervention: Procedure/Surgery: Histological examination of surgical specimen

Patients graded Stage III-IV according to OLGIM (Operative Link of Gastric Intestinal Metaplasia Assessment) staging system, Stage III-IV according to OLGA (Operative Link for Gastric Atrophy Assessment), and those with incomplete type of intestinal metaplasia, but excluding those with dysplasia Intervention: Diagnostic Test: Breath sampling Intervention: Procedure/Surgery: Upper endoscopy with biopsies Intervention: Procedure/Surgery: Whole blood/ Plasma / serum sampling Intervention: Diagnostic Test: Fecal sampling Intervention: Procedure/Surgery: Histological examination of surgical specimen Intervention: Headspace analysis for biological material

Staged 0-III according to OLGIM. Dysplasia should be excluded Intervention: Diagnostic Test: Breath sampling Intervention: Procedure/Surgery: Upper endoscopy with biopsies Intervention: Procedure/Surgery: Whole blood/ Plasma / serum sampling Intervention: Diagnostic Test: Fecal sampling Intervention: Headspace analysis for biological material

Patients with histologically confirmed colorectal cancer (adenocarcinoma) Intervention: Diagnostic Test: Breath sampling Intervention: Procedure/Surgery: Colonoscopy with biopsies Intervention: Procedure/Surgery: Whole blood/ Plasma / serum sampling Intervention: Diagnostic Test: Fecal sampling Intervention: Headspace analysis for biological material Intervention: Procedure/Surgery: Histological examination of surgical specimen

Patients without colorectal adenocarcinoma, but carrying high-risk adenomatous polyps being described by one of the following: 1) size≥1 cm; 2) high-grade dysplasia; 3) villous component. Prior to removal of the lesions Intervention: Diagnostic Test: Breath sampling Intervention: Procedure/Surgery: Colonoscopy with biopsies Intervention: Headspace analysis for biological material Intervention: Procedure/Surgery: Whole blood/ Plasma / serum sampling Intervention: Diagnostic Test: Fecal sampling Intervention: Procedure/Surgery: Histological examination of surgical specimen

Patients without colorectal adenocarcinoma and without colorectal high-risk lesions Intervention: Diagnostic Test: Breath sampling Intervention: Procedure/Surgery: Colonoscopy with biopsies Intervention: Procedure/Surgery: Whole blood/ Plasma / serum sampling Intervention: Diagnostic Test: Fecal sampling Intervention: Headspace analysis for biological material

Patients having undergone colonoscopy without an evidence for colorectal lesions Intervention: Diagnostic Test: Breath sampling Intervention: Procedure/Surgery: Colonoscopy with biopsies Intervention: Procedure/Surgery: Whole blood/ Plasma / serum sampling Intervention: Diagnostic Test: Fecal sampling Intervention: Headspace analysis for biological material Intervention: Procedure/Surgery: Histological examination of surgical specimen

Average risk population of both genders aged 40-64 at the time of inclusion lacking alarm symptoms for gastrointestinal cancer Intervention: Diagnostic Test: Breath sampling Intervention: Procedure/Surgery: Whole blood/ Plasma / serum sampling Intervention: Diagnostic Test: Fecal sampling Intervention: Headspace analysis for biological material

Patients with histologically confirmed pancreatic cancer Intervention: Diagnostic Test: Breath sampling Intervention: Procedure/Surgery: Whole blood/ Plasma / serum sampling Intervention: Headspace analysis for biological material

Patients with clinically and/or histologically and/or radiologically confirmed chronic pancreatitis Intervention: Diagnostic Test: Breath sampling Intervention: Procedure/Surgery: Whole blood/ Plasma / serum sampling Intervention: Headspace analysis for biological material

Patients with histologically confirmed primary liver cancer Intervention: Diagnostic Test: Breath sampling Intervention: Procedure/Surgery: Whole blood/ Plasma / serum sampling Intervention: Headspace analysis for biological material

Patients with histologically confirmed liver cirrhosis of viral or other ethiology Intervention: Diagnostic Test: Breath sampling Intervention: Procedure/Surgery: Whole blood/ Plasma / serum sampling Intervention: Headspace analysis for biological material

Patients with serologically confirmed infectious disease or individuals of high risk (e.g. population in season of flu epidemy). This group does not include tuberculosis Intervention: Diagnostic Test: Breath sampling Intervention: Procedure/Surgery: Whole blood/ Plasma / serum sampling Intervention: Headspace analysis for biological material

Patients with histologically confirmed oncological diseases, excluding gastric, colorectal, pancreatic and primary liver cancer Intervention: Diagnostic Test: Breath sampling Intervention: Procedure/Surgery: Whole blood/ Plasma / serum sampling Intervention: Headspace analysis for biological material

VOC will be detected in breath with off-line and on-line testing and in skin headspace with off-line testing

VOC detection in breath and in skin headspace

Breath sampling for VOCs detections will be carried out using nano-sensor based devices (electronic nose)

Breath sampling

Upper endoscopy with proper biopsy work-up will be used for identification and stratification of gastric lesions as well as acquisition of biopsies for microbiota testing

Upper endoscopy with biopsies

Colonoscopy with proper biopsy or polypectomy material work-up will be used for identification and stratification of colorectal lesions as well as acquisition of biopsies for microbiota testing

Colonoscopy with biopsies

Whole blood/Plasma/serum sampling will be used to obtain information for group stratification

Whole blood/ Plasma / serum sampling

Facal samples will be obtained for faecal occult blood testing as well as microbiota analysis

Faecal sampling

Routine histological exam for patients undergoing curative or palliative surgery. Indication for surgery are set based on underlying condition. Study does not interfere with decision making for surgical treatment

Histological examination of surgical specimen

VOC analysis from headspace of surgical specimen, biopsy materials, blood/plasma, microbiota etc.

Headspace analysis for biological material

Mārcis Leja, PhD, MD

Lelde Lauka, MD

Andra Cīrule, MD

Detection of Volatile Organic Compounds (VOC) directly from tissue by headspace analysis (skin, surgery material, other tissue) and exhaled breath is feasible using affordable user-friendly novel nano-chemo sensors that can accurately be used for screening and monitoring purpose

Study propose to explore a novel approach for the diagnosis and monitoring of diseases. The approach is based on the detection of volatile organic compounds (VOCs) that are emitted from the cells and detected directly from tissue, such as skin, surgery material, blood as well as from exhaled breath.

In the literature there are several reports on VOCs which can be detected by Gas Chromatography - Mass Spectrometry (GC-MS) means directly from: (i) the headspace of TB cells (i.e., the mixture of volatile biomarkers trapped above the TB cells in a sealed vessel); (ii) the exhaled breath or (iii) from urine. Excellent results in detection of the tuberculosis disease by using nanosensor array were shown by Nakhleh et al achieved 90% sensitivity, 93% specificity and 92% accuracy in discrimination between healthy and diseased patients using electronic nose devices with a single sensor. None of the reported studies identified the tentative recognition of the tuberculosis-related VOCs and quantified the concentration differences between samples from ill and healthy controls. Further investigation of the exhaled breath tuberculosis-related VOC by GC-MS means will improve the knowledge and simultaneously will help to improve the nanosensor array design.

Several studies have shown that disease-rated VOC patterns can be transmitted through the skin, and, therefore, skin can be used as a source for disease detection and identification. The principle of this detection approach is that disease-related changes are reflected in measurable changes in the skin through exchange via the blood. In addition, several studies have suggested that the VOC levels are elevated even in early stages of the disease, because they reflect a change in the human's body chemistry (as a result of the development of disease condition), rather than the amount of infected cells. Complementary studies have shown that VOCs can be emitted to the skin within minutes after they have emerged in the infected part of the human's body. What is particularly significant about this approach is that each type of (infectious) disease has its own unique pattern of VOCs, and, therefore, the presence of one (infectious) disease would not screen other disease types. Nevertheless, to the best of our knowledge, the detection of tuberculosis VOCs through skin has not been examined yet. Additionally, all studies targeting skin VOCs have been carried out by means of spectrometry and spectroscopy techniques. In few cases, electronic nose devices were used. These techniques are powerful tools for detecting VOCs. However, to date, the use of these techniques has been impeded by the need for moderately to highly expensive equipment's, the high levels of expertise required to operate such instruments, the speed required for sampling and analysis, and the need for preconcentration techniques. For VOC skin testing and breath testing of tuberculosis to become widely used in clinical practice, several advances in the knowledge of tuberculosis specific VOCs and sensor development need to occur. Nanoparticles containing flexible sensors, based on organic films, are more likely to become a clinical diagnostic tool, because they are significantly smaller, easier-to-use, and significantly less expensive.

In recent years comprehensive studies have shown excellent data for using VOCs from exhaled breath as tool for diagnosing gastric cancer. In one of the biggest studies carried out by Chinese and Latvian centers, malignancy could be identified with 89% sensitivity and 90% specificity after cross-validation, irrespective of important confounding factors in gastric patients such as tobacco or alcohol consumption and H. pylori infection. A breath test for GC staging could also be demonstrated by distinguishing stage I\&II cancers from stage III\&IV cancers with 89% sensitivity and 94% specificity. These studies used both - mass spectometry and nano-sensors technologies. Most recent study published in ASC Nano journal in January 2017 reported on more extended use of nanoarry sensors in breath analysis, blind experiments showed that 86% accuracy could be achieved with the artificially intelligent nanoarray, allowing both detection and discrimination between the different disease conditions examined (chronic kidney failure, idiopathic Parkinson's disease, atypical Parkinsonism , multiple sclerosis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, pulmonary arterial hypertension, pre-eclampsia in pregnant women, head and neck cancer, lung cancer, colorectal cancer, bladder cancer, kidney cancer, prostate cancer, gastric cancer, and ovarian cancer. Analysis of the artificially intelligent nanoarray also showed that each disease has its own unique breathprint, and that the presence of one disease would not screen out others.

Therefore, this study is aimed to test VOCs detecting technologies as diagnostic and monitoring tools for digestive tract and infectious diseases.

Surgery and biopsy material as well as blood samples will contain himan DNA

Volatiles in Breath and Headspace Analysis - Diagnostic Markers

Volatile Organic Compounds in Breath and Headspace Analysis - Diagnostic and Monitoring Markers for Diseases

Tuberculosis specific VOC detected in breath and in skin headspace

Sensitivity, specificity, overall accuracy of nanoarray sensor testing for VOCs to detect the target lesions in the blinded analysis

List of VOCs assayed by GC-MS with statistical difference between the study groups

VOC pattern changes after specific required treatment (medical eradication of bacteria/viruses, surgery/endoscopic removal for cancers or high risk lesion)

VOC pattern changes at the time of surveillance in case of relapse (malignant diseases).

List of gastrointestinal microbiota groups (phylum/genus level) with positive correlation to particular VOCs

Technion, Israel Institute of Technology

Riga East University Hospital

JLM Innovation GmbH

University of Latvia

Colorectal Neoplasms

Colonic Polyps

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Colonic Diseases

Rectal Diseases

Intestinal Polyps

Pathological Conditions, Anatomical

All participants will be asked to breathe into an electronic nose (eNose, the AeonoseTM, The eNose Company, Zutphen, the Netherlands) for 5 minutes during the pre-colonoscopy intake and just prior to the procedure to assess reproducibility (with \>2 weeks in between).

AeonoseTM

Peter D Siersema, MD, PhD

In the past decade, the demand for colonoscopy procedures has increased significantly since the introduction of population-based colorectal cancer (CRC) screening in many western countries. Post-polypectomy surveillance will increase the number of colonoscopy procedures conducted each year even further. The invasive nature of colonoscopy and the associated health-care costs warrant the development of a new non-invasive test to reduce the number of unnecessary colonoscopies.

These days, many countries use a non-invasive fecal test for CRC screening which is easy to perform at home, but test characteristics such as sensitivity and specificity are suboptimal. Multiple studies have already shown that volatile organic compound (VOC) analysis has a high diagnostic accuracy for CRC and Advanced Adenomas. An additional VOC analysis, for example through breath testing, in patients with a positive fecal immunochemical test (FIT) may reduce the number of unnecessary colonoscopies.

The aim of this study is to validate the diagnostic accuracy of the AeonoseTM to distinguish patients with CRC from healthy controls, and to assess reproducibility of test results.

Rationale: An electronic nose (eNose) is an artificial olfactory system that analyses volate organic compounds (VOCs) in exhaled breath. Exhaled human breath is mainly composed of inorganic compounds, inert gases and VOCs. VOCs are exhaled in very low concentrations and reflect pathological processes such as inflammation, oxidation, infection and neoplasms. The perspective is that metabolic and biochemical processes in several pathological situations cause different endogenous VOCs to arise, were they can serve as non-invasive biomarkers for certain diseases.

Primary objective: To evaluate if the use of an additional breath test (AeonoseTM) for patients with a positive FIT-test can reduce the number of unnecessary colonoscopies.

Secondary objectives:

1. External validation of results for CRC and (advanced) adenoma detection established in a previous studies (second study not yet published). (15)
2. To evaluate if VOC profiles in breath are similar at two different time points.
3. Acceptance rate of using the AeonoseTM device for VOC analysis in participating patients.

Study population: Patients between the ages of 55 and 75 years old with a positive FIT-test referred for a colonoscopy procedure.

Estimated sample size: 750 participants

Intervention: Participants will be asked to breath through the AeonoseTM for 5 minutes during pre-colonoscopy intake and just prior to the procedure to assess reproducibility (with \>2 weeks in between). There are no risks, nor benefits for the participants.

This is a multicenter prospective cohort study in participants eligible for colonoscopy with suspicion for (pre)malignant lesions of the colon

Breath Analysis as an Additional Test for Colorectal Cancer Screening to Reduce the Number of Unnecessary Colonoscopies

Breath analysiS as an Additional Test for ColoREctal cancEr screeNing to rEduce the Number of unnecessaRy Colonoscopies

The diagnostic accuracy, in terms of sensitivity and specificity, of the AeonoseTM in distinguishing between patients with and without CRC.

The variation in VOC analysis results between two separate time points. The binary results from the eNose analysis will be presented in a scatterplot and a receiver operating characteristics curve (ROC-curve). Cohen's kappa statistic will be applied to determine interobserver agreement between the eNose results of 2 different timepoints (\>2 weeks apart)

The acceptance rate of using the AeonoseTM in participating patients.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Validation of the Diagnostic Accuracy of the Electronic Nose in the Detection of Thyroid Cancer	NCT04883294	Thyroid Neoplas...	Electronic Nose	18 Years -	Maastricht University Medical Center
Volatiles in Breath and Headspace Analysis - Diagnostic Markers	NCT03228095	Tuberculosis Gastric Cancer Peptic Ulcer Atrophic Gastri... Intestinal Meta... Gastric Dysplas... Colorectal Canc... Colorectal Poly... Colorectal Aden... Pancreatic Canc... Pancreatitis, C... Liver Cancer Liver Cirrhosis Flu, Human Other Infectiou... Inflammatory Bo...	VOC detection i... Breath sampling Upper endoscopy... Colonoscopy wit... Whole blood/ Pl... Faecal sampling Histological ex... Headspace analy...	18 Years -	University of Latvia
Volatiles in Breath and Headspace Analysis - Diagnostic Markers	NCT03228095	Tuberculosis Gastric Cancer Peptic Ulcer Atrophic Gastri... Intestinal Meta... Gastric Dysplas... Colorectal Canc... Colorectal Poly... Colorectal Aden... Pancreatic Canc... Pancreatitis, C... Liver Cancer Liver Cirrhosis Flu, Human Other Infectiou... Inflammatory Bo...	VOC detection i... Breath sampling Upper endoscopy... Colonoscopy wit... Whole blood/ Pl... Faecal sampling Histological ex... Headspace analy...	18 Years -	University of Latvia
Breath Analysis as an Additional Test for Colorectal Cancer Screening to Reduce the Number of Unnecessary Colonoscopies	NCT04357158	Colorectal Canc... Polyp of Colon Colorectal Neop...	AeonoseTM	50 Years - 75 Years	Radboud University Medical Center
Breath Analysis as an Additional Test for Colorectal Cancer Screening to Reduce the Number of Unnecessary Colonoscopies	NCT04357158	Colorectal Canc... Polyp of Colon Colorectal Neop...	AeonoseTM	50 Years - 75 Years	Radboud University Medical Center

Spots Global Cancer Trial Database for electronic nose