Short summary

The aim of this study is to assess the diagnostic accuracy of advanced lung ultrasound (LUS) and measurement of volatile organic compounds (VOC) in patients with suspected malignancy in the chest and to assess the feasibility and diagnostic yield of advanced LUS guided biopsies in patients with suspected malignancy in the chest.

Rationale

In Denmark, patients with suspected malignancy of the chest are diagnosed in highly specialised centres using "diagnostic packages". For each patient diagnosed with malignancy in the chest at one of the centres, approximately two patients has completed a "diagnostic package" with no signs of malignancy. Patients with no signs of malignancy typically have been examined using a "package" comprised of imaging (e.g. CT and/or PET-CT) and invasive procedures (e.g. bronchoscopy, endobronchial ultrasound, transthoracic biopsy). Subsequently many patients are controlled for a further period in which additional imaging are performed in order to ensure that the condition is indeed not malignancy. The "diagnostic packages" are not without risks and are potentially harmful for the patients. The average radiation dose for a CT of the chest is approximately 6,5 mSv, and it is estimated that for each 10 mSv a patient is exposed for, the risk of developing a lethal cancer due to the examination is 1:2000. There is therefore a need to develop additional diagnostic modalities for the assessment of patients with suspected malignancy in the chest. A useful tool would ideally pose a very low risk of harm to the patient (e.g. non-invasive, radiation free) and be able to identify patients with a very low risk of malignancy. Improved early identification of patients with a very low risk of malignancy would mean that these patients could avoid additional possibly harmful examinations and at the same time reduce the resources and costs needed for these patients, resources that instead could be used to additionally improve the diagnostics of patients with a higher risk of malignancy.

Advanced Lung Ultrasound

Several studies have shown that LUS has a place as a diagnostic cornerstone for the assessment of patients with diseases in the chest such as pleural effusion, pneumothorax, pulmonary oedema, and lung consolidation (e.g. pneumonia, pulmonary embolism, tumour). When performing a LUS examination simple, conventional modalities such as 2D / B-mode supplemented Doppler are used. More advanced ultrasound modalities such as Contrast Enhanced UltraSound (CEUS), Image Fusion and elastography have been assessed and implemented for some of the extrathoracic organs and structures. Based on theoretical aspects and a few pilot studies, these advanced modalities have the potential to improve the diagnostic value of LUS and to expand its use in various clinical settings.

Measurement of volatile organic compounds

Measurement of exhaled VOC has been assessed in several settings and patient populations with promising results. The measurement is fast, cheap, and non-invasive. Apart from performing measurements of exhaled air, it is also technically possible to measure VOC evaporating from bodily fluids or tissue to the air. The method can therefore also possibly be used to assess pleural fluid or tissue samples. One possible clinical potential of VOC measurement would be as an initial screening tool in patients with suspected malignancy to identify those patients with either a low or high risk of malignancy, and thereby help to guide in which patients additional invasive procedures are needed or clinical follow-up is sufficient.

Clinical use of advanced LUS and VOC measurement

The aim of this project is to assess the clinical use of advanced LUS and VOC measurement in patients with suspected malignancy in the chest. More specifically to assess the individual and combined diagnostic accuracy of advanced LUS and VOC measurement and to assess the feasibility and diagnostic yield of advanced LUS guided biopsies these patients.

Description of the cohort

Study design

Studies are conducted as prospective, observational, clinical studies. Studies assessing diagnostic accuracy will be conducted according to STARD criteria.

Setting

At Odense University Hospital (OUH), the assessment and diagnosis of patients with suspected malignancy in the chest is conducted at the Department of Respiratory Medicine, as a part of the Center for ThoraxOncology (CTO). The department examines patients from the OUH catchment area as well as more complicated patients referred from other departments in the Region of Southern Denmark. More than 1000 patients are annually examined at the department due to suspected malignancy in the chest.

Patients

Patients are screened for study participation upon referral to the department for assessment of possible malignancy in the chest. Subsequent information to the patient and informed consent are given during the subsequent patient visits to the department's outpatient clinic.

Inclusion criteria

Patients are included if they are assessed at the outpatient clinic due to suspected malignancy in the chest and if the given criteria for each of the following categories are met.

Peripheral, well-defined consolidation, tumor or pleural thickening in the chest:

• Patient booked for transthoracic ultrasound guided biopsy.

Non-peripheral, well-defined consolidation / tumor in the lung:

Patients are included if the following three criteria are met:

• Patient has a well-defined consolidation / tumor in the lung
• The consolidation / tumor is not in contact with the visceral pleura
• The consolidation / tumor has a diameter of more than 2 cm

Large, diffuse lung consolidation:

Patients are included if the following three criteria are met:

• Patient has an ill-defined / diffuse lung consolidation
• The consolidation is in contact with the visceral pleura
• The consolidation involves more than 50% of a lobe

Possible malignant pleural effusion:

Patients are included if the following three criteria are met:

• Patient has a pleural effusion of unknown origin
• Patient are booked for a diagnostic thoracocenthesis

Exclusion criteria

One or more of the following:

• Permanent mental disability
• Informed consent not obtained
• Patient age < 18 years

Data and biological material

VOC measurement

Prior to the LUS examination VOC measurement of exhaled air are performed in each participant. If an invasive procedure is performed (e.g. biopsy, thoracocenthesis), VOC measurement of air evaporating from the extracted fluid or tissue are performed.

Advanced LUS

In each participant conventional LUS are performed and supplemented with the following advanced ultrasound modalities:

• Elastography
• Image fusion
• Contrast Enhanced LUS

Reference test

In the studies assessing diagnostic accuracy, pathologic diagnosis based on tissue sample(s) are used as reference test in malignant conditions and clinical follow-up is used as reference test in non-malignant conditions.

Registration after procedures

Following the VOC and advanced LUS procedures, the following data are registered:

• Time used by the staff for the examination (defined as the time spent by the staff in order to prepare, perform and complete the modality)
• Number of staff members needed for the examination
• Examination time (defined as the time from the patient enters the room in which the modality is performed to the patient the leaves the room)
• Whether the examination had to be cancelled due to lack of patient cooperation or patient safety issues
• Occurrence of adverse events while the examination was performed (e.g. clinical deterioration, acute treatment needed, cardiac arrest)

Additional data collection:

Apart from the separate data registration performed as part of the project it is planed to collect data from:

• Patient baseline information from the EMR (electronic patient record system)(e.g. patient symptoms, objective findings, vital signs, medication comorbidities, length of hospital stay, results of diagnostics tests performed)
• Information from the radiology departments electronic archiving system (e.g. types of imaging performed and results)

Collaborating researchers and departments

Department of Respiratory Medicine, Odense University Hospital

• Associate Professor Christian B. Laursen, MD, PhD
• Associate Professor Jesper Rømhild Davidsen, MD, PhD

Department of Radiology, Odense University Hospital

• Associate Professor Ole Graumann, MD, PhD

Centre for Respiratory Medicine and Allergy, University Hospital South Manchester NHS Foundation Trust and University of Manchester, United Kingdom

• Professor Jørgen Vestbo, MD, DMSc

Department of Oncology, Odense University Hospital

Institute of Mathematics and Computer Science, University of Southern Denmark

Department of Nuclear Medicine, Odense University Hospital

Department of Oncology, Odense University Hospital, Odense

Department of Clinical Chemistry and Pharmacology, Odense University Hospital