Title: DOLPHIN-VIVO - Diagnosis Of LymPHoma IN VIVO - using a smart Raman needle probe to detect and diagnose primary and secondary cancers in lymph nodes.
Funder: Department of Health and Social Care

Abstract: Research question Can a combined smart Raman/FNA needle be used to provide safe, rapid in vivo lymphoma diagnosis with minimal invasion in patients? Background Lymphomas are cancers of the lymphatic system affecting around 16,000 people p.a. in the UK [2]. Symptoms include tiredness and swollen neck lumps. Patients are often referred by their GP for investigation including ultrasound guided fine needle aspiration (FNA) biopsies to examine swellings under the skin. The few collected cells are then analysed by cytologists. 72% of those sent for FNA end up having surgical removal of the lump to ascertain its cause [3]. Only around 50% of these have malignancies, resulting in over 32,000 diagnostic operations p.a., many unnecessary, wasting time, resources, and subjecting patients to unnecessary procedures. Furthermore, analysis can take days, leading to elevated patient anxiety. Raman spectroscopy (RS) has been shown to identify cancers in the lymph nodes ex vivo, including lymphomas and secondary cancers metastasising from other primary tumour sites [4]. Rapid identification is critical when staging a disease, for treatment, and the likely prognosis. We propose to develop and test a &ldquo;smart needle&rdquo; for instantaneous identification of malignant nodes, negating the need for surgical diagnosis. This device uses light to analyse the molecular fingerprint of disease, measuring the light scattered by tissue when illuminated with a laser. This laser will be delivered to, and collected by, fibre optics contained within a needle. This technique is called Raman spectroscopy (RS) which detects the disease-specific molecular changes in cells. Aims and Objectives We will adapt our existing prototype smart needle probe for simultaneous FNA biopsy and RS measurements, to demonstrate safe collection of cells and spectra from the same location. This will enable a smooth introduction of our technique in parallel with existing clinical practice. We will evaluate its performance on excised tissue and in the patient to ascertain its potential for real-time diagnosis. Methods We will modify our existing device to obtain cells via FNA along the same needle. We shall demonstrate reproducible manufacture and performance of the device on surplus excised tissue, followed by proving the safe in vivo use in the first-in-human study, in 5 patients, after ethical and regulatory approvals. We will then undertake an in vivo observational study on 40 patients under surgical guidance, before conventional histopathological analysis of the node. FNA cytology, histopathology and Raman results will be compared. We will evaluate the health economic benefits of the approach, work with patients and clinicians to develop a device with high clinical utility and in parallel explore commercialisation strategies. Timelines for delivery The project is comprised of 6 work packages over 33 months. Anticipated Impact and Dissemination For translation to routine clinical use, we will seek further funding for a larger trial from various sources. To facilitate wider acceptance we will work with patient and clinical groups and potential commercial partners throughout. We will publish in journals, press and social media and brief NICE on the performance of the smart needle for rapid point of care diagnostics.

Lay abstract: We seek to improve the rapid, minimally invasive diagnosis of cancer, particularly in neck lymph nodes (glands under the skin), building on 20 years experience using light to diagnose diseases. Patients with lymphoma (UK s 5th most common cancer), will usually go to their doctor with an unknown lump. However, these lumps can just be due to an infection. To determine the cause of the lump, a sample of cells (fine needle aspiration &ndash; FNA) is taken using a needle and ultrasound imaging. This is then often followed by an operation to cut out the node to be certain of the diagnosis. Our new light-based technique is less invasive than current methods for diagnosis and can avoid expensive and often unnecessary surgery to remove the lump to determine if it is cancer. We have previously demonstrated that it is possible to differentiate healthy and diseased tissue in the laboratory by measuring the light emitted when a low power laser is shone upon the tissue; a technique called Raman spectroscopy (RS). Our results have shown it is possible to obtain an &ldquo;optical biopsy&rdquo; or fingerprint of disease that can be used to diagnose cancer to a high level of accuracy within 2 seconds. We have developed &ldquo;smart needle&rdquo; probes, consisting of fibre-optics within a fine needle for investigating cancer below the skin's surface, such as those related to glands in the neck. It is difficult to create a sensitive probe to fit inside a needle; however, we have demonstrated this approach in tissue samples from 68 patients in the laboratory, where we showed that our probe could detect cancer with a high level of accuracy. We will adapt our smart needle to provide both an &ldquo;optical biopsy&rdquo; and to collect a small number of cells (FNA) at the same rapid procedure. This would allow easy integration of Raman into existing pathways (in FNA clinics) and ease the hurdle of adoption. We expect to ultimately replace FNA as an initial triage between benign and malignant nodes. The interpretation of Raman data is automated and does not require specialist support thus dramatically improving the cost and speed of diagnosis and removing the problem of cytologist availability. We will test in patients for the first time. After ethical approval, will use the smart needle probes to investigate lumps in patients' necks demonstrating safety and effectiveness of the device. Results of the study will be published in patient newsletters, journals and presented at international conferences. We plan to ensure patients benefit from this innovation by working with partners to commercialise the approach. We will continue to engage with patients at Gloucestershire Hospitals to discuss the plans, results and dissemination as work progresses.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS