Innovating surgery for oral squamous cell carcinoma with targeted fluorescent and magnetic tracers

Oral squamous cell carcinoma (OSCC) is characterised by its locally aggressive nature and its high propensity to metastasise to regional lymph nodes (LN)s. It is well-established that margin status and the presence of LN metastases are two of the most important factors affecting prognosis. While patient and tumour factors cannot be changed after presentation, margin control during primary tumour resection and staging of the clinically occult neck are two components of treatment that are within the control of the head and neck surgeon. Despite this, positive margin rates have not improved over the last three decades and staging of the clinically negative neck continues to rely on elective neck dissection (END), which results in overtreatment of up to 75% of patients. Molecular imaging, with tracers designed to target specific tissue and tumour ligands, is a growing field that has significant potential to improve outcomes for patients with OSCC. This thesis evaluates how two different tracer technologies could be used to aid either margin assessment during resection of the primary tumour, and/or staging of the clinically negative neck with sentinel lymph node biopsy (SLNB). The tracers studied within this thesis are Panitumumab-IRDye800CW, an EGFR-targeting fluorophore used for fluorescence molecular imaging, and FerroTrace, a superparamagnetic iron oxide nanoparticle (SPION) that has been engineered with mannose end targets for macrophage-specific binding to aid SLNB.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 202

Optical biopsy of epithelial cancers by optical coherence tomography

Optical coherence tomography (OCT) is an optical technique that measures the backscattering of near-infrared light by tissue. OCT yields in 2D and 3D images at micrometer-scale resolution, thus providing optical biopsies, approaching the resolution of histopathological imaging. The technique has shown to allow in vivo differentiation between benign and malignant epithelial tissue, through qualitative assessment of OCT images, as well as by quantitative evaluation, e.g., functional OCT. This study aims to summarize the principles of OCT and to discuss the current literature on the diagnostic value of OCT in the diagnosis of epithelial (pre)malignant lesions. The authors did a systematic search of the electronic databases PubMed and Embase on OCT in the diagnostic process of (pre)malignant epithelial lesions. OCT is able to differentiate between benign and (pre)malignant lesions of epithelial origin in a wide variety of tissues. In this way, OCT can detect skin cancers, oral, laryngeal, and esophageal cancer as well as genital and bladder cancer. OCT is an innovative technique which enables an optical biopsy of epithelial lesions. The incorporation of OCT in specific tools, like handheld and catheter-based probes, will further improve the implementation of this technology in daily clinical practice

SURGICAL NAVIGATION AND AUGMENTED REALITY FOR MARGINS CONTROL IN HEAD AND NECK CANCER

I tumori maligni del distretto testa-collo rappresentano un insieme di lesioni dalle diverse caratteristiche patologiche, epidemiologiche e prognostiche. Per una porzione considerevole di tali patologie, l’intervento chirurgico finalizzato all’asportazione completa del tumore rappresenta l’elemento chiave del trattamento, quand’anche esso includa altre modalità quali la radioterapia e la terapia sistemica. La qualità dell’atto chirurgico ablativo è pertanto essenziale al fine di garantire le massime chance di cura al paziente. Nell’ambito della chirurgia oncologica, la qualità delle ablazioni viene misurata attraverso l’analisi dello stato dei margini di resezione. Oltre a rappresentare un surrogato della qualità della resezione chirurgica, lo stato dei margini di resezione ha notevoli implicazioni da un punto di vista clinico e prognostico. Infatti, il coinvolgimento dei margini di resezione da parte della neoplasia rappresenta invariabilmente un fattore prognostico sfavorevole, oltre che implicare la necessità di intensificare i trattamenti postchirurgici (e.g., ponendo indicazione alla chemioradioterapia adiuvante), comportando una maggiore tossicità per il paziente. La proporzione di resezioni con margini positivi (i.e., coinvolti dalla neoplasia) nel distretto testa-collo è tra le più elevate in ambito di chirurgia oncologica. In tale contesto si pone l’obiettivo del dottorato di cui questa tesi riporta i risultati. Le due tecnologie di cui si è analizzata l’utilità in termini di ottimizzazione dello stato dei margini di resezione sono la navigazione chirurgica con rendering tridimensionale e la realtà aumentata basata sulla videoproiezione di immagini. Le sperimentazioni sono state svolte parzialmente presso l’Università degli Studi di Brescia, parzialmente presso l’Azienda Ospedale Università di Padova e parzialmente presso l’University Health Network (Toronto, Ontario, Canada). I risultati delle sperimentazioni incluse in questo elaborato dimostrano che l'impiego della navigazione chirurgica con rendering tridimensionale nel contesto di procedure oncologiche ablative cervico-cefaliche risulta associata ad un vantaggio significativo in termini di riduzione della frequenza di margini positivi. Al contrario, le tecniche di realtà aumentata basata sulla videoproiezione, nell'ambito della sperimentazione preclinica effettuata, non sono risultate associate a vantaggi sufficienti per poter considerare tale tecnologia per la traslazione clinica.Head and neck malignancies are an heterogeneous group of tumors. Surgery represents the mainstay of treatment for the large majority of head and neck cancers, with ablation being aimed at removing completely the tumor. Radiotherapy and systemic therapy have also a substantial role in the multidisciplinary management of head and neck cancers. The quality of surgical ablation is intimately related to margin status evaluated at a microscopic level. Indeed, margin involvement has a remarkably negative effect on prognosis of patients and mandates the escalation of postoperative treatment by adding concomitant chemotherapy to radiotherapy and accordingly increasing the toxicity of overall treatment. The rate of margin involvement in the head and neck is among the highest in the entire field of surgical oncology. In this context, the present PhD project was aimed at testing the utility of 2 technologies, namely surgical navigation with 3-dimensional rendering and pico projector-based augmented reality, in decreasing the rate of involved margins during oncologic surgical ablations in the craniofacial area. Experiments were performed in the University of Brescia, University of Padua, and University Health Network (Toronto, Ontario, Canada). The research activities completed in the context of this PhD course demonstrated that surgical navigation with 3-dimensional rendering confers a higher quality to oncologic ablations in the head and neck, irrespective of the open or endoscopic surgical technique. The benefits deriving from this implementation come with no relevant drawbacks from a logistical and practical standpoint, nor were major adverse events observed. Thus, implementation of this technology into the standard care is the logical proposed step forward. However, the genuine presence of a prognostic advantage needs longer and larger study to be formally addressed. On the other hand, pico projector-based augmented reality showed no sufficient advantages to encourage translation into the clinical setting. Although observing a clear practical advantage deriving from the projection of osteotomy lines onto the surgical field, no substantial benefits were measured when comparing this technology with surgical navigation with 3-dimensional rendering. Yet recognizing a potential value of this technology from an educational standpoint, the performance displayed in the preclinical setting in terms of surgical margins optimization is not in favor of a clinical translation with this specific aim

Using deep learning to identify the recurrent laryngeal nerve during thyroidectomy

Surgeons must visually distinguish soft-tissues, such as nerves, from surrounding anatomy to prevent complications and optimize patient outcomes. An accurate nerve segmentation and analysis tool could provide useful insight for surgical decision-making. Here, we present an end-to-end, automatic deep learning computer vision algorithm to segment and measure nerves. Unlike traditional medical imaging, our unconstrained setup with accessible handheld digital cameras, along with the unstructured open surgery scene, makes this task uniquely challenging. We investigate one common procedure, thyroidectomy, during which surgeons must avoid damaging the recurrent laryngeal nerve (RLN), which is responsible for human speech. We evaluate our segmentation algorithm on a diverse dataset across varied and challenging settings of operating room image capture, and show strong segmentation performance in the optimal image capture condition. This work lays the foundation for future research in real-time tissue discrimination and integration of accessible, intelligent tools into open surgery to provide actionable insights.ope

Head and Neck Cancer Invasion: Contributions of Actin Regulatory Proteins and the Microenvironment

Metastasis of primary tumor lesions is the leading cause of cancer-related death. In head and neck cancer, a local-regional disease, metastasis is achieved mainly through invasion into surrounding tissue and spreads to cervical lymph nodes. Movement from the initial tumor site requires dynamic reorganization of the actin cytoskeleton, which utilizes the coordinated action of many actin regulatory proteins. However, there is increasing evidence that the tumor microenvironment is also a driver of invasion. This work aims to determine the contributions of proteins which regulate the actin cytoskeleton during head and neck cancer invasion both in vitro and in vivo, and provide details on how the HNSCC tumor microenvironment influences progression. This was accomplished, by the following Studies. In Study one, the actin binding protein coronin 1B is found to be amplified and overexpressed in invasive HNSCC patient samples, and a novel function in the regulation of protrusive membrane structures called invadopodia is described. Study two defines an in vivo role for the actin regulatory protein cortactin, which has been previously associated with more aggressive cancers in vitro and in patients. This work finds that cortactin expression is dispensable for tongue tumor invasion in a transgenic model of oral cancer, implicating the tumor microenvironment as being the major contributor to driving oral cancer invasion. Study three describes a technique for monitoring and biopsying cervical lymph nodes of mice using high frequency ultrasound. By using this technique, alterations in cervical lymph node size and blood flow were discovered in mice given the carcinogen 4-NQO to induce oral carcinogenesis. Collectively, these studies shed light on the importance of choosing comprehensive model systems for studying roles of actin binding proteins in cancer invasion

Multimodal Optical Spectroscopy and Imaging for improving Cancer Detection in the Head and Neck at Endoscopy

Ph.DDOCTOR OF PHILOSOPH

Near-infrared fluorescence-guided surgery : pre-clinical validation and clinical translation

This thesis focus on preclinical validation of novel fluorescent contrast agents for solid tumor imaging (Part I), the clinical introduction of NIR fluorescence sentinel lymph node imaging in several cancer types using indocyanine green (Part II) and the clinical translation of NIR fluorescence imaging using clinically available fluorescent contrast agents for solid tumor imaging (Part III)UBL - phd migration 201