Richard C. Newton

A Hand-held Instrument to Maintain Steady Tissue Contact during Probe-Based Confocal Laser Endomicroscopy

Probe-based confocal laser endomicroscopy (pCLE) provides high-resolution in vivo imaging for intraoperative tissue characterization. Maintaining a desired contact force between target tissue and the pCLE probe is important for image consistency, allowing large area surveillance to be performed. A hand-held instrument that can provide a predetermined contact force to obtain consistent images has been developed. The main components of the instrument include a linear voice coil actuator, a donut load-cell, and a pCLE probe. In this paper, detailed mechanical design of the instrument is presented and system level modeling of closed-loop force control of the actuator is provided. The performance of the instrument has been evaluated in bench tests as well as in hand-held experiments. Results demonstrate that the instrument ensures a consistent predetermined contact force between pCLE probe tip and tissue. Furthermore, it compensates for both simulated physiological movement of the tissue and involuntary movements of the operators hand. Using pCLE video feature tracking of large colonic crypts within the mucosal surface, the steadiness of the tissue images obtained using the instrument force control is demonstrated by confirming minimal crypt translation.

Progress Toward Optical Biopsy: Bringing the Microscope to the Patient

The investigation of many lung diseases currently requires bronchoscopic or surgical histopathological tissue biopsy. This creates risks for patients and entails processing costs and delays in diagnosis. However, several mainly probe-based biophotonic techniques that can image solitary lesions and diffuse lung diseases are fuelling a paradigm shift toward real-time in vivo diagnosis. Optical coherence tomography (OCT) uses near-infrared light in a process analogous to ultrasonography to image the mucosal and submucosal tissue boundaries of the bronchial tree. With 15-μm resolution, early work suggests it can differentiate between neoplasia, carcinoma in situ, dysplasia, and metaplasia based around epithelial thickness and breaches in the basement membrane. Probe-based confocal laser endomicroscopy (pCLE) has superior resolution but less penetration than OCT and employs blue argon laser light to fluoresce the endogenous elastin of (1) the acinar scaffold of the peripheral lung and (2) the basement membrane lying under bronchial mucosa. Initial studies suggest that the regular fibre arrangement of the basement membrane is altered in the presence of overlying malignant epithelium. pCLE produces detailed representations of the alveolar septal walls, microvessels, and some inflammatory cells. A third device, the endocytoscope, is a contact microscope requiring contrast agent to provide subcellular resolution of bronchial mucosa. Further development of these “optical biopsy” techniques and evaluation of diagnostic sensitivity and specificity of the acquired images are needed before they can be considered effective methods for eliminating the need for, and thus risks of, pinch biopsy to enable real-time diagnosis to streamline management.

Tracheobronchial amyloidosis and confocal endomicroscopy.

Tracheobronchial amyloidosis is one of many causes of endobronchial stenosis and nodularity, the concrete diagnosis of which currently requires the finding of apple-green birefringence from endobronchial biopsies. Bronchoscopic probe-based confocal endomicroscopy (pCLE) is a novel optical biopsy technique which provides real-time images of the lattice structure of the bronchial basement membrane – a finding lost in malignancy. This case study outlines the imperfect, essentially palliative management of this rare disease, and shows for the first time the unusual dappled in vivo pCLE images of amyloid-affected endobronchium.

Force adaptive multi-spectral imaging with an articulated robotic endoscope

Recent developments in optical spectroscopic techniques have permitted in vivo, in situ cellular and molecular sensing and imaging to allow for real-time tissue characterization, functional assessment, and intraoperative guidance. The small area sensed by these probes, however, presents unique challenges when attempting to obtain useful tissue information in-vivo due to the need to maintain constant distance or contact with the target, and tissue deformation. In practice, the effective area can be increased by translating the tip of the probe over the tissue surface and generating functional maps of the underlying tissue response. However, achieving such controlled motions under manual guidance is very difficult, particularly since the probe is typically passed down the instrument channel of a flexible endoscope. This paper describes a force adaptive multi-spectral imaging system integrated with an articulated robotic endoscope that allows a constant contact force to be maintained between the probe and the tissue as the robot tip is actuated across complex tissue profiles. Detailed phantom and ex-vivo tissue validation is provided.

An unusual case of haemoptysis

A 65-year-old Filipino man presented with a cough productive of heavily bloodstained sputum for 1 month with slight weight loss. He had chronic obstructive pulmonary disease from a 60 pack-year smoking history, having quit 20 years previously, and his chronic mild dyspnoea was stable. He had been treated for pulmonary tuberculosis 9 years previously but had not travelled abroad for 3 years. He had no …

Caecal herniation through the foramen of Winslow: a rare cause of bowel obstruction

Internal herniation through the foramen of Winslow is a rare cause of abdominal hernia. We describe a case in which caecal herniation through the foramen of Winslow was diagnosed using various imaging modalities, including computed tomography and managed operatively through hernia identification, caecal reduction and foramen closure. The literature is subsequently reviewed to highlight previous similar episodes and identify the optimal modalities for pre-operative diagnosis and describe the most appropriate intra-operative management.

Michelin-starred theatres

The recent universal adoption of pre-procedure surgical checklists illustrates how modern surgical practice has benefited from lessons in safety culture, courtesy of high-risk industries like commercial aviation1,2 and petroleum exploration.3 Such ideas are implemented to reduce risk and avert catastrophe, but perhaps surgery can also share tips with less hazardous professions. As celebrity chefs roll up their sleeves for more broadcasting of the perfect roast goose recipe, perhaps we can consider their more restaurant-tied comrades, and their skills and attributes. Cooking seems to have parallels with surgery. Modern surgical care and the finest commercial gastronomy have the shared aspiration of providing dependable excellence. Haute cuisine chefs and leading surgeons must deliver a personalized service which is self-critical and constantly improving in a high-pressure environment. A limp souffle may be less catastrophic to the recipient than a poorly-fashioned anastomosis, but errors must still be universally avoided. Knives apart, the working day in a Michelin-starred kitchen functions with the surgical precision of the most well-oiled theatre. There is a hierarchical division of labour from the kitchen assistant to the head chef. Even with exemplary assistance from the multidisciplinary team, ultimate responsibility for gastronomical governance rests with the chef. He or she must be an inspiring leader, effective communicator and proactive manager. The chef innovates with the menu and ingredients, audits the quality of dishes, deals with suppliers, monitors recruitment and staffing, still leaving time for communicating effectively with the occasional dissatisfied customer. He or she also ensures resources used are cost-effective without compromising quality, and oversees the safety and professional development of the team. Optimum success in surgery does not just require technical competence, but a Raymond Blanc style passion and work ethic to achieve the absolute best. With this personal focus, both professionals learn the importance of timing. Unplanned delays to surgery lead to poor outcomes,4 and glitches during operative lists create inefficiencies and frustration.5 Chefs also understand the sequelae of delays: spoilt food and hungry diners. They avoid this with meticulous timing as a product of anticipation, practice and clear communication. A restaurants success is judged by both reputation and, because of financial necessity, by the number of profitable diners fed. This is effectively ‘payment by performance’, and has been a strategy to shorten surgery waiting lists and improve care over the last decade.6 It remains to be seen how the proposed abolition of NHS targets will affect the reputation of surgical provision. While surgical training is changing,7 both professions are still taught through the apprenticeship model and necessarily dependent upon an effective teacher–apprentice dynamic. With reduced hours and the conversion to shift work patterns, many surgical trainees have no continuity with their trainers, and would be envious of the stable supervision that the head chef provides to underlings. Both experts pass on technical skills and understanding: the chef looks, smells and tastes; the surgeon looks, listens and feels. Admired techniques are adopted; others rejected. But with practice, careful supervision and encouragement, the successful trainee matures from assisting lipoma excisions to teaching endarterectomies, and the kitchen assistant graduates from peeling potatoes to demonstrating how to create sashimi and manage a restaurant. As the surgeon develops a subspecialist niche, the chef cultivates a signature dish. Cookery has even benefited from evidence-based practice. The structured methodological analysis of ‘molecular gastronomy’ elucidates which culinary dogma is relevant and why. It produces rationale for streamlining processes, improving outcome, reducing mishaps and facilitating innovation. There are international seminars and professorships in the discipline,8 and at El Bulli in Catalonia and the Fat Duck in Berkshire, virtual databases of structured culinary experiments.9 Surgeon scientists have modified practice, for example following the extensive investigation of the effect of temperature on patient outcome during surgery.10,11 Research has taught the gourmet chef to use liquid nitrogen to create smooth crystal-free ice cream, and sous-vide waterbaths to poach the perfect steaks.8 Technological developments provide novelty and excitement, and, as has been demonstrated with minimally invasive surgery, can improve patient care. Nevertheless, reminded that a well-honed traditional fruit crumble trumps any botched bacon and egg ice cream,12 we must be sure that surgical innovation provides a genuine improvement upon the status quo. For example, Da Vinci surgical robots (Intuitive Surgical, California) offer many theoretical advantages over open or laparoscopic surgery, but cost-effective clinical benefits must be proven before there is more widespread uptake.13 In some respects, the gourmet kitchen resembles the surgical firm of a previous era: extreme hours not protected by the European Working Time Directive, under the Ramsay-esque control of an autocratic consultant. But as surgery has learnt and borrowed concepts of incident reporting from aviation, and teamwork from the Ferrari pitlane,14 perhaps it can learn from high-end cuisine, even if just to marinate the thoughts and be reminded of the need for excellence and attention to detail.

Clinical Correlation between Real-Time Endocytoscopy, Confocal Endomicroscopy, and Histopathology in the Central Airways

Background: Lung cancer is one of the commonest malignancies with a worldwide incidence of 1.6 million cases each year. Although the main aetiological factor has been identified (cigarette smoking), the progression of lung cancer from early changes such as dysplasia through to cancer is still not fully understood. Furthermore, current research techniques are reliant on obtaining tissue biopsies, a process that alters the natural history of the very process under investigation. Hence, there is a need for developing optical biopsy techniques. Objectives: To prospectively evaluate the feasibility of endocytoscopy and confocal endomicroscopy in the detection of malignant and pre-malignant changes in the airways. Methods: Findings with endocytoscopy and endomicroscopy were compared with conventional biopsies obtained from the same areas in 25 patients undergoing bronchoscopy for evaluation of endobronchial abnormalities and in 5 healthy control subjects. Results: Endocytoscopy was technically more difficult, and interpretable images were only obtained in 21 of the patients evaluated, and hence, complete information including histopathological information was available in 21 patients. Endocytoscopy appeared to correlate with the histopathological findings on tissue biopsy, and was able to distinguish normal epithelium from dysplasia and carcinoma. Confocal endomicroscopy was a more reliable technique with adequate visual information obtained in all patients examined but was unable to distinguish between dysplasia and carcinoma. Conclusion: This feasibility study suggests that endocytoscopy may have the potential to fulfil the role of optical biopsy in the evaluation of the pathogenesis of lung cancer.

Multifunctional gold nanorods for image-guided surgery and photothermal therapy

Nanoparticles are viewed as a promising tool for numerous medical applications, for instance imaging and photothermal therapy (PTT) has been proposed using gold nanorods. We are developing multi-functional gold nanorods (m-GNRs) which have potential for image guided endoscopic surgery of tumour tissue with a modified laparoscope system. A new synthesis method potentially allows any useful acid functionalised molecules to be bonded at the surface. We have created fluorescent m-GNRs which can be used for therapy as they absorb light in the infrared, which may penetrate deep into the tissue and produce localised heating. We have performed a tissue based experiment to demonstrate the feasibility of fluorescence guided PTT using m- GNRs. Ex vivo tests were performed using sheep heart. This measurement, correlated with the fluorescence signal of the m-GNRs measured by the laparoscope allows the clear discrimination of the artery system containing m-GNRs. A laser diode was used to heat the m-GNRs and a thermal camera was able to record the heat distribution. These images were compared to the fluorescence images for validation.

Characterising ovarian cancer morphology and response to chemotherapy using fluorescence confocal endomicroscopy

Ovarian cancer is often diagnosed late, and the assessment of its response to chemotherapy typically takes several months using current methods. Utilising a novel probe-based fluorescence confocal endomicroscopy (FCE) approach, we have 1) established the most appropriate exogenous contrast agent for use in this setting, 2) demonstrated that cell attrition and morphological changes caused by platinum-based chemotherapy treatment can be tracked via this technique, 3) characterised the morphological differences between normal and cancerous ovarian epithelium, and 4) shown that the FCE imaging system can detect 5-aminolevulinic acid-induced protoporphyrin IX (PpIX) autofluorescence from in vitro ovarian cancer cell lines and ex vivo small cell lung cancer tissue. It is expected that FCE may play a role in morphological and functional imaging for the early diagnosis and treatment of ovarian cancer.