Modelling and Control in Biomedical Systems 2006

PAPERS

DYNAMIC MODELING IN DIABETES: FROM WHOLE BODY TO GENES

Claudio Cobelli,     Department of Information Engineering, University of Padova, Italy

Abstract

Diabetes is one of the major chronic diseases such that, together with its complications it can account for more than 10% of national healthcare expenditure. Mathematical modeling can enhance understanding of this disease in quantitative terms and is becoming an increasingly important aid in diagnosis, prognosis and in the planning of therapy. Mathematical modeling in relation to carbohydrate metabolism and diabetes has a long history stretching back some 45 years. Initially modeling has focused on the dynamics of glucose and insulin and their interactions, principally at the whole body and organ levels. However, over recent years the scope of mathematical modeling in relation to diabetes has seen dramatic expansion such that it is now being applied across the spectrum from populations of patients (public health) to the molecular level. This paper will explore recent developments of mathematical modeling in our laboratory across this ever increasing spectrum. Ingredients will include models to assess, at whole body, the efficacy of homeostatic control and system fluxes and, at organ level, unit processes in skeletal muscle, a key target tissue. To do so both whole body as well as regional tracer experiments, these last employing Positron Emission Tomography, will be discussed not only to understand the physiology but also the pathophysiology of glucose metabolism, like obesity and diabetes. Microarray technology offers an important tool to understand how genes change expression and interact as a consequence of external/internal stimuli. Dynamic stimulus/response experiments can provide time series expression data from which regulatory networks can be obtained by reverse engineering, and this is illustrated for insulin stimulation of muscle rat cells. Recent technological advances in diabetes include more reliable subcutaneous glucose sensors: interpretation and clinical use of continuous glucose monitoring time series data can be powered by dynamic modeling, in particular we show how critical hypoglycemic events can be predicted ahead in time. Finally, the importance of dynamic modeling in an important diabetes health care problem is discussed by showing its use in conjunction with gait analysis for preventing diabetic foot complications. Copyright © 2006 IFAC

LIDCO – FROM THE LABORATORY TO PROTOCOLIZED GOAL DIRECTED THERAPY

Terry O’Brien,     CEO LiDCO Group Plc; Research Fellow Dept. of Applied Physiology St Thomas’ Hospital, London

Abstract

A new generation of cardiovascular monitors, fueled by data from non or minimally invasive sensors, employing algorithms that model the cardiovascular system combined with user interfaces that facilitate decision support and protocolization of care are entering a new era where the costs and risks of applying the technology are going to be far outweighed by the clinical, human and financial returns. Copyright © 2006 IFAC

Keywords

Cardiovascular modelling

monitoring

critical care

visualization

protocol

oxygen delivery

1. INTRODUCTION

LiDCO Group Plc is based in London and was founded in the early 1990’s by Dr Terry O’Brien and Dr David Band in collaboration with the United Dental and Medical Schools of St Thomas’ and Guys Hospitals (now King’s College, London.) Since that time, the Group has developed inventions within the cardiovascular monitoring field. LiDCO’s products have been extensively validated and demonstrated to reduce the hospital stay of high risk surgery patients by twelve days - saving £4,800 per patient treated. Extrapolated to the whole of the UK this would equate to a saving of £500 million per annum for the National Health Service.

LiDCO applies a multi-disciplinary combination of physiological expertise, sensor and computing technology to monitor and display the relationship between linked physiological variables. The transformation of raw physiological data into useable information and then specific treatment protocols that can improve clinical outcome has been a key objective throughout the development of the Company’s products. LiDCO’s principal products are a sensor/in vivo diagnostic product (the LiDCO System) and a continuous waveform analysis algorithm (the PulseCO System) housed in a platform monitoring product (the LiDCOplus Hemodynamic Monitor), which when used together provide a range of data concerning the performance of a patient’s heart, blood volume and systemic oxygen delivery.

Our financing strategy was two stage, firstly to partner with our host Medical School for the start-up and pre product registration / product development phase. The funding of salaries, intellectual property development and all of the running costs were paid for though raising funds - seed capital from founders, followed by early corporate marketing license fees payments and private individuals. In this phase in total the Company raised £9.25 million. LiDCO Group became a Plc in July 2001 when it floated on the Alternative Investment Market (AIM, London) raising £15 million. Subsequent to the Aim listing we raised an additional £5 million - these funds were used for sales expansion purposes. In summary, to bring the technology to the international market has cost £29 million and taken more than ten years.

2. LIDCO’S TECHNOLOGY

Monitoring of the key cardiovascular parameters - blood pressure, cardiac output (blood flow in litres / minute) and oxygen delivery (total oxygen in mls / minute/ body surface area) - can provide a practical, early warning of cardiovascular change and adverse events in surgery and critical care patients. Improved care in this high-risk group should reduce the incidence of adverse events in hospitals and thereby reduce costs. The current market leader for the measurement of cardiac output and oxygen delivery is the highly invasive, thermodilution pulmonary artery catheter (PAC). Thermodilution derived cardiac output is the measurement of blood flow using a cold injection of an isotonic solution into the right atrium of the heart and the measurement via a thermister of the subsequent temperature change in the pulmonary artery. In addition to the risks of this technique, there are problems with the interpretation of this complex data set in the hospital acute care setting. Thus, despite being available for more than 30 years, the therapeutic value of the PAC has yet to be established and its use has been restricted to a small number of patients who could benefit from these measurements.

The LiDCO™plus is a cardiovascular monitor, providing continuous, reliable and accurate assessment of the hemodynamic status of critical care and surgery patients. This is achieved by running two proprietary algorithms: a continuous arterial waveform analysis system (PulseCO™) coupled to a single point lithium indicator dilution calibration system (LiDCO™). The design objective of the LiDCO™plus Monitor was to develop a novel platform monitor that would provide an easily interpretable user interface displaying real time: blood pressure, pre load (fluid management), cardiac output/oxygen delivery and after load (peripheral resistance) parameters. The technical innovation of the LiDCO technology is both in the method of using lithium as an intra vascular marker substance to accurately measure cardiac output and the design and clinical application of the lithium ion-selective electrode. The lithium method is at least as accurate a measurement of cardiac output as the older and more invasive PAC approach, but with the advantages of being simple and quick to set-up by a nurse or doctor, with no complications associated with its use. The LiDCOplus Monitor user interfaces are designed to simplify the setting and achievement of individualized target cardiovascular parameters in the acute care setting. The user, often a nurse, should be helped by interaction with the monitor interface to achieve the target by the appropriate administration of fluids and inotropic drugs and then with decision support to maintain the patient to the required target.

3. GOAL-DIRECTED THERAPY (GDT) AND IMPROVING OUTCOMES

Goal-directed therapy is a general term used to describe the use of pre-set cardiac output and oxygen delivery levels to guide intravenous fluid and inotropic drug therapy. GDT has not yet been introduced into routine practice. The principal reason for this is the limited availability of intensive care unit (ICU) facilities and staff coupled to safety concerns regarding the use of the invasive PAC to measure cardiac output. Clearly, LiDCO’s minimally invasive technology could be used to implement GDT by nursing staff in risk patients after major general surgery. Therefore, a study was undertaken to assess the effect of post-operative GDT on complication rates and duration of hospital stay in high-risk general surgical patients (Pearse et al., 2005). This was a randomised controlled study conducted in the adult ICU at St George’s Hospital, London. Patients were assigned to GDT (62 patients) or control group (60 patients) by computer-generated random sequence. Patients in the control group were administered intravenous colloid solution to achieve a sustained increase in central venous pressure (CVP) of at least 2 mmHg for 20 minutes. GDT patients received intravenous colloid solution to achieve a sustained rise in stroke volume (amount of blood in each heart beat; cardiac output = stroke volume × heart rate) of at least 10% for 20 minutes. The GDT group also received an inotrope (dopexamine) if the targeted oxygen delivery index (DO2I is oxygen delivery per square meter of body surface area) did not reach 600 ml min−1 m−2 with intravenous fluid alone.

The GDT group achieved significantly greater levels of oxygen delivery in the first 8 hours after surgery. Fewer patients developed complications in the GDT group (27 patients (44%) versus 41 patients (68%). The total number of complications per patient was also lower in the GDT group (0.7 per patient (SD 0.9) versus 1.5 per patient (SD 1.5); p = 0.002). The reduction in the number of post-operative complications in the GDT group was associated with a reduction in mean duration of hospital stay by 12 days (17.5 days versus 29.5 days, 41% reduction (95% confidence intervals 0 to 81); p = 0.001).

4. CONCLUSIONS

This is the first study to investigate the effects of post-operative GDT in high-risk patients undergoing major general surgery. The effect of the GDT protocol was to reduce the number of patients developing complications and shorten the hospital stay in comparison with a protocol designed to reflect standard care. LiDCO’s technology uniquely provides real-time measurement of the absolute level of oxygen delivery, minimally invasively, without the need for insertion of an invasive catheter into a major artery or the heart. Using this technology to apply a nurse led GDT protocol to high-risk surgery patients reduced total hospital stay by an average of 12 days saving £4,800 per patient treated. Implementation of a similar strategy in other hospitals across the UK National Health System could result in estimated savings of £500 million annually. This GDT protocol has now become a standard of care at this hospital and is targeted to save the hospital £2 million pounds per year in bed days. The next generation of more cardiovascular monitors, coupled to treatment protocols, can dramatically reduce complications and hospital stay in risk surgery patients.

REFERENCES

Pearse, R, Dawson, D, Fawcett, J, Rhodes, A, Grounds, M, Bennett, D. Early goal directed therapy following major surgery reduces complications and duration of hospital stay. A randomised controlled trial. Critical Care. 2005; 9:687–693.

ELASTIC SCATTERING SPECTROSCOPY FOR NONINVASIVE DETECTION OF CANCER

Irving J Bigio,     Departments of Biomedical Engineering, Electrical & Computer Engineering, and Physics, Boston University

Abstract

Optical spectroscopy mediated by fibre-optic probes can be used to perform noninvasive, or minimally-invasive, real-time assessment of tissue pathology in-situ The most common approaches have been based on UV-induced fluorescence spectroscopy and Raman spectroscopy, which are assumed to be responsive to biochemical changes in cells. On the other hand, our method of elastic-scattering spectroscopy (ESS) is sensitive to the sub-cellular architectural changes, such as nuclear grade or nuclear to cytoplasm ratio, mitochondrial size and density, etc., which correlate with features used in histological assessment. The ESS method senses those morphology changes in a semiquantitative manner, without actually imaging the microscopic structure. To aid in the design of optical probes and the understanding of the resulting spectroscopic signals, modelling of photon scattering and migration in tissue is carried out using Mie theory and Monte Carlo simulations. Clinical demonstrations of ESS have been conducted in a variety of organ sites, and promising results have been obtained. Larger-scale clinical studies are now starting. Copyright © 2006 IFAC

CLINICAL DECISION SUPPORT IN MONITORING AND INFORMATION SYSTEMS

Lorenzo Quinzio, MD,     Philips Medical Systems Böblingen GmbH, Germany

Abstract

Antidote to information overload: Clinical decision support systems offer built-in intelligence to assist healthcare teams with the many tasks that demand cross-referencing and analysis of clinical information. Thus patient monitors, clinical measurements and clinical information systems may be an antidote to information overload and may help clinicians to develop a coherent picture of their patient’s status. On a practical level, clinicians should implement clinical decision support systems that provide decision support automatically as part of clinician workflow, deliver decision support at the time and location of decision making, provide actionable recommendations, and use a computer to generate the decision support. The technical tools are invented, now we have to tailor them to meet the clinical users’ needs. Copyright © 2006 IFAC

Keywords

Decision support system

information systems

1. WHY IS THERE A NEED FOR CLINICAL DECISION SUPPORT?

Patient safety is universally recognized as the most important clinical topic in healthcare today. On the opposite the hospitals are struggling with limited resources and increasing patient acuity. Worldwide governments are trying to find solutions that enable a high standard of care without the price tag attached. Medical advancements allow people to live longer, often with the consequences of multiple chronic illnesses and a lengthened recovery period. Even more in some countries there is a shortage of clinicians, leaving nursing positions in hospitals unfilled. This leads to inexperienced and unqualified staff even in the critical care areas.

To address these deficiencies in care, healthcare organisations are increasingly turning to Clinical Decision Support Systems (CDSS), which provide clinicians with patient-specific assessments or recommendations to aid clinical decision making. CDSS have shown promise for reducing medical errors and improving patient care (Kawamoto et al, 2005).

2. WHAT IS CLINICAL DECISION SUPPORT?

Clinical Decision Support (CDS) refers broadly to providing clinicians with clinical knowledge and patient-related information, intelligently filtered or presented at appropriate times, to enhance patient care. They vary greatly in their complexity, function and application. Clinical knowledge of interest could range from simple facts and relationships to best practices for managing patients with specific disease states (HIMMS, 2006).

To be used in the clinical routine decision support systems often are designed as computer applications. They can simplify access to data needed to make decisions (Overview), assist in establishing a diagnosis and in entering appropriate orders (Review), provide reminders and prompts at the time of a patient encounter, and generate alerts or reminders when new patterns in patient data are recognized (Clinical Advisories).

Decision support systems that present patient-specific recommendations in a form that can save clinicians time have been shown to be highly effective, sustainable tools for changing clinician behaviour (Payne, 2000). Furthermore they can be used to check criteria and compliance of appropriate guidelines. To fulfil these requirements clinical decision support can be integrated into existing computer-based systems to provide decision support automatically as part of clinician workflow. Thus they could be implemented a) into diagnostic devices like the patient monitoring and b) into a documentation system like a computer based clinical information system.

Important criteria for a clinically useful CDSS are:

• Data actively used drawn from existing sources

• System improves clinical practice

• Knowledge based on best evidence

• Knowledge fully covers problem

• Clinician can control system

• The system is easy to use

• The system can be configured and updated

• The decisions made are transparent

3. CLINICAL DECISION SUPPORT IN MONITORING

Modern patient monitors like the Philips IntelliVue have built-in clinical decision support tools that reflect clinical thought processes. Clinical decision support tools built directly into patient monitors range from multi-parameter event detection and alarming (Advisories) to sophisticated graphic displays of real-time and trended data (ST Map and Horizon Trends).

A central Information Center is the heart of the Patient Monitoring Network, combining the real-time monitoring surveillance of a central station with sophisticated clinical analysis tools. The Information Center provides matchless surveillance – complete waveforms, alarms, and numerics – of networked monitors and telemetry systems. A suite of Clinical Review Applications on the Information Center provides a coherent environment for analyzing patients’ complete monitoring records from the past 96 hours. A range of carefully chosen, consistently applied display techniques makes it easier to discern physiological patterns or correlate different parameters.

3.1 Overview - A better overview with ST Map

Changes in the ST segment of an electrocardiograph tracing, for example, can indicate myocardial ischemia, or less-than-normal blood flow to the heart. The graphical display of ST Map (Fig. 1) is designed around the clinician and displays a mind’s-eye view of ST segment changes, with the goal of helping clinicians recognize patterns and track patient progress more easily.

Fig. 1 Comprehensive Overview with ST Map in acute phase: ST Elevation (III; aVF, II) and ST Depression (aVL, 1, V1, V2).

3.2 Review - Smart review with Horizon Trend

Trends have in the past been used to look at patient data retrospectively. Trends allow:

• Graphical representation of the patients status over a time period

• Allows for easy recognition of changes in patient status

• Layout can be organized to reflect a clinical scenario

By combining parameters on the display (Fig. 2), clinicians are assisted in their cognitive process of pattern recognition. For each parameter a baseline or target value can be set by the end user. Either the current value or a target value can be monitored for the patient. A scale can be selected to detect the baseline deviations. The arrow indicates as a Trend indicator how the patient’s value has changed in the preceding ten minutes.

Fig. 2 The Horizon view clearly demonstrates that patient’s condition is moving towards the targeted goals of therapy. Clinicians are alerted to changes that could lead to an adverse event for the patient (e.g., back to sleep and potential for airway obstruction).

3.3 Clinical Advisories with Advanced Event Surveillance

Events are electronic records of episodes in the patients’ condition. They are used to drive alert notification to assist with protocol compliance. An Event is generated with at least one or up to four different monitoring parameters e.g. heart rate, blood pressure, respiration rate or temperature.

Advanced Event Surveillance (Fig. 3) allows clinicians to enter protocol requirements (e.g., for sepsis bundle) and let them be notified when they are met.

Fig. 3 Advanced Event Surveillance for heart rate, respiration rate, blood pressure and temperature.

4. CLINICAL DECISION SUPPORT IN INFORMATION SYSTEMS

Information management systems are used every day in intensive care units, operating rooms, and obstetrical departments. All are optimized for their environments, and have key qualities, including the integration of clinical decision support systems:

• Automated data acquisition from patient monitors and scores of other bedside devices, which saves charting time and reduces transcription errors.

• Open databases for comprehensive longitudinal reporting and data analysis, which supports regulatory compliance efforts, quality improvement initiatives, and research

• HL7 data exchange capabilities, to facilitate interaction with other hospital systems (e.g., HIS, LIS, pharmacy).

• Networking and remote access capabilities, to facilitate consults and information sharing among all caregivers.

4.1 Overview - Patient Summary

Clinical Information systems are able to support the workflow by enhancing the clinical work with comprehensive documentation that focuses on significant information. Once entered automatically or manually into the system, the instant availability of patient information not only helps to automate discharge or transfer documentation, it also makes it easier to provide a patient summary as a global overview for example for shift changes.

4.2 Review - problem-oriented data flowsheets

In addition to quick overviews, a flexible data review is provided with problem-oriented data flowsheets and documentation forms. This time-scalable flowsheets present patient data that has already been documented in a different context. For example a haemodynamic review shows a combination of vital signs, cardiovascular medication and laboratory data, that refer to the stability of the circulation system. A review for infection monitoring presents certain laboratory results, vital parameter like temperature and microbiological findings. Overall the user can configure decision-support flowsheets to display patient information for specific purposes (Fig. 4).

Fig. 4 The Patient summary provides a quick overview of the patient’s status for easier handoffs between shifts, caregivers, etc.

4.3 Clinical advisories

Reminders, alerts and advisories draw on all the data in the chart – labs, monitoring, calculations, etc. – to provide early warning of potentially serious conditions. The available data for clinical advisories contains:

• Patient monitoring data

• Third-party devices (bedside monitors, ventilators, infusion pumps, etc.)

• Images (ultrasound, x-ray, CT, MR)

• Lab results (blood tests, urinalysis)

• Pharmacy – drug/drug interactions, dosing guidelines, Computer Physician Order Entry (CPOE), Medical Administration Record (MAR).

• Patient demographics and medical histories (e.g. ADT, microbiology)

• Documentation of patient care process, e.g. assessments and interventions

A significantly important component of this strategy is a real-time rules-based engine (Fig. 5). Integrating the aggregate patient data from the CIS and physiological measurements from the Clinical Network, this dynamic engine can trigger alerts and advisories and provide notification to the caregivers in case of any clinical significant changes, e.g. with pager or in-house phone.

Fig. 5 Rules engine of the clinical advisories.

CDSS can be customized to help to implement clinical guidelines and protocols. It synthesizes elements from multiple data sources and present them in clinically relevant ways to help care teams make well-informed treatment choices at the point of care. With a comprehensive, longitudinal clinical database, one can track the effectiveness of new guidelines, mine patient data for trends, and substantially increase the hospital’s efficiency in complying with regulatory bodies.

The guidelines for recognizing and treating sepsis put forward by the international Surviving Sepsis Campaign, for instance, call on caregivers to monitor and manage a number of parameters from many different sources, including urine output, central venous pressure, glucose levels, and blood cultures. Since CareVue Chart automatically receives lab results as well as data from patient monitors and other bedside devices, it is uniquely positioned to deliver early warnings and help nurses evaluate a patient’s response to therapy.

Fig. 6 Example of a clinical advisory.

5. DISCUSSION

From a technical point of view, clinical decision support systems have achieved a phase of maturity, but concerning the actual use in clinical settings, CDSS’s are still in their infancy. Overall it seems that the tools are invented, but that we need to change the daily habits.

The importance of Clinical Advisories is well accepted. They help the care team by quickly identifying situations to which the team may need to respond and thus save time to treat. CDSS can effectively implement guidelines by giving patient specific recommendations at points of care. Clinical decision support can measurably improve the quality, safety and cost-effectiveness of patient care (Osheroff, 2005)

Regarding the clinical use, Garg et al. (2005) who reviewed one hundred trials that evaluated the effect of a CDSS, formulate some important issues for CDSS implementation. They include CDSS user acceptance, workflow integration, compatibility with legacy applications, system maturity, and upgrade availability.

In addition Kawamoto et al (2005) analysed 70 randomised controlled trials identifying features strongly associated with a decision support system’s ability to improve clinical practice:

• Automatic provision of decision support as part of clinician workflow

• Provision of decision support at the time and location of decision making

• Provision of recommendations rather than just assessments

• Computer based decision support, e.g. workflow integration into an electronic medical record

• Improved practitioners performance associated with CDSSs that automatically prompt users compared with requiring users to activate the system

In conclusion to make the clinicians more familiar with CDSS and to make such systems more successful accepted medical standards like guidelines should be implemented, to be used in daily practice. A targeted approach of decision support may prove to be better and more effective than a blanket one (Atreja et al 2004). A smart integration into the clinical workflow seems to be crucial.

6. ANTIDOTE TO INFORMATION OVERLOAD

Clinical decision support systems offer built-in intelligence to assist healthcare teams with the many tasks that demand cross-referencing and analysis of clinical information. Thus patient monitors, clinical measurements and clinical information systems may be an antidote to information overload and may help clinicians to develop a coherent picture of their patient’s status. The technical tools are invented, now we have to tailor them to meet the clinical users’ needs.

REFERENCES

Atreja, A, Mehta, N, Jain, A, Harris, CM. Computer alerts for potassium testing: Resisting the Temptation of a blanket approach. JAMIA. 2004; 2004 Sep-Oct;11(5):4–433.

Garg, AX, Adhikari, NK, McDonald, H, Rosas-Arellano, MP, Devereaux, PJ, Beyene, J, Sam, J, Haynes, RB. Effects of Computerized Clinical Decision Support Systems on Practitioner Performance and Patient Outcomes: A Systematic Review. JAMA;. 2005; Vol 293(No. 10):38–1223.

HIMMS Website (2006) http://www. himss. org/asp/topics_clinicalDecision. asp).

Kawamoto, K, Houlihan, CA, Balas, EA, Lobach, DF. Improving clinical practice using clinical decision support systems: a systematic review of trials to identify features critical to success. BMJ;. 2005; 330(7494):765. [March 2005;].

Osheroff JA, Pifer EA, Teich JM, Sittig DF, Jenders RA (2005) Improving Outcomes with Clinical Decision Support: An Implementer’s Guide, HIMSS Publishing, 2005, ISBN: 0-9761277-2-5

Payne, TH. Computer Decision Support Systems. Chest. 2000; 118:47–52.

OPTICAL METHODS FOR IN-VIVO DIAGNOSIS / CLINICAL DIAGNOSIS BY IMAGE PROCESSING

ACOUSTO-OPTIC IMAGING TECHNIQUES FOR OPTICAL DIAGNOSIS

M. Lesaffrea, F. Jeana, A. Funkea, P. Santosa, M. Atlana, B.C. Forgeta, E. Bossya, F. Ramaza, A.C. Boccaraa, M. Grossb, P. Delayec and G. Roosenc,     aLaboratoire d’Optique, Ecole Supérieure de Physique et de Chimie Industrielles de la Ville de Paris, CNRS UPRA0005, Université Pierre et Marie Curie, 10 rue Vauquelin F-75231 Paris cedex 05; bLaboratoire Kastler-Brossel, UMR 8552 (ENS, CNRS, UMPC), Ecole Normale Supérieure, 10 rue Lhomond F-75231 Paris cedex 05; cLaboratoire Charles Fabry de l’Institut d’Optique, Unite Mixte de recherche du Centre National de la Recherche Scientifique, de l’Institut d’Optique et de l’Univeristé Paris-Sud, Bat 503, Centre Scientifique d’Orsay F-91403 Orsay Cedex

Abstract

The combination of light and ultrasound to measure optical properties through thick and highly scattering media is a tantalizing approach for \emph{in vivo} imaging. This is partly due to the ballistic nature of ultrasound in biological tissue and thus the well-defined localization of the signal with a mm³ resolution. Optics can reveal echography-silent tumors by monitoring the wavelength of the laser source and thus measuring the optical absorption linked to oxy- or deoxyhemoglobin. The coherent nature linked to the acousto-optic effect allows interferometric measurements. A difficulty arises from the speckle nature of the light to analyze, and two techniques with a high etendue are available at present in order to eliminate speckle blurring. They use either a CCD-camera that treats independently each grain of speckle, or a large area single detector and a photorefractive crystal that adapts the wavefront of the reference beam to the speckle output pattern. Copyright © 2006 IFAC

Keywords

Coherence imaging

Light propagation in tissues

Turbid medi

Holography

Holographic interferometry

Turbid media

1. INTRODUCTION

The transmission of light through some cm of biological tissue is weak, but still measurable with sensitive detectors and appropriate data post-treatment. This is essentially true for the red and near infrared region (typically between 600-1000 nm), and thus it is possible to send light inside the human body. From a practical point of view, many difficulties have to be overcome because of the weakness of the signal and the high level of multiple light scattering. But still, optical images within thick tissues could be obtained in a near future. The last two decades have seen the emergence of different methods in order to collect the small flux crossing thick tissues and to analyze it to obtain images of organs. One of these directions couples optics and acoustics with two approaches: the former consists of tagging photons crossing a small volume of the media with an ultrasound beam. Compared to pure optical techniques like Diffuse Optical Tomography (Gibson, et al., 2005), this technique offers a higher resolution (e.g mm³) thus close to the one obtained with conventional echography. The basis of acousto-optic imaging has been first proposed by François Micheron and Daniel Dolphi (Dolfi, et al., 1989), who looked for alternative solutions to X-ray mammographies, whose innocuity was subject to discussion. Though a patent has been deposited in 1987, the concept of imagery had been forgotten for a decade. More recently, a few teams have engaged on research in this field (Wang, et al., 1995; Leutz, et al., 1995; Wang, 2001; Kempe, et al., 1997; Lévêque, et al., 1999; Lev, et al., 2003). At present, we are developing experiments where the signal is recorded by holographic processes (Gross, et al., 2003; Ramaz, et al., 2004). This is a promising technique since it significantly improves the sensitivity of detection (Atlan, et al., 2005; Murray, et al., 2004; Gross, et al., 2005). We will see in the following paragraphs the principle of the techniques, and what kind of images can be obtained. Let us first detail the principle of acousto-optics imaging: it consists to illuminate the tissues or the organ and to detect the output flux. Such light is of low intensity; moreover, because of multiple scattering, its structure essentially consists in many waves that have followed random paths through the media. This is due to microstructures in the tissue (cells, intracellular organites, collagene fibers,…) that perturb the propagation of light when the distance becomes larger than roughly 50μm, which corresponds to the typical length between two scattering events. When the propagation length becomes larger than 1mm, the scattering events are so numerous that it is not possible any more to know the initial direction and polarization of an incoming photon. When light is produced by a laser, it is possible to work with a coherent wave, whose phase and wavelength are well defined in space and time, and thus optical waves scattered by the tissues can still keep trace of this coherence state. But in which form? This is an interference pattern, detectable for example on a screen put close to the organ under study. Since the different waves have followed many different paths, their relative phases on the screen differ significantly from one point to another. The resulting intensity distribution is called speckle. This is an interference pattern appearing granular and disordered, with many bright and dark spots. Laser users are familiar of this phenomenon, easily seen with a laser pointer directed on a sheet of paper, for example: the different points of the rough surface scatter light and constitute an ensemble of secondary, but dephased sources, whose interference produces speckle.

The speckle nature of the output light linked to the media is an inherent difficulty. We will see that an appropriate treatment allows to measure selectively waves that have crossed the region subjected to the ultrasound. We use acoustic waves at 2MHz, which corresponds to a wavelength of 0.7mm within biological tissues, containing essentially water. A short ultrasonic pulse (1μs) can be focused in a volume of 1mm³. At this frequency, the ultrasonic wave is weakly absorbed by the biological media, and exhibits a ballistic propagation.

Fig. 1 Illustration of acousto-optic imaging in thick biological tissues.

2. TAGGING LIGHT WITH THE ULTRASOUND

Why do we apply ultrasound in the region of interest? Because the US modulates the phase of the optical waves that cross this region by creating periodically a compression or a dilatation of the medium; the microstructures of the tissue vibrate at the same frequency as the US. Since they scatter optical waves, the optical paths (the phases) of these waves are modulated periodically. In addition to the frequency of the laser ωL, it appears within the optical waves new frequencies, so called sidebands. The main components correspond to the laser frequency shifted from plus or minus the US frequency (e.g ωL + ω US). The light exiting the media contains thus three frequency components. The dominant contribution corresponds to ω=ωL: it is related to the diffused photons (e.g untagged), that have not experienced the effect of ultrasound. The photons associated to the sidebands, much more scarce, result from the interaction between light and the US; they are called tagged photons.

The principle of acousto-optics imaging stands as follows: in order to obtain optical information about the region of interest, one has to detect selectively the photons tagged by the ultrasound. The image is built-up by scanning the US over the organ. Conveniently, such a scan is already done along one direction when an ultrasonic pulse is used: the small vibrating region moves at the sound velocity and thus the choice of the temporal window of detection determines the position of the acoustic zone at this time (the propagation time of light is negligible even for random paths that reach up to ten times the sample thickness).

As a consequence, the small zone affected by the US can be viewed as a source of tagged photons, thus a small virtual source that explores the medium and moves at the ultrasound velocity. Supposed we detect the tagged photons at different times t1, t2 . the insonified region is located respectively at R1, R2, …, whose position is calculated from the velocity of sound in the medium (e.g 1500 m.s−1 for water), as shown in Fig.2. At t=t1, the photons from zone R1 reaches the detector. The flux coming from this region depends essentially on optical properties of the medium; the more it absorbs, the weaker is the signal. Optical absorption generally has a spectral dependence. If measurements are done at many wavelengths, one can determine the nature of tissues and thus properties that are interesting from a medical point of view, such as the vascularization level or the degree of oxydation of hemoglobin.

Fig. 2 Axial localization of the acousto-optic signal with an ultrasonic pulse.

3. PHOTONS SELECTED BY INTERFERENCES

How is it possible to select the tagged photons from those that have not crossed the ultrasonic volume? Since the US frequency is very small compared to the optical one (a few 10⁶Hz compared to 3.10¹³Hz), the frequency difference between the three components is too small to be separated with an optical filter. The solution is then to analyze the speckle pattern produced by each of these fields, which are not correlated. One possibility is to measure on a CCD camera the interference between the signal and a reference beam at frequency ωL+ωUS: since such detectors have a long response time, only the tagged photons at ωL+ ωUS will be able to produce an interference signal stable enough to be detected. The other interference terms vary too fast for the CCD, and the latter can only record their average flux. In other words, the speckle that corresponds to frequencies other than ωL+ ωUS are blurred. The CCD camera is an ensemble of micro-detectors (pixels); in order to avoid averaging effects due to the speckle, the optical conjugation is adjusted so that a speckle grain matches the size of a single pixel of the camera. In these experiments, the CCD does not provide an ordinary image, but is considered as a multi-detector matrix, and thus improves the signal to noise ratio.

In the experimental setup, a laser source (frequency ωL) is divided into two beams (see Fig.3). One of the beam illuminates the sample that is subjected to the ultrasound. The second one (reference beam) is shifted in frequency with acousto-optic modulators such that its frequency equals one class of the tagged photons, e.g ωL+ ωUS or ωL− ωUS. A second beamsplitter recombines on the CCD the reference beam and the photons coming from the sample in order to measure the interference pattern. The summation of the intensities measured on each pixel gives the flux of the tagged photons. In fact, such a setup can give more information than the flux because it records the interference pattern at a time on all the pixels of the CCD, and this for different phase states of the reference: such a configuration determines entirely the amplitude and the phase of the optical field. The richness of this information permits to filter the noise components and thus control the quality of measurements.

Fig. 3 Interferometric selection of the tagged-photons.

4. A FASTER DETECTION WITH SELF-ADAPTIVE WAVEFRONT HOLOGRAPHY

The use of CCD cameras can be puzzling, depending on experimental situations. The amount of information required to realize an image is significant (more than a GB). The transfer of data and their treatment can be time consuming, which is prohibited if real-time measurement is required. An even more fundamental difficulty is due to in vivo motions of tissues, or blood circulation, because the fast variation of the phase of the photons blurs the speckle field on a time-scales between 0.1-1ms. This phenomenon is generally called speckle decorrelation, and an acquisition time longer than this decorrelation reduces the signal to noise ratio of the detection. Under these conditions, the use of CCD’s is not always appropriate, because acquisition rates hardly exceed a few kHz, the holographic technique that we develop gets rid of the camera and uses a single-element detector with a large area of 1cm², but still with a fast response. An efficient flux collection and a fast acquisition are thus possible. This technique has initially been used to characterize vibrational modes on rough surfaces; we have adapted it for acousto-optics imagery (Delaye, et al., 2000; Campagne, et al., 2001).

As in the previous setup, the laser frequency is shifted in order to produce a reference beam with the same frequency as the tagged photons. The object beam (speckle) and the reference beam are then recombined in a photorefractive crystal (see Fig.4). In such materials, the refractive index varies from one point to another as a function of the local light intensity (Yeh). The interference pattern of the two waves is recorded within the volume of the crystal via the spatial modulation of the refractive index, and thus a hologram is built. As the crystal takes a time of about 1/10ms to build a hologram, it records selectively the hologram of the tagged photons, whose temporal variation is slow.

Fig. 4 Principle of self-adaptive wavefront holography.

The signal is extracted as followings: as in conventional holography, the reference is diffracted by the hologram, and produces in output a wave that is the exact replica (amplitude and phase) of the object wave coming from the tagged photons: at the output of the photorefractive crystal stand two waves closely related. Their interference produces a signal that is detectable with a mono-element detector, in real-time. This configuration has the advantage to be rapid, relatively cheap, and requiring a limited data treatment, since a single position of the ultrasound requires a single measurement.

5. CONCLUSION

Another approach, somewhat inverse to the acousto-optic imagery, is based on the photo-acoustic effect. In this mode, a short laser pulse (e.g 1ns) is emitted and propagates through the scattering tissue. The light produces a local heating at position where it is absorbed. This heating generates a pressure wave, or rather a shock wave, that propagates in all directions at the velocity of sound. The detection of the acoustic signal created by the laser pulse is detected with many ultrasonic transducers positioned close to the region of interest and it is possible to construct a photo-acoustic image of the optical absorption of the tissue (Wang, 2003–2004). Photo-acoustic techniques appear to be promising, especially for imaging small animals, a situation where the thickness of organs is reduced. In addition, the photo-acoustic signal can be used to simulate non invasively a local acoustic emitter, dedicated to hyperthermal therapy using a phase conjugate acoustic technique.

Which images can be obtained with acousto-optic methods? The technique needs further improvements, and first images are of low details compared to the ones obtained by X-rays tomographies or MRI. Up to now the aim was to establish the feasibility of the principle and to evaluate its potential. We have performed tomographic images on phantoms models approaching the optical properties of human tissues (e.g turkey breast or calibrated scattering gels of thicknesses in the range of 2−4cm containing absorbing inclusions). One of the experiments consisted of a turkey breast of which a region has been overheated by an intense ultrasonic beam (hyperthermal therapy). The acousto-optic image, obtained with a few hundreds of points, reveals clearly the heated zone (Fig. 5).

Fig. 5 Evidence of an acousto-optic contrast after hyperthermal heating.

Though the acousto-optic method has been shown feasable, much work remains to be done in order to obtain images suited for medical diagnosis. Some clinical tests will be undertaken in the next months on female breasts, an organ well suited for this technique. The technique can be improved in many ways can be brought to the technique, for example by automation of the data acquisition, but one of main the difficulties remains the weakness of the signal. If coupled however, with other imagery techniques, acousto-optic tomography should reveal itself as useful to diagnosis as it gives access to information on the optical properties of tissues (color, absorption and scattering coefficient), which is impossible to obtain with X-rays, echography or MRI imaging techniques.

Seeing through highly scattering media such as biological tissues is still a goal difficult to reach. The main reason being that the scattering is heterogeneous which makes the inverse problem very complex. Here we have tried to demonstrate that coupling light and ultrasound can help to bypass the problems raised by purely optical techniques: we hope soon to be able to reveal in vivo optical contrasts with ultrasonic resolution though a few cm thick tissues.

ACKNOWLEDGEMENTS

This work is currently supported by a grant from the project Cancéropôle Ile-de-France.

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IMPROVEMENT OF THE CONTRAST IN CANCER DETECTION BY AUTOFLUORESCENCE BRONCHOSCOPY USING A NARROW SPECTRAL VIOLET EXCITATION: A PRELIMINARY STUDY

Blaise Lovisa¹, Tanja Gabrecht¹, Snezana Andrejevic², Pierre Grosjean², Alexandre Radu², Philippe Monnier², Bernd-Claus Weber³, Hubert van den Bergh¹ and Georges Wagnières*¹,     ¹Swiss Federal Institute of Technology (EPFL), Laboratory of Photomedicine, 1015 Lausanne, Switzerland; ²The CHUV University Hospital, ENT Department, CH-1011 Lausanne, Switzerland; ³Richard Wolf Endoscopes GmbH, D-75438 Knittlingen, Germany. E-mail address: georges.wagnieres@epfl.ch

Abstract

Autofluorescence (AF) bronchoscopy is a useful tool for early cancer detection. However the mechanisms involved in this diagnosis procedure are poorly understood. We present a clinical autofluorescence imaging study to assess the depth of the principal contrast mechanisms within the bronchial tissue comparing a narrowband (superficial) and broadband (penetrating) violet excitation. Knowledge of this parameter is crucial for the optimization of the spectral and optical design of clinical diagnostic AF imaging devices. An intensity contrast improvement was observed with the narrowband excitation, suggesting that the heme absorption plays a key role in the AF contrast mechanism. Copyright © 2006 IFAC

Keywords

medical systems

intensity contrast enhancement

autofluorescence imaging

bronchial cancer

clinical study

1. INTRODUCTION

Bronchial carcinoma is the leading cause of cancer deaths in the world with the highest incidence rate in North America and Europe. Most of the lesions are diagnosed at an advanced stage, which explains the very small 5-years survival rate corresponding to this condition (Jemal, et al., 2004). Thus, improved techniques for detection of early lesions are urgently needed. Bronchoscopy is the only established method that allows detection, localization and definitive histological diagnosis of endobronchial lesions.

Conventional white-light bronchoscopy (WLB) has nevertheless important diagnostic limitation; the most important being its small sensitivity for early cancerous and pre-cancerous lesions (Hirsch, et al., 2001). Therefore, one promising approach to overcome this limitation is based on the imaging of the tissue autofluorescence (AF) (Goujon, et al., 2003; Wagnières, et al., 2003). While WLB detects mostly minimal alterations of the tissues, autofluorescence bronchoscopy (AFB) exploits the spectral differences and intensity contrasts between normal and early cancerous tissues. More precisely, the spectral contrast in AFB is based on the decrease in the green spectral region of the tissue AF intensity of the spectrum for (pre-)cancerous lesions compared to healthy tissue under violet excitation (Hung, et al., 1991;Wagnières, et al., 2003;Zellweger, et al., 2001b). Such contrasts can be visualized with the help of specific endoscopic imaging devices (Wagnières, et al., 1998).

Numerous clinical studies have demonstrated that AFB is about twice more sensitive than WLB for the detection of bronchial CIS and dysplasia (Goujon, et al., 2003;Häuβinger, et al., 2005;Lam, et al., 1998;Pierard, et al., 2001;Sutedja, et al., 2001;Wagnières, et al., 2003). However, this high sensitivity comes along with a limited specificity (Wagnières, et al., 2003). Although the mechanisms underlying the tumor/healthy contrasts are poorly understood at the present time, it is likely that the decrease of hemoglobin concentration in the submucosa plays a significant role. This statement is supported by the study reported by (Zellweger, et al., 2001b). In an extensive spectral study of the bronchial tissue AF, it demonstrated that the best contrasts between healthy and (pre-)malignant tissues on one hand, and meta- and hyperplasia vs. (pre-) malignant lesions on the other hand, are observed with an excitation spectral domain much smaller (410nm, FWHM 3nm), than usually used in AFB (typically 430nm, FWHM 40nm). Therefore, the preliminary study described here aims to investigate the influence of the excitation spectrum bandwidth on the contrast with imaging AFB. More precisely, we report the contrast improvement between a broadband filtered light source from the DAFE system (Richard Wolf Endoscopes GmbH, Germany) and a line shape excitation from a Krypton laser.

2. MATERIALS AND METHODS

2.1 Imaging System

In this study, we compared AF images obtained with a broad- and a narrowband excitation light source, as illustrated schematically in Figure 1.

Fig. 1 The fluorescence imaging setup consisting of a filtered endoscopic light source and a filtered endoscopic camera. Light from the Kr+ laser can be coupled into the endoscope instead of the light from the endoscopic light.

The diagnostic autofluorescence endoscopic imaging system (DAFE) basically consists of a filtered endoscopic light source and a camera driver unit. An IR filtered 300W Xenon lamp (Richard Wolf Endoscopes GmbH, Germany) was used as a broadband excitation source. It is equipped with a flip-flop filter holder, allowing the operator to switch easily between white and violet excitation light, this light being delivered to the bronchoscope optics via a liquid light guide. The violet excitation filter has a central transmission wavelength at 430nm with a FWHM of 40nm.

Light from a Krypton (Kr+) laser (Spectra Physics Type 171) was used as the narrowband excitation. This light was injected into a 400μm optical quartz fiber and coupled into the liquid light guide mentioned above using a custom made fiber coupler. The latter allows the operator to change the injection angle, which can be useful to homogenize the illumination on the bronchi. The Kr+ laser was used in the multi-line mode (407nm, 413nm) with a maximal output power of 2.5W. However, due to the limited transmission of the light guide, the power of the violet light was about 150 mW with both excitation sources.

The white light and the AF images are detected in both setups by a 3 CCD endoscopic camera (Richard Wolf Endoscopes GmbH, Germany) clipped to the endoscopic optics. The zoom objective of the camera was equipped with a 475nm cut-on long pass filter, in order to reject all violet excitation light. The system can be used with conventional rigid optics or fibro-endoscope. The images are visualized on a monitor and tape- recorded on a digital video (DV) recorder.

2.2 Endoscopic procedure

All 3 patients participating in the study had known bronchial lesions which had been identified previously by AF bronchoscopy with the DAFE system in a former examination. The lesions were first examined under conventional white light (WL) illumination, and then with the broadband DAFE excitation. Eventually, the DAFE light source was replaced by the Krypton laser, and the same lesions were examined. At the end of each site observation, one biopsy per site was taken to perform a histopathological analysis of the site. All the examinations were performed under total anesthesia using rigid optics. The whole procedure was captured by the endoscopic camera and tape-recorded on the DV recorder.

2.3 Image analysis

Image analysis was performed offline in order to compute the green channel intensity ratio between the lesion and the surrounding healthy tissue. Still images from the DV recording were digitized via the IEEE1394 port of a portable PC. Several analysis zones (typically 3) were selected per biopsied site to accommodate the geometry artifacts resulting from different angles of view, distance between probe and tissue and position of the endoscope within the bronchi. Zones were classified according to their visual appearance on the image. Selection criteria for a lesion were an AF+ zone in the region of the later-taken biopsy and presence of no blood, whereas a healthy lesions has no suspect appearance. All the pixels intensity values were background-subtracted and gamma-corrected. The resulting green-to-green ratio is given by (Gt /Gh) = (Gtumor) / (Ghealthy). Consequently, a high contrast between a lesion and healthy tissue is associated with a small ratio.

Suspect sites under violet excitation were classified as autofluorescence positive (AF+), whereas unsuspicious sites were labeled AF–. According to (Gabrecht, et al., 2005a), the errors related to this image analysis procedure were estimated by computing and comparing the intensity level values and ratios from multiple AF+ and AF- zones selected arbitrarily within a sample image. They were in the order of ±10% for the intensity and ±20% for the intensity ratios. The errors related to the image analysis procedure

3. RESULTS

Three patients undergoing pre-therapeutic or therapeutic panendoscopy were included in the study. A total of 3 positive lesions were examined alternatively with the broadband and the narrowband excitation. Each lesion was AF+ in both excitation modes, but hardly visible under WL illumination. Two biopsies (1 and 3) were graded as CIS, and biopsy 2 was graded as severe dysplasia.

3.1 Visual results

Figure 2 depicts the green channel images of the AF images obtained with the broadband (DAFE) and line-shape (Kr+) excitation light. It shows two lesions on the spur and the inner wall of the intermediate bronchus. A distinct intensity decrease (i.e. contrast) in the lesion areas compared to the normal surrounding tissues is clearly distinguishable. For each site, the intensity decrease of the green AF is more marked with the Kr+ laser than with the broadband excitation.

Fig. 2 Green color channel of an image showing the intermediate bronchus excited with the broadband (DAFE) and the narrowband (Kr+) excitations. Arrows show a pre-cancerous lesion with sharp intensity decrease.

3.2 Image analysis

Figure 3 shows the mean Gt /Gh ratios obtained on the tree. The hatched bars show the mean Gt /Gh ratios per site obtained with the broadband (DAFE) excitation source, while the plain bars show ratios obtained with the line-shape (Kr+) excitation source. The error bars represent the 20% error resulting from the image analysis as described above. The ratios of the Gt /Gh compared between DAFE and the Kr+ excitations for the sites 1, 2 and 3 are 1.7, 1.1 and 1.4, respectively.

Fig. 3 Tumor vs. Healthy Tissue Intensity Contrast of the Green Autofluorescence excited with the DAFE or Krypton (Kr+) laser sources. The errors bars show the error resulting from the image analysis procedure (±20%).

4. DISCUSSION AND CONCLUSION

Over the past years, endoscopic autofluorescence imaging has been shown to be a powerful and highly sensitive tool for the detection of early cancerous lesions in the bronchi. Nevertheless, the mechanisms underlying the contrasts remain poorly understood. Investigating and understanding the origin of the contrast between (pre)neoplastic and healthy tissue will allow an optimization of the available devices. Spectrofluorometric in vivo studies conducted by (Qu, et al., 1995) and (Zellweger, et al., 2001a; Zellweger, et al., 2001b) have shown a sharp intensity decrease in the green part of the AF spectrum on tumoral lesions relative to normal tissues. These results are also in good agreement with the Gt /Gh ratios computed in our study, which are smaller than 1. As shown inFigure 3, our preliminary study suggests that a better intensity contrast between healthy tissues and lesions is achieved with the narrowband excitation. Indeed, the average Gt /Gh ratio is 1.4 ± 0.3. This is in reasonable agreement with the mean ratios adapted from Zellweger’s data (Gt /Gh =1.6).

Since only the ratio of the green AF was computed, we can not assess whether the spectral contrast is modified by the bandwidth. However, as suggested by (Gabrecht, et al., 2005b), the bandwidth of the excitation light has no detectable influence on the spectral contrast, i.e. the intensity ratio between the red and green channels.

The better contrasts obtained with the narrowband excitation suggests that the concentration of blood in the tissue can be regarded as a key factor underlying these contrast mechanisms. Indeed, the Kr+ laser light is centered on 410nm, which corresponds to the absorption peak of hemoglobin. The morphometric studies from (Fisseler-Eckhoff, et al., 1996) and (Fontanini, et al., 1999) showed an increase in the microvessel density (MVD) in the (pre)neoplastic bronchial tissues, the increase of MVD preferentially occuring in the vicinity of the basement membrane. Hence, the blood concentration is higher in/under the abnormal tissue than in its healthy surrounding tissue. Due to the light absorption properties of blood, the Kr+ excitation light will be strongly absorbed by the tissue blood in the superior layers of the submucosa. Moreover, the tissue blood in the submucosa shields the AF from detection at the tissue surface. This shielding effect is more important in (pre)neoplastic than in normal tissue and will consequently result in an additional amplification of the intensity contrast.

In conclusion, our results suggest that the tumor to healthy contrast can be improved using an excitation corresponding to the hemoglobin absoption peak. In addition, these results support the conclusions derived by Zellweger et al. (2001b) andGabrecht et al. (2005b) regarding the tumor to healthy intensity and spectral contrasts.

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