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Spectral optimization of the detection and characterization of early superficial carcinoma in the bladder by endoscopic fluorescence imaging and high magnification endoscopy.

English title Spectral optimization of the detection and characterization of early superficial carcinoma in the bladder by endoscopic fluorescence imaging and high magnification endoscopy.
Applicant Wagnières Georges
Number 128677
Funding scheme R'EQUIP
Research institution Institut des sciences et ingénierie chimiques EPFL - SB - ISIC
Institution of higher education EPF Lausanne - EPFL
Main discipline Other disciplines of Physics
Start/End 01.05.2010 - 31.07.2013
Approved amount 221'656.00
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All Disciplines (2)

Discipline
Other disciplines of Physics
Experimental Cancer Research

Keywords (11)

Fluorescence cystoscopy; Bladder cancer photodetection; Magnification endoscopy; Vasculature visualization; Fluorescence excitation spectroscopy; Tissue optical spectroscopy; Endoscopic fluorescence imaging; cancer photodetection; cancer characterization; bladder cancer; spectral optimization

Lay Summary (English)

Lead
Lay summary
BackgroundThe detection and quantitative removal of early bladder cancer by endoscopic fluorescence imaging represents a significant advance in the field of oncology. This procedure, that was to a large extent developed by our group, consists of filling the bladder during one hour or less with 50 ml of a solution called Hexvix® (Cysview® in the USA). This formulation induces the selective production of fluorescing molecules such as protoporphyrin IX (PpIX) in early stage bladder cancers, including those flat "in situ" lesions that are very difficult to detect by classical white light cystoscopy. Illuminating the bladder wall with violet light causes the cancers to light up in the red. However, other tissue abnormalities, such as inflammation, can induce false-positives. We have recently demonstrated that the visualization of the "micro"-vascularisation by high magnification cystoscopy (HMC) can help to distinguish between true and false positives. This approach is promising, but the spectral characteristics of the excitation/illumination sources used for this HMC procedure remain to be optimized. Similarly, the spectral characteristics of the excitation light used to induce the red fluorescence of the early bladder cancers have never been optimized. The latter is relevant because the fluorescence excitation maximum of PPIX partially overlaps with the strong absorption peak of the hemoglobin in the tissue and in the liquid filling the bladder. Therefore, finding the optimal wavelength for this cancer detection procedure is not trivial and requires investigating the bladder under an illumination provided by a "powerful" and continuous laser that can be continuously tuned between 370 and 460 nm.Aim-To determine the spectral domain of the PpIX excitation light producing the best tumor/normal tissue contrast and brightness during fluorescence cystoscopy with Hexvix®.-To perform a spectral optimization of the characterization of early superficial carcinoma in the bladder by high magnification endoscopy.SignificanceBladder cancer is the sixth most common cancer worldwide with approximately 200,000 new patients diagnosed annually. It is estimated that approximately $ 2.9 billion is spent in the United States each year on the treatment of bladder cancer. A significant part of these expenses is used for the approximately 4 millions cystoscopies that are performed in the US and Europe every year. The socio-economic impact of the planned research is very high since it has the potential to improve the performance of fluorescence cystoscopy, reduce the number of biopsies, as well as to improve the complete resection of the these early cancers.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Publications

Publication
Study of the influence of over-the-counter vitamin supplement intake on urine fluorescence to optimize cancer detection by fluorescence cystoscopy
Zellweger M. Martoccia C. Mengin M. Iselin C. Bergh H.v.D. Wagnières G. (2015), Study of the influence of over-the-counter vitamin supplement intake on urine fluorescence to optimize cancer detection by fluorescence cystoscopy, in Journal of Biomedical Optics, 20(6), 1/066011-5.
Detection of Bladder Cancer by Fluorescence Cystoscopy: From Bench to Bedside - the Hexvix Story
Wagnières G. Jichlinski P. Lange N. Kucera P. van den Bergh H. (2014), Detection of Bladder Cancer by Fluorescence Cystoscopy: From Bench to Bedside - the Hexvix Story, in M. R. Hamblin Y.-Y. Huang (ed.), CRC Press (Taylor & Francis), UK, 411-426.
Optical spectroscopy of the bladder washout fluid to optimize fluorescence cystoscopy with Hexvix®
Martoccia C. Zellweger M. Lovisa B. Jichlinski P. van Den Bergh H. Wagnières G. (2014), Optical spectroscopy of the bladder washout fluid to optimize fluorescence cystoscopy with Hexvix®, in Journal of Biomedical Optics, 19(9), 1/097002-6.
Near-Infrared 808 nm light boosts Complex IV-dependent respiration and rescues a Parkinson-related pink1 model
M. Vos B. Lovisa A. Geens V. A. Morais G. Wagnières H. van den Bergh A. Ginggen B. De Stroope (2013), Near-Infrared 808 nm light boosts Complex IV-dependent respiration and rescues a Parkinson-related pink1 model, in PLOS ONE, 8(11), 1-9.
Fluorescence of the bladder washout fluid following cystoscopy : a preliminary study
Lovisa B. Novello A.-M. Jichlinski P. van den Bergh H. Wagnières G. (2010), Fluorescence of the bladder washout fluid following cystoscopy : a preliminary study, in Proceeding SPIE, (7548B), 1-6.
High-magnification vascular imaging to reject false-positive sites in situ during Hexvix® fluorescence cystoscopy
Lovisa B. Jichlinski P. Weber B.-C. Aymon D. Van Den Bergh H. Wagnières G. (2010), High-magnification vascular imaging to reject false-positive sites in situ during Hexvix® fluorescence cystoscopy, in Journal of Biomedical Optics, 15(5), 1/051606-8.
PDT of non-muscle-invasive bladder cancer with Hexylester Aminolevulinate: optimization of the illumination wavelengths by fluorescence spectroscopy and imaging
Zellweger M. Porret C.-A. Lange N. Jichlinski P. van den Bergh H. Wagnières G., PDT of non-muscle-invasive bladder cancer with Hexylester Aminolevulinate: optimization of the illumination wavelengths by fluorescence spectroscopy and imaging, in Imaging in Phototherapy, 19.

Collaboration

Group / person Country
Types of collaboration
P. J. Safarik University, Kosice Slovakia (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel
Prof. P. Jichlinski, Urology Unit, CHUV University Hospital of Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
VIB Center for the Biology of Disease, Leuven Belgium (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
CTI Medtech Event Poster Implantable photo-stimulation system for the treatment of Parkinson's disease 27.08.2013 Bern, Switzerland Wagnières Georges;


Awards

Title Year
Research grant provided by the Program SCIEX for Dr. V. Huntosova. 2011

Associated projects

Number Title Start Funding scheme
116556 Improvement of cancer detection and photodynamic therapy based on the use of protoporphyrin IX precursors 01.04.2007 Project funding (Div. I-III)

Abstract

The purpose of this proposal is the procurement of a continuously tunable (from the mid-UV to the NIR) monochromatic quasi-cw and powerful (several hundreds of mW) laser source. This light source will be used for several purpose, but mainly to determine the optimal spectral conditions for the detection and characterization of early superficial cancer in the bladder by a combination of endoscopic fluorescence imaging and high magnification (HM) endoscopy. The specific equipment requested here is essential to illuminate the bladder wall with a monochromatic tunable light in the clinics, in either the so-called “macroscopic fluorescence” or the “High Magnification (HM) reflectance” modes.The project proposed here addresses research fields in which the “Medical Photonics Group” of the EPFL has a significant track record and in which important progress has recently been made, i.e. the detection and characterization of superficial bladder carcinoma using fluorescence and HM imaging cystoscopy. This project will be based on the long-term and fruitful collaboration established between our group and the Urology Unit of the CHUV Lausanne's University Hospital directed by Prof. P. Jichlinski.Fluorescence cystoscopy represents one of the major recent advances in urology. Pioneering work by our group demonstrated that hexylaminolevulinate, a potent amphiphilic derivative of aminolevulinic acid (ALA) instilled in the bladder during one hour before the photodetection procedure, generates a selective production of protoporphyrin IX (PPIX) in the flat and early superficial cancers that are very difficult to find in classical white light cystoscopy. The resulting pharmaceutical product, Hexvix®, obtained an approval in Europe in March 2005 for cancer diagnostic applications in the bladder (see the attached FN press releases). Hexvix® enables the detection of early lesions with a very high sensitivity and a more complete resection of these lesions. However, other tissue abnormalities, such as inflammations, induce false-positives (FP), resulting in supplementary biopsies.Since early stage epithelial cancers are frequently already associated with angiogenesis, the observation of the resulting changes in the architecture of the blood vessels can be used to identify and reject FPs. Our group investigates this approach, the visualization of this vascularization being performed by HM white light endoscopy. Dedicated cystoscopes were developed for this purpose in the context of a project supported by the SNF (project number: 205320-116556). Observations in the bladder are performed with a rigid cystoscope, allowing conventional magnification during “macroscopic” observation, as well as image acquisition with HM when the cystoscope is in contact with the tissue. The resolution of the cystoscopic images is about 3 µm in the HM mode. A preliminary clinical exploratory study demonstrated that FP lesions never exhibit tortuous or disorganized vascular patterns, even though they may show increased vessel diameters, whereas such altered patterns are observed on 90% of the true positive sites. Our tests so far show these detection and characterization approaches to be quite promising, even though the spectral characteristics of the excitation/illumination sources used in these procedures remain to be optimized. No comprehensive study to optimize this spectroscopy has been reported up to now because this is not trivial to do clinically. In addition, the factors influencing the performances of the detection and characterization approaches described above are complex and multi-factorial, some key information (optical properties, including the “auto”-fluorescence, of the tissues and fluids filling the bladder at the excitation and detection wavelengths; geometry, etc.) being still unknown.The laser requested here for fluorescence cancer detection and HM cystoscopy will enable us to obtain the essential spectroscopic information for two distinct applications:I) To record fluorescence images generated by different illumination wavelengths (between 380 and 450 nm; every 5 nm) during Hexvix®-based cystoscopies. Since the tumor/normal tissue contrast, which is essential to detect the early cancers, is a complex function depending among others on the PPIX excitation yield, the tissue’s optical properties, as well as the fluorescing and absorbing substances, including the hemoglobin, contained in the liquid filling the bladder, only this type of empirical approach is relevant. This information is even more important, now that many light sources in endoscopy will be based on “narrow band (10 nm)” LEDs positioned at the distal end of the endoscope.II) To detect and record images obtained with different illumination wavelengths (between 380 and 650 nm; every 5 nm) during HM cystoscopies. Since the penetration of this light in the tissues significantly increases with the wavelength, mainly due to the absorption spectroscopy of hemoglobin, The use of different wavelengths will enable to visualize “small” superficial, or “larger” deep-seated vessels. In addition, the strong absorption of hemoglobin in the violet enables to visualize small superficial vessels, whereas larger, deep-seated vessels can be visualized with longer wavelengths. Since the type of vessels exhibiting the most reliable differences between true and false positives is unknown, the creation of an atlas of different vessel types observed at different wavelengths in tissues that are histopathologically characterized will enable to solve this problem. This second application presents similarities with the well known principle of narrow-band imaging (NBI), excepting that the most important novelty of our study is to combine this approach with HM endoscopy in the bladder.It is anticipated that typically 40 patients, recruited among patients subject to "routine" fluorescence cystoscopies at the CHUV Lausanne’s University Hospital (Prof. P. Jichlinski), will be involved in this study.In summary, the main objective of this project is to develop a novel, fast, convenient and cheap method to characterize fluorescence positive spots in situ during fluorescence cystoscopy. This will enable to fully tap the important potential of this cancer detection approach. Consequently, the economic/sociologic impacts of this project are very important since bladder cancer remains one of the leading cause of cancer related death in the western world. This project will also enable us to study the basic mechanisms taking place in the mucosa of the bladder wall, such as the proteomics and tissue morphology those that are responsible for the fluorescence tumor/normal tissue contrast. Finally, this project will also provide useful information regarding the physiological, biochemical and mechanistic issues associated with the (micro)vasculature of various conditions (cancer, inflammation, scars, etc.) perfusing the bladder mucosa, and thus possibly help to open new research fields, and novel cancer detection strategies.The laser source to be purchased will also be a unique platform for numerous other studies in the field of biomedical optics. Consequently, it will also be used by other groups at the EPFL (Prof. Ch. Depeursinge, for the characterization of lesions in the gastrointestinal tract and to study the brain cortex optical fluorescence; Prof. Y. Barrandon, in the field of photonics assisted stem cell therapy).Finally, It should be noted that no similar equipment exists in Switzerland. Consequently, the procurement of the requested equipment will significantly improve the position of the Swiss scientific community active in this field of biomedical optics.
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