Spectro-imagerie endoscopique d'autofluorescence et cartographie 2D pour la localisation et le diagnostic in situ de lésions cancéreuses

Spectro-imagerie endoscopique d'autofluorescence et cartographie 2D pour la localisation et le diagnostic in situ de lésions cancéreuses

Autofluorescence endoscopic spectro-imaging and 2D-cartography for in situ localisation and diagnosis of cancerous lesions

W. C. P. M. Blondel Ch. Daul  S. Villette  R. Miranda-Luna  Y. Hernandez-Mier  G. Bourg-Heckly  D.Wolf 

Nancy Université

CRAN UMR 7039 CNRS-INPL-UHP, 2 avenue de la forêt 54500 Vandœuvre - Lès-Nancy, France

BioMoCeTi UMR 7033 CNRS-UPMC – génopôle Campus 1, 5 rue Henri Desbruères, 91030 Evry Cedex

Corresponding Author Email: 
walter.blondel@ensem.inpl-nancy.fr
Page: 
213-233
|
Received: 
8 July 2005
|
Accepted: 
N/A
|
Published: 
31 August 2006
| Citation

OPEN ACCESS

Abstract: 

Early diagnosis is the most efficient way to struggle against cancer. Among all the existing techniques, optical methods (photodiagnosis from NUV to NIR) show important characteristics required by the physicians: high sensitivity, non-ionising radiations and non-traumatic measurements. They are particularly well suited to the detection of cancers in hollow organs, that are usually superficial and hardly visible with classical endoscopy. This paper describes a methodological approach based on the use of tissue autofluorescence, applicable in clinical endoscopy, and leading to the definition of diagnosis indicators from the spectral parameters. Following a state-of-the-art on autofluorescence spectroscopic (LIFS) and endoscopic imaging methods, we present the efficiency of fibered LIFS in terms of sensitivity and specificity for the diagnosis of esophagus cancerous lesions (clinical study over 25 patients). We then present the technological characteristics of an autofluorescence endoscopic imaging prototype developed in our labs as well as its calibration. A second part is devoted to endoscopic image registration and mosaicing and to optics aberration correction in perspective of the automatic construction of a panoramic image (cartography) of the organ’s explored areas. Finally, exploiting the fluorescence data provided by the imager, the feasibility of the superimposition of spatial and spectral information is validated with a phantom.

Résumé

Le diagnostic précoce est le moyen le plus efficace de lutte contre le cancer. Parmi toutes les techniques possibles, les méthodes optiques (photodiagnostic du proche UV au proche IR) présentent des caractéristiques importantes recherchées par les médecins: grande sensibilité, radiations non ionisantes et mesures atraumatiques. Elles sont particulièrement bien adaptées à la détection des cancers des organes creux, par nature superficiels et difficilement décelables en endoscopie classique. Cet article décrit une approche méthodologique fondée sur l’exploitation de l’autofluorescence tissulaire, applicable en endoscopie clinique, et conduisant à l’élaboration d’indicateurs diagnostiques issus des paramètres spectraux. Après un état de l’art sur les méthodes spectroscopiques (LIFS) et d’imagerie endoscopique d’autofluorescence, nous montrons l’efficacité de la LIFS fibrée en terme de sensibilité et de spécificité pour le diagnostic de lésions cancéreuses de l’œsophage (étude clinique sur 25 patients). Nous présentons ensuite les caractéristiques technologiques et le calibrage du prototype d’imageur endoscopique d’autofluorescence développé. Une seconde partie traite du pré-traitement, du recalage et du mosaïquage des images endoscopiques appliqués à la construction automatique d’une image panoramique (cartographie) à partir de séquences vidéos des zones explorées de l’organe. Finalement, en exploitant les informations de fluorescence fournies par l’imageur, la faisabilité d’une superposition des informations spatiale et spectrale est validée sur fantôme.

Keywords: 

In vivo Spectroscopy, endoscopic image registration and pre-processing, mosaicing, autofluorescence, instrumentation, cancer

Mots clés

Spectroscopie in vivo, pré-traitement et recalage d’images endoscopiques, mosaïquage, autofluorescence, instrumentation, cancer

1. Introduction
2. État De L’art
3. Spectroscopie D’autofluorescence
4.Cartographie Endoscopique Multi-Bandes
5. Conclusions Et Perspectives
  References

[Anidjar] M. ANIDJAR, D. ETTORI, O. CUSSENOT, P. MERIA, F. DESGRANDCHAMPS, A. CORTESSE, P. TEILLAC, A. LE DUC, S. AVRILLIER “Laser induced autofluorescence diagnosis of bladder tumors: dependence on the excitation wavelength”, The Journal of Urology, Vol. 156, 1996, p.1590-1596.

[Asari] K. ASARI, S. KUMAR, R. RADHAKRISHNAN “A new approach for nonlinear distortion correction in endoscopic images based on least squares estimation”, IEEE Transactions on Medical Imaging, Vol. 18, 1999, p. 345-354.

[Backman] V. BACKMAN, M. WALLACE, L. PERELMAN, J. ARENDT, R. GURJAR, M. MULLER, Q. ZHANG, G. ZONIOS, E. KLINE, T. McGILLICAN, S. SHAPSHAY, T. VALDEZ, K. BADIZADEGAN, J. CRAWFORD, M. FITZMAURICE, S. KABANI, H. LEVIN, M. SEILER, R. DASARI, I. ITZKAN, J. VAN DAM, M. FELD “Detection of preinvasive cancer cells”, Nature, Vol. 406, 2000, p. 35-36.

[Bansal] R. BANSAL, L. H. STAIB, Z. CHEN, A RANGARAJAN, J. KRISELY, R. NATH, J. S. DUNCAN “Entropy-based, multipleportal-to-3DCT registration for prostate radiotherapy using iteratively estimated segmentation”, In Proceedings of the medical image computing and computer assisted intervention (MICCAI'99), Vol. 1679, Cambridge, Massachusetts, USA, 19-22 september 1999, p.378-389.

[Benavides] J.M. BENAVIDES, S. CHANG, S.Y. PARK, R. RICHARDSKORTUM, N. MACKINNON, C. MACAULAY, A. MILBOURNE, A.MALPICA, M. FOLLEN “Multispectral digital colposcopy for in vivo detection of cervical cancer”, Optics Express, Vol. 11, #10, 2003, p.1223-1236.

[Bergman] J. BERGMAN, M. KARA, M. SMITS, W. ROSMOLEN, T. KATE, G. TYTGAT “A randomised cross-over study comparing light-induced fluorescence endoscopy (LIFE) with standard endoscopy for detection of early neoplasia in Barrett’s esophagus (BE)”, Gastroenterology, Vol. 124(suppl1), 2003, p.A-49.

[Bigio] I.J. BIGIO, J.R. MOURANT “Ultraviolet and visible spectroscopies for tissue diagnostics: fluorescence spectroscopy and elasticscattering spectroscopy”, Physics in Medicine and Biology, Vol. 42, 1997, p.803-814.

[Bourg-Heckly] G. BOURG-HECKLY, J. BLAIS, J.J. PADILLA, O. BOURDON, J. ETIENNE, F. GUILLEMIN, L. LAFAY“Endoscopic ultraviolet-induced autofluorescence spectroscopy of the esophagus: tissue characterization and potential for early cancer diagnosis”, Endoscopy, Vol. 32, 2000, p.756-765.

[Brewer] M. BREWER, U. UTZINGER, E. SILVA, D. GERSHENSON, R. BAST, M. FOLLEN, R. RICHARDS-KORTUM “Fluorescence Spectroscopy for In Vivo Characterization of Ovarian Tissue”, Laser in Surgery and Medicine, Vol. 29, 2001, p.128-135.

[Can] A. CAN, C. V. STEWARD, B. ROYSAM “Robust hierarchical algorithm for constructing a mosaic of images of the curved retina”, IEEE Computer Society Conference on Computer Vision and Pattern Recognition, Fort Collins, Colorado, USA, June 1999, p.286-292.

[Chang] S. CHANG, M. FOLLEN, M. MALPICA, U. UTZINGER, G. STAERKEL, D. COX, E. ATKINSON, C. MACAULAY, R. RICHARDS-KORTUM “Optimal Excitation Wavelengths for Discrimination of Cervical Neoplasia”, IEEE Transactions on Biomedical Engineering, Vol. 49, #10, 2002, p. 1102-1111.

[Chou] J. S. CHOU, J. QIAN, Z. WU, H. SCHRAMM “Automatic mosaic and display from a sequence of peripheral angiographic images”, Proceedings of the SPIE Medical Imaging : Image Processing, Newport Beach, CA, USA, Vol. 3034, april 1997, p. 1077-1087.

[Coghlan] L. COGHLAN, U. UTZINGER, R. DREZEK, D. HEINTZELMAN, A. ZULUAGA, C. BROOKER, R. RICHARDS-KORTUM, I. GIMENEZ-CONTI, M. FOLLEN “Optimal fluorescence excitation wavelengths for detection of squamous intra-epithelial neoplasia : results from an animal model”, Optics express, Vol. 7, #12, 2000, p. 436-446.

[Demos] S.G. DEMOS, R. GANDOUR-EDWARDS, R. RAMSAMOOJ, R. DEVERE WHITE “Spectroscopic detection of bladder cancer using near-infrared imaging techniques”, Journal of Biomedical Optics, Vol. 9, #4, 2004, p. 767-771.

[Drezek] R. DREZEK, K. SOKOLOV, U. UTZINGER, I. BOIKO, A. MALPICA, M. FOLLEN, R. RICHARDS KORTUM“Understanding the contribution of NAD(P)H and collagen to cervical tissue fluorescence spectra: Modeling, measurement, and implications”, Journal of Biomedical Optics, Vol. 6, #4, 2001, p. 385-396.

[Ferris] D.G. FERRIS, R.A. LAWHEAD, E.D. DICKMAN, N. HOLTZAPPLE, J. MILLER, S. GROGAN, S. BAMBOT, A. AGRAWAL, M. FAUPEL “Multimodal Hyperspectral Imaging for the Noninvasive Diagnosis of CervicalNeoplasia”, Journal of Lower tract Disease, Vol. 5, #2, 2001, p. 65-72.

[Georgakoudi-01] I. GEORGAKOUDI, B. JACOBSON, J. VAN DAM, V. BACKMAN, M. WALLACE, M. MULLER, Q. ZHANG, K. BADIZADEGAN, D. SUN, G. THOMAS, L. PERELMAN, M. FELD“Fluorescence, reflectance, and light-scattering spectroscopy for evaluating dysplasia in patients with Barrett’s esophagus”, Journal of Lower tract Disease, Vol. 5, #2, 2001, p. 65-72.

[Georgakoudi-02] I. GEORGAKOUDI, B. JACOBSON, M. MULLER, E. SHEETS, K. BADIZADEGAN, D. CARR-LOCKE, C. CRUM, C. BOONE, R. DASARI, J. VAN DAM, M. FELD “NAD(P)H and collagen as in vivo quantitative fluorescent biomarkers of epithelial precancerous changes”, Cancer Research, Vol. 62, 2002, p. 682-687.

[Goujon] D. GOUJON, M. ZELLWEGER, A. RADU, P. GROSJEAN, B.C. WEBER, H. VAN DEN BERGH, P. MONNIER, G. WAGNIERES“In vivo autofluorescence imaging of early cancers in the human tracheobronchial tree with a spectrally optimised system”, Journal of Biomedical Optics, Vol. 8, #1, 2003, p. 17-25.

[Haringsma] J. HARINGSMA, G. TYGTAT, H. YANO, H. LISHI, M. TATSUTA, T. OGIHARA, H. WATANABE, N. SATO, N. MARCON, B. WILSON, R. CLINE “Autofluorescence endoscopy: feasibility of detection of GI neaplasms unapparent to white light endoscopy with an evolving technology”, Gastrointestinal Endoscopy, Vol. 53, #6, 2001, p. 642-650.

[Haussinger] K. HAUSSINGER, F. STANZEL, R.M. HUBER, J. PICHLER, H. STEPP “Autofluorescence Detection of Bronchial Tumors with the D-Light/AF”, Diagnostic and therapeutic Endoscopy, Vol. 5, 1999, p. 105-112.

[Heintzelman] L.D. HEINTZELMAN, U. UTZINGER, H. FUCHS, A. ZULUAGA, K. GOSSAGE, A. GILLENWATER, R. JACOB, B. KEMP, R. RICHARDS-KORTUM “Optimal excitation wavelengths for in vivo detection of oral neoplasia using fluorescence spectroscopy”, Photochemistry and Photobiology, Vol. 72, #1, 2000, p. 103-113.

[Helferty] J.P. HELFERTY, C. ZHANG, G. MACLENNAN, W.E. HIGGINS “Videoendoscopic distortion correction and its application to virtual guidance of endoscopy,” IEEE Transactions in Medical Imaging, Vol. 20, pp. 605-617, 2001.

[Hüttenberger] D. HUTTENBERGER, T. GABRECHT, G. WAGNIERES, B WEBER, A LINDER, H.G. FOTH, L. FREITAG“Autofluorescence detection of tumors in the human lung – comparison between in vivo and vitro measurements”, In SPIE-ECBO European Conference on Biomedical Optics, Munich, Allemagne, 12-16 juin, 2005.

[Jalink] A. JALINK, J. Mc ADOO, G. HAMALA, H. LIU “Mosaic techniques for large-field digital mammography” IEEE Ttransactions on Medical Imaging, Vol. 15, #3, 1996, p. 260-267.

[Kakihana] M. KAKIHANA, K.K. IL, T. OKUNAKA, K. FURUKAWA, T. HIRANO, C. KONAKA, H. KATO, Y. EBIHARA “Early Detection of Bronchial Lesions Using System of Autofluorescence Endoscopy (SAFE) 1000”, Diagnostic and Therapeutic Endoscopy, Vol. 5, 1999, p. 99-104.

[Kara] M. KARA, R.S. DACOSTA, B.C. WILSON, N.E. MARCON, J. BERGMAN “Autofluorescence-based detection of early neoplasia in patients with Barrett’s esophagus”, Digestive Diseases, Vol. 22, 2004, p. 134-141.

[Kobayashi] M. KOBAYASHI, K. SHIBUYA, H. HOSHINO, T. FUJISAWA “Spectroscopic analysis of the autofluorescence from human bronchus using an ultraviolet laser diode”, Journal of Biomedical Optics, Vol. 7, #4, 2002, p. 603-608.

[Koenig] F. KOENIG, F.J. McGOVERN, H. ENQUIST, R. LARNE, T. DEUTSCH, K. SCHOMACKER “Autofluorescence Guided Biopsy for the Early Diagnosis of Bladder Carcinoma”, The Journal of Urology, Vol. 159, 1998, p. 1871-1875.

[Kortum] R. RICHARDS-KORTUM, R. RAVA, R. PETRAS, M. FITZMAURICE, M. SIVAK, M. FELD “Spectroscopic diagnosis of colonic dysplasia”, Photochemistry and Photobiology, Vol. 53, #6, 1991, p. 777-786.

[Kumar] D. KUMAR, M. SINGH “Characterization and imaging of compositional variation in tissues”, IEEE Transactions on Biomedical Engineering, Vol. 50, #8, 2003, p. 1012-1019.

[Liu] Q. LIU “Experimental validation of Monte Carlo modelling of fluorescence in tissues in the UV-visible spectrum”, Journal of Biomedical Optics, Vol. 8, #2, 2003, p. 223-236.

[Miranda-04a] R. MIRANDA-LUNA, Y. HERNANDEZ-MIER, Ch. DAUL, W. BLONDEL, D. WOLF “Mosaïcing of medical videoendoscopic images: data quality improvement and algorithm testing”, IEEE International Conference on Electrical and Electronics Engineering (ICEEE) and Tenth Conference on Electrical Engineering (CIE 2004), Acapulco Guerrero, Mexico, September 2004, p. 530-535.

[Miranda-04b] R. MIRANDA-LUNA, W. BLONDEL, Ch. DAUL, Y. HERNANDEZ-MIER, R. POSADA, D. WOLF “A simplified method of video-endoscopic image barrel distortion correction based on greylevel registration”, IEEE International Conference on Image Processing (ICIP), Singapore, October 24-27 2004, p. 3383-3386.

[Miranda-05] R. MIRANDA-LUNA, Y. HERNANDEZ-MIER, W.C.P.M. BLONDEL, C. DAUL, D. WOLF “Mosaicing of videoendoscopic images and evaluation of the resulting cartography” In Imaging for medical and life sciences Symposium (IMVIE2). Strasbourg, France, March 1-3, 2005.

[Müller] M.G. MULLER, T.A. VALDEZ, I. GEORGAKOUDI, V. BACKMAN, C. FUENTES, S. KABANI, N. LAVER, Z. WANG, C.W. BOONE, R.R. DASARI, S.M. SHAPSHAI, M.S. FELD“Spectroscopic Detection and Evaluation of Morphologic and Biochemical Changes in Early Human Oral Carcinoma”, Cancer, Vol. 97, #7, 2003, p. 1681-1692.

[Padilla] J.J.PADILLA IBARRA, “Biopsie Optique par Spectroscopie de Fluorescence des Tissus Vivants: Spectroscopie UV, Microscopie, Spectroscopie Résolue dans le Temps. Conception Instrumental, Traitement Automatique du Signal et Modélisation”, Thèse de doctorat, Institut National Polytechnique de Lorraine; Novembre 1999.

[Palmer] G.M. PALMER, C. ZHU, T.M. BRESLIN, F. XU, K.W. GILCHRIST, N. RMANUJAM “Comparison of multiexcitation fluorescence and diffuse reflectance spectroscopy for the diagnosis of breast cancer (march 2003)”, IEEE Transactions on Biomedical Engineering, Vol. 50, #11, 2003, p. 1233-1242.

[Pfefer] T.J. PFEFER, D.Y. PAITHANKAR, J.M. PONEROS, K.T. SCHOMACKER, N.S. NISHIOKA “Temporally and spectrally resolved fluorescence spectroscopy for the detection of High Grade Dysplasia in Barrett’s Esophagus”, Lasers in Surgery and Medicine, Vol. 32, 2003, p. 10-16.

[Pluim] J.P.W. PLUIM, J.B.A. MAINTZ, M.A. VIERGEVER “Mutualinformation-based registration of medical images: a survey”, IEEE Transactions on Medical Imaging, Vol. 22, #8, 2003, p. 986-1004.

[Pradhan] A. PRADHAN, P. PAL, G. DUROCHER, L. VILLENEUVE, A. BALASSY, F. BABAI, L. GABOURY, L. BLANCHARD “Steady state and time-resolved fluorescence properties of metastatic and nonmetastatic malignant cells from different species”, Journal of Photochemistry and Photobiology, Vol. 31, 1995, p. 101-112.

[Ramanujam-96] N. RAMANUJAM, M. MITCHELL, A. JANSEN, S. THOMSEN, G. STAERKEL, A. MALPICA, T. WRIGHT, N. ATKINSON, R. RICHARDS-KORTUM “Cervical precancer detection using a multivariate statistical algorithm based on laser-induced fluorescence spectra at multiple excitation wavelengths”, Photochemestry and Photobiology, Vol. 64, #4, 1996, p. 720-735.

[Ramanujam-00] N. RAMANUJAM “Fluorescence Spectroscopy in Vivo”, Encyclopedia of Analytical Chemistry, 2000, Ed. R.A. Meyers.

[Rollins] A. ROLLINS, M.V. SIVAK “Potential new endoscopic techniques for the earlier diagnosis of pre-malignancy”, Best Practice & Research Clinical Gastroenterology, Vol. 15, #2, 2001, p. 227-247.

[Sarrut] D. SARRUT, S. CLIPPE “Patient positioning in radiotherapy by registration of 2D-portal to 3D-CT images by a content-based research with similarity measures”, In Proceedings. of the 14th Computer Assisted Radiology and Surgery, Elsevier Science, USA, june 2000.

[Sawhney] H.S. SAWHNEY, R. KUMAR “True multi-image alignement and its application to mosaicing and lens distortion correction,” IEEE Transactions on Pattern Analysis and Machine Intelligence, Vol. 18, pp. 235-243, 1999.

[Schindler] T. H. SCHINDLER, N. MAGOSAKI, M. JESERICH, U. OSER, T. KRAUSE, R. FISCHER, E. MOSER, E. NITZSCHE, M. ZEHNDER, H. JUST, U. SOLBACH “Fusion imaging: combined visualization of 3D-reconstructed coronary artery tree and 3D-myocardial scintigraphic image in coronary artery desease”, International Journal of Cardiac Imaging, Vol. 15, 1999, p. 357-368.

[Shahidi] R. SHAHIDI, M. BAX, C. MAURER, J. JOHNSON, E. WILKINSON, B. WANG, J. WEST, M. CITARDI, K. MANWARING, R. KHADEM “Implementation, calibration and accuracy testing of an image-enhanced endoscopy system”, IEEE transactions on Medical Imaging, Vol. 21, #12, 2002, p. 1524-1535.

[Skala] M.C. SKALA, G.M. PALMER, C. ZHU, Q. LIU, K.M. VROSTOS, C.L. MARSHEK-STONE, A. GENDRON-FITZPATRICK, N. RAMANUJAM “Investigation of fiber-optic probe designs for optical spectroscopic diagnosis of epithelial pre-cancers”, Lasers in Surgery and Medicine, Vol. 34, 2004, p. 25-38

[Sokolov] K. SOKOLOV, M. FOLLEN, K.R. RICHARD “Optical Spectroscopy for detection of neoplasia”, Current Opinion in Chemical Biology, Vol. 6, 2002, p. 665-658.

[Svistun] E. SVISTUN, R. ALIZADEH-NADERI, A. EL-NAGGAR, R. JACOB, A. GILLENWATER, R. RICHARDS-KORTUM “Vision enhancement system for detection of oral cavity neoplasia based on autofluorescence”, Head Neck, Vol. 26, 2004, p. 205-215

[Takehana] S. TAKEHANA, M. KANEKO, H. MIZUNO “Endoscopic Diagnostic System Using Autofluorescence”, Diagnostic and Therapeutic Endoscopy, Vol. 5, 1999, p. 59-63.

[Thueler] P. THUELER, I. CHARVET, F. BEVILACQUA, M. St. GHISLAIN, G. ORY, P. MARQUET, P. MEDA, B. VERMEULEN, C. DEPEURSINGE “In vivo endoscopic tissue diagnostics based on spectroscopic absorption, scattering, and phase function properties”, Journal of Biomedical Optics, Vol. 8, #3, 2003, p. 495-503

[Valet] G. VALET, S. SANCHEZ, J. LOPEZ, Ch. DAUL, D. WOLF, G. KARCHER “Towards a new diagnosis aid of cardiovascular diseases using 2D-multimodal data registration and 3D-data superimposition”, IEEE International Conference on Image Processing (ICIP), Singapore, October 24-27 2004, p. 1907-1910.

[Villette-04] S. VILLETTE “Analyse spectroscopique de l’autofluorescence de cellules oesophagiennes saines et tumorales in vitro et développement d’un microspectro-imageur confocal fibré destiné à l’exploration in vivo ”, Thèse de doctorat, Université Paris 6, octobre 2004.

[Villette-06] S. VILLETTE, S. PIGAGLIO-DESHAYES, C. VEVERBIZET, G. BOURG-HECKLY “Ultraviolet induced autofluorescence characterization of normal and tumoral esophageal epithelium cells with quantification of NAD(P)H”, Photochemical and Photobiological Sciences, Vol. 5, 2006, p. 483-492.

[Viola] P. VIOLA “Alignment by Maximization of Mutual Information”, PhD Thesis. AI Technical Report No.1548, Massachusetts Institute of Technology, 1995.

[Vogt] R C. VOGT, J. M. TRENKLE, L. A. HARMON “Mosaic construction, processing and review of very large electron micrograph composites”, Proceedings of the SPIE, Denver, Vol. 2847, August 1996, p. 2-15.

[Wagnières-98] G. WAGNIERES, W.M. STAR, B.C. WILSON “In Vivo Fluorescence Spectroscopy and Imaging for oncological applications”, Photochemistry and Photobiology, Vol. 68, #5, 1998, p. 603-632.

[Wagnières-00] G. WAGNIERES, M. ZELLWEGER, N. CHAUVIN, N. LANGE, U. ZANGER, A. STUDZINSKI, H. VAN DEN BERGH“Diagnosis apparatus for the picture providing recording of fluorescing biological tissue regions” US Patent 6,148,227, November 2000.

[Wallace] M. WALLACE, L. PERELMAN, V. BACKMAN, J. CRAWFORD, M. FITZMAURICE, M. SEILER, K. BADIZADEGAN, S. SHIELDS, I. ITZKAN, R. DASARI, J. VAN DAM, M. FELD“Endoscopic detection of dysplasia in patients with Barrett’s esophagus using light-scattering spectroscopy”, Gastroenterology, Vol. 119, 2000, p. 677-682.

[Weng] L. WENG, A. P. TURUMALAI “Method and apparatus for generating large compound ultrasound images” US Patent 5,575,286, November 1996.

[Zellweger] M. ZELLWEGER, P. GROSJEAN, D. GOUJON, P. MONNIER, H. VAN DEN BERGH, G. WAGNIERES “In vivo autofluorescence spectroscopy of human bronchial tissue to optimise the detection and imaging of early cancers” Journal of Biomedical Optics, Vol. 6, #1, 2001, p. 41-51.

[Zheng] W. ZHENG, W. LAU, C. CHENG, K.C. SOO, M. OLIVO“Optimal excitation-emission wavelengths for autofluorescence diagnosis of bladder tumors”, International Journal of Cancer, Vol. 104, 2003, p. 477-481.

[Zeng] H. ZENG, M. PETEK, M.T. ZORMAN, A. McWILLIAMS, B. PALCIC, S. LAM “Integrated endoscopy system for simultaneous imaging and spectroscopy for early lung cancer detection”, Optics Letters, Vol. 29, #6, 2004, p. 587-589

[Zonios] G. ZONIOS, R. COTHREN, J. ARENDT, J. WU, J. VAN DAM, J. CRAWFORD, R. MANOHARAN, M. FELD “Morphological model of human colon tissue fluorescence”, IEEE Transactions on Biomedical Engineering, Vol. 43, #2, 1996, p. 113-122.