Fluorescence Endoscopy in Veterinary Medicine

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Fluorescence Imaging

Fluorescence imaging is becoming increasingly popular as a visual tool in surgery as clinical studies in animals pave the way for applications in human medicine. KARL STORZ thus offers OPAL1® technologies for near infrared (NIR/ICG) and autofluorescence (AF) imaging as well as for photodynamic diagnosis (PDD). Each technology also holds great potential for enhanced diagnosis and treatment of disease in veterinary patients.

OPAL1® Technology NIR/ICGNear infrared (NIR) fluorescence cholangiography with indocyanine green (ICG)

In 1852, George Gabriel Stokes described the mineral Fluorite as emitting blue light following exposure to UV-light. He termed the phenomenon as “Fluorescence” and substances with this property as “Fluorophores”.

The ability to emit fluorescence is very common in nature. The sensitivity of delocalized electrons in aromatic ring structures is responsible for this. The light energy excites the delocalized electrons into a higher state of energy. When the electrons return to the ground state, the light energy is emitted as fluorescence. The emitted fluorescence is lower in energy as the exciting light energy is partly lost as heat.

Fig. 1: Principle of fluorescence/Stokes shift

Excitation Emission

- E

NE

RG

Y+

Non-Radiative Transition

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Aromatic ring structures are the main components of biological substances such as DNA, proteins and sugars. Since the 1960’s their ability to emit fluorescence has been used for fluorescence imaging in life sciences and in medicine.

The oldest known approved near-infrared (NIR) fluorescent dye in medicine, ICG, has been discovered as a tool to visualize the anatomy and the lymphatic system as well as to detect tumors and to assess perfusion. Therefore, a wide range of applications are possible.

ICG is a drug which has been approved for use in humans by the FDA since 1959 for cardiac and liver function testing. The tricarbon dye has an excitation maximum of λEm = 805 nm and an emission maximum of λEx = 835 nm. This results in tissue detection depth for NIR fluorescence of up to 1 cm.

ICG is usually intravenously administered where it binds to plasma proteins (albumin), thereby remaining in the bloodstream due to size exclusion. From the bloodstream, ICG is transported to the liver, where it is excreted via the bile into the duodenum. This exclusive excretion into bile makes it an ideal tool for the delineation of the extra-hepatic biliary tree.

1 Intravenous administration of ICG

2 ICG binds to plasma proteins

3 Visualization of ICG in the bloodstream with the KARL STORZ NIR system

4 NIR light source

Fig. 2: Principle of ICG

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The OPAL1® technology for NIR/ICG based on the IMAGE1 S™ platform has already been used for several different indications in veterinary medicine. The four main indications are:

• Blood perfusion assessment

• Lymphatic mapping

• Visualization of anatomical structures (e.g., bile duct imaging)

• Tumor identification

Indications in Veterinary Patients

The following list is a selection of the veterinary applications of the NIR/ICG technology to date:

• Identification of vascular integrity

• Lymphatic mapping for oncology

• Evaluation of lymphatic disease (chylothorax, lymphangiectasia, assessment of lymphedema)

• Biliary function and anatomy (obstruction, leakage)

• Tumor margin localization

• Identification of metastasis (primarily liver)

• Lung segmentectomy

• Ureteral identification

• Skin flap/graft viability

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The versatile usage of the OPAL1® technology based on the IMAGE1 S™ platform is demonstrated by the following examples:

Perfusion Assessment

Fig. 3: Perfusion assessment of a thoracoscopic thoracic duct ligation with NIR/ICG.

1 Images courtesy of: Michele A. Steffey, DVM, DACVS, University of California at Davis, School of Veterinary Medicine, USA

2 Images courtesy of: Jeffrey J. Runge, DVM, DACVS, University of Pennsylvania, School of Veterinary Medicine, USA

A) White light B) Perfusion assessment with ICG.1

Framing of Hypervascularized Tumors

Fig. 4: Perfusion assessment of hepatic mass in a dog with NIR/ICG.

A) White light B) Mass showing hypervascularization seen with ICG fluorescence.2

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2 Images courtesy of: Jeffrey J. Runge, DVM, DACVS, University of Pennsylvania, School of Veterinary Medicine, USA

Detecting a Metastasis with OPAL1® Technology for NIR/ICG

Fig. 5: Detection of metastasis in the cranial lung lobe of a dog.

A) White light B) Metastasis showing accumulation of ICG.2

Visualizing the Lymphatic System

Fig. 6: Visualization of the lymphatics associated with the cisterna in the region of the abdominal aorta of a dog

A) White light B) Lymphatic vessels showing ICG fluorescence.2

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OPAL1® Technology for NIR/ICG

1 IMAGE1 S™ camera system brilliant FULL HD image quality NIR/ICG mode + SPECTRA A lead to optimal illumination + contrast enhancement

with a display in the cyan spectral range

2 NIR/ICG telescope telescopes for optimal fluorescence excitation & detection, which can be used

for white light and NIR/ICG applications standard endoscopes can also be used with the NIR snap-on filter

3 Camera head 3-chip FULL HD camera head with high resolution and optimal NIR light sensitivity

4 D-LIGHT P light source (Xenon light source) best daylight spectrum NIR fluorescence with backlight no additional security measures (vs. Laser)

5 Autoclavable fiber optic light cable

optimal light transmission in the white light and NIR spectral range

Footswitch fast switch between white light and fluorescence mode

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2 3

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Literature, see pages 19 and 20

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The identification and total removal of malignant tissue determines the life expectancy of a cancer patient. Many researchers try to overcome this problem by developing specific tumor markers. One of the most promising substance groups are the protoporphyrin IX-producing (PPIX) drugs. 5-aminolevulinic acid (5-ALA) and its approved derivative Hexvix® from Photocure (Cysview® in USA) and Gliolan® from Medac are precursors of PPIX in the heme biosynthesis. The substances are internalized and metabolized by all cells in the body. Malignant cells have a metabolic defect, which results in the accumulation of PPIX in the cells. Since PPIX has fluorescent properties, malignant tissue can be visualized by enhancing the PPIX fluorescence (PPIX absorption maximum λEm = 420 nm, PPIX fluorescence emission maximum λEx = 630 nm).

OPAL1® Technology for Photodynamic Diagnosis (PDD)

Fluorescence imaging with 5-aminolevulinic acid (5-ALA)

Fig. 7: 5-ALA, Hexvix® or Gliolan® are converted into precursors of PPIX in the heme biosynthesis.

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Two primary indications for photodynamic diagnosis (PDD) with PPIX precursors are known: 5-ALA or Gliolan® is used for glioma identification in neurosurgery. Hexvix® (Cysview® in USA) is distilled into the bladder for bladder cancer detection (Fig. 8).

Indications

3 Images courtesy of PD Dr. med. Carsten Kempkensteffen, Charité University Medical Center Berlin, Germany

Demarcation of Bladder Tumors via Photodynamic Diagnosis

Fig. 8: Fluorescence diagnosis of a bladder tumor with Hexvix®

A) White light B) PDD mode with OPAL1® technology based on IMAGE1 STM 3

Fig. 9: Fluorescence diagnosis of a glioblastoma with Gliolan®

A) White light B) PPIX-accumulating glioblastoma (red) 4

4 Images courtesy of Prof. Potapov, Burdenkow Neurosurgical Institute Moscow, Russia

Visualization of Glioblastoma via Fluorescence

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OPAL1® Technology for PDD

1 IMAGE1 S™ camera system PDD mode + SPECTRA A and SPECTRA B lead to optimal illumination and contrast

enhancement with a display in the cyan spectral range

2 PDD telescope telescopes for optimal fluorescence excitation & detection, which can be used

for white light and PDD applications

3 Camera head 1-chip FULL HD HX camera head with high resolution and optimal PDD light

sensitivity standard endoscopes can also be used with the PDD snap-on filter

4 D-LIGHT C light source (Xenon light source) best daylight spectrum PDD fluorescence with backlight no additional security measures (vs. Laser)

5 Fluid light cable optimal light transmission of white light and fluorescence

Footswitch fast switch between white light and fluorescence mode

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Literature, see page 21

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Another application of fluorescence for diagnosis is the intrinsic autofluorescence (AF) of tissue components. AF focuses on the differentiation between healthy and malignant tissue in bronchoscopy and laryngoscopy. The underlying principle is simple: AF detects the green fluorescence of flavins in the healthy mucosa. Malignant tissues like bronchial or laryngeal carcinomas are identified by the lack of fluorescence since their compactness blocks the autofluorescence of the underlying healthy mucosa.

The Principle of Autofluorescence

to differentiate between healthy and malignant tissue

Fig. 10: Principle of autofluorescence

Mucosa

Submucosa

Light

CIS

Autofluorescence

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Autofluorescence (AF) facilitates early differentiation of malignant changes from benign tissue. The autofluorescence method is based on the fact that light with a certain wavelength induces fluorescence. Pathological findings appear as dark areas against an apple-green background (normal tissue).

Blue light and specialized equipment visualize information that remains undetected in the conventional light mode. For this purpose, the light of a specific spectral composition is introduced into the body via an almost loss-free light guide system. The major advantage of this technology is that marker substances are not required.

AF in Veterinary Medicine

A) White light B) AF mode

5 Images courtesy of Dr. Stanzel, Lung Clinic Hemer, Germany

Fluorescence Imaging with Endoscopes

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Autofluorescence

1 IMAGE1 S™ camera system brilliant FULL HD image quality

2 Camera head 1-chip FULL HD HX camera head with high resolution and optimal

AF light sensitivity

3 Endoscopes or fiberscopes all telescopes with the AF snap-on filter are suitable for both white light applications

as well as optimal fluorescence excitation & detection

4 D-LIGHT C/AF best daylight spectrum filters are variably adjustable no additional security measures (vs. Laser)

5 Fluid light cable optimal light transmission of white light and fluorescence

Footswitch fast switch between white light and fluorescence mode

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4

2

Literature, see page 22

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D-LIGHT P

modifiable for various fluorophores

Filters are available for the following fluorophores:

GFP, tdTomato/DsRed, CY5, Methylene blue, 5-ALA/PDD, ICG/NIR, AF, RFP/mCherry, CY7, Fluorescein blue

66100 M1 Modified D-LIGHT P VET M1, with integrated special filter, high-performance light unit for perfusion assessment, autofluorescence, and standard endoscopic diagnosis, including a 300 Watt Xenon bulb and KARL STORZ light cable connection, power supply 100-125/220-240 VAC, 50/60 Hz, for use with snap-on filters and special endoscopes for autofluorescence in veterinary medicine including: Cold Light Fountain D-LIGHT P Mains Cord One-Pedal Footswitch, digital, one-stage Demo Card Fluorescence Imaging

66100 M2 Same, with two integrated special filters

66100 M3 Same, with three integrated special filters

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Overview: Fluorophores and Suitable System Combinations (Date: 01.02.2020, subject to change)

Available Dyes

Compatible Camera Systems

(please use the latest software version)Light Sources

TRICAM®

20 2230 11-1

20 2210 37

IMAGE1 S™

TH 102

H3-Z FI

TC 201

TC 300

IMAGE1 S™

TH 112

HX FI

TC 201

TC 301

(Based on

20 1337 1-1)

D-LIGHT P VET

66100Mx

D-LIGHT C/AF

20 1336 01-133

D-LIGHT C

20 1336 01-1

CY7 • • •

GFP • • •

tdTomato/ DsRed/ tRFP

• • •

RFP/ mCherry • • •

Cy5 • • •

methylene blue • • •

ICG • • •

AF • • • •

fluorescein blue • • • • •

ALA/PDD • • • •

Please note:

Should you have any queries or require further information on the use of fluorescence in veterinary medicine, please contact VET@KARLSTORZ.com.

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60 1000 36 Snap-on Filter for RFP/mCherry

60 1000 38 Snap-on Filter for tdTomato

60 1000 37 Snap-on Filter for GFP

60 1000 39 Snap-on Filter for CY7

60 1000 41 Snap-on Filter for CY5/methylene blue

60 1000 40 Snap-on Filter for ICG

20 1000 33 Fluorescein Barrier Filter

20 1000 34 Snap-on Filter for 5-ALA/PDD

20 1000 35 Snap-on Filter for AF

Snap-on Filtersfor use with standard eyepieces and D-LIGHT P light source

Check out our schedule of upcoming hands-on training courses at http://go.karlstorz.com/eventsVET

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Cam

era

Sys

tem

s

PDD

D-LIGHT C/AF 20 1336 01-1/20 1336 01-133

D-LIGHT P 20 1337 01-1

IMAGE1 S™ H3-Z FI TH 102

IMAGE1 S™

System

IMAGE1 S CONNECT® TC 200/201

IMAGE1 S™ H3-LINK TC 300

VITOM® II PDD 20 9160 25 AIA28272 UGN/CN

28272 HC28172 HR/HM

VITOM® II ICG 20 9160 25 AGA28272 UGN/CN

28272 HC28172 HR/HM

Available soon: IMAGE1 S™ HX FI/HX-P FI

TH 112/TH 113

AF

D-LIGHT C/AF 20 1336 01-133

IMAGE1 S™ HX FI/HX-P FI TH 112/TH 113

NIR / ICG*

HOPKINS® Telescope 27005 AIA/FIA/BIA/CIA

8710 AP, 8711 AP, 8712 AP/BP/CP 7230 AP/BP/FP

HOPKINS® Telescope 8710 AP/8711 AP/8712 AP/BP/CP

7230 AP/BP/FP10320 AP/BP/DP

26003 AIA/BIA26003 AGA/BGA

8710 AGA/8711 AGA

Fluid Light Cable 495 FS/FO/FP/FR

Fluid Light Cable 495 FS/FO/FP/FR

Fiber Optic Light Cable 495 NAC/NCSC/TIP/NCS/VIT

HOPKINS® Telescope 26003 ACA/BCA/AGA/BGA8710 AGA/26046 ACA/BCA

8711 AGA

Fiberscope

IMAGE1 S™ X-LINK TC 301

IMAGE1 S™ X-LINK TC 301

Ligh

t Sou

rces

Cam

era

Hea

dsLi

ght C

able

sE

ndos

cope

sE

xosc

opes

Fibe

rsco

pes

CC

U

* Demonstration Card NIR/ICG 96240726

Fiberscope Fiberscope

VITOM® II PDD 20 9160 25 AA

28272 UGN/CN28272 HC

28172 HR/HM

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Cam

era

Sys

tem

sLi

ght S

ourc

esC

amer

a H

eads

Ligh

t Cab

les

Tele

scop

esE

xosc

opes

TRICAM® System

PDD ICG

D-LIGHT C/20 1336 01-1 D-LIGHT P/20 1337 01-1

TELECAM System for PDD & AF video endoscopes

TELECAM SL II FI CCU 20 2130 11-1

Fibe

rsco

pes

Fiberscope FiberscopeFiberscope

VITOM® II PDD 20 9160 25 AIA28272 UGN/CN

28272 HC28172 HR/HM

VITOM® II ICG 20 9160 25 AGA28272 UGN/CN

28272 HC28172 HR/HM

AF

D-LIGHT C/AF/20 1336 01-133

TRICAM® SL II CCU 20 2230 11-1

TRICAM® PDDThree-Chip Pendulum Camera

Head/Three-Chip Camera Head20 2210 39/20 221037

TRICAM® PDDThree-Chip Camera Head

20 2210 37

TRICAM® PDDThree-Chip Camera Head

20 2210 37

Fluid Light Cable 495 FS/FO/FP/FR

HOPKINS® Telescope 27005 AIA/FIA/BIA/CIA

8710 AP, 8711AP, 8712 AP/BP/CP 7230 AP/BP/FP, 26003 AIA/BIA

HOPKINS® Telescope 8710 AP/8711 AP/8712 AP/BP/CP

7230 AP/BP/FP 10320 AP/BP/DP

26003 AIA/BIA26003 AGA/BGA

8710 AGA/8711 AGA

Fluid Light Cable 495 FS/FO/FP/FR

Fiber Optic Light Cable 495 NAC/NCSC/TIP

HOPKINS® Telescope 26003 ACA/BCA/AGA/BGA

8710 AGA/8711 AGA

VITOM® II PDD 20 9160 25 AA

28272 UGN/CN28272 HC

28172 HR/HM

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Literature – NIR/ICG

[1] Cost analysis and effectiveness comparing the routine use of intraoperative fluorescent cholangiography with fluoroscopic cholangiogram in patients undergoing laparoscopic cholecystectomy.Dip FD, Asbun D, Rosales-Velderrain A, Menzo EL, Simpfendorfer CH, Szomstein S, Rosenthal RJ.SurgEndosc. 2014 Jan 11http://www.ncbi.nlm.nih.gov/pubmed/24414461

[2] Combined vascular and biliary fluorescence imaging in laparoscopic cholecystectomy.Rutger M. Schols, Nicole D. Bouvy, Ronald M. van Dam, Ad A. M. Masclee, Cornelis H. C. Dejong, Laurents P. S. StassenSpringer Science+Business Media New York 2013http://www.ncbi.nlm.nih.gov/pubmed/23877766

[3] Fluorescence guidance during radical prostatectomy.W. B. van Leeuwen, Stephan Hruby2013 Published by Elsevier B.V. on behalf of European Association of Urologyhttp://www.europeanurology.com/article/S0302-2838(13)01460-7/abstract

[4] Indocyanine green angiography in endoscopic third ventriculostomy.Wachter D, Behm T, von Eckardstein K, Rohde V.Neurosurgery. 2013 Sep;73(1 Suppl Operative):ons67-72; ons72-3. doi: 10.1227/NEU.0b013e318285b846.http://www.ncbi.nlm.nih.gov/pubmed/23313981

[5] Sentinel lymph node biopsy for prostate cancer:A hybrid approach.Nynke S. van den Berg, Renato A. Valde´s-Olmos, Henk G. van der Poel and Fijs W.B. van LeeuwenJournal of Nuclear Medicine, published on March 14, 2013http://www.ncbi.nlm.nih.gov/pubmed/23492883

[6] Endoscopic assessment of free flap perfusion in the upper aerodigestive tract using indocyanine green: a pilot study.Betz CS, Zhorzel S, Schachenmayr H, Stepp H, Matthias C, Hopper C, Harréus UJ PlastReconstrAesthet Surg. 2013 Ma http://www.ncbi.nlm.nih.gov/pubmed/23391541

[7] Visualisation of the lymph node pathway in real time by laparoscopic radioisotope- and fluorescence-guided sentinel lymph node dissection in prostate cancer staging.Jeschke S, Lusuardi L, Myatt A, Hruby S, Pirich C, Janetschek G.Urology. 2012 Nov;80(5):1080-6. doi: 10.1016/j.urology.2012.05.050. Epub 2012 Sep 15.http://www.ncbi.nlm.nih.gov/pubmed/22990053

[8] Laparoscopic fluorescence angiography with indocyanine green to control the perfusion of gastrointestinal anastomoses intraoperatively.Carus T, Dammer R.SurgTechnol Int.2012 Dec 30;XXII. pii: sti22/44. http://www.ncbi.nlm.nih.gov/pubmed/23315721

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[9] Indocyanine green fluorescence endoscopy for visual differentiation of pituitary tumor from surrounding structures.Zachary N. Litvack, Gabriel Zada, and Edward R. Laws Jr.J Neurosurg / February 24, 2012http://www.ncbi.nlm.nih.gov/pubmed/22360574

[10] Clinical applications of indocyanine green (ICG) enhanced fluorescence in laparoscopic surgery.Boni L, David G, Mangano A, Dionigi G, Rausei S, Spampatti S, Cassinotti E, Fingerhut A.http://www.ncbi.nlm.nih.gov/pubmed/25303914

[11] First Experience on Laparoscopic Near-Infrared Fluorescence Imaging of Hepatic Uveal Melanoma Metastases Using Indocyanine Green.Tummers QR, Verbeek FP, Prevoo HA, Braat AE, Baeten CI, Frangioni JV, van de Velde CJ, Vahrmeijer AL.SURG INNOV 1553350614535857, first published on June 5, 2014http://www.ncbi.nlm.nih.gov/pubmed/24902685

[12] Fluorescence cholangiography during laparoscopic cholecystectomy: a feasibility study on early biliary tract delineation.Schols RM, Bouvy ND, van Dam RM, Masclee AAM., Dejong CHC., Stassen LPS.SurgEndosc DOI 10.1007/s00464-012-2635-3http://www.ncbi.nlm.nih.gov/pubmed/23076461

[13] Indocyanine green angiography in endoscopic third ventriculostomy.Wachter D, Behm T, von Eckardstein K, Rohde V.Neurosurgery. 2013 Sep;73(1 Suppl Operative):ons67-72; ons72-3. doi: 10.1227/ NEU.0b013e318285b846.http://www.ncbi.nlm.nih.gov/pubmed/23313981

[14] Transrectal sentinel lymph node biopsy for early rectal cancer during transanal endoscopic microsurgery.Arezzo A, Arolfo S, Mistrangelo M, Mussa B, Cassoni P, Morino M.Minimally Invasive Therapy. 2013;Early Online:1–4http://www.ncbi.nlm.nih.gov/pubmed/23590395

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Literature – PDD

[1] Intraoperative fluorescence-guided resection of high-grade malignant gliomas using 5-aminolevulinic acid-induced porphyrins: a systematic review and meta-analysis of prospective studies.Zhao S, Wu J, Wang C, Liu H, Dong X, Shi C, Shi C, Liu Y, Teng L, Han D, Chen X, Yang G, Wang L, Shen C, Li H.PLoS One. 2013 May 28;8(5):e63682. Review. http://www.ncbi.nlm.nih.gov/pubmed/23723993

[2] Hexyl aminolevulinate-guided fluorescence cystoscopy in the diagnosis and follow-up of patients with non-muscle-invasive bladder cancer: a critical review of the current literature.Rink M, Babjuk M, Catto JW, Jichlinski P, Shariat SF, Stenzl A, Stepp H, Zaak D, Witjes JA.Eur Urol. 2013 Oct;64(4):624-38. http://www.ncbi.nlm.nih.gov/pubmed/23906669

[3] Safety of hexaminolevulinate for blue light cystoscopy in bladder cancer. A combined analysis of the trials used for registration and postmarketing data.Witjes JA, Gomella LG, Stenzl A, Chang SS, Zaak D, Grossman HB.Urology.2014 Jul;84(1):122-6. http://www.ncbi.nlm.nih.gov/pubmed/24768013

[4] Clinical and cost effectiveness of hexaminolevulinate-guided blue-light cystoscopy: Evidence review and updated expert recommendations.Witjes JA, Babjuk M, Gontero P, Jacqmin D, Karl A, Kruck S, Mariappan P, Palou Redorta J, Stenzl A, van Velthoven R, Zaak D.http://www.ncbi.nlm.nih.gov/pubmed/25001887

[5] Photodynamic Diagnosis of the Urinary Bladder using Flexible Instruments – Ready for the Outpatient Setting.Karl A, Weidlich P, Buchner A, Hofmann T, Schneevoigt B, Stiefl Ch., Zaak D.In: © 2014 Karl A et al. Brochure

[6] Clinical and Cost Effectiveness of Hexaminolevulinate-guided Blue-light Cystoscopy: Evidence Review and Updated Expert Recommendations.Witjes JA, Babjuk M, Gontero P, Jacqmin D, Karl A, Kruck S, Mariappan P, Palou Redorta J, Stenzl A, van Velthoven R, Zaak D.http://www.ncbi.nlm.nih.gov/pubmed/25001887

In: © 2014 European Association of Urology. Published by Elsevier B.V.[7] Fluorescence-Guided Surgery and Biopsy in Gliomas with an Exoscope System.José Piquer, Jose L. Llácer, Vicente Rovira, Pedro Riesgo, Ruben Rodriguez, Antonio Cremades.http://www.ncbi.nlm.nih.gov/pubmed/24971317

[8] 5-Aminolevulinic Acid-derived Tumor Fluorescence: The Diagnostic Accuracy of Visible Fluorescence Qualities as Corroborated by Spectrometry and Histology and Postoperative ImagingStummer W, Tonn J-Ch., Goetz C, Ullrich W, Stepp H, Bink A, Pietsch T, Pichlmeier U.http://www.ncbi.nlm.nih.gov/pubmed/24335821

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Literature – AF

[1] Value of fluorescence endoscopy for the early diagnosis of laryngeal cancer and its precursor lesions.Kraft M, Betz CS, Leunig A, Arens C.Head Neck. 2011 Jul;33(7):941-8. http://www.ncbi.nlm.nih.gov/pubmed/21674669

[2] Autofluorescence bronchoscopy: quantification of inter-patient variations of fluorescence intensity.Gabrecht T, Lovisa B, van den Bergh H, Wagnières G.Lasers Med Sci. 2009 Jan;24(1):45-51. Epub 2007 Nov 30http://www.ncbi.nlm.nih.gov/pubmed/18060444

[3] Indirect fluorescence laryngoscopy in the diagnosis of precancerous and cancerous laryngeal lesions.Arens C, Reussner D, Woenkhaus J, Leunig A, Betz CS, Glanz H.Eur Arch Otorhinolaryngol. 2007 Jun;264(6):621-6. Epub 2007 Feb 10.http://www.ncbi.nlm.nih.gov/pubmed/17294205

[4] Autofluorescence bronchoscopy with white light bronchoscopy compared with white light bronchoscopy alone for the detection of precancerous lesions: a European randomised controlled multicentre trial.Häussinger K, Becker H, Stanzel F, Kreuzer A, Schmidt B, Strausz J, Cavaliere S, Herth F, Kohlhäufl M, Müller KM, Huber RM, Pichlmeier U, Bolliger ChT. Thorax. 2005 Jun;60(6): 496-503http://www.ncbi.nlm.nih.gov/pubmed/15923251

[5] Cell migration leads to spatially distinct but clonally related airway cancer precursors.Pipinikas CP, Kiropoulos TS, Teixeira VH, Brown JM, Varanou A, Falzon M, Capitanio A, Bottoms SE, Carroll B, Navani N, McCaughan F, George JP, Giangreco A, Wright NA, McDonald SA, Graham TA, Janes SM.http://www.ncbi.nlm.nih.gov/pubmed/24550057

[6] Transformed lymphoplasmacytic lymphoma involving the main carina: A case report.Nakao M, Oguri T, Miyazaki M, Hijikata H, Yokoyama M, Kunii E, Uemura T, Takakuwa O, Ohkubo H, Maeno K, Niimi AIn: © 2013, Spandidos Publicationshttp://www.ncbi.nlm.nih.gov/pubmed/24137364

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