Abstract

Fiber bundle microendoscopic imaging of colorectal tissue has shown promising results, for both qualitative and quantitative analysis. A quantitative image quality control and image feature extraction algorithm was previously designed for quantitative image feature analysis of proflavine-stained ex vivo colorectal tissue. We investigated fluorescein as an alternative topical stain. Images of ex vivo porcine, caprine, and human colorectal tissue were used to compare microendoscopic images of tissue topically stained with fluorescein and proflavine solutions. Fluorescein was shown to be comparable for automated crypt detection, with an average crypt detection sensitivity exceeding 90% using a combination of three contrast limit pairs.

© 2017 Optical Society of America

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    [Crossref] [PubMed]
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    [Crossref] [PubMed]
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  32. R. Alford, H. M. Simpson, J. Duberman, G. C. Hill, M. Ogawa, C. Regino, H. Kobayashi, and P. L. Choyke, “Toxicity of organic fluorophores used in molecular imaging: literature review,” Mol. Imaging 8(6), 341–354 (2009).
  33. J. A. Eaden, J. F. Mayberry, British Society for GastroenterologyAssociation of Coloproctology for Great Britain and Ireland, “Guidelines for screening and surveillance of asymptomatic colorectal cancer in patients with inflammatory bowel disease,” Gut 51(Suppl 5), v10–v12 (2002).
    [Crossref] [PubMed]
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    [Crossref] [PubMed]

2016 (1)

S. P. Prieto, K. K. Lai, J. A. Laryea, J. S. Mizell, and T. J. Muldoon, “Quantitative analysis of ex vivo colorectal epithelium using an automated feature extraction algorithm for microendoscopy image data,” J. Med. Imaging (Bellingham) 3(2), 024502 (2016).
[Crossref] [PubMed]

2015 (3)

D. Shin, M.-A. Protano, A. D. Polydorides, S. M. Dawsey, M. C. Pierce, M. K. Kim, R. A. Schwarz, T. Quang, N. Parikh, and M. S. Bhutani, “Quantitative analysis of high-resolution microendoscopic images for diagnosis of esophageal squamous cell carcinoma,” Clin. Gastroenterol. 13(2), 272–279 (2015).

R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics, 2015,” CA Cancer J. Clin. 65(1), 5–29 (2015).
[Crossref] [PubMed]

S. P. Prieto, A. J. Powless, J. W. Boice, S. G. Sharma, and T. J. Muldoon, “Proflavine Hemisulfate as a Fluorescent Contrast Agent for Point-of-Care Cytology,” PLoS One 10(5), e0125598 (2015).
[Crossref] [PubMed]

2014 (1)

N. D. Parikh, D. Perl, M. H. Lee, B. Shah, Y. Young, S. S. Chang, R. Shukla, A. D. Polydorides, E. Moshier, J. Godbold, E. Zhou, J. Mitcham, R. Richards-Kortum, and S. Anandasabapathy, “In vivo diagnostic accuracy of high-resolution microendoscopy in differentiating neoplastic from non-neoplastic colorectal polyps: a prospective study,” Am. J. Gastroenterol. 109(1), 68–75 (2014).
[Crossref] [PubMed]

2013 (1)

P. Trivedi and B. Braden, “Indications, stains and techniques in chromoendoscopy,” QJM 106(2) 117–131 (2013).
[PubMed]

2012 (3)

T. J. Muldoon, D. Roblyer, M. D. Williams, V. M. Stepanek, R. Richards-Kortum, and A. M. Gillenwater, “Noninvasive imaging of oral neoplasia with a high-resolution fiber-optic microendoscope,” Head Neck 34(3), 305–312 (2012).
[Crossref] [PubMed]

W. Piyawattanametha, H. Ra, Z. Qiu, S. Friedland, J. T. Liu, K. Loewke, G. S. Kino, O. Solgaard, T. D. Wang, M. J. Mandella, and C. H. Contag, “In vivo near-infrared dual-axis confocal microendoscopy in the human lower gastrointestinal tract,” J. Biomed. Opt. 17(2), 021102 (2012).
[Crossref] [PubMed]

R. A. Wall and J. K. Barton, “Fluorescence-based surface magnifying chromoendoscopy and optical coherence tomography endoscope,” J. Biomed. Opt. 17(8), 086003 (2012).
[Crossref] [PubMed]

2011 (1)

S. J. Miller, B. P. Joshi, Y. Feng, A. Gaustad, E. R. Fearon, and T. D. Wang, “In vivo fluorescence-based endoscopic detection of colon dysplasia in the mouse using a novel peptide probe,” PLoS One 6(3), e17384 (2011).
[Crossref] [PubMed]

2010 (2)

T. J. Muldoon, N. Thekkek, D. Roblyer, D. Maru, N. Harpaz, J. Potack, S. Anandasabapathy, and R. Richards-Kortum, “Evaluation of quantitative image analysis criteria for the high-resolution microendoscopic detection of neoplasia in Barrett’s esophagus,” J. Biomed. Opt. 15, 026027 (2010).

M. B. Wallace, A. Meining, M. I. Canto, P. Fockens, S. Miehlke, T. Roesch, C. J. Lightdale, H. Pohl, D. Carr-Locke, M. Löhr, E. Coron, B. Filoche, M. Giovannini, J. Moreau, C. Schmidt, and R. Kiesslich, “The safety of intravenous fluorescein for confocal laser endomicroscopy in the gastrointestinal tract,” Aliment. Pharmacol. Ther. 31(5), 548–552 (2010).
[Crossref] [PubMed]

2009 (4)

R. Alford, H. M. Simpson, J. Duberman, G. C. Hill, M. Ogawa, C. Regino, H. Kobayashi, and P. L. Choyke, “Toxicity of organic fluorophores used in molecular imaging: literature review,” Mol. Imaging 8(6), 341–354 (2009).

G. A. Sonn, S.-N. E. Jones, T. V. Tarin, C. B. Du, K. E. Mach, K. C. Jensen, and J. C. Liao, “Optical biopsy of human bladder neoplasia with in vivo confocal laser endomicroscopy,” J. Urol. 182(4), 1299–1305 (2009).
[Crossref] [PubMed]

W. Zhong, J. P. Celli, I. Rizvi, Z. Mai, B. Q. Spring, S. H. Yun, and T. Hasan, “In vivo high-resolution fluorescence microendoscopy for ovarian cancer detection and treatment monitoring,” Br. J. Cancer 101(12), 2015–2022 (2009).
[Crossref] [PubMed]

J. K. Triantafillidis, G. Nasioulas, and P. A. Kosmidis, “Colorectal cancer and inflammatory bowel disease: epidemiology, risk factors, mechanisms of carcinogenesis and prevention strategies,” Anticancer Res. 29(7), 2727–2737 (2009).
[PubMed]

2008 (4)

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med. 14(4), 454–458 (2008).
[Crossref] [PubMed]

W. Curvers, L. Baak, R. Kiesslich, A. Van Oijen, T. Rabenstein, K. Ragunath, J. F. Rey, P. Scholten, U. Seitz, F. Ten Kate, P. Fockens, and J. Bergman, “Chromoendoscopy and narrow-band imaging compared with high-resolution magnification endoscopy in Barrett’s esophagus,” Gastroenterology 134(3), 670–679 (2008).
[Crossref] [PubMed]

H. Pohl, T. Rösch, M. Vieth, M. Koch, V. Becker, M. Anders, A. C. Khalifa, and A. Meining, “Miniprobe confocal laser microscopy for the detection of invisible neoplasia in patients with Barrett’s oesophagus,” Gut 57(12), 1648–1653 (2008).
[Crossref] [PubMed]

S. Srivastava, J. J. Rodríguez, A. R. Rouse, M. A. Brewer, and A. F. Gmitro, “Computer-aided identification of ovarian cancer in confocal microendoscope images,” J. Biomed. Opt. 13, 024021 (2008).

2006 (1)

S. Kitabatake, Y. Niwa, R. Miyahara, A. Ohashi, T. Matsuura, Y. Iguchi, Y. Shimoyama, T. Nagasaka, O. Maeda, T. Ando, N. Ohmiya, A. Itoh, Y. Hirooka, and H. Goto, “Confocal endomicroscopy for the diagnosis of gastric cancer in vivo,” Endoscopy 38(11), 1110–1114 (2006).
[Crossref] [PubMed]

2005 (2)

S. H. Itzkowitz and D. H. Present, “Consensus conference: colorectal cancer screening and surveillance in inflammatory bowel disease,” Inflamm. Bowel Dis. 11(3), 314–321 (2005).
[Crossref] [PubMed]

R. Kiesslich and M. F. Neurath, “Endoscopic confocal imaging,” Clin. Gastroenterol. Hepatol. 3(7Suppl 1), S58–S60 (2005).
[Crossref] [PubMed]

2004 (1)

R. Keerl, R. K. Weber, W. Draf, A. Wienke, and S. D. Schaefer, “Use of sodium fluorescein solution for detection of cerebrospinal fluid fistulas: an analysis of 420 administrations and reported complications in Europe and the United States,” Laryngoscope 114(2), 266–272 (2004).
[Crossref] [PubMed]

2002 (1)

J. A. Eaden, J. F. Mayberry, British Society for GastroenterologyAssociation of Coloproctology for Great Britain and Ireland, “Guidelines for screening and surveillance of asymptomatic colorectal cancer in patients with inflammatory bowel disease,” Gut 51(Suppl 5), v10–v12 (2002).
[Crossref] [PubMed]

1998 (1)

G. L. Tipoe and F. H. White, “Quantitative assessment of normal and potentially premalignant epithelium at different levels of human colorectal crypts,” Histol. Histopathol. 13(2), 395–404 (1998).
[PubMed]

1996 (1)

B. Hofstad, M. H. Vatn, S. N. Andersen, H. S. Huitfeldt, T. Rognum, S. Larsen, and M. Osnes, “Growth of colorectal polyps: redetection and evaluation of unresected polyps for a period of three years,” Gut 39(3), 449–456 (1996).
[Crossref] [PubMed]

1992 (2)

Y. Iwamoto, L. R. Ferguson, A. Pearson, and B. C. Baguley, “Photo-enhancement of the mutagenicity of 9-anilinoacridine derivatives related to the antitumour agent amsacrine,” Mutat. Res. 268(1), 35–41 (1992).
[Crossref] [PubMed]

R. P. Feenstra and S. C. Tseng, “Comparison of fluorescein and rose bengal staining,” Ophthalmology 99(4), 605–617 (1992).
[Crossref] [PubMed]

1988 (1)

D. M. DeMarini, K. H. Brock, C. L. Doerr, and M. M. Moore, “Mutagenicity and clastogenicity of proflavin in L5178Y/TK+/−− 3.7. 2. C cells,” Mutat. Res.- Genet. Tox. 204, 323–328 (1988).

1986 (1)

L. A. Yannuzzi, K. T. Rohrer, L. J. Tindel, R. S. Sobel, M. A. Costanza, W. Shields, and E. Zang, “Fluorescein angiography complication survey,” Ophthalmology 93(5), 611–617 (1986).
[Crossref] [PubMed]

1977 (1)

C. J. Alden and S. Arnott, “Stereochemical model for proflavin intercalation in A-DNA,” Nucleic Acids Res. 4(11), 3855–3861 (1977).
[Crossref] [PubMed]

1975 (1)

N. Otsu, “A threshold selection method from gray-level histograms,” Automatica 11, 23–27 (1975).

Alden, C. J.

C. J. Alden and S. Arnott, “Stereochemical model for proflavin intercalation in A-DNA,” Nucleic Acids Res. 4(11), 3855–3861 (1977).
[Crossref] [PubMed]

Alford, R.

R. Alford, H. M. Simpson, J. Duberman, G. C. Hill, M. Ogawa, C. Regino, H. Kobayashi, and P. L. Choyke, “Toxicity of organic fluorophores used in molecular imaging: literature review,” Mol. Imaging 8(6), 341–354 (2009).

Anandasabapathy, S.

N. D. Parikh, D. Perl, M. H. Lee, B. Shah, Y. Young, S. S. Chang, R. Shukla, A. D. Polydorides, E. Moshier, J. Godbold, E. Zhou, J. Mitcham, R. Richards-Kortum, and S. Anandasabapathy, “In vivo diagnostic accuracy of high-resolution microendoscopy in differentiating neoplastic from non-neoplastic colorectal polyps: a prospective study,” Am. J. Gastroenterol. 109(1), 68–75 (2014).
[Crossref] [PubMed]

T. J. Muldoon, N. Thekkek, D. Roblyer, D. Maru, N. Harpaz, J. Potack, S. Anandasabapathy, and R. Richards-Kortum, “Evaluation of quantitative image analysis criteria for the high-resolution microendoscopic detection of neoplasia in Barrett’s esophagus,” J. Biomed. Opt. 15, 026027 (2010).

Anders, M.

H. Pohl, T. Rösch, M. Vieth, M. Koch, V. Becker, M. Anders, A. C. Khalifa, and A. Meining, “Miniprobe confocal laser microscopy for the detection of invisible neoplasia in patients with Barrett’s oesophagus,” Gut 57(12), 1648–1653 (2008).
[Crossref] [PubMed]

Andersen, S. N.

B. Hofstad, M. H. Vatn, S. N. Andersen, H. S. Huitfeldt, T. Rognum, S. Larsen, and M. Osnes, “Growth of colorectal polyps: redetection and evaluation of unresected polyps for a period of three years,” Gut 39(3), 449–456 (1996).
[Crossref] [PubMed]

Ando, T.

S. Kitabatake, Y. Niwa, R. Miyahara, A. Ohashi, T. Matsuura, Y. Iguchi, Y. Shimoyama, T. Nagasaka, O. Maeda, T. Ando, N. Ohmiya, A. Itoh, Y. Hirooka, and H. Goto, “Confocal endomicroscopy for the diagnosis of gastric cancer in vivo,” Endoscopy 38(11), 1110–1114 (2006).
[Crossref] [PubMed]

Arnott, S.

C. J. Alden and S. Arnott, “Stereochemical model for proflavin intercalation in A-DNA,” Nucleic Acids Res. 4(11), 3855–3861 (1977).
[Crossref] [PubMed]

Baak, L.

W. Curvers, L. Baak, R. Kiesslich, A. Van Oijen, T. Rabenstein, K. Ragunath, J. F. Rey, P. Scholten, U. Seitz, F. Ten Kate, P. Fockens, and J. Bergman, “Chromoendoscopy and narrow-band imaging compared with high-resolution magnification endoscopy in Barrett’s esophagus,” Gastroenterology 134(3), 670–679 (2008).
[Crossref] [PubMed]

Baguley, B. C.

Y. Iwamoto, L. R. Ferguson, A. Pearson, and B. C. Baguley, “Photo-enhancement of the mutagenicity of 9-anilinoacridine derivatives related to the antitumour agent amsacrine,” Mutat. Res. 268(1), 35–41 (1992).
[Crossref] [PubMed]

Barton, J. K.

R. A. Wall and J. K. Barton, “Fluorescence-based surface magnifying chromoendoscopy and optical coherence tomography endoscope,” J. Biomed. Opt. 17(8), 086003 (2012).
[Crossref] [PubMed]

Becker, V.

H. Pohl, T. Rösch, M. Vieth, M. Koch, V. Becker, M. Anders, A. C. Khalifa, and A. Meining, “Miniprobe confocal laser microscopy for the detection of invisible neoplasia in patients with Barrett’s oesophagus,” Gut 57(12), 1648–1653 (2008).
[Crossref] [PubMed]

Bergman, J.

W. Curvers, L. Baak, R. Kiesslich, A. Van Oijen, T. Rabenstein, K. Ragunath, J. F. Rey, P. Scholten, U. Seitz, F. Ten Kate, P. Fockens, and J. Bergman, “Chromoendoscopy and narrow-band imaging compared with high-resolution magnification endoscopy in Barrett’s esophagus,” Gastroenterology 134(3), 670–679 (2008).
[Crossref] [PubMed]

Bhutani, M. S.

D. Shin, M.-A. Protano, A. D. Polydorides, S. M. Dawsey, M. C. Pierce, M. K. Kim, R. A. Schwarz, T. Quang, N. Parikh, and M. S. Bhutani, “Quantitative analysis of high-resolution microendoscopic images for diagnosis of esophageal squamous cell carcinoma,” Clin. Gastroenterol. 13(2), 272–279 (2015).

Boice, J. W.

S. P. Prieto, A. J. Powless, J. W. Boice, S. G. Sharma, and T. J. Muldoon, “Proflavine Hemisulfate as a Fluorescent Contrast Agent for Point-of-Care Cytology,” PLoS One 10(5), e0125598 (2015).
[Crossref] [PubMed]

Braden, B.

P. Trivedi and B. Braden, “Indications, stains and techniques in chromoendoscopy,” QJM 106(2) 117–131 (2013).
[PubMed]

Brewer, M. A.

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Brock, K. H.

D. M. DeMarini, K. H. Brock, C. L. Doerr, and M. M. Moore, “Mutagenicity and clastogenicity of proflavin in L5178Y/TK+/−− 3.7. 2. C cells,” Mutat. Res.- Genet. Tox. 204, 323–328 (1988).

Canto, M. I.

M. B. Wallace, A. Meining, M. I. Canto, P. Fockens, S. Miehlke, T. Roesch, C. J. Lightdale, H. Pohl, D. Carr-Locke, M. Löhr, E. Coron, B. Filoche, M. Giovannini, J. Moreau, C. Schmidt, and R. Kiesslich, “The safety of intravenous fluorescein for confocal laser endomicroscopy in the gastrointestinal tract,” Aliment. Pharmacol. Ther. 31(5), 548–552 (2010).
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Carr-Locke, D.

M. B. Wallace, A. Meining, M. I. Canto, P. Fockens, S. Miehlke, T. Roesch, C. J. Lightdale, H. Pohl, D. Carr-Locke, M. Löhr, E. Coron, B. Filoche, M. Giovannini, J. Moreau, C. Schmidt, and R. Kiesslich, “The safety of intravenous fluorescein for confocal laser endomicroscopy in the gastrointestinal tract,” Aliment. Pharmacol. Ther. 31(5), 548–552 (2010).
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Celli, J. P.

W. Zhong, J. P. Celli, I. Rizvi, Z. Mai, B. Q. Spring, S. H. Yun, and T. Hasan, “In vivo high-resolution fluorescence microendoscopy for ovarian cancer detection and treatment monitoring,” Br. J. Cancer 101(12), 2015–2022 (2009).
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Chang, S. S.

N. D. Parikh, D. Perl, M. H. Lee, B. Shah, Y. Young, S. S. Chang, R. Shukla, A. D. Polydorides, E. Moshier, J. Godbold, E. Zhou, J. Mitcham, R. Richards-Kortum, and S. Anandasabapathy, “In vivo diagnostic accuracy of high-resolution microendoscopy in differentiating neoplastic from non-neoplastic colorectal polyps: a prospective study,” Am. J. Gastroenterol. 109(1), 68–75 (2014).
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Choyke, P. L.

R. Alford, H. M. Simpson, J. Duberman, G. C. Hill, M. Ogawa, C. Regino, H. Kobayashi, and P. L. Choyke, “Toxicity of organic fluorophores used in molecular imaging: literature review,” Mol. Imaging 8(6), 341–354 (2009).

Contag, C. H.

W. Piyawattanametha, H. Ra, Z. Qiu, S. Friedland, J. T. Liu, K. Loewke, G. S. Kino, O. Solgaard, T. D. Wang, M. J. Mandella, and C. H. Contag, “In vivo near-infrared dual-axis confocal microendoscopy in the human lower gastrointestinal tract,” J. Biomed. Opt. 17(2), 021102 (2012).
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P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med. 14(4), 454–458 (2008).
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Coron, E.

M. B. Wallace, A. Meining, M. I. Canto, P. Fockens, S. Miehlke, T. Roesch, C. J. Lightdale, H. Pohl, D. Carr-Locke, M. Löhr, E. Coron, B. Filoche, M. Giovannini, J. Moreau, C. Schmidt, and R. Kiesslich, “The safety of intravenous fluorescein for confocal laser endomicroscopy in the gastrointestinal tract,” Aliment. Pharmacol. Ther. 31(5), 548–552 (2010).
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L. A. Yannuzzi, K. T. Rohrer, L. J. Tindel, R. S. Sobel, M. A. Costanza, W. Shields, and E. Zang, “Fluorescein angiography complication survey,” Ophthalmology 93(5), 611–617 (1986).
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P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med. 14(4), 454–458 (2008).
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Curvers, W.

W. Curvers, L. Baak, R. Kiesslich, A. Van Oijen, T. Rabenstein, K. Ragunath, J. F. Rey, P. Scholten, U. Seitz, F. Ten Kate, P. Fockens, and J. Bergman, “Chromoendoscopy and narrow-band imaging compared with high-resolution magnification endoscopy in Barrett’s esophagus,” Gastroenterology 134(3), 670–679 (2008).
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D. Shin, M.-A. Protano, A. D. Polydorides, S. M. Dawsey, M. C. Pierce, M. K. Kim, R. A. Schwarz, T. Quang, N. Parikh, and M. S. Bhutani, “Quantitative analysis of high-resolution microendoscopic images for diagnosis of esophageal squamous cell carcinoma,” Clin. Gastroenterol. 13(2), 272–279 (2015).

DeMarini, D. M.

D. M. DeMarini, K. H. Brock, C. L. Doerr, and M. M. Moore, “Mutagenicity and clastogenicity of proflavin in L5178Y/TK+/−− 3.7. 2. C cells,” Mutat. Res.- Genet. Tox. 204, 323–328 (1988).

Doerr, C. L.

D. M. DeMarini, K. H. Brock, C. L. Doerr, and M. M. Moore, “Mutagenicity and clastogenicity of proflavin in L5178Y/TK+/−− 3.7. 2. C cells,” Mutat. Res.- Genet. Tox. 204, 323–328 (1988).

Draf, W.

R. Keerl, R. K. Weber, W. Draf, A. Wienke, and S. D. Schaefer, “Use of sodium fluorescein solution for detection of cerebrospinal fluid fistulas: an analysis of 420 administrations and reported complications in Europe and the United States,” Laryngoscope 114(2), 266–272 (2004).
[Crossref] [PubMed]

Du, C. B.

G. A. Sonn, S.-N. E. Jones, T. V. Tarin, C. B. Du, K. E. Mach, K. C. Jensen, and J. C. Liao, “Optical biopsy of human bladder neoplasia with in vivo confocal laser endomicroscopy,” J. Urol. 182(4), 1299–1305 (2009).
[Crossref] [PubMed]

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med. 14(4), 454–458 (2008).
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Duberman, J.

R. Alford, H. M. Simpson, J. Duberman, G. C. Hill, M. Ogawa, C. Regino, H. Kobayashi, and P. L. Choyke, “Toxicity of organic fluorophores used in molecular imaging: literature review,” Mol. Imaging 8(6), 341–354 (2009).

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J. A. Eaden, J. F. Mayberry, British Society for GastroenterologyAssociation of Coloproctology for Great Britain and Ireland, “Guidelines for screening and surveillance of asymptomatic colorectal cancer in patients with inflammatory bowel disease,” Gut 51(Suppl 5), v10–v12 (2002).
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S. J. Miller, B. P. Joshi, Y. Feng, A. Gaustad, E. R. Fearon, and T. D. Wang, “In vivo fluorescence-based endoscopic detection of colon dysplasia in the mouse using a novel peptide probe,” PLoS One 6(3), e17384 (2011).
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R. P. Feenstra and S. C. Tseng, “Comparison of fluorescein and rose bengal staining,” Ophthalmology 99(4), 605–617 (1992).
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S. J. Miller, B. P. Joshi, Y. Feng, A. Gaustad, E. R. Fearon, and T. D. Wang, “In vivo fluorescence-based endoscopic detection of colon dysplasia in the mouse using a novel peptide probe,” PLoS One 6(3), e17384 (2011).
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Ferguson, L. R.

Y. Iwamoto, L. R. Ferguson, A. Pearson, and B. C. Baguley, “Photo-enhancement of the mutagenicity of 9-anilinoacridine derivatives related to the antitumour agent amsacrine,” Mutat. Res. 268(1), 35–41 (1992).
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Filoche, B.

M. B. Wallace, A. Meining, M. I. Canto, P. Fockens, S. Miehlke, T. Roesch, C. J. Lightdale, H. Pohl, D. Carr-Locke, M. Löhr, E. Coron, B. Filoche, M. Giovannini, J. Moreau, C. Schmidt, and R. Kiesslich, “The safety of intravenous fluorescein for confocal laser endomicroscopy in the gastrointestinal tract,” Aliment. Pharmacol. Ther. 31(5), 548–552 (2010).
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Fockens, P.

M. B. Wallace, A. Meining, M. I. Canto, P. Fockens, S. Miehlke, T. Roesch, C. J. Lightdale, H. Pohl, D. Carr-Locke, M. Löhr, E. Coron, B. Filoche, M. Giovannini, J. Moreau, C. Schmidt, and R. Kiesslich, “The safety of intravenous fluorescein for confocal laser endomicroscopy in the gastrointestinal tract,” Aliment. Pharmacol. Ther. 31(5), 548–552 (2010).
[Crossref] [PubMed]

W. Curvers, L. Baak, R. Kiesslich, A. Van Oijen, T. Rabenstein, K. Ragunath, J. F. Rey, P. Scholten, U. Seitz, F. Ten Kate, P. Fockens, and J. Bergman, “Chromoendoscopy and narrow-band imaging compared with high-resolution magnification endoscopy in Barrett’s esophagus,” Gastroenterology 134(3), 670–679 (2008).
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W. Piyawattanametha, H. Ra, Z. Qiu, S. Friedland, J. T. Liu, K. Loewke, G. S. Kino, O. Solgaard, T. D. Wang, M. J. Mandella, and C. H. Contag, “In vivo near-infrared dual-axis confocal microendoscopy in the human lower gastrointestinal tract,” J. Biomed. Opt. 17(2), 021102 (2012).
[Crossref] [PubMed]

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med. 14(4), 454–458 (2008).
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Gaustad, A.

S. J. Miller, B. P. Joshi, Y. Feng, A. Gaustad, E. R. Fearon, and T. D. Wang, “In vivo fluorescence-based endoscopic detection of colon dysplasia in the mouse using a novel peptide probe,” PLoS One 6(3), e17384 (2011).
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T. J. Muldoon, D. Roblyer, M. D. Williams, V. M. Stepanek, R. Richards-Kortum, and A. M. Gillenwater, “Noninvasive imaging of oral neoplasia with a high-resolution fiber-optic microendoscope,” Head Neck 34(3), 305–312 (2012).
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M. B. Wallace, A. Meining, M. I. Canto, P. Fockens, S. Miehlke, T. Roesch, C. J. Lightdale, H. Pohl, D. Carr-Locke, M. Löhr, E. Coron, B. Filoche, M. Giovannini, J. Moreau, C. Schmidt, and R. Kiesslich, “The safety of intravenous fluorescein for confocal laser endomicroscopy in the gastrointestinal tract,” Aliment. Pharmacol. Ther. 31(5), 548–552 (2010).
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Gmitro, A. F.

S. Srivastava, J. J. Rodríguez, A. R. Rouse, M. A. Brewer, and A. F. Gmitro, “Computer-aided identification of ovarian cancer in confocal microendoscope images,” J. Biomed. Opt. 13, 024021 (2008).

Godbold, J.

N. D. Parikh, D. Perl, M. H. Lee, B. Shah, Y. Young, S. S. Chang, R. Shukla, A. D. Polydorides, E. Moshier, J. Godbold, E. Zhou, J. Mitcham, R. Richards-Kortum, and S. Anandasabapathy, “In vivo diagnostic accuracy of high-resolution microendoscopy in differentiating neoplastic from non-neoplastic colorectal polyps: a prospective study,” Am. J. Gastroenterol. 109(1), 68–75 (2014).
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S. Kitabatake, Y. Niwa, R. Miyahara, A. Ohashi, T. Matsuura, Y. Iguchi, Y. Shimoyama, T. Nagasaka, O. Maeda, T. Ando, N. Ohmiya, A. Itoh, Y. Hirooka, and H. Goto, “Confocal endomicroscopy for the diagnosis of gastric cancer in vivo,” Endoscopy 38(11), 1110–1114 (2006).
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P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med. 14(4), 454–458 (2008).
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T. J. Muldoon, N. Thekkek, D. Roblyer, D. Maru, N. Harpaz, J. Potack, S. Anandasabapathy, and R. Richards-Kortum, “Evaluation of quantitative image analysis criteria for the high-resolution microendoscopic detection of neoplasia in Barrett’s esophagus,” J. Biomed. Opt. 15, 026027 (2010).

Hasan, T.

W. Zhong, J. P. Celli, I. Rizvi, Z. Mai, B. Q. Spring, S. H. Yun, and T. Hasan, “In vivo high-resolution fluorescence microendoscopy for ovarian cancer detection and treatment monitoring,” Br. J. Cancer 101(12), 2015–2022 (2009).
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Hill, G. C.

R. Alford, H. M. Simpson, J. Duberman, G. C. Hill, M. Ogawa, C. Regino, H. Kobayashi, and P. L. Choyke, “Toxicity of organic fluorophores used in molecular imaging: literature review,” Mol. Imaging 8(6), 341–354 (2009).

Hirooka, Y.

S. Kitabatake, Y. Niwa, R. Miyahara, A. Ohashi, T. Matsuura, Y. Iguchi, Y. Shimoyama, T. Nagasaka, O. Maeda, T. Ando, N. Ohmiya, A. Itoh, Y. Hirooka, and H. Goto, “Confocal endomicroscopy for the diagnosis of gastric cancer in vivo,” Endoscopy 38(11), 1110–1114 (2006).
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Hofstad, B.

B. Hofstad, M. H. Vatn, S. N. Andersen, H. S. Huitfeldt, T. Rognum, S. Larsen, and M. Osnes, “Growth of colorectal polyps: redetection and evaluation of unresected polyps for a period of three years,” Gut 39(3), 449–456 (1996).
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Hsiung, P.-L.

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med. 14(4), 454–458 (2008).
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Huitfeldt, H. S.

B. Hofstad, M. H. Vatn, S. N. Andersen, H. S. Huitfeldt, T. Rognum, S. Larsen, and M. Osnes, “Growth of colorectal polyps: redetection and evaluation of unresected polyps for a period of three years,” Gut 39(3), 449–456 (1996).
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Iguchi, Y.

S. Kitabatake, Y. Niwa, R. Miyahara, A. Ohashi, T. Matsuura, Y. Iguchi, Y. Shimoyama, T. Nagasaka, O. Maeda, T. Ando, N. Ohmiya, A. Itoh, Y. Hirooka, and H. Goto, “Confocal endomicroscopy for the diagnosis of gastric cancer in vivo,” Endoscopy 38(11), 1110–1114 (2006).
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Itoh, A.

S. Kitabatake, Y. Niwa, R. Miyahara, A. Ohashi, T. Matsuura, Y. Iguchi, Y. Shimoyama, T. Nagasaka, O. Maeda, T. Ando, N. Ohmiya, A. Itoh, Y. Hirooka, and H. Goto, “Confocal endomicroscopy for the diagnosis of gastric cancer in vivo,” Endoscopy 38(11), 1110–1114 (2006).
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S. H. Itzkowitz and D. H. Present, “Consensus conference: colorectal cancer screening and surveillance in inflammatory bowel disease,” Inflamm. Bowel Dis. 11(3), 314–321 (2005).
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Iwamoto, Y.

Y. Iwamoto, L. R. Ferguson, A. Pearson, and B. C. Baguley, “Photo-enhancement of the mutagenicity of 9-anilinoacridine derivatives related to the antitumour agent amsacrine,” Mutat. Res. 268(1), 35–41 (1992).
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Jemal, A.

R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics, 2015,” CA Cancer J. Clin. 65(1), 5–29 (2015).
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Jensen, K. C.

G. A. Sonn, S.-N. E. Jones, T. V. Tarin, C. B. Du, K. E. Mach, K. C. Jensen, and J. C. Liao, “Optical biopsy of human bladder neoplasia with in vivo confocal laser endomicroscopy,” J. Urol. 182(4), 1299–1305 (2009).
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Jones, S.-N. E.

G. A. Sonn, S.-N. E. Jones, T. V. Tarin, C. B. Du, K. E. Mach, K. C. Jensen, and J. C. Liao, “Optical biopsy of human bladder neoplasia with in vivo confocal laser endomicroscopy,” J. Urol. 182(4), 1299–1305 (2009).
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Joshi, B. P.

S. J. Miller, B. P. Joshi, Y. Feng, A. Gaustad, E. R. Fearon, and T. D. Wang, “In vivo fluorescence-based endoscopic detection of colon dysplasia in the mouse using a novel peptide probe,” PLoS One 6(3), e17384 (2011).
[Crossref] [PubMed]

Keerl, R.

R. Keerl, R. K. Weber, W. Draf, A. Wienke, and S. D. Schaefer, “Use of sodium fluorescein solution for detection of cerebrospinal fluid fistulas: an analysis of 420 administrations and reported complications in Europe and the United States,” Laryngoscope 114(2), 266–272 (2004).
[Crossref] [PubMed]

Khalifa, A. C.

H. Pohl, T. Rösch, M. Vieth, M. Koch, V. Becker, M. Anders, A. C. Khalifa, and A. Meining, “Miniprobe confocal laser microscopy for the detection of invisible neoplasia in patients with Barrett’s oesophagus,” Gut 57(12), 1648–1653 (2008).
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Kiesslich, R.

M. B. Wallace, A. Meining, M. I. Canto, P. Fockens, S. Miehlke, T. Roesch, C. J. Lightdale, H. Pohl, D. Carr-Locke, M. Löhr, E. Coron, B. Filoche, M. Giovannini, J. Moreau, C. Schmidt, and R. Kiesslich, “The safety of intravenous fluorescein for confocal laser endomicroscopy in the gastrointestinal tract,” Aliment. Pharmacol. Ther. 31(5), 548–552 (2010).
[Crossref] [PubMed]

W. Curvers, L. Baak, R. Kiesslich, A. Van Oijen, T. Rabenstein, K. Ragunath, J. F. Rey, P. Scholten, U. Seitz, F. Ten Kate, P. Fockens, and J. Bergman, “Chromoendoscopy and narrow-band imaging compared with high-resolution magnification endoscopy in Barrett’s esophagus,” Gastroenterology 134(3), 670–679 (2008).
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R. Kiesslich and M. F. Neurath, “Endoscopic confocal imaging,” Clin. Gastroenterol. Hepatol. 3(7Suppl 1), S58–S60 (2005).
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Kim, M. K.

D. Shin, M.-A. Protano, A. D. Polydorides, S. M. Dawsey, M. C. Pierce, M. K. Kim, R. A. Schwarz, T. Quang, N. Parikh, and M. S. Bhutani, “Quantitative analysis of high-resolution microendoscopic images for diagnosis of esophageal squamous cell carcinoma,” Clin. Gastroenterol. 13(2), 272–279 (2015).

Kino, G. S.

W. Piyawattanametha, H. Ra, Z. Qiu, S. Friedland, J. T. Liu, K. Loewke, G. S. Kino, O. Solgaard, T. D. Wang, M. J. Mandella, and C. H. Contag, “In vivo near-infrared dual-axis confocal microendoscopy in the human lower gastrointestinal tract,” J. Biomed. Opt. 17(2), 021102 (2012).
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Kitabatake, S.

S. Kitabatake, Y. Niwa, R. Miyahara, A. Ohashi, T. Matsuura, Y. Iguchi, Y. Shimoyama, T. Nagasaka, O. Maeda, T. Ando, N. Ohmiya, A. Itoh, Y. Hirooka, and H. Goto, “Confocal endomicroscopy for the diagnosis of gastric cancer in vivo,” Endoscopy 38(11), 1110–1114 (2006).
[Crossref] [PubMed]

Kobayashi, H.

R. Alford, H. M. Simpson, J. Duberman, G. C. Hill, M. Ogawa, C. Regino, H. Kobayashi, and P. L. Choyke, “Toxicity of organic fluorophores used in molecular imaging: literature review,” Mol. Imaging 8(6), 341–354 (2009).

Koch, M.

H. Pohl, T. Rösch, M. Vieth, M. Koch, V. Becker, M. Anders, A. C. Khalifa, and A. Meining, “Miniprobe confocal laser microscopy for the detection of invisible neoplasia in patients with Barrett’s oesophagus,” Gut 57(12), 1648–1653 (2008).
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Kosmidis, P. A.

J. K. Triantafillidis, G. Nasioulas, and P. A. Kosmidis, “Colorectal cancer and inflammatory bowel disease: epidemiology, risk factors, mechanisms of carcinogenesis and prevention strategies,” Anticancer Res. 29(7), 2727–2737 (2009).
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Lai, K. K.

S. P. Prieto, K. K. Lai, J. A. Laryea, J. S. Mizell, and T. J. Muldoon, “Quantitative analysis of ex vivo colorectal epithelium using an automated feature extraction algorithm for microendoscopy image data,” J. Med. Imaging (Bellingham) 3(2), 024502 (2016).
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Larsen, S.

B. Hofstad, M. H. Vatn, S. N. Andersen, H. S. Huitfeldt, T. Rognum, S. Larsen, and M. Osnes, “Growth of colorectal polyps: redetection and evaluation of unresected polyps for a period of three years,” Gut 39(3), 449–456 (1996).
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Laryea, J. A.

S. P. Prieto, K. K. Lai, J. A. Laryea, J. S. Mizell, and T. J. Muldoon, “Quantitative analysis of ex vivo colorectal epithelium using an automated feature extraction algorithm for microendoscopy image data,” J. Med. Imaging (Bellingham) 3(2), 024502 (2016).
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Lee, M. H.

N. D. Parikh, D. Perl, M. H. Lee, B. Shah, Y. Young, S. S. Chang, R. Shukla, A. D. Polydorides, E. Moshier, J. Godbold, E. Zhou, J. Mitcham, R. Richards-Kortum, and S. Anandasabapathy, “In vivo diagnostic accuracy of high-resolution microendoscopy in differentiating neoplastic from non-neoplastic colorectal polyps: a prospective study,” Am. J. Gastroenterol. 109(1), 68–75 (2014).
[Crossref] [PubMed]

Liao, J. C.

G. A. Sonn, S.-N. E. Jones, T. V. Tarin, C. B. Du, K. E. Mach, K. C. Jensen, and J. C. Liao, “Optical biopsy of human bladder neoplasia with in vivo confocal laser endomicroscopy,” J. Urol. 182(4), 1299–1305 (2009).
[Crossref] [PubMed]

Lightdale, C. J.

M. B. Wallace, A. Meining, M. I. Canto, P. Fockens, S. Miehlke, T. Roesch, C. J. Lightdale, H. Pohl, D. Carr-Locke, M. Löhr, E. Coron, B. Filoche, M. Giovannini, J. Moreau, C. Schmidt, and R. Kiesslich, “The safety of intravenous fluorescein for confocal laser endomicroscopy in the gastrointestinal tract,” Aliment. Pharmacol. Ther. 31(5), 548–552 (2010).
[Crossref] [PubMed]

Liu, J. T.

W. Piyawattanametha, H. Ra, Z. Qiu, S. Friedland, J. T. Liu, K. Loewke, G. S. Kino, O. Solgaard, T. D. Wang, M. J. Mandella, and C. H. Contag, “In vivo near-infrared dual-axis confocal microendoscopy in the human lower gastrointestinal tract,” J. Biomed. Opt. 17(2), 021102 (2012).
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Loewke, K.

W. Piyawattanametha, H. Ra, Z. Qiu, S. Friedland, J. T. Liu, K. Loewke, G. S. Kino, O. Solgaard, T. D. Wang, M. J. Mandella, and C. H. Contag, “In vivo near-infrared dual-axis confocal microendoscopy in the human lower gastrointestinal tract,” J. Biomed. Opt. 17(2), 021102 (2012).
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Löhr, M.

M. B. Wallace, A. Meining, M. I. Canto, P. Fockens, S. Miehlke, T. Roesch, C. J. Lightdale, H. Pohl, D. Carr-Locke, M. Löhr, E. Coron, B. Filoche, M. Giovannini, J. Moreau, C. Schmidt, and R. Kiesslich, “The safety of intravenous fluorescein for confocal laser endomicroscopy in the gastrointestinal tract,” Aliment. Pharmacol. Ther. 31(5), 548–552 (2010).
[Crossref] [PubMed]

Lowe, A. W.

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med. 14(4), 454–458 (2008).
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W. Curvers, L. Baak, R. Kiesslich, A. Van Oijen, T. Rabenstein, K. Ragunath, J. F. Rey, P. Scholten, U. Seitz, F. Ten Kate, P. Fockens, and J. Bergman, “Chromoendoscopy and narrow-band imaging compared with high-resolution magnification endoscopy in Barrett’s esophagus,” Gastroenterology 134(3), 670–679 (2008).
[Crossref] [PubMed]

Shah, B.

N. D. Parikh, D. Perl, M. H. Lee, B. Shah, Y. Young, S. S. Chang, R. Shukla, A. D. Polydorides, E. Moshier, J. Godbold, E. Zhou, J. Mitcham, R. Richards-Kortum, and S. Anandasabapathy, “In vivo diagnostic accuracy of high-resolution microendoscopy in differentiating neoplastic from non-neoplastic colorectal polyps: a prospective study,” Am. J. Gastroenterol. 109(1), 68–75 (2014).
[Crossref] [PubMed]

Sharma, S. G.

S. P. Prieto, A. J. Powless, J. W. Boice, S. G. Sharma, and T. J. Muldoon, “Proflavine Hemisulfate as a Fluorescent Contrast Agent for Point-of-Care Cytology,” PLoS One 10(5), e0125598 (2015).
[Crossref] [PubMed]

Shields, W.

L. A. Yannuzzi, K. T. Rohrer, L. J. Tindel, R. S. Sobel, M. A. Costanza, W. Shields, and E. Zang, “Fluorescein angiography complication survey,” Ophthalmology 93(5), 611–617 (1986).
[Crossref] [PubMed]

Shimoyama, Y.

S. Kitabatake, Y. Niwa, R. Miyahara, A. Ohashi, T. Matsuura, Y. Iguchi, Y. Shimoyama, T. Nagasaka, O. Maeda, T. Ando, N. Ohmiya, A. Itoh, Y. Hirooka, and H. Goto, “Confocal endomicroscopy for the diagnosis of gastric cancer in vivo,” Endoscopy 38(11), 1110–1114 (2006).
[Crossref] [PubMed]

Shin, D.

D. Shin, M.-A. Protano, A. D. Polydorides, S. M. Dawsey, M. C. Pierce, M. K. Kim, R. A. Schwarz, T. Quang, N. Parikh, and M. S. Bhutani, “Quantitative analysis of high-resolution microendoscopic images for diagnosis of esophageal squamous cell carcinoma,” Clin. Gastroenterol. 13(2), 272–279 (2015).

Shukla, R.

N. D. Parikh, D. Perl, M. H. Lee, B. Shah, Y. Young, S. S. Chang, R. Shukla, A. D. Polydorides, E. Moshier, J. Godbold, E. Zhou, J. Mitcham, R. Richards-Kortum, and S. Anandasabapathy, “In vivo diagnostic accuracy of high-resolution microendoscopy in differentiating neoplastic from non-neoplastic colorectal polyps: a prospective study,” Am. J. Gastroenterol. 109(1), 68–75 (2014).
[Crossref] [PubMed]

Siegel, R. L.

R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics, 2015,” CA Cancer J. Clin. 65(1), 5–29 (2015).
[Crossref] [PubMed]

Simpson, H. M.

R. Alford, H. M. Simpson, J. Duberman, G. C. Hill, M. Ogawa, C. Regino, H. Kobayashi, and P. L. Choyke, “Toxicity of organic fluorophores used in molecular imaging: literature review,” Mol. Imaging 8(6), 341–354 (2009).

Sobel, R. S.

L. A. Yannuzzi, K. T. Rohrer, L. J. Tindel, R. S. Sobel, M. A. Costanza, W. Shields, and E. Zang, “Fluorescein angiography complication survey,” Ophthalmology 93(5), 611–617 (1986).
[Crossref] [PubMed]

Soetikno, R.

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med. 14(4), 454–458 (2008).
[Crossref] [PubMed]

Solgaard, O.

W. Piyawattanametha, H. Ra, Z. Qiu, S. Friedland, J. T. Liu, K. Loewke, G. S. Kino, O. Solgaard, T. D. Wang, M. J. Mandella, and C. H. Contag, “In vivo near-infrared dual-axis confocal microendoscopy in the human lower gastrointestinal tract,” J. Biomed. Opt. 17(2), 021102 (2012).
[Crossref] [PubMed]

Sonn, G. A.

G. A. Sonn, S.-N. E. Jones, T. V. Tarin, C. B. Du, K. E. Mach, K. C. Jensen, and J. C. Liao, “Optical biopsy of human bladder neoplasia with in vivo confocal laser endomicroscopy,” J. Urol. 182(4), 1299–1305 (2009).
[Crossref] [PubMed]

Spring, B. Q.

W. Zhong, J. P. Celli, I. Rizvi, Z. Mai, B. Q. Spring, S. H. Yun, and T. Hasan, “In vivo high-resolution fluorescence microendoscopy for ovarian cancer detection and treatment monitoring,” Br. J. Cancer 101(12), 2015–2022 (2009).
[Crossref] [PubMed]

Srivastava, S.

S. Srivastava, J. J. Rodríguez, A. R. Rouse, M. A. Brewer, and A. F. Gmitro, “Computer-aided identification of ovarian cancer in confocal microendoscope images,” J. Biomed. Opt. 13, 024021 (2008).

Stepanek, V. M.

T. J. Muldoon, D. Roblyer, M. D. Williams, V. M. Stepanek, R. Richards-Kortum, and A. M. Gillenwater, “Noninvasive imaging of oral neoplasia with a high-resolution fiber-optic microendoscope,” Head Neck 34(3), 305–312 (2012).
[Crossref] [PubMed]

Tarin, T. V.

G. A. Sonn, S.-N. E. Jones, T. V. Tarin, C. B. Du, K. E. Mach, K. C. Jensen, and J. C. Liao, “Optical biopsy of human bladder neoplasia with in vivo confocal laser endomicroscopy,” J. Urol. 182(4), 1299–1305 (2009).
[Crossref] [PubMed]

Ten Kate, F.

W. Curvers, L. Baak, R. Kiesslich, A. Van Oijen, T. Rabenstein, K. Ragunath, J. F. Rey, P. Scholten, U. Seitz, F. Ten Kate, P. Fockens, and J. Bergman, “Chromoendoscopy and narrow-band imaging compared with high-resolution magnification endoscopy in Barrett’s esophagus,” Gastroenterology 134(3), 670–679 (2008).
[Crossref] [PubMed]

Thekkek, N.

T. J. Muldoon, N. Thekkek, D. Roblyer, D. Maru, N. Harpaz, J. Potack, S. Anandasabapathy, and R. Richards-Kortum, “Evaluation of quantitative image analysis criteria for the high-resolution microendoscopic detection of neoplasia in Barrett’s esophagus,” J. Biomed. Opt. 15, 026027 (2010).

Tindel, L. J.

L. A. Yannuzzi, K. T. Rohrer, L. J. Tindel, R. S. Sobel, M. A. Costanza, W. Shields, and E. Zang, “Fluorescein angiography complication survey,” Ophthalmology 93(5), 611–617 (1986).
[Crossref] [PubMed]

Tipoe, G. L.

G. L. Tipoe and F. H. White, “Quantitative assessment of normal and potentially premalignant epithelium at different levels of human colorectal crypts,” Histol. Histopathol. 13(2), 395–404 (1998).
[PubMed]

Triantafillidis, J. K.

J. K. Triantafillidis, G. Nasioulas, and P. A. Kosmidis, “Colorectal cancer and inflammatory bowel disease: epidemiology, risk factors, mechanisms of carcinogenesis and prevention strategies,” Anticancer Res. 29(7), 2727–2737 (2009).
[PubMed]

Trivedi, P.

P. Trivedi and B. Braden, “Indications, stains and techniques in chromoendoscopy,” QJM 106(2) 117–131 (2013).
[PubMed]

Tseng, S. C.

R. P. Feenstra and S. C. Tseng, “Comparison of fluorescein and rose bengal staining,” Ophthalmology 99(4), 605–617 (1992).
[Crossref] [PubMed]

Van Oijen, A.

W. Curvers, L. Baak, R. Kiesslich, A. Van Oijen, T. Rabenstein, K. Ragunath, J. F. Rey, P. Scholten, U. Seitz, F. Ten Kate, P. Fockens, and J. Bergman, “Chromoendoscopy and narrow-band imaging compared with high-resolution magnification endoscopy in Barrett’s esophagus,” Gastroenterology 134(3), 670–679 (2008).
[Crossref] [PubMed]

Vatn, M. H.

B. Hofstad, M. H. Vatn, S. N. Andersen, H. S. Huitfeldt, T. Rognum, S. Larsen, and M. Osnes, “Growth of colorectal polyps: redetection and evaluation of unresected polyps for a period of three years,” Gut 39(3), 449–456 (1996).
[Crossref] [PubMed]

Vieth, M.

H. Pohl, T. Rösch, M. Vieth, M. Koch, V. Becker, M. Anders, A. C. Khalifa, and A. Meining, “Miniprobe confocal laser microscopy for the detection of invisible neoplasia in patients with Barrett’s oesophagus,” Gut 57(12), 1648–1653 (2008).
[Crossref] [PubMed]

Wall, R. A.

R. A. Wall and J. K. Barton, “Fluorescence-based surface magnifying chromoendoscopy and optical coherence tomography endoscope,” J. Biomed. Opt. 17(8), 086003 (2012).
[Crossref] [PubMed]

Wallace, M. B.

M. B. Wallace, A. Meining, M. I. Canto, P. Fockens, S. Miehlke, T. Roesch, C. J. Lightdale, H. Pohl, D. Carr-Locke, M. Löhr, E. Coron, B. Filoche, M. Giovannini, J. Moreau, C. Schmidt, and R. Kiesslich, “The safety of intravenous fluorescein for confocal laser endomicroscopy in the gastrointestinal tract,” Aliment. Pharmacol. Ther. 31(5), 548–552 (2010).
[Crossref] [PubMed]

Wang, T. D.

W. Piyawattanametha, H. Ra, Z. Qiu, S. Friedland, J. T. Liu, K. Loewke, G. S. Kino, O. Solgaard, T. D. Wang, M. J. Mandella, and C. H. Contag, “In vivo near-infrared dual-axis confocal microendoscopy in the human lower gastrointestinal tract,” J. Biomed. Opt. 17(2), 021102 (2012).
[Crossref] [PubMed]

S. J. Miller, B. P. Joshi, Y. Feng, A. Gaustad, E. R. Fearon, and T. D. Wang, “In vivo fluorescence-based endoscopic detection of colon dysplasia in the mouse using a novel peptide probe,” PLoS One 6(3), e17384 (2011).
[Crossref] [PubMed]

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med. 14(4), 454–458 (2008).
[Crossref] [PubMed]

Weber, R. K.

R. Keerl, R. K. Weber, W. Draf, A. Wienke, and S. D. Schaefer, “Use of sodium fluorescein solution for detection of cerebrospinal fluid fistulas: an analysis of 420 administrations and reported complications in Europe and the United States,” Laryngoscope 114(2), 266–272 (2004).
[Crossref] [PubMed]

White, F. H.

G. L. Tipoe and F. H. White, “Quantitative assessment of normal and potentially premalignant epithelium at different levels of human colorectal crypts,” Histol. Histopathol. 13(2), 395–404 (1998).
[PubMed]

Wienke, A.

R. Keerl, R. K. Weber, W. Draf, A. Wienke, and S. D. Schaefer, “Use of sodium fluorescein solution for detection of cerebrospinal fluid fistulas: an analysis of 420 administrations and reported complications in Europe and the United States,” Laryngoscope 114(2), 266–272 (2004).
[Crossref] [PubMed]

Williams, M. D.

T. J. Muldoon, D. Roblyer, M. D. Williams, V. M. Stepanek, R. Richards-Kortum, and A. M. Gillenwater, “Noninvasive imaging of oral neoplasia with a high-resolution fiber-optic microendoscope,” Head Neck 34(3), 305–312 (2012).
[Crossref] [PubMed]

Wu, A. P.

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med. 14(4), 454–458 (2008).
[Crossref] [PubMed]

Yannuzzi, L. A.

L. A. Yannuzzi, K. T. Rohrer, L. J. Tindel, R. S. Sobel, M. A. Costanza, W. Shields, and E. Zang, “Fluorescein angiography complication survey,” Ophthalmology 93(5), 611–617 (1986).
[Crossref] [PubMed]

Young, Y.

N. D. Parikh, D. Perl, M. H. Lee, B. Shah, Y. Young, S. S. Chang, R. Shukla, A. D. Polydorides, E. Moshier, J. Godbold, E. Zhou, J. Mitcham, R. Richards-Kortum, and S. Anandasabapathy, “In vivo diagnostic accuracy of high-resolution microendoscopy in differentiating neoplastic from non-neoplastic colorectal polyps: a prospective study,” Am. J. Gastroenterol. 109(1), 68–75 (2014).
[Crossref] [PubMed]

Yun, S. H.

W. Zhong, J. P. Celli, I. Rizvi, Z. Mai, B. Q. Spring, S. H. Yun, and T. Hasan, “In vivo high-resolution fluorescence microendoscopy for ovarian cancer detection and treatment monitoring,” Br. J. Cancer 101(12), 2015–2022 (2009).
[Crossref] [PubMed]

Zang, E.

L. A. Yannuzzi, K. T. Rohrer, L. J. Tindel, R. S. Sobel, M. A. Costanza, W. Shields, and E. Zang, “Fluorescein angiography complication survey,” Ophthalmology 93(5), 611–617 (1986).
[Crossref] [PubMed]

Zhong, W.

W. Zhong, J. P. Celli, I. Rizvi, Z. Mai, B. Q. Spring, S. H. Yun, and T. Hasan, “In vivo high-resolution fluorescence microendoscopy for ovarian cancer detection and treatment monitoring,” Br. J. Cancer 101(12), 2015–2022 (2009).
[Crossref] [PubMed]

Zhou, E.

N. D. Parikh, D. Perl, M. H. Lee, B. Shah, Y. Young, S. S. Chang, R. Shukla, A. D. Polydorides, E. Moshier, J. Godbold, E. Zhou, J. Mitcham, R. Richards-Kortum, and S. Anandasabapathy, “In vivo diagnostic accuracy of high-resolution microendoscopy in differentiating neoplastic from non-neoplastic colorectal polyps: a prospective study,” Am. J. Gastroenterol. 109(1), 68–75 (2014).
[Crossref] [PubMed]

Aliment. Pharmacol. Ther. (1)

M. B. Wallace, A. Meining, M. I. Canto, P. Fockens, S. Miehlke, T. Roesch, C. J. Lightdale, H. Pohl, D. Carr-Locke, M. Löhr, E. Coron, B. Filoche, M. Giovannini, J. Moreau, C. Schmidt, and R. Kiesslich, “The safety of intravenous fluorescein for confocal laser endomicroscopy in the gastrointestinal tract,” Aliment. Pharmacol. Ther. 31(5), 548–552 (2010).
[Crossref] [PubMed]

Am. J. Gastroenterol. (1)

N. D. Parikh, D. Perl, M. H. Lee, B. Shah, Y. Young, S. S. Chang, R. Shukla, A. D. Polydorides, E. Moshier, J. Godbold, E. Zhou, J. Mitcham, R. Richards-Kortum, and S. Anandasabapathy, “In vivo diagnostic accuracy of high-resolution microendoscopy in differentiating neoplastic from non-neoplastic colorectal polyps: a prospective study,” Am. J. Gastroenterol. 109(1), 68–75 (2014).
[Crossref] [PubMed]

Anticancer Res. (1)

J. K. Triantafillidis, G. Nasioulas, and P. A. Kosmidis, “Colorectal cancer and inflammatory bowel disease: epidemiology, risk factors, mechanisms of carcinogenesis and prevention strategies,” Anticancer Res. 29(7), 2727–2737 (2009).
[PubMed]

Automatica (1)

N. Otsu, “A threshold selection method from gray-level histograms,” Automatica 11, 23–27 (1975).

Br. J. Cancer (1)

W. Zhong, J. P. Celli, I. Rizvi, Z. Mai, B. Q. Spring, S. H. Yun, and T. Hasan, “In vivo high-resolution fluorescence microendoscopy for ovarian cancer detection and treatment monitoring,” Br. J. Cancer 101(12), 2015–2022 (2009).
[Crossref] [PubMed]

CA Cancer J. Clin. (1)

R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics, 2015,” CA Cancer J. Clin. 65(1), 5–29 (2015).
[Crossref] [PubMed]

Clin. Gastroenterol. (1)

D. Shin, M.-A. Protano, A. D. Polydorides, S. M. Dawsey, M. C. Pierce, M. K. Kim, R. A. Schwarz, T. Quang, N. Parikh, and M. S. Bhutani, “Quantitative analysis of high-resolution microendoscopic images for diagnosis of esophageal squamous cell carcinoma,” Clin. Gastroenterol. 13(2), 272–279 (2015).

Clin. Gastroenterol. Hepatol. (1)

R. Kiesslich and M. F. Neurath, “Endoscopic confocal imaging,” Clin. Gastroenterol. Hepatol. 3(7Suppl 1), S58–S60 (2005).
[Crossref] [PubMed]

Endoscopy (1)

S. Kitabatake, Y. Niwa, R. Miyahara, A. Ohashi, T. Matsuura, Y. Iguchi, Y. Shimoyama, T. Nagasaka, O. Maeda, T. Ando, N. Ohmiya, A. Itoh, Y. Hirooka, and H. Goto, “Confocal endomicroscopy for the diagnosis of gastric cancer in vivo,” Endoscopy 38(11), 1110–1114 (2006).
[Crossref] [PubMed]

Gastroenterology (1)

W. Curvers, L. Baak, R. Kiesslich, A. Van Oijen, T. Rabenstein, K. Ragunath, J. F. Rey, P. Scholten, U. Seitz, F. Ten Kate, P. Fockens, and J. Bergman, “Chromoendoscopy and narrow-band imaging compared with high-resolution magnification endoscopy in Barrett’s esophagus,” Gastroenterology 134(3), 670–679 (2008).
[Crossref] [PubMed]

Gut (3)

B. Hofstad, M. H. Vatn, S. N. Andersen, H. S. Huitfeldt, T. Rognum, S. Larsen, and M. Osnes, “Growth of colorectal polyps: redetection and evaluation of unresected polyps for a period of three years,” Gut 39(3), 449–456 (1996).
[Crossref] [PubMed]

H. Pohl, T. Rösch, M. Vieth, M. Koch, V. Becker, M. Anders, A. C. Khalifa, and A. Meining, “Miniprobe confocal laser microscopy for the detection of invisible neoplasia in patients with Barrett’s oesophagus,” Gut 57(12), 1648–1653 (2008).
[Crossref] [PubMed]

J. A. Eaden, J. F. Mayberry, British Society for GastroenterologyAssociation of Coloproctology for Great Britain and Ireland, “Guidelines for screening and surveillance of asymptomatic colorectal cancer in patients with inflammatory bowel disease,” Gut 51(Suppl 5), v10–v12 (2002).
[Crossref] [PubMed]

Head Neck (1)

T. J. Muldoon, D. Roblyer, M. D. Williams, V. M. Stepanek, R. Richards-Kortum, and A. M. Gillenwater, “Noninvasive imaging of oral neoplasia with a high-resolution fiber-optic microendoscope,” Head Neck 34(3), 305–312 (2012).
[Crossref] [PubMed]

Histol. Histopathol. (1)

G. L. Tipoe and F. H. White, “Quantitative assessment of normal and potentially premalignant epithelium at different levels of human colorectal crypts,” Histol. Histopathol. 13(2), 395–404 (1998).
[PubMed]

Inflamm. Bowel Dis. (1)

S. H. Itzkowitz and D. H. Present, “Consensus conference: colorectal cancer screening and surveillance in inflammatory bowel disease,” Inflamm. Bowel Dis. 11(3), 314–321 (2005).
[Crossref] [PubMed]

J. Biomed. Opt. (4)

R. A. Wall and J. K. Barton, “Fluorescence-based surface magnifying chromoendoscopy and optical coherence tomography endoscope,” J. Biomed. Opt. 17(8), 086003 (2012).
[Crossref] [PubMed]

W. Piyawattanametha, H. Ra, Z. Qiu, S. Friedland, J. T. Liu, K. Loewke, G. S. Kino, O. Solgaard, T. D. Wang, M. J. Mandella, and C. H. Contag, “In vivo near-infrared dual-axis confocal microendoscopy in the human lower gastrointestinal tract,” J. Biomed. Opt. 17(2), 021102 (2012).
[Crossref] [PubMed]

T. J. Muldoon, N. Thekkek, D. Roblyer, D. Maru, N. Harpaz, J. Potack, S. Anandasabapathy, and R. Richards-Kortum, “Evaluation of quantitative image analysis criteria for the high-resolution microendoscopic detection of neoplasia in Barrett’s esophagus,” J. Biomed. Opt. 15, 026027 (2010).

S. Srivastava, J. J. Rodríguez, A. R. Rouse, M. A. Brewer, and A. F. Gmitro, “Computer-aided identification of ovarian cancer in confocal microendoscope images,” J. Biomed. Opt. 13, 024021 (2008).

J. Med. Imaging (Bellingham) (1)

S. P. Prieto, K. K. Lai, J. A. Laryea, J. S. Mizell, and T. J. Muldoon, “Quantitative analysis of ex vivo colorectal epithelium using an automated feature extraction algorithm for microendoscopy image data,” J. Med. Imaging (Bellingham) 3(2), 024502 (2016).
[Crossref] [PubMed]

J. Urol. (1)

G. A. Sonn, S.-N. E. Jones, T. V. Tarin, C. B. Du, K. E. Mach, K. C. Jensen, and J. C. Liao, “Optical biopsy of human bladder neoplasia with in vivo confocal laser endomicroscopy,” J. Urol. 182(4), 1299–1305 (2009).
[Crossref] [PubMed]

Laryngoscope (1)

R. Keerl, R. K. Weber, W. Draf, A. Wienke, and S. D. Schaefer, “Use of sodium fluorescein solution for detection of cerebrospinal fluid fistulas: an analysis of 420 administrations and reported complications in Europe and the United States,” Laryngoscope 114(2), 266–272 (2004).
[Crossref] [PubMed]

Mol. Imaging (1)

R. Alford, H. M. Simpson, J. Duberman, G. C. Hill, M. Ogawa, C. Regino, H. Kobayashi, and P. L. Choyke, “Toxicity of organic fluorophores used in molecular imaging: literature review,” Mol. Imaging 8(6), 341–354 (2009).

Mutat. Res. (1)

Y. Iwamoto, L. R. Ferguson, A. Pearson, and B. C. Baguley, “Photo-enhancement of the mutagenicity of 9-anilinoacridine derivatives related to the antitumour agent amsacrine,” Mutat. Res. 268(1), 35–41 (1992).
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Nat. Med. (1)

P.-L. Hsiung, J. Hardy, S. Friedland, R. Soetikno, C. B. Du, A. P. Wu, P. Sahbaie, J. M. Crawford, A. W. Lowe, C. H. Contag, and T. D. Wang, “Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy,” Nat. Med. 14(4), 454–458 (2008).
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Ophthalmology (2)

R. P. Feenstra and S. C. Tseng, “Comparison of fluorescein and rose bengal staining,” Ophthalmology 99(4), 605–617 (1992).
[Crossref] [PubMed]

L. A. Yannuzzi, K. T. Rohrer, L. J. Tindel, R. S. Sobel, M. A. Costanza, W. Shields, and E. Zang, “Fluorescein angiography complication survey,” Ophthalmology 93(5), 611–617 (1986).
[Crossref] [PubMed]

PLoS One (2)

S. J. Miller, B. P. Joshi, Y. Feng, A. Gaustad, E. R. Fearon, and T. D. Wang, “In vivo fluorescence-based endoscopic detection of colon dysplasia in the mouse using a novel peptide probe,” PLoS One 6(3), e17384 (2011).
[Crossref] [PubMed]

S. P. Prieto, A. J. Powless, J. W. Boice, S. G. Sharma, and T. J. Muldoon, “Proflavine Hemisulfate as a Fluorescent Contrast Agent for Point-of-Care Cytology,” PLoS One 10(5), e0125598 (2015).
[Crossref] [PubMed]

QJM (1)

P. Trivedi and B. Braden, “Indications, stains and techniques in chromoendoscopy,” QJM 106(2) 117–131 (2013).
[PubMed]

Other (2)

S. P. Prieto, A. J. Powless, K. Lai, J. A. Laryea, J. S. Mizell, and T. J. Muldoon, “Qualitative and quantitative comparison of colonic microendoscopy image features to histopathology,” in SPIE BiOS, (International Society for Optics and Photonics, 2015), 93280B–93280B–93288.

H. M. Said, F. K. Ghishan, J. D. Kaunitz, J. L. Merchant, and D. P. C. M. J. D. Wood, Physiology of the Gastrointestinal Tract, Two Volume Set (Elsevier Science, New York, UNITED STATES, 2012).

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Figures (9)

Fig. 1
Fig. 1

(a) Example of grid pattern on close-up of individual crypt (line profiles extracted every 40 pixels), a single pixel intensity line profile plotted as an example, and peaks and trough (red arrows) labelled. (b) Example of effect of changing the contrast limit pairs on conversion into a binary image. (c) Table of contrast limit combinations tested for automated crypt detection sensitivity. Contrast enhancement scales image intensity values (0 to 255) between 0 and 1. Both upper and lower contrast limits were iteratively increased by 10% to cover a range from [0.1 0.2] to [0.8 0.9]. Gray region depicts impractical contrast limit pairs. Scale bars are 100μm.

Fig. 2
Fig. 2

Qualitative comparison between microendoscopic images of bulk colorectal porcine and caprine tissue stained with proflavine and fluorescein. (a) and (b) Tissue stained with fluorescein (0.04% (w/v) in PBS), imaged at 50ms exposure and 5dB gain. (c) and (d) Tissue stained with proflavine (0.01% (w/v in PBS)), imaged at 100ms exposure and 5dB gain. (a) and (c) Porcine tissue; (b) and (d) caprine tissue. All images have been equally contrast-enhanced for publishing; colorbar shows intensity values from 0 to 255. Scale bar is 250µm.

Fig. 3
Fig. 3

Qualitative comparison between multiphoton images of bulk colorectal caprine tissue stained with (a) fluorescein and (b) proflavine. (a) Tissue stained with fluorescein (0.04% (w/v) in distilled water). Yellow arrow points to fluorescein pooling in the center of the crypt. (b) Tissue stained with proflavine (0.01% (w/v in PBS)); white box inset shows a single stained cell, with yellow arrow pointing to the nuclear membrane. Both images were taken at 100 cumulative frames, 15fps, 20mW at sample, and have been equally enhanced for publication. Red scale bar is 100µm.

Fig. 4
Fig. 4

Qualitative comparison of multiphoton images of bulk colorectal animal tissue stained with fluorescein and proflavine at 20μm, 60μm, and 100μm below the epithelial surface. Caprine tissue stained with fluorescein (0.04% (w/v) in distilled water). Porcine tissue stained with proflavine (0.05% (w/v) in 1x PBS). All images were taken at 100 cumulative frames, 15fps, 20mW at sample, and have been enhanced for publication. Scale bar is 100µm.

Fig. 5
Fig. 5

Comparison of different concentrations of topical contrast agents. Three different concentrations of each contrast agent, fluorescein and proflavine, were prepared at 0.01% (w/v), 0.05% (w/v), and 0.1% (w/v) in 1x PBS. Average image intensities (N = 10 images) of porcine colorectal tissue were plotted; error bars denote standard error. Fluorescein was significantly brighter than proflavine at each individual concentration, but fluorescein at 0.01% (w/v) was not significantly different from proflavine at 0.1% (w/v); statistical values were obtained from post-hoc testing of a one-way ANOVA using Tukey’s honestly significant difference (HSD), with p-value <0.05 as the criterion for significant difference. Microendoscopy images on the right are shown for qualitative comparison, and have not been contrast-enhanced; scale bar is 100μm.

Fig. 6
Fig. 6

Optimization of crypt detection sensitivity by combination of contrast limit pairs for porcine tissue stained with (a) and (b) proflavine (0.01% (w/v)) and (c) and (d) fluorescein (0.04% (w/v) in PBS). (a) and (c) Heatmaps of the average percent sensitivity for each contrast limit pair; colorbars are average percent sensitivity. As with Fig. 2, the x-axes display the upper contrast limits, and the y-axes display the lower contrast limits. (b) and (d) Average test sensitivity, after 10 iterations of fivefold cross-validation, for each contrast limit pair or combination of contrast limit pairs. Maximum standard deviation of averages among all points was <0.61%. Heatmaps (a) and (c) are internally numbered with the selection of the highest sensitivity values per row, for clear correlation of numbered contrast limit pairs to the x-axis combinations in plots (b) and (d).

Fig. 7
Fig. 7

Comparison of automated crypt detection between microendoscopy images of bulk colorectal caprine tissue stained with (a) fluorescein and (b) proflavine. Yellow asterisks mark the centroids determined with the QFEA. (a) Tissue stained with fluorescein (0.04% (w/v) in distilled water). (b) Tissue stained with proflavine (0.01% (w/v in PBS)). Both images have been equally enhanced for publishing. Scale bar is 200µm.

Fig. 8
Fig. 8

(a) Average sensitivity and positive predictive values (PPV) of the QFEA crypt detection versus the QR cutoff value; aggregate performance plotted against QR was calculated using images with QR values equal to or higher to the QR cutoff value labeled in the x-axis. PS: Proflavine Sensitivity; PP: Proflavine PPV; FS: Fluorescein Sensitivity; FP: Fluorescein PPV. (b) Percentage of images with QR values equal to or higher than the labeled QR cutoff value; one hundred images per group. F: Fluorescein; P: Proflavine.

Fig. 9
Fig. 9

Quantitative comparison of crypt area and circularity. (a) Example of microendoscopic images of normal and adenocarcinoma regions. Scale bar is 100μm. (b) Average crypt area for normal and adenocarcinoma regions (N = 416 crypts, N = 603 crypts, respectively). P-value = 0.035. (c) Average crypt circularity for normal and adenocarcinoma regions (N = 416 crypts, N = 603 crypts, respectively). P-value = 0.13.

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