Abstract

Cervical cancers are primarily diagnosed via colposcopy, in which the tissue is visually assessed by a clinician for abnormalities, followed by directed biopsies and histologic analysis of excised tissue. Optical biopsy technologies offer a less invasive method of imaging such that subcellular features can be resolved without removing tissue. These techniques, however, are limited in field-of-view by the distal end of the probe. We present a prototype that incorporates a rigid, machinable waveguide that is in direct contact with a fluorescently-labeled sample paired with a scanning fluorescent microscope. The system is capable of imaging large areas of tissue without the need to re-position the tissue-probe interface. A mosaicing algorithm was developed to quantify scanning shifts and stitch neighboring frames together to increase the field-of-view. Our prototype can yield a maximum axial resolution of <5 µm for individual frames and can produce mosaiced images with a field-of-view greater than 15 mm x 15 mm without sacrificing resolution. We validated the system with a 1951 USAF resolution target, fluorescent in vitro standards, and a patient study where ex vivo conization samples of squamous cervical epithelium were imaged. The results of the patient study indicate that architectural features of subcellular components could be detected and differentiated between normal tissue and precancerous lesions.

© 2019 Optical Society of America under the terms of the OSA Open Access Publishing Agreement

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2018 (1)

N. Pantano, B. Hunt, R. A. Schwarz, S. Parra, K. Cherry, J. C. Possati-Resende, A. Longatto-Filho, J. H. T. G. Fregnani, P. E. Castle, K. Schmeler, and R. Richards-Kortum, “Is proflavine exposure associated with disease progression in women with cervical dysplasia? A brief report,” Photochem. Photobiol. 94(6), 1308–1313 (2018).
[Crossref]

2017 (3)

S. P. Prieto, K. K. Lai, J. A. Laryea, J. S. Mizell, W. C. Mustain, and T. J. Muldoon, “Fluorescein as a topical fluorescent contrast agent for quantitative microendoscopic inspection of colorectal epithelium,” Biomed. Opt. Express 8(4), 2324–2338 (2017).
[Crossref]

B. Hill, S. F. Lam, P. Lane, C. MacAulay, L. Fradkin, and M. Follen, “Established and emerging optical technologies for the real-time detection of cervical neoplasia: a review,” J. Cancer Ther. 08(13), 1241–1278 (2017).
[Crossref]

N. Bodenschatz, C. F. Poh, S. Lam, P. M. Lane, M. Guillaud, and C. E. MacAulay, “Dual-mode endomicroscopy for detection of epithelial dysplasia in the mouth: a descriptive pilot study,” J. Biomed. Opt. 22(08), 1 (2017).
[Crossref]

2016 (3)

N. Bodenschatz, S. Lam, A. Carraro, J. Korbelik, D. M. Miller, J. N. McAlpine, M. Lee, A. Kienle, and C. E. MacAulay, “Diffuse optical microscopy for quantification of depth-dependent epithelial backscattering in the cervix,” J. Biomed. Opt. 21(6), 066001 (2016).
[Crossref]

L. T. Chuang, S. Temin, R. Camacho, A. Dueñas-Gonzalez, S. Feldman, M. Gultekin, V. Gupta, S. Horton, G. Jacob, E. A. Kidd, and K. Lishimpi, “Management and care of women with invasive cervical cancer: American Society of Clinical Oncology resource-stratified clinical practice guideline,” Journal of Global Oncology 2(5), 311–340 (2016).
[Crossref]

N. Benzerdjeb, C. Garbar, P. Camparo, and H. Sevestre, “Digital holographic microscopy as screening tool for cervical cancer preliminary study,” Cancer cytopathology 124(8), 573–580 (2016).
[Crossref]

2015 (1)

B. Obstoy, M. Salaun, L. Veresezan, R. Sesboüé, P. Bohn, F. X. Boland, and L. Thiberville, “Safety and performance analysis of acriflavine and methylene blue for in vivo imaging of precancerous lesions using fibered confocal fluorescence microscopy (FCFM): an experimental study,” BMC Pulm. Med. 15(1), 30 (2015).
[Crossref]

2014 (2)

J. S. Louie, R. Richards-Kortum, and S. Anandasbapathy, “Applications and advancements in the use of high-resolution microendoscopy for detection of gastrointestinal neoplasia,” Clin. Gastroenterol. Hepatol. 12(11), 1789–1792 (2014).
[Crossref]

S. Karbasi, R. J. Frazier, K. W. Koch, T. Hawkins, J. Ballato, and A. Mafi, “Image transport through a disordered optical fibre mediated by transverse Anderson localization,” Nat. Commun. 5(1), 3362 (2014).
[Crossref]

2012 (3)

2011 (1)

K. E. Loewke, D. B. Camarillo, W. Piyawattanametha, M. J. Mandella, C. H. Contag, S. Thrun, and J. K. Salisbury, “In vivo micro-image mosaicing,” IEEE Trans. Biomed. Eng. 58(1), 159–171 (2011).
[Crossref]

2009 (1)

J. Tan, M. A. Quinn, J. M. Pyman, P. M. Delaney, and W. J. McLaren, “Detection of cervical intraepithelial neoplasia in vivo using confocal endomicroscopy,” BJOG: An International Journal of Obstetrics & Gynaecology 116(12), 1663–1670 (2009).
[Crossref]

2008 (2)

M. Guizar-Sicairos, S. T. Thurman, and J. R. Fienup, “Efficient subpixel image registration algorithms,” Opt. Lett. 33(2), 156–158 (2008).
[Crossref]

S. B. Cantor, M. Cardenas-Turanzas, D. D. Cox, E. N. Atkinson, G. M. Norgueras-Gonzalez, J. R. Beck, M. Follen, and J. L. Benedet, “Accuracy of colposcopy in the diagnostic compared with the screening setting,” Obstet. Gynecol. 111(1), 7–14 (2008).
[Crossref]

2006 (2)

J. P. Baak, A. J. Krushe, S. J. Robboy, E. A. Janssen, B. van Dierman, and I. Skaland, “Dynamic behavioural interpretation of cervical intraepithelial neoplasia with molecular markers,” J. Clin. Pathol. 59(10), 1017–1028 (2006).
[Crossref]

T. Vercauteren, A. Perchant, G. Malandain, X. Pennec, and N. Ayache, “Robust mosaicing with correction of motion distortions and tissue deformations for in vivo fibered microscopy,” Med. Image Anal. 10(5), 673–692 (2006).
[Crossref]

2003 (1)

1989 (1)

H. De Raedt, A. D. Lagendijk, and P. de Vries, “Transverse localization of light,” Phys. Rev. Lett. 62(1), 47–50 (1989).
[Crossref]

Anandasbapathy, S.

J. S. Louie, R. Richards-Kortum, and S. Anandasbapathy, “Applications and advancements in the use of high-resolution microendoscopy for detection of gastrointestinal neoplasia,” Clin. Gastroenterol. Hepatol. 12(11), 1789–1792 (2014).
[Crossref]

Atkinson, E. N.

S. B. Cantor, M. Cardenas-Turanzas, D. D. Cox, E. N. Atkinson, G. M. Norgueras-Gonzalez, J. R. Beck, M. Follen, and J. L. Benedet, “Accuracy of colposcopy in the diagnostic compared with the screening setting,” Obstet. Gynecol. 111(1), 7–14 (2008).
[Crossref]

Ayache, N.

T. Vercauteren, A. Perchant, G. Malandain, X. Pennec, and N. Ayache, “Robust mosaicing with correction of motion distortions and tissue deformations for in vivo fibered microscopy,” Med. Image Anal. 10(5), 673–692 (2006).
[Crossref]

Baak, J. P.

J. P. Baak, A. J. Krushe, S. J. Robboy, E. A. Janssen, B. van Dierman, and I. Skaland, “Dynamic behavioural interpretation of cervical intraepithelial neoplasia with molecular markers,” J. Clin. Pathol. 59(10), 1017–1028 (2006).
[Crossref]

Ballato, J.

S. Karbasi, R. J. Frazier, K. W. Koch, T. Hawkins, J. Ballato, and A. Mafi, “Image transport through a disordered optical fibre mediated by transverse Anderson localization,” Nat. Commun. 5(1), 3362 (2014).
[Crossref]

Beck, J. R.

S. B. Cantor, M. Cardenas-Turanzas, D. D. Cox, E. N. Atkinson, G. M. Norgueras-Gonzalez, J. R. Beck, M. Follen, and J. L. Benedet, “Accuracy of colposcopy in the diagnostic compared with the screening setting,” Obstet. Gynecol. 111(1), 7–14 (2008).
[Crossref]

Bedard, N.

Benedet, J. L.

S. B. Cantor, M. Cardenas-Turanzas, D. D. Cox, E. N. Atkinson, G. M. Norgueras-Gonzalez, J. R. Beck, M. Follen, and J. L. Benedet, “Accuracy of colposcopy in the diagnostic compared with the screening setting,” Obstet. Gynecol. 111(1), 7–14 (2008).
[Crossref]

Benzerdjeb, N.

N. Benzerdjeb, C. Garbar, P. Camparo, and H. Sevestre, “Digital holographic microscopy as screening tool for cervical cancer preliminary study,” Cancer cytopathology 124(8), 573–580 (2016).
[Crossref]

Bodenschatz, N.

N. Bodenschatz, C. F. Poh, S. Lam, P. M. Lane, M. Guillaud, and C. E. MacAulay, “Dual-mode endomicroscopy for detection of epithelial dysplasia in the mouth: a descriptive pilot study,” J. Biomed. Opt. 22(08), 1 (2017).
[Crossref]

N. Bodenschatz, S. Lam, A. Carraro, J. Korbelik, D. M. Miller, J. N. McAlpine, M. Lee, A. Kienle, and C. E. MacAulay, “Diffuse optical microscopy for quantification of depth-dependent epithelial backscattering in the cervix,” J. Biomed. Opt. 21(6), 066001 (2016).
[Crossref]

Bohn, P.

B. Obstoy, M. Salaun, L. Veresezan, R. Sesboüé, P. Bohn, F. X. Boland, and L. Thiberville, “Safety and performance analysis of acriflavine and methylene blue for in vivo imaging of precancerous lesions using fibered confocal fluorescence microscopy (FCFM): an experimental study,” BMC Pulm. Med. 15(1), 30 (2015).
[Crossref]

Boland, F. X.

B. Obstoy, M. Salaun, L. Veresezan, R. Sesboüé, P. Bohn, F. X. Boland, and L. Thiberville, “Safety and performance analysis of acriflavine and methylene blue for in vivo imaging of precancerous lesions using fibered confocal fluorescence microscopy (FCFM): an experimental study,” BMC Pulm. Med. 15(1), 30 (2015).
[Crossref]

Bubi, T. C.

M. K. Quinn, T. C. Bubi, M. C. Pierce, M. K. Kayembe, D. Ramogola-Masire, and R. Richards-Kortum, “High-resolution microendoscopy for the detection of cervical neoplasia in low-resource settings,” PLoS One 7(9), e44924 (2012).
[Crossref]

Camacho, R.

L. T. Chuang, S. Temin, R. Camacho, A. Dueñas-Gonzalez, S. Feldman, M. Gultekin, V. Gupta, S. Horton, G. Jacob, E. A. Kidd, and K. Lishimpi, “Management and care of women with invasive cervical cancer: American Society of Clinical Oncology resource-stratified clinical practice guideline,” Journal of Global Oncology 2(5), 311–340 (2016).
[Crossref]

Camarillo, D. B.

K. E. Loewke, D. B. Camarillo, W. Piyawattanametha, M. J. Mandella, C. H. Contag, S. Thrun, and J. K. Salisbury, “In vivo micro-image mosaicing,” IEEE Trans. Biomed. Eng. 58(1), 159–171 (2011).
[Crossref]

Camparo, P.

N. Benzerdjeb, C. Garbar, P. Camparo, and H. Sevestre, “Digital holographic microscopy as screening tool for cervical cancer preliminary study,” Cancer cytopathology 124(8), 573–580 (2016).
[Crossref]

Cantor, S. B.

S. B. Cantor, M. Cardenas-Turanzas, D. D. Cox, E. N. Atkinson, G. M. Norgueras-Gonzalez, J. R. Beck, M. Follen, and J. L. Benedet, “Accuracy of colposcopy in the diagnostic compared with the screening setting,” Obstet. Gynecol. 111(1), 7–14 (2008).
[Crossref]

Cardenas-Turanzas, M.

S. B. Cantor, M. Cardenas-Turanzas, D. D. Cox, E. N. Atkinson, G. M. Norgueras-Gonzalez, J. R. Beck, M. Follen, and J. L. Benedet, “Accuracy of colposcopy in the diagnostic compared with the screening setting,” Obstet. Gynecol. 111(1), 7–14 (2008).
[Crossref]

Carraro, A.

N. Bodenschatz, S. Lam, A. Carraro, J. Korbelik, D. M. Miller, J. N. McAlpine, M. Lee, A. Kienle, and C. E. MacAulay, “Diffuse optical microscopy for quantification of depth-dependent epithelial backscattering in the cervix,” J. Biomed. Opt. 21(6), 066001 (2016).
[Crossref]

Castle, P. E.

N. Pantano, B. Hunt, R. A. Schwarz, S. Parra, K. Cherry, J. C. Possati-Resende, A. Longatto-Filho, J. H. T. G. Fregnani, P. E. Castle, K. Schmeler, and R. Richards-Kortum, “Is proflavine exposure associated with disease progression in women with cervical dysplasia? A brief report,” Photochem. Photobiol. 94(6), 1308–1313 (2018).
[Crossref]

Cherry, K.

N. Pantano, B. Hunt, R. A. Schwarz, S. Parra, K. Cherry, J. C. Possati-Resende, A. Longatto-Filho, J. H. T. G. Fregnani, P. E. Castle, K. Schmeler, and R. Richards-Kortum, “Is proflavine exposure associated with disease progression in women with cervical dysplasia? A brief report,” Photochem. Photobiol. 94(6), 1308–1313 (2018).
[Crossref]

Chuang, L. T.

L. T. Chuang, S. Temin, R. Camacho, A. Dueñas-Gonzalez, S. Feldman, M. Gultekin, V. Gupta, S. Horton, G. Jacob, E. A. Kidd, and K. Lishimpi, “Management and care of women with invasive cervical cancer: American Society of Clinical Oncology resource-stratified clinical practice guideline,” Journal of Global Oncology 2(5), 311–340 (2016).
[Crossref]

Contag, C. H.

K. E. Loewke, D. B. Camarillo, W. Piyawattanametha, M. J. Mandella, C. H. Contag, S. Thrun, and J. K. Salisbury, “In vivo micro-image mosaicing,” IEEE Trans. Biomed. Eng. 58(1), 159–171 (2011).
[Crossref]

Cox, D. D.

S. B. Cantor, M. Cardenas-Turanzas, D. D. Cox, E. N. Atkinson, G. M. Norgueras-Gonzalez, J. R. Beck, M. Follen, and J. L. Benedet, “Accuracy of colposcopy in the diagnostic compared with the screening setting,” Obstet. Gynecol. 111(1), 7–14 (2008).
[Crossref]

De Raedt, H.

H. De Raedt, A. D. Lagendijk, and P. de Vries, “Transverse localization of light,” Phys. Rev. Lett. 62(1), 47–50 (1989).
[Crossref]

de Vries, P.

H. De Raedt, A. D. Lagendijk, and P. de Vries, “Transverse localization of light,” Phys. Rev. Lett. 62(1), 47–50 (1989).
[Crossref]

Delaney, P. M.

J. Tan, M. A. Quinn, J. M. Pyman, P. M. Delaney, and W. J. McLaren, “Detection of cervical intraepithelial neoplasia in vivo using confocal endomicroscopy,” BJOG: An International Journal of Obstetrics & Gynaecology 116(12), 1663–1670 (2009).
[Crossref]

Descour, M. R.

Dueñas-Gonzalez, A.

L. T. Chuang, S. Temin, R. Camacho, A. Dueñas-Gonzalez, S. Feldman, M. Gultekin, V. Gupta, S. Horton, G. Jacob, E. A. Kidd, and K. Lishimpi, “Management and care of women with invasive cervical cancer: American Society of Clinical Oncology resource-stratified clinical practice guideline,” Journal of Global Oncology 2(5), 311–340 (2016).
[Crossref]

Feldman, S.

L. T. Chuang, S. Temin, R. Camacho, A. Dueñas-Gonzalez, S. Feldman, M. Gultekin, V. Gupta, S. Horton, G. Jacob, E. A. Kidd, and K. Lishimpi, “Management and care of women with invasive cervical cancer: American Society of Clinical Oncology resource-stratified clinical practice guideline,” Journal of Global Oncology 2(5), 311–340 (2016).
[Crossref]

Fienup, J. R.

Follen, M.

B. Hill, S. F. Lam, P. Lane, C. MacAulay, L. Fradkin, and M. Follen, “Established and emerging optical technologies for the real-time detection of cervical neoplasia: a review,” J. Cancer Ther. 08(13), 1241–1278 (2017).
[Crossref]

S. B. Cantor, M. Cardenas-Turanzas, D. D. Cox, E. N. Atkinson, G. M. Norgueras-Gonzalez, J. R. Beck, M. Follen, and J. L. Benedet, “Accuracy of colposcopy in the diagnostic compared with the screening setting,” Obstet. Gynecol. 111(1), 7–14 (2008).
[Crossref]

K. B. Sung, R. Richards-Kortum, M. Follen, A. Malpica, C. Liang, and M. R. Descour, “Fiber optic confocal reflectance microscopy: a new real-time technique to view nuclear morphology in cervical squamous epithelium in vivo,” Opt. Express 11(24), 3171–3181 (2003).
[Crossref]

Fradkin, L.

B. Hill, S. F. Lam, P. Lane, C. MacAulay, L. Fradkin, and M. Follen, “Established and emerging optical technologies for the real-time detection of cervical neoplasia: a review,” J. Cancer Ther. 08(13), 1241–1278 (2017).
[Crossref]

Frazier, R. J.

S. Karbasi, R. J. Frazier, K. W. Koch, T. Hawkins, J. Ballato, and A. Mafi, “Image transport through a disordered optical fibre mediated by transverse Anderson localization,” Nat. Commun. 5(1), 3362 (2014).
[Crossref]

S. Karbasi, C. R. Mirr, P. G. Yarandi, R. J. Frazier, K. W. Koch, and A. Mafi, “Observation of transverse Anderson localization in an optical fiber,” Opt. Lett. 37(12), 2304–2306 (2012).
[Crossref]

Fregnani, J. H. T. G.

N. Pantano, B. Hunt, R. A. Schwarz, S. Parra, K. Cherry, J. C. Possati-Resende, A. Longatto-Filho, J. H. T. G. Fregnani, P. E. Castle, K. Schmeler, and R. Richards-Kortum, “Is proflavine exposure associated with disease progression in women with cervical dysplasia? A brief report,” Photochem. Photobiol. 94(6), 1308–1313 (2018).
[Crossref]

Garbar, C.

N. Benzerdjeb, C. Garbar, P. Camparo, and H. Sevestre, “Digital holographic microscopy as screening tool for cervical cancer preliminary study,” Cancer cytopathology 124(8), 573–580 (2016).
[Crossref]

Guillaud, M.

N. Bodenschatz, C. F. Poh, S. Lam, P. M. Lane, M. Guillaud, and C. E. MacAulay, “Dual-mode endomicroscopy for detection of epithelial dysplasia in the mouth: a descriptive pilot study,” J. Biomed. Opt. 22(08), 1 (2017).
[Crossref]

Guizar-Sicairos, M.

Gultekin, M.

L. T. Chuang, S. Temin, R. Camacho, A. Dueñas-Gonzalez, S. Feldman, M. Gultekin, V. Gupta, S. Horton, G. Jacob, E. A. Kidd, and K. Lishimpi, “Management and care of women with invasive cervical cancer: American Society of Clinical Oncology resource-stratified clinical practice guideline,” Journal of Global Oncology 2(5), 311–340 (2016).
[Crossref]

Gupta, V.

L. T. Chuang, S. Temin, R. Camacho, A. Dueñas-Gonzalez, S. Feldman, M. Gultekin, V. Gupta, S. Horton, G. Jacob, E. A. Kidd, and K. Lishimpi, “Management and care of women with invasive cervical cancer: American Society of Clinical Oncology resource-stratified clinical practice guideline,” Journal of Global Oncology 2(5), 311–340 (2016).
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Hawkins, T.

S. Karbasi, R. J. Frazier, K. W. Koch, T. Hawkins, J. Ballato, and A. Mafi, “Image transport through a disordered optical fibre mediated by transverse Anderson localization,” Nat. Commun. 5(1), 3362 (2014).
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B. Hill, S. F. Lam, P. Lane, C. MacAulay, L. Fradkin, and M. Follen, “Established and emerging optical technologies for the real-time detection of cervical neoplasia: a review,” J. Cancer Ther. 08(13), 1241–1278 (2017).
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L. T. Chuang, S. Temin, R. Camacho, A. Dueñas-Gonzalez, S. Feldman, M. Gultekin, V. Gupta, S. Horton, G. Jacob, E. A. Kidd, and K. Lishimpi, “Management and care of women with invasive cervical cancer: American Society of Clinical Oncology resource-stratified clinical practice guideline,” Journal of Global Oncology 2(5), 311–340 (2016).
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J. P. Baak, A. J. Krushe, S. J. Robboy, E. A. Janssen, B. van Dierman, and I. Skaland, “Dynamic behavioural interpretation of cervical intraepithelial neoplasia with molecular markers,” J. Clin. Pathol. 59(10), 1017–1028 (2006).
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S. Karbasi, R. J. Frazier, K. W. Koch, T. Hawkins, J. Ballato, and A. Mafi, “Image transport through a disordered optical fibre mediated by transverse Anderson localization,” Nat. Commun. 5(1), 3362 (2014).
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S. Karbasi, C. R. Mirr, P. G. Yarandi, R. J. Frazier, K. W. Koch, and A. Mafi, “Observation of transverse Anderson localization in an optical fiber,” Opt. Lett. 37(12), 2304–2306 (2012).
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M. K. Quinn, T. C. Bubi, M. C. Pierce, M. K. Kayembe, D. Ramogola-Masire, and R. Richards-Kortum, “High-resolution microendoscopy for the detection of cervical neoplasia in low-resource settings,” PLoS One 7(9), e44924 (2012).
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L. T. Chuang, S. Temin, R. Camacho, A. Dueñas-Gonzalez, S. Feldman, M. Gultekin, V. Gupta, S. Horton, G. Jacob, E. A. Kidd, and K. Lishimpi, “Management and care of women with invasive cervical cancer: American Society of Clinical Oncology resource-stratified clinical practice guideline,” Journal of Global Oncology 2(5), 311–340 (2016).
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S. Karbasi, R. J. Frazier, K. W. Koch, T. Hawkins, J. Ballato, and A. Mafi, “Image transport through a disordered optical fibre mediated by transverse Anderson localization,” Nat. Commun. 5(1), 3362 (2014).
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S. Karbasi, C. R. Mirr, P. G. Yarandi, R. J. Frazier, K. W. Koch, and A. Mafi, “Observation of transverse Anderson localization in an optical fiber,” Opt. Lett. 37(12), 2304–2306 (2012).
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N. Bodenschatz, S. Lam, A. Carraro, J. Korbelik, D. M. Miller, J. N. McAlpine, M. Lee, A. Kienle, and C. E. MacAulay, “Diffuse optical microscopy for quantification of depth-dependent epithelial backscattering in the cervix,” J. Biomed. Opt. 21(6), 066001 (2016).
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J. P. Baak, A. J. Krushe, S. J. Robboy, E. A. Janssen, B. van Dierman, and I. Skaland, “Dynamic behavioural interpretation of cervical intraepithelial neoplasia with molecular markers,” J. Clin. Pathol. 59(10), 1017–1028 (2006).
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N. Bodenschatz, C. F. Poh, S. Lam, P. M. Lane, M. Guillaud, and C. E. MacAulay, “Dual-mode endomicroscopy for detection of epithelial dysplasia in the mouth: a descriptive pilot study,” J. Biomed. Opt. 22(08), 1 (2017).
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N. Bodenschatz, S. Lam, A. Carraro, J. Korbelik, D. M. Miller, J. N. McAlpine, M. Lee, A. Kienle, and C. E. MacAulay, “Diffuse optical microscopy for quantification of depth-dependent epithelial backscattering in the cervix,” J. Biomed. Opt. 21(6), 066001 (2016).
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B. Hill, S. F. Lam, P. Lane, C. MacAulay, L. Fradkin, and M. Follen, “Established and emerging optical technologies for the real-time detection of cervical neoplasia: a review,” J. Cancer Ther. 08(13), 1241–1278 (2017).
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B. Hill, S. F. Lam, P. Lane, C. MacAulay, L. Fradkin, and M. Follen, “Established and emerging optical technologies for the real-time detection of cervical neoplasia: a review,” J. Cancer Ther. 08(13), 1241–1278 (2017).
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N. Bodenschatz, C. F. Poh, S. Lam, P. M. Lane, M. Guillaud, and C. E. MacAulay, “Dual-mode endomicroscopy for detection of epithelial dysplasia in the mouth: a descriptive pilot study,” J. Biomed. Opt. 22(08), 1 (2017).
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Lee, M.

N. Bodenschatz, S. Lam, A. Carraro, J. Korbelik, D. M. Miller, J. N. McAlpine, M. Lee, A. Kienle, and C. E. MacAulay, “Diffuse optical microscopy for quantification of depth-dependent epithelial backscattering in the cervix,” J. Biomed. Opt. 21(6), 066001 (2016).
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L. T. Chuang, S. Temin, R. Camacho, A. Dueñas-Gonzalez, S. Feldman, M. Gultekin, V. Gupta, S. Horton, G. Jacob, E. A. Kidd, and K. Lishimpi, “Management and care of women with invasive cervical cancer: American Society of Clinical Oncology resource-stratified clinical practice guideline,” Journal of Global Oncology 2(5), 311–340 (2016).
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N. Pantano, B. Hunt, R. A. Schwarz, S. Parra, K. Cherry, J. C. Possati-Resende, A. Longatto-Filho, J. H. T. G. Fregnani, P. E. Castle, K. Schmeler, and R. Richards-Kortum, “Is proflavine exposure associated with disease progression in women with cervical dysplasia? A brief report,” Photochem. Photobiol. 94(6), 1308–1313 (2018).
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J. S. Louie, R. Richards-Kortum, and S. Anandasbapathy, “Applications and advancements in the use of high-resolution microendoscopy for detection of gastrointestinal neoplasia,” Clin. Gastroenterol. Hepatol. 12(11), 1789–1792 (2014).
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B. Hill, S. F. Lam, P. Lane, C. MacAulay, L. Fradkin, and M. Follen, “Established and emerging optical technologies for the real-time detection of cervical neoplasia: a review,” J. Cancer Ther. 08(13), 1241–1278 (2017).
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N. Bodenschatz, C. F. Poh, S. Lam, P. M. Lane, M. Guillaud, and C. E. MacAulay, “Dual-mode endomicroscopy for detection of epithelial dysplasia in the mouth: a descriptive pilot study,” J. Biomed. Opt. 22(08), 1 (2017).
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N. Bodenschatz, S. Lam, A. Carraro, J. Korbelik, D. M. Miller, J. N. McAlpine, M. Lee, A. Kienle, and C. E. MacAulay, “Diffuse optical microscopy for quantification of depth-dependent epithelial backscattering in the cervix,” J. Biomed. Opt. 21(6), 066001 (2016).
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S. Karbasi, R. J. Frazier, K. W. Koch, T. Hawkins, J. Ballato, and A. Mafi, “Image transport through a disordered optical fibre mediated by transverse Anderson localization,” Nat. Commun. 5(1), 3362 (2014).
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S. Karbasi, C. R. Mirr, P. G. Yarandi, R. J. Frazier, K. W. Koch, and A. Mafi, “Observation of transverse Anderson localization in an optical fiber,” Opt. Lett. 37(12), 2304–2306 (2012).
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T. Vercauteren, A. Perchant, G. Malandain, X. Pennec, and N. Ayache, “Robust mosaicing with correction of motion distortions and tissue deformations for in vivo fibered microscopy,” Med. Image Anal. 10(5), 673–692 (2006).
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Malpica, A.

Mandella, M. J.

K. E. Loewke, D. B. Camarillo, W. Piyawattanametha, M. J. Mandella, C. H. Contag, S. Thrun, and J. K. Salisbury, “In vivo micro-image mosaicing,” IEEE Trans. Biomed. Eng. 58(1), 159–171 (2011).
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McAlpine, J. N.

N. Bodenschatz, S. Lam, A. Carraro, J. Korbelik, D. M. Miller, J. N. McAlpine, M. Lee, A. Kienle, and C. E. MacAulay, “Diffuse optical microscopy for quantification of depth-dependent epithelial backscattering in the cervix,” J. Biomed. Opt. 21(6), 066001 (2016).
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J. Tan, M. A. Quinn, J. M. Pyman, P. M. Delaney, and W. J. McLaren, “Detection of cervical intraepithelial neoplasia in vivo using confocal endomicroscopy,” BJOG: An International Journal of Obstetrics & Gynaecology 116(12), 1663–1670 (2009).
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Miller, D. M.

N. Bodenschatz, S. Lam, A. Carraro, J. Korbelik, D. M. Miller, J. N. McAlpine, M. Lee, A. Kienle, and C. E. MacAulay, “Diffuse optical microscopy for quantification of depth-dependent epithelial backscattering in the cervix,” J. Biomed. Opt. 21(6), 066001 (2016).
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N. Pantano, B. Hunt, R. A. Schwarz, S. Parra, K. Cherry, J. C. Possati-Resende, A. Longatto-Filho, J. H. T. G. Fregnani, P. E. Castle, K. Schmeler, and R. Richards-Kortum, “Is proflavine exposure associated with disease progression in women with cervical dysplasia? A brief report,” Photochem. Photobiol. 94(6), 1308–1313 (2018).
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N. Pantano, B. Hunt, R. A. Schwarz, S. Parra, K. Cherry, J. C. Possati-Resende, A. Longatto-Filho, J. H. T. G. Fregnani, P. E. Castle, K. Schmeler, and R. Richards-Kortum, “Is proflavine exposure associated with disease progression in women with cervical dysplasia? A brief report,” Photochem. Photobiol. 94(6), 1308–1313 (2018).
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Pennec, X.

T. Vercauteren, A. Perchant, G. Malandain, X. Pennec, and N. Ayache, “Robust mosaicing with correction of motion distortions and tissue deformations for in vivo fibered microscopy,” Med. Image Anal. 10(5), 673–692 (2006).
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Perchant, A.

T. Vercauteren, A. Perchant, G. Malandain, X. Pennec, and N. Ayache, “Robust mosaicing with correction of motion distortions and tissue deformations for in vivo fibered microscopy,” Med. Image Anal. 10(5), 673–692 (2006).
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Pierce, M. C.

M. K. Quinn, T. C. Bubi, M. C. Pierce, M. K. Kayembe, D. Ramogola-Masire, and R. Richards-Kortum, “High-resolution microendoscopy for the detection of cervical neoplasia in low-resource settings,” PLoS One 7(9), e44924 (2012).
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K. E. Loewke, D. B. Camarillo, W. Piyawattanametha, M. J. Mandella, C. H. Contag, S. Thrun, and J. K. Salisbury, “In vivo micro-image mosaicing,” IEEE Trans. Biomed. Eng. 58(1), 159–171 (2011).
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Poh, C. F.

N. Bodenschatz, C. F. Poh, S. Lam, P. M. Lane, M. Guillaud, and C. E. MacAulay, “Dual-mode endomicroscopy for detection of epithelial dysplasia in the mouth: a descriptive pilot study,” J. Biomed. Opt. 22(08), 1 (2017).
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N. Pantano, B. Hunt, R. A. Schwarz, S. Parra, K. Cherry, J. C. Possati-Resende, A. Longatto-Filho, J. H. T. G. Fregnani, P. E. Castle, K. Schmeler, and R. Richards-Kortum, “Is proflavine exposure associated with disease progression in women with cervical dysplasia? A brief report,” Photochem. Photobiol. 94(6), 1308–1313 (2018).
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Pyman, J. M.

J. Tan, M. A. Quinn, J. M. Pyman, P. M. Delaney, and W. J. McLaren, “Detection of cervical intraepithelial neoplasia in vivo using confocal endomicroscopy,” BJOG: An International Journal of Obstetrics & Gynaecology 116(12), 1663–1670 (2009).
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Quinn, M. A.

J. Tan, M. A. Quinn, J. M. Pyman, P. M. Delaney, and W. J. McLaren, “Detection of cervical intraepithelial neoplasia in vivo using confocal endomicroscopy,” BJOG: An International Journal of Obstetrics & Gynaecology 116(12), 1663–1670 (2009).
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M. K. Quinn, T. C. Bubi, M. C. Pierce, M. K. Kayembe, D. Ramogola-Masire, and R. Richards-Kortum, “High-resolution microendoscopy for the detection of cervical neoplasia in low-resource settings,” PLoS One 7(9), e44924 (2012).
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Ramogola-Masire, D.

M. K. Quinn, T. C. Bubi, M. C. Pierce, M. K. Kayembe, D. Ramogola-Masire, and R. Richards-Kortum, “High-resolution microendoscopy for the detection of cervical neoplasia in low-resource settings,” PLoS One 7(9), e44924 (2012).
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Richards-Kortum, R.

N. Pantano, B. Hunt, R. A. Schwarz, S. Parra, K. Cherry, J. C. Possati-Resende, A. Longatto-Filho, J. H. T. G. Fregnani, P. E. Castle, K. Schmeler, and R. Richards-Kortum, “Is proflavine exposure associated with disease progression in women with cervical dysplasia? A brief report,” Photochem. Photobiol. 94(6), 1308–1313 (2018).
[Crossref]

J. S. Louie, R. Richards-Kortum, and S. Anandasbapathy, “Applications and advancements in the use of high-resolution microendoscopy for detection of gastrointestinal neoplasia,” Clin. Gastroenterol. Hepatol. 12(11), 1789–1792 (2014).
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M. K. Quinn, T. C. Bubi, M. C. Pierce, M. K. Kayembe, D. Ramogola-Masire, and R. Richards-Kortum, “High-resolution microendoscopy for the detection of cervical neoplasia in low-resource settings,” PLoS One 7(9), e44924 (2012).
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N. Bedard, T. Quang, K. Schmeler, R. Richards-Kortum, and T. S. Tkaczyk, “Real-time video mosaicing with a high-resolution microendoscope,” Biomed. Opt. Express 3(10), 2428–2435 (2012).
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K. B. Sung, R. Richards-Kortum, M. Follen, A. Malpica, C. Liang, and M. R. Descour, “Fiber optic confocal reflectance microscopy: a new real-time technique to view nuclear morphology in cervical squamous epithelium in vivo,” Opt. Express 11(24), 3171–3181 (2003).
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B. Obstoy, M. Salaun, L. Veresezan, R. Sesboüé, P. Bohn, F. X. Boland, and L. Thiberville, “Safety and performance analysis of acriflavine and methylene blue for in vivo imaging of precancerous lesions using fibered confocal fluorescence microscopy (FCFM): an experimental study,” BMC Pulm. Med. 15(1), 30 (2015).
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K. E. Loewke, D. B. Camarillo, W. Piyawattanametha, M. J. Mandella, C. H. Contag, S. Thrun, and J. K. Salisbury, “In vivo micro-image mosaicing,” IEEE Trans. Biomed. Eng. 58(1), 159–171 (2011).
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N. Pantano, B. Hunt, R. A. Schwarz, S. Parra, K. Cherry, J. C. Possati-Resende, A. Longatto-Filho, J. H. T. G. Fregnani, P. E. Castle, K. Schmeler, and R. Richards-Kortum, “Is proflavine exposure associated with disease progression in women with cervical dysplasia? A brief report,” Photochem. Photobiol. 94(6), 1308–1313 (2018).
[Crossref]

N. Bedard, T. Quang, K. Schmeler, R. Richards-Kortum, and T. S. Tkaczyk, “Real-time video mosaicing with a high-resolution microendoscope,” Biomed. Opt. Express 3(10), 2428–2435 (2012).
[Crossref]

Schwarz, R. A.

N. Pantano, B. Hunt, R. A. Schwarz, S. Parra, K. Cherry, J. C. Possati-Resende, A. Longatto-Filho, J. H. T. G. Fregnani, P. E. Castle, K. Schmeler, and R. Richards-Kortum, “Is proflavine exposure associated with disease progression in women with cervical dysplasia? A brief report,” Photochem. Photobiol. 94(6), 1308–1313 (2018).
[Crossref]

Sellors, J. W.

J. W. Sellors and R. Sankaranarayanan, Colposcopy and Treatment of Cervical Intraepithelial Neoplasia: A Beginner's Manual. (Diamond Pocket Books Ltd., 2003).

Sesboüé, R.

B. Obstoy, M. Salaun, L. Veresezan, R. Sesboüé, P. Bohn, F. X. Boland, and L. Thiberville, “Safety and performance analysis of acriflavine and methylene blue for in vivo imaging of precancerous lesions using fibered confocal fluorescence microscopy (FCFM): an experimental study,” BMC Pulm. Med. 15(1), 30 (2015).
[Crossref]

Sevestre, H.

N. Benzerdjeb, C. Garbar, P. Camparo, and H. Sevestre, “Digital holographic microscopy as screening tool for cervical cancer preliminary study,” Cancer cytopathology 124(8), 573–580 (2016).
[Crossref]

Skaland, I.

J. P. Baak, A. J. Krushe, S. J. Robboy, E. A. Janssen, B. van Dierman, and I. Skaland, “Dynamic behavioural interpretation of cervical intraepithelial neoplasia with molecular markers,” J. Clin. Pathol. 59(10), 1017–1028 (2006).
[Crossref]

Sung, K. B.

Tan, J.

J. Tan, M. A. Quinn, J. M. Pyman, P. M. Delaney, and W. J. McLaren, “Detection of cervical intraepithelial neoplasia in vivo using confocal endomicroscopy,” BJOG: An International Journal of Obstetrics & Gynaecology 116(12), 1663–1670 (2009).
[Crossref]

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L. T. Chuang, S. Temin, R. Camacho, A. Dueñas-Gonzalez, S. Feldman, M. Gultekin, V. Gupta, S. Horton, G. Jacob, E. A. Kidd, and K. Lishimpi, “Management and care of women with invasive cervical cancer: American Society of Clinical Oncology resource-stratified clinical practice guideline,” Journal of Global Oncology 2(5), 311–340 (2016).
[Crossref]

Thiberville, L.

B. Obstoy, M. Salaun, L. Veresezan, R. Sesboüé, P. Bohn, F. X. Boland, and L. Thiberville, “Safety and performance analysis of acriflavine and methylene blue for in vivo imaging of precancerous lesions using fibered confocal fluorescence microscopy (FCFM): an experimental study,” BMC Pulm. Med. 15(1), 30 (2015).
[Crossref]

Thrun, S.

K. E. Loewke, D. B. Camarillo, W. Piyawattanametha, M. J. Mandella, C. H. Contag, S. Thrun, and J. K. Salisbury, “In vivo micro-image mosaicing,” IEEE Trans. Biomed. Eng. 58(1), 159–171 (2011).
[Crossref]

Thurman, S. T.

Tkaczyk, T. S.

van Dierman, B.

J. P. Baak, A. J. Krushe, S. J. Robboy, E. A. Janssen, B. van Dierman, and I. Skaland, “Dynamic behavioural interpretation of cervical intraepithelial neoplasia with molecular markers,” J. Clin. Pathol. 59(10), 1017–1028 (2006).
[Crossref]

Vercauteren, T.

T. Vercauteren, A. Perchant, G. Malandain, X. Pennec, and N. Ayache, “Robust mosaicing with correction of motion distortions and tissue deformations for in vivo fibered microscopy,” Med. Image Anal. 10(5), 673–692 (2006).
[Crossref]

Veresezan, L.

B. Obstoy, M. Salaun, L. Veresezan, R. Sesboüé, P. Bohn, F. X. Boland, and L. Thiberville, “Safety and performance analysis of acriflavine and methylene blue for in vivo imaging of precancerous lesions using fibered confocal fluorescence microscopy (FCFM): an experimental study,” BMC Pulm. Med. 15(1), 30 (2015).
[Crossref]

Yarandi, P. G.

Biomed. Opt. Express (2)

BJOG: An International Journal of Obstetrics & Gynaecology (1)

J. Tan, M. A. Quinn, J. M. Pyman, P. M. Delaney, and W. J. McLaren, “Detection of cervical intraepithelial neoplasia in vivo using confocal endomicroscopy,” BJOG: An International Journal of Obstetrics & Gynaecology 116(12), 1663–1670 (2009).
[Crossref]

BMC Pulm. Med. (1)

B. Obstoy, M. Salaun, L. Veresezan, R. Sesboüé, P. Bohn, F. X. Boland, and L. Thiberville, “Safety and performance analysis of acriflavine and methylene blue for in vivo imaging of precancerous lesions using fibered confocal fluorescence microscopy (FCFM): an experimental study,” BMC Pulm. Med. 15(1), 30 (2015).
[Crossref]

Cancer cytopathology (1)

N. Benzerdjeb, C. Garbar, P. Camparo, and H. Sevestre, “Digital holographic microscopy as screening tool for cervical cancer preliminary study,” Cancer cytopathology 124(8), 573–580 (2016).
[Crossref]

Clin. Gastroenterol. Hepatol. (1)

J. S. Louie, R. Richards-Kortum, and S. Anandasbapathy, “Applications and advancements in the use of high-resolution microendoscopy for detection of gastrointestinal neoplasia,” Clin. Gastroenterol. Hepatol. 12(11), 1789–1792 (2014).
[Crossref]

IEEE Trans. Biomed. Eng. (1)

K. E. Loewke, D. B. Camarillo, W. Piyawattanametha, M. J. Mandella, C. H. Contag, S. Thrun, and J. K. Salisbury, “In vivo micro-image mosaicing,” IEEE Trans. Biomed. Eng. 58(1), 159–171 (2011).
[Crossref]

J. Biomed. Opt. (2)

N. Bodenschatz, C. F. Poh, S. Lam, P. M. Lane, M. Guillaud, and C. E. MacAulay, “Dual-mode endomicroscopy for detection of epithelial dysplasia in the mouth: a descriptive pilot study,” J. Biomed. Opt. 22(08), 1 (2017).
[Crossref]

N. Bodenschatz, S. Lam, A. Carraro, J. Korbelik, D. M. Miller, J. N. McAlpine, M. Lee, A. Kienle, and C. E. MacAulay, “Diffuse optical microscopy for quantification of depth-dependent epithelial backscattering in the cervix,” J. Biomed. Opt. 21(6), 066001 (2016).
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Figures (9)

Fig. 1.
Fig. 1. Conceptual probe-tissue interface of the CASP system. (A) A custom-designed waveguide is in contact with the tissue of interest. The waveguide translates the image of the epithelial tissue to the proximal end as detailed in (B) to an area outside of the vaginal cavity, where individual frames are scanned and reconstructed into a full image.
Fig. 2.
Fig. 2. (A) Design of epi-fluorescence scanning microscope. (B) Assembled CASP system.
Fig. 3.
Fig. 3. Machining process of Fiber Optic Faceplate. (A) is the faceplate prior to any machining where (C) represents the initial surface profile obtained using white-light interferometry. (B) represents the faceplate after the final cut with a ruler for scale, while (D) shows the improvement in surface quality after machining.
Fig. 4.
Fig. 4. Images of USAF targets taken with the CASP epifluorescence microscope illuminated with a white LED. In (A) no image guide is used. In (B) the microscope is coupled to a static fiber bundle with 4.4 µm core-to-core spacing, while (C) shows the performance of the system using the high-resolution waveguide.
Fig. 5.
Fig. 5. Mosiac image of fluorescently-labeled lens paper. The boxed region represents a single frame taken in the image sequence, while the mosaiced image shows a full 20 mm x 4 mm FOV of neighboring frames.
Fig. 6.
Fig. 6. Mosaiced image of ex vivo tissue with low-grade neoplasia. The excised sample is shown in the top left. The full mosaiced image is presented on the right, and the bottom left highlights a zoomed-in region to display the resolution of the system. The fluorescently-labeled features are nuclei in the squamous epithelium of the cervical tissue.
Fig. 7.
Fig. 7. (A) Histopathology of a patient with no neoplasia found. A CASP mosaic of a region of this sample’s tissue is shown in (D). (B) Histopathology of a patient with low-grade cervical intraepithelial neoplasia, with (E) a corresponding CASP image. (C) and (F) Histopathology and CASP image of patient with high-grade cervical intraepithelial neoplasia. Magnified FOVs are highlighted for each CASP image to highlight the much larger N/C ratio seen in high-grade neoplasia. Scale bars for highlighted regions are 100 µm.
Fig. 8.
Fig. 8. Histology map used to threshold for detection of abnormalities in patient data. (A) Pathology map of the junction between a detected lesion and the surrounding healthy tissue, while (B) is the corresponding CASP image of the area of the cervix the lesion was detected. (C) Magnified view of nuclei at the threshold of the lesion, while (D) displays nuclei outside the lesion. (E) is a map of measured nuclear-to-cytoplasmic ratio for calculated from the CASP image
Fig. 9.
Fig. 9. N/C ratio calculated at 20 sites for each tissue sample. Sites that had N/C ratio above 0.135 were flagged as abnormal and are displayed in the gray region and were only found in patients with high-grade neoplasia. Sites that were measured below the threshold were found in all samples except one patient with high-grade neoplasia. Error bars showing the standard deviation for all normal and abnormal sites are displayed for each dataset.

Tables (2)

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Table 1. Application Requirements and Specifications for Imaging Optics

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Table 2. Summary of histopathological diagnoses for clinical trial

Equations (1)

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r f g ( x i , y i ) = u , v F ( u , v ) G ( u , v ) exp [ i 2 π ( u x i M + v y i N ) ]