Abstract

Multimodal spectral histopathology (MSH), an optical technique combining tissue auto-fluorescence (AF) imaging and Raman micro-spectroscopy (RMS), was previously proposed for detection of residual basal cell carcinoma (BCC) at the surface of surgically-resected skin tissue. Here we report the development of a fully-automated prototype instrument based on MSH designed to be used in the clinic and operated by a non-specialist spectroscopy user. The algorithms for the AF image processing and Raman spectroscopy classification had been first optimised on a manually-operated laboratory instrument and then validated on the automated prototype using skin samples from independent patients. We present results on a range of skin samples excised during Mohs micrographic surgery, and demonstrate consistent diagnosis obtained in repeat test measurement, in agreement with the reference histopathology diagnosis. We also show that the prototype instrument can be operated by clinical users (a skin surgeon and a core medical trainee, after only 1-8 hours of training) to obtain consistent results in agreement with histopathology. The development of the new automated prototype and demonstration of inter-instrument transferability of the diagnosis models are important steps on the clinical translation path: it allows the testing of the MSH technology in a relevant clinical environment in order to evaluate its performance on a sufficiently large number of patients.

Published by The Optical Society under the terms of the Creative Commons Attribution 4.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI.

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References

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    [PubMed]

2017 (4)

D. J. Kadouch, M. M. Leeflang, Y. S. Elshot, C. Longo, M. Ulrich, A. C. van der Wal, A. Wolkerstorfer, M. W. Bekkenk, and M. A. de Rie, “Diagnostic accuracy of confocal microscopy imaging vs. punch biopsy for diagnosing and subtyping basal cell carcinoma,” J. Eur. Acad. Dermatol. Venereol. 31(10), 1641–1648 (2017).
[PubMed]

E. Manubens, A. Barreiro, A. Bennassar, S. Podlipnik, N. Moreno, P. Iglesias, J. Malvehy, and S. Puig, “Fast evaluation and monitoring of ingenol mebutate treatment of multiple basal cell carcinomas by in vivo hand-held reflectance confocal microscopy,” J. Eur. Acad. Dermatol. Venereol. 31(6), e284–e286 (2017).
[PubMed]

D. Shipp, F. Sinjab, and I. Notingher, “Raman spectroscopy: Techniques and applications in the life sciences,” Adv. Opt. Photonics 9(2), 315–428 (2017).

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

2016 (2)

2015 (1)

M. Ulrich, T. von Braunmuehl, H. Kurzen, T. Dirschka, C. Kellner, E. Sattler, C. Berking, J. Welzel, and U. Reinhold, “The sensitivity and specificity of optical coherence tomography for the assisted diagnosis of nonpigmented basal cell carcinoma: an observational study,” Br. J. Dermatol. 173(2), 428–435 (2015).
[PubMed]

2014 (2)

K. Kong, F. Zaabar, E. Rakha, I. Ellis, A. Koloydenko, and I. Notingher, “Towards intra-operative diagnosis of tumours during breast conserving surgery by selective-sampling Raman micro-spectroscopy,” Phys. Med. Biol. 59(20), 6141–6152 (2014).
[PubMed]

S. Takamori, K. Kong, S. Varma, I. Leach, H. C. Williams, and I. Notingher, “Optimization of multimodal spectral imaging for assessment of resection margins during Mohs micrographic surgery for basal cell carcinoma,” Biomed. Opt. Express 6(1), 98–111 (2014).
[PubMed]

2013 (1)

K. Kong, C. J. Rowlands, S. Varma, W. Perkins, I. H. Leach, A. A. Koloydenko, H. C. Williams, and I. Notingher, “Diagnosis of tumors during tissue-conserving surgery with integrated autofluorescence and Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 110(38), 15189–15194 (2013).
[PubMed]

2012 (2)

C. J. Rowlands, S. Varma, W. Perkins, I. Leach, H. Williams, and I. Notingher, “Rapid acquisition of Raman spectral maps through minimal sampling: applications in tissue imaging,” J. Biophotonics 5(3), 220–229 (2012).
[PubMed]

J. M. Baxter, A. N. Patel, and S. Varma, “Facial basal cell carcinoma,” BMJ 345, e5342 (2012).
[PubMed]

2009 (1)

M. Larraona-Puy, A. Ghita, A. Zoladek, W. Perkins, S. Varma, I. H. Leach, A. A. Koloydenko, H. Williams, and I. Notingher, “Development of Raman microspectroscopy for automated detection and imaging of Basal Cell Carcinoma,” J. Biomed. Opt. 14(5), 054031 (2009).
[PubMed]

2008 (2)

K. Mosterd, G. A. M. Krekels, F. H. Nieman, J. U. Ostertag, B. A. Essers, C. D. Dirksen, P. M. Steijlen, A. Vermeulen, H. Neumann, and N. W. Kelleners-Smeets, “Surgical excision versus Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up,” Lancet Oncol. 9(12), 1149–1156 (2008).
[PubMed]

C. A. Lieber, S. K. Majumder, D. L. Ellis, D. D. Billheimer, and A. Mahadevan-Jansen, “In vivo nonmelanoma skin cancer diagnosis using Raman microspectroscopy,” Lasers Surg. Med. 40(7), 461–467 (2008).
[PubMed]

2005 (3)

A. Kimyai-Asadi, M. Alam, L. H. Goldberg, S. R. Peterson, S. Silapunt, and M. H. Jih, “Efficacy of narrow-margin excision of well-demarcated primary facial basal cell carcinomas,” J. Am. Acad. Dermatol. 53(3), 464–468 (2005).
[PubMed]

I. Leibovitch, S. C. Huilgol, D. Selva, S. Richards, and R. Paver, “Basal cell carcinoma treated with Mohs surgery in Australia I. Experience over 10 years,” J. Am. Acad. Dermatol. 53(3), 445–451 (2005).
[PubMed]

A. Kimyai-Asadi, M. Alam, L. H. Goldberg, S. R. Peterson, S. Silapunt, and M. H. Jih, “Efficacy of narrow-margin excision of well-demarcated primary facial basal cell carcinomas,” J. Am. Acad. Dermatol. 53(3), 464–468 (2005).
[PubMed]

2004 (1)

N. W. J. Smeets, G. A. M. Krekels, J. U. Ostertag, B. A. Essers, C. D. Dirksen, F. H. Nieman, and H. A. Neumann, “Surgical excision vs Mohs’ micrographic surgery for basal-cell carcinoma of the face: randomised controlled trial,” Lancet 364(9447), 1766–1772 (2004).
[PubMed]

2002 (1)

A. Nijssen, T. C. Bakker Schut, F. Heule, P. J. Caspers, D. P. Hayes, M. H. Neumann, and G. J. Puppels, “Discriminating basal cell carcinoma from its surrounding tissue by Raman spectroscopy,” J. Invest. Dermatol. 119(1), 64–69 (2002).
[PubMed]

1998 (1)

J. T. Lear, I. Harvey, D. de Berker, R. C. Strange, and A. A. Fryer, “Basal cell carcinoma,” J. R. Soc. Med. 91(11), 585–588 (1998).
[PubMed]

1997 (1)

M. Gniadecka, H. C. Wulf, and N. N. Mortensen, “Diagnosis of basal cell carcinoma by Raman spectroscopy,” J. Invest. Dermatol. 28(2), 125–129 (1997).
[PubMed]

1991 (1)

H. Breuninger and K. Dietz, “Prediction of subclinical tumor infiltration in basal cell carcinoma,” J. Dermatol. Surg. Oncol. 17(7), 574–578 (1991).
[PubMed]

1987 (1)

D. J. Wolf and J. A. Zitelli, “Surgical margins for basal cell carcinoma,” Arch. Dermatol. 123(3), 340–344 (1987).
[PubMed]

Alam, M.

A. Kimyai-Asadi, M. Alam, L. H. Goldberg, S. R. Peterson, S. Silapunt, and M. H. Jih, “Efficacy of narrow-margin excision of well-demarcated primary facial basal cell carcinomas,” J. Am. Acad. Dermatol. 53(3), 464–468 (2005).
[PubMed]

A. Kimyai-Asadi, M. Alam, L. H. Goldberg, S. R. Peterson, S. Silapunt, and M. H. Jih, “Efficacy of narrow-margin excision of well-demarcated primary facial basal cell carcinomas,” J. Am. Acad. Dermatol. 53(3), 464–468 (2005).
[PubMed]

Baatenburg de Jong, R. J.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Bakker Schut, T. C.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

A. Nijssen, T. C. Bakker Schut, F. Heule, P. J. Caspers, D. P. Hayes, M. H. Neumann, and G. J. Puppels, “Discriminating basal cell carcinoma from its surrounding tissue by Raman spectroscopy,” J. Invest. Dermatol. 119(1), 64–69 (2002).
[PubMed]

Barreiro, A.

E. Manubens, A. Barreiro, A. Bennassar, S. Podlipnik, N. Moreno, P. Iglesias, J. Malvehy, and S. Puig, “Fast evaluation and monitoring of ingenol mebutate treatment of multiple basal cell carcinomas by in vivo hand-held reflectance confocal microscopy,” J. Eur. Acad. Dermatol. Venereol. 31(6), e284–e286 (2017).
[PubMed]

Barroso, E. M.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Baxter, J. M.

J. M. Baxter, A. N. Patel, and S. Varma, “Facial basal cell carcinoma,” BMJ 345, e5342 (2012).
[PubMed]

Bekkenk, M. W.

D. J. Kadouch, M. M. Leeflang, Y. S. Elshot, C. Longo, M. Ulrich, A. C. van der Wal, A. Wolkerstorfer, M. W. Bekkenk, and M. A. de Rie, “Diagnostic accuracy of confocal microscopy imaging vs. punch biopsy for diagnosing and subtyping basal cell carcinoma,” J. Eur. Acad. Dermatol. Venereol. 31(10), 1641–1648 (2017).
[PubMed]

Bennassar, A.

E. Manubens, A. Barreiro, A. Bennassar, S. Podlipnik, N. Moreno, P. Iglesias, J. Malvehy, and S. Puig, “Fast evaluation and monitoring of ingenol mebutate treatment of multiple basal cell carcinomas by in vivo hand-held reflectance confocal microscopy,” J. Eur. Acad. Dermatol. Venereol. 31(6), e284–e286 (2017).
[PubMed]

Berking, C.

M. Ulrich, T. von Braunmuehl, H. Kurzen, T. Dirschka, C. Kellner, E. Sattler, C. Berking, J. Welzel, and U. Reinhold, “The sensitivity and specificity of optical coherence tomography for the assisted diagnosis of nonpigmented basal cell carcinoma: an observational study,” Br. J. Dermatol. 173(2), 428–435 (2015).
[PubMed]

Billheimer, D. D.

C. A. Lieber, S. K. Majumder, D. L. Ellis, D. D. Billheimer, and A. Mahadevan-Jansen, “In vivo nonmelanoma skin cancer diagnosis using Raman microspectroscopy,” Lasers Surg. Med. 40(7), 461–467 (2008).
[PubMed]

Bradu, A.

Breuninger, H.

H. Breuninger and K. Dietz, “Prediction of subclinical tumor infiltration in basal cell carcinoma,” J. Dermatol. Surg. Oncol. 17(7), 574–578 (1991).
[PubMed]

Busstra, M. B.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Caspers, P. J.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

A. Nijssen, T. C. Bakker Schut, F. Heule, P. J. Caspers, D. P. Hayes, M. H. Neumann, and G. J. Puppels, “Discriminating basal cell carcinoma from its surrounding tissue by Raman spectroscopy,” J. Invest. Dermatol. 119(1), 64–69 (2002).
[PubMed]

Chin, C.

Choi, D. H.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

de Berker, D.

J. T. Lear, I. Harvey, D. de Berker, R. C. Strange, and A. A. Fryer, “Basal cell carcinoma,” J. R. Soc. Med. 91(11), 585–588 (1998).
[PubMed]

de Rie, M. A.

D. J. Kadouch, M. M. Leeflang, Y. S. Elshot, C. Longo, M. Ulrich, A. C. van der Wal, A. Wolkerstorfer, M. W. Bekkenk, and M. A. de Rie, “Diagnostic accuracy of confocal microscopy imaging vs. punch biopsy for diagnosing and subtyping basal cell carcinoma,” J. Eur. Acad. Dermatol. Venereol. 31(10), 1641–1648 (2017).
[PubMed]

Dietz, K.

H. Breuninger and K. Dietz, “Prediction of subclinical tumor infiltration in basal cell carcinoma,” J. Dermatol. Surg. Oncol. 17(7), 574–578 (1991).
[PubMed]

Dirksen, C. D.

K. Mosterd, G. A. M. Krekels, F. H. Nieman, J. U. Ostertag, B. A. Essers, C. D. Dirksen, P. M. Steijlen, A. Vermeulen, H. Neumann, and N. W. Kelleners-Smeets, “Surgical excision versus Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up,” Lancet Oncol. 9(12), 1149–1156 (2008).
[PubMed]

N. W. J. Smeets, G. A. M. Krekels, J. U. Ostertag, B. A. Essers, C. D. Dirksen, F. H. Nieman, and H. A. Neumann, “Surgical excision vs Mohs’ micrographic surgery for basal-cell carcinoma of the face: randomised controlled trial,” Lancet 364(9447), 1766–1772 (2004).
[PubMed]

Dirschka, T.

M. Ulrich, T. von Braunmuehl, H. Kurzen, T. Dirschka, C. Kellner, E. Sattler, C. Berking, J. Welzel, and U. Reinhold, “The sensitivity and specificity of optical coherence tomography for the assisted diagnosis of nonpigmented basal cell carcinoma: an observational study,” Br. J. Dermatol. 173(2), 428–435 (2015).
[PubMed]

Dirven, C. M. F.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Ellis, D. L.

C. A. Lieber, S. K. Majumder, D. L. Ellis, D. D. Billheimer, and A. Mahadevan-Jansen, “In vivo nonmelanoma skin cancer diagnosis using Raman microspectroscopy,” Lasers Surg. Med. 40(7), 461–467 (2008).
[PubMed]

Ellis, I.

K. Kong, F. Zaabar, E. Rakha, I. Ellis, A. Koloydenko, and I. Notingher, “Towards intra-operative diagnosis of tumours during breast conserving surgery by selective-sampling Raman micro-spectroscopy,” Phys. Med. Biol. 59(20), 6141–6152 (2014).
[PubMed]

Elshot, Y. S.

D. J. Kadouch, M. M. Leeflang, Y. S. Elshot, C. Longo, M. Ulrich, A. C. van der Wal, A. Wolkerstorfer, M. W. Bekkenk, and M. A. de Rie, “Diagnostic accuracy of confocal microscopy imaging vs. punch biopsy for diagnosing and subtyping basal cell carcinoma,” J. Eur. Acad. Dermatol. Venereol. 31(10), 1641–1648 (2017).
[PubMed]

Essers, B. A.

K. Mosterd, G. A. M. Krekels, F. H. Nieman, J. U. Ostertag, B. A. Essers, C. D. Dirksen, P. M. Steijlen, A. Vermeulen, H. Neumann, and N. W. Kelleners-Smeets, “Surgical excision versus Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up,” Lancet Oncol. 9(12), 1149–1156 (2008).
[PubMed]

N. W. J. Smeets, G. A. M. Krekels, J. U. Ostertag, B. A. Essers, C. D. Dirksen, F. H. Nieman, and H. A. Neumann, “Surgical excision vs Mohs’ micrographic surgery for basal-cell carcinoma of the face: randomised controlled trial,” Lancet 364(9447), 1766–1772 (2004).
[PubMed]

Ewing-Graham, P. C.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Fryer, A. A.

J. T. Lear, I. Harvey, D. de Berker, R. C. Strange, and A. A. Fryer, “Basal cell carcinoma,” J. R. Soc. Med. 91(11), 585–588 (1998).
[PubMed]

Ghita, A.

M. Larraona-Puy, A. Ghita, A. Zoladek, W. Perkins, S. Varma, I. H. Leach, A. A. Koloydenko, H. Williams, and I. Notingher, “Development of Raman microspectroscopy for automated detection and imaging of Basal Cell Carcinoma,” J. Biomed. Opt. 14(5), 054031 (2009).
[PubMed]

Gibson, G.

Gniadecka, M.

M. Gniadecka, H. C. Wulf, and N. N. Mortensen, “Diagnosis of basal cell carcinoma by Raman spectroscopy,” J. Invest. Dermatol. 28(2), 125–129 (1997).
[PubMed]

Goldberg, L. H.

A. Kimyai-Asadi, M. Alam, L. H. Goldberg, S. R. Peterson, S. Silapunt, and M. H. Jih, “Efficacy of narrow-margin excision of well-demarcated primary facial basal cell carcinomas,” J. Am. Acad. Dermatol. 53(3), 464–468 (2005).
[PubMed]

A. Kimyai-Asadi, M. Alam, L. H. Goldberg, S. R. Peterson, S. Silapunt, and M. H. Jih, “Efficacy of narrow-margin excision of well-demarcated primary facial basal cell carcinomas,” J. Am. Acad. Dermatol. 53(3), 464–468 (2005).
[PubMed]

Hardillo, J.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Harvey, I.

J. T. Lear, I. Harvey, D. de Berker, R. C. Strange, and A. A. Fryer, “Basal cell carcinoma,” J. R. Soc. Med. 91(11), 585–588 (1998).
[PubMed]

Hayes, D. P.

A. Nijssen, T. C. Bakker Schut, F. Heule, P. J. Caspers, D. P. Hayes, M. H. Neumann, and G. J. Puppels, “Discriminating basal cell carcinoma from its surrounding tissue by Raman spectroscopy,” J. Invest. Dermatol. 119(1), 64–69 (2002).
[PubMed]

Heule, F.

A. Nijssen, T. C. Bakker Schut, F. Heule, P. J. Caspers, D. P. Hayes, M. H. Neumann, and G. J. Puppels, “Discriminating basal cell carcinoma from its surrounding tissue by Raman spectroscopy,” J. Invest. Dermatol. 119(1), 64–69 (2002).
[PubMed]

Huilgol, S. C.

I. Leibovitch, S. C. Huilgol, D. Selva, S. Richards, and R. Paver, “Basal cell carcinoma treated with Mohs surgery in Australia I. Experience over 10 years,” J. Am. Acad. Dermatol. 53(3), 445–451 (2005).
[PubMed]

Iglesias, P.

E. Manubens, A. Barreiro, A. Bennassar, S. Podlipnik, N. Moreno, P. Iglesias, J. Malvehy, and S. Puig, “Fast evaluation and monitoring of ingenol mebutate treatment of multiple basal cell carcinomas by in vivo hand-held reflectance confocal microscopy,” J. Eur. Acad. Dermatol. Venereol. 31(6), e284–e286 (2017).
[PubMed]

Jih, M. H.

A. Kimyai-Asadi, M. Alam, L. H. Goldberg, S. R. Peterson, S. Silapunt, and M. H. Jih, “Efficacy of narrow-margin excision of well-demarcated primary facial basal cell carcinomas,” J. Am. Acad. Dermatol. 53(3), 464–468 (2005).
[PubMed]

A. Kimyai-Asadi, M. Alam, L. H. Goldberg, S. R. Peterson, S. Silapunt, and M. H. Jih, “Efficacy of narrow-margin excision of well-demarcated primary facial basal cell carcinomas,” J. Am. Acad. Dermatol. 53(3), 464–468 (2005).
[PubMed]

Kadouch, D. J.

D. J. Kadouch, M. M. Leeflang, Y. S. Elshot, C. Longo, M. Ulrich, A. C. van der Wal, A. Wolkerstorfer, M. W. Bekkenk, and M. A. de Rie, “Diagnostic accuracy of confocal microscopy imaging vs. punch biopsy for diagnosing and subtyping basal cell carcinoma,” J. Eur. Acad. Dermatol. Venereol. 31(10), 1641–1648 (2017).
[PubMed]

Kelleners-Smeets, N. W.

K. Mosterd, G. A. M. Krekels, F. H. Nieman, J. U. Ostertag, B. A. Essers, C. D. Dirksen, P. M. Steijlen, A. Vermeulen, H. Neumann, and N. W. Kelleners-Smeets, “Surgical excision versus Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up,” Lancet Oncol. 9(12), 1149–1156 (2008).
[PubMed]

Kellner, C.

M. Ulrich, T. von Braunmuehl, H. Kurzen, T. Dirschka, C. Kellner, E. Sattler, C. Berking, J. Welzel, and U. Reinhold, “The sensitivity and specificity of optical coherence tomography for the assisted diagnosis of nonpigmented basal cell carcinoma: an observational study,” Br. J. Dermatol. 173(2), 428–435 (2015).
[PubMed]

Khandwala, M.

Kimyai-Asadi, A.

A. Kimyai-Asadi, M. Alam, L. H. Goldberg, S. R. Peterson, S. Silapunt, and M. H. Jih, “Efficacy of narrow-margin excision of well-demarcated primary facial basal cell carcinomas,” J. Am. Acad. Dermatol. 53(3), 464–468 (2005).
[PubMed]

A. Kimyai-Asadi, M. Alam, L. H. Goldberg, S. R. Peterson, S. Silapunt, and M. H. Jih, “Efficacy of narrow-margin excision of well-demarcated primary facial basal cell carcinomas,” J. Am. Acad. Dermatol. 53(3), 464–468 (2005).
[PubMed]

Koljenovic, S.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Koloydenko, A.

K. Kong, F. Zaabar, E. Rakha, I. Ellis, A. Koloydenko, and I. Notingher, “Towards intra-operative diagnosis of tumours during breast conserving surgery by selective-sampling Raman micro-spectroscopy,” Phys. Med. Biol. 59(20), 6141–6152 (2014).
[PubMed]

Koloydenko, A. A.

K. Kong, C. J. Rowlands, S. Varma, W. Perkins, I. H. Leach, A. A. Koloydenko, H. C. Williams, and I. Notingher, “Diagnosis of tumors during tissue-conserving surgery with integrated autofluorescence and Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 110(38), 15189–15194 (2013).
[PubMed]

M. Larraona-Puy, A. Ghita, A. Zoladek, W. Perkins, S. Varma, I. H. Leach, A. A. Koloydenko, H. Williams, and I. Notingher, “Development of Raman microspectroscopy for automated detection and imaging of Basal Cell Carcinoma,” J. Biomed. Opt. 14(5), 054031 (2009).
[PubMed]

Kong, K.

F. Sinjab, K. Kong, G. Gibson, S. Varma, H. Williams, M. Padgett, and I. Notingher, “Tissue diagnosis using power-sharing multifocal Raman micro-spectroscopy and auto-fluorescence imaging,” Biomed. Opt. Express 7(8), 2993–3006 (2016).
[PubMed]

S. Takamori, K. Kong, S. Varma, I. Leach, H. C. Williams, and I. Notingher, “Optimization of multimodal spectral imaging for assessment of resection margins during Mohs micrographic surgery for basal cell carcinoma,” Biomed. Opt. Express 6(1), 98–111 (2014).
[PubMed]

K. Kong, F. Zaabar, E. Rakha, I. Ellis, A. Koloydenko, and I. Notingher, “Towards intra-operative diagnosis of tumours during breast conserving surgery by selective-sampling Raman micro-spectroscopy,” Phys. Med. Biol. 59(20), 6141–6152 (2014).
[PubMed]

K. Kong, C. J. Rowlands, S. Varma, W. Perkins, I. H. Leach, A. A. Koloydenko, H. C. Williams, and I. Notingher, “Diagnosis of tumors during tissue-conserving surgery with integrated autofluorescence and Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 110(38), 15189–15194 (2013).
[PubMed]

Koppert, L. B.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Krekels, G. A. M.

K. Mosterd, G. A. M. Krekels, F. H. Nieman, J. U. Ostertag, B. A. Essers, C. D. Dirksen, P. M. Steijlen, A. Vermeulen, H. Neumann, and N. W. Kelleners-Smeets, “Surgical excision versus Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up,” Lancet Oncol. 9(12), 1149–1156 (2008).
[PubMed]

N. W. J. Smeets, G. A. M. Krekels, J. U. Ostertag, B. A. Essers, C. D. Dirksen, F. H. Nieman, and H. A. Neumann, “Surgical excision vs Mohs’ micrographic surgery for basal-cell carcinoma of the face: randomised controlled trial,” Lancet 364(9447), 1766–1772 (2004).
[PubMed]

Kurzen, H.

M. Ulrich, T. von Braunmuehl, H. Kurzen, T. Dirschka, C. Kellner, E. Sattler, C. Berking, J. Welzel, and U. Reinhold, “The sensitivity and specificity of optical coherence tomography for the assisted diagnosis of nonpigmented basal cell carcinoma: an observational study,” Br. J. Dermatol. 173(2), 428–435 (2015).
[PubMed]

Larraona-Puy, M.

M. Larraona-Puy, A. Ghita, A. Zoladek, W. Perkins, S. Varma, I. H. Leach, A. A. Koloydenko, H. Williams, and I. Notingher, “Development of Raman microspectroscopy for automated detection and imaging of Basal Cell Carcinoma,” J. Biomed. Opt. 14(5), 054031 (2009).
[PubMed]

Leach, I.

S. Takamori, K. Kong, S. Varma, I. Leach, H. C. Williams, and I. Notingher, “Optimization of multimodal spectral imaging for assessment of resection margins during Mohs micrographic surgery for basal cell carcinoma,” Biomed. Opt. Express 6(1), 98–111 (2014).
[PubMed]

C. J. Rowlands, S. Varma, W. Perkins, I. Leach, H. Williams, and I. Notingher, “Rapid acquisition of Raman spectral maps through minimal sampling: applications in tissue imaging,” J. Biophotonics 5(3), 220–229 (2012).
[PubMed]

Leach, I. H.

K. Kong, C. J. Rowlands, S. Varma, W. Perkins, I. H. Leach, A. A. Koloydenko, H. C. Williams, and I. Notingher, “Diagnosis of tumors during tissue-conserving surgery with integrated autofluorescence and Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 110(38), 15189–15194 (2013).
[PubMed]

M. Larraona-Puy, A. Ghita, A. Zoladek, W. Perkins, S. Varma, I. H. Leach, A. A. Koloydenko, H. Williams, and I. Notingher, “Development of Raman microspectroscopy for automated detection and imaging of Basal Cell Carcinoma,” J. Biomed. Opt. 14(5), 054031 (2009).
[PubMed]

Lear, J. T.

J. T. Lear, I. Harvey, D. de Berker, R. C. Strange, and A. A. Fryer, “Basal cell carcinoma,” J. R. Soc. Med. 91(11), 585–588 (1998).
[PubMed]

Leeflang, M. M.

D. J. Kadouch, M. M. Leeflang, Y. S. Elshot, C. Longo, M. Ulrich, A. C. van der Wal, A. Wolkerstorfer, M. W. Bekkenk, and M. A. de Rie, “Diagnostic accuracy of confocal microscopy imaging vs. punch biopsy for diagnosing and subtyping basal cell carcinoma,” J. Eur. Acad. Dermatol. Venereol. 31(10), 1641–1648 (2017).
[PubMed]

Leibovitch, I.

I. Leibovitch, S. C. Huilgol, D. Selva, S. Richards, and R. Paver, “Basal cell carcinoma treated with Mohs surgery in Australia I. Experience over 10 years,” J. Am. Acad. Dermatol. 53(3), 445–451 (2005).
[PubMed]

Leick, L.

Lieber, C. A.

C. A. Lieber, S. K. Majumder, D. L. Ellis, D. D. Billheimer, and A. Mahadevan-Jansen, “In vivo nonmelanoma skin cancer diagnosis using Raman microspectroscopy,” Lasers Surg. Med. 40(7), 461–467 (2008).
[PubMed]

Lim, R.

Longo, C.

D. J. Kadouch, M. M. Leeflang, Y. S. Elshot, C. Longo, M. Ulrich, A. C. van der Wal, A. Wolkerstorfer, M. W. Bekkenk, and M. A. de Rie, “Diagnostic accuracy of confocal microscopy imaging vs. punch biopsy for diagnosing and subtyping basal cell carcinoma,” J. Eur. Acad. Dermatol. Venereol. 31(10), 1641–1648 (2017).
[PubMed]

Mahadevan-Jansen, A.

C. A. Lieber, S. K. Majumder, D. L. Ellis, D. D. Billheimer, and A. Mahadevan-Jansen, “In vivo nonmelanoma skin cancer diagnosis using Raman microspectroscopy,” Lasers Surg. Med. 40(7), 461–467 (2008).
[PubMed]

Majumder, S. K.

C. A. Lieber, S. K. Majumder, D. L. Ellis, D. D. Billheimer, and A. Mahadevan-Jansen, “In vivo nonmelanoma skin cancer diagnosis using Raman microspectroscopy,” Lasers Surg. Med. 40(7), 461–467 (2008).
[PubMed]

Malvehy, J.

E. Manubens, A. Barreiro, A. Bennassar, S. Podlipnik, N. Moreno, P. Iglesias, J. Malvehy, and S. Puig, “Fast evaluation and monitoring of ingenol mebutate treatment of multiple basal cell carcinomas by in vivo hand-held reflectance confocal microscopy,” J. Eur. Acad. Dermatol. Venereol. 31(6), e284–e286 (2017).
[PubMed]

Manubens, E.

E. Manubens, A. Barreiro, A. Bennassar, S. Podlipnik, N. Moreno, P. Iglesias, J. Malvehy, and S. Puig, “Fast evaluation and monitoring of ingenol mebutate treatment of multiple basal cell carcinomas by in vivo hand-held reflectance confocal microscopy,” J. Eur. Acad. Dermatol. Venereol. 31(6), e284–e286 (2017).
[PubMed]

Mast, H.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Meeuwis, C.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Monserez, D. A.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Moreno, N.

E. Manubens, A. Barreiro, A. Bennassar, S. Podlipnik, N. Moreno, P. Iglesias, J. Malvehy, and S. Puig, “Fast evaluation and monitoring of ingenol mebutate treatment of multiple basal cell carcinomas by in vivo hand-held reflectance confocal microscopy,” J. Eur. Acad. Dermatol. Venereol. 31(6), e284–e286 (2017).
[PubMed]

Mortensen, N. N.

M. Gniadecka, H. C. Wulf, and N. N. Mortensen, “Diagnosis of basal cell carcinoma by Raman spectroscopy,” J. Invest. Dermatol. 28(2), 125–129 (1997).
[PubMed]

Mosterd, K.

K. Mosterd, G. A. M. Krekels, F. H. Nieman, J. U. Ostertag, B. A. Essers, C. D. Dirksen, P. M. Steijlen, A. Vermeulen, H. Neumann, and N. W. Kelleners-Smeets, “Surgical excision versus Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up,” Lancet Oncol. 9(12), 1149–1156 (2008).
[PubMed]

Neumann, H.

K. Mosterd, G. A. M. Krekels, F. H. Nieman, J. U. Ostertag, B. A. Essers, C. D. Dirksen, P. M. Steijlen, A. Vermeulen, H. Neumann, and N. W. Kelleners-Smeets, “Surgical excision versus Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up,” Lancet Oncol. 9(12), 1149–1156 (2008).
[PubMed]

Neumann, H. A.

N. W. J. Smeets, G. A. M. Krekels, J. U. Ostertag, B. A. Essers, C. D. Dirksen, F. H. Nieman, and H. A. Neumann, “Surgical excision vs Mohs’ micrographic surgery for basal-cell carcinoma of the face: randomised controlled trial,” Lancet 364(9447), 1766–1772 (2004).
[PubMed]

Neumann, M. H.

A. Nijssen, T. C. Bakker Schut, F. Heule, P. J. Caspers, D. P. Hayes, M. H. Neumann, and G. J. Puppels, “Discriminating basal cell carcinoma from its surrounding tissue by Raman spectroscopy,” J. Invest. Dermatol. 119(1), 64–69 (2002).
[PubMed]

Nieman, F. H.

K. Mosterd, G. A. M. Krekels, F. H. Nieman, J. U. Ostertag, B. A. Essers, C. D. Dirksen, P. M. Steijlen, A. Vermeulen, H. Neumann, and N. W. Kelleners-Smeets, “Surgical excision versus Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up,” Lancet Oncol. 9(12), 1149–1156 (2008).
[PubMed]

N. W. J. Smeets, G. A. M. Krekels, J. U. Ostertag, B. A. Essers, C. D. Dirksen, F. H. Nieman, and H. A. Neumann, “Surgical excision vs Mohs’ micrographic surgery for basal-cell carcinoma of the face: randomised controlled trial,” Lancet 364(9447), 1766–1772 (2004).
[PubMed]

Nijssen, A.

A. Nijssen, T. C. Bakker Schut, F. Heule, P. J. Caspers, D. P. Hayes, M. H. Neumann, and G. J. Puppels, “Discriminating basal cell carcinoma from its surrounding tissue by Raman spectroscopy,” J. Invest. Dermatol. 119(1), 64–69 (2002).
[PubMed]

Nijsten, T.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Noordhoek Hegt, V.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Notingher, I.

D. Shipp, F. Sinjab, and I. Notingher, “Raman spectroscopy: Techniques and applications in the life sciences,” Adv. Opt. Photonics 9(2), 315–428 (2017).

F. Sinjab, K. Kong, G. Gibson, S. Varma, H. Williams, M. Padgett, and I. Notingher, “Tissue diagnosis using power-sharing multifocal Raman micro-spectroscopy and auto-fluorescence imaging,” Biomed. Opt. Express 7(8), 2993–3006 (2016).
[PubMed]

S. Takamori, K. Kong, S. Varma, I. Leach, H. C. Williams, and I. Notingher, “Optimization of multimodal spectral imaging for assessment of resection margins during Mohs micrographic surgery for basal cell carcinoma,” Biomed. Opt. Express 6(1), 98–111 (2014).
[PubMed]

K. Kong, F. Zaabar, E. Rakha, I. Ellis, A. Koloydenko, and I. Notingher, “Towards intra-operative diagnosis of tumours during breast conserving surgery by selective-sampling Raman micro-spectroscopy,” Phys. Med. Biol. 59(20), 6141–6152 (2014).
[PubMed]

K. Kong, C. J. Rowlands, S. Varma, W. Perkins, I. H. Leach, A. A. Koloydenko, H. C. Williams, and I. Notingher, “Diagnosis of tumors during tissue-conserving surgery with integrated autofluorescence and Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 110(38), 15189–15194 (2013).
[PubMed]

C. J. Rowlands, S. Varma, W. Perkins, I. Leach, H. Williams, and I. Notingher, “Rapid acquisition of Raman spectral maps through minimal sampling: applications in tissue imaging,” J. Biophotonics 5(3), 220–229 (2012).
[PubMed]

M. Larraona-Puy, A. Ghita, A. Zoladek, W. Perkins, S. Varma, I. H. Leach, A. A. Koloydenko, H. Williams, and I. Notingher, “Development of Raman microspectroscopy for automated detection and imaging of Basal Cell Carcinoma,” J. Biomed. Opt. 14(5), 054031 (2009).
[PubMed]

Ostertag, J. U.

K. Mosterd, G. A. M. Krekels, F. H. Nieman, J. U. Ostertag, B. A. Essers, C. D. Dirksen, P. M. Steijlen, A. Vermeulen, H. Neumann, and N. W. Kelleners-Smeets, “Surgical excision versus Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up,” Lancet Oncol. 9(12), 1149–1156 (2008).
[PubMed]

N. W. J. Smeets, G. A. M. Krekels, J. U. Ostertag, B. A. Essers, C. D. Dirksen, F. H. Nieman, and H. A. Neumann, “Surgical excision vs Mohs’ micrographic surgery for basal-cell carcinoma of the face: randomised controlled trial,” Lancet 364(9447), 1766–1772 (2004).
[PubMed]

Padgett, M.

Patel, A. N.

J. M. Baxter, A. N. Patel, and S. Varma, “Facial basal cell carcinoma,” BMJ 345, e5342 (2012).
[PubMed]

Paver, R.

I. Leibovitch, S. C. Huilgol, D. Selva, S. Richards, and R. Paver, “Basal cell carcinoma treated with Mohs surgery in Australia I. Experience over 10 years,” J. Am. Acad. Dermatol. 53(3), 445–451 (2005).
[PubMed]

Perkins, W.

K. Kong, C. J. Rowlands, S. Varma, W. Perkins, I. H. Leach, A. A. Koloydenko, H. C. Williams, and I. Notingher, “Diagnosis of tumors during tissue-conserving surgery with integrated autofluorescence and Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 110(38), 15189–15194 (2013).
[PubMed]

C. J. Rowlands, S. Varma, W. Perkins, I. Leach, H. Williams, and I. Notingher, “Rapid acquisition of Raman spectral maps through minimal sampling: applications in tissue imaging,” J. Biophotonics 5(3), 220–229 (2012).
[PubMed]

M. Larraona-Puy, A. Ghita, A. Zoladek, W. Perkins, S. Varma, I. H. Leach, A. A. Koloydenko, H. Williams, and I. Notingher, “Development of Raman microspectroscopy for automated detection and imaging of Basal Cell Carcinoma,” J. Biomed. Opt. 14(5), 054031 (2009).
[PubMed]

Peterson, S. R.

A. Kimyai-Asadi, M. Alam, L. H. Goldberg, S. R. Peterson, S. Silapunt, and M. H. Jih, “Efficacy of narrow-margin excision of well-demarcated primary facial basal cell carcinomas,” J. Am. Acad. Dermatol. 53(3), 464–468 (2005).
[PubMed]

A. Kimyai-Asadi, M. Alam, L. H. Goldberg, S. R. Peterson, S. Silapunt, and M. H. Jih, “Efficacy of narrow-margin excision of well-demarcated primary facial basal cell carcinomas,” J. Am. Acad. Dermatol. 53(3), 464–468 (2005).
[PubMed]

Podlipnik, S.

E. Manubens, A. Barreiro, A. Bennassar, S. Podlipnik, N. Moreno, P. Iglesias, J. Malvehy, and S. Puig, “Fast evaluation and monitoring of ingenol mebutate treatment of multiple basal cell carcinomas by in vivo hand-held reflectance confocal microscopy,” J. Eur. Acad. Dermatol. Venereol. 31(6), e284–e286 (2017).
[PubMed]

Podoleanu, A.

Puig, S.

E. Manubens, A. Barreiro, A. Bennassar, S. Podlipnik, N. Moreno, P. Iglesias, J. Malvehy, and S. Puig, “Fast evaluation and monitoring of ingenol mebutate treatment of multiple basal cell carcinomas by in vivo hand-held reflectance confocal microscopy,” J. Eur. Acad. Dermatol. Venereol. 31(6), e284–e286 (2017).
[PubMed]

Puppels, G. J.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

A. Nijssen, T. C. Bakker Schut, F. Heule, P. J. Caspers, D. P. Hayes, M. H. Neumann, and G. J. Puppels, “Discriminating basal cell carcinoma from its surrounding tissue by Raman spectroscopy,” J. Invest. Dermatol. 119(1), 64–69 (2002).
[PubMed]

Rakha, E.

K. Kong, F. Zaabar, E. Rakha, I. Ellis, A. Koloydenko, and I. Notingher, “Towards intra-operative diagnosis of tumours during breast conserving surgery by selective-sampling Raman micro-spectroscopy,” Phys. Med. Biol. 59(20), 6141–6152 (2014).
[PubMed]

Reinhold, U.

M. Ulrich, T. von Braunmuehl, H. Kurzen, T. Dirschka, C. Kellner, E. Sattler, C. Berking, J. Welzel, and U. Reinhold, “The sensitivity and specificity of optical coherence tomography for the assisted diagnosis of nonpigmented basal cell carcinoma: an observational study,” Br. J. Dermatol. 173(2), 428–435 (2015).
[PubMed]

Richards, S.

I. Leibovitch, S. C. Huilgol, D. Selva, S. Richards, and R. Paver, “Basal cell carcinoma treated with Mohs surgery in Australia I. Experience over 10 years,” J. Am. Acad. Dermatol. 53(3), 445–451 (2005).
[PubMed]

Rowlands, C. J.

K. Kong, C. J. Rowlands, S. Varma, W. Perkins, I. H. Leach, A. A. Koloydenko, H. C. Williams, and I. Notingher, “Diagnosis of tumors during tissue-conserving surgery with integrated autofluorescence and Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 110(38), 15189–15194 (2013).
[PubMed]

C. J. Rowlands, S. Varma, W. Perkins, I. Leach, H. Williams, and I. Notingher, “Rapid acquisition of Raman spectral maps through minimal sampling: applications in tissue imaging,” J. Biophotonics 5(3), 220–229 (2012).
[PubMed]

Santos, I. P.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Sattler, E.

M. Ulrich, T. von Braunmuehl, H. Kurzen, T. Dirschka, C. Kellner, E. Sattler, C. Berking, J. Welzel, and U. Reinhold, “The sensitivity and specificity of optical coherence tomography for the assisted diagnosis of nonpigmented basal cell carcinoma: an observational study,” Br. J. Dermatol. 173(2), 428–435 (2015).
[PubMed]

Schofield, J.

Selva, D.

I. Leibovitch, S. C. Huilgol, D. Selva, S. Richards, and R. Paver, “Basal cell carcinoma treated with Mohs surgery in Australia I. Experience over 10 years,” J. Am. Acad. Dermatol. 53(3), 445–451 (2005).
[PubMed]

Sewnaik, A.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Shipp, D.

D. Shipp, F. Sinjab, and I. Notingher, “Raman spectroscopy: Techniques and applications in the life sciences,” Adv. Opt. Photonics 9(2), 315–428 (2017).

Silapunt, S.

A. Kimyai-Asadi, M. Alam, L. H. Goldberg, S. R. Peterson, S. Silapunt, and M. H. Jih, “Efficacy of narrow-margin excision of well-demarcated primary facial basal cell carcinomas,” J. Am. Acad. Dermatol. 53(3), 464–468 (2005).
[PubMed]

A. Kimyai-Asadi, M. Alam, L. H. Goldberg, S. R. Peterson, S. Silapunt, and M. H. Jih, “Efficacy of narrow-margin excision of well-demarcated primary facial basal cell carcinomas,” J. Am. Acad. Dermatol. 53(3), 464–468 (2005).
[PubMed]

Sinjab, F.

Smeets, N. W. J.

N. W. J. Smeets, G. A. M. Krekels, J. U. Ostertag, B. A. Essers, C. D. Dirksen, F. H. Nieman, and H. A. Neumann, “Surgical excision vs Mohs’ micrographic surgery for basal-cell carcinoma of the face: randomised controlled trial,” Lancet 364(9447), 1766–1772 (2004).
[PubMed]

Smits, R. W. H.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Steijlen, P. M.

K. Mosterd, G. A. M. Krekels, F. H. Nieman, J. U. Ostertag, B. A. Essers, C. D. Dirksen, P. M. Steijlen, A. Vermeulen, H. Neumann, and N. W. Kelleners-Smeets, “Surgical excision versus Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up,” Lancet Oncol. 9(12), 1149–1156 (2008).
[PubMed]

Strange, R. C.

J. T. Lear, I. Harvey, D. de Berker, R. C. Strange, and A. A. Fryer, “Basal cell carcinoma,” J. R. Soc. Med. 91(11), 585–588 (1998).
[PubMed]

Takamori, S.

Ten Hove, I.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Ulrich, M.

D. J. Kadouch, M. M. Leeflang, Y. S. Elshot, C. Longo, M. Ulrich, A. C. van der Wal, A. Wolkerstorfer, M. W. Bekkenk, and M. A. de Rie, “Diagnostic accuracy of confocal microscopy imaging vs. punch biopsy for diagnosing and subtyping basal cell carcinoma,” J. Eur. Acad. Dermatol. Venereol. 31(10), 1641–1648 (2017).
[PubMed]

M. Ulrich, T. von Braunmuehl, H. Kurzen, T. Dirschka, C. Kellner, E. Sattler, C. Berking, J. Welzel, and U. Reinhold, “The sensitivity and specificity of optical coherence tomography for the assisted diagnosis of nonpigmented basal cell carcinoma: an observational study,” Br. J. Dermatol. 173(2), 428–435 (2015).
[PubMed]

van der Kamp, M. F.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

van der Wal, A. C.

D. J. Kadouch, M. M. Leeflang, Y. S. Elshot, C. Longo, M. Ulrich, A. C. van der Wal, A. Wolkerstorfer, M. W. Bekkenk, and M. A. de Rie, “Diagnostic accuracy of confocal microscopy imaging vs. punch biopsy for diagnosing and subtyping basal cell carcinoma,” J. Eur. Acad. Dermatol. Venereol. 31(10), 1641–1648 (2017).
[PubMed]

van Deurzen, C. H. M.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

van Doorn, H. C.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

van Doorn, R.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

van Lanschot, C. G. F.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

van Leenders, G. J. L. H.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Varma, S.

F. Sinjab, K. Kong, G. Gibson, S. Varma, H. Williams, M. Padgett, and I. Notingher, “Tissue diagnosis using power-sharing multifocal Raman micro-spectroscopy and auto-fluorescence imaging,” Biomed. Opt. Express 7(8), 2993–3006 (2016).
[PubMed]

S. Takamori, K. Kong, S. Varma, I. Leach, H. C. Williams, and I. Notingher, “Optimization of multimodal spectral imaging for assessment of resection margins during Mohs micrographic surgery for basal cell carcinoma,” Biomed. Opt. Express 6(1), 98–111 (2014).
[PubMed]

K. Kong, C. J. Rowlands, S. Varma, W. Perkins, I. H. Leach, A. A. Koloydenko, H. C. Williams, and I. Notingher, “Diagnosis of tumors during tissue-conserving surgery with integrated autofluorescence and Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 110(38), 15189–15194 (2013).
[PubMed]

J. M. Baxter, A. N. Patel, and S. Varma, “Facial basal cell carcinoma,” BMJ 345, e5342 (2012).
[PubMed]

C. J. Rowlands, S. Varma, W. Perkins, I. Leach, H. Williams, and I. Notingher, “Rapid acquisition of Raman spectral maps through minimal sampling: applications in tissue imaging,” J. Biophotonics 5(3), 220–229 (2012).
[PubMed]

M. Larraona-Puy, A. Ghita, A. Zoladek, W. Perkins, S. Varma, I. H. Leach, A. A. Koloydenko, H. Williams, and I. Notingher, “Development of Raman microspectroscopy for automated detection and imaging of Basal Cell Carcinoma,” J. Biomed. Opt. 14(5), 054031 (2009).
[PubMed]

Verdijk, R. M.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Vermeulen, A.

K. Mosterd, G. A. M. Krekels, F. H. Nieman, J. U. Ostertag, B. A. Essers, C. D. Dirksen, P. M. Steijlen, A. Vermeulen, H. Neumann, and N. W. Kelleners-Smeets, “Surgical excision versus Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up,” Lancet Oncol. 9(12), 1149–1156 (2008).
[PubMed]

von Braunmuehl, T.

M. Ulrich, T. von Braunmuehl, H. Kurzen, T. Dirschka, C. Kellner, E. Sattler, C. Berking, J. Welzel, and U. Reinhold, “The sensitivity and specificity of optical coherence tomography for the assisted diagnosis of nonpigmented basal cell carcinoma: an observational study,” Br. J. Dermatol. 173(2), 428–435 (2015).
[PubMed]

von der Thüsen, J. H.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Welzel, J.

M. Ulrich, T. von Braunmuehl, H. Kurzen, T. Dirschka, C. Kellner, E. Sattler, C. Berking, J. Welzel, and U. Reinhold, “The sensitivity and specificity of optical coherence tomography for the assisted diagnosis of nonpigmented basal cell carcinoma: an observational study,” Br. J. Dermatol. 173(2), 428–435 (2015).
[PubMed]

Williams, H.

F. Sinjab, K. Kong, G. Gibson, S. Varma, H. Williams, M. Padgett, and I. Notingher, “Tissue diagnosis using power-sharing multifocal Raman micro-spectroscopy and auto-fluorescence imaging,” Biomed. Opt. Express 7(8), 2993–3006 (2016).
[PubMed]

C. J. Rowlands, S. Varma, W. Perkins, I. Leach, H. Williams, and I. Notingher, “Rapid acquisition of Raman spectral maps through minimal sampling: applications in tissue imaging,” J. Biophotonics 5(3), 220–229 (2012).
[PubMed]

M. Larraona-Puy, A. Ghita, A. Zoladek, W. Perkins, S. Varma, I. H. Leach, A. A. Koloydenko, H. Williams, and I. Notingher, “Development of Raman microspectroscopy for automated detection and imaging of Basal Cell Carcinoma,” J. Biomed. Opt. 14(5), 054031 (2009).
[PubMed]

Williams, H. C.

S. Takamori, K. Kong, S. Varma, I. Leach, H. C. Williams, and I. Notingher, “Optimization of multimodal spectral imaging for assessment of resection margins during Mohs micrographic surgery for basal cell carcinoma,” Biomed. Opt. Express 6(1), 98–111 (2014).
[PubMed]

K. Kong, C. J. Rowlands, S. Varma, W. Perkins, I. H. Leach, A. A. Koloydenko, H. C. Williams, and I. Notingher, “Diagnosis of tumors during tissue-conserving surgery with integrated autofluorescence and Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 110(38), 15189–15194 (2013).
[PubMed]

Wolf, D. J.

D. J. Wolf and J. A. Zitelli, “Surgical margins for basal cell carcinoma,” Arch. Dermatol. 123(3), 340–344 (1987).
[PubMed]

Wolkerstorfer, A.

D. J. Kadouch, M. M. Leeflang, Y. S. Elshot, C. Longo, M. Ulrich, A. C. van der Wal, A. Wolkerstorfer, M. W. Bekkenk, and M. A. de Rie, “Diagnostic accuracy of confocal microscopy imaging vs. punch biopsy for diagnosing and subtyping basal cell carcinoma,” J. Eur. Acad. Dermatol. Venereol. 31(10), 1641–1648 (2017).
[PubMed]

Wolvius, E. B.

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Wulf, H. C.

M. Gniadecka, H. C. Wulf, and N. N. Mortensen, “Diagnosis of basal cell carcinoma by Raman spectroscopy,” J. Invest. Dermatol. 28(2), 125–129 (1997).
[PubMed]

Zaabar, F.

K. Kong, F. Zaabar, E. Rakha, I. Ellis, A. Koloydenko, and I. Notingher, “Towards intra-operative diagnosis of tumours during breast conserving surgery by selective-sampling Raman micro-spectroscopy,” Phys. Med. Biol. 59(20), 6141–6152 (2014).
[PubMed]

Zitelli, J. A.

D. J. Wolf and J. A. Zitelli, “Surgical margins for basal cell carcinoma,” Arch. Dermatol. 123(3), 340–344 (1987).
[PubMed]

Zoladek, A.

M. Larraona-Puy, A. Ghita, A. Zoladek, W. Perkins, S. Varma, I. H. Leach, A. A. Koloydenko, H. Williams, and I. Notingher, “Development of Raman microspectroscopy for automated detection and imaging of Basal Cell Carcinoma,” J. Biomed. Opt. 14(5), 054031 (2009).
[PubMed]

Adv. Opt. Photonics (1)

D. Shipp, F. Sinjab, and I. Notingher, “Raman spectroscopy: Techniques and applications in the life sciences,” Adv. Opt. Photonics 9(2), 315–428 (2017).

Analyst (Lond.) (1)

I. P. Santos, E. M. Barroso, T. C. Bakker Schut, P. J. Caspers, C. G. F. van Lanschot, D. H. Choi, M. F. van der Kamp, R. W. H. Smits, R. van Doorn, R. M. Verdijk, V. Noordhoek Hegt, J. H. von der Thüsen, C. H. M. van Deurzen, L. B. Koppert, G. J. L. H. van Leenders, P. C. Ewing-Graham, H. C. van Doorn, C. M. F. Dirven, M. B. Busstra, J. Hardillo, A. Sewnaik, I. Ten Hove, H. Mast, D. A. Monserez, C. Meeuwis, T. Nijsten, E. B. Wolvius, R. J. Baatenburg de Jong, G. J. Puppels, and S. Koljenović, “Raman spectroscopy for cancer detection and cancer surgery guidance: translation to the clinics,” Analyst (Lond.) 142(17), 3025–3047 (2017).
[PubMed]

Appl. Opt. (1)

Arch. Dermatol. (1)

D. J. Wolf and J. A. Zitelli, “Surgical margins for basal cell carcinoma,” Arch. Dermatol. 123(3), 340–344 (1987).
[PubMed]

Biomed. Opt. Express (2)

BMJ (1)

J. M. Baxter, A. N. Patel, and S. Varma, “Facial basal cell carcinoma,” BMJ 345, e5342 (2012).
[PubMed]

Br. J. Dermatol. (1)

M. Ulrich, T. von Braunmuehl, H. Kurzen, T. Dirschka, C. Kellner, E. Sattler, C. Berking, J. Welzel, and U. Reinhold, “The sensitivity and specificity of optical coherence tomography for the assisted diagnosis of nonpigmented basal cell carcinoma: an observational study,” Br. J. Dermatol. 173(2), 428–435 (2015).
[PubMed]

J. Am. Acad. Dermatol. (3)

A. Kimyai-Asadi, M. Alam, L. H. Goldberg, S. R. Peterson, S. Silapunt, and M. H. Jih, “Efficacy of narrow-margin excision of well-demarcated primary facial basal cell carcinomas,” J. Am. Acad. Dermatol. 53(3), 464–468 (2005).
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I. Leibovitch, S. C. Huilgol, D. Selva, S. Richards, and R. Paver, “Basal cell carcinoma treated with Mohs surgery in Australia I. Experience over 10 years,” J. Am. Acad. Dermatol. 53(3), 445–451 (2005).
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A. Kimyai-Asadi, M. Alam, L. H. Goldberg, S. R. Peterson, S. Silapunt, and M. H. Jih, “Efficacy of narrow-margin excision of well-demarcated primary facial basal cell carcinomas,” J. Am. Acad. Dermatol. 53(3), 464–468 (2005).
[PubMed]

J. Biomed. Opt. (1)

M. Larraona-Puy, A. Ghita, A. Zoladek, W. Perkins, S. Varma, I. H. Leach, A. A. Koloydenko, H. Williams, and I. Notingher, “Development of Raman microspectroscopy for automated detection and imaging of Basal Cell Carcinoma,” J. Biomed. Opt. 14(5), 054031 (2009).
[PubMed]

J. Biophotonics (1)

C. J. Rowlands, S. Varma, W. Perkins, I. Leach, H. Williams, and I. Notingher, “Rapid acquisition of Raman spectral maps through minimal sampling: applications in tissue imaging,” J. Biophotonics 5(3), 220–229 (2012).
[PubMed]

J. Dermatol. Surg. Oncol. (1)

H. Breuninger and K. Dietz, “Prediction of subclinical tumor infiltration in basal cell carcinoma,” J. Dermatol. Surg. Oncol. 17(7), 574–578 (1991).
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J. Eur. Acad. Dermatol. Venereol. (2)

D. J. Kadouch, M. M. Leeflang, Y. S. Elshot, C. Longo, M. Ulrich, A. C. van der Wal, A. Wolkerstorfer, M. W. Bekkenk, and M. A. de Rie, “Diagnostic accuracy of confocal microscopy imaging vs. punch biopsy for diagnosing and subtyping basal cell carcinoma,” J. Eur. Acad. Dermatol. Venereol. 31(10), 1641–1648 (2017).
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E. Manubens, A. Barreiro, A. Bennassar, S. Podlipnik, N. Moreno, P. Iglesias, J. Malvehy, and S. Puig, “Fast evaluation and monitoring of ingenol mebutate treatment of multiple basal cell carcinomas by in vivo hand-held reflectance confocal microscopy,” J. Eur. Acad. Dermatol. Venereol. 31(6), e284–e286 (2017).
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J. Invest. Dermatol. (2)

A. Nijssen, T. C. Bakker Schut, F. Heule, P. J. Caspers, D. P. Hayes, M. H. Neumann, and G. J. Puppels, “Discriminating basal cell carcinoma from its surrounding tissue by Raman spectroscopy,” J. Invest. Dermatol. 119(1), 64–69 (2002).
[PubMed]

M. Gniadecka, H. C. Wulf, and N. N. Mortensen, “Diagnosis of basal cell carcinoma by Raman spectroscopy,” J. Invest. Dermatol. 28(2), 125–129 (1997).
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J. R. Soc. Med. (1)

J. T. Lear, I. Harvey, D. de Berker, R. C. Strange, and A. A. Fryer, “Basal cell carcinoma,” J. R. Soc. Med. 91(11), 585–588 (1998).
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Lancet (1)

N. W. J. Smeets, G. A. M. Krekels, J. U. Ostertag, B. A. Essers, C. D. Dirksen, F. H. Nieman, and H. A. Neumann, “Surgical excision vs Mohs’ micrographic surgery for basal-cell carcinoma of the face: randomised controlled trial,” Lancet 364(9447), 1766–1772 (2004).
[PubMed]

Lancet Oncol. (1)

K. Mosterd, G. A. M. Krekels, F. H. Nieman, J. U. Ostertag, B. A. Essers, C. D. Dirksen, P. M. Steijlen, A. Vermeulen, H. Neumann, and N. W. Kelleners-Smeets, “Surgical excision versus Mohs’ micrographic surgery for primary and recurrent basal-cell carcinoma of the face: a prospective randomised controlled trial with 5-years’ follow-up,” Lancet Oncol. 9(12), 1149–1156 (2008).
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C. A. Lieber, S. K. Majumder, D. L. Ellis, D. D. Billheimer, and A. Mahadevan-Jansen, “In vivo nonmelanoma skin cancer diagnosis using Raman microspectroscopy,” Lasers Surg. Med. 40(7), 461–467 (2008).
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Phys. Med. Biol. (1)

K. Kong, F. Zaabar, E. Rakha, I. Ellis, A. Koloydenko, and I. Notingher, “Towards intra-operative diagnosis of tumours during breast conserving surgery by selective-sampling Raman micro-spectroscopy,” Phys. Med. Biol. 59(20), 6141–6152 (2014).
[PubMed]

Proc. Natl. Acad. Sci. U.S.A. (1)

K. Kong, C. J. Rowlands, S. Varma, W. Perkins, I. H. Leach, A. A. Koloydenko, H. C. Williams, and I. Notingher, “Diagnosis of tumors during tissue-conserving surgery with integrated autofluorescence and Raman scattering microscopy,” Proc. Natl. Acad. Sci. U.S.A. 110(38), 15189–15194 (2013).
[PubMed]

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Figures (9)

Fig. 1
Fig. 1 a). Schematic description of the intended use of MSH for checking completeness of tumour removal during BCC surgery (Mohs surgery and wide-local excision). b) Flow chart describing the automated measurement and diagnosis algorithms for MSH. c) Photographs of the manual Laboratory Instrument and the automated MSH Prototype. The tissue specimen is loaded in a purpose-built cassette with a quartz bottom window (2.5mm x 2.5cm, 1mm thick). The cassette is manually placed on the microscope stage of the Laboratory Instrument or loaded into the Prototype Instrument.
Fig. 2
Fig. 2 Optimisation and evaluation of segmentation algorithms for AF images of skin samples (recorded on Laboratory Instrument). a)-c) two typical examples: a) AF images; b) segmentation optimisation functions: fA = N, where N = segment number; fB = N*A, where A = area fraction captured by segments; c) segmentation images and quality parameters corresponding to the AF when using the MaxfA (A) and MaxfB (B) as intensity thresholds. Scale bars: 5mm. d) Statistical analysis of parameters ρ and ε based on AF images recorded on the Laboratory Instrument on 35 tissue samples with BCC (23 patients).
Fig. 3
Fig. 3 Evaluation of sampling points for Raman spectroscopy based on segmentation of AF images (Config. 2). Sample 1: typical sample containing BCC, Sample 2: the sample with the highest number of segments with BCC missed by the allocated sampling points. a) AF images; b) segmented images and sampling points using uniform distribution: pink points represent Raman measurements performed on healthy tissue and white points represent Raman measurements performed on BCC. The number of segments containing BCC detected and missed are indicated for each sample; Scale bars: 5mm. c) evaluation of tumour “Hit rate” and missed segments for: sampling points allocated selectively: sampling point at the position of the lowest and highest intensity within each segment, and uniform distribution of the remaining sampling points (Config. 1); sampling points distributed uniformly within segments (Config. 2).
Fig. 4
Fig. 4 Development of the Raman classification model for BCC. a) annotation of Raman spectra based on histopathology following k means clustering of Raman spectra collected by raster scanning; Scale bar: 0.5mm. b) Selected Raman spectra at the location indicated by arrows and coloured coded symbols in the annotated Raman map and circles in the adjacent H&E image.
Fig. 5
Fig. 5 Development of the Raman classification model for BCC. a) Average Raman spectra of BCC, healthy skin tissue structures and surgical dye. The spectral features selected for the ANN classifier are highlighted (red lines represent the local baseline); b) confusion matrix for the 5-fold cross validation on the training set of samples measured on the Laboratory instrument. Class EMI includes epidermis, muscle and inflammation.
Fig. 6
Fig. 6 Transferability testing of the optimised models on the automated MSH Prototype. a) typical examples of AF images and segmentation results; Scale bars: 5mm. b) statistical analysis of the performance parameters ρ, ε, hit rate and number of BCC segments missed; c) confusion matrix of the Raman model applied on independent samples; d) 5-fold cross-validation of the joint training and test sets as a function of patient numbers.
Fig. 7
Fig. 7 Comparison between MSH diagnosis (automated Prototype instrument) and the corresponding histopathology sections for typical skin layers excised during Mohs micrographic surgery. The diagnosis was based on the algorithm optimised on the training samples measured on the Laboratory Instrument. Sample 1 and 2 are BCC-positive and Sample 3 is BCC-negative. Tumours are encircled in blue circles and false positive segments in Sample 3 are highlighted by black arrows (circles and arrows were added manually).
Fig. 8
Fig. 8 Consistency of MSH diagnosis using the automated Prototype instrument. Sample 1 and 2 are BCC-positive and Sample 3 is BCC negative. Tumours are encircled in blue circles and false positive segments in Sample 3 are highlighted by black arrows (circles and arrows were added manually).
Fig. 9
Fig. 9 Consistency of MSH diagnosis among different users. User 1: spectroscopy specialist (R. Boitor), User 2: Mohs surgeon (S. Varma) with 1 h training, User 3 (B. Salence): core medical trainee with interest in dermatology (BS) with 8 hours training. Tumours are encircled in blue circles and false positive segments in Sample 3 are highlighted by black arrows (circles and arrows were added manually).

Equations (3)

Equations on this page are rendered with MathJax. Learn more.

ρ= Area(detected BCC) Area( detected BCC )+Area(missed BCC)
ε= Area (Healthy tissue) Area (detected BCC)+Area (Healthy tissue)
N sampling ( i )= N min + Var(i)×Area(i) i=1 k [ Var(i)×Area(i) ] × N rest

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