The goal of this project is to translate a bench-top line-scanning confocal microscope into a clinical instrument for intra-operative imaging during Mohs surgery, and to test feasibility for detecting basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) margins on patients, using aluminum chloride as a contrast agent for staining nuclear morphology in reflectance. Reaching clinically expected sensitivity and specificity will be the quantitative milestones to validate and demonstrate a technology platform for Mohs surgery in skin and other potentially diverse intra-operative imaging applications. The motivation is to create a relatively simple, small and low-cost confocal microscope for real-time imaging in reflectance, to guide surgery in diverse settings. The proposed immediate application is intra-operative mapping of BCCs and SCCs to guide Mohs surgery. Future applications may include mapping of cancers to guide surgery in oral, head-and-neck, breast, bladder, liver and other tissues. BCCs and SCCs occur with among the highest rates of incidence, with an estimated 1.3 million new cases diagnosed and an estimated 1 million surgeries performed every year in the USA alone. Surgery is guided by frozen pathology which is labor-intensive and time-consuming. Confocal microscopy images nuclear detail in vivo and thus may enable intra-operative mapping directly on the patient in real-time. Rapid examination of cancer margins may be performed on surgically exposed tissue in situ, to guide accurate and complete excision, while preserving surrounding normal tissue. The imaging may serve as an adjunct to pathology for guiding surgery, while saving labor and cost. Patients may benefit with more efficient procedures, less anesthesia and less time in the operating room. Preliminary results demonstrate the feasibility of detecting BCCs, with topically applied aluminum chloride to enhance cancer-to-normal tissue contrast, in surgically-exposed shave-biopsy wounds in situ on patients. Furthermore, a laboratory bench-top line-scanning confocal microscope demonstrates excellent imaging of nuclear and cellular detail in human skin in vivo. The optical sectioning is 1.7 ?m and lateral resolution is 0.8 ?m, which is comparable to that of pathology. The hardware cost of the bench-top microscope is less than $15,000. Our hypothesis is that the bench-top line-scanning instrumentation may be translated toward a compact confocal microscope for use at-the-bedside. Rapid and safe staining of nuclear morphology with aluminum chloride may enable intra-operative mapping, in reflectance contrast, of BCCs and SCCs to guide surgery.
The specific aims are (1) to build a compact line-scanning confocal microscope for intra-operative imaging in reflectance contrast, and (b) to test the microscope and aluminum chloride-based contrast for intra operative detection of BCC and SCC margins in surgical wounds in situ during Mohs surgery, in a pilot clinical study on 60 patients. Sensitivity and specificity will be determined, against the gold standard of Mohs frozen pathology, to validate the feasibility of the technology.

Public Health Relevance

Confocal microscopy may enable screening and diagnosis of skin cancers such as melanomas and basal- and squamous-cell carcinomas, or may guide surgery of such cancers, directly and in real-time on the patient. The screening, diagnosis or surgical guidance may be noninvasive, with minimal need for biopsy, minimal pain and minimal expense. In dermatology alone, US healthcare may potentially save $2 billion every year. Confocal microscopy may also prove useful for noninvasively diagnosing and treating many other types of cancers such as oral, head-and-neck, breast and cervical.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB012466-03
Application #
8323371
Study Section
Special Emphasis Panel (ZEB1-OSR-B (O1))
Program Officer
Krosnick, Steven
Project Start
2010-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$804,649
Indirect Cost
$383,146
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Sierra, Heidy; Damanpour, Shadi; Hibler, Brian et al. (2016) Confocal imaging of carbon dioxide laser-ablated basal cell carcinomas: An ex-vivo study on the uptake of contrast agent and ablation parameters. Lasers Surg Med 48:133-9
Hibler, B P; Sierra, H; Cordova, M et al. (2016) Carbon dioxide laser ablation of basal cell carcinoma with visual guidance by reflectance confocal microscopy: a proof-of-principle pilot study. Br J Dermatol 174:1359-64
Ghanta, Sindhu; Jordan, Michael I; Kose, Kivanc et al. (2016) A Marked Poisson Process Driven Latent Shape Model for 3D Segmentation of Reflectance Confocal Microscopy Image Stacks of Human Skin. IEEE Trans Image Process :
Kurugol, Sila; Kose, Kivanc; Park, Brian et al. (2015) Automated delineation of dermal-epidermal junction in reflectance confocal microscopy image stacks of human skin. J Invest Dermatol 135:710-7
Sierra, Heidy; Cordova, Miguel; Chen, Chih-Shan Jason et al. (2015) Confocal imaging-guided laser ablation of basal cell carcinomas: an ex vivo study. J Invest Dermatol 135:612-5
Flores, Eileen S; Cordova, Miguel; Kose, Kivanc et al. (2015) Intraoperative imaging during Mohs surgery with reflectance confocal microscopy: initial clinical experience. J Biomed Opt 20:61103
Li, Junwei; Arévalo, Maria T; Chen, Yanping et al. (2014) T-cell-mediated cross-strain protective immunity elicited by prime-boost vaccination with a live attenuated influenza vaccine. Int J Infect Dis 27:37-43
Chen, Chih-Shan Jason; Sierra, Heidy; Cordova, Miguel et al. (2014) Confocal microscopy-guided laser ablation for superficial and early nodular Basal cell carcinoma: a promising surgical alternative for superficial skin cancers. JAMA Dermatol 150:994-8
Kose, K; Cordova, M; Duffy, M et al. (2014) Video-mosaicing of reflectance confocal images for examination of extended areas of skin in vivo. Br J Dermatol 171:1239-41
Abeytunge, Sanjee; Li, Yongbiao; Larson, Bjorg et al. (2013) Confocal microscopy with strip mosaicing for rapid imaging over large areas of excised tissue. J Biomed Opt 18:61227

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