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Integration of a Raman spectroscopy system to a robotic-assisted surgical system for real-time tissue characterization during radical prostatectomy procedures

Surgical excision of the whole prostate through a radical prostatectomy procedure is part of the standard of care for prostate cancer. Positive surgical margins (cancer cells having spread into surrounding nonresected tissue) occur in as many as 1 in 5 cases and strongly correlate with disease recurrence and the requirement of adjuvant treatment. Margin assessment is currently only performed by pathologists hours to days following surgery and the integration of a real-time surgical readout would benefit current prostatectomy procedures. Raman spectroscopy is a promising technology to assess surgical margins: its in vivo use during radical prostatectomy could help ensure the extent of resected prostate and cancerous tissue is maximized. We thus present the design and development of a dual excitation Raman spectroscopy system (680- and 785-nm excitations) integrated to the robotic da Vinci surgical platform for in vivo use. Following validation in phantoms, spectroscopic data from 20 whole human prostates immediately following radical prostatectomy are obtained using the system. With this dataset, we are able to distinguish prostate from extra prostatic tissue with an accuracy, sensitivity, and specificity of 91%, 90.5%, and 96%, respectively. Finally, the integrated Raman spectroscopy system is used to collect preliminary spectroscopic data at the surgical margin in vivo in four patients.

Pinto, Michael et al. “Integration of a Raman spectroscopy system to a robotic-assisted surgical system for real-time tissue characterization during radical prostatectomy procedures.” Journal of biomedical optics vol. 24,2 (2019): 1-10. doi:10.1117/1.JBO.24.2.025001

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Mesoscopic characterization of prostate cancer using Raman spectroscopy: potential for diagnostics and therapeutics

Abstract

Objective: To test if Raman spectroscopy (RS) is an appropriate tool for the diagnosis and possibly grading of prostate cancer (PCa).

Patients and methods: Between 20 and 50 Raman spectra were acquired from 32 fresh and non-processed post-prostatectomy specimens using a macroscopic handheld RS probe. Each measured area was characterized and categorized according to histopathological criteria: tissue type (extraprostatic or prostatic); tissue malignancy (benign or malignant); cancer grade (Grade Groups [GGs] 1-5); and tissue glandular level. The data were analysed using machine-learning classification with neural network.

Results: The RS technique was able to distinguish prostate from extraprostatic tissue with a sensitivity of 82% and a specificity of 83% and benign from malignant tissue with a sensitivity of 87% and a specificity of 86%. In an exploratory fashion, RS differentiated benign from GG1 in 726/801 spectra (91%; sensitivity 80%, specificity 91%), from GG2 in 588/805 spectra (73%; sensitivity 76%, specificity 73%), from GG3 in 670/797 spectra (84%; sensitivity 86%, specificity 84%), from GG4 in 711/802 spectra (88%; sensitivity 77%, specificity 89%) and from GG5 in 729/818 spectra (89%; sensitivity 90%, specificity 89%).

Conclusion: Current diagnostic approaches of PCa using needle biopsies have suboptimal cancer detection rates and a significant risk of infection. Standard non-targeted random sampling results in false-negative biopsies in 15-30% of patients, which affects clinical management. RS, a non-destructive tissue interrogation technique providing vibrational molecular information, resolved the highly complex architecture of the prostate and detect cancer with high accuracy using a fibre optic probe to interrogate radical prostatectomy (RP) specimens from 32 patients (947 spectra). This proof-of-principle paves the way for the development of in vivo tumour targeting spectroscopy tools for informed biopsy collection to address the clinical need for accurate PCa diagnosis and possibly to improve surgical resection during RP as a complement to histopathological analysis.

Aubertin, Kelly et al. “Mesoscopic characterization of prostate cancer using Raman spectroscopy: potential for diagnostics and therapeutics.” BJU international vol. 122,2 (2018): 326-336. doi:10.1111/bju.14199

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Raman Spectroscopy and Imaging for Cancer Diagnosis

Raman scattering has long been used to analyze chemical compositions in biological systems. Owing to its high chemical specificity and non-invasive detection capability, Raman scattering has been widely employed in cancer screening, diagnosis, and intraoperative surgical guidance in the past ten years. In order to overcome the weak signal of spontaneous Raman scattering, coherent Raman scattering and surface-enhanced Raman scattering have been developed and recently applied in the field of cancer research. This review focuses on innovative studies of the use of Raman scattering in cancer diagnosis and their potential to transition from bench to bedside.

Cui, S. Zhang, and S. Yue, “Raman Spectroscopy and Imaging for Cancer Diagnosis,” J. Healthc. Eng., vol. 2018, pp. 1–11, 2018

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Real-time endoscopic Raman spectroscopy for in vivo early lung cancer detection

Currently, the most sensitive method for localizing lung cancers in central airways is autofluorescence bronchoscopy (AFB) in combination with white light bronchoscopy (WLB). The diagnostic accuracy of WLB + AFB for high-grade dysplasia (HGD) and carcinoma in situ is variable depending on physician’s experience. When WLB + AFB are operated at high diagnostic sensitivity, the associated diagnostic specificity is low. Raman spectroscopy probes molecular vibrations and gives highly specific, fingerprint-like spectral features and has high accuracy for tissue pathology classification. In this study we present the use of a real-time endoscopy Raman spectroscopy system to improve the specificity. A spectrum is acquired within 1 second and clinical data are obtained from 280 tissue sites (72 HGDs/malignant lesions, 208 benign lesions/normal sites) in 80 patients. Using multivariate analyses and waveband selection methods on the Raman spectra, we have demonstrated that HGD and malignant lung lesions can be detected with high sensitivity (90%) and good specificity (65%).

C. McGregor et al., “Real-time endoscopic Raman spectroscopy for in vivo early lung cancer detection,” J. Biophotonics, vol. 10, no. 1, pp. 98–110, 2017.

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Highly Accurate Detection of Cancer In Situ with Intraoperative, Label-Free, Multimodal Optical Spectroscopy

Effectiveness of surgery as a cancer treatment is reduced when all cancer cells are not detected during surgery, leading to recurrences that negatively impact survival. To maximize cancer cell detection during cancer surgery, we designed an in situ intraoperative, label-free, optical cancer detection system that combines intrinsic fluorescence spectroscopy, diffuse reflectance spectroscopy, and Raman spectroscopy. Using this multimodal optical cancer detection system, we found that brain, lung, colon, and skin cancers could be detected in situ during surgery with an accuracy, sensitivity, and specificity of 97%, 100%, and 93%, respectively. This highly sensitive optical molecular imaging approach can profoundly impact a wide range of surgical and noninvasive interventional oncology procedures by improving cancer detection capabilities, thereby reducing cancer burden and improving survival and quality of life. Cancer Res; 77(14); 3942–50. ©2017 AACR.

Jermyn, Michael et al. “Highly Accurate Detection of Cancer In Situ with Intraoperative, Label- Free, Multimodal Optical Spectroscopy.” Cancer research vol. 77,14 (2017): 3942-3950. doi:10.1158/0008-5472.CAN-17-0668 https://pubmed.ncbi.nlm.nih.gov/28659435/

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Raman spectroscopy in microsurgery: impact of operating microscope illumination sources on data quality and tissue classification

Ambient light artifacts can confound Raman spectroscopy measurements performed in a clinical setting such as during open surgery. However, requiring light sources to be turned off during intraoperative spectral acquisition can be impractical because it can slow down the procedure by requiring surgeons to acquire data under light conditions different from the routine clinical practice. Here a filter system is introduced allowing in vivo Raman spectroscopy measurements to be performed with the light source of a neurosurgical microscope turned on, without interfering with the standard procedure. Ex vivo and in vivo results on calf and human brain, respectively, show that when the new filter system is used there is no significant difference between Raman spectra acquired under pitch dark conditions or with the microscope light source turned on. This is important for the clinical translation of Raman spectroscopy because of the resulting decrease in total imaging time for each measurement and because the surgeon can now acquire spectroscopic data with no disruption of the surgical workflow.

Desroches et al., “Raman spectroscopy in microsurgery: impact of operating microscope illumination sources on data quality and tissue classification,” Analyst, vol. 142, no. 8, pp. 1185–1191, 2017.

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Raman spectroscopy detects distant invasive brain cancer cells centimeters beyond MRI capability in humans

Surgical treatment of brain cancer is limited by the inability of current imaging capabilities such as magnetic resonance imaging (MRI) to detect the entirety of this locally invasive cancer. This results in residual cancer cells remaining following surgery, leading to recurrence and death. We demonstrate that intraoperative Raman spectroscopy can detect invasive cancer cells centimeters beyond pathological T1-contrast-enhanced and T2-weighted MRI signals. This intraoperative optical guide can be used to detect invasive cancer cells and minimize post-surgical cancer burden. The detection of distant invasive cancer cells beyond MRI signal has the potential to increase the effectiveness of surgery and directly lengthen patient survival.

Michael Jermyn, Joannie Desroches, Jeanne Mercier, Karl St-Arnaud, Marie-Christine Guiot, Frederic Leblond, and Kevin Petrecca, “Raman spectroscopy detects distant invasive brain cancer cells centimeters beyond MRI capability in humans,” Biomed. Opt. Express 7, 5129-5137 (2016)

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Intraoperative brain cancer detection with Raman spectroscopy in humans

Cancers are often impossible to visually distinguish from normal tissue. This is critical for brain cancer where residual invasive cancer cells frequently remain after surgery, leading to disease recurrence and a negative impact on overall survival. No preoperative or intraoperative technology exists to identify all cancer cells that have invaded normal brain. To address this problem, we developed a handheld contact Raman spectroscopy probe technique for live, local detection of cancer cells in the human brain. Using this probe intraoperatively, we were able to accurately differentiate normal brain from dense cancer and normal brain invaded by cancer cells, with a sensitivity of 93% and a specificity of 91%. This Raman-based probe enabled detection of the previously undetectable diffusely invasive brain cancer cells at cellular resolution in patients with grade 2 to 4 gliomas. This intraoperative technology may therefore be able to classify cell populations in real-time, making it an ideal guide for surgical resection and decision-making.

Jermyn M, Mok K, Mercier J, Desroches J, Pichette J, Saint-Arnaud K, Bernstein L, Guiot MC, Petrecca K, Leblond F. Intraoperative brain cancer detection with Raman spectroscopy in humans. Sci Transl Med. 2015 Feb 11;7(274):274ra19. doi: 10.1126/scitranslmed.aaa2384. PMID: 25673764.

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