In situ brain tumor detection using a Raman spectroscopy system-results of a multicenter study.

Safe and effective brain tumor surgery aims to remove tumor tissue, not non-tumoral brain. This is a challenge since tumor cells are often not visually distinguishable from peritumoral brain during surgery. To address this, we conducted a multicenter study testing whether the Sentry System could distinguish the three most common types of brain tumors from brain tissue in a label-free manner. The Sentry System is a new real time, in situ brain tumor detection device that merges Raman spectroscopy with machine learning tissue classifiers. Nine hundred and seventy-six in situ spectroscopy measurements and colocalized tissue specimens were acquired from 67 patients undergoing surgery for glioblastoma, brain metastases, or meningioma to assess tumor classification. The device achieved diagnostic accuracies of 91% for glioblastoma, 97% for brain metastases, and 96% for meningiomas. These data show that the Sentry System discriminated tumor containing tissue from non-tumoral brain in real time and prior to resection.

Development and first in-human use of a Raman spectroscopy guidance system integrated with a brain biopsy needle.

Navigation-guided brain biopsies are the standard of care for diagnosis of several brain pathologies. However, imprecise targeting and tissue heterogeneity often hinder obtaining high-quality tissue samples, resulting in poor diagnostic yield. We report the development and first clinical testing of a navigation-guided fiberoptic Raman probe that allows surgeons to interrogate brain tissue in situ at the tip of the biopsy needle prior to tissue removal. The 900 µm diameter probe can detect high spectral quality Raman signals in both the fingerprint and high wavenumber spectral regions with minimal disruption to the neurosurgical workflow. The probe was tested in three brain tumor patients, and the acquired spectra in both normal brain and tumor tissue demonstrated the expected spectral features, indicating the quality of the data. As a proof-of-concept, we also demonstrate the consistency of the acquired Raman signal with different systems and experimental settings. Additional clinical development is planned to further evaluate the performance of the system and develop a statistical model for real-time tissue classification during the biopsy procedure.

A new method using Raman spectroscopy for in vivo targeted brain cancer tissue biopsy.

Modern cancer diagnosis requires histological, molecular, and genomic tumor analyses. Tumor sampling is often achieved using a targeted needle biopsy approach. Targeting errors and cancer heterogeneity causing inaccurate sampling are important limitations of this blind technique leading to non-diagnostic or poor quality samples, and the need for repeated biopsies pose elevated patient risk. An optical technology that can analyze the molecular nature of the tissue prior to harvesting could improve cancer targeting and mitigate patient risk. Here we report on the design, development, and validation of an in situ intraoperative, label-free, cancer detection system based on high wavenumber Raman spectroscopy. This optical detection device was engineered into a commercially available biopsy system allowing tumor analysis prior to tissue harvesting without disrupting workflow. Using a dual validation approach we show that high wavenumber Raman spectroscopy can detect human dense cancer with >60% cancer cells in situ during surgery with a sensitivity and specificity of 80% and 90%, respectively. We also demonstrate for the first time the use of this system in a swine brain biopsy model. These studies set the stage for the clinical translation of this optical molecular imaging method for high yield and safe targeted biopsy.

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.

Characterization of a Raman spectroscopy probe system for intraoperative brain tissue classification.

A detailed characterization study is presented of a Raman spectroscopy system designed to maximize the volume of resected cancer tissue in glioma surgery based on in vivo molecular tissue characterization. It consists of a hand-held probe system measuring spectrally resolved inelastically scattered light interacting with tissue, designed and optimized for in vivo measurements. Factors such as linearity of the signal with integration time and laser power, and their impact on signal to noise ratio, are studied leading to optimal data acquisition parameters. The impact of ambient light sources in the operating room is assessed and recommendations made for optimal operating conditions. In vivo Raman spectra of normal brain, cancer and necrotic tissue were measured in 10 patients, demonstrating that real-time inelastic scattering measurements can distinguish necrosis from vital tissue (including tumor and normal brain tissue) with an accuracy of 87%, a sensitivity of 84% and a specificity of 89%.

Combined fiber probe for fluorescence lifetime and Raman spectroscopy.

In this contribution we present a dual modality fiber optic probe combining fluorescence lifetime imaging (FLIm) and Raman spectroscopy for in vivo endoscopic applications. The presented multi-spectroscopy probe enables efficient excitation and collection of fluorescence lifetime signals for FLIm in the UV/visible wavelength region, as well as of Raman spectra in the near-IR for simultaneous Raman/FLIm imaging. The probe was characterized in terms of its lateral resolution and distance dependency of the Raman and FLIm signals. In addition, the feasibility of the probe for in vivo FLIm and Raman spectral characterization of tissue was demonstrated. Graphical Abstract An image comparison between FLIm and Raman spectroscopy acquired with the bimodal probe onseveral tissue samples.