Early Detection of Oral Potentially Malignant Disorders: A Review on Prospective Screening Methods with Regard to Global Challenges.

Oral cancer is a cancer type that is widely prevalent in low-and middle-income countries with a high mortality rate, and poor quality of life for patients after treatment. Early treatment of cancer increases patient survival, improves quality of life and results in less morbidity and a better prognosis. To reach this goal, early detection of malignancies using technologies that can be used in remote and low resource areas is desirable. Such technologies should be affordable, accurate, and easy to use and interpret. This review surveys different technologies that have the potentials of implementation in primary health and general dental practice, considering global perspectives and with a focus on the population in India, where oral cancer is highly prevalent. The technologies reviewed include both sample-based methods, such as saliva and blood analysis and brush biopsy, and more direct screening of the oral cavity including fluorescence, Raman techniques, and optical coherence tomography. Digitalisation, followed by automated artificial intelligence based analysis, are key elements in facilitating wide access to these technologies, to non-specialist personnel and in rural areas, increasing quality and objectivity of the analysis while simultaneously reducing the labour and need for highly trained specialists.

5-ALA fluorescence in randomly selected pediatric brain tumors assessed by spectroscopy and surgical microscope.

PURPOSE: Fluorescence-guided surgery applying 5-aminolevulinic acid (5-ALA) in high-grade gliomas is an established method in adults. In children, results have so far been ambiguous. The aim of this study was to investigate 5-ALA-induced fluorescence in pediatric brain tumors by using the surgical microscope and a spectroscopic hand-held probe. METHODS: Fourteen randomly selected children (age 4-17) with newly MRI-verified brain tumors were included. No selection was based on the suspected diagnosis prior to surgery. All patients received 5-ALA (20 mg /kg) either orally or via a gastric tube prior to surgery. Intratumoral fluorescence was detected with the microscope and the probe. Moreover, fluorescence in the skin of the forearm was measured. Histopathology samples revealed seven low-grade gliomas, four medulloblastomas, one diffuse intrinsic pontine glioma, one glioblastoma and one atypical meningioma. Blood samples were analyzed, and potential clinical side effects were monitored. RESULTS: Microscopically, vague fluorescence was visible in two patients. Intratumoral fluorescence could be detected in five patients with the probe, including the two patients with vague microscopic fluorescence. Three of the oldest children had PpIX fluorescence in the skin. Nine children did not show any fluorescence in the tumor or in the skin. No clinical side effects or laboratory adverse events were observed. CONCLUSION: Fluorescence could not be used to guide surgery in this study, neither with the surgical microscope nor with the hand-held probe. In nine children, no fluorescence was discerned and children with noticeable fluorescence were all older than nine years. 5-ALA was considered safe to apply in children.

Diseased thyroid tissue classification in OCT images using deep learning: Towards surgical decision support.

Intraoperative guidance tools for thyroid surgery based on optical coherence tomography (OCT) could aid distinguish between normal and diseased tissue. However, OCT images are difficult to interpret, thus, real-time automatic analysis could support the clinical decision-making. In this study, several deep learning models were investigated for thyroid disease classification on 2D and 3D OCT data obtained from ex vivo specimens of 22 patients undergoing surgery and diagnosed with several thyroid pathologies. Additionally, two open-access datasets were used to evaluate the custom models. On the thyroid dataset, the best performance was achieved by the 3D vision transformer model with a Matthew's correlation coefficient (MCC) of 0.79 (accuracy = 0.90) for the normal-versus-abnormal classification. On the open-access datasets, the custom models achieved the best performance (MCC > 0.88, accuracy > 0.96). Results obtained for the normal-versus-abnormal classification suggest OCT, complemented with deep learning-based analysis, as a tool for real-time automatic diseased tissue identification in thyroid surgery.

Inflation of test accuracy due to data leakage in deep learning-based classification of OCT images.

In the application of deep learning on optical coherence tomography (OCT) data, it is common to train classification networks using 2D images originating from volumetric data. Given the micrometer resolution of OCT systems, consecutive images are often very similar in both visible structures and noise. Thus, an inappropriate data split can result in overlap between the training and testing sets, with a large portion of the literature overlooking this aspect. In this study, the effect of improper dataset splitting on model evaluation is demonstrated for three classification tasks using three OCT open-access datasets extensively used, Kermany's and Srinivasan's ophthalmology datasets, and AIIMS breast tissue dataset. Results show that the classification performance is inflated by 0.07 up to 0.43 in terms of Matthews Correlation Coefficient (accuracy: 5% to 30%) for models tested on datasets with improper splitting, highlighting the considerable effect of dataset handling on model evaluation. This study intends to raise awareness on the importance of dataset splitting given the increased research interest in implementing deep learning on OCT data.

Does Anatomical Contextual Information Improve 3D U-Net-Based Brain Tumor Segmentation?

Effective, robust, and automatic tools for brain tumor segmentation are needed for the extraction of information useful in treatment planning. Recently, convolutional neural networks have shown remarkable performance in the identification of tumor regions in magnetic resonance (MR) images. Context-aware artificial intelligence is an emerging concept for the development of deep learning applications for computer-aided medical image analysis. A large portion of the current research is devoted to the development of new network architectures to improve segmentation accuracy by using context-aware mechanisms. In this work, it is investigated whether or not the addition of contextual information from the brain anatomy in the form of white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF) masks and probability maps improves U-Net-based brain tumor segmentation. The BraTS2020 dataset was used to train and test two standard 3D U-Net (nnU-Net) models that, in addition to the conventional MR image modalities, used the anatomical contextual information as extra channels in the form of binary masks (CIM) or probability maps (CIP). For comparison, a baseline model (BLM) that only used the conventional MR image modalities was also trained. The impact of adding contextual information was investigated in terms of overall segmentation accuracy, model training time, domain generalization, and compensation for fewer MR modalities available for each subject. Median (mean) Dice scores of 90.2 (81.9), 90.2 (81.9), and 90.0 (82.1) were obtained on the official BraTS2020 validation dataset (125 subjects) for BLM, CIM, and CIP, respectively. Results show that there is no statistically significant difference when comparing Dice scores between the baseline model and the contextual information models (p > 0.05), even when comparing performances for high and low grade tumors independently. In a few low grade cases where improvement was seen, the number of false positives was reduced. Moreover, no improvements were found when considering model training time or domain generalization. Only in the case of compensation for fewer MR modalities available for each subject did the addition of anatomical contextual information significantly improve (p < 0.05) the segmentation of the whole tumor. In conclusion, there is no overall significant improvement in segmentation performance when using anatomical contextual information in the form of either binary WM, GM, and CSF masks or probability maps as extra channels.

Optical Brain Biopsy with a Fluorescence and Vessel Tracing Probe.

BACKGROUND: Accurate stereotactic biopsies of brain tumors are imperative for diagnosis and tailoring of the therapy. Repetitive needle insertions enhance risks of brain lesioning, hemorrhage, and complications due to prolonged procedure. OBJECTIVE: To investigate clinical benefits of a combined 5-aminolaevulinic acid (5-ALA) fluorescence and laser Doppler flowmetry system for the detection of malignant brain tumor and blood vessels in stereotactic biopsies. METHODS: Planning of targets and trajectories was followed by optical measurements in 20 patients, using the Leksell Stereotactic System and a manual insertion device. Fluorescence spectra, microvascular blood flow, and tissue grayness were recorded each millimeter along the paths. Biopsies were taken at preplanned positions. The diagnoses were compared with the fluorescence signals. The recordings were plotted against measurement positions and compared. Sites indicating a risk of hemorrhage were counted as well as the time for the procedures. RESULTS: Signals were recorded along 28 trajectories, and 78 biopsies were collected. The final diagnosis showed 17 glioblastomas, 2 lymphomas, and 1 astrocytoma grade III. Fluorescence was seen along 23 of the paths with 4 having the peak of 5-ALA fluorescence 3 mm or more from the precalculated target. There was increased microcirculation in 40 of 905 measured positions. The measurement time for each trajectory was 5 to 10 min. CONCLUSION: The probe provided direct feedback of increased blood flow along the trajectory and of malignant tissue in the vicinity of the target. The method can increase the precision and the safety of the biopsy procedure and reduce time.

Optical coherence tomography for thyroid pathology: 3D analysis of tissue microstructure.

To investigate the potential of optical coherence tomography (OCT) to distinguish between normal and pathologic thyroid tissue, 3D OCT images were acquired on ex vivo thyroid samples from adult subjects (n=22) diagnosed with a variety of pathologies. The follicular structure was analyzed in terms of count, size, density and sphericity. Results showed that OCT images highly agreed with the corresponding histopatology and the calculated parameters were representative of the follicular structure variation. The analysis of OCT volumes provides quantitative information that could make automatic classification possible. Thus, OCT can be beneficial for intraoperative surgical guidance or in the pathology assessment routine.

Auditory and Visual User Interface for Optical Guidance During Stereotactic Brain Tumor Biopsies.

During stereotactic brain tumor biopsies, the detection of protoporphyrin IX (PpIX) fluorescence and microvascular perfusion using laser Doppler flowmetry (LDF) with a handheld fiber optic probe allows the identification of tumor tissue while decreasing the risk of intracranial hemorrhage. Neurosurgeons performing this procedure usually view the measurement values on a screen. When their visual focus is directed at the surgical site, they require an assistant to verbally relay the values. An auditory and visual user interface (UI), which displays measurement values accurately and allows fast and intuitive signal recognition, can improve this procedure. This paper experimentally evaluates an auditory and visual UI for providing real-time measurement feedback during stereotactic brain tumor biopsies. In a user study (n = 15), the accuracy of auditory and visual response was determined using function response tests, and user acceptance was evaluated. The auditory signals proved to be intuitive and easy to recognize and remember. The visual display of measurement values was easy to understand and facilitated the user's decision-making process. Moreover, the UI exhibited high user acceptance.

5-ALA fluorescence and laser Doppler flowmetry for guidance in a stereotactic brain tumor biopsy.

A fiber optic probe was developed for guidance during stereotactic brain biopsy procedures to target tumor tissue and reduce the risk of hemorrhage. The probe was connected to a setup for the measurement of 5-aminolevulinic acid (5-ALA) induced fluorescence and microvascular blood flow. Along three stereotactic trajectories, fluorescence (n = 109) and laser Doppler flowmetry (LDF) (n = 144) measurements were done in millimeter increments. The recorded signals were compared to histopathology and radiology images. The median ratio of protoporphyrin IX (PpIX) fluorescence and autofluorescence (AF) in the tumor was considerably higher than the marginal zone (17.3 vs 0.9). The blood flow showed two high spots (3%) in total. The proposed setup allows simultaneous and real-time detection of tumor tissue and microvascular blood flow for tracking the vessels.

Optical monitoring of cerebral microcirculation in neurointensive care.

Continuous optical monitoring of local cerebral microcirculation could benefit neurointensive care patients treated for subarachnoid hemorrhage (SAH). The aim of the study was to evaluate laser Doppler flowmetry (LDF) and diffuse reflectance spectroscopy (DRS) for long-term monitoring of brain microcirculation and oxygen saturation (SO2) in the neurointensive care unit (NICU). A fiber optic probe was designed for intraparenchymal use and connected to LDF and DRS for assessment of the local blood flow (perfusion and tissue reflectance (TLI)) and SO2 in the brain. The optically monitored parameters were compared with conventional NICU monitors and Xe-CT. The LDF signals were low with median and 25 to 75% interquartiles of perfusion = 70 (59 to 83) a.u. and TLI = 2.0 (1.0 to 2.4) a.u. and showed correlation with the NICU monitors in terms of heart rate. Median and interquartiles of SO2 were 17.4 (15.7 to 19.8) %. The lack of correlation between local perfusion and cerebral perfusion pressure indicated intact cerebral autoregulation. The systems were capable of monitoring both local perfusion and SO2 with stable signals in the NICU over 4 days. Further clinical studies are required to evaluate the optical systems' potential for assessing the onset of secondary brain injury.

Auditory display for fluorescence-guided open brain tumor surgery.

PURPOSE: Protoporphyrin (PpIX) fluorescence allows discrimination of tumor and normal brain tissue during neurosurgery. A handheld fluorescence (HHF) probe can be used for spectroscopic measurement of 5-ALA-induced PpIX to enable objective detection compared to visual evaluation of fluorescence. However, current technology requires that the surgeon either views the measured values on a screen or employs an assistant to verbally relay the values. An auditory feedback system was developed and evaluated for communicating measured fluorescence intensity values directly to the surgeon. METHODS: The auditory display was programmed to map the values measured by the HHF probe to the playback of tones that represented three fluorescence intensity ranges and one error signal. Ten persons with no previous knowledge of the application took part in a laboratory evaluation. After a brief training period, participants performed measurements on a tray of 96 wells of liquid fluorescence phantom and verbally stated the perceived measurement values for each well. The latency and accuracy of the participants' verbal responses were recorded. The long-term memorization of sound function was evaluated in a second set of 10 participants 2-3 and 7-12 days after training. RESULTS: The participants identified the played tone accurately for 98% of measurements after training. The median response time to verbally identify the played tones was 2 pulses. No correlation was found between the latency and accuracy of the responses, and no significant correlation with the musical proficiency of the participants was observed on the function responses. Responses for the memory test were 100% accurate. CONCLUSION: The employed auditory display was shown to be intuitive, easy to learn and remember, fast to recognize, and accurate in providing users with measurements of fluorescence intensity or error signal. The results of this work establish a basis for implementing and further evaluating auditory displays in clinical scenarios involving fluorescence guidance and other areas for which categorized auditory display could be useful.

Combination of hand-held probe and microscopy for fluorescence guided surgery in the brain tumor marginal zone.

BACKGROUND: Visualization of the tumor is crucial for differentiating malignant tissue from healthy brain during surgery, especially in the tumor marginal zone. The aim of the study was to introduce a fluorescence spectroscopy-based hand-held probe (HHF-probe) for tumor identification in combination with the fluorescence guided resection surgical microscope (FGR-microscope), and evaluate them in terms of diagnostic performance and practical aspects of fluorescence detection. MATERIAL AND METHODS: Eighteen operations were performed on 16 patients with suspected high-grade glioma. The HHF-probe and the FGR-microscope were used for detection of protoporphyrin (PpIX) fluorescence induced by 5-aminolevulinic acid (5-ALA) and evaluated against histopathological analysis and visual grading done through the FGR-microscope by the surgeon. A ratio of PpIX fluorescence intensity to the autofluorescence intensity (fluorescence ratio) was used to quantify the spectra detected by the probe. RESULTS: Fluorescence ratio medians (range 0 - 40) measured by the probe were related to the intensity of the fluorescence in the FGR-microscope, categorized as "none" (0.3, n=131), "weak" (1.6, n=34) and "strong" (5.4, n=28). Of 131 "none" points in the FGR-microscope, 88 (67%) exhibited fluorescence with the HHF-probe. For the tumor marginal zone, the area under the receiver operator characteristics (ROC) curve was 0.49 for the FGR-microscope and 0.65 for the HHF-probe. CONCLUSIONS: The probe was integrated in the established routine of tumor resection using the FGR-microscope. The HHF-probe was superior to the FGR-microscope in sensitivity; it detected tumor remnants after debulking under the FGR-microscope. The combination of the HHF-probe and the FGR-microscope was beneficial especially in the tumor marginal zone.

A method for monitoring of oxygen saturation changes in brain tissue using diffuse reflectance spectroscopy.

Continuous measurement of local brain oxygen saturation (SO2 ) can be used to monitor the status of brain trauma patients in the neurocritical care unit. Currently, micro-oxygen-electrodes are considered as the "gold standard" in measuring cerebral oxygen pressure (pO2 ), which is closely related to SO2 through the oxygen dissociation curve (ODC) of hemoglobin, but with the drawback of slow in response time. The present study suggests estimation of SO2 in brain tissue using diffuse reflectance spectroscopy (DRS) for finding an analytical relation between measured spectra and the SO2 for different blood concentrations. The P3 diffusion approximation is used to generate a set of spectra simulating brain tissue for various levels of blood concentrations in order to estimate SO2 . The algorithm is evaluated on optical phantoms mimicking white brain matter (blood volume of 0.5-2%) where pO2 and temperature is controlled and on clinical data collected during brain surgery. The suggested method is capable of estimating the blood fraction and oxygen saturation changes from the spectroscopic signal and the hemoglobin absorption profile.

405 nm versus 633 nm for protoporphyrin IX excitation in fluorescence-guided stereotactic biopsy of brain tumors.

Fluorescence diagnosis may be used to improve the safety and reliability of stereotactic brain tumor biopsies using biopsy needles with integrated fiber optics. Based on 5-aminolevulinic-acid-induced protoporphyrin IX (PpIX) fluorescence, vital tumor tissue can be localized in vivo during the excision procedure to reduce the number of necessary samples for a reliable diagnosis. In this study, the practical suitability of two different PpIX excitation wavelengths (405 nm, 633 nm) was investigated on optical phantoms. Violet excitation at 405 nm provides a 50-fold higher sensitivity for the bulk tumor; this factor increases up to 100 with decreasing fluorescent volume as shown by ray tracing simulations. Red excitation at 633 nm, however, is noticeably superior with regard to blood layers obscuring the fluorescence. Experimental results on the signal attenuation through blood layers of well-defined thicknesses could be confirmed by ray tracing simulations. Typical interstitial fiber probe measurements were mimicked on agarose-gel phantoms. Even in direct contact, blood layers of 20-40 µm between probe and tissue must be expected, obscuring 405-nm-excited PpIX fluorescence almost completely, but reducing the 633-nm-excited signal only by 25.5%. Thus, 633 nm seems to be the wavelength of choice for PpIX-assisted detection of high-grade gliomas in stereotactic biopsy. PpIX signal attenuation through clinically relevant blood layers for 405 nm (violet) and 633 nm (red) excitation.

Low dose 5-aminolevulinic acid: Implications in spectroscopic measurements during brain tumor surgery.

BACKGROUND: Using 5-aminolevulinic acid (ALA) as an intraoperative fluorescence contrast has been proven to improve the resection of glioblastoma and contribute to prolonged patient survival. ALA accumulates as protoporphyrin IX (PpIX) in the tumor cells and is administered in an advised dose of 20 mg/kg body weight (b.w.) for brain tumor resection using fluorescence surgical microscopes. PpIX fluorescence availability and intensities of a four folds lower ALA dose (5 mg/kgb.w.) has been investigated in glioblastomas and skin using a spectroscopy system adapted for surgical guidance. METHODS: A total of 30 adult patients diagnosed with high grade gliomas were included in the analysis. ALA was orally administered in doses of 5 mg/kg b.w. (n = 15) dissolved in orange juice or 20 mg/kgb.w. (n = 15) dissolved in water. A fluorescence spectroscopy system with a handheld fiber-optical probe was used for performing the quantitative fluorescence measurements. RESULTS: The binominal comparison of the diagnostic performance parameters showed no significant statistical difference (p > 0.05). The median fluorescence values in tumor were 2-3 times higher for the high ALA dose group. No PpIX was detected in the skin of the patients in the low dose group (0/4) while PpIX was detected in the skin of the majority of the patients in the high ALA dose group (13/14). CONCLUSIONS: Application of 5mg/kg ALA was evaluated as equally reliable as the higher dose regarding the diagnostic performance when guidance was performed using a spectroscopic system. Moreover, no PpIX was detected in the skin of the patients.

Fluorescence spectroscopy measurements in ultrasonic navigated resection of malignant brain tumors.

BACKGROUND AND OBJECTIVE: Glioblastoma multiforme is a highly malignant primary brain tumor. It has no border but at best a marginal zone, however, invisible to the surgeon. An optical touch pointer (OTP) enabling differentiation of healthy and tumor tissue by means of fiber-optic fluorescence spectroscopy has been developed. In combination with an ultrasonic navigation system, the OTP may be used for demarcation of resectable tumor tissue. The aim of the study was to evaluate the clinical performance of OTP during surgery of malignant brain tumors. STUDY DESIGN/MATERIALS AND METHODS: Nine patients were operated on with the standard surgical procedure, including white light microscopy and navigation. A total of 5 mg/kg bodyweight of 5-amino-levulin acid was orally administrated before surgery. The OTP was calibrated into the ultrasound-based navigation system and measurements were performed in tumor core and along the tumor border. The ratio between the protoporphyrin IX fluorescence at 635 nm and the autofluorescence was used for quantifications of data. Biopsies (n = 20), ultrasound images (n = 30), and visual inspection (n = 180) were compared to the fluorescence ratio. RESULTS/CONCLUSION: Healthy and tumor tissue could be identified and differentiated with the OTP (P < 0.001). The fluorescence ratio in average was 0 outside the tumor and low in the gliotic edema zone around the tumor. It increased in the marginal zone and was highest in the solid tumor tissue. In the necrotic tissue, in the center of the tumor, the ratio in average was 0. The OTP can be used in combination with ultrasound-based navigation and may help to determine whether to resect otherwise not identifiable tissue.

Optical touch pointer for fluorescence guided glioblastoma resection using 5-aminolevulinic acid.

BACKGROUND AND OBJECTIVE: Total tumor resection in patients with glioblastoma multiforme (GBM) is difficult to achieve due to the tumor's infiltrative way of growing and morphological similarity to the surrounding functioning brain tissue. The diagnosis is usually subjectively performed using a surgical microscope. The objective of this study was to develop and evaluate a hand-held optical touch pointer using a fluorescence spectroscopy system to quantitatively distinguish healthy from malignant brain tissue intraoperatively. STUDY DESIGN/MATERIALS AND METHODS: A fluorescence spectroscopy system with pulsed modulation was designed considering optimum energy delivery to the tissue, minimal photobleaching of PpIX and omission of the ambient light background in the operating room (OR). 5-Aminolevulinic acid (5-ALA) of 5 mg/kg body weight was given to the patients with a presumed GBM prior to surgery. During the surgery a laser pulse at 405 nm was delivered to the tissue. PpIX in glioblastoma tumor cells assigned with peaks at 635 and 704 nm was detected using a fiber optical probe. RESULTS/CONCLUSION: By using the pulsed fluorescence spectroscopy, PpIX fluorescence is quantitatively detected in the GBM. An effective suppression of low power lamp background from the recorded spectra in addition to a significant reduction of high power surgical lights is achieved.

Combined diffuse light reflectance and electrical impedance measurements as a navigation aid in deep brain surgery.

AIM: The aim of this study is to assess reflected light intensity combined with impedance as a navigation aid during stereotactic neurosurgery. METHODS: During creation of 21 trajectories for stereotactic implantation of deep brain stimulation electrodes in the globus pallidus internus or subthalamus (zona incerta or subthalamic nucleus), impedance at 512 kHz and reflected light intensity at 780 nm were measured continuously and simultaneously with a radio frequency electrode containing optical fibres. The signals were compared with the anatomy, determined from pre- and post-operative MRI and CT. The measurements were performed within minutes, and signal analysis was done post-operatively. RESULTS: Reflected light intensity was low from the cortex, lateral ventricle, caudate nucleus and putamen; intermediate from the globus pallidus and thalamus; while it was high from the subcortical white matter, internal capsule and subthalamus. The electrical impedance was less consistent, but generally low in the cortex, intermediate in the subcortical white matter, putamen, globus pallidus and thalamus, and high in the internal capsule and subthalamus. CONCLUSION: Reflected light intensity and electrical impedance give complementary information about passed tissue, and the combination seems promising as a navigation aid during stereotactic neurosurgery.