Prospects for Theranostics in Neurosurgical Imaging: Empowering Confocal Laser Endomicroscopy Diagnostics via Deep Learning

Confocal laser endomicroscopy (CLE) is an advanced optical fluorescence imaging technology that has the potential to increase intraoperative precision, extend resection, and tailor surgery for malignant invasive brain tumors because of its subcellular dimension resolution. Despite its promising diagnostic potential, interpreting the gray tone fluorescence images can be difficult for untrained users. In this review, we provide a detailed description of bioinformatical analysis methodology of CLE images that begins to assist the neurosurgeon and pathologist to rapidly connect on-the-fly intraoperative imaging, pathology, and surgical observation into a conclusionary system within the concept of theranostics. We present an overview and discuss deep learning models for automatic detection of the diagnostic CLE images and discuss various training regimes and ensemble modeling effect on the power of deep learning predictive models. Two major approaches reviewed in this paper include the models that can automatically classify CLE images into diagnostic/nondiagnostic, glioma/nonglioma, tumor/injury/normal categories and models that can localize histological features on the CLE images using weakly supervised methods. We also briefly review advances in the deep learning approaches used for CLE image analysis in other organs. Significant advances in speed and precision of automated diagnostic frame selection would augment the diagnostic potential of CLE, improve operative workflow and integration into brain tumor surgery. Such technology and bioinformatics analytics lend themselves to improved precision, personalization, and theranostics in brain tumor treatment.Comment: See the final version published in Frontiers in Oncology here: https://www.frontiersin.org/articles/10.3389/fonc.2018.00240/ful

Confocal Laser Endomicroscopy Image Analysis with Deep Convolutional Neural Networks

abstract: Rapid intraoperative diagnosis of brain tumors is of great importance for planning treatment and guiding the surgeon about the extent of resection. Currently, the standard for the preliminary intraoperative tissue analysis is frozen section biopsy that has major limitations such as tissue freezing and cutting artifacts, sampling errors, lack of immediate interaction between the pathologist and the surgeon, and time consuming. Handheld, portable confocal laser endomicroscopy (CLE) is being explored in neurosurgery for its ability to image histopathological features of tissue at cellular resolution in real time during brain tumor surgery. Over the course of examination of the surgical tumor resection, hundreds to thousands of images may be collected. The high number of images requires significant time and storage load for subsequent reviewing, which motivated several research groups to employ deep convolutional neural networks (DCNNs) to improve its utility during surgery. DCNNs have proven to be useful in natural and medical image analysis tasks such as classification, object detection, and image segmentation. This thesis proposes using DCNNs for analyzing CLE images of brain tumors. Particularly, it explores the practicality of DCNNs in three main tasks. First, off-the shelf DCNNs were used to classify images into diagnostic and non-diagnostic. Further experiments showed that both ensemble modeling and transfer learning improved the classifier’s accuracy in evaluating the diagnostic quality of new images at test stage. Second, a weakly-supervised learning pipeline was developed for localizing key features of diagnostic CLE images from gliomas. Third, image style transfer was used to improve the diagnostic quality of CLE images from glioma tumors by transforming the histology patterns in CLE images of fluorescein sodium-stained tissue into the ones in conventional hematoxylin and eosin-stained tissue slides. These studies suggest that DCNNs are opted for analysis of CLE images. They may assist surgeons in sorting out the non-diagnostic images, highlighting the key regions and enhancing their appearance through pattern transformation in real time. With recent advances in deep learning such as generative adversarial networks and semi-supervised learning, new research directions need to be followed to discover more promises of DCNNs in CLE image analysis.Dissertation/ThesisDoctoral Dissertation Neuroscience 201

Online Super-Resolution For Fibre-Bundle-Based Confocal Laser Endomicroscopy

Probe-based Confocal Laser Endomicroscopy (pCLE) produces microscopic images enabling real-time in vivo optical biopsy. However, the miniaturisation of the optical hardware, specifically the reliance on an optical fibre bundle as an imaging guide, fundamentally limits image quality by producing artefacts, noise, and relatively low contrast and resolution. The reconstruction approaches in clinical pCLE products do not fully alleviate these problems. Consequently, image quality remains a barrier that curbs the full potential of pCLE. Enhancing the image quality of pCLE in real-time remains a challenge. The research in this thesis is a response to this need. I have developed dedicated online super-resolution methods that account for the physics of the image acquisition process. These methods have the potential to replace existing reconstruction algorithms without interfering with the fibre design or the hardware of the device. In this thesis, novel processing pipelines are proposed for enhancing the image quality of pCLE. First, I explored a learning-based super-resolution method that relies on mapping from the low to the high-resolution space. Due to the lack of high-resolution pCLE, I proposed to simulate high-resolution data and use it as a ground truth model that is based on the pCLE acquisition physics. However, pCLE images are reconstructed from irregularly distributed fibre signals, and grid-based Convolutional Neural Networks are not designed to take irregular data as input. To alleviate this problem, I designed a new trainable layer that embeds Nadaraya- Watson regression. Finally, I proposed a novel blind super-resolution approach by deploying unsupervised zero-shot learning accompanied by a down-sampling kernel crafted for pCLE. I evaluated these new methods in two ways: a robust image quality assessment and a perceptual quality test assessed by clinical experts. The results demonstrate that the proposed super-resolution pipelines are superior to the current reconstruction algorithm in terms of image quality and clinician preference

Supervised cnn strategies for optical image segmentation and classification in interventional medicine

The analysis of interventional images is a topic of high interest for the medical-image analysis community. Such an analysis may provide interventional-medicine professionals with both decision support and context awareness, with the final goal of improving patient safety. The aim of this chapter is to give an overview of some of the most recent approaches (up to 2018) in the field, with a focus on Convolutional Neural Networks (CNNs) for both segmentation and classification tasks. For each approach, summary tables are presented reporting the used dataset, involved anatomical region and achieved performance. Benefits and disadvantages of each approach are highlighted and discussed. Available datasets for algorithm training and testing and commonly used performance metrics are summarized to offer a source of information for researchers that are approaching the field of interventional-image analysis. The advancements in deep learning for medical-image analysis are involving more and more the interventional-medicine field. However, these advancements are undeniably slower than in other fields (e.g. preoperative-image analysis) and considerable work still needs to be done in order to provide clinicians with all possible support during interventional-medicine procedures

Deep Learning Algorithm for the Confirmation of Mucosal Healing in Crohn’s Disease, Based on Confocal Laser Endomicroscopy Images

Background and Aims: Mucosal healing (MH) is associated with a stable course of Crohn’s disease (CD) which can be assessed by confocal laser endomicroscopy (CLE). To minimize the operator’s errors and automate assessment of CLE images, we used a deep learning (DL) model for image analysis. We hypothesized that DL combined with convolutional neural networks (CNNs) and long short-term memory (LSTM) can distinguish between normal and inflamed colonic mucosa from CLE images. Methods: The study included 54 patients, 32 with known active CD, and 22 control patients (18 CD patients with MH and four normal mucosa patients with no history of inflammatory bowel diseases). We designed and trained a deep convolutional neural network to detect active CD using 6,205 endomicroscopy images classified as active CD inflammation (3,672 images) and control mucosal healing or no inflammation (2,533 images). CLE imaging was performed on four colorectal areas and the terminal ileum. Gold standard was represented by the histopathological evaluation. The dataset was randomly split in two distinct training and testing datasets: 80% data from each patient were used for training and the remaining 20% for testing. The training dataset consists of 2,892 images with inflammation and 2,189 control images. The testing dataset consists of 780 images with inflammation and 344 control images of the colon. We used a CNN-LSTM model with four convolution layers and one LSTM layer for automatic detection of MH and CD diagnosis from CLE images. Results: CLE investigation reveals normal colonic mucosa with round crypts and inflamed mucosa with irregular crypts and tortuous and dilated blood vessels. Our method obtained a 95.3% test accuracy with a specificity of 92.78% and a sensitivity of 94.6%, with an area under each receiver operating characteristic curves of 0.98. Conclusions: Using machine learning algorithms on CLE images can successfully differentiate between inflammation and normal ileocolonic mucosa and can be used as a computer aided diagnosis for CD. Future clinical studies with a larger patient spectrum will validate our results and improve the CNN-SSTM model

Automatic Esophageal Abnormality Detection and Classification

Esophageal cancer is counted as one of the deadliest cancers worldwide ranking the sixth among all types of cancers. Early esophageal cancer typically causes no symp- toms and mainly arises from overlooked/untreated premalignant abnormalities in the esophagus tube. Endoscopy is the main tool used for the detection of abnormalities, and the cell deformation stage is confirmed by taking biopsy samples. The process of detection and classification is considered challenging for several reasons such as; different types of abnormalities (including early cancer stages) can be located ran- domly throughout the esophagus tube, abnormal regions can have various sizes and appearances which makes it difficult to capture, and failure in discriminating between the columnar mucosa from the metaplastic epithelium. Although many studies have been conducted, it remains a challenging task and improving the accuracy of auto- matically classifying and detecting different esophageal abnormalities is an ongoing field. This thesis aims to develop novel automated methods for the detection and classification of the abnormal esophageal regions (precancerous and cancerous) from endoscopic images and videos. In this thesis, firstly, the abnormality stage of the esophageal cell deformation is clas- sified from confocal laser endomicroscopy (CLE) images. The CLE is an endoscopic tool that provides a digital pathology view of the esophagus cells. The classifica- tion is achieved by enhancing the internal features of the CLE image, using a novel enhancement filter that utilizes fractional integration and differentiation. Different imaging features including, Multi-Scale pyramid rotation LBP (MP-RLBP), gray level co-occurrence matrices (GLCM), fractal analysis, fuzzy LBP and maximally stable extremal regions (MSER), are calculated from the enhanced image to assure a robust classification result. The support vector machine (SVM) and random forest (RF) classifiers are employed to classify each image into its pathology stage. Secondly, we propose an automatic detection method to locate abnormality regions from high definition white light (HD-WLE) endoscopic images. We first investigate the performance of different deep learning detection methods on our dataset. Then we propose an approach that combines hand-designed Gabor features with extracted convolutional neural network features that are used by the Faster R-CNN to detect abnormal regions. Moreover, to further improve the detection performance, we pro- pose a novel two-input network named GFD-Faster RCNN. The proposed method generates a Gabor fractal image from the original endoscopic image using Gabor filters. Then features are learned separately from the endoscopic image and the gen- erated Gabor fractal image using the densely connected convolutional network to detect abnormal esophageal regions. Thirdly, we present a novel model to detect the abnormal regions from endoscopic videos. We design a 3D Sequential DenseConvLstm network to extract spatiotem- poral features from the input videos that are utilized by a region proposal network and ROI pooling layer to detect abnormality regions in each frame throughout the video. Additionally, we suggest an FS-CRF post-processing method that incorpor- ates the Conditional Random Field (CRF) on a frame-based level to recover missed abnormal regions in neighborhood frames within the same clip. The methods are evaluated on four datasets: (1) CLE dataset used for the classific- ation model, (2) Publicly available dataset named Kvasir, (3) MICCAI’15 Endovis challenge dataset, Both datasets (2) and (3) are used for the evaluation of detection model from endoscopic images. Finally, (4) Gastrointestinal Atlas dataset used for the evaluation of the video detection model. The experimental results demonstrate promising results of the different models and have outperformed the state-of-the-art methods

Learning spatiotemporal features for esophageal abnormality detection from endoscopic videos

Esophageal cancer is categorized as a type of disease with a high mortality rate. Early detection of esophageal abnormalities (i.e. precancerous and early can- cerous) can improve the survival rate of the patients. Re- cent deep learning-based methods for selected types of esophageal abnormality detection from endoscopic images have been proposed. However, no methods have been introduced in the literature to cover the detection from endoscopic videos, detection from challenging frames and detection of more than one esophageal abnormality type. In this paper, we present an efficient method to automat- ically detect different types of esophageal abnormalities from endoscopic videos. We propose a novel 3D Sequen- tial DenseConvLstm network that extracts spatiotemporal features from the input video. Our network incorporates 3D Convolutional Neural Network (3DCNN) and Convolu- tional Lstm (ConvLstm) to efficiently learn short and long term spatiotemporal features. The generated feature map is utilized by a region proposal network and ROI pooling layer to produce a bounding box that detects abnormal- ity regions in each frame throughout the video. Finally, we investigate a post-processing method named Frame Search Conditional Random Field (FS-CRF) that improves the overall performance of the model by recovering the missing regions in neighborhood frames within the same clip. We extensively validate our model on an endoscopic video dataset that includes a variety of esophageal ab- normalities. Our model achieved high performance using different evaluation metrics showing 93.7% recall, 92.7% precision, and 93.2% F-measure. Moreover, as no results have been reported in the literature for the esophageal abnormality detection from endoscopic videos, to validate the robustness of our model, we have tested the model on a publicly available colonoscopy video dataset, achieving the polyp detection performance in a recall of 81.18%, precision of 96.45% and F-measure 88.16%, compared to the state-of-the-art results of 78.84% recall, 90.51% preci- sion and 84.27% F-measure using the same dataset. This demonstrates that the proposed method can be adapted to different gastrointestinal endoscopic video applications with a promising performance