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Ovarian cancer has the sixth-largest fatality rate in the United States among all cancers. A non-surgical assay capable of detecting ovarian cancer with acceptable sensitivity and specificity has yet to be developed. However, such a discovery would profoundly impact the pace of the treatment and improvement to patients’ quality of life. Achieving such a solution requires high-quality imaging, image processing, and machine learning to support an acceptably robust automated diagnosis. In this work, we propose an automated framework that learns to identify ovarian cancer in transgenic mice from optical coherence tomography (OCT) recordings. Classification is accomplished using a neural network that perceives spatially ordered sequences of tomograms. We present three neural network-based approaches, namely a VGG-supported feed-forward network, a 3D convolutional neural network, and a convolutional LSTM (Long Short-Term Memory) network. Our experimental results show that our models achieve a favorable performance with no manual tuning or feature crafting, despite the challenging noise inherent in OCT images. Specifically, our best performing model, the convolutional LSTM-based neural network, achieves a mean AUC (± standard error) of 0.81 ± 0.037. To the best of the authors’ knowledge, no application of machine learning to analyze depth-resolved OCT images of whole ovaries has been documented in the literature. A significant broader impact of this research is the potential transferability of the proposed diagnostic system from transgenic mice to human organs, which would enable medical intervention from early detection of an extremely deadly affliction.

Stomach (gastric) cancer survival depends significantly on the stage in which it is detected, and surveillance with white light endoscopy exhibits poor contrast between gastric cancer and healthy tissue, especially at early stages. Early gastric cancer can exhibit changes in epithelial microstructure, including loss of regular gastric pit structure and collagen alterations which increase tissue stiffness. To improve contrast between early cancer and normal tissue, we investigate the use of optical coherence tomography (OCT) and elastography (OCE) to visualize changes in tissue structure and stiffness consistent with gastric cancer. Images of eight samples of human stomach tissue from three patients were collected with a benchtop OCT system. OCT was performed for qualitative visualization of tissue structure. OCE was then performed on 17 regions of interest using a simplified optical palpation method to extract relative stiffness measurements. A transparent silicone reference layer was placed on the tissue, and axial compression was applied. The resulting deformation (strain) of the reference layer was measured, and the corresponding stress applied to the sample surface was extracted from the characteristic stress-strain curve of the reference material. Spatially resolved stress measurements were mapped and overlaid on en face OCT images. Tissue classification was confirmed by pathology. OCT image volumes showed more distinct gastric pit and tissue layer structure, as well as less optical attenuation, in normal tissue compared to gastric metaplasia and focal signet ring cell carcinoma (SRCC). Exemplary OCE-derived stress maps showed a trend of increasing measured stress with progression of precancer (metaplasia and dysplasia) and SRCC, suggesting increased tissue stiffness. This proof-of-concept study provides evidence that OCT and OCE may be capable of visualizing differences in tissue structure and stiffness between normal, metaplastic, dysplastic, and early cancerous gastric tissue, potentially providing the basis for improved screening tools with higher sensitivity.

Background Disruption of the Men1 locus in epithelial and endocrine tissues fails to generate the full spectrum of gastroenteropancreatic neuroendocrine tumors (GEP-NETs), raising the possibility of a potential stromal source for these cancers. Neural crest-derived glial cells were previously implicated in neuroendocrine tumors arising in the pituitary and pancreas, yet these studies lacked a clear mechanism for these events. Here, we investigated the hypothesis that Men1 -driven Hedgehog (HH) signaling redirects the glial cell fate to give rise to neuroendocrine tumors in the gastrointestinal tract. Methods Hyperactivation of the HH signaling pathway in human GEP-NETs was evaluated using immunofluorescent staining and clinicogenomic databases. Men1 was deleted in the glial lineage by expressing Cre recombinase downstream of the human GFAP and Sox10 promoters. Overexpression of HH signaling proteins in mouse GEP-NETs was confirmed by immunofluorescent staining and immunoblot analysis. We generated human and mouse GEP-NET tumoroids and exposed them to agonists and inhibitors of HH signaling. HH activation of Men1 -deficient glial cells was blocked by deleting the gene encoding primary ciliary protein KIF3A required for transducing SHH signaling. Results We demonstrated that human GEP-NETs overexpress HH signaling pathway components, including SHH and its cognate receptor PTCH1. We showed that patient-derived GEP-NET tumoroids proliferate in response to SHH pathway agonists. In contrast, pharmacologic inhibition of GLI1/2, but not inhibition of SMO alone, attenuated tumoroid growth. Genetic deletion of Men1 in GFAP + and SOX10 + glial cells caused the development of pancreatic and intestinal NETs that overexpress HH proteins. Further use of tdTomato + mice demonstrated the involvement of GFAP + and SOX10 + glial cells in these tumors. Tumoroid cultures of mouse pancreatic, duodenal, and jejunal NETs recapitulated the drug response shown by patient-derived tumoroids. Lastly, Men1 -deficient enteric glial cultures showed a glial-to-neuroendocrine transition that was alleviated upon HH inhibition, and these events were reproduced in genetic mice harboring GFAP + cells with impaired primary cilia. Conclusions Our study implicates the HH signaling pathway in GEP-NET development and underscores a glial cell of origin for these tumors.

The capillaries are the smallest blood vessels in the body, typically imaged using video capillaroscopy to aid diagnosis of connective tissue diseases, such as systemic sclerosis. Video capillaroscopy allows visualization of morphological changes in the nailfold capillaries but does not provide any physiological information about the blood contained within the capillary network. Extracting parameters such as hemoglobin oxygenation could increase sensitivity for diagnosis and measurement of microvascular disease progression. To design, construct, and test a low-cost multispectral imaging (MSI) system using light-emitting diode (LED) illumination to assess relative hemoglobin oxygenation in the nailfold capillaries. An LED ring light was first designed and modeled. The ring light was fabricated using four commercially available LED colors and a custom-designed printed circuit board. The experimental system was characterized and results compared with the illumination model. A blood phantom with variable oxygenation was used to determine the feasibility of using the illumination-based MSI system for oximetry. Nailfold capillaries were then imaged in a healthy subject. The illumination modeling results were in close agreement with the constructed system. Imaging of the blood phantom demonstrated sensitivity to changing hemoglobin oxygenation, which was in line with the spectral modeling of reflection. The morphological properties of the volunteer capillaries were comparable to those measured in current gold standard systems. LED-based illumination could be used as a low-cost approach to enable MSI of the nailfold capillaries to provide insight into the oxygenation of the blood contained within the capillary network.

Lineage tracing using fluorescent reporters is a common tool for monitoring the expression of genes and transcription factors in stem cell populations and their progeny. The zinc-binding protein 89 (ZBP-89/Zfp148 mouse gene) is a transcription factor that plays a role in gastrointestinal (GI) stem cell maintenance and cellular differentiation and has been linked to the progression of colon cancer. While lineage tracing is a useful tool, it is commonly performed with high-magnification microscopy on a small field of view within tissue sections, thereby limiting the ability to resolve reporter expression at the organ level. Furthermore, this technique requires extensive tissue processing, which is time consuming and requires euthanizing the animal. Further knowledge could be elucidated by measuring the expression of fluorescent reporters across entire organs with minimal tissue processing.SignificanceLineage tracing using fluorescent reporters is a common tool for monitoring the expression of genes and transcription factors in stem cell populations and their progeny. The zinc-binding protein 89 (ZBP-89/Zfp148 mouse gene) is a transcription factor that plays a role in gastrointestinal (GI) stem cell maintenance and cellular differentiation and has been linked to the progression of colon cancer. While lineage tracing is a useful tool, it is commonly performed with high-magnification microscopy on a small field of view within tissue sections, thereby limiting the ability to resolve reporter expression at the organ level. Furthermore, this technique requires extensive tissue processing, which is time consuming and requires euthanizing the animal. Further knowledge could be elucidated by measuring the expression of fluorescent reporters across entire organs with minimal tissue processing.We present the application of wide-field fluorescence imaging for whole-organ lineage tracing of an inducible Zfp148-tdTomato-expressing transgenic mouse line to assess the expression of ZBP-89/Zfp148 in the GI tract.AimWe present the application of wide-field fluorescence imaging for whole-organ lineage tracing of an inducible Zfp148-tdTomato-expressing transgenic mouse line to assess the expression of ZBP-89/Zfp148 in the GI tract.We measured tdTomato fluorescence in ex vivo organs at time points between 24 h and 6 months post-induction. Fluctuations in tdTomato expression were validated by fluorescence microscopy of tissue sections.ApproachWe measured tdTomato fluorescence in ex vivo organs at time points between 24 h and 6 months post-induction. Fluctuations in tdTomato expression were validated by fluorescence microscopy of tissue sections.Quantification of the wide field-of-view images showed a statistically significant increase in fluorescent signal across the GI tract between transgenic mice and littermate controls. The results also showed a gradient of decreasing reporter expression from proximal to distal intestine, suggesting a higher abundance of ZBP-89 expressing stem cells, or higher expression of ZBP-89 within the stem cells, in the proximal intestine.ResultsQuantification of the wide field-of-view images showed a statistically significant increase in fluorescent signal across the GI tract between transgenic mice and littermate controls. The results also showed a gradient of decreasing reporter expression from proximal to distal intestine, suggesting a higher abundance of ZBP-89 expressing stem cells, or higher expression of ZBP-89 within the stem cells, in the proximal intestine.We demonstrate that wide-field fluorescence imaging is a valuable tool for monitoring whole-organ expression of fluorescent reporters. This technique could potentially be applied in vivo for longitudinal assessment of a single animal, further enhancing our ability to resolve rare stem cell lineages spatially and temporally.ConclusionsWe demonstrate that wide-field fluorescence imaging is a valuable tool for monitoring whole-organ expression of fluorescent reporters. This technique could potentially be applied in vivo for longitudinal assessment of a single animal, further enhancing our ability to resolve rare stem cell lineages spatially and temporally.

Ovarian cancer is the deadliest gynecologic cancer due predominantly to late diagnosis. Early detection of ovarian cancer can increase 5-year survival rates from 40% up to 92%, yet no reliable early detection techniques exist. Multiphoton microscopy (MPM) is a relatively new imaging technique sensitive to endogenous fluorophores, which has tremendous potential for clinical diagnosis, though it is limited in its application to the ovaries. Wide-field fluorescence imaging (WFI) has been proposed as a complementary technique to MPM, as it offers high-resolution imagery of the entire organ and can be tailored to target specific biomarkers that are not captured by MPM imaging. We applied texture analysis to MPM images of a mouse model of ovarian cancer. We also conducted WFI targeting the folate receptor and matrix metalloproteinases. We find that texture analysis of MPM images of the ovary can differentiate between genotypes, which is a proxy for disease, with high statistical significance (p  <  0.001). The wide-field fluorescence signal also changes significantly between genotypes (p  <  0.01). We use the features to classify multiple tissue groups to over 80% accuracy. These results suggest that MPM and WFI are promising techniques for the early detection of ovarian cancer.

Phase and polarization of coherent light are highly perturbed by interaction with microstructural changes in premalignant tissue, holding promise for label-free detection of early tumors in endoscopically accessible tissues such as the gastrointestinal tract. Flexible optical multicore fiber (MCF) bundles used in conventional diagnostic endoscopy and endomicroscopy scramble phase and polarization, restricting clinicians instead to low-contrast amplitude-only imaging. We apply a transmission matrix characterization approach to produce full-field en-face images of amplitude, quantitative phase, and resolved polarimetric properties through an MCF. We first demonstrate imaging and quantification of biologically relevant amounts of optical scattering and birefringence in tissue-mimicking phantoms. We present an entropy metric that enables imaging of phase heterogeneity, indicative of disordered tissue microstructure associated with early tumors. Finally, we demonstrate that the spatial distribution of phase and polarization information enables label-free visualization of early tumors in esophageal mouse tissues, which are not identifiable using conventional amplitude-only information.

Epithelial cancers are among the most dangerous forms of cancer. Of this broad group of disease, ovarian and esophageal cancer are particularly deadly, with five-year survival rates of less than 50% and 20% respectively. The primary cause of this low survival rate is due to predominantly late diagnosis. Diagnosis at early stages leads to over 90% 5-year survival rates for ovarian cancer and over 40% for esophageal cancer, but fewer than 15% of cases for these two cancers are detected early. Screening is complicated by non-specific or complete lack of symptoms, as well as the heterogeneity of the diseases.For both esophageal and ovarian cancers, many screening tests including imaging, physical examination, and blood markers tests have been investigated; however, at this time no routine screening is recommended in average-risk patients. This study evaluates the feasibility and design of instruments to use multimodal optical imaging to improve ovarian and esophageal cancer screening. This includes optical coherence tomography (OCT), multiphoton microscopy (MPM), and wide-field fluorescence imaging.The study is subdivided into four sections. In the first two sections, advanced algorithms and processing techniques are presented for rapid analysis and quantitative diagnostic evaluation for optical coherence tomography images of ovarian cancer. The results show promise for automatic processing of OCT images using segmentation, combined with highly accurate diagnostic performance in identifying diseased tissue using texture features of OCT images.The third section details the application of MPM and wide-field fluorescence imaging using exogenous contrast agents to evaluate and classify tissue health. Two tissue studies using a mouse model of ovarian cancer are presented: one ex vivo and one in vivo study. The results of both demonstrate that these modalities provide high contrast for identifying diseased tissue and that the combination of these two modalities show an improvement in diagnostic performance over a single modality.Finally, the study concludes with the design for a multimodal forward-viewing esophageal endoscope using optical coherence tomography and autofluorescence imaging. The design implements a piezo-scanning fiber to deliver the light, and spatially separates the OCT and fluorescence return signal. The design provides high resolution and is compatible with working channels in existing gastroscopes to enable easy clinical translation.

Pancreatic neuroendocrine tumors (PNETs) are a rare but increasingly more prevalent cancer with heterogeneous clinical and pathological presentation. Surgery is the preferred treatment for all hormone-expressing PNETs and any PNET greater than 2 cm, but difficulties arise when tumors are multifocal, metastatic, or small in size due to lack of effective surgical localization. Existing techniques such as intraoperative ultrasound provide poor contrast and resolution, resulting in low sensitivity for such tumors. Somatostatin receptor type 2 (SSTR2) is commonly overexpressed in PNETs and presents an avenue for targeted tumor localization. SSTR2 is often used for pre-operative imaging and therapeutic treatment, with recent studies demonstrating that somatostatin receptor imaging (SRI) can be applied in radioguided surgery to aid in removal of metastatic lymph nodes and achieving negative surgical margins. However not all PNETs express SSTR2, indicating labeled SRI could benefit from using a supplemental label-free technique such as multiphoton microscopy (MPM), which has proven useful in improving the accuracy of diagnosing more common exocrine pancreatic cancers. Our work tests the suitability of combined SRI and MPM for localizing PNETs by imaging and comparing samples of PNETs and normal pancreatic tissue. Specimens were labeled with a novel SSTR2-targeted contrast agent and imaged using fluorescence microscopy, and subsequently imaged using MPM to collect four autofluorescent channels and second harmonic generation. Our results show that a combination of both SRI and MPM provides enhanced contrast and sensitivity for localizing diseased tissue, suggesting that this approach could be a valuable clinical tool for surgical localization and treatment of PNETs.

Gastrointestinal cancers continue to account for a disproportionately large percentage of annual cancer deaths in the US. Advancements in miniature imaging technology combined with a need for precise and thorough tumor detection in gastrointestinal cancer screenings fuel the demand for new, small-scale, and low-cost methods of localization and margin identification with improved accuracy. Here, we report the development of a miniaturized, chip-on-tip, multispectral, fluorescence imaging probe designed to port through a gastroscope working channel with the aim of detecting cancerous lesions in point-of-care endoscopy of the gastrointestinal lumen. Preclinical testing has confirmed fluorescence sensitivity and supports that this miniature probe can locate structures of interest via detection of fluorescence emission from exogenous contrast agents. This work demonstrates the design and preliminary performance evaluation of a miniaturized, single-use, chip-on-tip fluorescence imaging system, capable of detecting multiple fluorochromes, and devised for deployment via the accessory channel of a standard gastroscope. Competing Interest Statement The authors have declared no competing interest. Footnotes * Updated figures, wording, and formatting.