Intraoperative Tumor Detection Research Articles

Glioma Identification Based on Digital Multimodal Spectra Integrated With Deep Learning Feature Fusion Using a Miniature Raman Spectrometer.

The miniature fiber Raman spectroscopy detection technology can reflect the properties of biomolecules through spectral characteristics and has the advantages of noninvasiveness, real-time, safety, label-free operation, and potential for early cancer diagnosis. This technology holds promise for developing portable, low-cost, intraoperative tumor detection instruments. Glioma is one of the most common malignant tumors of the central nervous system with rapid growth and a short disease course. However, the considerable heterogeneity of the glioma sample leads to substantial intraclass variance in collected spectra, coupled with the miniature Raman spectrometer's low signal-to-noise ratio. These factors diminish the accuracy of the brain glioma recognition model. To address this issue, a glioma identification method based on digital multimodal spectra integrated with deep learning features fusion (DMS-DLFF) using the miniature Raman spectrometer is proposed. Different from existing multimodal tumor detection methods employing multiple spectral instruments, DMS-DLFF enhances tumor identification accuracy without increasing hardware costs. The method mathematically decomposes the original spectra to Raman and fluorescence spectra, so as to augment the biospectral information. Then, the deep learning method is used to extract the feature information of the two kinds of spectra, respectively, and the digital multimodal spectral fusion is realized at the feature level. Moreover, a two-layer pattern recognition model is constructed based on the ensemble strategy, amalgamating the strengths of diverse classifiers. Meanwhile, the bagging strategy is introduced to improve support vector machine algorithms, one of the basic classifiers. Compared with traditional methodologies, DMS-DLFF operates at both the feature level and decision level, employing high-information-density feature vectors to train ensemble classification models for increasing overall recognition accuracy. This study collected 260 Raman spectra of glioma and 151 Raman spectra of normal brain tissue. The accuracy, sensitivity, and specificity were 91.9%, 96.7%, and 80.8%, respectively. The proposed method outperforms traditional algorithms in brain glioma detection, which helps doctors formulate precise surgical plans and thereby improve patient prognosis.

Machine Learning-Assisted Classification of Paraffin-Embedded Brain Tumors with Raman Spectroscopy.

Raman spectroscopy (RS) has demonstrated its utility in neurooncological diagnostics, spanning from intraoperative tumor detection to the analysis of tissue samples peri- and postoperatively. In this study, we employed Raman spectroscopy (RS) to monitor alterations in the molecular vibrational characteristics of a broad range of formalin-fixed, paraffin-embedded (FFPE) intracranial neoplasms (including primary brain tumors and meningiomas, as well as brain metastases) and considered specific challenges when employing RS on FFPE tissue during the routine neuropathological workflow. We spectroscopically measured 82 intracranial neoplasms on CaF2 slides (in total, 679 individual measurements) and set up a machine learning framework to classify spectral characteristics by splitting our data into training cohorts and external validation cohorts. The effectiveness of our machine learning algorithms was assessed by using common performance metrics such as AUROC and AUPR values. With our trained random forest algorithms, we distinguished among various types of gliomas and identified the primary origin in cases of brain metastases. Moreover, we spectroscopically diagnosed tumor types by using biopsy fragments of pure necrotic tissue, a task unattainable through conventional light microscopy. In order to address misclassifications and enhance the assessment of our models, we sought out significant Raman bands suitable for tumor identification. Through the validation phase, we affirmed a considerable complexity within the spectroscopic data, potentially arising not only from the biological tissue subjected to a rigorous chemical procedure but also from residual components of the fixation and paraffin-embedding process. The present study demonstrates not only the potential applications but also the constraints of RS as a diagnostic tool in neuropathology, considering the challenges associated with conducting vibrational spectroscopic analysis on formalin-fixed, paraffin-embedded (FFPE) tissue.

Non-navigated 2D intraoperative ultrasound: An unsophisticated surgical tool to achieve high standards of care in glioma surgery.

In an era characterized by rapid progression in neurosurgical technologies, traditional tools such as the non-navigated two-dimensional intraoperative ultrasound (nn-2D-IOUS) risk being overshadowed. Against this backdrop, this study endeavors to provide a comprehensive assessment of the clinical efficacy and surgical relevance of nn-2D-IOUS, specifically in the context of glioma resections. This retrospective study undertaken at a single center evaluated 99 consecutive, non-selected patients diagnosed with both high-grade and low-grade gliomas. The primary objective was to assess the proficiency of nn-2D-IOUS in generating satisfactory image quality, identifying residual tumor tissue, and its influence on the extent of resection. To validate these results, early postoperative MRI data served as the reference standard. The nn-2D-IOUS exhibited a high level of effectiveness, successfully generating good quality images in 79% of the patients evaluated. With a sensitivity rate of 68% and a perfect specificity of 100%, nn-2D-IOUS unequivocally demonstrated its utility in intraoperative residual tumor detection. Notably, when total tumor removal was the surgical objective, a resection exceeding 95% of the initial tumor volume was achieved in 86% of patients. Additionally, patients in whom residual tumor was not detected by nn-2D-IOUS, the mean volume of undetected tumor tissue was remarkably minimal, averaging at 0.29 cm3. Our study supports nn-2D-IOUS's invaluable role in glioma surgery. The results highlight the utility of traditional technologies for enhanced surgical outcomes, even when compared to advanced alternatives. This is particularly relevant for resource-constrained settings and emphasizes optimizing existing tools for efficient patient care. NCT05873946 - 24/05/2023 - Retrospectively registered.

Single preoperative application of indocyanine green for liver function assessment and better intraoperative detection of liver tumors

Single preoperative application of indocyanine green for liver function assessment and better intraoperative detection of liver tumors

Advancements in Intraoperative Near-Infrared Fluorescence Imaging for Accurate Tumor Resection: A Promising Technique for Improved Surgical Outcomes and Patient Survival.

Clear surgical margins for solid tumor resection are essential for preventing cancer recurrence and improving overall patient survival. Complete resection of tumors is often limited by a surgeon's ability to accurately locate malignant tissues and differentiate them from healthy tissue. Therefore, techniques or imaging modalities are required that would ease the identification and resection of tumors by real-time intraoperative visualization of tumors. Although conventional imaging techniques such as positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), or radiography play an essential role in preoperative diagnostics, these cannot be utilized in intraoperative tumor detection due to their large size, high cost, long imaging time, and lack of cancer specificity. The inception of several imaging techniques has paved the way to intraoperative tumor margin detection with a high degree of sensitivity and specificity. Particularly, molecular imaging using near-infrared fluorescence (NIRF) based nanoprobes provides superior imaging quality due to high signal-to-noise ratio, deep penetration to tissues, and low autofluorescence, enabling accurate tumor resection and improved survival rates. In this review, we discuss the recent developments in imaging technologies, specifically focusing on NIRF nanoprobes that aid in highly specific intraoperative surgeries with real-time recognition of tumor margins.

A Systematic Review of New Imaging Technologies for Robotic Prostatectomy: From Molecular Imaging to Augmented Reality.

New imaging technologies play a pivotal role in the current management of patients with prostate cancer. Robotic assisted radical prostatectomy (RARP) is a standard of care for localized disease and through the already imaging-based console subject of research towards combinations of imaging technologies and RARP as well as their impact on surgical outcomes. Therefore, we aimed to provide a comprehensive analysis of the currently available literature for new imaging technologies for RARP. On 24 January 2023, we performed a systematic review of the current literature on Pubmed, Scopus and Web of Science according to the PRISMA guidelines and Oxford levels of evidence. A total of 46 studies were identified of which 19 studies focus on imaging of the primary tumor, 12 studies on the intraoperative tumor detection of lymph nodes and 15 studies on the training of surgeons. While the feasibility of combined approaches using new imaging technologies including MRI, PSMA-PET CT or intraoperatively applied radioactive and fluorescent dyes has been demonstrated, the prospective confirmation of improvements in surgical outcomes is currently ongoing.

First-in-human Evaluation of a Prostate-specific Membrane Antigen–targeted Near-infrared Fluorescent Small Molecule for Fluorescence-based Identification of Prostate Cancer in Patients with High-risk Prostate Cancer Undergoing Robotic-assisted Prostatectomy

BackgroundMen with high-risk prostate cancer undergoing surgery likely recur due to failure to completely excise regional and/or local disease. ObjectiveThe first-in-human evaluation of safety, pharmacokinetics, and exploratory efficacy of IS-002, a novel near-infrared prostate-specific membrane antigen (PSMA)-targeted fluorescence imaging agent, designed for intraoperative prostate cancer visualization. Design, setting, and participantsA phase 1, single-center, dose-escalation study was conducted in 24 men with high-risk prostate cancer scheduled for robotic-assisted radical prostatectomy with (extended) pelvic lymph node dissection using the da Vinci surgical system. Outcome measurements and statistical analysisAdverse events (AEs), vital signs, complete blood count, complete metabolic panel, urinalysis, and electrocardiogram were assessed over a 14-d period and compared with baseline. The pharmacokinetic profile of IS-002 was determined. Diagnostic accuracy was assessed for exploratory efficacy. Results and limitationsAEs predominantly included discoloration of urine (n = 22/24; expected, related, grade 1). There were no grade ≥2 AEs. IS-002 Cmax and area under the curve increased with increasing dose. Plasma concentrations declined rapidly in a biphasic manner, with the median terminal half-lives ranging from 5.0 to 7.6 h, independent of dose and renal function. At 25 μg/kg, the exploratory efficacy readouts for the negative and positive predictive values were, 97% and 45% for lymph nodes, and 100% and 80% for residual/locoregional disease detection, respectively. ConclusionsIS-002 is safe and well tolerated, and has the potential to enable intraoperative tumor detection that could not be identified using standard imaging. Patient summaryIS-002 is a new imaging agent that specifically targets the prostate-specific membrane antigen receptor. In this study, we tested IS-002 for the first time in men with high-risk prostate cancer undergoing surgery and found that IS-002 is safe, is cleared from the body quickly, and potentially allows identification of prostate cancer in areas that would not be identified by conventional white light imaging.

Raman Spectroscopic Imaging of Human Bladder Resectates towards Intraoperative Cancer Assessment.

Raman spectroscopy offers label-free assessment of bladder tissue for in vivo and ex vivo intraoperative applications. In a retrospective study, control and cancer specimens were prepared from ten human bladder resectates. Raman microspectroscopic images were collected from whole tissue samples in a closed chamber at 785 nm laser excitation using a 20× objective lens and 250 µm step size. Without further preprocessing, Raman images were decomposed by the hyperspectral unmixing algorithm vertex component analysis into endmember spectra and their abundancies. Hierarchical cluster analysis distinguished endmember Raman spectra that were assigned to normal bladder, bladder cancer, necrosis, epithelium and lipid inclusions. Interestingly, Raman spectra of microplastic particles, pigments or carotenoids were detected in 13 out of 20 specimens inside tissue and near tissue margins and their identity was confirmed by spectral library surveys. Hypotheses about the origin of these foreign materials are discussed. In conclusion, our Raman workflow and data processing protocol with minimal user interference offers advantages for future clinical translation such as intraoperative tumor detection and label-free material identification in complex matrices.

Data-Driven Identification of Targets for Fluorescence-Guided Surgery in Non-Small Cell Lung Cancer.

Intraoperative identification of lung tumors can be challenging. Tumor-targeted fluorescence-guided surgery can provide surgeons with a tool for real-time intraoperative tumor detection. This study evaluated cell surface biomarkers, partially selected via data-driven selection software, as potential targets for fluorescence-guided surgery in non-small cell lung cancers: adenocarcinomas (ADC), adenocarcinomas in situ (AIS), and squamous cell carcinomas (SCC). Formalin-fixed paraffin-embedded tissue slides of resection specimens from 15 patients with ADC and 15 patients with SCC were used and compared to healthy tissue. Molecular targets were selected based on two strategies: (1) a data-driven selection using > 275 multi-omics databases, literature, and experimental evidence; and (2) the availability of a fluorescent targeting ligand in advanced stages of clinical development. The selected targets were carbonic anhydrase 9 (CAIX), collagen type XVII alpha 1 chain (collagen XVII), glucose transporter 1 (GLUT1), G protein-coupled receptor 87 (GPR87), transmembrane protease serine 4 (TMPRSS4), carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), folate receptor alpha (FRα), integrin αvβ6 (αvβ6), and urokinase-type plasminogen activator receptor (uPAR). Tumor expression of these targets was assessed by immunohistochemical staining. A total immunostaining score (TIS, range 0-12), combining the percentage and intensity of stained cells, was calculated. The most promising targets in ADC were explored in six AIS tissue slides to explore its potential in non-palpable lesions. Statistically significant differences in TIS between healthy lung and tumor tissue for ADC samples were found for CEA, EpCAM, FRα, αvβ6, CAIX, collagen XVII, GLUT-1, and TMPRSS4, and of these, CEA, CAIX, and collagen XVII were also found in AIS. For SCC, EpCAM, uPAR, CAIX, collagen XVII, and GLUT-1 were found to be overexpressed. EpCAM, CAIX, and Collagen XVII were identified using concomitant use of data-driven selection software and clinical evidence as promising targets for intraoperative fluorescence imaging for both major subtypes of non-small cell lung carcinomas.

Novel rapid intraoperative qualitative tumor detection by a residual convolutional neural network using label-free stimulated Raman scattering microscopy

Determining the presence of tumor in biopsies and the decision-making during resections is often dependent on intraoperative rapid frozen-section histopathology. Recently, stimulated Raman scattering microscopy has been introduced to rapidly generate digital hematoxylin-and-eosin-stained-like images (stimulated Raman histology) for intraoperative analysis. To enable intraoperative prediction of tumor presence, we aimed to develop a new deep residual convolutional neural network in an automated pipeline and tested its validity. In a monocentric prospective clinical study with 94 patients undergoing biopsy, brain or spinal tumor resection, Stimulated Raman histology images of intraoperative tissue samples were obtained using a fiber-laser-based stimulated Raman scattering microscope. A residual network was established and trained in ResNetV50 to predict three classes for each image: (1) tumor, (2) non-tumor, and (3) low-quality. The residual network was validated on images obtained in three small random areas within the tissue samples and were blindly independently reviewed by a neuropathologist as ground truth. 402 images derived from 132 tissue samples were analyzed representing the entire spectrum of neurooncological surgery. The automated workflow took in a mean of 240 s per case, and the residual network correctly classified tumor (305/326), non-tumorous tissue (49/67), and low-quality (6/9) images with an inter-rater agreement of 89.6% (κ = 0.671). An excellent internal consistency was found among the random areas with 90.2% (Cα = 0.942) accuracy. In conclusion, the novel stimulated Raman histology-based residual network can reliably detect the microscopic presence of tumor and differentiate from non-tumorous brain tissue in resection and biopsy samples within 4 min and may pave a promising way for an alternative rapid intraoperative histopathological decision-making tool.

Creation of Non-Contact Device for Use in Metastatic Melanoma Margin Identification in ex vivo Mouse Brain.

Because contemporary intraoperative tumor detection modalities, such as intraoperative MRI, are not ubiquitously available and can disrupt surgical workflow, there is an imperative for an accessible diagnostic device that can meet the surgeon's needs in identifying tissue types. The objective of this paper is to determine the efficacy of a novel non-contact tumor detection device for metastatic melanoma boundary identification in a tissue-mimicking phantom, evaluate the identification of metastatic melanoma boundaries in ex vivo mouse brain tissue, and find the error associated with identifying this boundary. To validate the spatial and fluorescence resolution of the device, tissue-mimicking phantoms were created with modifiable optical properties. Phantom tissue provided ground truth measurements for fluorophore concentration differences with respect to spatial dimensions. Modeling metastatic disease, ex vivo melanoma brain metastases were evaluated to detect differences in fluorescence between healthy and neoplastic tissue. This analysis includes determining required-to-observe fluorescence differences in tissue. H&E staining confirmed tumor presence in mouse tissue samples. The device detected a difference in normalized average fluorescence intensity in all three phantoms. There were differences in fluorescence with the presence and absence of melanin. The estimated tumor boundary of all tissue phantoms was within 0.30 mm of the ground truth tumor boundary for all boundaries. Likewise, when applied to the melanoma-bearing brains from ex vivo mice, a difference in normalized fluorescence intensity was successfully detected. The potential prediction window for the tumor boundary location is less than 1.5 mm for all ex vivo mouse brain tumors boundaries. We present a non-contact, laser-induced fluorescence device that can identify tumor boundaries based on changes in laser-induced fluorescence emission intensity. The device can identify phantom ground truth tumor boundaries within 0.30 mm using instantaneous rate of change of normalized fluorescence emission intensity and can detect endogenous fluorescence differences in melanoma brain metastases in ex vivo mouse tissue.

Strain-Promoted Azide-Alkyne Cycloaddition-Based PSMA-Targeting Ligands for Multimodal Intraoperative Tumor Detection of Prostate Cancer.

Strain-promoted azide–alkyne cycloaddition (SPAAC) is a straightforward and multipurpose conjugation strategy. The use of SPAAC to link different functional elements to prostate-specific membrane antigen (PSMA) ligands would facilitate the development of a modular platform for PSMA-targeted imaging and therapy of prostate cancer (PCa). As a first proof of concept for the SPAAC chemistry platform, we synthesized and characterized four dual-labeled PSMA ligands for intraoperative radiodetection and fluorescence imaging of PCa. Ligands were synthesized using solid-phase chemistry and contained a chelator for 111In or 99mTc labeling. The fluorophore IRDye800CW was conjugated using SPAAC chemistry or conventional N-hydroxysuccinimide (NHS)–ester coupling. Log D values were measured and PSMA specificity of these ligands was determined in LS174T-PSMA cells. Tumor targeting was evaluated in BALB/c nude mice with subcutaneous LS174T-PSMA and LS174T wild-type tumors using μSPECT/CT imaging, fluorescence imaging, and biodistribution studies. SPAAC chemistry increased the lipophilicity of the ligands (log D range: −2.4 to −4.4). In vivo, SPAAC chemistry ligands showed high and specific accumulation in s.c. LS174T-PSMA tumors up to 24 h after injection, enabling clear visualization using μSPECT/CT and fluorescence imaging. Overall, no significant differences between the SPAAC chemistry ligands and their NHS-based counterparts were found (2 h p.i., p > 0.05), while 111In-labeled ligands outperformed the 99mTc ligands. Here, we demonstrate that our newly developed SPAAC-based PSMA ligands show high PSMA-specific tumor targeting. The use of click chemistry in PSMA ligand development opens up the opportunity for fast, efficient, and versatile conjugations of multiple imaging moieties and/or drugs.

Accumulation of Uroporphyrin I in Necrotic Tissues of Squamous Cell Carcinoma after Administration of 5-Aminolevulinic Acid.

5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) fluorescence is widely used for the intraoperative detection of malignant tumors. However, the fluorescence emission profiles of the accompanying necrotic regions of these tumors have yet to be determined. To address this, we performed fluorescence and high-performance liquid chromatography (HPLC) analyses of necrotic tissues of squamous cancer after 5-ALA administration. In resected human lymph nodes of metastatic squamous cell carcinoma, we found a fluorescence peak at approximately 620 nm in necrotic lesions, which was distinct from the PpIX fluorescence peak at 635 nm for viable cancer lesions. Necrotic lesions obtained from a subcutaneous xenograft model of human B88 oral squamous cancer also emitted the characteristic fluorescence peak at 620 nm after light irradiation: the fluorescence intensity ratio (620 nm/635 nm) increased with the energy of the irradiation light. HPLC analysis revealed a high content ratio of uroporphyrin I (UPI)/total porphyrins in the necrotic cores of murine tumors, indicating that UPI is responsible for the 620 nm peak. UPI accumulation in necrotic tissues after 5-ALA administration was possibly due to the failure of the heme biosynthetic pathway. Taken together, fluorescence imaging of UPI after 5-ALA administration may be applicable for the evaluation of tumor necrosis.

PD61-04 PRELIMINARY PHASE 1 SAFETY AND EFFICACY RESULTS OF A PROSTATE SPECIFIC MEMBRANE ANTIGEN (PSMA) TARGETING FLUOROPHORE IN PATIENTS UNDERGOING ROBOTIC PROSTATECTOMY

You have accessJournal of UrologyProstate Cancer: Localized: Surgical Therapy V (PD61)1 Sep 2021PD61-04 PRELIMINARY PHASE 1 SAFETY AND EFFICACY RESULTS OF A PROSTATE SPECIFIC MEMBRANE ANTIGEN (PSMA) TARGETING FLUOROPHORE IN PATIENTS UNDERGOING ROBOTIC PROSTATECTOMY Hao Nguyen, Alexander Antaris, Nynke Van den Berg, Lingru Xue, Scott Greenberg, Anna Muchnik, Alwin Klaassen, Jeff Simko, Sanjeev Dutta, Jonathan Sorger, and Peter Carroll Hao NguyenHao Nguyen More articles by this author , Alexander AntarisAlexander Antaris More articles by this author , Nynke Van den BergNynke Van den Berg More articles by this author , Lingru XueLingru Xue More articles by this author , Scott GreenbergScott Greenberg More articles by this author , Anna MuchnikAnna Muchnik More articles by this author , Alwin KlaassenAlwin Klaassen More articles by this author , Jeff SimkoJeff Simko More articles by this author , Sanjeev DuttaSanjeev Dutta More articles by this author , Jonathan SorgerJonathan Sorger More articles by this author , and Peter CarrollPeter Carroll More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002098.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Recurrence rates following surgery for high–risk prostate cancer remain unchanged due, in large part, to the failure to completely excise locally extensive and/or regional disease. This stems from a fundamental inability to differentiate cancer from healthy tissue. IS-002 is a novel near-infrared PSMA targeted fluorophore that is designed to enhance intraoperative cancer visualization during robotic prostatectomy for compete tumor removal. We hypothesize that IS-002 fluorescence-guided surgery (FGS) may improve oncological outcomes by assisting in cancer detection and thus enabling complete cancer excision. Objective: Evaluation of IS-002 safety, pharmacokinetics, and efficacy in a Phase I dose-escalation study (n=24) in patients undergoing robotic prostatectomy using the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, CA) equipped with Sensitive FireflyTM 800 nm near-infrared imaging capability (SF). METHODS: Patients with high-risk prostate cancer (CAPRA 6-10) received IS-002 intravenously 24 hr. prior to surgery. Six subjects per cohort were dosed at 50, 100, 150 or 200 µg/kg. Safety (adverse events, labs, UA, and ECG) was assessed during a 14-day period. Intraoperative and ex-vivo imaging results were confirmed using histopathology for ground truth cancer determination. RESULTS: IS-002 was studied in 9 subjects (24 planned) with adverse events limited to expected green urine and feces and no major adverse events. Among the 7 patients with complete histopathology data, IS-002 successfully achieved pathologically confirmed tumor fluorescence in 7/7 (100%). Ex vivo tumor-to-background ratio quantification spanned 38.8 – 220.6 in the 50 µg/kg dose cohort. Surgeons using SF + IS-002 reported excellent tumor discrimination over background (Figure 1), and fluorescence outperformed standard imaging (MRI,CT,TRUS, white light endoscopy) at revealing bladder neck invasion (2/2), seminal vesical invasion (2/2), neurovascular bundle involvement (2/2), and lymph node involvement (3/3). CONCLUSIONS: IS-002 is safe and well tolerated for FGS at evaluated doses for intraoperative tumor detection beyond the prostate and margin assessment during robotic prostatectomy. Source of Funding: Intuitive Surgical Inc. and Goldberg-Benioff Program in Translational Cancer Biology © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e1067-e1068 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hao Nguyen More articles by this author Alexander Antaris More articles by this author Nynke Van den Berg More articles by this author Lingru Xue More articles by this author Scott Greenberg More articles by this author Anna Muchnik More articles by this author Alwin Klaassen More articles by this author Jeff Simko More articles by this author Sanjeev Dutta More articles by this author Jonathan Sorger More articles by this author Peter Carroll More articles by this author Expand All Advertisement Loading ...

Unexpected Binding of Tozuleristide "Tumor Paint" to Cerebral Vascular Malformations: A Potentially Novel Application of Fluorescence-Guided Surgery.

Fluorescence-guided surgery (FGS) is under investigation as a means to improve the extent of resection for primary central nervous system (CNS) tumors. Tozuleristide, known also as "Tumor Paint," is an investigational tumor-targeting agent covalently conjugated to a derivative of the fluorescent dye indocyanine green. To report the finding of avid intraoperative fluorescence of tozuleristide on cerebral vascular malformations. Our institution is participating in a phase 2/3 study of intraoperative near-infrared fluorescence detection of pediatric primary CNS tumors in patients receiving intravenous tozuleristide and imaged with the Canvas system. Our site enrolled 2 patients with intracranial lesions, suspected preoperatively of possibly being gliomas that proved to be cavernous vascular malformations after resection. Each lesion had a dark blue mulberry appearance and each fluoresced avidly with tozuleristide. Each was completely resected, and the patients recovered without deficit. Pathological assessment showed cavernous angioma for both cases. Tozuleristide fluorescence is postulated to result from binding to matrix metalloproteinase-2 and annexin A2, and literature review demonstrates expression of both these ligands on multiple cerebrovascular lesions, including cavernous malformations. This finding deserves further investigation to determine if tozuleristide "Tumor Paint" may have a wider role in the identification of non-neoplastic intracranial pathologies.

A dual-mode tactile hardness sensor for intraoperative tumor detection and tactile imaging in robot-assisted minimally invasive surgery

Intraoperative tumor detection and shape identification through manual palpation are routinely performed in traditional open surgeries to ensure complete tumor resection. However, most existing robot-assisted minimally invasive surgery (RMIS) systems lack tactile feedback and rely on vision heavily. Traditional tactile sensing methods require the sensor to be placed normal to the tissue surface. But this requirement cannot always be met due to the limited degrees of freedom and the complexity of the environment in confined spaces. This paper proposes a miniaturized piezoelectric tactile sensor for tissue hardness detection by measuring its electrical impedance spectrum. It has two unique detection modes in two orthogonal directions—transverse and longitudinal, and can detect hardness even when the contact angle is large. It is verified by simulations and experiments that both detection modes can be used to detect hardness in the normal contact condition. However, in the case of hardness detection at a large contact angle, the sensitivity of the sensor in the transverse detection mode is significantly higher than that in the longitudinal mode, implying that this mode is more suitable for the large-angle detection. The sensor is then tested on silicone phantoms with hard inclusions and also on an ex vivo porcine liver. In addition, a tactile imaging algorithm based on Gaussian process regression is used to generate the complete hardness distribution of the test sample, which is further processed to extract the shape and boundary of the hard inclusion. The results show that the accuracy of shape detection is high (recall ⩾ 95%, specificity ⩾ 97%), and the smallest feature size it could detect is 1.3 mm. This proves that the proposed tactile sensor has the potential to perform high-accuracy tumor detection in RMIS.

Radiopharmaceutical and Eu3+ doped gadolinium oxide nanoparticles mediated triple-excited fluorescence imaging and image-guided surgery

Cerenkov luminescence imaging (CLI) is a novel optical imaging technique that has been applied in clinic using various radionuclides and radiopharmaceuticals. However, clinical application of CLI has been limited by weak optical signal and restricted tissue penetration depth. Various fluorescent probes have been combined with radiopharmaceuticals for improved imaging performances. However, as most of these probes only interact with Cerenkov luminescence (CL), the low photon fluence of CL greatly restricted it’s interaction with fluorescent probes for in vivo imaging. Therefore, it is important to develop probes that can effectively convert energy beyond CL such as β and γ to the low energy optical signals. In this study, a Eu3+ doped gadolinium oxide (Gd2O3:Eu) was synthesized and combined with radiopharmaceuticals to achieve a red-shifted optical spectrum with less tissue scattering and enhanced optical signal intensity in this study. The interaction between Gd2O3:Eu and radiopharmaceutical were investigated using 18F-fluorodeoxyglucose (18F-FDG). The ex vivo optical signal intensity of the mixture of Gd2O3:Eu and 18F-FDG reached 369 times as high as that of CLI using 18F-FDG alone. To achieve improved biocompatibility, the Gd2O3:Eu nanoparticles were then modified with polyvinyl alcohol (PVA), and the resulted nanoprobe PVA modified Gd2O3:Eu (Gd2O3:Eu@PVA) was applied in intraoperative tumor imaging. Compared with 18F-FDG alone, intraoperative administration of Gd2O3:Eu@PVA and 18F-FDG combination achieved a much higher tumor-to-normal tissue ratio (TNR, 10.24 ± 2.24 vs. 1.87 ± 0.73, P = 0.0030). The use of Gd2O3:Eu@PVA and 18F-FDG also assisted intraoperative detection of tumors that were omitted by preoperative positron emission tomography (PET) imaging. Further experiment of image-guided surgery demonstrated feasibility of image-guided tumor resection using Gd2O3:Eu@PVA and 18F-FDG. In summary, Gd2O3:Eu can achieve significantly optimized imaging property when combined with 18F-FDG in intraoperative tumor imaging and image-guided tumor resection surgery. It is expected that the development of the Gd2O3:Eu nanoparticle will promote investigation and application of novel nanoparticles that can interact with radiopharmaceuticals for improved imaging properties. This work highlighted the impact of the nanoprobe that can be excited by radiopharmaceuticals emitting CL, β, and γ radiation for precisely imaging of tumor and intraoperatively guide tumor resection.

A narrative review of near-infrared fluorescence imaging in hepatectomy for hepatocellular carcinoma.

Hepatectomy is a main therapeutic strategy for hepatocellular carcinoma (HCC), which requires removal of primary and disseminated tumors and maximum preservation of normal liver tissue. However, in a clinical operation, it is difficult to recognize the tumor tissue and its boundary with the naked eye and palpation, which often leads to insufficient or excessive resection. Near-infrared fluorescence (NIRF) imaging, a non-invasive, real-time, low-cost, and highly sensitive imaging technique has been extensively studied in surgical navigation. With the development of fluorescence imaging system and fluorescent probe, intraoperative tumor detection and margin definition can be achieved, making the operation more accurate. Advances in fluorescence imaging of HCC in the NIR region have focused on the traditional first NIR window (NIR-I, 700–900 nm), and have recently been extended to the second NIR window (NIR-II, 1,000–1,700 nm). Compared with NIR-I imaging, fluorescence imaging in the NIR-II exhibits great advantages, including higher spatial resolution, deeper penetration depth, and lower optical absorption and scattering from biological substrates with minimal tissue autofluorescence. There is no doubt that developing novel NIRF probes for in vivo imaging of HCC has high significance and direct impact on the field of liver surgery. In this article, the development of various NIRF probes for fluorescence image guided HCC hepatectomy is reviewed, and current challenges and potential opportunities of these imaging probes are discussed.

Intraoperative detection of colorectal and pancreatic liver metastases using SGM-101, a fluorescent antibody targeting CEA

BackgroundFluorescence-guided surgery can provide surgeons with an imaging tool for real-time intraoperative tumor detection. SGM-101, an anti-CEA antibody labelled with a fluorescent dye, is a tumor-specific imaging agent that can aid in improving detection and complete resection for CEA-positive tumors. In this study, the performance of SGM-101 for the detection of colorectal and pancreatic liver metastases was investigated. MethodsIn this open-label, non-randomized, single-arm pilot study, patients were included with liver metastases from colorectal origin and intraoperatively detected liver metastases from pancreatic origin (during planned pancreatic surgery). SGM-101 was administered two to four days before the scheduled surgery as a single intravenous injection. Intraoperative fluorescence imaging was performed using the Quest Spectrum® imaging system. The performance of SGM-101 was assessed by measuring the intraoperative fluorescence signal and comparing this to histopathology. ResultsA total of 19 lesions were found in 11 patients, which were all suspected as malignant in white light and subsequent fluorescence inspection. Seventeen lesions were malignant with a mean tumor-to-background ratio of 1.7. The remaining two lesions were false-positives as proven by histology. ConclusionCEA-targeted fluorescence-guided intraoperative tumor detection with SGM-101 is feasible for the detection of colorectal and pancreatic liver metastases.

Laparoscopic compatible device incorporating inductive proximity sensors for precise detection of gastric and colorectal small tumors

The accurate localization of small tumors of the digestive tract is of paramount importance in surgical oncology because it dictates the limits of resection and the extent of lymph node dissection. In this view, we have designed and fabricated a highly efficient sensing laparoscopic instrument focused on precise non-invasive extralumenal intraoperative detection of small colorectal or gastric tumors. The equipment is fully adapted for laparoscopic surgery and consists of an inductive proximity sensor encapsulated into a watertight stainless-steel case that is connected to an electronic functional block dimensionally scaled-down by the desired form and size for optimal surgical manipulation. The sensor-case unit and the electronic block are coupled together using a modular system which allows disconnection of the latter and sterilization by autoclavation of the former, followed by swift plugging of the electronic block just before surgery in a sterile-controlled environment. The instrument works in tandem with a modified endoscopic hemostatic clip which is attached endoscopically, before surgery, in the mucosa proximal and distal to the tumor. By scanning the serosal side of the digestive organ during the laparoscopic surgical procedure, the detector senses the modified clip and thus pinpoints to the location of the tumor. Additional engineering of the standard endoscopic hemostatic clips by coating them with various combinations of metallic alloys of Cu and Zn was necessary to improve the detection range and sensitivity without compromising on their functionality. The clips were also covered with nanometric layers of Au to ensure their biocompatibility. The ex-vivo dry-lab experiments showed a satisfactory detection distance which was later confirmed in ex-vivo wet-lab experiments on animal organs and human surgical specimens.