scholarly journals Detection by fluorescence of pituitary neuroendocrine tumour (PitNET) tissue during endoscopic transsphenoidal surgery using bevacizumab-800CW (DEPARTURE trial): study protocol for a non-randomised, non-blinded, single centre, feasibility and dose-finding trial

BMJ Open ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. e049109
Author(s):  
Rob A Vergeer ◽  
Mark R Postma ◽  
Iris Schmidt ◽  
Astrid GW Korsten-Meijer ◽  
Robert A Feijen ◽  
...  
Keyword(s):  
Fluorescence Imaging ◽  
Transsphenoidal Surgery ◽  
Ex Vivo ◽  
Single Fibre ◽  
Dose Finding ◽  
Histopathological Analysis ◽  
Single Centre ◽  
Endoscopic Transsphenoidal Surgery ◽  
Intraoperative Fluorescence

IntroductionAchieving gross total resection and endocrine remission in pituitary neuroendocrine tumours (PitNET) can be challenging, especially in PitNETs with cavernous sinus (CS) invasion, defined as a Knosp grade of 3 or 4. A potential target to identify PitNET tissue is vascular endothelial growth factor A (VEGF-A), which expression is known to be significantly higher in PitNETs with CS invasion.Methods and analysisThe aim of this non-randomised, non-blinded, single centre, feasibility and dose-finding phase 1 trial is to determine the feasibility of intraoperative fluorescence imaging detection of PitNET tissue during endoscopic transsphenoidal surgery using the VEGF-A targeting optical agent bevacizumab-800CW (4, 5, 10 or 25 mg). Nine to fifteen patients with a PitNET with a Knosp grade of 3 or 4 will be included. Secondary objectives are: (1) To identify the optimal tracer dose for imaging of PitNET tissue during transsphenoidal surgery for further development in a phase 2 fluorescence molecular endoscopy trial. (2) To quantify fluorescence intensity in vivo and ex vivo with multidiameter single-fibre reflectance, single-fibre fluorescence (MDSFR/SFF) spectroscopy. (3) To correlate and validate both the in vivo and ex vivo measured fluorescence signals with histopathological analysis and immunohistochemical staining. (4) To assess the (sub)cellular location of bevacizumab-800CW by ex vivo fluorescence microscopy. Intraoperative, three imaging moments are defined to detect the fluorescent signal. The tumour-to-background ratios are defined by intraoperative fluorescence in vivo measurements including MDSFR/SFF spectroscopy data and by ex vivo back-table fluorescence imaging. After inclusion of three patients in each dose group, an interim analysis will be performed to define the optimal dose.Ethics and disseminationApproval was obtained from the Medical Ethics Review Board of the University Medical Centre Groningen. Results will be disseminated through national and international journals. The participants and relevant patient support groups will be informed about the results.Trial registration numberNCT04212793

scholarly journals Site-Specific Dual-Labeling of a VHH with a Chelator and a Photosensitizer for Nuclear Imaging and Targeted Photodynamic Therapy of EGFR-Positive Tumors

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 428
Author(s):  
Emma Renard ◽  
Estel Collado Camps ◽  
Coline Canovas ◽  
Annemarie Kip ◽  
Martin Gotthardt ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Fluorescence Imaging ◽  
Ex Vivo ◽  
Growth Factor Receptor ◽  
Nuclear Imaging ◽  
A431 Cells ◽  
Site Specific ◽  
Variable Domains ◽  
Diagnostic Probe

Variable domains of heavy chain only antibodies (VHHs) are valuable agents for application in tumor theranostics upon conjugation to both a diagnostic probe and a therapeutic compound. Here, we optimized site-specific conjugation of the chelator DTPA and the photosensitizer IRDye700DX to anti-epidermal growth factor receptor (EGFR) VHH 7D12, for applications in nuclear imaging and photodynamic therapy. 7D12 was site-specifically equipped with bimodal probe DTPA-tetrazine-IRDye700DX using the dichlorotetrazine conjugation platform. Binding, internalization and light-induced toxicity of DTPA-IRDye700DX-7D12 were determined using EGFR-overexpressing A431 cells. Finally, ex vivo biodistribution of DTPA-IRDye700DX-7D12 in A431 tumor-bearing mice was performed, and tumor homing was visualized with SPECT and fluorescence imaging. DTPA-IRDye700DX-7D12 was retrieved with a protein recovery of 43%, and a degree of labeling of 0.56. Spectral properties of the IRDye700DX were retained upon conjugation. 111In-labeled DTPA-IRDye700DX-7D12 bound specifically to A431 cells, and they were effectively killed upon illumination. DTPA-IRDye700DX-7D12 homed to A431 xenografts in vivo, and this could be visualized with both SPECT and fluorescence imaging. In conclusion, the dichlorotetrazine platform offers a feasible method for site-specific dual-labeling of VHH 7D12, retaining binding affinity and therapeutic efficacy. The flexibility of the described approach makes it easy to vary the nature of the probes for other combinations of diagnostic and therapeutic compounds.

scholarly journals EANM recommendations based on systematic analysis of small animal radionuclide imaging in inflammatory musculoskeletal diseases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Erik H. J. G. Aarntzen ◽  
Edel Noriega-Álvarez ◽  
Vera Artiko ◽  
André H. Dias ◽  
Olivier Gheysens ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Radionuclide Imaging ◽  
Musculoskeletal Diseases ◽  
Ex Vivo ◽  
Imaging Techniques ◽  
Large Body ◽  
Therapeutic Interventions ◽  
Histopathological Analysis ◽  
Complementary Value

AbstractInflammatory musculoskeletal diseases represent a group of chronic and disabling conditions that evolve from a complex interplay between genetic and environmental factors that cause perturbations in innate and adaptive immune responses. Understanding the pathogenesis of inflammatory musculoskeletal diseases is, to a large extent, derived from preclinical and basic research experiments. In vivo molecular imaging enables us to study molecular targets and to measure biochemical processes non-invasively and longitudinally, providing information on disease processes and potential therapeutic strategies, e.g. efficacy of novel therapeutic interventions, which is of complementary value next to ex vivo (post mortem) histopathological analysis and molecular assays. Remarkably, the large body of preclinical imaging studies in inflammatory musculoskeletal disease is in contrast with the limited reports on molecular imaging in clinical practice and clinical guidelines. Therefore, in this EANM-endorsed position paper, we performed a systematic review of the preclinical studies in inflammatory musculoskeletal diseases that involve radionuclide imaging, with a detailed description of the animal models used. From these reflections, we provide recommendations on what future studies in this field should encompass to facilitate a greater impact of radionuclide imaging techniques on the translation to clinical settings.

scholarly journals Absorption by water increases fluorescence image contrast of biological tissue in the shortwave infrared

2018 ◽  
Vol 115 (37) ◽  
pp. 9080-9085 ◽  
Author(s):  
Jessica A. Carr ◽  
Marianne Aellen ◽  
Daniel Franke ◽  
Peter T. C. So ◽  
Oliver T. Bruns ◽  
...  
Keyword(s):  
Penetration Depth ◽  
Fluorescence Imaging ◽  
Biological Tissue ◽  
Ex Vivo ◽  
Scattered Light ◽  
Image Contrast ◽  
Fluorescence Image ◽  
Tissue Phantoms ◽  
Shortwave Infrared

Recent technology developments have expanded the wavelength window for biological fluorescence imaging into the shortwave infrared. We show here a mechanistic understanding of how drastic changes in fluorescence imaging contrast can arise from slight changes of imaging wavelength in the shortwave infrared. We demonstrate, in 3D tissue phantoms and in vivo in mice, that light absorption by water within biological tissue increases image contrast due to attenuation of background and highly scattered light. Wavelengths of strong tissue absorption have conventionally been avoided in fluorescence imaging to maximize photon penetration depth and photon collection, yet we demonstrate that imaging at the peak absorbance of water (near 1,450 nm) results in the highest image contrast in the shortwave infrared. Furthermore, we show, through microscopy of highly labeled ex vivo biological tissue, that the contrast improvement from water absorption enables resolution of deeper structures, resulting in a higher imaging penetration depth. We then illustrate these findings in a theoretical model. Our results suggest that the wavelength-dependent absorptivity of water is the dominant optical property contributing to image contrast, and is therefore crucial for determining the optimal imaging window in the infrared.

IN VIVO NEAR-INFRARED FLUORESCENCE IMAGING OF HUMAN COLON ADENOCARCINOMA BY SPECIFIC IMMUNOTARGETING OF A TUMOR-ASSOCIATED MUCIN

2009 ◽  
Vol 02 (04) ◽  
pp. 407-422 ◽  
Author(s):  
RALPH S. DACOSTA ◽  
YING TANG ◽  
TUULA KALLIOMAKI ◽  
RAYMOND M. REILLY ◽  
ROBERT WEERSINK ◽  
...  
Keyword(s):  
Fluorescence Microscopy ◽  
Fluorescence Imaging ◽  
Normal Tissue ◽  
Near Infrared ◽  
Ex Vivo ◽  
Colon Adenocarcinoma ◽  
Human Colon ◽  
Human Colon Adenocarcinoma

Background and Aims: Accurate endoscopic detection of premalignant lesions and early cancers in the colon is essential for cure, since prognosis is closely related to lesion size and stage. Although it has great clinical potential, autofluorescence endoscopy has limited tumor-to-normal tissue image contrast for detecting small preneoplastic lesions. We have developed a molecularly specific, near-infrared fluorescent monoclonal antibody (CC49) bioconjugate which targets tumor-associated glycoprotein 72 (TAG72), as a contrast agent to improve fluorescence-based endoscopy of colon cancer. Methods: The fluorescent anti-TAG72 conjugate was evaluated in vitro and in vivo in athymic nude mice bearing human colon adenocarcinoma (LS174T) subcutaneous tumors. Autofluorescence, a fluorescent but irrelevant antibody and the free fluorescent dye served as controls. Fluorescent agents were injected intravenously, and in vivo whole body fluorescence imaging was performed at various time points to determine pharmacokinetics, followed by ex vivo tissue analysis by confocal fluorescence microscopy and histology. Results: Fluorescence microscopy and histology confirmed specific LS174T cell membrane targeting of labeled CC49 in vitro and ex vivo. In vivo fluorescence imaging demonstrated significant tumor-to-normal tissue contrast enhancement with labeled-CC49 at three hours post injection, with maximum contrast after 48 h. Accumulation of tumor fluorescence demonstrated that modification of CC49 antibodies did not alter their specific tumor-localizing properties, and was antibody-dependent since controls did not produce detectable tumor fluorescence. Conclusions: These results show proof-of-principle that our near-infrared fluorescent-antibody probe targeting a tumor-associated mucin detects colonic tumors at the molecular level in real time, and offer a basis for future improvement of image contrast during clinical fluorescence endoscopy.

Abstract 2559: Reflectance, Fluorescence, and Raman Spectroscopy Identify Features of Vulnerable Atherosclerotic Plaque In Vivo Including a Thin Fibrous Cap, Necrotic Core or Superficial Foam Cells, and Thrombus

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Obrad R Šćepanović ◽  
Maryann Fitzmaurice ◽  
Arnold Miller ◽  
Chae-Ryon Kong ◽  
Ramachandra R Dasari ◽  
...  
Keyword(s):  
Raman Spectroscopy ◽  
Early Detection ◽  
Ex Vivo ◽  
Foam Cells ◽  
Necrotic Core ◽  
Histopathological Analysis ◽  
Artery Wall ◽  
Fibrous Cap ◽  
Vulnerable Plaques

Early detection and treatment of vulnerable atherosclerotic plaques, the lesions most prone to rupture, is critical to reducing patient mortality associated with cardiovascular disease. The combination of reflectance, fluorescence, and Raman spectroscopy - termed multimodal spectroscopy (MMS) - provides complementary and depth-sensitive information about tissue composition. We assessed the hypothesis that MMS can detect morphological features of vulnerable plaque: thin fibrous cap (TFC), necrotic core (NC), superficial foam cells (SFC), intralesional hemorrhage (IH), and thrombus. Methods. In vivo and ex vivo MMS spectra were collected from 12 patients undergoing peripheral vascular surgeries. The data collection was facilitated by means of a novel MMS probe catheter and a portable clinical instrument developed in our laboratory. During carotid endarterectomies, MMS spectra were collected in vivo from the intimal surface of the plaque with the probe held normal to the artery wall. During femoral bypasses, MMS spectra were collected in vivo either through the proximal anastomosis site from the posterior artery wall or adjacent to the incision. A tissue specimen was excised for additional MMS spectral collection ex vivo. Histopathological analysis was performed by a blinded cardiovascular pathologist to assess the vulnerability of each spectrally evaluated tissue site using a quantitative index based on the dimension or severity of the following: TFC, NC, SFC, IH, and thrombus. Across the total set of 76 evaluated tissue locations, MMS is shown to have the ability to detect vulnerability features including a TFC, NC or SFCs, and thrombus. A TFC is detected by measuring the relative amount of collagen assessed by fluorescence, a large NC or SFCs are detected through the combination of beta-carotene absorption and the Raman spectral signature of lipids, and thrombus is detected through its Raman signature. The results indicate that rupture-prone vulnerable plaques could be detected with a sensitivity of 96% and specificity of 72%. In conclusion, these encouraging results will help bring MMS into the clinical arena as a powerful, catheter-based diagnostic technique for early detection of vulnerable plaques.

scholarly journals Initial Harm Reduction by N-Acetylcysteine Alleviates Cartilage Degeneration after Blunt Single-Impact Cartilage Trauma in Vivo

2019 ◽  
Vol 20 (12) ◽  
pp. 2916 ◽  
Author(s):  
Jana Riegger ◽  
Frank Leucht ◽  
Hans-Georg Palm ◽  
Anita Ignatius ◽  
Rolf E. Brenner
Keyword(s):  
Harm Reduction ◽  
Ex Vivo ◽  
Cluster Formation ◽  
Type Ii Collagen ◽  
Cartilage Degeneration ◽  
Histopathological Analysis ◽  
Protective Effects ◽  
Group B ◽  
Trauma Model

Joint injuries are highly associated with the development of post-traumatic osteoarthritis. Previous studies revealed cell- and matrix-protective effects of N-acetylcysteine (NAC) after ex vivo cartilage trauma, while chondroanabolic stimulation with bone morphogenetic protein 7 (BMP7) enhanced type II collagen (COL2) expression. Here, as a next step, we investigated the combined and individual efficacy of intra-articular antioxidative and chondroanabolic treatment in a rabbit in vivo cartilage trauma model. Animals were randomly divided into group A (right joint: trauma (T); left joint: T+BMP7) and group B (right joint: T+NAC; left joint: T+BMP7+NAC). Condyles were impacted with the use of a spring-loaded impact device to ensure defined, single trauma administration. After 12 weeks, histopathological analysis was performed and the presence of matrix metalloproteinase 13 (MMP-13) and COL2 was assessed. Trauma-induced hypocellularity, MMP-13 expression, and cell cluster formation were reduced in NAC-treated animals. In contrast, BMP7 further increased cluster formation. Moreover, synovial concentrations of COL2 carboxy propeptide (CPII) and proteoglycan staining intensities were enhanced in NAC- and NAC+BMP7-treated joints. For the first time, the efficacy of NAC regarding early harm reduction after blunt cartilage trauma was demonstrated in vivo. However, parallel administration of BMP7 was not significantly superior compared to NAC alone.

scholarly journals Enzyme-Directed Assembly of Nanoparticles in Tumors Monitored by in Vivo Whole Animal Imaging and ex Vivo Super-Resolution Fluorescence Imaging

2013 ◽  
Vol 135 (50) ◽  
pp. 18710-18713 ◽  
Author(s):  
Miao-Ping Chien ◽  
Andrea S. Carlini ◽  
Dehong Hu ◽  
Christopher V. Barback ◽  
Anthony M. Rush ◽  
...  
Keyword(s):  
Fluorescence Imaging ◽  
Ex Vivo ◽  
Super Resolution ◽  
Directed Assembly ◽  
Animal Imaging

scholarly journals Retro-enantio isomer of angiopep-2 assists nanoprobes across the blood-brain barrier for targeted magnetic resonance/fluorescence imaging of glioblastoma

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ruoxi Xie ◽  
Zijun Wu ◽  
Fanxin Zeng ◽  
Huawei Cai ◽  
Dan Wang ◽  
...  
Keyword(s):  
Magnetic Resonance ◽  
Fluorescence Imaging ◽  
Near Infrared ◽  
Ex Vivo ◽  
Malignant Gliomas ◽  
Resonance Fluorescence ◽  
Malignant Tumours ◽  
Nir Fluorescence

AbstractGlioblastoma (GBM), one of the most common primary intracranial malignant tumours, is very difficult to be completely excised by surgery due to its irregular shape. Here, we use an MRI/NIR fluorescence dual-modal imaging nanoprobe that includes superparamagnetic iron oxide nanoparticles (SPIONs) modified with indocyanine (Cy7) molecules and peptides (ANG or DANG) to locate malignant gliomas and guide accurate excision. Both peptides/Cy7-SPIONs probes displayed excellent tumour-homing properties and barrier penetrating abilities in vitro, and both could mediate precise aggregation of the nanoprobes at gliomas sites in in vivo magnetic resonance imaging (MRI) and ex vivo near-infrared (NIR) fluorescence imaging. However, compared with ANG/Cy7-SPIONs probes, DANG/Cy7-SPIONs probes exhibited better enhanced MR imaging effects. Combining all these features together, this MRI/NIR fluorescence imaging dual-modal nanoprobes modified with retro-enantio isomers of the peptide have the potential to accurately display GBMs preoperatively for precise imaging and intraoperatively for real-time imaging.

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