Hybrid Tracer Research Articles

First-in-human evaluation of a hybrid modality that allows combined radio- and (near-infrared) fluorescence tracing during surgery.

The clinical introduction of the hybrid tracer indocyanine green (ICG)-(99m)Tc-nanocolloid, composed of a radioactive and a near-infrared (NIR) fluorescence component, has created the need for surgical (imaging) modalities that allow for simultaneous detection of both signals. This study describes the first-in-human use of a prototype opto-nuclear probe during sentinel node (SN) biopsy using ICG-(99m)Tc-nanocolloid. To allow for fluorescence tracing, a derivative of the conventional gamma probe technology was generated in which two optical fibers were integrated to allow for excitation (785 nm) and emission signal collection (> 810 nm). The ability of this opto-nuclear probe to detect the fluorescence signal of the hybrid tracer ICG-(99m)Tc-nanocolloid was firstly determined ex vivo in (non)SNs samples obtained from 41 patients who underwent hybrid tracer-based SN biopsy in the head and neck or urogenital area. In an in vivo proof-of-concept study in nine of these 41 patients, SNs were localized using combined gamma and fluorescence tracing with the opto-nuclear probe. Fluorescence tracing was performed in a similar manner as gamma tracing and under ambient light conditions. Ex vivo, the gamma tracing option of the opto-nuclear probe correctly identified the SN in all 150 evaluated (non)SN samples. Ex vivo fluorescence tracing in the low-sensitivity mode correctly identified 71.7% of the samples. This increased to 98.9% when fluorescence tracing was performed in the high-sensitivity mode. In vivo fluorescence tracing (high-sensitivity mode) accurately identified the SNs in all nine patients (20 SNs evaluated; 100%). This study demonstrates the first-in-human evaluation of a hybrid modality capable of detecting both gamma and fluorescence signals during a surgical procedure. Fluorescence tracing could be performed in ambient light.

Development of a Hybrid Tracer for SPECT and Optical Imaging of Bacterial Infections

In trauma and orthopedic surgery, infection of implants has a major impact on the outcome for patients. Infections may develop either during the initial implantation or during the lifetime of an implant. Both infections, as well as aseptic loosening of the implant, are reasons for revision of the implants. Therefore, discrimination between aseptic-mechanical-loosening and septic-bacterial-loosening of implants is critical during selection of a patient-tailored treatment policy. Specific detection and visualization of infections is a challenge because it is difficult to discriminate infections from inflammation. An imaging tracer that facilitates bacterial identification in a pre- and intraoperative setting may aid the workup for patients suspicious of bacterial infections. In this study we evaluated an antimicrobial peptide conjugated to a hybrid label, which contains both a radioisotope and a fluorescent dye. After synthesis of DTPA-Cy5-UBI29-41 and-when necessary-radiolabeling with (111)In (yield 96.3 ± 2.7%), in vitro binding to various bacterial strains was evaluated using radioactivity counting and confocal fluorescence microscopy. Intramuscular bacterial infections (S. aureus or K. pneumoniae) were also visualized in vivo using a combined nuclear and fluorescence imaging system. The indium-111 was chosen as label as it has a well-defined coordination chemistry, and in pilot studies labeling DTPA-Cy5-UBI29-41 with technetium-99m, we encountered damage to the Cy5 dye after the reduction with SnCl2. As a reference, we used the validated tracer (99m)Tc-UBI29-41. Fast renal excretion of (111)In-DTPA-Cy5-UBI29-41 was observed. Target to nontarget (T/NT) ratios were highest at 2 h post injection: radioactivity counting yielded T/NT ratios of 2.82 ± 0.32 for S. aureus and 2.37 ± 0.05 for K. pneumoniae. Comparable T/NT ratios with fluorescence imaging of 2.38 ± 0.09 for S. aureus and 3.55 ± 0.31 for K. pneumoniae were calculated. Ex vivo confocal microscopy of excised infected tissues showed specific binding of the tracer to bacteria. Using a combination of nuclear and fluorescence imaging techniques, the hybrid antimicrobial peptide conjugate DTPA-Cy5-UBI29-41 was shown to specifically accumulate in bacterial infections. This hybrid tracer may facilitate integration of noninvasive identification of infections and their extent as well as real-time fluorescence guidance during surgical resection of infected areas.

An innovative multimodality approach for sentinel node mapping and biopsy in head and neck malignancies

PurposeRecent innovations such as preoperative SPECT/CT, intraoperative imaging using portable devices and a hybrid tracer were evaluated in a multimodality approach for sentinel node (SN) mapping and biopsy in head and neck malignancies. Material and methodsThe evaluation included 25 consecutive patients with head and neck malignancies (16 melanomas and 9 oral cavity squamous cell carcinomas). Patients were peritumorally injected with the hybrid tracer ICG-99mTc-nanocolloid. SNs were initially identified with lymphoscintigraphy followed by single photon emission computed tomography (SPECT/CT) 2hours after tracer administration. During surgery a portable gamma camera in combination with a near-infrared fluorescence camera was used in addition to a handheld gamma ray detection probe to locate the SNs. ResultsIn all patients the use of conventional lymphoscintigraphy, SPECT/CT and the additional help of the portable gamma camera in one case were able to depict a total of 67 SNs (55 of them visualized on planar images, 11 additional on SPECT/CT and 1 additional with the portable gamma camera). A total of 67 of the preoperatively defined SNs together with 22 additional SNs were removed intraoperatively; 12 out of the 22 additional SNs found during operation were located in the vicinity of the injection site in anatomical areas such as the periauricular or submental regions. The other 10 additional SNs were found by radioguided post-resection control of the excision SN site. ConclusionIn the present series 26% additional SNs were found using the multimodal approach, that incorporates SPECT/CT and intraoperative imaging to the conventional procedure. This approach appears to be useful in malignancies located close to the area of lymphatic drainage such as the periauricular area and the oral cavity.

Optimisation of Fluorescence Guidance During Robot-assisted Laparoscopic Sentinel Node Biopsy for Prostate Cancer

BackgroundThe hybrid tracer was introduced to complement intraoperative radiotracing towards the sentinel nodes (SNs) with fluorescence guidance. ObjectiveImprove in vivo fluorescence-based SN identification for prostate cancer by optimising hybrid tracer preparation, injection technique, and fluorescence imaging hardware. Design, setting, and participantsForty patients with a Briganti nomogram–based risk >10% of lymph node (LN) metastases were included. After intraprostatic tracer injection, SN mapping was performed (lymphoscintigraphy and single-photon emission computed tomography with computed tomography (SPECT-CT)). In groups 1 and 2, SNs were pursued intraoperatively using a laparoscopic gamma probe followed by fluorescence imaging (FI). In group 3, SNs were initially located via FI. Compared with group 1, in groups 2 and 3, a new tracer formulation was introduced that had a reduced total injected volume (2.0ml vs 3.2ml) but increased particle concentration. For groups 1 and 2, the Tricam SLII with D-Light C laparoscopic FI (LFI) system was used. In group 3, the LFI system was upgraded to an Image 1 HUB HD with D-Light P system. InterventionHybrid tracer-based SN biopsy, extended pelvic lymph node dissection, and robot-assisted radical prostatectomy. Outcome measurements and statistical analysisNumber and location of the preoperatively identified SNs, in vivo fluorescence-based SN identification rate, tumour status of SNs and LNs, postoperative complications, and biochemical recurrence (BCR). Results and limitationsMean fluorescence-based SN identification improved from 63.7% (group 1) to 85.2% and 93.5% for groups 2 and 3, respectively (p=0.012). No differences in postoperative complications were found. BCR occurred in three pN0 patients. ConclusionsStepwise optimisation of the hybrid tracer formulation and the LFI system led to a significant improvement in fluorescence-assisted SN identification. Preoperative SPECT-CT remained essential for guiding intraoperative SN localisation. Patient summaryIntraoperative fluorescence-based SN visualisation can be improved by enhancing the hybrid tracer formulation and laparoscopic fluorescence imaging system.

An innovative multimodality approach for sentinel node mapping and biopsy in head and neck malignancies.

Recent innovations such as preoperative SPECT/CT, intraoperative imaging using portable devices and a hybrid tracer were evaluated in a multimodality approach for sentinel node (SN) mapping and biopsy in head and neck malignancies. The evaluation included 25 consecutive patients with head and neck malignancies (16 melanomas and 9 oral cavity squamous cell carcinomas). Patients were peritumorally injected with the hybrid tracer ICG-(99m)Tc-nanocolloid. SNs were initially identified with lymphoscintigraphy followed by single photon emission computed tomography (SPECT/CT) 2 hours after tracer administration. During surgery a portable gamma camera in combination with a near-infrared fluorescence camera was used in addition to a handheld gamma ray detection probe to locate the SNs. In all patients the use of conventional lymphoscintigraphy, SPECT/CT and the additional help of the portable gamma camera in one case were able to depict a total of 67 SNs (55 of them visualized on planar images, 11 additional on SPECT/CT and 1 additional with the portable gamma camera). A total of 67 of the preoperatively defined SNs together with 22 additional SNs were removed intraoperatively; 12 out of the 22 additional SNs found during operation were located in the vicinity of the injection site in anatomical areas such as the periauricular or submental regions. The other 10 additional SNs were found by radioguided post-resection control of the excision SN site. In the present series 26% additional SNs were found using the multimodal approach, that incorporates SPECT/CT and intraoperative imaging to the conventional procedure. This approach appears to be useful in malignancies located close to the area of lymphatic drainage such as the periauricular area and the oral cavity.

Multimodal imaging in radioguided surgery

Radioguided surgery (RGS) utilizes radiolabeled tracers that accumulate in the lesion of interest following local or systemic administration. RGS is an expanding surgical guidance technology, but unfortunately most currently available radiotracers are unable to provide intraoperative optical information regarding the location of the lesion. In 2011, a new hybrid tracer (both radioactive and fluorescent) was introduced for sentinel lymph node detection. This hybrid tracer (indocyanine green-99mTc-nanocolloid) has helped to generate a new hybrid surgical guidance concept, thereby expanding the traditional RGS-based approach. Based on its radioactive signature a hybrid tracer is able to preserve the “traditional” role for RGS. Furthermore, as an additional tool in the operating room, a hybrid tracer provides optical information via fluorescence guidance. This review discusses the most common RGS approaches. Different clinically used radioactive tracers and their potential hybrid derivatives are also discussed. Furthermore, the various imaging devices designed for radioactivity-based detection are reviewed in the context of generating hybrid-imaging modalities.

Multimodal surgical guidance towards the sentinel node in vulvar cancer

IntroductionConventional sentinel node (SN) mapping is performed by injecting a radiocolloid followed by lymphoscintigraphy (and SPECT/CT imaging). An extra intraoperative injection with blue dye can then allow for optical identification of the SN. In order to improve the current clinical standard, the hybrid tracer indocyanine green (ICG)-99mTc-nanocolloid was introduced, a tracer that is both radioactive and fluorescent. This feasibility study aimed to evaluate the value of a multimodal-based SN biopsy in vulvar cancer. Materials and methodsFifteen patients with vulvar cancer (29 groins) scheduled for SN biopsy were peritumorally injected with ICG-99mTc-nanocolloid followed by lymphoscintigraphy and SPECT/CT imaging to identify the SNs. In thirteen patients, shortly before the start of the operation, blue dye was intradermally injected around the lesion. SNs were harvested using a combination of radiotracing, fluorescence imaging, and optical blue dye detection. A portable gamma camera was used before and after SN excision to confirm excision of the preoperatively defined SNs. ResultsPreoperative lymphoscintigraphy and SPECT/CT imaging visualized drainage to 39 SNs in 28 groins. During the operation, 98% (ex vivo 100%) of the SNs were radioactive. With fluorescence imaging 96% of the SNs (ex vivo 100%) could be visualized. Only 65% of the SNs had stained blue at the time of excision. ConclusionICG-99mTc-nanocolloid can be used for preoperative SN identification and enables multimodal (radioactive and fluorescent) surgical guidance in patients with vulvar cancer. The addition of fluorescence-based optical guidance offers more effective SN visualization compared to blue dye.

Added value of the hybrid tracer indocyanine green-99mTc-nanocolloid for sentinel node biopsy in a series of patients with different lymphatic drainage patterns

IntroductionIndocyanine green (ICG)-99mTc-nanocolloid is a novel hybrid fluorescent radioactive tracer for sentinel node (SN) biopsy. This study has aimed to evaluate the added value of this novel versatile tracer in a series of patients with different malignancies. Material and methodsTwenty patients (with penile carcinoma, oral cavity tumors, melanoma) were consecutively included between March and May 2012. Planar lymphoscintigraphy was performed 15min and 2h after injection of ICG-99mTc-nanocolloid followed by SPECT/CT. Blue dye (1ml) was injected in 14 patients in surgery room. Intraoperatively, SNs were localized using a gamma probe and visualized by optical SN-detection using blue dye and fluorescence imaging. Finally, a portable gamma camera was used to confirm complete SN removal. ResultsAt least one SN was identified by SPECT/CT in all patients. All SNs (total 68, 100%) were excised using a combination of radio- and fluorescence guidance: 89.7% were intraoperatively localized with the gamma probe. The remaining SNs, located near the injection site, were localized using fluorescence imaging. During the surgery, 97% of the SNs were fluorescent while only 39.2% were stained blue. Ex vivo, all SNs were both radioactive and fluorescent. The SN was positive in 5 patients. ConclusionSynchronous radio- and fluorescence guided SN biopsy is feasible using ICG-99mTc-nanocolloid. This hybrid approach combines the beneficial properties of both modalities. Adding fluorescence imaging improves optical SN detection compared to blue dye. It has been shown to be especially useful in the localization of SNs near the injection site.

518. SLN Biopsy in Prostate Cancer Patients - Combined Pre-, Intra- and Post Operative Assessment Using a Hybrid Tracer

518. SLN Biopsy in Prostate Cancer Patients - Combined Pre-, Intra- and Post Operative Assessment Using a Hybrid Tracer

116. Hybrid radio- and fluorescence guided sentinel node biopsy in melanoma patients

Background: In melanoma patients, sentinel node (SN) mapping is generally performed by injecting a radiocolloid around the primary tumour followed by lymphoscintigraphy. Intraoperatively, SNs can then be localized using a handheld gamma ray detection probe and patent blue dye. The aim of this study was to assess the added value of intraoperative fluorescence imaging to the conventional radioguided procedure using ICG-99mTc-nanocolloid, a hybrid tracer that is both radioactive and fluorescent.

Relationship Between Intraprostatic Tracer Deposits and Sentinel Lymph Node Mapping in Prostate Cancer Patients

Intraprostatic injection of the hybrid tracer indocyanine green (ICG)-(99m)Tc-nanocolloid enables both preoperative sentinel node (SN) identification and intraoperative visualization of the SN. Relating the fluorescence deposits in embedded prostate tissue specimens to the preoperatively detected SNs also provides the opportunity to study the influence of their placement on lymphatic drainage pattern. Nineteen patients with prostate carcinoma scheduled for robot-assisted laparoscopic prostatectomy and lymph node (LN) dissection were included. ICG-(99m)Tc-nanocolloid was injected intraprostatically, guided by ultrasound. SN biopsy was performed using a combination of radioguidance and fluorescence guidance. Tracer distribution was visualized in paraffin-embedded prostate samples using ex vivo fluorescence imaging. This distribution was correlated to the number and location of the SNs identified on preoperative lymphoscintigraphy and SPECT/CT. ICG-(99m)Tc-nanocolloid helped guide surgical excision of the SNs. Ex vivo fluorescence imaging revealed a large variation in the locations of intraprostatic tracer deposits among patients. Tracer deposits in the peripheral zone correlated with a higher number of visualized LNs than deposits in the central zone (on average, 4.7 vs. 2.4 LNs per patient). Furthermore, tracer deposits in the mid gland correlated with a higher number of visualized LNs than deposits near the base or apex of the prostate (on average, 6 vs. 3.5 LNs per patient). The hybrid nature of the tracer not only enables surgical guidance but also provides an opportunity to study the correlation between the location of tracer deposits within the prostate and the number and location of preoperatively visualized SNs. These data suggest that the location at which a tracer deposit is placed influences the lymphatic drainage pattern.

Concomitant radio- and fluorescence-guided sentinel lymph node biopsy in squamous cell carcinoma of the oral cavity using ICG-99mTc-nanocolloid

For oral cavity malignancies, sentinel lymph node (SLN) mapping is performed by injecting a radiocolloid around the primary tumour followed by lymphoscintigraphy. Surgically, SLNs can then be localized using a handheld gamma ray detection probe. The aim of this study was to evaluate the added value of intraoperative fluorescence imaging to the conventional radioguided procedure. For this we used indocyanine green (ICG)-(99m)Tc-nanocolloid, a hybrid tracer that is both radioactive and fluorescent. Fourteen patients with oral cavity squamous cell carcinoma were peritumourally injected with ICG-(99m)Tc-nanocolloid. SLNs were preoperatively identified with lymphoscintigraphy followed by single photon emission computed tomography (SPECT)/CT for anatomical localization. During surgery, SLNs were detected with a handheld gamma ray detection probe and a handheld near-infrared fluorescence camera. Pre-incision and post-excision imaging with a portable gamma camera was performed to confirm complete removal of all SLNs. SLNs were preoperatively identified using the radioactive signature of ICG-(99m)Tc-nanocolloid. Intraoperatively, 43 SLNs could be localized and excised with combined radio- and fluorescence guidance. Additionally, in four patients, an SLN located close to the primary injection site (in three patients this SLN was located in level I) could only be intraoperatively localized using fluorescence imaging. Pathological analysis of the SLNs revealed a metastasis in one patient. Combined preoperative SLN identification and intraoperative radio- and fluorescence guidance during SLN biopsies for oral cavity cancer proved feasible using ICG-(99m)Tc-nanocolloid. The addition of fluorescence imaging was shown to be of particular value when SLNs were located in close proximity to the primary tumour.

Feasibility of Sentinel Node Biopsy in Head and Neck Melanoma Using a Hybrid Radioactive and Fluorescent Tracer

PurposeThis study was designed to examine the feasibility of combining lymphoscintigraphy and intraoperative sentinel node identification in patients with head and neck melanoma by using a hybrid protein colloid that is both radioactive and fluorescent.MethodsEleven patients scheduled for sentinel node biopsy in the head and neck region were studied. Approximately 5 h before surgery, the hybrid nanocolloid labeled with indocyanine green (ICG) and technetium-99m (99mTc) was injected intradermally in four deposits around the scar of the primary melanoma excision. Subsequent lymphoscintigraphy and single photon emission computed tomography with computed tomography (SPECT/CT) were performed to identify the sentinel nodes preoperatively. In the operating room, patent blue dye was injected in 7 of the 11 patients. Intraoperatively, sentinel nodes were acoustically localized with a gamma ray detection probe and visualized by using patent blue dye and/or fluorescence-based tracing with a dedicated near-infrared light camera. A portable gamma camera was used before and after sentinel node excision to confirm excision of all sentinel nodes.ResultsA total of 27 sentinel nodes were preoperatively identified on the lymphoscintigraphy and SPECT/CT images. All sentinel nodes could be localized intraoperatively. In the seven patients in whom blue dye was used, 43% of the sentinel nodes stained blue, whereas all were fluorescent. The portable gamma camera identified additional sentinel nodes in two patients. Ex vivo, all radioactive lymph nodes were fluorescent and vice versa, indicating the stability of the hybrid tracer.ConclusionsICG–99mTc-nanocolloid allows for preoperative sentinel node visualization and concomitant intraoperative radio- and fluorescence guidance to the same sentinel nodes in head and neck melanoma patients.Electronic supplementary materialThe online version of this article (doi:10.1245/s10434-011-2180-7) contains supplementary material, which is available to authorized users.

Structure in phase space associated with spiral and bar density waves in an N-body hybrid galactic disc

An N-body hybrid simulation, integrating both massive and tracer particles, of a Galactic disk is used to study the stellar phase space distribution or velocity distributions in different local neighborhoods. Pattern speeds identified in Fourier spectrograms suggest that two-armed and three-armed spiral density waves, a bar and a lopsided motion are coupled in this simulation, with resonances of one pattern lying near resonances of other patterns. We construct radial and tangential (uv) velocity distributions from particles in different local neighborhoods. More than one clump is common in these local velocity distributions regardless of the position in the disk. Features in the velocity distribution observed at one galactic radius are also seen in nearby neighborhoods (at larger and smaller radii) but with shifted mean v values. This is expected if the v velocity component of a clump sets the mean orbital galactic radius of its stars. We find that gaps in the velocity distribution are associated with the radii of kinks or discontinuities in the spiral arms. These gaps also seem to be associated with Lindblad resonances with spiral density waves and so denote boundaries between different dominant patterns in the disk. We discuss implications for interpretations of the Milky Way disk based on local velocity distributions. Velocity distributions created from regions just outside the bar's Outer Lindblad resonance and with the bar oriented at 45 degrees from the Sun-Galactic center line more closely resemble that seen in the solar neighborhood (triangular in shape at lower uv and with a Hercules like stream) when there is a strong nearby spiral arm, consistent with the observed Centaurus Arm tangent, just interior to the solar neighborhood.

Novel technologies: Hybrid tracer and multimodality imaging posters

Journal of Labelled Compounds and RadiopharmaceuticalsVolume 52, Issue S1 p. S225-S230 Poster Presentation Novel technologies: Hybrid tracer and multimodality imaging posters First published: 17 June 2009 https://doi.org/10.1002/jlcr.1642AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume52, IssueS1Supplement: Eighteenth International Symposium on Radiopharmaceutical Sciences2009Pages S225-S230 RelatedInformation

Session 8: Hybrid tracer and multimodality imaging

Session 8: Hybrid tracer and multimodality imaging

Image-Guided Oncologic Surgery Using Invisible Light: Completed Pre-Clinical Development for Sentinel Lymph Node Mapping

Invisible near-infrared (NIR) fluorescent light permits high sensitivity, real-time image-guidance during oncologic surgery without changing the look of the surgical field. In this study, we complete pre-clinical development of the technology for sentinel lymph node (SLN) mapping using a large animal model of spontaneous melanoma. Sinclair swine with spontaneous melanoma metastatic to regional lymph nodes were used because of their similarity to human melanoma. Organic lymphatic tracers tested included FDA-approved indocyanine green adsorbed non-covalently to human serum albumin (HSA), and NIR fluorophore CW800 conjugated covalently to HSA (HSA800). The inorganic/organic hybrid tracer tested was type II NIR quantum dots with an anionic coating. Primary tumors received four peri-tumoral injections of each tracer, with a fluorophore dose of 100 pmol to 1 nmol per injection. SLN mapping and image-guided resection were performed in real-time. Each of the 3 lymphatic tracers was injected into n = 4 separate primary melanomas in a total of 6 animals. All 12 injections resulted in identification of the SLN(s) and their associated lymphatic channels within 1 minute in 100% of cases, despite highly pigmented skin and black fur. Hydrodynamic diameter had a profound impact on tracer behavior in vivo. This study completes the pre-clinical development of NIR fluorescence-guided SLN mapping and provides insight into imaging system optimization and tracer choice for future human clinical trials. The technology is likely to eliminate the need for radioactive and colored tracers, permits real-time image guidance throughout the procedure, and assists the pathologist in tissue analysis.