Cyclodextrin (CD)-based supramolecular interactions have been proposed as nanocarriers for drug delivery. We previously explored the use of these supramolecular interactions to perform targeted ...hepatic radioembolization. In a two-step procedure the appropriate location of the diagnostic pre-targeting vector can first be confirmed, after which the therapeutic vector will be targeted through multivalent host–guest interactions. Such a procedure would prevent therapeutic errors that come from a mismatch between diagnostic and therapeutic procedures. In the current study we explored the use of dual-isotope imaging to assess the in vivo stability of the formed complex and individual components.
Dual-isotope imaging of the host and guest vectors was performed after labeling of the pre-targeted guest vector, being adamantane (Ad) functionalized macro-aggregated albumin (MAA) particles, with technetium-99 m (99mTc-MAA-Ad). The host vector, Cy50.5CD9PIBMA39, was labeled with indium-111 (111In-Cy50.5CD9PIBMA39). The in situ stability of both the individual vectors and the resulting MAA-Ad–111In-Cy50.5CD9PIBMA39 complexes was studied over 44 h at 37 °C in a serum protein-containing buffer. In vivo, the host vector 111In-Cy50.5CD9PIBMA39 was administered two hours after local deposition of 99mTc-MAA-Ad in mice. Dual-isotope SPECT imaging and quantitative biodistribution studies were performed between 2 and 44 h post intravenous host vector administration.
The individual vectors portrayed <5% dissociation of the radioisotope over the course of 20 h. Dissociation of MAA-Ad–111In-Cy50.5CD9PIBMA39 complexes remained within a 10–20% range after incubation in serum. In vivo dual-isotope SPECT imaging of host–guest interactions revealed co-localization of the tracer components. Quantitative assessment of the biodistribution revealed that the hepatic accumulation of the host vector nearly doubled between 2 h and 44 h post-injection (from 14.9 ± 6.1%ID/g to 26.2 ± 2.1%ID/g).
Assessment of intra-hepatic host–guest complexation was successfully achieved using dual isotope multiplexing, underlining the complex stability that was found in situ (up to 44 h in serum). Overall, the results obtained in this study highlight the potential of supramolecular chemistry as a versatile platform that could advance the field of nanomedicine.
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•Supramolecular interactions Ad-MAA (guest) & CD carrying polymers (host)•Pre-targeting of the liver with Ad-functionalized MAA•Dual-isotope imaging of the host–guest complex in the liver•In vivo stability of the host–guest complex and individual components•An alternative platform for hepatic radioembolization
Positron emission tomography (PET) is an important imaging modality for personalizing clinical management of patients with lung cancer. In this regard, PET imaging is essential for adequate clinical ...staging and monitoring of treatment response in patients with lung cancer. The key advantage of PET over other radiological imaging modalities is its high sensitivity for the detection of pulmonary lesions, normal-sized metastatic hilar and/or mediastinal lymph nodes, and distant metastases. Furthermore, with increasing clinical evidence, the role of PET imaging for treatment selection, adaptation, early response monitoring and follow up in patients with lung cancer is being increasingly recognized. At the heart of PET imaging lies the ability to visualize and quantify numerous biological parameters that are responsible for treatment resistance. In order to ensure accurate and reproducible image quantification, harmonization of patient preparation and imaging protocols is essential. Additionally, there are several technical factors during PET scanning that have to be taken care of to safeguard image quality and quantitative accuracy. One of these factors is the occurrence of respiratory motion artifacts, which is a well-known factor that can significantly influence image quality and quantitative accuracy of PET images. If left uncorrected, respiratory motion artifacts can introduce uncertainties in diagnosis and staging, inaccuracies in definition of target volumes for radiation treatment planning, and hinder adequate monitoring of therapy response. Although many different respiratory gating techniques have been developed to correct PET images for respiratory motion artifacts, respiratory gating has traditionally not been widely adopted in clinical practice. This is due to the fact that these methods tend to be disruptive for the clinical workflow due the lengthening of image acquisition times, higher amounts of activity being administered to the patient, and the requirement to synchronize additional hardware with the scanner. Developments in respiratory gating techniques over the last years have resulted in considerable technical improvements. These newer respiratory gating techniques can operate directly on the acquired PET data without the use of additional hardware to trace respiratory motion and can be seamlessly applied into clinical routine. Furthermore, instead of only using a fraction of the acquired PET data newer methods have the ability to use all of the acquired PET data for image reconstruction, thereby improving image quality. The clinically added value of respiratory gating lies in improving image quality by reducing the amount of respiration-induced image blurring. This considerably improves the detection and characterization of small lesions, potentially improving early diagnosis and staging of patients with lung cancer. Furthermore, the incorporation of (4D) respiratory gated PET for radiotherapy purposes has shown to improve target volume definition through more accurate tracking of tumor motion. In addition, the effect of respiratory motion artifacts on widely used volumetric and uptake parameters in PET have been described. Although respiratory gating improves quantitative accuracy of PET images, the exact impact of these corrections on clinical management of patients with lung cancer often still needs to be determined.
Molecular imaging technologies are increasingly used to diagnose, monitor, and guide treatment of i.e., cancer. In this review, the current status and future prospects of the use of molecular imaging ...as an instrument to help realize precision surgery is addressed with focus on the main components that form the conceptual basis of intraoperative molecular imaging. Paramount for successful interventions is the relevance and accessibility of surgical targets. In addition, selection of the correct combination of imaging agents and modalities is critical to visualize both microscopic and bulk disease sites with high affinity and specificity. In this context developments within engineering/imaging physics continue to drive the growth of image-guided surgery. Particularly important herein is enhancement of sensitivity through improved contrast and spatial resolution, features that are critical if sites of cancer involvement are not to be overlooked during surgery. By facilitating the connection between surgical planning and surgical execution, digital surgery technologies such as computer-aided visualization nicely complement these technologies. The complexity of image guidance, combined with the plurality of technologies that are becoming available, also drives the need for evaluation mechanisms that can objectively score the impact that technologies exert on the performance of healthcare professionals and outcome improvement for patients. Keywords: Image-guided therapy, Intraoperative molecular imaging, Surgery, Fluorescence imaging, Multimodal imaging, Digital surgery, Surgical navigation, Pharmacokinetics
Purpose
Surgical fluorescence guidance has gained popularity in various settings, e.g., minimally invasive robot-assisted laparoscopic surgery. In pursuit of novel receptor-targeted tracers, the ...field of fluorescence-guided surgery is currently moving toward increasingly lower signal intensities. This highlights the importance of understanding the impact of low fluorescence intensities on clinical decision making. This study uses kinematics to investigate the impact of signal-to-background ratios (SBR) on surgical performance.
Methods
Using a custom grid exercise containing hidden fluorescent targets, a da Vinci Xi robot with Firefly fluorescence endoscope and ProGrasp and Maryland forceps instruments, we studied how the participants’ (N = 16) actions were influenced by the fluorescent SBR. To monitor the surgeon’s actions, the surgical instrument tip was tracked using a custom video-based tracking framework. The digitized instrument tracks were then subjected to multi-parametric kinematic analysis, allowing for the isolation of various metrics (e.g., velocity, jerkiness, tortuosity). These were incorporated in scores for dexterity (
Dx
), decision making (
DM
), overall performance (
PS
) and proficiency. All were related to the SBR values.
Results
Multi-parametric analysis showed that task completion time, time spent in fluorescence-imaging mode and total pathlength are metrics that are directly related to the SBR. Below SBR 1.5, these values substantially increased, and handling errors became more frequent. The difference in
Dx
and
DM
between the targets that gave SBR < 1.50 and SBR > 1.50, indicates that the latter group generally yields a 2.5-fold higher
Dx
value and a threefold higher
DM
value. As these values provide the basis for the
PS
score, proficiency could only be achieved at SBR > 1.55.
Conclusion
By tracking the surgical instruments we were able to, for the first time, quantitatively and objectively assess how the instrument positioning is impacted by fluorescent SBR. Our findings suggest that in ideal situations a minimum SBR of 1.5 is required to discriminate fluorescent lesions, a substantially lower value than the SBR 2 often reported in literature.
Introduction: Radioguided surgery is an ever-evolving part of nuclear medicine. In fact, this nuclear medicine sub-discipline actively bridges non-invasive molecular imaging with surgical care. Next ...to relying on the availability of radio- and bimodal-tracers, the success of radioguided surgery is for a large part dependent on the imaging modalities and imaging concepts available for the surgical setting. With this review, we have aimed to provide a comprehensive update of the most recent advances in the field.
Areas covered: We have made an attempt to cover all aspects of radioguided surgery: 1) the use of radioisotopes that emit γ, β
+
, and/or β
−
radiation, 2) hardware developments ranging from probes to 2D cameras and even the use of advanced 3D interventional imaging solutions, and 3) multiplexing solutions such as dual-isotope detection or combined radionuclear and optical detection.
Expert opinion: Technical refinements in the field of radioguided surgery should continue to focus on supporting its implementation in the increasingly complex minimally invasive surgical setting, e.g. by accommodating robot-assisted laparoscopic surgery. In addition, hybrid concepts that integrate the use of radioisotopes with other image-guided surgery modalities such as fluorescence or ultrasound are likely to expand in the future.
Near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) has recently been introduced to improve the sentinel lymph node (SLN) procedure. Several optical tracers have been successfully ...tested. However, the optimal tracer formulation is still unknown. This study evaluates the performance of ICG-technetium-99m (99mTc)-nanocolloid in relation to 2 most commonly used ICG-based formulas during SLN biopsy in vulvar cancer.
Twelve women who planned to undergo SLN biopsy for stage I vulvar cancer were prospectively included. Sentinel lymph node mapping was performed using the dual-modality radioactive and NIR fluorescence tracer ICG-99mTc-nanocolloid. All patients underwent combined SLN localization using NIR fluorescence and the (current) gold standard using blue dye and radioactive guidance.
In all 12 patients, at least 1 SLN was detected during surgery. A total of 21 lymph nodes (median 2; range, 1-3) were resected. Median time between skin incision and first SLN detection was 8 (range, 1-22) minutes. All resected SLNs were both radioactive and fluorescent, although only 13 (62%) of 21 SLNs stained blue. Median brightness of exposed SLNs, expressed as signal-to-background ratio, was 5.4 (range, 1.8-11.8). Lymph node metastases were found in 3 patients.
Near-infrared fluorescence-guided SLN mapping is feasible and outperforms blue dye staining. Premixing ICG with 99mTc-nanocolloid provides real-time intraoperative imaging of the SN and seems to be the optimal tracer combination in terms of intraoperative detection rate of the SN (100%). Moreover, ICG-99mTc-nanocolloid allows the administration of a 5-times lower injected dose of ICG (compared with ICG and ICG absorbed to human serum albumin) and can be injected up to 20 hours before surgery.
Background
Combining radioactive colloids and a near‐infrared (NIR) fluorophore permits preoperative planning and intraoperative localization of deeply located sentinel lymph nodes (SLNs) with direct ...optical guidance by a single lymphatic tracer. The aim of this clinical trial was to evaluate and optimize a hybrid NIR fluorescence and radioactive tracer for SLN detection in patients with breast cancer.
Methods
Patients with breast cancer undergoing SLN biopsy were enrolled. The day before surgery, a periareolar injection of indocyanine green (ICG)–99mTc‐radiolabelled nanocolloid was administered and a lymphoscintigram acquired. Blue dye was injected immediately before surgery. Intraoperative SLN localization was performed using a γ probe and the Mini‐FLARETM NIR fluorescence imaging system. Patients were divided into two dose groups, with one group receiving twice the particle density of ICG and nanocolloid, but the same dose of radioactive 99mTc.
Results
Thirty‐two patients were enrolled in the trial. At least one SLN was identified before and during operation. All 48 axillary SLNs could be detected by γ tracing and NIR fluorescence imaging, but only 42 of them stained blue. NIR fluorescence imaging permitted detection of lymphatic vessels draining to the SLN up to 29 h after injection. Doubling the particle density did not yield a difference in fluorescence intensity (median 255 (range 98–542) versus 284 (90–921) arbitrary units; P = 0.590) or signal‐to‐background ratio (median 5·4 (range 3·0–15·4) versus 4·9 (3·5–16·3); P = 1·000) of the SLN.
Conclusion
The hybrid NIR fluorescence and radioactive tracer permitted accurate preoperative and intraoperative detection of the SLNs in patients with breast cancer. Registration number: NTR3685 (Netherlands Trial Register; http://www.trialregister.nl).
Go green
Purpose
The aim of this study was to investigate the biodistribution of (super-)selective trans-arterial radioembolization (TARE) with holmium-166 microspheres (
166
Ho-MS), when administered as ...adjuvant therapy after RFA of HCC 2–5 cm. The objective was to establish a treatment volume absorbed dose that results in an absorbed dose of ≥ 120 Gy on the hyperemic zone around the ablation necrosis (i.e., target volume).
Methods
In this multicenter, prospective dose-escalation study in BCLC early stage HCC patients with lesions 2–5 cm, RFA was followed by (super-)selective infusion of
166
Ho-MS on day 5–10 after RFA. Dose distribution within the treatment volume was based on SPECT-CT. Cohorts of up to 10 patients were treated with an incremental dose (60 Gy, 90 Gy, 120 Gy) of
166
Ho-MS to the treatment volume. The primary endpoint was to obtain a target volume dose of ≥ 120 Gy in 9/10 patients within a cohort.
Results
Twelve patients were treated (male 10; median age, 66.5 years (IQR, 64.3–71.7)) with a median tumor diameter of 2.7 cm (IQR, 2.1–4.0). At a treatment volume absorbed dose of 90 Gy, the primary endpoint was met with a median absorbed target volume dose of 138 Gy (IQR, 127–145). No local recurrences were found within 1-year follow-up.
Conclusion
Adjuvant (super-)selective infusion of
166
Ho-MS after RFA for the treatment of HCC can be administered safely at a dose of 90 Gy to the treatment volume while reaching a dose of ≥ 120 Gy to the target volume and may be a favorable adjuvant therapy for HCC lesions 2–5 cm.
Trial registration
Clinicaltrials.gov
NCT03437382
. (registered: 19-02-2018)
In early-stage vulvar squamous cell carcinoma (VSCC) a sentinel lymph node (SLN) procedure is regarded successful if at least one SLN is removed with minimal residual radioactivity. An inguinofemoral ...lymphadenectomy is considered if not all SLNs visualized on lymphoscintigraphy can be found, with subsequent increased morbidity. We correlated lymphoscintigraphy findings with surgical outcome and groin recurrence with focus on number of SLNs found.
This study concerns a retrospective cohort of 171 women treated for early-stage VSCC who underwent a SLN procedure between 2000 and 2020. The risk of groin recurrence was compared after either a successful or complete SLN procedure, i.e. removal of all SLNs that were visualized on lymphoscintigraphy.
In 13 (7.6%) groins of 171 patients SLN visualization on lymphoscintigraphy failed. In 230 of the 246 (93.5%) groins in which a SLN was visualized, at least one SLN was found during surgery. In 224 of the 246 (91.1%) groins the SLN procedure was regarded either successful (n = 14) or complete (n = 210). An isolated groin recurrence was documented in 5 out of 192 (2.6%, 95%-CI; 0.34 to 4.9) SLN-negative groins after a median follow-up of 47.0 months. All recurrences were noted in the complete SLN group (5/180 groins). The difference with the successful SLN group (0/12 groins) was not significant.
Risk of groin recurrence was 2.6% after SLN negative biopsy in early-stage VSCC. The risk appeared not increased if at least one SLN was found with minimal residual radioactivity, in case more SLNs were visualized on lymphoscintigraphy.
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