The targeted delivery of anti-cancer drugs and isotopes is one of the most pursued goals in anti-cancer therapy. One of the prime examples of such an application is the intra-arterial injection of microspheres containing cytostatic drugs or radioisotopes during hepatic embolization procedures. Therapy based on the application of microspheres revolves around vascular occlusion, complemented with local therapy in the form of trans-arterial chemoembolization (TACE) or radioembolization (TARE). The broadest implementation of these embolization strategies currently lies within the treatment of untreatable hepatocellular cancer (HCC) and metastatic colorectal cancer. This review aims to describe the state-of-the-art TACE and TARE technologies investigated in the clinical setting for HCC and addresses current trials and new developments. In addition, chemical properties and advancements in microsphere carrier systems are evaluated, and possible improvements in embolization therapy based on the modification of and functionalization with therapeutical loads are explored.

Rationale: In muscle-invasive bladder cancer (MIBC), lymph node invasion has proven to be an independent predictor of disease recurrence and cancer-specific survival. We evaluated the feasibility of targeting the sentinel node (SN) for biopsy in MIBC patients using the hybrid tracer indocyanine green (ICG)–^99mTc-nanocolloid for simultaneous radioguidance and fluorescence guidance. Methods: Twenty histologically confirmed cN0M0 MIBC patients (mean age, 63.3 years; range, 30–82 years), scheduled for radical cystectomy with SN biopsy and extended pelvic lymph node dissection (ePLND), were prospectively included. Twelve patients were operated on following neoadjuvant chemotherapy. The patients received lymphoscintigraphy as well as SPECT/CT after 4 transurethral injections of ICG-^99mTc-nanocolloid (mean, 208 MBq; range, 172–229 MBq) around the tumor/scar in the detrusor muscle of the bladder on the day before radical cystectomy. Sentinel node resection was performed under radioguidance and fluorescence guidance. Results: Nineteen patients could be analyzed. On preoperative imaging, SNs could be identified in 10 patients (53%; mean, 1.6 SN/patient), which revealed drainage pathways outside the ePLND in 20% of the patients. Interesting to note is that 2 patients (10%) with preoperative nonvisualization displayed fluorescent and radioactive SNs during surgery. Location of the primary tumor near the left lateral side of the bladder seemed to be a factor for nonvisualization. Nodal harvesting with ePLND varied among patients (mean, 23.3). Histopathology confirmed tumor-positive nodes in 4 (21%) of all patients. In the 2 patients where an SN could be identified, the ePLND specimens were tumor-negative. All patients with tumor-positive nodes had advanced disease (stage III). Conclusion: Sentinel node biopsy in bladder cancer using the hybrid tracer ICG-^99mTc-nanocolloid is feasible, and preoperative imaging is predictive for the ability to perform SN biopsy in 83% of the patients who displayed an SN. In patients with a successful preoperative SN mapping using lymphoscintigraphy and SPECT/CT, the intraoperative SN guidance and detection were effective, even outside the ePLND area. As such, this study underscores the critical role that preoperative imaging plays in challenging image-guided surgery applications.

Aim: Pre-targeting is a proven strategy for in vivo delivery of a diagnostic or therapeutic payload. The pre-targeting concept can be realized through various conjugation strategies, one of which is based on copper-free “click” chemistry. Copper-free click reactions have shown in vivo potential for imaging and radionuclide therapy, but this conjugation strategy has not yet been explored in combination with microspheres or unicellular organisms. This study aims to evaluate the in vivo efficacy of strain-promoted azide–alkyne cycloaddition (SPAAC) reactions to achieve imaging and targeting of azide-functionalized macro-aggregated albumin (MAA) microspheres and Staphylococcus aureus bacteria. Methods: MAA microspheres (diameter 10–90 μm) were functionalized with a biorthogonal Cy5 fluorophore, bearing an azide functionality (N₃), to generate MAA-Cy5-N₃. S. aureus (diameter ∼1 μm) were functionalized with ^99mTc-UBI_29–41-Cy5-N₃, generating S. aureus-^99mTc-UBI_29–41-Cy5-N₃. In situ and in vitro click conjugation on the –N₃ moieties was studied for 20 h using a radioactivity-based assay and fluorescence microscopy. For in vivo validation, both primary entities, radiolabeled with ^99mTc, were deposited into the microvasculature of the liver via intrasplenic injections. Secondary targeting was realized following the intravenous administration of indium-111-radiolabeled diethylenetriaminepentaacetic acid-dibenzocyclooctyne (¹¹¹In-DTPA-DBCO). To assess click reaction efficiency in vivo, ^99mTc and ¹¹¹In-biodistributions were measured (SPECT and %ID g⁻¹). Use of ¹¹¹In-DTPA-DBCO in mice without MAA deposits or mice infected with non-functionalized S. aureus served as controls. Ex vivo confocal fluorescence imaging was carried out in excised tissues to confirm the presence of functionalized MAA and bacteria. Results: In vitro data confirmed effective click reactions on both the MAA particles and the bacterial membrane. SPECT imaging and biodistribution studies revealed significantly (p < 0.05) increased accumulation of ¹¹¹In-DTPA-DBCO at the sites where MAA-Cy5-N₃ (7.5 ± 1.5%ID g⁻¹vs. 3.5 ± 0.5%ID g⁻¹ in control mice) and S. aureus-^99mTc-UBI_29–41-Cy5-N₃ (9.3 ± 1.3%ID g⁻¹vs. 6.0 ± 0.5%ID g⁻¹ in control mice) resided. Ex vivo fluorescence imaging confirmed the presence of either functionalized MAA or S. aureus in excised spleens and livers of mice. Conclusion: Copper-free click chemistry between a DBCO moiety and Cy5-N₃-functionalized microspheres or bacterial entities in the liver can be used to realize in vivo imaging and targeting.

Aims: Arthroplasty surgery of the knee and hip is performed in two to three million patients annually. Periprosthetic joint infections occur in 4% of these patients. Debridement, antibiotics, and implant retention (DAIR) surgery aimed at cleaning the infected prosthesis often fails, subsequently requiring invasive revision of the complete prosthetic reconstruction. Infection-specific imaging may help to guide DAIR. In this study, we evaluated a bacteria-specific hybrid tracer (^99mTc-UBI_29-41-Cy5) and its ability to visualize the bacterial load on femoral implants using clinical-grade image guidance methods. Methods: ^99mTc-UBI_29-41-Cy5 specificity for Stapylococcus aureus was assessed in vitro using fluorescence confocal imaging. Topical administration was used to highlight the location of S. aureus cultured on femoral prostheses using fluorescence imaging and freehand single photon emission CT (fhSPECT) scans. Gamma counting and fhSPECT were used to quantify the bacterial load and monitor cleaning with chlorhexidine. Microbiological culturing helped to relate the imaging findings with the number of (remaining) bacteria. Results: Bacteria could be effectively stained in vitro and on prostheses, irrespective of the presence of biofilm. Infected prostheses revealed bacterial presence on the transition zone between the head and neck, and in the screw hole. Qualitative 2D fluorescence images could be complemented with quantitative 3D fhSPECT scans. Despite thorough chlorhexidine treatments, 28% to 44% of the signal remained present in the locations of the infection that were identified using imaging, which included 500 to 2,000 viable bacteria. Conclusion: The hybrid tracer ^99mTc-UBI_29-41-Cy5 allowed effective bacterial staining. Qualitative real-time fluorescence guidance could be effectively combined with nuclear imaging that enables quantitative monitoring of the effectiveness of cleaning strategies. Cite this article: Bone Joint Res 2023;12(1):72–79.

(1) Background: Up to 50% of patients with colorectal cancer either have synchronous colorectal liver metastases (CRLM) or develop CRLM over the course of their disease. Surgery and thermal ablation are the most common local treatment options of choice. Despite development and improvement in local treatment options, (local) recurrence remains a significant clinical problem. Many different imaging modalities can be used in the follow-up after treatment of CRLM, lacking evidence-based international consensus on the modality of choice. In this systematic review, we evaluated ¹⁸F-FDG-PET-CT performance after surgical resection, thermal ablation, radioembolization, and neoadjuvant and palliative chemotherapy based on current published literature. (2) Methods: A systematic literature search was performed on the PubMed database. (3) Results: A total of 31 original articles were included in the analysis. Only one suitable study was found describing the role of ¹⁸F-FDG-PET-CT after surgery, which makes it hard to draw a firm conclusion. ¹⁸F-FDG-PET-CT showed to be of additional value in the follow-up after thermal ablation, palliative chemotherapy, and radioembolization. ¹⁸F-FDG-PET-CT was found to be a poor to moderate predictor of pathologic response after neoadjuvant chemotherapy. (4) Conclusions: ¹⁸F-FDG-PET-CT is superior to conventional morphological imaging modalities in the early detection of residual disease after thermal ablation and in the treatment evaluation and prediction of prognosis during palliative chemotherapy and after radioembolization, and ¹⁸F-FDG-PET-CT could be considered in selected cases after neoadjuvant chemotherapy and surgical resection.

Background: Lymph node (LN) metastasis is a relevant predictor for survival in patients with a.o. penile cancer (PeCa), malignant melanoma. The sentinel node (SN) procedure comprises targeted resection of the first tumour-draining SNs. Here, the hybrid tracer indocyanine green (ICG)-^99mTc-nanocolloid has been used for several years to combine optical and nuclear detection. Recently, the resource of the nanocolloid precursor stopped production and the precursor was replaced by a different but chemically comparable colloid, nanoscan. Our aim was to study the performance of ICG-^99mTc-nanoscan compared to ICG-^99mTc-nanocolloid from a nuclear and surgical perspective. Methods: Twenty-four patients with either PeCa or head-and-neck (H&N) melanoma and scheduled for a SN procedure were included. The initial group (n = 11) received ICG-^99mTc-nanocolloid until no longer available; the second group (n = 13) received ICG-^99mTc-nanoscan. Tracer uptake was assessed on lymphoscintigraphy and single-photon emission (SPECT). Intraoperatively, SNs were identified using gamma tracing and fluorescence imaging. Ex vivo (back-table) measurements were conducted to quantify the fluorescence emissions. Chemical analysis was performed to compare the ICG assembly on both precursors. Results: The mean tracer uptake in the SNs was similar for ICG-^99mTc-nanocolloid (2.2 ± 4.3%ID) and ICG-^99mTc-nanoscan (1.8 ± 2.6%ID; p = 0.68). 3 SNs (interquartile range (IQR) 3–4) were detected on lymphoscintigraphy in PeCa patients receiving ICG-^99mTc-nanoscan compared to 2 SNs (IQR 2–3) in PeCa patients receiving ICG-^99mTc-nanocolloid (p = 0.045), no differences were observed in H&N patients. Back-table measurements of resected SNs revealed a lower total fluorescence intensity in the ICG-^99mTc-nanoscan group (24*10⁹ arbitrary units (A.U) IQR 1.6*10⁹–14*10⁹ in the ICG-^99mTc-nanocolloid group versus 4.6*10⁹ A.U. IQR 2.4*10⁹–42*10⁹ in the ICG-^99mTc-nanoscan group, p = 0.0054). This was consistent with a larger degree of “stacked” ICG observed in the nanoscan formulation. No tracer-related adverse events were reported. Conclusions: Based on this retrospective analysis, we can conclude that ICG-^99mTc-nanoscan has similar capacity for SN identification as ICG-^99mTc-nanocolloid and can safely be implemented in SN procedures.