Location-Based Oncological Outcomes of Sentinel Node Dissection in Radical Prostatectomy.

PURPOSE: To assess the oncological outcomes of sentinel-node dissection during radical prostatectomy according to nodal location in comparison to extended pelvic lymph node dissection. MATERIALS AND METHODS: Prospectively collected data of clinically node negative patients that underwent prostatectomy and extended lymph node dissection with or without sentinel-node from 2013 to January 2023 was retrospectively analyzed. The primary endpoint was to assess oncological outcomes on the whole population. Kaplan-Meier curves were used to depict biochemical and clinical recurrence free survival. Multivariable Cox regression models assessed the impact of nodal location on SPECT on oncological outcomes. Adjustment for case mix included: pathological T stage, ISUP grade group, initial PSA, nodal burden, age at surgery and surgical margin status. Secondarily, a propensity score match was performed according to age at surgery, PSA, biopsy ISUP, clinical T stage and Briganti risk of nodal invasion. Survival and regression analyses were than performed also in the matched population. RESULTS: 55.8% patients had at least one sentinel node outside of lymph node dissection template at SPECT/CT. Log-rank test showed comparable 36-months biochemical (P = .3) and clinical recurrence-free survival (P = .6) among patients with sentinel-node inside template, outside template or ePLND alone. At Cox regression, sentinel-node location outside template was associated with lower hazard of metastases (HR 0.62; P = .04) in the overall cohort, while in the matched cohort benefits were observed only for biochemical recurrence (HR 0.57; P = .001). CONCLUSIONS: Wider nodal resection boundaries outside "classic" template, driven by sentinel node procedure, have a positive impact on oncological outcomes in selected patient.

Surgical radioguidance with beta-emitting radionuclides; challenges and possibilities: A position paper by the EANM.

Radioguidance that makes use of ß-emitting radionuclides is gaining in popularity and could have potential to strengthen the range of existing radioguidance techniques. While there is a strong tendency to develop new PET radiotracers, due to favorable imaging characteristics and the success of theranostics research, there are practical challenges that need to be overcome when considering use of ß-emitters for surgical radioguidance. In this position paper, the EANM identifies the possibilities and challenges that relate to the successful implementation of ß-emitters in surgical guidance, covering aspects related to instrumentation, radiation protection, and modes of implementation.

First-in-human validation of a DROP-IN ß-probe for robotic radioguided surgery: defining optimal signal-to-background discrimination algorithm.

PURPOSE: In radioguided surgery (RGS), radiopharmaceuticals are used to generate preoperative roadmaps (e.g., PET/CT) and to facilitate intraoperative tracing of tracer avid lesions. Within RGS, there is a push toward the use of receptor-targeted radiopharmaceuticals, a trend that also has to align with the surgical move toward minimal invasive robotic surgery. Building on our initial ex vivo evaluation, this study investigates the clinical translation of a DROP-IN ß probe in robotic PSMA-guided prostate cancer surgery. METHODS: A clinical-grade DROP-IN ß probe was developed to support the detection of PET radioisotopes (e.g., 68 Ga). The prototype was evaluated in 7 primary prostate cancer patients, having at least 1 lymph node metastases visible on PSMA-PET. Patients were scheduled for radical prostatectomy combined with extended pelvic lymph node dissection. At the beginning of surgery, patients were injected with 1.1 MBq/kg of [68Ga]Ga-PSMA. The ß probe was used to trace PSMA-expressing lymph nodes in vivo. To support intraoperative decision-making, a statistical software algorithm was defined and optimized on this dataset to help the surgeon discriminate between probe signals coming from tumors and healthy tissue. RESULTS: The DROP-IN ß probe helped provide the surgeon with autonomous and highly maneuverable tracer detection. A total of 66 samples (i.e., lymph node specimens) were analyzed in vivo, of which 31 (47%) were found to be malignant. After optimization of the signal cutoff algorithm, we found a probe detection rate of 78% of the PSMA-PET-positive samples, a sensitivity of 76%, and a specificity of 93%, as compared to pathologic evaluation. CONCLUSION: This study shows the first-in-human use of a DROP-IN ß probe, supporting the integration of ß radio guidance and robotic surgery. The achieved competitive sensitivity and specificity help open the world of robotic RGS to a whole new range of radiopharmaceuticals.

Steerable DROP-IN radioguidance during minimal-invasive non-robotic cervical and endometrial sentinel lymph node surgery.

PURPOSE: The recently introduced tethered DROP-IN gamma probe has revolutionized the way robotic radioguided surgery is performed, fully exploiting the nature of steerable robotic instruments. Given this success, the current first-in-human study investigates if the DROP-IN can also provide benefit in combination with steerable non-robotic instruments during conventional laparoscopic surgery, showing equivalence or even benefit over a traditional rigid gamma probe. METHODS: The evaluation was performed in ten patients during laparoscopic cervical (n = 4) and endometrial (n = 6) cancer sentinel lymph node (SLN) procedures. Surgical guidance was provided using the hybrid, or bi-modal, SLN tracer ICG-99mTc-nanocolloid. SLN detection was compared between the traditional rigid laparoscopic gamma probe, the combination of a DROP-IN gamma probe and a steerable laparoscopic instrument (LaproFlex), and fluorescence imaging. RESULTS: The gynecologists experienced an enlarged freedom of movement when using the DROP-IN + LaproFlex combination compared to the rigid laparoscopic probe, making it possible to better isolate the SLN signal from background signals. This did not translate into a change in the SLN find rate yet. In both cervical and endometrial cancer combined, the rigid probe and DROP-IN + LaproFlex combination provided an equivalent detection rate of 96%, while fluorescence provided 85%. CONCLUSION: We have successfully demonstrated the in-human use of steerable DROP-IN radioguidance during laparoscopic cervical and endometrial cancer SLN procedures, expanding the utility beyond robotic procedures. Indicating an improved surgical experience, these findings encourage further investigation and consideration on a path towards routine clinical practice and improved patient outcome. TRIAL REGISTRATION: HCB/2021/0777 and NCT04492995; https://clinicaltrials.gov/study/NCT04492995.

Ageing of Plasmodium falciparum malaria sporozoites alters their motility, infectivity and reduces immune activation in vitro.

BACKGROUND: Sporozoites (SPZ), the infective form of Plasmodium falciparum malaria, can be inoculated into the human host skin by Anopheline mosquitoes. These SPZ migrate at approximately 1 µm/s to find a blood vessel and travel to the liver where they infect hepatocytes and multiply. In the skin they are still low in number (50-100 SPZ) and vulnerable to immune attack by antibodies and skin macrophages. This is why whole SPZ and SPZ proteins are used as the basis for most malaria vaccines currently deployed and undergoing late clinical testing. Mosquitoes typically inoculate SPZ into a human host between 14 and 25 days after their previous infective blood meal. However, it is unknown whether residing time within the mosquito affects SPZ condition, infectivity or immunogenicity. This study aimed to unravel how the age of P. falciparum SPZ in salivary glands (14, 17, or 20 days post blood meal) affects their infectivity and the ensuing immune responses. METHODS: SPZ numbers, viability by live/dead staining, motility using dedicated sporozoite motility orienting and organizing tool software (SMOOT), and infectivity of HC-04.j7 liver cells at 14, 17 and 20 days after mosquito feeding have been investigated. In vitro co-culture assays with SPZ stimulated monocyte-derived macrophages (MoMɸ) and CD8+ T-cells, analysed by flow cytometry, were used to investigate immune responses. RESULTS: SPZ age did not result in different SPZ numbers or viability. However, a markedly different motility pattern, whereby motility decreased from 89% at day 14 to 80% at day 17 and 71% at day 20 was observed (p ≤ 0.0001). Similarly, infectivity of day 20 SPZ dropped to ~ 50% compared with day 14 SPZ (p = 0.004). MoMɸ were better able to take up day 14 SPZ than day 20 SPZ (from 7.6% to 4.1%, p = 0.03) and displayed an increased expression of pro-inflammatory CD80, IL-6 (p = 0.005), regulatory markers PDL1 (p = 0.02), IL-10 (p = 0.009) and cytokines upon phagocytosis of younger SPZ. Interestingly, co-culture of these cells with CD8+ T-cells revealed a decreased expression of activation marker CD137 and cytokine IFNγ compared to their day 20 counterparts. These findings suggest that older (day 17-20) P. falciparum SPZ are less infectious and have decreased immune regulatory potential. CONCLUSION: Overall, this data is a first step in enhancing the understanding of how mosquito residing time affects P. falciparum SPZ and could impact the understanding of the P. falciparum infectious reservoir and the potency of whole SPZ vaccines.

Near-infrared fluorescence lymph node template region dissection plus backup lymphadenectomy in open radical cystectomy for bladder cancer using an innovative handheld device: A single center experience.

BACKGROUND: The extent of pelvic lymphadenectomy (PLND) as part of radical cystectomy (RC) for bladder cancer (BC) remains unclear. Sentinel-based and lymphangiographic approaches could lead to reduced morbidity without sacrificing oncologic safety. OBJECTIVE: To evaluate the feasibility and diagnostic value of fluorescence-guided template sentinel region dissection (FTD) using a handheld near-infrared fluorescence (NIRF) camera in open radical cystectomy. DESIGN, SETTING, AND PARTICIPANTS: After peritumoral cystoscopic injection of indocyanine green (ICG) 21 patients underwent open RC with FTD due to BC between June 2019 and June 2021. Intraoperatively, the FIS-00 Hamamatsu Photonics® NIRF camera was used to identify and resect fluorescent template sentinel regions (FTRs) followed by extended pelvic lymphadenectomy (ePLND) as oncological back-up. OUTCOME MEASUREMENT AND STATISTICAL ANALYSIS: Descriptive analysis of positive and negative results per template region. RESULTS AND LIMITATIONS: FTRs were identified in all 21 cases. Median time (range) from ICG injection to fluorescence detection was 75 (55-125) minutes. On average (SD), 33.4 (9.6) lymph nodes were dissected per patient. Considering template regions as the basis of analysis, 67 (38.3%) of 175 resected regions were NIRF-positive, with 13 (7.4%) regions harboring lymph node metastases. We found no metastatic lymph nodes in NIRF-negative template regions. Outside the standard template, two NIRF-positive benign nodes were identified. CONCLUSION: The concept of NIRF-guided FTD proved for this group all lymph node metastases to be found in NIRF-positive template regions. Pending validation in a larger collective, resection of approximately 40% of standard regions may be sufficient and may result in less morbidity.

A hybrid radioactive and fluorescence approach is more than the sum of its parts; outcome of a phase II randomized sentinel node trial in prostate cancer patients.

OBJECTIVE: To determine the diagnostic accuracy of the hybrid tracer indocyanine green (ICG)-Technetium-99 m(99mTc)-nanocolloid compared to sequential tracers of 99mTc-nanocolloid and free-ICG in detecting tumor-positive lymph nodes (LN) during primary surgery in prostate cancer (PCa) patients. INTRODUCTION: Image-guided surgery strategies can help visualize individual lymphatic drainage patterns and sentinel lymph nodes (SLNs) in PCa patients. For lymphatic mapping radioactive, fluorescent and hybrid tracers are being clinically exploited. In this prospective randomized phase II trial, we made a head-to-head comparison between ICG-99mTc-nanocolloid (hybrid group) and 99mTc-nanocolloid and subsequent free-ICG injection (sequential group). METHODS: PCa patients with a >5% risk of lymphatic involvement according to the 2012 Briganti nomogram and planned for prostatectomy were included and randomized (1:1) between ultrasound-guided intraprostatic tracer administration of ICG-99mTc-nanocolloid (n = 69) or 99mTc-nanocolloid (n = 69) 5 h before surgery. Preoperative lymphoscintigraphy and SPECT/CT were performed to define the locations of the SLNs. Additionally, all participants in the sequential group received an injection of free-ICG at time of surgery. Subsequently, all (S)LNs were dissected using fluorescence guidance followed by an extended pelvic lymph node dissection (ePLND). The primary outcome was the total number of surgically removed (S)LNs and tumor-positive (S)LNs. RESULTS: The total number of surgically removed (S)LN packages was 701 and 733 in the hybrid and sequential groups, respectively (p = 0.727). The total number of fluorescent LNs retrieved was 310 and 665 nodes in the hybrid and sequential groups, respectively (p < 0.001). However, no statistically significant difference was observed in the corresponding number of tumor-positive nodes among the groups (44 vs. 33; p = 0.470). Consequently, the rate of tumor-positive fluorescent LNs was higher in the hybrid group (7.4%) compared to the sequential group (2.6%; p = 0.002), indicating an enhanced positive predictive value for the hybrid approach. There was no difference in complications within 90 days after surgery (p = 0.78). CONCLUSIONS: The hybrid tracer ICG-99mTc-nanocolloid improved the positive predictive value for tumor-bearing LNs while minimizing the number of fluorescent nodes compared to the sequential tracer approach. Consequently, the hybrid tracer ICG-99mTc-nanocolloid enables the most reliable and minimal invasive method for LN staging in PCa patients.

Comparison of two hybrid sentinel node tracers: indocyanine green (ICG)-99mTc-nanocolloid vs. ICG-99mTc-nanoscan from a nuclear medicine and surgical perspective.

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.

Delphi consensus project on prostate-specific membrane antigen (PSMA)-targeted surgery-outcomes from an international multidisciplinary panel.

PURPOSE: Prostate-specific membrane antigen (PSMA) is increasingly considered as a molecular target to achieve precision surgery for prostate cancer. A Delphi consensus was conducted to explore expert views in this emerging field and to identify knowledge and evidence gaps as well as unmet research needs that may help change practice and improve oncological outcomes for patients. METHODS: One hundred and five statements (scored by a 9-point Likert scale) were distributed through SurveyMonkey®. Following evaluation, a consecutive second round was performed to evaluate consensus (16 statements; 89% response rate). Consensus was defined using the disagreement index, assessed by the research and development project/University of California, Los Angeles appropriateness method. RESULTS: Eighty-six panel participants (72.1% clinician, 8.1% industry, 15.1% scientists, and 4.7% other) participated, most with a urological background (57.0%), followed by nuclear medicine (22.1%). Consensus was obtained on the following: (1) The diagnostic PSMA-ligand PET/CT should ideally be taken < 1 month before surgery, 1-3 months is acceptable; (2) a 16-20-h interval between injection of the tracer and surgery seems to be preferred; (3) PSMA targeting is most valuable for identification of nodal metastases; (4) gamma, fluorescence, and hybrid imaging are the preferred guidance technologies; and (5) randomized controlled clinical trials are required to define oncological value. Regarding surgical margin assessment, the view on the value of PSMA-targeted surgery was neutral or inconclusive. A high rate of "cannot answer" responses indicates further study is necessary to address knowledge gaps (e.g., Cerenkov or beta-emissions). CONCLUSIONS: This Delphi consensus provides guidance for clinicians and researchers that implement or develop PSMA-targeted surgery technologies. Ultimately, however, the consensus should be backed by randomized clinical trial data before it may be implemented within the guidelines.

Chemically Enhanced Immunogenicity of Bacteria by Supramolecular Functionalization with an Adjuvant.

Many pathogens blunt immune responses because they lack immunogenic structural features, which typically results in disease. Here, we show evidence suggesting that pathogen immunogenicity can be chemically enhanced. Using supramolecular host-guest chemistry, we complexed onto the surface of a poorly immunogenic bacterium (Staphylococcus aureus) a TLR7 agonist-based adjuvant. "Adjuvanted" bacteria were readily recognized by macrophages and induced a more pro-inflammatory immunophenotype. Future applications of this concept could yield treatment modalities that bolster the immune system's response to pathogenic microbes.

The impact of drainage pathways on the detection of nodal metastases in prostate cancer: a phase II randomized comparison of intratumoral vs intraprostatic tracer injection for sentinel node detection.

INTRODUCTION: Previous studies indicated that location and amount of detected sentinel lymph nodes (SLNs) in prostate cancer (PCa) are influenced where SLN-tracer is deposited within the prostate. To validate whether intratumoral (IT) tracer injection helps to increase identification of tumor-positive lymph nodes (LNs) better than intraprostatic (IP) tracer injection, a prospective randomized phase II trial was performed. METHODS: PCa patients with a > 5% risk of lymphatic involvement were randomized between ultrasound-guided transrectal injection of indocyanine green-[99mTc]Tc-nanocolloid in 2 depots of 1 mL in the tumor (n = 55, IT-group) or in 4 depots of 0.5 mL in the peripheral zone of the prostate (n = 58, IP-group). Preoperative lymphoscintigraphy and SPECT/CT were used to define the location of the SLNs. SLNs were dissected using combination of radio- and fluorescence-guidance, followed by extended pelvic LN dissection and robot-assisted radical prostatectomy. Outcome measurements were number of tumor-bearing SNs, tumor-bearing LNs, removed nodes, number of patients with nodal metastases, and metastasis-free survival (MFS) of 4-7-year follow-up data. RESULTS: IT-injection did not result in significant difference of removed SLNs (5.0 vs 6.0, p = 0.317) and histologically positive SLNs (28 vs 22, p = 0.571). However, in IT-group, the SLN-positive nodes were 73.7% of total positive nodes compared to 37.3% in IP-group (p = 0.015). Moreover, significantly more node-positive patients were found in IT-group (42% vs 24%, p = 0.045), which did not result in worse MFS. In two patients (3.6%) from whom the IT-tracer injection only partly covered intraprostatic tumor spread, nodal metastases in ePLND without tumor-positive SNs were yielded. CONCLUSIONS: The percentage-positive SLNs found after IT-injection were significantly higher compared to IP-injection. Significantly more node-positive patients were found using IT-injection, which did not affect MFS. IT-injection failed to detect nodal metastases from non-index satellite lesions. Therefore, we suggest to combine IT- and IP-tracer injections in men with visible tumor on imaging.

Incidence and risk factor analysis of complications after sentinel node biopsy for penile cancer.

OBJECTIVE: To determine the incidence and types of complications after dynamic sentinel node biopsy (DSNB) in patients with penile cancer (PeCa) and identify risk factors for the occurrence of postoperative complications. PATIENTS AND METHODS: We evaluated 644 patients with PeCa (1284 DSNB procedures) with at least one clinically node negative (cN0) groin who underwent DSNB between 2011 and 2020 at a single high-volume centre. The 30- and 30-90-day postoperative complications were collected according to the modified Clavien-Dindo classification and the standardised methodology proposed by the European Association of Urology panel. Uni- and multivariable generalised linear mixed models were used to identify risk factors for the occurrence of complications per groin. RESULTS: A 30-day postoperative complication occurred in 14% of groins (n = 186), of which 94% were mild to moderate. Wound infection and lymphocele formation were most common. A 30-90-day postoperative complication occurred in 3.4% of the groins, all of which were mild or moderate (Grade I-II). The number of removed lymph nodes (LNs) per groin was the main independent predictor for any 30-day complications and Grade ≥II complications (odds ratio 1.40; P < 0.001). There was an increase in the probability of postoperative complications with the number of LNs removed after accounting for all confounders. CONCLUSIONS: Despite being less morbid than (modified) inguinal LN dissection, DSNB is still associated with a considerable risk of postoperative mild-to-moderate complications. This risk increases with increasing number of LNs removed. Further procedural refinement aimed at removing the true sentinel node(s) only, may help further reduce the morbidity of surgical staging in PeCa.

Nerve Targeting via Myelin Protein Zero and the Impact of Dimerization on Binding Affinity.

BACKGROUND: Surgically induced nerve damage is a common but debilitating side effect. By developing tracers that specifically target the most abundant protein in peripheral myelin, namely myelin protein zero (P0), we intend to support fluorescence-guided nerve-sparing surgery. To that end, we aimed to develop a dimeric tracer that shows a superior affinity for P0. METHODS: Following truncation of homotypic P0 protein-based peptide sequences and fluorescence labeling, the lead compound Cy5-P0101-125 was selected. Using a bifunctional fluorescent dye, the dimeric Cy5-(P0101-125)2 was created. Assessment of the performance of the mono- and bi-labeled compounds was based on (photo)physical evaluation. This was followed by in vitro assessment in P0 expressing Schwannoma cell cultures by means of fluorescence confocal imaging (specificity, location of binding) and flow cytometry (binding affinity; KD). RESULTS: Dimerization resulted in a 1.5-fold increase in affinity compared to the mono-labeled counterpart (70.3 +/- 10.0 nM vs. 104.9 +/- 16.7 nM; p = 0.003) which resulted in a 4-fold increase in staining efficiency in P0 expressing Schwannoma cells. Presence of two targeting vectors also improves a pharmacokinetics of labeled compounds by lowering serum binding and optical stability by preventing dye stacking. CONCLUSIONS: Dimerization of the nerve-targeting peptide P0101-125 proves a valid strategy to improve P0 targeting.

Cyclodextrin/Adamantane-Mediated Targeting of Inoculated Bacteria in Mice.

Cyclodextrin (CD)-based host-guest interactions with adamantane (Ad) have demonstrated use for functionalizing living cells in vitro. The next step in this supramolecular functionalization approach is to explore the concept to deliver chemical cargo to living cells in vivo, e.g., inoculated bacteria, in order to study their dissemination. We validated this concept in two rodent Staphylococcus aureus models. Bacteria (1 × 108 viable S. aureus) were inoculated by (1) intramuscular injection or (2) intrasplenic injection followed by dissemination throughout the liver. The bacteria were prefunctionalized with 99mTc-UBI29-41-Ad2 (primary vector), which allowed us to both determine the bacterial load and create an in vivo target for the secondary host-vector (24 h post-inoculation). The secondary vector, i.e., chemical cargo delivery system, made use of a 111In-Cy50.5CD9PIBMA39 polymer that was administered intravenously. Bacteria-specific cargo delivery as a result of vector complexation was evaluated by dual-isotope SPECT imaging and biodistribution studies (111In), and by fluorescence (Cy5); these evaluations were performed 4 h post-injection of the secondary vector. Mice inoculated with nonfunctionalized S. aureus and mice without an infection served as controls. Dual-isotope SPECT imaging demonstrated that 111In-Cy50.5CD9PIBMA39 colocalized with 99mTc-UBI29-41-Ad2-labeled bacteria in both muscle and liver. In inoculated muscle, a 2-fold higher uptake level (3.2 ± 1.0%ID/g) was noted compared to inoculation with nonfunctionalized bacteria (1.9 ± 0.4%ID/g), and a 16-fold higher uptake level compared to noninfected muscle (0.2 ± 0.1%ID/g). The hepatic accumulation of the host-vector was nearly 10-fold higher (27.1 ± 11.1%ID/g) compared to the noninfected control (2.7 ± 0.3%ID/g; p < 0.05). Fluorescence imaging of the secondary vector corroborated SPECT-imaging and biodistribution findings. We have demonstrated that supramolecular host-guest complexation can be harnessed to achieve an in vivo cargo delivery strategy, using two different bacterial models in soft tissue and liver. This proof-of-principle study paves a path toward developing innovative drug delivery concepts via cell functionalization techniques.

How molecular imaging will enable robotic precision surgery : The role of artificial intelligence, augmented reality, and navigation.

Molecular imaging is one of the pillars of precision surgery. Its applications range from early diagnostics to therapy planning, execution, and the accurate assessment of outcomes. In particular, molecular imaging solutions are in high demand in minimally invasive surgical strategies, such as the substantially increasing field of robotic surgery. This review aims at connecting the molecular imaging and nuclear medicine community to the rapidly expanding armory of surgical medical devices. Such devices entail technologies ranging from artificial intelligence and computer-aided visualization technologies (software) to innovative molecular imaging modalities and surgical navigation (hardware). We discuss technologies based on their role at different steps of the surgical workflow, i.e., from surgical decision and planning, over to target localization and excision guidance, all the way to (back table) surgical verification. This provides a glimpse of how innovations from the technology fields can realize an exciting future for the molecular imaging and surgery communities.

EANM position paper on the role of radiobiology in nuclear medicine.

With an increasing variety of radiopharmaceuticals for diagnostic or therapeutic nuclear medicine as valuable diagnostic or treatment option, radiobiology plays an important role in supporting optimizations. This comprises particularly safety and efficacy of radionuclide therapies, specifically tailored to each patient. As absorbed dose rates and absorbed dose distributions in space and time are very different between external irradiation and systemic radionuclide exposure, distinct radiation-induced biological responses are expected in nuclear medicine, which need to be explored. This calls for a dedicated nuclear medicine radiobiology. Radiobiology findings and absorbed dose measurements will enable an improved estimation and prediction of efficacy and adverse effects. Moreover, a better understanding on the fundamental biological mechanisms underlying tumor and normal tissue responses will help to identify predictive and prognostic biomarkers as well as biomarkers for treatment follow-up. In addition, radiobiology can form the basis for the development of radiosensitizing strategies and radioprotectant agents. Thus, EANM believes that, beyond in vitro and preclinical evaluations, radiobiology will bring important added value to clinical studies and to clinical teams. Therefore, EANM strongly supports active collaboration between radiochemists, radiopharmacists, radiobiologists, medical physicists, and physicians to foster research toward precision nuclear medicine.

The Click-On gamma probe, a second-generation tethered robotic gamma probe that improves dexterity and surgical decision-making.

PURPOSE: Decision-making and dexterity, features that become increasingly relevant in (robot-assisted) minimally invasive surgery, are considered key components in improving the surgical accuracy. Recently, DROP-IN gamma probes were introduced to facilitate radioguided robotic surgery. We now studied if robotic DROP-IN radioguidance can be further improved using tethered Click-On designs that integrate gamma detection onto the robotic instruments themselves. METHODS: Using computer-assisted drawing software, 3D printing and precision machining, we created a Click-On probe containing two press-fit connections and an additional grasping moiety for a ProGrasp instrument combined with fiducials that could be video tracked using the Firefly laparoscope. Using a dexterity phantom, the duration of the specific tasks and the path traveled could be compared between use of the Click-On or DROP-IN probe. To study the impact on surgical decision-making, we performed a blinded study, in porcine models, wherein surgeons had to identify a hidden 57Co-source using either palpation or Click-On radioguidance. RESULTS: When assembled onto a ProGrasp instrument, while preserving grasping function and rotational freedom, the fully functional prototype could be inserted through a 12-mm trocar. In dexterity assessments, the Click-On provided a 40% reduction in movements compared to the DROP-IN, which converted into a reduction in time, path length, and increase in straightness index. Radioguidance also improved decision-making; task-completion rate increased by 60%, procedural time was reduced, and movements became more focused. CONCLUSION: The Click-On gamma probe provides a step toward full integration of radioguidance in minimal invasive surgery. The value of this concept was underlined by its impact on surgical dexterity and decision-making.

Multi-Wavelength Fluorescence in Image-Guided Surgery, Clinical Feasibility and Future Perspectives.

With the rise of fluorescence-guided surgery, it has become evident that different types of fluorescence signals can provide value in the surgical setting. Hereby a different range of targets have been pursued in a great variety of surgical indications. One of the future challenges lies in combining complementary fluorescent readouts during one and the same surgical procedure, so-called multi-wavelength fluorescence guidance. In this review we summarize the current clinical state-of-the-art in multi-wavelength fluorescence guidance, basic technical concepts, possible future extensions of existing clinical indications and impact that the technology can bring to clinical care.

Image-Guided Surgery: Are We Getting the Most Out of Small-Molecule Prostate-Specific-Membrane-Antigen-Targeted Tracers?

Expressed on virtually all prostate cancers and their metastases, the transmembrane protein prostate-specific membrane antigen (PSMA) provides a valuable target for the imaging of prostate cancer. Not only does PSMA provide a target for noninvasive diagnostic imaging, e.g., PSMA-positron emission tomography (PSMA-PET), it can also be used to guide surgical resections of PSMA-positive lesions. The latter characteristic has led to the development of a plethora of PSMA-targeted tracers, i.e., radiolabeled, fluorescent, or hybrid. With image-guided surgery applications in mind, this review discusses these compounds based on clinical need. Here, the focus is on the chemical aspects (e.g., imaging label, spacer moiety, and targeting vector) and their impact on in vitro and in vivo tracer characteristics (e.g., affinity, tumor uptake, and clearance pattern).

Near-infrared fluorescence imaging compared to standard sentinel lymph node detection with blue dye in patients with vulvar cancer - a randomized controlled trial.

OBJECTIVE: The aim of this study was to assess the superiority of ICG-99mTc-nanocolloid for the intraoperative visual detection of sentinel lymph nodes (SLNs) in vulvar squamous cell carcinoma (VSCC) patients compared to standard SLN detection using 99mTc-nanocolloid with blue dye. METHODS: In this multicenter, randomized controlled trial, VSCC patients underwent either the standard SLN procedure or with the hybrid tracer ICG-99mTc-nanocolloid. The primary endpoint was the percentage of fluorescent SLNs compared to blue SLNs. Secondary endpoints were successful SLN procedures, surgical outcomes and postoperative complications. RESULTS: Forty-eight patients were randomized to the standard (n = 24) or fluorescence imaging group (n = 24) using ICG-99mTc-nanocolloid. The percentage of blue SLNs was 65.3% compared to 92.5% fluorescent SLNs (p < 0.001). A successful SLN procedure was obtained in 92.1% of the groins in the standard group and 97.2% of the groins in the fluorescence imaging group (p = 0.33). Groups did not differ in surgical outcome, although more short-term postoperative complications were documented in the standard group (p = 0.041). CONCLUSIONS: Intraoperative visual detection of SLNs in patients with VSCC using ICG-99mTc-nanocolloid was superior compared to 99mTc-nanocolloid and blue dye. The rate of successful SLN procedures between both groups was not significantly different. Fluorescence imaging has potential to be used routinely in the SLN procedure in VSCC patients to facilitate the search by direct visualization. CLINICAL TRIAL REGISTRATION: Netherlands Trial Register (Trial ID NL7443).