The Rise of Molecular Image-Guided Robotic Surgery.

Following early acceptance by urologists, the use of surgical robotic platforms is rapidly spreading to other surgical fields. This empowerment of surgical perception via robotic advances occurs in parallel to developments in intraoperative molecular imaging. Convergence of these efforts creates a logical incentive to advance the decades-old image-guided robotics paradigm. This yields new radioguided surgery strategies set to optimally exploit the symbiosis between the growing clinical translation of robotics and molecular imaging. These strategies intend to advance surgical precision by increasing dexterity and optimizing surgical decision-making. In this state-of-the-art review, topic-related developments in chemistry (tracer development) and engineering (medical device development) are discussed, and future scientific robotic growth markets for molecular imaging are presented.

hHEPATO-Cy5, a Bimodal Tracer for Image-Guided Hepatobiliary Surgery.

Liver cancer is a leading cause of cancer deaths worldwide. Surgical resection of superficial hepatic lesions is increasingly guided by the disrupted bile excretion of the fluorescent dye indocyanine green (ICG). To extend this approach to deeper lesions, a dedicated bimodal tracer that facilitates both fluorescence guidance and radioguidance was developed. Methods: A tracer comprising a methylated cyanine-5 (Cy5) fluorescent dye and a mercaptoacetyltriserine chelate (hHEPATO-Cy5) was synthesized and characterized. Cellular uptake and excretion were evaluated in hepatocyte cultures (2-dimensional culture and in vitro lesion model), using a fluorescent bile salt, MitoTracker dye, and methylated Cy5 as a control. After radiolabeling, the pharmacokinetics of 99mTc-hHEPATO-Cy5 were assessed in mice over 24 h (percentage injected dose and percentage injected dose per gram of tissue, SPECT/CT imaging and fluorescence imaging). The ability to provide real-time fluorescence guidance during robot-assisted hepatobiliary surgery was evaluated in a porcine model using ICG as a reference. Results: The unique molecular signature of hHEPATO-Cy5 promotes hepatobiliary excretion. In vitro studies on hepatocytes showed that where methylated Cy5 remained internalized, hHEPATO-Cy5 showed fast clearance (10 min) similar to that of fluorescent bile salt. In vivo use of 99mTc-hHEPATO-Cy5 in mice revealed liver accumulation and rapid biliary clearance. The effectiveness of bile clearance was best exemplified by the 2-orders-of-magnitude reduction in count rate for the gallbladder (P = 0.008) over time. During hepatobiliary surgery in a porcine model, hHEPATO-Cy5 enabled fluorescence-based lesion identification comparable to that of ICG. Conclusion: The bimodal 99mTc-hHEPATO-Cy5 provides an effective means to identify liver lesions. Uniquely, it helps overcome the shortcomings of fluorescence-only approaches by allowing for an extension to in-depth radioguidance.

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.

Biochemical Response of <0.1 ng/ml Predicts Therapy-free Survival of Prostate Cancer Patients following Prostate-specific Membrane Antigen-targeted Salvage Surgery.

BACKGROUND: In a subset of patients with oligorecurrent prostate cancer (PCa), salvage surgery with prostate-specific membrane antigen (PSMA) radioguided surgery (PSMA-RGS) seems to be of value. OBJECTIVE: To evaluate whether a lower level of postoperative prostate-specific antigen (PSA; <0.1 ng/ml) is predictive of therapy-free survival (TFS) following salvage PSMA-RGS. DESIGN, SETTING, AND PARTICIPANTS: This cohort study evaluated patients with biochemical recurrence after radical prostatectomy and oligorecurrent PCa on PSMA positron emission tomography treated with PSMA-RGS in three tertiary care centers (2014-2022). INTERVENTION: PSMA-RGS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Postsalvage surgery PSA response was categorized as <0.1, 0.1-<0.2, or >0.2 ng/ml. Kaplan-Meier and multivariable Cox regression models evaluated TFS according to PSA response. RESULTS AND LIMITATIONS: Among 553 patients assessed, 522 (94%) had metastatic soft tissue lesions removed during PSMA-RGS. At 2-16 wk after PSMA-RGS, 192, 62, and 190 patients achieved PSA levels of <0.1, 0.1-<0.2, and >0.2 ng/ml, respectively. At 2 yr of follow-up, TFS rate was 81.1% versus 56.1% versus 43.1% (p < 0.001) for patients with PSA <0.1 versus 0.1-<0.2 versus >0.2 ng/ml. In multivariable analyses, PSA levels of 0.1-0.2 ng/ml (hazard ratio [HR]: 1.9, confidence interval [CI]: 1.1-3.1) and ≥0.2 ng/ml (HR: 3.2, CI: 2.2-4.6, p < 0.001) independently predicted the need for additional therapy after PSMA-RGS. The main limitation is the lack of a control group. CONCLUSIONS: For patients after salvage PSMA-RGS, a lower biochemical response (PSA <0.1 ng/ml) seems to predict longer TFS. This insight may help in counseling patients postoperatively as well as guiding the timely selection of additional therapy. PATIENT SUMMARY: We studied what happened to prostate cancer patients in three European centers who had salvage surgery using a special method called prostate-specific membrane antigen-targeted radioguidance. We found that patients who had low prostate-specific antigen levels soon after surgery were less likely to need further treatment for a longer time.

The realization of medical devices for precision surgery - development and implementation of 'stop-and-go' imaging technologies.

INTRODUCTION: Surgery and biomedical imaging encompass a big share of the medical-device market. The ever-mounting demand for precision surgery has driven the integration of these two into the field of image-guided surgery. A key-question herein is how imaging modalities can guide the surgical decision-making process. Through performance-based design, chemists, engineers, and doctors need to build a bridge between imaging technologies and surgical challenges. AREAS-COVERED: This perspective article highlights the complementary nature between the technological design of an image-guidance modality and the type of procedure performed. The specific roles of the involved professionals, imaging technologies, and surgical indications are addressed. EXPERT-OPINION: Molecular-image-guided surgery has the potential to advance pre-, intra- and post-operative tissue characterization. To achieve this, surgeons need the access to well-designed indication-specific chemical-agents and detection modalities. Hereby, some technologies stimulate exploration ('go'), while others stimulate caution ('stop'). However, failing to adequately address the indication-specific needs rises the risk of incorrect tool employment and sub-optimal surgical performance. Therefore, besides the availability of new technologies, market growth is highly dependent on the practical nature and impact on real-life clinical care. While urology currently takes the lead in the widespread implementation of image-guidance technologies, the topic is generic and its popularity spreads rapidly within surgical oncology.

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.

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.

Strong Correlation Between SUVmax on PSMA PET/CT and Numeric Drop-In γ-Probe Signal for Intraoperative Identification of Prostate Cancer Lesions.

Prostate-specific membrane antigen (PSMA) PET is used to select patients with recurrent prostate cancer for metastasis-directed therapy. A surgical approach can be achieved through radioguided surgery (RGS), using a Drop-In γ-probe that traces lesions that accumulate the radioactive signal. With the aim of guiding patient selection for salvage surgery, we studied the correlation between the SUVmax of lesions on preoperative PSMA PET/CT and their intraoperative counts/s measured using the Drop-In γ-probe. Methods: A secondary analysis based on the prospective, single-arm, and single-center feasibility study was conducted (NCT03857113). Patients (n = 29) with biochemical recurrence after previous curative-intent therapy and a maximum of 3 suggestive lesions within the pelvis on preoperative PSMA PET/CT were included. Patients treated with androgen deprivation therapy within 6 mo before surgery were excluded. All patients received an intravenous injection of 99mTc-PSMA-I&S 1 d before surgery. Radioguidance was achieved using a Drop-In γ-probe. Correlation was determined using the Spearman rank correlation coefficient (ρs). Subgroup analysis was based on the median SUVmax Results: In total, 33 lesions were visible on the PSMA PET/CT images, with a median overall SUVmax of 6.2 (interquartile range [IQR], 4.2-9.7). RGS facilitated removal of 31 lesions. The median Drop-In counts/s were 134 (IQR, 81-220) in vivo and 109 (IQR, 72-219) ex vivo. The intensity of the values correlated with SUVmax (ρs = 0.728 and 0.763, respectively; P < 0.001). Subgroup analysis based on median SUVmax in the group with an SUVmax of less than 6 showed no statistically significant correlation with the numeric signal in vivo (ρs = 0.382; P = 0.221) or the signal-to-background-ratio (ρs = 0.245; P = 0.442), whereas the group with an SUVmax of 6 or more showed respective statistically significant positive correlations (ρs = 0.774 [P < 0.001] and ρs = 0.647 [P = 0.007]). Conclusion: Our findings indicate that there is a direct relation between SUVmax on PSMA PET/CT and the readout recorded by the surgical Drop-In probe, thereby indicating that SUVmax can be used to select patients for PSMA RGS. For more definitive subgroup definitions for treatment recommendations, further studies are necessary to validate the present findings.

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.

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.

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.

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 augmented malaria sporozoites display an altered immunogenic profile.

Despite promising results in malaria-naïve individuals, whole sporozoite (SPZ) vaccine efficacy in malaria-endemic settings has been suboptimal. Vaccine hypo-responsiveness due to previous malaria exposure has been posited as responsible, indicating the need for SPZ vaccines of increased immunogenicity. To this end, we here demonstrate a proof-of-concept for altering SPZ immunogenicity, where supramolecular chemistry enables chemical augmentation of the parasite surface with a TLR7 agonist-based adjuvant (SPZ-SAS(CL307)). In vitro, SPZ-SAS(CL307) remained well recognized by immune cells and induced a 35-fold increase in the production of pro-inflammatory IL-6 (p < 0.001). More promisingly, immunization of mice with SPZ-SAS(CL307) yielded improved SPZ-specific IFN-γ production in liver-derived NK cells (percentage IFN-γ+ cells 11.1 ± 1.8 vs. 9.4 ± 1.5%, p < 0.05), CD4+ T cells (4.7 ± 4.3 vs. 1.8 ± 0.7%, p < 0.05) and CD8+ T cells (3.6 ± 1.4 vs. 2.5 ± 0.9%, p < 0.05). These findings demonstrate the potential of using chemical augmentation strategies to enhance the immunogenicity of SPZ-based malaria vaccines.

The Diagnostic Value of the Sentinel Node Procedure to Detect Occult Lymph Node Metastases in PSMA PET/CT Node-Negative Prostate Cancer Patients.

Our objective was to assess the diagnostic value of the sentinel node (SN) procedure for lymph node staging in primary intermediate- and high-risk prostate cancer patients with node-negative results on prostate-specific membrane antigen PET/CT (miN0). Methods: From 2016 to 2022, 154 patients with primary, miN0 PCa were retrospectively included. All patients had a Briganti nomogram-assessed nodal risk of more than 5% and underwent a robot-assisted SN procedure for nodal staging. The prevalence of nodal metastases at histopathology and the occurrence of surgical complications according to the Clavien-Dindo classification were evaluated. Results: The SN procedure yielded 84 (14%) tumor-positive lymph nodes with a median metastasis size of 3 mm (interquartile range, 1-4 mm). In total, 55 patients (36%) were reclassified as pN1. A complication of Clavien-Dindo grade 3 or higher occured in 1 patient (0.6%). Conclusion: The SN procedure classified 36% of patients with miN0 prostate cancer with an elevated risk of nodal metastases as pN1.

State of the Art in Prostate-specific Membrane Antigen-targeted Surgery-A Systematic Review.

Context: Identifying malignant tissue and leaving adjacent structures undisturbed constitute an ongoing challenge in prostate cancer (PCa) surgery. Image and radioguided surgical technologies targeting the prostate-specific membrane antigen (PSMA) receptor may facilitate identification and removal of diseased tissue. Objective: To perform a systematic review of the clinical studies on PSMA-targeted surgery. Evidence acquisition: The MEDLINE (OvidSP), Embase.com, and Cochrane Library databases were searched. Identified reports were critically appraised according to the Idea, Development, Exploration, Assessment, Long-term framework criteria. The risk of bias (RoB) was assessed as per the Risk Of Bias In Non-randomized Studies-of Interventions tool. The strengths and limitations of the techniques and corresponding oncological outcomes were extracted as areas of interest. Data were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Evidence synthesis: In total, 29 reports were selected, including eight prospective studies, 12 retrospective analyses, and nine case reports, all with a high or an unclear RoB. In 72.4% of studies, PSMA targeting was achieved via radioguided surgery (RGS), predominantly using 99mTc-PSMA-I&S (66.7%). Hybrid approaches that complement RGS with optical guidance are emerging. The majority of studies retrieved were pilot studies with a short follow-up. In 13 reports, salvage lymph node surgery was discussed (44.8%). In 12 more recent reports (41.4%), PSMA targeting was studied in primary PCa surgery (50.0% lymph nodes and 50.0% surgical margins), and four studied both primary and salvage surgery (13.8%). Overall, specificity was higher than sensitivity (median 98.9% and 84.8%, respectively). Oncological outcomes were discussed only in reports on the use of 99mTc-PSMA-I&S in salvage surgery (median follow-up of 17.2 mo). A decline in prostate-specific antigen level of >90% ranged from 22.0% to 100.0%, and biochemical recurrence ranged from 50.0% to 61.8% of patients. Conclusions: In PSMA-targeted surgery, most studies address salvage PSMA-RGS using 99mTc-PSMA-I&S. Available evidence suggests that the specificity of intraoperative PSMA targeting is higher than the sensitivity. The studies that included follow-up did not yet objectify a clear oncological benefit. Lacking solid outcome data, PSMA-targeted surgery remains investigational. Patient summary: In this paper, we review recent advances in prostate-specific membrane antigen (PSMA)-targeted surgery, which is used to help identify and remove prostate cancer. We found good evidence to suggest that PSMA targeting helps identify prostate cancer during surgery. The oncological benefits have yet to be investigated further.

A Truncated 14-Amino-Acid Myelin Protein-Zero-Targeting Peptide for Fluorescence-Guided Nerve-Preserving Surgery.

BACKGROUND: The occurrence of accidental nerve damage during surgery and the increasing application of image guidance during head-and-neck surgery have highlighted the need for molecular targeted nerve-sparing interventions. The implementation of such interventions relies on the availability of nerve-specific tracers. In this paper, we describe the development of a truncated peptide that has an optimized affinity for protein zero (P0), the most abundant protein in myelin. METHODS AND MATERIALS: Further C- and N-terminal truncation was performed on the lead peptide Cy5-P0101-125. The resulting nine Cy5-labelled peptides were characterized based on their photophysical properties, P0 affinity, and in vitro staining. These characterizations were combined with evaluation of the crystal structure of P0, which resulted in the selection of the optimized tracer Cy5-P0112-125. A near-infrared Cy7-functionalized derivative (Cy7-P0112-125) was used to perform an initial evaluation of fluorescence-guided surgery in a porcine model. RESULTS: Methodological truncation of the 26-amino-acid lead compound Cy5-P0101-125 resulted in a size reduction of 53.8% for the optimized peptide Cy5-P0112-125. The peptide design and the 1.5-fold affinity gain obtained after truncation could be linked to interactions observed in the crystal structure of the extracellular portion of P0. The near-infrared analogue Cy7-P0112-125 supported nerve illumination during fluorescence-guided surgery in the head-and-neck region in a porcine model. CONCLUSIONS: Methodological truncation yielded a second-generation P0-specific peptide. Initial surgical evaluation suggests that the peptide can support molecular targeted nerve imaging.

Real-Time Identification of Nodal Metastases With 99m Tc-Prostate-Specific Membrane Antigen-Based Radioguidance and Indocyanine Green Fluorescence Imaging in Primary Prostate Cancer Surgery-On the Road to Hybrid Image-Guided Surgery.

ABSTRACT: Recent developments in image-guided prostate cancer surgery focus on extending prostate-specific membrane antigen-directed radioguidance with optical tumor detection using fluorescence, as radio- and fluorescence signals complement each other with in-depth detection and real-time visualization, respectively. As a step in this direction, we report here the integration of indocyanine green fluorescence imaging into a 99m Tc-prostate-specific membrane antigen-targeted radioguided surgery workflow.

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.