Simple Summary Prostate-specific membrane antigen (PSMA)-targeted PET/CT imaging is increasingly being used for (re)staging in prostate cancer. Although PSMA suggests specificity to prostate cancer... Show moreSimple Summary Prostate-specific membrane antigen (PSMA)-targeted PET/CT imaging is increasingly being used for (re)staging in prostate cancer. Although PSMA suggests specificity to prostate cancer, previous preclinical studies and case reports have shown this protein to be overexpressed by multiple other tumor types. This study aims to investigate the applicability of a PSMA-targeted PET/CT tracer to detect gastrointestinal cancers, including colon, pancreatic and gastric cancer. Current imaging modalities frequently misjudge disease stage in colorectal, gastric and pancreatic cancer. As treatment decisions are dependent on disease stage, incorrect staging has serious consequences. Previous preclinical research and case reports indicate that prostate-specific membrane antigen (PSMA)-targeted PET/CT imaging might provide a solution to some of these challenges. This prospective clinical study aims to assess the feasibility of [F-18]DCFPyL PET/CT imaging to target and visualize primary colon, gastric and pancreatic cancer. In this prospective clinical trial, patients with colon, gastric and pancreatic cancer were included and underwent both [F-18]DCFPyL and [F-18]FDG PET/CT scans prior to surgical resection or (for gastric cancer) neoadjuvant therapy. Semiquantitative analysis of immunohistochemical PSMA staining was performed on the surgical resection specimens, and the results were correlated to imaging parameters. The results of this study demonstrate detection of the primary tumor by [F-18]DCFPyL PET/CT in 7 out of 10 patients with colon, gastric and pancreatic cancer, with a mean tumor-to-blood pool ratio (TBR) of 3.3 and mean SUVmax of 3.6. However, due to the high surrounding uptake, visual distinction of these tumors was difficult, and the SUVmax and TBR on [F-18]FDG PET/CT were significantly higher than on [F-18]DCFPyL PET/CT. In addition, no correlation between PSMA expression in the resection specimen and SUVmax on [F-18]DCFPyL PET/CT was found. In conclusion, the detection of several gastrointestinal cancers using [F-18]DCFPyL PET/CT is feasible. However, low tumor expression and high uptake physiologically in organs/background hamper the clear distinction of the tumor. As a result, [F-18]FDG PET/CT was superior in detecting colon, gastric and pancreatic cancers. Show less
Background: With the rise of prostate-specific membrane antigen (PSMA) radioguided surgery, which is performed using a microdosing regime, demand for visual target confirmation via fluorescence... Show moreBackground: With the rise of prostate-specific membrane antigen (PSMA) radioguided surgery, which is performed using a microdosing regime, demand for visual target confirmation via fluorescence guidance is growing. While proven very effective for radiotracers, microdosing approaches the detection limit for fluorescence imaging. Thus, utility will be highly dependent on the tracer performance, the sensitivity of the fluorescence camera used, and the degree of background signal. Using a porcine model the ability to perform robot-assisted radical prostatectomy under fluorescence guidance using the bimodal or rather hybrid PSMA tracer (Tc-99m-EuK-(SO3)Cy5-mas(3)) was studied, while employing the tracer in a microdosing regime. This was followed by ex vivo evaluation in surgical specimens obtained from prostate cancer patients. Results: T-50% blood and T-50% urine were reached at 85 min and 390 min, in, respectively, blood and urine. Surgical fluorescence imaging allowed visualization of the prostate gland based on the basal PSMA-expression in porcine prostate. Together, in vivo visualization of the prostate and urinary excretion suggests at least an interval of > 7 h between tracer administration and surgery. Confocal microscopy of excised tissues confirmed tracer uptake in kidney and prostate, which was confirmed with PSMA IHC. No fluorescence was detected in other excised tissues. Tumor identification based on ex vivo fluorescence imaging of human prostate cancer specimens correlated with PSMA IHC. Conclusion: Intraoperative PSMA-mediated fluorescence imaging with a microdosing approach was shown to be feasible. Furthermore, EuK-(SO3)Cy5-mas(3) allowed tumor identification in human prostate samples, underlining the translational potential of this novel tracer. Trial registration Approval for use of biological material for research purposes was provided by the Translational Research Board of the Netherlands Cancer Institute-Antoni van Leeuwenhoek hospital (NKI-AvL) under reference IRBm19-273 (22/10/2019). Show less
Collamati, F.; Oosterom, M.N. van; Simoni, M. de; Faccini, R.; Fischetti, M.; Terracciano, C.M.; ... ; Morganti, S. 2020
Background Recently, a flexible DROP-IN gamma-probe was introduced for robot-assisted radioguided surgery, using traditional low-energy SPECT-isotopes. In parallel, a novel approach to achieve... Show moreBackground Recently, a flexible DROP-IN gamma-probe was introduced for robot-assisted radioguided surgery, using traditional low-energy SPECT-isotopes. In parallel, a novel approach to achieve sensitive radioguidance using beta-emitting PET isotopes has been proposed. Integration of these two concepts would allow to exploit the use of PET tracers during robot-assisted tumor-receptor-targeted. In this study, we have engineered and validated the performance of a novel DROP-IN beta particle (DROP-IN beta) detector. Methods Seven prostate cancer patients with PSMA-PET positive tumors received an additional intraoperative injection of similar to 70 MBq(68)Ga-PSMA-11, followed by robot-assisted prostatectomy and extended pelvic lymph node dissection. The surgical specimens from these procedures were used to validate the performance of our DROP-IN(beta)probe prototype, which merged a scintillating detector with a housing optimized for a 12-mm trocar and prograsp instruments. Results After optimization of the detector and probe housing via Monte Carlo simulations, the resulting DROP-IN(beta)probe prototype was tested in a robotic setting. In the ex vivo setting, the probe-positioned by the robot-was able to identify(68)Ga-PSMA-11 containing hot-spots in the surgical specimens: signal-to-background (S/B) was > 5 when pathology confirmed that the tumor was located < 1 mm below the specimen surface.Ga-68-PSMA-11 containing (and PET positive) lymph nodes, as found in two patients, were also confirmed with the DROP-IN(beta)probe (S/B > 3). The rotational freedom of the DROP-IN design and the ability to manipulate the probe with the prograsp tool allowed the surgeon to perform autonomous beta-tracing. Conclusions This study demonstrates the feasibility of beta-radioguided surgery in a robotic context by means of a DROP-IN(beta)detector. When translated to an in vivo setting in the future, this technique could provide a valuable tool in detecting tumor remnants on the prostate surface and in confirmation of PSMA-PET positive lymph nodes. Show less
Introduction Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) has a significant impact on prostate cancer (PCa) patient's clinical management. PSMA PET/CT has changed... Show moreIntroduction Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) has a significant impact on prostate cancer (PCa) patient's clinical management. PSMA PET/CT has changed both the paradigm of metastases spread pathway, and the PSMA specificity for detecting PCa lesions. Currently, it is accepted that PCa can spread to cervical and mediastinal lymph nodes without other intermediate lesions. PSMA expression in non-prostate cancers or benign lesions is known as well. However, information about PSMA functional specificity in clinical practice is still missing. Methods A retrospective analysis of PSMA PET/CT studies was done to select relevant clinical cases with complete clinical history, histology results and follow-up information. Each clinical case was organized from a holistic perspective, including clinical information,Ga-68-PSMA PET/CT images, pathology results and clinical outcome. Results Nine clinical cases were selected to illustrate synchronous primary cancers (gastric gastrointestinal stromal tumours and clear cell renal cell carcinoma), atypical sites of PCa metastases (thyroid, liver, cervical and mediastinal lymph nodes) and some examples of PCa lung metastases with discordant PSMA findings between PET/CT examinations and immunohistochemistry. Discussion In this pictorial essay and review, the meaning of high PSMA expression in neovasculature and uncommon PCa metastatic spread were addressed. Furthermore, recent information about the possible explanation of (1) PCa metastases without PSMA expression due to dedifferentiation and specific PCa subtypes, and (2) some discordant findings on PSMA expression evaluated by PET/CT and immunohistochemistry related to the anti-PSMA antibody used in each technique is presented. Show less
Hinsenveld, F.J.; Wit, E.M.K.; Leeuwen, P.J. van; Brouwer, O.R.; Donswijk, M.L.; Tillier, C.N.; ... ; Poel, H.G. van der 2020
Our objective was to determine the diagnostic capabilities of combined prostate-specific membrane antigen (PSMA) PET/CT and sentinel node (SN) biopsy in PSMA PET/CT-negative patients for primary... Show moreOur objective was to determine the diagnostic capabilities of combined prostate-specific membrane antigen (PSMA) PET/CT and sentinel node (SN) biopsy in PSMA PET/CT-negative patients for primary lymph node (LN) staging in prostate cancer (PCa) patients. Methods: Between January 2017 and March 2019, retrospectively, all consecutive patients with diagnosed intermediate- or high-risk primary PCa who underwent preoperative PSMA PET/CT (Ga-68 or F-18-DCFPyL) followed by robot-assisted radical prostatectomy and extended pelvic LN dissection (ePLND) were included. All patients without suspected LN metastases on PSMA PET/CT were considered candidates for SN biopsy with indocyanine green-Tc-99m-nanocolloid or Tc-99m-nanocolloid with free indocyanine green used as tracers. The ePLND was used as a reference standard. Results: Of 53 patients, 22 had positive PSMA PET/CT results and 31 underwent subsequent SN biopsy after negative PSMA PET/CT results. In total, 23 patients (43%) were pN1, of whom 6 (26%) had negative PSMA PET/CT results and underwent subsequent SN biopsy. The combined use of SN biopsy and PSMA PET/CT identified all pN1 patients (100% sensitivity; 95% confidence interval, 86%-100%) and performed correct nodal staging in 50 of 53 patients (94% diagnostic accuracy; 95% confidence interval, 84%-99%). SN biopsy identified significantly smaller LN metastases (median diameter, 2.0 mm; interquartile range, 1.0-3.8 mm) than PSMA PET/CT (median diameter, 5.5 mm; interquartile range, 2.6-9.3 mm; P = 0.007). Conclusion: Combining both modalities led to a 94% accuracy for nodal staging in diagnosed intermediate- and high-risk primary PCa. Adding SN biopsy in patients with negative PSMA PET/CT results increased the combined sensitivity to 100% for detecting nodal metastases at ePLND. This diagnostic accuracy may provide valuable information for directing further treatment in PCa patients, such as the use of PSMA PET/CT and SN biopsy rather than ePLND as the preferred approach for staging before radiotherapy. Show less
With the rapid expansion of robot-assisted surgical procedures, the need for robot-compliant image guidance technologies has also increased. Examples hereof are the integrated firefly fluorescence... Show moreWith the rapid expansion of robot-assisted surgical procedures, the need for robot-compliant image guidance technologies has also increased. Examples hereof are the integrated firefly fluorescence camera, the drop-in ultrasound probe, and the recently introduced DROP-IN gamma probe. Combined with Ga-68-prostate-specific membrane antigen-(PSMA)-11 PET/CT (staging) and Tc-99m-PSMA-I&S SPECT/CT (preoperative imaging), the latter DROP-IN gamma probe technology recently allowed us to perform the first clinical cases of robot-assisted PSMA-guided salvage surgery of lymphatic metastases. Show less
Schottelius, M.; Wurzer, A.; Wissmiller, K.; Beck, R.; Koch, M.; Gorpas, D.; ... ; Wester, H.J. 2019
The prostate-specific membrane antigen (PSMA)-targeted radiotracers Ga-68/Lu-177-PSMA-I&T and Tc-99m-PSMA-I&S (for imaging and surgery) are currently successfully used for clinical PET... Show moreThe prostate-specific membrane antigen (PSMA)-targeted radiotracers Ga-68/Lu-177-PSMA-I&T and Tc-99m-PSMA-I&S (for imaging and surgery) are currently successfully used for clinical PET imaging, radionuclide therapy, and radioguided surgery of metastatic prostate cancer. To additionally exploit the high sensitivity and spatial resolution of fluorescence imaging for improved surgical guidance, a PSMA-I&T-based hybrid tracer, PSMA-I&F (DOTAGA-k(Sulfo-Cy5)-y-nal-k-Sub-KuE), has been developed and evaluated. Methods: The in vitro PSMA-targeting efficiency of PSMA-I&F, the reference PSMA-I&T, and their corresponding Ga-nat-/Ga-68- and Lu-nat/Lu-177 counterparts was determined in LNCaP cells via competitive binding assays (IC50) and dual-tracer radioligand and fluorescence internalization studies. Biodistribution and small-animal PET imaging studies were performed in CB17 SCID and LNCaP xenograft-bearing SHO mice, respectively, and complemented by intraoperative far-red fluorescence imaging using a clinical laparoscope. Additionally, fully automated serial cryosectioning and fluorescence imaging of 1 tumor-bearing animal as well as PSMA immunohistochemistry and fluorescence microscopy of organ cryosections (tumor, kidney, spleen) were also performed. Results: Compared with the parent PSMA-I&T analogs, the PSMA affinities of PSMA-I&F and its Ga-nat-/Lu-nat-complexes remained high and unaffected by dye conjugation (7.9 < IC50 < 10.5 nM for all ligands). The same was observed for the internalization of Ga-68- and Lu-177-PSMA-I&F. In vivo, blood clearance of Ga-68- and Lu-177-PSMA-I&F was only slightly delayed by high plasma protein binding (94%-95%), and very low accumulation in nontarget organs was observed already at 1 h after injection. Dynamic PET imaging confirmed PSMA-specific (as demonstrated by coinjection of 2-PMPA) uptake into the LNCaP xenograft (4.5% +/- 1.8 percentage injected dose per gram) and the kidneys (106% +/- 23 percentage injected dose per gram). Tumor-to-background ratios of 2.1, 5.2, 9.6, and 9.6 for blood, liver, intestines, and muscle, respectively, at 1 h after injection led to excellent imaging contrast in Ga-68-PSMA-I&F PET and in intraoperative fluorescence imaging. Furthermore, fluorescence imaging of tissue cryosections allowed high-resolution visualization of intraorgan PSMA-I&F distribution in vivo and its correlation with PSMA expression as determined by immunohistochemistry. Conclusion: Thus, with its high PSMA-targeting efficiency and favorable pharmacokinetic profile, Ga-68/Lu-177-PSMA-I&F serves as an excellent proof-of-concept compound for the general feasibility of PSMA-I&T-based hybrid imaging. The PSMA-I&T scaffold represents a versatile PSMA-targeted lead structure, allowing relatively straightforward adaptation to the different structural requirements of dedicated nuclear or hybrid imaging agents. Show less
Schottelius, M.; Wurzer, A.; Wissmiller, K.; Beck, R.; Koch, M.; Gorpas, D.; ... ; Wester, H.J. 2019
