DROP-INb Probe Development
The β-detection probe used in this study was based on a cylindrical scintillator (6 mm diameter and 3 mm height) made of mono-crystalline para-terphenyl (doped with 0,1% in mass of (E,E)-1,4-Diphenyl-1,3-butadiene) (15). Being a non-hygroscopic organic scintillator with high light yield (∼140% of anthracene) and low density (1.23 g/cm3), this material provides a high sensitivity to b particles and elevated transparency to photons (e.g. the 511 keV g rays as induced by PET-radiopharmaceuticals). To improve light collection from the scintillator, the detector was surrounded with a 2 mm thick white diffusing Delrin ring and covered in front with two 4 mm layers of a reflective aluminized-Mylar film. The light tightness of this assembly was achieved by adding an external black poly-vinyl-chloride ring of 2 mm, covered on the front by a 15 mm layer of aluminum. Light-collection efficiency was maximized using a 3×3 mm2 silicon photomultiplier (SiPM C-series 30035, SensL Ltd.). After a first Monte Carlo based study of such a probe in a Ga-PSMA context (16), a dedicated laboratory characterization has been performed. A detection efficiency of ~90% for 68Ga b particles and ~2.5% for 511 keV g rays has been found (17).
The β detector was placed at the tip of the DROP-IN probe housing. Similarly to the previously optimized DROP-INg probe (11), a 45° angle grip was incorporated at the end of longitudinal axis of the probe, tailored to the ProGrasp Forceps (Intuitive Surgical Inc.); an instrument that is often used during a prostatectomy and lymph node dissection. Maintaining its compatibility with the daVinci (Intuitive Surgical Inc.) apparatus, this ensured the maneuverability needed to fully exploit the specificity of beta-RGS. In fact, differently from gamma probes, beta detection requires the probe to have full access to the surface to be examined, due to the significant signal attenuation in tissue.
The housing was printed using acrylonitril-butadieen-styreen plastics and a Dimension Elite 3D printer (Stratasys Ltd.). Final dimensions of the whole probe were a length of 55 mm and a diameter of 12 mm, due to the available detector prototype. In the future, however, this diameter could be reduced (e.g. to 8mm) if necessary.
Portable electronics based on an Arduino Due (Arduino AG) equipped with a custom analog shield providing signal conditioning and trigger logic, were used for the readout (18). Sampling time was 1 second. At the end of the chain, the output in terms of counts per second (CPS) was displayed on a tablet, via wireless connection.
Optimization of the DROP-INb Probe Design
In order to optimize the design of the b-probe, a dedicated Monte Carlo simulation was performed in Geant4 (19). In this simulation, the whole detector was reconstructed, and all physical processes of interest were taken into account to effectively reproduce particle scattering, absorption, energy deposition and secondary particles generation. These simulations indicated that a cavity behind the β particle detector would result in a lower noise-background: additional layers of material could in fact promote β+ to g conversion close to the detector, creating noise-background (Fig. 1B). This design concept yielded a light-weight probe construction (Fig. 1A), mostly transparent to 511 keV g-induced noise.
First ex vivo probe evaluation
In total 7 patients with primary diagnosed locally (advanced) high-risk prostate cancer were included (see Table 1). Inclusion criteria consisted of a primary tumor ≥2 cm (based on MRI) with a minimal average PSMA tracer uptake of 1.7 kBq/mL (based on PSMA PET/CT). These patients were mostly redirected to our clinical institute for prostate cancer treatment, initial diagnostics was performed at the referring hospital. Therefore, based on local availability and preferences, diagnostic PSMA-PET/CT was performed with 18F-DCFPyl. This should however provide comparable uptake as 6[68Ga]Ga-PSMA-11(20). SUVmean measurements were performed by manually defining a Volume Of Interest in the prostate tumor, using OsiriX medical imaging software (Pixmeo SARL). All patients were scheduled for a robot-assisted radical prostatectomy and extended pelvic lymph node dissection. In order to minimize radioactive exposure to both patient and medical personnel, a limited dose of ~70 MBq (median 68, IQR: 63.5-82) [68Ga]Ga-PSMA-11 for radioguidance was intravenously administered in the operating room (OR), after docking the da Vinci robot. The study was approved by the local ethics committee (NL66218.031.18, trial NL8256 at trialregister.nl) and all patients provided a written informed consent.
At the end of the surgical procedure, roughly 2.5 hours after injection (median 150 minutes; IQR: 120 - 172.5), the surgical specimens (prostate and lymph node packages if present) were rinsed with saline and scanned using the DROP-INb probe mounted on a Da Vinci robot using the ProGrasp forceps instrument. Rinsing of the ex vivo specimens was performed to remove possible urine contamination, since [68Ga]Ga-PSMA-11is known to undergo renal clearance (20). For prostate samples, “signal” was defined as the highest counting area, as confirmed with preoperative imaging information. The “background” was defined as the area nearby the “signal” where the counting rate dropped to the plateau value that was found in the rest of the sample (thus representing tracer uptake in the healthy prostate tissue). For lymph node samples, the “signal” was acquired on the lymph node itself, and “background” on the surrounding tissue (i.e. fat tissue and negative lymph nodes).
Following analysis, all specimens were sent to pathology for assessment using standard histopathological procedures (21). Additionally, distances between the tumor and the inked specimen borders were measured at marked locations.
Monitoring of radioactive exposure in the operating room
To investigate the feasibility of radioguided surgery using [68Ga]Ga-PSMA-11, radiation safety was considered an important topic. Therefore, radiation dose, as received by the operating room staff, was carefully monitored (22). The surgeon (located behind the robotic console), the scrub nurse (located next to the patient in the sterile field), the assisting nurse (moving around the operating room, outside the sterile field), the anesthetist (located at the head of the patient, outside the sterile field) and the researcher (located >1 m away from the patient, outside the sterile field) all had their own electronic radiation dosimeter (MGPInstruments DMC 2000; Mirion Technologies, Ltd.).