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.

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).

Click-on fluorescence detectors: using robotic surgical instruments to characterize molecular tissue aspects.

Fluorescence imaging is increasingly being implemented in surgery. One of the drawbacks of its application is the need to switch back-and-forth between fluorescence- and white-light-imaging settings and not being able to dissect safely under fluorescence guidance. The aim of this study was to engineer 'click-on' fluorescence detectors that transform standard robotic instruments into molecular sensing devices that enable the surgeon to detect near-infrared (NIR) fluorescence in a white-light setting. This NIR-fluorescence detector setup was engineered to be press-fitted onto standard forceps instruments of the da Vinci robot. Following system characterization in a phantom setting (i.e., spectral properties, sensitivity and tissue signal attenuation), the performance with regard to different clinical indocyanine green (ICG) indications (e.g., angiography and lymphatic mapping) was determined via robotic surgery in pigs. To evaluate in-human applicability, the setup was also used for ICG-containing lymph node specimens from robotic prostate cancer surgery. The resulting Click-On device allowed for NIR ICG signal identification down to a concentration of 4.77 × 10-6 mg/ml. The fully assembled system could be introduced through the trocar and grasping, and movement abilities of the instrument were preserved. During surgery, the system allowed for the identification of blood vessels and assessment of vascularization (i.e., bowel, bladder and kidney), as well as localization of pelvic lymph nodes. During human specimen evaluation, it was able to distinguish sentinel from non-sentinel lymph nodes. With this introduction of a NIR-fluorescence Click-On sensing detector, a next step is made towards using surgical instruments in the characterization of molecular tissue aspects.

Translation of c-Met Targeted Image-Guided Surgery Solutions in Oral Cavity Cancer-Initial Proof of Concept Data.

Intraoperative tumor identification (extension/margins/metastases) via receptor-specific targeting is one of the ultimate promises of fluorescence-guided surgery. The translation of fluorescent tracers that enable tumor visualization forms a critical component in the realization of this approach. Ex vivo assessment of surgical specimens after topical tracer application could help provide an intermediate step between preclinical evaluation and first-in-human trials. Here, the suitability of the c-Met receptor as a potential surgical target in oral cavity cancer was explored via topical ex vivo application of the fluorescent tracer EMI-137. Freshly excised tumor specimens obtained from ten patients with squamous cell carcinoma of the tongue were incubated with EMI-137 and imaged with a clinical-grade Cy5 prototype fluorescence camera. In-house developed image processing software allowed video-rate assessment of the tumor-to-background ratio (TBR). Fluorescence imaging results were related to standard pathological evaluation and c-MET immunohistochemistry. After incubation with EMI-137, 9/10 tumors were fluorescently illuminated. Immunohistochemistry revealed c-Met expression in all ten specimens. Non-visualization could be linked to a more deeply situated lesion. Tumor assessment was improved via video representation of the TBR (median TBR: 2.5 (range 1.8-3.1)). Ex vivo evaluation of tumor specimens suggests that c-Met is a possible candidate for fluorescence-guided surgery in oral cavity cancer.

Multi-wavelength fluorescence imaging with a da Vinci Firefly-a technical look behind the scenes.

The field of fluorescence-guided surgery builds on colored fluorescent tracers that have become available for different clinical applications. Combined use of complementary fluorescent emissions can allow visualization of different anatomical structures (e.g. tumor, lymphatics and nerves) in the same patient. With the aim to assess the requirements for multi-color fluorescence guidance under in vivo conditions, we thoroughly characterized two FDA-approved laparoscopic Firefly camera systems available on the da Vinci Si or da Vinci Xi surgical robot. In this process, we studied the cameras' performance with respect to the photophysical properties of the FDA-approved dyes Fluorescein and ICG. Our findings indicate that multi-wavelength fluorescence imaging of Fluorescein and ICG is possible using clinical-grade fluorescence laparoscopes, but critical factors for success include the photophysical dye properties, imaging system performance and the amount of accumulated dye. When comparing the camera performance, the Xi system provided more effective excitation (adaptions in the light source) and higher detection sensitivity (chip-on-a-tip and/or enhanced image processing) for both Fluorescein and ICG. Both systems can readily be used for multi-wavelength fluorescence imaging of Fluorescein and ICG under clinically relevant conditions. With that, another step has been made towards the routine implementation of multi-wavelength image-guided surgery concepts.

Structural and functional brain abnormalities in children with schizotypal disorder: a pilot study.

Schizotypal disorder lies in the schizophrenia spectrum and is widely studied in adult populations. Schizotypal disorder in children (SDc) is less well described. This study examined brain morphological and functional connectivity abnormalities in SDc (12 SDc and 9 typically developing children), focusing on the default mode and executive control brain networks. Results indicated that SDc is associated with reduced grey matter volume (GMV) in superior and medial frontal gyri, and increased resting-state functional connectivity between the superior frontal gyrus and inferior parietal lobule, compared to typically developing children (cluster-level FWE-corrected p < 0.05). The brain structure abnormality (GMV in left superior frontal gyrus) was correlated with clinical symptoms in SDc (r = -0.66, p = 0.026) and functional connectivity abnormality was correlated with extra-dimensional shifting impairments in all participants (r = 0.62, p = 0.011), suggesting their contribution to the underlying mechanisms of clinical presentation. These preliminary results motivate further work to characterize the neural basis of SDc and its significance as a risk factor for later psychosis.

A DROP-IN beta probe for robot-assisted 68Ga-PSMA radioguided surgery: first ex vivo technology evaluation using prostate cancer specimens.

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 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-INß) detector. METHODS: Seven prostate cancer patients with PSMA-PET positive tumors received an additional intraoperative injection of ~ 70 MBq 68Ga-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-INß 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-INß probe prototype was tested in a robotic setting. In the ex vivo setting, the probe-positioned by the robot-was able to identify 68Ga-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. 68Ga-PSMA-11 containing (and PET positive) lymph nodes, as found in two patients, were also confirmed with the DROP-INß 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-INß 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.