Gijs H. KleinJan

Optimisation of Fluorescence Guidance During Robot-assisted Laparoscopic Sentinel Node Biopsy for Prostate Cancer

BACKGROUND The hybrid tracer was introduced to complement intraoperative radiotracing towards the sentinel nodes (SNs) with fluorescence guidance. OBJECTIVE Improve in vivo fluorescence-based SN identification for prostate cancer by optimising hybrid tracer preparation, injection technique, and fluorescence imaging hardware. DESIGN, SETTING, AND PARTICIPANTS Forty patients with a Briganti nomogram-based risk >10% of lymph node (LN) metastases were included. After intraprostatic tracer injection, SN mapping was performed (lymphoscintigraphy and single-photon emission computed tomography with computed tomography (SPECT-CT)). In groups 1 and 2, SNs were pursued intraoperatively using a laparoscopic gamma probe followed by fluorescence imaging (FI). In group 3, SNs were initially located via FI. Compared with group 1, in groups 2 and 3, a new tracer formulation was introduced that had a reduced total injected volume (2.0 ml vs. 3.2 ml) but increased particle concentration. For groups 1 and 2, the Tricam SLII with D-Light C laparoscopic FI (LFI) system was used. In group 3, the LFI system was upgraded to an Image 1 HUB HD with D-Light P system. INTERVENTION Hybrid tracer-based SN biopsy, extended pelvic lymph node dissection, and robot-assisted radical prostatectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Number and location of the preoperatively identified SNs, in vivo fluorescence-based SN identification rate, tumour status of SNs and LNs, postoperative complications, and biochemical recurrence (BCR). RESULTS AND LIMITATIONS Mean fluorescence-based SN identification improved from 63.7% (group 1) to 85.2% and 93.5% for groups 2 and 3, respectively (p=0.012). No differences in postoperative complications were found. BCR occurred in three pN0 patients. CONCLUSIONS Stepwise optimisation of the hybrid tracer formulation and the LFI system led to a significant improvement in fluorescence-assisted SN identification. Preoperative SPECT-CT remained essential for guiding intraoperative SN localisation. PATIENT SUMMARY Intraoperative fluorescence-based SN visualisation can be improved by enhancing the hybrid tracer formulation and laparoscopic fluorescence imaging system.

Multimodal surgical guidance towards the sentinel node in vulvar cancer

INTRODUCTION Conventional sentinel node (SN) mapping is performed by injecting a radiocolloid followed by lymphoscintigraphy (and SPECT/CT imaging). An extra intraoperative injection with blue dye can then allow for optical identification of the SN. In order to improve the current clinical standard, the hybrid tracer indocyanine green (ICG)-(99m)Tc-nanocolloid was introduced, a tracer that is both radioactive and fluorescent. This feasibility study aimed to evaluate the value of a multimodal-based SN biopsy in vulvar cancer. MATERIALS AND METHODS Fifteen patients with vulvar cancer (29 groins) scheduled for SN biopsy were peritumorally injected with ICG-(99m)Tc-nanocolloid followed by lymphoscintigraphy and SPECT/CT imaging to identify the SNs. In thirteen patients, shortly before the start of the operation, blue dye was intradermally injected around the lesion. SNs were harvested using a combination of radiotracing, fluorescence imaging, and optical blue dye detection. A portable gamma camera was used before and after SN excision to confirm excision of the preoperatively defined SNs. RESULTS Preoperative lymphoscintigraphy and SPECT/CT imaging visualized drainage to 39 SNs in 28 groins. During the operation, 98% (ex vivo 100%) of the SNs were radioactive. With fluorescence imaging 96% of the SNs (ex vivo 100%) could be visualized. Only 65% of the SNs had stained blue at the time of excision. CONCLUSION ICG-(99m)Tc-nanocolloid can be used for preoperative SN identification and enables multimodal (radioactive and fluorescent) surgical guidance in patients with vulvar cancer. The addition of fluorescence-based optical guidance offers more effective SN visualization compared to blue dye.

Advances in sentinel node dissection in prostate cancer from a technical perspective.

The most important feature of sentinel node biopsy for prostate cancer procedure is that staging can be improved. Sentinel nodes might be found outside the extended pelvic lymph node dissection template what renders the sentinel node additive of extended pelvic lymph node dissection. At the same time, staging within the template can be further refined. We reviewed the literature regarding the sentinel node biopsy procedure for prostate cancer. PubMed and Embase were searched for all English‐language publications from January 1999 to September 2014 by using the keywords as “prostate cancer” and “sentinel lymph node” plus “biopsy” “dissection” and/or “procedure.” The present review discusses step‐by‐step sentinel node biopsy for prostate cancer. Topics of discussion are: (i) preoperative sentinel node mapping (tracers and imaging); (ii) intraoperative sentinel node identification (surgical procedure and outcome); and (iii) novelties to improve sentinel node identification (pre‐ and intraoperative approaches). Conventional sentinel node mapping is carried out after the injection of a 99mTc‐based tracer and subsequent preoperative imaging; for example, lymphoscintigraphy and single‐photon emission computed tomography/computed tomography. This approach allowed the detection of sentinel nodes outside the extended lymph node dissection template in 3.6–36% of men with intermediate‐ and high‐risk prostate cancer. Hereby, an overall false negative rate of sentinel nodes was reported between 0% and 24.4%. To further refine the intraoperative sampling procedure, novel imaging methods such as fluorescence imaging have been introduced. Prospective randomized comparison studies are required to confirm the added benefit of sentinel template directed nodal dissection. A proper and obtainable end‐point of such a study could be the number of removed positive nodes for carrying out nodal dissection with or without sentinel template directed dissection. Similarly, the clinical impact of novel imaging technologies requires further investigation.

Toward (Hybrid) Navigation of a Fluorescence Camera in an Open Surgery Setting

With the introduction of the hybrid tracer indocyanine green (ICG)-99mTc-nanocolloid, a direct relation between preoperative imaging and intraoperative fluorescence guidance was established. However, fluorescence guidance remains limited by its superficial nature. This study evaluated the feasibility of a nuclear medicine–based navigation concept that allowed intraoperative positioning of a fluorescence camera (FC) in the vicinity of preoperatively defined ICG-99mTc-nanocolloid containing sentinel nodes (SNs). Methods: Five patients with penile cancer scheduled for SN biopsy were injected with ICG-99mTc-nanocolloid followed by preoperative SPECT/CT imaging. The navigation device was used to provide a real-time augmented reality overlay of the SPECT/CT images and video output of the FC. This overlay was then used for FC navigation. Results: SPECT/CT identified 13 SNs in 9 groins. FC navigation was successful for all 12 intraoperatively evaluated SNs (average error, 8.8 mm; range, 0–20 mm). Conclusion: This study reveals the potential benefits of FC navigation during open surgery procedures.

Introducing navigation during melanoma-related sentinel lymph node procedures in the head-and-neck region

BackgroundIntraoperative sentinel node (SN) identification in patients with head-and-neck malignancies can be challenging due to unexpected drainage patterns and anatomical complexity. Here, intraoperative navigation-based guidance technologies may provide outcome. In this study, gamma camera-based freehandSPECT was evaluated in combination with the hybrid tracer ICG-99mTc-nanocolloid.Materials and methodsEight patients with melanoma located in the head-and-neck area were included. Indocyanine green (ICG)-99mTc-nanocolloid was injected preoperatively, whereafter lymphoscintigraphy and SPECT/CT imaging were performed in order to define the location of the SN(s). FreehandSPECT scans were generated in the operation room using a portable gamma camera. For lesion localization during surgery, freehandSPECT scans were projected in an augmented reality video-view that was used to spatially position a gamma-ray detection probe. Intraoperative fluorescence imaging was used to confirm the accuracy of the navigation-based approach and identify the exact location of the SNs.ResultsPreoperatively, 15 SNs were identified, of which 14 were identified using freehandSPECT. Navigation towards these nodes using the freehandSPECT approach was successful in 13 nodes. Fluorescence imaging provided optical confirmation of the navigation accuracy in all patients. In addition, fluorescence imaging allowed for the identification of (clustered) SNs that could not be identified based on navigation alone.ConclusionsThe use of gamma camera-based freehandSPECT aids intraoperative lesion identification and, with that, supports the transition from pre- to intraoperative imaging via augmented reality display and directional guidance.

Multispectral Fluorescence Imaging During Robot-assisted Laparoscopic Sentinel Node Biopsy: A First Step Towards a Fluorescence-based Anatomic Roadmap

BACKGROUND During (robot-assisted) sentinel node (SN) biopsy procedures, intraoperative fluorescence imaging can be used to enhance radioguided SN excision. For this combined pre- and intraoperative SN identification was realized using the hybrid SN tracer, indocyanine green-99mTc-nanocolloid. Combining this dedicated SN tracer with a lymphangiographic tracer such as fluorescein may further enhance the accuracy of SN biopsy. OBJECTIVE Clinical evaluation of a multispectral fluorescence guided surgery approach using the dedicated SN tracer ICG-99mTc-nanocolloid, the lymphangiographic tracer fluorescein, and a commercially available fluorescence laparoscope. DESIGN, SETTING, AND PARTICIPANTS Pilot study in ten patients with prostate cancer. Following ICG-99mTc-nanocolloid administration and preoperative lymphoscintigraphy and single-photon emission computed tomograpy imaging, the number and location of SNs were determined. Fluorescein was injected intraprostatically immediately after the patient was anesthetized. A multispectral fluorescence laparoscope was used intraoperatively to identify both fluorescent signatures. SURGICAL PROCEDURE Multispectral fluorescence imaging during robot-assisted radical prostatectomy with extended pelvic lymph node dissection and SN biopsy. MEASUREMENTS (1) Number and location of preoperatively identified SNs. (2) Number and location of SNs intraoperatively identified via ICG-99mTc-nanocolloid imaging. (3) Rate of intraoperative lymphatic duct identification via fluorescein imaging. (4) Tumor status of excised (sentinel) lymph node(s). (5) Postoperative complications and follow-up. RESULTS AND LIMITATIONS Near-infrared fluorescence imaging of ICG-99mTc-nanocolloid visualized 85.3% of the SNs. In 8/10 patients, fluorescein imaging allowed bright and accurate identification of lymphatic ducts, although higher background staining and tracer washout were observed. The main limitation is the small patient population. CONCLUSION Our findings indicate that a lymphangiographic tracer can provide additional information during SN biopsy based on ICG-99mTc-nanocolloid. The study suggests that multispectral fluorescence image-guided surgery is clinically feasible. PATIENT SUMMARY We evaluated the concept of surgical fluorescence guidance using differently colored dyes that visualize complementary features. In the future this concept may provide better guidance towards diseased tissue while sparing healthy tissue, and could thus improve functional and oncologic outcomes.

Hybrid radioguided occult lesion localization (hybrid ROLL) of 18F-FDG-avid lesions using the hybrid tracer indocyanine green-99mTc-nanocolloid

PURPOSE To assess if combined fluorescence- and radio-guided occult lesion localization (hybrid ROLL) is feasible in patients scheduled for surgical resection of non-palpable (18)F-FDG-avid lesions on PET/CT. METHODS Four patients with (18)F-FDG-avid lesions on follow-up PET/CT that were not palpable during physical examination but were suspected to harbor metastasis were enrolled. Guided by ultrasound, the hybrid tracer indocyanine green (ICG)-(99m)Tc-nanocolloid was injected centrally in the target lesion. SPECT/CT imaging was used to confirm tracer deposition. Intraoperatively, lesions were localized using a hand-held gamma ray detection probe, a portable gamma camera, and a fluorescence camera. After excision, the gamma camera was used to check the wound bed for residual activity. RESULTS A total of six (18)F-FDG-avid lymph nodes were identified and scheduled for hybrid ROLL. Comparison of the PET/CT images with the acquired SPECT/CT after hybrid tracer injection confirmed accurate tracer deposition. No side effects were observed. Combined radio- and fluorescence-guidance enabled localization and excision of the target lesion in all patients. Five of the six excised lesions proved tumor-positive at histopathology. CONCLUSION The hybrid ROLL approach appears to be feasible and can facilitate the intraoperative localization and excision of non-palpable lesions suspected to harbor tumor metastases. In addition to the initial radioguided detection, the fluorescence component of the hybrid tracer enables high-resolution intraoperative visualization of the target lesion. The procedure needs further evaluation in a larger cohort and wider range of malignancies to substantiate these preliminary findings.

Fluorescent lectins for local in vivo visualization of peripheral nerves.

Damage to peripheral nerves caused during a surgical intervention often results in function loss. Fluorescence imaging has the potential to improve intraoperative identification and preservation of these structures. However, only very few nerve targeting agents are available. This study describes the in vivo nerve staining capabilities of locally administered fluorescent lectin-analogues. To this end WGA, PNA, PHA-L and LEL were functionalized with Cy5 (λex max 640 nm; λem max 680 nm). Transfer of these imaging agents along the sciatic nerve was evaluated in Thy1-YFP mice (n = 12) after intramuscular injection. Migration from the injection site was assessed in vivo using a laboratory fluorescence scanner and ex vivo via fluorescence confocal microscopy. All four lectins showed retrograde movement and staining of the epineurium with a signal-to-muscle ratio of around two. On average, the longest transfer distance was obtained with WGA-Cy5 (0.95 cm). Since WGA also gave minimal uptake in the lymphatic system, this lectin type revealed the highest potential as a migration imaging agent to visualize nerves.

Multimodal imaging in radioguided surgery

Radioguided surgery (RGS) utilizes radiolabeled tracers that accumulate in the lesion of interest following local or systemic administration. RGS is an expanding surgical guidance technology, but unfortunately most currently available radiotracers are unable to provide intraoperative optical information regarding the location of the lesion. In 2011, a new hybrid tracer (both radioactive and fluorescent) was introduced for sentinel lymph node detection. This hybrid tracer (indocyanine green-99mTc-nanocolloid) has helped to generate a new hybrid surgical guidance concept, thereby expanding the traditional RGS-based approach. Based on its radioactive signature a hybrid tracer is able to preserve the “traditional” role for RGS. Furthermore, as an additional tool in the operating room, a hybrid tracer provides optical information via fluorescence guidance. This review discusses the most common RGS approaches. Different clinically used radioactive tracers and their potential hybrid derivatives are also discussed. Furthermore, the various imaging devices designed for radioactivity-based detection are reviewed in the context of generating hybrid-imaging modalities.

Diffusion-weighted-preparation (D-prep) MRI as a future extension of SPECT/CT based surgical planning for sentinel node procedures in the head and neck area?

PURPOSE Even when guided by SPECT/CT planning of nodal resection in the head-and-neck area is challenging due to the many critical anatomical structures present within the surgical field. In this study the potential of a (SPECT/)MRI-based surgical planning method was explored. Hereby MRI increases the identification of SNs within clustered lymph nodes (LNs) and vital structures located adjacent to the SN (such as cranial nerve branches). METHOD AND PATIENTS SPECT/CT and pathology reports from 100 head-and-neck melanoma and 40 oral cavity cancer patients were retrospectively assessed for SN locations in levels I-V and degree of nodal clustering. A diffusion-weighted-preparation magnetic resonance neurography (MRN) sequence was used in eight healthy volunteers to detect LNs and peripheral nerves. RESULTS In 15% of patients clustered nodes were retrospectively shown to be present at the location where the SN was identified on SPECT/CT (level IIA: 37.2%, level IIB: 21.6% and level III: 15.5%). With MRN, improved LN delineation enabled discrimination of individual LNs within a cluster. Uniquely, this MRI technology also provided insight in LN distribution (23.2±4 LNs per subject) and size (range 21-372mm(3)), and enabled non-invasive assessment of anatomical variances in the location of the LNs and facial nerves. CONCLUSION Diffusion-weighted-preparation MRN enabled improved delineation of LNs and their surrounding delicate anatomical structures in the areas that most often harbor SNs in the head-and-neck. Based on our findings a combined SPECT/MRI approach is envisioned for future surgical planning of complex SN resections in this region.