Renato A. Valdés Olmos

A Hybrid Radioactive and Fluorescent Tracer for Sentinel Node Biopsy in Penile Carcinoma as a Potential Replacement for Blue Dye

BACKGROUNDnSentinel node (SN) biopsy in penile cancer is typically performed using a combination of radiocolloid and blue dye. Recently, the hybrid radioactive and fluorescent tracer indocyanine green (ICG)-(99m)Tc-nanocolloid was developed to combine the beneficial properties of both radio-guidance and fluorescence imaging.nnnOBJECTIVEnTo explore the added value of SN biopsy using ICG-(99m)Tc-nanocolloid in patients with penile carcinoma.nnnDESIGN, SETTING, AND PARTICIPANTSnSixty-five patients with penile squamous cell carcinoma were prospectively included (January 2011 to December 2012). Preoperative SN mapping was performed using lymphoscintigraphy and single-proton emission computed tomography supplemented with computed tomography (SPECT/CT) after peritumoural injection of ICG-(99m)Tc-nanocolloid. During surgery, SNs were initially approached using a gamma probe, followed by patent blue dye and/or fluorescence imaging. A portable gamma camera was used to confirm excision of all SNs.nnnSURGICAL PROCEDUREnPatients underwent SN biopsy of the cN0 groin and treatment of the primary tumour.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnThe number and location of preoperatively identified SNs were documented. Intraoperative SN identification rates using radio- and/or fluorescence guidance were assessed and compared with blue dye. Statistical evaluation was performed using a two-sample test for equality of proportions with continuity correction.nnnRESULTS AND LIMITATIONSnPreoperative imaging after injection of ICG-(99m)Tc-nanocolloid enabled SN identification in all patients (a total of 183 SNs dispersed over 119 groins). Intraoperatively, all SNs identified by preoperative SN mapping were localised using combined radio-, fluorescence-, and blue dye guidance. Fluorescence imaging enabled visualisation of 96.8% of SNs, while only 55.7% was stained by blue dye (p<0.0001). The tissue penetration of the fluorescent signal, and the rapid flow of blue dye limited the detection sensitivity. A tumour-positive SN was found in seven patients.nnnCONCLUSIONSnICG-(99m)Tc-nanocolloid allows for both preoperative SN mapping and combined radio- and fluorescence-guided SN biopsy in penile carcinoma patients and significantly improves optical SN detection compared with blue dye.

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

BACKGROUNDnThe hybrid tracer was introduced to complement intraoperative radiotracing towards the sentinel nodes (SNs) with fluorescence guidance.nnnOBJECTIVEnImprove in vivo fluorescence-based SN identification for prostate cancer by optimising hybrid tracer preparation, injection technique, and fluorescence imaging hardware.nnnDESIGN, SETTING, AND PARTICIPANTSnForty 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.nnnINTERVENTIONnHybrid tracer-based SN biopsy, extended pelvic lymph node dissection, and robot-assisted radical prostatectomy.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnNumber 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).nnnRESULTS AND LIMITATIONSnMean 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.nnnCONCLUSIONSnStepwise 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.nnnPATIENT SUMMARYnIntraoperative fluorescence-based SN visualisation can be improved by enhancing the hybrid tracer formulation and laparoscopic fluorescence imaging system.

Optical imaging as an expansion of nuclear medicine: Cerenkov-based luminescence vs fluorescence-based luminescence

Integration of optical imaging technologies can further strengthen the field of radioguided surgery. Rather than using two separate chemical entities to achieve this extension, hybrid imaging agents can be used that contain both radionuclear and optical properties. Two types of such hybrid imaging agents are available: (1) hybrid imaging agents generated by Cerenkov luminescence imaging (CLI) of β-emitters and (2) hybrid imaging agents that contain both a radioactive moiety and a fluorescent dye. One major challenge clinicians are now facing is to determine the potential value of these approaches. With this tutorial review we intend to clarify the differences between the two approaches and highlight the clinical potential of hybrid imaging during image-guided surgery applications.

The EANM clinical and technical guidelines for lymphoscintigraphy and sentinel node localization in gynaecological cancers

The accurate harvesting of a sentinel node in gynaecological cancer (i.e. vaginal, vulvar, cervical, endometrial or ovarian cancer) includes a sequence of procedures with components from different medical specialities (nuclear medicine, radiology, surgical oncology and pathology). These guidelines are divided into sectione entitled: Purpose, Background information and definitions, Clinical indications and contraindications for SLN detection, Procedures (in the nuclear medicine department, in the surgical suite, and for radiation dosimetry), and Issues requiring further clarification. The guidelines were prepared for nuclear medicine physicians. The intention is to offer assistance in optimizing the diagnostic information that can currently be obtained from sentinel lymph node procedures. If specific recommendations given cannot be based on evidence from original scientific studies, referral is made to “general consensus” and similar expressions. The recommendations are designed to assist in the practice of referral to, and the performance, interpretation and reporting of all steps of the sentinel node procedure in the hope of setting state-of-the-art standards for high-quality evaluation of possible metastatic spread to the lymphatic system in gynaecological cancer. The final result has been discussed by a group of distinguished experts from the EANM Oncology Committee and the European Society of Gynaecological Oncology (ESGO). The document has been endorsed by the SNMMI Board.

Feasibility of Intraoperative Navigation to the Sentinel Node in the Groin Using Preoperatively Acquired Single Photon Emission Computerized Tomography Data: Transferring Functional Imaging to the Operating Room

PURPOSEnWe explored the clinical feasibility and accuracy of intraoperative navigation based on preoperatively acquired 3-dimensional functional imaging data.nnnMATERIALS AND METHODSnTen patients with penile carcinoma scheduled for sentinel node biopsy were prospectively included in study. After tracer injection preoperative single photon emission computerized tomography/computerized tomography was performed with a reference target fixed on the patient. Repositioning a sterile reference target shortly before surgery allowed 3-dimensional single photon emission computerized tomography/computerized tomography mixed reality based navigation of the γ probe (also containing a reference target) to the sentinel node. The accuracy of the declipse®SPECT navigation approach was determined in relation to the incision site indicated by the conventional γxa0probe in the coronal plane and the depth estimation measured on axial computerized tomography slices in the sagittal/axial plane.nnnRESULTSnThe 3-dimensional mixed reality approach enabled γ probe navigation toward the sentinel node in all 10 patients. The average ± SD navigation error inxa0the coronal and saggital/axial planes was 5.0 ± 3.9 and 5.3 ± 3.9 mm, respectively.nnnCONCLUSIONSnTo our knowledge this is the first study demonstrating the feasibility of intraoperative navigation based on preoperatively acquired 3-dimensional single photon emission computerized tomography/computerized tomography images. Although confirmation of successful target localization (egxa0using γ tracing orxa0fluorescence imaging) remains indispensable, this opens the way to translate 3-dimensional functional imaging data to the operating room.

Sentinel Node Procedure in Prostate Cancer: A Systematic Review to Assess Diagnostic Accuracy

CONTEXTnExtended pelvic lymph node dissection (ePLND) is the gold standard for detecting lymph node (LN) metastases in prostate cancer (PCa). The benefit of sentinel node biopsy (SNB), which is the first draining LN as assessed by imaging of locally injected tracers, remains controversial.nnnOBJECTIVEnTo assess the diagnostic accuracy of SNB in PCa.nnnEVIDENCE ACQUISITIONnA systematic literature search of Medline, Embase, and the Cochrane Library (1999-2016) was undertaken using PRISMA guidelines. All studies of SNB in men with PCa using PLND as reference standard were included. The primary outcomes were the nondiagnostic rate (NDR), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and false positive (FP) and false negative (FN) rates. Relevant sensitivity analyses based on SN definitions, ePLND as reference standard, and disease risk were undertaken, including a risk of bias (RoB) assessment.nnnEVIDENCE SYNTHESISnOf 373 articles identified, 21 studies recruiting a total of 2509 patients were eligible for inclusion. Median cumulative percentage (interquartile range) results were 4.1% (1.5-10.7%) for NDR, 95.2% (81.8-100%) for sensitivity, 100% (95.0-100%) for specificity, 100% (87.0-100%) for PPV, 98.0% (94.3-100%) for NPV, 0% (0-5.0%) for the FP rate, and 4.8% (0-18.2%) for the FN rate. The findings did not change significantly on sensitivity analyses. Most studies (17/22) had low RoB for index test and reference standard domains.nnnCONCLUSIONSnSNB appears to have diagnostic accuracy comparable to ePLND, with high sensitivity, specificity, PPV and NPV, and a low FN rate. With a low FP rate (rate of detecting positive nodes outside the ePLND template), SNB may not have any additional diagnostic value over and above ePLND, although SNB appears to increase nodal yield by increasing the number of affected nodes when combined with ePLND. Thus, in high-risk disease it may be prudent to combine ePLND with SNB.nnnPATIENT SUMMARYnThis literature review showed a high diagnostic accuracy for sentinel node biopsy in detecting positive lymph nodes in prostate cancer, but further studies are needed to explore the effect of sentinel node biopsy on complications and oncologic outcome.

Fluorescence guided surgery and tracer-dose, fact or fiction?

IntroductionFluorescence guidance is an upcoming methodology to improve surgical accuracy. Challenging herein is the identification of the minimum dose at which the tracer can be detected with a clinical-grade fluorescence camera. Using a hybrid tracer such as indocyanine green (ICG)-99mTc-nanocolloid, it has become possible to determine the accumulation of tracer and correlate this to intraoperative fluorescence-based identificationxa0rates. In the current study, we determined the lower detection limit of tracer at which intraoperative fluorescence guidance was still feasible.MethodsSize exclusion chromatography (SEC) provided a laboratory set-up to analyze the chemical content and to simulate the migratory behavior of ICG-nanocolloid in tissue. Tracer accumulation and intraoperative fluorescence detection findings were derived from a retrospective analysis of 20 head-and-neck melanoma patients, 40 penile and 20 prostate cancer patients scheduled for sentinel node (SN) biopsy using ICG-99mTc-nanocolloid. In these patients, following tracer injection, single photon emission computed tomography fused with computed tomography (SPECT/CT) was used to identify the SN(s). The percentage injected dose (% ID), the amount of ICG (in nmol), and thexa0concentration of ICG in the SNs (in μM) was assessed for SNs detected on SPECT/CT and correlated with the intraoperative fluorescence imaging findings.ResultsSEC determined that in the hybrid tracer formulation, 41xa0% (standard deviation: 12xa0%) of ICG was present in nanocolloid-bound form. In the SNs detected using fluorescence guidance a median of 0.88xa0% ID was present, compared to a median of 0.25xa0% ID in the non-fluorescent SNs (p-valueu2009<u20090.001). The % ID values could be correlated to the amount ICG in a SN (range: 0.003–10.8xa0nmol) and the concentration ofxa0ICG in a SN (range: 0.006–64.6xa0μM).DiscussionThe ability to provide intraoperative fluorescence guidance is dependent on the amount and concentration of the fluorescent dye accumulated in the lesion(s) of interest. Our findings indicate that intraoperative fluorescence detection with ICG is possible above a μM concentration.

Fluorescent radiocolloids: are hybrid tracers the future for lymphatic mapping?

The metastatic status of regional lymph nodes is one of the most significant prognostic factors in melanoma, breast cancer, and other solid tumours with lymphatic spread. After the seminal description of the modern sentinel lymph node (SLN) concept by Morton et al. [1], there have been a number of studies showing that the status of the SLN constitutes an accurate indicator of the status of the regional nodal basins [2–4]. Biopsy of the SLN has become the standard of care for melanoma and breast cancer patients with non-clinically detectable metastases and has improved the clinical outcome on morbidity and, potentially, mortality [5]. Preoperative identification of the SLNs has been traditionally performed using radiotracer injection, lymphoscintigraphy, and, more recently, single photon emission computed tomography combined with computed tomography (SPECT/CT) [6, 7]. Radiocolloids such as nanocolloid enable a high rate of SLN detection (more than 95 %), a convenient time window to locate the SLNs, and the possibility to map the lymphatic system preoperatively. Such an anatomical roadmap may be used to plan the optimal approach towards the SLNs before surgery and, subsequently, to recognize their location intraoperatively [8]. Up to 24 h after initial administration, the same radiotracers still allow for intraoperative identification with a hand-held gamma probe and/or a portable gamma camera [9]. The ability of radiocolloids to be retained in the SLNs for longer periods of time, in combination with high detection rates, is the reason for the success of this radioguidance approach. However, in spite of a high sensitivity, the radiotracer method has poor spatial resolution. As a result, when the SLNs are located within close proximity of the injection site, the activity emitted from the lymph nodes cannot be distinguished from the background signal (shine-through effect). This effect is particularly problematic in head and neck malignancies [10]. To provide visible feedback during the surgical excision radioguidance can be complemented by the use of vital dyes. The complementary use of blue dye, for instance, allows visual identification of the SLNs throughout the procedure. Thus, a majority of SLN procedures and their guidelines currently advise on the use of radiocolloids in combination with blue dyes [11]. By combining dyes with radiocolloids, the accuracy of SLN detection can be significantly improved [12, 13]. In this combined approach, the radiocolloids help to determine the initial location of the SLNs (which in part may be located too deep to be initially visible via dye staining), whereas the dye provides the visual feedback on the exact location on the node. Small organic compounds such as blue dyes are lymphangiographic agents that quickly migrate through the lymphatics, thereby yielding a real-time, but very superficial and short-period (30–45 min), feedback on the lymphatics. Blue dyes are easy to prepare as well as inject, but as a result of their superficial nature and quick diffusion, a percentage of SLNs in expected basins of drainage can be missed. For instance, in This Editorial Commentary refers to the article http://dx.doi.org/10.1007/ s00259-015-3093-7.

The sentinel node approach in gynaecological malignancies

This review discusses the state-of-the-art of sentinel lymph node mapping in gynaecological malignancies, including cervical cancer, endometrial cancer, and vulvar cancer, with an emphasis on new technological advances. For this objective, PubMed/MEDLINE was searched for relevant studies about the sentinel lymph node procedure in gynaecology. In particular, the use of preoperative lymphatic mapping with lymphoscintigraphy and single photon emission tomography/computed tomography (SPECT/CT) was identified in 18 studies. Other recent advances as hybrid tracers (e.g. ICG-99mTc-nanocolloid) and intraoperative tools (portable γ-camera and 3D navigation devices) appear to also represent a useful guide for the surgeon during the operation. Concerning vulvar and cervical cancers, the sentinel lymph node procedure has been incorporated to the current guidelines in Europe and North America, whereas for endometrial cancer it is considered investigative.

The use of SPECT/CT for anatomical mapping of lymphatic drainage in vulvar cancer: possible implications for the extent of inguinal lymph node dissection

PurposeTo determine the lymphatic drainage pattern using SPECT/CT in clinically node-negative (cN0) patients with vulvar cancer, and to evaluate the possible implications for the extent of inguinal lymph node dissection.MethodsA total of 83 patients with vulvar cancer scheduled for sentinel node (SN) biopsy were injected peritumorally with radioactive nanocolloid particles followed by lymphoscintigraphy and SPECT/CT for anatomical localization. The SN and higher-echelon nodes on SPECT/CT were located in different zones in the groin and pelvic region. The groin was divided into five zones according to Daseler et al.: four zones obtained by drawing two perpendicular lines over the saphenofemoral junction and one zone directly overlying this junction. The nodes in the pelvic region were classified into three zones: external iliac/obturator, the common iliac and the paraaortic zones.ResultsA total of 217 SNs and 202 higher-echelon nodes were localized on SPECT/CT. All SNs were located in the five zones according to Daseler et al.: 149 (69xa0%) in the medial superior region, 31 (14xa0%) in the medial inferior region, 22 (10xa0%) in the central region, 14 (6.5xa0%) in the lateral superior region and only 1 (0.5xa0%) in the lateral inferior region. The higher-echelon nodes were located both in the groin (15xa0%) and in the pelvic region (85xa0%).ConclusionIn patients with cN0 vulvar cancer, lymphatic drainage occurs predominantly to the medial regions of the groin. Drainage to the lateral inferior region of the groin is only incidental and in SN-positive patients this zone might be spared in subsequent extended lymph node dissection. This may lead to a decrease in the morbidity associated with this procedure. SPECT/CT is able to personalize lymphatic mapping, providing detailed information about the number and anatomical location of SNs for adequate surgical planning in the groin.