Background: Sentinel lymph node biopsy (SLNB) has been introduced as a diagnostic staging modality for detection of occult metastases in patients with early stage oral cancer. Comparisons regarding accuracy to the routinely used elective neck dissection (END) are lacking in literature. Methods: A retrospective, multicenter cohort study included 390 patients staged by END and 488 by SLNB. Results: The overall sensitivity (84% vs. 81%, p = 0.612) and negative predictive value (NPV) (93%, p = 1.000) were comparable between END and SLNB patients. The END cohort contained more pT2 tumours (51%) compared to the SLNB cohort (23%) (p < 0.001). No differences were found for sensitivity and NPV between SLNB and END divided by pT stage. In floor-of-mouth (FOM) tumours, SLNB had a lower sensitivity (63% vs. 92%, p = 0.006) and NPV (90% vs. 97%, p = 0.057) compared to END. Higher disease-specific survival (DSS) rates were found for pT1 SLNB patients compared to pT1 END patients (96% vs. 90%, p = 0.048). Conclusion: In the absence of randomized clinical trials, this study provides the highest available evidence that, in oral cancer, SLNB is as accurate as END in detecting occult lymph node metastases, except for floor-of-mouth tumours.

Introduction: Nowadays, two strategies are available for the management of the clinically negative neck in early-stage (cT1-2N0) oral squamous cell carcinoma (OSCC): elective neck dissection (END) and sentinel lymph node biopsy (SLNB). SLNB stages both the ipsilateral and the contralateral neck in early-stage OSCC patients, whereas the contralateral neck is generally not addressed by END in early-stage OSCC not involving the midline. This study compares both incidence and hazard of contralateral regional recurrences (CRR) in those patients who underwent END or SLNB.Materials and Methods: A retrospective multicenter cohort study, including 816 lateralized or paramedian early-stage OSCC patients, staged by either unilateral or bilateral END (n = 365) or SLNB (n = 451).Results: The overall rate of occult contralateral nodal metastasis was 3.7% (30/816); the incidence of CRR was 2.5% (20/816). Patients who underwent END developed CRR during follow-up more often than those who underwent SLNB (3.8 vs. 1.3%; p = 0.018). Moreover, END patients had a higher hazard for developing CRR than SLNB patients (HR = 2.585; p = 0.030). In addition, tumor depth of invasion was predictive for developing CRR (HR = 1.922; p = 0.009). Five-year disease-specific survival in patients with CRR was poor (42%) compared to patients in whom occult contralateral nodal metastases were detected by SLNB or bilateral END (88%), although not statistically different (p = 0.066).Conclusion: Our data suggest that SLNB allows for better control of the contralateral clinically negative neck in patients with lateralized or paramedian early-stage OSCC, compared to END as performed in a clinical setting. The prognosis of those in whom occult contralateral nodal metastases are detected at an earlier stage may be favorable compared to those who eventually develop CRR, which highlights the importance of adequate staging of the contralateral clinically negative neck.

αβ integrins play an important role in angiogenesis and cell migration in cancer and are highly expressed on the activated endothelial cells of newly formed blood vessels. Here, we compare the targeting characteristics of 4 Ga-labeled multimeric cyclic arginine-glycine-aspartate (RGD)-based tracers in an αβ integrin-expressing tumor model and a tumor model in which αβ integrin is expressed solely on the neovasculature. Female BALB/c nude mice were subcutaneously injected with SK-RC-52 (αβ integrin-positive) or FaDu (αβ integrin-negative) tumor cells. Ga-labeled DOTA-(RGD), TRAP-(RGD), FSC-(RGD), or THP-(RGD) was intravenously administered to the mice (0.5 nmol per mouse, 10-20 MBq), followed by small-animal PET/CT imaging and ex vivo biodistribution studies 1 h after injection. Nonspecific uptake of the tracers in both models was determined by coinjecting an excess of unlabeled DOTA-(RGD) (50 nmol) along with the radiolabeled tracers. Imaging and biodistribution data showed specific uptake in the tumors for each tracer in both models. Tumor uptake ofGa-FSC-(RGD) was significantly higher than that of Ga-DOTA-(RGD), Ga-TRAP-(RGD), or Ga-THP-(RGD) in the SK-RC-52 model but not in the FaDu model, in which Ga-FSC-(RGD) showed significantly higher tumor uptake than Ga-TRAP-(RGD) Most importantly, differences were also observed in normal tissues and in tumor-to-blood ratios. All tracers showed sufficient targeting of αβ integrin expression to allow for tumor detection. Although the highest tumor uptake was found for Ga-FSC-(RGD) and Ga-THP-(RGD) in the SK-RC-52 and FaDu models, respectively, selection of the optimal tracer for specific diagnostic applications also depends on tumor-to-blood ratio and uptake in normal tissues; these factors should therefore also be considered.

Purpose Angiogenesis plays an important role in the growth and metastatic spread of solid tumours and is characterised by the expression of integrins on the cell surface of endothelial cells. Radiolabelled RGD peptides specifically target angiogenesis-related α v β 3 integrins, expressed on the activated endothelial cells of sprouting blood vessels. Here, we validated the feasibility of 68 Ga[Ga]-DOTA-E-[c(RGDfK)] 2 (68 Ga-RGD) PET/CT to visualise angiogenesis in patients with oral squamous cell carcinoma (OSCC). Methods Ten patients with OSCC and scheduled for surgical resection including elective neck dissection received an intravenously administration of 68 Ga-RGD (42 ± 8 μg; 214 ± 9 MBq). All patients subsequently underwent dynamic (n = 5) or static PET/CT imaging (n = 5) for 60 min or for 4 min/bed position at 30, 60 and 90 min after injection, respectively. Quantitative tracer uptake in tumour lesions was expressed as standardised uptake values (SUV). Additionally, tumour tissue was immunohistochemically stained for α v β 3 integrin to assess the expression pattern. Results 68 Ga-RGD tumour accumulation was observed in all patients. At 60 min post injection, tumour SUV max ranged between 4.0 and 12.7. Tracer accumulation in tumour tissue plateaued at 10 min after injection. Uptake in background tissue did not change over time, resulting in tumour-to-muscle tissue of 6.4 ± 0.7 at 60 min post injection. Conclusions 68 Ga-RGD PET/CT of α v β 3 integrin expression in OSCC patients is feasible with adequate tumour-to-background ratios. It will provide more insight in angiogenesis as a hallmark of the head and neck squamous cell carcinomas' tumour microenvironment. Trial registration https://eudract.ema.europa.eu no. 2015-000917-31 Keywords RGD-PET/CT. Angiogenesis. Squamous cell carcinoma. Head and neck cancer. α v β 3 integrin This article is part of the Topical Collection on Oncology-Head and Neck Electronic supplementary material The online version of this article (

Purpose In this phase I study, we evaluated the safety, biodistribution and dosimetry of [89Zr]Zr-DFO-girentuximab (89Zr-girentuximab) PET/CT imaging in patients with suspicion of clear cell renal cell carcinoma (ccRCC). Methods Ten eligible patients received an intravenous administration of 37 MBq (± 10%) of 89Zr-girentuximab at mass doses of 5 mg or 10 mg. Safety was evaluated according to the NCI CTCAE (version 4.03). Biodistribution and normal organ dosimetry was performed based on PET/CT images acquired at 0.5, 4, 24, 72 and 168 h post-administration. Additionally, tumour dosimetry was performed in patients with confirmed ccRCC and visible tumour uptake on PET/CT imaging. Results 89Zr-girentuximab was administered in ten patients as per protocol. No treatment-related adverse events ≥ grade 3 were reported. 89Zr-girentuximab imaging allowed successful differentiation between ccRCC and non-ccRCC lesions in all patients, as confirmed with histological data. Dosimetry analysis using OLINDA/EXM 2.1 showed that the organs receiving the highest doses (mean ± SD) were the liver (1.86 ± 0.40 mGy/MBq), the kidneys (1.50 ± 0.22 mGy/MBq) and the heart wall (1.45 ± 0.19 mGy/MBq), with a mean whole body effective dose of 0.57 ± 0.08 mSv/MBq. Tumour dosimetry was performed in the 6 patients with histologically confirmed ccRCC resulting in a median tumour-absorbed dose of 4.03 mGy/MBq (range 1.90–11.6 mGy/MBq). Conclusions This study demonstrates that 89Zr-girentuximab is safe and well tolerated for the administered activities and mass doses and allows quantitative assessment of 89Zr-girentuximab PET/CT imaging in patients with suspicion of ccRCC. Trial registration NCT03556046—14th of June, 2018

A Clinical Feasibility Study to Image Angiogenesis in Patients with Arteriovenous http://jnm.snmjournals.org/content/61/2/270 This article and updated information are available at: http://jnm.snmjournals.org/site/subscriptions/online.xhtml Information about subscriptions to JNM can be found at: http://jnm.snmjournals.org/site/misc/permission.xhtml

Purpose This study aimed to elucidate whether muscle activity (in terms of glucose uptake) between the legs can be considered symmetrical during walking. Furthermore, we aimed to determine whether the [ 18 F]-fluorodeoxyglucose was distributed heterogeneously throughout each muscle, and if so, whether areas of high uptake would be clustered. Methods Ten healthy participants walked on a treadmill at self-selected comfortable walking speed for a total of 90 minutes, 60 minutes before and 30 minutes after intravenous injection of 50 MBq [ 18 F]-fluorodeoxyglucose. Thereafter, a positron emission tomography/computed tomography scan of the lower limb was acquired. Three-dimensional muscle contours of 78 (= 39x2) muscles of the left and right lower limb were semi-automatically determined from magnetic resonance imaging scans. After non-rigid registration, those muscle contours were used to extract [ 18 F]-fluorodeoxyglucose uptake from the positron emission tomography scans. Results Large asymmetries were observed in the lower leg muscles (e.g. median absolute asymmetry index of 42% in the gastrocnemius medialis) and in the gluteus minimus (30% asymmetry) and gluteus medius (15% asymmetry), whereas the uptake in the thighs was relatively symmetrical between the limbs (<6% asymmetry). These were not related to limb-dominance nor to inter-limb differences in muscle volume. The [ 18 F]-fluorodeoxyglucose distribution was not distributed normally; most voxels had a relatively low standardized uptake value, and a minority of voxels had a relatively high standardized uptake value. The voxels with higher [ 18 F]-fluorodeoxyglucose uptake were distributed heterogeneously; they were clustered in virtually all muscles. Conclusion The findings in this study challenge the common assumption of symmetry in muscle activity between the limbs in healthy subjects. The clustering of voxels with high uptake suggests that even in this prolonged repetitive task, different spatial regions of muscles contribute differently to walking than others.

Background Transarterial radioembolization (TARE) is a treatment modality for liver tumors during which radioactive microspheres are injected into the hepatic arterial system. These microspheres distribute throughout the liver as a result of the blood flow until they are trapped in the arterioles because of their size. Holmium‐166 (166Ho)‐loaded microspheres used for TARE can be visualized and quantified with MRI, as holmium is a paramagnetic metal and locally increases the transverse relaxation rate R2∗$R_2^*$. The current 166Ho quantification method does not take regional differences in baseline R2∗$R_2^*$ values (such as between tumors and healthy tissue) into account, which intrinsically results in a systematic error in the estimated absorbed dose distribution. As this estimated absorbed dose distribution can be used to predict response to treatment of tumors and potential toxicity in healthy tissue, a high accuracy of absorbed dose estimation is required. Purpose To evaluate pre‐existing differences in R2∗$R_2^*$ distributions between tumor tissue and healthy tissue and assess the feasibility and accuracy of voxelwise subtraction‐based normalΔR2∗$\Delta R_2^*$ calculation for MRI‐based dosimetry of holmium‐166 transarterial radioembolization (166Ho TARE). Methods MRI data obtained in six patients who underwent 166Ho TARE of the liver as part of a clinical study was retrospectively evaluated. Pretreatment differences in R2∗$R_2^*$ distributions between tumor tissue and healthy tissue were characterized. Same‐day pre‐ and post‐treatment R2∗$R_2^*$ maps were aligned using a deformable registration algorithm and subsequently subtracted to generate voxelwise normalΔR2∗$\Delta R_2^*$ maps and resultant absorbed dose maps. Image registration accuracy was quantified using the dice similarity coefficient (DSC), relative overlay (RO), and surface dice (≤4 mm; SDSC). Voxelwise subtraction‐based absorbed dose maps were quantitatively (root‐mean‐square error, RMSE) and visually compared to the current MRI‐based mean subtraction method and routinely used SPECT‐based dosimetry. Results Pretreatment R2∗$R_2^*$ values were lower in tumors than in healthy liver tissue (mean 36.8 s−1 vs. 55.7 s−1, P = 0.004). Image registration improved the mean DSC of 0.83 (range: 0.70–0.88) to 0.95 (range: 0.92–0.97), mean RO of 0.71 (range 0.53–0.78) to 0.90 (range: 0.86–0.94), and mean SDSC ≤4 mm of 0.47 (range: 0.28–0.67) to 0.97 (range: 0.96–0.98). Voxelwise subtraction‐based absorbed dose maps yielded a higher tumor‐absorbed dose (median increase of 9.0%) and lower healthy liver‐absorbed dose (median decrease of 13.8%) compared to the mean subtraction method. Voxelwise subtraction‐based absorbed dose maps corresponded better to SPECT‐based absorbed dose maps, reflected by a lower RMSE in three of six patients. Conclusions Voxelwise subtraction presents a robust alternative method for MRI‐based dosimetry of 166Ho microspheres that accounts for pre‐existing R2∗$R_2^*$ differences, and appears to correspond better with SPECT‐based...