Achieving an optimal 131I absorbed dose in differentiated thyroid carcinoma lesions is crucial for the success of radioiodine therapy. Sufficient thyroid-stimulating hormone (TSH) stimulation before radioiodine therapy can be achieved with either thyroid hormone withdrawal (THW) or by injection of recombinant human TSH (rhTSH). We compared the predicted 131I lesion absorbed dose between THW and rhTSH stimulation in patients assessed by pretherapeutic 124I PET/CT dosimetry. Methods: This retrospective study included patients with differentiated thyroid carcinoma who had undergone total thyroidectomy with or without cervical lymph node dissection and had received 124I PET/CT lesion dosimetry. All patients underwent TSH stimulation with either rhTSH injection or THW. For lesion dosimetry, 2 124I PET/CT examinations were performed after 124I administration. Using 124I PET data, the lesion absorbed dose per unit of administered activity (LDpA) of 131I was calculated for each lesion. Patients and lesions were categorized by the TSH stimulation method used and the clinical indication for dosimetry (adjuvant, residual/recurrent, or metastatic disease). Lesions were further categorized by location (thyroid remnants, cervical lymph node metastases, or distant metastases). Results: In total, 453 dosimetry cycles and 949 lesions were analyzed in 367 patients. TSH levels were significantly higher after rhTSH stimulation in the overall patient group (P < 0.001) and across all subgroups (P = 0.038 for adjuvant; P = 0.002 for residual/recurrent; P < 0.001 for metastatic). Thyroglobulin levels were significantly elevated after rhTSH stimulation in both the overall patient group (P < 0.001) and the metastatic subgroup (P = 0.030). LDpA values were significantly higher after THW in the overall patient group (P < 0.001) and in the adjuvant subgroup (P = 0.049). LDpA values of thyroid remnants did not significantly differ between both stimulation methods. Conversely, LDpA values were significantly higher after THW in cervical lymph node (P = 0.005) and distant (P = 0.001) metastases. Conclusion: As assessed by pretherapeutic 124I PET/CT dosimetry, absorbed doses to metastatic lesions were higher after THW compared with rhTSH, whereas absorbed doses of thyroid remnants were comparable between both stimulation methods. In this interpatient comparison, data support the use of THW in patients with an elevated risk of metastatic disease; however, a large intrapatient study is warranted for further validation.

[131I]Metaiodobenzylguanidine (MIBG) therapy in patients with neural crest tumors has demonstrated sustained control of catecholamine-associated hypertension and corresponding partial response. Details on how neural crest tumors respond to an absorbed dose delivered by [131I]MIBG-targeted therapies is insufficiently known. The primary aim of this retrospective study was to assess the tumor dose-response relationship by means of quantitative analysis of [124I]MIBG PET data. Methods: The tumor dose-response relationship was studied in patients with advanced malignant pheochromocytoma, neuroblastoma, or paraganglioma receiving [131I]MIBG treatment, as well as pretherapeutic and follow-up [124I]MIBG-based dosimetry. [124I]MIBG PET imaging was performed around 4, 24, 48, and 120 h after injection. Lesion uptake was projected to [131I]MIBG for every time point, and respective time-integrated activity coefficients (TIACs) for [131I]MIBG were calculated and used for tumor-absorbed dose estimation. Functional response was denoted for decrease of maximal lesion uptake or TIAC by at least 30% in the follow-up examination. In a consecutive analysis, the predictive value of a single tumor-uptake assessment from PET imaging at 24 h after administration was investigated with respect to receiving the derived target dose. Results: In total, 46 lesions from 9 patients were available for dose-response analysis. The mean ± SD tumor-absorbed dose coefficient was 13.4 ± 15.4 Gy/GBq (median, 7.2 Gy/GBq; range, 1.1-64.7 Gy/GBq). A high correlation (-0.60, P < 0.001) was found between uptake decrease and tumor dose. In addition, a very high correlation (0.91, P < 0.001) was found between uptake and TIAC decrease. The estimated targeted tumor dose was 200 Gy, that is, the dose at which the response rate exceeded the 90% threshold. A single 24-h uptake assessment showed predictive value with respect to receiving the target dose. Conclusion: This study demonstrated a clear correlation between tumor-absorbed dose and functional response in [131I]MIBG therapy and proposes a target dose for response at the tumor level.

The 'Positron emission tomography-guided therapy of aggressive non-Hodgkin lymphomas' trial (PETAL; ClinicalTrials.gov NCT00554164) investigated whether treatment intensification after two cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; plus rituximab [R] for CD20-positive lymphomas) improved survival in aggressive non-Hodgkin lymphoma. A total of 754 patients (87.5%) had a negative and 108 (12.5%) had a positive interim PET scan. Interim PET-positive patients were randomly assigned to receive another 6 (R-)CHOP cycles or 6 blocks of a more intensive protocol. Interim PET-negative patients received another 4 cycles of R-CHOP with or without two additional doses of rituximab. After a median follow-up of four years, treatment intensification had not improved outcome. These results were confirmed after 10.3 years of follow-up. The present analysis also describes the management of relapse that was part of the study. Among 240 relapsing patients, 94 of 133 autologous transplantation-eligible patients (70.7%) and 16 of 107 ineligible patients (15.0%) received the salvage treatments recommended in the study protocol. Adherence to recommendations had no impact on outcome. Best results were seen after allogeneic transplantation, followed by autologous transplantation and treatment without transplantation (5-year overall survival rate, 64.3% versus 45.5% versus 22.6%), but patients undergoing allogeneic transplantation were significantly younger and their disease was well controlled at the time of transplantation. Early outcome prediction by interim PET, alone or in combination with other methods, is a powerful tool to investigate the value of immunological treatment options for patients with a poor response to chemotherapy.

Aim Positron emission tomography (PET) using 124 I-mIBG has been established for imaging and pretherapeutic dosimetry. Here, we report the first systematic analysis of the biodistribution and radiation dosimetry of 124 I-mIBG in patients with neural crest tumours and project the results to paediatric patient models. Methods Adult patients with neural crest tumours who underwent sequential 124 I-mIBG PET were included in this retrospective single-center analysis. PET data were acquired 4, 24, 48, and/or 120 h after administration of a mean of 43 MBq 124 I-mIBG. Whole-body counting and blood sampling were performed at 2, 4, 24, 48 and 120 h after administration. Absorbed organ dose and effective dose coefficients were estimated in OLINDA/EXM 2.2 according to the MIRD formalism. Extrapolation to paediatric models was performed based on mass-fraction scaling of the organ-specific residence times. Biodistribution data for adults were also projected to 123 I-mIBG and 131 I-mIBG. Results Twenty-one patients (11 females, 10 males) were evaluated. For adults, the organs exposed to the highest dose per unit administered activity were urinary bladder (1.54 ± 0.40 mGy/MBq), salivary glands (0.77 ± 0.28 mGy/MBq) and liver (0.65 ± 0.22 mGy/MBq). Mean effective dose coefficient for adults was 0.25 ± 0.04 mSv/MBq (male: 0.24 ± 0.03 mSv/MBq, female: 0.26 ± 0.06 mSv/MBq), and increased gradually to 0.29, 0.44, 0.69, 1.21, and 2.94 mSv/MBq for the 15-, 10-, 5-, 1-years-old, and newborn paediatric reference patients. Projected mean effective dose coefficients for 123 I-mIBG and 131 I-mIBG for adults were 0.014 ± 0.002 mSv/MBq and 0.18 ± 0.04 mSv/MBq, respectively. Conclusion PET-based derived radiation dosimetry data for 124 I-mIBG from this study agreed well with historical projected data from ICRP 53. The effective dose coefficients presented here may aid in guidance for establishing weight-based activity administration protocols.

Transarterial chemoembolization (TACE) is currently the standard of care in patients with unresectable hepatocellular carcinoma (HCC), and selective internal radionuclide therapy (SIRT) with 90Y microspheres is mainly used as an alternative modality in patients considered poor candidates for TACE. Treatment with sorafenib is the recommended option for patients with progressive disease after TACE. This study aims to evaluate the safety and efficacy of SIRT with glass microspheres in patients with progressive HCC after repeated TACE who are not eligible for treatment with sorafenib. Forty-seven patients with progressive HCC after a median of three TACE sessions (range 2–14) underwent SIRT (3.5 ± 1.5 GBq; liver target dose 110–120 Gy). Toxicity was recorded 4 and 12 weeks after treatment and reported according to the Common Terminology Criteria for Adverse Events Version 5.0. Treatment response was assessed three months after SIRT using multiphase computed tomography and modified criteria in solid tumors (mRECIST). Survival analyses were performed using Kaplan–Meier curves and a Cox proportional hazards model for uni- and multivariate analyses. Significant but reversible hepatotoxicity (≥grade 3) occurred in five patients (11%). No radioembolization-induced liver disease (REILD) was observed. The number of previous TACE sessions and cumulative administered activity did not predict the incidence of post-SIRT significant hepatotoxicity. Treatment responses consisted of partial responses in 26 (55%), stable disease in 12 (26%), and progressive disease in 9 (19%) patients. The median overall survival (OS) was 11 months (95% confidence interval (CI), 9–13), and objective responses to SIRT were associated with a longer OS (p = 0.008). Significant hepatotoxicity (≥grade 3) after SIRT was a contributor to impaired survival (median OS 6 months (95% CI, 4–8) vs. 12 months (95% CI, 10–14), p < 0.001). SIRT with glass microspheres is a safe and effective salvage treatment for patients with progressive HCC refractory to TACE who are considered poor candidates for sorafenib treatment.

We aim to evaluate the efficacy and safety of 124I-metaiodobenzylguanidine (MIBG) dosimetry-guided high-activity 131I-MIBG therapy of advanced pheochromocytoma or neuroblastoma. Methods: Fourteen patients with advanced pheochromocytoma or neuroblastoma, age 9-69 y, underwent 124I-MIBG PET scans and whole-body retention measurements to assess the whole-body dose as a surrogate of bone marrow toxicity and tumor (absorbed) dose per unit of administered activity. Dosimetry results together with individual patient characteristics were combined to guide a single therapeutic activity to achieve a high tumor dose without exceeding toxicity threshold. Toxicity was assessed for hematologic, hepatic, and renal function. Response was evaluated by RECIST, International Society of Pediatric Oncology Europe Neuroblastoma-like score, change in PET uptake, and quantitative PET parameters (SUVmax, SUVpeak, metabolic tumor volume, total lesion glycolysis), as well as visual decrease in number or in visual intensity of lesions on baseline to follow-up 124I-MIBG PET/CT. Results: The average therapeutic activity was 14 GBq. Eleven of 14 patients (79%) received each more than 10 GBq. One male patient was treated with a single activity of 50 GBq. Three patients were treated with lower activities between 3.5 and 7.0 GBq. Median overall survival was 85 mo (95% CI), and median progression-free survival was 25 mo (95% CI). Four (29%) and 5 (36%) patients demonstrated response (complete response or partial response) by RECIST and functional imaging, respectively. One patient exceeded whole-body dose of 2 Gy and demonstrated grade 3 hematologic toxicity, which resolved spontaneously within 12 mo after the therapy without the need for further treatment. Three patients (21%) demonstrated transient grade 1 renal toxicity. Conclusion:124I-MIBG dosimetry-guided high-activity 131I-MIBG therapy in patients with advanced pheochromocytoma or neuroblastoma resulted in durable responses with a low rate of manageable adverse events. Efficacy of 124I-MIBG-guided activity escalation should further be assessed in a prospective setting.

Supplementary Figure from Enhancing Radioiodine Incorporation into Radioiodine-Refractory Thyroid Cancer with MAPK Inhibition (ERRITI): A Single-Center Prospective Two-Arm Study

Background [ 18 F]Fluoro-deoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is the standard imaging procedure in diffuse large B-cell lymphoma (DLBCL). Disease presentation, FDG-PET/CT performance, and outcome may be influenced by germline single nucleotide polymorphisms (SNP) in genes regulating glucose uptake. Methods Clinical variables, FDG-PET findings, and outcome were analysed in relation to SNPs in 342 DLBCL patients participating in the ‘Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas’ (PETAL) trial. Genes analysed included SLC2A1 (SNPs rs1385129, referred to as HaeIII; rs710218, HpyCH4V; rs841853, XbaI), VEGFA (rs3025039), HIF1A (rs11549465, P582S; rs11549467, A588T), and APEX1 (rs1130409, D148E). Statistical significance was assumed at p ≤ 0.05. Results The SLC2A1 HaeIII and HpyCH4V SNPs were tightly linked and statistically significantly associated with baseline maximum standardized uptake value (SUV max ) and Ann Arbor stage, with slightly lower SUV max (HaeIII, median 18.9, interquartile range [IQR] 11.5–26.6, versus 21.6, IQR 14.4–29.7; p = 0.019) and more frequent stage IV disease (HaeIII, 44.5% versus 30.8%; p = 0.011) in minor allele carriers. As previously reported for lung cancer, the association was dependent upon the coexistent APEX1 D148E genotype. The HIF1A A588T SNP was associated with total metabolic tumour volume (TMTV) and time-to-progression, with significantly lower TMTV (median 16 cm 3 , IQR 7–210, versus 146 cm 3 , IQR 34–510; p = 0.034) and longer time-to-progression in minor allele carriers (log-rank p = 0.094). Time-to-progression was also associated with the SLC2A1 XbaI and APEX1 D148E SNPs, with shorter time-to-progression in homozygous and heterozygous SLC2A1 XbaI (HR 1.456; CI 0.930–2.280; p = 0.099) and homozygous APEX1 D148E minor allele carriers (HR 1.6; CI 1.005–2.545; p = 0.046). In multivariable analyses including SNPs, International Prognostic Index factors, sex, and B symptoms, HIF1A A588T, SLC2A1 XbaI, and APEX1 D148E retained statistical significance for time-to-progression, and SLC2A1 XbaI was also significantly associated with overall survival. Conclusions Common SNPs in genes regulating glucose uptake may impact SUV max , tumour distribution, tumour volume, and outcome in DLBCL. The effects on SUV max are of low magnitude and appear clinically negligible. The results are consistent with findings in other types of cancer. They need to be confirmed in an independent DLBCL population of sufficient size. Trial registration Trial registration: ClinicalTrials.gov NCT00554164; EudraCT 2006-001641-33. Registration date November 5, 2007, https://www.clinicaltrials.gov/ct2/show/NCT00554164

Die Begriffe benignes und malignes Phäochromzytom sollten nicht mehr verwendet werden, da jedes Phäochromozytom das Potenzial zur Metastasierung in sich trägt. Man spricht von einem metastasierten Phäochromozytom oder Paragangliom. Bei Tumoren >5 cm sowie bei extraadrenaler Lokalisation steigt das Risiko metastasierter Formen wie auch bei postoperativ persistierendem Hypertonus. Zur Beurteilung des Metastasierungspotenzials können der PAS-Score und GAPP-Score eine einschätzende Beurteilung erlauben. Konventionelle Schnittbildgebung (CT/MRT) wird zur Umfelddiagnostik primär eingesetzt und kann durch eine [123I] MIBG-Szintigrafie und [124I] MIBG PET/CT ergänzt werden kann. Die chirurgische Resektion stellt den Goldstandard dar. Sollte der Befund nicht resektabel sein, so stehen [123I] MIBG oder radiomarkierte Somatostatin Analoga zur Verfügung. Die Chemotherapie ergänzt die Therapie im fortgeschrittenen Stadium und in therapierefraktären Situationen.

ZusammenfassungAus fachfremder Sicht wird der Stellenwert der „konventionellen“ Schilddrüsenszintigrafie zur Klärung diverser thyreologischer Fragestellungen international mittlerweile weit niedriger eingeschätzt, als dies dem hierzulande tätigen Nuklearmediziner bewusst ist. Dieser Aufsatz gibt einen Überblick über häufig geäußerte Kritikpunkte an der Schilddrüsenszintigrafie und möchte einiges hierzu klarstellen sowie in berechtigten Fällen fundierte Gegenargumente liefern. In diesem Rahmen wird ein Überblick über die weiterhin bestehenden Indikationen gegeben, es werden aber auch Aspekte angeschnitten, bei denen Verbesserungsbedarf besteht. Abschließend erfolgt eine Aussicht auf zukünftige Perspektiven und Weiterentwicklungen der funktionellen Charakterisierung von thyreoidalem Gewebe.

Currently, there is no imaging procedure for radionuclide therapy utilizing Erbium-169 (Er-169). We have recently published the first post-radiosynovectomy imaging of Er-169 citrate in a case report (Farahati et al., 2017). In this study, we performed in-vitro and in-vivo studies to evaluate the feasibility to assess the distribution of Er-169 citrate after radiosynovectomy in fourteen patients with seventeen affected joints treated for refractory chronic synovitis. Post-radiosynovectomy imaging revealed the feasibility of post-radiosynovectomy detection and distribution utilizing Er-169 citrate in all cases. However, additional in-vitro studies including in-vitro imaging, gamma spectrometry and analysis of half-life indicated that emitted gamma-rays of the Ytterbium-169 in the radiopharmaceutical together with bremsstrahlung induced by Er-169 are the imaging source of emitted counts. Post-radiosynovectomy imaging utilizing Er-169 citrate is feasible and should be implemented in the guidelines for theranostics for quality control, patient safety and therapy monitoring.

Abstract Aim to evaluate the time trend of epidemiology of follicular cell derived thyroid cancer (TC) based on data from a well documented cancer registry. Methods Population based data on TC from Lower Franconia (LF), Germany, within 1981 and 2015 were analysed to estimate the regional epidemiology of TC. The incidence was assessed in 5-year-intervals for gender, histology, and tumor stage. Results Incidence of TC solely attributable to papillary TC (PTC) doubled mainly in T1- and T2-stages within the evaluation period from 4.5 to 8.7/100.000/y in females and 1.7 to 4.1/100.000/y in males. There was no significant change of follicular TC (FTC), whereas anaplastic TC (ATC) decreased in the same interval. The number of lymph-node metastases and T3-cases increased, while the frequency of T4-stage and distant metastases decreased. Increased incidences of T1- and T2-stages suggest an over-diagnosis. In contrast, increasing number of tumors at T3-stage and with lymph node involvement contradict the over-diagnosis as the only reason for rising incidence. Declining of T4-stages in spite of increasing of T3-stages and N1-cases indicates the value of timely detection and treatment of TC. In accordance, reduced incidence of advanced cancers with M1-stage and ATC cases promote our current management of TC. Conclusion Timely diagnosis and adequate risk-adopted treatment of thyroid cancer reduce the frequency of high-risk cases with distant metastases and the possible protracted dedifferentiation of TC to anaplastic features. Our analyses support the management algorithm in thyroid cancer according to the recent guidelines of German Nuclear Medicine Society.

In patients with non-resectable hepatic malignancies selective internal radiotherapy (SIRT) with yttrium-90 is an effective therapy. However, previous data indicate that SIRT leads to impaired immune function. The aim of the current study was to determine the extent of DNA lesions in peripheral blood mononuclear cells of SIRT patients and to correlate these lesions with cellular immune responses. In ten patients γH2AX and 53BP1 foci were determined. These foci are markers of DNA double-strand breaks (DSBs) and occur consecutively. In parallel, lymphocyte proliferation was assessed after stimulation with the T cell mitogen phytohemagglutinin. Analyses of vital cells were performed prior to and 1 h and 1 week after SIRT. 1 h and 1 week after SIRT numbers of γH2AX and of 53BP1 foci were more than threefold larger than before (p < 0.01). Already at baseline, foci were more abundant than published in healthy controls. Lymphocyte proliferation at baseline was below the normal range and further decreased after SIRT. Prior to therapy, there was an inverse correlation between lymphocyte proliferation and the quotient 53BP1/γH2AX; which could be considered as a measure of the course of DNA DSB repair (r = − 0.94, p < 0.0001). Proliferative responses were inversely correlated with 53BP1 foci prior to therapy and γH2AX and 53BP1 foci 1 h after therapy (r < − 0.65, p < 0.05). In conclusion, DNA foci in SIRT patients were correlated with impaired in vitro immune function. Unrepaired DNA DSBs or cell cycle arrest due to repair may cause this impairment.

Radioiodine therapy of thyroid cancer was the first successful radionuclide therapy in the treatments of cancer, although its clinical use is empirical and not based on precise dosimetry. 124I is a positron-emitting radionuclide and positron emission tomography/computed tomography (PET/CT) with 124I currently provides the most accurate estimation of the absorbed (radiation) dose to thyroid cancer lesions. In the application, serial 124I PET/CT scans are performed to determine the time uptake curves and to delineate the volumes of the lesions. The 124I data are then used to project the absorbed dose per unit administered 131I activity. The results are part of the decision-making process to individually guide treatment plans, in particular by tailoring the therapeutic 131I activity in radioiodine therapy. The aim of this review is to provide an overview of 124I PET/CT lesion dosimetry of differentiated thyroid cancer including: 1) an historical overview; 2) the general properties of 124I and its activity measurement; 3) the main factors impairing PET image quantification; 4) an optimized lesion dosimetry protocol used in our group to make this manuscript self-contained; as well as 5) a summary of important clinical studies.

470 Objectives: Salivary gland toxicity is a quality of life concern in radioiodine treatment of thyroid cancer. Clinically observed toxicity is inconsistent with absorbed doses (AD) to the salivary glands calculated by absorbed fraction methods, or even by personalized Monte Carlo-based voxelized 3-dimensional radiobiological dosimetry (3D-RD) calculations, which includes accounting for dose rate effects as well as contribution to AD from outside the salivary glands. Small scale anatomical modeling has been proven to reconcile discrepancies between whole organ AD values and clinically or pre-clinically observed toxicities. Methods: Uptake in the salivary glands has been shown to be primarily confined to the epithelial striated ducts which contain sodium iodine symporters. Dimensions of typical striated duct cells were obtained from the literature and S-values for the striated cells for various isotopes of iodine and astatine (131I, 124I, 123I, 125I, 211At) used in clinical or pre-clinical scenarios were calculated using GEANT4 Monte Carlo. Based on the fraction of occupancy of these cells within the salivary glands (5.1 %), a grid of striated cells placed randomly in spheres of increasing size was used to simulate decay of activity in these cells from which ratios of striated duct AD and acinar cell AD to whole organ AD were calculated for these same isotopes. Results were applied to the calculation of AD and biological effective dose (BED) to the striated ducts and acinar cells of the salivary glands of 5 patients treated for thyroid cancer using 131I therapy at the University of Duisburg-Essen. Results: S-values for striated duct to striated duct as well as striated duct to acinar cells as a function of distance from the striated duct were calculated, as were S-values for contents (saliva) inside the tube formed by the striated ducts to the same target cells. The grid-based Monte Carlo results showed a ductal cell AD to salivary whole organ AD ratio of 3.5 - 3.3 for 131I and 14.6 for 211At dependent on salivary gland size (5 - 25 ml). BED for the striated ducts ranged from 3 - 25 Gy, as opposed to the 1-5 Gy calculated to the whole gland. Conclusions: This is a significant step in quantifying the discrepancy between clinically observed toxicity and predicted toxicity based on whole organ AD values and is based on small scale dosimetry, which has been shown to explain similar discrepancies in different cases, particularly alpha-particle dosimetry. This study shows that while the salivary glands may be considered as parallel organs for external beam radiation, the physiology for iodine uptake means that for radiodine therapy, they have a more complex structure.

Radium Ra-223 dichloride (radium-223, Xofigo®) is a targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease. Radium-223 is the first targeted alpha therapy in this indication providing a new treatment option, with evidence of a significant survival benefit, both in overall survival and in the time to the first symptomatic skeletal-related event. The skeleton is the most common metastatic site in patients with advanced prostate cancer. Bone metastases are a clinically significant cause of morbidity and mortality, often resulting in bone pain, pathologic fracture, or spinal cord compression necessitating treatment. Radium-223 is selectively accumulated in the bone, specifically in areas of high bone turnover, by forming complexes with the mineral hydroxyapatite (the inorganic matrix of the bone). The alpha radiation generated during the radioactive decay of radium-223 produces a palliative anti-tumour effect on the bone metastases. The purpose of this guideline is to assist nuclear medicine specialists in evaluating patients who might be candidates for treatment using radium-223, planning and performing this treatment, understanding and evaluating its consequences, and improving patient management during therapy and follow-up.

Although recent data are contradictory, it is still claimed that Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) would deliver an aerosol which distributes homogeneously throughout the entire abdominal cavity.