Questions and Controversies in the Clinical Application of Tyrosine Kinase Inhibitors to Treat Patients with Radioiodine-Refractory Differentiated Thyroid Carcinoma: Expert Perspectives.

Notwithstanding regulatory approval of lenvatinib and sorafenib to treat radioiodine-refractory differentiated thyroid carcinoma (RAI-R DTC), important questions and controversies persist regarding this use of these tyrosine kinase inhibitors (TKIs). RAI-R DTC experts from German tertiary referral centers convened to identify and explore such issues; this paper summarizes their discussions. One challenge is determining when to start TKI therapy. Decision-making should be shared between patients and multidisciplinary caregivers, and should consider tumor size/burden, growth rate, and site(s), the key drivers of RAI-R DTC morbidity and mortality, along with current and projected tumor-related symptomatology, co-morbidities, and performance status. Another question involves choice of first-line TKIs. Currently, lenvatinib is generally preferred, due to greater increase in progression-free survival versus placebo treatment and higher response rate in its pivotal trial versus that of sorafenib; additionally, in those studies, lenvatinib but not sorafenib showed overall survival benefit in subgroup analysis. Whether recommended maximum or lower TKI starting doses better balance anti-tumor effects versus tolerability is also unresolved. Exploratory analyses of lenvatinib pivotal study data suggest dose-response effects, possibly favoring higher dosing; however, results are awaited of a prospective comparison of lenvatinib starting regimens. Some controversy surrounds determination of net therapeutic benefit, the key criterion for continuing TKI therapy: if tolerability is acceptable, overall disease control may justify further treatment despite limited but manageable progression. Future research should assess potential guideposts for starting TKIs; fine-tune dosing strategies and further characterize antitumor efficacy; and evaluate interventions to prevent and/or treat TKI toxicity, particularly palmar-plantar erythrodysesthesia and fatigue.

Analysis of risk factors and prognosis in differentiated thyroid cancer with focus on minimal extrathyroidal extension.

AIMS: In contrast to all prior AJCC/TNM classifications for differentiated thyroid cancer (DTC) the 8th edition does not take minimal extrathyroidal extension (M-ETE) into consideration for local tumor staging. We therefore aimed to retrospectively assess the specific impact of M-ETE on the outcome of M-ETE patients treated in our clinic. METHODS: DTC patients with M-ETE and a follow-up time of ≥ 5 years were included and matched with an identical number of patients without M-ETE, but with equal histopathological tumor subtype and size. The frequency of initially metastatic disease among groups was compared using Fisher's exact test, the recurrence rate by virtue of log-rank test. Fisher's exact test and multivariate analysis were used to account for the presence of confounding risk factors. RESULTS: One hundred sixty patients (80 matching pairs) were eligible. With other confounding risk factors being equal, the prevalence of N1-/M1-disease at initial diagnosis was comparable among groups (M-ETE: 42.5 %; no M-ETE: 32.5 %; p = 0.25). No differences with regard to the recurrence rate were shown. However, M-ETE patients were treated with external beam radiation therapy more often (16.3 % vs. 1.3 %; p = 0.004) and received higher median cumulative activities of 131I (10.0 vs. 8.0 GBq; p < 0.001). DISCUSSION: Although having played a pivotal role for local tumor staging of DTC for decades M-ETE did not increase the risk for metastases at initial diagnosis and the recurrence rate in our cohort. Patients with M-ETE had undergone intensified treatment, which entails a possible confounding factor that warrants further investigation in randomized controlled trials.

18 F-FDG-PET/MRI in patients with Graves' orbitopathy.

PURPOSE: Currently, therapeutic management of patients with Graves' orbitopathy (GO) relies on clinical assessments and MRI. However, monitoring of inflammation remains difficult since external inflammatory signs do not necessarily represent the orbital disease activity. Therefore, we aimed to evaluate the diagnostic value of 18F-FDG-PET/MRI to assess the inflammation of GO patients. METHODS: Enrolled patients with new onset of GO underwent ophthalmological examinations to evaluate the activity (CAS) and severity of GO (NOSPECS), as well as an 18F-FDG-PET/MRI (Siemens Biograph mMR) with dual time point imaging (immediately post-injection and 60 min p.i.). A subset of PET parameters including maximum standardized uptake value (SUVmax), metabolic target volume (MTV), and total lesion glycolysis (TLG) were obtained separately per eye and per extraocular eye muscle (EOM). EOM thickness was measured on the co-registered MRI. RESULTS: Of 14 enrolled patients, three showed mild, seven moderate-to-severe, and four sight-threatening GO. Patients with severe GO showed statistically significant higher TLG than patients with mild GO (p = 0.02) and higher MTV than patients with mild (p = 0.03) and moderate (p = 0.04) GO. Correlation between NOSPECS on one hand and MTV and TLG on the other was significant (R2 = 0.49-0.61). CONCLUSION: TLG and MTV derived from FDG-PET appear to be good discriminators for severe vs. mild-to-moderate GO and show a significant correlation with NOSPECS. As expected, PET parameters of individual eye muscles were not correlated with associated eye motility, since fibrosis, and not inflammation, is mainly responsible for restricted motility. In conclusion, 18F-FDG-PET/MRI can be used for assessment of GO inflammation.

The role of 124I PET/CT lesion dosimetry in differentiated thyroid cancer.

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.

Distinguishing synchronous from metachronous manifestation of distant metastases: a prognostic feature in differentiated thyroid carcinoma.

AIM: Distant metastasis has a negative impact on survival in differentiated thyroid carcinoma (DTC). The timing of this manifestation, however, is of unknown prognostic relevance. The aim of this retrospective study was to investigate the potential significance of discriminating synchronous versus metachronous distant metastases (SDM vs. MDM) for the outcome of patients with DTC. METHODS: We retrospectively analyzed a consecutive cohort of n = 89 patients with distant metastases of DTC (43 with follicular, 46 with papillary DTC histology; mean age 52.6 ± 17.7 years) undergoing radioiodine treatment at our institution. All patients were treated with the same protocol consisting of ablative radioiodine therapy (RIT, 3.7 GBq) and one post-ablation treatment after 3 months (3.7-11.1 GBq). Further cycles of RIT were administered for recurrent, progressive or newly developed metastatic disease. We distinguished 2 types of distant metastases according to the time of manifestation: SDM (within ≤12 months after DTC diagnosis) and MDM (occurring >12 months after diagnosis). Tumor-related survival was analyzed using the Kaplan-Meier method. Uni- and multivariate analyses including the Cox proportional hazards model were performed with a significance level of p < 0.05. RESULTS: The mean follow-up period was 13.8 ± 1.2 years. SDM were present in 49 (55.1 %), MDM in 40 (44.9 %) patients. MDM were associated with shorter tumor-related survival (p = 0.002). 5-year and 10-year survival rates were 68.5 % and 34.8 % for MDM, and 84.3 % and 66.9 % for SDM, respectively. Within both age subgroups of <45 and ≥45 years, SDM were also linked with longer survival. No effect on tumor-related survival was found for the co-variables sex, lymph node metastases and histologic type. CONCLUSION: Distinguishing synchronous from metachronous manifestation of distant metastases may add an important prognostic feature to risk stratification in DTC, as proven metachronous appearance is associated with impaired survival.

Response assessment of bevacizumab therapy in GBM with integrated 11C-MET-PET/MRI: a feasibility study.

BACKGROUND: The objective of this study was to evaluate the potential of integrated 11C-MET PET/MR for response assessment of relapsed glioblastoma (GBM) receiving bevacizumab treatment. METHODS: Eleven consecutive patients with relapsed GBM were enrolled for an integrated 11C-MET PET/MRI at baseline and at follow-up. Treatment response for MRI was evaluated according to Response Assessment in Neuro-oncology (RANO) criteria and integrated 11C-MET PET was assessed by the T/N ratio. RESULTS: MRI showed no patient with complete response (CR), six of 11 patients with PR, four of 11 patients with SD, and one of 11 patients with progressive disease (PD). PET revealed metabolic response in five of the six patients with partial response (PR) and in two of the four patients with stable disease (SD), whereas metabolic non-response was detected in one of the six patients with PR, in two of the four patients with SD, and in the one patient with PD. Morphological imaging was predictive for PFS and OS when response was defined as CR, PR, SD, and non-response as PD. Metabolic imaging was predictive when using T/N ratio reduction of >25 as discriminator. Based on the morphologic and metabolic findings of this study a proposal for applying integrated PET/MRI for treatment response in relapsed GBM was developed, which was significantly predictive for PFS and OS (P = 0.010 respectively 0,029, log). CONCLUSIONS: This study demonstrates the potential of integrated 11C-MET-PET/MRI for response assessment of GBM and the utility of combined assessment of morphologic and metabolic information with the proposal for assessing relapsed GBM.

Discrepant salivary gland response after radioiodine and MIBG therapies.

BACKGROUND: A retrospective study using PET/CT imaging with 124I-labeled metaiodobenzylguanidine (124I-MIBG) was performed to estimate the (radiation) absorbed dose to the salivary glands in neuroendocrine cancer patients undergoing 131I-MIBG therapy and to compare these results with those in radioiodine (131I-iodide) therapy. METHODS: Twenty-seven patients received individual 124I-MIBG-PET/CT dosimetries, among whom 18 had not previously undergone any MIBG therapies (patient group before treatment) and 9 had already received MIBG therapies prior to the tracer dosimetries (patient group after treatment). For each patient, three or four 124I-MIBG PET/CT scans were performed at approximately 4 and 24 hours, as well as at approximately 48 or/and ≥96 hours after tracer injection. The absorbed doses per administered 131I-MIBG activity to the submandibular and parotid glands were calculated based on the MIRD concept, with its assumption of a uniform glandular activity distribution. RESULTS: The mean±standard deviation of the (self-)absorbed dose per activity averaged over both patient groups and salivary gland types was 0.53±0.24 Gy/GBq (median, 0.49 Gy/GBq; range, 0.17-1.38 Gy/GBq). The absorbed doses per activity of the patient group before treatment did not significantly deviate from those of the patient group after treatment (P=0.67). In the patient group after treatment, the mean±standard deviation of the cumulative 131I-MIBG activity was 20±12 GBq (median, 16 GBq; range, 10-50 GBq). Among the patient groups, no significant absorbed dose difference was found between the submandibular and parotid glands (P>0.24). In comparison to radioiodine therapy, the estimated absorbed dose per activity in MIBG was significantly higher (P<0.001), on average twice as high, contradicting the relationship between the absorbed dose and clinical observation of glandular side effects. CONCLUSIONS: The discrepant salivary gland responses in MIBG and radioiodine therapies suggest a different radiotherapeutical distribution on microscopic scale within the glandular tissue and prove the clinical relevance of a microdosimetric analysis.

Prognostic impact of incomplete surgical clearance of radioiodine sensitive local lymph node metastases diagnosed by post-operative (124)I-NaI-PET/CT in patients with papillary thyroid cancer.

PURPOSE: Nodal involvement is an independent risk factor of recurrence in papillary thyroid cancer (PTC). Neither the international guidelines nor the recently introduced ongoing risk adaptation concept consider the extent of initial surgical clearance of radioiodine sensitive lymph node metastases in their stratification systems. We investigated the prognostic relevance of incomplete initial surgical clearance in patients with purely lymphogeneous metastatic PTC (pN1 M0) despite successful radioiodine therapy. Accurate assessment of pre-ablative nodal status was attempted using PET/CT studies with both (124)I-NaI and (18)F-FDG along with high-resolution cervical ultrasound. METHODS: Sixty-five patients with histologically diagnosed lymph node metastases (pN1 M0) were retrospectively analyzed. Patients with iodine-negative lymph node metastases diagnosed by (18)F-FDG PET/CT or distant metastases were excluded from the analysis. The association of disease recurrence with the pre-ablative nodal status, as well as other baseline characteristics, were examined applying nonparametric tests for independent samples and multiple regression analysis. Patients with persistent lymph node metastases in (124)I-NaI PET/CT were further divided according to the additional presence or absence of FDG-uptake in (18)F-FDG PET/CT. Survival analyses were performed using Kaplan-Meier curves and the Cox proportional hazards model for uni- and multivariate analyses to assess the influence of prognostic factors on progression free survival (PFS). RESULTS: Incomplete metastatic lymph node resection captured by (124)I-NaI PET/CT (n = 33) was an independent risk factor for recurrence (61 % vs 25 %, p = 0.006) and shorter PFS (46 months vs not reached, HR 4.0 [95 %-CI, 1.7-9.2], p = 0.001). Ultrasound could detect lymph node metastases only in 19/33 patients (58 %). Among patients with positive nodal status, FDG-avidity of metastatic iodine positive lymph nodes worsened the outcome (16 vs 69 months, p = 0.047). From all other investigated factors including age, N-stage (N1a vs N1b), and T-Stage (T4 vs T1-3), only large tumor size (pT4) had a significant impact on PFS (HR 2.9 [95 %-CI, 1.3-6.4], p = 0.007). CONCLUSIONS: Incomplete initial surgical clearance of lymph node metastases even after successful radioiodine therapy may increase the chances of recurrence and is an independent risk factor for impaired survival of patients with PTC. Pre-ablative (dual tracer PET/CT) imaging with (124)I-Na and (18)F provides a prognostic tool for these patients and may considerably complement the current risk stratification systems.

Differential uptake of (68)Ga-DOTATOC and (68)Ga-DOTATATE in PET/CT of gastroenteropancreatic neuroendocrine tumors.

PURPOSE: Abundant expression of somatostatin receptors (sst) is a characteristic of neuroendocrine tumors (NET). Thus, radiolabeled somatostatin analogs have emerged as important tools for both in vivo diagnosis and therapy of NET. The two compounds most often used in functional imaging with positron emission tomography (PET) are (68)Ga-DOTATATE and (68)Ga-DOTATOC. Both analogs share a quite similar sst binding profile. However, the in vitro affinity of (68)Ga-DOTATATE in binding the sst subtype 2 (sst2) is approximately tenfold higher than that of (68)Ga-DOTATOC. This difference may affect their efficiency in detection of NET lesions, as sst2 is the predominant receptor subtype on gastroenteropancreatic NET. We thus compared the diagnostic value of PET/CT with both radiolabeled somatostatin analogs ((68)Ga-DOTATATE and (68)Ga-DOTATOC) in the same patients with gastroenteropancreatic NET. PATIENTS AND METHODS: Twenty-seven patients with metastatic gastroenteropancreatic NET underwent (68)Ga-DOTATOC and (68)Ga-DOTATATE PET/CT as part of the workup before prospective peptide receptor radionuclide therapy (PRRT). The performance of both imaging methods was analyzed and compared for detection of individual lesions per patient and for eight defined body regions. A region was regarded as positive if at least one lesion was detected in that region. In addition, radiopeptide uptake in terms of the maximal standardized uptake value (SUV(max)) was compared for concordant lesions and renal parenchyma. RESULTS: Fifty-one regions were found positive with both (68)Ga-DOTATATE and (68)Ga-DOTATOC. Overall, however, significantly fewer lesions were detected with (68)Ga-DOTATATE in comparison with (68)Ga-DOTATOC (174 versus 179, p < 0.05). Mean (68)Ga-DOTATATE SUV(max) across all lesions was significantly lower compared with (68)Ga-DOTATOC (16.9 ± 6.8 versus 22.1 ± 12.0, p < 0.01). Mean SUV(max) for renal parenchyma was not significantly different between (68)Ga-DOTATATE and (68)Ga-DOTATOC (12.6 ± 2.6 versus 12.6 ± 2.7). CONCLUSIONS: (68)Ga-DOTATOC and (68)Ga-DOTATATE possess similar diagnostic accuracy for detection of gastroenteropancreatic NET lesions (with a potential advantage of (68)Ga-DOTATOC) despite their evident difference in affinity for sst2. Quite unexpectedly, maximal uptake of (68)Ga-DOTATOC tended to be higher than its (68)Ga-DOTATATE counterpart. However, tumor uptake shows high inter- and intraindividual variance with unpredictable preference of one radiopeptide. Thus, our data encourage the application of different sst ligands to enable personalized imaging and therapy of gastroenteropancreatic NET with optimal targeting of tumor receptors.

¹8F-FDG PET/CT changes therapy management in high-risk DTC after first radioiodine therapy.

PURPOSE: Advanced tumour stage and initial metastases are associated with reduced general and tumour-free survival in patients with differentiated thyroid carcinoma. Optimal initial therapy is mandatory for a positive patient outcome, but can only be performed if all non-iodine-avid tumour lesions are known before planning treatment. We analysed the benefit of (18)F-FDG PET/CT at initial diagnosis in patients with high-risk differentiated thyroid carcinoma and determined whether the (18)F-FDG PET/CT results led to a deviation from the standard procedure, which consists of two consecutive radioiodine treatments with thyroid hormone suppression in between and no additional imaging, with individual patient management. METHODS: The study group comprised 90 consecutive patients with either extensive or metastasized high-risk differentiated thyroid carcinoma who received (18)F-FDG PET/CT after the first radioiodine treatment approximately 4 weeks after thyroidectomy under endogenous TSH stimulation. We carried out PET/CT imaging with low-dose CT without contrast medium, which we only used for attenuation correction of PET images. RESULTS: (18)F-FDG PET/CT was positive in 26 patients (29%) and negative in 64 patients (71%). Compared to the results of posttherapeutic (131)I whole-body scintigraphy, the same lesions were PET-positive in 7 of the 26 patients, different lesions were PET-positive in 15 patients, and some PET-positive lesions were the same and some were different in 4 patients. TNM staging was changed due to the PET results in 8 patients. Management was changed in 19 of the 90 patients (21%), including all patients with only FDG-positive lesions and all patients with both FDG-positive and iodine-positive lesions. Age was not a predictive factor for the presence of FDG-positive lesions. FDG-positive and iodine-positive lesions were associated with high serum thyroglobulin. However, at low serum thyroglobulin values, tumour lesions (iodine- and/or FDG-avid) were also diagnosed. Thus, the serum thyroglobulin value prior to the first radioiodine treatment cannot be used as a predictor of the presence of FDG-positive lesions. CONCLUSION: (18)F-FDG PET/CT resulted in a change of therapeutic procedure in 11 of 90 patients and in a change of patient management through additional diagnostic measures in 8 of 90 patients, and is consequently very helpful in initial staging. At our hospital, (18)F-FDG PET/CT in high-risk patients with differentiated thyroid carcinoma has been established as an initial staging modality.

Intra-Individual Comparison of 124I-PET/CT and 124I-PET/MR Hybrid Imaging of Patients with Resected Differentiated Thyroid Carcinoma: Aspects of Attenuation Correction.

BACKGROUND: This study evaluates the quantitative differences between 124-iodine (I) positron emission tomography/computed tomography (PET/CT) and PET/magnetic resonance imaging (PET/MR) in patients with resected differentiated thyroid carcinoma (DTC). METHODS: N = 43 124I PET/CT and PET/MR exams were included. CT-based attenuation correction (AC) in PET/CT and MR-based AC in PET/MR with bone atlas were compared concerning bone AC in the head-neck region. AC-map artifacts (e.g., dentures) were noted. Standardized uptake values (SUV) were measured in lesions in each PET data reconstruction. Relative differences in SUVmean were calculated between PET/CT and PET/MR with bone atlas. RESULTS: Overall, n = 111 124I-avid lesions were detected in all PET/CT, while n = 132 lesions were detected in PET/MR. The median in SUVmean for n = 98 congruent lesions measured in PET/CT was 12.3. In PET/MR, the median in SUVmean was 16.6 with bone in MR-based AC. CONCLUSIONS: 124I-PET/CT and 124I-PET/MR hybrid imaging of patients with DTC after thyroidectomy provides overall comparable quantitative results in a clinical setting despite different patient positioning and AC methods. The overall number of detected 124I-avid lesions was higher for PET/MR compared to PET/CT. The measured average SUVmean values for congruent lesions were higher for PET/MR.

Intraoperative 68Ga-PSMA Cerenkov Luminescence Imaging for Surgical Margins in Radical Prostatectomy: A Feasibility Study.

Our objective was to assess the feasibility and accuracy of Cerenkov luminescence imaging (CLI) for assessment of surgical margins intraoperatively during radical prostatectomy. Methods: A single-center feasibility study included 10 patients with high-risk primary prostate cancer (PC). 68Ga-prostate-specific membrane antigen (PSMA) PET/CT scans were performed followed by radical prostatectomy and intraoperative CLI of the excised prostate. In addition to imaging the intact prostate, in the first 2 patients the prostate gland was incised and imaged with CLI to visualize the primary tumor. We compared the tumor margin status on CLI to postoperative histopathology. Measured CLI intensities were determined as tumor-to-background ratio. Results: Tumor cells were successfully detected on the incised prostate CLI images as confirmed by histopathology. Three of 10 men had histopathologically positive surgical margins (PSMs), and 2 of 3 PSMs were accurately detected on CLI. Overall, 25 (72%) of 35 regions of interest proved to visualize a tumor signal according to standard histopathology. The median tumor radiance in these areas was 11,301 photons/s/cm2/sr (range, 3,328-25,428 photons/s/cm2/sr), and median tumor-to-background ratio was 4.2 (range, 2.1-11.6). False-positive signals were seen mainly at the prostate base, with PC cells overlaid by benign tissue. PSMA immunohistochemistry revealed strong PSMA staining of benign gland tissue, which impacts measured activities. Conclusion: This feasibility showed that 68Ga-PSMA CLI is a new intraoperative imaging technique capable of imaging the entire specimen's surface to detect PC tissue at the resection margin. Further optimization of the CLI protocol, or the use of lower-energy imaging tracers such as 18F-PSMA, is required to reduce false-positives. A larger study will be performed to assess diagnostic performance.

Risk Stratification of Thyroid Nodules Using the Thyroid Imaging Reporting and Data System (TIRADS): The Omission of Thyroid Scintigraphy Increases the Rate of Falsely Suspected Lesions.

Thyroid nodules are a common finding, especially in iodine-deficient regions. Ultrasonographic scoring systems such as the Thyroid Imaging Reporting and Data System (TIRADS) are helpful in differentiating between benign and malignant thyroid nodules by offering a risk stratification model. Depending on the constellation or number of suspicious ultrasound features, a fine-needle biopsy is recommended. However, none of the previous TIRADS publications considered the functional status of the nodules. Hyperfunctioning thyroid nodules (HTNs) were presumed to exclude malignancy with a very high negative predictive value. Particularly in regions where the iodine supply is low, most HTNs are seen in patients with normal thyroid-stimulating hormone levels. Therefore, thyroid scintigraphy is essential for the detection of HTNs. We investigated whether TIRADS identifies HTNs as nonsuspicious. Methods: We evaluated 615 HTNs (23.2 ± 10.0 mm in maximum diameter in 582 patients ([442 women, 57.7 ± 13.2 y old, and 140 men, 60.1 ± 12.7 y old) detected by 99mTc-pertechnetate or 123I scintigraphy. Before evaluating the scintigraphic appearance, all nodules were analyzed prospectively with sonography, using the TIRADS model referenced in Kwak et al., wherein fine-needle biopsy is recommended for TIRADS 4A or higher. We also investigated 2 subgroups, 42 nodules with available histology and 117 patients with subclinical or overt hyperthyroidism. Results: Whereas 15.9% of the nodules were classified as TIRADS 3 or lower and less than 0.1% as TIRADS 5, most of the nodules were classified as TIRADS 4A (29.3%), 4B (29.3%), or 4C (24.9%). Altogether, more than 80% of the autonomous thyroid nodules were classified as TIRADS 4A or higher, a grade that would result in a recommendation of fine-needle biopsy. Focusing on those 117 HTNs that were already associated with hyperthyroid laboratory values, the rates were similar: 81.2% were categorized as TIRADS 4A or higher (4A, 33.3%; 4B, 29.9%; 4C,17.1%; 5, 0.9%). In the subgroup of patients who underwent thyroid surgery, all nodules were benign, confirming the known negative predictive value of HTNs with regard to malignancy exclusion. Conclusion: Integration of thyroid scintigraphy into the TIRADS model is essential to prevent unnecessary fine-needle biopsy and thyroid surgery.

Changing trends of incidence and prognosis of thyroid carcinoma.

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.

Thyroid stunning in radioiodine-131 therapy of benign thyroid diseases.

PURPOSE: Existence and cause of thyroid stunning was controversially discussed for decades but the underlying mechanism remains unclear. Numerous studies describe thyroid stunning in radioiodine-131 therapy (RIT) of differentiated thyroid carcinoma. However, there are no studies evaluating thyroid stunning in benign thyroid diseases caused by the radioiodine uptake test (RIUT). Therefore, the influence of pre-therapeutic tracer radiation dose on therapeutic iodine-131 uptake was evaluated retrospectively. METHODS: A total of 914 RIT patients were included. Exclusion criteria were anti-thyroid drugs, pre- and/or intra-therapeutic effective half-lives (EHL) beyond 8.04 days and externally performed RIUT or 24 h RIUT. All patients received RIUT 1 week before RIT. Thyroid volume was estimated via ultrasound. Tracer radiation dose to the thyroid was calculated retrospectively. The dependence of changes in the pre-therapeutic to the therapeutic extrapolated-maximum-131I-uptake (EMU) from the dose in RIUT was evaluated statistically. RESULTS: EMU in RIUT ranged from 0.10 to 0.82 (median: 0.35) and EMU in RIT ranged from 0.10 to 0.74 (median: 0.33). Averaged over the whole cohort the therapeutic EMU decreased significantly (2.3% per Gray intra-thyroidal tracer radiation dose). A disease-specific evaluation showed dose-dependent thyroid stunning from 1.2% per Gray in solitary toxic nodules (n = 327) to 21% per Gray in goiters (n = 135) which was significant for the subgroups of disseminated autonomies (n = 114), multifocal autonomies (n = 178) and goiters (p < 0.05) but not for Graves' diseases (n = 160) and solitary toxic nodules (p > 0.05). CONCLUSIONS: The presented data indicate for the first time a significant dependence of pre-therapeutic radiation dose on thyroid stunning in goiter and disseminated and multifocal autonomy. To achieve the desired intra-thyroidal radiation dose, RIT activity should be adapted depending on the dose in RIUT.

Pretherapeutic 124I dosimetry reliably predicts intratherapeutic blood kinetics of 131I in patients with differentiated thyroid carcinoma receiving high therapeutic activities.

AIM: The aim of this study was to assess the agreement between predicted blood uptake values using I and actually measured I blood uptake values (reference) in patients with differentiated thyroid carcinoma receiving largely high therapeutic activities. PATIENTS AND METHODS: Fourteen patients were analyzed retrospectively, who underwent a series of both pretherapeutic and intratherapeutic blood sampling using median I activities of 23 MBq and median therapy I activities of 10 GBq. Data of five blood samples from each patient were analyzed. Lin's concordance correlation coefficient analysis was carried out to assess the kinetic agreement. The time-integrated I activity coefficient (TIAC) for the blood compartment and the effective I clearance time (ECT), expressed as effective I half-life on the basis of a monoexponential model, were ascertained. For each patient, the (intrapatient) percentage differences between pretherapeutic and intratherapeutic TIACs and ECTs were calculated. The (interpatient) difference in TIACs and ECTs between pretherapy and intratherapy groups was evaluated using the Mann-Whitney U-test. RESULTS: Lin's concordance correlation coefficient was at least 0.97, indicating substantial kinetic agreement between pretherapeutic and intratherapeutic radioiodine kinetics. The mean (median)±SD (range) of the absolute percentage difference was 9% (11%)±7% (0.33-20%) for the TIAC and 11% (10%)±10% (0-23%) for the ECT. A slightly higher median TIAC was observed in intratherapy (2.8 vs. 3.3 h), but this was not statistically significant (P=0.15), whereas no remarkable ECT difference (P=0.62) was found. CONCLUSION: The pretherapeutic blood kinetics derived from diagnostic I activities provides a reliable estimation of the intratherapeutic I blood kinetics in patients receiving largely high therapy activities, showing its potential for radioiodine treatment planning.

Impact of prompt gamma coincidence correction on absorbed dose estimation in differentiated thyroid cancer using 124I PET/CT imaging.

INTRODUCTION: Iodine-124 positron emission tomography/computed tomography (I PET/CT) is increasingly being used in the absorbed dose estimation in the radioiodine treatment of differentiated thyroid cancer (DTC). However, the produced prompt gamma coincidences (PGCs) associated with the I decay result in a bias in the absorbed dose estimation. The impact of a sinogram-based PGC correction approach on the absorbed dose estimation in I PET/CT DTC imaging is investigated. METHODS: I phantom and patient measurements were performed on a Siemens Biograph mCT PET/CT system. All images were reconstructed with (PGCon) and without PGC correction (PGCoff). The phantom contained seven spheres (diameters: 6.6-37 mm). The spheres and background compartment were filled with a I solution, resulting in a low (9.4 : 1) and a high sphere-to-background activity concentration ratio (750 : 1). Sphere recovery coefficient (RC) values were determined. In addition, the impact of PGC correction on measured lesion uptake and calculated lesion-absorbed dose was assessed for 66 lesions identified in 24 DTC patients. RESULTS: PGC correction systematically increased sphere RC values up to 71% for the smallest spheres. For the patient data, PGC correction significantly increased both the measured I uptake (P<0.005) and the calculated lesion-absorbed dose (P=0.008) by ∼3%. The percentage difference in the calculated lesion-absorbed dose ranged from -19% to 50%, showing that PGC correction had a variable and large impact for a few lesions. CONCLUSION: PGC correction resulted in significantly higher sphere RC values, I lesion uptake values and estimated lesion-absorbed doses.

Quantitative performance of 124I PET/MR of neck lesions in thyroid cancer patients using 124I PET/CT as reference.

BACKGROUND: In patients with differentiated thyroid cancer (DTC), serial 124I PET/CT imaging is, for instance, used to assess the absorbed (radiation) dose to lesions. Frequently, the lesions are located in the neck and they are close to or surrounded by different tissue types. In contrast to PET/CT, MR-based attenuation correction in PET/MR may be therefore challenging in the neck region. The aim of this retrospective study was to assess the quantitative performance of 124I PET/MRI of neck lesions by comparing the MR-based and CT-based 124I activity concentrations (ACs). Sixteen DTC patients underwent PET/CT scans at 24 and 120 h after administration of about 25 MBq 124I. Approximately 1 h before or after PET/CT examination, each patient additionally received a 24-h PET/MR scan and sometimes a 120-h PET/MR scan. PET images were reconstructed using the respective attenuation correction approach. Appropriate reconstruction parameters and corrections were used to harmonize the reconstructed PET images to provide, for instance, similar spatial resolution. For each lesion, two types of ACs were ascertained: the maximum AC (max-AC) and an average AC (avg-AC). The avg-AC is the average activity concentration obtained within a spherical volume of interest with a diameter of 7 mm, equaling the PET scanner resolution. For each type of AC, the percentage AC difference between MR-based and CT-based ACs was determined and Lin's concordance correlation analysis was applied. Quantitative performance was considered acceptable if the standard deviation was ± 25% (precision), and the mean value was within ± 10% (accuracy). RESULTS: The avg-ACs (max-ACs within parentheses) of 74 lesions ranged from 0.20 (0.33) to 657 (733) kBq/mL. Excluding two lesions with ACs of approximately 1 kBq/mL, the mean (median) ± standard deviation (range) was - 4% (- 5%) ± 14% (- 28 to 29%) for the avg-AC and - 9% (- 11%) ± 14% (- 33 to 33%) for the max-AC. Lin's concordance correlation coefficients were ≥ 0.97, indicating substantial AC agreement. CONCLUSIONS: Quantification of lesions in the neck region using 124I PET/MR showed acceptable quantitation performance to 124I PET/CT for AC above 1 kBq/mL. The PET/MRI-based 124I ACs in the neck region can be therefore reliably used in pre-therapy dosimetry planning.

The Impact of Somatostatin Receptor-Directed PET/CT on the Management of Patients with Neuroendocrine Tumor: A Systematic Review and Meta-Analysis.

Somatostatin receptor (SSTR) imaging is widely used for guiding the management of neuroendocrine tumor (NET) patients. 68Ga-DOTATATE approval by the U.S. Food and Drug Administration has triggered widespread clinical interest in SSTR PET/CT throughout the United States. Here, we performed a systematic review and meta-analysis to evaluate the impact of SSTR PET/CT on the management of patients with NETs. Methods: A comprehensive literature search was performed using The National Center for Biotechnology Information PubMed online database, applying the following key words: "management" AND "PET" AND "neuroendocrine". Fourteen of 190 studies were deemed suitable based on the following inclusion criteria: original research, cohort study, number of patients 10 or more, and reported change in management after SSTR PET/CT. Change in management across studies was determined by a random-effects model. Results: A total of 1,561 patients were included. Overall, change in management occurred in 44% (range, 16%-71%) of NET patients after SSTR PET/CT. In 4 of 14 studies, SSTR PET/CT was performed after an 111In-Octreotide scan. In this subgroup, additional information by SSTR PET/CT led to a change in management in 39% (range, 16%-71%) of patients. Seven of 14 studies differentiated between inter- and intramodality changes, with most changes being intermodality (77%; intramodality, 23%). Conclusion: The management was changed in more than one third of patients undergoing SSTR PET/CT even when performed after an 111In-Octreotide scan. Intermodality changes were 3 times more likely than intramodality changes, underlining the clinical impact of SSTR PET/CT.