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Purpose Positron emission tomography (PET) with O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) is a well-established tool for non-invasive assessment of adult central nervous system (CNS) tumors. However, data on its diagnostic utility and impact on clinical management in children and adolescents are limited. Methods Twenty-one children and young adults (13 males; mean age, 8.6 ± 5.2 years; range, 1–19 at initial diagnosis) with either newly diagnosed (n = 5) or pretreated (n = 16) CNS tumors were retrospectively analyzed. All patients had previously undergone neuro-oncological work-up including cranial magnetic resonance imaging. In all cases, [18F]FET-PET was indicated in a multidisciplinary team conference. The impact of PET imaging on clinical decision-making was assessed. Histopathology (n = 12) and/or clinical and imaging follow-up (n = 9) served as the standard of reference. Results The addition of [18F]FET-PET to the available information had an impact on further patient management in 14 out of 21 subjects, with avoidance of invasive surgery or biopsy in four patients, biopsy guidance in four patients, change of further treatment in another five patients, and confirmation of diagnosis in one patient. Conclusion [18F]FET-PET may provide important additional information for treatment guidance in pediatric and adolescent patients with CNS tumors.

We aimed to determine the impact of fibroblast activation protein inhibitor (FAPI)-directed molecular imaging on staging and therapeutic management in patients affected with digestive system tumors when compared with guideline-compatible imaging (GCI).Thirty-two patients with tumors of the digestive system were included: colon adenocarcinoma, 2/32 (6.3%); hepatocellular carcinoma (HCC), 6/32 (18.8%); pancreatic duct adenocarcinoma (PDAC), 6/32 (18.8%), and gastroenteropancreatic neuroendocrine neoplasms, 18/32 (56.3%). All patients underwent GCI and 68 Ga-FAPI-04 PET/CT within median 4 days. Staging outcomes and subsequent treatment decisions were compared between GCI and 68 Ga-FAPI-04 PET/CT.Compared with GCI, 68 Ga-FAPI-04 PET/CT led to staging changes in 15/32 patients (46.9%). Among those, downstaging was recorded in 3/15 cases (20.0%) and upstaging in the remaining 12/15 patients (HCC, 4/12 [33.3%]; PDAC, 4/12 [33.3%]; neuroendocrine neoplasms, 3/12 [25%]; colon adenocarcinoma, 1/12 [8.3%]). Therapeutic management was impacted in 8/32 patients (25.0%), including 4 instances of major and 4 instances of minor therapeutic changes. The highest proportion of treatment modifications was observed in patients diagnosed with PDAC and HCC in 6/8 (75%).In patients affected with digestive system tumors, 68 Ga-FAPI-04 PET/CT resulted in staging changes in more than 46% and therapeutic modifications in 25% of the cases, in particular in patients with HCC and PDAC. In clinical routine, such findings may favor a more widespread adoption of FAP-directed imaging in those tumor types.We aimed to determine the impact of fibroblast activation protein inhibitor (FAPI)–directed molecular imaging on staging and therapeutic management in patients affected with digestive system tumors when compared with guideline-compatible imaging (GCI).Thirty-two patients with tumors of the digestive system were included: colon adenocarcinoma, 2/32 (6.3%); hepatocellular carcinoma (HCC), 6/32 (18.8%); pancreatic duct adenocarcinoma (PDAC), 6/32 (18.8%), and gastroenteropancreatic neuroendocrine neoplasms, 18/32 (56.3%). All patients underwent GCI and 68 Ga-FAPI-04 PET/CT within median 4 days. Staging outcomes and subsequent treatment decisions were compared between GCI and 68 Ga-FAPI-04 PET/CT.Compared with GCI, 68 Ga-FAPI-04 PET/CT led to staging changes in 15/32 patients (46.9%). Among those, downstaging was recorded in 3/15 cases (20.0%) and upstaging in the remaining 12/15 patients (HCC, 4/12 [33.3%]; PDAC, 4/12 [33.3%]; neuroendocrine neoplasms, 3/12 [25%]; colon adenocarcinoma, 1/12 [8.3%]). Therapeutic management was impacted in 8/32 patients (25.0%), including 4 instances of major and 4 instances of minor therapeutic changes. The highest proportion of treatment modifications was observed in patients diagnosed with PDAC and HCC in 6/8 (75%).In patients affected with digestive system tumors, 68 Ga-FAPI-04 PET/CT resulted in staging changes in more than 46% and therapeutic modifications in 25% of the cases, in particular in patients with HCC and PDAC. In clinical routine, such findings may favor a more widespread adoption of FAP-directed imaging in those tumor types.

Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is increasingly incorporated in the therapeutic algorithm of patients with metastatic castration-resistant prostate cancer (mCRPC). We aimed to elucidate the predictive performance of early biochemical response for overall survival (OS).In this bicentric analysis, we included 184 mCRPC patients treated withA total of 114/184 patients (62.0%) showed any PSA decline (PSA response50%, 55/184 [29.9%]). For individuals exhibiting a PSA decline50%, OS of 19 months was significantly longer relative to nonresponders (13 months; hazard ratio of death [HR] = 0.64, 95% confidence interval [95% CI] = 0.44-0.93; p = 0.02). However, the difference was even more pronounced for any PSA decline, with an OS of 19 months in responders, but only 8 months in nonresponders (HR = 0.39, 95% CI = 0.25-0.60; p 0.001).In mCRPC patients scheduled for RLT, early biochemical response was tightly linked to prolonged survival, irrespective of the magnitude of PSA decline. As such, even in patients with PSA decrease of less than 50%, RLT should be continued.

Introduction In men with metastatic castration-resistant prostate cancer (mCRPC) scheduled for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), biochemical response is assessed based on repeated measurements of prostate-specific antigen (PSA) levels. We aimed to determine overall survival (OS) in patients experiencing sustained PSA increase, decrease, or fluctuations during therapy. Materials and methods In this bicentric study, we included 176 mCRPC patients treated with PSMA-directed RLT. PSA levels were determined using blood samples prior to the first RLT and on the admission days for the following cycles. We calculated relative changes in PSA levels compared to baseline. Kaplan–Meier curves as well as log-rank test were used to compare OS of different subgroups, including patients with sustained PSA increase, decrease, or fluctuations (defined as change after initial decrease or increase after the first cycle). Results Sixty-one out of one hundred seventy-six (34.7%) patients showed a sustained increase and 86/176 (48.8%) a sustained decrease in PSA levels. PSA fluctuations were observed in the remaining 29/176 (16.5%). In this subgroup, 22/29 experienced initial PSA decrease followed by an increase (7/29, initial increase followed by a decrease). Median OS of patients with sustained decrease in PSA levels was significantly longer when compared to patients with sustained increase of PSA levels (19 vs. 8 months; HR 0.35, 95% CI 0.22–0.56; P P P = 0.20). In addition, in men experiencing PSA fluctuations, median OS did not differ significantly between patients with initial decrease or initial increase of tumor marker levels (16 vs. 18 months; HR 1.2, 95% CI 0.38–4.05; P = 0.68). Conclusion Initial increase or decrease of PSA levels is sustained in the majority of patients undergoing RLT. Sustained PSA decrease was linked to prolonged survival and men with PSA fluctuations under treatment experienced comparable survival benefits. As such, transient tumor marker oscillations under RLT should rather not lead to treatment discontinuation, especially in the absence of radiological progression.

Purpose As α-emitters for radiopharmaceutical therapies are administered systemically by intravenous injection, blood will be irradiated by α-particles that induce clustered DNA double-strand breaks (DSBs). Here, we investigated the induction and repair of DSB damage in peripheral blood mononuclear cells (PBMCs) as a function of the absorbed dose to the blood following internal ex vivo irradiation with [223Ra]RaCl2. Methods Blood samples of ten volunteers were irradiated by adding [223Ra]RaCl2 solution with different activity concentrations resulting in absorbed doses to the blood of 3 mGy, 25 mGy, 50 mGy and 100 mGy. PBMCs were isolated, divided in three parts and either fixed directly (d-samples) or after 4 h or 24 h culture. After immunostaining, the induced γ-H2AX α-tracks were counted. The time-dependent decrease in α-track frequency was described with a model assuming a repair rate R and a fraction of non-repairable damage Q. Results For 25 mGy, 50 mGy and 100 mGy, the numbers of α-tracks were significantly increased compared to baseline at all time points. Compared to the corresponding d-samples, the α-track frequency decreased significantly after 4 h and after 24 h. The repair rates R were (0.24 ± 0.05) h−1 for 25 mGy, (0.16 ± 0.04) h−1 for 50 mGy and (0.13 ± 0.02) h−1 for 100 mGy, suggesting faster repair at lower absorbed doses, while Q-values were similar. Conclusion The results obtained suggest that induction and repair of the DSB damage depend on the absorbed dose to the blood. Repair rates were similar to what has been observed for irradiation with low linear energy transfer.

C-X-C motif chemokine receptor 4 (CXCR4)–targeted radioligand therapy (RLT) has already been applied to advanced blood cancers, such as multiple myeloma or diffuse large B-cell lymphoma. We present a series of patients with advanced T-cell lymphoma (TCL) who were scheduled for CXCR4-directed therapy as a conditioning regimen, followed by hematopoietic stem cell transplantation (HSCT). Methods: Four patients with advanced, heavily pretreated, and relapsed TCL (2 men, 2 women; median age, 50 y) without suitable alternative therapeutic options underwent CXCR4-directed PET and pretherapeutic dosimetry. We then conducted CXCR4-targeted RLT in combination with allogeneic (3/4, 75%) or autologous (1/4, 25%) HSCT. One patient also underwent radioimmunotherapy targeting CD66 to enhance therapeutic efficacy. We investigated safety, best response, progression-free survival, and overall survival. Results: Pretherapeutic dosimetry indicated lymphoma-absorbed doses of up to 33.2 Gy from CXCR4-targeted RLT. Except for 1 patient who developed tumor lysis syndrome along with transient grade 3 kidney failure, no acute toxicity, allergic reactions, or other adverse events were recorded during therapy. One patient developed septicemia and subsequently died 16 d after RLT, whereas engraftment was achieved in the remaining 3 patients (75%). During follow-up, a partial response was recorded in 1 of 3 patients (33.3%) and a complete metabolic response in the other two (66.7%, with 1 patient also receiving additional radioimmunotherapy). Median progression-free survival was 7 mo (range, 4–25 mo). After a median follow-up of 54 mo (range, 4–56 mo), 3 patients were still alive at the date of censoring. Conclusion: For advanced, heavily pretreated TCL, CXCR4-directed RLT may serve as an effective conditioning therapy before HSCT and can cause substantial antilymphoma activity, leading to a remarkable response in selected cases.

A growing body of literature reports on the upregulation of C-X-C motif chemokine receptor 4 (CXCR4) in a variety of cancer entities, rendering this receptor as suitable target for molecular imaging and endoradiotherapy in a theranostic setting. For instance, the CXCR4-targeting positron emission tomography (PET) agent [68 Ga]PentixaFor has been proven useful for a comprehensive assessment of the current status quo of solid tumors, including adrenocortical carcinoma or small-cell lung cancer. In addition, [68 Ga]PentixaFor has also provided an excellent readout for hematological malignancies, such as multiple myeloma, marginal zone lymphoma, or mantle cell lymphoma. PET-based quantification of the CXCR4 capacities in vivo allows for selecting candidates that would be suitable for treatment using the theranostic equivalent [177Lu]/[90Y]PentixaTher. This CXCR4-directed theranostic concept has been used as a conditioning regimen prior to hematopoietic stem cell transplantation and to achieve sufficient anti-lymphoma/-tumor activity in particular for malignant tissues that are highly sensitive to radiation, such as the hematological system. Increasing the safety margin, pretherapeutic dosimetry is routinely performed to determine the optimal activity to enhance therapeutic efficacy and to reduce off-target adverse events. The present review will provide an overview of current applications for CXCR4-directed molecular imaging and will introduce the CXCR4-targeted theranostic concept for advanced hematological malignancies.

Background Radioligand therapy (RLT) with 177Lu-labeled prostate-specific membrane antigen (PSMA) ligands is associated with prolonged overall survival (OS) in patients with advanced, metastatic castration-resistant prostate cancer (mCRPC). A substantial number of patients, however, are prone to treatment failure. We aimed to determine clinical baseline characteristics to predict OS in patients receiving [177Lu]Lu-PSMA I&T RLT in a long-term follow-up. Materials and methods Ninety-two mCRPC patients treated with [177Lu]Lu-PSMA I&T with a follow-up of at least 18 months were retrospectively identified. Multivariable Cox regression analyses were performed for various baseline characteristics, including laboratory values, Gleason score, age, prior therapies, and time interval between initial diagnosis and first treatment cycle (intervalDiagnosis-RLT, per 12 months). Cutoff values for significant predictors were determined using receiver operating characteristic (ROC) analysis. ROC-derived thresholds were then applied to Kaplan–Meier analyses. Results Baseline C-reactive protein (CRP; hazard ratio [HR], 1.10, 95% CI 1.02–1.18; P = 0.01), lactate dehydrogenase (LDH; HR, 1.07, 95% CI 1.01–1.11; P = 0.01), aspartate aminotransferase (AST; HR, 1.16, 95% CI 1.06–1.26; P = 0.001), and intervalDiagnosis-RLT (HR, 0.95, 95% CI 0.91–0.99; P = 0.02) were identified as independent prognostic factors for OS. The following respective ROC-based thresholds were determined: CRP, 0.98 mg/dl (area under the curve [AUC], 0.80); LDH, 276.5 U/l (AUC, 0.83); AST, 26.95 U/l (AUC, 0.73); and intervalDiagnosis-RLT, 43.5 months (AUC, 0.68; P intervalDiagnosis-RLT (P ≤ 0.01, respectively). Conclusion In mCRPC patients treated with [177Lu]Lu-PSMA I&T, baseline CRP, LDH, AST, and time interval until RLT initiation (thereby reflecting a possible indicator for tumor aggressiveness) are independently associated with survival. Our findings are in line with previous findings on [177Lu]Lu-PSMA-617, and we believe that these clinical baseline characteristics may support the nuclear medicine specialist to identify long-term survivors.

Objectives We evaluated 18F-DCFPyL test–retest repeatability of uptake in normal organs. Methods Twenty-two prostate cancer (PC) patients underwent two 18F-DCFPyL PET scans within 7 days within a prospective clinical trial (NCT03793543). In both PET scans, uptake in normal organs (kidneys, spleen, liver, and salivary and lacrimal glands) was quantified. Repeatability was determined by using within-subject coefficient of variation (wCOV), with lower values indicating improved repeatability. Results For SUVmean, repeatability was high for kidneys, spleen, liver, and parotid glands (wCOV, range: 9.0%–14.3%) and lower for lacrimal (23.9%) and submandibular glands (12.4%). For SUVmax, however, the lacrimal (14.4%) and submandibular glands (6.9%) achieved higher repeatability, while for large organs (kidneys, liver, spleen, and parotid glands), repeatability was low (range: 14.1%–45.2%). Conclusion We found acceptable repeatability of uptake on 18F-DCFPyL PET for normal organs, in particular for SUVmean in the liver or parotid glands. This may have implications for both PSMA-targeted imaging and treatment, as patient selection for radioligand therapy and standardized frameworks for scan interpretation (PROMISE, E-PSMA) rely on uptake in those reference organs.

Purpose We aimed to assess prevalence, distribution, and intensity of in-vivo arterial wall fibroblast activation protein (FAP) uptake, and its association with calcified plaque burden, cardiovascular risk factors (CVRFs), and FAP-avid tumor burden. Methods We analyzed 69 oncologic patients who underwent [68 Ga]Ga-FAPI-04 PET/CT. Arterial wall FAP inhibitor (FAPI) uptake in major vessel segments was evaluated. We then investigated the associations of arterial wall uptake with calcified plaque burden (including number of plaques, plaque thickness, and calcification circumference), CVRFs, FAP-positive total tumor burden, and image noise (coefficient of variation, from normal liver parenchyma). Results High focal arterial FAPI uptake (FAPI +) was recorded in 64/69 (92.8%) scans in 800 sites, of which 377 (47.1%) exhibited concordant vessel wall calcification. The number of FAPI + sites per patient and (FAPI +)-derived target-to-background ratio (TBR) correlated significantly with the number of calcified plaques (FAPI + number: r = 0.45, P r = − 0.26, P = 0.04), calcified plaque thickness (FAPI + number: r = 0.33, P r = − 0.29, P = 0.02), and calcification circumference (FAPI + number: r = 0.34, P r = − 0.26, P = 0.04). In univariate analysis, only body mass index was significantly associated with the number of FAPI + sites (OR 1.06; 95% CI, 1.02 − 1.12, P r = 0.30) and the number of FAPI + sites (r = 0.28; P = 0.02, respectively). In addition, there was no significant interaction between FAP-positive tumor burden and arterial wall FAPI uptake (P ≥ 0.13). Conclusion [68 Ga]Ga-FAPI-04 PET identifies arterial wall lesions and is linked to marked calcification and overall calcified plaque burden, but is not consistently associated with cardiovascular risk. Apparent wall uptake may be partially explained by image noise.

Fibroblast activation protein (FAP) has emerged as a novel target for FAP inhibitor (FAPI)-directed molecular imaging and endoradiotherapy (ERT). We aimed to assess the interobserver agreement rates for interpretation of 68Ga-FAPI-4 PET/CT and decision for ERT.A random order of 68Ga-FAPI-4 PET/CTs from 49 oncology patients were independently interpreted by 4 blinded readers. Per scan, visual assessment was performed, including overall scan impression, number of organ/lymph node (LN) metastases, and number of affected organs/LN regions. Moreover, a maximum of 3 target lesions, defined as largest in size and/or most intense, per organ compartment were identified, which allowed for an additional quantitative interobserver assessment of LN and organ lesions. To investigate potential reference tissues, quantification also included unaffected liver parenchyma and blood pool. Readers also had to indicate whether FAPI-directed ERT should be considered (based on intensity of uptake and widespread disease). Interobserver agreement rates were evaluated using intraclass correlation coefficients (ICCs) and interpreted according to Cicchetti (with 0.4-0.59 indicating fair, and 0.6-0.74 good, agreement).On a visual basis, the agreement rate for an overall scan impression was fair (ICC, 0.42; 95% confidence interval [CI], 0.27-0.57). The concordance rate for number of affected LN areas was also fair (ICC, 0.59; 95% CI, 0.45-0.72), whereas the number of LN metastases, number of affected organs, and number of organ metastases achieved good agreement rates (ICC, ≥0.63). In a quantitative analysis, concordance rates for LN were good (ICC, 0.70; 0.48-0.88), but only fair for organ lesions (ICC, 0.43; 0.26-0.60). In regards to background tissues, ICCs were good for unaffected liver parenchyma (0.68; 0.54-0.79) and fair for blood pool (0.43; 0.29-0.58). When readers should decide on ERT, concordance rates were also fair (ICC, 0.59; 95% CI, 0.46-0.73).For FAPI-directed molecular imaging and therapy, a fair to good interobserver agreement rate was achieved, supporting the adoption of this radiotracer for clinical routine and multicenter trials.

Background CXCR4-directed positron emission tomography/computed tomography (PET/CT) has been used as a diagnostic tool in patients with solid tumors. We aimed to determine a potential correlation between tumor burden and radiotracer accumulation in normal organs. Methods Ninety patients with histologically proven solid cancers underwent CXCR4-targeted [68Ga]Ga-PentixaFor PET/CT. Volumes of interest (VOIs) were placed in normal organs (heart, liver, spleen, bone marrow, and kidneys) and tumor lesions. Mean standardized uptake values (SUVmean) for normal organs were determined. For CXCR4-positive tumor burden, maximum SUV (SUVmax), tumor volume (TV), and fractional tumor activity (FTA, defined as SUVmean x TV), were calculated. We used a Spearman's rank correlation coefficient (ρ) to derive correlative indices between normal organ uptake and tumor burden. Results Median SUVmean in unaffected organs was 5.2 for the spleen (range, 2.44 – 10.55), 3.27 for the kidneys (range, 1.52 – 17.4), followed by bone marrow (1.76, range, 0.84 – 3.98), heart (1.66, range, 0.88 – 2.89), and liver (1.28, range, 0.73 – 2.45). No significant correlation between SUVmax in tumor lesions (ρ ≤ 0.189, P ≥ 0.07), TV (ρ ≥ -0.204, P ≥ 0.06) or FTA (ρ ≥ -0.142, P ≥ 0.18) with the investigated organs was found. Conclusions In patients with solid tumors imaged with [68Ga]Ga-PentixaFor PET/CT, no relevant tumor sink effect was noted. This observation may be of relevance for therapies with radioactive and non-radioactive CXCR4-directed drugs, as with increasing tumor burden, the dose to normal organs may remain unchanged.

Background Labelled with lutetium-177, the urea-based small molecules PSMA I&T and PSMA-617 are the two agents most frequently used for radioligand therapy (RLT) in patients with advanced metastatic castration-resistant and prostate-specific membrane antigen (PSMA) expressing prostate cancer (mCRPC). In this matched-pair analysis, we aimed to compare the toxicity and efficacy of both agents for PSMA-directed RLT. Materials and methods A total of 110 mCRPC patients from two centres were accrued, 55 individuals treated with [177Lu]Lu-PSMA I&T, and a matched cohort of 55 patients treated with [177Lu]Lu-PSMA-617. Matching criteria included age at the first cycle, Gleason score, prostate-specific antigen (PSA) values, and previous taxane-based chemotherapy. Using common terminology criteria for adverse events (CTCAE v. 5.0), toxicity profiles were investigated (including bone marrow and renal toxicity). Overall survival (OS) between both groups was compared. Results Toxicity assessment revealed grade III anaemia in a single patient (1.8%) for [177Lu]Lu-PSMA I&T and five (9.1%) for [177Lu]Lu-PSMA-617. In addition, one (1.9%) grade III thrombopenia for [177Lu]Lu-PSMA-617 was recorded. Apart from that, no other grade III/IV toxicities were present. A median OS of 12 months for patients treated with [177Lu]Lu-PSMA I&T did not differ significantly when compared to patients treated with [177Lu]Lu-PSMA-617 (median OS, 13 months; P = 0.89). Conclusion In this matched-pair analysis of patients receiving one of the two agents most frequently applied for PSMA RLT, the rate of clinically relevant toxicities was low for both compounds. In addition, no relevant differences for OS were observed.

Abstract Purpose For somatostatin receptor (SSTR)-positron emission tomography/computed tomography (PET/CT), a standardized framework termed SSTR-reporting and data system (RADS) has been proposed. We aimed to elucidate the impact of a RADS-focused training on reader’s anxiety to report on SSTR-PET/CT, the motivational beliefs in learning such a system, whether it increases reader’s confidence, and its implementation in clinical routine. Procedures A 3-day training course focusing on SSTR-RADS was conducted. Self-report questionnaires were handed out prior to the course (Pre) and thereafter (Post). The impact of the training on the following categories was evaluated: (1) test anxiety to report on SSTR-PET/CT, (2) motivational beliefs, (3) increase in reader’s confidence, and (4) clinical implementation. To assess the effect size of the course, Cohen’s d was calculated (small, d = 0.20; large effect, d = 0.80). Results Of 22 participants, Pre and Post were returned by 21/22 (95.5%). In total, 14/21 (66.7%) were considered inexperienced (IR, 1 year). Applying SSTR-RADS, a large decrease in anxiety to report on SSTR-PET/CT was noted for IR (d = − 0.74, P = 0.02), but not for ER (d = 0.11, P = 0.78). For the other three categories motivational beliefs, reader’s confidence, and clinical implementation, agreement rates were already high prior to the training and persisted throughout the course (P ≥ 0.21). Conclusions A framework-focused reader training can reduce anxiety to report on SSTR-PET/CTs, in particular for inexperienced readers. This may allow for a more widespread adoption of this system, e.g., in multicenter trials for better intra- and interindividual comparison of scan results.

Objective Reliable results of wash-out CT in the diagnostic workup of adrenal incidentalomas are scarce. Thus, we evaluated the diagnostic accuracy of delayed wash-out CT and determined thresholds to accurately differentiate adrenal masses. Design Retrospective, single-center cohort study including 216 patients with 252 adrenal lesions who underwent delayed wash-out CT. Definitive diagnoses based on histopathology (n = 92) or comprehensive follow-up. Methods Size, average attenuation values of the adrenal lesions in all CT scan phases, and absolute and relative percentage wash-out (APW/RPW) were determined by an expert radiologist blinded for clinical data. Adrenal lesions with unenhanced attenuation values >10 Hounsfield units (HU) built a subgroup (n = 142). Diagnostic accuracy was calculated. Results The study group consisted of 171 adenomas, 32 other benign tumors, 11 pheochromocytomas, 9 adrenocortical carcinomas, and 29 other malignant tumors. All (potentially) malignant and 46% of benign lesions showed unenhanced attenuation values >10 HU. In this most relevant subgroup, the established thresholds of 60% for APW and 40% for RPW misclassified 35.9 and 35.2% of the masses, respectively. When we applied optimized cutoffs (APW >83%; RPW >58%) and excluded pheochromocytomas, we missed only one malignant tumor by APW and none by RPW. However, only 11 and 15% of the benign tumors were correctly identified. Conclusions Wash-out CT with the established thresholds for APW and RPW is insufficient to reliably diagnose adrenal masses. Using the proposed cutoff of 58% for RPW, malignant tumors will be correctly identified, but the added value is limited, namely 15% of patients with benign tumors can be prevented from additional imaging or even unnecessary surgery.

Objectives PET-based radiomic metrics are increasingly utilized as predictive image biomarkers. However, the repeatability of radiomic features on PET has not been assessed in a test–retest setting. The prostate-specific membrane antigen-targeted compound 18F-DCFPyL is a high-affinity, high-contrast PET agent that we utilized in a test-retest cohort of men with metastatic prostate cancer (PC). Methods Data of 21 patients enrolled in a prospective clinical trial with histologically proven PC underwent two 18F-DCFPyL PET scans within 7 days, using identical acquisition and reconstruction parameters. Sites of disease were segmented and a set of 29 different radiomic parameters were assessed on both scans. We determined repeatability of quantification by using Pearson's correlations, within-subject coefficient of variation (wCOV), and Bland–Altman analysis. Results In total, 230 lesions (177 bone, 38 lymph nodes, 15 others) were assessed on both scans. For all investigated radiomic features, a broad range of inter-scan correlation was found (r, 0.07–0.95), with acceptable reproducibility for entropy and homogeneity (wCOV, 16.0% and 12.7%, respectively). On Bland–Altman analysis, no systematic increase or decrease between the scans was observed for either parameter (±1.96 SD: 1.07/−1.30, 0.23/−0.18, respectively). The remaining 27 tested radiomic metrics, however, achieved unacceptable high wCOV (≥21.7%). Conclusion Many common radiomic features derived from a test–retest PET study had poor repeatability. Only Entropy and homogeneity achieved good repeatability, supporting the notion that those image biomarkers may be incorporated in future clinical trials. Those radiomic features based on high frequency aspects of images appear to lack the repeatability on PET to justify further study.

ZusammenfassungNeuroendokrine Neoplasien (NEN) stellen ein komplexes, heterogenes Krankheitsbild dar, wobei der Primärtumorlokation meist im Gastrointestinaltrakt lokalisiert ist. Als „Orphan Disease“ sind NEN zwar selten, werden aber primär durch eine verbesserte bildgebende Diagnostik in den letzten Jahren verstärkt diagnostiziert. Hierbei spielt die Somatostatinrezeptor (SSTR)-gerichtete molekulare Bildgebung eine große Rolle, insbesondere die Einzelphotonen-Emissions-Computertomografie (SPECT) sowie die Positronen-Emissions-Tomografie (PET). Neben einer exakten Ausbreitungsdiagnostik generiert die SSTR-gerichtete Bildgebung auch eine Therapierationale für eine Peptidradiorezeptortherapie (PRRT) in einem sog. „theranostischen“ Ansatz. Hierbei wird ein β-Strahler mit dem identischen Peptid des diagnostischen SPECT-/PET-Gegenstücks gekoppelt, um somit eine gezielte, SSTR-gerichtete Bestrahlung von NEN und metastatischer Läsionen zu ermöglichen. Das daraus resultierende „heiße“ Somatostatinanalogon kann als hocheffektives Radiotherapeutikum mit akzeptablem Nebenwirkungsprofil eingesetzt werden, was bereits in einer randomisierten, prospektiven, multizentrischen Studie belegt wurde. Die PRRT erfolgt in Deutschland stationär auf einer nuklearmedizinischen Isotopenstation, wobei Indikation, Durchführung und Nachsorge dieser zielgerichteten Therapie in einem interdisziplinären Ansatz in enger Absprache mit Kolleg*innen der Inneren Medizin, der Medizinphysik und Nuklearmedizin erfolgen sollte. Mit Lutathera (177Lu-Oxodotreotid) steht seit Kurzem ein in Deutschland zugelassenes Arzneimittel zur SSTR-gerichteten Therapie zur Verfügung, womit die PRRT verstärkt Anwendung finden dürfte.

Aim The aim of this study was to provide a systematic approach to characterize DNA damage induction and repair in isolated peripheral blood mononuclear cells (PBMCs) after internal ex vivo irradiation with [131I]NaI. In this approach, we tried to mimic ex vivo the irradiation of patient blood in the first hours after radioiodine therapy. Material and methods Blood of 33 patients of two centres was collected immediately before radioiodine therapy of differentiated thyroid cancer (DTC) and split into two samples. One sample served as non-irradiated control. The second sample was exposed to ionizing radiation by adding 1 ml of [131I]NaI solution to 7 ml of blood, followed by incubation at 37 °C for 1 h. PBMCs of both samples were isolated, split in three parts each and (i) fixed in 70% ethanol and stored at − 20 °C directly (0 h) after irradiation, (ii) after 4 h and (iii) 24 h after irradiation and culture in RPMI medium. After immunofluorescence staining microscopically visible co-localizing γ-H2AX + 53BP1 foci were scored in 100 cells per sample as biomarkers for radiation-induced double-strand breaks (DSBs). Results Thirty-two of 33 blood samples could be analysed. The mean absorbed dose to the blood in all irradiated samples was 50.1 ± 2.3 mGy. For all time points (0 h, 4 h, 24 h), the average number of γ-H2AX + 53BP1 foci per cell was significantly different when compared to baseline and the other time points. The average number of radiation-induced foci (RIF) per cell after irradiation was 0.72 ± 0.16 at t = 0 h, 0.26 ± 0.09 at t = 4 h and 0.04 ± 0.09 at t = 24 h. A monoexponential fit of the mean values of the three time points provided a decay rate of 0.25 ± 0.05 h−1, which is in good agreement with data obtained from external irradiation with γ- or X-rays. Conclusion This study provides novel data about the ex vivo DSB repair in internally irradiated PBMCs of patients before radionuclide therapy. Our findings show, in a large patient sample, that efficient repair occurs after internal irradiation with 50 mGy absorbed dose, and that the induction and repair rate after 131I exposure is comparable to that of external irradiation with γ- or X-rays.

Objectives 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET/CT can be utilized in patients with giant cell arteritis (GCA), but pretest probability of established laboratory marker such as C-reactive protein (CRP) and white blood cell count (WBC) has not been defined yet. We aimed to elucidate the clinical utility of CRP and WBC for scheduling an [18F]FDG scan. Methods 18 treatment-naïve GCA patients and 14 GCA subjects with anti-inflammatory treatment (glucocorticoids or comparable drugs), who underwent [18F]FDG PET/CT and who had no other inflammatory disease at time of scan, were identified. A semi-quantitative analysis in 11 vessel segments was conducted, with averaged jugular vein, healthy liver and lung tissue (Target-to-background ratio [TBR]VJ/liver/lung) serving as background. Derived TBR were then correlated with CRP and WBC at time of PET using Spearman’s correlation. Results For all treatment-naïve patients, TBRVJ was 2.3±1.1 (95%CI, 2.2–2.5), TBRliver was 1.0±0.5 (95%CI, 0.9–1.0) and average TBRlung was 6.3±3.6 (95%CI, 5.8–6.8). No significant correlation was noted for either CRP (TBRVJ: R=–0.19; TBRliver: R=–0.03; TBRlung: R=–0.17; each P ≥ 0.44) or for WBC (TBRVJ: R=–0.40; TBRliver: R=–0.32; TBRlung: R=–0.37; each P ≥ 0.10). Similar results were recorded for patients under treatment at time of PET. Again, no significant correlation was reached for either CRP (TBRVJ: R=–0.17; TBRliver: R=–0.28; TBRlung: R=–0.09; each P ≥ 0.32) or WBC (TBRVJ: R=–0.06; TBRliver: R=–0.13; TBRlung: R=0.06; each P ≥ 0.65). Conclusions In GCA patients with and without anti-inflammatory treatment, CRP and WBC did not substantially correlate with TBR at time of scan. Given the rather limited pretest probability of those parameters, such laboratory values may have less diagnostic utility to order an [18F]FDG PET/CT.

Beyond being a key factor for tumor growth and metastasis in human cancer, C-X-C motif chemokine receptor 4 (CXCR4) is also highly expressed by a number of immune cells, allowing for non-invasive read-out of inflammatory activity. With two recent studies reporting on prognostic implications of the spleen signal in diffusion-weighted magnetic resonance imaging in patients with plasma cell dyscrasias, the aim of this study was to correlate splenic

Purpose Repeat surgery in patients with primary hyperparathyroidism (pHPT) is associated with an increased risk of complications and failure. This stresses the need for optimized strategies to accurately localize a parathyroid adenoma before repeat surgery is performed. However, evidence on the extent of required diagnostics for a structured approach is sparse. Methods A retrospective single-center evaluation of 28 patients with an indication for surgery due to pHPT and previous thyroid or parathyroid surgery was performed. Diagnostic workup, surgical approach, and outcome in terms of complications and successful removement of parathyroid adenoma with biochemical cure were evaluated. Results Neck ultrasound, sestamibi scintigraphy, C11-methionine PET-CT, and selective parathyroid hormone venous sampling, but not MRI imaging, effectively detected the presence of a parathyroid adenoma with high positive predictive values. Biochemical cure was revealed by normalization of calcium and parathormone levels 24–48h after surgery and was achieved in 26/28 patients (92.9%) with an overall low rate of complications. Concordant localization by at least two diagnostic modalities enabled focused surgery with success rates of 100%, whereas inconclusive localization significantly increased the rate of bilateral explorations and significantly reduced the rate of biochemical cure to 80%. Conclusion These findings suggest that two concordant diagnostic modalities are sufficient to accurately localize parathyroid adenoma before repeat surgery for pHPT. In cases of poor localization, extended diagnostic procedures are warranted to enhance surgical success rates. We suggest an algorithm for better orientation when repeat surgery is intended in patients with pHPT.

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.

Purpose The radiolabelled somatostatin analogue [177Lu]Lu-DOTA-EB-TATE binds to albumin via Evans blue, thereby increasing the residence time in the blood and potentially allowing more therapeutic agent to be absorbed into the target tissue during peptide receptor radionuclide therapy. It was tested in selected patients whether the substance is superior to [177Lu]Lu-DOTA-TOC. Methods Activity kinetics in organs and tumours after [177Lu]Lu-DOTA-EB-TATE and [177Lu]Lu-DOTA-TOC were compared intraindividually in five patients with progressive somatostatin receptor-positive disease scheduled for radionuclide therapy. Results In comparison to [177Lu]Lu-DOTA-TOC, tumour doses per administered activity were higher for [177Lu]Lu-DOTA-EB-TATE in 4 of 5 patients (median ratio: 1.7; range: 0.9 to 3.9), kidney doses (median ratio: 3.2; range: 1.6 to 9.8) as well as spleen doses (median ratio: 4.7; range 1.2 to 6.2) in all patients, and liver doses in 3 of 4 evaluable patients (median ratio: 4.0; range: 0.7 to 4.9). The tumour to critical organs absorbed dose ratios were higher after [177Lu]Lu-DOTA-TOC in 4 of 5 patients. Conclusions Prior to a treatment with [177Lu]Lu-DOTA-EB-TATE, it should be assessed individually whether the compound is superior to established substances.

Background Somatostatin receptor (SSTR) positron emission tomography/computed tomography (PET/CT) is increasingly deployed in the diagnostic algorithm of patients affected with medullary thyroid carcinoma (MTC). We aimed to assess the role of SSTR-PET/CT for therapeutic decision making upon restaging. Methods 23 pretreated MTC patients underwent SSTR-PET/CT and were discussed in our interdisciplinary tumor board. Treatment plans were initiated based on scan results. By comparing the therapeutic regimen before and after the scan, we assessed the impact of molecular imaging on therapy decision. SSTR-PET was also compared to CT portion of the SSTR-PET/CT (as part of hybrid imaging). Results SSTR-PET/CT was superior in 9/23 (39.1%) subjects when compared to conventional CT and equivalent in 14/23 (60.9%). Those findings were further corroborated on a lesion-based level with 27/73 (37%) metastases identified only by functional imaging (equivalent to CT in the remaining 46/73 (63%)). Investigating therapeutic decision making, no change in treatment was initiated after PET/CT in 7/23 (30.4%) patients (tyrosine kinase inhibitor (TKI), 4/7 (57.2%); surveillance, 3/7 (42.8%)). Imaging altered therapy in the remaining 16/23 (69.6%). Treatment prior to PET/CT included surgery in 6/16 (37.5%) cases, followed by TKI in 4/16 (25%), active surveillance in 4/16 (25%), and radiation therapy (RTx) in 2/16 (12.5%) subjects. After SSTR-PET/CT, the therapeutic regimen was changed as follows: In the surgery group, 4/6 (66.7%) patients underwent additional surgery, and 1/6 (16.7%) underwent surveillance and TKI, respectively. In the TKI group, 3/4 (75%) individuals received another TKI and the remaining subject (1/4, 25%) underwent peptide receptor radionuclide therapy. In the surveillance group, 3/4 (75%) underwent surgery (1/4, (25%), RTx). In the RTx group, one patient was switched to TKI and another individual was actively monitored (1/2, 50%, respectively). Moreover, in the 16 patients in whom treatment was changed by molecular imaging, control disease rate was achieved in 12/16 (75%) during follow-up. Conclusions In patients with MTC, SSTR-PET/CT was superior to CT alone and provided relevant support in therapeutic decision-making in more than two thirds of cases, with most patients being switched to surgical interventions or systemic treatment with TKI. As such, SSTR-PET/CT can guide the referring treating physician towards disease-directed treatment in various clinical scenarios.

Here, we report a case of a 52-year-old woman with a well-differentiated, metastasized neuroendocrine tumor (NET G1) of the duodenum. Initial imaging with 68 Ga-DOTATOC revealed multiple sites of disease with intense uptake. Peptide receptor radionuclide therapy (PRRT) with 177 Lu-DOTATOC induced partial remission. Treatment was then switched to cold somatostatin analog as a maintenance therapy. After 2 years of follow-up, progressive disease with multiple lesions in the skeleton was noted. Given the initial response to PRRT, a rechallenge with another 2 cycles of PRRT were given, and the patient had an excellent response to treatment, in particular in the skeleton.

Recently, a standardized framework system for interpreting somatostatin receptor (SSTR)–targeted PET/CT, termed the SSTR reporting and data system (RADS) 1.0, was introduced, providing reliable standards and criteria for SSTR-targeted imaging. We determined the interobserver reliability of SSTR-RADS for interpretation of (68)Ga-DOTATOC PET/CT scans in a multicentric, randomized setting. Methods: A set of 51 randomized (68)Ga-DOTATOC PET/CT scans was independently assessed by 4 masked readers with different levels of experience (2 experienced readers and 2 inexperienced readers) trained on the SSTR-RADS 1.0 criteria (based on a 5-point scale from 1 [definitively benign] to 5 [high certainty that neuroendocrine neoplasia is present]). For each scan, SSTR-RADS scores were assigned to a maximum of 5 target lesions (TLs). An overall scan impression based on SSTR-RADS was indicated, and interobserver agreement rates on a TL-based, on an organ-based, and on an overall SSTR-RADS score–based level were computed. The readers were also asked to decide whether peptide receptor radionuclide therapy (PRRT) should be considered on the basis of the assigned RADS scores. Results: Among the selected TLs, 153 were chosen by at least 2 readers (all 4 readers selected the same TLs in 58 of 153 [37.9%] instances). The interobserver agreement for SSTR-RADS scoring among identical TLs was good (intraclass correlation coefficient [ICC] ≥ 0.73 for 4, 3, and 2 identical TLs). For lymph node and liver lesions, excellent interobserver agreement rates were derived (ICC, 0.91 and 0.77, respectively). Moreover, the interobserver agreement for an overall scan impression based on SSTR-RADS was excellent (ICC, 0.88). The SSTR-RADS–based decision to use PRRT also demonstrated excellent agreement, with an ICC of 0.80. No significant differences between experienced and inexperienced readers for an overall scan impression and TL-based SSTR-RADS scoring were observed (P ≥ 0.18), thereby suggesting that SSTR-RADS seems to be readily applicable even for less experienced readers. Conclusion: SSTR-RADS–guided assessment demonstrated a high concordance rate, even among readers with different levels of experience, supporting the adoption of SSTR-RADS for trials, clinical routine, or outcome studies.