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Background: In patients affected with adrenocortical carcinoma (ACC), C-X-C motif chemokine receptor 4 (CXCR4) is highly expressed in sites of disease in an ex-vivo setting. We aimed to determine the predictive value of CXCR4-targeting [ 68 Ga]Ga-PentixaFor PET/CT for outcome when compared to clinical parameters., Methods: We identified 41 metastasized ACC patients imaged with [ 68 Ga]Ga-PentixaFor PET/CT. Scans were assessed visually and on a quantitative level by manually segmenting the tumor burden (providing tumor volume [TV], peak/mean/maximum standardized uptake values [SUV] and tumor chemokine receptor binding on the cell surface [TRB], defined as SUV mean multiplied by tumor volume). Clinical parameters included sex, previous therapies, age, Weiss-Score, and Ki67 index. Following imaging, overall survival (OS) was recorded., Results: After [ 68 Ga]Ga-PentixaFor PET/CT, median OS was 9 months (range, 1-96 months). On univariable analysis, only higher TRB (per 10 ml, HR 1.004, 95%CI: 1.0001-1.007, P = 0.005) and presence of CXCR4-positive peritoneal metastases (PM) were associated with shorter OS (HR 2.03, 95%CI: 1.03-4.02, P = 0.04). Presence of CXCR4-positive liver metastases (LM) trended towards significance (HR 1.85, 0.9-4.1, P = 0.11), while all other parameters failed to predict survival. On multivariable analysis, only TRB was an independent predictor for OS (HR 1.0, 95%CI: 1.00-1.001, P = 0.02). On Kaplan-Meier analysis, TRB above median (13.3 months vs. below median, 6.4 months) and presence of CXCR4-positive PM (6.4 months, vs. no PM, 11.4 months) were associated with shorter survival (P < 0.05, respectively). Presence of LM, however, was also linked to less favorable outcome (8.5 months vs. no LM, 18.1 months), without reaching significance (P = 0.07)., Conclusions: In advanced ACC, elevated tumor chemokine receptor binding on the tumor cell surface detected through [ 68 Ga]Ga-PentixaFor PET/CT is an independent predictor for OS, while other imaging and clinical parameters failed to provide relevant prognostic information., (© 2024. The Author(s).)

Background: C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in various solid cancers and can be targeted by CXCR4-directed molecular imaging. We aimed to characterize the in-vivo CXCR4 expression in patients affected with solid tumors, along with a comparison to ex-vivo findings., Methods: A total 142 patients with 23 different histologically proven solid tumors were imaged with CXCR4-directed PET/CT using [ 68  Ga]Ga-pentixafor (total number of scans, 152). A semi-quantitative analysis of the CXCR4-positive tumor burden including maximum standardized uptake values (SUV max ) and target-to-background ratios (TBR) using blood pool was conducted. In addition, we performed histopathological staining to determine the immuno-reactive score (IRS) from patients' tumor tissue and investigated possible correlations with SUV max (by providing Spearman's rho ρ). Based on imaging, we also assessed the eligibility for CXCR4-targeted radioligand therapy or non-radioactive CXCR4 inhibitory treatment (defined as more than five CXCR4-avid target lesions [TL] with SUV max above 10)., Results: One hundred three of 152 (67.8%) scans showed discernible uptake above blood pool (TBR > 1) in 462 lesions (52 primary tumors and 410 metastases). Median TBR was 4.4 (1.05-24.98), thereby indicating high image contrast. The highest SUV max was observed in ovarian cancer, followed by small cell lung cancer, desmoplastic small round cell tumor, and adrenocortical carcinoma. When comparing radiotracer accumulation between primary tumors and metastases for the entire cohort, comparable SUV max was recorded (P > 0.999), except for pulmonal findings (P = 0.013), indicative for uniform CXCR4 expression among TL. For higher IRS, a weak, but statistically significant correlation with increased SUV max was observed (ρ = 0.328; P = 0.018). In 42/103 (40.8%) scans, more than five TL were recorded, with 12/42 (28.6%) exhibiting SUV max above 10, suggesting eligibility for CXCR4-targeted treatment in this subcohort., Conclusions: In a whole-body tumor read-out, a substantial portion of prevalent solid tumors demonstrated increased and uniform [ 68  Ga]Ga-pentixafor uptake, along with high image contrast. We also observed a respective link between in- and ex-vivo CXCR4 expression, suggesting high specificity of the PET agent. Last, a fraction of patients with [ 68  Ga]Ga-pentixafor-positive tumor burden were rendered potentially suitable for CXCR4-directed therapy., (© 2023. The Author(s).)

Background: In patients with marginal zone lymphoma (MZL), [ 18 F]FDG PET/CT provided inconsistent diagnostic accuracy. C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in MZL and thus, may emerge as novel theranostic target. We aimed to evaluate the diagnostic performance of CXCR4-targeting [ 68 Ga]Ga-PentixaFor when compared to [ 18 F]FDG PET/CT in MZL., Methods: Thirty-two untreated MZL patients (nodal, n = 17; extranodal, n = 13; splenic, n = 2) received [ 68 Ga]Ga-PentixaFor and [ 18 F]FDG PET/CT within median 2 days. We performed a visual and quantitative analysis of the total lymphoma volume by measuring maximum/peak standardized uptake values (SUV max/peak ), and calculating target-to-background ratios (TBR, defined as lesion-based SUV peak divided by SUV mean from blood pool). Visual comparisons for both radiotracers were carried out for all target lesions (TL), and quantitative analysis of concordant TL evident on both scans. Last, MZL subtype analyses were also conducted., Results: On a patient-based level, [ 68 Ga]Ga-PentixaFor identified MZL manifestations in 32 (100%) subjects (vs. [ 18 F]FDG, 25/32 [78.1%]). Of the 256 identified TL, 127/256 (49.6%) manifestations were evident only on CXCR4-directed imaging, while only 7/256 (2.7%) were identified on [ 18 F]FDG but missed by [ 68 Ga]Ga-PentixaFor. In the remaining 122/256 (47.7%) concordant TL, [ 68 Ga]Ga-PentixaFor consistently provided increased metrics when compared to [ 18 F]FDG: SUV max , 10.3 (range, 2.53-37.2) vs. 5.72 (2.32-37.0); SUV peak , 6.23 (1.58-25.7) vs. 3.87 (1.54-27.7); P < 0.01, respectively. Concordant TL TBR on [ 68 Ga]Ga-PentixaFor (median, 3.85; range, 1.05-16.0) was also approximately 1.8-fold higher relative to [ 18 F]FDG (median, 2.08; range, 0.81-28.8; P < 0.01). Those findings on image contrast, however, were driven by nodal MZL (P < 0.01), and just missed significance for extranodal MZL (P = 0.06)., Conclusions: In newly diagnosed MZL patients, [ 68 Ga]Ga-PentixaFor identified more sites of disease when compared to [ 18 F]FDG, irrespective of MZL subtype. Quantitative PET parameters including TBR were also higher on [ 68 Ga]Ga-PentixaFor PET/CT, suggesting improved diagnostic read-out using chemokine receptor-targeted imaging., (© 2023. The Author(s).)

Purpose: The aim of this study was to investigate very early radiographic PSMA PET response after one cycle of [ 177 Lu]Lu-PSMA I&T radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC) and to assess its role in predicting overall response and survival., Methods: This retrospective study enrolled 40 mCRPC patients who were treated with a median of 3 (2-9) [ 177 Lu]Lu-PSMA I&T RLT cycles. Biochemical response was based on the relative change of serum PSA according to PCWG3 criteria, while radiographic response referred to the relative change of PSMA-derived total viable tumor volumes expressed as total lesion PSMA (TLP)., Results: After one cycle of RLT, biochemical partial response (PR) was seen in 8/40 (20.0%), stable disease (SD) in 22/40 (55.0%), and progressive disease (PD) in 10/40 (25%) patients. In PSMA PET, very early molecular PR was observed in 12 (30.0%), SD in 19 (47.5%), and PD in 9 (22.5%) subjects. The PSA and TLP nadir were achieved after a median of 1 (1-5) and 2 (1-6) cycles, respectively. Nineteen (47.5%) patients showed overall biochemical PR, 11 (27.5%) had SD, and 10 (25%) experienced PD. In PSMA-directed PET, 4 patients experienced molecular complete response (CR), 24 (60.0%) had PR, 4 (10.0%) SD, and 8 (20.0%) PD. Early biochemical or radiographic response was not associated with longer overall survival (OS). Overall biochemical responders had a nearly significantly longer median OS (22.7 months) than non-responders (14.4 months, p = 0.08). Early PSA progression was associated with shorter OS (12.2 months), compared to biochemical SD/PR (18.7 months, p = 0.09)., Conclusion: In this retrospective cohort, there was no association between early PSMA PET radiographic response and overall survival; hence, treatment should not be prematurely discontinued. In contrast, early PSA progression after one cycle of [ 177 Lu]Lu-PSMA I&T RLT was an indicator of overall progression and poor clinical outcome., (© 2023. The Author(s).)

Background: Quantification of [ 68  Ga]-labeled PSMA PET predicts response in patients with prostate cancer (PC) who undergo PSMA-targeted radioligand therapy (RLT). Given the increasing use [ 18 F]-labeled radiotracers, we aimed to determine whether the uptake derived from [ 18 F]PSMA-1007 PET can also identify responders and to assess its prognostic value relative to established clinical parameters., Methods: We retrospectively analyzed 103 patients with metastatic, castration-resistant PC who were treated with [ 177 Lu]Lu-PSMA I&T. We calculated SUV mean , SUV max , PSMA-avid tumor volume (TV), and total lesion PSMA (defined as PSMA-TV*SUV mean ) on pre-therapeutic [ 18 F]PSMA-1007 PET. Laboratory values for hemoglobin, C-reactive protein (CRP), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alkaline phosphatase (AP) were also collected prior to RLT. We performed univariable Cox regression followed by multivariable and Kaplan-Meier analyses with overall survival (OS) serving as endpoint. Last, we also computed a risk factor (RF) model including all items reaching significance on multivariable analysis to determine whether an increasing number of RFs can improve risk stratification., Results: A total of 48 patients died and median OS was 16 months. On univariable Cox regression, SUV mean , CRP, LDH, hemoglobin, and the presence of liver metastases were significantly associated with OS. On multivariable Cox regression, the following significant prognostic factors for OS were identified: SUV mean (per unit, HR, 0.91; P = 0.04), the presence of liver metastases (HR, 2.37; P = 0.03), CRP (per mg/dl, HR, 1.13; P = 0.003), and hemoglobin (per g/dl, HR, 0.76; P < 0.01). Kaplan-Meier analysis showed significant separation between patients with a SUV mean below or above a median SUV mean of 9.4 (9 vs 19 months, HR 0.57; P = 0.03). Of note, patients with only one RF (median OS not reached) showed longest survival compared to patients with two (11 months; HR 2.43 95% CI 1.07-5.49, P = 0.02) or more than two RFs (7 months; HR 3.37 95% CI 1.62-7.03, P < 0.001)., Conclusion: A lower SUV mean derived from [ 18 F]PSMA-1007, higher CRP, lower hemoglobin, and the presence of liver metastases are associated with reduced OS in patients undergoing RLT. An early RF model also demonstrated that an increasing number of those factors is linked to worse outcome, thereby emphasizing the importance of clinical and imaging parameters for adequate risk stratification., (© 2023. The Author(s).)

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 < 0.01; TBR: r =  - 0.26, P = 0.04), calcified plaque thickness (FAPI + number: r = 0.33, P < 0.01; TBR: r =  - 0.29, P = 0.02), and calcification circumference (FAPI + number: r = 0.34, P < 0.01; TBR: 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 < 0.01). The numbers of FAPI + sites and FAPI + TBR, however, were not associated with other investigated CVRFs in univariate and multivariate regression analyses. Image noise, however, showed significant correlations with FAPI + TBR (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., (© 2023. The Author(s).)

Purpose: Positron emission tomography (PET) with O-(2-[ 18 F]fluoroethyl)-L-tyrosine ([ 18 F]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, [ 18 F]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 [ 18 F]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: [ 18 F]FET-PET may provide important additional information for treatment guidance in pediatric and adolescent patients with CNS tumors., (© 2023. The Author(s).)

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 &lt; 0.001). Patients with PSA fluctuations showed a significantly longer median OS compared to patients with sustained increase of PSA levels (18 vs. 8 months; HR 0.49, 95% CI 0.30-0.80; P &lt; 0.01), but no significant difference relative to men with sustained PSA decrease (18 vs. 19 months; HR 1.4, 95% CI 0.78-2.49; 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., (© 2022. The Author(s).)

Background: Radioligand therapy (RLT) with 177 Lu-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 [ 177 Lu]Lu-PSMA I&T RLT in a long-term follow-up., Materials and Methods: Ninety-two mCRPC patients treated with [ 177 Lu]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 (interval Diagnosis-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 interval Diagnosis-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 interval Diagnosis-RLT , 43.5 months (AUC, 0.68; P < 0.01, respectively). Respective Kaplan-Meier analyses demonstrated a significantly longer median OS of patients with lower CRP, lower LDH, and lower AST, as well as prolonged interval Diagnosis-RLT (P ≤ 0.01, respectively)., Conclusion: In mCRPC patients treated with [ 177 Lu]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 [ 177 Lu]Lu-PSMA-617, and we believe that these clinical baseline characteristics may support the nuclear medicine specialist to identify long-term survivors., (© 2022. The Author(s).)

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 [ 177 Lu]/[ 90 Y]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., (© 2022. The Author(s).)

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 [ 223 Ra]RaCl 2 ., Methods: Blood samples of ten volunteers were irradiated by adding [ 223 Ra]RaCl 2 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., (© 2022. The Author(s).)

Purpose: The purpose of this study was to immunohistochemically validate the primary tumor PSMA expression in prostate cancer (PCa) patients imaged with [ 68 Ga]Ga-PSMA PET/CT prior to surgery, with special consideration of PET-negative cases., Methods: The study included 40 men with newly diagnosed treatment-naïve PCa imaged with [ 68 Ga]Ga-PSMA I&T PET/CT as part of the diagnostic work-up prior to radical prostatectomy. All primary tumors were routinely stained with H&E. In addition, immunohistochemical staining of PSMA was performed and the immunoreactive score (IRS) was computed as semiquantitative measure. Subsequently, imaging findings were correlated to histopathologic results., Results: Eighty-three percent (33/40) of patients presented focal uptake of [ 68 Ga]Ga-PSMA I&T in the primary tumor in at least one prostate lobe. Among PSMA-PET positive patients, one-third had lymph node metastases (LNM) detected by post-operative histopathology, while in PET negative patients, only 1 out of 7 presented with regional LN involvement; PSMA-avid distant lesions, predominantly in bones, were observed in 15% and 0% of patients, respectively. The median IRS classification of PSMA expression in tumor tissue was 2 (range, 1-3) both in PSMA-PET positive and negative prostate lobes, with significantly different interquartile range: 2-3 vs. 2-2, respectively (p = 0.03). The median volume of PSMA-PET positive tumors was 5.4 mL (0.2-32.9) as compared to 1.6 mL (0.3-18.3) of PET-negative tumors (p < 0.001). There was a significant but weak correlation between SUV max and percentage of PSMA-positive tumor cells (r = 0.46, p < 0.001). A total of 35/44 (~80%) lobes were positive in PSMA-PET imaging, when a cut-off percentage of PSMA-positive cells was ≥ 90%, while 19/36 (~53%) lobes with < 90% PSMA-positive cells were PSMA-PET negative., Conclusion: Positive [ 68 Ga]Ga-PSMA I&T PET/CT scan of primary tumor of PCa results from a combination of factors, such as homogeneity and intensity of PSMA expression, tumor volume and grade, with a cutoff value of ≥ 90% PSMA-positive cells strongly determining PET-positivity. Focal accumulation of [ 68 Ga]Ga-PSMA in the primary tumor may correlate positively with aggressiveness of prostate cancer, harboring higher risk of regional LN involvement and distant metastatic spread., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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 [ 177 Lu]Lu-PSMA I&T, and a matched cohort of 55 patients treated with [ 177 Lu]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 [ 177 Lu]Lu-PSMA I&T and five (9.1%) for [ 177 Lu]Lu-PSMA-617. In addition, one (1.9%) grade III thrombopenia for [ 177 Lu]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 [ 177 Lu]Lu-PSMA I&T did not differ significantly when compared to patients treated with [ 177 Lu]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., (© 2022. The Author(s).)

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 [ 131 I]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 [ 131 I]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 131 I exposure is comparable to that of external irradiation with γ- or X-rays., (© 2021. The Author(s).)

Purpose: Adrenal tumors represent a diagnostic and therapeutic challenge. Promising results have been obtained through targeting the cytochrome P450 enzymes CYP11B1 and CYP11B2 for molecular imaging, and [ 123/131 I]iodometomidate ([ 123/131 I]IMTO) has even been successfully introduced as a theranostic agent. As this radiopharmaceutical shows rapid metabolic inactivation, we aimed at developing new improved tracers., Methods: Several IMTO derivatives were newly designed by replacing the unstable methyl ester by different carboxylic esters or amides. The inhibition of aldosterone and cortisol synthesis was tested in different adrenocortical cell lines. The corresponding radiolabeled compounds were assessed regarding their stability, in vitro cell uptake, in vivo biodistribution in mice, and their binding specificity to cryosections of human adrenocortical and non-adrenocortical tissue. Furthermore, a first investigation was performed in patients with known metastatic adrenal cancer using both [ 123 I]IMTO and the most promising compound (R)-1-[1-(4-[ 123 I]iodophenyl)ethyl]-1H-imidazole-5-carboxylic acid azetidinylamide ([ 123 I]IMAZA) for scintigraphy. Subsequently, a first endoradiotherapy with [ 131 I]IMAZA in one of these patients was performed., Results: We identified three analogues to IMTO with high-affinity binding to the target enzymes and comparable or higher metabolic stability and very high and specific accumulation in adrenocortical cells in vitro and in vivo. Labeled IMAZA exhibited superior pharmacokinetic and imaging properties compared to IMTO in mice and 3 patients, too. An endoradiotherapy with [ 131 I]IMAZA induced a 21-month progression-free interval in a patient with rapidly progressing ACC prior this therapy., Conclusion: We developed the new radiopharmaceutical [ 123/131 I]IMAZA with superior properties compared to the reference compound IMTO and promising first experiences in humans., (© 2021. The Author(s).)

Purpose: While [ 18 F]-fluorodeoxyglucose ([ 18 F]FDG) is the standard for positron emission tomography/computed tomography (PET/CT) imaging of oral squamous cell carcinoma (OSCC), diagnostic specificity is hampered by uptake in inflammatory cells such as neutrophils or macrophages. Recently, molecular imaging probes targeting fibroblast activation protein α (FAP), which is overexpressed in a variety of cancer-associated fibroblasts, have become available and might constitute a feasible alternative to FDG PET/CT., Methods: Ten consecutive, treatment-naïve patients (8 males, 2 females; mean age, 62 ± 9 years) with biopsy-proven OSCC underwent both whole-body [ 18 F]FDG and [ 68 Ga]FAPI-04 (FAP-directed) PET/CT for primary staging prior to tumor resection and cervical lymph node dissection. Detection of the primary tumor, as well as the presence and number of lymph node and distant metastases was analysed. Intensity of tracer accumulation was assessed by means of maximum (SUV max ) and peak (SUV peak ) standardized uptake values. Histological work-up including immunohistochemical staining for FAP served as standard of reference., Results: [ 18 F]FDG and FAP-directed PET/CT detected all primary tumors with a SUV max of 25.5 ± 13.2 (FDG) and 20.5 ± 6.4 (FAP-directed) and a SUV peak of 16.1 ± 10.3 ([ 18 F]FDG) and 13.8 ± 3.9 (FAP-directed), respectively. Regarding cervical lymph node metastases, FAP-directed PET/CT demonstrated comparable sensitivity (81.3% vs. 87.5%; P = 0.32) and specificity (93.3% vs. 81.3%; P = 0.16) to [ 18 F]FDG PET/CT. FAP expression on the cell surface of cancer-associated fibroblasts in both primary lesions as well as lymph nodes metastases was confirmed in all samples., Conclusion: FAP-directed PET/CT in OSCC seems feasible. Future research to investigate its potential to improve patient staging is highly warranted., (© 2021. The Author(s).)

Purpose: The radiolabelled somatostatin analogue [ 177 Lu]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 [ 177 Lu]Lu-DOTA-TOC., Methods: Activity kinetics in organs and tumours after [ 177 Lu]Lu-DOTA-EB-TATE and [ 177 Lu]Lu-DOTA-TOC were compared intraindividually in five patients with progressive somatostatin receptor-positive disease scheduled for radionuclide therapy., Results: In comparison to [ 177 Lu]Lu-DOTA-TOC, tumour doses per administered activity were higher for [ 177 Lu]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 [ 177 Lu]Lu-DOTA-TOC in 4 of 5 patients., Conclusions: Prior to a treatment with [ 177 Lu]Lu-DOTA-EB-TATE, it should be assessed individually whether the compound is superior to established substances.

Background: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with 177 Lu-labeled PSMA ligands has achieved remarkable results in advanced disease stages of metastatic castration-resistant prostate cancer (mCRPC). However, not all patients benefit from this therapy. Different treatment responses could be explained by tumor heterogeneity triggered by progression and the number of prior treatments. PSMA-negative lesions can be missed on PSMA ligand PET/CT, which subsequently results in an underestimation of tumor burden. Conversely, high FDG uptake may also be an indicator of tumor aggressiveness and thus a poor prognostic marker for response to RLT and overall survival (OS). The aim of this analysis was to investigate the prognostic value of combined PSMA ligand PET/CT and [ 18 F]fluorodeoxyglucose (FDG) PET/CT for outcome prediction in patients undergoing RLT., Materials and Methods: This bicentric analysis included 54 patients with mCRPC who underwent both FDG and PSMA ligand PET/CT imaging before RLT. In all patients, the pattern of PSMA ligand and FDG uptake was visually assessed. Patients with at least one FDG-positive, but PSMA-negative (FDG+/PSMA-) lesions were compared to patients without any FDG+/PSMA- lesions. A log-rank analysis was used to assess the difference in OS between subgroups., Results: Median OS was 11 ± 1.8 months (95% CI 7.4-14.6). A significantly lower OS (p < 0.001) was found in patients with at least one FDG+/PSMA- lesion at baseline PET/CTs (n = 18) with a median OS of 6.0 ± 0.5 months (95% CI: 5.0-7.0 months). In comparison, patients without any FDG+/PSMA- lesions (n = 36) had a median OS of 16.0 ± 2.5 months (95% CI: 11.2-20.8 months)., Conclusion: FDG+/PSMA- lesions are a negative predictor of overall survival in patients with mCRPC undergoing RLT. However, it remains to be determined if patients with FDG+/PSMA- lesions should be excluded from PSMA RLT.

Purpose: In cancer of unknown primary (CUP), positron emission tomography/computed tomography (PET/CT) with the glucose analog [ 18 F]FDG represents the standard imaging approach for localization of the malignant primary. Frequently, however, [ 18 F]FDG PET/CT cannot precisely distinguish between small occult tumors and chronic inflammation, especially in Waldeyer's tonsillar ring. To improve the accuracy for detecting primary tumors in the Waldeyer's tonsillar ring, the novel PET tracer [ 68 Ga]Ga-FAPI-4 for specific imaging of fibroblast activation protein (FAP) expression was used as a more specific target for cancer imaging., Methods: Eight patients with suspicion of a malignant tumor in Waldeyer's tonsillar ring or a CUP syndrome were examined. PET/CT scans with [ 18 F]-FDG and [ 68 Ga]Ga-FAPI-4 were performed for pre-operative tumor localization. After surgical resection, histopathological and immunohistochemical results were compared to PET/CT findings., Results: Histopathology revealed a palatine or lingual tonsil carcinoma in all patients. In case of lymph node metastases smaller than 7 mm in size, the [ 18 F]FDG PET/CT detection rate of cervical lymph node metastases was higher than that of [ 68 Ga]FAPI PET/CT, while both tracers identified the primary tumors in all eight cases. The size of the primary and the lymph node metastases was directly correlated to the respective FAP expression, as detected by immunohistochemistry. The mean SUV max for the primary tumors was 21.29 ± 7.97 for 18 F-FDG and 16.06 ± 6.29 for 68 Ga-FAPI, respectively (p = 0.2). The mean SUV max for the healthy contralateral tonsils was 8.38 ± 2.45 for [ 18 F]FDG and 3.55 ± 0.47 for [ 68 Ga]FAPI (p < 0.001). The SUV max ratio of [ 68 Ga]FAPI was significantly different from [ 18 F] FDG (p = 0.03). Mean TBR max for the [ 68 Ga]Ga-FAPI-4 tracer was markedly higher in comparison to [ 18 F]FDG (10.90 vs. 4.11)., Conclusion: Non-invasive imaging of FAP expression by [ 68 Ga]FAPI PET/CT resulted in a better visual detection of the malignant primary in CUP, as compared to [ 18 F]FDG imaging. However, the detection rate of lymph node metastases was inferior, presumably due to low FAP expression in small metastases. Nevertheless, by offering a detection method for primary tumors with the potential of lower false positive rates and thus avoiding biopsies, patients with CUP syndrome may benefit from [ 68 Ga]FAPI PET/CT imaging.

Purpose: The present study is based on a retrospective analysis of Gallium-68 ( 68 Ga)-labelled prostate-specific membrane antigen ( 68 Ga-PSMA I&T) PET/CT performed in newly diagnosed, treatment-naïve prostate cancer (PCa) patients prior to definitive treatment., Methods: A total of 82 men were included in the study and were imaged with 68 Ga-PSMA I&T PET/CT to assess the distribution of PSMA-avid disease for staging purposes (11 with low-risk, 32 with intermediate-risk, and 39 with high-risk PCa). Forty patients (20 with intermediate- and 20 with high-risk disease) underwent subsequent radical prostatectomy with extended pelvic lymph node dissection which allowed for correlation of imaging findings with histopathologic data., Results: PSMA-positive disease was detected in 83% of patients with 66/82 (80.5%) primary tumours being visualized. PSMA-avid lymph nodes were recorded in 17/82 patients (20.7%, 3 with intermediate-risk and 14 with high-risk PCa); distant disease was found in 14/82 subjects (17.1%, 2 with intermediate-risk and 12 with high-risk PCa). No extraprostatic disease was found in low-risk PCa. SUV max of primary tumours showed a weak but significant correlation with serum PSA values (r = 0.51, p < 0.001) and Gleason scores (GSC; r = 0.35, p = 0.001), respectively. In correlation with histopathology, calculated per-region sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for detection of lymph node metastases were 35.0%, 98.4%, 63.6%, 95.0%, and 93.0%, respectively., Conclusions: In patients with initial diagnosis of intermediate- and high-risk prostate cancer, 68 Ga-PSMA I&T PET/CT emerges as a relevant staging procedure by identifying nodal and/or distant metastases. Due to the low prevalence of extraprostatic disease, its value seems to be limited in low-risk disease.

Purpose: Cardiac amyloidosis (CA) is a rare cause of heart failure with frequently delayed diagnosis, because specific early signs or symptoms are missing. Recently, direct amyloid imaging using positron emission tomography/computed tomography (PET/CT) has emerged. The aim of this study was to examine the performance of 18 F-florbetaben-PET/CT in detection of CA, and compare it to echocardiography (echo), cardiac MRI (CMR) and scintigraphy. Additionally, the use of 18 F-florbetaben-PET/CT for quantification of amyloid burden and monitoring of treatment response was assessed., Methods: Twenty-two patients with proven (n = 5) or clinical suspicion (n = 17) of CA underwent 18 F-florbetaben-PET/CT for diagnostic work-up. Qualitative and quantitative assessment including calculation of myocardial tracer retention (MTR) was performed, and compared to echo (n = 20), CMR (n = 16), scintigraphy (n = 16) and serologic biomarkers (NT-proBNP, cTnT, free light chains). In four patients, follow-up PET/CT was available (after treatment initiation, n = 3; surveillance, n = 1)., Results: PET demonstrated myocardial 18 F-florbetaben retention consistent with CA in 14/22 patients. Suspicion of CA was subsequently dropped in all eight PET-negative patients. Amyloid subtypes showed characteristic retention patterns (AL > AA > ATTR; all p < 0.005). MTR correlated with morphologic and functional parameters, as measured by CMR and echo (all r| > 0.47|, all p < 0.05), but not with cardiac biomarkers. Changes in MTR from baseline to follow-up corresponded well to treatment response, as assessed by cardiac biomarkers and performance status., Conclusions: Imaging of cardiac amyloidosis (CA) with 18 F-florbetaben-PET/CT is feasible and might be useful in differentiating CA subtypes.

Purpose: Despite improved treatment options, multiple myeloma (MM) remains an incurable disease. The aim of this study was to investigate the prognostic value of positron emission tomography/computed tomography (PET/CT) using 18 F-2'-deoxy-2'-fluorodeoxyglucose ([ 18 F]FDG) in MM patients shortly before and ~100 days after allogeneic hematopoietic cell transplantation (allo-HCT)., Methods: In this retrospective analysis, we evaluated [ 18 F]FDG-PET/CT-scans of 45 heavily pre-treated MM patients before and 27 patients after scheduled allo-HCT. All scans were qualitatively and semi-quantitatively assessed for the presence of active disease. Serological response was recorded according to International Myeloma Working Group (IMWG) criteria. Progression-free (PFS) and overall survival (OS) were correlated with different PET/CT-derived parameters, such as presence, number and maximum standardized uptake value (SUV max ) of focal myeloma lesions. The impact of extramedullary disease on patient outcome was also assessed., Results: PET/CT negativity -prior to or following allo-HCT- was a favorable prognostic factor for progression-free and overall survival (both, PFS and OS: pre-HSCT p < 0.001, post-HCT p < 0.005). High FDG-uptake (SUV max  > 6.5) revealed a significantly shortened survival compared to patients with a lower SUV max (<6.5) (OS, 5.0 ± 1.1 m vs. not reached - longest 122.0 m; p < 0.001). Moreover, our data prove that a higher number (>3) of focal lesions (pre-HCT: both PFS and OS: p < 0.001; post-HCT PFS: p < 0.001, OS: p = 0.139) as well as the presence of extramedullary disease serve as adverse prognostic factors prior to and after allo-HCT. At response assessment after allo-HCT, [ 18 F]FDG-PET/CT had a complementary value in prognostication in addition to IMWG criteria alone., Conclusion: [ 18 F]FDG-PET/CT before and shortly after allogeneic HCT is a powerful predictor for progression-free and overall survival in MM patients.

Purpose: Radioguided sentinel lymph node biopsy (SLNB) is the standard of care in breast cancer and melanoma. Additional preoperative Single-photon emission computed tomography (SPECT/CT) for improved anatomical co-registration of the SLNs causes additional radiation exposure and is time-consuming and expensive. The aim of this prospective study was to evaluate a novel approach involving real-time fusion of freehand SPECT (fhSPECT) and ultrasound (US) for anatomical co-registration of SLNs., Methods: From February 2015 to February 2016, 153 patients were included in this prospective study. All patients underwent lymphoscintigraphy according to practical guidelines and 151 (118 cases of breast cancer, 30 cutaneous malignancies, and three cases of vulvar cancer) of the 153 patients were additionally investigated with fhSPECT-US. FhSPECT connected to a hand-held gamma detector generates three-dimensional images of the radioactivity distribution in the scanned area. For co-registration and real-time fusion of fhSPECT and subsequently performed US, an infrared stereo tracking system was used., Results: In all patients an SLN was found on lymphoscintigraphy, and the fhSPECT detected corresponding hotspots in all but one patient. In 72 % of patients and 73 % of lymph node basins, real-time anatomical co-registration with US was feasible. The rate of success in achieving good co-registration increased from 60 to 75 % after training by a radiologist specialized in breast imaging. A higher co-registration rate (78 %) was observed in patients with only one SLN than in those with two SLNs (68 %) or three or more SLNs (0 %)., Conclusions: Real-time fusion of fhSPECT and US for preoperative anatomical co-registration of SLNs is feasible. However, before this approach can completely replace preoperative lymphatic imaging, further technical developments are needed.

Purpose: The aim of this study was to synthesize and preclinically evaluate an 18 F-PSMA positron emission tomography (PET) tracer. Prostate-specific membrane antigen (PSMA) specificity, biodistribution, and dosimetry in healthy and tumor-bearing mice were determined., Methods: Several conditions for the labeling of 18 F-PSMA-11 via 18 F-AlF-complexation were screened to study the influence of reaction temperature, peptide amount, ethanol volume, and reaction time. After synthesis optimization, biodistribution and dosimetry studies were performed in C57BL6 mice. For proof of PSMA-specificity, mice were implanted with PSMA-negative (PC3) and PSMA-positive (LNCaP) tumors in contralateral flanks. Static and dynamic microPET/computed tomography (CT) imaging was performed., Results: Quantitative labeling yields could be achieved with >97 % radiochemical purity. The 18 F-PSMA-11 uptake was more than 24-fold higher in PSMA-high LNCaP than in PSMA-low PC3 tumors (18.4 ± 3.3 %ID/g and 0.795 ± 0.260 %ID/g, respectively; p < 4.2e-5). Results were confirmed by ex vivo gamma counter analysis of tissues after the last imaging time point. The highest absorbed dose was reported for the kidneys. The maximum effective dose for an administered activity of 200 MBq was 1.72 mSv., Conclusion: 18 F-PSMA-11 using direct labeling of chelate-attached peptide with aluminum-fluoride detected PSMA-expressing tumors with high tumor-to-liver ratios. The kidneys were the dose-limiting organs. Even by applying the most stringent dosimetric calculations, injected activities of up to 0.56 GBq are feasible., Competing Interests: Johannes Czernin is founder of Sofie Biosciences, which manufactures the Genisys4 scanner used in this manuscript. No other potential conflicts of interest are reported.

Purpose: To prospectively evaluate the feasibility of 3-D radioguided occult lesion localization (iROLL) and to compare iROLL with wire-guided localization (WGL) in patients with early-stage breast cancer undergoing breast-conserving surgery and sentinel lymph node biopsy (SLNB)., Methods: WGL (standard procedure) and iROLL in combination with SLNB were performed in 31 women (mean age 65.1 ± 11.2 years) with early-stage breast cancer and clinically negative axillae. Patient comfort in respect of both methods was assessed using a ten point scale. SLNB and iROLL were guided by freehand SPECT (fhSPECT). The results of the novel 3-D image-based method were compared with those of WGL, ultrasound-based lesion localization, and histopathology., Results: iROLL successfully detected the malignant primary and at least one sentinel lymph node in 97% of patients. In a single patient (3%), only iROLL, and not WGL, enabled lesion localization. The variability between fhSPECT and ultrasound-based depth localization of breast lesions was low (1.2 ± 1.4 mm). Clear margins were achieved in 81% of the patients; however, precise prediction of clear histopathological surgical margins was not feasible using iROLL. Patients rated iROLL as less painful than WGL with a pain score 0.8 ± 1.2 points (p < 0.01) lower than the score for iROLL., Conclusion: iROLL is a well-tolerated and feasible technique for localizing early-stage breast cancer in the course of breast-conserving surgery, and is a suitable replacement for WGL. As a single image-based procedure for localization of breast lesions and sentinel nodes, iROLL may improve the entire surgical procedure. However, no advantages of the image-guided procedure were found with regard to prediction of complete tumour resection.

Purpose: The aim of the study was to investigate DNA double strand break (DSB) formation and its correlation with the absorbed dose to the blood lymphocytes of patients undergoing their first peptide receptor radionuclide therapy (PRRT) with (177)Lu-labelled DOTATATE/DOTATOC., Methods: The study group comprised 16 patients receiving their first PRRT. At least six peripheral blood samples were obtained before, and between 0.5 h and 48 h after radionuclide administration. From the time-activity curves of the blood and the whole body, residence times for blood self-irradiation and whole-body irradiation were determined. Peripheral blood lymphocytes were isolated, fixed with ethanol and subjected to immunofluorescence staining for colocalizing γ-H2AX/53BP1 DSB-marking foci. The average number of DSB foci per cell per patient sample was determined as a function of the absorbed dose to the blood and compared with an in vitro calibration curve established in our laboratory with (131)I and (177)Lu., Results: The average number of radiation-induced foci (RIF) per cell increased over the first 5 h after radionuclide administration and decreased thereafter. A linear fit from 0 to 5 h as a function of the absorbed dose to the blood agreed with our in vitro calibration curve. At later time-points the number of RIF decreased, indicating progression of DNA repair., Conclusion: Measurements of RIF and the absorbed dose to the blood after systemic administration of (177)Lu may be used to obtain data on the individual dose-response relationships in vivo. Individual patient data were characterized by a linear dose-dependent increase and an exponential decay function describing repair.

Purpose: The aim of this study was to prospectively evaluate the feasibility and potential advantages of freehand single-photon emission computed tomography (fhSPECT) compared with conventional intraoperative localization techniques for sentinel lymph node biopsy (SLNB) in oral cancer., Methods: Between November 2012 and February 2014, 23 consecutive patients with clinical T1/T2 oral squamous cell carcinoma and a cN0 neck were recruited. All patients underwent SLNB followed by elective neck dissection (END). All patients received preoperative lymphoscintigraphy. To detect the SLNs intraoperatively, fhSPECT with a combination of conventional acoustic SLN localization and 3-D visual navigation was used., Results: All but one of the SLNs detected by preoperative imaging were successfully mapped intraoperatively by fhSPECT (detection rate 98%), including those in six patients with a tumour in the floor of the mouth. A histopathology analysis revealed positive SLNs in 22% of patients. No further metastases were found in LNs resected during END. SLNB correctly predicted the final LN stage in all patients (accuracy 100%). Additional radioactive LNs, which were not present on preoperative lymphoscintigraphy, were observed in three patients., Conclusion: FhSPECT is a feasible technology that allows the accurate identification of SLNs in oral cancer. FhSPECT overcomes the shine-through phenomenon, one of the most important limitations of SLNB, thereby confirming the importance of SLNB in patients with cN0 oral cancer.

Purpose: To assess the risk of differentiated thyroid cancer (DTC) recurrence, DTC-related mortality and life expectancy in relation to the number of courses of (131)I therapy (RIT) and cumulative (131)I activities required to achieve complete remission (CR)., Methods: The study was a database review of 1,229 patients with DTC, 333 without and 896 with CR (negative TSH-stimulated thyroglobulin and negative (131)I diagnostic whole-body scintigraphy) after one or more courses of RIT., Results: The median follow-up was 9.0 years (range 0.1 - 31.8 years) after CR. Recurrence rates at 5 years, 10 years and the end of follow-up were 1.0 ± 0.3%, 4.0 ± 0.7 % and 6.2 ± 1.1 %, and DTC-related mortality was 0.1 ± 0.1%, 0.5 ± 0.3% and 3.4 ± 1.1%, respectively. Recurrence rates also increased with an increasing number of RIT courses required (p = 0.001). DTC-related mortality increased from four RIT courses. In patients with CR after one RIT course, there were no differences in recurrence or DTC-related mortality rates between low-risk and high-risk patients. In patients requiring two RIT courses these rates remain elevated in high-risk patients. Recurrence and DTC-related mortality rates were only significantly elevated in those requiring a cumulative activity over 22.2 GBq (600 mCi) from multiple RIT courses for CR. Regardless of the number of RIT courses or activity needed, life expectancy was not significantly lowered., Conclusion: If more than one RIT course is needed to achieve CR, higher recurrence and DTC-related mortality rates are observed, especially in high-risk patients. Patients requiring >22.2 GBq (131)I for CR should be followed in the same way as patients in whom CR is never reached as long-term mortality rates are similar.

Purpose: The aim of this retrospective two-centre study was to investigate the clinical impact of (11)C-choline PET/CT on treatment management decisions in patients with recurrent prostate cancer (rPCa) after radical therapy., Methods: Enrolled in this retrospective study were 150 patients (95 from Bologna, 55 from Würzburg) with rPCa and biochemical relapse (PSA mean ± SD 4.3 ± 5.5 ng/mL, range 0.2-39.4 ng/mL) after radical therapy. The intended treatment before PET/CT was salvage radiotherapy of the prostatic bed in 95 patients and palliative androgen deprivation therapy (ADT) in 55 patients. The effective clinical impact of (11)C-choline PET/CT was rated as major (change in therapeutic approach), minor (same treatment, but modified therapeutic strategy) or none. Multivariate binary logistic regression analysis included PSA level, PSA kinetics, ongoing ADT, Gleason score, TNM, age and time to relapse., Results: Changes in therapy after (11)C-choline PET/CT were implemented in 70 of the 150 patients (46.7%). A major clinical impact was observed in 27 patients (18%) and a minor clinical impact in 43 (28.7%). (11)C-choline PET/CT was positive in 109 patients (72.7%) detecting local relapse (prostate bed and/or iliac lymph nodes and/or pararectal lymph nodes) in 64 patients (42.7%). Distant relapse (paraaortic and/or retroperitoneal lymph nodes and/or bone lesions) was seen in 31 patients (20.7%), and both local and distant relapse in 14 (9.3%). A significant difference was observed in PSA level and PSA kinetics between PET-positive and PET-negative patients (p < 0.05). In multivariate analysis, PSA level, PSA doubling time and ongoing ADT were significant predictors of a positive scan (p < 0.05). In statistical analysis no significant differences were observed between the Bologna and Würzburg patients (p > 0.05). In both centres the same criteria to validate PET-positive findings were used: in 17.3% of patients by histology and in 82.7% of patients by correlative imaging and/or clinical follow-up (follow-up mean 20.5 months, median 18.3 months, range 6.2-60 months)., Conclusion: (11)C-Choline PET/CT had a significant impact on therapeutic management in rPCa patients. It led to an overall change in 46.7% of patients, with a major clinical change implemented in 18% of patients. Further prospective studies are needed to evaluate the effect of such treatment changes on patient survival.

Purpose: Positron emission tomography (PET) with the thymidine analogue [(18)F]fluorothymidine ([(18)F]FLT) has been shown to detect early response to chemotherapy in high-grade lymphoma. In this preclinical in vitro and in vivo study we compared [(18)F]FLT to the glucose analogue [(18)F]fluorodeoxyglucose ([(18)F]FDG) regarding dose-dependent visualization and prediction of early therapy response., Methods: Immunodeficient mice bearing human diffuse large B-cell lymphoma (SUDHL-4) xenotransplants were treated intraperitoneally with increasing doses of the cytotoxic agent doxorubicin. Metabolic and antiproliferative effects were assessed 2 days after therapy by [(18)F]FLT and [(18)F]FDG PET. Explanted lymphomas were analysed histologically and by immunostaining against Ki67 and caspase 3. In vitro, lymphoma cells were incubated with increasing concentrations of doxorubicin and analysed using the tetrazolium assay, fluorescence-activated cell sorting, and [(18)F]FLT and [(18)F]FDG uptake 48 h later., Results: In vivo, tumour growth was inhibited by doses of doxorubicin ranging from 25 μg to 200 μg. The mean tumour-to-background ratio (TBR) of [(18)F]FLT on day +2 was significantly reduced in all dose groups compared to control and baseline values and preceded changes in tumour volume. Importantly, there was a significant inverse correlation between reduction in TBR and dose of chemotherapy (r = -0.54, p = 0.021). The mean TBR of [(18)F]FDG, however, increased after therapy and differed considerably between groups (r = -0.13, p = 0.668). Explanted tumours showed a dose-dependent decrease in the proliferation marker Ki67, but no change in the apoptotic marker caspase 3. In vitro, doxorubicin led to a dose-dependent reduction in cell viability and a decrease in S phase. Lymphoma cells showed a dose-dependent reduction in [(18)F]FLT uptake, in contrast to a variable and decelerated reduction in [(18)F]FDG uptake. Thus, the increase in [(18)F]FDG uptake in vivo presumably reflected nonspecific glucose metabolism of inflammatory cells, as confirmed by histology of explanted lymphomas., Conclusion: Early responses to dose-dependent antiproliferative treatment in high-grade lymphoma are more accurately visualized with [(18)F]FLT PET than with [(18)F]FDG PET.

Purpose: To investigate whether the tumour uptake of radionuclide in peptide receptor radionuclide therapy (PRRT) of meningioma can be predicted by a PET scan with (68)Ga-labelled somatostatin analogue., Methods: In this pilot trial, 11 meningioma patients with a PET scan indicating somatostatin receptor expression received PRRT with 7.4 GBq (177)Lu-DOTATOC or (177)Lu-DOTATATE, followed by external beam radiotherapy. A second PET scan was scheduled for 3 months after therapy. During PRRT, multiple whole-body scans and a SPECT/CT scan of the head and neck region were acquired and used to determine the kinetics and dose in the voxel with the highest radionuclide uptake within the tumour. Maximum voxel dose and retention of activity 1 h after administration in PRRT were compared to the maximum standardized uptake values (SUV(max)) in the meningiomas from the PET scans before and after therapy., Results: The median SUV(max) in the meningiomas was 13.7 (range 4.3 to 68.7), and the maximum fractional radionuclide uptake in voxels of size 0.11 cm³ was a median of 23.4 × 10(-6) (range 0.4 × 10(-6) to 68.3 × 10(-6)). A strong correlation was observed between SUV(max) and the PRRT radionuclide tumour retention in the voxels with the highest uptake (Spearman's rank test, P < 0.01). Excluding one patient who showed large differences in biokinetics between PET and PRRT and another patient with incomplete data, linear regression analysis indicated significant correlations between SUV(max) and the therapeutic uptake (r = 0.95) and between SUV(max) and the maximum voxel dose from PRRT (r = 0.76). Observed absolute deviations from the values expected from regression were a median of 5.6 × 10(-6) (maximum 9.3 × 10(-6)) for the voxel fractional radionuclide uptake and 0.40 Gy per GBq (maximum 0.85 Gy per GBq) (177)Lu for the voxel dose from PRRT., Conclusion: PET with (68)Ga-labelled somatostatin analogues allows the pretherapeutic assessment of tumour radionuclide uptake in PRRT of meningioma and an estimate of the achievable dose.

Purpose: Despite recent advances in clinical imaging modalities, differentiation of pancreatic masses remains difficult. Here, we tested the diagnostic accuracy of molecular-based imaging including 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) positron emission tomography (PET) and [(18)F]fluorodeoxyglucose (FDG) PET/CT in patients with suspected pancreatic masses scheduled to undergo surgery., Methods: A total of 46 patients with pancreatic tumours suspicious for malignancy and scheduled for resective surgery were recruited prospectively. In 41 patients, FLT PET and FDG PET/CT scans were performed. A diagnostic CT performed on a routine basis was available in 31 patients. FLT PET and FDG PET/CT emission images were acquired according to standard protocols. Tracer uptake in the tumour [FDG and FLT standardized uptake value (SUV)] was quantified by the region of interest (ROI) technique. For FDG PET/CT analysis, correct ROI placement was ensured via side-by-side reading of corresponding CT images., Results: Of 41 patients, 33 had malignancy, whereas 8 patients had benign disease. Visual analysis of FDG and FLT PET resulted in sensitivity values of 91% (30/33) and 70% (23/33), respectively. Corresponding specificities were 50% (4/8) for FDG PET and 75% (6/8) for FLT PET. In the subgroup of patients with contrast-enhanced CT (n = 31), sensitivities were 96% (PET/CT), 88% (CT alone), 92% (FDG PET) and 72% (FLT PET), respectively. Mean FLT uptake in all malignant tumours was 3.0 (range SUV(max) 1.1-6.5; mean FDG SUV(max) 7.9, range 3.3-17.8; p < 0.001)., Conclusion: For differentiation of pancreatic tumours, FDG PET and FDG PET/CT showed a higher sensitivity but lower specificity than FLT PET. Interestingly, visual analysis of FLT PET led to two false-positive findings by misinterpreting physiological bowel uptake as pathological FLT uptake in the pancreas. Due to the limited number of patients, the clinical value of adding FLT PET to the diagnostic workup of pancreatic tumours remains to be determined.

Purpose: [(11)C]Choline has been established as a PET tracer for imaging prostate cancer. The aim of this study was to determine whether [(11)C]choline can be used for monitoring the effects of therapy in a prostate cancer mouse xenograft model., Methods: The androgen-independent human prostate cancer cell line PC-3 was implanted subcutaneously into the flanks of 13 NMRI (nu/nu) mice. All mice were injected 4-6 weeks after xenograft implantation with 37 MBq [(11)C]choline via a tail vein. Dynamic imaging was performed for 60 min with a small-animal PET/CT scanner (Siemens Medical Solutions). Six mice were subsequently injected intravenously with docetaxel twice (days 1 and 5) at a dose of 3 mg/kg body weight. Seven mice were treated with PBS as a control. [(11)C]Choline imaging was performed prior to and 1, 2 and 3 weeks after treatment. To determine choline uptake the images were analysed in terms of tumour-to-muscle (T/M) ratios. Every week the size of the implanted tumour was determined with a sliding calliper., Results: The PC-3 tumours could be visualized by [(11)C]choline PET. Before treatment the T/M(mean) ratio was 1.6+/-0.5 in the control group and 1.8+/-0.4 in the docetaxel-treated group (p=0.65). There was a reduction in the mean [(11)C]choline uptake after docetaxel treatment as early as 1 week after initiation of therapy (T/M ratio 1.8+/-0.4 before treatment, 0.9+/-0.3 after 1 week, 1.1+/-0.3 after 2 weeks and 0.8+/-0.2 after 3 weeks). There were no decrease in [(11)C]choline uptake in the control group following treatment (T/M ratio 1.6+/-0.5 before treatment, 1.7+/-0.4 after 1 week, 1.8+/-0.7 after 2 weeks and 1.7+/-0.4 after 3 weeks). For analysis of the dynamic data, a generalized estimation equation model revealed a significant decrease in the T/M(dyn) ratios 1 week after docetaxel treatment, and the ratio remained at that level through week 3 (mean change -0.93+/-0.24, p<0.001, after 1 week; -0.78+/-0.21, p<0.001, after 2 weeks; -1.08+/-0.26, p<0.001, after 3 weeks). In the control group there was no significant decrease in the T/M(dyn) ratios (mean change 0.085+/-0.39, p=0.83, after 1 week; 0.31+/-0.48, p=0.52, after 2 weeks; 0.11+/-0.30, p=0.72, after 3 weeks). Metabolic changes occurred 1 week after therapy and preceded morphological changes of tumour size during therapy., Conclusion: Our results demonstrate that [(11)C]choline has the potential for use in the early monitoring of the therapeutic effect of docetaxel in a prostate cancer xenograft animal model. The results also indicate that PET with radioactively labelled choline derivatives might be a useful tool for monitoring responses to taxane-based chemotherapy in patients with advanced prostate cancer.

Purpose: Freehand SPECT is a 3-D tomographic imaging modality based on data acquisition with a hand-held detector that is moved freely, in contrast to conventional, fixed gamma camera systems. In this pilot study, the feasibility of freehand SPECT for 3-D lymphatic mapping in breast cancer was evaluated., Methods: A total of 85 patients (age: 29-88 years) with an initial diagnosis of invasive breast cancer and no clinical evidence of nodal involvement prospectively underwent sentinel lymph node (SLN) biopsy. Preoperative lymphatic mapping (35-87 MBq (99m)Tc-Nanocoll) included tomographic imaging with a SPECT/CT device (Siemens Symbia T6) serving as reference. Initially, the freehand SPECT approach was assessed in a pilot study consisting of 50 patients. The quality of each freehand SPECT acquisition was assessed and ranked as good, intermediate or poor. In another series comprising a further 35 patients (validation study), a guidance system for the acquisition was implemented based on the results of the pilot study, ensuring acquisitions with good quality. For 3-D tomographic image reconstruction, ad hoc models and iterative reconstruction algorithms were used in all 85 patients. To allow for adequate comparison, SPECT/CT data and freehand SPECT data were registered within the same coordinate system., Results: In the pilot study, freehand SPECT enabled mapping of 24 of 83 SLNs in 20 of 44 patients (3 dropouts, 3 patients without SLN either in SPECT/CT or in freehand SPECT). Using SPECT/CT as reference, the accuracy of freehand SPECT was 77.8% (7/9 nodes) in scans with good quality, while for intermediate and poor quality scans, the accuracy was reduced to 34.3 and 12.8%, respectively. In the validation study, quality feedback improved the results significantly and freehand SPECT enabled the mapping of at least one SLN in 87.5% of the patients (28/32 - 3 dropouts). Compared to the reference method, freehand SPECT showed a sensitivity of 83.3% (35/42 nodes). False-negative findings were related to insufficient scanning time, insufficient coverage of the axillary region, close proximity of the SLN to the injection site and low tracer uptake in the SLNs., Conclusion: In this preliminary study, we could demonstrate that 3-D localization of SLNs is feasible using freehand SPECT technology. Prerequisites for acquisition of a good scan quality, most likely allowing precise SLN mapping, have been defined. This approach has high potential to allow image-guided biopsy and further standardization of SLN dissection, thus bringing 3-D nuclear imaging into the operating room.

Purpose: In detecting pheochromocytoma (PHEO), positron emission tomography (PET) with the radiolabelled amine precursor (18)F-fluorodihydroxyphenylalanine ((18)F-DOPA) offers excellent specificity, while computed tomography (CT) provides high sensitivity and ability to localize lesions; therefore, the combination of these modalities could be advantageous in this setting. The aim of this study was to investigate whether combined (18)F-DOPA PET/CT more accurately detects and localizes PHEO lesions than does each modality alone., Methods: (18)F-DOPA PET, CT and (18)F-DOPA PET/CT images of 25 consecutive patients undergoing diagnostic scanning of suspected sporadic or multiple endocrine neoplasia type 2 syndrome-associated PHEO were reviewed retrospectively in randomized sequence. Two blinded observers scored the images regarding the likelihood of PHEO being present and localizable. Results were correlated with subsequent clinical history and, when available, histology., Results: Of the 19 lesions detected by all three modalities, PET identified each as positive for PHEO, but was unable to definitively localize 15 of 19 (79%). CT could definitively localize all 19 lesions, but could not definitively diagnose or exclude PHEO in 18 of 19 (95%) lesions. Furthermore, CT falsely identified as negative for PHEO one lesion which was judged to be positive for this tumor by both PET and PET/CT. Only in PET/CT scans were all 19 lesions accurately characterized and localized. On a per-patient basis, the sensitivity of (18)F-DOPA PET/CT for PHEO was 100% and the specificity 88%, with a 100% positive predictive value and an 88% negative predictive value., Conclusion: (18)F-DOPA PET/CT more accurately diagnoses and localizes adrenal and extra-adrenal masses suspicious for PHEO than do (18)F-DOPA PET or CT alone.

Purpose: The aim of the study was to compare the diagnostic accuracy of (18)F-fluorodeoxyglucose (FDG) PET/CT versus standard planar bone scintigraphy (BS) and (18)F-labelled NaF ((18)F) PET for the detection of bone metastases (BM) in non-small cell lung cancer (NSCLC)., Methods: (18)F-FDG PET/CT was performed in 126 patients with NSCLC. Within 7 days BS (n = 58) or (18)F PET (n = 68) was performed. (18)F-FDG PET/CT, BS and (18)F PET were evaluated by two experienced readers. Lesions were graded on a scale from 1 (definite BM) to 5 (degenerative lesion), and equivocal lesions were determined as indifferent (grade 3)., Results: A total of 92 patients showed degenerative lesions (grade 4/5) on PET/CT, BS or (18)F PET. In 34 patients (27%) BM lesions were diagnosed (grades 1 and 2). In 13 of 18 patients BM were concordantly diagnosed with PET/CT and (18)F PET. PET/CT showed more BM compared to (18)F PET (53 vs 40). In one patient one osteolytic BM was false-negative on (18)F PET. However, (18)F PET identified four patients with BM compared to negative findings on PET/CT. Of 16 patients, 11 had concordant findings of BM on PET/CT and BS. In three patients BS was false-negative and in two patients BM were diagnosed as indifferent., Conclusion: Integrated (18)F-FDG PET/CT is superior to BS in the detection of osteolytic BM in NSCLC. Thus, PET/CT may obviate the need to perform additional BS or (18)F PET in the staging of NSCLC, which significantly reduces costs.

Purpose: An increase of the serum PSA-level is a sensitive in vitro marker for recurrent prostate cancer. However, it remains difficult to differentiate between local, regional or distant recurrent disease. The aim of this study was to assess the relationship between the detection rate of [(11)C]Choline-PET/CT and the serum PSA-level in patients with a biochemical recurrence of prostate cancer with the view towards localisation of recurrent disease., Methods: Sixty-three patients (mean age, 68.8 +/- 6.9; range, 45-83 years) with biochemical recurrence after primary therapy for prostate cancer were included in the analysis. Mean PSA-levels were 5.9 +/- 9.7 ng/ml (range, 0.2-39 ng/ml; median, 2.15). Of the 63 patients, 17 were under anti-androgen therapy at the time of [(11)C]Choline PET/CT. Patients underwent a [(11)C]Choline-PET/CT study after injection of 656 +/- 119 MBq [(11)C]Choline on a Sensation 16 Biograph PET/CT scanner., Results: Of the 63 patients, 35 (56%) showed a pathological [(11)C]Choline uptake. The detection rate of [(11)C]Choline-PET/CT showed a relationship with the serum PSA-level: The detection rate was 36% for a PSA-value <1 ng/ml, 43% for a PSA-value 1-<2 ng/ml, 62% for a PSA-value 2-<3 ng/ml and 73% for a PSA-value >or=3 ng/ml. Anti-androgen therapy did not show a significant effect on the detection rate of [(11)C]Choline-PET/CT (p = 0.374)., Conclusion: As an important result our study shows that even for PSA-values <1.0 ng/ml the detection efficiency of [(11)C]Choline-PET/CT is 36%. Furthermore, the detection rate of [(11)C]Choline-PET/CT shows a positive relationship with serum PSA-levels in patients with biochemical recurrence of prostate cancer after primary therapy. Therefore, in these patients, [(11)C]Choline PET/CT allows not only to diagnose but also to localise recurrent disease with implications on disease management (localised vs systemic therapy).

Purpose: The aim of this study was to determine whether the thymidine analogue 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) is adequate for early evaluation of the response of malignant lymphoma to antiproliferative treatment in a mouse xenotransplant model., Methods: Immunodeficient mice bearing a follicular lymphoma xenotransplant were treated with high-dose chemotherapy (cyclophosphamide, n = 10), immunotherapy (CD20 mAb, ibritumomab-tiuxetan, n = 10) or radioimmunotherapy ([(90)Y]CD20 mAb, Zevalin, n = 10). Forty-eight hours after treatment, antiproliferative effects were assessed with [(18)F]FLT. Ninety minutes after i.v. injection of 5-10 MBq [(18)F]FLT, mice were sacrificed and radioactivity within the tumour and normal organs was measured using a gamma counter and calculated as % ID/g. The proliferation fraction in tissue samples derived from treated and untreated tumours was evaluated by Ki-67 immunohistochemistry, which served as the reference for proliferative activity., Results: In untreated lymphoma, the mean proliferation fraction was 83.6%. After chemotherapy, the mean proliferation fraction decreased to 39.3% (p = 0.0001), after immunotherapy to 77.6% (p = 0.0078) and after radioimmunotherapy to 78.8% (p = 0.014). In none of the animals was a significant change in tumour size observed. In untreated lymphoma, tumoural [(18)F]FLT uptake was 5.4% ID/g, after chemotherapy it was 1.5% (p = 0.0005), after immunotherapy, 3.9% (non-significant), and after radioimmunotherapy, 5.8% (non-significant)., Conclusion: In a lymphoma xenotransplant model, [(18)F]FLT detects early antiproliferative drug activity before changes in tumour size are visible. These findings further support the use of [(18)F]FLT-PET for imaging early response to treatment in malignant lymphoma.

Purpose: The purpose of this retrospective, blinded study was to evaluate the additional value of [18F]FDG PET/CT in comparison with PET alone and with side-by-side PET and CT in patients with malignant melanoma (MM)., Methods: A total of 127 consecutive studies of patients with known MM referred for a whole-body PET/CT examination were included in this study. PET alone, side-by-side PET and CT and integrated PET/CT study were independently and separately interpreted without awareness of the clinical information. One score each was applied for certainty of lesion localisation and for certainty of lesion characterisation. Verification of the findings was subsequently performed using all available clinical, pathological (n=30) and follow-up information., Results: The number of lesions with an uncertain localisation was significantly (p<0.001) reduced by PET/CT and side-by-side PET and CT (p<0.05) in comparison with PET alone. In line with this increase in certainty integrated PET/CT reading also improved certainty in characterisation of lesions, however, this did not reach significance (p=0.057) compared versus PET alone. Respectively, PET, side-by-side PET and CT and PET/CT showed a sensitivity of 86%, 89% and 91%, a specificity of 94%, 94% and 94%, a positive predictive value of 96%, 96% and 96% and a negative predictive value of 80%, 83% and 87%., Conclusion: Integrated PET/CT offers a significant benefit in lesion localisation and an improvement in lesion characterisation compared with PET alone or with side-by-side PET and CT. The benefit is not as great as that reported for other tumour entities, which may be due to the high avidity of MM for [18F]FDG.

Purpose: Recently, the thymidine analogue 3'-deoxy-3'[18F]fluorothymidine (FLT) has been introduced for imaging proliferation with positron emission tomography (PET). In this prospective study, we examined the accuracy of FLT for differentiation of benign from malignant lung lesions and for tumour staging., Methods: A total of 47 patients with newly diagnosed pulmonary nodules on chest CT suspicious for malignancy were examined with FLT-PET in addition to routine staging procedures. A total of 43 patients also underwent 2-[18F]fluoro-2-deoxy-D-glucose (FDG) PET imaging. Within 2 weeks, patients underwent resective surgery or core biopsy of the pulmonary lesion., Results: Histopathology revealed malignant lung tumours in 32 patients (20 non-small cell lung cancer, 1 small cell lung cancer, 1 pulmonary carcinoid, 1 non-Hodgkin's lymphoma, nine metastases from extrapulmonary tumours) and benign lesions in 15 patients. Increased FLT uptake was exclusively related to malignant tumours. FLT-PET was false negative in two patients with non-small cell lung cancer, in the patient with a pulmonary carcinoid and in three patients with lung metastases. The sensitivity of FLT-PET for detection of lung cancer was 90%, the specificity 100% and the accuracy 94%. Fifteen out of 21 patients with lung cancer had mediastinal lymph node metastases. FLT-PET was true positive in 7/15 patients, resulting in a sensitivity of 53% for N-staging (specificity 100%, accuracy 67%). Clinical TNM stage was correctly identified in 67% (20/30) patients, compared to 85% (23/27) with FDG-PET., Conclusion: FLT-PET has a high specificity for the detection of malignant lung tumours. Compared with FDG, FLT-PET is less accurate for N-staging in patients with lung cancer and for detection of lung metastases. FLT-PET therefore cannot be recommended for staging of lung cancer.