Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

BACKGROUND: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development. RESULTS: This commentary of highlights has resulted in 23 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals and also a contribution in relation to MRI-agents is included. CONCLUSION: Trends in (radio)chemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry.

[18F]-Fluciclovine PET/CT for preoperative nodal staging in high-risk primary prostate cancer: final results of a prospective trial.

PURPOSE: The conventional imaging flowchart for prostate cancer (PCa) staging may fail in correctly detecting lymph node metastases (LNM). Pelvic lymph node dissection (PLND) represents the only reliable method, although invasive. A new amino acid PET compound, [18F]-fluciclovine, was recently authorized in suspected PCa recurrence but not yet included in the standard staging work-up of primary PCa. A prospective monocentric study was designed to evaluate [18F]-fluciclovine PET/CT diagnostic performance for preoperative LN staging in primary high-risk PCa. METHODS: Consecutive patients (pts) with biopsy-proven PCa, standard staging (including [11C]choline PET/CT), eligible for PLND, were enrolled to undergo an investigational [18F]-fluciclovine PET/CT. Nodal uptake higher than surrounding background was reported by at least two readers (blinded to [11C]choline) using a visual 5-point scale (1-2 probably negative; 4-5 probably positive; 3 equivocal); SUVmax, target-to-background (aorta-A; bone marrow-BM) ratios (TBRs), were also calculated. PET results were validated with PLND. [18F]-fluciclovine PET/CT performance using visual score and semi-quantitative indexes was analyzed both per patient and per LN anatomical region, compared to conventional [11C]choline and clinical predictive factors (to note that diagnostic performance of [18F]-fluciclovine was explored for LNM but not examined for intrapelvic or extrapelvic M1 lesions). RESULTS: Overall, 94 pts underwent [18F]-fluciclovine PET/CT; 72/94 (77%) high-risk pts were included in the final analyses (22 pts excluded: 8 limited PLND; 3 intermediate-risk; 2 treated with radiotherapy; 4 found to be M1; 5 neoadjuvant hormonal therapy). Median LNM risk by Briganti nomogram was 19%. LNM confirmed on histology was 25% (18/72 pts). Overall, 1671 LN were retrieved; 45/1671 (3%) LNM detected. Per pt, median no. of removed LN was 22 (mean 23 ± 10; range 8-51), of LNM was 2 (mean 3 ± 2; range 1-10). Median LNM size was 5 mm (mean 5 ± 2.5; range 2-10). On patient-based analyses (n = 72), diagnostic performance for LNM resulted significant with [18F]-fluciclovine (AUC 0.66, p 0.04; 50% sensitivity, 81% specificity, 47% PPV, 83% NPV, 74% accuracy), but not with [11C]choline (AUC 0.60, p 0.2; 50%, 70%, 36%, 81%, and 65% respectively). Briganti nomogram (OR = 1.03, p = 0.04) and [18F]-fluciclovine visual score (≥ 4) (OR = 4.27, p = 0.02) resulted independent predictors of LNM at multivariable analyses. On region-based semi-quantitative analyses (n = 576), PET/CT performed better using TBR parameters (TBR-A similar to TBR-BM; TBR-A fluciclovine AUC 0.61, p 0.35, vs choline AUC 0.57 p 0.54; TBR-BM fluciclovine AUC 0.61, p 0.36, vs choline AUC 0.58, p 0.52) rather than using absolute LN SUVmax (fluciclovine AUC 0.51, p 0.91, vs choline AUC 0.51, p 0.94). However, in all cases, diagnostic performance was not statistically significant for LNM detection, although slightly in favor of the experimental tracer [18F]-fluciclovine for each parameter. On the contrary, visual interpretation significantly outperformed PET semi-quantitative parameters (choline and fluciclovine: AUC 0.65 and 0.64 respectively; p 0.03) and represents an independent predictive factor of LNM with both tracers, in particular [18F]-fluciclovine (OR = 8.70, p 0.002, vs OR = 3.98, p = 0.03). CONCLUSION: In high-risk primary PCa, [18F]-fluciclovine demonstrates some advantages compared with [11C]choline but sensitivity for metastatic LN detection is still inadequate compared to PLND. Visual (combined morphological and functional), compared to semi-quantitative assessment, is promising but relies mainly on readers' experience rather than on unquestionable LN avidity. TRIAL REGISTRATION: EudraCT number: 2014-003,165-15.

The Role of [18F]Fluciclovine PET/CT in the Characterization of High-Risk Primary Prostate Cancer: Comparison with [11C]Choline PET/CT and Histopathological Analysis.

The primary aim of the study was to evaluate the role of [18F]Fluciclovine PET/CT in the characterization of intra-prostatic lesions in high-risk primary PCa patients eligible for radical prostatectomy, in comparison with conventional [11C]Choline PET/CT and validated by prostatectomy pathologic examination. Secondary aims were to determine the performance of PET semi-quantitative parameters (SUVmax; target-to-background ratios [TBRs], using abdominal aorta, bone marrow and liver as backgrounds) for malignant lesion detection (and best cut-off values) and to search predictive factors of malignancy. A six sextants prostate template was created and used by PET readers and pathologists for data comparison and validation. PET visual and semi-quantitative analyses were performed: for instance, patient-based, blinded to histopathology; subsequently lesion-based, un-blinded, according to the pathology reference template. Among 19 patients included (mean age 63 years, 89% high and 11% very-high-risk, mean PSA 9.15 ng/mL), 45 malignant and 31 benign lesions were found and 19 healthy areas were selected (n = 95). For both tracers, the location of the "blinded" prostate SUVmax matched with the lobe of the lesion with the highest pGS in 17/19 cases (89%). There was direct correlation between [18F]Fluciclovine uptake values and pISUP. Overall, lesion-based (n = 95), the performance of PET semiquantitative parameters, with either [18F]Fluciclovine or [11C]Choline, in detecting either malignant/ISUP2-5/ISUP4-5 PCa lesions, was moderate and similar (AUCs ≥ 0.70) but still inadequate (AUCs ≤ 0.81) as a standalone staging procedure. A [18F]Fluciclovine TBR-L3 ≥ 1.5 would depict a clinical significant lesion with a sensitivity and specificity of 85% and 68% respectively; whereas a SUVmax cut-off value of 4 would be able to identify a ISUP 4-5 lesion in all cases (sensitivity 100%), although with low specificity (52%). TBRs (especially with threshold significantly higher than aorta and slightly higher than bone marrow), may be complementary to implement malignancy targeting.

Evaluation of an Automated Module Synthesis and a Sterile Cold Kit-Based Preparation of 68Ga-PSMA-11 in Patients with Prostate Cancer.

68Ga-labeled urea-based inhibitors of the prostate-specific membrane antigen (PSMA), such as 68Ga-PSMA-11, are promising small molecules for targeting prostate cancer (PCa). Although this radiopharmaceutical was produced mostly by means of manual synthesis and automated synthesis modules, a sterile cold kit was recently introduced. The aim of our study was to evaluate the image quality of 68Ga-PSMA-11 PET/CT (PSMA-PET) in a population of PCa patients after the injection of comparable activities of 68Ga-PSMA-11 obtained with the 2 different synthetic procedures. A secondary aim was to identify secondary factors that may have an impact on image quality and, thus, final interpretation. Methods: Two different groups of 100 consecutive PCa patients who underwent PSMA-PET were included in the study. The first group of patients was imaged with 68Ga-PSMA-11 obtained using synthesis modules, whereas the second group's tracer activity was synthesized using a sterile cold kit. All PET images were independently reviewed by 2 nuclear medicine diagnosticians with at least 2 y of experience in PSMA-based imaging and unaware of the patients' clinical history. The 2 reviewers independently rated the quality of each PSMA-PET scan using a 3-point Likert-type scale. In cases of discordance, the operators together reviewed the images and reached a consensus. Performance was evaluated on the basis of the expected biodistribution, lesion detection rate, and physiologic background uptake. Results: Overall, 104 of 200 (52%) PSMA-PET scans were positive for PCa-related findings. No significant differences in image quality between cold kits and synthesis modules were found (P = 0.13), although a higher proportion of images was rated as excellent by the observers for kits than for modules (45% vs. 34%). Furthermore, after image quality had been dichotomized as excellent or not excellent, multivariate regression analysis found several factors to be significantly associated with a not-excellent quality: an increase in patient age (+5 y: odds ratio [OR], 1.40; 95% confidence interval [CI], 1.12-1.75), an increase in patient weight (+5 kg: OR, 1.89; 95% CI, 1.53-2.32), an increase in 68Ga-PSMA-11 uptake time (+10 min: OR, 1.45; 95% CI, 1.08-1.96), and a decrease in injected activity (-10 MBq: OR, 1.28; 95% CI, 1.07-1.52). Conclusion: No significant differences were identified between the 2 groups of patients undergoing PSMA-PET; therefore, we were not able to ascertain any significant influences of tracer production methodology on final scan quality. However, increased patient age, increased patient weight, decreased injected activity, and increased 68Ga-PSMA-11 uptake time were significantly associated with an overall poorer image quality.

Role of 18F-FLT PET/CT in suspected recurrent or residual lymphoma: final results of a pilot prospective trial.

PURPOSE: To evaluate the role of F-18-Fluorothymidine (FLT) PET/CT in lymphoma patients with suspected recurrent or residual disease. METHODS: Adult lymphoma patients presenting with positive or equivocal F-18-FDG PET/CT at end-treatment or follow-up were prospectively addressed to an additional F-18-FLT-PET/CT. SUV max and tumour-to-background ratios (TBRs) were recorded for the most avid lesion. Biopsy or, when not available, clinical or imaging assessment were employed as standard of reference. RESULTS: Overall 52 patients were recruited. Histology was available in 20/52 patients (38%), proliferation-index (Ki-67) in 14/20. Disease was excluded in 13/52 patients (25%) (one reactive follicular hyperplasia, five reactive-inflammatory tissues, four reactive nodes, two nodal sarcoid-like and one non-specific peri-caecal finding). FDG and FLT scans were concordant in disease restaging in 34/52 patients (65%), whereas in 18/52 cases (35%) relevant discrepancies were recorded. SUV max and TBR were significantly higher in the disease versus the disease-free group, with both tracers (p = 0.0231 and 0.0219 for FDG; p = 0.0008 and 0.0016 for FLT). FLT-SUVmax demonstrated slightly better performance in discriminating benign from malignant lesions (ROC-AUC: 0.8116 and 0.7949 for FLT-SUV max and TBR; 0.7120 and 0.7140 for FDG). Optimal FLT-SUV max cut-offs were searched: three would lead to 95% sensitivity, 81% accuracy, and 39% specificity, whereas seven led to 100%, 41%, and 56% respectively. No statistically significant correlation was observed between the two FLT indices and Ki-67. CONCLUSIONS: According to our results in a clinical setting of recurrent or residual lymphoma, FLT is not significantly superior to FDG and it is unlikely that it will be employed independently. FLT may be restricted to a few specific cases, as complementary to standard FDG imaging, to confirm a diagnosis or to define a better target to biopsy. However, due to FLT suboptimal performance, many findings would remain inconclusive, requiring further diagnostic procedures and reducing the effectiveness of performing an additional FLT scan.

68Ga-PSMA-11 PET/CT in prostate cancer patients with biochemical recurrence after radical prostatectomy and PSA <0.5 ng/ml. Efficacy and impact on treatment strategy.

PURPOSE: The primary aim of this retrospective, single-centre analysis was to assess the performance of 68Ga-PSMA-11 PET/CT in prostate cancer (PCa) patients in early PSA failure after radical prostatectomy (RP). The secondary aim was to assess the potential impact of 68Ga-PSMA-11 PET/CT on treatment strategy. METHODS: 68Ga-PSMA-11 PET/CT is performed in our institution within an investigational new drug (IND) trial in PCa patients with biochemical recurrence (BCR). The records of all patients enrolled between March 2016 and July 2017 were evaluated. These records were retrospectively analysed according to the following inclusion criteria: (a) RP as primary therapy, (b) proven BCR, ©) PSA levels in the range 0.2-0.5 ng/ml at the time of the 68Ga-PSMA-11 PET/CT investigation, and (d) no salvage radiotherapy (S-RT) performed after recurrence. The performance of 68Ga-PSMA-11 PET/CT was evaluated in terms of detection rate on a per-patient and a per-region basis (local vs. distant lesions). We further performed an intention-to-treat (ITT) analysis. The patient cohort was grouped into three subpopulations, blinded to the 68Ga-PSMA-11 PET/CT results, according to the patients' characteristics and different patterns of treatment: (1) S-RT (with or without systemic treatment), (2) stereotactic body radiotherapy (SBRT) (with or without systemic treatment), and (3) systemic treatment. The treatment strategy was re-evaluated for each patient taking into consideration the 68Ga-PSMA-11 PET/CT images. RESULTS: We enrolled 119 PCa patients (mean age 66 years, range 44-78 years) with a mean PSA level at the time of 68Ga-PSMA-11 PET/CT of 0.34 ng/ml (median 0.32 ng/ml, SD ±0.09, range 0.20-0.50 ng/ml). 68Ga-PSMA-1 1 PET/CT was positive in 41 of the 119 patients, resulting in an overall detection rate of 34.4%. 68Ga-PSMA-11 uptake was observed in the prostate bed (3 patients, 2.5%), in the pelvic lymph nodes (21, 17.6%), in the retroperitoneal lymph nodes (4, 3.4%) and in the skeleton (21, 17.6%). Regarding ITT, 81 patients (68.1%) were considered possible candidates for S-RT only in the prostate bed and none of the patients (0%) for SBRT. According to the 68Ga-PSMA-11 PET/CT results, the intended treatment was changed in 36 patients (30.2%). According to the PET/CT results, S-RT was recommended in 70 patients (58.8%), only to the prostate bed in 58 (48.7%) and SBRT in 29 (24.4%). The intended RT planning was modified in 36 (87.8%) of 41 patients with a positive 68Ga-PSMA-11 PET/CT result. CONCLUSION: In our patient series with PSA levels <0.5 ng/ml, 68Ga-PSMA-11 PET/CT had a detection rate of 34.4%. In the ITT analysis, 30.2% of patients had a change in the intended treatment. These data support the hypothesis that 68Ga-PSMA-11 PET/CT is a useful procedure in the management of PCa patients showing early recurrence after RP, and should be implemented in routine clinical practice.

68Ga-PSMA-11 PET/CT in recurrent prostate cancer: efficacy in different clinical stages of PSA failure after radical therapy.

OBJECTIVES: The primary objective was the evaluation of Gallium 68 (68Ga)-prostate-specific membrane antigen (PSMA)-11 positron emission tomography/computed tomography (PET/CT) detection rate, for identifying the site of prostate cancer (PCa) relapse (local vs systemic), stratifying the population according to different clinical stages of biochemical recurrence (BCR). Secondary aims were: 1) to evaluate the association of clinical/pathologic features and 68Ga-PSMA-11 PET/CT detection rate, 2) to compare 68Ga-PSMA-11 PET/CT with other imaging procedures, and 3) to evaluate the positive predictive value (PPV) in a per-patient analysis. MATERIAL AND METHODS: This population was enrolled through a prospective, open label, single-center trial performed at the Nuclear Medicine of the University Hospital of Bologna (Eudract: 2015-004589-27 OsSC). The inclusion criteria were: (1) proven PCa, (2) surgery or radiotherapy as definitive therapy, (3) proven BCR, (4) prostate-specific antigen (PSA) 0.2-2 ng/ml, (5) age ≥ 35 years, and 6() willing to sign an informed consent. Three-hundred and thirty-two (332) patients were enrolled between March 2016 and June 2017; mean/median PSA was 0.84/0.61 ng/ml, 97.9% (325/332) of patients received radical prostatectomy and 2.1% (7/332) radiotherapy. Different patterns of BCR were identified by referent physicians as follows: (a) persisting detectable PSA after radical prostatectomy in 13.5% (45/332) of patients (subgroup 1), (b) first-time PSA failure after radical therapy in 44.9% (149/332) (subgroup 2), and (c) PSA increase after salvage or hormonal therapy in 41.6% (138/332) (subgroup 3). RESULTS: Primary objective: 68Ga-PSMA-11 PET/CT detection rate was 53.6% (CI 95% 48.1%-59.1%). In a patient-based analysis, disease confined to pelvis (prostate bed and/or lymph-nodes) was detected in 24.7% of cases (82/332). The presence of at least one distant lesion was observed in 28.9% of cases (96/332). The detection rate in different subgroups was: subgroup 1 = 64.5%, subgroup 2 = 45.6%, and subgroup-3 = 58.7%. Secondary objectives: 1) PSA (p = 0.041) and PSAdt (p = 0.001) showed association with 68Ga-PSMA-11 PET/CT detection rate, and 2) correlative imaging was available in 73.2% of patients (243/332). When 68Ga-PSMA-11 PET/CT was positive, correlative imaging resulted negative in 83% of cases (108/130). 3) The calculated PPV was 96.2%. CONCLUSION: Our data confirmed the efficacy of 68Ga-PSMA-11 PET/CT for detecting local vs systemic disease in PCa patients presenting PSA failure after radical therapy. Furthermore, 68Ga-PSMA-11 PET/CT detection rate is different depending on the clinical stage of BCR, and this information should be taken into consideration by referring physicians.

Production of Ga-68 with a General Electric PETtrace cyclotron by liquid target.

PURPOSE: In recent years the use of 68Ga (t1/2 = 67.84 min, ß+: 88.88%) for the labelling of different PET radiopharmaceuticals has significantly increased. This work aims to evaluate the feasibility of the production of 68Ga via the 68Zn(p,n)68Ga reaction by proton irradiation of an enriched zinc solution, using a biomedical cyclotron, in order to satisfy its increasing demand. METHODS: Irradiations of 1.7 Msolution of 68Zn(NO3)2 in 0.2 N HNO3 were conducted with a GE PETtrace cyclotron using a slightly modified version of the liquid target used for the production of fluorine-18. The proton beam energy was degraded to 12 MeV, in order to minimize the production of 67Ga through the68Zn(p,2n)67Ga reaction. The product's activity was measured using a calibrated activity meter and a High Purity Germanium gamma-ray detector. RESULTS: The saturation yield of68Ga amounts to (330 ±â€¯20) MBq/µA, corresponding to a produced activity of68Ga at the EOB of (4.3 ±â€¯0.3) GBq in a typical production run at 46 µA for 32 min. The radionuclidic purity of the68Ga in the final product, after the separation, is within the limits of the European Pharmacopoeia (>99.9%) up to 3 h after the EOB. Radiochemical separation up to a yield not lower than 75% was obtained using an automated purification module. The enriched material recovery efficiency resulted higher than 80-90%. CONCLUSIONS: In summary, this approach provides clinically relevant amounts of68Ga by cyclotron irradiation of a liquid target, as a competitive alternative to the current production through the68Ge/68Ga generators.

Early and delayed evaluation of solid tumours with 64Cu-ATSM PET/CT: a pilot study on semiquantitative and computer-aided fractal geometry analysis.

OBJECTIVE: The aim of this study was to analyse early and delayed acquisition on copper-64 diacetyl-bisN4-methylthiosemicarbazone (Cu-ATSM) PET/CT in a small cohort of patients by comparing semiquantitative and computer-aided fractal geometry analyses. PATIENTS AND METHODS: Five cancer patients, including non-small-cell lung cancer and head and neck cancer, were investigated with Cu-ATSM PET/CT. Participants received an intravenous injection of Cu-ATSM according to body size and were imaged 60 min (early) and 16 h (delayed) later on hybrid PET/CT. Reconstructed images were visualized on advanced workstations for the definition of semiquantitative parameters: standardized uptake value (SUV)max, SUVratio-to-muscle, SUVmean, hypoxic volume (HV) and hypoxic burden (HB=HV×SUVmean). DICOM data retrieved from both scans were analysed using an ad-hoc computer program to determine the mean intensity value, SD, relative dispersion, three-dimensional histogram fractal dimension and three-dimensional fractal dimension. RESULTS: All tumour lesions showed increased uptake of Cu-ATSM at early evaluation, with a median SUVratio-to-muscle of 4.42 (range: 1.58-5.62), a median SUVmax of 5.3 (range: 1.9-7.3), a median SUVmean of 2.8 (range: 1.5-3.9), a median HV of 41.6 cm (range: 2.8-453.7) and a median HB of 161.5 cm (range: 4.4-1112.5). All semiquantitative data obtained at 1 h were consistent with the parameters obtained on delayed imaging (P>0.05). A borderline statistically significant difference was found only for SUVmax of the muscle (P=0.045). Fractal geometry analysis on DICOM images showed that all parameters at early imaging showed no statistically significant difference with late acquisition (P>0.05). CONCLUSION: Our findings support the consistency of Cu-ATSM PET/CT images obtained at early and delayed acquisition for the assessment of tumour lesions.

Does the etiology of cardiac amyloidosis determine the myocardial uptake of [18F]-NaF PET/CT?

Cardiac amyloidosis (CA) leads to variable degrees of myocardial infiltration with a final echocardiographic phenotype of "hypertrophy." Although many non-invasive imaging techniques (MRI, CT, scintigraphy, PET) are useful, the definitive diagnosis is still based on myocardial histology. We explored the possible role of [18F]-NaF PET/CT in the diagnosis of this disease in two cases with wild-type (ATTRwt) or mutant (ATTRm) Ile68Leu transthyretin (TTR)-related CA.

(11)C-Choline PET/CT for restaging prostate cancer. Results from 4,426 scans in a single-centre patient series.

PURPOSE: To evaluate (11)C-choline PET/CT as a diagnostic tool for restaging prostate cancer (PCa), in a large, homogeneous and clinically relevant population of patients with biochemical recurrence (BCR) of PCa after primary therapy. The secondary aim was to assess the best timing for performing (11)C-choline PET/CT during BCR. METHODS: We retrospectively analysed 9,632 (11)C-choline PET/CT scans performed in our institution for restaging PCa from January 2007 to June 2015. The inclusion criteria were: (1) proven PCa radically treated with radical prostatectomy (RP) or with primary external beam radiotherapy (EBRT); (2) PSA serum values available; (3) proven BCR (PSA >0.2 ng/mL after RP or PSA >2 ng/mL above the nadir after primary EBRT with rising PSA levels). Finally, 3,203 patients with recurrent PCa matching all the inclusion criteria were retrospectively enrolled and 4,426 scans were analysed. RESULTS: Overall, 52.8 % of the (11)C-choline PET/CT scans (2,337/4,426) and 54.8 % of the patients (1,755/3,203) were positive. In 29.4 % of the scans, at least one distant finding was observed. The mean and median PSA values were, respectively, 4.9 and 2.1 ng/mL at the time of the scan (range 0.2 - 50 ng/mL). In our series, 995 scans were performed in patients with PSA levels between 1 and 2 ng/mL. In this subpopulation the positivity rate in the 995 scans was 44.7 %, with an incidence of distant findings of 19.2 % and an incidence of oligometastatic disease (one to three lesions) of 37.7 %. The absolute PSA value at the time of the scan and ongoing androgen deprivation therapy were associated with an increased probability of a positive (11)C-choline PET/CT scan (p < 0.0001). In the ROC analysis, a PSA value of 1.16 ng/mL was the optimal cut-off value. In patients with a PSA value <1.16 ng/mL, 26.8 % of 1,426 (11)C-choline PET/CT scans were positive, with oligometastatic disease in 84.7 % of positive scans. CONCLUSION: In a large cohort of patients, the feasibility of (11)C-choline PET/CT for detecting the sites of metastatic disease in PCa patients with BCR was confirmed. The PSA level was the main predictor of a positive scan with 1.16 ng/mL as the optimal cut-off value. In the majority of positive scans oligometastatic disease, potentially treatable with salvage therapies, was observed.

Synthesis and preclinical evaluation of an Al18F radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand.

PURPOSE: The aim of this study was to synthesize and preclinically evaluate an 18F-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 18F-PSMA-11 via 18F-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 18F-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: 18F-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.

(18)F-FACBC (anti1-amino-3-(18)F-fluorocyclobutane-1-carboxylic acid) versus (11)C-choline PET/CT in prostate cancer relapse: results of a prospective trial.

PURPOSE: To compare the accuracy of (18)F-FACBC and (11)C-choline PET/CT in patients radically treated for prostate cancer presenting with biochemical relapse. METHODS: This prospective study enrolled 100 consecutive patients radically treated for prostate cancer and presenting with rising PSA. Of these 100 patients, 89 were included in the analysis. All had biochemical relapse after radical prostatectomy (at least 3 months previously), had (11)C-choline and (18)F-FACBC PET/CT performed within 1 week and were off hormonal therapy at the time of the scans. The two tracers were compared directly in terms of overall positivity/negativity on both a per-patient basis and a per-site basis. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were calculated for both the tracers; follow-up at 1 year (including correlative imaging, PSA trend and pathology when available) was considered as the standard of reference. RESULTS: In 51 patients the results were negative and in 25 patients positive with both the tracers, in eight patients the results were positive with (18)F-FACBC but negative with (11)C-choline, and in five patients the results were positive with (11)C-choline but negative with (18)F-FACBC. Overall in 49 patients the results were false-negative (FN), in two true-negative, in 24 true-positive (TP) and in none false-positive (FP) with both tracers. In terms of discordances between the tracers: (1) in one patient, the result was FN with (11)C-choline but FP with (18)F-FACBC (lymph node), (2) in seven, FN with (11)C-choline but TP with (18)F-FACBC (lymph node in five, bone in one, local relapse in one), (3) in one, FP with (11)C-choline (lymph node) but TP with (18)F-FACBC (local relapse), (4) in two, FP with (11)C-choline (lymph nodes in one, local relapse in one) but FN with (18)F-FACBC, and (5) in three, TP with (11)C-choline (lymph nodes in two, bone in one) but FN with (18)F-FACBC. With (11)C-choline and (18)F-FACBC, sensitivities were 32 % and 37 %, specificities 40 % and 67 %, accuracies 32 % and 38 %, PPVs 90 % and 97 %, and NPVs 3 % and 4 %, respectively. Categorizing patients by PSA level (<1 ng/ml 28 patients, 1 - <2 ng/ml 28 patients, 2 - <3 ng/ml 11 patients, ≥3 ng/ml 22 patients), the number (percent) of patients with TP findings were generally higher with (18)F-FACBC than with (11)C-choline: six patients (21 %) and four patients (14 %), eight patients (29 %) and eight patients (29 %), five patients (45 %) and four patients (36 %), and 13 patients (59 %) and 11 patients (50 %), respectively. CONCLUSION: (18)F-FACBC can be considered an alternative tracer superior to (11)C-choline in the setting of patients with biochemical relapse after radical prostatectomy.

Prognostic Evaluation of Disease Outcome in Solid Tumors Investigated With 64Cu-ATSM PET/CT.

PURPOSE: Cu-ATSM is a very promising PET radiopharmaceutical for tumor imaging of hypoxia. One of the advantages of this compound compared with other hypoxia-avid tracers is the high tumor-to-background signal offered, which guaranties facilitated tumor delineation. This study analyzes optimal semiquantitative and quantitative parameters obtained by Cu-ATSM PET/CT in the same cohort of patients with special focus on their correlation to disease outcome. PATIENTS AND METHODS: A prospective recruitment of 18 consecutive patients (M:F, 13:5; mean age, 60.7 years) with locally advanced non-small cell lung cancer (n = 7) or head and neck cancer (HNC) was performed. Each participant received 105 to 500 MBq of tracer according to body size and was scanned in a 3-dimensional mode PET/CT 60 minutes after tracer injection. PET images were reconstructed and visualized on a GE Advanced 4.6 workstation for the definition of semiquantitative and quantitative parameters: SUVmax, SUVratio-to-muscle, hypoxic tumor volume (HTV), and hypoxic burden (HB = HTV × SUVmean). These data were subsequently correlated to disease outcome, expressed in terms of progression-free survival calculated on a follow-up period with a median of 14.6 months. RESULTS: All patients showed a moderately to highly increased uptake of Cu-ATSM in tumor lesions, with a mean SUVmax of 5.2 (range, 1.9-8.3) and mean SUVratio of 4.4 (range, 1.6-6.8). In addition, a broad range of HTV and HB was defined as mean values of 99.3 cm (range, 2.5-453.7 cm) and 301 (4.2-1134), respectively. Receiver operating characteristic analysis identified as reference cutoffs with respect to disease outcome with the following values: SUVmax >2.5 (AUC, 0.57; sensitivity, 88.9%; specificity, 50%), SUVratio ≤4.4 (AUC, 0.60; sensitivity, 50; specificity, 83.3%), HTV >160.7 cm (AUC, 0.61; sensitivity, 55.6%; specificity, 75%), and HB >160.7 (AUC, 0.67; sensitivity, 58.3%; specificity, 83.3%). In our cohort, HB showed a statistically significant difference in terms of mean values on the analysis of variance test with respect to disease progression (P = 0.04). On univariate analysis, Cox regression confirmed these findings and showed a significant correlation to progression-free survival for HB (P = 0.05) and HTV (P = 0.02). CONCLUSIONS: In our cohort, the definition of optimal semiquantitative and quantitative parameters on Cu-ATSM PET/CT seems feasible and in line with previously published data. However, when considering the prognostic role with respect to disease outcome, the more robust parameters are represented by HTV and HB.

11C-meta-hydroxyephedrine: a promising PET radiopharmaceutical for imaging the sympathetic nervous system.

Dysfunction of the sympathetic nervous system underlies many cardiac diseases and can be assessed by molecular imaging using SPECT tracers as I-metaiodobenzylguanidine (I-MIBG). The norepinephrine analog C-meta-hydroxyephedrine (HED) has been used with PET to map the regional distribution of cardiac sympathetic neurons. Hydroxyephedrine is rapidly transported into sympathetic neurons by the norepinephrine transporter and stored in vesicles. This review describes the mechanism of action, radiosynthesis, and application of HED in the assessment of the cardiac sympathetic nervous system in heart failure, myocardial infarction, and arrhythmias. Noncardiac applications of HED in the clinical setting of sympathetic nervous system tumors and other emerging research applications are described.

PET radiopharmaceuticals for imaging of tumor hypoxia: a review of the evidence.

Hypoxia is a pathological condition arising in living tissues when oxygen supply does not adequately cover the cellular metabolic demand. Detection of this phenomenon in tumors is of the utmost clinical relevance because tumor aggressiveness, metastatic spread, failure to achieve tumor control, increased rate of recurrence, and ultimate poor outcome are all associated with hypoxia. Consequently, in recent decades there has been increasing interest in developing methods for measurement of oxygen levels in tumors. Among the image-based modalities for hypoxia assessment, positron emission tomography (PET) is one of the most extensively investigated based on the various advantages it offers, i.e., broad range of radiopharmaceuticals, good intrinsic resolution, three-dimensional tumor representation, possibility of semiquantification/quantification of the amount of hypoxic tumor burden, overall patient friendliness, and ease of repetition. Compared with the other non-invasive techniques, the biggest advantage of PET imaging is that it offers the highest specificity for detection of hypoxic tissue. Starting with the 2-nitroimidazole family of compounds in the early 1980s, a great number of PET tracers have been developed for the identification of hypoxia in living tissue and solid tumors. This paper provides an overview of the principal PET tracers applied in cancer imaging of hypoxia and discusses in detail their advantages and pitfalls.

Early biochemical relapse after radical prostatectomy: which prostate cancer patients may benefit from a restaging 11C-Choline PET/CT scan before salvage radiation therapy?

UNLABELLED: The aim of the study was to assess which factors may influence (11)C-choline PET/CT detection rate in a population of recurrent prostate cancer (PCa) patients listed for salvage radiation therapy (S-RT) in an early phase of biochemical relapse, to select which patients could obtain the most benefit by performing restaging (11)C-choline PET/CT before S-RT. METHODS: The study comprised 605 patients, treated with radical prostatectomy (RP) with curative intent for PCa who showed rising PSA levels after primary therapy and listed for S-RT. Prostate-specific antigen (PSA) values were >0.2 ng/mL and <2 ng/mL (mean, 1.05 ng/mL; median, 1.07 ng/mL; range, 0.2-2 ng/m; SD, ±0.59). All patients were classified as N0 after RP. Seventeen of 605 patients received adjuvant RT together with RP, whereas 148 of 605 patients received androgen-deprivation therapy (ADT) at the time of PET/CT. PSA, PSA kinetics, Gleason score, age, time to biochemical relapse, ADT, and initial tumor stage were statistically analyzed to assess which factor could influence PET/CT positivity and the detection of local versus distant relapse. RESULTS: (11)C-choline PET/CT was positive in 28.4% of patients (172/605). Eighty-three of 605 patients were positive in the pelvis (group A), distant metastasis (group B) were detected in 72 of 605 patients, and local and distant sites of relapse were detected in 17 of 605 patients (group C). At multivariate analysis, PSA, PSA doubling time (PSAdt), and ongoing ADT were significant predictors for positive scan results, whereas PSA and PSAdt were significantly related to distant relapse detection (P < 0.05). At the receiver-operating-characteristic analysis, a PSA value of 1.05 ng/mL and PSAdt of 5.95 mo were determined to be the optimal cutoff values in the prediction of a positive (11)C-choline PET/CT scan, with an area under the curve (AUC) of 0.625 for PSA and 0.677 for PSAdt. CONCLUSION: (11)C-choline PET/CT may be suggested before S-RT during the early phase of biochemical relapse, to select patients who may benefit from this aggressive treatment. Particularly, patients showing fast PSA kinetics or PSA increasing levels despite ongoing ADT should be studied with (11)C-choline PET/CT before S-RT, considering the higher probability to detect positive findings outside the pelvis.

11C-choline PET/CT detects the site of relapse in the majority of prostate cancer patients showing biochemical recurrence after EBRT.

PURPOSE: The aim of this retrospective study was to evaluate the usefulness and the detection rate of (11)C-choline PET/CT in a population of patients with prostate cancer (PC), exclusively treated with external beam radiotherapy (EBRT) as primary treatment, who showed biochemical relapse. MATERIALS AND METHODS: We enrolled 140 patients showing a serum PSA level >2 ng/mL (mean 8.6 ng/mL, median 5 ng/mL, range 2 - 60 ng/mL). All patients had been treated with EBRT to the prostate gland and prostatic fossa with doses ranging from 70 to 76 Gy in low-risk patients (T1/T2 and/or serum PSA <10 ng/mL) and escalating to >76 Gy (range 76 - 81 Gy) in high-risk patients (T3/T4 and/or serum PSA >10 ng/mL). Of the 140 patients, 53 were receiving androgen deprivation therapy at the time of the scan. All positive (11)C-choline PET/CT findings were validated by transrectal ultrasound-guided biopsy or at least 12 months of follow-up with contrast-enhanced CT, MR, bone scintigraphy or a repeated (11)C-choline PET/CT scan. The relationships between the detection rate of (11)C-choline PET/CT and the factors PSA level, PSA kinetics, Gleason score, age, time to relapse and SUV max in patients with positive findings were analysed. RESULTS: (11)C-Choline PET/CT detected the site of relapse in 123 of the 140 patients with a detection rate of 87.8 % (46 patients showed local relapse, 31 showed local and distant relapse, and 46 showed only distant relapse). In patients with relapse the mean serum PSA level was 9.08 ng/mL (median 5.1 ng/mL, range 2 - 60 ng/mL), the mean PSA doubling time was 5.6 months (median 3.5 months, range 0.4 - 48 months), and the mean PSA velocity was 15 ng/mL/year (median 8.8 ng/mL/year, range 0.4 - 87 ng/mL/year). Of the 123 patients with relapse, 77 (62.6 %) showed distant relapse with/without local relapse, and of these 77, 31 (40.2 %) showed oligometastatic disease (one or two distant lesions: lymph node lesions only in 16, bone lesions only in 14, and lymph node lesions and bone lesions in 1). In univariate and multivariate analyses PSA kinetics was the only variable affecting (11)C-choline PET/CT detection rate. A significant correlation between PSA kinetics and site of recurrence (local relapse only vs. distant metastasis) was also observed. CONCLUSION: The detection rate of (11)C-choline PET/CT in patients with PC showing biochemical recurrence after EBRT as primary treatment is relatively high (87.8 %). (11)C-Choline PET/CT was able to detect extraprostatic disease in the 62.6 % of patients. Considering this high detection rate, (11)C-choline PET/CT could have clinical usefulness in the management of these PC patients, but this should be confirmed in future studies.

(11)C-meta-hydroxyephedrine PET/CT imaging allows in vivo study of adaptive thermogenesis and white-to-brown fat conversion.

Several lines of evidence suggest that novel pharmacological approaches aimed at converting white adipose tissue (WAT) into brown adipose tissue (BAT) may represent an effective therapeutic strategy for obesity and related disorders. ((18))F-fluorodeoxyglucose ((18)F-FDG) is the only positron emission tomography (PET) tracer commonly used to study BAT function, and so far no functional tools have been described to investigate in vivo white-to-brown fat conversion. In this report, we show that the PET tracer (11)C-meta-hydroxyephedrine ((11)C-MHED, a norepinephrine analogue) is a useful tool to investigate the sympathetic nervous system (SNS) activity in BAT of lean and dietary obese mice. Moreover, we demonstrate that (11)C-MHED is a specific marker of the SNS-mediated thermogenesis in typical BAT depots, and that this tracer can detect in vivo WAT to BAT conversion.