Production and Quality Control of [177Lu]Lu-PSMA-I&T: Development of an Investigational Medicinal Product Dossier for Clinical Trials.

Since prostate cancer is the most commonly diagnosed malignancy in men, the theranostic approach has become very attractive since the discovery of urea-based PSMA inhibitors. Different molecules have been synthesized starting from the Glu-urea-Lys scaffold as the pharmacophore and then optimizing the linker and the chelate to improve functional characteristics. This article aimed to highlight the quality aspects, which could have an impact on clinical practice, describing the development of an Investigational Medicinal Product Dossier (IMPD) for clinical trials with [177Lu]Lu-PSMA-I&T in prostate cancer and other solid tumors expressing PSMA. The results highlighted some important quality issues of the final preparation: radiolabeling of PSMA-I&T with lutetium-177 needs a considerably longer time compared with the radiolabeling of the well-known [177Lu]Lu-PSMA-617. When the final product was formulated in saline, the stability of [177Lu]Lu-PSMA-I&T was reduced by radiolysis, showing a decrease in radiochemical purity (<95% in 24 h). Different formulations of the final product with increasing concentrations of ascorbic acid have been tested to counteract radiolysis and extend stability. A solution of 20 mg/mL of ascorbic acid in saline prevents radiolysis and ensures stability over 30 h.

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.

Cardiac resynchronization therapy and cardiac sympathetic function.

BACKGROUND: Cardiac resynchronization therapy (CRT) is an established therapy for advanced congestive heart failure, improving both survival and hospitalization. The mechanism beneath these improvements still needs to be defined as about one-third of the patients do not benefit from resynchronization. Restoration of sympatho-vagal function can play a significant role in the process, but available data are limited. In this scenario, positron emission tomography scans with (11) C-hydroxyephedrine, a noradrenaline analogous, has the potential to characterize the modifications of the sympathetic nervous system induced by CRT in decompensated patients. MATERIALS AND METHODS: Ten patients (six males, age 68 ± 10 years) with primary dilated cardiomyopathy were studied before and after resynchronization (acutely and after 3 months), from a clinical and echocardiographic point of view. Their cardiac sympathetic nerve activity was evaluated by (11) C-hydroxyephedrine positron emission tomography before resynchronization, at short and medium term after resynchronization. RESULTS: Responders to CRT (patients showing ≥ 15% decrease in left ventricular end-systolic volume) showed a higher level of left ventricular radiotracer uptake both at baseline and after resynchronization with respect to nonresponders. This was coupled with a progressive improvement in homogeneity in left ventricular tracer uptake mainly in responders. CONCLUSIONS: Cardiac resynchronization therapy improves cardiac sympathetic nerve activity in responders since its activation, while nonresponders do not show any significant change at any time of evaluation. CRT seems to be more effective in those patients with a still structurally preserved, yet functionally impaired, neuroautonomic system.

Comparison of 18F-FACBC and 11C-choline PET/CT in patients with radically treated prostate cancer and biochemical relapse: preliminary results.

PURPOSE: We assessed the rate of detection rate of recurrent prostate cancer by PET/CT using anti-3-(18)F-FACBC, a new synthetic amino acid, in comparison to that using (11)C-choline as part of an ongoing prospective single-centre study. METHODS: Included in the study were 15 patients with biochemical relapse after initial radical treatment of prostate cancer. All the patients underwent anti-3-(18)F-FACBC PET/CT and (11)C-choline PET/CT within a 7-day period. The detection rates using the two compounds were determined and the target-to-background ratios (TBR) of each lesion are reported. RESULTS: No adverse reactions to anti-3-(18)F-FACBC PET/CT were noted. On a patient basis, (11)C-choline PET/CT was positive in 3 patients and negative in 12 (detection rate 20%), and anti-3-(18)F-FACBC PET/CT was positive in 6 patients and negative in 9 (detection rate 40%). On a lesion basis, (11)C-choline detected 6 lesions (4 bone, 1 lymph node, 1 local relapse), and anti-3-(18)F-FACBC detected 11 lesions (5 bone, 5 lymph node, 1 local relapse). All (11)C-choline-positive lesions were also identified by anti-3-(18)F-FACBC PET/CT. The TBR of anti-3-(18)F-FACBC was greater than that of (11)C-choline in 8/11 lesions, as were image quality and contrast. CONCLUSION: Our preliminary results indicate that anti-3-(18)F-FACBC may be superior to (11)C-choline for the identification of disease recurrence in the setting of biochemical failure. Further studies are required to assess efficacy of anti-3-(18)F-FACBC in a larger series of prostate cancer patients.

(11)C-Choline PET/CT in patients with hormone-resistant prostate cancer showing biochemical relapse after radical prostatectomy.

PURPOSE: To determine the diagnostic efficacy of (11)C-choline PET/CT in patients with prostate cancer (PC) after radical prostatectomy who presented with increasing PSA levels during follow-up in spite of being on hormone treatment (HT), and therefore showing HT resistance. METHODS: We evaluated a large series of 157 consecutive PC patients previously treated by radical prostatectomy who presented with biochemical recurrence with increasing PSA levels in spite of ongoing HT (HT-resistant patients). At the time of (11)C-choline PET/CT, the mean value of trigger PSA level was 8.3 (range 0.2 - 60.6 ng/mL), the mean PSA doubling time (PSAdt) was 5.3 (range 0.4 - 35 months), and the mean PSA velocity (PSAvel) was 22.1 ng/mL/year (range 0.12 - 82 ng/mL/year). (11)C-Choline PET/CT was performed following a standard procedure at our centre to investigate increasing PSA levels, either as the first imaging procedure or in patients with negative conventional imaging. At the time of (11)C-choline PET/CT all patients were receiving HT (61 were receiving monotherapy and 96 multidrug therapy). PET-positive findings were validated by: (a) transrectal US-guided biopsy in patients with recurrence in the prostatic bed, (b) surgical pelvic lymphadenectomy, (c) other imaging modalities, including repeated (11)C-choline PET/CT, performed during a minimum follow-up of 12-months. RESULTS: (11)C-Choline PET/CT showed positive findings in 104 of the 157 patients (66 %). (11)C-choline PET/CT detected: a single lesion in 40 patients (7 in the prostate bed, 10 in lymph nodes, 22 in bone, 1 at another site); two lesions in 18 patients (7 in lymph nodes, 7 in bone, 4 in both lymph nodes and bone); three or four lesions in 7 patients (4 in lymph nodes, 2 in bone, 1 at another site); and more than four lesions in the remaining 39 patients (2 in the prostate bed, 12 in lymph nodes, 12 in bone, 11 in both lymph nodes and bone, 2 at other sites). In (11)C-choline PET-negative patients, the mean values of trigger PSA, PSAdt and PSAvel were 3.8 ng/mL (range 0.2-11.9 ng/mL) 7.0 months (range 1.21 - 35 months) and 5.8 ng/mL/year (range 0.12 - 30.1) respectively, while in (11)C-Choline-PET-positive patients they were 10.5 ng/mL (range 0.2 - 60.6), 4.4 months (range 0.4 - 19.7) and 15.9 ng/mL/year (range 0.5 - 82.0) respectively. The differences between PET-negative and PET-positive patients were statistically significant for all these parameters: trigger PSA, p < 0.01; PSAdt, p < 0.01; PSAvel, p = 0.03. CONCLUSION: In our patient population, (11)C-choline PET/CT was able to detect relapsed disease in a large proportion of HT-resistant PC patients during HT. These data, obtained in a large series, suggest that HT withdrawal before performing a (11)C-choline PET/CT scan may not be necessary for the detection of recurrent disease if PSA levels are increasing and PSA kinetics are rapid.

Overview and perspectives on automation strategies in (68)Ga radiopharmaceutical preparations.

The renaissance of (68)Ga radiopharmacy has led to great advances in automation technology. The availability of a highly efficient, reliable, long-lived (68)Ge/(68)Ga generator system along with a well-established coordination chemistry based on bifunctional chelating agents have been the bases of this development in (68)Ga radiopharmacy. Syntheses of (68)Ga peptides were originally performed by manual or semiautomated systems, but increasing clinical demand, radioprotection, and regulatory issues have driven extensive automation of their production process. Several automated systems, based on different post-processing of the (68)Ga generator eluate, on different engineering, and on fixed tubing or disposable cassette approaches, have been developed and are discussed in this chapter. Since automatic systems for preparation of radiopharmaceuticals should comply with qualification and validation protocols established by regulations such as current Good Manufacturing Practices (cGMP) and local regulations, some regulatory issues and the more relevant qualification protocols are also discussed.

Optimization of Precursor Preparation in PSMA-11 Radiolabeling to Obtain a Highly Reproducible Radiochemical Yield.

[68Ga]Ga-PSMA-11 PET/CT plays a pivotal role in the diagnosis and staging of prostate cancer because of its higher sensitivity and detection rate compared with traditional choline PET/CT. A highly reproducible radiochemical yield of the radiopharmaceutical to be used in the clinical routine is an important parameter for planning and optimization of clinical activity. During radiometallation of PSMA-11, the presence of metal ion contaminants in the peptide precursor may cause a decrease in the [68Ga]Ga-PSMA-11 radiochemical yield because of metal ion contaminants competition with gallium-68. To optimize the radiochemical yield of [68Ga]Ga-PSMA-11 radiosynthesis, data obtained by preparing the solution of the PSMA-11 precursor with three different methods (A, B, and C) were compared. Methods A and B consisted of the reconstitution of different quantities of precursor (1000 µg and 30 µg, respectively) to obtain a 1 µg/mL solution. In Method A, the precursor solution was aliquoted and stored frozen, while the precursor solution obtained with Method B was entirely used. Method C consisted of the reconstitution of 1000 µg of precursor taking into account net peptide content as described in European Pharmacopoeia. Radiosynthesis data demonstrated that reconstitution methods B and C gave a consistently higher and reproducible radiochemical yield, highlighting the role of metals and precursor storage conditions on the synthesis performance.

Is there a role for ¹¹C-choline PET/CT in the early detection of metastatic disease in surgically treated prostate cancer patients with a mild PSA increase <1.5 ng/ml?

PURPOSE: The aim of this study was to evaluate the potential usefulness of whole-body (11)C-choline PET/CT in the re-staging of prostate cancer (PC) patients previously treated with radical prostatectomy (RP), who presented a mild increase of prostate-specific antigen (PSA) <1.5 ng/ml (early biochemical relapse) during follow-up (FU). METHODS: We evaluated 102 consecutive patients (mean age = 68 years, range = 54-82 years) previously treated with RP and who presented during FU a mild increase of trigger PSA serum levels <1.5 ng/ml: mean 0.86 ± 0.40 ng/ml (range 0.2-1.5) and median 0.93 ng/ml (range 0.67-1.10). In this patient series (11)C-choline PET/CT was used as the first imaging examination at the time of the detection of a mild serum PSA increase <1.5 ng/ml. (11)C-Choline PET/CT was performed following standard procedures in our centre. At the time of PET/CT, 86 patients were not receiving any pharmacologic treatment, while 16 were under anti-androgenic therapy. Positive PET findings were validated by: (a) transrectal ultrasound (TRUS)-guided biopsy in cases of local recurrence, (b) surgical lymphadenectomy, (c) other imaging procedures or (d) FU lasting for at least 12 months. Univariate and multivariate analyses were used to evaluate the following variables: age, TNM staging, Gleason score, time from RP to the biochemical relapse, anti-androgen therapy at the time of (11)C-choline PET/CT scan, trigger PSA value and PSA kinetics, i.e. PSA doubling time (PSAdt) and PSA velocity (PSAvel), in order to assess the significant predictive factors related to the findings of a positive (11)C-choline PET/CT scan. RESULTS: Overall, (11)C-choline PET/CT showed positive findings in 29 of 102 patients (28% of cases). In detail, (11)C-choline PET/CT detected: local relapse in 7 patients, bone metastases in 13 patients (4 single and 9 multiple) and lymph node metastases in 9 patients (6 single and 3 multiple). Positive PET findings were validated by: (a) TRUS-guided biopsy in 7 patients with local recurrence, (b) surgery and lymphadenectomy in 3 patients, (c) other targeted imaging procedures (MR or bone scan) in 5 patients and (d) clinical FU lasting a minimum of 12 months and including also a contrast-enhanced CT (CECT), an MR, a bone scan and a repeated (11)C-choline PET/CT in 14 patients. Age, time to biochemical relapse (TTR), initial T staging, Gleason score and trigger PSA were not statistically significant in predicting a positive (11)C-choline PET/CT scan both at univariate and multivariate analysis. Instead, PSA kinetics (PSAdt and PSAvel), N status and anti-androgenic therapy at the time of PET scan were statistically significant predictive factors at univariate analysis. Of note, only PSAdt and initial N status were found to be significant and independent predictive factors at multivariate analysis. The mean PSAdt in PET-positive patients was 4.34 months (SD 2.82) while in PET-negative patients it was 13.30 months (SD 9.75) (p = 0.0001). The optimal threshold for PSAdt established by receiver-operating characteristic (ROC) analysis was 7.25 months (AUC 0.85; 95% confidence interval 0.77-0.91) providing 93% sensitivity, 74% specificity, 60% positive predictive value and 96% negative predictive value. CONCLUSION: In our study, (11)C-choline PET/CT was able to detect recurrent disease in 28% of the patients with mild biochemical relapse characterized by very low trigger PSA levels (PSA <1.5 ng/ml). Very interestingly (11)C-choline PET/CT detected distant unexpected metastases in 21% of the patients. At multivariate statistical analysis only PSAdt and node status were shown to be significant and independent predictive factors for positive (11)C-choline PET/CT. Therefore, (11)C-choline could be suggested to be performed early during initial biochemical relapse in patients presenting with fast PSA kinetics. The early detection of the site of recurrence could lead to a prompt instauration of the most appropriate treatment, i.e. local surgery or radiation treatment vs systemic treatment. In this view, one of the main advantages should be the avoidance of unnecessary local radiotherapy in those patients showing distant metastasis at (11)C-choline PET/CT.

An HPLC and UHPLC-HRMS approach to study PSMA-11 instability in aqueous solution.

BACKGROUND: The stability of precursors and reagents is of utmost importance for developing a robust radiolabelling method that provides high and constant radiochemical yield and radiochemical purity. While performing the QC of the [68Ga]Ga-PSMA-11 injectable solutions according to Ph. Eur. Monograph that has recently been published, a trend to the instability of the standard PSMA-11, the same used as a precursor for [68Ga]Ga-PSMA-11 radiosynthesis, has been observed. This instability led to the formation of a side product in a time-dependent manner. The formation of this compound, besides making the implementation of the Ph. Eur. analytical method more difficult, negatively influenced the radiochemical yield and the radiochemical purity by increasing gallium-68 in colloidal and ionic forms. RESULTS: The nature of the side product was investigated by adding chelators, such as EDTA, to PSMA-11 solutions and using the combination of UHPLC-HRMS. The results led to the definition of the side product structure, as natFe-PSMA-11, from the combination of the high-affinity chelator HBED-CC, present in the molecule of PSMA-11, and environmental Fe (III). CONCLUSIONS: Strategies to reduce the risk of low radiolabeling yields and to increase the stability of the PSMA-11 in an aqueous solution were also discussed.

[18F]F-PSMA-1007 Radiolabelling without an On-Site Cyclotron: A Quality Issue.

Radiopharmaceuticals targeting the prostate-specific membrane antigen (PSMA) has become the gold standard for PET imaging of prostate cancer. [68Ga]Ga-PSMA-11 has been the forerunner but a [18F]F-PSMA ligand has been developed because of the intrinsic advantages of Fluorine-18. Fluorine-18 labelled compounds are usually prepared in centers with an on-site cyclotron. Since our center has not an on-site cyclotron, we decided to verify the feasibility of producing the experimental 18F-labelled radiopharmaceutical [18F]F-PSMA-1007 with [18F]F- from different external suppliers. A quality agreement has been signed with two different suppliers, and a well-established and correctly implemented quality assurance protocol has been followed. The [18F]F- was produced with cyclotrons, on Nb target, but with different beam energy and current. Extensive validation of the [18F]F-PSMA-1007 synthesis process has been performed. The aim of this paper was the description of all the quality documentation which allowed the submission and approval of the Investigational Medicinal Product Dossier (IMPD) to the Competent Authority, addressing the quality problems due to different external suppliers. The result indicates that no significant differences have been found between the [18F]F- from the two suppliers in terms of radionuclidic and radiochemical purity and [18F]F- impacted neither the radiochemical yield of the labelling reaction nor the quality control parameters of the IMP [18F]F-PSMA-1007. These results prove how a correct quality assurance system can overcome some Regulatory Authorities issue that may represent an obstacle to the clinical use of F-18-labelled radiopharmaceuticals without an on-site cyclotron.

11C-acetate PET for early prediction of sunitinib response in metastatic renal cell carcinoma.

Sunitinib is an oral multitargeted tyrosine kinase inhibitor with antiangiogenic properties used for treatment of renal cell carcinoma and gastrointestinal stromal tumors at a dose of 50 mg/day consecutively for 4 weeks followed by 2 weeks off per cycle. At present, no data are available on the early prediction of sunitinib response in renal cell carcinoma. We report a clinical case of a patient with metastatic renal cell carcinoma diagnosed with 11C-acetate PET and conventional CT and treated with sunitinib. Partial and complete remission documented by CT was preceded by early functional tumor inhibition shown by 11C-acetate-PET after only 14 days of therapy. This case report highlights some interesting points related to the potential role of a novel non-FDG PET tracer, 11C-acetate, in the early prediction of the response to targeted therapies in metastatic renal cell carcinoma.

Reliability and reproducibility of N-[11C]methyl-choline and L-(S-methyl-[11C])methionine solid-phase synthesis: a useful and suitable method in clinical practice.

BACKGROUND AND OBJECTIVE: N-[11C]methyl-choline ([11C]choline) and L-(S-methyl-[11C])methionine ([11C]methionine) are PET radiopharmaceuticals which have gained interest as oncological tracers. The increasing demand of these radiopharmaceuticals needs robust methods of synthesis with high and reproducible yield which provide enough activity for multiple patient administration in a short synthesis time. METHODS: Different synthetic approaches have been described in the literature but exhaustive reports on performance and reliability of different methods have not been described yet. RESULTS AND CONCLUSION: In the present study, we demonstrated the reliability and reproducibility of the solid-phase [11C]methylation method for the synthesis of [11C]choline and [11C]methionine as a suitable tool for the routine clinical use.

Assessment of radionuclidic impurities in 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG) routine production.

In this paper, radionuclidic impurities generated during the bombardment of [18 O]water in the routine production of 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG) were studied. In order to assess such impurities and the efficacy of purification methods through the different steps of the synthesis, samples of the target filters, purification columns, [18 O]water recovered after the synthesis, and the final solution was collected and their activities measured and analyzed by means of a gamma-ray spectrometry system. The data demonstrated that purification methods adopted for the synthesis provide the [18F]FDG radionuclidically pure, as requested by the EU Pharmacopeia.

A simple Tracerlab module modification for automated on-column [11C]methylation and [11C]carboxylation.

A modification of commercial [11C]methylation module which can be implemented for both on-column [11C]methylation and [11C]carboxylation in the same automated system is described. This module configuration was applied to the solid-phase synthesis of N-[11C]methyl-choline ([11C]choline) and L-(S-methyl-[11C])methionine ([11C]methionine), using [11C]CH(3)I as methylating agent, as well as to the synthesis of [11C]acetate by [11C]carboxylation with [11C]CO2 of methylmagnesium chloride with high and reproducible radiochemical yields in short reaction time, demonstrating to be a fast and reliable tool for the production of these [11C]radiopharmaceuticals for clinical use.

Detection and localization of prostate cancer: correlation of (11)C-choline PET/CT with histopathologic step-section analysis.

UNLABELLED: This study evaluated the potential usefulness of (11)C-choline PET/CT for detection and localization of tumors within the prostate. We used the results of step-section histopathologic examination as the standard of reference. METHODS: The results were analyzed on a sextant basis. We reviewed the results of the (11)C-choline PET/CT scans of 36 patients with prostate cancer and of 5 control subjects with bladder cancer. All patients underwent (11)C-choline PET/CT and, subsequently, radical prostatectomy with lymph node dissection within 1 mo. (11)C-Choline PET/CT scans were obtained 5-10 min after intravenous injection of 370-555 MBq of (11)C-choline. Images were reviewed visually and semiquantitatively using maximum SUV and tumor-to-background ratio. RESULTS: On a sextant basis, histopathologic analysis detected cancer foci in 143 of 216 sextants; high-grade prostate intraepithelial neoplasm foci were detected in 89 of 216 sextants (in 59 sextants in association with carcinoma, in 30 sextants alone), acute prostatitis was detected in 7 of 216 sextants (in 3 sextants in association with carcinoma, in 4 sextants alone), and 39 of 216 sextants were normal. PET/CT demonstrated focal (11)C-choline uptake in 108 sextants (94 of which involved tumor), and 108 sextants showed no abnormal (11)C-choline uptake (49 of which were false negative). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of PET/CT were 66%, 81%, 71%, 87%, and 55%, respectively. In the 5 control subjects, high-grade prostate intraepithelial neoplasm was detected at histologic examination in 16 of 30 sextants. PET/CT showed increased (11)C-choline uptake in 5 of 16 sextants. CONCLUSION: This study demonstrated the feasibility of using (11)C-choline PET/CT to identify cancer foci within the prostate. However, we also found that (11)C-choline PET/CT has a relative high rate of false-negative results on a sextant basis and that prostatic disorders other than cancer may accumulate (11)C-choline. Therefore, our data do not support the routine use of PET/CT with (11)C-choline as a first-line screening procedure for prostate cancer in men at high risk.

Focal lung uptake of 18F-fluorodeoxyglucose (18F-FDG) without computed tomography findings.

BACKGROUND: Integrated positron emission tomography/computed tomography (PET/CT) systems represent a major development allowing functional and anatomical information to be acquired in a single examination session and therefore providing a more accurate definition of suspected lesion characteristics. Together with the increasing number of clinical settings in which PET/CT scans have been advocated, however, pitfalls in image interpretation have been reported. METHODS: Four female subjects presenting a focal area of increased F-fluorodeoxyglucose (F-FDG) uptake with no evidence of a corresponding CT abnormality were included in the study. PET/CT scans were performed in all cases after the administration of 5.3 MBq . kg of F-FDG through a venous cannula. RESULTS: Focal high uptake of F-FDG was observed in lung lesions without anatomical counterparts on CT in four female cases. The only common feature to all was the paravenous injection of the radiotracer. CONCLUSION: The lesions detected by PET may be related to distal lung microembolism originating from the site of paravenous injection.

Potential pitfalls of 18F-FDG PET in a large series of patients treated for malignant lymphoma: prevalence and scan interpretation.

OBJECTIVE: To evaluate the prevalence and scan interpretation criteria useful in identifying non-tumoural F-FDG focal uptakes (potential pitfalls) in patients who had been previously treated for a malignant lymphoma studied by positron emission tomography (PET). MATERIALS: Nine hundred and ninety-six consecutive PET scans obtained in 706 patients with malignant lymphoma were reviewed. All patients had been previously treated by first-line chemo-radiotherapy, plus surgery when required, and were then studied by FDG PET to investigate suspected recurrence at doubtful or inconclusive conventional radiological imaging (ultrasound, computed tomography, magnetic resonance imaging). PET was obtained with patients in the fasted condition and after i.v. injection of 370 MBq of F-FDG; imaging was acquired 60-90 min later. In patients with focal FDG uptake the final diagnosis was reached on the basis of histological findings or long-term follow-up. RESULTS: Thirty-one of 134 PET scans (23.1%) showing focal FDG uptake were diagnosed as non-tumoural radiotracer uptake, related to the presence of brown fat in seven cases, thymic hyperplasia in five, muscles contraction in four, lymph node unspecific inflammation in four, mediastinal/pulmonary unspecific inflammation in four, gastritis in two, colitis in two, bacterial abscess in one, lactating breast in one, and herpes zoster in one. Each of the above cited situations has been reported in the literature, generally in the form of sporadic reports, as a potential cause of misinterpretation (false positive) in reading a PET scan with the potential for incorrect patient management. An accurate diagnosis in these patients was important for the following therapeutic decision making. CONCLUSIONS: In the whole series of patients with treated malignant lymphoma, the prevalence of non-tumoural FDG focal uptake during follow-up was relatively low (3.1%); conversely, it was relatively high when considering the sub-group of 'positive' PET only (23.1%). The importance of knowing these situations in order to avoid misinterpretation in reading PET scans needs to be emphasized. In this light, an accurate patient's history and a skilful nuclear medicine physician are very important factors. For the same purpose, it is reasonable to think that the use of hybrid PET/CT tomographs could also play an important role in helping to identify non-tumoural FDG focal uptake.