Filippo Lodi

Influence of Trigger PSA and PSA Kinetics on 11C-Choline PET/CT Detection Rate in Patients with Biochemical Relapse After Radical Prostatectomy

The purpose of this study was to investigate the effect of total prostate-specific antigen (PSA) at the time of 11C-choline PET/CT (trigger PSA), PSA velocity (PSAvel), and PSA doubling time (PSAdt) on 11C-choline PET/CT detection rate in patients treated with radical prostatectomy for prostate cancer, who showed biochemical failure during follow-up. Methods: A total of 190 patients treated with radical prostatectomy for prostate cancer who showed an increase in PSA (mean, 4.2; median, 2.1; range, 0.2–25.4 ng/mL) were retrospectively enrolled. All patients were studied with 11C-choline PET/CT. Patients were grouped according to trigger PSA (PSA ≤ 1 ng/mL, 1 < PSA ≤ 2 ng/mL, 2 < PSA ≤ 5 ng/mL, and PSA > 5 ng/mL). In 106 patients, data were available for calculation of PSAvel and PSAdt. Logistic regression analysis was used to determine whether there was a relationship between PSA levels and PSA kinetics and the rate of detection of relapse using PET. Results: 11C-choline PET/CT detected disease relapse in 74 of 190 patients (38.9%). The detection rate of 11C-choline PET/CT was 19%, 25%, 41%, and 67% in the 4 subgroups—PSA ≤ 1 ng/mL (51 patients), 1 < PSA ≤ 2 ng/mL (39 patients), 2 < PSA ≤ 5 ng/mL (51 patients), and PSA > 5 ng/mL (49 patients)—respectively. Trigger PSA values were statistically different between PET-positive patients (median PSA, 4.0 ng/mL) and PET-negative patients (median PSA, 1.4 ng/mL) (P = 0.0001). Receiver-operating-characteristic analysis showed an optimal cutoff point for trigger PSA of 2.43 ng/mL (area under the curve, 0.76). In 106 patients, PSAdt and PSAvel values were statistically different between patients with PET-positive and -negative scan findings (P = 0.04 and P = 0.03). The 11C-choline PET/CT detection rate was 12%, 34%, 42%, and 70%, respectively, in patients with PSAvel < 1 ng/mL/y (33 patients), 1 < PSAvel ≤ 2 ng/mL/y (26 patients), 2 < PSAvel ≤ 5 ng/mL/y (19 patients), and PSAvel > 5 ng/mL/y (28 patients). The 11C-choline PET/CT detection rate was 20%, 40%, 48%, and 60%, respectively, in patients with PSAdt > 6 mo (45 patients), 4 < PSAdt ≤ 6 mo (20 patients), 2 < PSAdt ≤ 4 mo (31 patients), and PSAdt ≤ 2 mo (10 patients). There was no statistical difference between PET-positive and -negative scan detection rates according to the Gleason score, pT and N status, patient age, or duration between surgery and biochemical relapse. Trigger PSA and PSAvel were found to be independent predictive factors for a PET-positive result (P = 0.002; P = 0.04) and PSAdt was found to be an independent factor only in patients with trigger PSA less than 2 ng/mL (P = 0.05) using multivariate analysis. Conclusion: The 11C-choline PET/CT detection rate is influenced by trigger PSA, PSAdt, and PSAvel. This finding could be used to improve the selection of patients for scanning by reducing the number of false-negative scans and increasing the detection rate of disease in patients with early relapse and potentially curative disease.

Early Biochemical Relapse After Radical Prostatectomy: Which Prostate Cancer Patients May Benefit from a Restaging 11C-Choline PET/CT Scan Before Salvage Radiation Therapy?

The aim of the study was to assess which factors may influence 11C-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 11C-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: 11C-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 11C-choline PET/CT scan, with an area under the curve (AUC) of 0.625 for PSA and 0.677 for PSAdt. Conclusion: 11C-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 11C-choline PET/CT before S-RT, considering the higher probability to detect positive findings outside the pelvis.

Incidence of Increased 68Ga-DOTANOC Uptake in the Pancreatic Head in a Large Series of Extrapancreatic NET Patients Studied with Sequential PET/CT

The aim of our retrospective study was to assess the incidence of increased uptake of 68Ga-DOTANOC in the head of the pancreas among a large population of patients with extrapancreatic neuroendocrine tumors studied with serial 68Ga-DOTANOC PET/CT. Methods: Patients who had undergone at least two 68Ga-DOTANOC PET/CT studies over time were included. Uptake in the head of the pancreas was measured and compared with uptake in normal liver parenchyma (target-to-liver ratio). Patients were followed up for 6–24 mo. Results: We reviewed 245 studies performed on 100 patients and classified the pancreatic uptake as either diffuse or focal. Twenty-three patients (66 scans) showed diffuse uptake; 8 patients (16 scans) showed focal uptake. None of these 31 patients had negative findings on their subsequent scans, and vice versa. During follow-up, localization of neuroendocrine tumors in the pancreas was not suspected in any patient. Conclusion: Focal and diffuse uptake of 68Ga-DOTANOC in the head of the pancreas occurred, respectively, in 23% and 8% of the patients. The main finding of our study was that increased pancreatic uptake was stable over time.

Experimental results and related clinical implications of PET detection of epidermal growth factor receptor (EGFr) in cancer

The epidermal growth factor receptor (EGFr) is one of the most studied molecules as a target for cancer therapy. Over these last few years, several studies attempting to identify predictive biomarkers of treatment response, such as the receptor status or other molecules related to the downstream signalling pathway, have been conducted. However, from a clinical point of view, the information obtained from ex vivo analyses still has various limitations that may be overcome by the combination with molecular imaging technologies which may provide a noninvasive, global, in vivo evaluation of the molecular tumour background. The aim of this review is to report the preclinical results of all positron emission tomography (PET) tracers synthesized until now for in vivo detection of EGFr in cancer. Two classes of PET compounds have been developed: labelled small molecules such as tyrosine kinase inhibitors and labelled monoclonal antibodies. The in vitro and in vivo results of these PET tracers are very different depending on the chemical properties, positron emission radionuclide, or animal models. As a consequence, various critical questions are still open, and the implications of a translation in the clinical setting for EGFr imaging in cancer patients is discussed.

Automation synthesis modules review.

The introduction of (68)Ga labelled tracers has changed the diagnostic approach to neuroendocrine tumours and the availability of a reliable, long-lived (68)Ge/(68)Ga generator has been at the bases of the development of (68)Ga radiopharmacy. The huge increase in clinical demand, the impact of regulatory issues and a careful radioprotection of the operators have boosted for extensive automation of the production process. The development of automated systems for (68)Ga radiochemistry, different engineering and software strategies and post-processing of the eluate were discussed along with impact of automation with regulations.

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.

Synthesis and quality control of 68Ga citrate for routine clinical PET.

Introduction and aimScintigraphic imaging of infection and inflammation with 67Ga-citrate is an established and powerful diagnostic tool in the management of patients with infectious or inflammatory diseases. 68Ga is a short-lived positron-emitting radionuclide (half-life 67.6 min, positron energy 2.92 MeV), which allows better imaging qualities than 67Ga using the high spatial resolution and the quantitative features of PET. The aim of this study was to develop a method of synthesis for 68Ga citrate with high and reproducible radiochemical yield using a commercial 68Ga-labelling module. The resultant 68Ga citrate would be suitable for use in the detection of infectious or inflammatory diseases in routine clinical practice. MethodsA simplified method of producing 68Ga citrate is described. Radiochemical purity, pyrogen testing were performed as per the standard protocols. ResultsAfter performing 10 syntheses of 68Ga citrate, the radiochemical yield was 64.1±6.0% (mean±standard deviation) with an average activity of 971.2±103.4 MBq available for labelling. Radiochemical purity determined by instant thin-layer chromatography-silica gel was higher than 98%. All the synthesized products were found to be sterile and pyrogen-free. In this study, the quality control step provided good and reproducible results. This is worth noting, especially in view of the stringent new rules adopted in most European countries for the in-house good manufacturing practice (GMP) synthesis of radiopharmaceuticals. ConclusionThe high radiochemical yield and purity showed that this method is a reliable tool for the production of 68Ga citrate to be used in the detection of inflammatory and infectious diseases using high resolution and qualitative PET.

Synthesis of oncological [11C]radiopharmaceuticals for clinical PET

Positron emission tomography (PET) is a nuclear medicine modality which provides quantitative images of biological processes in vivo at the molecular level. Several PET radiopharmaceuticals labeled with short-lived isotopes such as (18)F and (11)C were developed in order to trace specific cellular and molecular pathways with the aim of enhancing clinical applications. Among these [(11)C]radiopharmaceuticals are N-[(11)C]methyl-choline ([(11)C]choline), l-(S-methyl-[(11)C])methionine ([(11)C]methionine) and 1-[(11)C]acetate ([(11)C]acetate), which have gained an important role in oncology where the application of 2-[(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG) is suboptimal. Nevertheless, the production of these radiopharmaceuticals did not reach the same level of standardization as for [(18)F]FDG synthesis. This review describes the most recent developments in the synthesis of the above-mentioned [(11)C]radiopharmaceuticals aiming to increase the availability and hence the use of [(11)C]choline, [(11)C]methionine and [(11)C]acetate in clinical practice.

C-11 acetate does not enhance usefulness of F-18 FDG PET/CT in differentiating between focal nodular hyperplasia and hepatic adenoma.

Purpose of the Report: We assessed the usefulness of F-18 fluorodeoxyglucose positron emission tomography (FDG PET) and C-11 acetate PET (AC PET) in distinguishing hepatic lesions due to consequential disease (hepatocellular adenoma and malignant lesions) from focal nodular hyperplasia (FNH) in patients at low risk of malignancy. Materials and Methods: Thirty-one patients with 43 lesions were prospectively enrolled. The diagnostic work-up included Doppler and contrast-enhanced ultrasonography, contrast-enhanced computed tomography, and/or magnetic resonance imaging. Fine needle biopsy was performed if the imaging study was inconclusive. The work-up revealed 36 FNH and 7 consequential lesions (5 hepatocellular adenoma, 1 hepatoma, and 1 metastasis). All patients underwent FDG and AC PET. FDG PET with target/background ratio (T/Br) grater than 1.2 and AC PET with T/Br of less than 1.2 were considered positive test for consequential disease. Results: On FDG PET, we had 6 true-positive out of 7 lesions due to consequential diseases, with a sensitivity of 85.7%, and 33 true-negative out of 36 lesions with FNH, with a specificity of 91.7%. Using AC PET, there were 2 true-positive lesions out of 7 caused by neoplasms, with a sensitivity of 28.6%, and 34 true-negative lesions out of 36 FNH, with a specificity of 94.4%. Conclusions: When the goal is differentiating FNH from liver neoplasms, AC PET offered no additional diagnostic advantage over what is achieved with FDG PET.

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

Purpose 64Cu-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 64Cu-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 64Cu-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 cm3 (range, 2.5–453.7 cm3) 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 cm3 (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 64Cu-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.