Meltem Ocak

Evaluation of PSMA PET/CT imaging using a 68Ga-HBED-CC ligand in patients with prostate cancer and the value of early pelvic imaging.

PurposeThe aim of the study was to evaluate the diagnostic value of the prostate-specific membrane antigen (PSMA) ligand 68Ga-HBED-CC (PSMA PET/CT) in patients with prostate cancer and evaluate the value of early imaging of the pelvis. Materials and methodsThe files of 28 patients were retrospectively evaluated. All patients had a histopatological confirmation of prostate cancer. PSMA PET/CT images were obtained at 5 and 60 min after injection from all patients. ResultsIntense pathologic radiotracer uptake was observed in 23 patients (77%) at the site of primary tumour. Lymph node metastases were detected in 10 patients (36%) and bone metastases were detected in seven patients (25%). Bone scan (n=25) results revealed metastatic bone lesions in four patients, equivocal results in nine patients and normal results in 12 patients. PSMA PET/CT confirmed bone metastases in all four patients. Pathologic radiotracer uptake in PSMA PET/CT scans was observed only in one patient among those who had equivocal bone scans. PSMA PET/CT showed additional bone lesions in two patients who had a normal bone scan. When we compared early and late pelvic images we found no difference in the number of lesions detected. The maximum standardized uptake value (SUVmax) for primary tumour, lymph nodes and bone metastases was significantly higher in late images. ConclusionPSMA PET/CT imaging seems to be a valuable imaging modality for evaluation of primary prostate cancer and it seems to have potential for the detection of lymph node and bone metastases. Early images 5 min p.i. can help to better distinguish between urinary bladder (before tracer accumulation occurs) and tumour lesions.

68 Ga-PSMA PET/CT imaging of metastatic clear cell renal cell carcinoma

Prostate-specific membrane antigen (PSMA) is a type II transmembrane protein with high expression in prostate carcinoma cells. Glu-NH-CO-NH-Lys-(Ahx)-[Ga(HBED-CC)] (GaPSMA) has been suggested as a novel tracer that can detect prostate carcinoma relapses and metastases with high contrast by targeting PSMA [1]. Besides prostate cancer, PSMA has been shown to be expressed in the neovasculature of various solid malignant tumours including clear cell renal cell carcinoma (ccRCC) [2, 3]. RCC is a potentially lethal cancer with aggressive behaviour, and has a propensity for distant metastatic spread. The common sites of metastases from ccRCC include lungs (33 – 72 %), intraabdominal lymph nodes (3 – 35 %) and brain (7 – 13 %) [4]. Bone metastases are also a frequent complication in patients with ccRCC [4]. We present to our knowledge the first reported case of a patient with a diagnosis of ccRCC with Ga-PSMA uptake. A 65-yearold woman, status post-nephrectomy, underwent GaPSMA (b) and F-FDG (a) PET/CT for staging. GaPSMA PET/CT showed multiple pathological bone lesions with intense uptake of the tracer in the seventh cervical vertebra and acromion of the left scapula (c, d, e; SUVmax=35 for PSMA, 7.2 for FDG), sternum (f, g, h; SUVmax=28.3 for PSMA, 5.15 for FDG), and right tuber ischiadicum (i, j, k; SUVmax 34.1 for PSMA, 5.3 for FDG). F-FDG PET/CT provided lower visual detectability of the bone metastasis. This case indicates the clinical utility of Ga-PSMA for the imaging of RCC.

Full automation of 68Ga labelling of DOTA-peptides including cation exchange prepurification

Here we describe a fully automated approach for the synthesis of (68)Ga-labelled DOTA-peptides based on pre-concentration and purification of the generator eluate by using a cation exchange-cartridge and its comparison with fully automated direct labelling applying fractionated elution. Pre-concentration of the eluate on a cation exchange cartridge both using a resin-based and a disposable cation-exchange cartridge efficiently removed (68)Ge as well as major metal contaminations with Fe and Zn. This resulted in a high labelling efficiency of DOTA-peptides at high specific activity (SA) with short synthesis times.

Normal distribution pattern and physiological variants of 68Ga-PSMA-11 PET/CT imaging.

Purpose68Ga-PSMA-11 is a novel PET tracer suggested to be used for imaging of advanced prostate cancer. In this study, we aimed to present a detailed biodistribution of 68Ga-PSMA-11, including physiological and benign variants of prostate-specific membrane antigen (PSMA) imaging. Materials and methodsWe carried out a retrospective analysis of 40 patients who underwent PSMA PET/computed tomography (CT) imaging and who had no evidence of residual or metastatic disease on the scans. In addition, 16 patients who underwent PSMA PET/CT imaging with any indication other than prostate cancer were included in the study to evaluate physiological uptake in the normal prostate gland. The median, minimum–maximum, and mean standardized uptake value (SUV) values were calculated for visceral organs, bone marrow and lymph nodes, and mucosal areas. Any physiological variants or benign lesions with 68Ga-PSMA-11 were also noted. Results68Ga-PSMA-11 uptake was noted in the kidneys, parotid and submandibular glands, duodenum, small intestines, spleen, liver, and lacrimal glands, and mucosal uptake in the nasopharynx, vocal cords, pancreas, stomach, mediastinal blood pool, thyroid gland, adrenal gland, rectum, vertebral bone marrow, and testes. Celiac ganglia showed slight 68Ga-PSMA-11 uptake in 24 of 40 patients without the presence of any other pathologic lymph nodes in abdominal and pelvic areas. Variable uptake of 68Ga-PSMA-11 was observed in calcified choroid plexus, a thyroid nodule, an adrenal nodule, axillary lymph nodes and celiac ganglia, occasional osteophytes, and gallbladder. The patient group with PSMA PET/CT for indications other than prostate cancer (n=16) showed a slight radiotracer uptake in normal prostate gland (SUVmax: 5.5±1.6, range: 3.5–8.3). ConclusionThis study shows normal distribution pattern, range of SUVs, and physiological variants of 68Ga-PSMA-11. In addition, several potential pitfalls were documented to prevent misinterpretations of the scan.

Cyclic minigastrin analogues for gastrin receptor scintigraphy with technetium-99m: preclinical evaluation.

Two cyclized minigastrin analogues for gastrin receptor scintigraphy were synthesized and derivatized with HYNIC at the N-terminus for labeling with 99mTc. Radiolabeling efficiency, stability, cell internalization, and receptor binding on CCK-2 receptor expressing AR42J cells were studied and the biodistribution evaluated in tumor bearing nude mice, including NanoSPECT/CT imaging. Metabolites in urine, liver, and kidneys were analyzed by radio-HPLC. Radiolabeled cyclic MG showed high stability in vitro and receptor mediated uptake in AR42J cells. In the animal tumor model, fast renal clearance and low nonspecific uptake in most organs were observed. A tumor uptake >3% was calculated ex vivo 1 h p.i. for both 99mTc-EDDA-HYNIC-cyclo-MG1 and 99mTc-EDDA-HYNIC-cyclo-MG2. In an imaging study with 99mTc-EDDA-HYNIC-cyclo-MG1, the tumor was clearly visualized. The metabolite analysis indicated rapid enzymatic degradation in vivo.

Radiolabelling of peptides for PET, SPECT and therapeutic applications using a fully automated disposable cassette system.

ObjectivesRadiolabelled somatostatin analogues have found wide clinical use in nuclear medicine for both diagnostic and therapeutic applications. Here, we describe the development of a fully automated synthesis system allowing radiolabelling of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-derivatized peptides with 68Ga/111In/177Lu and 90Y, meeting radiation safety and pharmaceutical requirements. Materials and methodsThe system consists of a syringe pump, a holder for insertion of a single use multivalve cassette, a heater and a removable radiation shielding. 68Ga labelling was performed in acetate buffer and 177Lu, 90Y and 111In labelling in ascorbate buffer, respectively, followed by purification on a C18 cartridge and final sterile filtration. Cross-contamination was prevented by using disposable cassettes and also by ensuring pharmaceutical standards. Radiochemical purity (RCP) was determined by instant thin-layer chromatography on silica gel impregnated glass fibres and reversed-phase high performance liquid chromatography. Results68Ga-DOTA-peptides were prepared with high RCP (>91%) and radiochemical yields (RCY>80% decay corrected) and 68Ge content was less than 0.0001% in all cases. Synthesis time did not exceed 30 min. 111In, 177Lu and 90Y labelling of DOTA-peptides resulted again in high yields (approximately 90%) and RCP (approximately 95%) and total synthesis time of less than 45 min. Radiation dose to fingers was considerably reduced when compared with manual labelling procedures. ConclusionThe described system allows fully automated, aseptic preparation of DOTA-peptides radiolabelled with different radionuclides in high radiochemical yields and pharmaceutical quality suitable for clinical application.

Evaluation and comparison of Ga-68 DOTA-TATE and Ga-68 DOTA-NOC PET/CT imaging in well-differentiated thyroid cancer.

BackgroundSomatostatin receptor (Sstr) scintigraphy with radiolabelled somatostatin analogues has been used extensively for the diagnosis and therapy of Sstr-expressing tumours. It has been shown that well-differentiated thyroid cancer (WDTC) cells have a high expression of Sstr2, Sstr3 and Sstr5. Hence, WDTC cells could be an ideal target for the evaluation of lesion uptake of Ga-68 DOTA-1-NaI3-octreotide (DOTA-NOC), which has a high affinity not only to Sstr2 but also to Sstr3 and Sstr5. The aim of the present study was to evaluate the value of Ga-68 DOTA-NOC as a target for Sstr2-expressing, Sstr3-expressing and Sstr5-expressing tumours in WDTC patients and to compare the results with those of Ga-68 DOTA-TATE in the same patient population. MethodThirteen patients with WDTC were included in our study: nine with papillary thyroid cancer, three with Hurthle cell carcinoma and one with follicular thyroid carcinoma. All patients had elevated serum thyroglobulin levels and negative post-therapeutic I-131 whole-body scans, which were obtained after the last radioiodine treatment. All patients had undergone two consecutive PET imaging studies with Ga-68 DOTA-D-Phe1-Tyr3-octreotate (DOTA-TATE) and Ga-68 DOTA-NOC, respectively. All images were evaluated visually, and maximum standardized uptake values were calculated. ResultsBoth Ga-68 DOTA-TATE and Ga-68 DOTA-NOC PET images gave comparable results. Among the 13 patients, imaging with both Ga-68 DOTA-TATE and Ga-68 DOTA-NOC gave negative results in five (38%) patients and positive results in eight (62%) patients. A total of 45 lesions were identified on Ga-68 DOTA-TATE images and 42 on Ga-68 DOTA-NOC images; three lesions were missed. Lesion uptake was significantly higher on Ga-68 DOTA-TATE images. Maximum standardized uptake values of Ga-68 DOTA-TATE and Ga-68 DOTA-NOC were 12.9±9.1 and 6.3±4.1 (n=54, P<0.001), respectively. ConclusionOur study suggested that Ga-68 DOTA-TATE has a higher lesion uptake even in WDTC patients and may have potential advantage over Ga-68 DOTA-NOC.

The accuracy of 68Ga-PSMA PET/CT in primary lymph node staging in high-risk prostate cancer

PurposeTo assess the diagnostic accuracy of 68Ga-PSMA PET in predicting lymph node (LN) metastases in primary N staging in high-risk and very high-risk nonmetastatic prostate cancer in comparison with morphological imaging.MethodsThis was a multicentre trial of the Society of Urologic Oncology in Turkey in conjunction with the Nuclear Medicine Department of Cerrahpasa School of Medicine, Istanbul University. Patients were accrued from eight centres. Patients with high-risk and very high-risk disease scheduled to undergo surgical treatment with extended LN dissection between July 2014 and October 2015 were included. Either MRI or CT was used for morphological imaging. PSMA PET/CT was performed and evaluated at a single centre. Sensitivity, specificity and accuracy were calculated for the detection of lymphatic metastases by PSMA PET/CT and morphological imaging. Kappa values were calculated to evaluate the correlation between the numbers of LN metastases detected by PSMA PET/CT and by histopathology.ResultsData on 51 eligible patients are presented. The sensitivity, specificity and accuracy of PSMA PET in detecting LN metastases in the primary setting were 53%, 86% and 76%, and increased to 67%, 88% and 81% in the subgroup with of patients with ≥15 LN removed. Kappa values for the correlation between imaging and pathology were 0.41 for PSMA PET and 0.18 for morphological imaging.ConclusionsPSMA PET/CT is superior to morphological imaging for the detection of metastatic LNs in patients with primary prostate cancer. Surgical dissection remains the gold standard for precise lymphatic staging.

Influence of biological assay conditions on stability assessment of radiometal-labelled peptides exemplified using a 177Lu-DOTA-minigastrin derivative

INTRODUCTION Lack of correlation between in vitro and in vivo stability is a general problem for the development of radiopeptides especially in the case of minigastrin derivatives for therapeutic applications. In this study, we compared the influence of experimental conditions on radiopeptide stability results in vitro using a model Minigastrin (MG) analogue labelled with Lu-177. Additionally, we attempted to characterize the main serum enzymatic cleavage sites by matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS) analysis. METHODS In vitro stability of a DOTA-minigastrin derivative ((177)Lu-DOTA-His-His-Glu-Ala-Tyr-Gly-Trp-NIe-Asp-Phe-NH(2)) was tested in serum, rat tissue homogenates and two different standardised enzymatic mixtures. Quantification of the metabolised radiopeptides at different time intervals was performed using reversed-phase high-performance liquid chromatography (RP-HPLC). Metabolites were characterised by MALDI-TOF-MS. Urine was collected after 15 min p.i. into the mice and compared with in vitro metabolites by RP-HPLC. RESULTS Faster degradation of the radiopeptide was found in blood in comparison with plasma and serum incubation and in components from rats faster than from human origin. Fast degradation was observed in kidney and liver homogenates as well as in standardised enzymatic mixtures, also revealing variations in the metabolic profile. In urine, no intact peptide was detected already 5 min post injection. MALDI-TOF-MS revealed major cleavage sites at the carboxy terminus of the peptide. CONCLUSION Very variable results may be found when different kind of incubation media for testing radiopeptide stabilities is used. Serum incubation studies may overestimate stability; therefore, results should be interpreted with care and combined with alternative in vitro and in vivo investigations.

The role of PSMA PET/CT imaging in restaging of prostate cancer patients with low prostate-specific antigen levels.

Introduction Prostate-specific membrane antigen (PSMA) is increasingly being recognized as a novel target for the PET imaging of prostate cancer (PCa) and 68Ga-DKFZ-11 (68Ga-PSMA) has been suggested as a novel tracer for detection of PCa relapses and metastases. The aim of this study was to evaluate the diagnostic value of PSMA PET/CT in the diagnosis of recurrent PCa with low prostate-specific antigen (PSA) levels. Patients and methods We carried out a retrospective analysis of patients who underwent PSMA PET/CT from November 2013 to December 2014 in our department. Among these patients, 50 out of 178 who had increasing PSA levels (<5 ng/ml) and did not have known metastasis were included in this study. Results Patients had an average PSA of 1.41 ng/ml. A total of 29 patients (58%) showed at least one positive lesion. PET positivity rates of 31% (n=4), 54% (n=13), and 88% (n=14) were observed in patients with a PSA level of less than 0.2, 0.2–2, and 2–5 ng/ml, respectively. A positive correlation was observed between positivity rate and Gleason scores and blood PSA levels. Verification was performed in 46 patients, with biopsy (n=3) and follow-up, and conventional imaging studies at the time of the PET/CT or during follow-up with a mean period of 10.6±3.3 months and ranged from 3.8 to 16.4 months. According to patient-based analysis of 46 cases, 57% of patients had true positive, 24% of patients had true negative, 2% of patients had false positive, an 18% of patients had false-negative findings. A sensitivity of 76.47% (95% confidence interval: 58.83–89.25%) and a specificity of 91.67% (95% confidence interval: 61.52–99.79%) were found. Conclusion PET/CT with 68Ga-PSMA is a valuable tool for assessing recurrence of PCa with a high sensitivity in patients who have PSA levels between 0.2 and 5 ng/ml. In addition, this study suggests that PSMA PET/CT can be used in patients with very low (<0.2 ng/ml) but increasing PSA levels, which, in many cases, may influence further clinical management.