Development of in-House Synthesis and Quality Control of [99mTc]Tc-PSMA-I&S.

Many radioactive PSMA inhibitory substances have already been developed for PET diagnostics and therapy of prostate cancer. Because PET radionuclides and instrumentation may not be available, technetium-99 m labelled tracers can be considered as a diagnostic alternative. A suitable tracer is [99mTc]Tc-PSMA-I&S, primarily developed for radio-guided surgery, which has been identified for diagnostics of prostate cancer. However, there is no commercial kit approved for the preparation of [99mTc]Tc-PSMA-I&S on the market. This work presents an automated process for the synthesis of [99mTc]Tc-PSMA-I&S concerning good manufacturing practice (GMP). We used a Scintomics GRP 4 V module, with the SCC software package for programming sequences for this development. The optimum reaction conditions were evaluated in preliminary experiments. The pH of the reaction solution was found to be crucial for the radiochemical yield and radiochemical purity. The validation of [99mTc]Tc-PSMA-I&S (n = 3) achieved a stable radiochemical yield of 58.7 ± 1.5% and stable radiochemical purities of 93.0 ± 0.3%. The amount of free [99mTc]TcO4− in the solution and reduced hydrolysed [99mTc]TcO2 was <2%. Our automated preparation of [99mTc]Tc-PSMA-I&S has shown reliability and applicability in the clinical setting.

Atypical Presentation of Liver Metastases of Prostate Cancer in 68Ga-PSMA-11 PET/CT.

ABSTRACT: 68Ga-PSMA-11 (68Ga-prostate-specific membrane antigen-11) PET/CT continues to have a great clinical value for staging in prostate cancer. Lymph nodes and bone are the most typical metastatic sites of prostate cancer, whereas liver metastases are rare and usually show focally increased tracer uptake in 68Ga-PSMA-11 PET/CT. Here, we present an 88-year-old man with histologically proven metastatic castration-resistant prostate cancer and extensive PSMA-negative liver metastases identified by 68Ga-PSMA-11 PET/CT. This finding is remarkable because the decreased liver uptake of 68Ga-PSMA-11 may resemble a primary hepatic tumor.

Automated Synthesis of [68Ga]Ga-FAPI-46 on a Scintomics GRP Synthesizer.

[68Ga]Ga-FAPI-46 is a radiolabelled fibroblast activation protein inhibitor that selectively binds to fibroblast activation protein (FAP), which is overexpressed by cancer-associated fibroblasts (CAFs) in the tumour microenvironment. In recent years, radiolabelled FAP inhibitors (FAPIs) are becoming increasingly important in cancer diagnostics and also for targeted radionuclide therapy. Because of the increasing demand for radiolabelled FAPIs, automating the synthesis of these compounds is of great interest. In this work, we present a newly programmed automatic synthesis process of [68Ga]Ga-FAPI-46 on a Scintomics GRP module using two Galli Ad generators as a radionuclide source. Dedicated cassettes for the labelling of 68Ga-peptides were used without any modifications. The generators were connected via a three-way valve to the module and eluted automatically over a strong cation exchange (SCX) cartridge by using the vacuum pump of the synthesis module, eliminating the need to transfer the eluates into a separate vial. After a reaction step in HEPES buffer, the compound was purified by solid-phase extraction (SPE) over a Sep-Pak Light C18 cartridge. The evaluation of 10 routine syntheses of [68Ga]Ga-FAPI-46 resulted in a radiochemical yield of 72.6 ± 4.9%. The radiochemical purity was 97.6 ± 0.3%, and the amount of free gallium-68 and colloid was <2%. The final product fulfilled the quality criteria, which were adapted from relevant monographs of the European Pharmacopoeia (Ph. Eur.). This work presents the successful preparation of multiple doses of [68Ga]Ga-FAPI-46 in a GMP-compliant automated process for clinical use.

Radioiodination and Purification of [131I]ß-CIT and [131I]FP-CIT with an Automated Radiosynthesizer.

Dopaminergic transporter (DAT) imaging with single photon emission computed tomography (SPECT) is used to diagnose Parkinson's disease and to differentiate it from other neurodegenerative disorders without presynaptic dopaminergic dysfunction. The radioiodinated tropane alkaloids [123I]FP-CIT and [123I]ß-CIT enable the evaluation of the integrity of DATs. Commonly, the labeling of these compounds is performed by electrophilic substitution of the alkylstannylated precursors with radioactive iodine and following purification by HPLC or solid phase extraction (SPE). This work presents the first radioiodination of ß-CIT and FP-CIT with no carrier added [131I]NaI on a Scintomics GRP synthesis module. Free iodine-131 and impurities were removed by SPE over a C-18 Sep-Pak cartridge. We achieved a radiochemical yield of >75% and a radiochemical purity of >98% with both compounds. Our development of an automated synthesis on a commercially available synthesizer ensures robust and efficient labeling of [131I]FP-CIT and [131I]ß-CIT starting with low concentrated radioiodine.

Oligodendroglioma in 68Ga-PSMA-11 and 18F-Fluciclovine PET/CT.

ABSTRACT: Prostate cancer (PC) is one of the most common cancers affecting men worldwide, with a high recurrence rate after therapy. 68Ga-PSMA-11 and 18F-fluciclovine are PET imaging tracers for the detection of recurrence sites in PC patients. 68Ga-PSMA-11 is a membrane antigen overexpressed by tumor cells, whereas 18F-fluciclovine targets increased amino acid transporter in the membrane of cancer cells. We report a case of an 83-year-old man with known oligodendroglioma and biochemically recurrent PC who shows a high focal 68Ga-PSMA-11 and 18F-fluciclovine uptake in the brain.

Is there a place for FET PET in the initial evaluation of brain lesions with unknown significance?

PURPOSE: The aim of this study was to evaluate the clinical value of the use of O-(2-[(18)F]fluoroethyl)-L: -tyrosine (FET) positron emission tomography (PET)/computed tomography (CT) in patients of a neurological clinic for evaluation of brain lesions newly diagnosed by magnetic resonance imaging (MRI). METHODS: We evaluated 88 patients (44 women and 44 men) with a mean age of 50 +/- 19 years who were sent consecutively for evaluation of an intracerebral mass or lesion observed by MRI from 2006 to 2008. Hospitalization was necessary due to neurological clinical symptoms. Images were obtained by PET/CT 30 min after i.v. injection of 185 MBq FET. Coregistration with MRI was done by HERMES workstation. RESULTS: FET uptake above the cortical level was observed in 60 patients. Neurosurgery was performed in 60 patients (51 with FET-positive imaging); 36 high-grade and 19 low-grade tumours were verified histologically. The sensitivity of FET PET for high-grade tumours (WHO III-IV) was 94% in this setting. Among the low-grade brain tumours (WHO I-II) 13 of 19 were FET positive, which indicates a sensitivity of 68%. Five of ten (50%) astrocytomas I and II could not be visualized by FET. Histological data were not provided for 28 of 88 patients, so the diagnostic approach is based upon longitudinal observation. Radiological and/or clinical control was done at a median of 7 months later. Three patients (all FET positive) died a few months after the examination because of rapid progression of the malignant brain tumour. A malignant entity could be excluded in the other 25 patients. Considering the whole cohort of 88 patients, 43 patients with malignant tumour could be identified, including high-grade glioma, intracerebral lymphoma (n = 1) and metastasis (n = 3). The sensitivity of FET PET for detecting a malignant tumour entity was 93%. We observed two false-positive cases with postischaemic lesions. Remarkably, the two patients with cerebral gliomatosis were false-negative on FET PET imaging. The negative predictive value for a malignant entity was calculated to be 89%. CONCLUSION: Our results indicate a high sensitivity of FET PET for detecting high-grade glioma in patients with neurological symptoms and recently observed brain lesions by MRI. In the setting of evaluating new brain lesions of unknown significance via FET PET a negative image can encourage a wait and see strategy-of course in accordance with the clinical picture and morphological imaging.

Systematic Assessment of the Adsorption of 99mTc-Radiopharmaceuticals onto Plastic Syringes.

The phenomenon of adsorption of several 99mTc-radiopharmaceuticals onto disposable syringes is common knowledge and can reach a level of up to 50%, with the result being inadequate dosing. The resulting underdosing has a substantial influence on the quality of imaging, especially in pediatric patients. Therefore, we aimed to establish a standardized in vitro assessment to investigate the adsorption of several 99mTc-radiopharmaceuticals on various brands of syringes. Methods: The 99mTc-radiopharmaceuticals were prepared according to manufacturer instructions. For the assessment, the disposable syringes (n = 3) were filled to one third of capacity with the 99mTc preparation and incubated for 30 min at room temperature. The syringes were emptied into evacuated vials, and the radioactivity of the syringes was measured before and after they were emptied. Furthermore, the dilution effect of 99mTc preparations was studied. We used 2 different brands of syringes and systematically examined 99mTc-pertechnetate, 99mTc-butedronate, 99mTc-oxidronate, 99mTc-medronate, 99mTc-tetrofosmin, 99mTc-sestamibi, 99mTc(V)-dimercaptosuccinic acid, and 99mTc-succimer. Additionally, 99mTc-succimer was retested with 5 brands of syringes. Results: 99mTc-pertechnetate, 99mTc-phosphonates, and 99mTc(V)-dimercaptosuccinic acid showed no significant adsorption. The measured radioactive retention of 2%-5% was equivalent to the determined dead volume. Using 99mTc-tetrofosmin, we found a slight but significant adsorption of 4%-7%. The 99mTc-sestamibi preparation showed a nonsignificant retention of 3%-5%. However, when the 99mTc-sestamibi was diluted 1:10 with saline, the adsorption rate increased to 9%-13%. 99mTc-succimer displayed different adsorption levels depending on the brand of syringe and the preparation technique. The adsorption of 99mTc-succimer, prepared from kits according to the instructions, did not exceed 15%. The 1:10 saline dilution of a 99mTc-succimer kit preparation, as well as an in-house preparation, demonstrated a radioactive syringe adsorption rate of more than 30%. Conclusion: The results revealed the significance of syringe adsorption of radiopharmaceuticals in the prevention of underdosing. Therefore, a quality assurance assessment is recommended before the introduction of new brands of plastic syringes or routine application of diluted or in-house radiopharmaceuticals.

Lymphoscintigraphy for Sentinel Lymph Node Biopsy in Breast Cancer: Do We Need a Delayed Image?

BACKGROUND: Sentinel lymph node biopsy has become a standard of care in the treatment of patients with early breast cancer, but clinical guidelines continue to be vague on details of the procedure. We were interested in the results of our 2-day protocol, which includes delayed lymphoscintigraphy at 18 h. METHODS: We reviewed the results of preoperative lymphoscintigrams in patients undergoing surgery for breast cancer. Lymphoscintigraphy was performed 2 h after periareolar injection of 4 × 37 MBq 99mTc nanocolloid (early lymphoscintigraphy) and 18 h following injection (delayed lymphoscintigraphy). The early results were compared with the late results. RESULTS: A total of 238 lymphoscintigraphies were performed in 232 patients (6 bilateral). At 2 h, ≥1 sentinel nodes were visualized in 154/238 (65%) cases; in 84 (35%), no sentinel node was visualized. Delayed lymphoscintigraphy visualized a sentinel node in 40 of 76 (53%) cases with no visualization at 2 h and failed to show a sentinel node in 36 (47%) of these cases (in 8 cases, no delayed lymphoscintigram was obtained). CONCLUSIONS: Delayed lymphoscintigraphy was useful in about 50% of the breast cancer patients in whom immediate scintigraphy failed to demonstrate a sentinel lymph node.

A Prospective Head-to-Head Comparison of 18F-Fluciclovine With 68Ga-PSMA-11 in Biochemical Recurrence of Prostate Cancer in PET/CT.

PURPOSE: One of the major challenges for all imaging modalities is accurate detection of prostate cancer (PCa) recurrence. Beyond the established Ga-PSMA, a novel promising PET tracer in PCa imaging is F-fluciclovine. For evaluating the advantages and disadvantages and the comparability, we conducted a prospective head-to-head comparison on F-fluciclovine and Ga-PSMA-11 in patients with biochemical recurrence of PCa. METHODS: 58 patients with biochemical recurrence of PCa after definitive primary therapy were included. Both scans were performed within a time window of mean 9.4 days. All scans were visually analyzed independently on a patient-, region- and lesion-based analysis. All the examinations were performed in the same medical department using identical scanners at any time. RESULTS: The overall detection rate for PCa recurrence was 79.3% in F-fluciclovine and 82.8% in Ga-PSMA-11 (P = 0.64). Local recurrence was detected in 37.9% on F-fluciclovine and in 27.6% on Ga-PSMA-11 (P = 0.03). Local pelvic lymph node recurrence was detected on F-fluciclovine versus Ga-PSMA-11 in 46.6% versus 50%, in extrapelvic lymph node metastases in 41.4% versus 51.7% and in bone metastases in 25.9% versus 36.2%. Lesion-based analysis showed identical findings in local pelvic lymph nodes in 39.7%, in extrapelvic lymph nodes in 22.4%, and in bone metastases in 13.8%. CONCLUSIONS: The advantage of F-fluciclovine is detecting curable localized disease in close anatomical relation to the urinary bladder, whereas Ga-PSMA-11 fails because of accumulation of activity in the urinary bladder. F-fluciclovine is almost equivalent to Ga-PSMA-11 in detecting distant metastases of PCa recurrence.

Diagnostic and prognostic value of additional SPECT/CT in sentinel lymph node mapping in breast cancer patients.

THE AIM: of the study was to demonstrate the diagnostic and prognostic value of SPECT/CT in sentinel lymph node mapping (SLNM) in patients with invasive breast cancer. METHODS: 114 patients with invasive breast cancer with clinically negative lymph nodes were included in this retrospective study as they were referred for SLNM with 99mTc-nanocolloid. Planar image acquisition was accomplished in a one-day or two-day protocol depending on the schedule of the surgical procedure. Low dose SPECT/CT was performed after the planar images. The sentinel lymph node biopsy (SLNB) was considered false negative if a primary recurrence developed within 12 months after SLNB in the axilla from which a tumor-free SLN had been removed. RESULTS: Between December 2009 and December 2011, 114 patients (pts.) underwent SLNM with additional SPECT/CT. Planar imaging identified in 109 pts. 139 SLNs, which were tumor-positive in 42 nodes (n = 41 pts.). SPECT/CT identified in 81 pts. 151 additional SLNs, of which 19 were tumor-positive and led to therapy change (axillary lymph node dissection) in 11 pts. (9.6 %). Of overall 61 tumor-positive SLNs (n = 52 pts.) SPECT/CT detected all, whereas planar imaging detected only 42 of 61 (P < 0.0001). No patient had lymph node metastasis within 12 months after SLNB in the axilla from which a tumor-free SLN had been removed resulting in a false-negative rate of 0 %. The local relapse rate was 1.8 % leading to a 4-year disease-free survival rate of 90 %. CONCLUSION: Among patients with breast cancer, the use of SPECT/CT-aided SLNM correlated due to a better anatomical localization and identification of planar not visible SLNs with a higher detection rate of SLNs. This led to therapeutic consequences and an excellent false-negative and 4-year disease-free survival rate.

Minimal invasive biopsy of intraconal expansion by PET/CT/MRI image-guided navigation: a new method.

UNLABELLED: Intraorbital tumours are often undetected for a long period and may lead to compression of the optic nerve and loss of vision. Although CT, MRI's and ultrasound can help in determining the probable diagnosis, most orbital tumours are only diagnosed by surgical biopsy. In intraconal lesions this may prove especially difficult as the expansions are situated next to sensitive anatomical structures (eye bulb, optic nerve). In search of a minimally invasive access to the intraconal region, we describe a method of a three-dimensional, image-guided biopsy of orbital tumours using a combined technique of hardware fusion between (18)F-FDG Positron Emission Tomography ((18)F-FDG PET), magnetic resonance imaging (MRI) and Computed Tomography (CT). METHOD AND MATERIAL: We present 6 patients with a total of 7 intraorbital lesions, all of them suffering from diplopia and/or exophthalmos. There were 3 female and 3 male patients. The patients age ranged from 20 to 75 years. One of the patients showed beginning loss of vision. Another of the patients had lesions in both orbits. The decision to obtain image-guided needle biopsies for treatment planning was discussed and decided at an interdisciplinary board comprising other sub-specialities (ophthalmology, neurosurgery, maxillofacial surgery, ENT, plastic surgery). All patients underwent 3D imaging preoperatively ((18)F-FDG PET/CT or (18)F-FDG PET/CT plus MRI). Data was transferred to 3D navigation system. Access to the lesions was planned preoperatively on a workstation monitor. Biopsy-needles were then calibrated intraoperatively and all patients underwent three-dimensional image-guided needle biopsies under general anaesthesia. RESULTS: 7 biopsies were performed. The histologic subtype was idiopathic orbital inflammation in 2 lesions, lymphoma in 2, Merkel cell carcinoma in 1, hamartoma in 1 and 1 malignant melanoma. The different pathologies were subsequently treated in consideration of the actual state of the art. In cases where surgical removal of the lesion was performed the histological diagnosis was confirmed in all cases. CONCLUSION: There is a wide range of possible treatment modalities for orbital tumours depending on the nature of the lesion. Histological diagnosis is mandatory to select the proper management and operation. The presented method allows minimal-invasive biopsy even in deep intraconal lesions, enabling the surgeon to spare critical anatomical structures. Vascular lesions such as cavernous haemangioma, tumour of the lacrimal gland or dermoid cysts present a contraindication and have to be excluded.

[Malignant melanoma: diagnostic value of F-18 FDG positron emission tomography]. / Malignes Melanom: diagnostischer Stellenwert der F-18-FDG-Positronenemissionstomographie.

Malignant melanoma is one of those malignancies with worldwide increasing incidence. The prognosis of malignant melanoma is bad because of its early hematogenous and lymphogenous metastases. Earliest possible diagnosis and sensitive follow-up of disease are important parameters to improve prognosis. In the literature a sensitivity of 92% and a specificity of 77% is found for blinded reading of F-18-FDG-PET of the whole body, and a specificity of 100% when clinical information was provided.

Diagnostic and prognostic value of 99mTc-tetrofosmin scintigraphy in maxillofacial flaps.

In oro-maxillofacial malignancies, new therapeutic approaches are placing changing demands on the diverse diagnostic modalities. In contradistinction to mandibular reconstruction of former years, the transplants (microvascular anastomosed pedicled flaps, "flaps") now consist of one or more arteries feeding a soft tissue component attached to a piece of bone suitably fitted to fill the defect. We addressed the diagnostic value of technetium-99m tetrofosmin scintigraphy in differentiating between viability and non-viability of the soft tissue portion of flaps in the immediate postoperative assessment. A total of 60 patients who had received flaps for reconstruction of the mandible after partial resection were investigated with (99m)Tc-tetrofosmin 3-5 days after surgery. Scintigraphy consisted of (a) radionuclide angiography, (b) static planar imaging in four projections starting at 10 min post injection, and (c) single-photon emission tomography (SPET) performed immediately after the planar imaging. Normal perfusion associated with no defects throughout the soft tissue portion of the transplant was observed in 46/60 patients. This scintigraphic pattern was identical to viability and normal postoperative follow-up. Hypoperfusion and small defects on planar and SPET images indicated viability and uncomplicated postoperative healing in 6/60 patients, but non-viability/inadequate healing of the flap in 4/60 patients. Absence of perfusion combined with a large defect on static planar and SPET images definitively showed the non-viability of the flap (4/60 patients). It is concluded that (99m)Tc-tetrofosmin scintigraphy is a sensitive diagnostic tool for the immediate postoperative assessment of the viability and the adequacy of implantation of the soft tissue portion of flaps. Therefore tetrofosmin scintigraphy is an important modality in order (a) to define the optimal therapeutic regimen in the immediate postoperative period and (b) to provide better prognosis.

Groin recurrence after micrometastasis in a sentinel lymph node in a patient with vulvar cancer.

BACKGROUND: The sentinel lymph node concept is attractive in vulvar cancer because of the potential to avoid the morbidity associated with formal groin dissection. CASE: An 84-year-old patient with a T2 carcinoma of the anterior vulva underwent surgery including bilateral sentinel node excision after identification with technetium-labeled nanocolloid. Frozen section histology showed a tumor deposit <1 mm in diameter in a left groin node whereas four nodes in the right groin were apparently negative. Completion lymphadenectomy was performed only for the left groin. Final histology including serial sectioning showed a micrometastasis in one of seven nodes from the right groin; no further treatment was given. Sixteen months postoperatively the patient developed a recurrence in the right groin; the left groin was free of tumor. CONCLUSION: This case indicates that groins with a micrometastasis detected by sentinel lymph node excision require further treatment.

The 936C>T polymorphism of the gene for vascular endothelial growth factor is associated with 18F-fluorodeoxyglucose uptake.

BACKGROUND: Positron emission tomography (PET) is a an important technology for detection and staging of breast cancer. The method is based upon assessment of glucose metabolism using the 18F-fluorodeoxyglucose (18F-FDG) as glucose analog. A strong variability of 18F-FDG uptake by breast cancer tissue has been reported, the reason for which is not fully understood but may involve vascular density and integrity. A 936C>T polymorphism in the gene for the vascular endothelial growth factor (VEGF) has been associated with VEGF plasma levels and breast cancer risk. METHODS: To analyze the role of this polymorphism for 18F-FDG uptake in breast cancer patients, we determined the VEGF genotype in 37 patients in whom PET was performed for detection of metastases. An 18F-FDG uptake score of 1 (low uptake), 2 (medium uptake) or 3 (high uptake) was assigned to each patient. RESULTS: VEGF CC, CT and TT genotypes were found in 28, 8 and 1 patient. Uptake score of 1 was found in three patients, score 2 in 12 patients and score 3 in 22 patients. VEGF genotype was significantly associated with FDG uptake score (chi2 test, p=0.007). The number of 936-T alleles correlated with a lower 18F-FDG uptake score (Spearman correlation test, p=0.032). CONCLUSION: In the present study the common VEGF 936C>T polymorphisms had a major impact on 18F-FDG uptake in breast cancer patients. If this result can be confirmed in following studies, it might have strong relevance for the use of PET as diagnostic tool.

Non-small cell lung cancer: evaluation of pleural abnormalities on CT scans with 18F FDG PET.

PURPOSE: To evaluate the accuracy of fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in differentiation of pleural malignancy and cancer-unrelated pleural disease in patients with non-small cell lung cancer (NSCLC) and pleural abnormalities at computed tomography (CT). MATERIALS AND METHODS: In 92 patients, pleural abnormalities were detected at contrast material-enhanced thoracic CT, which was performed for newly diagnosed NSCLC (n = 41) or restaging (n = 51). CT findings were negative for pleural malignancy when pleural effusion with attenuation of 10 HU or less and/or rib fractures with no evidence of pathologic fracture were present; findings were indeterminate when pleural effusion with attenuation greater than 10 HU and/or solid pleural abnormalities without osseous destruction of the chest wall were present; and findings were positive if any osseous destruction of the chest wall adjacent to a pleural mass was present. All patients underwent FDG PET. Findings were negative for pleural malignancy if pleural activity was absent, equal to, or less than mediastinal background activity; findings were positive if pleural activity was higher than mediastinal background activity. Reading of CT and FDG PET scans was first performed separately and then was combined. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPP), and accuracy were calculated for CT and FDG PET separately and for CT and FDG PET combined, with cytologic and/or histologic analysis as standard of reference. RESULTS: In detection of pleural malignancies, CT findings were indeterminate in 65 (71%) patients and true-negative in 27 (29%). Respective sensitivity, specificity, PPV, NPV, and accuracy of FDG PET in detection of pleural malignancies were 100%, 71%, 63%, 100%, and 80%; and those of CT and FDG PET combined, 100%, 76%, 67%, 100%, and 84%. CONCLUSION: Findings suggest that a negative FDG PET scan for indeterminate pleural abnormalities at CT indicates a benign character, while positive findings on an FDG PET scan are sensitive for malignancy.