Annals of Nuclear Medicine (v.25, #5)
GMP production of [18F]FDOPA and issues concerning its quality analyses as in USP “Fluorodopa F 18 Injection” by Chih-Hao K. Kao; Wen-Lin Hsu; Heng-Li Xie; Ming-Chi Lin; Wen-Chun Lan; Hao-Yu Chao (309-316).
Lately, 6-[18F]fluoro-l-DOPA (FDOPA) has found increase in its clinical demand for whole-body positron emission tomography (PET) scans, and two key issues in fulfilling this demand are the difficulties in producing FDOPA under the recently imposed PET drug good manufacturing practice (GMP) regulations and in providing it in the quality meeting the terms of major compendia. This paper describes the approaches for the GMP production of FDOPA and for the product testing to meet the standard of United States Pharmacopeia (USP) “Fluorodopa F 18 Injection.”FDOPA was produced by the carrier-added electrophilic aromatic substitution reaction in the facility complying Pharmaceutical Inspection Cooperation Scheme clean room standard. The special aseptic handling technique was applied to minimize the bioburden. The product quality control followed all testing items and procedures, including three different settings of HPLC.The process yielded FDOPA average 2.60 ± 0.26 GBq (N = 22) in every batch. All qualities of the product were within the specifications described in the USP “Fluorodopa F 18 Injection.” The entire production was audited by the government authority and certified to comply with the latest PET drug GMP regulation.Our efforts in producing FDOPA following all aspects of GMP requirements have resulted in a product with the USP quality and certified as GMP complied. The routine production yields enough doses for three to four whole-body scans in each batch. The issues discussed in the report provide good reference for producers planning in routine production for PET drugs that are not commonly produced or with complicated compendial quality control tests.
Keywords: Fluorodopa F 18 Injection; 6-[18F]Fluoro-l-DOPA; PET drug GMP; United States Pharmacopeia
Radiosynovectomy using yttrium-90, phosphorus-32 or rhenium-188 radiocolloids versus corticoid instillation for rheumatoid arthritis of the knee by Knut Liepe; John J. Zaknun; Ajit Padhy; Emerita Barrenechea; Victoria Soroa; Solav Shrikant; Paijit Asavatanabodee; Ming J. Jeong; Maurizio Dondi (317-323).
Radiosynovectomy (RSO) is widely used in rheumatoid arthritis (RA). Commercially available radiopharmaceuticals are costly, and therefore new agents may be of interest. Radiocolloids labelled with less costly and more accessible radionuclides are of interest to developing countries. We investigated the efficacy of different formulations in RA.In a multicentre effort, a cohort of 99 RA patients with knee involvement underwent RSO. Sixty-eight patients were treated with 184 ± 4 MBq Y-90 silicate (Y-90), 15 patients with 53 ± 11 MBq P-32 colloid (P-32), and 16 patients with 451 ± 110 MBq of Re-188 tin colloid (Re-188). Corticosteroid group (CSG) consisting of 46 patients received an intra-articular instillation of 20–40 mg triamcinolone. Pain response was evaluated by a 10-step visual analogue scale (VAS) before, 1 month, 3 months, 6 months and 12 months following the procedure.In the RSO group (n = 99), pain relief by VAS from 6 ± 2 before to 5 ± 3, 4 ± 2, 3 ± 2 and 4 ± 2 at 1, 3, 6, 12 months after RSO was documented (Y-90 group: 6 ± 2 to 3 ± 2; P-32: 5 ± 2 to 3 ± 2, Re-188: 7 ± 2 to 4 ± 2 before vs. 6 months after therapy, respectively). The CSG VAS values were 6 ± 2 before and 5 ± 2, 4 ± 3, 5 ± 2 and 6 ± 2 at 1, 3, 6 and 12 months after corticosteroid instillation, respectively. Pain relief achieved with the three radiocolloid formulations did not differ significantly (P > 0.1). Pain relief at 12 months was more durable in RSO compared to CSG, P < 0.05. At 3 months, pain relief (>2 steps) was reported by 86% of RSO versus 67% of CSG, at 6 months 72 versus 46% and at 12 months 46 versus 21%. Side effects, i.e. swelling or transient pain increase, were recorded in 16% of patients but resolved within 1 month.Therapeutic efficacy of RSO for RA of the knee applying either P-32, Re-188 or Y-90 provides comparable results. Pain relief by RSO is longer lasting as compared to corticosteroid instillation.
Keywords: Radiosynovectomy; Comparative analysis; Re-188; Y-90; P-32
Esophageal transit study using a sliding sum image: application to patients with probable and definite systemic sclerosis by Kenichi Nakajima; Minoru Hasegawa; Anri Inaki; Hiroshi Wakabayashi; Tetsuo Hosoya; Kazuhiko Takehara; Seigo Kinuya (325-331).
Esophageal complication is common in systemic sclerosis (SSc), but scintigraphic transit patterns based on each subtype have not been understood well. The aim of this study was to develop a new algorithm for integrating a dynamic esophageal transit study and to apply the method to patients with SSc.A total of 40 patients suspected of having SSc were examined by a dynamic esophageal transit study. The subtypes included 32 with definite SSc (15 limited cutaneous type and 17 diffuse cutaneous type) and 8 with probable SSc. The serial esophageal images were shifted and summed to a functional image (sliding sum image) and compared to a conventional condensed image analysis. Esophageal retention fraction at 90 s (R 90) and half-time (T 1/2) of transit were also measured.The four patterns of the sliding sum image and condensed image agreed in all patients. Abnormal retention patterns were observed in none of the 8 (0%) patients with the probable SSc and in 15 of 32 (47%) patients with definite SSc (p = 0.014). The severity of scleroderma assessed by modified Rodnan skin thickness score correlated with that of esophageal retention R 90 (p = 0.04).The sliding sum image is a simple and effective method for integrating esophageal transit. Patients with definite SSc and severe scleroderma had significantly higher retention patterns, while probable SSc patients showed no esophageal dysmotility.
Keywords: Esophageal transit study; Functional imaging; Sliding sum image; Condensed image; Systemic sclerosis
First automatic radiosynthesis of 11C labeled Telmisartan using a multipurpose synthesizer for clinical research use by Hitoshi Iimori; Yoshinobu Hashizume; Masahiro Sasaki; Yoshinobu Kajiwara; Yuichi Sugimoto; Yuichi Sugiyama; Yasuyoshi Watanabe; Michio Senda (333-337).
Telmisartan, a nonpeptide angiotensin II AT1 receptor antagonist, is an antihypertensive drug. Positron emission tomography (PET) imaging with [11C]Telmisartan is expected to provide information about the whole body pharmacokinetics of telmisartan as well as the transport function of hepatic OATP1B3. We developed a first automatic preparation system of [11C]Telmisartan to applicable clinical research using a new 11C and 18F multipurpose synthesizer.Two milligrams of precursor (1) in 5 μl of 1 M KOH in 0.5 ml of dimethyl sulfoxide was reacted with [11C]CH3I for 5 min at 120°C. The resultant solution was hydrolyzed with 1 M NaOH at 100°C for 3 min. The neutralization was carried out with acetic acid, followed by purification with high-performance liquid chromatography. The desired radioactive fraction was collected and solvent was replaced by 10 ml saline containing 0.3 ml of EtOH and 0.5 ml of PEG400, and then passed through a sterile 0.22 μm filter (Millex-GV, Millipore) to a pyrogen-free vial as the final product.The yield of [11C]Telmisartan for clinical research use was 16.8 ± 2.9% EOB as decay corrected (n = 8, mean ± SD) in 32–36 min. The radiochemical purity of [11C]Telmisartan was >97%, and specific activity was higher than 86.3 MBq/nmol.We succeeded in the first synthesis of [11C]Telmisartan for clinical research use by appropriate quality tests.
Keywords: Telmisartan; 11C; CFN-100MPS; Positron emission tomography (PET)
Assessment of tumor hypoxia by 62Cu-ATSM PET/CT as a predictor of response in head and neck cancer: a pilot study by Yumiko Minagawa; Kazuya Shizukuishi; Izumi Koike; Choichi Horiuchi; Kei Watanuki; Masaharu Hata; Motoko Omura; Kazumasa Odagiri; Iwai Tohnai; Tomio Inoue; Ukihide Tateishi (339-345).
In radiotherapy and chemotherapy tumor hypoxia is recognized as a major obstacle to effective treatment. We undertook a pilot study in patients with locally advanced head and neck cancer to determine whether there is a relationship between tumor uptake of 62Cu-ATSM and response to chemoradiotherapy.Seventeen patients were studied using PET/CT with 62Cu-ATSM and 18F-FDG prior to the initiation of radiotherapy and chemotherapy. All patients had locally advanced head and neck cancer (stage III or IV). Tumor uptake in all patients was measured by region of interest analysis using the maximal standardized uptake value (SUVmax). A total dose of 50.4–70.2 Gy (median 70.2 Gy) was delivered in 29–39 fractions (median 39 fractions) to tumor. In patients with (non CR) and without (CR) residual/recurrent tumors at 2-year post irradiation, the statistical significance of the differences in tumor 62Cu-ATSM SUVmax, T/M ratio, 18F-FDG SUVmax and tumor volume were analyzed using Student’s t test and Welch test. The relationship between clinical outcome and 62Cu-ATSM/18F-FDG uptake patterns was analyzed using Kruskal–Wallis test. The correlation between SUVmax of 62Cu-ATSM and 18F-FDG was compared by Spearman’s rank correlation test.Two of the 17 patients that were enrolled in our study were excluded from the final analysis. Of the 15 remaining patients, 9 patients were free of disease and 6 patients had residual/recurrent tumors. The SUVmax differed significantly (p < 0.05) between patients with or without residual/recurrent tumor on 62Cu-ATSM PET/CT. Six of the 10 patients with tumors SUVmax >5.00 had residual/recurrent tumor, whereas all of the 5 patients with tumors SUVmax <5.00 were free of disease. There was no significant difference in FDG uptake between patients with and without residual/recurrent tumor.The results of this pilot study suggested that 62Cu-ATSM uptake may be a predictive indicator of tumor response to chemoradiotherapy in patients with locally advanced head and neck cancer.
Keywords: 62Cu-ATSM; Hypoxia; Head and neck cancer; Response; PET
Limited diagnostic and predictive values of dual-time-point 18F FDG PET/CT for differentiation of incidentally detected thyroid nodules by Seong-Jang Kim; Bo Hyun Kim; Yun Kyung Jeon; Sang Soo Kim; In Joo Kim (347-353).
To assess usefulness of dual-time-point 18F FDG PET/CT to differentiate malignant from benign thyroid nodules and predict the potential factor for malignancy.Fifty patients (age 38–83 years, mean 58 ± 10.6 years) with thyroid nodule were recruited. The 18F FDG PET/CT images were analyzed visually and quantitatively.The optimal visual grade of early and delayed images was >grade 3. When SUVmax1 of >2.9 was used as cut off point, the sensitivity and specificity were 55.5 and 63.4%. When SUVmax2 was >3.1, the sensitivity and specificity were 88.8 and 43.9%. When %ΔSUVmax was ≤9.09%, the sensitivity and specificity were 33.3 and 87.8%. ROC analyses showed that all indices had similar efficacy without significances. No definite predictor could be found for malignant nodules.The dual-time-point 18F FDG PET/CT is not a useful method for differentiating malignant and benign nodules.
Keywords: 18F FDG; PET/CT; Dual-time-point imaging; SUV; Thyroid nodule
FDG-PET for the diagnosis of fever of unknown origin: a Japanese multi-center study by Kazuo Kubota; Yuji Nakamoto; Nagara Tamaki; Kakuko Kanegae; Hiroshi Fukuda; Tomohiro Kaneda; Kazuhiro Kitajima; Ukihide Tateishi; Miyako Morooka; Kimiteru Ito; Ryogo Minamimoto; Koji Murakami (355-364).
To evaluate the clinical value of 2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) for the diagnosis of fever of unknown origin (FUO), we performed a Japanese multi-center retrospective survey.A total of 81 consecutive patients with FUO who underwent FDG-PET at 6 institutions between July 2006 and December 2007 were retrospectively evaluated. FDG uptake was visually evaluated using a 4-grade scale. The efficacy of FDG-PET for the evaluation of FUO, the provision of additional diagnostic information, the clinical impact on therapeutic decisions (4-grade scale), and the diagnostic performance compared with the final diagnosis were evaluated.The diagnostic results were analyzed according to 4 groups of final diagnoses: infection, arthritis/vasculitis/autoimmune/collagen disease (A/V), tumor/granuloma (T/G), and other/unknown (O/U). Sensitivity was highest in T/G, followed by infection, A/V and O/U [100%(7/7), 89%(24/27), 65%(11/17), 0%(0/1) respectively]. Clinical impact and mean FDG score showed the same tendency. Additional information was highest in infection followed by T/G, A/V, and O/U [76%(22/29), 75%(6/8), 43%(9/21), 23%(5/22), respectively]. The O/U group showed a high specificity (84%, 16/19) and accurately excluded active focal inflammatory diseases and malignancy. The use of steroids for the treatment of fever seemed to mask the lesions and modified the results, especially in the A/V group (4 false negatives in 8 steroid users out of 21 A/V patients). The prevalence of each disease in each hospital significantly affected the effectiveness of FDG-PET for the diagnosis of FUO. The mean FDG uptake score and additional information (70%, 31/44 vs. 30%, 11/37, respectively) in national hospital (NH) was significantly higher than in university hospitals (UH). A Grade 3 clinical impact, in which the FDG PET results changed the clinical decision, was seen in 50% (22/44) of the patients in the NH group and 13.5% (5/37) of the patients in the UH group. The sensitivity (91%, 30/33; 63%, 12/19) and specificity (60%, 6/10; 86%, 12/14) of the results in the NH and UH groups differed. The total sensitivity was 81% (42/52), specificity was 75% (18/24). The NH group included a large number of cases with infectious diseases (50%, 23/44), while the UH group included a large number of A/V cases (38%, 14/37) and O/U cases (41%, 15/37).FDG-PET for the diagnosis of FUO provided additional diagnostic information and had a high clinical impact, especially among patients with infectious diseases. It was also helpful in cases with unknown or other miscellaneous diseases by allowing the exclusion of focally active diseases. The prevalence of diseases in hospitals significantly affected the effectiveness of FDG-PET for the diagnosis of FUO. FDG-PET is a useful examination providing various degrees of clinical impact for the management of FUO, depending on the characteristics of the patient and the hospital.
Keywords: FDG-PET; Fever of unknown origin; Infectious disease; Inflammation; Multi-center study
Hepatic falciform ligament Tc-99m-macroaggregated albumin activity on SPECT/CT prior to Yttrium-90 microsphere radioembolization: prophylactic measures to prevent non-target microsphere localization via patent hepatic falciform arteries by Yung Hsiang Kao; Andrew E. H. Tan; Li Ser Khoo; Richard H. G. Lo; Pierce K. H. Chow; Anthony S. W. Goh (365-369).
Yttrium-90 (Y-90) selective internal radiation therapy (SIRT) is increasingly used to treat inoperable hepatocellular carcinoma. We describe two patients where hepatic falciform ligament Technetium-99m-macroaggregated albumin (Tc-99m-MAA) activity was identified on single photon emission computed tomography with integrated low-dose CT (SPECT/CT) scan during pre-therapy planning, and the steps taken to prevent radiation dermatitis. The first patient underwent prophylactic coil embolization of the patent hepatic falciform artery; the second patient underwent super-selective infusion of Y-90 resin microspheres to avoid the patent hepatic falciform artery. The incidence of falciform ligament Tc-99m-MAA activity detected on SPECT/CT at our institution is 10%. Tc-99m-MAA SPECT/CT scan provides valuable diagnostic information for treatment planning prior to Y-90 SIRT.
Keywords: Falciform ligament; Yttrium-90 microsphere; Hepatocellular carcinoma; Tc-99m-macroaggregated albumin; SPECT/CT
Investigation of dose distribution of TheraSeed 200 103Pd brachytherapy seed on coaxial cylindrical phantom shells using Monte Carlo simulation by Berkay Camgöz; Mehmet Nurullah Kumru (371-379).
In this study, radial dosimetric characterization for specific internal geometry of seed source was determined. In this study, the separate contribution of radioactive components of the seed’s unlikely single radioactive rod on dose distribution was investigated using model seed TheraSeed 200 source at parallel shells in a water phantom.TheraSeed 200 brachytherapy seed was modeled using EGSnrc-MP Monte Carlo simulation code. Dose contributions of radioactive components inside the seed were calculated on coaxial shells with different radii in a water phantom. Dose calculation points on shells were determined as only spatial. The study’s spatial geometrical approach was considered.Dose distributions of two radiation emitters were compared on plotted data. In 0°–90° rotation area, left emitter’s efficiency varied with distance. On shells with small radius, dose contribution (D1) of left emitter was weakly effective on total distribution; right emitter was the determinant factor on the total dose. By increasing shell radius, efficiency of two emitters comes close.It seems that geometrical specification of a seed is markedly effective on dose distribution. Differences between doses of two radioactive materials decrease rapidly beyond the seed borders. Consideration of this study can be applied for other seeds that have multiple radiation emitters to research the effects of their geometrical specification on dose distributions.
Keywords: Theragenic 200; Brachytherapy; Monte Carlo; Radiation dose
The impact of adenosine pharmacologic stress combined with low-level exercise in patients undergoing myocardial perfusion imaging (BIWAKO adenosine-Ex trial) by Hajime Monzen; Masatake Hara; Makoto Hirata; Takatoshi Suzuki; Makoto Ogasawara; Hirokazu Higuchi; Tomohiro Matsuoka; Hisato Kobayashi; Rumio Yuki; Kunihiko Hirose (381-386).
The combination of adenosine infusion with low-level exercise has become a common approach for inducing stress during stress myocardial perfusion imaging (MPI). We investigated stress MPI performed by combined low-level exercise and adenosine infusion. This combined protocol can decrease adverse reactions and reduce the effect of scattered rays from the liver.Subjects were clinically referred for a 53-min rest-stress Tc-99m Sestamibi MPI procedure using BIWAKO PROTOCOL. Ninety-eight patients (44.5%) underwent adenosine infusion with ergometer exercise testing and 122 patients (55.5%) underwent adenosine infusion without exercise testing. We evaluated the liver/heart (L/H) uptake ratio, background activity in the upper mediastinum, and adverse reactions.The L/H ratio and background activity were lower in the adenosine-exercise group than in the adenosine-non-exercise group (1.8 ± 0.54 vs. 2.1 ± 0.62, P < 0.0056; 43.1 ± 12.2 vs. 61.5 ± 15.4, P < 0.0001). The adenosine-exercise group had fewer adverse reactions than the adenosine–non-exercise group (11.2 vs. 19.7%). All of the adverse reactions were minor, with the exception of severe back pain in one case. The incidence of adverse reactions in our study was lower than that in previous studies for unknown reason.Adenosine infusion in combination with low-level exercise seems to result in higher-quality images and fewer adverse reactions than adenosine infusion without exercise. The combined protocol decreases adverse reactions and improves the quality of myocardial perfusion images by decreasing background activity.
Keywords: MPI; Adenosine; Low-level exercise