A robust lyophilized kit for convenient one-step formulation of [68Ga]Ga-DOTA-E-[c(RGDfK)]2 in hospital radiopharmacy for clinical PET imaging.

The present article describes the development of robust lyophilized kit for convenient formulation of [68Ga]Ga-DOTA-E-[c(RGDfK)]2 (E = glutamic acid, R = arginine, G = glycine, D = aspartic acid, f = phenylalanine, K = lysine) radiopharmaceutical for clinical use in non-invasive monitoring of malignancies overexpressing integrin αvß3 receptors. Five batches of the kit were prepared with optimized kit contents, all of which showed high 68Ga-radiolabeling yield (>98%). Pre-clinical evaluation of the [68Ga]Ga-radiotracer in SCID mice bearing FTC133 tumour exhibited significant accumulation in the tumor xenograft. Preliminary human clinical investigation carried out in a 60 year old male patient with metastatic lung cancer revealed high radiotracer uptake in the tumor along with satisfactory target to non-target contrast. The developed kit formulation also showed a long shelf-life of at least 12 months on storage at 0 °C. All these results point towards the promising attributes of the developed kit formulation for convenient preparation of [68Ga]Ga-DOTA-E-[c(RGDfK)]2 for routine clinical use.

Clinical utility of 188Rhenium-hydroxyethylidene-1,1-diphosphonate as a bone pain palliative in multiple malignancies.

188Rhenium-hydroxyethylidene-1,1-diphosphonate (188Re-HEDP) is a clinically established radiopharmaceutical for bone pain palliation of patients with metastatic bone cancer. Herein, the effectiveness of 188Re-HEDP for the palliation of painful bone metastases was investigated in an uncontrolled initial trial in 48 patients with different types of advanced cancers. A group of 48 patients with painful bone metastases of lung, prostate, breast, renal, and bladder cancer was treated with 2.96-4.44 GBq of 188Re-HEDP. The overall response rate in this group of patients was 89.5%, and their mean visual analog scale score showed a reduction from 9.1 to 5.3 (P < 0.003) after 1 week posttherapy. The patients did not report serious adverse effects either during intravenous administration or within 24 h postadministration of 188Re-HEDP. Flare reaction was observed in 54.2% of patients between day 1 and day 3. There was no correlation between flare reaction and response to therapy (P < 0.05). Although bone marrow suppression was observed in patients receiving higher doses of 188Re-HEDP, it did not result in any significant clinical problems. The present study confirmed the clinical utility and cost-effectiveness of 188Re-HEDP for palliation of painful bone metastases from various types of cancer in developing countries.

Preliminary PET/CT Imaging with Somatostatin Analogs [68Ga]DOTAGA-TATE and [68Ga]DOTAGA-TOC.

PURPOSE: Somatostatin receptor positron emission tomography/X-ray computed tomography (SSTR-PET/CT) is a well-established technique for staging and detection of neuroendocrine tumors (NETs). Ga-68-labeled DOTA-conjugated octreotide analogs are the privileged radiotracers for diagnosis and therapeutic monitoring of NETs. Hence, we were interested in assessing the influence of promising, newer variant DOTAGA on the hydrophilicity, pharmacokinetics, and lesion pick-up of somatostatin analogs. Herein, the potential of ([68Ga]DOTAGA, Tyr3, Thr8) octreotide ([68Ga]DOTAGA-TATE) and ([68Ga]DOTAGA, Tyr3) octreotide ([68Ga]DOTAGA-TOC) as NET imaging agents has been investigated. PROCEDURES: Amenability of [68Ga]DOTAGA-(TATE/TOC) to kit-type formulation has been demonstrated. Biodistribution studies were carried out in normal rats at 1 h post-injection (p.i.). [68Ga]DOTAGA-(TATE/TOC) PET/CT scans were carried out in patients (70-170 MBq, 1 h p.i.) with histologically confirmed well-differentiated NETs. RESULTS: [68Ga]DOTAGA-TATE exhibited hydrophilicity similar to [68Ga]DOTA-TATE (log P = -3.51 vs -3.69) whereas [68Ga]DOTAGA-TOC was more hydrophilic than [68Ga]DOTA-TOC (log P = -3.27 vs -2.93). [68Ga]DOTAGA-TATE and [68Ga]DOTA-TATE showed almost identical blood and kidney uptake in normal rats whereas significantly fast clearance (p < 0.05) of [68Ga]DOTAGA-TATE was observed from other non-specific organs (liver, lungs, spleen, intestine). [68Ga]DOTAGA-TOC also demonstrated rapid clearance from blood and kidneys (p < 0.05) in comparison to [68Ga]DOTA-TOC. The metastatic lesions in NET patients were well identified by [68Ga]DOTAGA-TATE and [68Ga]DOTAGA-TOC. CONCLUSION: The phenomenal analogy was observed between [68Ga]DOTAGA-TATE and [68Ga]DOTA-TATE as well as between [68Ga]DOTAGA-TOC and [68Ga]DOTA-TOC in biodistribution studies in rats. The good lesion detection ability of the two radiotracers indicates their potential as NET imaging radiotracers.

Convenient Preparation of [(68)Ga]DKFZ-PSMA-11 Using a Robust Single-Vial Kit and Demonstration of Its Clinical Efficacy.

PURPOSE: [(68)Ga]DKFZ-PSMA-11 has proved to be an important diagnostic radiotracer for targeting prostate-specific membrane antigen (PSMA) overexpression in both recurrent prostate cancer (PC) and relevant metastatic sites. However, the widespread, routine clinical use of such a potential radiopharmaceutical demands availability of a ready-to-use kit formulation to enable convenient radiopharmaceutical preparation. Herein, we report the development of a freeze-dried kit vial for the formulation of [(68)Ga]DKFZ-PSMA-11 and its clinical use in patients using a "shake-bake-inject" methodology. PROCEDURES: The freeze-dried kit vial was developed after optimization of ligand content (PSMA-11) and pH conditions. The kit was formulated using (68)Ga from two different commercially available generators. Positron emission tomography/X-ray computed tomography (PET/CT) images of PC patients were obtained using the kit-formulated radiotracer. RESULTS: [(68)Ga]DKFZ-PSMA-11 was prepared in >98 % radiochemical yield and purity using the freeze-dried kit vials. Kits were optimized for the preparation of four patient doses. The clinical utility was evaluated in patients with histologically confirmed prostate cancer, and the images were of good quality as well as conforming to tumor marker and clinical expectations. CONCLUSION: The development of a simple and ready-to-use freeze-dried DKFZ-PSMA-11 kit for the preparation of Ga-68-based radiotracers constitutes a major step towards the expedition of the widespread and economical screening of PC patients.

Utility of (99m)Tc-Hynic-TOC in 131I Whole-Body Scan Negative Thyroid Cancer Patients with Elevated Serum Thyroglobulin Levels.

Several studies have reported on the expression of somatostatin receptors (SSTRs) in patients with differentiated thyroid cancer (DTC). The aim of this study was to evaluate the imaging abilities of a recently developed Technetium-99m labeled somatostatin analog, (99m)Tc-Hynic-TOC, in terms of precise localization of the disease. The study population consisted of 28 patients (16 men, 12 women; age range: 39-72 years) with histologically confirmed DTC, who presented with recurrent or persistent disease as indicated by elevated serum thyroglobulin (Tg) levels after initial treatment (serum Tg > 10 ng/ml off T4 suppression for 4-6 weeks). All patients were negative on the Iodine-131 posttherapy whole-body scans. Fluorine-18 fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) was performed in all patients. SSTR scintigraphy was true positive in 23 cases (82.1%), true negative in two cases (7.1%) and false negative in three cases (10.7%) which resulted in a sensitivity of 88.46%, specificity of 100% and an accuracy of 89.2%. Sensitivity of (99m)Tc-Hynic-TOC scan was higher (93.7%) for patients with advanced stages, that is stages III and IV. (18)F-FDG showed a sensitivity of 93.7%, a specificity of 50% and an accuracy of 89.3%. (18)F-FDG PET was found to be more sensitive, with lower specificity due to false positive results in 2 patients. Analysis on a lesion basis demonstrated substantial agreement between the two imaging techniques with a Cohen's kappa of 0.66. Scintigraphy with (99m)Tc-Hynic-TOC might be a promising tool for treatment planning; it is easy to perform and showed sufficient accuracy for localization diagnostics in thyroid cancer patients with recurrent or metastatic disease.

Radiosynovectomy of Painful Synovitis of Knee Joints Due to Rheumatoid Arthritis by Intra-Articular Administration of (177)Lu-Labeled Hydroxyapatite Particulates: First Human Study and Initial Indian Experience.

The aim of this study is to assess the effectiveness of Radiosynovectomy (RSV) using (177)Lu-labeled hydroxyapatite ((177)Lu-HA) in the treatment of painful synovitis and recurrent joint effusion of knee joints in rheumatoid arthritis (RA). Ten patients, diagnosed with RA and suffering from chronic painful resistant synovitis of the knee joints were referred for RSV. The joints were treated with 333 ± 46 MBq of (177)Lu-HA particles administered intra-articularly. Monitoring of activity distribution was performed by static imaging of knee joint and whole-body gamma imaging. The patients were evaluated clinically before RSV and at 6 months after the treatment by considering the pain improvement from baseline values in terms of a 100-point visual analog scale (VAS), the improvement of knee flexibility and the pain remission during the night. RSV response was classified as poor (VAS < 25), fair (VAS ≥ 25-50), good (VAS ≥ 50-75) and excellent (VAS ≥ 75), with excellent and good results considered to be success, while fair and poor as failure and also by range of motion. Three phase bone scan (BS) was repeated after 6 months and changes in the second phase of BS3 were assessed visually, using a four-degree scale and in the third phase, semiquantitatively with J/B ratio to see the response. Biochemical analysis of C-reactive protein (CRP) and fibrinogen was repeated after 48 h, 4 and 24 weeks. In all 10 patients, no leakage of administered activity to nontarget organs was visible in the whole-body scan. Static scans of the joint at 1 month revealed complete retention of (177)Lu-HA in the joints. All patients showed decreased joint swelling and pains, resulting in increased joint motion after 6 months. The percentage of VAS improvement from baseline values was 79.5 ± 20.0% 6 months after RS and found to be significantly related to patients' age (P = 0.01) and duration of the disease (P = 0.03). Knees with Steinbrocker's Grades 0 and I responded better than those with more advanced changes (Steinbrocker's Grades III and IV) in terms of VAS improvement (75% vs. 45.8%) (P < 0.001). The overall success rate (VAS ≥ 50) was 80%. Remission of pain during the night was achieved in 100%, and knee flexibility was improved in 80%. The changes in the blood pool phase before RSV were 3.2 ± 0.7 and after the therapy 1.4 ± 0.7 (P < 0.001). The J/B ratio was: Before RSV 2.4 ± 0.3; after treatment 1.0 ± 0.2 (P < 0.05). CRP concentration 4 and 24 weeks after the therapy was significantly lower than before treatment. The fibrinogen level was not different before and after RSV. RSV side-effects assessed for the whole follow-up period were minor and not significant. RSV with (177)Lu-HA was safe and effective in patients with knee joint chronic painful synovitis of rheumatoid origin. It exhibited significant therapeutic effect after 6 months follow-up period with no significant side-effects. The preliminary investigations reveal that (177)Lu-labeled HA particles hold considerable promise as a cost-effective agent for RSV. More elaborate and controlled clinical trials are necessary to evaluate the therapeutic efficacy and safety of the agent compared with the treatment with other radionuclides and glucocorticosteroids.

Single vial freeze-dried TRODAT-1 kit: preparation and demonstration of clinical efficacy of [(99m)Tc]TRODAT-1 in Indian scenario.

A single vial freeze-dried kit formulation for preparation of three patients' dose of [(99m)Tc]TRODAT-1 has been developed for early diagnosis of Parkinson's disease (PD). Kits were evaluated to ascertain the purity, stability and batch to batch variations. Preclinical evaluation was carried out in laboratory animals and clinical imaging was performed in human patients with PD. The labeling yield and purity of [(99m)Tc]TRODAT-1 was >90%. Swiss mice showed retention of [(99m)Tc]TRODAT-1 in the mid brain region. Clinical studies showed decreased striatal uptake with increasing severity of PD.

Persistent high grade flurodeoxyglucose uptake in lipomatous hypertrophy of the interatrial septum on dual time point imaging and with ambient warming.

Lipomatous hypertrophy of the interatrial septum (LHIS) is a relatively uncommon disorder of the heart characterized by benign fatty infiltration of the interatrial septum that usually spares the fossa ovalis. LHIS showing flurodeoxyglucose uptake has been reported, and is presumed to be due to activated brown adipose tissue (BAT). We here report a case of a patient who had isolated mediastinal uptake in interatrial septum, mimicking metastasis. Rescanning with external warming to deactivate BAT and a delayed time point image was done, which showed persistent and progressively increasing metabolic uptake respectively, suggesting that LHIS uptake might be unrelated to activated BAT or inflammation.

"Hyperfrontality" as seen on FDG PET in unmedicated schizophrenia patients with positive symptoms.

INTRODUCTION: Decreased frontal activity has been reported widely in unmedicated schizophrenic patients with predominantly negative symptoms. Not many studies have assessed the frontal lobe status in unmedicated patients with positive symptoms. PATIENTS AND METHODS: Fifty-one patients with schizophrenia (all unmedicated, 38 never medicated) and 12 healthy age-matched controls were evaluated with FDG PET CT. The patients met ICD-10 and DSM-IV criteria for schizophrenia, and all reported psychotic, "positive" symptoms when tested. RESULTS: Schizophrenic patients with positive symptoms had a hypermetabolic frontal metabolic pattern on quantification by region to occipital ratio comparison. Associated statistically significant differences were also found when comparing ratios of occipital to thalamic, striatal and temporal cortex in schizophrenic patients. CONCLUSION: The finding of a hyperfrontality in unmedicated and never medicated psychotic schizophrenic patients is observed when there is a predominance of positive symptoms. There could be a possible disruption of cortico-striato-thalamic feedback loops causing hyperfrontality as seen in experimentally induced models of psychosis .

Preparation of therapeutic dose of 177Lu-DOTA-TATE using a novel single vial freeze-dried kit: a comparison with 'in-situ' preparation at hospital radiopharmacy.

OBJECTIVE: Patient dose of (177)Lu-DOTA-TATE, used for providing radiotherapeutic treatment to the patients suffering from cancers of neuroendocrine origin, could be prepared at the hospital radiopharmacy either 'in-situ' or by using freezedried kits. The objective of the present work is to formulate and evaluate a single vial freeze-dried DOTA-TATE kit, which is capable of producing up to 7.4 GBq (200 mCi) dose of (177)Lu-DOTA-TATE and to compare the two methodologies presently used for the preparation of the agent. EXPERIMENTAL: Freeze-dried DOTA-TATE kits, comprising a lyophilized mixture of DOTA-TATE, gentisic acid and ammonium acetate, were prepared and used for the formulation of patient doses of (177)Lu-DOTA-TATE. The kits were subjected to detailed radiochemical evaluation and the shelf-life of the kits was determined. The pharmacokinetic behavior of the agent was studied in normal Wistar rats. These kits were utilized for treating the patients suffering from various types of neuroendocrine cancers. RESULTS: The freeze-dried kits were used for the preparation of up to 7.4 GBq (200 mCi) therapeutic doses of (177)Lu- DOTA-TATE with a radiochemical purity of >99% and were found to have sufficiently long shelf-life. Biological studies carried out in normal Wistar rats exhibited no significant accumulation of activity in any of the vital organs/tissue except in kidneys and non-accumulated activity showed major renal clearance. Clinical studies carried out in cancer patients exhibited accumulation of activity in the cancerous lesions and metastatic sites. CONCLUSION: The kit was useful for the convenient preparation of therapeutic dose of (177)Lu-DOTA-TATE, suitable for human administration. The use of kit is expected to reduce the batch failure and radiation exposure to the working personnel.

Empiric Therapy with Low-Dose I-131 in Differentiated Cancer Thyroid: What is the Magic Number?

Low dose radioactive iodine-131 (RAI) has been widely reported in the treatment of patients with differentiated thyroid cancer (DTC) since 1970's. However, the clinical outcomes, dosage of I-131 and criteria for successful ablation are different in various studies. The aim of this study was to assess clinical outcome 18-month after RAI therapy in selected DTC patients and identify factors associated with a good response. In this experimental study, among patients with DTC referred to the Nuclear Medicine Department and had an indication for RAI therapy in the period between December 2008 and January 2011, 108 subjects were selected randomly. The patients were randomly divided into three groups and empiric low dose therapy with 30, 50 or 75 mCi of I-131 was administered. Patients were monitored closely clinically and with serum thyroglobulin assays and I-131 whole-body scans at 6 monthly intervals for 18-month after treatment. Among 105 patients who completed follow-up, 86% were successfully ablated with a single low dose of I-131. There was no statistically significant difference in ablation rates in the subgroups receiving 30.50 or 75 mCi of I-131. Cumulative ablation rate was 99% in patients after the second dose of low dose therapy. If appropriate selection criteria are used in DTC, successful remnant ablation can be achieved with low doses of I-131 in the range of 30-75 mCi. No significant differences were found in results achieved with 30.50 or 75 mCi of I-131. As the majority of the DTC patients fall within the inclusion criteria of this study, they can be treated on an ambulatory basis with associated low cost, convenience, and low whole-body radiation-absorbed dose to the patients.