Clinical Management of Liver Cancer in India and Other Developing Nations: A Focus on Radiation Based Strategies.

Hepatocellular carcinoma (HCC) is a global killer with preponderance in Asian and African countries. It poses a challenge for successful management in less affluent or developing nations like India, with large populations and limited infrastructures. This review aims to assess the available options and future directions for management of HCC applicable to such countries. While summarizing current and emerging clinical strategies for detection, staging and therapy of the disease, it highlights radioisotope- and radioactivity-based strategies as part of an overall program. Using the widely accepted Barcelona Clinic Liver Cancer (BCLC) staging system as a base, it evaluates the applicability of different therapeutic approaches and their synergistic combination(s) in the context of a patient-specific dynamic results-based strategy. It distills the conclusions of multiple HCC management-focused consensus recommendations to provide a picture of clinical strategies, especially radiation-related approaches. Additionally, it discusses the logistical and economic feasibility of these approaches in the context of the limitations of the burdened public health infrastructure in India (and like nations) and highlights possible strategies both at the clinical level and in terms of an administrative health policy on HCC to provide the maximum possible benefit to the widest swathe of the affected population.

Convenient Formulation of 68Ga-BPAMD Patient Dose Using Lyophilized BPAMD Kit and 68Ga Sourced from Different Commercial Generators for Imaging of Skeletal Metastases.

PURPOSE: 68Ga-BPAMD has recently emerged as one of the preferred radiopharmaceuticals for imaging of bone lesions due to its ability to produce high-resolution images and uncomplicated availability of 68Ga, a positron emission tomography (PET) radionuclide, from commercial 68Ge/68Ga generators. The primary objective of this work is to develop freeze-dried BPAMD kit, for the easy and convenient formulation of 68Ga-BPAMD patient dose at the hospital radiopharmacy. In addition, the kit should be compatible with 68Ga, eluted using HCl of various molarities from the 68Ge/68Ga generators sourced from different suppliers. PROCEDURES: Freeze-dried BPAMD kit, comprising 50 µg of BPAMD and 150 mg of HEPES, was prepared and evaluated using 68Ga eluted from three different 68Ge/68Ga generators. Radiochemical purity (RCP) of 68Ga-BPAMD was determined by both thin-layer chromatography and high-performance liquid chromatography studies. The maximum volume of 68Ga, which can be added in the kit, was determined. The biological behavior of 68Ga-BPAMD, prepared using the freeze-dried kit, was evaluated by both in vitro and in vivo studies. Clinical studies were also performed in limited number of patients suffering from metastatic bone cancer. RESULTS: 68Ga-BPAMD could be prepared with >95% RCP using the freeze-dried BPAMD kit and 68Ga eluted from 68Ge/68Ga generators obtained from three different suppliers. 68Ga-BPAMD, prepared using the freeze-dried kit, exhibited adequate serum stability and ∼91% binding with the hydroxyapatite particles. Biodistribution studies in normal Wistar rats exhibited selective uptake of the agent in skeleton and fast clearance of the nonaccumulated activity through urinary route. Clinical studies in cancer patients showed excellent accumulation of the agent in bone lesions. CONCLUSION: The preliminary studies exhibited the potential of the developed BPAMD kit toward its utilization for the PET scanning of skeletal metastases.

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.

A "mix-and-use" approach for formulation of human clinical doses of 177 Lu-DOTMP at hospital radiopharmacy for management of pain arising from skeletal metastases.

Use of bone-seeking radiopharmaceuticals is an established modality in the palliative care of pain due to skeletal metastases. 177 Lu-DOTMP is a promising radiopharmaceutical for this application owing to the ideally suited decay properties of 177 Lu and excellent thermodynamic stability and kinetic rigidity of the macrocyclic complex. The aim of the present study is to develop a robust and easily adaptable protocol for formulation of clinical doses of 177 Lu-DOTMP at hospital radiopharmacy. After extensive radiochemical studies, an optimized strategy for formulation of clinical doses of 177 Lu-DOTMP was developed, which involves simple mixing of approximately 3.7 GBq of 177 Lu activity as 177 LuCl3 solution to an aqueous solution containing 5 mg of DOTMP and 8 mg of NaHCO3 . The proposed protocol yielded 177 Lu-DOTMP with >98% radiochemical purity, and the resultant formulation showed excellent in vitro stability and desired pharmacokinetic properties in animal model. Preliminary clinical investigations in 5 patients showed specific skeletal accumulation with preferential localization in the osteoblastic lesion sites and almost no uptake in soft tissue or any other major nontarget organ. The developed "mix-and-use" strategy would be useful for large number of nuclear medicine centers having access to 177 Lu activity and would thereby accelerate the clinical translation of 177 Lu-DOTMP.

Clinical utility of 99mTc-ubiquicidin (29-41) as an adjunct to bone scan in differentiating infected versus noninfected loosening of prosthesis before revision surgery.

PURPOSE: The aim of this study was to evaluate the utility of Tc-ubiquicidin (Tc-UBI) (29-41) as an adjunct to an methylene diphosphonate (MDP) bone scan in differentiating septic versus aseptic loosening in patients with painful prosthesis posted for revision surgery. PATIENTS AND METHODS: A two-vial cold kit of UBI (29-41) was prepared and utilized for the preparation of patient dose of Tc-UBI (29-41). Twenty two patients with painful hip or knee prosthesis and scheduled for revision surgery were included in the study. Overall, 370-555 MBq of Tc-UBI (29-41) was injected intravenously in all the patients. A blood pool image at 20 min after injection was followed by spot views of the suspected region of infection (target) and a corresponding normal area (nontarget) at 60 min. All patients underwent a routine Tc-MDP three-phase whole-body bone scan, followed by single-photon emission computed tomography/computed tomography of the prosthesis within a week of the Tc-UBI (29-41) study. For Tc-UBI scans, a visual score (0-3) was used to categorize studies as positive or negative, with scores of 0 (minimal or no uptake; less than soft tissue or contralateral extremity) and 1 (mild; equivalent to soft tissue or contralateral extremity) being considered negative and scores of 2 (moderate; uptake greater than soft tissue or contralateral extremity, but less than the liver) or 3 (intense; uptake greater than soft tissue or contralateral extremity and equivalent to the liver) being considered positive. The final correlation was on the basis of bacterial culture as the major criterion and the results of clinical tests, radiography, fluorine-18-fluorodeoxyglucose PET-CT, and three-phase bone scanning as the minor criteria. RESULTS: In all, 22 studies were carried out with Tc-UBI (29-41). Of these, 16 scans were considered positive and six were negative for infection foci. All negative scans were subsequently confirmed to be true negative. Adverse reactions were not observed during image acquisition and within 5 days after the study. The overall sensitivity, specificity, and positive and negative predictive values were 100, 85.7, 93.75, and 100%, respectively. A combination of an MDP bone scan and UBI scans was considered to yield maximum confidence toward reporting for the presence of infection. CONCLUSION: Patient dose of Tc-UBI (29-41) was prepared successfully and a simple quality control method to check radiolabeling yield was used at the hospital radiopharmacy. Tc-UBI (29-41) showed promise in localizing foci of infection, with optimal visualization at 20-60 min, for the evaluation of prosthesis loosening.

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.

Correlative (99m)tc-labeled tropane derivative single photon emission computer tomography and clinical assessment in the staging of Parkinson disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by a selective loss of dopamine in the striatum. Problems remain in the accurate diagnosis of PD. The diagnosis of idiopathic PD is based on the interpretation of clinical signs and symptoms could be incorrect at the time of initial presentation. In vivo imaging of the dopaminergic system has the potential to improve the diagnosis of PD in its early stages. The imaging of dopamine transporter (DAT) with (99m)Tc-labeled tropane derivative (TRODAT-1) single photon emission computer tomography/computer tomography (SPECT/CT) has been proposed to be a valuable and feasible means of assessment of the integrity of dopamine neurons. The purpose of this study was to investigate the potential usefulness of (99m)Tc-TRODAT-1 imaging in the evaluation of patients with PD and classify into different stages of the disease. SPECT imaging with (99m)Tc-TRODAT-1 was conducted in 16 consecutive PD patients (9 men; 7 women) and in 6 age matched healthy volunteers (4 men; 2 women). The images were obtained 3 h after the intra-venous injection of the tracer. Specific uptake in the striatum and its sub-regions, including the putamen and caudate nucleus was calculated and the ratios of specific striatal binding to nonspecific occipital binding were calculated. ANOVA with Dunnett C post-hoc analysis was conducted using SPSS 20. A stepwise reduction in specific striatal uptake of (99m)Tc-TRODAT-1 with increasing disease severity between healthy control versus Stage I versus Stage II versus Stage III was found in PD patients (i.e., 3.77 vs. 2.56 vs. 1.57 vs. 0.63, P < 0.05). The changes were magnified by measurement of specific putaminal uptake (1.43 vs. 0.79 vs. 0.54 vs. 0.19, P < 0.05) and specific caudate uptake (1.90 vs. 1.47 vs. 0.73 vs. 0.27, P < 0.05). No remarkable adverse reactions were found in either healthy volunteers or PD patients during or after imaging. (99m)Tc-TRODAT-1 is accurate and widely available for the assessment of DAT activity, which might shed light on the integrity of the presynaptic nigrostriatal function. Our preliminary study results confirm the potential of using (99m)Tc-TRODAT-1 for DAT measurement, which is clinically important for the staging of PD.

"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 .

¹77Lu-EDTMP for treatment of bone pain in patients with disseminated skeletal metastases.

UNLABELLED: (177)Lu-labeled ethylenediaminetetramethylene phosphonic acid ((177)Lu-EDTMP) is an agent that concentrates in areas of enhanced osteoblastic activity. The potential of (177)Lu-EDTMP for palliation of metastatic bone pain has been documented in the recent literature. The objective of the present work was to study the efficacy and safety of the agent after administration to a limited number of patients. METHODS: Ten patients (median age, 68.5 y) with disseminated skeletal metastases received a single bolus infusion of (177)Lu-EDTMP (3.7 GBq). All patients had painful bone metastases in more than one anatomic region that were not relieved by narcotic analgesics. The efficacy of the agent was studied by following pain scores assessed at baseline and at 4, 8, and 12 wk after therapy, by using Karnofsky indices and mobility scores, and by determining the requirement for analgesics at baseline and 4 wk after therapy. The toxicity of the agent was assessed by analyzing complete blood counts. RESULTS: A significant reduction in the mean pain score was noted in all patients. The initial mean pain score of 8.44 dropped to 5.73 within 1 mo of treatment. Six patients who required analgesics for pain management had either reduced or completely withdrawn from their use by 4 wk. Compared with initial scans, scans obtained 1 mo after therapy also showed a decreased uptake of the radiotracer. The mobility scores of all patients were higher at 4 wk. The mean Karnofsky performance score of all patients was initially 45 and increased markedly to 69 at 4 wk. None of the patients experienced blood-related toxicity. CONCLUSION: (177)Lu-EDTMP, with only low bone marrow toxicity, provided significant pain relief to patients and considerably increased their mobility, resulting in an overall improvement in the quality of life. The results of the preliminary clinical studies indicate that (177)Lu-EDTMP can be considered an effective and safe therapeutic radiopharmaceutical for pain palliation of patients with disseminated skeletal disease.

Clinical utility of indigenously formulated single-vial lyophilized HYNIC-TOC kit in evaluating Gastro-entero Pancreatic neuro endocrine tumours.

OBJECTIVES: The objective of this study was to evaluate the performance and utility of (99m)Tc HYNIC-TOC planar scintigraphy and SPECT/CT in the diagnosis, staging and management of gastroenteropancreatic neuroendocrine tumors (GPNETs). METHODS: 22 patients (median age, 46 years) with histologically proven gastro- entero- pancreatic NETs underwent (99m)Tc HYNIC-TOC whole body scintigraphy and regional SPECT/CT as indicated. Scanning was performed after injection of 370-550 MBq (10-15 mCi) of (99m)Tc HYNIC-TOC intravenously. Images were evaluated by two experienced nuclear medicine physicians both qualitatively as well as semi quantitatively (tumor to background and tumor to normal liver ratios on SPECT -CT images). Results of SPECT/CT were compared with the results of conventional imaging. Histopathology results and follow-up somatostatin receptor scintigraphy with (99m)Tc HYNIC TOC or conventional imaging with biochemical markers were considered to be the reference standards. RESULTS: (99m)Tc HYNIC TOC showed sensitivity and specificity of 87.5% and 85.7%, respectively, for primary tumor and 100% and 86% for metastases. It was better than conventional imaging modalities for the detection of both primary tumor (P<0.001) and metastases (P<0.0001). It changed the management strategy in 6 patients (31.8%) and supported management decisions in 8 patients (36.3%). CONCLUSION: (99m)Tc HYNIC TOC SPECT/CT appears to be a highly sensitive and specific modality for the detection and staging of GPNETs. It is better than conventional imaging for the evaluation of GPNETs and can have a significant impact on patient management and planning further therapeutic options.

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.

Unexpectedly Diagnosed Caroli's Disease on HIDA Scintigraphy in a Patient with Calculous Cholecystitis.

Caroli's disease, which is a rare condition with congenital dilatation of the intrahepatic bile ducts, is usually diagnosed postoperatively. The clinical suspicion in a patient with gallstones and choledocholithiasis presenting with dilated intrahepatic biliary radicles and jaundice is usually an obstructive etiology. However, scintigraphic evaluation of this entity, as in this case, gives additional information on liver function, biliary drainage and predisposing conditions like Caroli's disease, which could be missed otherwise.