Sarika Sharma

Preliminary evaluation of technetium-99m-labeled ceftriaxone: infection imaging agent for the clinical diagnosis of orthopedic infection

OBJECTIVE In this study we sought to assess the efficacy of a technetium-99m (Tc-99m)-labeled third-generation cephalosporin as an infection imaging agent in the accurate detection of the sites of bacterial infection in vivo. DESIGN Ceftriaxone (CRO) was formulated into a ready-to-use single-vial cold kit with a shelf-life of over 6 months and was successfully labeled with technetium. The radiolabeled drug, Tc-99m-CRO, was subjected to the following preclinical evaluations: radiochemical purity, in vitro and in vivo stability, bacterial binding assay, and pharmacokinetic studies in animals and in human patients. RESULTS The kit formulation exhibited excellent radiolabeling efficiency (∼99%) and high in vitro and in vivo stability. The radiolabeled drug exhibited slow blood clearance (12% at 4 h), and the high protein binding and excretion pattern of the labeled formulation mimics the reported pharmacokinetic profile of the drug alone. In the animal model, scintigraphy scans showed higher uptake of the radiopharmaceutical in infectious lesions, even at 1 h post-administration, in comparison to inflammatory lesions. The clinical evaluation of Tc-99m-labeled CRO showed a diagnostic accuracy of 83.3%, and a sensitivity and specificity of 85.2% and 77.8%, respectively. CONCLUSIONS This kit formulation has the potential for imaging bacterial infections with much higher sensitivity and specificity as compared to other Tc-99m-labeled antibiotics available as convenient ready-to-use kits in routine clinical practice.

PET/CT with 18F-FDG–Labeled Autologous Leukocytes for the Diagnosis of Infected Fluid Collections in Acute Pancreatitis

Early detection of infection in acute pancreatitis (AP) affects the choice of treatment and clinical outcome. We used PET/CT with 18F-FDG–labeled autologous leukocytes to detect infection in pancreatic or peripancreatic fluid collections in patients with AP. Methods: Forty-one patients (28 men and 13 women) who were 21–69 y old (mean ± SD, 41 ± 11.5) and had AP and radiologic evidence of a fluid collection in or around the pancreas were studied. Leukocytes were separated from the patient’s venous blood, labeled with 18F-FDG, and reinjected intravenously; PET/CT images were acquired 2 h later. A final diagnosis of infection was based on microbiologic culture of fluid aspirated from the collection. Patients were treated with supportive care and antibiotics; percutaneous drainage or laparotomy was performed when indicated. Results: Blood glucose level, total leukocyte count, neutrophil count, and leukocyte labeling efficiency varied from 83 to 212 mg/100 mL (118 ± 30), 4,600 to 24,200/mm3 (11,648 ± 5,376), 55% to 90% (73 ± 10), and 31% to 97% (81 ± 17), respectively. Increased tracer uptake in the fluid collection was seen in 12 of 41 patients; 10 had culture-proven infection and underwent percutaneous drainage, and aspiration was unsuccessful in 2. The scan results were negative for infection in 29 patients; 25 had fluid culture results that were negative for infection, and aspiration was unsuccessful in 4. The sensitivity, specificity, and accuracy of the scan were all 100% in 35 patients for whom fluid culture reports were available. Conclusion: PET/CT with 18F-FDG–labeled leukocytes is a noninvasive and reliable method for the diagnosis of infection in pancreatic or peripancreatic fluid collections in patients with AP.

Infection of pancreatic pseudocyst demonstrated on PET/CT using 18F-fluorodeoxyglucose-labeled autologous leucocytes.

Labeled leukocyte scintigraphy has been used as an indicator of pancreatic necrosis in patients with acute pancreatitis and proposed for the detection of infection in peripancreatic fluid collections. The authors present a PET/CT scan showing abnormal uptake of 18F-Fluorodeoxyglucose-labeled autologous leukocytes in a pancreatic pseudocyst, from which aspirated fluid subsequently showed growth of Pseudomonas aeruginosa.

Incidental detection of colonic inflammation on PET/CT using 18F-FDG-labeled autologous leukocytes.

Labeled leukocyte scintigraphy and (18)F-FDG PET are well-documented techniques for the assessment of inflammatory bowel disease. In this study, a 28-year-old man with abdominal pain, vomiting, and raised serum amylase and lipase levels underwent PET/CT imaging using FDG-labeled autologous leukocytes to assess for pancreatic infection. While the pancreas showed no abnormal tracer uptake, colonic inflammation was incidentally detected, and a diagnosis of pseudomembranous colitis was subsequently confirmed on colonoscopy and biopsy.

Preclinical Evaluation of [99m]Tc-Labeled Doxorubicin as a Potential Scintigraphic Probe for Tumor Imaging

BACKGROUND The currently available radiopharmaceuticals are not specific for tumor imaging. PURPOSE The present study was conducted to radiolabel doxorubicin with Technetium-99m ([99m]Tc) as a scintigraphic marker of high DNA turnover/intercalation in malignant cells. METHODS Labeling was done by direct method and the developed radiotracer was subjected to quality control tests. The blood kinetics, scintigraphy of tumor-bearing mice, and biodistribution were studied after intravenous injection of about 7.4 MBq of [99m]Tc-doxorubicin. The isotime (5 minutes) anterior images were acquired at different time intervals of 1.5, 3, and 4 hours. RESULTS The labeling efficiency of [99m]Tc-doxorubicin was estimated to be more than 95%. The protein-binding efficiency was greater than 88% and in vitro stability was up to 24 hours. The biodistribution data support the clearance of the radioligand by dual (renal and hepatic) pathways. A semiquantitative data analysis of the anterior images indicated that a focal concentration of the radiotracer was seen in the tumor at 1.5 hours, which persisted in 3-hour and 4-hour images, respectively. CONCLUSIONS This scintigraphic approach, therefore, could be a powerful tool for cancer detection at early stage. The technique, however, needs further validation through animal experimentation and clinical studies.

Comparison of Encapsulated Versus Nonencapsulated 14C‐urea Breath Test for the Detection of Helicobacter pylori Infection: A Scintigraphy Study

14C‐urea breath test (14C‐UBT) is considered as “gold standard” for detection of active gastric H. pylori infection. However, till date no comparative study using encapsulated and non‐encapsulated 14C‐UBT protocols has been conducted in same subjects in identical conditions. We monitored gastric fate of capsule containing 14C‐urea with real time display and compared sensitivities of these protocols at different time points of breath collection.

Terminalia arjuna bark extract improves diuresis and attenuates acute hypobaric hypoxia induced cerebral vascular leakage

ETHNOPHARMACOLOGICAL RELEVANCE Terminalia arjuna (Roxb. ex DC.) Wight & Arn. (T. arjuna) has been widely used in the traditional ayurvedic system of medicine as a cardioprotectant and for acute and chronic renal diseases supporting its ethnopharmacological use. AIM OF THE STUDY The present study aimed at evaluating the diuretic action of an alcoholic extract of T. arjuna and its possible use as a prophylactic to prevent vascular leakage during acute mountain sickness at high altitude. MATERIALS AND METHODS Rats were exposed to hypobaric hypoxia simulated to an altitude of 27,000 ft. in a decompression chamber for 12h. T. arjuna bark extract was administered at a single dose of 150 mg/kg (p.o.) to male Sprague Dawley rats (200 ± 20 g) 30 min prior to exposure. Total urine volume was measured during exposure to hypobaric hypoxia. The animals were then investigated for cerebral vascular leakage and serum concentration of sodium, potassium, renin, angiotensin-II, aldosterone and atrial natriuretic peptide (ANP). RESULTS T. arjuna ameliorated acute hypobaric hypoxia induced decrease in glomerular filtration rate (p<0.5), increased total urine output (p<0.5) and prevented cerebral vascular leakage in hypoxic rats. T. arjuna treated animals also showed decrease in serum levels of renin (p<0.001) and angiotensin-II (p<0.5) as compared to placebo treated animals. Administration of T. arjuna attenuated acute hypobaric hypoxia induced oxidative stress, improved aldosterone levels and altered electrolyte balance in animals through ANP dependent mechanism. CONCLUSION Results of the present study indicate towards diuretic potential of hydro-alcoholic extract of T. arjuna bark and provide evidence for its novel application as a prophylactic to attenuate acute hypobaric hypoxia induced cerebral vascular leakage through ANP mediated modulation of renin-angiotensin-aldosterone system.

LAT-1 based primary breast cancer detection by [99m]Tc-labeled DTPA-bis-methionine scintimammography: first results using indigenously developed single vial kit preparation.

OBJECTIVE To evaluate the diagnostic utility of a single vial ready to label with [99m]Tc kit preparation of DTPA-bis-methionine (DTPA-bis-MET) for the detection of primary breast cancer. METHODS The conjugate (DTPA-bis-MET) was synthesized by covalently conjugating two molecules of methionine to DTPA and formulated as a single vial ready to label with [99m]Tc lyophilized kit preparations. Thirty female patients (mean age=47.5±11.8 years; range=21-69 years) with radiological/clinical evidence of having primary breast carcinoma were subjected to [99m]Tc-methionine scintigraphy. The whole body (anterior and posterior) imaging was performed on all the patients at 5 minutes, 10 minutes, 1 hour, 2 hours, and 4 hours following an intravenous administration of 555-740 MBq radioactivity of [99m]Tc-methionine. In addition, scintimammography (static images; 256×256 matrix) at 1, 2, and 4 hours was also performed on all the patients. RESULTS The resultant radiolabel, that is, [99m]Tc-DTPA-bis-MET, yielded high radiolabeling efficiency (>97.0%), radiochemical purity (166-296 MBq/μmol), and shelf life (>3 months). The radiotracer primarily gets excreted through the kidneys and localizes in the breast cancer lesions with high target-to-nontarget ratios. The mean±SD ratios on the scan-positive lesions acquired at 1, 2, and 4 hours postinjection were 3.6±0.48, 3.10±0.24, and 2.5±0.4, respectively. [99m]Tc-methionine scintimammography demonstrated an excellent sensitivity and positive predictive value of 96.0% each for the detection of primary breast cancer. CONCLUSION Ready to label single vial kit formulations of DTPA-bis-MET can be easily synthesized as in-house production and conveniently used for the scintigraphic detection of breast cancer and other methionine-dependent tumors expressing the L-type amino acid transporter-1 receptor. The imaging technique thus could be a potential substitute for the conventional single-photon emission computed tomography (SPECT)-based tumor imaging agents, especially for tracers with nonspecific mitochondrial uptake. However, the diagnostic efficacy of [99m]Tc-methionine needs to be evaluated in a large cohort of patients through further multicentric trials.

Comparative Therapeutic Efficacy of 153Sm-EDTMP and 177Lu-EDTMP for Bone Pain Palliation in Patients with Skeletal Metastases: Patients’ Pain Score Analysis and Personalized Dosimetry

Introduction The aim of the present study was to compare the therapeutic efficacy of 153Sm-EDTMP and 177Lu-EDTMP in pain palliation in cancer patients with skeletal metastases. Materials and methods Thirty patients (25 M:5 F, mean age: 66.0 ± 14.7 years) of breast/prostate cancer with documented skeletal metastases were recruited prospectively. Twenty patients were considered randomly for treatment with 153Sm-EDTMP and with 177Lu-EDTMP in 10 patients, respectively. Using fixed dose of 37.0 MBq/kg body weight of each, the mean administered doses of 153Sm-EDTMP and 177Lu-EDTMP were 2,155.2 ± 419.6 MBq (1,347–2,857) and 1,935.1 ± 559.4 MBq (1,073–2,627), respectively. Anterior and posterior whole body images were acquired at different time points following radioactivity administration. The first data set of pre-void images (acquired at 0.5 h) representing the total activity of either of 153Sm-EDTMP or 177Lu-EDTMP was considered as reference images. All the serial images were used for patients’ dosimetry analysis by using organ level internal dosimetry assessment algorithm. Reduction in pain scoring was assessed clinically over 8 weeks by using appropriate WHO criteria and correlated with the absorbed dose to the metastatic sites. Results A total of 86 metastatic lesions clearly visualized on post-therapy serial images (matching on bone scans) were evaluated for absorbed dose calculations. Both 153Sm-EDTMP and 177Lu-EDTMP delivered similar absorbed dose to the metastatic sites, i.e., 6.22 ± 4.21 and 6.92 ± 3.92 mSv/MBq, respectively. The mean absorbed doses to various other organs were found to be comparable and within the safe limits. A complete response (CR) for each radionuclide was evaluated as 80.0%. No significant alternation in blood parameters and no untoward reaction were observed. However, a mild to severe toxicity was observed in two patients (1 each with 153Sm-EDTMP and 177Lu-EDTMP). Kaplan–Meier survival analysis demonstrated that 27/30 patients had pain-free survival (CR) up to the observational period of 8 weeks. However, no statistically significant correlation could be established between the pain scoring and absorbed dose to metastatic sites. Conclusion Both the radionuclides thus offer an effective and comparable therapeutic efficacy for bone pain palliation at an affordable cost and can be used interchangeably as per the availability.

Utility of PET/CT with fluorine-18-fluorodeoxyglucose-labeled autologous leukocytes for diagnosing diabetic foot osteomyelitis in patients with Charcot's neuroarthropathy.

ObjectiveDiabetic foot osteomyelitis (DFO) is difficult to diagnose in the presence of Charcot’s neuroarthropathy (CN) and bone biopsy is not always possible. We aimed to assess the efficacy of PET/computed tomography using 18F-fluoride (18F-fluoride PET/CT) and fluorine-18-fluorodeoxyglucose-labeled autologous leukocytes (18F-FDG-LL PET/CT) in comparison with contrast-enhanced MRI (CEMRI) for the detection of DFO. Patients and methodsThirty-two patients with chronic CN and foot ulcer suspected of having DFO were prospectively evaluated. All patients underwent radiography, CEMRI, 18F-fluoride PET/CT, and 18F-FDG-LL PET/CT of the feet. Bone biopsy and microbiological culture from the suspected site of osteomyelitis was considered the gold standard. ResultsTwenty-three patients fulfilled the inclusion criteria. Bone culture was suggestive of DFO in 12 patients. CEMRI identified 10 of the 12 cases of osteomyelitis. 18F-fluoride PET/CT and 18F-FDG-LL PET/CT showed increased tracer uptake (SUVmax=22.7±18.1 and 8.4±4.7, respectively) at the clinically involved site in 10 of the 12 patients (TP). Among 11 biopsy-negative patients, CEMRI reported DFO in four (false positive); there were no false positives with 18F-FDG-LL PET/CT. The sensitivity and specificity of 18F-FDG-LL PET/CT was 83.3 and 100% compared with 83.3 and 63.6% for CEMRI, respectively, for the diagnosis of DFO in the background of CN. Conclusion18F-FDG-LL PET/CT has high specificity for the diagnosis of DFO in complicated diabetic foot. The 18F-fluoride PET/CT helps in the characterization the extent of underlying CN. An early and accurate diagnosis with 18F-FDG-LL PET/CT aids the rational initiation of antibiotics for DFO.