(90) Y/(177) Lu-labelled Cetuximab immunoconjugates: radiochemistry optimization to clinical dose formulation.

Radiolabelled monoclonal antibodies (mAbs) are increasingly being utilized in cancer theranostics, which is a significant move toward tailored treatment for individual patients. Cetuximab is a recombinant, human-mouse chimeric IgG1 mAb that binds to the epidermal growth factor receptor with high affinity. We have optimized a protocol for formulation of clinically relevant doses (~2.22 GBq) of (90) Y-labelled Cetuximab and (177) Lu-labelled Cetuximab by conjugation of the mAb with a suitable bifunctional chelator, N-[(R)-2-amino-3-(paraisothiocyanato-phenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N',N″,N″-pentaacetic acid (CHX-A″-DTPA). The radioimmunoconjugates demonstrated reasonably high specific activity (1.26 ± 0.27 GBq/mg for (90) Y-CHX-A″-DTPA-Cetuximab and 1.14 ± 0.15 GBq/mg for (177) Lu-CHX-A″-DTPA-Cetuximab), high radiochemical purity (>95%) and appreciable in vitro stability under physiological conditions. Preliminary biodistribution studies with both (90) Y-CHX-A″-DTPA-Cetuximab and (177) Lu-CHX-A″-DTPA-Cetuximab in Swiss mice bearing fibrosarcoma tumours demonstrated significant tumour uptake at 24-h post-injection (p.i.) (~16%ID/g) with good tumour-to-background contrast. The results of the biodistribution studies were further corroborated by ex vivo Cerenkov luminescence imaging after administration of (90) Y-CHX-A″-DTPA-Cetuximab in tumour-bearing mice. The tumour uptake at 24 h p.i. was significantly reduced with excess unlabelled Cetuximab, suggesting that the uptake was receptor mediated. The results of this study hold promise, and this strategy should be further explored for clinical translation.

Identification and diagnosis of Secondary Progressive Multiple Sclerosis during the clinical encounter: Results from a physician survey.

BACKGROUND: It is difficult to characterize the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS), due to symptomatic variability across patients. Diagnosis of SPMS is prolonged and often established retrospectively, as it is based on patient clinical history and symptoms. This cross-sectional study aimed to identify MS neurologist reported clinical indicators deemed important in diagnosing SPMS in clinical practice. METHODS: A web-based quantitative survey was conducted among MS-treating neurologists across the United States in January 2019. The questionnaire comprised of 17 questions evaluating primary clinical indicators used by neurologists in assessing patient progression to SPMS. Treatment approach and factors influencing treatment decision-making following SPMS diagnosis were also analyzed in the survey. RESULTS: Overall, 300 neurologists completed the survey; most of the respondents were general MS-treating neurologists (63%) and from private care setting (58%). The overall respondents as well as MS-focused neurologists ranked patient history (45% and 42%, respectively) and patients' neurological exam (39% and 44%, respectively) as -primary clinical indicators of SPMS diagnosis. 57% of neurologists always or mostly switched disease modifying therapies after progression to SPMS, and mostly considered 3-6 months' assessment interval to diagnose SPMS. CONCLUSION: The survey indicated that neurologists are able to recognize signs of SPMS within six months of symptomatic assessment. The diagnosis is primarily based on patient history among MS-treating neurologists. Therefore, continued education to neurologists may facilitate early diagnosis and timely introduction of effective treatment to manage the progression of SPMS.

Reactor produced [64Cu]CuCl2 as a PET radiopharmaceutical for cancer imaging: from radiochemistry laboratory to nuclear medicine clinic.

OBJECTIVE: Copper-64 is a useful theranostic radioisotope that is attracting renewed interest from the nuclear medicine community in the recent times. This study aims to demonstrate the utility of research reactors to produce clinical-grade 64Cu via 63Cu(n,γ)64Cu reaction and use it in the form of [64Cu]CuCl2 as a radiopharmaceutical for PET imaging of cancer in human patients. METHODS: Copper-64 was produced by irradiation of natural CuO target in a medium flux research reactor. The irradiated target was radiochemically processed and detailed quality control analyses were carried out. Sub-acute toxicity studies were carried out with different doses of Cu in Wistar rats. The biological efficacy of the radiopharmaceutical was established in preclinical setting by biodistribution studies in melanoma tumor bearing mice. After getting regulatory approvals, [64Cu]CuCl2 formulation was clinically used for PET imaging of prostate cancer and glioblastoma patients. RESULTS: Large-scale (~ 30 GBq) production of 64Cu could be achieved in a typical batch and it was adequate for formulation of clinical doses for multiple patients. The radiopharmaceutical met all the purity requirements for administration in human subjects. Studies carried out in animal model showed that the toxicity due to "cold" Cu in clinical dose of [64Cu]CuCl2 for PET scans would be negligible. Clinical PET scans showed satisfactory uptake of the radiopharmaceutical in the primary cancer and its metastatic sites. CONCLUSIONS: To the best of our knowledge, this is the first study on use of reactor produced [64Cu]CuCl2 for PET imaging of cancer in human patients. It is envisaged that this route of production of 64Cu would aid towards affordable availability of this radioisotope for widespread clinical use in countries with limited cyclotron facilities.

Clinical scale synthesis of intrinsically radiolabeled and cyclic RGD peptide functionalized 198Au nanoparticles for targeted cancer therapy.

INTRODUCTION: The emerging concept of intrinsically radiolabeled nanoparticles has the potential to transform the preclinical and clinical studies by improving the in vivo stability and demonstrating minimal alteration in the inherent pharmacokinetics of the nanoparticles. In this paper, a simple and efficient single-step method for clinical scale synthesis of intrinsically radiolabeled 198Au nanoparticles conjugated with cyclic arginine-glycine-aspartate peptide (198AuNP-RGD) is reported for potential use in targeted cancer therapy. METHODS: Large radioactive doses (>37 GBq) of 198AuNP-RGD were synthesized by reaction of 198Au-HAuCl4 with cyclic RGD peptide. The synthesized nanoparticles were characterized by various analytical techniques. In vitro cell binding studies were carried out in B16F10 (murine melanoma) cell line. Biodistribution studies were carried out in melanoma tumor bearing C57BL/6 mice to demonstrate the tumor targeting ability of 198AuNP-RGD. The therapeutic efficacy of 198AuNP-RGD was evaluated by carrying out systematic tumor regression studies in melanoma tumor bearing mice after intravenous administration of the radioactive doses. RESULTS: Well dispersed and biocompatible nanoparticles (~12.5 nm diameter) could be synthesized with excellent radiochemical and colloidal stability. In vitro studies exhibited the cell binding affinity and specificity of 198AuNP-RGD towards melanoma cell line. A high uptake of 8.7 ±â€¯2.1%ID/g in the tumor was observed within 4 h post-injection (p.i.). Significant decrease in tumor uptake of 198AuNP-RGD (2.9 ±â€¯0.8%ID/g) at 4 h p.i. on co-injection of a blocking dose of the peptide suggested that tumor localization of the intrinsically radiolabeled nanoparticles was receptor mediated. Administration of 37.0 MBq of 198AuNP-RGD resulted in significant regression of tumor growth with no apparent body weight loss over a period of 15 d. CONCLUSIONS: Overall, these promising results demonstrate the suitability of 198AuNP-RGD as an advanced functional nanoplatform for targeted cancer therapy.

Environmental physiology of the mole crab Emerita asiatica, at a power plant discharge area on the east coast of India.

Cage experiments at the discharge area of Madras Atomic Power Station (MAPS) facilitated studies of thermal tolerance in Emerita asiatica. At the laboratory, oxygen consumption at various temperatures and varying salinities was also investigated. In the field 100% mortality of crabs was recorded at the Condenser Cooling Water Pumps (CCWP) discharge site compared to no mortality at the Processed Sea Water Pumps (PSWP) site. This observation implicated temperature as a stress factor at the CCWP outfall, because other factors, including residual chlorine and water velocity, were the same at the PSWP and CCWP sites. Laboratory experiments on tolerance revealed that 38.5 degrees C was lethal to mole crabs. The time taken for 100% mortality decreased as the temperature increased from 35 to 40 degrees C. Oxygen metabolism showed a progressive increase with temperature from 29 to 36 degrees C, and declined at 37 degrees C. The influence of salinity on oxygen consumption was marginal at salinities of 20 to 35 per thousand but, when reduced to 15 per thousand, the oxygen consumption declined. The present study thus indicates that temperature could be the lethal factor, determining the distribution of mole crabs near the power station, where water temperature can exceed 40 degrees C.

Lethal and sub-lethal effects of chlorination on green mussel Perna viridis in the context of biofouling control in a power plant cooling water system.

Continuous chlorination is a widely followed cooling water treatment practice used in the power industry to combat biofouling. The green mussel Perna viridis is one of the dominant fouling organisms ( > 70%) in the Madras Atomic Power Station. Mortality pattern as well as physiological responses such as oxygen consumption, filtration rate, byssus thread production and faecal matter production of three different size groups of this mussel were studied at different chlorination concentrations. At 0.7 mg l(-1) residual chlorine, 3-4 cm size mussels showed 100% mortality in 553.3 h while 8-9 cm size group mussels died within 588 h. At a relatively high level of residual chlorine (9.1 mg l(-1)), 100% mortality in 3-4 cm and 8-9 cm size groups took 94 and 114 h, respectively. All physiological activities studied showed a progressive reduction as chlorine residuals were increased from 0 to 0.55 mg l(-1). The data indicated that the green mussel can sense a residual chlorine level as low as < 0.15 mg l(-1) and complete valve closure occurs only at 0.55 mg l(-1). The paper also shows that the sub-lethal physiological responses are better indices than lethal responses in planning chlorination strategies.

Influence of temperature on the physiological responses of the bivalve Brachidontes striatulus and its significance in fouling control.

Heat treatment offers an alternative method of fouling control to chlorination in power plants. In order to optimise such a procedure it is important to understand the responses of fouling organisms to elevated water temperatures. In this paper we report results of experiments on the lethal and sub-lethal effects of temperature on the bivalve Brachidontes striatulus which is one of the major foulants in the process seawater heat exchangers of Madras Atomic Power Station located at Kalpakkam, on the east coast of India. The important physiological activities, such as, oxygen consumption, filtration rate, byssus thread production and faecal matter production were studied at temperatures varying from 20 to 38 degrees C. Three different size groups [3-5 mm shell length (group 1), 6-10 mm (group 2), 11-15 mm (group 3)] of B. striatulus were used for the experiments. The results showed physiological activities were maximum at 35 degrees C, minimum at 20 and 38 degrees C. Physiological activities increased with size except for byssus thread production, which did not show any trend. Survival times showed a reduction from 30 h at 39 degrees C to < 1 h at 45 degrees C and were independent of body size.

Tricalcium phosphate ceramic as immediate root implants for the maintenance of alveolar bone in partially edentulous mandibular jaws. A clinical study.

This study was undertaken to probe the efficacy of tricalcium phosphate ceramic (TCP) as an immediate root implant in the maintenance of alveolar bone. Three patients had five TCP root implants placed in fresh extraction sockets with soft tissue closure. The control and implant areas were evaluated at the 20th and 78th week on the basis of radiographic and clinical measurements. Tricalcium phosphate ceramic root implants in extraction sockets produced a significant increase in height and width of alveolar bone compared with control sites. It is believed that this method is a more effective and efficient procedure to preserve alveolar bone for the retention of dentures than other methods.

Randomised double blind placebo controlled clinical trial of sucralfate and ranitidine in chronic duodenal ulcer.

A double blind, randomised, placebo controlled clinical trial was carried out in endoscopically proved chronic duodenal ulcer patients to compare the efficacy of sucralfate and ranitidine. Sucralfate 1 g four times daily and ranitidine 150 mg twice daily were found to be equally effective in inducing ulcer healing (73.1% and 82.1% respectively) during the 6-week treatment period. The rate of recurrence of the ulcer within six months after the initial treatment (84.2% and 82.6%) was also comparable in the sucralfate and ranitidine groups. Sucralfate and ranitidine are equally effective in ulcer healing and prevention of ulcer relapse.

Vitamin E prevents deleterious effects of di (2-ethyl hexyl) phthalate, a plasticizer used in PVC blood storage bags.

Vitamin E administration prevented DEHP induced deleterious effects like (i) degenerative changes in the brain and thyroid, (ii) decrease in the activity of neuronal membrane Na+ - K+ ATPase, (iii) decrease in the concentration of insulin, cortisol and TSH, and (iv) the increase in T3 and T4 in female Albino rats. The results suggest use of vitamin E to prevent harmful effects of repeated transfusion of DEHP containing blood as in thalassemia patient. The possibility of using vitamin E to prevent the harmful effects of repeated transfusion of DEHP containing blood, as in thalassemia patients, is discussed.

Evaluation of health and pharmacy benefit information in health plan information packages.

Consumers have ready access to their health plan information packages, and the utility of this source in providing information about health and pharmacy benefits to consumers should be evaluated. A preliminary evaluation using a sample of student consumers enrolled in a variety of health plans was conducted. Findings revealed that consumer information is lacking in areas related to the definition of pharmacy benefit terminology, cost sharing for medications and services, provider selection, and referral processes. Managed care decision makers will benefit from understanding the informational needs of their members and from designing health care benefit information to accommodate these needs.

Determining the cost of obesity and its common comorbidities from a commercial claims database.

What is already known about this subject Obesity is highly prevalent and costly in the US. Obesity often leads to other comorbid conditions, including diabetes and hypertension. Obesity prevention efforts can reduce healthcare costs. What this study adds Obesity combined with other comorbidities significantly increases healthcare costs per patient visit. The combination of obesity and depression exacerbates costs. The most expensive series of chronic conditions in this study included obesity, diabetes, hypertension and depression. Our objectives were to determine payments made by commercial healthcare providers in the US for adults diagnosed with obesity, and those comorbid with any combination of selected chronic conditions. Using a commercial claims and encounters database (n = 3,562,717), we evaluated an adult study population that had at least one in-patient visit, outpatient visit or emergency department visit, and received a primary or secondary diagnosis of obesity. Persons were categorized by one or more comorbid diagnoses for diabetes mellitus, hypertension, depression or congestive heart failure. We adjusted for age and gender, and calculated the mean total net expenditures (in 2012, $US) for each combination of comorbid conditions based on individual visits to an in-patient, outpatient or emergency department setting. Among 50,717 claims with diagnosis of obesity, the mean net expenditure for in-patient and outpatient services was $ 1907 per patient per visit. Persons diagnosed with obesity and other comorbidities observed an increase in total net expenditures. Obesity and congestive heart failure observed the highest increase among single comorbidities at $ 5275. For persons with obesity and two other comorbidities, diabetes mellitus and depression was the highest at $ 15,226. The most expensive condition was obesity, diabetes mellitus, hypertension and depression at $ 15,733. Compared with average medical claims, persons diagnosed with obesity and other common chronic conditions experience significant increases in medical costs. These costs are often driven higher by time spent as in-patients. By controlling and reducing the prevalence of obesity, we may see significant decreases in medical expenditures.