Production, isolation, and shipment of clinically relevant quantities of astatine-211: A simple and efficient approach to increasing supply.

The alpha emitter astatine-211 (211At) is a promising candidate for cancer treatment based on Targeted Alpha (α) Therapy (TAT). A small number of facilities, distributed across the United States, are capable of accelerating α-particle beams to produce 211At. However, challenges remain regarding strategic methods for shipping 211At in a form adaptable to advanced radiochemistry reactions and other uses of the radioisotope. PURPOSE: Our method allows shipment of 211At in various quantities in a form convenient for further radiochemistry. PROCEDURES: For this study, a 3-octanone impregnated Amberchrom CG300M resin bed in a column cartridge was used to separate 211At from the bismuth matrix on site at the production accelerator (Texas A&M) in preparation for shipping. Aliquots of 6 M HNO3 containing up to ≈2.22 GBq of 211At from the dissolved target were successfully loaded and retained on columns. Exempt packages (<370 MBq) were shipped to a destination radiochemistry facility, University of Texas MD Anderson Cancer Center, in the form of a convenient air-dried column. Type A packages have been shipped overnight to University of Alabama at Birmingham. MAIN FINDINGS: Air-dried column hold times of various lengths did not inhibit simple and efficient recovery of 211At. Solution eluted from the column was sufficiently high in specific activity to successfully radiolabel a model compound, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1), with 211At. The method to prepare and ship 211At described in this manuscript has also been used to ship larger quantities of 211At a greater distance to University of Alabama at Birmingham. PRINCIPAL CONCLUSIONS: The successful proof of this method paves the way for the distribution of 211At from Texas A&M University to research institutions and clinical oncology centers in Texas and elsewhere. Use of this simple method at other facilities has the potential increase the overall availability of 211At for preclinical and clinical studies.

Complexation of Astatine(III) with Ketones: Roles of NO3- Counterion and Exploration of Possible Binding Modes.

Ketones have been proven effective in extracting astatine(III) from aqueous solvents. Previous theoretical studies suggested a mechanism where the "sp2" lone pair on the carbonyl oxygen donates electron density into the π system of the AtO+ molecular cation to form a dative-type bond. In this study, co-extraction of NO3- as AtO(NO3)·(O═CR1R2) species into the organic phase appears to be a key factor. Adjusting the electronic properties of the ketone, by having an aryl group instead of an alkyl group in the alpha position of the ketone, increased the electron density on C═O, increased the bond strength between the ketone and AtO+, and in turn increased the extraction of 211At into the organic phase. Extraction with diketones shows dependence on the bridging distance between the two carbonyl moieties, where a C3 or longer bridge results in a 10-fold increase in extraction into the organic phase. DFT calculations show the longer bridge allows for the chelation of AtO(NO3) by either the second carbonyl or the phenyl ring.

Letter to the Editor Re: Borschel M., et al. Comparison of Growth of Healthy Term Infants Fed Extensively Hydrolyzed Protein- and Amino Acid-Based Infant Formulas. Nutrients 2018, 10, 289.

We read with interest the recently published narrative review of seven growth studies in healthy infants fed extensively hydrolyzed protein-based formulas (eHF) and amino acid-based formulas (AAF) [...].

Mineral Intake and Status of Cow's Milk Allergic Infants Consuming an Amino Acid-based Formula.

Data on the mineral status of infants with cow's milk allergy (CMA) consuming an amino acid-based formula (AAF) have not been published. The present study aims to assess mineral status of term infants age 0 to 8 months diagnosed with CMA receiving an AAF for 16 weeks. Serum concentrations of calcium, phosphorus, chloride, sodium, potassium, magnesium, and ferritin were determined in 82 subjects at baseline and in 66 subjects after 16 weeks on AAF using standard methods and evaluated against age-specific reference ranges. In addition to this, individual estimated energy and mineral intakes were compared to Adequate Intakes defined by the European Food Safety Authority and the US Institute of Medicine. The results of this study show that the AAF was effective in providing an adequate mineral status in infants with CMA. The vast majority of infants aged 0 to 6 months (formula only) and aged 6 to 12 months (formula and complementary foods) had adequate mineral intakes.

Impact of the extent of extraprostatic extension defined by Epstein's method in patients with negative surgical margins and negative lymph node invasion.

BACKGROUND: To assess the impact of the degree of extraprostatic extension (EPE) on biochemical recurrence (BCR) and utility of the original Epstein's criteria to define EPE in a cohort of pT3aN0 without positive surgical margin (PSM). METHODS: A two-center retrospective analysis was performed on data from 490 pT3aN0 patients who underwent radical prostatectomy between 2000 and 2012. Patients with neoadjuvant and/or adjuvant therapy, detectable PSA and PSM were excluded. Our pathologists used Epstein's criteria to report the degree of EPE. When pathology reports did not reflect the terms 'focal' or 'established' (non-focal), slides were analyzed by a single genitourinary pathologist for final evaluation. The end point was defined by BCR. RESULTS: Selection criteria yielded 247 patients. Mean follow-up was 56.3±4.6 months; mean age at surgery was 62.5 years. Sixty-one (24.7%) patients experienced BCR during follow-up. Patients with focal extension had a 5-year recurrence-free survival of 89% versus 80% for those with non-focal extension (P=0.0018). In multivariate analysis, both pathologic Gleason score (hazard ratio 2.5; 95% confidence interval 1.4-4.5; P=0.002) and the extent of EPE (hazard ratio 1.8; 95% confidence interval 1.1-3.5; P=0.029) were significant predictors of BCR. CONCLUSIONS: The extent of EPE is an independent predictor of BCR in pT3aN0 prostate cancer without PSM. This study reinforces the utility of the subjective Epstein approach already adopted by most pathologists for quantification of the extent of EPE.

Synbiotics-supplemented amino acid-based formula supports adequate growth in cow's milk allergic infants.

BACKGROUND: Children with cow's milk allergy (CMA) are at risk for inadequate nutritional intake and growth. Dietary management of CMA, therefore, requires diets that are not only hypoallergenic but also support adequate growth in this population. This study assessed growth of CMA infants when using a new amino acid-based formula (AAF) with prebiotics and probiotics (synbiotics) and evaluated its safety in the intended population. METHODS: In a prospective, randomized, double-blind controlled study, full-term infants with diagnosed CMA received either an AAF (control; n = 56) or AAF with synbiotics (oligofructose, long-chain inulin, acidic oligosaccharides, Bifidobacterium breve M-16V) (test; n = 54) for 16 wk. Primary outcome was growth, measured as weight, length and head circumference. Secondary outcomes included allergic symptoms and stool characteristics. RESULTS: Average age (±SD) of infants at inclusion was 4.5 ± 2.4 months. Both formulas equally supported growth according to WHO 2006 growth charts and resulted in similar increases of weight, length and head circumference. At week 16, differences (90% CI) in Z-scores (test-control) were as follows: weight 0.147 (-0.10; 0.39, p = 0.32), length -0.299 (-0.69; 0.09, p = 0.21) and head circumference 0.152 (-0.15; 0.45, p = 0.40). Weight-for-age and length-for-age Z-scores were not significantly different between the test and control groups. Both formulas were well tolerated and reduced allergic symptoms; the number of adverse events was not different between the groups. CONCLUSIONS: This is the first study that shows that an AAF with a specific synbiotic blend, suitable for CMA infants, supports normal growth and growth similar to the AAF without synbiotics. This clinical trial is registered as NCT00664768.

How to diagnose and treat focal therapy failure and recurrence?

PURPOSE OF REVIEW: Focal therapy presents an alternative option for disease-targeted therapy while preserving erectile and urinary function without compromising oncological outcome. Such treatment, which preserves normal prostate parenchyma, presents a clinical challenge to the urologist, as typical disease surveillance parameters are not as reliable in post-ablation follow-up. We propose an integrated approach to post-ablation surveillance to identify treatment failure as well as recurrence. RECENT FINDINGS: Post-ablation prostate-specific antigen kinetics, imaging based on multiparametric MRI and control biopsies are the tools currently used to follow patients after focal therapy. Good treatment response is indicated by a negative control biopsy, absence of persistent lesion on post-treatment imaging and a reduction in prostate-specific antigen of at least 50%. SUMMARY: When histological evidence of therapeutic failure or recurrence is present, different options of management may be proposed to the patient including active surveillance, focal salvage therapy or radical salvage treatment, depending on the characteristics of the lesion found. A recommended post-ablation surveillance protocol is presented as well as a discussion of management strategies based on the data currently available.

Effects on growth and tolerance and hypoallergenicity of an amino acid-based formula with synbiotics.

BACKGROUND: To evaluate the effects of an amino acid-based formula (AAF) with synbiotics on growth and tolerance in healthy infants. The hypoallergenicity of this AAF with synbiotics was evaluated in subjects with cow's milk allergy (CMA). METHODS: Study 1: 115 full-term, healthy infants randomly received an AAF with synbiotics or a commercially available AAF for 16 wk. Subjects' weight, length, and head circumference were primary outcome measures. Stool characteristics and gastrointestinal (GI) symptoms were secondary outcome measures. Clinical examinations, dietary intake, clinical laboratory results, and adverse events were recorded. Study 2: hypoallergenicity of the AAF with synbiotics was evaluated in 30 infants and children with immunoglobulin E (IgE)-mediated CMA using a double-blind, placebo-controlled food challenge, and a 7-d feeding period. RESULTS: Study 1: comparable results in growth parameters and tolerance were observed for both groups. Minimal differences were observed in stool characteristics and GI symptoms throughout the study. Study 2: all 30 subjects with IgE-mediated CMA completed the study with no allergic reactions detected to challenges. CONCLUSION: These studies demonstrate that an AAF with synbiotics is safe and well tolerated and promotes normal growth when fed to healthy full-term infants as the sole source of nutrition and is hypoallergenic in subjects with CMA.

Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted vaccine coadministered with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine and/or meningococcal conjugate vaccine to healthy girls 11 to 18 years of age: results from a randomized open trial.

BACKGROUND: A combined immunization strategy for administration of human papillomavirus (HPV) vaccine with other routine vaccines may lead to better compliance. Reactions and immunologic interference with concomitantly administered vaccines are unpredictable, necessitating clinical evaluation. METHODS: This was a randomized, open study conducted at 48 centers in the United States (NCT00369824). Healthy girls 11 to 18 years of age were randomized equally to 1 of 6 groups to receive 3 doses of HPV-16/18 AS04-adjuvanted vaccine administered at 0, 1, and 6 or 1, 2, and 7 months, with or without 1 dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) and/or 1 dose of meningococcal polysaccharide diphtheria toxoid conjugate vaccine (MCV4) in different coadministration regimens (1283 girls vaccinated). Coadministered vaccines were injected at separate sites. Antibodies were measured for all vaccine components. Reactogenicity and safety were monitored. RESULTS: The prespecified criteria for noninferiority were met for all primary and secondary immunogenicity end points, demonstrating similar immunogenicity of Tdap and MCV4 when given alone or coadministered with the HPV vaccine. Immunogenicity of the HPV vaccine (in terms of seroconversion rates and geometric mean antibody titers to HPV antigens) was similar, regardless of whether it was given alone or coadministered with Tdap and/or MCV4. No differences were observed in the reactogenicity profile of the HPV vaccine administered alone or coadministered with either Tdap and/or MCV4 in different regimens. CONCLUSIONS: Concomitant administration of HPV-16/18 AS04-adjuvanted vaccine with Tdap and/or MCV4 in different regimens did not interfere with the immune response to any of the vaccines and had an acceptable safety profile.

Growth of microorganisms in propofol and methohexital mixtures.

PURPOSE: The purpose of this study was to evaluate the growth of 4 different microorganisms in propofol, methohexital, and 1:1 and 1:3 mixtures of propofol and methohexital. MATERIALS AND METHODS: The microbial growth of Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Escherichia coli in 1:1 and 3:1 mixtures of methohexital and 2 types of propofol was measured for 48 hours after mixing the solutions. Two of the 4 test solutions were composed of 1% methohexital combined with Diprivan (AstraZeneca Pharmaceuticals, Wilmington, DE), which uses EDTA as a microbial growth inhibitor. The growth of the same 4 microorganisms was also evaluated in 1:1 and 3:1 mixtures of 1% methohexital and a recently introduced generic propofol marketed by Baxter Pharmaceuticals (Deerfield, IL) that uses sodium metabisulfite as a preservative. RESULTS: Combining either Diprivan or generic propofol with methohexital in a 1:1 or 1:3 mixture ratio resulted in a solution that, like methohexital alone, significantly resisted the growth of C albicans, E coli, S aureus, and P aeruginosa for 48 hours. CONCLUSION: The results of our study suggest that 1:1 and 1:3 mixtures of propofol (either Diprivan or generic propofol) and methohexital behave similarly to methohexital alone by resisting growth of the microorganisms studied over the 48-hour time period. If, as has been reported elsewhere, the mixture of these 2 agents results in a solution with desirable anesthetic properties, its ability to resist microbial growth becomes clinically significant by extending the shelf-life of propofol in these mixtures.