18F-Fluoroestradiol PET/CT Measurement of Estrogen Receptor Suppression during a Phase I Trial of the Novel Estrogen Receptor-Targeted Therapeutic GDC-0810: Using an Imaging Biomarker to Guide Drug Dosage in Subsequent Trials.

Purpose: Evaluate 18F-fluoroestradiol (FES) PET/CT as a biomarker of estrogen receptor (ER) occupancy and/or downregulation during phase I dose escalation of the novel ER targeting therapeutic GDC-0810 and help select drug dosage for subsequent clinical trials.Experimental Design: In a phase I clinical trial of GDC-0810, patients with ER-positive metastatic breast cancer underwent FES PET/CT before beginning therapy and at cycle 2, day 3 of GDC-0810 therapy. Up to five target lesions were selected per patient, and FES standardized uptake value (SUV) corrected for background was recorded for each lesion pretherapy and on-therapy. Complete ER downregulation was defined as ≥90% decrease in FES SUV. The effect of prior tamoxifen and fulvestrant therapy on FES SUV was assessed.Results: Of 30 patients who underwent paired FES-PET scans, 24 (80%) achieved ≥90% decrease in FES avidity, including 1 of 3 patients receiving 200 mg/day, 2 of 4 patients receiving 400 mg/day, 14 of 16 patients receiving 600 mg/day, and 7 of 7 patients receiving 800 mg/day. Withdrawal of tamoxifen 2 months prior to FES PET/CT and withdrawal of fulvestrant 6 months prior to FES PET/CT both appeared sufficient to prevent effects on FES SUV. A dosage of 600 mg GDC-0810 per day was selected for phase II in part due to decreases in FES SUV achieved in phase I.Conclusions: FES PET/CT was a useful biomarker of ER occupancy and/or downregulation in a phase I dose escalation trial of GDC-0810 and helped select the dosage of the ER antagonist/degrader for phase II trials. Clin Cancer Res; 23(12); 3053-60. ©2016 AACR.

Dose Optimization of the Administered Activity in Pediatric Bone Scintigraphy: Validation of the North American Consensus Guidelines.

UNLABELLED: The 2010 North American Consensus Guidelines (NACG) for pediatric administered doses and the European Association of Nuclear Medicine (EANM) Dosage Card guidelines recommend lower activities than those administered at our institution. We compared the quality of the lower-activity images with the higher-activity images to determine whether the reduction in counts affects overall image quality. METHODS: Twenty patients presenting to our pediatric radiology department for bone scintigraphy were evaluated. Their mean weight was 20 kg. The patients were referred for oncologic (n = 10), infectious/inflammatory (n = 5), and pain (n = 5) evaluation. Dynamic anterior and posterior images were acquired for 5 min for each patient. Data were subsampled to represent different administered activities corresponding to the activities recommended by the NACG and the EANM Dosage Card. Images were evaluated twice, first for diagnostic quality and then for acceptability for daily clinical use. RESULTS: There was no statistically significant difference in the diagnostic quality of the images from any of the 3 protocols. Pathologic uptake was correctly identified independent of the administered activity, although there was a single false-positive result for an EANM image. When images were subjectively evaluated as acceptable for daily clinical use, there was a slight preference for the higher-activity images over the NACG (P = 0.04). CONCLUSION: The recommended administered activities of the NACG produce images of diagnostic quality while reducing patient radiation exposure.

Humoral immunity following chickenpox is influenced by geography and ethnicity.

OBJECTIVES: To investigate the contribution of ethnicity and geographical location to varicella-zoster virus (VZV) serostatus and antibody concentrations. METHODS: The presence and concentrations of antibodies to VZV were measured in 639 Bangladeshi women born in Bangladesh (BBB), 94 Bangladeshi women born in the UK (BUK) and 262 White women born in the UK (WUK). The results were analysed in relation to demographic and social data. RESULTS: BBB women were significantly less likely to be VZV seropositive at all ages than both BUK and WUK women. However, the odds of a Bangladeshi-born woman being seropositive increased by 1.04 for each year under the age of 15 spent in the UK. In contrast, antibody concentrations were significantly lower in ethnic Bangladeshi women, irrespective of country of birth. White, but not Bangladeshi women, showed evidence of antibody boosting over time despite the latter having more exposure to children. CONCLUSION: Geographical location during childhood is the major influence on age of primary infection with VZV while the level of antibody is related to ethnicity. Since the risk of re-infection with VZV following both natural infection and vaccination is increased as antibody concentrations fall, these results have implications for VZV vaccination programmes particularly in non-White populations.

The expected performance of single nucleotide polymorphism loci in paternity testing.

We discuss the utility of single nucleotide polymorphism loci for full trio and mother-unavailable paternity testing cases, in the presence of population substructure and relatedness of putative and actual fathers. We focus primarily on the expected number of loci required to gain specified probabilities of mismatches, and report the expected proportion of paternity indices greater than three threshold values for these loci.

Calculating the exclusion probability and paternity index for X-chromosomal loci in the presence of substructure.

There has been recent interest in the use of X-chromosomal loci for forensic and relatedness testing casework, with many authors developing new X-linked short tandem repeat (STR) loci suitable for forensic use. Here we present formulae for two key quantities in paternity testing, the average probability of exclusion and the paternity index, which are suitable for X-chromosomal loci in the presence of population substructure.

Gene conversion and evolution of Xq28 duplicons involved in recurring inversions causing severe hemophilia A.

Inversions breaking the 1041 bp int1h-1 or the 9.5-kb int22h-1 sequence of the F8 gene cause hemophilia A in 1/30,000 males. These inversions are due to homologous recombination between the above sequences and their inverted copies on the same DNA molecule, respectively, int1h-2 and int22h-2 or int22h-3. We find that (1) int1h and int22h duplicated more than 25 million years ago; (2) the identity of the copies (>99%) of these sequences in humans and other primates is due to gene conversion; (3) gene conversion is most frequent in the internal regions of int22h; (4) breakpoints of int22h-related inversions also tend to involve the internal regions of int22h; (5) sequence variations in a sample of human X chromosomes defined eight haplotypes of int22h-1 and 27 of int22h-2 plus int22h-3; (6) the latter two sequences, which lie, respectively, 500 and 600 kb telomeric to int22h-1 are five-fold more identical when in cis than when in trans, thus suggesting that gene conversion may be predominantly intrachromosomal; (7) int1h, int22h, and flanking sequences evolved at a rate of about 0.1% substitutions per million years during the divergence between humans and other primates, except for int1h during the human-chimpanzee divergence, when its rate of evolution was significantly lower. This is reminiscent of the slower evolution of palindrome arms in the male specific regions of the Y chromosome and we propose, as an explanation, that intrachromosomal gene conversion and cosegregation of the duplicated regions favors retention of the ancestral sequence and thus reduces the evolution rate.

Detecting non-multiplicative genotype relative risks from transmissions of parental alleles to affected children.

The differential transmission of alleles from parents to affected children indicates that the locus under investigation is either directly involved in the occurrence of the disease or that there are allelic associations with other loci that are directly involved. Conditional logistic regression applied to a diallelic locus leads to a test with two degrees of freedom. The power of a single degree of freedom test to detect non-multiplicative allelic effects is discussed here.

Implications for DNA identification arising from an analysis of Australian forensic databases.

Previous analyses of Australian samples have suggested that populations of the same broad racial group (Caucasian, Asian, Aboriginal) tend to be genetically similar across states. This suggests that a single national Australian database for each such group may be feasible, which would greatly facilitate casework. We have investigated samples drawn from each of these groups in different Australian states, and have quantified the genetic homogeneity across states within each racial group in terms of the "coancestry coefficient" F(ST). In accord with earlier results, we find that F(ST) values, as estimated from these data, are very small for Caucasians and Asians, usually <0.5%. We find that "declared" Aborigines (which includes many with partly Aboriginal genetic heritage) are also genetically similar across states, although they display some differentiation from a "pure" Aboriginal population (almost entirely of Aboriginal genetic heritage).