Measuring cancer burden in prostatic needle core biopsies: simplified assessments outperform complex measurements in assessing outcome: evidence to assist pathologist efficiency and minimize datasets.

AIMS: The optimal method of measuring cancer extent in prostate cancer (PCa) biopsies is unknown. METHODS AND RESULTS: Nine hundred eighty-one men with clinically localised PCa managed conservatively were reviewed with follow up. The number of positive cores (NPC), the Maximum Cancer Length in a core (MCL), Total Cancer Length (TCL), and percentage of positive cores (%+cores) was calculated and univariate and multivariate analysis performed using prostate-specific antigen (PSA), T-stage, and Gleason score. The presence of stromal gaps (SG) was recorded. Univariate models were run where SG made a difference to the MCL. All variables showed significant association with PCa death in univariate models. In multivariate models, incorporating PSA, T-stage, and Gleason score, only %+cores was a significant predictor of outcome, with a 10% increase in %+cores resulting in a hazard ratio (HR) of 1.07 (likelihood-ratio test P > Χ2  = 0.01). There were 120 patients where SG made a difference to the MCL and a total of 20 events in this group. Including SG, on univariate analysis the median MCL was 10 mm and HR was 1.16 (P = 0.007), not including SG, the median MCL was 6 mm and HR was 1.23 (P = 6.3 × 10-4 ). Inclusion or exclusion of SG made no significant difference to TCL as a predictor of outcome. CONCLUSION: Cancer extent is a strong predictor of PCa death but only %+cores added to the multivariate model. Expressed as a fraction of NPC/total number of cores, this is the simplest method of assessment, which we favour over more complicated methods in nontargeted biopsies.

Social gaze in preterm infants may act as an early indicator of atypical lateralization.

Visual field biases have been identified as markers of atypical lateralization in children with developmental conditions, but this is the first investigation to consider early lateralized gaze behaviors for social stimuli in preterm infants. Eye-tracking methods with 51 preterm (33 male, 92.1% White) and 61 term-born (31 male, 90.1% White) infants aged 8-10 months from Edinburgh, UK, captured the development of visual field biases, comparing gaze behavior to social and non-social stimuli on the left versus right of the screen. Preterm infants showed a significantly reduced interest to social stimuli on the left versus right compared to term children (d = .58). Preterm children exhibit early differential orienting preferences that may be an early indicator of atypical lateralized function.

Feasibility of aspirin and/or vitamin D3 for men with prostate cancer on active surveillance with Prolaris® testing.

Objectives: To test the feasibility of a randomised controlled trial (RCT) of aspirin and/or vitamin D3 in active surveillance (AS) low/favourable intermediate risk prostate cancer (PCa) patients with Prolaris® testing. Patients and Methods: Newly-diagnosed low/favourable intermediate risk PCa patients (PSA ≤ 15 ng/ml, International Society of Urological Pathology (ISUP) Grade Group ≤2, maximum biopsy core length <10 mm, clinical stage ≤cT2c) were recruited into a multi-centre randomised, double-blind, placebo-controlled study (ISRCTN91422391, NCT03103152). Participants were randomised to oral low dose (100 mg), standard dose (300 mg) aspirin or placebo and/or vitamin D3 (4000 IU) versus placebo in a 3 × 2 factorial RCT design with biopsy tissue Prolaris® testing. The primary endpoint was trial acceptance/entry rates. Secondary endpoints included feasibility of Prolaris® testing, 12-month disease re-assessment (imaging/biochemical/histological), and 12-month treatment adherence/safety. Disease progression was defined as any of the following (i) 50% increase in baseline PSA, (ii) new Prostate Imaging-Reporting and Data System (PI-RADS) 4/5 lesion(s) on multi-parametric MRI where no previous lesion, (iii) 33% volume increase in lesion size, or radiological upstaging to ≥T3, (iv) ISUP Grade Group upgrade or (v) 50% increase in maximum cancer core length. Results: Of 130 eligible patients, 104 (80%) accepted recruitment from seven sites over 12 months, of which 94 patients represented the per protocol population receiving treatment. Prolaris® testing was performed on 76/94 (81%) diagnostic biopsies. Twelve-month disease progression rate was 43.3%. Assessable 12-month treatment adherence in non-progressing patients to aspirin and vitamin D across all treatment arms was 91%. Two drug-attributable serious adverse events in 1 patient allocated to aspirin were identified. The study was not designed to determine differences between treatment arms. Conclusion: Recruitment of AS PCa patients into a multi-centre multi-arm placebo-controlled RCT of minimally-toxic adjunctive oral drug treatments with molecular biomarker profiling is acceptable and safe. A larger phase III study is needed to determine optimal agents, intervention efficacy, and outcome-associated biomarkers.

Assignment of Serotype-Specific IgG1, IgG2, and IgA Weight-Based Antibody Units to the Human Pneumococcal Standard Reference Serum, 007sp.

In 2011, the human pneumococcal standard reference serum, 007sp, was established as a replacement for the previous standard, lot 89SF, supplies of which were dwindling. The pneumococcal reference serum is used primarily in the standardized pneumococcal enzyme-linked immunosorbent assay (World Health Organization reference enzyme-linked immunosorbent assay) but has also been used in functional assays. Serotype-specific IgG values for 24 pneumococcal capsular serotypes have previously been assigned to 007sp by bridging to the original values derived for lot 89SF. In this study, by bridging to existing values in lot 89SF, we assign weight-based serotype-specific IgA, IgG1, and IgG2 to 007sp for 11 pneumococcal capsular serotypes (1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F), as well as serotype 19A-specific IgA. Concentrations for serotype-specific IgA, IgG1, and IgG2 present in 007sp were comparable to those previously assigned to lot 89SF. In addition, the concentration of serotype-specific IgG1 plus IgG2 assigned to 007sp significantly correlated to previously assigned 007sp IgG values. The accuracy of antibody assignments to 007sp from lot 89SF was assessed by comparing the concentration of serotype-specific IgA, IgG1, and IgG2 in 16 unknown samples using both 007sp and lot 89SF as the standard. Interpolated values for the unknown samples were highly correlated with average R2 values of 0.9729, 0.9951, and 0.9933 for IgA, IgG1, and IgG2, respectively, for all serotypes demonstrating the precise nature assignments to 007sp made in this study. Nonparallelism between 007sp and lot 89SF has precluded the derivation of serotype-specific IgM values.IMPORTANCE A well-characterized antibody standard is an indispensable reagent for use in assays designed to measure antibodies with precision and where assays between laboratories need to be comparable. The human pneumococcal standard reference serum, lot 89SF, greatly facilitated the standardization of enzyme-linked immunosorbent assay methodologies during a critical period when the first pneumococcal polysaccharide-conjugate vaccines were being evaluated for licensure. Due to dwindling supplies of lot 89SF, a new reference standard, 007sp, was produced in 2011. Understanding the isotype and subclass composition of either natural or vaccine induced responses to pathogens has assumed increasing importance. In this study, we have assigned IgA, IgG1, and IgG2 values to pneumococcal serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F by bridging to existing values in lot 89SF.

Comparison of two schedules of two-dose priming with the ten-valent pneumococcal conjugate vaccine in Nepalese children: an open-label, randomised non-inferiority controlled trial.

BACKGROUND: Nepalese infants receive ten-valent pneumococcal conjugate vaccine (PCV10) with a 1 month interval between priming doses for programmatic reasons. We aimed to investigate whether immune responses to PCV10 serotypes were non-inferior if the second priming dose of PCV10 was delivered at a 1 month interval as opposed to a 2 month interval. METHODS: We did an open-label, randomised, parallel group trial in healthy Nepalese infants aged 40-60 days at Patan Hospital, Kathmandu, Nepal. Children were eligible for inclusion if they were healthy, were born at more than or equal to 37 weeks' gestation, were residing in Kathmandu, and had not had any previous vaccinations other than BCG, and oral polio vaccine. Participants were randomly assigned (1:1) by means of a computer-generated list with randomly varying permuted block sizes accessed through a validated web-based interface, to receive PCV10 either at 6 weeks and 10 weeks of age (6 + 10 group) or at 6 weeks and 14 weeks of age (6 + 14 group), with both groups receiving a booster at 9 months of age. Laboratory staff, masked to study intervention, analysed serum samples for antibodies against PCV10 serotypes by ELISA. The primary outcome was to determine whether the 6 + 10 schedule was non-inferior to the 6 + 14 schedule at 9 months of age, on the basis of the proportion of infants with serotype-specific IgG greater than or equal to 0·35 µg/mL. Non-inferiority was established with a 10% margin, and the primary endpoint was measured in a modified intention-to-treat population, which included only participants who successfully had a blood sample collected. This trial is registered at ClinicalTrials.gov, number NCT02385513. FINDINGS: Between Aug 21, 2015, and April 4, 2016, 304 Nepalese children were randomly assigned to either the 6 + 10 group (n=152) or the 6 + 14 group (n=152). At 9 months of age, the 6 + 10 schedule was non-inferior for serotype 5 (79 [55·2%] of 143 vs 78 [53·4%] of 146, difference 1·82% [95% CI -9·6 to 13·25], p=0·021), serotype 9V (66 [46·1%] of 143 vs 55 [37·6%] of 146, difference 8·48% [-2·84 to 19·8], p=0·001), serotype 14 (110 [77·4%] of 142 vs 110 [74·8%] of 147, difference 2·63% [-7·27 to 12·54], p=0·006), and serotype 19F (135 [95%] of 142 vs 146 [100%] of 146, difference -4·92% [-9·86 to 0], p=0·022). At the same timepoint, non-inferiority was not shown for serotype 1 (36 [25·1%] of 143 vs 42 [28·5%] of 147, difference -3·39% [95% CI -13·56 to 6·77], p=0·102), serotype 4 (70 [48·9%] of 143 vs 87 [59·1%] of 147, difference -10·23% [-21·64 to 1·18], p=0·516), serotype 6B (96 [67·1%] of 143 vs 114 [77·5%] of 147, difference -10·41% [-20·65 to -0·18], p=0·532), serotype 7F (99 [69·2%] of 143 vs 109 [74·1%] of 147, difference -4·91% [-15·26 to 5·42], p=0·168), serotype 18C (89 [62·2%] of 143 vs 114 [77·5%] of 147, difference -15·31% [-25·78 to -4·83], p=0·840), and serotype 23F (37 [25·8%] of 143 vs 41 [27·8%] of 147, difference -2·01% [-12·19 to 8·16], p=0·062). After the booster dose, at 10 months of age, there were no significant differences in immunogenicity (proportion of children with antibody greater than or equal to 0.35 µg/mL) for any of the ten serotypes, when comparing the two schedules. Serious adverse events occurred in 32 participants, 11 (7%) of 152 in the 6 + 10 group and 21 (14%) of 152 in the 6  +  14 group. INTERPRETATION: The 6 week, 14 week, and 9 month schedule should be implemented where possible. However, post-booster responses, which are thought to drive herd immunity, were similar in the two schedules. Therefore, the 6 week, 10 week, and 9 month schedule is an alternative that can be used when logistically necessary, and is expected to provide herd protection. FUNDING: Gavi, the Vaccine Alliance.