Structures for clinical follow-up: Newborn screening

Summary Clinical follow-up of children identified by newborn screening is critical in ensuring that the short-term and long-term needs of the newborn infant are managed. Within the United States, one of the biggest challenges in the newborn screening programme is clinical follow-up, and there still remains wide variation in practice patterns among states on how infants are followed up. In addition, there is lack of consistency in the treatment and diagnostic protocols used by health care providers. There is growing interest in the establishment of a systematic process for follow-up and for the development of a nationwide infrastructure that will ensure that all children will be provided consistent and effective treatment in a timely manner. Within this framework of optimal diagnosis and therapy, there must also be opportunities to study the natural history of these conditions, to monitor short- and long-term health outcomes, to assist with policy decision-making, to validate the effectiveness of screening, to define the clinical spectrum of the diseases, and to provide opportunities for the advancement of novel therapeutic interventions and screening/diagnostic technologies. It will only be through the development of a structured clinical follow-up system that we will be able to make certain these newborn infants are provided the most appropriate treatment for their disease variants and allow researchers to make more rapid advances in improving the clinical management of these conditions. Competing interests: None declared     

Evaluation of efficacy and safety markers in a phase II study of metastatic colorectal cancer treated with aflibercept in the first-line setting

Background:

Aflibercept (ziv-aflibercept) is an anti-angiogenic agent recently approved in combination with FOLFIRI for the treatment of metastatic colorectal cancer (mCRC) patients previously treated with oxaliplatin. Despite heterogeneity in response to aflibercept, no biomarkers for efficacy or adverse effects have been identified. Here we present biomarker data from the randomised phase II AFFIRM trial assessing aflibercept in combination with mFOLFOX6 first line in mCRC.

Methods:

Ninety-six somatic mutations in key oncogenic drivers of mCRC and 133 common single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) pathway genes were analysed, and 27 plasma markers measured at baseline, during and after treatment. We assessed correlations of these three classes of biomarkers with progression-free survival (PFS) and adverse events (AEs).

Results:

Somatic mutations identified in KRAS, BRAF, NRAS, PIK3CA and PIK3R1 did not significantly correlate with PFS (multiple testing-adjusted false discovery rate (FDR) or multiple testing-adjusted FDR>0.3). None of the individual SNPs correlated with PFS (multiple testing-adjusted FDR>0.22), but at the gene level variability in VEGFB significantly correlated with PFS (multiple testing-adjusted FDR=0.0423). Although none of the plasma markers measured at baseline significantly correlated with PFS, high levels of circulating IL8 at baseline together with increased levels of IL8 during treatment were significantly associated with reduced PFS (multiple testing-adjusted FDR=0.0478). No association was found between biomarkers and AEs.

Conclusions:

This represents the first biomarker study in mCRC treated with aflibercept. High IL8 plasma levels at baseline and subsequent increases in IL8 were associated with worse PFS, suggesting that IL8 may act as a potentially predictive biomarker of aflibercept treatment outcome.     

Vitamin D status at breast cancer diagnosis: correlation with tumor characteristics, disease outcome, and genetic determinants of vitamin D insufficiency

We correlated serum 25-hydroxyvitamin D(3) (25OHD) levels with tumor characteristics and clinical disease outcome in breast cancer patients and assessed the impact of genetic determinants of vitamin D insufficiency. We collected serum from 1800 early breast cancer patients at diagnosis, measured 25OHD by radioimmunoassay (RIA), and determined genetic variants in vitamin D-related genes by Sequenom. Multivariable regression models were used to correlate 25OHD levels with tumor characteristics. Cox proportional hazard models were used to assess overall survival (OS), disease-specific survival (DSS), and disease-free interval (DFI). Lower 25OHD serum levels significantly correlated with larger tumor size at diagnosis (P = 0.0063) but not with lymph node invasion, receptor status, or tumor grade. Genetic variants in 25-hydroxylase (CYP2R1) and vitamin D-binding (DBP) protein significantly determined serum 25OHD levels but did not affect the observed association between serum 25OHD and tumor size. High serum 25OHD (>30 ng/mL) at diagnosis significantly correlated with improved OS (P = 0.0101) and DSS (P = 0.0192) and additionally had a modest effect on DFI, which only became apparent after at least 3 years of follow-up. When considering menopausal status, serum 25OHD had a strong impact on breast cancer-specific outcome in postmenopausal patients [hazards ratios for 25OHD >30 ng/mL versus ≤30 ng/mL were 0.15 (P = 0.0097) and 0.43 (P = 0.0172) for DSS and DFI, respectively], whereas no association could be demonstrated in premenopausal patients. In conclusion, high vitamin D levels at early breast cancer diagnosis correlate with lower tumor size and better OS, and improve breast cancer-specific outcome, especially in postmenopausal patients.     

Seroprevalence of hepatitis C virus in haemophiliacs in Jamaica

Haemophilic patients (n = 90) and household contacts (n = 40) were tested for serological markers of hepatitis B virus (HBV), hepatitis C virus (HCV) and elevated serum aminotransferases using commercially prepared reagents. Of the haemophiliacs 41% (37/90) tested positive for antibodies to HCV (anti-HCV); 36% (32/90) antibodies to hepatitis B core antigen (anti-HBc); 54% (49/90) antibodies to hepatitis B surface antigen (anti-HBs) and 2% (2/90) hepatitis B surface antigen. On the other hand, 29% (26/90) of the patients and 90% (36/40) of the household contacts tested negative for all of the viral markers. Anti-HCV positivity in the haemophilic patients correlated positively with anti-HBc (p < 0.025). Increasing age (odds ratio 2.09; p < 0.01), severity of disease (odds ratio 6.2; p < 0.05) and the requirement for transfusion (odds ratio 3.2; p < 0.05) were risk factors for anti-HCV positivity. The presence of anti-HBc (odds ratio 3.8; p < 0.01) and coinfection with HCV and HBV also correlated positively with age (odds ratio 2.5; p < 0.01). The provision of anti-HCV screened donor blood and virally inactivated blood products for treatment of all haemophilic patients are goals that must be achieved.     

Safety,efficacy, and pharmacokinetics/pharmacodynamics of daclizumab (anti-CD25) in patients with adult T-cell leukemia/lymphoma

Interleukin-2 receptor α chain (CD25) is overexpressed in human T-cell leukemia virus 1 associated adult T-cell leukemia/lymphoma (ATL). Daclizumab a humanized monoclonal antibody blocks IL-2 binding by recognizing the interleukin-2 receptor α chain (CD25). We conducted a phase I/II trial of daclizumab in 34 patients with ATL. Saturation of surface CD25 on circulating ATL cells was achieved at all doses; however saturation on ATL cells in lymph nodes required 8 mg/kg. Up to 8 mg/kg of daclizumab administered every 3 weeks was well tolerated. No responses were observed in 18 patients with acute or lymphoma ATL; however, 6 partial responses were observed in 16 chronic and smoldering ATL patients. The pharmacokinetics/pharmacodynamics of daclizumab suggest that high-dose daclizumab would be more effective than low-dose daclizumab in treatment of lymphoid malignancies and autoimmune diseases (e.g., multiple sclerosis) since high-dose daclizumab is required to saturate IL-2R alpha in extravascular sites.     

Clinical,biochemical and molecular findings of 24 Brazilian patients with glutaric acidemia type 1: 4 novel mutations in the GCDH gene

Metabolic Brain Disease - Glutaric aciduria type 1 (GA-1) is a rare but treatable inherited disease caused by deficiency of glutaryl-CoA dehydrogenase activity due to GCDH gene mutations. In this...     

Multimodal neuroimaging measures and intelligence influence pedophile child sexual offense behavior

Pedophilia is a heterogeneous disorder for which the neurobiological correlates are not well established. In particular, there are no biological markers identifying individuals with high risk to commit child sexual offense (CSO). Pedophiles with CSO (P+CSO; N = 73), pedophiles without CSO (P-CSO; N = 77), and non-pedophilic controls (NPC; N = 133) were assessed using multimodal structural neuroimaging measures including: cortical thickness (CT), surface area (SA), and white matter fractional anisotropy (FA), as well as full scale IQ (FSIQ) performance. Cortex-wise mediation analyses were used to assess the relationships among brain structure, FSIQ and CSO behavior. Lower FSIQ performance was strongly predict with P+CSO (Wald Chi² = 13.0, p = 3.1 × 10^-5). P+CSO had lower CT in the right motor cortex and pronounced reductions in SA spanning the bilateral frontal, temporal, cingulate, and insular regions (P_{FWE-corrected} < 0.05). P+CSO also had lower FA particularly in the corpus callosum (P_{FWE-corrected} < 0.05). The relationship between SA and P+CSO was significantly mediated by FSIQ, particularly in the prefrontal and anterior insular cortices (P_{FWE-corrected} < 0.05). Within P+CSO, left prefrontal and right anterior cingulate SA negatively correlated with number of CSOs (P_{FWE-corrected} < 0.05). This study demonstrates converging neurobiological findings in which P+CSO had lower FSIQ performance, reduced CT, reduced SA, and reduced FA, compared to P-CSO as well as NPC. Further, FSIQ potentially mediates abuse by pedophiles via aberrant SA, whereas the CT and FA associations were independent of FSIQ differences. These findings suggest aberrant neuroanatomy and lower intelligence as a potential core feature underlying child sexual abuse behavior by pedophiles.     

Cortisol,testosterone, and insulin action during intense swimming training in humans

An increase in the amounts of circulating plasma cortisol or a decrease in testosterone can result in whole-body insulin resistance. The purpose of this study was to determine if the increase in cortisol and/or decrease in testosterone concentrations commonly evident with intense endurance training is associated with insulin resistance. Male (n = 9) and female (n = 10) swimmers were examined during the off-season, after 9 weeks (9 WKS) of training averaging 5,500 m·day^–1 and after an additional 9 weeks (18 WKS) of training averaging 8,300 m·day^–1. Resting plasma cortisol concentration was (P <– 0.05) higher in the women compared to the men at 9 WKS; values were not significantly different between genders at 18 WKS. Plasma testosterone concentration decreased significantly (P <– 0.05) in the men at 9 and 18 WKS, but did not change in the women. Whole-body insulin action, as determined by insulin and glucose responses during a 120 min, 75-g oral glucose tolerance test, did not change with training in either the men or women. These data indicated that plasma testosterone concentration can decrease in male swimmers during intense endurance training; this alteration does not affect whole-body insulin action. There would also appear to be a gender-specific response of plasma cortisol to endurance training, which does not influence insulin action.