Lexicon for guidance terminology in pediatric hematology/oncology: A White Paper

Terms used to label types of clinical recommendations and guidance are applied inconsistently and do not reflect the methods used to create each type. Here, the international Pediatric Oncology Supportive Care Guideline Network proposes a lexicon for types of recommendations and guidance documents. A lexicon describing three types of recommendations (clinical practice guideline–derived, good practice statement, and expert opinion statement) and two types of guidance documents (clinical practice guideline and expert opinion) is presented. Consistent use of this lexicon will allow pediatric oncology clinicians to readily appreciate the methods used to create clinical guidance.     

Left ventricular isovolumic relaxation and renin-angiotensin system in the growth restricted fetus

OBJECTIVE: To determine left ventricular isovolumic relaxation time (LV IRT) in normally developing and growth restricted fetuses (FGR) as an indicator of fetal cardiac afterload and neonatal systolic blood pressure. STUDY DESIGN: A prospective longitudinal study in 124 normally developing and 47 growth restricted fetuses (FGR). LV IRT, fetal heart rate (FHR) and umbilical artery pulsatility index (PI) were determined at 2-3 week intervals starting at 22-26 weeks of gestation until delivery. Renin and angiotensin I levels were measured by radioimmunoassay in umbilical venous blood after delivery. Systolic blood pressure was measured at day 1 and day 5 of postnatal life. To evaluate the association between LV IRT, gestational age and FHR, bivariate regression analyses were performed. RESULTS: Mean LV IRT (62+/-8ms) was 29 percent longer in FGR as compared to the normal subset (47+/-6ms) at all gestational ages (p<0.001). Mean postnatal active plasma renin level (7.78+/-S.D. 1.03ng/ml) and postnatal angiotensin I level (4.21+/-0.70ng/ml) in the FGR subset were significantly higher (p<0.001) than in the normal subset (4.81+/-1.04ng/ml, renin and 2.69+/-0.44ng/ml, angiotensin I). There was a significant difference (p<0.01) in systolic blood pressure between the two subsets on postnatal day 1 (FGR 52+/-6mmHg vs. normal 46+/-4mmHg) and day 5 (FGR 76+/-5mmHg vs. normal 60+/-6mmHg). CONCLUSION: Left ventricular isovolumic relaxation time may act as a sensitive index of increased arterial afterload in the growth retarded fetus and may herald raised systolic blood pressure in the early neonatal period.     

Prenatal diagnosis of xeroderma pigmentosum and trichothiodystrophy in 76 pregnancies at risk

OBJECTIVE: Evaluation of results in a consecutive series of 76 prenatal diagnoses for xeroderma pigmentosum (XP) and trichothiodystrophy (TTD) made since 1977. METHODS: UV-induced DNA repair synthesis was assessed by the autoradiographic measurement of the incorporation of (3)H-thymidine. RESULTS: XP was diagnosed in 19 of the 76 investigated pregnancies at risk; cultured chorionic villus (CV) cells were used in 33 pregnancies with ten affected fetuses and cultured amniocytes in 43 pregnancies with nine affected fetuses. In four cases, CVS results were corroborated by subsequent investigation of amniocytes because maternal cell contamination in the CV cell culture was either present or could not be excluded. Uncertain results in two other cases with intermediate DNA repair capacity and severe maternal cell contamination required further investigation. Median time needed for cell culture and analysis was 25 days. To reduce intra-assay variations, a modification of the DNA repair synthesis assay has recently been developed. In this assay, patients and controls are investigated simultaneously in mixed cultures of cells labelled with polystyrene beads. CONCLUSION: Reliable prenatal diagnosis for XP and TTD can be made by the demonstration of clearly reduced UV-induced DNA repair synthesis due to defective global genome nucleotide excision repair.     

Adjuvant capecitabine-containing chemotherapy benefit and homologous recombination deficiency in early-stage triple-negative breast cancer patients

Background The addition of adjuvant capecitabine to standard chemotherapy of early-stage triple-negative breast cancer (TNBC) patients has improved survival in a few randomised trials and in meta-analyses. However, many patients did not benefit. We evaluated the BRCA1-like DNA copy number signature, indicative of homologous recombination deficiency, as a predictive biomarker for capecitabine benefit in the TNBC subgroup of the FinXX trial.Methods Early-stage TNBC patients were randomised between adjuvant capecitabine-containing (TX + CEX: capecitabine-docetaxel, followed by cyclophosphamide-epirubicin-capecitabine) and conventional chemotherapy (T + CEF: docetaxel, followed by cyclophosphamide-epirubicin-fluorouracil). Tumour BRCA1-like status was determined on low-coverage, whole genome next-generation sequencing data using an established DNA comparative genomic hybridisation algorithm.Results For 129/202 (63.9%) patients the BRCA1-like status could be determined, mostly due to lack of tissue. During a median follow-up of 10.7 years, 35 recurrences and 32 deaths occurred. Addition of capecitabine appears to improve recurrence-free survival more among 61 (47.3%) patients with non-BRCA1-like tumours (HR 0.23, 95% CI 0.08–0.70) compared to 68 (52.7%) patients with BRCA1-like tumours (HR 0.66, 95% CI 0.24–1.81) (P-interaction = 0.17).Conclusion Based on our data, patients with non-BRCA1-like TNBC appear to benefit from the addition of capecitabine to adjuvant chemotherapy. Patients with BRCA1-like TNBC may also benefit. Additional research is needed to define the subgroup within BRCA1-like TNBC patients who may not benefit from adjuvant capecitabine.Subject terms: Breast cancer, Translational research, Predictive markers, Breast cancer     

A new familial sclerosing bone dysplasia

Osteoscleroses are a heterogeneous group of bone remodeling disorders characterized by an increase in bone density. Here we report on a consanguineous Lebanese family in which two sisters, aged 39 and 36 years, exhibit a severe genu varum, a square‐face appearance, high forehead, slight proptosis of the eyes, symmetric enlargement of the jaw, protruding chin, and short stature. Bone X‐rays showed the presence of hyperostosis of the cranial base and vault with increased density of the orbits, hyperostosis of the bones, thickening of the cortices, diaphyseal modeling defects, cortical thickening of the medullary cavity, mild enlargement of the medullary cavity of the short long bones, short femoral necks, increased width of the ribs, and narrow interpedicular distances of the lower lumbar spine. Osteodensitometry showed values 200% to 300% above values for age. A cervical MRI revealed the presence of a diffuse osteosclerosis with calcification of the posterior vertebral ligament and a narrow canal between C2 and T2. Blood test results were unremarkable. Serum osteocalcin levels were in the normal range, whereas high values of serum C ‐ telopeptide were noted. A bone biopsy showed only the presence of compact bone and did not allow for histomorphometric analysis. Molecular studies excluded genes known to be involved in sclerosing bone dysplasias as the cause of this condition. In vitro analysis of osteoclast function indicated that contrary to most cases of autosomal recessive osteopetrosis, osteoclasts both formed and resorbed but exhibited a small decrease in resorptive activity compared with osteoclasts generated from normal control individuals. Differential diagnoses are discussed, and the possibility that this may be a novel clinical entity is raised. © 2010 American Society for Bone and Mineral Research.     

Considerations on the EU definition of a nanomaterial: Science to support policy making

In recent years, an increasing number of applications and products containing or using nanomaterials have become available. This has raised concerns that some of these materials may introduce new risks for humans or the environment. A clear definition to discriminate nanomaterials from other materials is prerequisite to include provisions for nanomaterials in legislation. In October 2011 the European Commission published the ‘Recommendation on the definition of a nanomaterial’, primarily intended to provide unambiguous criteria to identify materials for which special regulatory provisions might apply, but also to promote consistency on the interpretation of the term ‘nanomaterial’. In this paper, the current status of various regulatory frameworks of the European Union with regard to nanomaterials is described, and major issues relevant for regulation of nanomaterials are discussed. This will contribute to better understanding the implications of the choices policy makers have to make in further regulation of nanomaterials. Potential issues that need to be addressed and areas of research in which science can contribute are indicated. These issues include awareness on situations in which nano-related risks may occur for materials that fall outside the definition, guidance and further development of measurement techniques, and dealing with changes during the life cycle.     

Oxidation of Therapeutic Proteins and Peptides: Structural and Biological Consequences

Oxidation is a common degradation pathway that affects therapeutic proteins and peptides during production, purification, formulation, transportation, storage and handling of solid and liquid preparations. In the present work we review the scientific literature about structural and biological consequences of protein/peptide oxidation. Representative examples are discussed of specific products whose oxidation has been recently studied, including monoclonal antibodies, calcitonin, granulocyte colony-stimulating factor, growth hormone, insulin, interferon alpha and beta, oxytocin and parathyroid hormone. These examples illustrate that oxidation often leads to modifications of higher-order structures, including aggregate induction, and can generate products that are pharmacokinetically different, biologically less active and/or potentially more immunogenic than their native counterpart. It is therefore crucially important during the pharmaceutical development of therapeutic proteins and peptides to comprehensively characterize oxidation products and evaluate the impact of oxidation-induced structural modifications on the biological properties of the drug.     

The Impact of Food Assistance on Dietary Diversity and Food Consumption among People Living with HIV/AIDS

Little is known about the outcomes of food assistance targeted to food insecure people living with HIV/AIDS. Using primary data from Zambia, we estimated the impact of food assistance on the dietary diversity and consumption expenditures of households with HIV infected members receiving antiretroviral therapy. Propensity score matching estimates show that food assistance increased dietary diversity by 9.8 points (23%) mainly through the consumption of food items provided in the ration. Food assistance recipients were 20% points more likely to have acceptable food consumption and 15% points less likely to have poor food consumption than non-recipients. Food assistance also increased food consumption expenditures but had no significant impact on food purchases and total consumption expenditures. Overall, our findings demonstrate that food assistance can be an effective instrument for improving diets and enhancing the food security of people living with HIV/AIDS.