First-line oxaliplatin-based chemotherapy and nivolumab for metastatic microsatellite-stable colorectal cancer-the randomised METIMMOX trial.

BACKGROUND: We evaluated first-line treatment of metastatic microsatellite-stable colorectal cancer with short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade. METHODS: Patients were randomly assigned to chemotherapy (the FLOX regimen; control group) or alternating two cycles each of FLOX and nivolumab (experimental group). Radiographic response assessment was done every eight weeks with progression-free survival (PFS) as the primary endpoint. Cox proportional-hazards regression models estimated associations between PFS and relevant variables. A post hoc analysis explored C-reactive protein as signal of responsiveness to immune checkpoint blockade. RESULTS: Eighty patients were randomised and 38 in each group received treatment. PFS was comparable-control group: median 9.2 months (95% confidence interval (CI), 6.3-12.7); experimental group: median 9.2 months (95% CI, 4.5-15.0). The adjusted Cox model revealed that experimental-group subjects aged ≥60 had significantly lowered progression risk (p = 0.021) with hazard ratio 0.17 (95% CI, 0.04-0.76). Experimental-group patients with C-reactive protein <5.0 mg/L when starting nivolumab (n = 17) reached median PFS 15.8 months (95% CI, 7.8-23.7). One-sixth of experimental-group cases (all KRAS/BRAF-mutant) achieved complete response. CONCLUSIONS: The investigational regimen did not improve the primary outcome for the intention-to-treat population but might benefit small subgroups of patients with previously untreated, metastatic microsatellite-stable colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03388190 (02/01/2018).

The association of urine markers of iodine intake with development and growth among children in rural Uganda: a secondary analysis of a randomised education trial.

OBJECTIVE: We examined associations of urine iodide excretion, proxy for iodine intake, with child development and growth. DESIGN: This is a secondary analysis of a 1:1 cluster-randomised trial with a 6-month nutrition/stimulation/hygiene education intervention among mothers of children aged 6-8 months to improve child development and growth. Development was assessed using Bayley Scales of Infant and Toddler Development-III (BSID-III) and Ages and Stages Questionnaire (ASQ), whereas anthropometry was used to assess growth. Urine iodide concentration (UIC) and urine iodide/creatinine ratio (ICR) were measured. SETTING: The current study was conducted in southern Uganda. PARTICIPANTS: We randomly selected 155 children from the 511 enrolled into the original trial and analysed data when they were aged 20-24 and 36 months. RESULTS: Median UIC for both study groups at 20-24 and 36 months were similar (P > 0·05) and within the normal range of 100-199 µg/l (0·79-1·60 µmol/l), whereas the intervention group had significantly higher ICR at 20-24 months. The BSID-III cognitive score was positively associated (P = 0·028) with ICR at 20-24 months in the intervention group. The ASQ gross motor score was negatively associated (P = 0·020) with ICR at 20-24 months among the controls. ICR was not significantly associated with anthropometry in the two study groups at either time-point. CONCLUSIONS: Following the intervention, a positive association was noted between ICR and child's cognitive score at 20-24 months, whereas no positive association with ICR and growth was detected. Iodine sufficiency may be important for child's cognitive development in this setting.

Longitudinal plasma metabolic profiles, infant feeding, and islet autoimmunity in the MIDIA study.

AIMS: The aim of this study was to investigate the longitudinal plasma metabolic profiles in healthy infants and the potential association with breastfeeding duration and islet autoantibodies predictive of type 1 diabetes. METHOD: Up to four longitudinal plasma samples from age 3 months from case children who developed islet autoimmunity (n = 29) and autoantibody-negative control children (n = 29) with the HLA DR4-DQ8/DR3-DQ2 genotype were analyzed using two-dimensional gas chromatography coupled to a time-of-flight mass spectrometer for detection of small polar metabolites. RESULTS: Plasma metabolite levels were found to depend strongly on age, with fold changes varying up to 50% from age 3 to 24 months (p < 0.001 after correction for multiple testing). Tyrosine levels tended to be lower in case children, but this was not significant after correction for multiple testing. Ornithine levels were lower in case children compared with the controls at the time of seroconversion, but the difference was not statistically significant after correcting for multiple testing. Breastfeeding for at least 3 months as compared with shorter duration was associated with higher plasma levels of isoleucine, and lower levels of methionine and 3,4-dihydroxybutyric acid at 3 months of age. CONCLUSIONS: Plasma levels of several small, polar metabolites changed with age during early childhood, independent of later islet autoimmunity status and sex. Breastfeeding was associated with higher levels of branched-chain amino acids, and lower levels of methionine and 3,4-dihydroxybutyric acid.

HbA1c analysis by capillary electrophoresis - comparison with chromatography and an immunological method.

BACKGROUND: Haemoglobin A1c (HbA1c) has become an even more important analyte for clinical laboratories during recent years with the introduction of its diagnostic use for diabetes mellitus. Several different analytical principles can be used, each with their advantages and disadvantages. AIM: We wanted to compare Sebia Capillarys 2 Flex Piercing (Capillarys) with our routine HbA1c methods, which were an HPLC method (Tosoh G7) and an immunoassay (Tina-Quant on Roche Modular P) by analysing a large clinical material. Furthermore, we investigated sample stability. METHODS: HbA1c analysis was performed in parallel by all three methods for more than 600 patient samples including common and some rare haemoglobin variants, as well as for several controls, some with set target values. Sample stability at room temperature and refrigerated was assessed for up to seven days. RESULTS: Capillarys produced generally somewhat lower HbA1c values than both comparison methods, apparently due to positive bias for the comparison methods. Leaving out samples with haemoglobin variants, we found a mean bias (95% CI) for Capillarys compared to Tosoh G7 (without factorization) and Modular of -0.39 (-0.40 to -0.38) and -0.16 (-0.17 to -0.14) % HbA1c, respectively. HbA1c results were similar between instruments for samples from dialysis patients and for samples with heterozygous common haemoglobin variants, except that Tosoh G7 reported too low results in the presence of Hb E. For heterozygous Hb Raleigh, Capillarys and the immunoassay gave similar results. CONCLUSION: Capillarys is a convenient instrument for routine HbA1c analysis.

Analytical Bias Exceeding Desirable Quality Goal in 4 out of 5 Common Immunoassays: Results of a Native Single Serum Sample External Quality Assessment Program for Cobalamin, Folate, Ferritin, Thyroid-Stimulating Hormone, and Free T4 Analyses.

BACKGROUND: We undertook this study to evaluate method differences for 5 components analyzed by immunoassays, to explore whether the use of method-dependent reference intervals may compensate for method differences, and to investigate commutability of external quality assessment (EQA) materials. METHODS: Twenty fresh native single serum samples, a fresh native serum pool, Nordic Federation of Clinical Chemistry Reference Serum X (serum X) (serum pool), and 2 EQA materials were sent to 38 laboratories for measurement of cobalamin, folate, ferritin, free T4, and thyroid-stimulating hormone (TSH) by 5 different measurement procedures [Roche Cobas (n = 15), Roche Modular (n = 4), Abbott Architect (n = 8), Beckman Coulter Unicel (n = 2), and Siemens ADVIA Centaur (n = 9)]. The target value for each component was calculated based on the mean of method means or measured by a reference measurement procedure (free T4). Quality specifications were based on biological variation. Local reference intervals were reported from all laboratories. RESULTS: Method differences that exceeded acceptable bias were found for all components except folate. Free T4 differences from the uncommonly used reference measurement procedure were large. Reference intervals differed between measurement procedures but also within 1 measurement procedure. The serum X material was commutable for all components and measurement procedures, whereas the EQA materials were noncommutable in 13 of 50 occasions (5 components, 5 methods, 2 EQA materials). CONCLUSIONS: The bias between the measurement procedures was unacceptably large in 4/5 tested components. Traceability to reference materials as claimed by the manufacturers did not lead to acceptable harmonization. Adjustment of reference intervals in accordance with method differences and use of commutable EQA samples are not implemented commonly.

Urine NMR metabolomics analysis of breastfeeding biomarkers during and after pregnancy in a large prospective cohort study.

BACKGROUND: Modern metabolomic profiling has not yet been applied to human breastfeeding research. A common reason for breastfeeding cessation is perceived insufficient milk production. We investigated broad biochemical profiles in maternal urine collected during and after pregnancy to identify biomarkers related to reduced reported breastfeeding. METHODS: Fasting urine was collected at three consultations (visit V1: gestational week 8-20; V2: week 28 ± 2; V3: 10-16 weeks postpartum) in the STORK Groruddalen program, a prospective, multiethnic cohort study of gestational diabetes involving healthy, pregnant women in Oslo, Norway, and analyzed using NMR spectroscopy. Breastfeeding at V3 was recorded in three categories: Exclusively breastfeeding (n = 326), partially breastfeeding (n = 156) and formula feeding (n = 67). RESULTS: Five metabolites were relevant to breastfeeding. Lactose was detected at V1 and increased to 0.1 mM/mM creatinine at V2. Postpartum excretion at V3 was significantly higher in exclusively breastfeeding women than partially or non-breastfeeding (median = 0.29, 0.23 and 0.04 mM/mM creatine, respectively; ANOVA p-value = 2e-70). Glycine excretion at V3 (0.12, 0.10 and 0.06, respectively; p = 2e-5) and at V2 were associated with breastfeeding (0.34, 0.33 and 0.26, respectively; p = 4e-5). Creatine and two unidentified substances also correlated with breastfeeding. NMR metabolomics found no other metabolites differing between categories during pregnancy (V1, V2), and did not predict individual breastfeeding postpartum (V3). CONCLUSION: Decreased glycine excretion at V2 may indicate difficulties meeting the metabolic demands of the growing fetus, but urine profiles contained otherwise little indication of early adaptations during pregnancy towards reduced biological potential to breastfeed.

PCSK1N as a tumor size marker and an ER stress response protein in corticotroph pituitary adenomas.

PURPOSE: Silent corticotroph adenoma (SCA) exhibits more tumor aggressiveness features than functioning adenomas (FCA). We aimed to investigate PCSK1N expression in CA and examine if ER stress-induced responses affect cell survival in a corticotroph tumor cell model. METHODS: Clinical and imaging characteristics were recorded in 33 patients with FCA (20 women, 11 macroadenomas) and 18 SCA (8 women, all macroadenomas). Gene expression of proopiomelanocortin (POMC), T-box transcription factor 19(TBX19)/TPIT, proprotein convertase subtilisin/kexin type 1(PCSK1)/PC1/3, and its inhibitor PCSK1N, was measured by RT-qPCR in adenoma tissue.Mouse pituitary corticotroph tumor (AtT-20) cells were treated with tanespimycin (17-AAG), a HSP90 chaperone inhibitor, to induce ER stress, followed by gene and protein analyses. RESULTS: POMC, TPIT, and PCSK1 expression were higher, whereas PCSK1N was lower in FCA compared to SCA. PCSK1N correlated with POMC (rs= -0.514, p <0.001), TPIT (rs= -0.386, p = 0.005), PCSK1 (rs= -0.3691, p = 0.008), and tumor largest diameter (rs= 0.645, p <0.001), in all CA. Induction of ER stress by 17-AAG in AtT-20 cells led to a decrease of POMC and an increase of PCSK1N gene expression at 24h. Moreover, a downregulation of cell cycle, apoptosis, and senescence pathways, and alterations in cell adhesion and cytoskeleton were observed at the protein level. CONCLUSIONS: PCSK1N is higher in SCA compared with FCA, and associated with corticotroph cell markers and tumor size. PCSK1N is likely to be part of the adaptive response to ER stress, potentially conferring a survival advantage to the corticotroph tumor cell in conjunction with other proteins.

Glyoxalase 1 enzyme activity in erythrocytes and Ala111Glu polymorphism in type 1-diabetes patients.

AIMS/HYPOTHESIS: The enzyme glyoxalase 1 (GLO1) can inactivate the glycoxidation product methylglyoxal that is thought to be an important contributor to the pathogenesis of vascular complications in diabetes. We aimed to study erythrocyte GLO1 activity and whether the Ala111Glu GLO1 gene polymorphism affected GLO1 activity. METHODS: Fasting erythrocyte GLO1 activity was measured spectrophotometrically. The A111G gene polymorphism, assessed in DNA from leucocytes was analyzed in patients with type 1-diabetes and normal kidney function and compared with a control group. RESULTS: Sixty-one patients with type 1-diabetes duration of 26.1 (10.7) years, mean (SD) with a HbA1c of 7.8 (0.9)%, 61.7 (9.9) mmol/mol and normal glomerular filtration rate were compared with 62 age- and sex-matched healthy controls. GLO1 activity was 0.206 (0.183-0.231) median (25-75% percentiles) U/mg Hb in the control group vs. 0.192 (0.165-0.224) in the diabetes group, (p = 0.149). In the diabetes group GLO1 correlated with HbA1c (r = 0.33, p < 0.01) and oxidized glutathione (GSSG) (r = - 0.34, p < 0.01) and in the control group with GSH (r = 0.37, p < 0.005) and fasting glucose (r = 0.26, p < 0.04). In a multiple regression analysis with GLO1 activity as the dependent variable, including the Ala111Glu polymorphism, the significant independent variables were log GSSG (ß - 0.318, p = 0.02) and HbA1c (ß 0.285, p = 0.041) in the diabetes group and log GSH, (ß 0.407, p = 0.004) in the control group. CONCLUSIONS/INTERPRETATION: Erythrocyte glyoxalase 1 activity did not differ between patients with type 1-diabetes and controls. The Ala111Glu glyoxalase gene polymorphism did not have an effect on glyoxalase 1 activity in either group.