Phosphorylation of intracellular signalling molecules in peripheral blood cells from patients with psoriasis on originator or biosimilar infliximab.

BACKGROUND: Psoriasis vulgaris is a chronic, inflammatory skin disease characterized by a dysregulated immune response and it is associated with substantial systemic comorbidities. Biological drugs such as tumour necrosis factor (TNF)-α inhibitors can ameliorate the disease but are expensive. Biosimilar drugs have the same amino-acid sequence as the originator, but differences in manufacturing can affect biological activity, efficacy and tolerability. OBJECTIVES: To explore potential differences in intracellular phosphorylation of signalling molecules in peripheral blood cells from patients with psoriasis treated with the TNF-α inhibitor infliximab compared with healthy controls, and to investigate if the phosphorylation pattern was influenced by switching from the originator infliximab to the biosimilar CT-P13. METHODS: By flow cytometry, we measured phosphorylation of nuclear factor kappa B, extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase and signal transducer and activator of transcription 3, before and after TNF-α stimulation in monocytes and T, B, natural killer and CD3+  CD56+ cells from 25 patients with psoriasis treated with infliximab and 19 healthy controls. RESULTS: At inclusion, phosphorylation levels of peripheral blood mononuclear cells (PBMCs) were increased in patients with psoriasis compared with healthy controls, even though clinical remission had already been achieved. Phosphorylation levels declined in patients on both originator infliximab and biosimilar during continued treatment. No significant differences were detected between the two medications after 12 months. CONCLUSIONS: Patients with psoriasis on infliximab have higher activation levels of PBMCs than do healthy controls, possibly reflecting systemic inflammation. Switching from the originator infliximab to biosimilar CT-P13 did not affect phosphorylation levels or clinical parameters, suggesting that CT-P13 is a noninferior treatment alternative to the originator infliximab.

Growth rates of pulmonary metastases after liver transplantation for unresectable colorectal liver metastases.

BACKGROUND: The previously reported SECA study demonstrated a dramatic 5-year survival improvement in patients with unresectable colorectal liver metastases (CLM) treated with liver transplantation (LT) compared with chemotherapy. The objective of this study was to assess whether immunosuppressive therapy accelerates the growth of pulmonary metastases in patients transplanted for unresectable CLM. METHODS: Chest CT scans from 11 patients in the SECA study resected for 18 pulmonary metastases were reviewed retrospectively. Tumour diameter, volume and CT characteristics were registered and tumour volume doubling time was calculated. Findings in the SECA group were compared with those of a control group consisting of 12 patients with non-transplanted rectal cancer resected for 26 pulmonary metastases. Disease-free survival (DFS) and overall survival (OS) after first pulmonary resection were determined. RESULTS: Median doubling time based on tumour diameter and volume in the SECA and control groups were 125 and 130 days (P = 0·658) and 110 and 129 days (P = 0·632) respectively. The metastases in both groups were distributed to all lung lobes and were mostly peripheral. Median DFS after LT in the SECA group and after primary pelvic surgery in the control group was 17 (range 6-42) and 18 (2-57) months respectively (P = 0·532). In the SECA group, estimated 5-year DFS and OS rates after first pulmonary resection were 39 and 51 per cent respectively. CONCLUSION: Patients treated by LT for unresectable CLM have a good prognosis following resection of pulmonary metastases. Doubling time did not appear to be worse with the immunosuppression used after LT.

Assays for Infliximab Drug Levels and Antibodies: A Matter of Scales and Categories.

Immunogenicity is a frequent cause of secondary non-response to tumour necrosis factor (TNF) inhibitors. Drug level measurement and detection of antidrug antibodies have been shown to be cost effective and clinically relevant, and a large number of assays are available for these purposes. It is, however, difficult to compare assays and translate results into clinical meaningful information due to different methodological approaches and a lack of assay standardization. We have analysed infliximab drug levels and antidrug antibodies in 107 patient samples using enzyme-linked immunoassays (ELISA), immunofluorometric assays (IFMA) and reporter-gene assays (RGA). The RGA gave the lowest results for drug levels, whereas the IFMA detected the highest number of antidrug antibody positive sera. Applying individualized therapeutic ranges to each assay resulted in agreement among all three assays in 74% of samples for drug levels and 98% of samples for antidrug antibodies. We found that TNF inhibitor monitoring assays measure on different scales and that the agreement between quantitative results is limited. However, interassay differences can partially be overcome by assay-individualized translations of quantities into categories, which also is necessary for a meaningful clinical application. Our data demonstrate that assays should not be used interchangeably and that direct comparison of quantitative drug levels obtained with different assays should be avoided.

High number of kinome-mutations in non-small cell lung cancer is associated with reduced immune response and poor relapse-free survival.

Lung cancer is the leading cause of cancer related death, and the past years' improved insight into underlying molecular events has significantly improved outcome for specific subsets of patients. In particular, several new therapies that target protein kinases have been implemented, and many more are becoming available. We have investigated lung cancer specimens for somatic mutations in a targeted panel of 612 human genes, the majority being protein kinases. The somatic mutation profiles were correlated to profiles of immune cell infiltration as well as relapse-free survival. Targeted deep sequencing was performed on 117 tumour/normal pairs using the SureSelect Human Kinome kit (Agilent Technologies), with capture probes targeting 3.2 Mb of the human genome, including exons and untranslated regions of all known kinases, kinase receptors and selected cancer-related genes (612 genes in total). CD8 staining was determined using Ventana Benchmark. Survival analyses were performed using SPSS. The number of mutations per sample ranged from 0 to 50 (within the 612 genes tested), with a median of nine. The prognosis was worse for patients with more than the median number of mutations. A significant correlation was found between mutations in one of selected DNA-repair genes and the total number of mutations in that tumour (p < 0.001). There was a significant inverse correlation between the number of infiltrating stromal CD8+ lymphocytes and the presence of EGFR mutations.

Strategies for clinical implementation of TNM-Immunoscore in resected nonsmall-cell lung cancer.

Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates and appears highly promising as a supplement to the tumor-node-metastasis (TNM) classification of various tumors. In colorectal cancer, an international task force has initiated prospective multicenter studies aiming to implement TNM-Immunoscore (TNM-I) in a routine clinical setting. In breast cancer, recommendations for the evaluation of tumor-infiltrating lymphocytes (TILs) have been proposed by an international working group. Regardless of promising results, there are potential obstacles related to implementing TNM-I into the clinic. Diverse methods may be needed for different malignancies and even within each cancer entity. Nevertheless, a uniform approach across malignancies would be advantageous. In nonsmall-cell lung cancer (NSCLC), there are several previous reports indicating an apparent prognostic importance of TILs, but studies on TILs in a TNM-I setting are sparse and no general recommendations are made. However, recently published data is promising, evoking a realistic hope of a clinical useful NSCLC TNM-I. This review will focus on the TNM-I potential in NSCLC and propose strategies for clinical implementation of a TNM-I in resected NSCLC.

Modelling atmospheric oxidation of 2-aminoethanol (MEA) emitted from post-combustion capture using WRF-Chem.

Carbon capture and storage (CCS) is a technological solution that can reduce the amount of carbon dioxide (CO2) emissions from the use of fossil fuel in power plants and other industries. A leading method today is amine based post-combustion capture, in which 2-aminoethanol (MEA) is one of the most studied absorption solvents. In this process, amines are released to the atmosphere through evaporation and entrainment from the CO2 absorber column. Modelling is a key instrument for simulating the atmospheric dispersion and chemical transformation of MEA, and for projections of ground-level air concentrations and deposition rates. In this study, the Weather Research and Forecasting model inline coupled with chemistry, WRF-Chem, was applied to quantify the impact of using a comprehensive MEA photo-oxidation sequence compared to using a simplified MEA scheme. Main discrepancies were found for iminoethanol (roughly doubled in the detailed scheme) and 2-nitro aminoethanol, short MEA-nitramine (reduced by factor of two in the detailed scheme). The study indicates that MEA emissions from a full-scale capture plant can modify regional background levels of isocyanic acid. Predicted atmospheric concentrations of isocyanic acid were however below the limit value of 1 ppbv for ambient exposure. The dependence of the formation of hazardous compounds in the OH-initiated oxidation of MEA on ambient level of nitrogen oxides (NOx) was studied in a scenario without NOx emissions from a refinery area in the vicinity of the capture plant. Hourly MEA-nitramine peak concentrations higher than 40 pg m(-3) did only occur when NOx mixing ratios were above 2 ppbv. Therefore, the spatial variability and temporal variability of levels of OH and NOx need to be taken into account in the health risk assessment. The health risk due to direct emissions of nitrosamines and nitramines from full-scale CO2 capture should be investigated in future studies.

Carotid atherosclerosis and relation to growth of infrarenal aortic diameter and follow-up diameter: the Tromsø Study.

OBJECTIVES: This research aims to study how carotid atherosclerosis is related to growth of infrarenal aortic diameter and aneurysmal formation. DESIGN: Population-based follow-up study. MATERIALS AND METHODS: At baseline, ultrasound examination of the carotid artery and the abdominal aorta was performed in 4241 persons from a general population with no evidence of abdominal aortic aneurysm (AAA). The burden of atherosclerosis was assessed as carotid total plaque area (TPA). After a mean follow-up of 6.3 years, a new ultrasound examination was performed and measurements of the aortic diameter and carotid TPA were repeated. The effects on aortic diameter progression, follow-up diameter and risk for AAA were assessed in multiple linear and logistic regression models according to carotid TPA, adjusted for known risk factors. RESULTS: When analysing AAA as a dichotomous variable, a borderline association between atherosclerosis and AAA could be demonstrated. When modelling aortic diameter as a continuous variable, a 1-SD increase in 5 years' carotid plaque area (ΔTPA) was associated with a 0.12-mm growth in infrarenal aortic diameter (standard error (SE) 0.04) and a 0.20-mm wider aorta at follow-up (SE 0.06). No independent relation was seen for baseline atherosclerosis. CONCLUSIONS: Carotid plaque progression was positively related to growth in infrarenal aortic diameter and aortic diameter at follow-up. Whether this co-variation between plaque growth and aortic diameter growth is causally related or independent events is still an open question.

Diameter of the infrarenal aorta as a risk factor for abdominal aortic aneurysm: the Tromsø Study, 1994-2001.

OBJECTIVES: We aim to study whether the diameter of the non-aneurysmatic infrarenal aorta influences the risk for abdominal aortic aneurysm (AAA) and whether the larger diameter in men can explain the male predominance in AAA. DESIGN: This is a population-based follow-up study. MATERIALS AND METHODS: In 4265 men and women with a normal-sized aorta in 1994-1995, 116 incident cases of AAA were diagnosed 7 years later. The risk of an incident AAA was analysed in a multiple logistic regression model according to baseline maximal infrarenal aortic diameter, adjusted for known risk factors. RESULTS: Compared with subjects with aortic diameter in the 21-23 mm bracket, men and women with a diameter <18mm and > or =27mm had an adjusted odds ratio (OR) of 0.30 (95% confidence interval (CI): 0.10-0.88) and 4.22 (95% CI: 1.94-9.19), respectively, for an incident AAA. When adjusted for age and baseline aortic diameter, male sex was not statistically significantly associated with the incidence of AAA (OR=1.45, 95% CI: 0.93-2.30, P=0.10). CONCLUSIONS: Increased baseline diameter of the infrarenal aorta was a highly significant, strong and independent risk factor for developing an AAA. The larger aortic diameter in men than in women may be the most important explanation for the higher AAA risk in men.

Increased growth rate of abdominal aortic aneurysms in women. The Tromsø study.

OBJECTIVES: The present study was undertaken in order to assess the effect of gender on the growth rate of abdominal aortic aneurysms (AAAs). METHODS: One hundred and eighty-five men and 49 women with AAAs were studied, mean follow-up 62 months, giving 14,544 patient-months of follow-up. A mean of 16 ultrasound examinations was performed on each patient. RESULTS: The mean growth rate was 1.82; 1.65 and 2.43 mm per year in men and women, respectively. In a weighted linear regression analysis, high initial diameter and female gender were independent and significant (p < 0.001 and p = 0.003, respectively) predictors for increased growth rate of AAAs. None of the other considered risk factors predicted the growth rate. CONCLUSIONS: This is the first study to report a significantly different growth rate of AAAs in females compared to males. It, thus, adds evidence to the view that AAA is a more malignant condition in females than in males and could have implications for the frequency of follow-up in women.

The difference between ultrasound and computed tomography (CT) measurements of aortic diameter increases with aortic diameter: analysis of axial images of abdominal aortic and common iliac artery diameter in normal and aneurysmal aortas. The Tromsø Study, 1994-1995.

OBJECTIVE: To assess agreement between ultrasound and computed tomography (CT) measurements from axial images of normal and aneurysmatic aortic and common iliac artery diameter. DESIGN: Part of a population health screening for abdominal aortic aneurysm conducted in 1994-1995. MATERIALS AND METHODS: Three hundred and thirty-four subjects with and 221 subjects without ultrasound-detected aneurysm were scanned with CT. Three technicians and one radiologist measured ultrasonographic diameters and five radiologists measured CT diameters. The paired ultrasound-CT measurement differences were analyzed to assess agreement. RESULTS: Compared to CT measurements, ultrasound slightly underestimated the diameter in normal aortas and tended to overestimate the diameter in aneurysmal aortas. In 555 ultrasound-CT pairs of measurements, the absolute differences for measurements of maximal aortic diameter were 2 mm or less in 62, 60 and 77% in anterior-posterior, transverse and maximum diameter in any plane, respectively. The corresponding figures for an absolute difference of 5 mm or more were 14, 18 and 8%, respectively. Variability increased with increasing diameter. CONCLUSIONS: Both ultrasound and CT measurements of abdominal aortic diameter are liable to variability and neither of these methods can be considered to be 'gold standard'. Both methods can be used, while taking variability into consideration when making clinical decisions.

Intra- and interobserver variability in the measurements of abdominal aortic and common iliac artery diameter with computed tomography. The Tromsø study.

OBJECTIVES: to assess intra- and interobserver variability in the measurement of aortic and common iliac artery diameter by means of computed tomography (CT). DESIGN: reproducibility study. MATERIAL AND METHODS: three radiologists performed measurements of aortic diameter at five different levels and of both common iliac arteries with CT. Fifty-nine subjects were examined, 29 with and 30 without abdominal aortic aneurysms (AAA) as assessed by ultrasound. RESULTS: intraobserver variability varied between radiologists, measurement plane (anterior-posterior vs transverse) and measurement level. The interobserver variability was markedly higher at the bifurcation than at the suprarenal level and higher than intraobserver variability for measurements at all levels. Both intraobserver and interobserver variability increased with increasing vessel diameter and were largest in patients with AAA. The absolute intraobserver difference of the maximal infrarenal aortic diameter was 2mm or less in 94% of intraobserver pairs. The corresponding interobserver difference was 82%. CONCLUSIONS: interobserver variability of CT measurements of aortic and common iliac artery diameter is not negligible and should be taken into account when making clinical decisions. When assessing change in aortic diameter, previous CT-scans should be reviewed simultaneously as a routine to exclude interobserver variability.

Time series study of concentrations of SO4(2-) and H+ in precipitation and soil waters in Norway.

Along with a steady reduction of acid inputs during 14 years of intensive forest monitoring in Norway, the influence of acid deposition upon soil water acidity is gradually reduced in favour of other and internal sources of H+ and sulphate, in particular from processes in the upper soil layer. We used statistical analyses in two steps for precipitation, throughfall and soil water at 5, 15 and 40 cm depths. Firstly, we employed time series analyses to model the temporal variation as a long-term linear trend and a monthly variation, and by this filtered out residual, weekly variation. Secondly, we used the parameter estimates and the residuals from this to show that the long term, the monthly and the weekly variation in one layer were correlated to similar temporal variation in the above, adjacent layer. This was strongly evident for throughfall correlated to precipitation, but much weaker for soil water. Continued acidification in soil water on many plots suggests that the combined effects of anthropogenic and natural acid inputs exceed in places the buffering capacity of the soil.

Prevalence of and risk factors for abdominal aortic aneurysms in a population-based study : The Tromsø Study.

In a population-based study of 6,386 men and women aged 25--84 years in Tromsø, Norway, in 1994--1995, the authors assessed the age- and sex-specific distribution of the abdominal aortic diameter and the prevalence of and risk factors for abdominal aortic aneurysm. Renal and infrarenal aortic diameters were measured with ultrasound. The mean infrarenal aortic diameter increased with age. The increase was more pronounced in men than in women. The age-related increase in the median diameter was less than that in the mean diameter. An aneurysm was present in 263 (8.9%) men and 74 (2.2%) women (p < 0.001). The prevalence of abdominal aortic aneurysm increased with age. No person aged less than 48 years was found with an abdominal aortic aneurysm. Persons who had smoked for more than 40 years had an odds ratio of 8.0 for abdominal aortic aneurysm (95% confidence interval: 5.0, 12.6) compared with never smokers. Low serum high density lipoprotein cholesterol was associated with an increased risk for abdominal aortic aneurysm. Other factors associated with abdominal aortic aneurysm were a high level of plasma fibrinogen and a low blood platelet count. Antihypertensive medication (ever use) was significantly associated with abdominal aortic aneurysm, but high systolic blood pressure was a risk factor in women only. This study indicates that risk factors for atherosclerosis are also associated with increased risk for abdominal aortic aneurysm.

Intra- and interobserver variability in ultrasound measurements of abdominal aortic diameter. The Tromsø Study.

OBJECTIVES: To assess the variability of ultrasonographic measurements at different levels of the abdominal aorta. DESIGN: Reproducibility study as part of a population health screening for abdominal aortic aneurysm. MATERIALS AND METHODS: In 1994/1995 a total of 6892 subjects underwent ultrasound examination of the abdominal aorta. Variability of measurements was assessed in the beginning and end of the survey period by inviting 112 randomly selected participants to a second ultrasound scan within 3 weeks of the first scan. The subjects were examined by an experienced radiologist and three sonographers who had been given a short course in ultrasonography. All examiners were blinded to each other's results. RESULTS: Variability was similar in the beginning and end of the survey period. Both the intra- and interobserver variability were less than 4 mm for all sonographers in measurements of maximal infrarenal aortic diameter, and variability was similar for measurements in the anterior-posterior and transverse plane. Variability was greater for measurements at the renal level than aortic bifurcation level. The radiologist had lower variability than the other sonographers. CONCLUSION: Ultrasound measurements of the maximal diameter can be obtained with a high degree of accuracy. Inexperienced sonographers may achieve acceptable performance given appropriate training and surveillance.

[Curriculum vitae aortae]. / Curriculum vitae aortae.

The Greek word aorta means lifter. The vessel was so termed because Aristotle, who first described it, assumed that the heart was lifted by/hanging in aorta. Leonardo da Vinci described the detailed anatomy of aorta. During the 17th century our present understanding of the aorta and the circulation of blood took form due to the descriptions given by William Harvey. The first known operation for abdominal aortic aneurysm was performed in London in 1817 by Sir Astley Cooper who ligated the infrarenal aorta above the aneurysm. Puncture with needles and application of electricity were later tried in order to induce thromboses in the aneurysm. In 1948 Albert Einstein was operated with wrapping of his abdominal aneurysm with cellophane. In 1955 he suffered rupture and died after having refused operation. In 1951 the first successful operation for abdominal aortic aneurysm was performed in Paris by Charles Dubost. With slight modifications, the same operative technique is used today.

Crown condition of Norway spruce in relation to sulphur and nitrogen deposition and soil properties in southeast Norway.

Atmospheric deposition of sulphur and nitrogen compounds may lead to enhanced leaching of base cations, accumulation of nitrogen in organic matter, lowered pH and increased concentration of toxic aluminium in soil, which in turn may affect the vitality of forest trees. A general monitoring of forest condition has been initiated in many European countries, partly in order to reveal stresses caused by acidification. However, forest condition is also affected by many other factors. This paper examines a seven-year series of crown-condition data from Local County Monitoring Plots in Norway spruce stands in Norway. Average, time trend and lability variables were calculated for crown density and crown colour for each plot. Wet deposition of sulphate, ammonium and nitrate for each plot were estimated using data from the national air and precipitation monitoring programmes. Soil data are based on soil sampling within the plots. The analysis gave no evident support for the hypothesized negative effect on crown condition from sulphur and nitrogen deposition and related alterations in soil.