The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma.

BACKGROUND: For patients with peripheral T-cell lymphoma (PTCL), outcomes using frontline treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapy are typically poor. The ECHELON-2 study demonstrated that brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) exhibited statistically superior progression-free survival (PFS) per independent central review and improvements in overall survival versus CHOP for the frontline treatment of patients with systemic anaplastic large cell lymphoma or other CD30-positive PTCL. PATIENTS AND METHODS: ECHELON-2 is a double-blind, double-dummy, randomized, placebo-controlled, active-comparator phase III study. We present an exploratory update of the ECHELON-2 study, including an analysis of 5-year PFS per investigator in the intent-to-treat analysis group. RESULTS: A total of 452 patients were randomized (1 : 1) to six or eight cycles of A+CHP (N = 226) or CHOP (N = 226). At median follow-up of 47.6 months, 5-year PFS rates were 51.4% [95% confidence interval (CI): 42.8% to 59.4%] with A+CHP versus 43.0% (95% CI: 35.8% to 50.0%) with CHOP (hazard ratio = 0.70; 95% CI: 0.53-0.91), and 5-year overall survival (OS) rates were 70.1% (95% CI: 63.3% to 75.9%) with A+CHP versus 61.0% (95% CI: 54.0% to 67.3%) with CHOP (hazard ratio = 0.72; 95% CI: 0.53-0.99). Both PFS and OS were generally consistent across key subgroups. Peripheral neuropathy was resolved or improved in 72% (84/117) of patients in the A+CHP arm and 78% (97/124) in the CHOP arm. Among patients who relapsed and subsequently received brentuximab vedotin, the objective response rate was 59% with brentuximab vedotin retreatment after A+CHP and 50% with subsequent brentuximab vedotin after CHOP. CONCLUSIONS: In this 5-year update of ECHELON-2, frontline treatment of patients with PTCL with A+CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP, with a manageable safety profile, including continued resolution or improvement of peripheral neuropathy.

Combining electrokinetic transport and bioremediation for enhanced removal of crude oil from contaminated marine sediments: Results of a long-term, mesocosm-scale experiment.

Marine sediments represent an important sink of harmful petroleum hydrocarbons after an accidental oil spill. Electrobioremediation techniques, which combine electrokinetic transport and biodegradation processes, represent an emerging technological platform for a sustainable remediation of contaminated sediments. Here, we describe the results of a long-term mesocosm-scale electrobioremediation experiment for the treatment of marine sediments contaminated by crude oil. A dimensionally stable anode and a stainless-steel mesh cathode were employed to drive seawater electrolysis at a fixed current density of 11 A/m2. This approach allowed establishing conditions conducive to contaminants biodegradation, as confirmed by the enrichment of Alcanivorax borkumensis cells harboring the alkB-gene and other aerobic hydrocarbonoclastic bacteria. Oil chemistry analyses indicated that aromatic hydrocarbons were primarily removed from the sediment via electroosmosis and low molecular weight alkanes (nC6 to nC10) via biodegradation.

Beneficial effect of n-3 polyunsaturated fatty acids on inflammation and analgesic use in psoriatic arthritis: a randomized, double blind, placebo-controlled trial.

OBJECTIVE: This study aimed to investigate the effects of marine n-3 polyunsaturated fatty acids (PUFAs) on disease activity, use of analgesics, and inflammatory biomarkers in patients with psoriatic arthritis (PsA). METHOD: Patients with established PsA (n = 145) were investigated in a randomized, double-blind, placebo-controlled study. The participants received a supplement of 3 g n-3 PUFA/day or 3 g olive oil/day (control) for 24 weeks. Outcome measures for disease activity, use of analgesics, and leukotriene formation from activated granulocytes were assessed at baseline and at study end. RESULTS: In total, 145 patients were included and 133 completed the study. After 24 weeks, the n-3 PUFA group showed a decrease in Disease Activity Score (DAS28-CRP), 68 tender joint count, enthesitis score, and psoriasis area and severity index, although not significantly different from the controls. There was a significant reduction in non-steroidal anti-inflammatory drug (NSAID) and paracetamol use compared with controls (p = 0.04). In addition, the participants in the n-3 PUFA group had significantly lower formation of leukotriene B4 (p = 0.004) from stimulated granulocytes and significantly higher formation of leukotriene B5 (p < 0.001) compared with controls. CONCLUSION: The n-3 PUFA-supplemented group showed improvement in outcome measures for disease activity, although the difference between the groups was not statistically significant. However, use of NSAIDs and paracetamol was significantly reduced in the n-3 PUFA group compared to the control group. Finally, there was a significant decrease in leukotriene B4 formation in the n-3 PUFA group compared with controls.

An untargeted gas chromatography mass spectrometry metabolomics platform for marine polychaetes.

The development of an appropriate extraction method for untargeted environmental metabolomic analysis of marine polychaetes could promote their use for environmental monitoring purposes. To this end, we compared four extraction methods on the marine polychaete Nereis virens both exposed to crude oil and non-exposed. XCMS was used for feature detection and preprocessing; different normalization and scaling approaches were tested; and principal component analysis (PCA) was used together with basic statistical tests to ascertain common metabolic patterns and determine the most suitable extraction method. We conclude that a two-step extraction procedure with 80:20 (v/v) methanol:water on freeze dried polychaete tissue provides the best trade-off between analysis time, and extraction efficiency and intermediate reproducibility. No definitive conclusions could be drawn about the ability of the method to discriminate controls and crude oils in actual biological replicates because the experiment was carried out by design on analytical replicates only. We show that the normalization to the sum of all the common features, and the use of a weighted least squares criterion to fit the PCA by means of scaling to the median absolute deviation (MAD) of the pooled quality control samples significantly improved the clustering of controls and crude oil exposed samples. The scaling alone led to an increase of 19% in explained variance compared to ordinary PCA.

Baseline patterns of adipose tissue fatty acids and long-term risk of breast cancer: a case-cohort study in the Danish cohort Diet, Cancer and Health.

BACKGROUND/OBJECTIVES: The evidence regarding fatty acids and breast cancer risk is inconclusive. Adipose tissue fatty acids can be used as biomarkers of fatty acid intake and of endogenous fatty acid exposure. Fatty acids in adipose tissue are correlated owing to common dietary sources and shared metabolic pathways, which group fatty acids into naturally occurring patterns. We aimed to prospectively investigate associations between adipose tissue fatty acid patterns and long-term risk of total breast cancer and breast cancer subtypes characterised by oestrogen and progesterone receptor status (ER and PR). SUBJECTS/METHODS: This case-cohort study was based on data from the Danish cohort Diet, Cancer and Health. At baseline, a fat biopsy and information on lifestyle and reproductive factors were collected. From the 31 original fatty acids measured, patterns of fatty acids were identified using the treelet transform. During a median follow-up of 5.3 years, 474 breast cancer cases were identified. Hazard ratios and 95% confidence intervals of risk of total breast cancer and of subtypes according to quintiles of factor score were determined by weighted Cox proportional hazards regression. RESULTS: After adjustment for potential confounders, factor scores for the seven patterns identified by the treelet transform were not associated with risk of total breast cancer, nor with risk of ER+, ER-, PR+ or PR- tumours. CONCLUSIONS: No clear associations between the patterns of fatty acids at baseline and long-term risk of total breast cancer or ER+, ER-, PR+ or PR- tumours were observed.

Fish oil-supplementation from 9 to 12 months of age affects infant attention in a free-play test and is related to change in blood pressure.

INTRODUCTION: This intervention examined whether fish-oil-supplementation in late infancy modifies free-play test scores and if this is related to blood pressure (BP) and mean RR interval. PATIENTS AND METHODS: 83 Danish 9-month-old infants were randomized to ±fish oil (FO) (3.4±1.1mL/d) for 3months and 61 of these completed the free-play-test before and after the intervention. RESULTS: Most of the free-play scores changed during the intervention, but the intervention affected only the number of looks away from the toy, which was increased in +FO and decreased in -FO (p=0.037). The increased numbers of looks away were associated with an increase in erythrocyte eicosapentaenoic acid (r=0.401, p=0.017, n=35) and were also associated with a decrease in systolic-BP (r=-0.511, p<0.001, n=52). CONCLUSIONS: The results indicate that n-3 fatty acid intake also in late infancy can influence brain development and that the cognitive and cardiovascular effects may be related.

Fluorochemicals used in food packaging inhibit male sex hormone synthesis.

Polyfluoroalkyl phosphate surfactants (PAPS) are widely used in food contact materials (FCMs) of paper and board and have recently been detected in 57% of investigated materials. Human exposure occurs as PAPS have been measured in blood; however knowledge is lacking on the toxicology of PAPS. The aim of this study was to elucidate the effects of six fluorochemicals on sex hormone synthesis and androgen receptor (AR) activation in vitro. Four PAPS and two metabolites, perfluorooctanoic acid (PFOA) and 8:2 fluorotelomer alcohol (8:2 FTOH) were tested. Hormone profiles, including eight steroid hormones, generally showed that 8:2 diPAPS, 8:2 monoPAPS and 8:2 FTOH led to decreases in androgens (testosterone, dehydroepiandrosterone, and androstenedione) in the H295R steroidogenesis assay. Decreases were observed for progesterone and 17-OH-progesterone as well. These observations indicated that a step prior to progestagen and androgen synthesis had been affected. Gene expression analysis of StAR, Bzrp, CYP11A, CYP17, CYP21 and CYP19 mRNA showed a decrease in Bzrp mRNA levels for 8:2 monoPAPS and 8:2 FTOH indicating interference with cholesterol transport to the inner mitochondria. Cortisol, estrone and 17ß-estradiol levels were in several cases increased with exposure. In accordance with these data CYP19 gene expression increased with 8:2 diPAPS, 8:2 monoPAPS and 8:2 FTOH exposures indicating that this is a contributing factor to the decreased androgen and the increased estrogen levels. Overall, these results demonstrate that fluorochemicals present in food packaging materials and their metabolites can affect steroidogenesis through decreased Bzrp and increased CYP19 gene expression leading to lower androgen and higher estrogen levels.

No effect of high-dose atorvastatin on leukotriene B4 formation from neutrophils in patients treated with coronary bypass surgery: a randomized placebo-controlled double-blinded trial with a crossover design.

Inflammation plays a pivotal role in the pathophysiology of cardiovascular disease, (CVD) and leukotrienes may play a role in atherogenesis. Statins reduce mortality from CVD by reducing LDL cholesterol and potentially by other (pleiotropic) mechanisms. The aim of this study was to investigate if atorvastatin exerts an anti-inflammatory effect by reducing leukotriene B4 (LTB4) formation from stimulated neutrophils in patients treated with coronary artery bypass grafting. The study was a randomized, placebo-controlled, double-blinded crossover study. Patients (n=80) were allocated to 80 mg atorvastatin or placebo for 6 weeks before crossing over to the opposite treatment for another 6 weeks. There was no significant correlation between baseline LDL cholesterol levels on formation of LTB4, and atorvastatin had no effect on LTB4 formation. Hence, this study does not support any effect of atorvastatin on LTB4 formation as part of the explanation for its beneficial effect on CVD.

Chemometric analysis of gas chromatography with flame ionisation detection chromatograms: a novel method for classification of petroleum products.

Most oil characterisation procedures are time consuming, labour intensive and utilise only part of the acquired chemical information. Oil spill fingerprinting with multivariate data processing represents a fast and objective evaluation procedure, where the entire chromatographic profile is used. Methods for oil classification should be robust towards changes imposed on the spill fingerprint by short-term weathering, i.e. dissolution and evaporation processes in the hours following a spill. We propose a methodology for the classification of petroleum products. The method consists of: chemical analysis; data clean-up by baseline removal, retention time alignment and normalisation; recognition of oil type by classification followed by initial source characterisation. A classification model based on principal components and quadratic discrimination robust towards the effect of short-term weathering was established. The method was tested successfully on real spill and source samples.

Influence of smoking parameters on the concentration of polycyclic aromatic hydrocarbons (PAHs) in Danish smoked fish.

A new method for the analysis of 25 polycyclic aromatic hydrocarbon (PAH) compounds in fish was developed, validated, and used for the quantification of PAHs in 180 industrially smoked fish products. The method included pressurized liquid extraction, gel-permeation chromatography (Bio-beads S-X3), solid-phase extraction (silica gel), and gas chromatography-mass spectrometry analysis. The sum concentration of 25 PAHs ([summation operator]PAH(25)) was highest in smoked herring (n = 3) and mackerel fillets (n = 13), with an average concentration of 320 and 235 microg kg(-1), respectively. Lowest average [summation operator]PAH(25) concentrations were obtained for indirectly smoked trout (26 microg kg(-1)). Principal component analysis was used to correlate processing parameters to PAH concentrations and to identify the effects of these parameters. The analysis showed that for salmon hot-smoking conditions lead to higher SigmaPAH(25) than cold smoking, and for other fish species direct smoking leads to higher SigmaPAH(25) than indirect smoking. Also, the usage of common alder increases the PAH contamination compared with beech. The effects of smoking time, combustion temperatures, and two types of smoke-generating material on the [summation operator]PAH(25) were also tested in a pilot plant study with smoked trout as a model fish. In addition to confirming that increased combustion temperatures and usage of common alder in comparison with beech increased [summation operator]PAH(25), it was also revealed that the PAH concentration decreased in the order fish skin >> outer layer of the fish muscle > inner part of the fish muscle.

Marine n-3 fatty acids, wine intake, and heart rate variability in patients referred for coronary angiography.

BACKGROUND: Dietary n-3 polyunsaturated fatty acids (PUFAs) derived from fish may reduce the incidence of sudden cardiac death (SCD). In addition, wine drinking is suggested to have a protective effect against cardiovascular death. METHODS AND RESULTS: We included 291 patients referred for coronary angiography in whom ischemic heart disease was suspected and all of whom completed a food questionnaire regarding fish and wine intake. The n-3 PUFA composition of granulocyte membranes and of adipose tissue was measured. In addition, 24-hour heart rate variability (HRV) was analyzed. Fish intake was positively associated with the level of n-3 PUFAs in adipose tissue. Significant positive correlation coefficients were found between HRV indices and the levels of n-3 PUFAs in granulocytes. Wine intake was also significantly positively related to HRV, but the patients with the highest wine intake also had the highest intake of fish, as documented by a high n-3 PUFA content in adipose tissue. Multiple linear regression analysis revealed that traditional factors such as treatment with ss-blockers, smoking, age, and previous myocardial infarction were independently related to HRV, and furthermore that n-3 PUFAs (but not wine intake) were significantly independently associated with HRV. CONCLUSIONS: The close positive association between n-3 PUFAs and HRV in patients suspected of having ischemic heart disease may indicate a protective effect of n-3 PUFAs against SCD. This may partly explain the reduction in SCD observed in humans with a modest intake of n-3 PUFA. Wine intake was also positively correlated with HRV, but this correlation was no longer significant after controlling for the cellular level of n-3 PUFA.

Alpha-linolenic acid and heart rate variability.

BACKGROUND AND AIM: The marine long-chained n-3 polyunsaturated fatty acids seem to have antiarrhythmic effects in humans. Similar effect has also been postulated for alpha-linolenic acid, a plant-derived polyunsaturated fatty acid--from the n-3 family. The purpose of the study was to examine the relation between the content of alpha-linolenic acid in cell membranes and the risk of malignant arrhythmias as assessed by determination of heart rate variability (HRV). METHODS AND RESULTS: Patients at high risk of sudden cardiac death (52 with a previous myocardial infarction and 29 with chronic renal failure on dialysis) were enrolled as well as 64 healthy volunteers. The cell membrane content of alpha-linolenic acid was analyzed by gas chromatography and related to 24-hour HRV, which was measured in all subjects. No correlations were found between levels of alpha-linolenic acid and 24-hour HRV. CONCLUSION: The present study was unable to demonstrate a positive correlation between cell membrane levels of alpha-linolenic acid and HRV. Our results suggest that alpha-linolenic acid per se is devoid of an antiarrhythmic effect, though this effect could arise from its conversion to the longer chained n-3 PUFA, usually derived from fish.

Subacute cor pulmonale due to microscopic pulmonary tumour cell embolization.

A case of a clinically occult ovarian carcinoma leading to subacute cor pulmonale in a 62-year-old woman is described. The patient was admitted to hospital with increasing respiratory distress. Physical examination and echocardiography showed signs of pulmonary hypertension. She died from circulatory failure. Autopsy revealed a bilateral ovarian carcinoma with diffuse carcinosis of the peritoneum. No gross evidence of pulmonary embolism was present, but microscopic investigation revealed tumour-related microangiopathic lesions causing the lethal pulmonary hypertension.

ACE inhibitor premedication attenuates sympathetic responses during surgery.

We studied cardiovascular and catecholamine responses for 3 days in three groups of patients undergoing abdominal hysterectomy. The night before surgery and again 2 h before induction of anaesthesia, patients received the ACE inhibitor, ramipril, the beta 1 blocker, metoprolol, or placebo. In the actively treated groups, mean diastolic pressure was reduced during surgery and increases in heart rate and arterial pressure after surgical incision were attenuated. During operation, stroke volume (SV) and cardiac output (CO) were significantly higher in the ramipril group. In contrast, beta 1, adrenergic block caused no significant changes in SV or CO. The concentration of noradrenaline in plasma and urine indicated that ACE inhibition caused attenuated release of noradrenaline. The results support the concept that angiotensin II facilitates release of noradrenaline from sympathetic nerves and that ACE inhibition inhibits this release.

[Combination therapy with pamidronate and calcitonin in hypercalcemic crisis caused by primary hyperparathyroidism]. / Kombinationsterapi med pamidronat og kalcitonin i behandlingen af hyperkalcaemisk krise forårsaget af primaer hyperparatyreoidisme.

Pamidronate (aminopropylidene diphosphonate, APD) is known to be an effective agent in lowering plasma calcium in cancer associated hypercalcaemia and in primary hyperparathyroidism. Combined therapy with pamidronate and calcitonin has proved efficient in the treatment of severe cancer-associated hypercalcaemia. A 66-year-old woman in hypercalcaemic crisis caused by primary hypreparathyroidism was successfully treated with this combined therapy. Albumin corrected plasma calcium was 5.26 mmol/l on arrival and the PTH level was very high. The combined therapy lowered the plasma calcium to normal and made it possible to perform elective parathyreoidectomy. A 5.8 g parathyroid adenoma was removed. It is recommended to consider combined therapy with pamidronate and calcitonin in the emergency management of hypercalcaemic crisis.

[Angiotensin I converting inhibitors in connection with anesthesia and surgery]. / Angiotensin I konverteringshaemmere i forbindelse med anaestesi og operation.

The renin angiotensin system is activated during anaesthesia and operation, and the degree to which this activation takes place depends on the hydration and circulation of the patient. The anaesthetic agent used is also important for the activation. Treatment with ACE-inhibitors blunts or abolishes the sympathetic response to anaesthesia/operation. ACEI treatment reduces the need for other hypotensive agents in controlled hypotensive anaesthesia. Some studies suggest that ACEI-treatment should be continued peroperatively on account of its stabilising effect on the circulation to avoid sudden fluctuations in blood pressure and organ perfusion. On the other hand measurements of the cerebral blood flow under anaesthesia in patients treated with ACEI have shown low values in a few patients and this led the authors to recommend discontinuation before anaesthesia. We conclude that controlled clinical trials to evaluate the haemodynamic and neurohumoral consequences of the interaction between ACEI and anaesthetics are required.

Immunologic observations in close relatives of two sisters with mammary Burkitt's lymphoma. Mammary Burkitt's lymphoma in sisters.

In a sibship of four sisters, two had Burkitt's lymphoma localized to the breast. Their pretreatment Epstein-Barr virus (EBV) serology were not examined. No EBV genome was demonstrated in the tumors using an in situ hybridization technique. The mother showed an abnormal antibody response to EBV infection consisting of elevated IgA and IgG antibody titers to viral capsid antigen (VCA) and high IgG antibody titer to early antigen. Furthermore, one of the two healthy sisters showed elevated IgG antibody titer to VCA. The EBV serology is mimicking the findings in female carriers of the X-linked lymphoproliferative syndrome.