Radiation dose to multidisciplinary staff members during complex interventional procedures.

INTRODUCTION: Complex interventional radiology procedures involve extensive fluoroscopy and image acquisition while staff are in-room. Monitoring occupational radiation dose is crucial in optimization. The purpose was to determine radiation doses received by staff involved in complex interventional procedures performed in a dedicated vascular or neuro intervention room. METHODS: Individual real-time radiation dose for all staff involved in vascular and neuro-interventional procedures in adult patients was recorded over a one-year period using wireless electronic dosimeters attached to the apron thyroid shield. A reference dosimeter was attached to the C-arm near the tube housing to measure scattered, unshielded radiation. Radiology staff carried shoulder thermo-luminescent dosimeters with monthly read-out to monitor dose over time. RESULTS: Occupational radiation dose was measured in 99 interventional procedures. In many cases prostate artery embolization procedures exposed radiologists to high radiation doses with a median of 15.0 µSv and a very large spread, i.e. 0.2-152.5 µSv. In all procedures except uterine fibroid embolization radiographers were exposed to lower doses than those of radiologists, with endovascular aortic repair being the procedure with highest median exposure to assisting radiographers, i.e. 2.2 µSv ranging from 0.1 to 36.1 µSv. Median radiation dose for the reference dosimeter was 670 µGy while median staff dose for all procedures combined was 3.2 µGy. CONCLUSION: Radiation doses for multiple staff were determined and the ratio between staff dose and reference dosimeter indicated proper use of shielding in general. Some high-dose procedures may need further optimization for certain staff members, especially those not primarily employed in radiology. IMPLICATIONS FOR PRACTICE: The study provides benchmark doses that may be used widely in audits and in the ongoing effort to optimize radiation protection for staff in interventional radiology.

Aeromonas spp. isolated from ready-to-eat seafood on the Norwegian market: prevalence, putative virulence factors and antimicrobial resistance.

AIMS: We aim to investigate the prevalence, putative virulence factors and antimicrobial resistance of mesophilic Aeromonas isolated from ready-to-eat (RTE) seafood available on the Norwegian market, and to assess the potential risks by consuming RTE seafood to consumers. METHODS AND RESULTS: The prevalence of mesophilic Aeromonas in 148 RTE seafood was investigated and the highest prevalence was found in retail sushi (17%), followed by oysters (10%), fresh salmon loins (10%) and scallops (4%). Among 43 Aeromonas isolates, 75% of them were identified as A. media, 23% as A. salmonicida and 2% as A. bestiarum based on partial gryB gene sequencing. Aeromonas isolates were potentially pathogenic due to the presence of four virulence genes: alt (73%), hylA (22%), aerA (17%) and act (6%). In addition, all isolates were resistant to ampicillin and erythromycin. Most of the isolates (98%) were multidrug resistant. CONCLUSIONS: The occurrence of potentially pathogenic and multidrug-resistant Aeromonas strains in RTE seafood implies a potential risk to consumers. Our finding suggests that RTE seafood could be a potential vehicle for the transfer of virulent and multidrug-resistant Aeromonas. SIGNIFICANCE AND IMPACT OF THE STUDY: To our knowledge, this is the first study to report multiple antibiotic resistance in Aeromonas associated with RTE seafood in Norway.

Growth and spoilage metabolites production of a mesophilic Aeromonas salmonicida strain in Atlantic salmon (Salmo salar L.) during cold storage in modified atmosphere.

AIMS: The aim of the study was to quantify the growth kinetic parameters and spoilage-associated metabolites of an inoculated strain of Aeromonas salmonicida in pre-rigor filleted Atlantic salmon (Salmo salar L.) stored in vacuum (VP) or modified atmosphere (MAP 60/40% CO2 /N2 ) at 4 and 8°C. METHODS AND RESULTS: The maximum growth rate of A. salmonicida in VP salmon stored at 4°C was 0·56 ± 0·04 day-1 with no detectable lag-phase and the concentration of Aeromonas reached 8·33 log CFU per g after 10 days. The growth rates and maximum population density of Aeromonas in MAP salmon were lower but the applied atmosphere did not inhibit the growth. A selection of metabolites associated with fish spoilage were quantified using 1 H nuclear magnetic resonance (NMR) spectroscopy. The concentration of trimethylamine (TMA) was significantly affected by storage time and temperature, packaging atmosphere and inoculation with A. salmonicida (General Linear Model (GLM), P < 0·001 for all factors). CONCLUSION: The study presents preliminary results on A. salmonicida as a potential spoilage organism in vacuum-packaged salmon during cold storage. The combination of refrigeration and a packaging atmosphere consisting of 60/40 % CO2 /N2 did not completely inhibit the growth but prevented the formation of TMA. SIGNIFICANCE AND IMPACT OF THE STUDY: Little information is available on the spoilage potential of Aeromonas spp. in minimally processed salmon products under different packaging conditions. The study clearly demonstrates the importance of hurdle technology and provides data to further elucidate the significance of Aeromonas spp. as a spoilage organism.

Amisulpride prevents nausea and vomiting associated with highly emetogenic chemotherapy: a randomised, double-blind, placebo-controlled, dose-ranging trial.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) remain significant clinical problems, especially in the delayed phase (24-120 h after chemotherapy). Amisulpride is a dopamine D2/D3-receptor antagonist previously shown to be an effective intravenous antiemetic. We conducted a randomised, double-blind study to characterise the dose response of oral amisulpride in delayed phase CINV. METHODS: Chemotherapy-naïve patients receiving cisplatin ≥ 70 mg/m2 or an anthracycline-cyclophosphamide regimen for breast cancer received, on day 1, 20 mg amisulpride and 8-16 mg ondansetron intravenously followed, once daily on days 2-4, by 10, 20 or 40 mg oral amisulpride or placebo. A control group receiving standard three-drug prophylaxis was enrolled for assay sensitivity purposes. The primary endpoint was complete response (CR), defined as no emesis or rescue medication use, in the delayed phase. RESULTS: Three hundred eighteen subjects were evaluable per protocol. CR rate (24-120 h) was 20% with placebo and 46% with 10 mg amisulpride (p = 0.006 after multiplicity adjustment); in the three-drug control group, it was 59%. Emesis, nausea and 0-120-h CR rate were significantly improved with 10 mg amisulpride compared to placebo. Higher doses of amisulpride were not more effective than 10 mg. In patients with acute phase CR, delayed phase CR rate was 44% for placebo, 75% for 10 mg amisulpride (p = 0.022) and 70% for the 3-drug control. No significant differences were seen between groups in safety parameters. CONCLUSIONS: Amisulpride 10 mg orally is safe and superior to placebo at preventing delayed CINV caused by highly emetogenic chemotherapy. TRIAL REGISTRATION: NCT01857232.

Monitoring the effect of first line treatment in RAS/RAF mutated metastatic colorectal cancer by serial analysis of tumor specific DNA in plasma.

BACKGROUND: Precision medicine calls for an early indicator of treatment efficiency. Circulating tumor DNA (ctDNA) is a promising marker in this setting. Our prospective study explored the association between disease development and change of ctDNA during first line chemotherapy in patients with RAS/RAF mutated metastatic colorectal cancer (mCRC). METHODS: The study included 138 patients with mCRC receiving standard first line treatment. In patients with RAS/RAF mutated tumor DNA the same mutation was quantified in the plasma using droplet digital PCR. The fractional abundance of ctDNA was assessed in plasma before treatment start and at every treatment cycle until radiologically defined progressive disease. RESULTS: RAS/RAF mutations were detected in the plasma from 77 patients. Twenty patients progressed on treatment and 57 stopped treatment without progression. The presence of mutated DNA in plasma was correlated with poor overall survival. A low level of ctDNA after the first cycle of chemotherapy was associated with a low risk of progression. On the other hand, a significant increase of ctDNA at any time during the treatment course was associated with a high risk of progression on continuous treatment. The first increase in ctDNA level occurred at a median of 51 days before radiologically confirmed progression. CONCLUSIONS: The results indicate that the ctDNA level holds potential as a clinically valuable marker in first line treatment of mCRC. A rapid decrease was associated with a prolonged progression free interval, whereas a significant increase gave notice of early progression with a relevant lead time.

Effects of storage temperature on bacterial growth rates and community structure in fresh retail sushi.

AIMS: This study was conducted to assess the effects of different storage temperatures (4-20°C), on bacterial concentrations, growth rates and community structure in fresh retail sushi, a popular retail product with a claimed shelf life of 2-3 days. METHODS AND RESULTS: The maximum specific growth rate based on aerobic plate count (APC) at 4°C was 0·06 h-1 and displayed a sixfold increase (0·37 h-1 ) at 20°C. Refrigeration resulted in no growth of hydrogen sulphide (H2 S)-producing bacteria, but this group had the strongest temperature response. The bacterial community structure was determined by PCR/DGGE (denaturing gradient gel electrophoresis). Multivariate analysis based on Bray-Curtis similarities demonstrated that temperature alone was not the major determinant for the bacterial community structure. The total concentration of aerobic bacteria was the variable that most successfully explained the differences between the communities. The dominating organisms, detected by sequencing of DNA bands excised from the DGGE gel, were Brochothrix thermosphacta and genera of lactic acid bacteria (LAB). CONCLUSION: The relationship between growth rates and storage temperatures clearly demonstrates that these products are sensitive to deviations from optimal storage temperature, possibly resulting in loss of quality during shelf life. Regardless of the storage temperature, the bacterial communities converged towards a similar structure and density, but the storage temperature determined how fast the community reached its carrying capacity. SIGNIFICANCE AND IMPACT OF THE STUDY: Little information is available on the microbial composition of ready-to-eat food that are prepared with raw fish, subjected to contamination during handling, and susceptible to microbial growth during cold storage. Moreover, the data are a good first possibility to simulate growth of APC, H2 S-producing bacteria and LAB under different temperature scenarios that might occur during production, distribution or storage.

Report of mecC-carrying MRSA in domestic swine.

OBJECTIVES: We unexpectedly identified MRSA isolates carrying mecC (mecC-MRSA) from a Danish swine farm located in eastern Zealand. The objective of the present study was to investigate the origin of these isolates and their genetic relatedness to other mecC-MRSA isolates from Zealand. METHODS: WGS was used to infer the phylogenetic relationship between 19 identified mecC-MRSA isolates from the swine farm and 34 additional epidemiologically unrelated human isolates from the same geographical region of Denmark. Variations in the accessory genome were investigated by bioinformatics tools, and antibiotic susceptibility profiles were assessed by MIC determination. RESULTS: mecC-MRSA was isolated from a domestic swine farm, but not from cattle reared at the same farm. Phylogenetic analysis revealed that all mecC-MRSA isolates from both farm animals and workers formed a separate cluster, whereas human isolates from the same municipality belonged to a closely related cluster. Analysis of the accessory genome supported this relationship. CONCLUSIONS: To the best of our knowledge, this is the first report of mecC-MRSA isolated from domestic swine. The investigation strongly indicates that transmission of mecC-MRSA has taken place on the swine farm between the farmers and swine. The close clustering of farm isolates and isolates from the same municipality suggests a local transmission of mecC-MRSA.

Changes in circulating microRNA-126 during treatment with chemotherapy and bevacizumab predicts treatment response in patients with metastatic colorectal cancer.

BACKGROUND: This study investigated the predictive value of circulating microRNA-126 (cir-miRNA-126) in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy combined with bevacizumab. METHODS: The study included 68 patients. Blood samples (plasma) were collected before the treatment initiation, at the first clinical evaluation after 3 weeks and at progression. Levels of cir-miRNA-126 were determined by qRT-PCR after purification of total RNA from plasma. Primary clinical end points were response rates evaluated according to the Response Evaluation Criteria In Solid Tumours (RECIST) and progression-free survival (PFS). RESULTS: Changes in circulating miRNA-126 during treatment were predictive of tumour response. Non-responding patients had a median increase in cir-miRNA-126 of 0.244 (95% confidence interval (CI), 0.050-0.565) compared with a median decrease of -0.374 (95% CI, -0.472 to -0.111) in the responding patients, P=0.002. A significant positive correlation was demonstrated by comparing the changes in tumour size with the changes in cir-miRNA-126, r=0.48, P=0.0001. Grouping the patients according to the changes in cir-miRNA-126 disclosed a borderline significant separation of the groups in the PFS analysis favouring patients with decreasing miRNA-126 levels, hazard ratio (HR) 0.60 (95% CI, 0.33-1.09), P=0.07. CONCLUSIONS: The present results indicate that changes in cir-miRNA-126 during treatment are related to the response to chemotherapy and bevacizumab in patients with mCRC, thus representing a possible biomarker for the resistance to anti-angiogenic containing treatments.

Safety of Etoricoxib, Celecoxib, and Nonselective Nonsteroidal Antiinflammatory Drugs in Ankylosing Spondylitis and Other Spondyloarthritis Patients: A Swedish National Population-Based Cohort Study.

OBJECTIVE: Safety data regarding the use of etoricoxib and other nonsteroidal antiinflammatory drugs (NSAIDs) in ankylosing spondylitis (AS) and other spondyloarthritis (SpA) patients are rather limited. Our objective was to estimate and compare rates of gastrointestinal, renovascular, and cardiovascular adverse events in patients exposed to etoricoxib, celecoxib, or nonselective NSAIDs or totally unexposed to NSAIDs. METHODS: We performed a national register-based cohort study on patients with AS or SpA (n = 21,872) identified in the Swedish national patient register from 1987-2009. Treatment exposure was assessed time dependently based on the prescription drug register from 2006-2009, adjusting for sociodemographics and comorbidities derived from national population-based registers. RESULTS: Exposure to etoricoxib, celecoxib, and nonselective NSAIDs was 7.6%, 3.9%, and 71.2%, respectively. No major risk differences for serious cardiovascular, gastrointestinal, or renal adverse events were seen among the 3 exposure groups. Patients unexposed to NSAIDs had more baseline comorbidities and an increased relative risk for congestive heart failure events during the study period (2.0, 95% confidence interval [95% CI] 1.3-3.2). The relative risk for atherosclerotic events was nonsignificant when compared to the nonselective NSAID group (1.0, 95% CI 0.7-1.5), while the relative risk for gastrointestinal events was lower for unexposed patients (0.5, 95% CI 0.4-0.7). CONCLUSION: Overall, serious adverse events related to nonselective NSAIDs, etoricoxib, and celecoxib were similar and in the range of what would be expected in a group of SpA patients. Patients unexposed to NSAIDs had considerably more baseline comorbidities and increased risk for congestive heart failure, reflecting a selection of patients being prescribed NSAIDs in clinical practice.

Redefining high-risk patients with stage II colon cancer by risk index and microRNA-21: results from a population-based cohort.

BACKGROUND: The aim of the present study was to analyse the prognostic value of microRNA-21 (miRNA-21) in patients with stage II colon cancer aiming at a risk index for this group of patients. METHODS: A population-based cohort of 554 patients was included. MicroRNA-21 was analysed by qPCR based on tumour tissue. An index was created using the coefficients obtained from a collective multiple Cox regression. The entire procedure was cross-validated (10-fold). The performance of the index was quantified by time-dependent receiver operating characteristics curves. RESULTS: High miRNA-21 expression was associated with an unfavourable recurrence-free cancer-specific survival (RF-CSS), hazard ratio 1.35 (95% confidence interval, 1.03-1.76) (P=0.028). The generated RF-CSS index divided the traditional high-risk patients into subgroups with 5-year RF-CSS rates of 87% and 73%, respectively (P<0.001). The overall survival (OS) index identified three different subgroups (P<0.001). Cross-validated 5-year OS rates were 88%, 68%, and 50%, respectively. CONCLUSIONS: This population-based study supports miRNA-21 as an additional prognostic biomarker in patients with stage II colon cancer. Furthermore, the introduction of a risk index may guide the use of postoperative adjuvant treatment in a more appropriate way compared with current practice.

The correlation between cell-free DNA and tumour burden was estimated by PET/CT in patients with advanced NSCLC.

BACKGROUND: Cell-free DNA (cfDNA) circulating in the blood holds a possible prognostic value in malignant diseases. Under malignant conditions, the level of cfDNA increases but the biological mechanism remains to be fully understood. We aimed to examine the correlation between cfDNA and total tumour burden defined by positron emission tomography (PET) parameters. METHODS: Patients with advanced non-small cell lung cancer (NSCLC) were enrolled into a prospective biomarker trial. Before treatment, plasma was extracted and the level of cfDNA was determined by qPCR. An (18)F-fluorodeoxyglucose ((18)F-FDG) PET/computed tomography (CT) scan was performed and evaluated in terms of metabolic tumour volume (MTV) and total lesion glycolysis (TLG). Tumour contours were delineated semi-automatically by a threshold standardised uptake value (SUV) of 2.5. The primary end point was correlation among cfDNA, MTV and TLG. The secondary end point was overall survival (OS) according to cfDNA, MTV and TLG. RESULTS: Fifty-three patients were included. There were no correlations between cfDNA and MTV (r=0.1) or TLG (r=0.1). cfDNA >75th percentile was correlated with shorter OS (P=0.02), confirmed in a multivariate analysis. MTV>the median was associated with a significantly shorter OS (P=0.02). There was no significant difference in OS according to TLG (P=0.08). CONCLUSION: Cell-free DNA may not be a simple measure of tumour burden, but seems to reflect more complex mechanisms of tumour biology, making it attractive as an independent prognostic marker.

KRAS-mutated plasma DNA as predictor of outcome from irinotecan monotherapy in metastatic colorectal cancer.

BACKGROUND: We investigated the clinical implications of KRAS and BRAF mutations detected in both archival tumor tissue and plasma cell-free DNA in metastatic colorectal cancer patients treated with irinotecan monotherapy. METHODS: Two hundred and eleven patients receiving second-line irinotecan (350 mg m(-2) q3w) were included in two independent cohorts. Plasma was obtained from pretreatment EDTA blood-samples. Mutations were detected in archival tumour and plasma with qPCR methods. RESULTS: Mutation status in tumor did not correlate to efficacy in either cohort, whereas none of the patients with mutations detectable in plasma responded to therapy. Response rate and disease control rate in plasma KRAS wt patients were 19 and 66% compared with 0 and 37%, in patients with pKRAS mutations, (P=0.04 and 0.01). Tumor KRAS status was not associated with PFS but with OS in the validation cohort. Plasma BRAF and KRAS demonstrated a strong influence on both PFS and OS. The median OS was 13.0 mo in pKRAS wt patients and 7.8 in pKRAS-mutated, (HR=2.26, P<0.0001). PFS was 4.6 and 2.7 mo, respectively (HR=1,69, P=0.01). Multivariate analysis confirmed the independent prognostic value of pKRAS status but not KRAS tumor status. CONCLUSION: Tumor KRAS has minor clinical impact, whereas plasma KRAS status seems to hold important predictive and prognostic information.

MicroRNA-126 and epidermal growth factor-like domain 7-an angiogenic couple of importance in metastatic colorectal cancer. Results from the Nordic ACT trial.

BACKGROUND: This study investigated the clinical importance of linked angiogenetic biomarkers to chemotherapy, combined with the anti-vascular endothelial growth factor A (anti-VEGF-A), as a first-line treatment in patients with metastatic colorectal cancer (mCRC). METHODS: A total of 230 patients from a randomised phase III study were included. The primary microRNA-126 (pri-miRNA-126) A24G single-nucleotide polymorphism and the mature miRNA-126 were analysed by PCR using genomic DNA (full blood) and formalin-fixed paraffin-embedded tissue sections, respectively. The epidermal growth factor-like domain 7 (EGFL7) protein was visualised and quantified using immunohistochemistry. RESULTS: High tumour expression of miRNA-126 was significantly related to a longer progression-free survival. The independent prognostic value of miRNA-126 was confirmed using a Cox regression analysis (hazard ratio=0.49, 95% confidence interval=0.29-0.84, P=0.009). Although not significant, a relationship between EGFL7 expression and response rates is suggested, with EGFL7 expression at the invasive front being lower in responding patients than in the non-responders (P=0.063). CONCLUSION: The results validate the previous findings on the prognostic value of miRNA-126 in mCRC and may suggest a relationship between treatment efficacy and EGFL7 expression. As miRNA-126 may target VEGF-A as well as EGFL7, the results may provide predictive information in relation to next-generation anti-angiogenetics.

A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial.

BACKGROUND: The main objective was to study the effect on progression-free survival (PFS) of adding erlotinib to bevacizumab as maintenance treatment following chemotherapy and bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with untreated mCRC received doublet chemotherapy + bevacizumab during 18 weeks and those without tumor progression were eligible for randomization to bevacizumab + erlotinib (arm A) or bevacizumab alone (arm B), until progression or unacceptable toxic effect. RESULTS: Of the 249 patients enrolled, 80 started maintenance treatment in arm A and 79 in arm B. The rate of any grade 3/4 toxic effect was 53% in arm A and 13% in arm B. Median PFS was 5.7 months in arm A and 4.2 months in arm B (HR = 0.79; 95% confidence interval 0.55-1.12; P = 0.19). Overall survival (OS) from start of induction chemotherapy was 26.7 months in the randomized population, with no difference between the two arms. CONCLUSIONS: The addition of erlotinib to bevacizumab as maintenance treatment after first-line chemotherapy in mCRC did not improve PFS significantly. On-going clinical and translational studies focus on identifying subgroups of patients that may benefit from erlotinib in the maintenance setting. CLINICAL TRIALS NUMBER: NCT00598156.

Ultrasound elastography in patients with rectal cancer treated with chemoradiation.

OBJECTIVE: The current literature has described several predictive markers in rectal cancer patients treated with chemoradiation, but so far none of them have been validated for clinical use. The purpose of the present study was to compare quantitative elastography based on ultrasound measurements in the course of chemoradiation with tumor response based on T stage classification and the Mandard tumor regression grading (TRG). MATERIALS AND METHODS: We prospectively examined 31 patients with rectal cancer planned for high dose radiochemotherapy. The tumor and the mesorectal fat elasticity were measured using the Acoustic Radiation Force Impulse to generate information on the mechanical properties of the tissue. The objective quantitative elastography shear wave velocity was compared to the T stage classification and TRG. RESULTS: The baseline mean tumor elasticity was 3.13 m/s. Two and six weeks after the start of chemoradiation the velocities were 2.17 m/s and 2.11 m/s, respectively. The difference between baseline velocity and velocities during the treatment course was statistically significant, (p<0.0001). Patients with tumor confined to the rectal wall at histopathology (ypT1-2) had a mean elasticity measurement after two weeks of treatment of 1.95 m/s, whereas tumors invading the mesorectal fat (ypT3-4) had a velocity of 2.47 m/s, (p<0.05). The mean elasticity tended to be lower (1.99m/s) after two weeks in patients with TRG 1-2 responses in contrast to 2.24 m/s in those with TRG 3-4. CONCLUSION: Ultrasound elastography after two weeks of chemoradiation seems to hold early predictive information to the pathological T stage.

The prognostic importance of miR-21 in stage II colon cancer: a population-based study.

BACKGROUND: Despite several years of research and attempts to develop prognostic models a considerable fraction of stage II colon cancer patients will experience relapse within few years from their operation. The aim of the present study was to investigate the prognostic importance of miRNA-21 (miR-21), quantified by in situ hybridisation, in a unique, large population-based cohort. PATIENTS AND METHODS: The study included 764 patients diagnosed with stage II colon cancer in Denmark in the year 2003. One section from a representative paraffin-embedded tumour tissue specimen from each patient was processed for analysis of miR-21 and quantitatively assessed by image analysis. RESULTS: The miR-21 signal was predominantly observed in fibroblast-like cells located in the stromal compartment of the tumours. We found that patients expressing high levels of miR-21 had significantly inferior recurrence-free cancer-specific survival (RF-CSS): HR=1.26; 95% CI: 1.15-1.60; P<0.001. In Cox regression analysis, a high level of miR-21 retained its prognostic importance and was found to be significantly related to poor RF-CSS: HR=1.41; 95% CI: 1.19-1.67; P<0.001. CONCLUSION: The present study showed that increasing miR-21 expression levels were significantly correlated to decreasing RF-CSS. Further investigations of the clinical importance of miR-21 in the selection of high-risk stage II colon cancer patients are merited.

Phase II marker-driven trial of panitumumab and chemotherapy in KRAS wild-type biliary tract cancer.

BACKGROUND: Combination chemotherapy has proven beneficial in biliary tract cancer and further improvements may be achieved by individualizing treatment based on biomarkers and by adding biological agents. We report the effect of chemotherapy with panitumumab as first-line therapy for KRAS wild-type irresectable biliary tract cancer. PATIENTS AND METHODS: Patients were treated with gemcitabine 1000 mg/m(2), oxaliplatin 60 mg/m(2), and panitumumab 6 mg/kg i.v. every 2 weeks followed by two daily administrations of capecitabine 1000 mg/m(2) in 7 days. RESULTS: During 22 months, 46 patients were included in a single institution. The primary end point, fraction of progression-free survival (PFS) at 6 months, was 31/42 [74%; 95% confidence interval (CI) 58% to 84%]. Forty-two patients had measurable disease. Response rate was 33% and disease control rate 86%. Median PFS was 8.3 months (95% CI 6.7-8.7 months) and median overall survival was 10.0 months (95% CI 7.4-12.7 months). Toxicity was manageable including eight cases of epidermal growth factor receptor-related skin adverse events of grade 2 or more. CONCLUSIONS: Marker-driven patient selection is feasible in the systemic treatment of biliary tract cancer. Combination chemotherapy with panitumumab in patients with KRAS wild-type tumors met the efficacy criteria for future testing in a randomized trial.

IL-6 regulates exercise and training-induced adaptations in subcutaneous adipose tissue in mice.

AIM: The aim of this study was to test the hypothesis that IL-6 regulates exercise-induced gene responses in subcutaneous adipose tissue in mice. METHODS: Four-month-old male IL-6 whole body knockout (KO) mice and C57B wild-type (WT) mice performed 1 h of treadmill exercise, where subcutaneous adipose tissue (AT) was removed either immediately after, 4 h or 10 h after exercise as well as from mice not running acutely. Moreover, AT was sampled at resting conditions after 5 weeks of exercise training. RESULTS: AT leptin mRNA decreased immediately after a single running exercise bout in both genotypes and returned to baseline within 10 h of recovery in IL-6 KO mice, but not WT mice. Leptin mRNA content decreased in WT and increased in IL-6 KO mice with training, but without significant alterations in leptin protein. Acute exercise induced a decrease in the AT TNFα mRNA content in WT, but not in IL-6-KO mice, while training lowered resting levels of TNFα mRNA in both genotypes. In addition, an exercise-induced decline in AT PPARγ mRNA content was absent in IL-6 KO mice and in line training increased PPARγ mRNA only in IL-6 KO mice. CONCLUSION: The present findings indicate a role of IL-6 in regulating exercise- and training-induced leptin and PPARγ expression in adipose tissue. In addition, while IL-6 is required for TNF-α mRNA reduction in response to acute exercise, IL-6 does not appear to be mandatory for anti-inflammatory effects of exercise training in adipose tissue.

Interleukin-6 modifies mRNA expression in mouse skeletal muscle.

AIM: The aim of this study was to test the hypothesis that interleukin (IL)-6 plays a role in exercise-induced peroxisome proliferator-activated receptor γ co-activator (PGC)-1α and tumor necrosis factor (TNF)-α mRNA responses in skeletal muscle and to examine the potential IL-6-mediated AMP-activated protein kinase (AMPK) regulation in these responses. METHODS: Whole body IL-6 knockout (KO) and wildtype (WT) male mice (4 months of age) performed 1 h treadmill exercise. White gastrocnemius (WG) and quadriceps (Quad) muscles were removed immediately (0') or 4 h after exercise and from mice not run acutely. RESULTS: Acute exercise reduced only in WT muscle glycogen concentration to 55 and 35% (P < 0.05) of resting level in Quad and WG respectively. While AMPK and Acetyl CoA carboxylase (ACC) phosphorylation increased 1.3-fold (P < 0.05) in WG and twofold in Quad immediately after exercise in WT mice, no change was detected in WG in IL-6 KO mice. The PGC-1α mRNA content was in resting WG 1.8-fold higher (P < 0.05) in WT mice than in IL-6 KO mice. Exercise induced a delayed PGC-1α mRNA increase in Quad in IL-6 KO mice (12-fold at 4 h) relative to WT mice (fivefold at 0'). The TNF-α mRNA content was in resting Quad twofold higher (P < 0.05) in IL-6 KO than in WT, and WG TNF-α mRNA increased twofold (P < 0.05) immediately after exercise only in IL-6 KO. CONCLUSION: In conclusion, IL-6 affects exercise-induced glycogen use, AMPK signalling and TNF-α mRNA responses in mouse skeletal muscle.