Bariatric surgery, osteoarthritis and arthroplasty of the hip and knee in Swedish Obese Subjects - up to 31 years follow-up of a controlled intervention study.

OBJECTIVE: To study the long-term effect of obesity and bariatric surgery on incidences of osteoarthritis and arthroplasty of hip and knee. DESIGN: Hazard ratios (HR) and incidence rates (IR) of osteoarthritis and arthroplasty of hip and knee were studied in the prospective, controlled, non-randomized Swedish Obese Subjects (SOS) study (bariatric surgery group, n = 2007; matched controls given usual obesity care, n = 2040) and the SOS reference cohort (n = 1135, general population). Osteoarthritis diagnosis and arthroplasty for osteoarthritis were captured from the National Swedish Patient Register. Median follow-up time was 21.2 (IQR 16.4-24.8), 22.9 (IQR 19.1-25.7), and 20.1 years (IQR 18.7-20.9) for the control group, surgery group and reference cohort, respectively. RESULTS: The surgery group displayed lower incidence of hip osteoarthritis (IR 5.3, 95% CI 4.7-6.1) compared to controls (IR 6.6, 95% CI 5.9-7.5, adjHR 0.83, 95% CI 0.69-1.00) but similar incidence of hip arthroplasty. Similar incidence of knee osteoarthritis was observed in the surgery group and controls, but knee arthroplasty was more common in the surgery group (IR 7.4, 95% CI 6.6-8.2 and 5.6, 95% CI 4.9-6.4, adjHR 1.45, 95% CI 1.22-1.74). The reference cohort displayed lower incidences of osteoarthritis and arthroplasty of hip and knee compared with the surgery group and controls. CONCLUSION: Bariatric surgery did not normalize the increased risk of knee and hip osteoarthritis in patients with obesity but was associated with an increased incidence of knee arthroplasty compared to the control group. With the limitations inherent to the present data, additional studies are needed to confirm these results. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01479452.

Health status and health care utilization after discharge from geriatric in-hospital stay - description of a register-based study.

BACKGROUND: This study is the first part of a register-based research program with the overall aim to increase the knowledge of the health status among geriatric patients and to identify risk factors for readmission in this population. The aim of this study was two-fold: 1) to evaluate the validity of the study cohorts in terms of health care utilization in relation to regional cohorts; 2) to describe the study cohorts in terms of health status and health care utilization after discharge. METHODS: The project consist of two cohorts with data from patient records of geriatric in-hospital stays, health care utilization data from Stockholm Regional Healthcare Data Warehouse 6 months after discharge, socioeconomic data from Statistics Sweden. The 2012 cohort include 6710 patients and the 2016 cohort, 8091 patients; 64% are women, mean age is 84 (SD 8). RESULTS: Mean days to first visit in primary care was 12 (23) and 10 (19) in the 2012 and 2016 cohort, respectively. Readmissions to hospital was 38% in 2012 and 39% in 2016. The validity of the study cohorts was evaluated by comparing them with regional cohorts. The study cohorts were comparable in most cases but there were some significant differences between the study cohorts and the regional cohorts, especially regarding amount and type of primary care. CONCLUSION: The study cohorts seem valid in terms of health care utilization compared to the regional cohorts regarding hospital care, but less so regarding primary care. This will be considered in the analyses and when interpreting data in future studies based on these study cohorts. Future studies will explore factors associated with health status and re-admissions in a population with multi-morbidity and disability.

Prognostic role of serum thymidine kinase 1 kinetics during neoadjuvant chemotherapy for early breast cancer.

BACKGROUND: Emerging data support the use of thymidine kinase 1 (TK1) activity as a prognostic marker and for monitoring of response in breast cancer (BC). The long-term prognostic value of TK1 kinetics during neoadjuvant chemotherapy is unclear, which this study aimed to elucidate. METHODS: Material from patients enrolled to the single-arm prospective PROMIX trial of neoadjuvant epirubicin, docetaxel and bevacizumab for early BC was used. Ki67 in baseline biopsies was assessed both centrally and by automated digital imaging analysis. TK1 activity was measured from blood samples obtained at baseline and following two cycles of chemotherapy. The associations of TK1 and its kinetics as well as Ki67 with event-free survival and overall survival (OS) were evaluated using multivariable Cox regression models. RESULTS: Central Ki67 counting had excellent correlation with the results of digital image analysis (r = 0.814), but not with the diagnostic samples (r = 0.234), while it was independently prognostic for worse OS [adjusted hazard ratio (HRadj) = 2.72, 95% confidence interval (CI) 1.19-6.21, P = 0.02]. Greater increase in TK1 activity after two cycles of chemotherapy resulted in improved event-free survival (HRadj = 0.50, 95% CI 0.26-0.97, P = 0.04) and OS (HRadj = 0.46, 95% CI 0.95, P = 0.04). There was significant interaction between the prognostic value of TK1 kinetics and Ki67 (pinteraction 0.04). CONCLUSION: Serial measurement of serum TK1 activity during neoadjuvant chemotherapy provides long-term prognostic information in BC patients. The ease of obtaining serial samples for TK1 assessment motivates further evaluation in larger studies.

Remission and progression of pre-existing micro- and macroalbuminuria over 15 years after bariatric surgery in Swedish Obese Subjects study.

BACKGROUND: Bariatric surgery reduces incidence of albuminuria and end-stage renal disease in patients with obesity. Effects of bariatric surgery on long-term remission and progression of pre-existing obesity-related renal damage are mainly unexplored. Here we investigate the long-term effects of bariatric surgery compared with conventional obesity care on remission and progression of albuminuria. METHODS: 4047 patients were included in the Swedish Obese Subjects study. Inclusion criteria were age 37-60 years, BMI ≥ 34 kg/m2 in men and BMI ≥ 38 kg/m2 in women. Our analysis comprised 803 patients (19.8% of total population, 357 control, 446 surgery) with pre-existing albuminuria including 693 patients (312 control, 381 surgery) with microalbuminuria, and 110 patients (45 control, 65 surgery) with macroalbuminuria. Surgery patients were treated with banding, vertical banded gastroplasty, or gastric bypass. Control patients received conventional obesity care. RESULTS: Total urinary albumin excretion was 36.5% lower in all patients with albuminuria after 15 years, 44.5% lower in patients with microalbuminuria after 15 years, and 27.8% lower in patients with macroalbuminuria after 2 years following bariatric surgery compared with conventional care. In surgery patients with microalbuminuria, remission to normoalbuminuria was higher (OR, 5.9, 2.2, 3.2, p < 0.001) and progression to macroalbuminuria was lower (OR, 0.28, 0.26, 0.25, p ≤ 0.02) at 2, 10, and 15 years, respectively, compared with control patients. In surgery patients with macroalbuminuria remission to normo- or microalbuminuria was higher (OR, 3.67, p = 0.003) after 2 years. No differences between surgery and control patients with macroalbuminuria were observed after 10 and 15 years. Surgery slowed progression of eGFR decline after 2 years in patients with microalbuminuria and macroalbuminuria (treatment effect: 1.0 ml/min/1.73 m2/year, p = 0.001 and 1.4 ml/min/1.73 m2/year, p = 0.047, respectively). CONCLUSION: Bariatric surgery had better effects than conventional obesity care on remission of albuminuria and prevention of eGFR decline, indicating that patients with obesity-related renal damage benefit from bariatric surgery.

Fracture risk after three bariatric surgery procedures in Swedish obese subjects: up to 26 years follow-up of a controlled intervention study.

BACKGROUND: Previous studies have reported an increased fracture risk after bariatric surgery. OBJECTIVE: To investigate the association between different bariatric surgery procedures and fracture risk. METHODS: Incidence rates and hazard ratios for fracture events were analysed in the Swedish Obese Subjects study; an ongoing, nonrandomized, prospective, controlled intervention study. Hazard ratios were adjusted for risk factors for osteoporosis and year of inclusion. Information on fracture events were captured from the Swedish National Patient Register. The current analysis includes 2007 patients treated with bariatric surgery (13.3% gastric bypass, 18.7% gastric banding, and 68.0% vertical banded gastroplasty) and 2040 control patients with obesity matched on group level based on 18 variables. Median follow-up was between 15.1 and 17.9 years for the different treatment groups. RESULTS: During follow-up, the highest incidence rate for first-time fracture was observed in the gastric bypass group (22.9 per 1000 person-years). The corresponding incidence rates were 10.4, 10.7 and 9.3 per 1000 person-years for the vertical banded gastroplasty, gastric banding and control groups, respectively. The risk of fracture was increased in the gastric bypass group compared with the control group (adjusted hazard ratio [adjHR] 2.58; 95% confidence interval [CI] 2.02-3.31; P < 0.001), the gastric banding group (adjHR 1.99; 95%CI 1.41-2.82; P < 0.001), and the vertical banded gastroplasty group (adjHR 2.15; 95% CI 1.66-2.79; P < 0.001). CONCLUSIONS: The risk of fracture is increased after gastric bypass surgery. Our findings highlight the need for long-term follow-up of bone health for patients undergoing this treatment.

Incidence of end-stage renal disease following bariatric surgery in the Swedish Obese Subjects Study.

BACKGROUND: Obesity is a major public health problem leading to co-morbidities such as diabetes, hypertension and kidney failure. Bariatric surgery results in pronounced and maintained weight loss and prevention of obesity-related diseases and their complications. Most studies of bariatric surgery on kidney disease show improvements after surgery. However, long-term studies analyzing hard end-points are lacking. Here we report on the long-term effects of bariatric surgery compared to usual obesity care on incidence of end-stage renal disease (ESRD) alone and in combination with chronic kidney disease stage 4 (CKD4/ESRD). METHODS: 4047 patients were included in the Swedish Obese Subjects (SOS) study. Inclusion criteria were age 37-60 years and BMI ≥ 34 in men and BMI ≥ 38 in women. Patients in the bariatric surgery group (N = 2010) underwent banding (18%), vertical banded gastroplasty (69%), or gastric bypass (13%); controls (N = 2037) received usual obesity care. In this analysis, patients were followed up for a median time of 18 years. The incidence of ESRD and CKD4 was obtained by crosschecking the SOS database with the Swedish National Patient Register. RESULTS: During follow-up, ESRD occurred in 13 patients in the surgery group and in 26 patients in the control group (adjusted hazard ratio (HR) = 0.27; 95% CI 0.12-0.60; p = 0.001). The number of CKD4/ESRD events was 23 in the surgery group and 39 in the control group (adjusted HR = 0.33; 95% CI 0.18-0.62; p < 0.001). In both analyses, bariatric surgery had a more favorable effect in patients with baseline serum insulin levels above median compared to those with lower insulin levels (interaction p = 0.010). Treatment benefit of bariatric surgery was also greater in patients with macroalbuminuria at baseline compared to those without macroalbuminuria (interaction p < 0.001). CONCLUSIONS: Our study showed for the first time that bariatric surgery is associated with a long-term protection against ESRD and CKD4/ESRD.

Life situation 5 years after subarachnoid haemorrhage.

OBJECTIVES: Subarachnoid haemorrhage (SAH) has high mortality and morbidity among survivors. SAH mainly affects young people and may result in long-term disabilities such as decreased Health-related Quality of Life (HRQoL), mental health and cognitive function. The aim of this study was to investigate the life situation 5 years after a SAH including physical/emotional status, participation and HRQoL. MATERIALS & METHODS: In this cross-sectional descriptive study, a mail survey was sent to all persons treated at a neurosurgery unit in Gothenburg, Sweden, for non-traumatic SAH in 2009-2010, approximately 5 years post-SAH. The survey included questions regarding HRQoL; EuroQol 5-Dimensions (EQ-5D), the impact of the SAH; Stroke Impact Scale (SIS), Occupational Gaps Questionnaire and participation in society; Impact of Participation and Autonomy (IPA). RESULTS: Forty-two 5 year survivors were sent the survey, of whom 26 (62%) responded (59 years old, range 33-85). The participants had generally low HRQoL and scored low in the domain of anxiety and depression. Many reported problems with emotions, fatigue, memory and executive function, but few problems with physical condition. However, nearly all participants reported to have an acceptable level of participation and 64% were independent in their daily life. CONCLUSIONS: In this 5-year follow-up after SAH, the participants reported to have a greater number of hidden disabilities compared to physical problems, whereas most had acceptable participation in society. A yearly follow-up after a SAH could be suggested aiming to improving the cognitive and mental health.

Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance. METHODS: We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at-risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population-based Dallas Heart Study (DHS). RESULTS: Hepatic fat was epidemiologically associated with liver damage, insulin resistance, dyslipidemia and hypertension. The impact of genetic variants on liver damage was proportional to their effect on hepatic fat accumulation. Genetically determined hepatic fat was associated with aminotransferases, and with inflammation, ballooning and fibrosis in the LBC. Furthermore, in the LBC, the causal association between hepatic fat and fibrosis was independent of disease activity, suggesting that a causal effect of long-term liver fat accumulation on liver disease is independent of inflammation. Genetically determined hepatic steatosis was associated with insulin resistance in the LBC and SOS. However, this association was dependent on liver damage severity. Genetically determined hepatic steatosis was associated with liver fibrosis/cirrhosis and with a small increase in risk of type 2 diabetes in publicly available databases. CONCLUSION: These data suggest that long-term hepatic fat accumulation plays a causal role in the development of chronic liver disease.

Low energy Ne ion beam induced-modifications of magnetic properties in MnAs thin films.

Investigations of the complex behavior of the magnetization of manganese arsenide thin films due to defects induced by irradiation of slow heavy ions are presented. In addition to the thermal hysteresis suppression already highlighted in Trassinelli et al (2014 Appl. Phys. Lett. 104 081906), we report here on new local magnetic features recorded by a magnetic force microscope at different temperatures close to the characteristic sample phase transition. Complementary measurements of the global magnetization in different conditions (applied magnetic field and temperatures) enable the film characterization to be completed. The obtained results suggest that the ion bombardment produces regions where the local mechanical constraints are significantly different from the average, promoting the local presence of magneto-structural phases far from the equilibrium. These regions could be responsible for the thermal hysteresis suppression previously reported, irradiation-induced defects acting as seeds in the phase transition.

Prenatal ultrasound and childhood autism: long-term follow-up after a randomized controlled trial of first- vs second-trimester ultrasound.

OBJECTIVE: To analyze whether the frequency of autism spectrum disorder (ASD) in a cohort of Swedish children differs between those exposed to ultrasound in the 12(th) week and those exposed to ultrasound in the 18(th) week of gestation. METHODS: The study cohort consisted of approximately 30 000 children born between 1999 and 2003 to mothers who had been randomized to a prenatal ultrasound examination at either 12 or 18 weeks' gestation as part of the framework for a study on nuchal translucency screening. The outcome measure in the present study was the rate of ASD diagnoses among the children. Information on ASD diagnoses was based on data from the Swedish social insurance agency concerning childcare allowance granted for ASD. RESULTS: Between 1999 and 2003, a total of 14 726 children were born to women who underwent a 12-week ultrasound examination and 14 596 to women who underwent an 18-week ultrasound examination. Of these, 181 (1.2%) and 176 (1.2%) children, respectively, had been diagnosed with ASD. There was no difference in ASD frequency between the early and late ultrasound groups. CONCLUSIONS: Women subjected to at least one prenatal ultrasound examination at either 12 or 18 weeks' gestation had children with similar rates of ASD. However, this result reflects routine care 10-15 years ago in Sweden. Today, higher intensity ultrasound scans are performed more frequently, at earlier stages during pregnancy and for non-medical purposes, implying longer exposure time for the fetus. This change in the use of ultrasound necessitates further follow-up study of the possible effects that high exposure to ultrasound during the gestational period has on the developing brain. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Molecular subtype and tumor characteristics of breast cancer metastases as assessed by gene expression significantly influence patient post-relapse survival.

BACKGROUND: We and others have recently shown that tumor characteristics are altered throughout tumor progression. These findings emphasize the need for re-examination of tumor characteristics at relapse and have led to recommendations from ESMO and the Swedish Breast Cancer group. Here, we aim to determine whether tumor characteristics and molecular subtypes in breast cancer metastases confer clinically relevant prognostic information for patients. PATIENTS AND METHODS: The translational aspect of the Swedish multicenter randomized trial called TEX included 111 patients with at least one biopsy from a morphologically confirmed locoregional or distant breast cancer metastasis diagnosed from December 2002 until June 2007. All patients had detailed clinical information, complete follow-up, and metastasis gene expression information (Affymetrix array GPL10379). We assessed the previously published gene expression modules describing biological processes [proliferation, apoptosis, human epidermal receptor 2 (HER2) and estrogen (ER) signaling, tumor invasion, immune response, and angiogenesis] and pathways (Ras, MAPK, PTEN, AKT-MTOR, PI3KCA, IGF1, Src, Myc, E2F3, and ß-catenin) and the intrinsic subtypes (PAM50). Furthermore, by contrasting genes expressed in the metastases in relation to survival, we derived a poor metastasis survival signature. RESULTS: A significant reduction in post-relapse breast cancer-specific survival was associated with low-ER receptor signaling and apoptosis gene module scores, and high AKT-MTOR, Ras, and ß-catenin module scores. Similarly, intrinsic subtyping of the metastases provided statistically significant post-relapse survival information with the worst survival outcome in the basal-like [hazard ratio (HR) 3.7; 95% confidence interval (CI) 1.3-10.9] and HER2-enriched (HR 4.4; 95% CI 1.5-12.8) subtypes compared with the luminal A subtype. Overall, 25% of the metastases were basal-like, 32% HER2-enriched, 10% luminal A, 28% luminal B, and 5% normal-like. CONCLUSIONS: We show that tumor characteristics and molecular subtypes of breast cancer metastases significantly influence post-relapse patient survival, emphasizing that molecular investigations at relapse provide prognostic and clinically relevant information. CLINICALTRIALS.GOV: This is the translational part of the Swedish multicenter and randomized trial TEX, clinicaltrials.gov identifier nct01433614 (http://www.clinicaltrials.gov/ct2/show/nct01433614).

Body composition through adult life: Swedish reference data on body composition.

BACKGROUND/OBJECTIVES: The prevalence of obesity, defined as body mass index (BMI) ⩾30 kg/m(2), differs between populations; however, there is a need for data on description on body composition in reference populations of different ages and from different countries. The objective of this study was to pool dual-energy X-ray absorptiometry (DXA) body composition reference data from population-based Swedish cohorts. SUBJECTS/METHODS: Four population-based cross-sectional cohort studies including 1424 adult Swedes were divided into five age groups (20-29, 30-39, 40-49, 50-61 and 75 years of age); BMI 24.6±3.9 kg/m(2) were pooled. Body composition was measured with DXA. RESULTS: The difference in BMI from the youngest to the oldest age group was 3.2 and 4.3 kg/m(2) in men and women, respectively (P<0.001, both sexes), and fat mass (FM) was 9.9 and 9.1% higher in the oldest compared with the youngest men and women (P<0.001, both sexes). Fat-free mass (FFM) remained stable up to 60 years of age in men (P=0.83) and was lower at 75 years of age compared with the younger ages. In women, FFM was lower from age 60. From youngest to oldest age groups, height-adjusted FM differed from 4.6 to 7.8 kg/m(2) in men and from 6.8 to 10.8 kg/m(2) in women (P<0.001, both sexes). CONCLUSIONS: Our results provide reference data on body composition in Swedish populations. BMI and FM were higher among older age groups compared with the younger ones. FFM remained stable up to 60 years of age and was lower first among the 75 years of age.

The incidence of albuminuria after bariatric surgery and usual care in Swedish Obese Subjects (SOS): a prospective controlled intervention trial.

BACKGROUND: Obesity is associated with increased risk of chronic kidney disease and albuminuria is a predictor of renal impairment. Bariatric surgery reduces body weight in obese subjects, but it is not known whether surgery can prevent development of albuminuria. This study aims to determine the long-term effect of bariatric surgery on the incidence of albuminuria. SUBJECTS: The Swedish Obese Subjects study is a non-randomized, prospective, controlled study conducted at 25 public surgical departments and 480 primary health care centers in Sweden. Between 1 September 1987 and 31 January 2001, 2010 participants who underwent bariatric surgery and 2037 controls were recruited. Inclusion criteria were age 37-60 years and BMI ⩾ 34 in men and BMI ⩾ 38 in women. In this analysis, we included 1498 patients in the surgery group and 1610 controls without albuminuria at baseline. Patients in the bariatric surgery group underwent banding (18%), vertical banded gastroplasty (69%) or gastric bypass (13%); controls received usual obesity care. Date of analysis was 1 January 2011. Median follow-up was 10 years, and the rates of follow-up were 87%, 74 and 52% at 2, 10 and 15 years, respectively. The main outcome of this report is incidence of albuminuria (defined as urinary albumin excretion >30 mg per 24 h) over up to 15 years. RESULTS: During the follow-up, albuminuria developed in 246 participants in the control group and in 126 in the bariatric surgery group, corresponding to incidence rates of 20.4 and 9.4 per 1000 person years, respectively (adjusted hazard ratio, 0.37; 95% confidence interval, 0.30-0.47; P < 0.001). The expected number of surgeries needed to prevent the development of albuminuria in one patient at 10 years was nine. CONCLUSIONS: Bariatric surgery is associated with reduced incidence of albuminuria compared with usual obesity care.

The osseointegration stimulatory effect of macrogeometry-modified implants: a study in the rabbit.

OBJECTIVE: To investigate the bone stimulatory effect of compression forces through histomorphometric analyses of macrothreaded implants with microthreads in between. MATERIAL AND METHODS: Two sets of turned implants with different macrogeometries were prepared. The test group possessed microthreads in between macrothreads, and the control group had macrothreads only. The two-implant groups were placed in both the femur and the tibiae of 10 rabbits. After 4 weeks, the animals were sacrificed and were subjected to histologic processing and histomorphometry. On the prepared stained sections, the total bone area (BA), new BA and bone-to-implant (BIC) were calculated. RESULTS: The mean new BA% (SD) for the test group in the femur presented significantly higher values compared with the control group, being 32.84 (32.5) ± 6.04 and 27.31 (28.19) ± 5.66, respectively (P = 0.04). There were no differences for the new BA in the tibia or the total BA% for both bone types (P = 0.86, P = 0.131, and P = 0.131, respectively). The mean BIC% (SD) in the femur was 13.66 (11.49) ± 6.86 for the test group and 8.48 (7.92) ± 3.31 for the control group and in the tibia, 11.4 (11.88) ± 4.21 for the test group and 13.91 (12.06) ± 6.07 for the control group, respectively. There was no statistical significance among the groups tested. CONCLUSION: The modified implant macrogeometry with microthreads in between promoted effect in the femur. However, no statistical differences could be seen in the tibia, suggesting that the modification may be more effective in bone with poor bone quality, such as in the maxillary bone.

Influence of nanoparticle size on the nonlinear optical properties of magnetite ferrofluids.

The nonlinear index of refraction (n_{2}) and the two-photon absorption coefficient (ß) of water-based ferrofluids made of magnetite nanocrystals of different sizes and with different coatings have been measured through the Z-scan technique, with ultrashort (femtoseconds) laser pulses. Their third-order susceptibility is calculated from the values of n_{2} and ß. The influence of different particles' coatings and sizes on these nonlinear optical properties are investigated. The values of n_{2} and ß depend more significantly on the nanoparticles' size than on the particular coating. We observe a decrease of ß as the nanoparticles' diameters decrease, although the optical gap is found to be the same for all samples. The results are interpreted considering modifications in the electronic orbital shape due to the particles' nanosize effect.

Angiogenic factors in relation to clinical effect in a phase II trial of weekly paclitaxel.

BACKGROUND: Several anticancer agents including paclitaxel have an inhibitory effect on angiogenesis. AIMS: To compare the overall response rate and time to progression with changes in circulating angiogenic factors during palliative treatment with weekly paclitaxel. MATERIAL AND METHODS: Patients with metastatic BC, ECOG 0-2, received weekly paclitaxel, concomitant with trastuzumab if HER2+ BC (n = 7). Circulating vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were determined at base-line and before start of new course. RESULTS: Fifty-five of 63 included patients were evaluable. The overall response rate including stable disease ≥24 weeks (CR + PD + SD) was obtained in 25 of the evaluable patients (45%). The median time to progression (TTP) was 5.3 months and overall survival (OS) 16.7 months. Patients with triple negative breast cancer (TNBC) showed a trend towards higher base-line VEGF compared with hormone receptor positive or HER2+ tumours and had shorter TTP. Significant differences in VEGF and bFGF levels at 12 weeks were found between patients with longer versus shorter TTP (VEGF: p = 0.046, bFGF: p = 0.005) and between patients gaining versus lacking clinical benefit (VEGF: p = 0.05, bFGF: p = 0.02). CONCLUSIONS: The clinical utility of circulating VEGF may be a useful tool for monitoring treatment efficacy.

Serum thymidine kinase activity compared with CA 15-3 in locally advanced and metastatic breast cancer within a randomized trial.

The primary objective was to estimate serum thymidine kinase 1 (TK1) activity, reflecting total body cell proliferation rate including cancer cell proliferation, in women with loco regional inoperable or metastatic breast cancer participating in a prospective and randomized study. Secondary objectives were to analyze TK1 in relation to progression-free survival (PFS), overall survival (OS), therapy response and other tumour characteristics, including CA 15-3, widely used as a standard serum marker for disease progression. TK1 and CA 15-3 were analysed in 198 serum samples collected prospectively from women included in the randomized TEX trial between December 2002 and June 2007. TK1 activity was determined by the ELISA based DiviTum™ assay, and CA 15-3 analyses was generated with the electrochemiluminescence immunoassay Cobas Elecsys CA 15-3 II. High pre-treatment TK1 activity predicted shorter PFS (10 vs. 15 months p = 0.02) and OS (21 vs. 38 months, p < 0.0001), respectively. After adjustment for age, metastatic site and study treatment TK1 showed a trend as predictor of PFS (p = 0.059) and was an independent prognostic factor for OS, (HR 1.81, 95 % confidence interval (CI) 1.26-2.61, p = 0.001). There was a trend of shortened OS for women with high CA 15-3 (p = 0.054) in univariate analysis, but not after adjustment for the above mentioned covariates. Both TK1 (p = 0.0011) and CA 15-3 (p = 0.0004) predicted response to treatment. There were statistically different distributions of TK1 and CA 15-3 in relation to the site of metastases. TK1 activity measured by DiviTum™ predicted therapy response, PFS and OS in loco regional inoperable or disseminated breast cancer. These results suggest that this factor is a useful serum marker. In the present material, a prognostic value of CA 15-3 could not be proven.

Macrophage gene expression in adipose tissue is associated with insulin sensitivity and serum lipid levels independent of obesity.

OBJECTIVE: Obesity is linked to both increased metabolic disturbances and increased adipose tissue macrophage infiltration. However, whether macrophage infiltration directly influences human metabolism is unclear. The aim of this study was to investigate if there are obesity-independent links between adipose tissue macrophages and metabolic disturbances. DESIGN AND METHODS: Expression of macrophage markers in adipose tissue was analyzed by DNA microarrays in the SOS Sib Pair study and in patients with type 2 diabetes and a BMI-matched healthy control group. RESULTS: The expression of macrophage markers in adipose tissue was increased in obesity and associated with several metabolic and anthropometric measurements. After adjustment for BMI, the expression remained associated with insulin sensitivity, serum levels of insulin, C-peptide, high density lipoprotein cholesterol (HDL-cholesterol) and triglycerides. In addition, the expression of most macrophage markers was significantly increased in patients with type 2 diabetes compared to the control group. CONCLUSION: Our study shows that infiltration of macrophages in human adipose tissue, estimated by the expression of macrophage markers, is increased in subjects with obesity and diabetes and associated with insulin sensitivity and serum lipid levels independent of BMI. This indicates that adipose tissue macrophages may contribute to the development of insulin resistance and dyslipidemia.

Risk of new onset diabetes mellitus in patients with asthma or COPD taking inhaled corticosteroids.

BACKGROUND: A recent case-controlled study reported an increased risk of diabetes mellitus in patients treated with inhaled corticosteroids for asthma or COPD, versus age-matched controls. OBJECTIVE: The purpose of the current study was to evaluate whether there was an increased risk of new onset diabetes mellitus or hyperglycaemia among patients with asthma or COPD treated with inhaled corticosteroids. METHODS: A retrospective analysis evaluated all double-blind, placebo-controlled, trials in patients ≥4 years of age involving budesonide or budesonide/formoterol in asthma (26 trials; budesonide: n = 9067; placebo: n = 5926), and in COPD (8 trials; budesonide: n = 4616; non-ICS: n = 3643). A secondary dataset evaluated all double-blind, controlled trials in asthma involving the use of inhaled corticosteroids (60 trials; budesonide: n = 33,496; fluticasone: n = 2773). RESULTS: In the primary asthma dataset, the occurrence of diabetes mellitus/hyperglycaemia adverse events (AEs) was 0.13% for budesonide and 0.13% for placebo (HR 0.98 [95% CI: 0.38-2.50], p = 0.96) and serious adverse events (SAEs) was 0% for budesonide and 0.05% for placebo. In the secondary dataset, the occurrence of diabetes/hyperglycaemia as AE and SAE was 0.19% and 0.03%, respectively. In the COPD dataset, the occurrence of diabetes mellitus/hyperglycaemia AEs was 1.3% for budesonide and 1.2% for non-ICS (HR 0.99 [95% CI: 0.67-1.46], p = 0.96) and SAEs was 0.1% for budesonide and 0.03% for non-ICS. CONCLUSION AND CLINICAL RELEVANCE: Treatment with inhaled corticosteroids in patients with asthma or COPD was not associated with increased risk of new onset diabetes mellitus or hyperglycaemia.

High levels of cathepsins B, L and S in human seminal plasma and their association with prostasomes.

Semen is a heterogenous and complex fluid with different functions, some of them well known, others still obscure. The aim of this study was to investigate the presence of cathepsins B, S and L in human seminal plasma and their possible associations with other semen variables. Cathepsin B, L and S concentrations were measured in seminal plasma from 99 men utilising commercial ELISA kits. Seminal plasma cathepsin B was approximately 70 times higher, while the cathepsin L values were approximately 500 times higher and the cathepsin S values approximately 40 times higher in seminal plasma than in a group of serum samples. The study shows that seminal plasma contains high levels of cathepsins B, L and S. All three cathepsins were also bound to the surface of prostasomes.