Conventional versus reverse sequence of neoadjuvant epirubicin/cyclophosphamide and docetaxel: sequencing results from ABCSG-34.

BACKGROUND: Preoperative chemotherapy containing anthracyclines and taxanes is well established in early-stage breast cancer. Previous studies have suggested that the chemotherapy sequence may matter but definitive evidence is missing. ABCSG trial 34 evaluated the activity of the MUC1 vaccine tecemotide when added to neoadjuvant treatment; the study provided the opportunity for the second randomisation to compare two different anthracycline/taxane sequences. METHODS: HER2-negative early-stage breast cancer patients were recruited to this randomised multicentre Phase 2 study. Patients in the chemotherapy cohort (n = 311) were additionally randomised to a conventional or reversed sequence of epirubicin/cyclophosphamide and docetaxel. Residual cancer burden (RCB) with/without tecemotide was defined as primary study endpoint; RCB in the two chemotherapy groups was a key secondary endpoint. RESULTS: No significant differences in terms of RCB 0/I (40.1% vs. 37.2%; P = 0.61) or pathologic complete response (pCR) rates (24.3% vs. 25%, P = 0.89) were observed between conventional or reverse chemotherapy sequence. No new safety signals were reported, and upfront docetaxel did not result in decreased rates of treatment delay or discontinuation. CONCLUSION: Upfront docetaxel did not improve chemotherapy activity or tolerability; these results suggest that upfront neoadjuvant treatment with anthracyclines remains a valid option.

Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In postmenopausal women with hormone receptor-positive, early-stage breast cancer, treatment with adjuvant aromatase inhibitors is the standard of care, but it increases risk for osteoporosis and fractures. Results from the ABCSG-18 trial showed that use of denosumab as an adjuvant to aromatase inhibitor therapy significantly reduced clinical fractures. Disease-free survival outcomes from ABCSG-18 have not yet been reported. METHODS: Postmenopausal patients with early, hormone receptor-positive, non-metastatic adenocarcinoma of the breast, who had completed their initial adjuvant treatment pathway (surgery, radiotherapy, or chemotherapy, or a combination) and were receiving adjuvant aromatase inhibitors, were enrolled at 58 trial centres in Austria and Sweden into this prospective, double-blind, placebo-controlled, phase 3 trial. With permuted block randomisation (block sizes 2 and 4, stratified by previous aromatase inhibitor use, total lumbar spine bone mineral density score at baseline, and type of centre), patients were assigned (1:1) to receive subcutaneous denosumab (60 mg) or matching placebo every 6 months during aromatase inhibitor therapy. The primary endpoint (previously reported) was the time to first clinical fracture after randomisation. The secondary endpoint reported here is disease-free survival (defined as time from randomisation to first evidence of local or distant metastasis, contralateral breast cancer, secondary carcinoma, or death from any cause) in the intention-to-treat population. This study is registered with EudraCT (number 2005-005275-15) and ClinicalTrials.gov (number NCT00556374), and is ongoing for long-term follow-up. FINDINGS: Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled and randomly assigned; 1711 to the denosumab group and 1709 to the placebo group (with five others withdrawing consent). After a median follow-up of 73 months (IQR 58-95), 240 (14·0%) patients in the denosumab and 287 (16·8%) in the placebo group had disease-free survival events. Disease-free survival was significantly improved in the denosumab group versus the placebo group (hazard ratio 0·82, 95% CI 0·69-0·98, Cox p=0·0260; descriptive analysis, without controlling for multiplicity). In the denosumab group, disease-free survival was 89·2% (95% CI 87·6-90·8) at 5 years and 80·6% (78·1-83·1) at 8 years of follow-up, compared with 87·3% (85·7-89·0) at 5 years and 77·5% (74·8-80·2) and 8 years in the placebo group. No independently adjudicated cases of osteonecrosis of the jaw or confirmed atypical femoral fractures were recorded. The total number of adverse events was similar in the denosumab group (1367 [including 521 serious] adverse events) and the placebo group (1339 [515 serious]). The most common serious adverse events were osteoarthritis (62 [3·6%] of 1709 in the denosumab group vs 58 [3·4%] of 1690 in the placebo group), meniscus injury (23 [1·3%] vs 24 [1·4%]), and cataract (16 [0·9%] vs 28 [1·7%]). One (<0·1%) treatment-related death (due to pneumonia, septic kidney failure, and cardiac decompensation) occurred in the denosumab group. INTERPRETATION: Denosumab constitutes an effective and safe adjuvant treatment for patients with postmenopausal hormone receptor-positive early breast cancer receiving aromatase inhibitor therapy. FUNDING: Amgen.

A prospective, multicenter pilot study to investigate the feasibility and safety of a 1-year controlled exercise training after adjuvant chemotherapy in colorectal cancer patients.

INTRODUCTION: Despite advances in adjuvant chemotherapy, 20-30% of patients in stages II-III colorectal cancer will eventually relapse. Observational studies showed a reduction in relapse rate, colon cancer-specific mortality, and overall mortality by physical activity. Results from prospective randomized interventional studies to confirm these observational data are lacking. The aims of this prospective single-arm multicenter pilot study are to evaluate feasibility and safety of exercise training after adjuvant chemotherapy in colorectal cancer patients. PATIENTS AND METHODS: The training was performed three times per week for 1 year and was increased gradually in three phases until reaching 18 metabolic equivalent task hours per week. RESULTS: Overall, 30 patients were included. The planned training intensity could be achieved in all three phases. Patients experienced a performance increase of median 35.5 watt, a weight-loss of a median of 3.0 kg, and a reduction in body fat content of median 1.0% during this exercise training. The analysis showed early study termination due to non-compliance in 10/30 patients (33.3%), disease progression in 4 patients (13.3%), and serious adverse events in 2 patients (6.7%). About half of patients (46.7%) completed the pilot study as planned. Biomarker analysis from 20 patients showed a non-significant reduction in insulin-like growth factor 1 (IGF-1), insulin-like growth factor 2 (IGF-2) and insulin-like growth factor binding protein 3 (IGF-BP3) levels, significant increases in adiponectin and leptin levels, and a non-significant increase in C-peptide levels. CONCLUSION: Exercise training is feasible in patients with colorectal cancer after completion of adjuvant chemotherapy. The main problem encountered during the study was compliance. To improve compliance of exercise training, several measures were adapted for the upcoming prospective randomized ABCSG C08 Exercise II study.

Self-rated health, nutritional intake and mortality in adult hospitalized patients.

BACKGROUND: In the general population, poor self-rated health (SRH) is associated with malnutrition; however, these associations have not been studied in hospitalized patients. We aimed to evaluate SRH, indicators of nutrition, nutritional status and their association with in-hospital mortality. MATERIALS AND METHODS: The study is based on data from the nutritionDay, a multinational, multicentre European-wide standardized 1-day cross-sectional survey of nutritional factors, food intake and in-hospital mortality in hospitalized patients. A data set of surveys on SRH in 2010 and 2011 was used in the analysis. RESULTS: Complete sets of data were available for 28 106 patients (64 ± 18 years, 50% men, 7% terminally ill). In relation to body mass index, 7% were undernourished and 16% were obese. Fair/poor SRH was reported by 59% of patients and was associated with low food intake during the previous week or on survey day (P < 0·005). Thirty-day in-hospital mortality was 3%; in adjusted multivariate survival analysis, fair/poor SRH [hazard ratio (HR) 1·53, 95% confidence interval (CI) 1·14-2·05] and reduced food intake [nothing eaten (HR 2·13, 95% CI 1·46-3·11) or not allowed to eat on nutritionDay (HR 2·01, 95% CI 1·30-3·11)] predicted fatal outcome. At particularly high risk were patients who rated their health poor and had reduced food intake on the survey day or within the previous week with relative risks of 7·37 and 8·80, respectively. CONCLUSIONS: We demonstrated high prevalence of poor SRH and insufficient food intake in hospitalized patients. This was associated, particularly in combination, with increased risk of in-hospital mortality.

Do nocturnal headaches matter? A prospective diary study on subjective sleep parameters in snorers and their bed partners.

BACKGROUND: The objective of this study was to assess the influence of nocturnal headaches (NH) on subjective sleep parameters prospectively in habitual snorers and their bed partners. METHODS: We recruited habitual snorers and their bed partners via newspaper articles. The participants completed a semistructured interview, filled in questionnaires about quality of sleep (PSQI), daytime sleepiness (ESS), depression (SDS) and anxiety (SAS) and they kept a 90-day headache and sleep diary. RESULTS: Seventy-six snorers (25 female) and 41 bed partners (31 female) completed the study recording a total of 6690 and 3497 diary days, respectively. NH were recorded on 222 (3.3%) and 79 (2.2%) days in 32 (42%) snorers and 17 (41%) bed partners, respectively. Snorers with NH showed significantly higher PSQI (5 ± 3 vs. 4 ± 2, p = 0.004), SAS (38 ± 11 vs. 31 ± 10, p = 0.011) and SDS scores (39 ± 12 vs. 34 ± 10, p = 0.048) than snorers without NH. For bed partners with NH we found a significant female predominance (sex ratio f:m = 16:1 vs. 12:12, p = 0.005) and significantly higher SAS scores (38 ± 6 vs. 33 ± 8, p = 0.030) compared with bed partners without NH. The subjective quality of sleep in habitual snorers (p < 0.001) as well as their bed partners (p = 0.017) was negatively influenced by NH, but not total sleep time. DISCUSSION: NH occurred in around 40% of snorers and their bed partners at least once during the 90-day observation period. Our results confirmed a negative impact on the subjective quality of sleep in both groups.

Decanucleotide insertion polymorphism of F7 significantly influences the risk of thrombosis in patients with essential thrombocythemia.

OBJECTIVE: There is strong evidence that certain thrombophilic single nucleotide polymorphisms (SNPs) account for an increased risk of thrombosis. The additive impact of inherited thrombotic risk factors to a certain disease- immanent thrombotic risk is vastly unknown. Therefore, we aimed to investigate the influence of three novel, preselected SNPs on the risk of thrombosis in patients diagnosed with myeloproliferative neoplasm (MPN). METHOD: In 167 patients with a diagnosis of essential thrombocythemia (ET) or prefibrotic primary myelofibrosis (PMF) thrombophilic SNPs in the genes of factor VII (F7), nitric oxide synthase 3 (NOS3) and FcɣRIIa (FCGR2A) were determined. Subsequently, the polymorphic variants were correlated with the incidence of major thrombosis after diagnosis. RESULTS: Decanucleotide insertion polymorphism of F7 emerged as an independent, significant risk factor for total thrombosis and arterial thrombosis in particular in the whole group of patients (P = 0.0007) as well as in the separate analysis of patients with ET (P = 0.0002). CONCLUSION: Our results illustrate that the risk of thrombosis in MPN is significantly multiplied by inherited thrombophilic SNPs. This result points to the importance of a combined consideration of the inherited and the acquired hypercoagulable state in patients with MPN. Larger studies are needed to confirm and extend these important findings.

Fetal cardiac disease and fetal lung volume: an in utero MRI investigation.

OBJECTIVES: Magnetic resonance imaging (MRI) is a powerful, noninvasive tool to study fetal lung volumes after 18 weeks of gestation in vivo. In neonates with congenital heart disease (CHD), proper lung function is essential for postnatal survival. Antenatal detection of abnormal pulmonary development may help to optimize prenatal and perinatal management of at-risk fetuses. We aimed to investigate lung volumes in fetuses with prenatally diagnosed heart disease. METHODS: A cross-sectional, retrospective study of 105 consecutive singleton pregnancies with CHD and a control, non-CHD group (n = 115), that underwent fetal MRI was performed. The heart defects detected were divided into four groups. Lung volumes of fetuses with heart disease were compared with control, non-CHD fetuses. In addition, z-scores of lung volumes were calculated for the CHD group (normal range z-scores from -2-+2). RESULTS: As a group, fetuses with CHD have significantly smaller lung volumes compared with control fetuses when corrected by gestational age (GA) (p = 0.049). Of the 105 CHD fetuses studied, 18 had lung volumes with a z-score < -2. Fetuses with different types of CHD showed similar lung volumes. CONCLUSION: Our data indicate that postpartum pulmonary symptoms and outcome in neonates with congenital heart disease may be attributed to the cardiac disease itself and in part to smaller lung volumes.

Total hip arthroplasty using imageless computer-assisted hip navigation: a prospective randomized study.

In a prospective randomized study of two groups of 65 patients each, we compared the acetabular component position when using the imageless navigation system compared to the freehand conventional technique for cementless total hip arthroplasty. The position of the component was determined postoperatively on computed tomographic scans of the pelvis. There was no significant difference for postoperative mean inclination (P = 0.29), but a significant difference for mean postoperative acetabular component anteversion (P = 0.007), for mean deviation of the postoperative anteversion from the target position of 15° (P = 0.02) and for the outliers regarding inclination (P = 0.02) and anteversion (P < 0.05) between the computer-assisted and the freehand-placement group. Our results demonstrate the importance of imageless navigation for the accurate positioning of the acetabular component.

Role of endothelin-A receptors in optic nerve head red cell flux regulation during isometric exercise in healthy humans.

Endothelin-1 (ET-1) is an important regulator of vascular tone in the eye. It appears to play a role in ocular disease because of its strong vasoconstrictor action, its role in intraocular pressure homeostasis, and its neurotoxic potential. We have previously shown that ET-1 is involved in choroidal red cell flux (RCF) regulation during isometric exercise in healthy humans. In the present study we hypothesized that ET-1 also plays a role in optic nerve head (ONH) RCF regulation during isometric exercise. To test this hypothesis, we performed a randomized, double-masked, placebo-controlled, two-way crossover study in 15 healthy volunteers. Subjects were randomized to receive intravenous infusions of the specific endothelin type A receptor antagonist BQ-123 and placebo on two different study days. During these infusion periods, subjects performed squatting for 6 min to increase ocular perfusion pressure (OPP). ONH RCF was assessed with laser-Doppler flowmetry, and OPP was calculated from mean arterial pressure and intraocular pressure. BQ-123 did not change OPP or ONH RCF at baseline. The relative increase in OPP during isometric exercise was comparable between both groups (between 84 and 88%, P = 0.76 between groups; P < 0.001 vs. baseline). Isometric exercise increased ONH RCF during placebo and BQ-123, but the increase was more pronounced when the endothelin type-A receptor antagonist was administered (placebo, 27.3 ± 5.4%; and BQ-123, 39.2 ± 4.4%; P = 0.007 between groups). The present data indicate that ET-1 regulates red cell flux in the ONH beyond the autoregulatory range.

Significant differences in B-cell subpopulations characterize patients with chronic graft-versus-host disease-associated dysgammaglobulinemia.

Manifestations of chronic graft-versus-host disease (cGVHD) can resemble those seen in immunodeficiency states and autoimmune disorders. Reports by us and others suggest an involvement of B cells in the pathogenesis of cGVHD. We investigated B-lymphocyte subpopulations in cGVHD cohorts defined by serum immunoglobulin G (IgG) levels to characterize novel biomarkers for impairment of humoral immunity after allogeneic hematopoietic stem cell transplantation. Seventy-six patients were enrolled a median of 46 months after hematopoietic stem cell transplantation. The hypogammaglobulinemia group had significantly diminished CD19(+) B cells (165 vs 454 vs 417 × 106L) with elevated CD19(+)CD21(low) immature (16.5%, 7.7%, and 9.1%) and CD19(+)CD21(int-high)CD38(high)IgM(high) transitional (10.5% vs 4.2% vs 6.3%) B-cell proportions compared with the normogammaglobulinemia and hypergammaglobulinemia groups. CD19(+)CD10(-)CD27(-)CD21(high) naive B cells were highly elevated in all patients with cGVHD. CD19(+)CD27(+)IgD(+) non-class-switched (4 vs 12 vs 11 × 106/L) and class-switched (7 vs 35 vs 42 × 106/L) memory B cells were significantly lower in the hypogammaglobulinemia group compared with the others. Besides significantly higher B-cell activation factor/B-cell ratios, significantly more cGVHD patients with hypergammaglobulinemia had autoantibodies compared with the hypogammaglobulinemia subgroup (68% vs 24%, P = .024). In conclusion, B-cell subpopulations can serve as novel cellular biomarkers for immunodeficiency and autoimmunity indicating different pathogenetic mechanisms of cGVHD and encouraging future prospective longitudinal studies.

Obstetric and perinatal outcomes in IVF versus ICSI-conceived pregnancies at a tertiary care center--a pilot study.

BACKGROUND: Although most pregnancies after IVF result in normal healthy outcomes, an increased risk for a number of obstetric and neonatal complications, compared to naturally conceived pregnancies, has been reported. While there are many studies that compare pregnancies after assisted reproductive techniques with spontaneously conceived pregnancies, fewer data are available that evaluate the differences between IVF and ICSI-conceived pregnancies. The aim of our present study was, therefore, to compare obstetric and perinatal outcomes in pregnancies conceived after in vitro fertilization (IVF) versus intracytoplasmatic sperm injection (ICSI). METHODS: Three-hundred thirty four women who had become pregnant after an IVF or ICSI procedure resulted in a total of 530 children referred between 2003 und 2009 to the Department of Obstetrics and Gynecology of the Medical University of Vienna, a tertiary care center, and were included in this retrospective cohort study. We assessed maternal and fetal parameters in both groups (IVF and ICSI). The main study outcomes were preterm delivery, the need for neonatal intensive care, and congenital malformations. Moreover, we compared the course of pregnancy between both groups and the occurrence of complications that led to maternal hospitalization during pregnancy. RESULTS: There were 80 children conceived via ICSI and 450 children conceived via IVF.Mean gestational age was significantly lower in the ICSI group (p = 0.001). After ICSI, the birth weight (p = 0.008) and the mean APGAR values after 1 minute and after 10 minutes were lower compared to that of the IVF group (p = 0.016 and p = 0.047, respectively). Moreover, ICSI-conceived children had to be hospitalized more often at a neonatal intensive care unit (p = 0.004). There was no difference in pH of the umbilical artery or in major congenital malformations between the two groups. Pregnancy complications (i.e., premature rupture of membranes, cervical insufficiency, and premature uterine contractions) and the need for maternal hospitalization during pregnancy were found significantly more often after IVF (p = 0.0016 and p = 0.0095, respectively), compared to the ICSI group. CONCLUSIONS: When comparing IVF versus ICSI-conceived pregnancies at a tertiary care center, we found the course of pregnancy to be more complicated after IVF, whereas the primary fetal outcome seemed to be better in this group than after ICSI treatment.

Long-term absolute and relative survival after aortic valve replacement: a prospective cohort study.

BACKGROUND: Aortic valve replacement is one of the most common cardiac surgical procedures, especially in elderly patients. Whether or not there is a net life gain over a long period of time is a matter for debate. OBJECTIVE: To compare survival of patients with that of the age, sex, and follow-up year-matched normal population (relative survival). DESIGN: Single-centre, prospectively collected data. SETTING: Tertiary care centre, Vienna, Austria. PATIENTS: We enrolled 1848 patients undergoing elective aortic valve replacement between 1997 and the end of 2008. INTERVENTIONS: None. MAIN OUTCOME MEASUREMENT: Relative survival at the end of 2011 as determined by relative Cox regression analysis. RESULTS: Sixty-nine patients (3.7%) died within the first 30 days. Another 70 patients (3.8%) died within the first year and 429 (23.2%) died during the remaining follow-up period. The longest follow-up period was 14 years (median, 5.8; interquartile range, 3.2 to 8.9). Medical risk indicators for relative survival were diabetes mellitus [hazard ratio 1.69, 95% confidence interval, CI 1.37 to 2.07, P<0.001], pulmonary disease (hazard ratio 1.45, 95% CI 1.16 to 1.81, P=0.001), history of atrial fibrillation (hazard ratio 1.35, 95% CI 1.10 to 1.66, P=.005) and angiotensin-converting enzyme inhibitor medication (hazard ratio 1.21, 95% CI 1.02 to 1.44, P=0.031). Perioperative risk indicators were urgent surgery (hazard ratio 1.40, 95% CI 1.00 to 1.94, P=0.047), resternotomy at 48 h or less (hazard ratio 1.87, 95% CI 1.29 to 2.70, P=0.001), resternotomy at more than 48 h (hazard ratio 1.80, 95% CI 1.32 to 2.45, P<0.001), blood transfusion (hazard ratio 1.06, 95% CI 1.01 to 1.12, P=0.018) and renal replacement therapy (hazard ratio 2.02, 95% CI 1.41 to 2.90, P<0.001). Relative survival was highest in the oldest age quartile (76 to 94 years) and lowest in the youngest (19 to 58 years) (hazard ratio 0.27, 95% CI 0.21 to 0.36; P<0.001). CONCLUSION: Patients who survived the first year after aortic valve replacement had a similar chance of survival as the matched normal population. Relative survival benefit was higher in the oldest age quartile.

No difference in ROM and knee function between mobile and floating platforms in TKA.

PURPOSE: The purpose of this study was to determine whether the floating platforms (FP) were superior to rotating platforms (RP) in computer-navigated total knee arthroplasty (TKA) comparing the range of motion (ROM) as well as clinical and subjective function of the knee. METHODS: This retrospective non-randomized single-centre cohort study includes 255 patients with a primary implanted computer-navigated e.motion™ (Aesculap B. Braun) TKA system, implanted because of clinical and radiological verified gonarthrosis. In 129 patients, the FP platform was implanted, and in 126 patients, the RP platform. As statistical procedures for differences between inlay type RP/FP in ROM and Knee Society Score (KSS) after 3- and 24-month follow-up, an analysis of covariance (with risk factors gender, age, BMI, preoperative ROM and preoperative KSS) was performed. RESULTS: Although preoperative ROM and knee society function score (KSS part II) were significantly higher in the FP group before surgery, there was no significant difference between RP and FP in ROM and KSS at 3- and 24-month follow-up. CONCLUSION: The FP platform design did not have an advantage in ROM as well as in clinical and subjective knee function compared with the RP platform in computer-navigated TKA neither in early follow-up examinations at 3 months postoperatively nor at long-time follow-up at 24 months postoperatively.

Differential immunomodulatory effects of epirubicin/cyclophosphamide and docetaxel in breast cancer patients.

BACKGROUND: Epirubicin/cyclophosphamide (EC) and docetaxel (D) are commonly used in a sequential regimen in the neoadjuvant treatment of early, high-risk or locally advanced breast cancer (BC). Novel approaches to increase the response rate combine this treatment with immunotherapies such as PD-1 inhibition. However, the expected stimulatory effect on lymphocytes may depend on the chemotherapy backbone. Therefore, we separately compared the immunomodulatory effects of EC and D in the setting of a randomized clinical trial. METHODS: Tumor and blood samples of 154 patients from the ABCSG-34 trial were available (76 patients received four cycles of EC followed by four cycles of D; 78 patients get the reverse treatment sequence). Tumor-infiltrating lymphocytes, circulating lymphocytes and 14 soluble immune mediators were determined at baseline and at drug change. Furthermore, six BC cell lines were treated with E, C or D and co-cultured with immune cells. RESULTS: Initial treatment with four cycles of EC reduced circulating B and T cells by 94% and 45%, respectively. In contrast, no comparable effects on lymphocytes were observed in patients treated with initial four cycles of D. Most immune mediators decreased under EC whereas D-treatment resulted in elevated levels of CXCL10, urokinase-type plasminogen activator (uPA) and its soluble receptor (suPAR). Accordingly, only the exposure of BC cell lines to D induced similar increases as compared to E. While treatment of BC cells with E was associated with cell shrinkage and apoptosis, D induced cell swelling and accumulation of cells in G2 phase. CONCLUSION: The deleterious effect of EC on lymphocytes indicates strong immunosuppressive properties of this combination therapy. D, in contrast, has no effect on lymphocytes, but triggers the secretion of stimulatory proteins in vivo and in vitro, indicating a supportive effect on the immune system. Underlying differences in the induced cell death might be causal. These divergent immunomodulatory effects of epirubicin/cyclophosphamide and docetaxel should be considered when planning future combinations with immunotherapies in breast cancer.

Role of vascular endothelial growth factor polymorphisms in the treatment success in patients with wet age-related macular degeneration.

PURPOSE: Along with environmental risk factors such as smoking, hypertension, and atherosclerosis, genetic susceptibility is a primary contributor to the development and progression of exudative age-related macular degeneration (AMD). Vascular endothelial growth factor (VEGF) is a central angiogenic regulator and there has been general agreement now that it is an important trigger for the progression of exudative AMD. In the present study, we tested the hypothesis that VEGF gene polymorphisms play a role in the treatment success with VEGF inhibitors in patients with exudative AMD. DESIGN: Prospective cohort study. PARTICIPANTS: We included 185 eyes of 141 patients with exudative AMD who were scheduled for their first treatment with intravitreally administered bevacizumab in this trial. METHODS: All patients were aged >50 years and had angiographically verified exudative AMD. Blood from the finger pad was collected on blood cards for genotyping for the VEGF polymorphisms rs1413711, rs3025039, rs2010963, rs833061, rs699947, rs3024997, and rs1005230. At each follow-up visit, visual acuity was reassessed and an ophthalmic examination was carried out. Visual acuity outcome, number of retreatments, and overall time of treatment were analyzed in dependence of the VEGF polymorphisms. MAIN OUTCOME MEASURES: Mean change in visual acuity at the end of the treatment period. RESULTS: The included patients were reinjected with bevacizumab 1 to 15 times, resulting in a total treatment period of 42 to 1182 days. In univariate analysis only the G/G genotypes of rs3024997 and rs2010963 compared with all other 5 single nucleotide polymorphisms (SNPs) showed a significantly lower visual acuity at the end of treatment. In multivariate analysis including parameters such as time, baseline visual acuity, and number of reinjections, none of the SNPs showed a significant correlation. CONCLUSIONS: The current study indicates that VEGF polymorphisms are not major predictors of anti-VEGF treatment success in patients with exudative AMD.

Repeat percutaneous coronary revascularization: indications and outcomes in a "real world" cohort.

OBJECTIVES: To investigate rates of and reasons for second and subsequent stent procedures in an unselected, "real-world" population. BACKGROUND: Repeat stenting is the primary difference reported in clinical trials of alternative revascularization strategies. The incidence, indication, and outcome for repeat stenting in contemporary practice outside the more selective populations of trials and registries has not been described. METHOD: All patients undergoing a first percutaneous coronary intervention (PCI) procedure with stenting from January 2001 to August 2009 (10,509) from a large UK tertiary referral and district general hospital were identified. Mortality and the incidence, timing, and indication for repeat revascularization in this population were investigated from patient records. RESULTS: Of 10,509 patients undergoing a first PCI and stent implant 23.5% underwent repeat angiography of which 11.2% required repeat PCI and 2% coronary artery bypass grafting (median follow-up of 3.8 years). A total of 1.3% went on to a third PCI. The commonest indication for repeat stenting was disease progression remote from the original stent (46%) and planned staged PCI (23%); 21% had a stent-related indication. Functional assessment before repeat stenting was used in one-third of stable patients. Mortality was 2.5% per annum. CONCLUSIONS: In contemporary practice, patients undergoing a first stenting procedure have a low subsequent mortality, and the substantial majority (86.4%) requires no further revascularization over a median 3.8 year follow-up. For those who do require repeat stenting, this is most commonly at a site remote from the first stent.

Morning headaches in snorers and their bed partners: a prospective diary study.

BACKGROUND: The prevalence and characteristics of morning headaches (MH) in habitual snorers are not well known, with only one retrospective study reporting MH in 23.5% of snorers. The role of MH in bed partners of snorers has not yet been examined. Therefore, the objective of this study was to assess MH prospectively in habitual snorers and their bed partners. METHODS: We recruited habitual snorers and their bed partners via newspaper articles. The participants completed a semistructured interview, filled in questionnaires about sleep quality, daytime sleepiness, depression and anxiety and kept a 90-day headache and sleep diary. RESULTS: We included a total of 102 snorers and 63 bed partners. Seventy-six snorers (25 female) and 41 bed partners (31 female) completed the study, recording a total of 6690 and 3497 diary days, respectively. MH was present on at least 1 day in 57% of the snorers and in 61% of the bed partners and recorded on 7.2% and 3.6% of the diary days, respectively. Independent predictors of MH in snorers were pre-study headache frequency (p < 0.001), anxiety disorder (p < 0.001), waking up because of pain (p = 0.002) and waking up too early (p < 0.001); and independent predictors in bed partners were migraine (p = 0.02), difficulties breathing during sleep (p < 0.001), waking up because of pain (p = 0.01) and waking up too early (p < 0.001). The analysis of couples only (n = 41) revealed pre-study headache frequency (p < 0.001), waking up too early (p < 0.001) and nocturnal confusion (p < 0.001) as independent predictors of MH in snorers, and migraine (p = 0.02), difficulties breathing during sleep (p < 0.001), waking up because of pain (p = 0.01) and waking up too early (p < 0.001) as independent predictors in bed partners. DISCUSSION: MH shows a 90-day prevalence of around 60% in habitual snorers as well as in their bed partners. Predictors of MH are related to sleep, headache and psychiatric comorbidity.

Leukocytosis as an important risk factor for arterial thrombosis in WHO-defined early/prefibrotic myelofibrosis: an international study of 264 patients.

We aimed to determine risk factors for thrombotic events in early/prefibrotic myelofibrosis diagnosed according to the World Health Organization criteria. Multivariate Cox regression analysis was calculated on a total number of 264 patients derived from an international database. After a median follow-up of 6.28 years, 42 (15.9%) patients experienced arterial (n = 31) or venous thrombosis (n = 11). A higher leukocyte count correlated with an increased risk for total thrombosis and in particular, with an increased risk for arterial thrombosis (P = 0.005, HR 1.15 and P = 0.047, HR 1.12, respectively). A platelet count above 870 × 109/L was associated with a lower risk for total thrombosis and also for venous thrombosis (P = 0.022, HR 0.44 and P = 0.027, HR 0.19). Moreover, a lower hemoglobin level was associated with an increased risk for venous thrombosis (P = 0.007, HR 0.59). Our data indicate that leukocytosis is a prominent risk factor for thrombosis in early/prefibrotic MF.

Prospective analysis of factors related to migraine aura--the PAMINA study.

OBJECTIVES: The aim of this study was to examine factors increasing and decreasing the risk of occurrence of migraine aura and of headache and migraine not associated with aura (HoA, MoA) prospectively by means of a daily diary. METHODS: Of 327 patients with migraine completing a comprehensive diary up to 90 days, we selected all patients who recorded at least 1 episode of migraine aura. To find risk indicators and triggers of aura, HoA, and MoA, we analyzed 56 variables and calculated univariate and multivariate generalized linear mixed models. RESULTS: Fifty-four patients recorded a total of 4562 patient days including 354 days with migraine aura. In the multivariate analysis, the risk of aura was statistically significantly increased by smoking, menstruation, and hunger, and it was decreased by holidays and days off. The risk of HoA and/or MoA was increased during menstruation, by psychic tension, tiredness, and odors, and it was decreased by smoking. CONCLUSION: Menstruation is the most prominent factor increasing the risk of aura as well as that of HoA and MoA. Smoking shows the most striking difference increasing the risk of aura, but decreasing the risk of HoA and MoA.