Tenosynovial Giant Cell Tumor Observational Platform Project (TOPP) Registry: A 2-Year Analysis of Patient-Reported Outcomes and Treatment Strategies.

BACKGROUND: The Tenosynovial giant cell tumor Observational Platform Project (TOPP) registry is an international prospective study that -previously described the impact of diffuse-type tenosynovial giant cell tumour (D-TGCT) on patient-reported outcomes (PROs) from a baseline snapshot. This analysis describes the impact of D-TGCT at 2-year follow-up based on treatment strategies. MATERIAL AND METHODS: TOPP was conducted at 12 sites (EU: 10; US: 2). Captured PRO measurements assessed at baseline, 1-year, and 2-year follow-ups were Brief Pain Inventory (BPI), Pain Interference, BPI Pain Severity, Worst Pain, EQ-5D-5L, Worst Stiffness, and -Patient-Reported Outcomes Measurement Information System. Treatment interventions were no current/planned treatment (Off-Treatment) and systemic treatment/surgery (On-Treatment). RESULTS: A total of 176 patients (mean age: 43.5 years) were included in the full analysis set. For patients without active treatment strategy -(Off-Treatment) at baseline (n = 79), BPI Pain Interference (1.00 vs. 2.86) and BPI Pain Severity scores (1.50 vs. 3.00) were numerically favorable in patients remaining Off-Treatment compared with those who switched to an active treatment strategy at year 1. From 1-year to 2-year -follow-ups, patients who remained Off-Treatment had better BPI Pain Interference (0.57 vs. 2.57) and Worst Pain (2.0 vs. 4.5) scores compared with patients who switched to an alternative treatment strategy. In addition, EQ-5D VAS scores (80.0 vs. 65.0) were higher in patients who remained -Off-Treatment between 1-year and 2-year follow-ups compared with patients who changed treatment strategy. For patients receiving systemic treatment at baseline, numerically favorable scores were seen in patients remaining on systemic therapy at 1-year follow-up: BPI Pain Interference (2.79 vs. 5.93), BPI Pain Severity (3.63 vs. 6.38), Worst Pain (4.5 vs. 7.5), and Worst Stiffness (4.0 vs. 7.5). From 1-year to 2-year follow-up, EQ-5D VAS scores (77.5 vs. 65.0) were higher in patients who changed from systemic treatment to a different treatment strategy. CONCLUSION: These findings highlight the impact D-TGCT has on patient quality of life, and how treatment strategies may be influenced by these outcome measures. (ClinicalTrials.gov number: NCT02948088).

Healthcare resource utilization in patients on lipid-lowering therapies outside Western Europe and North America: findings of the cross-sectional observational International ChoLesterol management Practice Study (ICLPS).

BACKGROUND: Few recent large-scale studies have examined healthcare consumption associated with dyslipidemia in countries outside Western Europe and North America. METHODS: This analysis, from a cross-sectional observational study conducted in 18 countries in Eastern Europe, Asia, Africa, the Middle East and Latin America, evaluated avoidable healthcare consumption (defined as ≥1 hospitalization for cardiovascular reasons or ≥1 visit to the emergency room for any reason in the previous 12 months) in patients receiving stable lipid-lowering therapy (LLT). A total of 9049 patients (aged ≥18 years) receiving LLT for ≥3 months and who had had their low-density lipoprotein cholesterol (LDL-C) value measured on stable LLT in the previous 12 months were enrolled between August 2015 and August 2016. Patients who had received a proprotein convertase subtilisin/kexin type 9 inhibitor in the previous 6 months were excluded. Patients were stratified by cardiovascular risk level using the Systematic Coronary Risk Estimation chart for high-risk countries. RESULTS: The proportion of patients at their LDL-C goal was 32.1% for very-high risk patients compared with 55.7 and 51.9% for patients at moderate and high cardiovascular risk, respectively. Overall, 20.1% of patients had ≥1 reported hospitalization in the previous 12 months (7.9% for cardiovascular reasons), 35.2% had ≥1 intensive care unit stay and 13.8% visited the emergency room. Avoidable healthcare resource consumption was reported for 18.7% patients overall, and in 27.8, 7.7, 7.7 and 13.2% of patients at very-high, high, moderate and low risk, respectively. Across all risk groups 22.4% of patients not at LDL-C goal and 16.6% of patients at LDL-C goal had avoidable healthcare resource consumption. Being at very-high cardiovascular risk, having cardiovascular risk factors (including hypertension and smoking), and having factors indicating that the patient may be difficult to treat (including statin intolerance, comorbidities and chronic medication), were independent risk factors for avoidable healthcare resource consumption (all p <0.05). CONCLUSIONS: Healthcare resource consumption associated with adverse clinical outcomes was observed in patients on stable LLT in countries outside Western Europe and North America, particularly those at very-high cardiovascular risk and those who were difficult to treat.

Safety and efficacy of 2-weekly cabazitaxel in metastatic castration-resistant prostate cancer.

OBJECTIVES: To evaluate the safety and efficacy of a 2-weekly cabazitaxel schedule in patients with metastatic castration-resistant prostate cancer (mCRPC). MATERIALS AND METHODS: During the period October 2013 to February 2016, 43 patients with mCRPC were treated with cabazitaxel (16 mg/m2 , on days 1 and 15 of a 4-week cycle) together with prophylactic granulocyte colony-stimulating factor (G-CSF). The safety profile and efficacy (prostate-specific antigen [PSA] response; biological, clinical or radiological progression-free survival [PFS] and overall survival [OS]) of the treatment were analysed. RESULTS: All patients had received prior docetaxel and 79.1% abiraterone acetate. At inclusion, 46.5% were aged >70 years and 27.9% had an Eastern Cooperative Oncology Group performance status ≥2. Six patients stopped treatment because of toxicity. Grade ≥3 toxicities were: asthenia (16.3%); neutropenia (11.6%); thrombocytopenia (9.3%); diarrhoea (7%), anaemia (4.7%), febrile neutropenia (4.7%) and haematuria (2.3%). In all, 52.4% achieved a ≥30% PSA response and 40.5% had a ≥50% PSA response. The median OS was 15.2 months. CONCLUSION: This prospective pilot study suggests that cabazitaxel 16 mg/m² given 2-weekly has a manageable toxicity profile in docetaxel- and abiraterone acetate-pretreated patients with mCRPC. A prospective phase III trial comparing this regimen with the standard cabazitaxel regimen is planned to confirm these results.

Treatment patterns and survival in an exhaustive French cohort of pazopanib-eligible patients with metastatic soft tissue sarcoma (STS).

BACKGROUND: The French EMS study prospectively collected exhaustive data from STS patients diagnosed in the Rhone-Alpes region from 2005 to 07. METHODS: The database included diagnosis/histology, surgery, radiotherapy, systemic treatments and treatment response. Treatment patterns and outcomes of patients with metastatic disease, excluding adipocytic sarcoma and GIST were analyzed. RESULTS: Of 888 total patients, 145 were included based on having metastatic disease and appropriate subtypes. All patients received treatment with systemic therapy being most common (74%, n = 107), followed by radiotherapy (30%, n = 44) and surgery (23%, n = 33). Doxorubicin, alone or in combination, was the most common first line systemic therapy (65%, n = 46). Drugs without license in sarcoma were used in 38-83% of treatments depending on treatment line. 24% of frontline patients demonstrated an objective response, decreasing to 11% objective responses in second line but no responses were documented beyond second line, with median PFS declining with each additional line. Median PFS also declined in patients receiving surgery compared to those receiving no surgery (8-15 m vs 5 m). Median OS from metastatic diagnosis for patients receiving systemic therapy was double that of patients without systemic treatment (24 m vs 12 m, p = 0.007). CONCLUSIONS: Outcomes in this population were poor and declined with successive treatment. However, results suggest that further anticancer therapies in recurrent sarcoma might be beneficial.

Treatment patterns, clinical outcomes and health care costs associated with HER2-positive breast cancer with central nervous system metastases: a French multicentre observational study.

BACKGROUND: The population of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) who develop central nervous system (CNS) metastases is growing. Treatment strategies in this population are highly diverse. The objective of the study was to assess health care costs for the management of HER2 positive BC with CNS metastases. METHODS: This multicentre, retrospective, observational study was conducted on HER2-positive BC patients diagnosed with CNS metastases between 2006 and 2008. Data were extracted from patient medical records to estimate health care resource use. A partitioned estimator was used to adjust censoring costs by use of the Kaplan-Meier survival estimate. RESULTS: 218 patients were included and costs were estimated for 200 patients. The median time to detection of CNS metastases was 37.6 months. The first metastatic event involved the CNS in 39 patients, and this was the unique first metastatic site in 31 of these patients. Two years following diagnosis of CNS metastases, 70.3% of patients had died. The mean per capita cost of HER2-positive BC with CNS metastases in the first year following diagnosis was €35,735 [95% CI: 31,716-39,898]. The proportion of costs attributed to expensive drugs and those arising from hospitalisation were in the same range. CONCLUSION: A range of individualised disease management strategies are used in HER2-positive BC patients with CNS metastases and the treatments used in the first months following diagnosis are expensive. The understanding of cost drivers may help optimise healthcare expenditure and inform the development of appropriate prevention policies.

One-year effectiveness of a 3-week balneotherapy program for the treatment of overweight or obesity.

Objective. To assess the one-year effectiveness on weight loss of a 3-week balneotherapy program (BT). Method. A Zelen double consent randomised controlled trial to compare one-year BMI loss between a 3-week BT program versus usual care (UC) for overweight or obese patients (BMI: 27-35 kg/m(2)), associated or not with a dietary motivational interview (DMI) during the follow-up, using a 2 × 2 factorial design. Main analysis was a per protocol analysis comparing patients attending BT to patients managed by UC, matched on sex, overweight or obese status, DMI randomisation and a propensity score to attend BT or to be managed by UC. Results. From the 257 patients who completed the follow-up, 70 patients of each group could be matched. Mean BMI loss was 1.91 kg/m(2) [95%CI: 1.46; 2.35] for the BT patients and 0.20 kg/m(2) [-0.24; 0.64] for the UC patients (P < 0.001), corresponding to a significant BT benefit of 1.71 kg/m(2) [1.08; 2.33]. There was no significant effect of DMI and no interaction with BT or UC. No adverse reaction was observed for patients attending BT. Conclusion. A 3-week BT program provided a significant one-year benefit over the usual GP dietary advice for overweight and obese patients.

Management of osteoporosis and associated quality of life in post menopausal women.

BACKGROUND: The study aimed to describe the characteristics of women treated for recently-diagnosed osteoporosis, to identify variables associated with different treatment regimens and to assess impact on quality of life. METHODS: This is an observational, cross-sectional pharmacoepidemiological study performed in France. A random sample of 684 general practitioners, gynaecologists and rheumatologists included the first three post-menopausal osteoporotic women consulting in the previous six months on the basis of densitometry or fracture. Data on osteoporosis, fracture risk factors, treatments and comorbidities was collected with a physician questionnaire. Data on quality of life was collected using the SF-12. RESULTS: Data were analysed for 1,306 patients, of whom 1,117 (85.5%) had been evaluated by densitometry within the previous six months and 554 (42.4%) had experienced a fracture, most frequently of the spine or wrist within the previous six months. Osteoporotic fracture risk factors were reported in 1,028 women (78.7%). 746 women (57.1%) were currently receiving treatment, most frequently weekly or monthly bisphosphonates. Five variables were associated with prescription choice: age (p < 0.0001), physician speciality (p < 0.0001), previous fracture history (p = 0.0002), ongoing treatment at the time of consultation (p = 0.0091) and paraclinical investigations performed in the previous six months (p = 0.0060). SF-12 scores were lower in women complaining of pain, with recent fractures and with spine or hip fractures and in women consulting rheumatologists. CONCLUSIONS: A high proportion of women diagnosed with osteoporosis had been evaluated by densitometry, in agreement with national guidelines. Treatment choice varied between physician groups.

Pain Progression at Initiation of Cabazitaxel in Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Post Hoc Analysis of the PROSELICA Study.

BACKGROUND: In the PROSELICA phase III trial (NCT01308580), cabazitaxel 20 mg/m2 (CABA20) was non-inferior to cabazitaxel 25 mg/m2 (CABA25) in mCRPC patients previously treated with docetaxel (DOC). The present post hoc analysis evaluates how the type of progression at randomization affected outcomes. METHODS: Progression type at randomization was defined as follows: PSA progression only (PSA-p; no radiological progression (RADIO-p), no pain), RADIO-p (±PSA-p, no pain), or pain progression (PAIN-p, ±PSA-p, ±RADIO-p). Relationships between progression type and overall survival (OS), radiological progression-free survival (rPFS), and PSA response (confirmed PSA decrease ≥ 50%) were analyzed. RESULTS: All randomized patients (n = 1200) had received prior DOC, and 25.7% had received prior abiraterone or enzalutamide. Progression type at randomization was evaluable in 1075 patients (PSA-p = 24.4%, RADIO-p = 20.8%, PAIN-p = 54.8%). Pain progression was associated with clinical and biological features of aggressive disease. Median OS from CABA initiation or date of mCRPC diagnosis, all arms combined, was shorter in the PAIN-p group than in the RADIO-p or the PSA-p groups (12.0 versus 16.8 and 18.4 months, respectively, p < 0.001). In multivariate analysis, all arms combined, PAIN-p was an independent predictor of poor OS (HR = 1.44, p < 0.001). PSA response, rPFS, and OS were numerically higher with CABA25 versus CABA20 in patients with PAIN-p. CONCLUSIONS: This post hoc analysis of the PROSELICA phase III study shows that pain progression at initiation of CABA in mCRPC patients previously treated with DOC is associated with a poor prognosis. Disease progression should be carefully monitored, even in the absence of PSA rise.

An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer.

Durvalumab is a programmed death-ligand 1 (PD-L1) inhibitor with clinical activity in advanced urothelial cancer (AUC)1. AUC is characterized by several recurrent targetable genomic alterations2-5. This study ( NCT02546661 , BISCAY) combined durvalumab with relevant targeted therapies in biomarker-selected chemotherapy-refractory AUC populations including: (1) fibroblast growth factor receptor (FGFR) inhibitors in tumors with FGFR DNA alterations (FGFRm); (2) pharmacological inhibitor of the enzyme poly-ADP ribose polymerase (PARP) in tumors with and without DNA homologous recombination repair deficiency (HRRm); and (3) TORC1/2 inhibitors in tumors with DNA alteration to the mTOR/PI3K pathway3-5.This trial adopted a new, biomarker-driven, multiarm adaptive design. Safety, efficacy and relevant biomarkers were evaluated. Overall, 391 patients were screened of whom 135 were allocated to one of six study arms. Response rates (RRs) ranged 9-36% across the study arms, which did not meet efficacy criteria for further development. Overall survival (OS) and progression-free survival (PFS) were similar in the combination arms and durvalumab monotherapy arm. Biomarker analysis showed a correlation between circulating plasma-based DNA (ctDNA) and tissue for FGFRm. Sequential circulating tumor DNA analysis showed that changes to FGFRm correlated with clinical outcome. Our data support the clinical activity of FGFR inhibition and durvalumab monotherapy but do not show increased activity for any of the combinations. These findings question the targeted/immune therapy approach in AUC.

Compliance and treatment satisfaction of post menopausal women treated for osteoporosis. Compliance with osteoporosis treatment.

BACKGROUND: Adherence to anti-osteoporosis treatments is poor, exposing treated women to increased fracture risk. Determinants of poor adherence are poorly understood. The study aims to determine physician- and patient- rated treatment compliance with osteoporosis treatments and to evaluate factors influencing compliance. METHODS: This was an observational, cross-sectional pharmacoepidemiological study with a randomly-selected sample of 420 GPs, 154 rheumatologists and 110 gynaecologists practicing in France. Investigators included post-menopausal women with a diagnosis of osteoporosis and a treatment initiated in the previous six months. Investigators completed a questionnaire on clinical features, treatments and medical history, and on patient compliance. Patients completed a questionnaire on sociodemographic features, lifestyle, attitudes and knowledge about osteoporosis, treatment compliance, treatment satisfaction and quality of life. Treatment compliance was evaluated with the Morisky Medication-taking Adherence Scale. Variables collected in the questionnaires were evaluated for association with compliance using multivariate logistic regression analysis. RESULTS: 785 women were evaluated. Physicians considered 95.4% of the sample to be compliant, but only 65.5% of women considered themselves compliant. The correlation between patient and physician perceptions of compliance was low (κ: 0.11 [95% CI: 0.06 to 0.16]). Patient-rated compliance was highest for monthly bisphosphonates (79.7%) and lowest for hormone substitution therapy (50.0%). Six variables were associated with compliance: treatment administration frequency, perceptions of long-term treatment acceptability, perceptions of health consequences of osteoporosis, perceptions of knowledge about osteoporosis, exercise and mental quality of life. CONCLUSION: Compliance to anti-osteoporosis treatments is poor. Reduction of dosing regimen frequency and patient education may be useful ways of improving compliance.

The challenge of multiple cardiovascular risk factor control outside Western Europe: Findings from the International ChoLesterol management Practice Study.

BACKGROUND: Comprehensive control of multiple cardiovascular risk factors reduces cardiovascular risk but is difficult to achieve. DESIGN: A multinational, cross-sectional, observational study. METHODS: The International ChoLesterol management Practice Study (ICLPS) investigated achievement of European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guideline low-density lipoprotein cholesterol (LDL-C) targets in patients receiving lipid-modifying therapy in countries outside Western Europe. We examined the rate of, and association between, control of multiple risk factors in ICLPS participants with dyslipidaemia, diabetes and hypertension (N = 2377). RESULTS: Mean (standard deviation) age of patients was 61.4 (10.4) years; 51.3% were male. Type 2 diabetes was the most common form of diabetes (prevalence, 96.9%). The prevalence of metabolic syndrome was 67.8%, obesity 40.4%, atherosclerotic disease 39.6% and coronary artery disease 33.5%. All patients were at high (38.2%) or very high (61.8%) cardiovascular risk according to ESC/EAS guidelines. Body mass index (BMI) was <25 kg/m2 in 20.3% of patients, 62.8% had never smoked and 25.2% were former smokers. Overall, 12.2% achieved simultaneous control of LDL-C, diabetes and blood pressure. Risk factor control was similar across all participating countries. The proportion of patients achieving individual guideline-specified treatment targets was 43.9% for LDL-C, 55.5% for blood pressure and 39.3% for diabetes. Multiple correspondence analysis indicated that control of LDL-C, control of blood pressure, control of diabetes, BMI and smoking were associated. CONCLUSION: Comprehensive control of multiple cardiovascular risk factors in high-risk patients is suboptimal worldwide. Failure to control one risk factor is associated with poor control of other risk factors.

Impact of progression at baseline and on-treatment progression events in three large prostate cancer trials.

BACKGROUND: There is a discussion about the optimal timing to initiate or switch treatment in metastatic castration-resistant prostate cancer (mCRPC). This post hoc analysis of 3 large trials for men with mCRPC examined the influence of the type of progression at initiation of first-line chemotherapy, as well as the type of progression during treatment, on treatment outcomes. METHODS: Data from the phase III studies VENICE (n = 1224), TAX327 (n = 1006) and FIRSTANA (n = 1168) were used as independent data sets. Type of progression was defined as follows: prostate-specific antigen (PSA) only (group 1), radiological (±PSA) (group 2) or pain (±PSA, ± radiological) progression (group 3). The impact of baseline type of progression on overall survival (OS) was evaluated in multivariate Cox regression analysis with backward elimination, stratified for the Eastern Cooperative Oncology Group performance score and treatment arm. RESULTS: The median OS (arms combined) from treatment initiation in VENICE was 28.6, 26.3 and 16.9 months for G1, G2 and G3, respectively (hazard ratio: 1.14 [95% confidence interval {CI}: 0.92-1.41%] in G2 and 2.13 [95% CI: 1.75-2.59%] in G3 compared with G1). Multivariate analysis (arms combined) showed that pain progression at baseline was an independent predictor of poor OS. Similar findings were observed in the TAX327 and FIRSTANA data sets. During treatment, pain or radiological progression preceded PSA progression in ~55% of the patients. The retrospective characteristic of this study is a limitation. CONCLUSIONS: The type of progression at baseline strongly predicts OS in men with mCRPC treated with first-line chemotherapy. During treatment, pain and/or radiological progression preceded PSA progression as the first progression event in ~55% of the patients. This finding has the prospect to be incorporated in clinical guidelines and to be practice changing because it implies the need for regular imaging and not to rely on PSA progression alone.

Low-density lipoprotein cholesterol goal achievement in patients with familial hypercholesterolemia in countries outside Western Europe: The International ChoLesterol management Practice Study.

BACKGROUND: The cross-sectional observational International ChoLesterol management Practice Study study assessed achievement of European Society of Cardiology/European Atherosclerosis Society low-density lipoprotein cholesterol (LDL-C) targets in patients outside Western Europe. OBJECTIVE: The aim of the study was to assess LDL-C goal achievement in International ChoLesterol management Practice Study participants with familial hypercholesterolemia (FH). METHODS: A total of 334 patients (aged ≥18 years) with definite or probable FH (Dutch Lipid Clinic Network score ≥6; 43.1% genetically confirmed) who had been receiving stable lipid-modifying therapy (LMT) for ≥3 months were enrolled. RESULTS: The mean ± standard deviation age of the patients was 58.5 ± 13.1 years, 49.1% were male, and 48.2% had coronary artery disease. Most were receiving statin (∼99%). Of these, 57.6% were on high-intensity statin therapy, 49.1% on the highest dose available, and 13.0% used a statin together with a cholesterol absorption inhibitor (CAI). Mean ± standard deviation LDL-C level was 5.6 ± 3.0 mmol/L before LMT and 3.3 ± 2.0 mmol/L at enrollment. Overall, 32.0% of patients achieved their LDL-C target. Target achievement rates were 36.6% for patients with coronary artery disease, and 27.5% for those without, and 27.9%, 28.0%, and 37.5% for patients treated with a statin plus CAI, highest-dose statin (no CAI), and lower-dose statin (no CAI), respectively. CONCLUSIONS: LDL-C target achievement rates were low in patients with FH, even in those receiving intensive LMT. Factors that are likely to have contributed to the low LDL-C target achievement rates include high baseline LDL-C, inadequate statin dosages, and low use of CAI. Many patients would have been eligible for proprotein convertase subtilisin/kexin type 9 inhibitor therapy.

Relationship between compliance and persistence with osteoporosis medications and fracture risk in primary health care in France: a retrospective case-control analysis.

BACKGROUND: Nonadherence to treatment is an important determinant of long-term outcomes in women with osteoporosis. OBJECTIVES: This study was conducted to investigate the association between adherence and osteoporotic fracture risk and to identify optimal thresholds for good compliance and persistence. A secondary objective was to perform a preliminary evaluation of the cost consequences of adherence. METHOD: This was a retrospective case-control analysis. Data were derived from the Thales prescription database, which contains information on >1.6 million patients in the primary health care setting in France. Cases were women aged >or=50 years who had an osteoporosis-related fracture in 2006. For each case, 5 matched controls were randomly selected. Both compliance and persistence aspects of treatment adherence were examined. Compliance was estimated based on the medication possession ratio (MPR). Persistence was calculated as the time from the initial filling of a prescription for osteoporosis medication until its discontinuation. RESULTS: The mean (SD) MPR was lower in cases compared with controls (58.8% [34.7%] vs 72.1% [28.8%], respectively; P < 0.001). Cases were more likely than controls to discontinue osteoporosis treatment (50.0% vs 25.3%; P < 0.001), yielding a significantly lower proportion of patients who were still persistent at 1 year (34.1% vs 40.9%; P < 0.001). MPR was the best predictor of fracture risk, with an area under the receiver-operating-characteristic curve that was higher than that for persistence (0.59 vs 0.55). The optimal MPR threshold for predicting fracture risk was >or=68.0%. Compared with less-compliant women, women who achieved this threshold had a 51% reduction in fracture risk. The difference in annual drug expenditure between women achieving this threshold and those who did not was approximately euro300. The optimal threshold for persistence with therapy was at least 6 months. Attaining this threshold was associated with a 28% reduction in fracture risk compared with less-persistent women. CONCLUSIONS: In this study, better treatment adherence was associated with a greater reduction in fracture risk. Compliance appeared to predict fracture risk better than did persistence.

Achievement of low-density lipoprotein cholesterol goals in 18 countries outside Western Europe: The International ChoLesterol management Practice Study (ICLPS).

Background Little is known about the achievement of low density lipoprotein cholesterol (LDL-C) targets in patients at cardiovascular risk receiving stable lipid-lowering therapy (LLT) in countries outside Western Europe. Methods This cross-sectional observational study was conducted in 452 centres (August 2015-August 2016) in 18 countries in Eastern Europe, Asia, Africa, the Middle East and Latin America. Patients ( n = 9049) treated for ≥3 months with any LLT and in whom an LDL-C measurement on stable LLT was available within the previous 12 months were included. Results The mean±SD age was 60.2 ± 11.7 years, 55.0% of patients were men and the mean ± SD LDL-C value on LLT was 2.6 ± 1.3 mmol/L (101.0 ± 49.2 mg/dL). At enrolment, 97.9% of patients were receiving a statin (25.3% on high intensity treatment). Only 32.1% of the very high risk patients versus 51.9% of the high risk and 55.7% of the moderate risk patients achieved their LDL-C goals. On multivariable analysis, factors independently associated with not achieving LDL-C goals were no (versus lower dose) statin therapy, a higher (versus lower) dose of statin, statin intolerance, overweight and obesity, female sex, neurocognitive disorders, level of cardiovascular risk, LDL-C value unknown at diagnosis, high blood pressure and current smoking. Diabetes was associated with a lower risk of not achieving LDL-C goals. Conclusions These observational data suggest that the achievement of LDL-C goals is suboptimal in selected countries outside Western Europe. Efforts are needed to improve the management of patients using combination therapy and/or more intensive LLTs.

New versus established drugs in venous thromboprophylaxis: efficacy and safety considerations related to timing of administration.

European surgeons generally administer thromboprophylaxis with low-molecular-weight heparins (LMWHs) at high doses 12 hours preoperatively in response to findings that surgery-related deep-vein thrombosis typically originates at the time of major orthopedic surgery or shortly afterwards. North American surgeons, in contrast, generally administer LMWHs at an almost 50% higher dose than that given in Europe 12-24 hours postoperatively, even though both pre- and postoperative administration are considered suitable in current guidelines. This review therefore examines how close to major orthopedic surgery thromboprophylaxis is administered, and the subsequent effect of timing on clinically relevant efficacy and safety parameters. The trials examined involve fondaparinux sodium (fondaparinux) and (xi)melagatran, in comparison with the established LMWHs enoxaparin sodium (enoxaparin) and dalteparin. In key trials, fondaparinux reduced the risk of asymptomatic and clinical venous thromboembolism (VTE) by 55% compared with enoxaparin, at the expense of a 1.6-fold higher risk of bleeding. While the studies were not designed to compare efficacy endpoints based on clinical outcomes, no significant difference was demonstrated for symptomatic VTE. The fact that the enoxaparin regimen was started at the upper limits of its recommended initiation timeframe may have significantly influenced the results of comparative studies, given that several meta-analyses found that the timing of LMWH initiation significantly influenced its effectiveness on asymptomatic VTE and major bleedings. Compared with once-daily LMWH in European trials, early postoperative doses/regimens of twice-daily (xi)melagatran did not increase severe bleeding and was significantly less effective at preventing asymptomatic total VTE in patients who had undergone total hip-replacement surgery. When used according to the 'knife-to-skin' protocol, the melagatran regimen was superior to enoxaparin in preventing major asymptomatic VTE, but at the cost of a higher rate of major bleeding. In North America, the delayed postoperative administration of (xi)melagatran (oral only) was less effective than the postoperative twice-daily enoxaparin regimen with regard to asymptomatic total and major VTE. Our analysis highlights the fact that differences in efficacy and safety data in clinical trials of thromboprophylaxis might also be linked to differences in the timing of initiation. However, it is not possible to assess the importance of this 'time effect' among other factors considered as drug-specific properties (pharmacokinetics, mode of action, dosage) and evaluate their respective contribution in the observed differences. To avoid unbiased comparison in further studies, the possible effect of timing should be taken into account and, when feasible, both therapies started at the same time. For instance, harmonizing the initiation of thromboprophylaxis 6-8 or 12 hours postoperatively could be two acceptable harmonized options for scheduling in clinical trials.

Improvement in quality of life after initiation of lamotrigine therapy in patients with epilepsy in a naturalistic treatment setting.

Quality of life is impaired in patients with epilepsy and can be improved by effective therapy. Randomised clinical trials have shown that lamotrigine treatment is associated with improved quality of life. However, little information is available on quality of life or treatment effects in patients with epilepsy in the general population. The objective of this study was to estimate the impact of lamotrigine on quality of life in a naturalistic treatment setting. The study included adult patients with epilepsy in whom lamotrigine therapy was initiated. Each subject completed the Quality of Life in Epilepsy Inventory (QOLIE)-31 quality of life questionnaire at inclusion and at a follow-up visit in the next 4 months. Demographic information and medical history were provided by the investigator. These were evaluated as potential determinants of change in quality of life using logistic regression. Three hundred and forty-one patients were evaluated, 192 starting lamotrigine in combination with another drug, 90 as a first-line monotherapy, 45 as a switch from another drug and 14 as a reduction to monotherapy from a previous combination. Baseline scores on the QOLIE-31 ranged from 53.8 in the combination group to 69.5 in the first-line group. 34.6% of patients were considered to be responders, with no significant differences between treatment regimen. Most improvement was seen for the energy-fatigue and medication effects subscales and, for the first-line group, seizure worry. Seizure type was the only determinant of improvement of quality of life identified. In conclusion, lamotrigine treatment is associated with improved quality of life, regardless of treatment regimen.

Effect of aqueous acetic, oxalic, and carbonic acids on the adsorption of europium(III) onto alpha-alumina.

Chemical retention, i.e., partition of the element between aqueous solution and mineral surface, is a key phenomenon for assessing the safety of possible nuclear waste disposal. For this purpose, the sorption of Eu(III) onto a model mineral-alpha-alumina-is studied here, including the effects of groundwater chemistry: pH and concentrations of small organic and inorganic ligands (acetate, oxalate, and carbonate anions). This work presents some experimental evidence for a synergic mechanism of sorption of europium-ligand complexes onto the alumina. Only cationic complexes were necessary to consider to model experimental results. Using the ion-exchange theory (IET) and a corresponding restricted set of parameters-exchange capacities and thermodynamic equilibrium constants-the whole set of sorption experiments of Eu(III) cationic species onto the alpha-alumina was modeled under various chemical conditions.

Sorption of aqueous carbonic, acetic, and oxalic acids onto alpha-alumina.

The presence of organic complexing agents can modify the behavior of a surface. This study aims to better understand the impact of carboxylic acids (acetic, oxalic, and carbonic acids) issued from cellulose degradation and equally naturally present in soils. First, evidence of two different kinds of sites for chloride adsorption onto alpha-alumina and another for sodium sorption was provided. Consequently, no competition between these cation and anion sorptions occurs on alpha-alumina. The associated exchange capacities and ionic exchange constants were measured. Second, the adsorption behavior of the carboxylic acids was studied as a function of aqueous -log[H(+)] and 0.01 to 0.1 M ionic strength (NaCl), and modeled by using mass action law for ideal biphasic systems. The carboxylic acids were found to be adsorbed on the same sites as chloride ions. The competition between organic ligands and chloride ions was satisfactorily accounted for by the model assuming the deprotonated form of the ligands was sorbed on alpha-alumina. The model also allowed us to interpret the adsorption of all species under various conditions without any extra fitting parameters.

Prostate-specific antigen flare induced by cabazitaxel-based chemotherapy in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: A prostate-specific antigen (PSA) flare occurs in about 15% of metastatic castration-resistant prostate cancer (mCRPC) patients receiving docetaxel. This flare has no standard definition. Its impact on treatment efficacy is unclear. We sought to evaluate the incidence and characteristics of PSA flare on cabazitaxel, and its impact on survival. METHODS: Multicentre retrospective review of consecutive patients treated with cabazitaxel second-line chemotherapy for mCRPC. Collection of baseline characteristics, disease history and PSA levels before and during cabazitaxel therapy. Overall survival (OS) and radiological/clinical progression-free survival (PFS) for patient groups corresponding to different definitions of PSA flare estimated by the Kaplan-Meier method and compared using the log-rank test. RESULTS: Overall, 125 patients were included. Median PFS and OS were 6.5 and 13.3 months, respectively. Depending upon the definition used, flare incidence ranged from 8.3% to 30.6%. The flare lasted <2.6 months. A PSA flare followed by a ⩾ 50% decrease was associated with a median PFS and OS of 11.2 and 25.2 months, respectively. Median PFS and OS for a ⩾ 30% rather than ⩾ 5 0% decrease were 10.4 and 16.5 months. These outcomes were not significantly different from those in patients with immediate PSA decreases of ⩾ 50% or ⩾ 30% from baseline, but were significantly better than in patients experiencing no PSA decrease (p = 0.006 and 0.015, respectively, for OS). CONCLUSION: The PSA response to cabazitaxel, with or without initial flare, was associated with a strong survival benefit. The taxane-induced flare during the first 12 weeks of therapy can be ignored when evaluating PSA response.