Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study.

BACKGROUND: Ischemic stroke is the leading cause of mortality worldwide and a major contributor to neurological disability and dementia. Terutroban is a specific TP receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which may be of interest for the secondary prevention of ischemic stroke. This article describes the rationale and design of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic Attack (PERFORM) Study, which aims to demonstrate the superiority of the efficacy of terutroban versus aspirin in secondary prevention of cerebrovascular and cardiovascular events. METHODS AND RESULTS: The PERFORM Study is a multicenter, randomized, double-blind, parallel-group study being carried out in 802 centers in 46 countries. The study population includes patients aged > or =55 years, having suffered an ischemic stroke (< or =3 months) or a transient ischemic attack (< or =8 days). Participants are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy endpoint is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is being evaluated by assessing hemorrhagic events. Follow-up is expected to last for 2-4 years. Assuming a relative risk reduction of 13%, the expected number of primary events is 2,340. To obtain statistical power of 90%, this requires inclusion of at least 18,000 patients in this event-driven trial. The first patient was randomized in February 2006. CONCLUSIONS: The PERFORM Study will explore the benefits and safety of terutroban in secondary cardiovascular prevention after a cerebral ischemic event.

Multi institutional phase II study of concomitant stereotactic reirradiation and cetuximab for recurrent head and neck cancer.

PURPOSE: Recurrent head and neck cancer is associated to a poor survival prognosis. A high toxicity rate is demonstrated when surgery and/or radiotherapy and/or chemotherapy are combined. Furthermore, the duration of treatment is often not ethically compatible with the expected survival (median survival<1year). Normal tissues tolerance limits the use of reirradiation and stereotactic body radiotherapy (SBRT) could offer precise irradiation while sparing healthy tissues. After completion of a feasibility study, results of a multicentric study (Lille, Nancy & Nice) using SBRT with cetuximab are reported. The aim of the study was to deliver non toxic short course SBRT (2weeks) in order to get the same local control as the one demonstrated with longer protocols. METHODS AND MATERIALS: Patients with inoperable recurrent, or new primary tumor in a previously irradiated area, were included (WHO<3). Reirradiation (RT) dose was 36Gy in six fractions of 6Gy to the 85% isodose line covering 95% of the PTV with 5 injections of concomitant cetuximab (CT). All patients had previous radiotherapy, 85% had previous surgery and 48% previous chemotherapy. RESULTS: Between 11/2007 and 08/2010, 60 were included (46 men and 14 women), 56 received CT+RT, 3 were not treated and 1 received only CT. Median age was 60 (42-87)) and all 56 patients had squamous carcinoma and received concomitant cetuximab. Mean time between previous radiotherapy and the start of SBRT was 38months. Cutaneous toxicity was observed for 41 patients. There was one toxic death from hemorrhage and denutrition. Median follow-up was 11.4months. At 3months, response rate was 58.4% (95% CI: 43.2-72.4%) and disease control rate was 91.7% (95% CI: 80.0-97.7%). The one-year OS rate was 47.5% (95% CI: 30.8-62.4). CONCLUSION: These results suggest that short SBRT with cetuximab is an effective salvage treatment with good response rate in this poor prognosis population with previously irradiated HNC. Treatment is feasible and, with appropriate care to limiting critical structure, acute toxicities are acceptable. This combination may be the reference treatment is this population.

Association of calcemia and serum vitamin D with 24H-urinary calcium excretion in a swiss population-based study

Background: Elevated urinary calcium excretion is associated with reduced bone mineral density. Population-based data on urinary calcium excretion are scarce. We explored the association of serum calcium and circulating levels of vitamin D (including 25(OH)D2 and 25(OH)D3) with urinary calcium excretion in men and women in a population-based study. Methods: We used data from the "Swiss Survey on Salt" conducted between 2010 and 2012 and including people aged 15 years and over. Twenty-four hour urine collection, blood analysis, clinical examination and anthropometric measures were collected in 11 centres from the 3 linguistic regions of Switzerland. Vitamin D was measured centrally using liquid chromatography - tandem mass spectrometry. Hypercalciuria was defined as urinary calcium excretion >0.1 mmol/kg/24h. Multivariable linear regression was used to explore factors associated with 24-hour urinary calcium excretion (mmol/24h) squared root transformed, taken as the dependant variable. Vitamin D was divided into monthspecific tertiles with the first tertile having the lowest value and the third tertile having the highest value. Results: The 669 men and 624 women had mean (SD) age of 49.2 (18.1) and 47 (17.9) years and a prevalence of hypercalciuria of 8.9% and 8.0%, respectively. In adjusted models, the association of urinary calcium excretion with protein-corrected serum calcium was (β coefficient } standard error, according to urinary calcium squared root transformed) 1.125 } 0.184 mmol/L per square-root (mmol/24h) (P<0.001) in women and 0.374 } 0.224 (P=0.096) in men. Men in the third month-specific vitamin D tertile had higher urinary calcium excretion than men in the first tertile (0.170 } 0.05 nmol/L per mmol/24h, P=0.001) and the corresponding association was 0.048 } 0.043, P= 0.272 in women. Conclusion: About one in eleven person has hypercalciuria in the Swiss population. The positive association of serum calcium with urinary calcium excretion was steeper in women than in men, independently of menopausal status. Circulating vitamin D was associated positively with urinary calcium excretion only in men. The reasons underlying the observed sex differences in the hormonal control of urinary calcium excretion need to be explored in further studies.

Determination of 241Pu in nuclear waste slurries: a comparative study using LSC and ICP-MS.

(241)Pu was determined in slurry samples from a nuclear reactor decommissioning project at the Paul Scherrer Institute (Switzerland). To validate the results, the (241)Pu activities of five samples were determined by LSC (TriCarb and Quantulus) and ICP-MS, with each instrument at a different laboratory. In lack of certified reference materials for (241)Pu, the methods were further validated using the (241)Pu information values of two reference sediments (IAEA-300 and IAEA-384). Excellent agreement with the results was found between LSC and ICP-MS in the nuclear waste slurries and the reference sediments.

An international validation study of the EORTC brain cancer module (EORTC QLQ-BN20) for assessing health-related quality of life and symptoms in brain cancer patients.

Aims: The psychometric properties of the EORTC QLQ-BN20, a brain cancer-specific HRQOL questionnaire, have been previously determined in an English-speaking sample of patients. This study examined the validity and reliability of the questionnaire in a multi-national, multi-lingual study. Methods: QLQ-BN20 data were selected from two completed phase III EORTC/NCIC clinical trials in brain cancer (N=891), including 12 languages. Experimental treatments were surgery followed by radiotherapy (RT) and adjuvant PCV chemotherapy or surgery followed by concomitant RT plus temozolomide (TMZ) chemotherapy and adjuvant TMZ chemotherapy. Standard treatment consisted of surgery and postoperative RT alone. The psychometrics of the QLQ-BN20 were examined by means of multi-trait scaling analyses, reliability estimation, known groups validity testing, and responsiveness analysis. Results: All QLQ-BN20 items correlated more strongly with their own scale (r>0.70) than with other QLQ-BN20 scales. Internal consistency reliability coefficients were high (all alpha0.70). Known-groups comparisons yielded positive results, with the QLQ-BN20 distinguishing between patients with differing levels of performance status and mental functioning. Responsiveness of the questionnaire to changes over time was acceptable. Conclusion: The QLQ-BN20 demonstrates adequate psychometric properties and can be recommended for use in conjunction with the QLQ-C30 in assessing the HRQOL of brain cancer patients in international studies.

Combined effect of tobacco and alcohol on laryngeal cancer risk : a case-control study

OBJECTIVE: To provide information on the effects of alcohol and tobacco on laryngeal cancer and its subsites. METHODS: This was a case-control study conducted between 1992 and 2000 in northern Italy and Switzerland. A total of 527 cases of incident squamous-cell carcinoma of the larynx and 1297 hospital controls frequency-matched with cases on age, sex, and area of residence were included. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using multiple logistic regression. RESULTS: In comparison with never smokers, ORs were 19.8 for current smokers and 7.0 for ex-smokers. The risk increased in relation to the number of cigarettes (OR = 42.9 for > or = 25 cigarettes/day) and for duration of smoking (OR = 37.2 for > or = 40 years). For alcohol, the risk increased in relation to number of drinks (OR = 5.9 for > or = 56 drinks per week). Combined alcohol and tobacco consumption showed a multiplicative (OR = 177) rather than an additive risk. For current smokers and current drinkers the risk was higher for supraglottis (ORs 54.9 and 2.6, respectively) than for glottis (ORs 7.4 and 1.8) and others subsites (ORs 10.9 and 1.9). CONCLUSIONS: Our study shows that both cigarette smoking and alcohol drinking are independent risk factors for laryngeal cancer. Heavy consumption of alcohol and cigarettes determined a multiplicative risk increase, possibly suggesting biological synergy.

How Reliable Is Ki-67 Immunohistochemistry in Grade 2 Breast Carcinomas? A QA Study of the Swiss Working Group of Breast- and Gynecopathologists.

Adjuvant chemotherapy decisions in breast cancer are increasingly based on the pathologist's assessment of tumor proliferation. The Swiss Working Group of Gyneco- and Breast Pathologists has surveyed inter- and intraobserver consistency of Ki-67-based proliferative fraction in breast carcinomas. METHODS: Five pathologists evaluated MIB-1-labeling index (LI) in ten breast carcinomas (G1, G2, G3) by counting and eyeballing. In the same way, 15 pathologists all over Switzerland then assessed MIB-1-LI on three G2 carcinomas, in self-selected or pre-defined areas of the tumors, comparing centrally immunostained slides with slides immunostained in the different laboratoires. To study intra-observer variability, the same tumors were re-examined 4 months later. RESULTS: The Kappa values for the first series of ten carcinomas of various degrees of differentiation showed good to very good agreement for MIB-1-LI (Kappa 0.56-0.72). However, we found very high inter-observer variabilities (Kappa 0.04-0.14) in the read-outs of the G2 carcinomas. It was not possible to explain the inconsistencies exclusively by any of the following factors: (i) pathologists' divergent definitions of what counts as a positive nucleus (ii) the mode of assessment (counting vs. eyeballing), (iii) immunostaining technique, and (iv) the selection of the tumor area in which to count. Despite intensive confrontation of all participating pathologists with the problem, inter-observer agreement did not improve when the same slides were re-examined 4 months later (Kappa 0.01-0.04) and intra-observer agreement was likewise poor (Kappa 0.00-0.35). CONCLUSION: Assessment of mid-range Ki-67-LI suffers from high inter- and intra-observer variability. Oncologists should be aware of this caveat when using Ki-67-LI as a basis for treatment decisions in moderately differentiated breast carcinomas.

Hypertension and intra-operative incidents: a multicentre study of 125000 surgical procedures in Swiss hospitals

Background: It is debated whether chronic hypertension increases the risk of cardiovascular incidents during anaesthesia. Methods: We studied all elective surgical operations performed in adults under general or regional anaesthesia between 2000 and 2004, in 24 hospitals collecting computerised clinical data on all anaesthetia since 1996. The focus was on cardiovascular incidents, though other anaesthesia-related incidents were also evaluated. Results: Among 124 939 interventions, 27 881 (22%) were performed in hypertensive patients. At least one cardiovascular incident occurred in 7549 interventions (6% [95% CI 5.9-6.2%]). The average adjusted odds ratio of cardiovascular risk in patients with chronic hypertension was 1.38 (95% CI 1.27-1.49). However, across hospitals, adjusted odd ratios varied from 0.41 up to 2.25. Hypertension did not increase the risk of other incidents. Conclusions: Hypertensive patients are still at risk of intra-operative cardiovascular incidents. The heterogeneity of the risk to develop cardiovascular incidents varied across hospitals, despite taking into account casemix and hospital characteristics. These variations suggest that anaesthetic practices differ across anesthesia services

Longitudinal study of informed consent in innovative therapy research: experience and provisional recommendations from a multicenter trial of intracerebral grafting.

BACKGROUND: There is an urgent need to assess and improve the consent process in clinical trials of innovative therapies for neurodegenerative disorders. METHODS: We performed a longitudinal study of the consent of Huntington's disease patients during the Multicenter Fetal Cell Intracerebral Grafting Trial in Huntington's Disease (MIG-HD) in France and Belgium. Patients and their proxies completed a consent questionnaire at inclusion, before signing the consent form and after one year of follow-up, before randomization and transplantation. The questionnaire explored understanding of the protocol, satisfaction with the information delivered, reasons for participating in the trial and expectations regarding the transplant. Forty-six Huntington's disease patients and 27 proxies completed the questionnaire at inclusion, and 27 Huntington's disease patients and 16 proxies one year later. RESULTS: The comprehension score was high and similar for Huntington's disease patients and proxies at inclusion (72.6% vs 77.8%; P > 0.1) but only decreased in HD patients after one year. The information satisfaction score was high (73.5% vs 66.5%; P > 0.1) and correlated with understanding in both patients and proxies. The motivation and expectation profiles were similar in patients and proxies and remained unchanged after one year. CONCLUSIONS: Cognitively impaired patients with Huntington's disease were capable of consenting to participation in this trial. This consent procedure has presumably strengthened their understanding and should be proposed before signing the consent form in future gene or cell therapy trials for neurodegenerative disorders. Because of the potential cognitive decline, proxies should be designated as provisional surrogate decision-makers, even in competent patients.

Early Recurrence and Cerebral Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation: effect of Anticoagulation and Its Timing: the RAF Study.

BACKGROUND AND PURPOSE: The best time for administering anticoagulation therapy in acute cardioembolic stroke remains unclear. This prospective cohort study of patients with acute stroke and atrial fibrillation, evaluated (1) the risk of recurrent ischemic event and severe bleeding; (2) the risk factors for recurrence and bleeding; and (3) the risks of recurrence and bleeding associated with anticoagulant therapy and its starting time after the acute stroke. METHODS: The primary outcome of this multicenter study was the composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding within 90 days from acute stroke. RESULTS: Of the 1029 patients enrolled, 123 had 128 events (12.6%): 77 (7.6%) ischemic stroke or transient ischemic attack or systemic embolism, 37 (3.6%) symptomatic cerebral bleeding, and 14 (1.4%) major extracranial bleeding. At 90 days, 50% of the patients were either deceased or disabled (modified Rankin score ≥3), and 10.9% were deceased. High CHA2DS2-VASc score, high National Institutes of Health Stroke Scale, large ischemic lesion and type of anticoagulant were predictive factors for primary study outcome. At adjusted Cox regression analysis, initiating anticoagulants 4 to 14 days from stroke onset was associated with a significant reduction in primary study outcome, compared with initiating treatment before 4 or after 14 days: hazard ratio 0.53 (95% confidence interval 0.30-0.93). About 7% of the patients treated with oral anticoagulants alone had an outcome event compared with 16.8% and 12.3% of the patients treated with low molecular weight heparins alone or followed by oral anticoagulants, respectively (P=0.003). CONCLUSIONS: Acute stroke in atrial fibrillation patients is associated with high rates of ischemic recurrence and major bleeding at 90 days. This study has observed that high CHA2DS2-VASc score, high National Institutes of Health Stroke Scale, large ischemic lesions, and type of anticoagulant administered each independently led to a greater risk of recurrence and bleedings. Also, data showed that the best time for initiating anticoagulation treatment for secondary stroke prevention is 4 to 14 days from stroke onset. Moreover, patients treated with oral anticoagulants alone had better outcomes compared with patients treated with low molecular weight heparins alone or before oral anticoagulants.

Biological variation of established and novel biomarkers for atherosclerosis: Results from a prospective, parallel-group cohort study.

BACKGROUND: Biomarkers are a promising tool for the management of patients with atherosclerosis, but their variation is largely unknown. We assessed within-subject and between-subject biological variation of biomarkers in peripheral artery disease (PAD) patients and healthy controls, and defined which biomarkers have a favorable variation profile for future studies. METHODS: Prospective, parallel-group cohort study, including 62 patients with stable PAD (79% men, 65±7years) and 18 healthy control subjects (44% men, 57±7years). Blood samples were taken at baseline, and after 3-, 6-, and 12-months. We calculated within-subject (CVI) and between-subject (CVG) coefficients of variation and intra-class correlation coefficient (ICC). RESULTS: Mean levels of D-dimer, hs-CRP, IL-6, IL-8, MMP-9, MMP-3, S100A8/A9, PAI-1, sICAM-1, and sP-selectin levels were higher in PAD patients than in healthy controls (P≤.05 for all). CVI and CVG of the different biomarkers varied considerably in both groups. An ICC≥0.5 (indicating moderate-to-good reliability) was found for hs-CRP, D-Dimer, E-selectin, IL-10, MCP-1, MMP-3, oxLDL, sICAM-1 and sP-selectin in both groups, for sVCAM in healthy controls and for MMP-9, PAI-1 and sCD40L in PAD patients. CONCLUSIONS: Single biomarker measurements are of limited utility due to large within-subject variation, both in PAD patients and healthy subjects. D-dimer, hs-CRP, MMP-9, MMP-3, PAI-1, sP-selectin and sICAM-1 are biomarkers with both higher mean levels in PAD patients and a favorable variation profile making them most suitable for future studies.

Clinical and course characteristics of depression and all-cause mortality: A prospective population-based study.

BACKGROUND: Given the large heterogeneity of depressive disorders (DD), studying depression characteristics according to clinical manifestations and course is a more promising approach than studying depression as a whole. The purpose of this study was to determine the association between clinical and course characteristics of DD and incident all-cause mortality. METHODS: CoLaus|PsyCoLaus is a prospective cohort study (mean follow-up duration=5.2 years) including 35-66 year-old randomly selected residents of an urban area in Switzerland. A total of 3668 subjects (mean age 50.9 years, 53.0% women) underwent physical and psychiatric baseline evaluations and had a known vital status at follow-up (98.8% of the baseline sample). Clinical (diagnostic severity, atypical features) and course characteristics (recency, recurrence, duration, onset) of DD according to the DSM-5 were elicited using a semi-structured interview. RESULTS: Compared to participants who had never experienced DD, participants with current but not remitted DD were more than three times as likely to die (Hazard Ratio: 3.2, 95% CI: 1.1-10.0) after adjustment for socio-demographic and lifestyle characteristics, comorbid anxiety disorders, antidepressant use, and cardiovascular risk factors and diseases. There was no evidence for associations between other depression characteristics and all-cause mortality. LIMITATIONS: The small proportion of deceased subjects impeded statistical analyses of cause-specific mortality. CONCLUSIONS: A current but not remitted DD is a strong predictor of all-cause mortality, independently of cardiovascular or lifestyle factors, which suggests that the effect of depression on mortality diminishes after remission and further emphasizes the need to adequately treat current depressive episodes.

Procedural Results and Clinical Outcomes of Transcatheter Aortic Valve Implantation in Switzerland: An Observational Cohort Study of Sapien 3 Versus Sapien XT Transcatheter Heart Valves.

BACKGROUND: New generation transcatheter heart valves (THV) may improve clinical outcomes of transcatheter aortic valve implantation. METHODS AND RESULTS: In a nationwide, prospective, multicenter cohort study (Swiss Transcatheter Aortic Valve Implantation Registry, NCT01368250), outcomes of consecutive transfemoral transcatheter aortic valve implantation patients treated with the Sapien 3 THV (S3) versus the Sapien XT THV (XT) were investigated. An overall of 153 consecutive S3 patients were compared with 445 consecutive XT patients. Postprocedural mean transprosthetic gradient (6.5±3.0 versus 7.8±6.3 mm Hg, P=0.17) did not differ between S3 and XT patients, respectively. The rate of more than mild paravalvular regurgitation (1.3% versus 5.3%, P=0.04) and of vascular (5.3% versus 16.9%, P<0.01) complications were significantly lower in S3 patients. A higher rate of new permanent pacemaker implantations was observed in patients receiving the S3 valve (17.0% versus 11.0%, P=0.01). There were no significant differences for disabling stroke (S3 1.3% versus XT 3.1%, P=0.29) and all-cause mortality (S3 3.3% versus XT 4.5%, P=0.27). CONCLUSIONS: The use of the new generation S3 balloon-expandable THV reduced the risk of more than mild paravalvular regurgitation and vascular complications but was associated with an increased permanent pacemaker rate compared with the XT. Transcatheter aortic valve implantation using the newest generation balloon-expandable THV is associated with a low risk of stroke and favorable clinical outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01368250.

A single-blind, randomised controlled trial on the effects of lithium and quetiapine monotherapy on the trajectory of cognitive functioning in first episode mania: A 12-month follow-up study.

BACKGROUND: Cognitive deficits have been reported during the early stages of bipolar disorder; however, the role of medication on such deficits remains unclear. The aim of this study was to compare the effects of lithium and quetiapine monotherapy on cognitive performance in people following first episode mania. METHODS: The design was a single-blind, randomised controlled trial on a cohort of 61 participants following first episode mania. Participants received either lithium or quetiapine monotherapy as maintenance treatment over a 12-month follow-up period. The groups were compared on performance outcomes using an extensive cognitive assessment battery conducted at baseline, month 3 and month 12 follow-up time-points. RESULTS: There was a significant interaction between group and time in phonemic fluency at the 3-month and 12-month endpoints, reflecting greater improvements in performance in lithium-treated participants relative to quetiapine-treated participants. After controlling for multiple comparisons, there were no other significant interactions between group and time for other measures of cognition. CONCLUSION: Although the effects of lithium and quetiapine treatment were similar for most cognitive domains, the findings imply that early initiation of lithium treatment may benefit the trajectory of cognition, specifically verbal fluency in young people with bipolar disorder. Given that cognition is a major symptomatic domain of bipolar disorder and has substantive effects on general functioning, the ability to influence the trajectory of cognitive change is of considerable clinical importance.