A Multi-Center Phase II Study (SAKK 36/06) of Single Agent Everolimus (RAD001) In Patients with Relapsed or Refractory Mantle Cell Lymphoma

Introduction: Mantle cell lymphoma (MCL) accounts for 6% of all B-cell lymphomas and remains incurable for most patients. Those who relapse after first line therapy or hematopoietic stem cell transplantation have a dismal prognosis with short response duration after salvage therapy. On a molecular level, MCL is characterised by the translocation t[11;14] leading to Cyclin D1 overexpression. Cyclin D1 is downstream of the mammalian target of rapamycin (mTOR) kinase and can be effectively blocked by mTOR inhibitors such as temsirolimus. We set out to define the single agent activity of the orally available mTOR inhibitor everolimus (RAD001) in a prospective, multi-centre trial in patients with relapsed or refractory MCL (NCT00516412). The study was performed in collaboration with the EU-MCL network. Methods: Eligible patients with histologically/cytologically confirmed relapsed (not more than 3 prior lines of systemic treatment) or refractory MCL received everolimus 10 mg orally daily on day 1 - 28 of each cycle (4 weeks) for 6 cycles or until disease progression. The primary endpoint was the best objective response with adverse reactions, time to progression (TTP), time to treatment failure, response duration and molecular response as secondary endpoints. A response rate of ≤ 10% was considered uninteresting and, conversely, promising if ≥ 30%. The required sample size was 35 pts using the Simon's optimal two-stage design with 90% power and 5% significance. Results: A total of 36 patients with 35 evaluable patients from 19 centers were enrolled between August 2007 and January 2010. The median age was 69.4 years (range 40.1 to 84.9 years), with 22 males and 13 females. Thirty patients presented with relapsed and 5 with refractory MCL with a median of two prior therapies. Treatment was generally well tolerated with anemia (11%), thrombocytopenia (11%), neutropenia (8%), diarrhea (3%) and fatigue (3%) being the most frequent complications of CTC grade III or higher. Eighteen patients received 6 or more cycles of everolimus treatment. The objective response rate was 20% (95% CI: 8-37%) with 2 CR, 5 PR, 17 SD, and 11 PD. At a median follow-up of 6 months, TTP was 5.45 months (95% CI: 2.8-8.2 months) for the entire population and 10.6 months for the 18 patients receiving 6 or more cycles of treatment. Conclusion: This study demonstrates that single agent everolimus 10 mg once daily orally is well tolerated. The null hypothesis of inactivity could be rejected indicating a moderate anti-lymphoma activity in relapsed/refractory MCL. Further studies of either everolimus in combination with chemotherapy or as single agent for maintenance treatment are warranted in MCL.

Doctors without borders: The returns to an occupational license for Soviet immigrant physicians in Israel

Re-licensing requirements for professionals that move across borders arewidespread. In this paper, we measure the returns to an occupationallicense using novel data on Soviet trained physicians that immigrated toIsrael. An immigrant re-training assignment rule used by the IsraelMinistry of Health provides an exogenous source of variation inre-licensing outcomes. Instrumental variables and quantile treatmenteffects estimates of the returns to an occupational license indicate excesswages due to occupational entry restrictions and negative selectioninto licensing status. We develop a model of optimal license acquisitionwhich suggests that the wages of high-skilled immigrant physicians in thenonphysician sector outweigh the lower direct costs that these immigrantsface in acquiring a medical license. Licensing thus leads to lower averagequality of service. However, the positive earnings effect of entry restrictionsfar outweighs the lower practitioner quality earnings effect that licensinginduces.

Revue des arthroplasties totales de la hanche et du genou infectées--à propos de 28 cas [Review of infected total arthroplasties of the hip and knee--apropos of 28 cases]

This study is a long-term analysis of a group of patients with infected arthroplasties of the hip or the knee. We identified 28 patients with an infected arthroplasty (22 hips, 6 knees) documented by bacterial culture or on direct examination. At the time of diagnosis and on follow-up (a mean of 46 months after treatment) we evaluated the clinical picture, the radiological appearances of the articulation and the biological parameters. 19/28 patients showed a typical clinical picture, whereas in 9 others the picture was more doubtful. The treatments were 14 two-stage replacements of the arthroplasties, 7 simple resections, 5 conservative treatments and 2 one-stage replacements. On follow-up, 25 patients were considered as cured of their infection and 3 as failures. From a functional viewpoint, 9 patients showed no limitation, whereas 19 were limited in the daily activity. Half of the patients had no pain. Radiology showed that 20/26 evaluated patients had no signs of recurrence. Paraclinical examinations are important in the diagnosis of persistent low grade infections, particularly the demonstration of bacteria by pre-surgical sampling (fine needle aspiration, culture from draining sinuses). In spite of the cure of infection, the functional and painful sequellae are often considerable. As a result of our experience, we recommend a two-stage surgical procedure. Only when the general condition of the patient is poor, or when the infection is not under control, would we envisage an alternative procedure (arthrodesis, girdelstone, conservative).

The effects of uncertainty avoidance on brand performance: Marketing creativity, product innovation and the brand duration

This paper investigates the link between brand performance and cultural primes in high-risk,innovation-based sectors. In theory section, we propose that the level of cultural uncertaintyavoidance embedded in a firm determine its marketing creativity by increasing the complexityand the broadness of a brand. It determines also the rate of firm product innovations.Marketing creativity and product innovation influence finally the firm marketingperformance. Empirically, we study trademarked promotion in the Software Security Industry(SSI). Our sample consists of 87 firms that are active in SSI from 11 countries in the period1993-2000. We use the data coming from SSI-related trademarks registered by these firms,ending up with 2,911 SSI-related trademarks and a panel of 18,213 observations. We estimatea two stage model in which first we predict the complexity and the broadness of a trademarkas a measure of marketing creativity and the rate of product innovations. Among severalcontrol variables, our variable of theoretical interest is the Hofstede s uncertainty avoidancecultural index. Then, we estimate the trademark duration with a hazard model using thepredicted complexity and broadness as well as the rate of product innovations, along with thesame control variables. Our evidence confirms that the cultural avoidance affects the durationof the trademarks through the firm marketing creativity and product innovation.

Secret information acquisition in Cournot markets

Two-stage game models of information acquisition in stochastic oligopoliesrequire the unrealistic assumption that firms observe the precision ofinformation chosen by their competitors before determining quantities. Thispaper analyzes secret information acquisition as a one-stage game. Relativeto the two-stage game firms are shown to acquire less information. Policyimplications based on the two-stage game yield, therefore, too high taxes ortoo low subsidies for research activities. For the case of heterogeneousduopoly it is shown that comparative statics results partly depend on theobservability assumption.

Strategic ambiguity in electoral competition

Many have observed that political candidates running for election areoften purposefully expressing themselves in vague and ambiguous terms. In thispaper we provide a simple formal model of this phenomenon. We model theelectoral competition between two candidates as a two--stage game. In thefirst stage of the game two candidates simultaneously choose their ideologies,and in the second stage they simultaneously choose their level of ambiguity.Our results show that ambiguity, although disliked by voters, may be sustainedin equilibrium. The introduction of ambiguity as a strategic choice variablefor the candidates can also serve to explain why candidates with the sameelectoral objectives end up ``separating'', that is, assuming different ideological positions.

Measuring and explaining farm inefficiency in a panel data set of mixed farms

This paper aims to estimate a translog stochastic frontier production function in the analysis of a panel of 150 mixed Catalan farms in the period 1989-1993, in order to attempt to measure and explain variation in technical inefficiency scores with a one-stage approach. The model uses gross value added as the output aggregate measure. Total employment, fixed capital, current assets, specific costs and overhead costs are introduced into the model as inputs. Stochasticfrontier estimates are compared with those obtained using a linear programming method using a two-stage approach. The specification of the translog stochastic frontier model appears as an appropriate representation of the data, technical change was rejected and the technical inefficiency effects were statistically significant. The mean technical efficiency in the period analyzed was estimated to be 64.0%. Farm inefficiency levels were found significantly at 5%level and positively correlated with the number of economic size units.

Characteristics and outcome of knee prosthetic joint infections (PJI): A 10-year cohort study (2000-2009)

Background: Prosthetic joint infections (PJI) lead to significant long-term morbidity with high cost of healthcare. We evaluated characteristics of infections and the infection and functional outcome of knee PJI over a 10-year period. Methods: All patients hospitalized at our institution from 1/2000 through 12/2009 with knee PJI (defined as growth of the same microorganism in ≥2 tissue or synovial fluid cultures, visible purulence, sinus tract or acute inflammation on tissue histopathology) were included. Patients, their relatives and/or treating physicians were contacted to determine the outcome. Results: During the study period, 61 patients with knee PJI were identified. The median age at the time of diagnosis of infection was 73 y (range, 53-94 y); 52% were men. Median hospital stay was 37 d (range, 1-145 d). Most reasons for primary arthroplasty was osteoarthritis (n = 48), trauma (n = 9) and rheumatoid arthritis (n = 4). 23 primary surgeries (40%) were performed at CHUV, 34 (60%) elsewhere. After surgery, 8 PJI were early (<3 months), 16 delayed (3-24 months) and 33 late (>24 months). PJI were treated with (i) open or arthroscopic debridement with prosthesis retention in 26 (46%), (ii) one-stage exchange in 1, (iii) two-stage exchange in 22 (39%) and (iv) prosthesis removal in 8 (14%). Isolated pathogens were S. aureus (13), coagulase-negative staphylococci (10), streptococci (5), enterococci (3), gram-negative rods (3) and anaerobes (3). Patients were followed for a median of 3.1 years, 2 patients died (unrelated to PJI). The outcome of infection was favorable in 50 patients (88%), whereas the functional outcome was favorable in 33 patients (58%). Conclusions: With the current treatment concept, the high cure rate of infection (88%) is associated with a less favorable functional outcome o 58%. Earlier surgical intervention and more rapid and improved diagnosis of infection may improve the functional outcome of PJI.

Social value orientation as a moral intuition: Decision-making in the dictator game

We studied the decision making process in the Dictator Game and showed that decisions are the result of a two-step process. In a first step, decision makers generate an automatic, intuitive proposal. Given sufficient motivation and cognitive resources, they adjust this in a second, more deliberated phase. In line with the social intuitionist model, we show that one s Social Value Orientation determines intuitive choice tendencies in the first step, and that this effect is mediated by the dictator s perceived interpersonal closeness with the receiver. Self-interested concerns subsequently leadto a reduction of donation size in step 2. Finally, we show that increasing interpersonal closeness can promote pro-social decision-making.

The Georgian adolescent health survey: methodological and strategic issues.

OBJECTIVES: To conduct a national survey on adolescent health and lifestyles in Georgia and to thus set up a database on adolescent. METHODS: A two-stage cluster sample of around 8000-10000 in-school 15-18 years adolescents are being reached through a random selection of classes in Georgia. The sample has been stratified by age, region, type of school and language. A self-administered questionnaire of 87 questions has been developed and translated into the four main languages used in Georgia. RESULTS: Up to June 2004, the researchers have reached 511 classes (9306 pupils). In total, 8039 questionnaires have been considered valid. The main concerns encountered for this survey are linked with acceptance of the survey, cross-cultural issues, political and strategic problems as well as inadequate physical environmental support. CONCLUSION: Despite Georgia's unfavourable economical and political situation, it has been possible to run a national survey on the health of adolescents, according to the usual standards used in the field. This survey should allow for 1) the identification of priorities in the field of health care and health promotion 2) the monitoring of adolescent health in the future.

Numerical simulation of ambient seismic wavefield modification caused by pore-fluid effects in an oil reservoir

We have modeled numerically the seismic response of a poroelastic inclusion with properties applicable to an oil reservoir that interacts with an ambient wavefield. The model includes wave-induced fluid flow caused by pressure differences between mesoscopic-scale (i.e., in the order of centimeters to meters) heterogeneities. We used a viscoelastic approximation on the macroscopic scale to implement the attenuation and dispersion resulting from this mesoscopic-scale theory in numerical simulations of wave propagation on the kilometer scale. This upscaling method includes finite-element modeling of wave-induced fluid flow to determine effective seismic properties of the poroelastic media, such as attenuation of P- and S-waves. The fitted, equivalent, viscoelastic behavior is implemented in finite-difference wave propagation simulations. With this two-stage process, we model numerically the quasi-poroelastic wave-propagation on the kilometer scale and study the impact of fluid properties and fluid saturation on the modeled seismic amplitudes. In particular, we addressed the question of whether poroelastic effects within an oil reservoir may be a plausible explanation for low-frequency ambient wavefield modifications observed at oil fields in recent years. Our results indicate that ambient wavefield modification is expected to occur for oil reservoirs exhibiting high attenuation. Whether or not such modifications can be detected in surface recordings, however, will depend on acquisition design and noise mitigation processing as well as site-specific conditions, such as the geologic complexity of the subsurface, the nature of the ambient wavefield, and the amount of surface noise.

Koulusaavutusaineiston analyysi asetelmaperusteisilla ja kaksitasoisilla logit-regressiomalleilla

Summary: The analysis of educational data with design-based and two-level logistic regression models

A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis.

BACKGROUND: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS). METHODS/PRINCIPAL FINDINGS: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated. CONCLUSION/SIGNIFICANCE: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole. TRIAL REGISTRATION: Clinicaltrials.gov NCT00690118.

The Mont-Mort metapelites: Variscan metamorphism and geodynamic context (Brianconnais basement, Western Alps, Switzerland)

The Mont-Mort metapelites are one of the best preserved relies of the Variscan unit in the Brianconnais basement. These micaschists crystallized during a poly-phase metamorphic cycle, under amphibolite facies conditions. Mineral parageneses and geothermobarometric calculations indicate a two-stage evolution. Stage (1) (550-600 degrees C and 5-8 kbar) is documented by assemblages of zoned garnet, staurolite, kyanite(?), biotite, muscovite, quartz and pla gioclase. Stage (2) (550-600 degrees C and 2 kbar) is illustrated by assemblages of andalusite, sillimanite, muscovite, biotite. This metamorphic evolution is characterized by a nearly isothermal decompression path, terminating with the formation of andalusite-bearing veins. U-Pb monazite dates at 330 Ma and Ar-40/Ar-39 muscovite dates at 290-310 Ma (without substantial evidence of argon resetting) point to Variscan metamorphism and yield an estimate of the time interval between the thermal peak and the retrogression stage within this part of the Brianconnais basement. Restoring the Brianconnais and other Alpine basement units within an existing geodynamic model of Cordillera construction and destruction, it is possible to understand better the transition from a medium pressure/high temperature regime (collision with a peak metamorphism around 330 Ma) to low-P/high-T conditions (decompression in an extensional regime) with high geothermal gradient, as recorded by the successive Variscan parageneses within the Mont-Mort metapelites.

Generational effects on adult height in individual heterogeneity

As adult height is a well-established retrospective measure of health and standard of living, it is important to understand the factors that determine it. Among them, the influence of socio-environmental factors has been subjected to empirical scrutiny. This paper explores the influence of generational (or environmental) effects and individual and gender-specific heterogeneity on adult height. Our data set is from contemporary Spain, a country governed by an authoritarian regime between 1939 and 1977. First, we use normal position and quantile regression analysis to identify the determinants of self-reported adult height and to measure the influence of individual heterogeneity. Second, we use a Blinder-Oaxaca decomposition approach to explain the `gender height gap¿ and its distribution, so as to measure the influence on this gap of individual heterogeneity. Our findings suggest a significant increase in adult height in the generations that benefited from the country¿s economic liberalization in the 1950s, and especially those brought up after the transition to democracy in the 1970s. In contrast, distributional effects on height suggest that only in recent generations has ¿height increased more among the tallest¿. Although the mean gender height gap is 11 cm, generational effects and other controls such as individual capabilities explain on average roughly 5% of this difference, a figure that rises to 10% in the lowest 10% quantile.