Bladder cancer is the seventh most common cancer worldwide in men and occurs at a median age of 73 years old [ 1 ]. Age-standardized incidence rates are higher in men (9 per 1000.000) than in women (2.2 per 100.000), which parallel the mortality rates of 3.2 and 0.9, respect- ively [ 2 ]. More than half of cases are occurring in the most developed areas including Europe and North America, but significant variations can be observed de- pending on the countries [ 2 ]. Though several risk factors have been invoked, it is admitted that tobacco use is the most prevalent one and could be associated with a fu- ture rise in incidence [ 3 ]. This represents a serious healthcare burden as bladder cancer is associated with one of the highest treatment costs [ 4 ]. Most bladder can- cers are urothelial carcinomas and include the two cat- egories of non-muscle-invasive and muscle-invasive tumors, the latter representing 20–30% of newly diag- nosed cases [ 5 ]. While non-muscle invasive tumors are usually of good prognosis, up to 25% of them progress to the invasive form of the disease [ 6 ]. Transurethral re- section of the bladder is the treatment of choice for non-muscle-invasive bladder cancers and cystectomy is used for non-metastatic forms of muscle invasive tumors [ 7 ]. In the case of locally advanced tumors or in meta- static diseases, two first-line chemotherapies where cis- platin is associated with either gemcitabine (GC) or methotrexate, vinblastine, and doxorubicin (MVAC) have been approved and show overall response rates above 50% with a median progression-free survival (PFS) of 7–9 months and a median overall survival (OS) of 12 –15 months [ 8 ]. Vinflunine was the only drug ap- proved in 2009 as secondline therapy based on a 2.4 months benefit as compared to best supportive care [ 9 ], emphasizing the need for new treatment options. For these patients, blockade of the PD1/PD-L1 immune checkpoint is an attractive strategy as recent phase II/III clinical trials showed significant improvement in tumor response, with a higher response rate for patients with PD-L1 positive tumor-infiltrating immune cells and a good tolerability [ 10 ]. This led to the approval of pem- brolizumab, atezolizumab, durvalumab, nivolumab and avelumab as secondlinetreatment for platinum pre- treated patients [ 11 – 15 ].
“I actually do not doubt, should I say that? . . . I trust the doctor completely. If he decides that he should change the treatment for such or such reason. . .well. . . we discuss it. Some- times I give up. But if that’s what it takes, then you have to. I know it’s for the best.” Two attitudes have been observed: The first one was a slow process along a formal pathway from initial proposal of chemotherapy for acceptance. This pathway needed knowledge acqui- sition. During this process, participants’ cognition balanced between 2 thoughts: “I should accept” in order to go forward, and “I need searching” in an attempt to consent to chemother- apy protocol in full knowledge of the facts. This back and forth reflexions allowed participants to manage personal views with medical discourse regarding treatment by slowing down the acceptance process. As a final result, interviews demonstrated that knowledge participated in the trusted process that helped maintain a positive perception of the future. Therefore, the pro- cess might hesitate during an undefined time between the two categories: rational decision or decision by default.
Fluoropyrimidine (FP) plus platinum chemotherapy has been recently established as a second- line (L2) preferred option in advanced biliary tract cancer (aBTC) (ABC-06 phase III trial). However, the overall survival (OS) benefit was limited and comparison with FP monotherapy was not available. Our aim was to assess the OS of patients treated with a FP monotherapy compared to a doublet with irinotecan or platinum in L2.
DURIGAST is a randomised, multicenter, non-comparative, phase II study, evaluating safety and efficacy of FOLFIRI plus Durvalumab (anti-PD-L1) versus FOLFIRI plus Durvalumab and Tremelimumab (anti-CTLA-4) as second-linetreatment of advanced gastric and GEJ adenocarcinoma. The primary objective is the rate of patients alive and without progression at 4 months. The main inclusion criteria are: patients with advanced gastric or GEJ adenocarcinoma, pre-treated with fluoropyrimidine + platinum salt ± taxane. Due to a lack of data on FOLFIRI, Durvalumab and Tremelimumab combination, a 2-step safety run-in phase has been performed before the randomised phase II. The safety run-in phase did not show any safety issue and the randomised phase II starts in September 2020.
Conclusions: We conclude that, despite evidence of tumor-specific indisulam-induced apoptosis, neither of
these treatment schedules has single-agent activity as second-linetreatment of non -small cell lung cancer.
Lung cancer is the leading cause of cancer death in the world and is associated with a 5-year survival of only 15% (1). For non-small cell lung cancer (NSCLC), surgery is the only curative option for early-stage disease. However, the majority of patients present with advanced disease, for which treatment is palliative. First-line platinum-based chemotherapy results in significant, although modest, improvement in clinical outcome (2-4). Second- or third-line therapies prolong survival when compared with supportive care alone but have objective response rates of only 7% to 9% (5, 6). There is clearly a clinical need to develop effective second-line therapies that deliver improved response, survival, and toxicity profiles.
This study has limitations. First, QALYs were estimated in the base-case analysis using utility estimates derived
from the literature, as data were not available in the trial or post-trial data [ 16 , 31 ]. The utility values used in the base-case analysis were estimated using preference-based methods from a large sample of patients within the DART (Development of Anti-Retroviral Therapy in Africa) trial in Uganda [ 16 ]. In scenario analysis, we also considered an alternative source of data, specifically a meta-analysis pool- ing data from studies conducted in high-income countries [ 31 ]. QALYs per patient were still not significantly different between arms, and consequently, TDF/FTC LPV/r remained the optimal second-line therapy. Second, the structure of the simulated patient-level Markov model and the defini- tion of heath states were constrained by the size of the study population, which was too small to consider a larger number of health states. In particular, we were not able to consider an additional health state for patients with CD4 < 50 cells/ mL or define health states by combining CD4 cell count and VL as the model did not converge due to an insuffi- cient number of transitions observed. However, the effect of virological failure on disease progression was taken into account through the introduction of this variable in the model used to estimate transition probabilities. In addition, our model does not account for HIV transmission. Although we recognise that dynamic models are the most suitable to assess long-term public health impacts in the field of HIV, we believe that for our study purpose, such a model was not indispensable as the alternative regimens considered in the analysis offered very similar benefits, including benefits in terms of virological suppression. Not taking into account HIV transmission may have led to an underestimation of health benefits for each strategy, but it is unlikely to have biased our cost-effectiveness results as a similar number of HIV transmissions are expected to occur in the three alterna- tive second-line regimens assessed. Finally, our study was conducted using data collected in a trial setting, which may limit the generalisability of the results. Nevertheless, this study included PLHIV followed in the largest HIV treatment centres of the three study countries. It is therefore likely that the trial population reflected patients switching to second- linetreatment in real-life contexts where viral load monitor- ing and genotyping are generally not available [ 8 ].
In 2010, a multi-cohort analysis of 27 ART programs in resource-limited settings [only four with routine viral load (VL) monitoring] including three countries of Southeast Asia (Cambodia, Myanmar, and Laos) reported treatment failure, defined as the first diagnosis of clinical, immunological or viro- logical failure, for 19% of patients receiving PI-based second-line therapy for more than 6 months (10). In Vietnam, the cumulative incidence of PI-based treatment failure (as defined clinically or immunologically) by 1, 2, 3, and 4 years were 13.1, 18.6, 20.4, and 22.8%, respectively (11). More recently, the TREAT Asia HIV Observational Database reports outcomes of 302 patients under PI-based regimen followed for more than 6 months (12) from different Asian sites with a rate of mortality of 1.1 deaths per 100 patients/year and an overall rate of second-linetreatment failure of 8.8 failures per 100 patients/year. As the definition of treatment failure relying on CD4 cell count and clinical evalua- tion underestimates true virological failure rates, little data about virological second-linetreatment outcomes are in fact currently available. Such information is of great importance for National HIV Programs to prevent failures of second-line regimen and anticipate the needs of third-line regimen.
are reported not to have supplementary health cover compared to 4% of the higher quintile population [ 27 ]. This survey assumes that 17% of patients with overall health insurance cover for chronic disease do not have supplementary health cover. Out-of-pocket medical expendi- ture can be significant in MS patients with a low SES and can discourage them from having regular follow-up and consultations. However, in France, second-line DMT initiation is strictly reserved to public or private hospital neurological care. For these reasons, patients receive second-line DMT only in hospital, at least regarding initiation, and are mainly followed up in MS centres where health costs directly or indirectly related to MS are fully covered by public health insurance. Thus, if financial criteria were to impact upon neurological follow-up, the effect on second-linetreatment initiation would be fairly weak.
On se propose de résoudre par une construction géométrique toute équation du second degré. Les seules notions nécessaires sont : équations de droite, droites orthogonales, cercles et équation du second degré.
1. Méthode de K. Von Staudt
Fig. 4. Description of data generation on the host and temperature and pressure corrections in the first steps of the graphics pipeline.
visible but partially hidden or seen through other objects. This process ends with the images ready be displayed.
GPUs can be programmed following various paradigms but we obtain efficiency, portability and re-usability by implement- ing our application as if it were a graphics application using OpenGL  . We apply temperature and pressure correction on line intensity and line half-width in the vertex shaders as de- scribed in Section 2 . Discretization on the wavenumber axis is later performed by the rasterizer. The pixel shaders compute Lorentz profile on the discretized lines as presented in Section 3 and the optical depth of various lines and component gases are summed in the blending unit. When this process is over, the
1. Gilks CF, Crowley S, Ekpini R, Gove S, Perriens J, Souteyrand Y, et al. The WHO public‑health approach to antiretroviral treatment against HIV in resource‑limited settings. Lancet. 2006;368:505–10.
2. Aghokeng AF, Monleau M, Eymard‑Duvernay S, Dagnra A, Kania D, Ngo‑Giang‑Huong N, et al. Extraordinary heterogeneity of virologi‑ cal outcomes in patients receiving highly antiretroviral therapy and monitored with the World Health Organization public health approach in sub‑saharan Africa and southeast Asia. Clin Infect Dis. 2014;58:99–109. 3. Rusine J, Asiimwe‑Kateera B, Van de Wijgert J, Boer KR, Mukantwali E,
First-Stage Independence. For any α ∈ (0, 1] and lotteries P, Q, R ∈ L(H), αP + (1 − α)R αQ + (1 − α)R ⇐⇒ P Q.
As before, the interpretation of the First-Stage Independence axiom becomes transparent when the mixture lottery αP + (1 − α)Q is viewed as a compound lottery compounded from two roulette wheels which spins occur before the realization of the subjective uncertainty (represented by the states in S). The prizes associated to the first spin are lotteries over acts, while the prize associated to the second spin are acts.
- minimum requirements for a simulator to be labeled "DEVS-compliant"
- model libraries, aimed at providing a collection of models usable out of the box
This paper focuses on the second point, namely the standardization of model representation. To achieve this goal, the choice of XML seems obvious; indeed, a consensus emerged among the M&S community about XML being the best tool to describe models in a standardized way [Brutzman et al. 2002] [Fishwick 2002]. This general agreement is due to numerous reasons, such as the wide use of XML in Service Oriented Architecture [Newcomer and Lomow 2005], the great number of existing XML tools, its platform independence and many others.
Keywords: Hypergraphs, Line Hypergraphs, De Bruijn and Kautz net- works, Connectivity
In the beginning of the 80’s one of the authors - JCB - started working on the design of bus networks in order to answer a problem asked by engineers of the French telecommunications operator France Telecom. At that time he met Jean- Jacques (JJQ) who was working for Philips Research Labs and knew well how to design networks. Jean-Jacques kindly shared his knowledge and experience in particular on de Bruijn and Kautz networks and their generalizations. It was the birth of a fruitful and friendly collaboration on the topic of designing classical networks by using various tools of graph theory (see for example [2–5, 7]). In the 90’s, following ideas of JJQ, we extended the de Bruijn and Kautz digraphs to dihypergraphs, generalizing both their alphabetical and arithmetical definitions. There is another definition of de Bruijn and Kautz digraphs (see ) based on the fact that they are iterated line digraphs. This is useful to prove results using induction. We generalized this definition and used it in an unpublished manuscript (first version in 1993) which was announced in ). Unfortunately, this manuscript was never completely finished and never published. However, the results included have been used and some of them generalized in [9, 10].
reinforcement of the red wing of each component of the corresponding 7 Li line, with respect to its blue wing.
Aims. The present paper studies the halo star HD 74000 and estimates the impact of convection-related asymmetries on the Li isotopic ratio determination.
Methods. Two methods are used to meet this aim. The first, which is purely empirical, consists in deriving a template profile from another element that can be assumed to originate in the same stellar atmospheric layers as Li , producing absorption lines of approximately the same equivalent width as individual components of the 7 Li resonance line. The second method consists in
Table I calculates 4 line outage rates with the data available after the 1st year, after the 7th year, and after the 14th year. In Table I, line 29 has no outage except in the 9th and 10th year. The Bayesian estimate of the outage rate of line 29 for the 1st year is 0.32, which is informed by correlations with other lines. By the 7th year, more years with no outages have been observed, so that the estimated outage rate decreases to 0.17. Line 29 outages several times in the 9th and 10th years, so its estimated rate over 14 years increases. There are also many zeros for lines 11 and 2, but the two outage rates vary differently as the distribution of zeros has different patterns. Most counts for line 11 are zeros, and single outages appear every several years. So we believe that the outage rate is roughly constant and small, which is captured by the Bayesian estimator. At the beginning, line 2 had several outages, and then it stops having outages. So this line has a decreasing outage rate. Line 8 is an example of a line with a high and increasing outage rate.