Concurrent or sequential adjuvant letrozole and radiotherapy after conservative surgery for early-stage breast cancer (CO-HO-RT): a phase 2 randomised trial.

BACKGROUND: Letrozole radiosensitises breast cancer cells in vitro. In clinical settings, no data exist for the combination of letrozole and radiotherapy. We assessed concurrent and sequential radiotherapy and letrozole in the adjuvant setting. METHODS: This phase 2 randomised trial was undertaken in two centres in France and one in Switzerland between Jan 12, 2005, and Feb 21, 2007. 150 postmenopausal women with early-stage breast cancer were randomly assigned after conserving surgery to either concurrent radiotherapy and letrozole (n=75) or sequential radiotherapy and letrozole (n=75). Randomisation was open label with a minimisation technique, stratified by investigational centres, chemotherapy (yes vs no), radiation boost (yes vs no), and value of radiation-induced lymphocyte apoptosis (< or = 16% vs >16%). Whole breast was irradiated to a total dose of 50 Gy in 25 fractions over 5 weeks. In the case of supraclavicular and internal mammary node irradiation, the dose was 44-50 Gy. Letrozole was administered orally once daily at a dose of 2.5 mg for 5 years (beginning 3 weeks pre-radiotherapy in the concomitant group, and 3 weeks post-radiotherapy in the sequential group). The primary endpoint was the occurrence of acute (during and within 6 weeks of radiotherapy) and late (within 2 years) radiation-induced grade 2 or worse toxic effects of the skin. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00208273. FINDINGS: All patients were analysed apart from one in the concurrent group who withdrew consent before any treatment. During radiotherapy and within the first 12 weeks after radiotherapy, 31 patients in the concurrent group and 31 in the sequential group had any grade 2 or worse skin-related toxicity. The most common skin-related adverse event was dermatitis: four patients in the concurrent group and six in the sequential group had grade 3 acute skin dermatitis during radiotherapy. At a median follow-up of 26 months (range 3-40), two patients in each group had grade 2 or worse late effects (both radiation-induced subcutaneous fibrosis). INTERPRETATION: Letrozole can be safely delivered shortly after surgery and concomitantly with radiotherapy. Long-term follow-up is needed to investigate cardiac side-effects and cancer-specific outcomes. FUNDING: Novartis Oncology France.

Concurrent or Sequential Adjuvant Letrozole and Radiotherapy after Conservative Surgery for Early-stage Breast Cancer: Long-term Results of the Cohort Phase 2 Randomized Trial

Purpose/Objective(s): Letrozole radiosensitizes breast cancer cells in vitro. In clinical settings, no data exist for the combination of letrozole and radiotherapy. We assessed concurrent and sequential radiotherapy and letrozole in the adjuvant setting.Materials/Methods: The present study is registered with ClinicalTrials.gov, number NCT00208273. This Phase 2 randomized trial was undertaken in two centers in France and one in Switzerland between January 12, 2005, and February 21, 2007. One hundred fifty postmenopausal women with early-stage breast cancer were randomly assigned after conserving surgery to either concurrent radiotherapy and letrozole (n = 75) or sequential radiotherapy and letrozole (n = 75). Randomization was open label with a minimization technique, stratified by investigational centers, chemotherapy (yes vs. no), radiation boost (yes vs. no), and value of radiation-induced lymphocyte apoptosis (#16% vs. .16%). The whole breast was irradiated to a total dose of 50 Gy in 25 fractions over 5 weeks. In the case of supraclavicular and internal mammary node irradiation, the dose was 44 - 50 Gy. Letrozole was administered orally once daily at a dose of 2 - 5 mg for 5 years (beginning 3 weeks pre-radiotherapy in the concomitant group, and 3 weeks postradiotherapy in the sequential group). The primary endpoint was the occurrence of acute (during and within 6 weeks of radiotherapy) and late (within 2 years) radiation-induced Grade 2 or worse toxic effects of the skin and lung (functional pulmonary test and lung CT-scan). Analyses were by intention-to-treat. The long-term follow-up after 2 years was only performed in Montpellier (n = 121) and evaluated skin toxicity (clinical examination every 6 months), lung fibrosis (one CT-scan yearly), cosmetic outcome.Results: All patients were analyzed apart from 1 in the concurrent group who withdrew consent before any treatment.Within the first 2 years (n = 149), no lung toxicity was identified by CT scan and no modification from baseline was noted by the lung diffusion capacity test. Two patients in each group had Grade 2 or worse late effects (both radiation-induced subcutaneous fibrosis [RISF]). After 2 years (n = 121), and with a median follow-up of 50 months (38-62), 2 patients (1 in each arm) presented a Grade 3 RISF. No lung toxicity was identified by CT scan. Cosmetic results (photographies) and quality of life was good to excellent. All patients who had Grade 3 subcutaneous fibrosis had an RILA value of 16% or less, irrespective of the sequence with letrozole.Conclusions:With long-term follow-up, letrozole can be safely delivered shortly after surgery and concomitantly with radiotherapy.

Effects of preset sequential administrations of sunitinib and everolimus on tumour differentiation in Caki-1 renal cell carcinoma.

BACKGROUND: Sunitinib (VEGFR/PDGFR inhibitor) and everolimus (mTOR inhibitor) are both approved for advanced renal cell carcinoma (RCC) as first-line and second-line therapy, respectively. In the clinics, sunitinib treatment is limited by the emergence of acquired resistance, leading to a switch to second-line treatment at progression, often based on everolimus. No data have been yet generated on programmed alternating sequential strategies combining alternative use of sunitinib and everolimus before progression. Such strategy is expected to delay the emergence of acquired resistance and improve tumour control. The aim of our study was to assess the changes in tumours induced by three different sequences administration of sunitinib and everolimus. METHODS: In human Caki-1 RCC xenograft model, sunitinib was alternated with everolimus every week, every 2 weeks, or every 3 weeks. Effects on necrosis, hypoxia, angiogenesis, and EMT status were assessed by immunohisochemistry and immunofluorescence. RESULTS: Sunitinib and everolimus programmed sequential regimens before progression yielded longer median time to tumour progression than sunitinib and everolimus monotherapies. In each group of treatment, tumour growth control was associated with inhibition of mTOR pathway and changes from a mesenchymal towards an epithelial phenotype, with a decrease in vimentin and an increase in E-cadherin expression. The sequential combinations of these two agents in a RCC mouse clinical trial induced antiangiogenic effects, leading to tumour necrosis. CONCLUSIONS: In summary, our study showed that alternate sequence of sunitinib and everolimus mitigated the development of mesenchymal phenotype compared with sunitinib as single agent.

Can resistance to trastuzumab be reversed by endocrine therapy? Combination of trastuzumab and letrozole after resistance to sequential trastuzumab and aromatase inhibitor monotherapies in patients with ER-positive, HER-2 positive, advanced breast cancer: a proof-of-concept trial (SAKK 23/03)

Introduction: Trastuzumab (T) is a cornerstone in the treatment of patients with HER2-overexpressing advanced breast cancer and development of resistance to T is a major therapeutic problem. HER-2 is part of a highly interactive signaling network that may impair efficacy of endocrine therapy. A sequential treatment design was chosen in this trial to ensure complete resistance to single agent therapy before receiving both a non-steroidal aromatase inhibitor (AI) and T. Any kind of clinical activity with combined treatment of AI and T after progression of single agent treatments could indicate restoration of sensitivity as a consequence of cross-talking and networking between both pathways. Methods: Key eligibility criteria included postmenopausal patients (pts.) with advanced, measurable, HER-2 positive (assessed by FISH, ratio (≥2)), HR positive disease and progression on prior treatment with a non-steroidal AI, e.g. letrozole or anastrozole, either in an adjuvant or advanced setting. Pts. received standard dose T monotherapy either weekly or three-weekly in step 1 and upon disease progression, continued T in combination with letrozole in step 2. The primary endpoint was clinical benefit response (CBR: CR, PR or SD for at least 24 weeks (+/- 1 week) according to RECIST) in step 2. Results: Thirteen pts. were enrolled in five centers in Switzerland. In step 1, six pts. (46%) achieved CBR. Median time to progression (TTP) was 161 days (Range: 50 - 627). Based on data collected until the end of May 2010, CBR was observed in seven out of the eleven evaluable pts. (64%) in step 2, including one pt. with partial response. Four of the seven pts. within step 2 that achieved CBR also had CBR in step 1. Seven out of eleven pts. have documented tumor progression during step 2 treatment. Median TTP for all eleven pts. was 184 days (range 61 - 471). Mean time on study treatment (TTP in step 1 plus TTP in step 2) for pts. reaching step 2 was 380 days (range 174 - 864). Adverse events were generally mild. Conclusion: Results of this proof-of-principle trial suggest that complete resistance to both AI and T can be overcome in a proportion of pts. by combined treatment of AI and T, as all pts. served as their own control. Our results appear promising for a new treatment strategy which offers a chemotherapy-free and well-tolerated option for at least a subset of the pts. with HR positive, HER-2 positive breast cancer. Further trials will need to corroborate this finding.

Optimization of the procedure for removing iron deposits on ceramic filter media

In this thesis, cleaning of ceramic filter media was studied. Mechanisms of fouling and dissolution of iron compounds, as well as methods for cleaning ceramic membranes fouled by iron deposits were studied in the literature part. Cleaning agents and different methods were closer examined in the experimental part of the thesis. Pyrite is found in the geologic strata. It is oxidized to form ferrous ions Fe(II) and ferric ions Fe(III). Fe(III) is further oxidized in the hydrolysis to form ferric hydroxide. Hematite and goethite, for instance, are naturally occurring iron oxidesand hydroxides. In contact with filter media, they can cause severe fouling, which common cleaning techniques competent enough to remove. Mechanisms for the dissolution of iron oxides include the ligand-promoted pathway and the proton-promoted pathway. The dissolution can also be reductive or non-reductive. The most efficient mechanism is the ligand-promoted reductive mechanism that comprises two stages: the induction period and the autocatalytic dissolution.Reducing agents(such as hydroquinone and hydroxylamine hydrochloride), chelating agents (such as EDTA) and organic acids are used for the removal of iron compounds. Oxalic acid is the most effective known cleaning agent for iron deposits. Since formulations are often more effective than organic acids, reducing agents or chelating agents alone, the citrate¿bicarbonate¿dithionite system among others is well studied in the literature. The cleaning is also enhanced with ultrasound and backpulsing.In the experimental part, oxalic acid and nitric acid were studied alone andin combinations. Also citric acid and ascorbic acid among other chemicals were tested. Soaking experiments, experiments with ultrasound and experiments for alternative methods to apply the cleaning solution on the filter samples were carried out. Permeability and ISO Brightness measurements were performed to examine the influence of the cleaning methods on the samples. Inductively coupled plasma optical emission spectroscopy (ICP-OES) analysis of the solutions was carried out to determine the dissolved metals.

A novel procedure for establishing clinching parameters for high strength steel sheet

The building industry has a particular interest in using clinching as a joining method for frame constructions of light-frame housing. Normally many clinch joints are required in joining of frames.In order to maximise the strength of the complete assembly, each clinch joint must be as sound as possible. Experimental testing is the main means of optimising a particular clinch joint. This includes shear strength testing and visual observation of joint cross-sections. The manufacturers of clinching equipment normally perform such experimental trials. Finite element analysis can also be used to optimise the tool geometry and the process parameter, X, which represents the thickness of the base of the joint. However, such procedures require dedicated software, a skilled operator, and test specimens in order to verify the finite element model. In addition, when using current technology several hours' computing time may be necessary. The objective of the study was to develop a simple calculation procedure for rapidly establishing an optimum value for the parameter X for a given tool combination. It should be possible to use the procedure on a daily basis, without stringent demands on the skill of the operator or the equipment. It is also desirable that the procedure would significantly decrease thenumber of shear strength tests required for verification. The experimental workinvolved tests in order to obtain an understanding of the behaviour of the sheets during clinching. The most notable observation concerned the stage of the process in which the upper sheet was initially bent, after which the deformation mechanism changed to shearing and elongation. The amount of deformation was measured relative to the original location of the upper sheet, and characterised as the C-measure. By understanding in detail the behaviour of the upper sheet, it waspossible to estimate a bending line function for the surface of the upper sheet. A procedure was developed, which makes it possible to estimate the process parameter X for each tool combination with a fixed die. The procedure is based on equating the volume of material on the punch side with the volume of the die. Detailed information concerning the behaviour of material on the punch side is required, assuming that the volume of die does not change during the process. The procedure was applied to shear strength testing of a sample material. The sample material was continuously hot-dip zinc-coated high-strength constructional steel,with a nominal thickness of 1.0 mm. The minimum Rp0.2 proof stress was 637 N/mm2. Such material has not yet been used extensively in light-frame housing, and little has been published on clinching of the material. The performance of the material is therefore of particular interest. Companies that use clinching on a daily basis stand to gain the greatest benefit from the procedure. By understanding the behaviour of sheets in different cases, it is possible to use data at an early stage for adjusting and optimising the process. In particular, the functionality of common tools can be increased since it is possible to characterise the complete range of existing tools. The study increases and broadens the amount ofbasic information concerning the clinching process. New approaches and points of view are presented and used for generating new knowledge.

A mathematical study of fuzzy logic; an algebraic approach

Fuzzy set theory and Fuzzy logic is studied from a mathematical point of view. The main goal is to investigatecommon mathematical structures in various fuzzy logical inference systems and to establish a general mathematical basis for fuzzy logic when considered as multi-valued logic. The study is composed of six distinct publications. The first paper deals with Mattila'sLPC+Ch Calculus. THis fuzzy inference system is an attempt to introduce linguistic objects to mathematical logic without defining these objects mathematically.LPC+Ch Calculus is analyzed from algebraic point of view and it is demonstratedthat suitable factorization of the set of well formed formulae (in fact, Lindenbaum algebra) leads to a structure called ET-algebra and introduced in the beginning of the paper. On its basis, all the theorems presented by Mattila and many others can be proved in a simple way which is demonstrated in the Lemmas 1 and 2and Propositions 1-3. The conclusion critically discusses some other issues of LPC+Ch Calculus, specially that no formal semantics for it is given.In the second paper the characterization of solvability of the relational equation RoX=T, where R, X, T are fuzzy relations, X the unknown one, and o the minimum-induced composition by Sanchez, is extended to compositions induced by more general products in the general value lattice. Moreover, the procedure also applies to systemsof equations. In the third publication common features in various fuzzy logicalsystems are investigated. It turns out that adjoint couples and residuated lattices are very often present, though not always explicitly expressed. Some minor new results are also proved.The fourth study concerns Novak's paper, in which Novak introduced first-order fuzzy logic and proved, among other things, the semantico-syntactical completeness of this logic. He also demonstrated that the algebra of his logic is a generalized residuated lattice. In proving that the examination of Novak's logic can be reduced to the examination of locally finite MV-algebras.In the fifth paper a multi-valued sentential logic with values of truth in an injective MV-algebra is introduced and the axiomatizability of this logic is proved. The paper developes some ideas of Goguen and generalizes the results of Pavelka on the unit interval. Our proof for the completeness is purely algebraic. A corollary of the Completeness Theorem is that fuzzy logic on the unit interval is semantically complete if, and only if the algebra of the valuesof truth is a complete MV-algebra. The Compactness Theorem holds in our well-defined fuzzy sentential logic, while the Deduction Theorem and the Finiteness Theorem do not. Because of its generality and good-behaviour, MV-valued logic can be regarded as a mathematical basis of fuzzy reasoning. The last paper is a continuation of the fifth study. The semantics and syntax of fuzzy predicate logic with values of truth in ana injective MV-algerba are introduced, and a list of universally valid sentences is established. The system is proved to be semanticallycomplete. This proof is based on an idea utilizing some elementary properties of injective MV-algebras and MV-homomorphisms, and is purely algebraic.

A Sequential Allocation Problem: The Asymptotic Distribution of Resources

In this paper we consider a sequential allocation problem with n individuals. The first individual can consume any amount of some endowment leaving the remaining for the second individual, and so on. Motivated by the limitations associated with the cooperative or non-cooperative solutions we propose a new approach. We establish some axioms that should be satisfied, representativeness, impartiality, etc. The result is a unique asymptotic allocation rule. It is shown for n = 2; 3; 4; and a claim is made for general n. We show that it satisfies a set of desirable properties. Key words: Sequential allocation rule, River sharing problem, Cooperative and non-cooperative games, Dictator and ultimatum games. JEL classification: C79, D63, D74.

A 3-step therapeutic strategy for severe alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of lipoproteinaceous material in the terminal airways. Whole lung lavage (WLL) remains the gold standard treatment but may be particularly challenging in cases of severe hypoxemia. We present a 3-step strategy that was used in a patient with PAP-associated refractory hypoxemia and that combined venovenous extracorporeal membrane oxygenation (vvECMO), double-lumen orotracheal intubation, and bilateral multisegmental sequential lavage (MSL). The procedure was well tolerated and permitted weaning from the ventilator.

Acylation of chiral alcohols: a simple procedure for chiral GC analysis

The use of iodine as a catalyst and either acetic or trifluoroacetic acid as a derivatizing reagent for determining the enantiomeric composition of acyclic and cyclic aliphatic chiral alcohols was investigated. Optimal conditions were selected according to the molar ratio of alcohol to acid, the reaction time, and the reaction temperature. Afterwards, chiral stability of chiral carbons was studied. Although no isomerization was observed when acetic acid was used, partial isomerization was detected with the trifluoroacetic acid. A series of chiral alcohols of a widely varying structural type were then derivatized with acetic acid using the optimal conditions. The resolution of the enantiomeric esters and the free chiral alcohols was measured using a capillary gas chromatograph equipped with a CP Chirasil-DEX CB column. The best resolutions were obtained with 2-pentyl acetates (α = 3.00) and 2-hexyl acetates (α = 1.95). This method provides a very simple and efficient experimental workup procedure for analyzing chiral alcohols by chiral-phase GC.

Responsiveness et changement thérapeutique au travers de l'études de cas

Le concept de responsiveness ou « responsivité » a été proposé dans le domaine de la recherche en psychothérapie pour décrire l'influence mutuelle qui s'exerce continuellement entre patient et thérapeute. La nature responsive des psychothérapies pose alors un problème majeur aux chercheurs, qui adoptent généralement des plans de recherche impliquant des liens de cause à effet et sont en échec dans leur entreprise de mieux comprendre le changement thérapeutique. L'objectif de notre travail est de proposer des pistes pour répondre à ce problème. Nous avons adopté la méthode d'étude de cas, qui permet une analyse en profondeur et en contexte des processus de changement. Dans les deux premières phases de la recherche, nous nous situions dans une approche spécifique à la recherche qualitative en psychothérapie. Nous avons tout d'abord analysé comment le changement s'effectuait chez le patient, en identifiant pas à pas le niveau d'assimilation de ses expériences problématiques. Nous avons ensuite tenté d'appréhender le rôle du thérapeute dans le processus de changement. Notre objectif était d'analyser comment la responsivité du thérapeute pouvait faciliter le processus de changement chez le patient à chaque instant de la thérapie. En suivant une procédure inspirée de l'analyse de la tâche, nous avons identifié pour chaque niveau d'assimilation des interventions thérapeutiques suivies de progression, et élaboré un modèle empirique séquentiel. Dans la troisième phase de la recherche, nous avons effectué un tournant dans notre parcours et sommes allée du côté des sciences du langage. En adoptant une approche dialogique du discours, notre objectif était d'éclairer notre objet d'étude à partir d'une nouvelle perspective et d'ouvrir la réflexion. Nous avons ainsi pu répondre à certaines limites rencontrées dans les premières phases de la recherche, et faire émerger de nouvelles questions et perspectives pour l'étude des processus de changement dans une dimension interactive. -- The concept of responsiveness was developed in psychotherapy research to describe the mutual and constant influence between patient and therapist. The responsive nature of psychotherapy is a serious problem for researchers, who generally adopt research designs involving cause-effect reasoning and fail to better understand therapeutic change. The purpose of our work is to propose some viable possibilities to respond to this problem. We chose the case study method, which enables an analysis in depth and in context of change processes. In the two first phases of research, our approach was specific to qualitative psychotherapy research. We first analyzed how change occurred in the patient, by identifying moment-by-moment the level of assimilation of his or her problematic experiences. We then tried to apprehend the therapist role in the change process. Our aim was to analyze how the therapist responsiveness could facilitate the patient change process at any moment of psychotherapy. We followed a procedure inspired by task analysis and, for each level of assimilation, we identified therapist interventions followed by progression, and elaborated an empirical sequential model. The third phase of research was a turning point, as we went in the field of linguistics. We adopted a dialogical approach of discourse to open up reflection. Thus, we could answer some limitations encountered in the first phases of research, and new questions and perspectives to study change process taking into account the interactive dimension emerged.