Cetuximab in combination with chemoradiotherapy prior to surgery in patients with resectable, locally advanced esophageal carcinoma : a prospective, multicenter phase lb-ll trial of the Swiss Group for Clinical Cancer Research (SAKK 75/06) : 4570

Background: Cetuximab significantly enhances efficacy of radiotherapy and chemotherapy in head and neck cancer. We investigated the safety and feasibility of adding cetuximab to neoadjuvant chemoradiation of locally advanced esophageal cancer. Methods: Pts with resectable, locally advanced squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the thoracic esophagus or gastroesophageal junction (staged by EUS, CT and PET scan) were treated with 2 cycles of induction chemotherapy (docetaxel 75mg/m2, cisplatin 75mg/m2 q3w and weekly cetuximab 250mg/m2), followed by concomitant chemo- immuno-radiation therapy (CIRT: docetaxel 20mg/m2, cisplatin 25mg/m2 and cetuximab 250mg/m2 weekly five times concomitant with 45 Gy radiotherapy in 25 fractions); followed by surgery 4-8 weeks later. The phase I part consisted of 2 cohorts of 7 patients each, without and with docetaxel during CIRT, respectively. Interpatient dose-escalation (adding docetaxel during CIRT) was possible if < 2 out of 7 pts of the 1st cohort experienced limiting toxicity. Having finished the phase 1 part, 13 additional patients were treated with docetaxel-containing CIRT in a phase II part. Pathological response was evaluated according to the Mandard classification. Results: 27 pts from 12 institutions were included. As of today, results from 20 pts are available (cohort 1: 7, cohort 2: 7, phase ll : 6). Median age was 64yrs (range 47-71). 11 AC; 9 SCC. 19 pts (95%) completed CIRT (1 pt stopped treatment during induction therapy due to sepsis). 17 pts underwent resection (no surgery: 1pt for PD, 1pt for cardiac reasons). Grade 3 toxicities during CIRT included anorexia 15%, dysphagia/esophagitis 15%, fatigue 10%, nausea 10%, pruritus 5%, dehydration 5%, nail changes 5% and rash 5% .1 pt suffered from pulmonary embolism. 13 pts (65%, intention-to-treat) showed a complete or near complete pathological remission (cohort 1: 5, cohort 2: 4, phase II: 4). Conclusions: Adding cetuximab to preoperative chemoradiation for esophageal cancer is safe and feasible in a community-based multicenter setting. Antineoplastic activity is encouraging with 65% pathological responders.

Paleoenvironmental evolution of the Helvetic shallow-water carbonate platform near the Barremian-Aptian boundary, and its relationship with paleoceanographic and paleoclimatic change in the Tethys

Abstract:During my doctoral research, I focused on deciphering the interactions between sea-level and climate change during the Late Barremian-Early Aptian, their expression in the Tethys basin and in the Helvetic carbonate platform. The research highlights are summarized here in three points: In the Helvetic Alps, the transition between the Lower Schrattenkalk (Upper Barremian) and the Rawil Member (Lowermost Aptian) is characterized by a change from a predominantly photozoan to a heterozoan carbonate-producing system, which coincides in time with a general increase in detrital and nutrient input. The clay mineral record shows the appearance of kaolinite within the Rawil Member, whereas this mineral is absent from the uppermost Lower and lowermost Upper Schrattenkalk Members. This indicates the installation of a warmer and more humid climate during this time period. A negative peak in 513C is recorded at the top of the Lower Schrattenkalk Member, and correlates with the well-known negative excursion of -l%o occurring in other basins and dated as latest Barremian, thus confirming a latest Barremian and earliest Aptian age for the Lower Schrattenkalk and Rawil Members, respectively. Furthermore, a sequence stratigraphie framework has been defined for the Rawil Member, based on both the ecology of faunal and floral assemblages, and their palaeoenvironmental interpretation, as well as on the stacking pattern of limestone beds observed during field prospection. The presence of a sequence boundary is postulated near the top of the Lower Schrattenkalk Member, which is correlated with the earliest Aptian SbAl defined in Vercors (France). The SbAl is characterized by a maximum of proximal assemblages and by the disappearance of several benthic foraminiferal species. Within the Rawil Member itself, the stacking pattern and microfacies trends are interpreted to represent the TST of the first Aptian sequence. With regards to the pelagic setting in the Tethyan realm, I investigated the Gorgo a Cerbara section (central Italy). There, thin organic-rich layers occur episodically in pelagic carbonates of the upper Barremian portion of the Maiolica Formation. They are associated with high Corg:Ptot ratios, which indicate the presence of intermittent dysoxic to anoxic conditions. Coarse correlations are also observed between TOC, Ρ and biogenic silica contents, indicating links between Ρ availability, productivity, and organic matter preservation. The corresponding 813Ccarb and δ180 records remain, however, quite stable, indicating that these brief periods of enhanced TOC preservation did not have sufficient impact on the marine carbon household to deviate 6,3C records, and are probably not the consequence of major climate change. On the other hand, organic-rich layers become more frequent around the Barremian-Aptian boundary in both pelagic and hemi-pelagic environments (Gorgo a Cerbara and La Bédoule, France), which are correlated with negative excursions in 6l3Ccarb and 613Corg records. During the earliest Aptian, at Gorgo a Cerbara, the frequency of organic-rich intervals progressively increases and redox-sensitive trace-element enrichments become more frequent, until the highest TOC-enriched level just below the "Livello Selli", indicator of Oceanic Anoxic Event la (OAEla). The latter is associated with the well-known negative spike in 613Ccarb and S,3Corg records, a diminution in the δ,80 record interpreted as the consequence of a wanning interval, an important peak in Ρ accumulation and high Cor::Ptot ratios indicating the prevalence of anoxic conditions. The Selli Level (OAEla) documents a general cooling phase and coincides with maximum RSTE enrichments as well as high Corg:Ptot ratios, which confirm the importance of anoxic conditions during OAE1 a at this site.During the Early Aptian, environmental change on the platform is expressed by orbitolinids proliferation that may be induced by both climate change and sea-level rise. In the basin, the successive black shales horizons from the Late Barremian until the OAE la are interpreted as the progressive impact of palaeoenvironmental change probably linked to the formation of the Ontong- Java plate-basalt plateau.RésuméCe travail de thèse a permis d'investiguer les interactions entre les variations du niveau marin et les changements climatiques sur la plate-forme helvétique ainsi qu'en domaine pélagique à la limite Barrémien-Aptien (Crétacé).Dans les Alpes helvétiques, la limite Barrémien-Aptien est marquée par la transition du Schrattenkalk inférieur, caractérisé par des carbonates photozaires, au Membre de Rawil caractérisé par des carbonates héterozoaires. Cette transition est marquée par une arrivée massive d'éléments détritiques et un apport de nutriments ayant entraîné la prolifération de foraminifères agglutinés tels que les orbitolines. L'analyse des minéraux argileux indique l'apparition de la kaolinite durant le Membre de Rawil, interprétée comme l'installation d'un climat plus chaud et humide. Un pic négatif en 513C est enregistré au sommet du Schrattenkalk inférieur correspond à l'excursion négative de -1%0 bien connue en domaine pélagique et datée comme Barrémien terminal. Cette corrélation apporte un contrôle chronostratigraphique supplémentaire permettant de dater le Schrattenkalk inférieur du Barrémien sup. et le Membre de Rawil de l'Aptien inf. D'autre part, une étude stratigraphique, basée sur des observations de terrain et sur l'interprétation d'assemblages floristiques et faunistiques en terme de paléoenvironnement a permis de mettre en évidence une limite de séquence au sommet du Schrattenkalk inf., corrélable avec la SbAl définie dans le Vercors. Durant la mise en place du Membre de Rawil, l'évolution des microfaciès est interprétée comme le « Transgressive System Tract » de la première séquence aptienne.En domaine pélagique, de minces couches riches en matière organique (MO) apparaissent dès le Barrémien sup. dans la coupe de Gorgo a Cerbara (Italie). Elles sont associées à un ratio C:P élevé indiquant des conditions épisodiquement dysoxiques à anoxiques. De plus, une corrélation nette entre Carbone Organique Total (TOC), phosphore (P) et silice biogénique est observée correspondant à un lien entre Ρ disponible, productivité et préservation de la MO. Pourtant, dans le même temps, le ÔI3C et le δ1βΟ restent constants indiquant des conditions environnementales stables et un cycle du carbone non perturbé par la préservation de MO qui ne serait pas la conséquence d'un changement climatique global mais juste d'un effet local.Ala limite Barrémien-Aptien, en domaine hémi-pélagique (La Bédoule, France) et pélagique (Gorgo a Cerbara), les couches riches en MO sont plus fréquentes et plus épaisses, elles se sont déposées en même temps qu'un pic négatif en 513CCARB et ô13Coib probablement dû à un épisode volcanique. A l'Aptien inf. le TOC des niveaux riches en MO augmente progressivement en même temps que la teneur en éléments traces jusqu'au dernier enrichissement avant l'événement anoxique océanique la (OAE la) correspondant au « niveau critique inf. », indiquant des conditions anoxiques moins restreintes. Celui-ci est également caractérisé par le fameux pic négatif en Ô13C (C3), une diminution du δ180 interprétée comme un réchauffement, par un pic en Ρ et un ratio C:P élevé. L'OAE 1 a, quant à lui, enregistre un refroidissement et coïncide avec le maximum en éléments traces ainsi qu'un fort ratio C:P mettant en valeur l'importance des conditions anoxiques pendant 1ΌΑΕ la dans cette coupe alors qu'aucune perturbation n'est enregistrés à La Bédoule probablement à cause de conditions paléogéographiques locales.Durant l'Aptien inf., les changements environnementaux sur la plate-forme se marquent par la prolifération d'orbitolines due à un changement climatique et une hausse du niveau marin. En domaine profond, la succession de niveaux riches en MO du Barrémien sup. jusqu'à l'OAE la documente l'impact progressif de changements paléoenvironnementaux, probablement liés à la formation du plateau d'Ontong Java à l'ouest de l'océan Pacifique.

Neonatal steroids induce a down-regulation of tenascin-C and elastin and cause a deceleration of the first phase and an acceleration of the second phase of lung alveolarization.

Pre- and postnatal corticosteroids are often used in perinatal medicine to improve pulmonary function in preterm infants. To mimic this clinical situation, newborn rats were treated systemically with dexamethasone (Dex), 0.1-0.01 mg/kg/day on days P1-P4. We hypothesized that postnatal Dex may have an impact on alveolarization by interfering with extracellular matrix proteins and cellular differentiation. Morphological alterations were observed on 3D images obtained by high-resolution synchrotron radiation X-ray tomographic microscopy. Alveolarization was quantified stereologically by estimating the formation of new septa between days P4 and P60. The parenchymal expression of tenascin-C (TNC), smooth muscle actin (SMA), and elastin was measured by immunofluorescence and gene expression for TNC by qRT-PCR. After Dex treatment, the first phase of alveolarization was significantly delayed between days P6 and P10, whereas the second phase was accelerated. Elastin and SMA expressions were delayed by Dex treatment, whereas TNC expression was delayed and prolonged. A short course of neonatal steroids impairs the first phase of alveolarization, most likely by altering the TNC and elastin expression. Due to an overshooting catch-up during the second phase of alveolarization, the differences disappear when the animals reach adulthood.

Evaluation de la stratégie de lutte contre le cancer en Suisse, Phase 1, 1999: document de synthèse

[Table des matières] 1.1. Bref historique de la stratégie nationale de lutte contre le cancer. 1.2. Mandat d'évaluation. 1. 3. Approche d'évaluation choisie. 1.4. Phase 1 : programme d'évaluation 1999. 2. Conclusions et recommandations générales. 2.1. Stratégie et concept directeur. 2.2. Structure soutenant le programme national de lutte contre le cancer. 2.3. Rôle et fonctionnement des différents organes du programme national. 2.4. Collaborations. 2.5. Monitoring des programmes, évaluation de projets spécifiques et indicateurs à disposition pour l'évaluation globale. 3. Propositions pour la suite de l'évaluation. 4. Résumé de l'étude 1 : évaluation de la conception et de la mise en oeuvre de la stratégie au niveau national. 5. Studie 2 : Inventar der vorhandene Datenquellen und Indikatoren. 5.1. Zusammenfassung. 5.2. Allgemeine Schlussfolgerungen und Empfehlungen. 6. Studie 3 : Konzeptualisierung und Stand der Umsetzung der vier Krebsbekämpfungsprogramme. 6.1. Einleitung. 6.2. Zusammenfassung der programmübergreifende Ergebnisse : zum Konzeptualisierungsprozess, zum Steuerungsprozess, zur Vernetzung innerhalb der Programme und im relevanten Umfeld. 6.3. Zusammenfassung der programmspezifischen Ergebnisse : Brustkrebs, Hautkrebs, Lungenkrebs, Darmkrebs. 6.4. Empfehlungen : Programmübergreifende Empfehlungen, ergänzende programmspezifische Empfehlungen.

Cetuximab In Combination With Docetaxel In Patients (Pts) With Metastatic Castration Resistant (Mcrpc) And Docetaxel-Refractory Prostate Cancer: Final Analysis Of The Multicenter Phase Ii Trial Sakk 08/07

There is no registered treatment (ttr) for pts with mCRPC who have progressive disease during or shortly after docetaxel (doc). EGFR overexpression increases in prostate cancer during the course of the disease. We investigated efficacy and safety of the combination of the monoclonal EGFR antibody cetuximab (cet) and doc in pts with mCRPC who are doc-refractory. Methods: Pts with mCRPC progressing during or < 90 days after at least 12 weeks of doc were included. Ttr consisted of the same doc regimen as prior to progression (35mg/m2 d1,8,15 q4w or 75mg/m2 q3w) in combination with cet (400mg/m2 d1, then 250mg/m2 weekly). Primary endpoint was progression free survival (PFS) at 12 weeks defined as absence of PSA progression or progression of metastases (mets). Secondary endpoints included toxicity, PFS at 24 weeks, PSA response, response of measureable disease and overall survival. 35 pts were needed in a Simon's two stage optimal design with a power of 90% and a significance level of 5% in order to test PFS rate at 12 weeks of £10% vs ?30%. Results: 35 evaluable pts were enrolled at 15 Swiss centers between 7/08 and 9/09. Median follow up was 14.8 months. Confirmed PFS at 12 weeks was 34% (95%CI 19-52%), PFS at 24 weeks was 20% and overall survival was 12.0 months (95%CI 7.1 -15.6). 20% (7/35) had a confirmed decline in PSA ? 50% and 31% (11/35) had a confirmed PSA decline ? 30%. Of pts with measurable disease (n=24) PR, SD and PD at week 12 was 4%, 54% and 25%, respectively (17% not evaluable). 3/9 (33%) pts with PDduring last doc ttr before inclusion reached the primary endpoint compared to 7/18 (39%) with PR or SD to last doc. 54% of evaluable pts experienced grade 3 and 6% grade 4 toxicity. Discussion: The result of the primary endpoint was promising in this first trial to test cet in combination with doc in pts with docetaxel-refractory mCRPC. Because this goal was achieved in such a highly pretreated pts population it appears that inhibition of the EGFR pathway may play a more important and persistent role in the treatment of prostate cancer than perceived so far. Further research is therefore warranted. Disclosure: R. Cathomas: - Membership on advisory board for sanofi aventis (suisse) and Merck. S. Gillessen: - Membership in advisory board for Sanofi Aventis. All other authors have declared no conflicts of interest.

Low-dose, simple, and fast grating-based X-ray phase-contrast imaging.

Phase sensitive X-ray imaging methods can provide substantially increased contrast over conventional absorption-based imaging and therefore new and otherwise inaccessible information. The use of gratings as optical elements in hard X-ray phase imaging overcomes some of the problems that have impaired the wider use of phase contrast in X-ray radiography and tomography. So far, to separate the phase information from other contributions detected with a grating interferometer, a phase-stepping approach has been considered, which implies the acquisition of multiple radiographic projections. Here we present an innovative, highly sensitive X-ray tomographic phase-contrast imaging approach based on grating interferometry, which extracts the phase-contrast signal without the need of phase stepping. Compared to the existing phase-stepping approach, the main advantages of this new method dubbed "reverse projection" are not only the significantly reduced delivered dose, without the degradation of the image quality, but also the much higher efficiency. The new technique sets the prerequisites for future fast and low-dose phase-contrast imaging methods, fundamental for imaging biological specimens and in vivo studies.

Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. METHODS: In this multicentre, open-label, phase 3 study, we investigated the efficacy of cilengitide in patients from 146 study sites in 25 countries. Eligible patients (newly diagnosed, histologically proven supratentorial glioblastoma, methylated MGMT promoter, and age ≥18 years) were stratified for prognostic Radiation Therapy Oncology Group recursive partitioning analysis class and geographic region and centrally randomised in a 1:1 ratio with interactive voice response system to receive temozolomide chemoradiotherapy with cilengitide 2000 mg intravenously twice weekly (cilengitide group) or temozolomide chemoradiotherapy alone (control group). Patients and investigators were unmasked to treatment allocation. Maintenance temozolomide was given for up to six cycles, and cilengitide was given for up to 18 months or until disease progression or unacceptable toxic effects. The primary endpoint was overall survival. We analysed survival outcomes by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00689221. FINDINGS: Overall, 3471 patients were screened. Of these patients, 3060 had tumour MGMT status tested; 926 patients had a methylated MGMT promoter, and 545 were randomly assigned to the cilengitide (n=272) or control groups (n=273) between Oct 31, 2008, and May 12, 2011. Median overall survival was 26·3 months (95% CI 23·8-28·8) in the cilengitide group and 26·3 months (23·9-34·7) in the control group (hazard ratio 1·02, 95% CI 0·81-1·29, p=0·86). None of the predefined clinical subgroups showed a benefit from cilengitide. We noted no overall additional toxic effects with cilengitide treatment. The most commonly reported adverse events of grade 3 or worse in the safety population were lymphopenia (31 [12%] in the cilengitide group vs 26 [10%] in the control group), thrombocytopenia (28 [11%] vs 46 [18%]), neutropenia (19 [7%] vs 24 [9%]), leucopenia (18 [7%] vs 20 [8%]), and convulsion (14 [5%] vs 15 [6%]). INTERPRETATION: The addition of cilengitide to temozolomide chemoradiotherapy did not improve outcomes; cilengitide will not be further developed as an anticancer drug. Nevertheless, integrins remain a potential treatment target for glioblastoma. FUNDING: Merck KGaA, Darmstadt, Germany.

An EORTC phase I itudy of bortezomib in combination with oxaliplatin, leucovorin and 5-fluorouracil in patients with advanced colorectal cancer.

The combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX-4) is still a reference regimen in advanced colorectal cancer; however, the addition of new biologic compounds represents a significant way forward. Bortezomib is an inhibitor of proteasome, a multicatalytic enzyme complex that degrades several intracellular proteins. In this study, escalating doses of Bortezomib were administered along with the standard FOLFOX-4 doses, in order to evaluate the dose-limiting toxicity (DLT), toxicity profile and activity of the combination. Patients with advanced colorectal cancer, unpretreated for metastatic disease, were enroled in the study. Bortezomib starting dose was 1.3mg/m(2), which was to be escalated in the subsequent steps according to the toxicities observed after first cycle. Exploratory pharmacogenetics research was conducted by analysing the association between clinical outcomes and polymorphisms in candidate genes for response to each of the used drugs. Correlation between tumour marker changes and response was also investigated. One mg/m(2) (DL-1) was defined as being the maximum tolerated dose since only 1 DLT was observed in 6 patients. The main toxicities were haematologic, neuropathy, diarrhoea and fatigue. Amongst 13 evaluable patients, five had a partial response, five had a stable disease and three patients progressed. Two patients are long-term survivors after a combined chemosurgical approach. Further trials of the current combination may be justified.

Monitoring tumor antigen specific T-cell responses in cancer patients and phase I clinical trials of peptide-based vaccination.

Numerous phase I and II clinical trials testing the safety and immunogenicity of various peptide vaccine formulations based on CTL-defined tumor antigens in cancer patients have been reported during the last 7 years. While specific T-cell responses can be detected in a variable fraction of immunized patients, an even smaller but significant fraction of these patients have objective tumor responses. Efficient therapeutic vaccination should aim at boosting naturally occurring antitumor T- and B-cell responses and at sustaining a large number of tumor antigen specific and fully functional effector T cells at tumor sites. Recent progress in our ability to quantitatively and qualitatively monitor tumor antigen specific CD8 T-cell responses will greatly help in making rapid progress in this field.