Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy.

PURPOSE: Studies of diffuse large B-cell lymphoma (DLBCL) are typically evaluated by using a time-to-event approach with relapse, re-treatment, and death commonly used as the events. We evaluated the timing and type of events in newly diagnosed DLBCL and compared patient outcome with reference population data. PATIENTS AND METHODS: Patients with newly diagnosed DLBCL treated with immunochemotherapy were prospectively enrolled onto the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource (MER) and the North Central Cancer Treatment Group NCCTG-N0489 clinical trial from 2002 to 2009. Patient outcomes were evaluated at diagnosis and in the subsets of patients achieving event-free status at 12 months (EFS12) and 24 months (EFS24) from diagnosis. Overall survival was compared with age- and sex-matched population data. Results were replicated in an external validation cohort from the Groupe d'Etude des Lymphomes de l'Adulte (GELA) Lymphome Non Hodgkinien 2003 (LNH2003) program and a registry based in Lyon, France. RESULTS: In all, 767 patients with newly diagnosed DLBCL who had a median age of 63 years were enrolled onto the MER and NCCTG studies. At a median follow-up of 60 months (range, 8 to 116 months), 299 patients had an event and 210 patients had died. Patients achieving EFS24 had an overall survival equivalent to that of the age- and sex-matched general population (standardized mortality ratio [SMR], 1.18; P = .25). This result was confirmed in 820 patients from the GELA study and registry in Lyon (SMR, 1.09; P = .71). Simulation studies showed that EFS24 has comparable power to continuous EFS when evaluating clinical trials in DLBCL. CONCLUSION: Patients with DLBCL who achieve EFS24 have a subsequent overall survival equivalent to that of the age- and sex-matched general population. EFS24 will be useful in patient counseling and should be considered as an end point for future studies of newly diagnosed DLBCL.

MPI-DING reference glasses for in situ microanalysis: New reference values for element concentrations and isotope ratios

[1] We present new analytical data of major and trace elements for the geological MPI-DING glasses KL2-G, ML3B-G, StHs6/80-G, GOR128-G, GOR132-G, BM90/21-G, T1-G, and ATHO-G. Different analytical methods were used to obtain a large spectrum of major and trace element data, in particular, EPMA, SIMS, LA-ICPMS, and isotope dilution by TIMS and ICPMS. Altogether, more than 60 qualified geochemical laboratories worldwide contributed to the analyses, allowing us to present new reference and information values and their uncertainties ( at 95% confidence level) for up to 74 elements. We complied with the recommendations for the certification of geological reference materials by the International Association of Geoanalysts (IAG). The reference values were derived from the results of 16 independent techniques, including definitive ( isotope dilution) and comparative bulk ( e. g., INAA, ICPMS, SSMS) and microanalytical ( e. g., LA-ICPMS, SIMS, EPMA) methods. Agreement between two or more independent methods and the use of definitive methods provided traceability to the fullest extent possible. We also present new and recently published data for the isotopic compositions of H, B, Li, O, Ca, Sr, Nd, Hf, and Pb. The results were mainly obtained by high-precision bulk techniques, such as TIMS and MC-ICPMS. In addition, LA-ICPMS and SIMS isotope data of B, Li, and Pb are presented.

Multifactorial ERβ and NOTCH1 control of squamous differentiation and cancer.

Downmodulation or loss-of-function mutations of the gene encoding NOTCH1 are associated with dysfunctional squamous cell differentiation and development of squamous cell carcinoma (SCC) in skin and internal organs. While NOTCH1 receptor activation has been well characterized, little is known about how NOTCH1 gene transcription is regulated. Using bioinformatics and functional screening approaches, we identified several regulators of the NOTCH1 gene in keratinocytes, with the transcription factors DLX5 and EGR3 and estrogen receptor β (ERβ) directly controlling its expression in differentiation. DLX5 and ERG3 are required for RNA polymerase II (PolII) recruitment to the NOTCH1 locus, while ERβ controls NOTCH1 transcription through RNA PolII pause release. Expression of several identified NOTCH1 regulators, including ERβ, is frequently compromised in skin, head and neck, and lung SCCs and SCC-derived cell lines. Furthermore, a keratinocyte ERβ-dependent program of gene expression is subverted in SCCs from various body sites, and there are consistent differences in mutation and gene-expression signatures of head and neck and lung SCCs in female versus male patients. Experimentally increased ERβ expression or treatment with ERβ agonists inhibited proliferation of SCC cells and promoted NOTCH1 expression and squamous differentiation both in vitro and in mouse xenotransplants. Our data identify a link between transcriptional control of NOTCH1 expression and the estrogen response in keratinocytes, with implications for differentiation therapy of squamous cancer.

Metallogenic model of the Trepca Pb-Zn-Ag skarn deposit, Kosovo: Evidence from fluid inclusions, Rare Earth Elements, and stable isotope data

The Trepca Pb-Zn-Ag skarn deposit (29 Mt of ore at 3.45% Pb, 2.30% Zn, and 80 g/t Ag) is located in the Kopaonik block of the western Vardar zone, Kosovo. The mineralization, hosted by recrystallized limestone of Upper Triassic age, was structurally and lithologically controlled. Ore deposition is spatially and temporally related with the postcollisional magmatism of Oligocene age (23-26 Ma). The deposit was formed during two distinct mineralization stages: an early prograde closed-system and a later retrograde open-system stage. The prograde mineralization consisting mainly of pyroxenes (Hd(54-100)Jo(0-45)Di(0-45)) resulted from the interaction of magmatic fluids associated with Oligocene (23-26 Ma) postcollisional magmatism. Whereas there is no direct contact between magmatic rocks and the mineralization, the deposit is classified as a distal Pb-Zn-Ag skarn. Abundant pyroxene reflects low oxygen fugacity (<10(-31) bar) and anhydrous environment. Fluid inclusion data and mineral assemblage limit the prograde stage within a temperature range between 390 degrees and 475 degrees C. Formation pressure is estimated below 900 bars. Isotopic composition of aqueous fluid, inclusions hosted by hedenbergite (delta D = -108 to -130 parts per thousand; delta O-18 = 7.5-8.0 parts per thousand), Mn-enriched mineralogy and high REE content of the host carbonates at the contact with the skarn mineralization suggest that a magmatic fluid was modified during its infiltration through the country rocks. The retrograde mineral assemblage comprises ilvaite, magnetite, arsenopyrite, pyrrhotite, marcasite, pyrite, quartz, and various carbonates. Increases in oxygen and sulfur fugacities, as well as a hydrous character of mineralization, require an open-system model. The opening of the system is related to phreatomagmatic explosion and formation of the breccia. Arsenopyrite geothermometer limits the retrograde stage within the temperature range between 350 degrees and 380 degrees C and sulfur fugacity between 10(-8.8) and 10(-7.2) bars. The principal ore minerals, galena, sphalerite, pyrite, and minor chalcopyrite, were deposited from a moderately saline Ca-Na chloride fluid at around 350 degrees C. According to the isotopic composition of fluid inclusions hosted by sphalerite (delta D = -55 to -74 parts per thousand; delta O-18 = -9.6 to -13.6 parts per thousand), the fluid responsible for ore deposition was dominantly meteoric in origin. The delta S-31 values of the sulfides spanning between -5.5 and +10 parts per thousand point to a magmatic origin of sulfur. Ore deposition appears to have been largely contemporaneous with the retrograde stage of the skarn development. Postore stage accompanied the precipitation of significant amount of carbonates including the travertine deposits at the deposit surface. Mineralogical composition of travertine varies from calcite to siderite and all carbonates contain significant amounts of Mn. Decreased formation temperature and depletion in the REE content point to an influence of pH-neutralized cold ground water and dying magmatic system.

Magmatic-dominated fluid evolution in the Jurassic Nambija gold skarn deposits (southeastern Ecuador)

The Jurassic (approximately 145 Ma) Nambija oxidized gold skarns are hosted by the Triassic volcanosedimentary Piuntza unit in the sub-Andean zone of southeastern Ecuador. The skarns consist dominantly of granditic garnet (Ad(20-98)) with subordinate pyroxene (Di(46-92)Hd(17-42)Jo(0-19)) and epidote and are spatially associated with porphyritic quartz-diorite to granodiorite intrusions. Endoskarn is developed at the intrusion margins and grades inwards into a potassic alteration zone. Exoskarn has an outer K- and Na-enriched zone in the volcanosedimentary unit. Gold mineralization is associated with the weakly developed retrograde alteration of the exoskarn and occurs mainly in sulfide-poor vugs and milky quartz veins and veinlets in association with hematite. Fluid inclusion data for the main part of the prograde stage indicate the coexistence of high-temperature (500A degrees C to > 600A degrees C), high-salinity (up to 65 wt.% eq. NaCl), and moderate- to low-salinity aqueous-carbonic fluids interpreted to have been trapped at pressures around 100-120 MPa, corresponding to about 4-km depth. Lower-temperature (510-300A degrees C) and moderate- to low-salinity (23-2 wt.% eq. NaCl) aqueous fluids are recorded in garnet and epidote of the end of the prograde stage. The microthermometric data (Th from 513A degrees C to 318A degrees C and salinity from 1.0 to 23 wt.% eq. NaCl) and delta(18)O values between 6.2aEuro degrees and 11.5aEuro degrees for gold-bearing milky quartz from the retrograde stage suggest that the ore-forming fluid was dominantly magmatic. Pressures during the early retrograde stage were in the range of 50-100 MPa, in line with the evidence for CO(2) effervescence and probable local boiling. The dominance of magmatic low-saline to moderately saline oxidizing fluids during the retrograde stage is consistent with the depth of the skarn system, which could have delayed the ingression of external fluids until relatively low temperatures were reached. The resulting low water-to-rock ratios explain the weak retrograde alteration and the compositional variability of chlorite, essentially controlled by host rock compositions. Gold was precipitated at this stage as a result of cooling and pH increase related to CO(2) effervescence, which both result in destabilization of gold-bearing chloride complexes. Significant ingression of external fluids took place after gold deposition only, as recorded by delta(18)O values of 0.4aEuro degrees to 6.2aEuro degrees for fluids depositing quartz (below 350A degrees C) in sulfide-rich barren veins. Low-temperature (< 300A degrees C) meteoric fluids (delta(18)O(water) between -10.0aEuro degrees and -2.0aEuro degrees) are responsible for the precipitation of late comb quartz and calcite in cavities and veins and indicate mixing with cooler fluids of higher salinities (about 100A degrees C and 25 wt.% eq. NaCl). The latter are similar to low-temperature fluids (202-74.5A degrees C) with delta(18)O values of -0.5aEuro degrees to 3.1aEuro degrees and salinities in the range of 21.1 to 17.3 wt.% eq. CaCl(2), trapped in calcite of late veins and interpreted as basinal brines. Nambija represents a deep equivalent of the oxidized gold skarn class, the presence of CO(2) in the fluids being partly a consequence of the relatively deep setting at about 4-km depth. As in other Au-bearing skarn deposits, not only the prograde stage but also the gold-precipitating retrograde stage is dominated by fluids of magmatic origin.

Do youths gamble? You bet! A Swiss population-based study

Cette recherche sur les jeux d'argent et de hasard au sein de la population des jeunes résidents Suisses avait trois objectifs. Pour avoir des données de base, nous nous sommes d'une part intéressés à la prévalence de ce comportement et, basé sur des critères de fréquence, avons mis en évidence une population plus à risque de subir des conséquences néfastes du jeu;à savoir ceux qui jouent au minimum une fois par semaine. Le deuxième objectif était de déterminer s'il existait une association entre la fréquence du jeu et 1) l'utilisation de substances, 2) une mauvaise santé mentale et/ou 3) un faible support social, comme cela a été décrit dans la littérature pour les joueurs pathologiques. Finalement, pour savoir si les joueurs fréquents étaient «fixés» sur un seul type de jeu ou au contraire jouaient de manière non-sélective, nous avons effectué la corrélation entre la fréquence de jeu et le nombre de jeux différents dans lesquels les jeunes étaient impliqués.Pour ces analyses, nous avons utilisé la base de données de l'Enquête Suisse sur la Santé 2007, une étude transversale interrogeant des résidents suisses âgés de 15 ans ou plus. Cette enquête a été menée en deux étapes: 1) un questionnaire téléphonique (taux de réponse: 66.3%) puis 2) un questionnaire écrit (taux de réponse: 80.5% de ceux qui ont répondu à l'interview téléphonique). En tenant compte de la pondération pour l'échantillon de participants ayant répondu aux deux types d'interviews, nous avons considéré uniquement les personnes âgées de 15 à 24 ans. Au total 1116 (582 hommes) participants ont été retenus pour notre étude.Pour répondre au second objectif, nous avons comparé trois groupes. Les non-joueurs (NJ, n=577), les joueurs occasionnels (JO, n=388) et les joueurs fréquents (JF, n=151) ont été étudiés d'abord grâce à des analyses bivariées, puis à une régression multinomiale permettant de tenir compte des facteurs confondants. La sélection des variables pour la régression a été basée sur une méthode «bootstrap» permettant de produire des résultats représentatifs de la population entière et pas uniquement de l'échantillon analysé.Nous avons procédé de manière similaire pour répondre à la troisième question de recherche, mais en comparant uniquement les joueurs occasionnels et les joueurs fréquents.Les résultats ont mis en évidence que 48.3% des jeunes résidents suisses étaient impliqués dans au moins un type de jeu dans l'année précédente. Par ailleurs, 13.5% (n=151) des 15 à 24 ans jouaient au minimum une fois par semaine.Au niveau bivarié, la fréquence de jeu était associée à des facteurs sociodémographiques comme le sexe masculin, l'âge (les JO étant les plus âgés), et le revenu personnel. La fréquence de jeu était également significativement associée au fait de fumer du tabac quotidiennement, d'être actuellement fumeur de cannabis et d'avoir une consommation d'alcool à risque (beuveries). La mauvaise santé mentale (épisode de dépression majeure ou détresse psychologique) et le faible support relationnel (personne de confiance dans l'entourage ou activités de loisirs) n'étaient pas associés à la fréquence de jeu de manière significative, bien qu'une nette tendance en faveur des NJ ait pu être mise en évidence. Au niveau multivarié, les JO et JF étaient plus âgés, plus souvent de sexe masculin et habitaient plus souvent en Suisse romande que les NJ. Les JO étaient plus à risque que les NJ de se soumettre à des beuveries de manière occasionnelle et les JF étaient plus à risque que les NJ d'être des fumeurs de tabac quotidiens.En comparant les JO et les JF, nous avons obtenu une correlation élevée (r=0.85;p<0.0001) entre la fréquence de jeu et le nombre de jeux dans lesquels les jeunes étaient impliqués. Ceci indiquant que les JF ne semblent pas très sélectifs quant au type de jeu auquel ils jouent.Dans la mesure où le jeu est un comportement très prévalent au sein de la population des jeunes résidents suisses, il doit probablement être vu comme une conduite faisant partie des comportements exploratoires de l'adolescence. Néanmoins, au vu des comportements à risque qui y sont associés, la question du jeu devrait être soulevée par les médecins s'occupant de jeunes adultes à des fins de prévention.

Prevalence and predictors of suicide attempt in an incidence cohort of 661 young people with first-episode psychosis

OBJECTIVES: Studies investigating suicidal behaviour in psychosis rarely focus on incidence cohorts of first-episode patients. This is important, because patients who refuse study participation have higher rates of comorbid substance use disorders and longer duration of untreated psychosis as well as worse course illness, variables potentially linked to higher prevalence of suicidal behaviour. The aims of the present study were therefore to examine the prevalence and predictors of suicide and suicide attempt before and during the first 18-24 months of treatment. METHOD: A retrospective file audit of 661 patients was carried out. RESULTS: Six patients (0.9%) died by suicide, 93 (14.3%) attempted suicide prior to entry, and 57 (8.7%) did so during treatment. Predictors of suicide attempt were: previous attempt (odds ratio (OR)=45.54, 95% confidence interval (CI)=9.46-219.15), sexual abuse (OR=8.46, 95%CI=1.88-38.03), comorbid polysubstance (OR=13.63, 95%CI=2.58-71.99), greater insight (OR=0.17, 95%CI=0.06-0.49), lower baseline Global Assessment of Functioning Scale and Scale of Occupational and Functional Assessment score (OR=0.96, 95%CI=0.62-0.91; OR=0.98, 95%CI=0.95-0.99), and longer time in treatment (OR=1.05, 95%CI=1.03-1.08). CONCLUSIONS: The prevalence of suicidal behaviour was high, indicating that suicidal behaviour in incidence populations is higher than in non-epidemiological cohorts of first-episode patients. The rate of repetition of suicide attempt among the sample, however, was lower than expected, suggesting that specialist services can play a role in reducing suicide risk.

Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation.

Stromal fibroblast senescence has been linked to ageing-associated cancer risk. However, density and proliferation of cancer-associated fibroblasts (CAFs) are frequently increased. Loss or downmodulation of the Notch effector CSL (also known as RBP-Jκ) in dermal fibroblasts is sufficient for CAF activation and ensuing keratinocyte-derived tumours. We report that CSL silencing induces senescence of primary fibroblasts from dermis, oral mucosa, breast and lung. CSL functions in these cells as a direct repressor of multiple senescence- and CAF-effector genes. It also physically interacts with p53, repressing its activity. CSL is downmodulated in stromal fibroblasts of premalignant skin actinic keratosis lesions and squamous cell carcinomas, whereas p53 expression and function are downmodulated only in the latter, with paracrine FGF signalling as the probable culprit. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effectors and promotes stromal and cancer cell expansion. The findings support a CAF activation-stromal co-evolution model under convergent CSL-p53 control.