Prognostic factors affecting long-term outcomes in patients with resected stage IIIA pN2 non-small-cell lung cancer: 5-year follow-up of a phase II study

The aim was to investigate the efficacy of neoadjuvant docetaxel-cisplatin and identify prognostic factors for outcome in locally advanced stage IIIA (pN2 by mediastinoscopy) non-small-cell lung cancer (NSCLC) patients. In all, 75 patients (from 90 enrolled) underwent tumour resection after three 3-week cycles of docetaxel 85 mg m-2 (day 1) plus cisplatin 40 or 50 mg m-2 (days 1 and 2). Therapy was well tolerated (overall grade 3 toxicity occurred in 48% patients; no grade 4 nonhaematological toxicity was reported), with no observed late toxicities. Median overall survival (OS) and event-free survival (EFS) times were 35 and 15 months, respectively, in the 75 patients who underwent surgery; corresponding figures for all 90 patients enrolled were 28 and 12 months. At 3 years after initiating trial therapy, 27 out of 75 patients (36%) were alive and tumour free. At 5-year follow-up, 60 and 65% of patients had local relapse and distant metastases, respectively. The most common sites of distant metastases were the lung (24%) and brain (17%). Factors associated with OS, EFS and risk of local relapse and distant metastases were complete tumour resection and chemotherapy activity (clinical response, pathologic response, mediastinal downstaging). Neoadjuvant docetaxel-cisplatin was effective and tolerable in stage IIIA pN2 NSCLC, with chemotherapy contributing significantly to outcomes.

Long-term followup results of 1 cycle of adjuvant bleomycin, etoposide and cisplatin chemotherapy for high risk clinical stage I nonseminomatous germ cell tumors of the testis

PURPOSE: We evaluated the long-term outcome after 1 cycle of adjuvant modified bleomycin, etoposide and cisplatin chemotherapy in patients who underwent orchiectomy for high risk clinical stage I nonseminomatous germ cell tumor of the testis. MATERIALS AND METHODS: Between 1995 and 1999 a consecutive series of 44 patients underwent orchiectomy for clinical stage I nonseminomatous germ cell tumor of the testis, followed by a single postoperative cycle of adjuvant modified bleomycin, etoposide and cisplatin for vascular or lymphatic tumor invasion, and/or a predominance (50% or greater) of embryonal carcinoma. RESULTS: Four of the 44 patients were excluded from analysis. Of the patients 35 had no evidence of disease at a median followup of 99 months (range 60 to 134). One patient with progression after 13 months showed complete remission after 3 cycles of salvage bleomycin, etoposide and cisplatin chemotherapy but he died of pneumonia 4 weeks after the third course. Two patients underwent orchiectomy for contralateral testis cancer at 18 and 42 months, respectively, followed by an additional 3 cycles of adjuvant chemotherapy. They remained relapse-free for 4 and 92 months, respectively. The former patient was lost to followup after 4 months. Two other patients were disease-free at 10 and 31 months, respectively, and were lost to followup thereafter. Late side effects were tinnitus in 3 patients and involuntary childlessness in 3, of whom 2 had cryptorchidism of the contralateral testis. Nine patients fathered children. CONCLUSIONS: One cycle of bleomycin, etoposide and cisplatin effectively decreases the risk of relapse in patients with high risk stage I nonseminomatous germ cell tumor of the testis. It has minimal side effects and can be a valuable alternative to retroperitoneal lymph node dissection.

Possible Effects of Anthropogenically-Increased CO2 on the Dynamics of Climate: Implications for Ice-Age Cycles

A dynamical model, developed to account for the observed major variations of global ice mass and atmospheric CO2 during the late Cenozoic, is used to provide a quantitative demonstration of the possibility that the anthropogenically-forced increase of atmospheric CO2, if maintained over a long period of time (perhaps by tectonic forcing), could displace the climatic system from an unstable regime of oscillating ice ages into a more stable regime representative of the pre-Pleistocene. This stable regime is characterized by orbitally-forced oscillations that are of much weaker amplitude than prevailed during the Pleistocene.

Observing Biogeochemical Cycles at Global Scales With Profiling Floats and Gliders Prospects for a Global Array

Chemical and biological sensor technologies have advanced rapidly in the past five years. Sensors that require low power and operate for multiple years are now available for oxygen, nitrate, and a variety of bio-optical properties that serve as proxies for important components of the carbon cycle (e.g., particulate organic carbon). These sensors have all been deployed successfully for long periods, in some cases more than three years, on platforms such as profiling floats or gliders. Technologies for pH, pCO(2), and particulate inorganic carbon are maturing rapidly as well. These sensors could serve as the enabling technology for a global biogeochemical observing system that might operate on a scale comparable to the current Argo array. Here, we review the scientific motivation and the prospects for a global observing system for ocean biogeochemistry.

Long-term storage affects adhesion between titanium and zirconia using resin cements.

PURPOSE To determine the impact of long-term storage on adhesion between titanium and zirconia using resin cements. MATERIALS AND METHODS Titanium grade 4 blocks were adhesively fixed onto zirconia disks with four resin cements: Panavia F 2.0 (Kuraray Europe), GC G-Cem (GC Europe), RelyX Unicem (3M ESPE), and SmartCem 2 (Dentsply DeguDent). Shear bond strength was determined after storage in a water bath for 24 h, 16, 90, and 150 days at 37°C, and after 6000 cycles between 5°C and 55°C. Fracture behavior was evaluated using scanning electron microscopy. RESULTS After storage for at least 90 days and after thermocycling, GC G-Cem (16.9 MPa and 15.1 MPa, respectively) and RelyX Unicem (10.8 MPa and 15.7 MPa, respectively) achieved higher shear bond strength compared to SmartCem 2 (7.1 MPa and 4.0 MPa, respectively) and Panavia F2 (4.1 MPa and 7.4 MPa, respectively). At day 150, GC G-Cem and RelyX Unicem caused exclusively mixed fractures. SmartCem 2 and Panavia F2 showed adhesive fractures in one-third of the cases; all other fractures were of mixed type. After 24 h (GC G-Cem: 26.0, RelyX Unicem: 20.5 MPa, SmartCem 2: 16.1 MPa, Panavia F2: 23.6 MPa) and 16 days (GC G-Cem: 12.8, RelyX Unicem: 14.2 MPa, SmartCem 2: 9.8 MPa, Panavia F2: 14.7 MPa) of storage, shear bond strength was similar among the four cements. CONCLUSION Long-term storage and thermocycling differentially affects the bonding of resin cement between titanium and zirconia.

Long-term outcome of patients with clinical stage I high-risk nonseminomatous germ-cell tumors 15 years after one adjuvant cycle of bleomycin, etoposide, and cisplatin chemotherapy

BACKGROUND To report the long-term results of adjuvant treatment with one cycle of modified bleomycin, etoposide, and cisplatin (BEP) in patients with clinical stage I (CS I) nonseminomatous germ-cell tumors (NSGCT) at high risk of relapse. PATIENTS AND METHODS In a single-arm, phase II clinical trial, 40 patients with CS I NSGCT with vascular invasion and/or >50% embryonal cell carcinoma in the orchiectomy specimen received one cycle of adjuvant BEP (20 mg/m(2) bleomycin as a continuous infusion over 24 h, 120 mg/m(2) etoposide and 40 mg/m(2) cisplatin each on days 1-3). Primary end point was the relapse rate. RESULTS Median follow-up was 186 months. One patient (2.5%) had a pulmonary relapse 13 months after one BEP and died after three additional cycles of BEP chemotherapy. Three patients (7.5%) presented with a contralateral metachronous testicular tumor, and three (7.5%) developed a secondary malignancy. Three patients (7.5%) reported intermittent tinnitus and one had grade 2 peripheral polyneuropathy (2.5%). CONCLUSIONS Adjuvant chemotherapy with one cycle of modified-BEP is a feasible and safe treatment of patients with CS I NSGCT at high risk of relapse. In these patients, it appears to be an alternative to two cycles of BEP and to have a lower relapse rate than retroperitoneal lymph node dissection. If confirmed by other centers, 1 cycle of adjuvant BEP chemotherapy should become a first-line treatment option for this group of patients.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

BACKGROUND Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. METHODS Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). FINDINGS 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. INTERPRETATION Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. FUNDING Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

(Table 2) Stratigraphic position of midpoints of reddish and beige layers of lithologic cycles in the Loulja-A Section and their astronomical ages after tuning to the ETP and Summer Insolation Curves of the La2004 solution

An integrated high-resolution stratigraphy and orbital tuning is presented for the Loulja sections located in the Bou Regreg area on the Atlantic side of Morocco. The sections constitute the upward continuation of the upper Messinian Ain el Beida section and contain a well-exposed, continuous record of the interval straddling the Miocene-Pliocene (M-P) boundary. The older Loulja-A section, which covers the interval from ~5.59 to 5.12 Ma, reveals a dominantly precession-controlled color cyclicity that allows for a straightforward orbital tuning of the boundary interval and for detailed cyclostratigraphic correlations to the Mediterranean; the high-resolution and high-quality benthic isotope record allows us to trace the dominantly obliquity-controlled glacial history. Our results reveal that the M-P boundary coincides with a minor, partly precession-related shift to lighter "interglacial" values in d18O. This shift and hence the M-P boundary may not correlate with isotope stage TG5, as previously thought, but with an extra (weak) obliquity-controlled cycle between TG7 and TG5. Consequently, the M-P boundary and basal Pliocene flooding of the Mediterranean following the Messinian salinity crisis are not associated with a major deglaciation and glacio-eustatic sea level rise, indicating that other factors, such as tectonics, must have played a fundamental role. On the other hand, the onset of the Upper Evaporites in the Mediterranean marked by hyposaline conditions coincides with the major deglaciation step between marine isotope stage TG12 and TG11, suggesting that the associated sea level rise is at least partly responsible for the apparent onset of intermittently restricted marine conditions following the main desiccation phase. Finally, the Loulja-A section would represent an excellent auxiliary boundary stratotype for the M-P boundary as formally defined at the base of the Trubi marls in the Eraclea Minoa section on Sicily.

40-year long monthly-resolved Sr/Ca record from 2.35 ka Bonaire coral, sample BON-6-A

We present a 40-year long monthly resolved Sr/Ca record from a fossil Diploria strigosa coral from Bonaire (Southern Caribbean Sea) dated with U/Th at 2.35 ka before present (BP). Secondary modifiers of this sea surface temperature (SST) proxy in annually-banded corals such as diagenetic alteration of the skeleton and skeletal growth-rate are investigated. Extensive diagenetic investigations reveal that this fossil coral skeleton is pristine which is further supported by clear annual cycles in the coral Sr/Ca record. No significant correlation between annual growth rate and Sr/Ca is observed, suggesting that the Sr/Ca record is not affected by coral growth. Therefore, we conclude that the observed interannual Sr/Ca variability was influenced by ambient SST variability. Spectral analysis of the annual mean Sr/Ca record reveals a dominant frequency centred at 6-7 years that is not associated with changes of the annual growth rate. The first monthly resolved coral Sr/Ca record from the Southern Caribbean Sea for preindustrial time suggests that fossil corals from Bonaire are suitable tools for reconstructing past SST variability. Coastal deposits on Bonaire provide abundant fossil D. strigosa colonies of Holocene age that can be accurately dated and used to reconstruct climate variability. Comparisons of long monthly resolved Sr/Ca records from multiple fossil corals will provide a mean to estimate seasonality and interannual to interdecadal SST variability of the Southern Caribbean Sea during the Holocene.

Orbital control on carbonate-lignite cycles on sediment core KAP-107 in the Ptolemais Basin, northern Greece

Time control is essential for the reconstruction of geological processes. We use a combination of relative and absolute methods to establish the chronology and related paleoclimatic processes for Late Neogene lacustrine sediment from the Ptolemais Basin, northern Greece. We determined changes in magnetic polarity and correlated them to the global magnetic polarity time scale, which again is calibrated by radiometric methods, to provide a low-resolution age model for the Upper Miocene to Lower Pliocene (7 - 3 Ma). Sedimentary successions show rhythmic alterations of lignites, clays, and marls. Using photospetrometry we measured this variability at 1-cm resolution, and correlated the pattern to known changes in earth's orbital parameters, namely to eccentricity and precession. For 230-m long borehole KAP-107 from the Amynteon Sub-Basin we obtained a high-resolution age model that spans 2 myr from 5.1 to 3.1 Ma, with age control points at insolation maxima (20-kyr resolution). We recommend using photospectrometry as reliable tool to establish orbital-based chronologies and to reconstruct paleoclimate variability at high resolution.

The effects of long (C20/22) and short (C18) chain omega-3 fatty acids on keel bone fractures, bone biomechanics, behavior, and egg production in free-range laying hens.

Keel fractures in the laying hen are the most critical animal welfare issue facing the egg production industry, particularly with the increased use of extensive systems in response to the 2012 EU directive banning conventional battery cages. The current study is aimed at assessing the effects of 2 omega-3 (n3) enhanced diets on bone health, production endpoints, and behavior in free-range laying hens. Data was collected from 2 experiments over 2 laying cycles, each of which compared a (n3) supplemented diet with a control diet. Experiment 1 employed a diet supplemented with a 60:40 fish oil-linseed mixture (n3:n6 to 1.35) compared with a control diet (n3:n6 to 0.11), whereas the n3 diet in Experiment 2 was supplemented with a 40:60 fish oil-linseed (n3:n6 to 0.77) compared to the control diet (n3:n6 to 0.11). The n3 enhanced diet of Experiment 1 had a higher n3:n6 ratio, and a greater proportion of n3 in the long chain (C20/22) form (0.41 LC:SC) than that of Experiment 2 (0.12 LC:SC). Although dietary treatment was successful in reducing the frequency of fractures by approximately 27% in Experiment 2, data from Experiment 1 indicated the diet actually induced a greater likelihood of fracture (odds ratio: 1.2) and had substantial production detriment. Reduced keel breakage during Experiment 2 could be related to changes in bone health as n3-supplemented birds demonstrated greater load at failure of the keel, and tibiae and humeri that were more flexible. These results support previous findings that n3-supplemented diets can reduce fracture likely by increasing bone strength, and that this can be achieved without detriment to production. However, our findings suggest diets with excessive quantities of n3, or very high levels of C20/22, may experience health and production detriments. Further research is needed to optimize the quantity and type of n3 in terms of bone health and production variables and investigate the potential associated mechanisms.

Long wave theory for experimental devices with compressed/expanded surfactant monolayers

Surfactant monolayers are of interest in a variety of phenomena, including thin film dynamics and the formation and dynamics of foams. Measurement of surface properties has received a continuous attention and requires good theoretical models to extract the relevant physico- chemical information from experimental data. A common experimental set up consists in a shallow liquid layer whose free surface is slowly com- pressed/expanded in periodic fashion by moving two slightly immersed solid barriers, which varies the free surface area and thus the surfactant concentration. The simplest theory ignores the fluid dynamics in the bulk fluid, assuming spatially uniform surfactant concentration, which requires quite small forcing frequencies and provides reversible dynamics in the compression/expansion cycles. Sometimes, it is not clear whether depar- ture from reversibility is due to non-equilibrium effects or to the ignored fluid dynamics. Here we present a long wave theory that takes the fluid dynamics and the symmetries of the problem into account. In particular, the validity of the spatially-uniform-surfactant-concentration assumption is established and a nonlinear diffusion equation is derived. This allows for calculating spatially nonuniform monolayer dynamics and uncovering the physical mechanisms involved in the surfactant behavior. Also, this analysis can be considered a good means for extracting more relevant information from each experimental run.