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Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB–IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0–2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin–carboplatin, or 15 mg/kg every 21 days combined with gemcitabine–carboplatin or paclitaxel–carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4–9·3) in the standard chemotherapy group and 11·8 months (10·8–12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41–0·65; log-rank p<0·0001). Most common grade 3–4 adverse events were hypertension (20 [10%] in the standard chemotherapy group vs 58 (29%) in the bevacizumab group), neutrophil count decrease (81 [41%] vs 80 [40%]), and platelet count decrease (43 [22%] vs 61 [30%]). 68 patients (33%) died in the standard chemotherapy group and 79 (39%) died in the bevacizumab group; two deaths (1%) in the standard chemotherapy group and one death (<1%) in the bevacizumab group were deemed to be treatment-related. Continuing bevacizumab beyond progression combined with chemotherapy in patients with platinum-sensitive recurrent ovarian cancer improves progression-free survival compared with standard chemotherapy alone and might be considered in clinical practice. Hoffmann–La Roche and Associazione Italiana per la Ricerca sul Cancro.

The stability of marine ice sheets grounded on beds that slope upwards in the overall direction of flow is investigated numerically in two horizontal dimensions. We give examples of stable grounding lines on such retrograde slopes illustrating that marine ice sheets are not unconditionally unstable in two horizontal dimensions. Retrograde bed slopes at the grounding lines of marine ice sheets, such as the West Antarctic Ice Sheet (WAIS), do not per se imply an instability, nor do they imply that these regions are close to a threshold of instability. We therefore question those estimates of the potential near-future contribution of WAIS to global sea level change based solely on the notion that WAIS, resting on a retrograde slope, must be inherently unstable.

Background: Patients with recurrent/metastatic endometrial cancer that progresses after chemotherapy have limited treatment options and poor outcomes. Preclinical data suggest the oral mammalian target of rapamycin inhibitor everolimus may provide clinical benefit in these patients. Methods: In this multicenter, open-label, phase 2 study, patients with advanced or metastatic endometrial cancer refractory to one or two previous chemotherapy regimens received everolimus 10 mg per day until progression or unacceptable toxicity. Primary end point was the non-progressive disease rate at 3 months. Secondary end points included duration of response, progression-free, and overall survival (OS), and safety. Results: Forty-four patients were enrolled (median age, 65 years); 66% received one previous chemotherapy regimen. The 3-month non-progressive disease rate was 36% (95% confidence interval 22–52%), including two patients (5%) with partial response (PR). At 6 months, two additional patients experienced PR. Median duration of response was 3.1 months. Median progression-free and OS were 2.8 months and 8.1 months, respectively. The most common adverse events were anaemia (100%), fatigue (93%), hypercholesterolaemia (81%), and lymphopenia (81%). Conclusion: Everolimus demonstrated efficacy and acceptable tolerability in patients with chemotherapy-refractory advanced or metastatic endometrial cancer. These results support the further development of phosphatidylinositol 3-kinase-targeted therapies in endometrial cancer.

Ice-shelf channels are long curvilinear tracts of thin ice found on Antarctic ice shelves. Many of them originate near the grounding line, but their formation mechanisms remain poorly understood. Here we use ice-penetrating radar data from Roi Baudouin Ice Shelf, East Antarctica, to infer that the morphology of several ice-shelf channels is seeded upstream of the grounding line by large basal obstacles indenting the ice from below. We interpret each obstacle as an esker ridge formed from sediments deposited by subglacial water conduits, and calculate that the eskers’ size grows towards the grounding line where deposition rates are maximum. Relict features on the shelf indicate that these linked systems of subglacial conduits and ice-shelf channels have been changing over the past few centuries. Because ice-shelf channels are loci where intense melting occurs to thin an ice shelf, these findings expose a novel link between subglacial drainage, sedimentation and ice-shelf stability. The formation mechanisms of ice-shelf channels remain poorly understood. Here, using ice-penetrating radar data, the authors propose that ice-shelf channel morphology in the Roi Baudouin Ice Shelf, East Antarctica, is seeded by esker ridges, indenting the ice from below.

Backround: Patients with metastatic endometrial carcinoma have a poor prognosis and PIK3CA mutations and amplifications are common in these cancers. This study evaluated the efficacy and safety of the pure PI3K inhibitor BKM120 in advanced or recurrent endometrial carcinoma. Methods: This phase II, multicentre, single-arm, double strata (histological low grade (LG) or high grade (HG)) open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma who had received not more than one prior chemotherapy regimen. Patients received initially BKM120 100 mg tablets once daily. Primary end points were proportion of patients free of progression at 2 months (HG strata) or at 3 months (LG strata), objective response rate (ORR), and safety. Results: A total of 40 patients were enrolled, of whom 16 patients had received BKM120 at 100 mg. Because of high toxicities (cutaneous rash (54%), depressive events (47%), and anxiety (40%), the IDMC has proposed to stop recruitment at 100 mg and to continue the clinical trial with a lower dose of 60 mg per day. In addition, 24 patients (median age 67 years old) were newly enrolled (14 in the LG strata and 10 in the HG strata). Rate of nonprogression at 2 months in the HG strata was 70% and at 3 months was 60% in the LG strata. Median progression-free survival (PFS) for all patients is 4.5 months (CI 95% 2.8–6.1), and the median PFS for LG strata is 8.3 months compared with 3.8 months for the HG strata. No response was reported. At 60 mg per day, the most commonly reported treatment-related adverse events (AEs) were hyperglycaemia (58%), cognitive (31%), digestive (28%), hepatic liver functions (26%), and rash (23%). The most commonly reported treatment-related grade ⩾3 AEs were HTA (17%), hyperglycaemia (17%), and increased alanine aminotransferase (24%). Five patients (21%) stopped BKM120 for toxicity. Conclusions: The BKM120 was associated with an unfavourable safety profile and minimal antitumour activity in monotherapy in advanced or recurrent endometrial carcinoma. The clinical trial was stopped before end of recruitment for toxicity.

The West Antarctic ice sheet is confined by a large area of ice shelves, fed by inland ice through fast flowing ice streams. The dynamics of the grounding line, which is the line-boundary between grounded ice and the downstream ice shelf, has a major influence on the dynamics of the whole ice sheet. However, most ice sheet models use simplifications of the flow equations, as they do not include all the stress components, and are known to fail in their representation of the grounding line dynamics. Here, we present a 3-D full Stokes model of a marine ice sheet, in which the flow problem is coupled with the evolution of the upper and lower free surfaces, and the position of the grounding line is determined by solving a contact problem between the shelf/sheet lower surface and the bedrock. Simulations are performed using the open-source finite-element code Elmer/Ice within a parallel environment. The model's ability to cope with a curved grounding line and the effect of a pinning point beneath the ice shelf are investigated through prognostic simulations. Starting from a steady state, the sea level is slightly decreased to create a contact point between a seamount and the ice shelf. The model predicts a dramatic decrease of the shelf velocities, leading to an advance of the grounding line until both grounded zones merge together, during which an ice rumple forms above the contact area at the pinning point. Finally, we show that once the contact is created, increasing the sea level to its initial value does not release the pinning point and has no effect on the ice dynamics, indicating a stabilising effect of pinning points.

Recent glaciological surveys have revealed a significant increase of ice discharge from polar ice caps into the ocean. In parallel, ice flow models have been greatly improved to better reproduce current changes and forecast the future behavior of ice sheets. For these models, surface topography and bedrock elevation are crucial input parameters that largely control the dynamics and the ensuing overall mass balance of the ice sheet. For obvious reasons of inaccessibility, only sparse and uneven bedrock elevation data is available. This raw data is processed to produce Digital Elevation Models (DEMs) on a regular 5 km grid. These DEMs are used to constrain the basal boundary conditions of all ice sheet models. Here, by using a full‐Stokes finite element code, we examine the sensitivity of an ice flow model to the accuracy of the bedrock description. In the context of short‐term ice sheet forecast, we show that in coastal regions, the bedrock elevation should be known at a resolution of the order of one kilometer. Conversely, a crude description of the bedrock in the interior of the continent does not affect modeling of the ice outflow into the ocean. These findings clearly indicate that coastal regions should be prioritized during future geophysical surveys. They also indicate that a paradigm shift is required to change the current design of DEMs describing the bedrock below the ice sheets: they must give users the opportunity to incorporate high‐resolution bedrock elevation data in regions of interest. Key Points Kilometric resolution of bedrock description in ice sheet coastal region Poor knowledge of the bedrock is needed for remote inland regions Adding roughness may improve numerical results when no data is available

Cotton cloth waste was used as a precursor to prepare activated carbon (ACCs) chemically activated with phosphoric acid. Adsorption behavior of prepared ACCs was correlated with physicochemical proprieties. The pore volume and BET surface of ACCs were determined by nitrogen adsorption isotherms and scanning electron microscopy was used to observe their surface morphologies. Fourier transform infrared (FTIR) spectroscopy analysis and pH point zero charge (pHPZC) were conducted to determine chemical properties. Under the optimal conditions: 50% impregnation ratio and thermal treatment under N2 flow at 600 °C during 60 min, the activated carbon prepared exhibits a high surface area 1,150 m2/g, 0.501 cm3/g micropore volume and an excellent adsorption performance. The adsorbed amount of clofibric acid is found to be 9.98 and 83 mg/g at, respectively, initial CA concentration of 10 and 100 mg/L at pH 3.0 and 20 °C. Diffusion and chemisorption are the steps controlling the adsorption of CA onto ACC 50% and the equilibrium data were well described by Freundlich isotherm.

The busbars for the HL-LHC magnets are made of Nb-Ti/Cu conductor, the insulation system, and the auxiliary equipment to align the busbars with respect to the magnet coldmasses. This paper presents design options concerning the integration of the busbars inside the coldmass with a fixed point, and a reinforced insulation system for the flexible busbar part using thin PEEK tubes. Prototype splices for interconnecting Nb3Sn and Nb-Ti Rutherford cables, and round and flat 18 kA Nb-Ti cable have been produced and first test results are presented.

Introduction/BackgroundThe rare vaginal and vulvar cancers are considered to be histologically similar to cervical squamous cell carcinoma. However, mutational landscape differences between them are unclear. In the time of precision medicine and immunotherapy, a personalized therapy approach based on a detailed biological characterization of each tumor entity should be considered. This study aimed to identify differences and specific genetic alterations in vaginal and vulvar compared to cervical squamous cell carcinoma.MethodologyUsing next generation sequencing (NGS), both somatic and germline exome sequencing of vulvar (n=11), vaginal (n=') and cervical cancer (n=11) were analyzed. To determine a potential sensitivity to immunotherapy, we studied tumor mutation burden, ratio indels, TCR clonality, neopeptides, Alexandrov's signatures, and copy number variation. Additionally a signaling pathway analysis was performed applying 2 different approaches (NCI and KEGG).ResultsNo significant differences were seen in the respective immunologic predictive biomarkers comparing the three tumor entities. The signaling pathway analysis revealed an alteration of antigen processing and presentation pathways in vulvar and vaginal cancer compared to cervical cancer (77 genes). Moreover, an activation of Notch signaling was found in vulvar and vaginal tumors. Vulvar and vaginal cancer reveal a comparable mutational landscape in the analyzed genes.ConclusionNGS determines a potential immune evasion strategy of vulvar and vaginal tumors related to an alteration of antigen presentation. Our findings suggest that immunotherapy might be less efficient compared to cervical cancer. Targeting Notch and mTOR pathway may be a promising therapy approach in these rare tumors.DisclosureNothing to disclose