Benefit From Fractionated Dose-Dense Chemotherapy in Patients With Poor Prognostic Ovarian Cancer: ICON-8 Trial

PURPOSE: An international meta-analysis identified a group of patients with advanced epithelial ovarian cancer (EOC) with a very poor survival because of two unfavorable features: (1) a poor chemosensitivity defined by an unfavorable modeled CA-125 ELIMination rate constant K (KELIM) score <1.0 with the online calculator CA-125-Biomarker Kinetics, and (2) an incomplete debulking surgery. We assumed that patients belonging to this poor prognostic group would benefit from a fractionated densified chemotherapy regimen. METHODS: The data set of ICON-8 phase III trial (ClinicalTrials.gov identifier: NCT01654146), where patients with EOC were treated with the standard three-weekly, or the weekly dose-dense, carboplatin-paclitaxel regimens and debulking primary surgery (immediate primary surgery [IPS] or delayed primary [or interval] surgery [DPS]), was investigated. The association between treatment arm efficacy, standardized KELIM (scored as favorable ≥1.0, or unfavorable <1.0), and surgery completeness was assessed by univariate/multivariate analyses in IPS and DPS cohorts. RESULTS: Of 1,566 enrolled patients, KELIM was calculated with the online model in 1,334 with ≥3 CA-125 available values (85%). As previously reported, both KELIM and surgery completeness were complementary prognostic covariates, and could be combined into three prognostic groups with large OS differences: (1) good if favorable KELIM and complete surgery; (2) intermediate if either unfavorable KELIM or incomplete surgery; and (3) poor if unfavorable KELIM and incomplete surgery. Weekly dose-dense chemotherapy was associated with PFS/OS improvement in the poor prognostic group in both the IPS cohort (PFS: hazard ratio [HR], 0.50; 95% CI, 0.31 to 0.79; OS: HR, 0.58; 95% CI, 0.35 to 0.95) and the DPS cohort (PFS: HR, 0.53; 95% CI, 0.37 to 0.76; OS: HR, 0.57; 95% CI, 0.39 to 0.82). CONCLUSION: Fractionated dose-dense chemotherapy might be beneficial for patients belonging to the poor prognostic group characterized by lower tumor chemosensitivity assessed with the online calculator CA-125-Biomarker Kinetics and incomplete debulking surgery. Further investigation in the future SALVOVAR trial is warranted

Bevacizumab for newly diagnosed ovarian cancers: Best candidates among high-risk disease patients (icon-7)

Bevacizumab is approved as a maintenance treatment in first-line setting in advanced-stage III-IV ovarian cancers, because GOG-0218 and ICON-7 phase III trials demonstrated progression-free survival benefits. However, only the subgroup of patients with high-risk diseases (stage IV, and incompletely resected stage III) derived an overall survival (OS) gain in the ICON-7 trial (4.8 months). The modeled CA-125 elimination rate constant K (KELIM) parameter, based on the longitudinal CA- 125 kinetics during the first 100 days of chemotherapy, is a potential indicator of the tumor primary chemo-sensitivity. In the ICON-7 trial dataset, the OS of patients within the low- and high-risk disease groups was assessed according to treatment arms and KELIM. Among the patients with high-risk diseases, those with favorable standardized KELIM of at least 1.0 (n=214, 46.7%) had no survival benefit from bevacizumab, whereas those with unfavorable KELIM less than 1.0 (n=244, 53.2%) derived the highest OS benefit (absolute difference = 9.1 months, 2-sided log-rank P=.10; Cox hazard ratio = 0.78, 95% confidence interval = 0.58 to 1.04, 2-sided P=.09)

Bevacizumab for Newly Diagnosed Ovarian Cancers: Best Candidates Among High-Risk Disease Patients (ICON-7)

Bevacizumab is approved as a maintenance treatment in first-line setting in advanced-stage III-IV ovarian cancers, because GOG-0218 and ICON-7 phase III trials demonstrated progression-free survival benefits. However, only the subgroup of patients with high-risk diseases (stage IV, and incompletely resected stage III) derived an overall survival (OS) gain in the ICON-7 trial (4.8 months). The modeled CA-125 elimination rate constant K (KELIM) parameter, based on the longitudinal CA-125 kinetics during the first 100 days of chemotherapy, is a potential indicator of the tumor primary chemo-sensitivity. In the ICON-7 trial dataset, the OS of patients within the low- and high-risk disease groups was assessed according to treatment arms and KELIM. Among the patients with high-risk diseases, those with favorable standardized KELIM of at least 1.0 (n = 214, 46.7%) had no survival benefit from bevacizumab, whereas those with unfavorable KELIM less than 1.0 (n = 244, 53.2%) derived the highest OS benefit (absolute difference = 9.1 months, 2-sided log-rank P = .10; Cox hazard ratio = 0.78, 95% confidence interval = 0.58 to 1.04, 2-sided P = .09)

Whistler waves generated inside magnetic dips in the young solar wind: observations of the Search-Coil Magnetometer on board Parker Solar Probe

Context. Whistler waves are electromagnetic waves produced by electron-driven instabilities, that in turn can reshape the electron distributions via wave-particle interactions. In the solar wind, they are one of the main candidates for explaining the scattering of the strahl electron population into the halo at increasing radial distances from the Sun and for subsequently regulating the solar wind heat flux. However, it is unclear what type of instability dominates to drive whistlers in the solar wind. Aims. Our goal is to study whistler wave parameters in the young solar wind sampled by Parker Solar Probe (PSP). The wave normal angle (WNA) in particular is a key parameter to discriminate between the generation mechanisms of these waves. Methods. We analyze the cross-spectral matrices of magnetic fieldfluctuations measured by the Search-Coil Magnetometer (SCM) and processed by the Digital Fields Board (DFB) from the FIELDS suite during PSP's first perihelion. Results. Among the 2701 wave packets detected in the cross spectra, namely individual bins in time and frequency, most were quasi-parallel to the background magnetic field but a significant part (3%) of observed waves had oblique (> 45{\deg}) WNA. The validation analysis conducted with the time-series waveforms reveal that this percentage is a lower limit. Moreover, we find that about 64% of the whistler waves detected in the spectra are associated with at least one magnetic dip. Conclusions. We conclude that magnetic dips provides favorable conditions for the generation of whistler waves. We hypothesize that the whistlers detected in magnetic dips are locally generated by the thermal anisotropy as quasi-parallel and can gain obliqueness during their propagation. We finally discuss the implication of our results for the scattering of the strahl in the solar wind.Comment: 15 pages, 14 figures, recommended for publication in A&

Epsilon iron oxide: origin of the high coercivity stable low Curie temperature magnetic phase found in heated archeological materials

The identification of epsilon iron oxide (ɛ-Fe2O3) as the low Curie temperature high coercivity stable phase (HCSLT) carrying the remanence in heated archeological samples has been achieved in samples from two archeological sites that exhibited the clearest evidence of the presence of the HCSLT. This uncommon iron oxide has been detected by Confocal Raman Spectroscopy (CRS) and characterized by rock magnetic measurements. Large numbers of ɛ-Fe2O3 microaggregates (in CO) or isolated clusters (in HEL) could be recognized, distributed over the whole sample, and embedded within the ceramic matrix, along with hematite and pseudobrookite and with minor amounts of anatase, rutile, and maghemite. Curie temperature estimates of around 170°C for CO and 190°C for HEL are lower than for pure, synthetic ɛ-Fe2O3 (227°C). This, together with structural differences between the Raman spectra of the archeologically derived and synthetic samples, is likely due to Ti substitution in the ɛ-Fe2O3 crystal lattice. The γ-Fe2O3-ɛ-Fe2O3-α-Fe2O3 transformation series has been recognized in heated archeological samples, which may have implications in terms of their thermal history and in the factors that govern the formation of ɛ-Fe2O3

Eukaryotic virus composition can predict the efficiency of carbon export in the global ocean

海洋ウイルスの種組成と炭素の鉛直輸送の相関を確認 --ウイルスによる地球環境の制御を示唆. 京都大学プレスリリース. 2021-01-15.The biological carbon pump, in which carbon fixed by photosynthesis is exported to the deep ocean through sinking, is a major process in Earth's carbon cycle. The proportion of primary production that is exported is termed the carbon export efficiency (CEE). Based on in-lab or regional scale observations, viruses were previously suggested to affect the CEE (i.e., viral “shunt” and “shuttle”). In this study, we tested associations between viral community composition and CEE measured at a global scale. A regression model based on relative abundance of viral marker genes explained 67% of the variation in CEE. Viruses with high importance in the model were predicted to infect ecologically important hosts. These results are consistent with the view that the viral shunt and shuttle functions at a large scale and further imply that viruses likely act in this process in a way dependent on their hosts and ecosystem dynamics

Influence of environment on the corrosion of glass–metal connections

'Glass sensors' of the eighteenth century Backer glass and the sixteenth century enamel from Limoges have been chosen for a series of experiments. Combinations of these materials with different base materials such as copper and bronze has been investigated. To create surface changes on the 'glass sensor', a corrosion process was induced in a controlled environment. A variety of corrosive agents such as hydrochloric acid, sulfuric acid, water and formaldehyde were used. The sample immersed in the corrosive solution was exposed alternately to light and high temperature for a total of 38 weeks. During this period, macroscopic and microscopic observations were made and series of tests such as SEM/EDS and Raman spectroscopy were performed on the surface of the samples. ICP-MS methods were used to determine the change in the chemical composition of the solutions where the samples had corroded. The primary aim of this study was to identify the impact of a number of external corrosive variables such as temperature, humidity and local environment to identify the most damaging environments for glass–metal objects. The obtained results showed the chemical and physical phenomena acting on the surface of the glass, metal or in the place of their joints. Information obtained on this study was used to explain the influence of the environment on the surface of glass–metal materials. Results can be used in the design of conservation work as well as for sustainable conservation

Initial Steps of Thermal Decomposition of Dihydroxylammonium 5,5′-bistetrazole-1,1′-diolate Crystals from Quantum Mechanics

Dihydroxylammonium 5,5?-bistetrazole-1,1?-diolate (TKX-50) is a recently synthesized energetic material (EM) with most promising performance, including high energy content, high density, low sensitivity, and low toxicity. TKX-50 forms an ionic crystal in which the unit cell contains two bistetrazole dianions {c-((NO)N3C)-[c-(CN3(NO)], formal charge of ?2} and four hydroxylammonium (NH3OH)+ cations (formal charge of +1). We report here quantum mechanics (QM)-based reaction studies to determine the atomistic reaction mechanisms for the initial decompositions of this system. First we carried out molecular dynamics simulations on the periodic TKX-50 crystal using forces from density functional based tight binding calculations (DFTB-MD), which finds that the chemistry is initiated by proton transfer from the cation to the dianion. Continuous heating of this periodic system leads eventually to dissociation of the protonated or diprotonated bistetrazole to release N2 and N2O. To refine the mechanisms observed in the periodic DFTB-MD, we carried out finite cluster quantum mechanics studies (B3LYP) for the unimolecular decomposition of the bistetrazole. We find that for the bistetrazole dianion, the reaction barrier for release of N2 is 45.1 kcal/mol, while release of N2O is 72.2 kcal/mol. However, transferring one proton to the bistetrazole dianion decreases the reaction barriers to 37.2 kcal/mol for N2 release and 59.5 kcal/mol for N2O release. Thus, we predict that the initial decompositions in TKX-50 lead to N2 release, which in turn provides the energy to drive further decompositions. On the basis of this mechanism, we suggest changes to make the system less sensitive while retaining the large energy release. This may help improve the synthesis strategy of developing high nitrogen explosives with further improved performance

Meeting the International Health Regulations (2005) surveillance core capacity requirements at the subnational level in Europe: the added value of syndromic surveillance

BACKGROUND: The revised World Health Organization's International Health Regulations (2005) request a timely and all-hazard approach towards surveillance, especially at the subnational level. We discuss three questions of syndromic surveillance application in the European context for assessing public health emergencies of international concern: (i) can syndromic surveillance support countries, especially the subnational level, to meet the International Health Regulations (2005) core surveillance capacity requirements, (ii) are European syndromic surveillance systems comparable to enable cross-border surveillance, and (iii) at which administrative level should syndromic surveillance best be applied? DISCUSSION: Despite the ongoing criticism on the usefulness of syndromic surveillance which is related to its clinically nonspecific output, we demonstrate that it was a suitable supplement for timely assessment of the impact of three different public health emergencies affecting Europe. Subnational syndromic surveillance analysis in some cases proved to be of advantage for detecting an event earlier compared to national level analysis. However, in many cases, syndromic surveillance did not detect local events with only a small number of cases. The European Commission envisions comparability of surveillance output to enable cross-border surveillance. Evaluated against European infectious disease case definitions, syndromic surveillance can contribute to identify cases that might fulfil the clinical case definition but the approach is too unspecific to comply to complete clinical definitions. Syndromic surveillance results still seem feasible for comparable cross-border surveillance as similarly defined syndromes are analysed. We suggest a new model of implementing syndromic surveillance at the subnational level. In this model, syndromic surveillance systems are fine-tuned to their local context and integrated into the existing subnational surveillance and reporting structure. By enhancing population coverage, events covering several jurisdictions can be identified at higher levels. However, the setup of decentralised and locally adjusted syndromic surveillance systems is more complex compared to the setup of one national or local system. SUMMARY: We conclude that syndromic surveillance if implemented with large population coverage at the subnational level can help detect and assess the local and regional effect of different types of public health emergencies in a timely manner as required by the International Health Regulations (2005)