REGOMA-OSS: a large, Italian, multicenter, prospective, observational study evaluating the efficacy and safety of regorafenib in patients with recurrent glioblastoma.

BACKGROUND: In the randomized phase II REGOMA trial, regorafenib showed promising activity in patients with recurrent glioblastoma. We conducted a large, multicenter, prospective, observational study to confirm the REGOMA data in a real-world setting. PATIENTS AND METHODS: The major inclusion criteria were histologically confirmed diagnosis of glioblastoma according to the World Health Organization (WHO) 2016 classification and relapse after radiotherapy with concurrent/adjuvant temozolomide treatment, good performance status [Eastern Cooperative Oncology Group performance status (ECOG PS 0-1)] and good liver function. Regorafenib was administered at the standard dose of 160 mg/day for 3 weeks on/1 week off. Brain magnetic resonance imaging was carried out within 14 days before starting regorafenib and every 8-12 weeks. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate, disease control rate (DCR), safety and health-related quality of life. The Response Assessment in Neuro-Oncology (RANO) criteria were used for response evaluation and Common Terminology Criteria for Adverse Events (CTCAE) version 5 for assessment of adverse events (AEs). RESULTS: From September 2020 to October 2022, 190 patients with recurrent glioblastoma were enrolled from 30 cancer centers in Italy: their median age was 58.5 years [interquartile range (IQR) 53-67 years], 68% were male and 85 (44.7%) were in optimal clinical condition (ECOG PS 0). The number of patients taking steroids at baseline was 113 (60%); the second surgery was carried out in 39 (20.5%). O6-methylguanine-DNA methyltransferase (MGMT) was methylated in 80 patients (50.3%) and 147 (92.4%) of the patients analyzed had isocitrate dehydrogenase (IDH) wild type. The median follow-up period was 20 months (IQR 15.6-25.5 months). The median OS was 7.9 months ([95% confidence interval (CI) 6.5-9.2 months] and the median PFS was 2.6 months (95% CI 2.3-2.9 months). Radiological response was partial response and stable disease in 13 (7.3%) and 26 (14.6%) patients, respectively, with a DCR of 21.9%. The median number of regorafenib cycles per patient was 3 (IQR 2.0-4.0). Grade 3-4 drug-related adverse events were reported in 22.6% of patients. A dose reduction due to AEs was required in 36% of patients. No deaths were considered as treatment-related AEs. CONCLUSIONS: This large, real-world observational study showed similar OS with better tolerability of regorafenib in patients with relapsed glioblastoma compared with the REGOMA study.

Zooplankton as an indicator of the status of contamination of the Mediterranean Sea and temporal trends.

Zooplankton has been intensively used as bioindicators of water pollution at global level, however, only few comprehensive studies have been conducted from the Mediterranean Sea and manly dated back to the 1970s. To redress the urgent need for updated data, this study provides information on the presence and levels of contaminants in zooplankton from the Tyrrhenian Sea. Although banned, both PCBs (46.9 ± 37.2 ng g-1) and DDT (8.9 ± 10.7 ng g-1) are still present and widespread, but their contamination appears to be a local problem and to be declining over the past 50 years. Zooplankton accumulates high levels of certain TEs, including Zn (400 ± 388 ppm) and Pb (35.3 ± 45.5 ppm), but shows intermediate concentrations of other TEs, including Cd (1.6 ± 0.9 ppm) and Hg (0.1 ± 0.1 ppm), comparing with both strongly polluted and more pristine marine habitats, which may reflect a general improvement.

Localized aliphatic organic material on the surface of Ceres.

Organic compounds occur in some chondritic meteorites, and their signatures on solar system bodies have been sought for decades. Spectral signatures of organics have not been unambiguously identified on the surfaces of asteroids, whereas they have been detected on cometary nuclei. Data returned by the Visible and InfraRed Mapping Spectrometer on board the Dawn spacecraft show a clear detection of an organic absorption feature at 3.4 micrometers on dwarf planet Ceres. This signature is characteristic of aliphatic organic matter and is mainly localized on a broad region of ~1000 square kilometers close to the ~50-kilometer Ernutet crater. The combined presence on Ceres of ammonia-bearing hydrated minerals, water ice, carbonates, salts, and organic material indicates a very complex chemical environment, suggesting favorable environments to prebiotic chemistry.

Seasonal exposure of carbon dioxide ice on the nucleus of comet 67P/Churyumov-Gerasimenko.

Carbon dioxide (CO2) is one of the most abundant species in cometary nuclei, but because of its high volatility, CO2 ice is generally only found beneath the surface. We report the infrared spectroscopic identification of a CO2 ice-rich surface area located in the Anhur region of comet 67P/Churyumov-Gerasimenko. Spectral modeling shows that about 0.1% of the 80- by 60-meter area is CO2 ice. This exposed ice was observed a short time after the comet exited local winter; following the increased illumination, the CO2 ice completely disappeared over about 3 weeks. We estimate the mass of the sublimated CO2 ice and the depth of the eroded surface layer. We interpret the presence of CO2 ice as the result of the extreme seasonal changes induced by the rotation and orbit of the comet.

Distribution of phyllosilicates on the surface of Ceres.

The dwarf planet Ceres is known to host phyllosilicate minerals at its surface, but their distribution and origin have not previously been determined. We used the spectrometer onboard the Dawn spacecraft to map their spatial distribution on the basis of diagnostic absorption features in the visible and near-infrared spectral range (0.25 to 5.0 micrometers). We found that magnesium- and ammonium-bearing minerals are ubiquitous across the surface. Variations in the strength of the absorption features are spatially correlated and indicate considerable variability in the relative abundance of the phyllosilicates, although their composition is fairly uniform. These data, along with the distinctive spectral properties of Ceres relative to other asteroids and carbonaceous meteorites, indicate that the phyllosilicates were formed endogenously by a globally widespread and extensive alteration process.

Bright carbonate deposits as evidence of aqueous alteration on (1) Ceres.

The typically dark surface of the dwarf planet Ceres is punctuated by areas of much higher albedo, most prominently in the Occator crater. These small bright areas have been tentatively interpreted as containing a large amount of hydrated magnesium sulfate, in contrast to the average surface, which is a mixture of low-albedo materials and magnesium phyllosilicates, ammoniated phyllosilicates and carbonates. Here we report high spatial and spectral resolution near-infrared observations of the bright areas in the Occator crater on Ceres. Spectra of these bright areas are consistent with a large amount of sodium carbonate, constituting the most concentrated known extraterrestrial occurrence of carbonate on kilometre-wide scales in the Solar System. The carbonates are mixed with a dark component and small amounts of phyllosilicates, as well as ammonium carbonate or ammonium chloride. Some of these compounds have also been detected in the plume of Saturn's sixth-largest moon Enceladus. The compounds are endogenous and we propose that they are the solid residue of crystallization of brines and entrained altered solids that reached the surface from below. The heat source may have been transient (triggered by impact heating). Alternatively, internal temperatures may be above the eutectic temperature of subsurface brines, in which case fluids may exist at depth on Ceres today.

Exposed water ice on the nucleus of comet 67P/Churyumov-Gerasimenko.

Although water vapour is the main species observed in the coma of comet 67P/Churyumov-Gerasimenko and water is the major constituent of cometary nuclei, limited evidence for exposed water-ice regions on the surface of the nucleus has been found so far. The absence of large regions of exposed water ice seems a common finding on the surfaces of many of the comets observed so far. The nucleus of 67P/Churyumov-Gerasimenko appears to be fairly uniformly coated with dark, dehydrated, refractory and organic-rich material. Here we report the identification at infrared wavelengths of water ice on two debris falls in the Imhotep region of the nucleus. The ice has been exposed on the walls of elevated structures and at the base of the walls. A quantitative derivation of the abundance of ice in these regions indicates the presence of millimetre-sized pure water-ice grains, considerably larger than in all previous observations. Although micrometre-sized water-ice grains are the usual result of vapour recondensation in ice-free layers, the occurrence of millimetre-sized grains of pure ice as observed in the Imhotep debris falls is best explained by grain growth by vapour diffusion in ice-rich layers, or by sintering. As a consequence of these processes, the nucleus can develop an extended and complex coating in which the outer dehydrated crust is superimposed on layers enriched in water ice. The stratigraphy observed on 67P/Churyumov-Gerasimenko is therefore the result of evolutionary processes affecting the uppermost metres of the nucleus and does not necessarily require a global layering to have occurred at the time of the comet's formation.

Ammoniated phyllosilicates with a likely outer Solar System origin on (1) Ceres.

Studies of the dwarf planet (1) Ceres using ground-based and orbiting telescopes have concluded that its closest meteoritic analogues are the volatile-rich CI and CM carbonaceous chondrites. Water in clay minerals, ammoniated phyllosilicates, or a mixture of Mg(OH)2 (brucite), Mg2CO3 and iron-rich serpentine have all been proposed to exist on the surface. In particular, brucite has been suggested from analysis of the mid-infrared spectrum of Ceres. But the lack of spectral data across telluric absorption bands in the wavelength region 2.5 to 2.9 micrometres--where the OH stretching vibration and the H2O bending overtone are found--has precluded definitive identifications. In addition, water vapour around Ceres has recently been reported, possibly originating from localized sources. Here we report spectra of Ceres from 0.4 to 5 micrometres acquired at distances from ~82,000 to 4,300 kilometres from the surface. Our measurements indicate widespread ammoniated phyllosilicates across the surface, but no detectable water ice. Ammonia, accreted either as organic matter or as ice, may have reacted with phyllosilicates on Ceres during differentiation. This suggests that material from the outer Solar System was incorporated into Ceres, either during its formation at great heliocentric distance or by incorporation of material transported into the main asteroid belt.

Cometary science. The organic-rich surface of comet 67P/Churyumov-Gerasimenko as seen by VIRTIS/Rosetta.

The VIRTIS (Visible, Infrared and Thermal Imaging Spectrometer) instrument on board the Rosetta spacecraft has provided evidence of carbon-bearing compounds on the nucleus of the comet 67P/Churyumov-Gerasimenko. The very low reflectance of the nucleus (normal albedo of 0.060 ± 0.003 at 0.55 micrometers), the spectral slopes in visible and infrared ranges (5 to 25 and 1.5 to 5% kÅ(-1)), and the broad absorption feature in the 2.9-to-3.6-micrometer range present across the entire illuminated surface are compatible with opaque minerals associated with nonvolatile organic macromolecular materials: a complex mixture of various types of carbon-hydrogen and/or oxygen-hydrogen chemical groups, with little contribution of nitrogen-hydrogen groups. In active areas, the changes in spectral slope and absorption feature width may suggest small amounts of water-ice. However, no ice-rich patches are observed, indicating a generally dehydrated nature for the surface currently illuminated by the Sun.

A rise in NAD precursor nicotinamide mononucleotide (NMN) after injury promotes axon degeneration.

NAD metabolism regulates diverse biological processes, including ageing, circadian rhythm and axon survival. Axons depend on the activity of the central enzyme in NAD biosynthesis, nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2), for their maintenance and degenerate rapidly when this activity is lost. However, whether axon survival is regulated by the supply of NAD or by another action of this enzyme remains unclear. Here we show that the nucleotide precursor of NAD, nicotinamide mononucleotide (NMN), accumulates after nerve injury and promotes axon degeneration. Inhibitors of NMN-synthesising enzyme NAMPT confer robust morphological and functional protection of injured axons and synapses despite lowering NAD. Exogenous NMN abolishes this protection, suggesting that NMN accumulation within axons after NMNAT2 degradation could promote degeneration. Ectopic expression of NMN deamidase, a bacterial NMN-scavenging enzyme, prolongs survival of injured axons, providing genetic evidence to support such a mechanism. NMN rises prior to degeneration and both the NAMPT inhibitor FK866 and the axon protective protein Wld(S) prevent this rise. These data indicate that the mechanism by which NMNAT and the related Wld(S) protein promote axon survival is by limiting NMN accumulation. They indicate a novel physiological function for NMN in mammals and reveal an unexpected link between new strategies for cancer chemotherapy and the treatment of axonopathies.

Olivine in an unexpected location on Vesta's surface.

Olivine is a major component of the mantle of differentiated bodies, including Earth. Howardite, eucrite and diogenite (HED) meteorites represent regolith, basaltic-crust, lower-crust and possibly ultramafic-mantle samples of asteroid Vesta, which is the lone surviving, large, differentiated, basaltic rocky protoplanet in the Solar System. Only a few of these meteorites, the orthopyroxene-rich diogenites, contain olivine, typically with a concentration of less than 25 per cent by volume. Olivine was tentatively identified on Vesta, on the basis of spectral and colour data, but other observations did not confirm its presence. Here we report that olivine is indeed present locally on Vesta's surface but that, unexpectedly, it has not been found within the deep, south-pole basins, which are thought to be excavated mantle rocks. Instead, it occurs as near-surface materials in the northern hemisphere. Unlike the meteorites, the olivine-rich (more than 50 per cent by volume) material is not associated with diogenite but seems to be mixed with howardite, the most common surface material. Olivine is exposed in crater walls and in ejecta scattered diffusely over a broad area. The size of the olivine exposures and the absence of associated diogenite favour a mantle source, but the exposures are located far from the deep impact basins. The amount and distribution of observed olivine-rich material suggest a complex evolutionary history for Vesta.

Candidemia in Neurosurgical Intensive Care Unit: preliminary analysis of the effect of topical Nystatin prophylaxis and adequate source control on patients with early tracheostomy intubation.

INTRODUCTION: The present study represents a preliminary evaluation of the impact of topical nystatin prophylaxis administration and adequate CVC management on reducing the chance of developing candidemia in neurosurgical intensive care unit (NICU) patients. MATERIALS AND METHODS: We conducted a case-control study at the nine bed NICU of the Policlinico "Umberto I" teaching hospital in Rome, Italy, during the period from January 2011 to July 2012. We compared eight patients with culture proven Candida bloodstream infection (CBSI) with a control group of 19 patients who did not have evidence of CBSI. RESULTS: When the CBSI group was compared with the control group, the former were more likely than controls to not have received nystatin prophylaxis and adequate catheter care (p= 0,008). When CBSI group was matched with patients with no adequate source control and nystatin prophylaxis, average NICU stay (71.13 days vs 19.0 days) was significant (mean difference = -52.12 days, 95% CI -97.11 to -7.14, p= 0.028). The same was true for mean time of glucocorticoid exposure (mean difference = -10.5 days, 95% CI -17.35 to -3.65, p<0.01). Binary logistic regression analysis demonstrated no significant association between topical nystatin prophylaxis (p= 0.99), length of NICU stay (p= 0.99), time of glucocorticoid exposure (p= 0.99) and candidemia. CONCLUSION: Topical prophylaxis with nystatin and adequate source control proved to be effective in preventing invasive candidiasis in patients admitted to the NICU.

Spectroscopic characterization of mineralogy and its diversity across Vesta.

The mineralogy of Vesta, based on data obtained by the Dawn spacecraft's visible and infrared spectrometer, is consistent with howardite-eucrite-diogenite meteorites. There are considerable regional and local variations across the asteroid: Spectrally distinct regions include the south-polar Rheasilvia basin, which displays a higher diogenitic component, and equatorial regions, which show a higher eucritic component. The lithologic distribution indicates a deeper diogenitic crust, exposed after excavation by the impact that formed Rheasilvia, and an upper eucritic crust. Evidence for mineralogical stratigraphic layering is observed on crater walls and in ejecta. This is broadly consistent with magma-ocean models, but spectral variability highlights local variations, which suggests that the crust can be a complex assemblage of eucritic basalts and pyroxene cumulates. Overall, Vesta mineralogy indicates a complex magmatic evolution that led to a differentiated crust and mantle.

The surface composition and temperature of asteroid 21 Lutetia as observed by Rosetta/VIRTIS.

The Visible, InfraRed, and Thermal Imaging Spectrometer (VIRTIS) on Rosetta obtained hyperspectral images, spectral reflectance maps, and temperature maps of the asteroid 21 Lutetia. No absorption features, of either silicates or hydrated minerals, have been detected across the observed area in the spectral range from 0.4 to 3.5 micrometers. The surface temperature reaches a maximum value of 245 kelvin and correlates well with topographic features. The thermal inertia is in the range from 20 to 30 joules meter(-2) kelvin(-1) second(-0.5), comparable to a lunarlike powdery regolith. Spectral signatures of surface alteration, resulting from space weathering, seem to be missing. Lutetia is likely a remnant of the primordial planetesimal population, unaltered by differentiation processes and composed of chondritic materials of enstatitic or carbonaceous origin, dominated by iron-poor minerals that have not suffered aqueous alteration.

Unique expression pattern of human nicotinamide mononucleotide adenylyltransferase isozymes in red blood cells.

Nicotinamide mononucleotide adenylyltransferase (NMNAT) catalyzes the formation of nicotinamide adenine dinucleotide (NAD). In humans, three isozymes have been identified: NMNAT1, which is widely expressed in all tissues, NMNAT2 and NMNAT3, which show a tissue-specific expression and whose mRNA levels are generally lower compared to NMNAT1. In the present study we determined the individual NMNAT isozymes activity in human red blood cells (RBCs) by using a biochemical discrimination assay based on the distinctive catalytic properties of the three proteins. We found that isozyme 3 predominates over isozyme 1, whereas isozyme 2 is absent. This high prevalence of NMNAT3 is cell-aging independent and was also confirmed by analyzing the mRNA and protein levels. RBC represent the first human cell type with a remarkable predominance of NMNAT3, and this unique expression pattern is discussed in light of the catalytic properties of the isozymes and in consideration of the biochemical microenvironment of RBC.

WldS can delay Wallerian degeneration in mice when interaction with valosin-containing protein is weakened.

Axon degeneration is an early event in many neurodegenerative disorders. In some, the mechanism is related to injury-induced Wallerian degeneration, a proactive death program that can be strongly delayed by the neuroprotective slow Wallerian degeneration protein (Wld(S)) protein. Thus, it is important to understand the Wallerian degeneration mechanism and how Wld(S) blocks it. Wld(S) location is influenced by binding to valosin-containing protein (VCP), an essential protein for many cellular processes including membrane fusion and endoplasmic reticulum-associated degradation. In mice, the N-terminal 16 amino acids (N16), which mediate VCP binding, are essential for Wld(S) to protect axons, a role which another VCP binding sequence can substitute. In Drosophila, the Wld(S) phenotype is weakened by a similar N-terminal truncation and by knocking down the VCP homologue ter94. Neither null nor floxed VCP mice are viable so it is difficult to confirm the requirement for VCP binding in mammals in vivo. However, the hypothesis can be tested further by introducing a Wld(S) missense mutation, altering its affinity for VCP but minimizing the risk of disturbing other aspects of its structure or function. We introduced the R10A mutation, which weakens VCP binding in vitro, and expressed it in transgenic mice. R10AWld(S) fails to co-immunoprecipitate VCP from mouse brain, and only occasionally and faintly accumulates in nuclear foci for which VCP binding is necessary but not sufficient. Surprisingly however, axon protection remains robust and indistinguishable from that in spontaneous Wld(S) mice. We suggest that either N16 has an additional, VCP-independent function in mammals, or that the phenotype requires only weak VCP binding which may be driven forwards in vivo by the high VCP concentration.

NAD(P) biosynthesis enzymes as potential targets for selective drug design.

NAD(P) biosynthetic pathways can be considered a generous source of enzymatic targets for drug development. Key reactions for NAD(P) biosynthesis in all organisms, common to both de novo and salvage routes, are catalyzed by NMN/NaMN adenylyltransferase (NMNAT), NAD synthetase (NADS), and NAD kinase (NADK). These reactions represent a three-step pathway, present in the vast majority of living organisms, which is responsible for the generation of both NAD and NADP cellular pools. The validation of these enzymes as drug targets is based on their essentiality and conservation among a large variety of pathogenic microorganisms, as well as on their differential structural features or their differential metabolic contribution to NAD(P) homeostasis between microbial and human cell types. This review describes the structural and functional properties of eubacterial and human enzymes endowed with NMNAT, NADS, and NADK activities, as well as with nicotinamide phosphoribosyltransferase (NamPRT) and nicotinamide riboside kinase (NRK) activities, highlighting the species-related differences, with emphasis on their relevance for drug design. In addition, since the overall NMNAT activity in humans is accounted by multiple isozymes differentially involved in the metabolic activation of antineoplastic compounds, their individual diagnostic value for early therapy optimization is outlined. The involvement of human NMNAT in neurodegenerative disorders and its role in neuroprotection is also discussed.

Clinical features of bacterial meningitis in Italy: a multicenter prospective observational study.

We carried out a prospective observational study on clinical features of bacterial meningitis. Between October 2002 and June 2005, 322 adult bacterial meningitis cases in 49 infectious disease wards in Italy (MENTORE study group) were enrolled in the study. 133 cases were due to Streptococcus pneumoniae, 44 to Neisseria meningitidis and 145 to other microorganisms. A high SAPS score and coma on admission, as well as need for mechanical ventilation, were more frequent in the pneumococcal meningitis group. Neurological impairment was present in 151 out of 311 patients, and was more frequent in pneumococcal meningitis. A single antibiotic was employed in only 90 of 315 cases; a combination of ceftriaxone and ampicillin was the most frequently administered treatment. Ceftriaxone was also the single most used drug. Adjunctive treatment with steroids was administered in 210 out of 303 patients for a median duration of 7 days. Median duration of fever was 4 days, and median hospital stay was 16 days; hospitalization was significantly longer in the pneumococcal meningitis group. At discharge, neurological impairment was still present in 59 (21%) of 277 patients. Twenty (6.9%) out of 289 patients died during hospitalization. Distribution of adverse outcome (death and neurological impairment) in patients treated with or without steroids and within different time zones between onset of symptoms and commencement of antibiotics was studied; a trend toward a worse prognosis was seen in patients treated more than 24 hours after onset of the disease.In our study, infectious disease clinicians made extensive use of steroids as adjuvant therapy for bacterial meningitis, even in absence of detailed national and local guidelines. Mortality seemed to be lower in comparison with the literature.

End-of-life decision-making in respiratory intermediate care units: a European survey.

A survey was performed on behalf of the European Respiratory Society to assess end-of-life practices in patients admitted to European respiratory intermediate care units and high dependency units over a 6-month period. A 33-item questionnaire was sent by e-mail to physicians throughout Europe and the response rate was 28 (29.5%) out of 95. A total of 6,008 patients were admitted and an end-of-life decision was taken in 1,292 (21.5%). The mortality rate in these patients was 68% (884 out of 1,292). The patients received similar proportions of withholding of treatment (298 (23%) out of 1292), do-not-resuscitate or do-not-intubate orders (442 (34%) out of 1,292) and noninvasive mechanical ventilation as the ceiling of ventilatory care (402 (31%) out of 1,292). Withdrawal of therapy was employed in 149 (11%) out of 1,292 patients and euthanasia in one. Do-not-intubate/do-not-resuscitate orders were more frequently used in North compared with South Europe. All of the 473 competent patients directly participated in the decision, whereas, in 722 (56%) out of 1,292 cases, decision-making was reported to be shared with the nurses. In European respiratory intermediate care units and high dependency units, an end-of-life decision is taken for 21.5% of patients admitted. Withholding of treatment, do-not-intubate/do-not-resuscitate orders and noninvasive mechanical ventilation as the ventilatory care ceiling are the most common procedures. Competent patients are often involved, together with nurses.