Romain Delunel
email: romain.delunel@geo.unibe.ch

Pierre-Henri Blard
email: p.-h.blard@crpg.cnrs-nancy.fr

Léo C P Martin

Sébastien Nomade
email: sebastien.nomade@lsce.ipsl.frf.schlunegger

Fritz Schlunegger
email: fritz.schlunegger@geo.unibe.ch

Long term low latitude and high elevation cosmogenic 3 He production rate inferred from a 107 ka-old lava flow in Northern Chile; 22°S-3400 m a.s.l

Abstract

Available geological calibration sites used to estimate the rate at which cosmogenic 3 He is produced at the Earth's surface are mostly clustered in medium to high latitudes. Moreover, most of them have exposure histories shorter than tens of thousands of years. This lack of sites prevents a qualitative assessment of available production models used to convert cosmogenic 3 He concentrations into exposure ages and/or denudation rates. It thus limits our ability to take into account the atmospheric, geomagnetic and solar modulation conditions that might have affected the production of cosmogenic nuclides in the past for longer exposure histories and in low latitude regions. We present the cosmogenic 3 He production rate inferred from a new geological calibration site located in northern Chile. Five samples were collected on the surface of the largest and best-preserved lava flow of the San Pedro volcano (21.934°S-68.510°W-3390 m a.s.l), which displays pristine crease-structure features. 40 Ar/ 39 Ar dating yielded a reliable plateau age of 107±12 ka for the eruption of this lava flow. Eight pyroxene aliquots separated from the surface samples yield a weighted average cosmogenic 3 He concentration of 99.3±1.2 Mat.g -1 from which a local cosmogenic 3 He production rate of 928±101 at.g -1 .yr -1 is calculated.

The local production rate is then scaled to a sea level high latitude (SLHL) reference position using different combinations of geographic spatialization schemes, atmosphere models and geomagnetic field reconstructions, yielding SLHL production rates between 103±11 and 130±14 at.g -1 .yr -1 consistent with the most recent estimates available from the literature. Finally, we use the same scaling frameworks to re-evaluate the mean global-scale cosmogenic 3 He production rate in olivine and pyroxene minerals at 120±16 at.g -1 .yr -1 from the compilation of previously published calibration datasets.

Introduction

Studies relying on dating landforms and quantifying rates of Earth surface processes have greatly benefitted from the recent development of Terrestrial Cosmogenic Nuclides (TCN; see von Blanckenburg and Willenbring, 2014 and references therein for a review). Since the mid-80s (e.g. [START_REF] Craig | Cosmogenic 3 He in terrestrial rocks: The summit lavas of Maui[END_REF][START_REF] Kurz | In situ production of terrestrial cosmogenic helium and some applications to geochronology[END_REF], cosmogenic helium-3 ( 3 He) has been successfully used to date geologic features in various environments and over periods of times ranging from hundreds to millions of years (e.g. [START_REF] Kurz | Cosmic ray exposure dating with in situ produced cosmogenic 3 He: results from young Hawaiian lava flows[END_REF][START_REF] Licciardi | Calibration of cosmogenic 3 He production rates from Holocene lava flows in Oregon, USA, and effects of the Earth's magnetic field[END_REF][START_REF] Schäfer | Cosmogenic noble gas studies in the oldest landscape on earth: surface exposure ages of the Dry Valleys, Antarctica[END_REF][START_REF] Evenstar | Multiphase development of the Atacama Planation Surface recorded by cosmogenic 3 He exposure ages: Implications for uplift and Cenozoic climate change in western South America[END_REF]. Cosmogenic 3 He combines high production rates (> 100 at.g -1 .yr -1 at sea level and high latitude) and low analytical detection limits (ca. 10 5 at.g -1 in most favorable cases) with the absence of radioactive decay (i.e. 3 He is stable). Cosmogenic 3 He also has the advantage to be produced and quantitatively retained over geological timescales in mafic minerals such as olivines and pyroxenes, which offers an interesting alternative for applying surface exposure dating in volcanic terrains where quartz-bearing lithologies might not be available for 10 Be and 26 Al measurements.

The rate at which cosmogenic 3 He is produced at the Earth's surface has been estimated between 100 and 140 at.g -1 .yr -1 (see [START_REF] Dunai | Cosmogenic nuclides: principles, concepts and applications in the earth surface sciences[END_REF] and reference therein) from several geological calibration datasets with independent age assignments (e.g. [START_REF] Ackert | Long-term cosmogenic 3 He production rates from 40 Ar/ 39 Ar and K-Ar dated Patagonian lava flows at 47°S[END_REF][START_REF] Amidon | Cosmogenic 3 He production rates in apatite, zircon and pyroxene inferred from Bonneville flood erosional surfaces[END_REF][START_REF] Blard | Applications of ancient cosmic-ray exposures: Theory, techniques and limitations[END_REF]2013;[START_REF] Cerling | Cosmogenic 3 He production rates from 39°N to 46°N latitude, western USA and France[END_REF][START_REF] Dunai | Long-term cosmogenic 3 He production rates (152 ka-1.35 Ma) from 40 Ar/ 39 Ar dated basalt flows at 29°N latitude[END_REF][START_REF] Fenton | 40 Ar/ 39 Ar dating of the SP and Bar Ten lava flows AZ, USA: Laying the foundation for the SPICE cosmogenic nuclide production-rate calibration project[END_REF]2014[START_REF] Foeken | Long-term low latitude cosmogenic 3 He production rate determined from a 126 ka basalt from Fogo, Cape Verdes[END_REF][START_REF] Goehring | A reevaluation of in situ cosmogenic 3 He production rates[END_REF][START_REF] Licciardi | Calibration of cosmogenic 3 He production rates from Holocene lava flows in Oregon, USA, and effects of the Earth's magnetic field[END_REF]2006). At a global scale, cosmogenic 3 He production rates at sea level and high latitude (SLHL) were estimated using the time-dependent adaptation of the Lal (1991)/ [START_REF] Stone | Air pressure and cosmogenic isotope production[END_REF] scaling scheme ("Lm"; [START_REF] Balco | A complete and easily accessible means of calculating surface exposure ages or erosion rates from 10 Be and 26 Al measurements[END_REF]. The available calibration datasets yielded values of 119±9.9 at.g -1 .yr -1 for pyroxene [START_REF] Goehring | A reevaluation of in situ cosmogenic 3 He production rates[END_REF] and 116±13 [START_REF] Goehring | A reevaluation of in situ cosmogenic 3 He production rates[END_REF], 122±15 (Blard et al., 2013) and ca. 117 at.g -1 .yr -1 [START_REF] Borchers | Geological calibration of spallation production rates in the CRONUS-Earth Project[END_REF]) when 3 He concentrations of both pyroxene and olivine minerals are considered. Although the global-scale SLHL cosmogenic 3 He production rates are consistent within associated uncertainties, [START_REF] Phillips | Where now? Reflections on future directions for cosmogenic nuclide research from the CRONUS Projects[END_REF] recently emphasized that the initial datasets used in these compilations are clustered both in space (medium to high latitudes) and time (ca. 5-20 ka). According to these authors, this circumstance prevents reliable integrations of past atmospheric, geomagnetic and solar modulation conditions that might have affected the production of cosmogenic nuclides at the Earth's surface. In particular, cosmogenic 3 He calibration data are lacking at latitudes < 25° (Blard et al., 2013), where large temporal variations in the paleo magneticfield intensity might have significantly affected the production of cosmogenic nuclides (e.g. [START_REF] Dunai | The nuts and bolts of cosmogenic nuclide production[END_REF]. Accordingly, improving the accuracy of time dependent corrections requires more low latitude calibration sites with exposure durations significantly longer than 20 ka. This article presents a new calibration of the cosmogenic 3 He production rate from a site located in the hyperarid region of Northern Chile (3400 m a.s.l., ca.

22°S), over a long exposure time (ca. 107 ka). The aim is to reduce the lack of long exposure calibration sites located at high elevation/low latitude. Five samples were collected for helium analyses on top of an andesitic lava flow. This surface is characterized by pristine crease-structure features, which are common on silicic volcanic flows and previously identified as reliable targets for surface exposure dating [START_REF] Anderson | Criteria for recognition of constructional silicic lava flow surfaces[END_REF]. First we document the age of a lava flow of the San Pedro volcano using 40 Ar/ 39 Ar dating techniques. We then report the results of the cosmogenic 3 He measurements from five samples (8 aliquots) from which we infer the local production rate of cosmogenic 3 He, as well as the production normalized to sea level and high latitude (SLHL), both integrated over the age of the lava flow. Finally, we combine our results with previously reported cosmogenic 3 He calibration datasets, based on which we re-evaluate the global 3 He production rate at SLHL.

Geological setting and sampling

Volcanic architecture

The San Pedro volcano (6159 m a.s.l., Figure 1) is situated in the El Loa province of Northern Chile ca. 80 km north east of Calama and 100 km north of San Pedro de Atacama. While the San Pedro volcano is located on the western slope of the High Andean Cordillera and therefore does not belong to the Atacama Desert stricto sensu, it is characterized by a hyperarid climate, with annual precipitation < 100 mm/y [START_REF] Houston | The central Andean west-slope rainshadow and its potential contribution to the origin of hyper-aridity in the Atacama Desert[END_REF]. The San Pedro volcano is paired with the San Pablo volcano (6118 m a.s.l.) located 5 km further to the east. It represents one of the highest and best-preserved volcanic edifices of the Central Volcanic Zone (de Silva and Francis, 1991), one of the four active volcanic zones in the Andes (see Hora et al., 2007 and reference therein). Only few studies [START_REF] Francis | The San Pedro and San Pablo volcanoes of northern Chile and their hot avalanche deposits[END_REF][START_REF] Thorpe | Rare Earth data and petrogenesis of andesite from the North Chilean Andes[END_REF][START_REF] O'callaghan | Volcanological and petrological evolution of San Pedro volcano, Provincia EI Loa, North Chile[END_REF][START_REF] O'callaghan | Volcanological and petrological evolution of San Pedro volcano, Provincia EI Loa, North Chile[END_REF] described and identified the nature and composition of erupted materials and the history of eruption of these volcanoes. The San Pedro volcano represents a composite andesitic stratovolcano (Figure 2) made of two east-west oriented coalescent cones that have been successively built as the volcanic belt shifted westward [START_REF] O'callaghan | Volcanological and petrological evolution of San Pedro volcano, Provincia EI Loa, North Chile[END_REF]. The cones stand >2 km above an extensive ignimbrite plateau (Figure 1) that has formed since the Late Miocene at ca. 10.4 Ma during the development of the Altiplano-Puna volcanic complex [START_REF] De Silva | Altiplano-Puna volcanic complex of the central Andes[END_REF]). The San Pedro cones have been built due to the eruption of silicic materials ranging from basaltic andesite to potassium-rich dacite [START_REF] O'callaghan | Volcanological and petrological evolution of San Pedro volcano, Provincia EI Loa, North Chile[END_REF]. Structural mapping and petrologic investigations [START_REF] Francis | The San Pedro and San Pablo volcanoes of northern Chile and their hot avalanche deposits[END_REF][START_REF] O'callaghan | Volcanological and petrological evolution of San Pedro volcano, Provincia EI Loa, North Chile[END_REF] revealed that the San Pedro Volcano records three evolutionary steps, comprising i) the edification and subsequent collapse of an "old cone", whose summit marks the highest peak of the volcano, ii) the construction, c.a. 5 km to the west, of the "young cone" that has produced several large lava flows and is still marked by fumarolic activity and iii) the formation of the South West Dome and La Poruña scoria cone, representing the last eruptive episode and associated with the emission of two large and well preserved lava flows (Figure 1). Above 4500 m a.s.l., [START_REF] Francis | The San Pedro and San Pablo volcanoes of northern Chile and their hot avalanche deposits[END_REF] reported the presence of glacial moraines and cirques on the southern flanks of both the San Pablo and San Pedro volcanoes. Thus, the last eruptions are probably older than the last large glacial advances in the region (i.e. ca. > 15 ka; Blard et al., 2013). In addition, [START_REF] Wörner | Geochronology ( 40 Ar/ 39 Ar, K-Ar and He-exposure ages) of Cenozoic magmatic rocks from Northern Chile (18-22°S): implications for magmatism and tectonic evolution of the central Andes[END_REF] reported an exposure age of ca. 103 ka based on the cosmogenic-3 He analysis of one sample collected on La Poruña (Figure1), suggesting that the lava flow emitted by the SW Dome might be at least 100 ka old, or even older.

The SW Dome of the San Pedro volcano

The lava flow emitted by the SW Dome is the largest of the San Pedro volcano. It extends towards the south west for ca. 13 km from ca. 4800 m to 3370 m a.s.l (Figure 1) and covers an area of ca. 20 km 2 with a volume estimated at 2.8 km 3 (O'Callaghan and Francis, 1986). The lava flow is considered the product of a 200-m-thick early pyroxene dacite lava flow that was locally overlain by subsequent hornblende dacite flows (Figure 1). Although most of the surface of the lava flow displays a rough blocky structure typical of low-viscosity Andean andesite/dacite flows, its distal part presents smooth stream-oriented and elongated features (Figure 2). These features correspond to crease structures [START_REF] Anderson | Crease structures: indicators of emplacement rates and surface stress regimes of lava flows[END_REF] as inferred from the curved and striated walls situated on both sides of a main central fracture (Figure 2). Such crease structures have been identified as typical constructional volcanic features materializing excellent landforms for surface exposure dating with in-situ produced cosmogenic nuclides [START_REF] Anderson | Criteria for recognition of constructional silicic lava flow surfaces[END_REF].

Sampling site

Samples were collected on the top of one crease structure immediately above the main lava flow front. The site is characterized by a perfectly preserved rind crust displaying stream-parallel striations (Table 1, Figures 1 and2). We collected 5 different samples at a few meters interval in order to capture variations in noble gas concentrations that might be related with differences in the preservation of the flow surface. All sampled surfaces showed no sign of post-eruptive erosion or burial. Seasonal snow cover is unlikely given the hyperaridity of the local climate.

Samples were collected with a combination of drill-hammer, sledge-hammer and chisels in order to extract homogeneous <10-cm-thick rock cuboids. Samples' locations were recorded with a hand-GPS, and both the local surface geometry and its surrounding topography were measured with a sighting compass and inclinometer. These measurements were later used to correct for geomorphic shielding using equations from [START_REF] Dunne | Scaling factors for the rates of production of cosmogenic nuclides for geometric shielding and attenuation at depth on sloped surfaces[END_REF].

Experimental procedures

The following sections provide a description of the sample preparation and analytical experiments conducted for the determination of the eruption age of the San Pedro volcano lava flow via 40 Ar/ 39 Ar dating and the quantification of the cosmogenic 3 He concentrations of the collected samples.

Sample preparation

Before proceeding to the preparation of samples for 40 Ar/ 39 Ar dating and helium analyses, the rocks were sawed and 3 separates of each sample were used for estimating the lava density. In addition, the bulk rock composition of major elements was measured on one additional sample separate (Table 1, Table 2). Each sample's average density was determined by weighing several times the sample fragments in air and immersed. Bulk rock composition of collected samples was obtained from mass-spectrometry analyses conducted by Activation Laboratories Ltd. (Canada).

After measuring the sample thickness, materials for 40 Ar/ 39 Ar and helium analyses were crushed via electrodynamic disaggregation using the high-voltage pulsed power selFrag-Lab instrument at the Institute of Geological Sciences of the University of Bern. This crushing equipment was preferred to a usual jaw crusher because of its efficiency in liberating mono-mineral phenocrysts. It also results in a lower loss of material due to mechanical fining, thereby increasing the recovery of mineral separates. Moreover, it has been shown that the electrodynamic disaggregation of rocks do not affect the noble gas content of liberated minerals (Giese et al., 2009). After crushing, the samples were sieved.

The 65-125 microns fraction of the sample SP12-02A was processed in order to extract the potassium-rich groundmass for 40 Ar/ 39 Ar dating purposes. Mafic minerals such as pyroxene, amphibole and associated oxides where first removed using a magnetic separator, after which the remaining material was leached in 10% HNO3 and rinsed several times with deionized water before small aggregates of clean groundmass were hand-picked under a binocular microscope. About 150 mg were finally used for the 49 Ar/ 39 Ar dating.

Sample preparation for helium analyses consisted of the separation of heavy minerals from the 250-500 microns fraction using bromoform (CHBr3, 2.9 g.cm - 3 ) and methylene iodide (CH2I2, 3.3 g.cm -3 ) heavy liquids. Pure separates of pyroxenes without any adhering lava or solid-inclusions were carefully handpicked under a binocular microscope. Clinopyroxene (augite, prismatic greenish grains) and orthopyroxene (enstatite, orthorhombic brownish grains) were isolated. We used color and shape as criteria for mineral separation during picking. Mineral separates were then sonicated with acetone and rinsed several times with deionized water. About 15 grains of each separate were mounted on epoxy-resin discs in order to measure the equivalent spherical radius of the phenocrysts and to determine the composition in major elements of the mineral separates. This was accomplished using the electron microprobe (JEOL-8200) of the Institute of Geological Sciences in Bern. Laser ablation (LA) ICP-MS analyses were subsequently conducted at the University of Bern on the two discs of sample SP12-02D (i.e. both the clino-and orthopyroxene separates) in order to measure the concentration of a selection of trace elements, notably U, Th, Sm, Li and Gd (Table 3). These data were later used for correcting the helium analyses for the inherited nucleogenic and radiogenic components.

40 Ar/ 39 Ar analytical method

About 150 mg of groundmass from SP12-02A was irradiated for 1 hour in the OSIRIS nuclear reactor1 tube, CEA Saclay, France). After irradiation, ca. 40 mg of the sample was transferred into a stainless steel sample holder and then loaded into a differential vacuum Cleartran® window. Argon isotopes were then extracted from the groundmass by step heating using a 25 W CO2 laser (Synrad®). Ar isotopes were analyzed using a VG5400 mass spectrometer equipped with a single ion counter following the protocol reported in [START_REF] Nomade | 40 Ar/ 39 Ar temporal framework for the Alleret maar lacustrine sequence (French Massif-Central): Volcanological and paleoclimatic implications[END_REF]. Each Ar isotope measurement consisted of 20 cycles of peak jumping over the argon isotopes. Neutron fluence (J) was monitored by co-irradiation of Alder Creek Sanidine (ACs-2, [START_REF] Nomade | Alder Creek sanidine (ACs-2): a Quaternary 40 Ar/ 39 Ar dating standard tied to the Cobb Mountain geomagnetic event[END_REF] placed in the same pit as the sample. J values were determined from analyses of three ACs-2 single grains.

Corresponding J value was calculated using an age of 1.194 Ma [START_REF] Nomade | Alder Creek sanidine (ACs-2): a Quaternary 40 Ar/ 39 Ar dating standard tied to the Cobb Mountain geomagnetic event[END_REF] and the total decay constant reported by [START_REF] Steiger | Subcommission on geochronology: convention on the use of decay constants in geo-and cosmochronology[END_REF]. An 40 Ar/ 36 Ar atmospheric ratio of 298.56 was then applied [START_REF] Lee | A redetermination of the isotopic abundances of atmospheric Ar[END_REF], consistent with the value reported by [START_REF] Valkiers | Preparation of argon primary measurement standards for the calibration of ion current ratios measured in argon[END_REF]. Recent revisions of decay and monitor constants suggest values about 0.64 % (Kuiper et al., 2008, 1.201 Ma for ACs-2) and 1.0 % [START_REF] Renne | Response to the comment by WH Schwarz et al. on "Joint determination of 40 K decay constants and 40 Ar * /40 K for the Fish Canyon sanidine standard, and improved accuracy for 40 Ar/39 Ar geochronology[END_REF]1.2059 Ma for ACs-2) older than used here. However, the implied difference in calibrated age is negligible for our samples (ca. 1 ka) and therefore remains identical within uncertainty with the age reported here. Procedural blanks were measured every three to four steps depending on the beam size. For a typical 10-minutes static blank, typical backgrounds were about (2-5) × 10 -17 and(4-5) × 10 -19 moles for 40 Ar and36 Ar, respectively. The precision and accuracy of the mass discrimination correction was monitored by daily measurements of air argon at various pressures [START_REF] Nomade | 40 Ar/ 39 Ar temporal framework for the Alleret maar lacustrine sequence (French Massif-Central): Volcanological and paleoclimatic implications[END_REF]. Nucleogenic production ratios used to correct for reactor produced Ar isotopes from K and Ca could be found in the full data table (Table A1). Data reductions were done using ArArCalc [START_REF] Koppers | ArArCALC-software for 40 Ar/39 Ar age calculations[END_REF]. Plateau age and corresponding uncertainty were calculated using IsoPlot 3.0 [START_REF] Ludwig | User manual for Isoplot 3.0[END_REF].

Helium analyses

Helium analyses were carried out at the CRPG noble-gas lab in Nancy, France. 3 He and 4 He isotope concentrations were measured using the Split Flight Tube mass spectrometer designed by GV. The magmatic contribution to the measured 3 He and 4 He concentrations was estimated by a 6 min in-vacuo crushing [START_REF] Kurz | In situ production of terrestrial cosmogenic helium and some applications to geochronology[END_REF][START_REF] Scarsi | Fractional extraction of helium by crushing of olivine and clinopyroxene phenocrysts: effects on the 3 He/ 4 He measured ratio[END_REF] of 97 mg of an aliquot of orthopyroxene of sample SP12-02D. These values were then used for all other samples, assuming that the magmatic contribution is the same in all pyroxenes collected on the San Pedro lava flow.

Following [START_REF] Williams | Using pyroxene microphenocrysts to determine cosmogenic 3 He concentrations in old volcanic rocks: an example of landscape development in central Gran Canaria[END_REF] and Blard et al. (2013), we also considered that a potential magmatic contribution is negligible in these micro-phenocrysts.

Between ca. 12 and 28 mg of clino-and orthopyroxene were packed in tin foils and fused in-vacuo for 15 min at 1400°C, within an in-house-built single vacuum furnace [START_REF] Zimmermann | A new single vacuum furnace design for cosmogenic 3 He dating[END_REF]. The extracted gas was purified using a succession of activated-charcoal cold traps, Ti-foam and SAES getters. Cryo-focusing of the gas at various temperatures (12 K and 70 K) thus allowed suppression of neon before helium analysis. Following the purification steps, the total 3 He and 4 He concentrations were analyzed with the SFT mass spectrometer.

Re-extraction procedure were conducted on 3 aliquots by heating the furnace to 1400°C for an additional 15 min to ensure a complete degasing of the samples.

Blank signatures were systematically obtained for these tests. Typical furnace blanks were (3.3±1.1)×10 4 and (1.8±0.4)×10 9 atoms for 3 He and 4 He, respectively, which represent <3% of the total 3 He concentrations and ca. 50-80% of the total 4 He measured. We emphasize that such a large contribution by the furnace blank to the total 4 He signal of the samples is actually not related to the quality of the blanks (i.e. blank values obtained during the experiments were consistent with long term blank values) but rather to the very low 4 He content of the samples. The SFT sensitivity was calibrated using a known amount of helium gas standard with a 3 He/ 4 He ratio of 20.63 Ra (1Ra=1.384×10 -6 corresponds to the atmospheric ratio) [START_REF] Matsuda | The 3 He/ 4 He ratio of the new internal He standard of Japan (HESJ)[END_REF]. The reproducibility at the 1-sigma level on the gas standard was 1.5% for 3 He and 0.3% for 4 He over a 2-monthperiod overlapping with our analyses (1 week).

Potential contributions in radiogenic 4 He due to U, Th and Sm decay were estimated following Blard and Farley (2008). The contribution due to nucleogenic 3 He was calculated following [START_REF] Andrews | The isotopic composition of radiogenic helium and its use to study groundwater movement in confined aquifers[END_REF], Andrews and Kay (1982) and using 1) Li concentrations measured in both clino-and orthopyroxene separates of SP12-02D, 2) the compositions in major and trace elements measured in bulk rocks as well as 3) the eruption age of the lava inferred from the 40 Ar/ 39 Ar dating (Table 2,Table 3,Table 4). The concentration of cosmogenic 3 He in our samples ( 3 Hec) was finally determined using the equations reported by [START_REF] Kurz | In situ production of terrestrial cosmogenic helium and some applications to geochronology[END_REF] assuming a negligible contribution from radiogenic 4 He (Blard and Farley, 2008):

3 Hec = 3 Het -3 Hen -3 Hem

(1)

where 3 Het is the quantity of 3 He measured when fusing the sample, 3 Hen is the nucleogenic component predicted from geochemical analyses of the minerals and bulk rock and 3 Hem the magmatic contribution measured from the in-vacuo crushing of an aliquot of the sample. Note that we do consider here 3 Hec as the product of both spallogenic (induced by high-energy neutrons) and capture reactions (induced by cosmogenic thermal neutrons, CTN). Previous studies reported by e.g. Dunai et al. (2007) and [START_REF] Amidon | Cosmogenic 3 He production rates in apatite, zircon and pyroxene inferred from Bonneville flood erosional surfaces[END_REF] have shown that the contribution of CTN to the cosmogenic 3 He concentration depends on the Li concentration of the analyzed minerals and the thermal neutrons flux that irradiates the considered surface. We emphasize, however, that the CTN contribution to the San Pedro samples is likely negligible due to the limited content in Li (<30 ppm) in both the bulk rocks and pyroxene separates (Table 3)

and because of the extreme local climate aridity that strongly reduces the probability of H-rich material (e.g. snow) covering the sampled surfaces, and consequently the thermal neutrons flux (see Dunai et al., 2007). We thus anticipate a CTN contribution lower than 5% to the cosmogenic 3 He concentrations inferred for the San Pedro samples based on observations reported by [START_REF] Amidon | Cosmogenic 3 He and 21 Ne production rates calibrated against 10 Be in minerals from the Coso volcanic field[END_REF] and Blard et al. (2013b).

Results

40 Ar/ 39 Ar dating of the eruption of the San Pedro Lava flow

The eruption age of the San Pedro volcano lava flow has been estimated from the (2002) for the eruption of La Poruña.

Helium isotopic results and corrections applied to 3 He.

Helium isotope analyses are reported in Table 5 and cosmogenic 3 He concentrations ( 3 Hec) calculated for the San Pedro volcano samples are plotted in Figure 4. Note that helium concentrations are reported in "Mat.g -1 " (i.e. 10 6 atoms per gram of pyroxene or ca. 3.7  10 -14 cc STP/g) in the following sections.

Total concentrations released by melting ranged between 89±3 and 97±3 Mat.g -1 for 3 He ( 3 Het) and between 29±14 and 90±16  10 3 Mat.g -1 for 4 He ( 4 Het). 3 He concentrations cluster around ca. 94±2 Mat.g -1 , while the 4 He data show a large scatter, which is probably due to the low amount of released gas and the significant contribution of the furnace blank correction (Table 5). In-vacuo crushing of the aliquot of sample SP12-02D yielded concentrations of (0.29±0.09) Mat.g -1 and (17.0±0.6)  10 3 Mat.g -1 for 3 He and 4 He, respectively (Table 5). The gas liberated during crushing has thus a 3 He/ 4 He isotopic ratio of 12±4 Ra that is higher than the values usually reported for volcanic rocks in the Central Andes [START_REF] Hilton | Helium isotope characteristics of Andean geothermal fluids and lavas[END_REF]Blard et al., 2013). This result suggests that unquantifiable amounts of cosmogenic 3 He might have been released during invacuo crushing, with the consequence that the magmatic correction applied to the samples must be considered as a maximum. However, the impact of this magmatic correction is most likely negligible because the 3 He released during crushing ( 3 Hem) only represents ca. 0.3% of the total 3 He released during melting ( 3 Het, Table 5). Note that the magmatic 3 He correction applied to all the samples was realized using the 3 He concentration measured from the prolonged in-vacuo crushing experiment of the sample SP12-02D. This correction systematically represented less than 0.4% of the total 3 He extracted by fusion in all samples and thus does not induce a significant source of uncertainty.

Regarding 4 He, the concentration we measured during the crushing experiment (17 ± 0.6) 10 3 Mat.g -1 represents ca. 20% of 4 Het determined in the orthopyroxene aliquot of SP12-02D (77±23)  10 3 Mat.g -1 (Table 5). If we consider that this 4 He concentration measured during crushing is magmatic and representative for all samples, then 40 to 80% of 4 Het is most likely radiogenic in other samples. Using the radiogenic production rates estimated from the minerals composition (P4r: ca. 1.1±0.1 Mat.g -1 .yr -1 , Table 3), the calculated (U-Th-Sm)/ 4 He ages vary from 12 to 54 ka, i.e. significantly younger than the 40 Ar/ 39 Ar age of 107±12 ka. Assuming no magmatic 4 He correction, these (U-Th-Sm)/ 4 He ages range from 26 to 76 ka. Such a difference with the 40 Ar/ 39 Ar age may indicate that the U, Th and Sm decay chains are out of secular equilibrium [START_REF] Farley | The effects of secular disequilibrium on (U-Th)/He systematics and dating of Quaternary volcanic zircon and apatite[END_REF]. In any case, given the large uncertainties related to the measurement of 4 He concentrations and to the production rate, the (U-Th-Sm)/ 4 He approach cannot be used to thoroughly constrain the age of the flow eruption. We will therefore rely on the 40 Ar/ 39 Ar age only to calibrate the cosmogenic 3 He production rate at the San Pedro volcano.

The nucleogenic 3 He ( 3 Hen) production rates range between ca. 0.1 and 0.2 at.g - 1 .yr -1 (Table 5). The Li concentrations used for this calculation are 20 ppm Li for clinopyroxene and 15 ppm Li for orthopyroxene (from LA ICP-MS analyses of sample SP12-02D, Table 3). Although these values have been used for all 5 samples, we emphasize that this simplification does not induce significant uncertainties on the nucleogenic 3 He correction as 3 Hen represents indeed less than 0.03% of 3 Het (Table 5).

Calculation of cosmogenic 3 He concentrations

Cosmogenic 3 He ( 3 Hec) reported in Table 5 are corrected for inherited magmatic and nucleogenic components. They range between 89±3 and 96±3 Mat.g -1 .

Subsequent corrections for thickness, geomorphic shielding and normalization to a geographic position of 21.934°S-68.510°W-3390 m a.s.l. (i.e. total relative correction of ca. 4.5-8.7 %, see Table 1) yield surface cosmogenic 3 He concentrations ( 3 Hec(S)) that range from 93±3 to 102±3 Mat.g -1 , with an arithmetic mean of 99±3 Mat.g -1 .

The 3 Hec(S) concentrations obtained for clinopyroxene and orthopyroxene separates are similar within uncertainties. This is consistent with results from elemental production models (e.g. [START_REF] Masarik | Monte Carlo simulation of in-situ-produced cosmogenic nuclides[END_REF] that do not predict any significant differences in production rate between these two pyroxene phases. Weighted average values can therefore be calculated from clino-and orthopyroxene for the same samples. The narrow distribution displayed by the data thus suggests that all sampled surfaces have experienced the same exposure history. This indicates that the surface of the San Pedro lava flow has not been affected by post-eruptive erosion or burial, consistent with our observations in the field. This also implies that the San Pedro site is suitable for calibrating the production rate of cosmogenic 3 He. In summary, the five samples finally yield a weighted average of 99.3±1.2 Mat(3He).g(pyroxene) -1 with a relative standard deviation of ca. 1% and a MSWD of 1.2 (Figure 4).

Discussion

Estimations of cosmogenic 3 He production rates

The production rate of cosmogenic 3 He can be estimated locally, at the geographic position of the calibration site, and/or scaled to a sea level high latitude (SLHL) reference position. Locally, the cosmogenic 3 He production rate is obtained by dividing the average cosmogenic 3 He concentration obtained for the calibration site by the age of the considered landform deduced from an independent dating technique (e.g. 14 C, K/Ar, 40 Ar/ 39 Ar). Note that individual concentrations are first normalized to the surface, an open-sky topography and the mean geographic coordinates (latitude, longitude and elevation) in order to identify potential outliers due to erosion or inheritance (see e.g. Martin et al., 2015, and reference therein). Scaling the cosmogenic 3 He production rate to SLHL (referred to as SLHL P3 in following sections) is, however, not straightforward. The scaling procedure indeed requires the combination of a geographic spatialization model with an atmosphere model and the reconstruction of the past geomagnetic field conditions (see [START_REF] Balco | A complete and easily accessible means of calculating surface exposure ages or erosion rates from 10 Be and 26 Al measurements[END_REF][START_REF] Lifton | Scaling in situ cosmogenic nuclide production rates using analytical approximations to atmospheric cosmic-ray fluxes[END_REF]. Here we followed a calculation procedure based on a leastsquare minimization technique (see [START_REF] Martin | In situ cosmogenic 10 Be production rate in the High Tropical Andes[END_REF], for details) and the scaling frameworks presented bellow. SLHL P3 estimates were inferred from the San Pedro samples using the time-independent Lal/Stone scaling model [START_REF] Lal | Cosmic ray labelling of erosion surfaces: in situ nuclide production rates and erosion models[END_REF][START_REF] Stone | Air pressure and cosmogenic isotope production[END_REF], noted "St", as well as two time-dependent schemes: "Lm", the adaptation of the Lal/Stone model [START_REF] Balco | A complete and easily accessible means of calculating surface exposure ages or erosion rates from 10 Be and 26 Al measurements[END_REF] and "LSD", recently developed by [START_REF] Lifton | Scaling in situ cosmogenic nuclide production rates using analytical approximations to atmospheric cosmic-ray fluxes[END_REF]. SLHL P3 estimates were thus obtained by dividing the local production rate by a scaling factor representative for a given combination of scaling, atmosphere and geomagnetic reconstruction models.

Regarding scaling schemes, we favored the "Lm" and "LSD" time-dependent models. Indeed, recent studies [START_REF] Lifton | Scaling in situ cosmogenic nuclide production rates using analytical approximations to atmospheric cosmic-ray fluxes[END_REF][START_REF] Borchers | Geological calibration of spallation production rates in the CRONUS-Earth Project[END_REF][START_REF] Phillips | Where now? Reflections on future directions for cosmogenic nuclide research from the CRONUS Projects[END_REF] have demonstrated that these scaling schemes yield more consistent and reliable spatial and temporal estimates of cosmogenic nuclide production rates than former neutron-monitor based models [START_REF] Desilets | Spatial and temporal distribution of secondary cosmic-ray nucleon intensities and applications to in situ cosmogenic dating[END_REF][START_REF] Desilets | Extended scaling factors for in situ cosmogenic nuclides: New measurements at low latitude[END_REF][START_REF] Dunai | Influence of secular variation of the geomagnetic field on production rates of in situ produced cosmogenic nuclides[END_REF][START_REF] Lifton | Addressing solar modulation and long-term uncertainties in scaling secondary cosmic rays for in situ cosmogenic nuclide applications[END_REF]. These "Lm" and "LSD" models thus represent the most widely used and recently available scaling schemes, respectively (see e.g. [START_REF] Lifton | Scaling in situ cosmogenic nuclide production rates using analytical approximations to atmospheric cosmic-ray fluxes[END_REF][START_REF] Martin | In situ cosmogenic 10 Be production rate in the High Tropical Andes[END_REF]. We then calculated SLHL P3s for "St", "Lm" and "LSD" using the Standard atmosphere model (National Oceanic and Atmospheric Administration, 1976) and the ERA-40 reanalysis dataset [START_REF] Uppala | The ERA-40 re-analysis[END_REF], which allows accounting for the regional variations in height-pressure relationship. Finally, we inferred SLHL P3s for the time-dependent "Lm" and "LSD" scaling schemes with three paleomagnetic-field reconstruction models (see details regarding the geomagnetic field reconstructions in [START_REF] Martin | In situ cosmogenic 10 Be production rate in the High Tropical Andes[END_REF]. The first two geomagnetic models rely on Virtual Dipole Moment values based on 1) [START_REF] Muscheler | Geomagnetic field intensity during the last 60,000 years based on 10 Be and 36 Cl from the Summit ice cores and 14[END_REF] for 0-62 ka BP and SINT-2000 [START_REF] Valet | Geomagnetic dipole strength and reversal rate over the past two million years[END_REF] beyond and 2) GLOPIS-75 [START_REF] Laj | High Resolution Global Paleointensity Stack Since 75 kyr (GLOPIS-75) Calibrated to Absolute Values[END_REF] for 0-75 ka BP and SINT-2000 beyond. The third model is based on the composite reconstruction of temporal variations in geomagnetic and solar intensity modulations implemented in the LSD model [START_REF] Lifton | Scaling in situ cosmogenic nuclide production rates using analytical approximations to atmospheric cosmic-ray fluxes[END_REF]. 3 Hec production rates at 21.934°S-68.510°W-3390 m a.s.l.

Calibration of

The local cosmogenic 3 He production rate, estimated for the San Pedro calibration site at a geographic position of 21.934°S-68.510°W and 3390 m a.s.l., is obtained by dividing the weighted average 3 Hec(s) with the eruption age of the San Pedro lava flow obtained from the 40 Ar/ 39 Ar dating. This approach yields a local production rate of 928±11 at.g -1 .yr -1 , and 928±101 at.g -1 .yr -1 when propagating both the cosmogenic 3 He and 40 Ar/ 39 Ar uncertainties respectively, at the 1-sigma level (Table 5). This rate combines all production pathways of cosmogenic 3 He including spallation, thermal neutron capture and muogenic production. We note however, that the contribution of cosmogenic thermal neutrons to the production of cosmogenic 3 He at the San Pedro calibration site is likely lower than 5% and therefore negligible, based on the predictions obtained with the model reported by [START_REF] Amidon | Cosmogenic 3 He production rates in apatite, zircon and pyroxene inferred from Bonneville flood erosional surfaces[END_REF] for pyroxenes with 15-20 ppm apparent Li and a He-closure age of ca. 100 ka.

The local cosmogenic 3 He production rate is then scaled to a sea level and high latitude (SLHL) reference position. SLHL P3s inferred from the San Pedro samples are presented in Table 6. SLHL P3s obtained from the time-independent "St" scheme with the Standard and ERA-40 atmosphere models are 132±14 and 143±16 at.g -1 .yr -1 , respectively. SLHL P3s estimated with the time-dependent "Lm" and "LSD" schemes, with various combinations of atmosphere and geomagnetic models, vary from 103±11 to 130±14 at.g -1 .yr -1 (Table 6). In general, the inferred values agree well with the SLHL P3 reported from globalscale compilations by [START_REF] Goehring | A reevaluation of in situ cosmogenic 3 He production rates[END_REF] and more recently by Blard et al. (2013a). Moreover, SLHL P3s that we estimated using the time-dependent adaptation of the Lal/Stone scaling scheme ("Lm") with the Muscheler-SINT2000 geomagnetic reconstruction and considering both the Standard and ERA-40 atmosphere models are 120±13 and 130±14 at.g -1 .yr -1 , respectively.

Interestingly, these SLHL P3 estimates fit perfectly with the values reported by Blard et al. (2013a) from a ca. 15-ka-old calibration site located at 3800 m a.s.l.

on the Bolivian Altiplano (Figure 1).

Note that all applied time-dependent scaling frameworks predict that at the San Pedro volcano calibration site, the production of cosmogenic nuclides, including cosmogenic 3 He, has been generally higher during the last 100 to 150 ka than at present (Figure 5). Such a situation can be explained by the persistence of a weaker geomagnetic field intensity that has induced lower cutoff rigidities, thereby allowing more cosmic-ray particles to enter the Earth's magnetic field (see Dunai and Lifton, 2015 and references therein). This effect is particularly amplified in high tropical areas integrating >50-ka exposure histories (e.g. [START_REF] Balco | A complete and easily accessible means of calculating surface exposure ages or erosion rates from 10 Be and 26 Al measurements[END_REF], since it yields relative corrections between 10 and 20% of the modern rate (Figure 5). It thus explains why the San Pedro calibration site yields time-independent "St" scaling factors that are higher than those inferred from time-dependent schemes ("Lm" and "LSD"). Figure 5 and Table 6 illustrate that geomagnetic field reconstructions relying on the Muscheler-SINT2000 and "LSD" frameworks systematically yield the highest and lowest SLHL P3s, respectively, independently of the scaling scheme and atmosphere model considered. The geomagnetic field and solar modulation reconstructions implemented in the "LSD" frameworks predict time-integrated scaling factors that are up to ca. 10%

higher than with the Muscheler-SINT2000 for an exposure length > 60 ka.

Re-evaluation of the global SLHL cosmogenic 3 He production rate

Cosmogenic 3 He production rates have rarely been calibrated to sea level high latitude positions using a common calculation framework that included similar scaling schemes, atmosphere model and geomagnetic field reconstructions. Here we re-evaluate the global SLHL P3 by compiling and processing available calibration datasets for both olivine and pyroxene within a common calculation framework that combines the scaling schemes, atmosphere and geomagnetic field models presented above (see section 3.4). Twenty different calibration sites and ca. 150 cosmogenic 3 He analyses have been compiled from the literature and combined with the San Pedro samples (see Table A2). This new compilation includes the studies of [START_REF] Ackert | Long-term cosmogenic 3 He production rates from 40 Ar/ 39 Ar and K-Ar dated Patagonian lava flows at 47°S[END_REF], [START_REF] Amidon | Cosmogenic 3 He production rates in apatite, zircon and pyroxene inferred from Bonneville flood erosional surfaces[END_REF], [START_REF] Blard | Applications of ancient cosmic-ray exposures: Theory, techniques and limitations[END_REF]Blard et al. ( , 2013a)), [START_REF] Cerling | Cosmogenic 3 He production rates from 39°N to 46°N latitude, western USA and France[END_REF]; [START_REF] Dunai | Long-term cosmogenic 3 He production rates (152 ka-1.35 Ma) from 40 Ar/ 39 Ar dated basalt flows at 29°N latitude[END_REF], [START_REF] Fenton | 40 Ar/ 39 Ar dating of the SP and Bar Ten lava flows AZ, USA: Laying the foundation for the SPICE cosmogenic nuclide production-rate calibration project[END_REF][START_REF] Fenton | Surface exposure dating of young basalts (1-200 ka) in the San Francisco volcanic field (Arizona, USA) using cosmogenic 3 He and 21 Ne[END_REF], [START_REF] Foeken | Long-term low latitude cosmogenic 3 He production rate determined from a 126 ka basalt from Fogo, Cape Verdes[END_REF], [START_REF] Goehring | A reevaluation of in situ cosmogenic 3 He production rates[END_REF] and [START_REF] Licciardi | Calibration of cosmogenic 3 He production rates from Holocene lava flows in Oregon, USA, and effects of the Earth's magnetic field[END_REF][START_REF] Licciardi | Cosmogenic 3 He production rates from Holocene lava flows in Iceland[END_REF]. We do note that we only considered dataset originating from absolute calibration studies and therefore excluded those from cross calibrations (e.g. [START_REF] Amidon | Cosmogenic 3 He and 21 Ne production rates calibrated against 10 Be in minerals from the Coso volcanic field[END_REF]. Some of the studies included in this compilation did not address the impact of radiogenic 4 He on the measured cosmogenic 3 He concentrations. In several of these previous studies indeed, the authors overestimated the amount of 4 He that was derived from trapped magmatic gases and thus over-corrected for magmatic 3 He, thereby resulting in an underestimation of cosmogenic 3 He concentrations. To tackle this issue, the compiled data were first corrected for this radiogenic contribution, either using the reported U-Th-Sm concentrations in the phenocrysts or considering the global mean of these elements as proposed by Blard and Farley (2008, see Table A2). The resulting corrections slightly increase the cosmogenic 3 He concentrations by 4% on average, as illustrated in the inset of Figure 6A.

Subsequently, the cosmogenic 3 He concentrations available for each calibration site were 1) normalized to the surface, an open-sky topography and the sites' mean geographic coordinates, 2) used to calculate a weighted average concentration and 3) inverted to SLHL P3s, following the procedure outlined in section 3.4. SLHL P3s inferred from all possible combinations in scaling, atmosphere and geomagnetic field models cover the range 76±4 -186±12 at.g - 1 .yr -1 (see Table A2). When considering each scaling framework separately, the values yield arithmetic means that range between 115±19 and 122±20 at.g -1 .yr -1 , therefore identical within uncertainty (1σ-level). These re-evaluated global SLHL P3s are consistent with values reported from previous compilations that also considered olivine and pyroxene minerals together (e.g. [START_REF] Goehring | A reevaluation of in situ cosmogenic 3 He production rates[END_REF]Blard et al., 2013a;[START_REF] Borchers | Geological calibration of spallation production rates in the CRONUS-Earth Project[END_REF]. We emphasize, however, that SLHL P3s estimated from the combination of the "Lm" scaling scheme with the ERA-40 atmosphere model and the geomagnetic field reconstruction based on Muscheler (2004) and SINT2000 (Valet et al., 2004) yield the least scatter in the distribution, with a 14% relative standard deviation and an arithmetic mean of 120±16 at.g -1 .yr -1 . Figure 6 represents the distribution of SLHL P3s inferred from this latter scaling framework. It does not show any correlation with elevation nor with latitude. This confirms previous observations reported by [START_REF] Goehring | A reevaluation of in situ cosmogenic 3 He production rates[END_REF] and Blard et al. (2013a) that there is no anomalous production of cosmogenic 3 He at high elevations, at least in pyroxene and olivine. It is, however, important to emphasize that the estimated Mean Square Weighted Deviation is significantly higher than 1 (MSWD = 10.4; Figure 6), indicating that the observed variability in the data is larger than a statistical dispersion that would result from analytical uncertainties only. In other words, the global SLHL P3 compilation unlikely represents a single population. Note that while Figure 6 only represents SLHL P3s estimated from the combination of the "Lm" scaling scheme with the ERA-40 atmosphere model and Muscheler-SINT2000 based geomagnetic field reconstruction, all other scaling frameworks present a similar picture. Part of this over-dispersion might result from calibration sites older than ca. 120 ka that systematically yield SLHL P3s lower than ca. 110 at.g -1 .yr -1 when considering the "Lm" scaling scheme (Figure 6). This inference, however, should be tuned down when considering the "LSD" scaling scheme, as P3s estimates do not show such temporal pattern. In any cases and for all considered scaling frameworks, the variability in SLHL P3s seems independent from the exposure age for calibration sites younger than 110 ka (Figure 6). The observed variability in SLHL P3s might result from unrecognized erosion, variations in atmospheric pressure, inaccurate correction of the time-dependent production rate variability, and/or unaccounted excess in Li concentrations of crustally contaminated magmas (e.g. [START_REF] Amidon | Cosmogenic 3 He production rates in apatite, zircon and pyroxene inferred from Bonneville flood erosional surfaces[END_REF][START_REF] Dunai | Long-term cosmogenic 3 He production rates (152 ka-1.35 Ma) from 40 Ar/ 39 Ar dated basalt flows at 29°N latitude[END_REF]Dunai et al., 2007;[START_REF] Foeken | Long-term low latitude cosmogenic 3 He production rate determined from a 126 ka basalt from Fogo, Cape Verdes[END_REF][START_REF] Staiger | Atmospheric scaling of cosmogenic nuclide production : climate effect[END_REF]. Excluding calibration sites older than 120 ka from the global compilation leads to slightly higher average cosmogenic 3 He production rates by ca. 2-4% and reduces the standard deviations from 14-17% to ca. 11-17%, depending on the considered scaling framework (see Table A2), but do not fundamentally change the overall picture.

In summary, SLHL P3s inferred from the combination of the "Lm" scaling scheme with the ERA-40 atmosphere model and Muscheler-SINT2000 based geomagnetic field reconstruction yield the best constrained mean global-scale cosmogenic 3 He production rate. This scaling framework therefore represents a qualitative combination of currently available geographic spatialization schemes, atmosphere as well as geomagnetic field reconstruction models to estimate exposure ages from cosmogenic 3 He concentrations. Similar statements were also reported by [START_REF] Martin | In situ cosmogenic 10 Be production rate in the High Tropical Andes[END_REF] regarding the production of in-situ 10 Be in the high tropical Andes.

Conclusion

We report a new geological calibration site located in northern Chile (21.934°S-68.510°W) at 3390 m a.s.l. that we used to infer the production rate of cosmogenic 3 He in pyroxenes. 40 Ar/ 39 Ar dating gives a consistent plateau age of 107±12 ka. Eight mineral separates of clino-and orthopyroxene from five different surface samples yield clustered 3 He concentrations, for both pyroxene phases. Magmatic and nucleogenic 3 He corrections are negligible (< 1%) in this lava flow. The weighted average cosmogenic 3 He concentration is 99.3±1.2 Mat.g - 1 , which represents the highest cosmogenic 3 He concentrations ever measured so far in natural calibration samples.

We then used this data to constrain a local cosmogenic 3 He production rate of 928±101 at.g -1 .yr -1 at 21.934°S-68.510°W and 3390 m a.s.l. After scaling to sea level and high latitudes (SLHL), cosmogenic 3 He production rate estimates vary from 103±11 to 130±14 at.g -1 .yr -1 , which depends on different combinations of scaling schemes, atmosphere models and geomagnetic field reconstructions.

Finally we combined the SLHL P3s inferred from the San Pedro lava flow samples with cosmogenic 3 He production rates (in both olivine and pyroxene) inferred from various calibration sites and re-evaluated the mean global SLHL P3. This compilation, where cosmogenic 3 He production rates were scaled to SLHL with two scaling schemes, two atmosphere models and three different geomagnetic field reconstructions, yield arithmetic means for SLHL P3s that vary between 115±19 and 122±20 at.g -1 .yr -1 . These values are identical within uncertainty and consistent with values previously reported from similar compilation studies (e.g. [START_REF] Goehring | A reevaluation of in situ cosmogenic 3 He production rates[END_REF]Blard et al., 2013a;[START_REF] Borchers | Geological calibration of spallation production rates in the CRONUS-Earth Project[END_REF]. This new compilation thus illustrates that a calculation framework including the (1) time-dependent adaptation of the Lal (1991) / [START_REF] Stone | Air pressure and cosmogenic isotope production[END_REF] scheme, (2) ERA-40 atmosphere model [START_REF] Uppala | The ERA-40 re-analysis[END_REF], and a (3) geomagnetic field reconstruction relying on the Virtual Dipole Moment values based on Muscheler et al. (2004) and SINT-2000[START_REF] Valet | Geomagnetic dipole strength and reversal rate over the past two million years[END_REF] currently yields the best constrained mean global-scale cosmogenic 3 He production rate.

Our observations also appear perfectly in line with the recent findings reported by [START_REF] Lifton | Implications of two Holocene time-dependent geomagnetic models for cosmogenic nuclide production rate scaling[END_REF]. We thus suggest that the update of the scaling framework presented here, together with the inferred mean global SLHL P3 of 120±16 at.g - 1 .yr -1 , should be favored when calculating exposure ages from cosmogenic 3 He concentrations. a Local atmospheric pressure was calculated using the ICAO standard atmosphere equation with sea level temperature and pressure derived from the ERA-40 reanalysis dataset [START_REF] Uppala | The ERA-40 re-analysis[END_REF] b Correction factors used to scale cosmogenic 3 He concentrations to 21.934°S-68.510°W, 3390m (679.468 hPa). Values are calculated as the ratio between the scaling factor obtained using the Lal (1991) / Stone (2000) scheme with the ERA-40 atmosphere model for the sampling position and at 21.934°S-68.510°W, 3390 m a.s.l. c Thickness corrections are calculated using an attenuation length of 160 g.cm -2 and the sample densities measured. d Total geomorphic shielding, including self-shielding by the sampled surface and the topography around the sampling site, are calculated according to [START_REF] Dunne | Scaling factors for the rates of production of cosmogenic nuclides for geometric shielding and attenuation at depth on sloped surfaces[END_REF] and an algorithm provided by G. Balco (http://hess.ess.washington.edu/). e Calculated as the product of altitude, thickness and geomorphic shielding factors. a 3 He and 4He concentrations measured by fusing the sample and corrected for blanks. Typical 3 He and 4 He blanks during the measurements were (3.3±1.1)  10 4 atoms and (1.8±0.4)  10 9 atoms, respectively, or <3% of 3 He and ca. 50-80% of 4 He measured in the samples. Associated errors (1σ) include sample and blank counting statistics as well as the one-sigma reproducibility on standard analyses over a 2 months period (1.5% for 3He and 0.3% for 4He). b Nucleogenic 3 He production rates were calculated according to [START_REF] Andrews | The isotopic composition of radiogenic helium and its use to study groundwater movement in confined aquifers[END_REF] and Andrews and Kay (1982) using Li concentration measured in pyroxene aliquots and major and trace element compositions of lava (Table 2). c Total nucleogenic 3 He calculated as the product of P3n and the age of the lava based on the Ar/Ar dating. d Radiogenic 4 He production rate were predicted from equations described in Farley et al. (2006) and Blard and Farley (2008).

Calculations are based on U, Th and Sm concentrations measured both in bulk rocks and clinopyroxene and orthopyroxene aliquots of sample SP12-02D (see Table 3) together with a measured equivalent spherical radius of 215 μm for pyroxene grains and an estimated 20-μm alpha-nuclei stopping distance.

e Corrected for magmatic ( 3 Hem) and nucleogenic ( 3 Hen) contributions to 3 HeT. The magmatic contribution was inferred from a 6 min invacuo crushing of an aliquot of sample SP12-02D that yielded concentrations of (0.29±0.09) Mat.g -1 and (17.0±0.6)  10 3 Mat.g -1 for 3 He and 4 He, respectively, which represented a 3 He/ 4 He isotopic ratio of 12±4 Ra. Reported errors (1σ) integrate ca. 3% uncertainty on 3 Het measurements and 10% and 31% uncertainties on nucleogenic and magmatic contribution estimates, respectively. f Local cosmogenic 3 He production rates estimated from a Cosmogenic 3 He production rates are scaled to the reference sea level high latitude (SLHL) position using the calculation procedures and employed the scaling frameworks reported by [START_REF] Martin | In situ cosmogenic 10 Be production rate in the High Tropical Andes[END_REF]. "St" refers to Lal (1991) / [START_REF] Stone | Air pressure and cosmogenic isotope production[END_REF], "Lm" to the timedependent adaptation of the Lal/Stone scheme (see e.g. [START_REF] Balco | A complete and easily accessible means of calculating surface exposure ages or erosion rates from 10 Be and 26 Al measurements[END_REF] and "LSD" to [START_REF] Lifton | Scaling in situ cosmogenic nuclide production rates using analytical approximations to atmospheric cosmic-ray fluxes[END_REF].

b The Standard atmosphere model is based on the National Oceanic and Atmospheric Administration (1976) and the ERA-40 reanalysis dataset on [START_REF] Uppala | The ERA-40 re-analysis[END_REF]. c Geomagnetic models rely on Virtual Dipole Moment values based on [START_REF] Muscheler | Geomagnetic field intensity during the last 60,000 years based on 10 Be and 36 Cl from the Summit ice cores and 14[END_REF], GLOPIS-75 [START_REF] Laj | High Resolution Global Paleointensity Stack Since 75 kyr (GLOPIS-75) Calibrated to Absolute Values[END_REF] and SINT-2000[START_REF] Valet | Geomagnetic dipole strength and reversal rate over the past two million years[END_REF]. Numbers in brackets refer to scaling factor curves as labeled in Figure 5. d SLHL P3 estimates are obtained by dividing the local production rate by a scaling factor inferred for a given combination of scaling, atmosphere and geomagnetic reconstruction models (see text for details). Reported errors correspond to external (total) uncertainties at 1σ-level and comprise a ca. 1% uncertainty associated with the weighted average cosmogenic 3 He concentration and ca. 11% from the 40 Ar/ 39 Ar dating. 510°W-3390 m a.s.l. using calculation procedures and scaling frameworks reported by [START_REF] Martin | In situ cosmogenic 10 Be production rate in the High Tropical Andes[END_REF]. All scaling factors are calculated based on the atmospheric pressure derived from the ERA-40 reanalysis dataset [START_REF] Uppala | The ERA-40 re-analysis[END_REF]. Numbers in brackets are the same as in Table 6 and represent predictions from different combinations of scaling schemes and geomagnetic field reconstructions. (B) Time-integrated scaling factors using the "Lm" scaling scheme and the ERA-40 atmosphere model with geomagnetic field reconstructions based on Musheler-SINT2000 (black curve) and as implemented in the "LSD" model (green curve). The red curves represent the production ratio between "Lm-LSD" and "Lm-Muscheler". ) 1 0 10 20 30

1.04

Figure captions Figure 1 .

 captions1 Figure captions

Figure 2 .

 2 Figure 2. Photograph collection of the sampling site. (A) General overview of the San Pedro volcano photographed from the SW lava flow at ca. 3600 m a.s.l. toward the NE. (B) Satellite image(Google Earth) showing the situation of samples (see red star in Figure1). Note the lobate morphology of the lava front and the stream-oriented elongated features that correspond to crease structures. For representation purposes sample labels are shortened but should be read SP12-02(letter). (C) Picture taken from the sampling site (see position of SP12-02A) looking East toward the apex of the lava; a large crease structure can be seen in the background (see close up in D). Note that the sampled surface is perfectly smooth though fractured in m-scale compartments and displays stream-parallel striations that are characteristics of pristine crease-structures surfaces. (D) Close-up of the surface sampled for SP12-02A showing ~5-cm wide and few-mm high striations marked on top of the ca. 2-cm-thick rind. (E) Left half-part of the large crease structure situated at the apex of the sampled lava flow showing the general smooth and convex morphology of the rock wall as well as the subhorizontal striations and subvertical wall offsets characteristics of these features. Note the person (for scale) is located in the central valley of the crease structure. The materials forming this structure were exhumed from the central valley up. The second half of this structure can be seen on the right of the person.

Figure 3 .

 3 Figure 3. 40 Ar/ 39 Ar ages obtained plotted vs. the cumulated amount of 39 Ar released for SP12-02A. The calculated plateau ages (ka±1σ) is presented with the MSWD value (n=8).

Figure 4 .

 4 Figure 4. Camel diagram showing the distribution of cosmogenic3 He concentrations obtained for the San Pedro volcano samples.3 He concentrations are corrected for magmatic and nucleogenic contributions, scaled for geomorphic shielding and sample thickness and normalized to 21.934°S-68.510°W and 3390 m. Note that normalizing each sample's concentration to the surface, an open-sky topography and to a common coordinate allow to better identifying any potential outliers due to erosion or inheritance. Each individual cosmogenic3 He concentration is represented as a Gaussian distribution, considering the concentration value and its 1σ-error. Green and dashed-brown curves represent clinopyroxene (n=5) and orthopyroxene (n=3) aliquots, respectively. Black curve represents the sum of individual curves. The weighted average concentration is calculated after averaging clino-and orthopyroxene values and is reported with its associated MSWD value.

Figure 5 .

 5 Figure5. (A) 150-ka-long variations of TCN scaling-factors and magnetic-field cutoff rigidity calculated for 21.934°S-68.510°W-3390 m a.s.l. using calculation procedures and scaling frameworks reported by[START_REF] Martin | In situ cosmogenic 10 Be production rate in the High Tropical Andes[END_REF]. All scaling factors are calculated based on the atmospheric pressure derived from the ERA-40 reanalysis dataset[START_REF] Uppala | The ERA-40 re-analysis[END_REF]. Numbers in brackets are the same as in Table6and represent predictions from different combinations of scaling schemes and geomagnetic field reconstructions. (B) Time-integrated scaling factors using the "Lm" scaling scheme and the ERA-40 atmosphere model with geomagnetic field reconstructions based on Musheler-SINT2000 (black curve) and as implemented in the "LSD" model (green curve). The red curves represent the production ratio between "Lm-LSD" and "Lm-Muscheler".

Figure 6 .

 6 Figure6. Distribution of the reevaluated SLHL P3s inferred from the compilation of previous geological calibration sites as well as the San Pedro lava flow. Values represented are inferred from the combination of the "Lm" scaling scheme with the ERA-40 atmosphere model and the geomagnetic field reconstruction relying on the VDM values based on[START_REF] Muscheler | Geomagnetic field intensity during the last 60,000 years based on 10 Be and 36 Cl from the Summit ice cores and 14[END_REF] for the period 0-62 ka and SINT2000[START_REF] Valet | Geomagnetic dipole strength and reversal rate over the past two million years[END_REF] beyond. (A) Camel diagram showing the distribution of reevaluated SLHL P3s. Inset illustrates the impact of the radiogenic correction applied on cosmogenic3 He concentrations followingBlard and Farley (2008) (see text). (B), (C) and (D) show the distribution of SLHL P3s as a function of latitude, elevation and calibration age, respectively. Note the absence of statistically significant relationships between the production rate and these parameters. Red data represents the San Pedro volcano calibration site.

SF

  Figure1

  40 Ar/ 39 Ar analyses. Results are presented in table 4 and figure3. The stepheating degasing spectrum yielded a statistically robust plateau age of 107±12 ka (1σ, Mean Square Weighted Deviates, MSWD=0.07) with 100% of the released 39 Ar and no rejected heating steps. The age obtained for the total fusion step is consistent with the plateau age at 109±13 ka (Table4). Alternatively, Ar data were also cast as inverse isochron age. However, this age is poorly constrained at 100±52 ka, mainly because of the low radiogenic content in the sample resulting in a very limited spread on the isochron. We therefore discarded this age when calculating the production rates of cosmogenic 3 He. Instead, we applied the

40

Ar/ 39 Ar plateau age of 107±12 ka for the calibration of the cosmogenic 3 He production rate, as this age yields a good reproducibility at all heating steps. This age is also consistent with the exposure age ca. 103 ka reported by

Wörner et al.

Table 1 .

 1 Sample characteristics

	Sample name	Latitude	Longitude	Elevation	Atmospheric pressure	Altitude	Sample	Density	Thickness	Geomorphic	Total
						factor b	thickness		correction c	shielding d	correction e
		(°)	(°)	(m)	(hPa) a		(cm)	(g.cm -3 )			(%)
	SP12-02A	-21.93434	-68.50980	3389	679.55	0.999	6	2.44	0.956	0.996	4.9
	SP12-02C	-21.93431	-68.50974	3394	679.13	1.002	6	2.41	0.956	0.995	4.6
	SP12-02D	-21.93440	-68.50966	3393	679.22	1.002	6	2.43	0.956	0.998	4.5
	SP12-02E	-21.93435	-68.50983	3391	679.38	1.001	7	2.22	0.953	0.998	4.9
	SP12-02F	-21.93437	-68.51005	3384	679.97	0.997	7.5	2.21	0.950	0.964	8.7

Table 2 .

 2 Major element composition of lava and pyroxene phenocrysts

	Sample name	Type	SiO2	Al2O3	Fe2O3	MnO	MgO	CaO	Na2O	K2O	TiO2	P2O5	LOI	Total
			(wt %)	(wt %)	(wt %)	(wt %)	(wt %)	(wt %)	(wt %)	(wt %)	(wt %)	(wt %)	(wt %)	(%)
	SP12-02A	Bulk rock	63.3	15.6	5.5	0.08	2.4	4.1	4.0	3.3	0.8	0.2	1.2
	SP12-02A	Clinopyroxene	52.1	2.4	9.8	-	14.7	19.6	0.5	0.0	0.5	-	-
	SP12-02A	Orthopyroxene	54.0	0.9	20.0	-	22.9	1.2	0.0	0.0	0.4	-	-
	SP12-02C	Bulk rock	65.1	14.7	5.4	0.08	2.2	3.9	3.7	3.1	0.8	0.2	1.5
	SP12-02C	Clinopyroxene	52.7	2.2	8.9	-	14.9	20.4	0.4	0.0	0.4	-	-
	SP12-02D	Bulk rock	62.8	15.2	5.5	0.08	2.3	4.1	3.7	3.0	0.8	0.2	1.7
	SP12-02D	Clinopyroxene	52.0	2.4	10.0	-	14.8	19.3	0.5	0.0	0.6	-	-
	SP12-02D	Orthopyroxene	53.6	1.1	20.5	-	23.1	1.3	0.0	0.0	0.2	-	-
	SP12-02E	Bulk rock	61.4	15.2	5.4	0.07	2.2	4.6	3.9	3.0	0.8	0.2	2.0
	SP12-02E	Clinopyroxene	53.0	1.9	8.8	-	14.8	20.3	0.4	0.0	0.4	-	-
	SP12-02F	Bulk rock	63.8	14.8	5.2	0.08	2.1	4.2	3.7	2.9	0.7	0.2	1.7
	SP12-02F	Clinopyroxene	52.7	2.0	9.9	-	14.3	20.0	0.5	0.0	0.4	-	-
	SP12-02F	Orthopyroxene	54.1	0.8	19.4	-	23.4	1.1	0.0	0.0	0.3	-	-

Table 3 .

 3 Trace element composition of lava and pyroxene phenocrystsMajor and trace elements in lava (bulk rock) were measured by ICP-OES and ICP-MS, respectively, in aliquots of ca. 1 g. Major element concentrations in phenocrysts represent mean values that were determined by electron-microprobe on 10-15 grains per sample. Absolute standard deviations associated with mean values are <1% in mass (1σ).

	MnO and P2O5 analyses in phenocrysts were substituted by NiO and Cr2O3 (values are shown as traces and represent <0.2 % in mass of
	the total pyroxene composition)
	Trace element concentrations in phenocrysts represent mean values that were determined by Laser ICP-MS on ca. 15 grains per
	samples. Relative standard deviations (1σ) represent ca. <15% (Li), 40% (B, Gd and Sm) and >50% (U and Th).

Table 4 .

 4 Summary of the SP12-02A 40 Ar-39 step heating experiment.

	Incremental	40 Ar/ 39 Ar	37 Ar/ 39 Ar	36 Ar/ 39 Ar	40 Ar	K/Ca	39 Ar	Age ± 1σ
	heating				(%)		(%)	(ka)
	#1	0.1547	0.1727	0.0381	1.36	2.49	9.87	98.9±24.9
	#2	0.1708	0.1384	0.0587	0.98	3.11	19.14	109.2±39.8
	#3	0.1476	0.2527	0.0507	0.98	1.70	7.50	94.3±35.6
	#4	0.1805	0.1416	0.0407	1.48	3.04	22.30	115.4±23.8
	#5	0.1873	0.3236	0.0529	1.18	1.33	10.31	119.8±40.1
	#6	0.1765	0.2447	0.0580	1.02	1.76	14.77	112.8±37.5
	#7	0.1752	0.4887	0.0904	0.65	0.88	5.70	112.0±73.5
	#8	0.1587	0.3469	0.0509	1.04	1.24	10.40	101.5±30.3
	Total fusion	0.1712	0.2275	0.1042		1.89		109.4±13.2
	Plateau	0.1674				1.40		107.0±11.6

Table 6 .

 6 3 Hec concentrations scaled to the surface, an open-sky topography and 21.934°S-68.510°W and 3390 m a.s.l. and the age of the lava based on the 40 Ar/ 39 Ar dating. Bracketed values correspond to external errors (1σ) and include the ca. 3% uncertainty on 3 Hec concentrations and 11% on the 40 Ar/ 39 Ar inferred age of the lava. SLHL 3 He production rates from the San Pedro calibration site

	Scaling scheme a	Atmosphere model b	Geomagnetic reconstruction c	SLHL P3 (at.g -1 .yr -1 ) d
	"St"	Standard ERA-40 (1)	--	132±14 143±16
			Musheler-SINT2000	120±13
		Standard	GLOPIS75-SINT2000	118±13
	"Lm"		LSD Musheler-SINT2000 (2)	109±12 130±14
		ERA-40	GLOPIS75-SINT2000 (3)	128±14
			LSD (4)	118±14
			Musheler-SINT2000	116±13
		Standard	GLOPIS75-SINT2000	113±12
	"LSD"		LSD Musheler-SINT2000 (5)	103±11 127±14
		ERA-40	GLOPIS75-SINT2000 (6)	124±14
			LSD (7)	112±12

Acknowledgments

This project received financial supports by the Swiss National Science Foundation awarded to Schlunegger (grant No. 137516). We thank Christine Lemp, Martin Robyr and Thomas Pettke for their support during sample preparation and geochemical analyses. We thank David L. Shuster for his careful editorial handling, as well as Will Amidon and an anonymous reviewer who provided constructive comments on the submitted manuscript.


Idbaih Pr

MD Ahmed

Seyve Antoine

Idbaih Ahmed
email: ahmed.idbaih@aphp.fr

Lozano-Sanchez Fernando

Thomas Alice

Mathon Bertrand

Tran Suzanne

Mokhtari Karima

Giry Marine

Marie Yannick

Capelle Laurent

Peyre Matthieu

Carpentier Alexandre

Feuvret Loic

Sanson Marc

Hoang-Xuan Khé

Delattre Honnorat Jérome

Jean-Yves Ducray

François Project

Ducray François

Keywords: IDH wild-type, overall survival, progression-free survival, recurrent glioblastoma, reoperation

6 Highlights  IDH-wildtype glioblastoma is the most common and aggressive primary brain cancer in adults.

 At tumor recurrence, treatment decision-making is not standardized with several option including second surgery, reirradiation and/or second line of chemotherapy.

 We conducted a retrospective monocentric study to analyzed the clinical benefit of second surgery at recurrence and the prognostic factors in resected recurrent glioblastoma patients in a well-defined patient population at the era of WHO 2016 classification.



We enrolled 229 IDH-wildtype newly glioblastoma patients meeting the inclusion criteria.

 25% of patients were reoperated and these patients had longer post-progression median overall survival compared to their non-reoperated couterparts (14 versus 9 months, p < .05).

 Initial surgical resection and long time to first recurrence from initial diagnosis were independent prognostic factors of good outcome in resected recurrent IDH-wildtype glioblastoma patients while tumor size before and after surgery does not impact post-surgical survival.

 Further prospective and larger studies are warranted to validate our findings.

Abstract

Objective IDH-wildtype glioblastoma is the most common and aggressive primary brain cancer in adults. At tumor recurrence, treatment decision-making is not standardized with several options including second surgery, reirradiation and/or second line of chemotherapy. In this retrospective monocentric study conducted at the era of WHO 2016 classification, we investigated in IDH-wildtype glioblastoma patients, aged below 70, in good clinical conditions and treated according to first line SOC: (i) the clinical benefit of second surgery at recurrence and (ii) the prognostic factors in resected recurrent glioblastoma patients.

Methods

229 IDH-wildtype newly diagnosed glioblastoma patients aged below 70, treated with the SOC, were enrolled in the current study and stratified into two subgroups according to treatment at recurrence: re-resection and no re-resection groups.

Results

All experienced tumor recurrence with a median progression free survival of 11 months. 25% of patients were reoperated. Patients reoperated at recurrence had longer post-progression median overall survival compared to their non-reoperated counterparts (14 versus 9 months, p < .05). Initial surgical resection and long time to first recurrence from initial diagnosis were independent prognostic factors of good outcome in resected recurrent IDH-wildtype glioblastoma patients while tumor size before and after surgery does not impact post-surgical survival.

Conclusion

Our study supports surgical resection at recurrence as one therapeutic in IDH-wildtype glioblastoma patients aged below 70 and in good clinical conditions, regardless preoperative tumor size; particularly in patients with longer time to first recurrence and surgery at initial diagnosis. Further prospective and larger studies are warranted to validate our findings.

Introduction

Glioblastoma exhibiting Isocitrate DeHydrogenase wildtype (IDH-wildtype) status is the most common and the most aggressive primary malignancy of central nervous system (CNS) in adults. The incidence rate is estimated to approximately 3 new cases per year per 100 000 population 1 2 .

Since 2005, the standard of care (SOC) of newly diagnosed glioblastoma patients includes maximal safe surgical resection followed by external beam radiotherapy with concomitant and adjuvant temozolomide-based chemotherapy [START_REF] Weller | EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma[END_REF] . Despite this intensive therapeutic regimen, the median overall survival remains below 18 months [START_REF] Stupp | Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial[END_REF][START_REF] Nava | Survival effect of first-and second-line treatments for patients with primary glioblastoma: a cohort study from a prospective registry, 1997-2010[END_REF] .

Virtually all glioblastoma patients experience tumor recurrence after the first-line SOC treatment. At first tumor recurrence, treatment options are not standardized and limited 6 : reresection, reirradiation and second line of chemotherapy including Lomustine or Lomustine plus Bevacizumab [START_REF] Wick | Lomustine and Bevacizumab in Progressive Glioblastoma[END_REF] .

At initial diagnosis, many studies have shown the positive impact of surgical resection on overall survival and progression-free survival [START_REF] Kreth | Gross total but not incomplete resection of glioblastoma prolongs survival in the era of radiochemotherapy[END_REF][START_REF] Stummer | Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias[END_REF][START_REF] Senft | Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial[END_REF] . However, its benefit in terms of survival is matter of controversies with patients exposed to surgical morbimortality [START_REF] Sl | Reoperation for recurrent high-grade glioma: a current perspective of the literature[END_REF][START_REF] Oppenlander | An extent of resection threshold for recurrent glioblastoma and its risk for neurological morbidity[END_REF][START_REF] Zhao | A Meta-Analysis of Survival Outcomes Following Reoperation in Recurrent Glioblastoma: Time to Consider the Timing of Reoperation[END_REF] . Mortality after first resection is estimated at 36.2 for 1000 cases [START_REF] De La Garza-Ramos | Surgical complications following malignant brain tumor surgery: An analysis of 2002-2011 data[END_REF] ; the morbimortality after reoperation at recurrence is not well established but is higher than at initial diagnosis [START_REF] Oppenlander | An extent of resection threshold for recurrent glioblastoma and its risk for neurological morbidity[END_REF] . Extent of resection (EOR) and Karnofsky performance status (KPS) at recurrence have been shown as the most important prognostic factors in recurrent glioblastoma patients [START_REF] Oppenlander | An extent of resection threshold for recurrent glioblastoma and its risk for neurological morbidity[END_REF][START_REF] Bloch | Impact of extent of resection for recurrent glioblastoma on overall survival: clinical article[END_REF][START_REF] Ringel | Clinical benefit from resection of recurrent glioblastomas: results of a multicenter study including 503 patients with recurrent glioblastomas undergoing surgical resection[END_REF][START_REF] Woodroffe | Survival after reoperation for recurrent glioblastoma[END_REF] . In 2010, Park and al. had proposed a preoperative scale including poor prognostic factors in recurrent glioblastoma patients : involvement of eloquent or critical brain areas, low KPS (≤ 80%) and tumor volume ≥ 50 cm [START_REF] Weller | EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma[END_REF][START_REF] Park | Scale to predict survival after surgery for recurrent glioblastoma multiforme[END_REF] .

The aim of this retrospective study was to interrogate the impact of second surgical resection and to identify prognostic factors in an homogeneous group of recurrent glioblastoma patients, aged below 70 years, in good clinical conditions (i.e. KPS ≥ 70% at initial diagnosis and recurrence) and, treated according the SOC first line treatment, at the era of the 2016 World Health Organization classification of primary brain tumors [START_REF] Louis | The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary[END_REF] .

Methods

Patients and tumors

We retrospectively reviewed all patients diagnosed and treated for IDH-wildtype newly diagnosed glioblastoma at our institution between 2005 and 2018. The neuropathological diagnosis was performed according to World Health Organization 2016 criteria.

Our study was based on concurrent eligibility criteria at initial diagnosis of glioblastoma and at first recurrence.

At initial diagnosis inclusion criteria were: (i) age ≥ 18 years, (ii) KPS ≥ 70%, (iii) IDH-wildtype glioblastoma, (iv) treatment with the SOC and, (v) available follow-up data. At first recurrence: (i) KPS ≥ 70%, (ii) available follow-up data.

For each patient, the following parameters were recorded at initial diagnosis: (i) gender, (ii) age, (iii) tumor lateralization (right, left or bilateral), (iv) date of initial surgery, (v) EOR according to the post-operative reportgross total resection of contrast enhancement, GTR, subtotal resection, STR, biopsy-and, (vi) KPS. The following parameters were recorded for first recurrence: (i) date second surgery, (ii) tumor lateralization (right, left or bilateral) and tumor site, (iii) KPS. For the second surgery, we collected: (i) date of surgery, (ii) EOR (GTR or STR according to the post-operative report), (iii) tumor size on both contrast T1-weighted images and on T2-weighted Fluid Attenuated Inversion Recovery images on MRI before and after second surgery according to RANO criteria (product of maximal diameter and maximal perpendicular diameter) and, (iv) pathological examination.

Progression free survival was defined between initial surgery and first tumor recurrence (PFS1) and between the date of first progression and the date of second progression (PFS2). Overall survival was calculated from date of initial surgery and last follow-up or death (OS1) and post-progression overall survival between the date of first recurrence and the date of last follow up or death (OS2).

Written consent obtained from the patients for data collection and molecular analysis. Tumor tissue was stored in the certified OncoNeuroTek tumor tissue bank linked to a clinical database. The IDH1 Arg132His (IDH1R132H) mutation was investigated by immunohistochemistry on paraffin (paraffin-embedded tissue sections or FFPE) [START_REF] Sanson | Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas[END_REF] . For patients under 55 years of age with negative IDH1R132H immunohistochemistry, the mutational status of IDH1 and IDH2 was determined by Sanger technique as previously described [START_REF] Louis | The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary[END_REF] . Promoter methylation status of O6methylguanine DNA-methyltransferase gene (MGMT) was determined on DNA from FFPE tumor samples using methylation-specific polymerase chain reaction, as previously described [START_REF] Everhard | MGMT methylation: a marker of response to temozolomide in lowgrade gliomas[END_REF] .

Statistical analysis

Statistical analyses were performed using SPSS 23.0. Categorical variables were presented as frequencies and percentages, and continuous variables as medians and range. To evaluate the normality of the quantitative data distributions, the Kolmogorov-Smirnov was performed. Assessment of the qualitative variables was performed using chi-square test or Fischer exact test. For the quantitative variables, t-test or Wilcoxon test (two-tailed) was used.

Patients lost to follow-up were censored for survival at the last date of follow-up. We used a Kaplan-Meier method to estimate overall survival and progression free-survival and log-rank tests for comparisons of subgroups. For multivariate analyses, we used a Cox proportional hazard ratio model. Variables with p-value<0.2 in univariate analysis were included as covariates in the multivariate analysis. All statistical tests were 2-sided with a significance level of 0.05.

Results

Patients population and tumors at initial diagnosis

229 patients met the inclusion criteria at both time points of the disease. The characteristics of patients and tumors are reported in Table 1. The median age at first surgery was 56 years (range 24-70). 146 were male (64%) and 83

were female (36%). All patients had KPS ≥ 70%. The first surgery was GTR in 62 patients (27%), STR in 133 patients (58%) and biopsy was performed in 34 patients (15%). 120 (52%) had a tumor in the left hemisphere, 107 (47%) in the right hemisphere and 2 (1%) in both hemispheres. All the patients had an IDH-wildtype glioblastoma.

MGMT promoter status was available in 119 patients (52%) including 47% MGMT-methylated glioblastoma patients. After initial surgery, all the patients were treated with the first line SOC. Of these 229 patients, all relapsed.

The median PFS and OS from initial diagnosis (i.e. PFS1 and OS1) were 11 and 27 months respectively (Table 1).

Patients with MGMT methylated tumor had a better outcome compared to their unmethylated counterparts for OS1 and OS2 (41 vs. 23 months, p < .05; 14 vs. 11 months, p <.05, respectively).

Patients population and tumors at first recurrence

At first relapse, median age of patients was 57 years (range 24-75). KPS was above 70% in all patients in line with inclusion criteria. The recurrence was in tumor initial site in all patients. 60 (26%) underwent a second surgery (re-resection group) and 169 (74%) were treated with second medical treatment (no re-resection group). Age, gender, KPS, tumor lateralization and location were well-balanced between both groups (i.e. re-resection versus no re-resection). In the re-resection group, a limited number of patients underwent a biopsy at initial diagnosis (10 vs. 17%, p < 0.05). The median PFS1 was similar in each group (11 vs. 11 months, p = 0.9).

In the re-resection group, 15 (25%) had gross GTR and 45 (75%) STR. Before surgery, the median tumor size on contrast-T1 MRI and FLAIR-MRI were 38 and 62 mm2 respectively. After surgery, the median tumor size on contrast-T1 MRI and FLAIR-MRI were 23 and 71 mm2 respectively. Neuropathological examination showed 58 IDH-wildtype glioblastomas and 2 gliosarcomas. MGMT status at recurrence was available for 10 patients only with 5 methylated and 5 unmethylated MGMT glioblastoma. Chemotherapy was the main adjuvant treatment used in each group.

Clinical impact of re-resection

In univariate analysis, OS1 were 29 and 25 months in the re-resection and the no re-resection group, respectively.

Although a trend is observed, no significant statistical difference was observed (p = 0.3). The survival rates at 2 years after diagnosis were 48% and 39% in the re-resection and the no re-resection group, respectively (p = 0.2).

Post-progression median overall survival or median overall survival after first recurrence (OS2) was significantly longer in the re-resection group patients, 14 months vs 9 months in no re-resection group (p < 0.05).

The median time between first and second recurrences (PFS2) was longer in the re-resection group than in the nonreresection group (6 vs. 4 months respectively, p-value = 0.002).

Prognostic factors in resected recurrent glioblastoma patients

Multivariate analysis identified biopsy at initial diagnosis and short PFS1 as independent poor prognostic factors for OS2 in the reresected group (p<.05) (Table 2). In contrast, gender, age at recurrence, KPS at diagnosis and KPS at recurrence, tumor size on both contast-T1 and FLAIR weighted MRI before and after reresection did not add independent prognostic information for OS2 (Table 2).

Discussion

Our retrospective study included a homogeneous cohort of glioblastoma patients in good performance status and initially treated with the SOC first line treatment. Indeed, all patients fulfilled the selection criteria of the phase III clinical trial that has established the SOC [START_REF] Stupp | Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma[END_REF] . In addition, pathological diagnosis was established according to the last classification of primary brain tumors published by the WHO and requiring IDH status for most glioblastoma patients [START_REF] Louis | The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary[END_REF] .

As expected and demonstrated in multiple studies, in our population, MGMT promoter methylation is associated with better prognosis for both OS1 and OS2. The number of patients analyzed for MGMT status is limited in our study and does not allow robust statistical analysis in the subgroup of patients (i.e. reoperated and non-reoperated at recurrence).

The prognosis of patients with newly diagnosed IDH-wildtype glioblastoma remains poor. The median OS1 is 14 months and the median OS2 is 5.8 to 8.1 months in literature [START_REF] Weller | Standards of care for treatment of recurrent glioblastoma--are we there yet?[END_REF] . Second line of treatment after first tumor progression is not standardized. Chemotherapies such as alkylating agents [START_REF] Song | Effectiveness of lomustine and bevacizumab in progressive glioblastoma: a meta-analysis[END_REF] and platinum-derivative agents [START_REF] Field | Randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma[END_REF] have limited efficacy on PFS and OS. Bevacizumab, an anti-angiogenic agent, has shown an effect on PFS but not on OS in recurrent glioblastoma patients [START_REF] Wick | Lomustine and Bevacizumab in Progressive Glioblastoma[END_REF][START_REF] Song | Effectiveness of lomustine and bevacizumab in progressive glioblastoma: a meta-analysis[END_REF] . Many trials are underway to develop new therapies for recurrence, including immunotherapies [START_REF] Filley | Recurrent glioma clinical trial, CheckMate-143: the game is not over yet[END_REF] and molecular targeted therapies [START_REF] Lombardi | Regorafenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial[END_REF][START_REF] Weller | Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial[END_REF] . The role of surgery in first recurrence glioblastoma patients is debated. Many studies are retrospective and the results remain conflicting with some studies showing a benefit on survival while others were negative [START_REF] Nava | Survival effect of first-and second-line treatments for patients with primary glioblastoma: a cohort study from a prospective registry, 1997-2010[END_REF][START_REF] Oppenlander | An extent of resection threshold for recurrent glioblastoma and its risk for neurological morbidity[END_REF][START_REF] Ringel | Clinical benefit from resection of recurrent glioblastomas: results of a multicenter study including 503 patients with recurrent glioblastomas undergoing surgical resection[END_REF][START_REF] Franceschi | The effect of re-operation on survival in patients with recurrent glioblastoma[END_REF][START_REF] Ening | Repeat-surgery at Glioblastoma recurrence, when and why to operate?[END_REF][START_REF] Sastry | The impact of surgery on survival after progression of glioblastoma: A retrospective cohort analysis of a contemporary patient population[END_REF][START_REF] Helseth | Overall survival, prognostic factors, and repeated surgery in a consecutive series of 516 patients with glioblastoma multiforme[END_REF][START_REF] Van Linde | Treatment outcome of patients with recurrent glioblastoma multiforme: a retrospective multicenter analysis[END_REF] . Meta-analyses have been conducted and pinpoint a trend towards increased overall survival in young patients with good performance status and long time to first recurrence [START_REF] Montemurro | Second surgery for recurrent glioblastoma: A concise overview of the current literature[END_REF][START_REF] Lu | Survival Benefit of Maximal Resection for Glioblastoma Reoperation in the Temozolomide Era: A Meta-Analysis[END_REF][START_REF] Lu | The Survival Effect of Repeat Surgery at Glioblastoma Recurrence and its Trend: A Systematic Review and Meta-Analysis[END_REF] . The most robust factor for increased survival after re-operation in recurrent glioblastoma patients is EOR at diagnosis and at recurrence [START_REF] Bloch | Impact of extent of resection for recurrent glioblastoma on overall survival: clinical article[END_REF][START_REF] Perrini | Survival outcomes following repeat surgery for recurrent glioblastoma: a single-center retrospective analysis[END_REF][START_REF] Suchorska | Complete resection of contrast-enhancing tumor volume is associated with improved survival in recurrent glioblastoma-results from the DIRECTOR trial[END_REF] .

In the literature, about 20-30% of glioblastoma patients are eligible for second surgery at tumor recurrence [START_REF] Weller | EANO guideline for the diagnosis and treatment of anaplastic gliomas and glioblastoma[END_REF] . Our data are in line with these data in a patient population with a good clinical condition. Indeed, 25% of our patients were reoperated at first recurrence.

Although reoperation has been shown to relieve neurological symptoms related to tumor first recurrence in glioblastoma patients [START_REF] Wann | Outcomes after second surgery for recurrent glioblastoma: a retrospective case-control study[END_REF][START_REF] Easaw | Canadian recommendations for the treatment of recurrent or progressive glioblastoma multiforme[END_REF] , its impact on survival benefit has been poorly documented. In our study, post-progression progression free survival (PFS2) and overall survival (OS2) were increased in patients who undergone second surgery at first recurrence (6 vs 4 months for PFS2 and 14 vs. 9 months for OS2, p < 0.05).

Among reoperated patients, the multivariate analysis showed two independent prognostic factors associated with outcome: EOR at diagnosis and PFS1. Indeed, first surgical resection and longer PFS1 are associated with longer PFS2 and OS2 in reoperated glioblastoma patients. Tumor size on both contast-T1 and FLAIR weighted MRI before and after reresection do not appear as a prognostic factor (Table 2).

There are no guidelines for surgical indications at first recurrence in glioblastoma patients. Our study assessing the clinical impact of surgical resection in recurrent glioblastoma patients is the first including the diagnostic criteria of the integrated classification of primary brain tumor published by the WHO in 2016 (i.e. IDH status) [START_REF] Louis | The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary[END_REF] . Our study is in line with the literature for: (i) proportion of glioblastoma patients reoperated at recurrence, (ii) prognostic value of MGMT promoter methylation in newly diagnosed glioblastoma patients and, (iii) clinical benefit of surgical

Table 2 . Prognostic analysis in reresected recurrent glioblastoma

 2

	Variable	Categories	n	14-months OS2 (%)	P-value HR [CI 95%] P-value2
	Gender	Male Female	43 17	33 35	.88
	Age	≤50 >50	16 44	31 34	.83
	Primary surgery	Biopsy STR GTR	6 27 27	0 33 41	.16	3.492 [1.115-10.936]	< .05
	PFS1	>11 months ≤11 months	29 31	48 19	.02	.965 [.035-.997]	< .05
	KPS at first	70-80%	37	27	.22
	recurrence	90-100%	23	44
	Tumor	Left Hemisph.	35	34	.85
	lateralization	Right Hemisph.	25	32
		Parietal lobe	8	25	.38
	Tumor	Frontal lobe	11	36
	location	Occipital lobe	10	40
		Temporal lobe	17	47
	Tumor size	≤38mm2	19	47	.27
	on contrast-		17	29
	T1 MRI before re-	>38mm2
	resection
	Tumor size	≤23mm2	21	38	.85
	on contrast-		17	35
	T1 MRI after	>23mm2
	re-resection
	Tumor size	≤62mm2	16	44	.46
	on FLAIR		16	31
	MRI before	>62mm2
	re-resection
	Tumor size	≤71mm2	20	40	.58
	on FLAIR		19	32
	MRI after re-	>71mm2
	resection
	MGMT	Methylated	23	39	.82
	status	Unmethylated	25	36
	Surgery at	STR	45	31	.52
	recurrence	GTR	15	40
	Adjuvant	CT	48	29	.31
	oncologic	Reirradiation + CT	3	67
	treatment	No adjuvant treatment 9	44

resection at recurrence. Interestingly, our study suggests that patients with surgical resection (i.e. STR or GTR) at initial diagnosis and long PFS1 (i.e ≥ 11 months) would get greater clinical benefit from a new surgical procedure at recurrence. Indeed, both criteria have independent positive prognostic value in reoperated patients. Surgery at recurrence therefore has multiple interests: to facilitate a new anatomopathological examination to explore targeted therapies or radiosurgery, to improve symptoms and to be a treatment option for a better survival of the patients.However, our study has the limitations of retrospective studies. The definition of EOR at diagnosis and recurrence was specified in the post-operative report only. MGMT status at recurrence was available for few patients and could not be tested in univariate. Further prospective studies are warranted to interrogate our findings.

The research leading to these results has received funding from the program Investissements d'avenir" ANR-10-IAIHU-06.

Institut Universitaire de Cancérologie INCA-DGOS-Inserm_12560 SiRIC CURAMUS is financially supported by the French National Cancer Institute, the French Ministry of Solidarity and Health and Inserm.

Availability of data and material

Not applicable

Code availability

Not applicable

Conflict of interest: None

Disclosure of funding:

Declarations

Funding:

The research leading to these results has received funding from the program Investissements d'avenir" ANR-10-IAIHU-06.