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Introduction Atezolizumab, an anti-programmed death-ligand 1 (PD-L1) antibody, inhibits PD-L1:PD-1 and PD-L1:B7.1 interactions, restoring anticancer immunity. Here, we report final analyses from the non-small-cell lung cancer (NSCLC) cohort of the first atezolizumab phase I study. Methods Patients with NSCLC received atezolizumab 1–20 mg/kg or 1200 mg intravenously every 3 weeks. Baseline PD-L1 expression on tumour cells (TCs) and tumour-infiltrating immune cells (ICs) was assessed (VENTANA SP142 immunohistochemistry assay). Exploratory subgroup analyses investigated responses by baseline PD-L1 expression and oncogenic mutational status. Results Eighty-nine patients, 98% of whom had received previous systemic therapy, were evaluable for safety and antitumour activity. Atezolizumab was well tolerated, with grade III/IV treatment-related adverse events (TRAEs) observed in 10 patients (11%). All-grade TRAEs occurring in >10% of patients were fatigue, nausea and decreased appetite; grade III/IV TRAEs occurring in >2% of patients were fatigue, dyspnoea, hyponatremia and hypoxia. One patient died from treatment-unrelated pneumonia. Objective response rate (ORR) was 50% (95% confidence interval [CI], 28%–72%), 33% (20%–48%), 29% (18%–41%) and 11% (1%–35%) for the TC3 or IC3, TC2/3 or IC2/3, TC1/2/3 or IC1/2/3 and TC0 and IC0 subgroups, respectively. All-patient ORR was 23% (95% CI, 14%–33%). Median duration of response was 16.4 months (range, 7.2–53.4+). One-, 2-, and 3-year survival rates were 63% (95% CI, 53%–73%), 37% (26%–47%) and 28% (18%–38%), respectively. Conclusions Single-agent atezolizumab was well tolerated with long-term clinical benefits, including durable responses and survival, in pretreated NSCLC. Improved responses and survival rates were seen with increasing baseline PD-L1 expression. ClinicalTrials.gov identifier NCT01375842 .

Background Programmed death-ligand 1 (PD-L1) protein is expressed in various cancers, including small-cell lung cancer (SCLC). Atezolizumab inhibits PD-L1 signaling, thus restoring tumor-specific T-cell immunity. Here, we report results from the first-in-human phase 1 PCD4989g study ( NCT01375842 ) of atezolizumab, in a cohort of patients with relapsed/refractory SCLC. Patients and Methods Eligible patients with incurable or metastatic SCLC, which was advanced or recurrent since the last antitumor therapy, received atezolizumab 15 mg/kg or 1200 mg intravenously every 3 weeks for 16 cycles or until loss of clinical benefit. The primary endpoint was safety. Efficacy and biomarkers of antitumor activity were also assessed. Results Seventeen patients were enrolled. Any-grade and grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 (64.7%) and 5 (29.4%) patients, respectively. The most common any-grade TRAE was fatigue (4 patients [23.5%]). Partial response to atezolizumab was achieved in 1 patient (5.9%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and 3 (17.6%) per immune-related response criteria (irRC). Durations of response were 2.8 to > 45.7 months. Median investigator-assessed progression-free survival (PFS) per RECIST v1.1 and irRC was 1.5 (95% confidence interval [CI], 1.2-2.7) and 2.9 (95% CI, 1.2-6.1) months, respectively. Median overall survival (OS) was 5.9 months (95% CI, 4.3-12.6). Patients with high (≥ median expression) T-effector gene signature and PD-L1 mRNA expression appeared to show a trend toward improved PFS (per irRC) and OS. Conclusion Atezolizumab was generally well tolerated and exhibited antitumor activity in a small cohort of patients with relapsed/refractory SCLC.

Radiocarbon and U-series methods ( 230 Th/U and 231 Pa/ 235 U) for absolute age determination have been applied to some fossil samples from Grotta Juntu, in North Eastern Sardinia (Italy). The remains belong to the endemic deer species Praemegaceros cazioti , which is here represented by an almost complete skeleton. The three dating methods lead to concordant ages of about 7500 years BP, indicating that the skeleton was maintained as closed system after burial. Taking into consideration these results, Praemegaceros cazioti from Grotta Juntu is now the youngest representative of this species in Sardinia.

The FLUKA Monte Carlo transport code is widely used for fundamental research, radioprotection and dosimetry, hybrid nuclear energy system and cosmic ray calculations. The validity of its physical models has been benchmarked against a variety of experimental data over a wide range of energies, ranging from accelerator data to cosmic ray showers in the earth atmosphere. The code is presently undergoing several developments in order to better fit the needs of space applications. The generation of particle spectra according to up-to-date cosmic ray data as well as the effect of the solar and geomagnetic modulation have been implemented and already successfully applied to a variety of problems. The implementation of suitable models for heavy ion nuclear interactions has reached an operational stage. At medium/high energy FLUKA is using the DPMJET model. The major task of incorporating heavy ion interactions from a few GeV/n down to the threshold for inelastic collisions is also progressing and promising results have been obtained using a modified version of the RQMD-2.4 code. This interim solution is now fully operational, while waiting for the development of new models based on the FLUKA hadron-nucleus interaction code, a newly developed QMD code, and the implementation of the Boltzmann master equation theory for low energy ion interactions. c2004 COSPAR. Published by Elsevier Ltd. All rights reserved.

We compare several different second-order splitting algorithms for the asymmetric rigid body, with the aim of determining which one produces the smallest energy error for a given rigid body, namely, for given moments of inertia. The investigation is based on the analysis of the dominant term of the modified Hamiltonian and indicates that different algorithms can produce energy errors which differ by several orders of magnitude. As a byproduct of this analysis we remark that, for the special case of a flat rigid body with moments of inertia proportional to (1, 0.75, 0.25), one of the considered algorithms is in fact of order four.

Samples of soil, water, aluminum, copper and iron were irradiated in the stray radiation field generated by the interaction of a 28.5 GeV electron beam in a copper-dump in the Beam Dump East facility at the Stanford Linear Accelerator Center. The specific activity induced in the samples was measured by gamma spectroscopy and other techniques. In addition, the isotope production in the samples was calculated with detailed Monte Carlo simulations using the F luka code. The calculated activities are compared to the experimental values and differences are discussed.

Double differential distributions of neutrons produced by 100, 150, 200, 250 and 400 MeV protons stopped in thick iron and soft tissue targets were calculated by two Monte Carlo codes, FLUKA and LCS, from 0 (forward shielding) to 180°. The results are compared with calculated and experimental data available in the literature. The attenuation in ordinary concrete of the dose equivalent due to neutrons and other particles was calculated. The contribution due to photons and protons was found to range from a few percent up to 50% of the total dose equivalent. Source terms and attenuation lengths are given as a function of energy and emission angle.

The Advanced Photon Source (APS) currently under construction at Argonne National Laboratory will be one of the world's brightest synchrotron radiation (SR) facilities. The storage ring, capable of storing currents up to 300 mA at 7.0 GeV, or 200 mA at 7.5 GeV, will produce very intense and energetic synchrotron radiation (Ec = 24 keV for bending magnets, and Ec = 37.4 keV for wigglers, where Ec is the critical energy). The synchrotron radiation beam lines, consisting of experimental enclosures and transport lines, will have to be shielded against synchrotron radiation and gas bremsstrahlung scattered from beam line components. For insertion devices placed in the straight sections (length = 15 m), the gas bremsstrahlung produced by the interaction of the primary stored beam with residual gas molecules or ions in the storage ring vacuum chamber dominates the SR beam line shielding. Gas bremsstrahlung in the forward direction will be stopped by a tungsten beam stop, 18cm thick, located at the back of the experimental enclosure and placed in the median plane of the storage ring. The forward-directed gas bremsstrahlung is characterized, and the effectiveness of the tungsten beam stop is assessed. The Monte Carlo code FLUKA was used to determine the dose equivalent rates from gas bremsstrahlung in a cylindrical tissue phantom with and without the tungsten beam stop. Simulations were performed using an air target of length 15 m at a pressure of 1 atm and 1 10 atm (1 atm = 101.325 kPa = 760 torr) both with and without suppressing positron multiple scattering (M.S.) and Bhabha and Moller scattering in the air target. At a given pressure the dose equivalent rates are higher without positron multiple scattering in the air target than with multiple scattering. For simulations at Ps = 1 atm, the minimization of Bhabha/Moller scattering is important for areas with scoring radii less than 0.4 cm. The maximum dose equivalent rate (for E0 = 7 Gev, I = 300 mA, and P = 0.133 μPa or 10−9 torr) in the phantom (at a depth of 29.5 cm) for a scoring area of 0.0013 cm2 (radius = 0.02 cm) is 2.1 Sv/h, whereas for a scoring area of 0.5 cm2 (radius = 0.4 cm) it is 0.57 Sv/h. Scoring photon fluence and converting it to dose equivalent using Rogers' fluence-to-dose equivalent conversion factors results in an overestimation of dose equivalent. The maximum dose equivalent rate behind the tungsten beam stop, at a depth of 2.5 cm in the tissue, is 0.1 + 0.04 μSv/h for a scoring radius of 1 cm. The corresponding dose equivalent rates without the stop are 32 mSv/h (depth = 2.5 cm) and 0.17 Sv/h (depth = 29.5 cm). A simple expression has been derived for the upper limit on the dose equivalent that an individual can receive due to loss of vacuum in the straight section.

An electron-positron collider (LEP) has recently been put into operation at CERN. Two 46 GeV beams circulate around the 27 km accelerator ring and these produce intense synchrotron radiation with photon energies up to more than 1 MeV. A lead shiedl 8 mm thick has been provided in most places around the vacuum chamber to minimize radiation damage to sensitive machine components. Monte-Carlo techniques using a modified version of MORSE have been used to estimate dose-rate levels in the tunnel due to radiation escaping from the vacuum pipe and scattered by magnets and the tunnel walls. The results have been confirmed by dosimetry measurements.

Aim: PD-L1, which can mediate cancer immune evasion, is broadly expressed in RCC. As RCC can respond to immune-based therapy, blocking PD-L1 represents a strategy to restore tumor-specific T-cell immunity. MPDL3280A, a human mAb containing an engineered Fc-domain, targets PD-L1 to prevent binding to its receptors PD-1 and B7.1 on activated T cells. Interim results showed that MPDL3280A had a manageable safety profile and clinical activity in advanced NSCLC, melanoma and mRCC pts. Here, we report long term follow up and correlative data for the RCC cohort. Methods: mRCC pts were enrolled in a Ph I expansion study. All pts who received MPDL3280A IV q3w at doses of 3-20 mg/kg were evaluable for safety. Pts were treated for ≤ 1 y. Response was assessed by RECIST v1.1. PD-L1 IHC was centrally assessed in tumor biopsies. Results: As of Jan 1, 2014, among 69 mRCC pts evaluable for safety, median age was 61 y and all were ECOG PS 0-1 (48% PS 1). 94% of pts had prior nephrectomy and 87% received prior systemic therapy, including cytokines (39%), VEGF-inhibition (64%) and mTOR inhibitors (26%). Pts received MPDL3280A for a median duration of 7.7 m (0.7-24.3 m). 80% of pts had a treatment-related AE; however, the frequency of G3 related events was 16%, including anemia, dehydration, fatigue and hypophosphatemia (3% each). No related G4 AEs or deaths occurred. Clinical activity was evaluated in 58 pts with clear cell histology dosed prior to Jul 1, 2013; 51 pts (88%) had an evaluable baseline PD-L1 IHC status. The ORR was 14% (8/58 PRs, 95% CI: 6, 25) and the median duration of response was 54 wks (2.7+ to 68.1+ wks). The 24-wk PFS rate was 53% (95% CI: 40, 66). An association was seen between PD-L1 intensity and response to MPDL3280A. Finally, antitumor activity that included immune-related responses was observed in non-clear cell histology pts (n = 10). Updated data including biomarkers will be presented. Conclusions: MPDL3280A was well tolerated, with no treatment-related deaths. Evidence of increased activity was observed in pts with elevated PD-L1. Durable responses and prolonged SD were observed in mRCC pts, warranting further study. Disclosure: D.F. McDermott: has participated in advisory boards for Genentech, BMS and Merck; M. Sznol: has consulted for Immune Design, Merus, Lion Biotechnologies, Kyowa-Kirin, Aztra-Zeneca-Medimmune, BMS, Amgen, Medimmune, Genentech, Symphogen, Nektar, and Anaeropharma; J. Soria: has received honoraria from Genentech and Roche; M.S. Gordon: has served in an advisory/consultant role and has received research funding from Roche/Genentech; O. Hamid: has been a speaker and consultant for Genentech, and research funding has been provided by Genentech; M. Fasso, Y. Wang, J. Bruey and G. Fine: is employed by Genentech. All other authors have declared no conflicts of interest.