Pathologic Complete Response in Urothelial Carcinoma Patients Receiving Neoadjuvant Immune Checkpoint Inhibitors: A Meta-Analysis

Background. Immune checkpoint inhibitors (ICIs) have been evaluated as neoadjuvant treatment in urothelial carcinoma (UC) patients, with these agents reporting encouraging pathologic complete response (pCR) rates. Herein, we performed a systematic review and meta-analysis aimed at evaluating the incidence of pCR in UC patients treated with neoadjuvant ICI. Moreover, we investigated the impact of PD-L1 expression in this patient population, exploring the possible role of PD-L1 status as predictive biomarker. Materials and Methods. We retrieved all the relevant trials through PubMed/Medline, Cochrane Library and EMBASE; moreover, proceedings of the main international oncological meetings were also searched for relevant abstracts. Eligible trials assessed pre-operative ICI in UC patients. Results. Our meta-analysis has highlighted a pooled pCR rate of 36.6% in the overall population; interestingly, pCR was higher in PD-L1 positive compared with PD-L1 negative UCs (49.5% versus 35.1%, respectively). Conclusions. Positive signals emanating from neoadjuvant immunotherapy should encourage the scientific community to persist in the long road toward finding more effective treatments for UC patients

Systemic Treatment for Metastatic Biliary Tract Cancer: State of the Art and a Glimpse to the Future

Recent years have seen some breakthroughs in the therapeutic landscape of advanced biliary tract cancer (BTC). Firstly, a better understanding of the molecular background of BTC has led to important improvements in the management of these hepatobiliary malignancies, with the advent of targeted agents representing an unprecedented paradigm shift, as witnessed by the FDA approval of pemigatinib and infigratinib for FGFR2-rearranged and ivosidenib in IDH1-mutant cholangiocarci-noma. In addition, several novel treatments are under assessment, including immune checkpoint inhibitors and combination chemotherapies. In the current review, we provide an overview of systemic treatment for metastatic BTC, summarizing recent clinical data on chemotherapy as well as the main results of targeted therapies and immunotherapy

The Impact of Concomitant Proton Pump Inhibitors on Immunotherapy Efficacy Among Patients with Urothelial Carcinoma: A Meta-Analysis

Background. Immune checkpoint inhibitors (ICIs) have recently represented a breakthrough in urothelial carcinoma (UC). Proton pump inhibitors (PPIs) are routinely used for extended time periods in UC patients, with these agents having potentially and frequently undervalued effects on ICIs efficacy. Methods. We performed a meta-analysis aimed at investigating the impact of concomitant PPI administration on progression-free survival (PFS) and overall survival (OS) among patients receiving immunotherapy for metastatic UC. Results. Two studies encompassing a total of 1015 patients were included. The pooled Hazard Ratios (HRs) for OS and PFS were 1.55 (95% CI, 1.31–1.84) and 1.43 (95% CI, 1.23–1.66), respectively, suggesting that the administration of PPIs was negatively associated with PFS and with OS in UC patients treated with ICIs. Conclusions. The current meta-analysis represents the first study to provide a systematic evaluation of the impact of concomitant PPI use in UC patients treated with ICIs. Further studies are warranted on this topic to clarify the relationship between gut microbiome, antiacid exposure, and cancer immunotherapy. In the current era of medical oncology, progress in this setting will require the collaboration of basic science and clinical research to optimize systemic treatment and to improve the outcomes of UC patients receiving ICIs

Development of a coupled dynamics code with transport theory capability and application to accelerator driven systems transients

The VARIANT-K and DIF3D-K nodal spatial kinetics computer codes have been coupled to the SAS4A and SASSYS-1 liquid metal reactor accident and systems analysis codes. SAS4A and SASSYS-1 have been extended with the addition of heavy liquid metal (Pb and Pb-Bi) thermophysical properties, heat transfer correlations, and fluid dynamics correlations. The coupling methodology and heavy liquid metal modeling additions are described. The new computer code suite has been applied to analysis of neutron source and thermal-hydraulics transients in a model of an accelerator-driven minor actinide burner design proposed in an OECD/NEA/NSC benchmark specification. Modeling assumptions and input data generation procedures are described. Results of transient analyses are reported, with emphasis on comparison of P1 and P3 variational nodal transport theory results with nodal diffusion theory results, and on significance of spatial kinetics effects

Status report on SHARP coupling framework.

This report presents the software engineering effort under way at ANL towards a comprehensive integrated computational framework (SHARP) for high fidelity simulations of sodium cooled fast reactors. The primary objective of this framework is to provide accurate and flexible analysis tools to nuclear reactor designers by simulating multiphysics phenomena happening in complex reactor geometries. Ideally, the coupling among different physics modules (such as neutronics, thermal-hydraulics, and structural mechanics) needs to be tight to preserve the accuracy achieved in each module. However, fast reactor cores in steady state mode represent a special case where weak coupling between neutronics and thermal-hydraulics is usually adequate. Our framework design allows for both options. Another requirement for SHARP framework has been to implement various coupling algorithms that are parallel and scalable to large scale since nuclear reactor core simulations are among the most memory and computationally intensive, requiring the use of leadership-class petascale platforms. This report details our progress toward achieving these goals. Specifically, we demonstrate coupling independently developed parallel codes in a manner that does not compromise performance or portability, while minimizing the impact on individual developers. This year, our focus has been on developing a lightweight and loosely coupled framework targeted at UNIC (our neutronics code) and Nek (our thermal hydraulics code). However, the framework design is not limited to just using these two codes

NUCLEAR DATA NEEDS FOR ADVANCED REACTOR SYSTEMS. A NEA NUCLEAR SCIENCE COMMITTEE INITIATIVE.

The Working Party on Evaluation Cooperation (WPEC) of the OECD Nuclear Energy Agency Nuclear Science Committee has established an International Subgroup to perform an activity in order to develop a systematic approach to define data needs for Gen-IV and, in general, for advanced reactor systems. A methodology, based on sensitivity analysis has been agreed and representative core configurations for Sodium, Gas and Lead cooled Fast Reactors (SFR, GFR, LFR) have been defined as well as a high burn-up VHTR and a high burn-up PWR. In the case of SFRs, both a TRU burner (called in fact SFR) and a core configuration with homogeneous recycling of not separated TRU (called EFR) have been considered

Dose intensity and efficacy of the combination of everolimus and exemestane (EVE/EXE) in a real-world population of hormone receptor-positive (ER+/PgR+), HER2-negative advanced breast cancer (ABC) patients: a multicenter Italian experience

Aim: This retrospective analysis focused on the effect of treatment with EVE/EXE in a real-world population outside of clinical trials. We examined the efficacy of this combination in terms of PFS and RR related to dose intensity (5 mg daily versus 10 mg daily) and tolerability. Methods: 163 HER2-negative ER+/PgR+ ABC patients, treated with EVE/EXE from May 2011 to March 2016, were included in the analysis. The primary endpoints were the correlation between the daily dose and RR and PFS, as well as an evaluation of the tolerability of the combination. Secondary endpoints were RR, PFS, and OS according to the line of treatment. Patients were classified into three different groups, each with a different dose intensity of everolimus (A, B, C). Results: RR was 29.8% (A), 27.8% (B) (p = 0.953), and not evaluable (C). PFS was 9 months (95% CI 7–11) (A), 10 months (95% CI 9–11) (B), and 5 months (95% CI 2–8) (C), p = 0.956. OS was 38 months (95% CI 24–38) (A), median not reached (B), and 13 months (95% CI 10–25) (C), p = 0.002. Adverse events were stomatitis 57.7% (11.0% grade 3–4), asthenia 46.0% (6.1% grade 3–4), hypercholesterolemia 46.0% (0.6% grade 3–4), and hyperglycemia 35.6% (5.5% grade 3–4). The main reason for discontinuation/interruption was grade 2–3 stomatitis. Conclusions: No correlation was found between dose intensity (5 vs. 10 mg labeled dose) and efficacy in terms of RR and PFS. The tolerability of the higher dose was poor in our experience, although this had no impact on efficacy

Status report on high fidelity reactor simulation.

This report presents the effort under way at Argonne National Laboratory toward a comprehensive, integrated computational tool intended mainly for the high-fidelity simulation of sodium-cooled fast reactors. The main activities carried out involved neutronics, thermal hydraulics, coupling strategies, software architecture, and high-performance computing. A new neutronics code, UNIC, is being developed. The first phase involves the application of a spherical harmonics method to a general, unstructured three-dimensional mesh. The method also has been interfaced with a method of characteristics. The spherical harmonics equations were implemented in a stand-alone code that was then used to solve several benchmark problems. For thermal hydraulics, a computational fluid dynamics code called Nek5000, developed in the Mathematics and Computer Science Division for coupled hydrodynamics and heat transfer, has been applied to a single-pin, periodic cell in the wire-wrap geometry typical of advanced burner reactors. Numerical strategies for multiphysics coupling have been considered and higher-accuracy efficient methods proposed to finely simulate coupled neutronic/thermal-hydraulic reactor transients. Initial steps have been taken in order to couple UNIC and Nek5000, and simplified problems have been defined and solved for testing. Furthermore, we have begun developing a lightweight computational framework, based in part on carefully selected open source tools, to nonobtrusively and efficiently integrate the individual physics modules into a unified simulation tool

Requirements for advanced simulation of nuclear reactor and chemicalseparation plants.

This report presents requirements for advanced simulation of nuclear reactor and chemical processing plants that are of interest to the Global Nuclear Energy Partnership (GNEP) initiative. Justification for advanced simulation and some examples of grand challenges that will benefit from it are provided. An integrated software tool that has its main components, whenever possible based on first principles, is proposed as possible future approach for dealing with the complex problems linked to the simulation of nuclear reactor and chemical processing plants. The main benefits that are associated with a better integrated simulation have been identified as: a reduction of design margins, a decrease of the number of experiments in support of the design process, a shortening of the developmental design cycle, and a better understanding of the physical phenomena and the related underlying fundamental processes. For each component of the proposed integrated software tool, background information, functional requirements, current tools and approach, and proposed future approaches have been provided. Whenever possible, current uncertainties have been quoted and existing limitations have been presented. Desired target accuracies with associated benefits to the different aspects of the nuclear reactor and chemical processing plants were also given. In many cases the possible gains associated with a better simulation have been identified, quantified, and translated into economical benefits