Pembrolizumab for locally advanced or metastatic urothelial cancer where cisplatin is unsuitable: an evidence review group perspective of a NICE single technology appraisal

As part of its Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Merck Sharp & Dohme) of pembrolizumab (Keytruda®) to submit evidence of its clinical and cost effectiveness for the treatment of locally advanced or metastatic urothelial cancer where cisplatin is unsuitable. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company’s submission (CS) to NICE. The clinical effectiveness evidence in the CS for pembrolizumab was based on one phase II, single-arm, open-label, non-randomised study (KEYNOTE-052), while the evidence for the comparator (carboplatin plus gemcitabine) was based on four studies, including one randomised controlled trial and three cohort studies. In the absence of head-to-head trials, the company conducted an indirect treatment comparison for both progression-free survival (PFS) and overall survival (OS), by firstly adjusting cross-study differences using a simulated treatment comparison approach and then synthesizing the evidence based on an assumption of constant hazard ratios using a standard meta-analysis model and time-varying hazard ratios using fractional polynomial models. The treatment effect of pembrolizumab was more favourable in the adjusted population compared with the observed effect in the KEYNOTE-052 study. The company submitted a de novo partitioned survival cohort simulation model, which partitions the OS time into PFS and post-progression survival. The probabilistic incremental cost-effectiveness ratio (ICER) for pembrolizumab compared with carboplatin plus gemcitabine was estimated to be £37,081 per quality-adjusted life-year (QALY) gained, based on the results within the company’s health economic model. Following a critique of the model, for their preferred base case the ERG corrected some minor model errors, chose a progression approach for estimating utilities, and revised the extrapolation of PFS and OS. The ERG’s probabilistic base case ICER was estimated to be £67,068 per QALY gained. The ERG also undertook a range of exploratory sensitivity analyses which suggested that the ICER was highly uncertain. In particular, the choices of extrapolation for the OS of pembrolizumab and the stopping rule for pembrolizumab had the largest impacts on the ICER. The NICE Appraisal Committee recommended pembrolizumab for use within the Cancer Drugs Fund as an option for treating locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy, provided that pembrolizumab was stopped at 2 years of uninterrupted treatment, or earlier if the disease progresses, and the conditions of the managed access agreement for pembrolizumab are followed

Recurring pulmonary hamartomas: cause for concern?

We report the case of a well-controlled female asthmatic who developed \u27multiple pulmonary hamartomas\u27 on three separate occasions over a period of 25 years that necessitated surgical resection. To our knowledge, this is the first report of recurrent hamartomas in a single individual necessitating multiple thoracotomies

An agenda for future Social Sciences and Humanities research on energy efficiency : 100 priority research questions

Decades of techno-economic energy policymaking and research have meant evidence from the Social Sciences and Humanities (SSH)-including critical reflections on what changing a society's relation to energy (efficiency) even means-have been underutilised. In particular, (i) the SSH have too often been sidelined and/or narrowly pigeonholed by policymakers, funders, and other decision-makers when driving research agendas, and (ii) the setting of SSH-focused research agendas has not historically embedded inclusive and deliberative processes. The aim of this paper is to address these gaps through the production of a research agenda outlining future SSH research priorities for energy efficiency. A Horizon Scanning exercise was run, which sought to identify 100 priority SSH questions for energy efficiency research. This exercise included 152 researchers with prior SSH expertise on energy efficiency, who together spanned 62 (sub-)disciplines of SSH, 23 countries, and a full range of career stages. The resultant questions were inductively clustered into seven themes as follows: (1) Citizenship, engagement and knowledge exchange in relation to energy efficiency; (2) Energy efficiency in relation to equity, justice, poverty and vulnerability; (3) Energy efficiency in relation to everyday life and practices of energy consumption and production; (4) Framing, defining and measuring energy efficiency; (5) Governance, policy and political issues around energy efficiency; (6) Roles of economic systems, supply chains and financial mechanisms in improving energy efficiency; and (7) The interactions, unintended consequences and rebound effects of energy efficiency interventions. Given the consistent centrality of energy efficiency in policy programmes, this paper highlights that well-developed SSH approaches are ready to be mobilised to contribute to the development, and/or to understand the implications, of energy efficiency measures and governance solutions. Implicitly, it also emphasises the heterogeneity of SSH policy evidence that can be produced. The agenda will be of use for both (1) those new to the energy-SSH field (including policyworkers), for learnings on the capabilities and capacities of energy-SSH, and (2) established energy-SSH researchers, for insights on the collectively held futures of energy-SSH research.Peer reviewe

TIA-1 Cytotoxic Granule-Associated RNA Binding Protein Improves the Prognostic Performance of CD8 in Mismatch Repair-Proficient Colorectal Cancer

Evidence suggests a confounding effect of mismatch repair (MMR) status on immune response in colorectal cancer. The identification of innate and adaptive immune cells, that can complement the established prognostic effect of CD8 in MMR-proficient colorectal cancers patients, representing 85% of all cases, has not been performed

A Temporal Gate for Viral Enhancers to Co-opt Toll-Like-Receptor Transcriptional Activation Pathways upon Acute Infection

Viral engagement with macrophages activates Toll-Like-Receptors (TLRs) and viruses must contend with the ensuing inflammatory responses to successfully complete their replication cycle. To date, known counter-strategies involve the use of viral-encoded proteins that often employ mimicry mechanisms to block or redirect the host response to benefit the virus. Whether viral regulatory DNA sequences provide an opportunistic strategy by which viral enhancer elements functionally mimic innate immune enhancers is unknown. Here we find that host innate immune genes and the prototypical viral enhancer of cytomegalovirus (CMV) have comparable expression kinetics, and positively respond to common TLR agonists. In macrophages but not fibroblasts we show that activation of NFκB at immediate-early times of infection is independent of virion-associated protein, M45. We find upon virus infection or transfection of viral genomic DNA the TLR-agonist treatment results in significant enhancement of the virus transcription-replication cycle. In macrophage time-course infection experiments we demonstrate that TLR-agonist stimulation of the viral enhancer and replication cycle is strictly delimited by a temporal gate with a determined half-maximal time for enhancer-activation of 6 h; after which TLR-activation blocks the viral transcription-replication cycle. By performing a systematic siRNA screen of 149 innate immune regulatory factors we identify not only anticipated anti-viral and pro-viral contributions but also new factors involved in the CMV transcription-replication cycle. We identify a central convergent NFκB-SP1-RXR-IRF axis downstream of TLR-signalling. Activation of the RXR component potentiated direct and indirect TLR-induced activation of CMV transcription-replication cycle; whereas chromatin binding experiments using wild-type and enhancer-deletion virus revealed IRF3 and 5 as new pro-viral host transcription factor interactions with the CMV enhancer in macrophages. In a series of pharmacologic, siRNA and genetic loss-of-function experiments we determined that signalling mediated by the TLR-adaptor protein MyD88 plays a vital role for governing the inflammatory activation of the CMV enhancer in macrophages. Downstream TLR-regulated transcription factor binding motif disruption for NFκB, AP1 and CREB/ATF in the CMV enhancer demonstrated the requirement of these inflammatory signal-regulated elements in driving viral gene expression and growth in cells as well as in primary infection of neonatal mice. Thus, this study shows that the prototypical CMV enhancer, in a restricted time-gated manner, co-opts through DNA regulatory mimicry elements, innate-immune transcription factors to drive viral expression and replication in the face of on-going pro-inflammatory antiviral responses in vitro and in vivo and; suggests an unexpected role for inflammation in promoting acute infection and has important future implications for regulating latency

Predictors of breakthrough clinically significant cytomegalovirus infection during letermovir prophylaxis in high-risk hematopoietic cell transplant recipients

Letermovir prophylaxis in allogeneic hematopoietic cell transplant recipients significantly reduces the incidence of clinically significant cytomegalovirus infection. However, breakthrough infections still occur despite adequate prophylaxis. In the present retrospective cohort study, we identified clinically relevant predictive factors for clinically significant CMV breakthrough infection during letermovir prophylaxis. Low-grade CMV replication (21-149 IU/ml), both at the time of letermovir initiation or during prophylaxis, was a significant risk factor for breakthrough clinically significant CMV infection. In addition, development of acute gastrointestinal graft-versus-host disease was significantly associated with breakthrough infection. Altogether these findings could call clinicians' attention to closer CMV monitoring and allow for prompt preemptive treatment initiation

Letermovir Primary Prophylaxis in High-Risk Hematopoietic Cell Transplant Recipients: A Matched Cohort Study

Background: Real-life data on the administration of letermovir as cytomegalovirus (CMV) primary prophylaxis after allogeneic hematopoietic cell transplantation (HCT) remain limited. Methods: We conducted a retrospective single-center matched cohort study, comparing consecutive high-risk allogeneic HCT recipients (cases) receiving primary prophylaxis with letermovir and untreated matched historical controls, during a study period of 180 days. The primary outcome was the incidence of clinically significant (cs) CMV infection. Secondary outcomes included duration and costs of CMV-antiviral treatments, hospital resource utilization, hematology and laboratory parameters. Results: Letermovir prophylaxis decreased csCMV infection incidence from 82.7% (controls) to 34.5% (cases; p-value 1 episode of csCMV infection (59.6%) compared to cases (11.5%; p-value < 0.0001). Letermovir was associated with: shorter overall CMV-associated treatment duration (49 days vs. 77.8 days; p-value: 0.02) and a trend for lower costs of CMV-associated treatments ($4096 vs.$9736; p-value: 0.07) and reduced length of stay (44.8 days vs. 59.8 days; p-value: 0.16). Letermovir administration was associated with significantly shorter duration (27.3 days vs. 57.1 days; p-value: 0.008) and lower costs ($1089 vs.$2281; p-value: 0.008) of valganciclovir treatment. Compared to controls, higher platelet counts were observed in cases (138 G/L vs. 92 G/L; p-value: 0.03) and renal function was improved (94 mL/min/1.73 m2 vs. 74 mL/min/1.73 m2; p-value: 0.006). Conclusions: Primary anti-CMV letermovir prophylaxis decreased the incidence of csCMV infection and the administration of CMV-associated treatments and costs, particularly those associated with valganciclovir. An effect of letermovir on platelet reconstitution and renal function of csCMV post-HCT was observed and needs further investigation

HIGH-FIDELITY EX-CORE CAPABILITIES IN VERA

High-fidelity nuclear reactor calculations have become increasingly important when considering lifetime extensions of the current nuclear fleet. The need for performing large calculations has led to development of advanced, novel methods for faster and more efficient computing system use. Under the Consortium for Advanced Simulation of Light Water Reactors (CASL), we have enabled the capability to perform high-fidelity ex-core calculations in the Virtual Environment for Reactor Applications (VERA) by coupling with the Shift Monte Carlo (MC) radiation transport package. The codes are coupled inmemory, allowing for the pin-by-pin fission source from the core simulator to be used by Shift. This unique capability allows the user to obtain both in-core and ex-core quantities by running a single simulation. Examples of ex-core calculations that can be performed include multicycle vessel fluence, detector response during reactor start-up and operation, and coupon fluence. One main advantage of the VERA ex-core capability is its flexibility and ease of use; users can select default settings with the standard VERA input for typical calculations or create their own ex-core geometry for specific cases. Also, Shift takes advantage of hybrid deterministic-MC methods to reduce variance and computational time. This paper details the full suite of VERA ex-core capabilities and provides input examples, simulation results, and computing resource use suggestions. These new capabilities have the potential to impact a wide user group in the nuclear community by enhancing and enabling high-fidelity light water reactor (LWR) ex-core calculations