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Background: Current guidelines recommend bone modifying agents (BMAs), such as bisphosphonates and denosumab, every 4 to 12 weeks to reduce the incidence of and delay the onset of symptomatic skeletal events (SSEs) in patients with bone metastases from breast cancer and castration-resistant prostate cancer (CRPC). Given the absence of level one evidence, the optimal frequency and duration of BMAs after 2 years of treatment is unknown. This is an important clinical question as the risk of SSEs decreases with time, while the risk of treatment-related toxicities increases. Methods: Patients with bone metastases from breast cancer or CRPC who have received ≥ two years of BMA treatment will be approached for this pragmatic, multicenter, open-label RCT. Using the Rethinking Clinical Trials (REaCT) methodology that incorporates the integrated oral consent model, eligible and consented patients will be randomized to either continue standard schedule BMA (every 4 or 12 weeks) or de-escalated BMA (every 24 weeks). This is a non-inferiority study. The co-primary endpoints are the physical functioning subscale of EORTC-QLQ-C30 and functional interference subscale of EORTC-QLQ-BM22. Secondary endpoints include number of patients with ≥ 1 SSE, time to development of SSE, SSE-free survival, skeletal morbidity rate, EORTC-QLQ-C30 and BM22 scores, BMA-related toxicity, and treatment adherence. To achieve 80% power for both co-primary endpoints and assuming a 10% non-compliance and 20% death rate, the planned sample size is 240 patients (120 per arm). Randomization (1:1 ratio) will be stratified by cancer type (breast vs prostate) and treatment schedule prior to randomization (Q4weeks vs. Q12weeks). A subgroup analysis comparing patients with 2-3 years vs. > 3 years of prior BMA treatment will be conducted. Results: The study has been open for enrollment since Oct 2020. As of July 5, 2021, the study has opened at 2 sites, 48 patients have been randomized and 8 are in screening. The study needs 60 patients randomized by September 2021 to continue to receive funding. There is a plan to open the study at two other academic centers in Ontario, Canada. Conclusion: This will be the first RCT providing level one evidence regarding the optimal frequency of BMA treatment that accounts for health-related quality of life after ≥ two years of prior BMA in this patient population. Citation Format: Terry L. Ng, Gregory R. Pond, Marta Sienkiewicz, Kednapa Thavorn, Mark Clemons. A randomised trial comparing continuation or de-escalation of bone modifying agents (BMA) in patients treated for over 2 years for bone metastases from either breast or castration-resistant prostate cancer (REaCT-HOLD BMA) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-06-01.

The article is an analysis and presentation of the overview of economic systems to which the popes of that time referred in their documents, most often in encyclicals. The article presents the image of society in the economic and social perspective as well as interpretations and comments on a specific system, which were included in the papal encyclicals. The article is a presentation of how popes in encyclicals responded to the emerging changes in the political system and new economic ideas.

Background Optimal use of bone-modifying agent (BMA) therapy in patients with bone metastases from breast and castrate-resistant prostate cancer (CRPC) is evolving. Methods Patients receiving BMA for bone metastases from breast or CRPC were surveyed. Information was collected on patient and disease characteristics, BMA treatments and perceptions regarding BMA benefits and side effects. Interest in participation in trials of de-escalated BMA therapy was also gauged. Results Of 220 patients contacted, 172 eligible patients responded (response rate 78%). Median age was 67 (range: 21–91); 137 (80%) had breast cancer and 35 (20%) CRPC. Symptomatic skeletal events (SSEs) occurred prior to starting BMAs in 61% (84/137) of breast and 48% (17/35) of CRPC patients. Among breast cancer patients, 47, 33 and 13% received zoledronate, pamidronate and denosumab, respectively. Eighty-five percent (30/35) of CRPC patients received denosumab. De-escalation of therapy was more common among breast cancer patients. Although most patients correctly reported the goals of BMA therapy were to “help stop fractures” (62%) and “[improve] quality of life” (63%), 46.5% felt it prolonged survival and 54% felt it reduced bone progression. Most respondents (102/129, 79%) were comfortable with de-escalating to 6-monthly treatment after 2 years of BMA therapy. Patients considered the most important endpoints of de-escalation studies to be “stability of bone metastases” (45%), “quality of life” (22%) and “SSE rates” (14%). Conclusion Twelve weekly BMA was more common in breast than in prostate cancer. There remain misconceptions about the benefits of BMAs, highlighting potential gaps in patient education. Patients were interested in further BMA de-escalation after 2 years of prior BMA and provided study endpoints that were most important to them. Supplementary Information The online version contains supplementary material available at 10.1007/s00520-021-06238-1.

Background: Despite extensive use of bone modifying agents (BMA) in patients with bone metastases from breast cancer (BC), the optimal choice, frequency, and duration of BMA treatment remains unclear. A physician survey was performed to identify current practices and attitudes towards performing trials of de-escalation after 2 years of treatment, where very little prospective data exists. Methods: Canadian oncologists treating breast cancer were surveyed from May to June 2020 via an anonymized online survey. Physicians were approached by e-mail invitation, and a follow-up e-mail was sent 2 weeks later. The study was approved by the Ontario Cancer Research Ethics Board. The survey collected physician demographics, current practice patterns, perception on risk of symptomatic skeletal events (SSE) and BMA-associated toxicity. It also assessed attitudes towards conducting a study evaluating further de-escalation of BMAs after 2 years of treatment. Results: Of 238 potentially eligible breast oncologists on initial screening, 40 responded (response rate 16.8%; 97.5% medical oncologist). The most common BMA regimens during the first 2 years in patients with no limitations in drug coverage were denosumab q4wks for 3-4 months then q12wks [13/40 physicians (32.5%)], denosumab q4wks [7/40 (17.5%)], and zoledronate q12wks [8/40 (20%)]. For patients with no public funding for denosumab, the most common regimens were zoledronate q4wks for 3-4 months then q12wks [14/40 (35%)] and zoledronate q12wks [12/40 (30%)]. Most physicians [33/40 (82.5%)] routinely de-escalated BMA, with the most common approaches being de-escalation from the start of treatment [9/33 (27.3%)], after 3 months [7/33 (21.2%)], 6 months [6/33 (18.2%)], or 12 months [5/33 (15.2%)]. In terms of continuing BMA after 2 years, 11/40 (27.5%) felt there was benefit, 5/40 (12.5%) felt there was no benefit, and 24/40 (60%) were unsure. There was no consensus on the perceived risk of SSE or BMA-related toxicity after ≥ 2 years of BMA in breast cancer. Most physicians treating breast cancer-related bone metastases felt a de-escalation study after more than 2 years of BMA would be clinically important [i.v. bisphosphonate (BP) q12wks vs q24wks: 65%; i.v. BP q12wks vs. discontinue: 70%; denosumab q12wks vs q24wks: 57.5%; denosumab q12wks vs. discontinue: 67.5%]. Most physicians would accept SSE rate increase of < 5% with BMA de-escalation. If a study of BMA de-escalation showing non-inferiority in terms of SSE rate was not feasible, physicians would consider changing practice to de-escalated therapy if: BMA toxicity was reduced (64.1%), pain was no worse (48.7%), physical function was no worse (48.7%), or cost-utility or cost-effectiveness was improved (41%). 38.5% would only change practice if the SSE rate was not significantly worse. Conclusion: Despite their extensive use and costs, questions around optimal use of BMAs still exist. It is evident that practice varies according to patient insurance coverage, however most physicians are de-escalating BMAs. There is interest amongst clinicians in performing trials of de-escalation, especially after 2 years of treatment. Citation Format: Mashari Alzahrani, Mark Clemons, Lisa Vandermeer, Marta Sienkiewicz, Arif Awan, Brian Hutton, Gregory Pond, Terry Ng. A physician survey evaluating real-world practice patterns and attitudes towards de-escalation of bone-modifying agents in patients with bone metastases from breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-18.

Highlights • Questions around optimal use of bone-modifying agents (BMAs) still exist. • Most physicians are de-escalating BMAs in patients with metastatic breast cancer. • Practice varies according to patient insurance coverage. • There is interest performing further trials of de-escalation especially after 2 years of treatment., Background There remain questions around the optimal use of bone-modifying agents (BMAs) in patients with bone metastases from breast and castration-resistant prostate cancer (CRPC). A physician survey was performed to identify current practices, as well as perceptions around long-term BMA use, BMA de-escalation, and further BMA de-escalation after 2 years of use. Methods Canadian oncologists treating breast cancer or CRPC were surveyed via an anonymized online survey. The survey collected physician demographics, current practice patterns, perception on risk of symptomatic skeletal events (SSE) and BMA-associated toxicities, and attitudes towards further de-escalation of BMAs after 2 years of treatment. Results A total of 334 physicians in Canada were contacted, of which 295 were eligible on initial screening, and 65 completed the survey (response rate 22%): 35 treated breast cancer, 25 treated prostate cancer and 5 treated both. The most common BMA regimens in patients with no limitation in drug coverage were denosumab q4wks for 3–4 months followed by a de-escalation to q12wks (breast cancer) and denosumab q4wks (prostate cancer). In patients with provincial health coverage only the common choices were zoledronate q4wks for 3–4 months followed by de-escalation to q12wks (breast cancer) and denosumab q4wks (prostate cancer). There was equipoise regarding the benefit of continuing BMA beyond 2 years and interest in further trials of de-escalation of BMA in both breast and prostate cancer. The most favored alternative primary study endpoints to SSE were BMA toxicity (67.2%), pain (46.9%), and physical function (48.4%). Conclusion Despite their extensive use and costs, questions around optimal use of BMAs still exist. Practice varies according to patient insurance coverage. However, most physicians are de-escalating BMAs. There is interest amongst clinicians in performing trials of de-escalation, especially after 2 years of treatment.

Purpose Despite triple antiemetic therapy use for breast cancer patients receiving emetogenic chemotherapy, nausea remains a clinical challenge. We evaluated adding olanzapine (5 mg) to triple therapy on nausea control in patients at high personal risk of chemotherapy-induced nausea and vomiting (CINV). Methods This multi-centre, placebo-controlled, double-blind trial randomized breast cancer patients scheduled to receive neo/adjuvant chemotherapy with anthracycline-cyclophosphamide or platinum-based chemotherapy to olanzapine (5 mg, days 1–4) or placebo. Primary endpoint was frequency of self-reported significant nausea, repeated for all cycles of chemotherapy. Secondary endpoints included: duration of nausea, overall total control of CINV, Health Related Quality of Life (HRQoL) using FLIE questionnaire, use of rescue mediation and treatment-related adverse events. Results 218 eligible patients were randomised to placebo (105) or olanzapine (113). From days 0–5 following each cycle of chemotherapy, 41.3% (95%CI: 36.1–46.7%) of patients in the placebo group reported significant nausea compared to 27.7% (95%CI: 23.2–32.4%) in the olanzapine group (p = 0.001). Across all cycles of chemotherapy, patients receiving olanzapine experienced a statistically significant improvement in HRQoL (p, Highlights • Double-blind trial evaluated the addition of olanzapine to triple therapy in patients at high personal risk of CINV. • Adding 5 mg olanzapine was associated with significantly improved nausea control with no unexpected toxicities. • Olanzapine plus triple therapy should be considered standard of care for breast cancer patients at high risk of CINV.

Highlights • Artificial Intelligence (AI) has potential to improve chemical risk assessment (CRA) and associated regulatory decisions. • AI could influence the scientific-technical evaluation process and the social aspects of the CRA decision making process. • Systematic Reviews are among the CRA processes that will profit most from the application of AI techniques. • Using AI as external objective monitor could make Weight of Evidence considerations less subjective and more trustable. • AI could identify pitfalls not observable by individuals participating in the CRA process., As the basis for managing the risks of chemical exposure, the Chemical Risk Assessment (CRA) process can impact a substantial part of the economy, the health of hundreds of millions of people, and the condition of the environment. However, the number of properly assessed chemicals falls short of societal needs due to a lack of experts for evaluation, interference of third party interests, and the sheer volume of potentially relevant information on the chemicals from disparate sources. In order to explore ways in which computational methods may help overcome this discrepancy between the number of chemical risk assessments required on the one hand and the number and adequateness of assessments actually being conducted on the other, the European Commission's Joint Research Centre organised a workshop on Artificial Intelligence for Chemical Risk Assessment (AI4CRA). The workshop identified a number of areas where Artificial Intelligence could potentially increase the number and quality of regulatory risk management decisions based on CRA, involving process simulation, supporting evaluation, identifying problems, facilitating collaboration, finding experts, evidence gathering, systematic review, knowledge discovery, and building cognitive models. Although these are interconnected, they are organised and discussed under two main themes: scientific-technical process and social aspects and the decision making process.

This chapter stresses the importance of cocreation between researchers and policymakers regarding decisions on what to study and which questions to answer with scientific evidence in order to gather knowledge for policy making processes and decisions. The chapter outlines why a new approach to scoping the research questions (in a science for policy context) by scientists and policymakers is needed, i.e. due to a separation between research and policy cultures, differing natures of problems in science (tame) and in policy (wicked), as well as a need for a translation from policy issues to research questions, and appropriate framing of issues, which is in itself a non-trivial, non-neutral process of potential inclusion and exclusion of knowledge. Collaboration and iterative cocreation between researchers and policymakers, these ‘two communities’, help bridge these distinctions. The skills framework contains eight skills that, in an ideal-type organisation, contribute to an overall vision for effective science for policy. The chapter then provides examples of concrete practices which the JRC has introduced in order to allow for more interaction and collaboration in identifying research questions which can generate useful knowledge for policy . The examples include dedicated Knowledge Centres, work programme planning, staff exchanges, collaboration facilitators and local events.

Policy impact of scientific research does not happen by itself. It requires strategic planning for engaging relevant audiences with the science, including active participation in policymaking environment. This chapter presents Joint Research Centre's (JRC) lessons on how to increase the chances of achieving impact on policy with one's scientific research. As research competes with other sources of knowledge and evidence for attention of policymakers, politicians and decision-makers, scientists interested in policy impact need to adopt new practices and behaviours, differing from their classical academic training. The chapter covers three such main areas: (1) understanding different policy actors and roles in the policy process, in order to better tailor their communication and engagement with different groups; (2) adapting the language to fit the bandwidth of policymakers and provide constructive input into their processes; (3) building relationships and gathering policy intelligence about drivers and developments in policy areas relevant to their research.

This chapter considers how to navigate interests, pressures and dangers of bringing science and policy closer together stemming from tighter relationships between researchers, policymakers and other policy actors. It provides some nuances to the notions of legitimacy, impartiality and objectivity of scientific advice and support to policymaking. It considers values and interests of scientists, policymakers, lobbyists and other stakeholders or interest representatives, and provides some considerations from the JRC on how to navigate them. In particular, it covers what lobbying is and what it means for scientists and their organisations who compete with lobbies' inputs to policymaking but can also become their target. It finishes with some thoughts on managing conflicts of interest and the need for openness and engagement more than just transparency.

This chapter discusses the need for a transition from Science for Policy 1.0, detached scientific advice provided ad hoc, or even unsolicited, to policymakers, towards Science for Policy 2.0, an integrated system of collaboration between scientists and policymakers, as well as stakeholders and citizens. It discusses some reasons why providing science for policy and engaging in evidence-informed policymaking are a difficult task. It provides reasons for why evidence should play an important role in policymaking, seeing evidence-informed policymaking as an important component and a value of liberal democracy. It discusses why not all science would automatically constitute evidence useful and usable in policymaking, and sketches the main reasons for why the divisions between the 'two communities', two cultures of scientists and policymakers, are exacerbated by wider societal, political and institutional context. It ends with a plea for more systemic co-creation and cooperation between science and policy, the idea which is elaborated and concretised throughout the remaining chapters of this handbook.

Purpose While routine, in-person follow-up of early-stage breast cancer patients (EBC) after completion of initial treatment is common, the COVID-19 pandemic has resulted in unprecedented changes in clinical practice. A systematic review was performed to evaluate the evidence supporting different frequencies of routine follow-up. Methods MEDLINE and the Cochrane Collaboration Library were searched from database inception to July 16, 2020 for randomized controlled trials (RCTs) and prospective cohort studies (PCS) evaluating different frequencies of routine follow-up. Citations were assessed by pairs of independent reviewers. Risk of Bias (RoB) was assessed using the Cochrane RoB tool for RCTs and the Newcastle-Ottawa Quality Assessment Scale for Cohort Studies. Findings were summarized narratively. Results The literature search identified 3316 studies, of which 7 (6 RCTs and 1 PCS) were eligible. Study endpoints included; quality of life (QoL; 5 RCTs and 1 PCS), disease free survival (DFS) (1 RCT), overall survival (OS) (1 RCT) and cost-effectiveness (1 RCT). The results showed reduction in follow-up frequency had no adverse effect on: QoL (6 studies, n = 920), DFS (1 trial, n = 472) or OS (1 trial, n = 472), but improved cost-effectiveness (1 trial, n = 472). Four RCTs specifically examined follow-up on-demand versus scheduled follow-up visits and found no statistically significant differences in QoL (n = 544). Conclusion While no evidence-based guidelines suggest that follow-up of EBC patients improves DFS or OS, routinely scheduled in-person assessment is common. RCT data suggests that reduced frequency of follow-up has no adverse effects.

The article deals with the place and role of the sacrament of Confirmation in the pastoral mission of the Church. In the theoretical part it presents current teaching of the Church concerning the Confirmation in dogmatic, legal, catechetical and confessional aspects. It also analyzes the meaning of Confirmation as well as the way of preparing to it. In the research part it presents the results of research conducted among middle school students. On the basis of this research it describes religious maturity of today's candidates for Confirmation and formulates pastoral guidelines related to both preparation and administering this sacrament.