Radiation Adverse Outcome pathways (AOPs): examining priority questions from an international horizon-style exercise.

PURPOSE: The Organisation for Economic Co-operation and Development (OECD) Adverse Outcome Pathway (AOP) Development Programme is being explored in the radiation field, as an overarching framework to identify and prioritize research needs that best support strengthening of radiation risk assessment and risk management strategies. To advance the use of AOPs, an international horizon-style exercise (HSE) was initiated through the Radiation/Chemical AOP Joint Topical Group (JTG) formed by the OECD Nuclear Energy Agency (NEA) High-Level Group on Low Dose Research (HLG-LDR) under the auspices of the Committee on Radiological Protection and Public Health (CRPPH). The intent of the HSE was to identify key research questions for consideration in AOP development that would help to reduce uncertainties in estimating the health risks following exposures to low dose and low dose-rate ionizing radiation. The HSE was conducted in several phases involving the solicitation of relevant questions, a collaborative review of open-ended candidate questions and an elimination exercise that led to the selection of 25 highest priority questions for the stated purpose. These questions were further ranked by over 100 respondents through an international survey. This final set of questions was judged to provide insights into how the OECD's AOP approach can be put into practice to meet the needs of hazard and risk assessors, regulators, and researchers. This paper examines the 25 priority questions in the context of hazard/risk assessment framework for ionizing radiation. CONCLUSION: By addressing the 25 priority questions, it is anticipated that constructed AOPs will have a high level of specificity, making them valuable tools for simplifying and prioritizing complex biological processes for use in developing revised radiation hazard and risk assessment strategies.

Considerations for application of benchmark dose modeling in radiation research: workshop highlights.

BACKGROUND: Exposure to different forms of ionizing radiation occurs in diverse occupational, medical, and environmental settings. Improving the accuracy of the estimated health risks associated with exposure is therefore, essential for protecting the public, particularly as it relates to chronic low dose exposures. A key aspect to understanding health risks is precise and accurate modeling of the dose-response relationship. Toward this vision, benchmark dose (BMD) modeling may be a suitable approach for consideration in the radiation field. BMD modeling is already extensively used for chemical hazard assessments and is considered statistically preferable to identifying low and no observed adverse effects levels. BMD modeling involves fitting mathematical models to dose-response data for a relevant biological endpoint and identifying a point of departure (the BMD, or its lower bound). Recent examples in chemical toxicology show that when applied to molecular endpoints (e.g. genotoxic and transcriptional endpoints), BMDs correlate to points of departure for more apical endpoints such as phenotypic changes (e.g. adverse effects) of interest to regulatory decisions. This use of BMD modeling may be valuable to explore in the radiation field, specifically in combination with adverse outcome pathways, and may facilitate better interpretation of relevant in vivo and in vitro dose-response data. To advance this application, a workshop was organized on June 3rd, 2022, in Ottawa, Ontario that brought together BMD experts in chemical toxicology and the radiation scientific community of researchers, regulators, and policy-makers. The workshop's objective was to introduce radiation scientists to BMD modeling and its practical application using case examples from the chemical toxicity field and demonstrate the BMDExpress software using a radiation dataset. Discussions focused on the BMD approach, the importance of experimental design, regulatory applications, its use in supporting the development of adverse outcome pathways, and specific radiation-relevant examples. CONCLUSIONS: Although further deliberations are needed to advance the use of BMD modeling in the radiation field, these initial discussions and partnerships highlight some key steps to guide future undertakings related to new experimental work.

Radiation adverse outcome pathways (AOPs) are on the horizon: advancing radiation protection through an international Horizon-Style exercise.

PURPOSE: The Adverse Outcome Pathway (AOP) framework, a systematic tool that can link available mechanistic data with phenotypic outcomes of relevance to regulatory decision-making, is being explored in areas related to radiation risk assessment. To examine the challenges including the use of AOPs to support the radiation protection community, an international horizon-style exercise was initiated through the Organisation for Economic Co-operation and Development Nuclear Energy Agency High-Level Group on Low Dose Research Radiation/Chemical AOP Joint Topical Group. The objective of the HSE was to facilitate the collection of ideas from a range of experts, to short-list a set of priority research questions that could, if answered, improve the description of the radiation dose-response relationship for low dose/dose-rate exposures, as well as reduce uncertainties in estimating the risk of developing adverse health outcomes following such exposures. MATERIALS AND METHODS: The HSE was guided by an international steering committee of radiation risk experts. In the first phase, research questions were solicited on areas that can be supported by the AOP framework, or challenges on the use of AOPs in radiation risk assessment. In the second phase, questions received were refined and sorted by the SC using a best-worst scaling method. During a virtual 3-day workshop, the list of questions was further narrowed. In the third phase, an international survey of the broader radiation protection community led to an orderly ranking of the top questions. RESULTS: Of the 271 questions solicited, 254 were accepted and categorized into 9 themes. These were further refined to the top 25 prioritized questions. Among these, the higher ranked questions will be considered as 'important' to drive future initiatives in the low dose radiation protection community. These included questions on the ability of AOPs to delineate responses across different levels of biological organization, and how AOPs could be applied to address research questions on radiation quality, doses or dose-rates, exposure time patterns and deliveries, and uncertainties in low dose/dose-rate effects. A better understanding of these concepts is required to support the use of the AOP framework in radiation risk assessment. CONCLUSION: Through dissemination of these results and considerations on next steps, the JTG will address select priority questions to advance the development and use of AOPs in the radiation protection community. The major themes observed will be discussed in the context of their relevance to areas of research that support the system of radiation protection.

Adverse outcome pathway: a path toward better data consolidation and global co-ordination of radiation research.

BACKGROUND: The purpose of toxicology is to protect human health and the environment. To support this, the Organisation for Economic Co-operation and Development (OECD), operating via its Extended Advisory Group for Molecular Screening and Toxicogenomics (EAGMST), has been developing the Adverse Outcome Pathway (AOP) approach to consolidate evidence for chemical toxicity spanning multiple levels of biological organization. The knowledge transcribed into AOPs provides a structured framework to transparently organize data, examine the weight of evidence of the AOP, and identify causal relationships between exposure to stressors and adverse effects of regulatory relevance. The AOP framework has undergone substantial maturation in the field of hazard characterization of chemicals over the last decade, and has also recently gained attention from the radiation community as a means to advance the mechanistic understanding of human and ecological health effects from exposure to ionizing radiation at low dose and low dose-rates. To fully exploit the value of such approaches for facilitating risk assessment and management in the field of radiation protection, solicitation of experiences and active cooperation between chemical and radiation communities are needed. As a result, the Radiation and Chemical (Rad/Chem) AOP joint topical group was formed on June 1, 2021 as part of the initiative from the High Level Group on Low Dose Research (HLG-LDR). HLG-LDR is overseen by the OECD Nuclear Energy Agency (NEA) Committee on Radiation Protection and Public Health (CRPPH). The main aims of the joint AOP topical group are to advance the use of AOPs in radiation research and foster broader implementation of AOPs into hazard and risk assessment. With global representation, it serves as a forum to discuss, identify and develop joint initiatives that support research and take on regulatory challenges. CONCLUSION: The Rad/Chem AOP joint topical group will specifically engage, promote, and implement the use of the AOP framework to: (a) organize and evaluate mechanistic knowledge relevant to the protection of human and ecosystem health from radiation; (b) identify data gaps and research needs pertinent to expanding knowledge of low dose and low dose-rate radiation effects; and (c) demonstrate utility to support risk assessment by developing radiation-relevant case studies. It is envisioned that the Rad/Chem AOP joint topical group will actively liaise with the OECD EAGMST AOP developmental program to collectively advance areas of common interest and, specifically, provide recommendations for harmonization of the AOP framework to accommodate non-chemical stressors, such as radiation.

COHERE - strengthening cooperation within the Canadian government on radiation research.

PURPOSE: Canadian Organization on Health Effects from Radiation Exposure (COHERE) is a government initiative to better understand biological and human health risks from ionizing radiation exposures relevant to occupational and environmental settings (<100 mGy, <6 mGy/h). It is currently a partnership between two federal agencies, Health Canada (HC) and the Canadian Nuclear Safety Commission (CNSC). COHERE's vision is to contribute knowledge to reduce scientific uncertainties from low dose and dose-rate exposures. COHERE will advance our understanding by bridging the knowledge gap between human health risks and linkages to molecular- and cellular-level responses to radiation. Research focuses on identifying sensitive, early, and key molecular events of relevance to risk assessment. CONCLUSIONS: The initiative will address questions of relevance to better apprize Canadians, including radiation workers and members of the public and Indigenous peoples, on health risks from low dose radiation exposure and inform radiation protection frameworks at a national and international level. Furthermore, it will support global efforts to conduct collaborative undertakings and better coordinate research. Here, we describe a historical overview of the research conducted, the strategic research agenda that outlines the scientific framework, stakeholders, opportunities to harmonize internationally, and how research outcomes will better inform communication of risk to Canadians.

Celiac Disease After Administration of Immune Checkpoint Inhibitors: A Case Report.

Immune checkpoint inhibitors (ICI) reinvigorate the immune system to recognize and destroy tumor cells. Because of this biological mechanism, patients might develop autoimmune toxicities, notably in the digestive tract (most frequently, hepatitis or colitis). A 70-year-old man with relapsed mesothelioma was treated with nivolumab in 3rd line. He was hospitalized for watery and foul-smelling diarrhea. He underwent gastrointestinal endoscopy, showing duodenitis and villous atrophy and measurement of serum IgA antibodies to tissue transglutaminase (tTG-IgA+), leading to the diagnosis of ICI-induced celiac disease. He was treated with steroids, proton pump inhibitors, and a gluten-free diet. If ICI-induced celiac disease is rare in the literature, increasing reports suggest that celiac disease might represent an underestimated ICI toxicity. This case highlights the necessity of complementary investigation (including tTG-IgA and endoscopic biopsies) in patients with atypical digestive symptoms during immunotherapy.

Agranulocytosis Induced by Tamoxifen in a Breast Cancer Patient.

BACKGROUND: The main side effects of tamoxifen are menopausal symptoms. We report a case of agranulocytosis induced by tamoxifen in a 33-year-old woman treated in the adjuvant setting. CASE PRESENTATION: Ten days after the beginning of tamoxifen treatment, the patient complained of asthenia and mucositis. Blood testing showed a grade 4 neutropenia (0.06 G/L) without any other major hematologic disorder. Tamoxifen was discontinued, and the patient received granulocyte colony-stimulating factor. Within 2 days, she recovered to a normal granulocyte count. Tamoxifen was then switched to the combination of ovarian suppression (triptorelin) and aromatase inhibitor (anastrozole). CONCLUSION: Agranulocytosis is a very rare adverse event of tamoxifen.

Fulvestrant and palbociclib combination in heavily pretreated hormone receptor-positive, HER2-negative metastatic breast cancer patients.

PURPOSE: We report the results of a retrospective analysis of the fulvestrant and palbociclib combination within a temporary authorization of use (TAU) program in 77 heavily pretreated patients with hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. METHODS: All patients who received the fulvestrant and palbociclib combination within this TAU program were included. Toxicities were graded using the CTCAE v5 scale. RESULTS: The majority of patients (62.3%) were previously treated with the mTOR inhibitor everolimus. The median number of previous treatments for their metastatic disease was 4. With a median follow-up of 14 months, the median progression-free survival (PFS) was 7.6 months. The median PFS significantly (p < 0.0001) decreased with the number of previous treatment lines in the metastatic setting. The median PFS was 5.5 months in patients who had previously progressed on everolimus compared to 9.3 months in the everolimus non-pretreated subgroup. No significant difference in median PFS was detected in patients according to age. The median overall survival rate was not reached. The clinical benefit rate was 64%, including 4% of complete responses, 26% partial responses, and 34% stable diseases for the entire cohort. CONCLUSIONS: The fulvestrant and palbociclib combination exerts an appreciable effect on metastatic heavily pretreated patients with a tolerable toxicity profile.

Radiation Biology and Its Role in the Canadian Radiation Protection Framework.

The linear no-threshold (linear-non-threshold) model is a dose-response model that has long served as the foundation of the international radiation protection framework, which includes the Canadian regulatory framework. Its purpose is to inform the choice of appropriate dose limits and subsequent as low as reasonably achievable requirements, social and economic factors taken into account. The linear no-threshold model assumes that the risk of developing cancer increases proportionately with increasing radiation dose. The linear no-threshold model has historically been applied by extrapolating the risk of cancer at high doses (>1,000 mSv) down to low doses in a linear manner. As the health effects of radiation exposure at low doses remain ambiguous, reducing uncertainties found in cancer risk dose-response models can be achieved through in vitro and animal-based studies. The purpose of this critical review is to analyze whether the linear no-threshold model is still applicable for use by modern nuclear regulators for radiation protection purposes, or if there is sufficient scientific evidence supporting an alternate model from which to derive regulatory dose limits.

Is there a role for the adverse outcome pathway framework to support radiation protection?

PURPOSE: In 2012, the Organization for Economic Cooperation and Development (OECD) formally launched the Adverse Outcome Pathway (AOP) Programme. The AOP framework has the potential for predictive utility in identifying early biological endpoints linked to adverse effects. It uses the weight of correlative evidence to identify a minimal set of measurable key events that link molecular initiating events to an adverse outcome. AOPs have the capability to identify knowledge gaps and priority areas for future research based on relevance to an adverse outcome. In addition, AOPs can identify pathways that are common among multiple stressors, thereby allowing for the possibility of refined risk assessments based on co-exposure considerations. The AOP framework is increasingly being used in chemical and ecological risk assessment; however, its use in the development of radiation-specific pathways has yet to be fully explored. To bring awareness of the AOP framework to the Canadian radiation community, a workshop was held in Canada in June 2018 that brought together radiation experts from Health Canada, the Canadian Nuclear Laboratories, and the Canadian Nuclear Safety Commission. METHODS: The purpose of the workshop was to share knowledge on the AOP framework, specifically (1) to introduce the concept of the AOP framework and its possible utility to Canadian radiation experts; (2) to provide examples on how it has advanced risk assessment; (3) to discuss an illustrative example specific to ionizing radiation; and lastly (4) to identify the broad benefits and challenges of the AOP framework to the radiation community. RESULTS: The participants showed interest in the framework, case examples were described and areas of challenge were identified. Herein, we summarize the outcomes of the workshop. CONCLUSIONS: Overall, participants agreed that by building AOPs in the radiation field, a network of data-sharing initiatives will enhance our interpretation of existing knowledge where current scientific evidence is minimal. They would provide new avenues to understand effects at low-dose and dose-rates and help to quantify the combined effect of multiple stressors on shared mechanistic pathways.

Practice Patterns in the Treatment and Monitoring of Acute T Cell-Mediated Kidney Graft Rejection in Canada.

BACKGROUND: One of the goals of the Canadian National Transplant Research Program (CNTRP) is to develop novel therapies for acute rejection that could positively affect graft outcomes with greater efficacy or less toxicity. To develop innovative management strategies for kidney graft rejection, new modalities need to be compared with current clinical practices. However, there are no standardized practices concerning the management of acute T cell-mediated rejection (TCMR). OBJECTIVES: To describe clinicians' practice patterns in the diagnosis, treatment, and monitoring of acute TCMR in Canada. DESIGN: Survey. SETTING PATIENTS/PARTICIPANTS: Canadian transplant nephrologists and transplant surgeons involved in the management of acute TCMR. METHODS AND MEASUREMENTS: We developed an anonymous, web-based survey consisting of questions related to the diagnosis, treatment, and monitoring of TCMR. The survey was disseminated on 3 occasions between June and October 2016 through the Canadian Society of Transplantation (CST) kidney group electronic mailing list. RESULTS: Forty-seven respondents, mostly transplant nephrologists (97%), originating from at least 18 of the 25 Canadian centers offering adult or pediatric kidney transplantation, participated in the study. Surveillance biopsies were used by 28% of respondents to screen for kidney graft rejection. High-dose steroids were used by most of the respondents to treat clinical and subclinical Banff grade 1A and 1B rejections. Nine percent (95% confidence interval [CI]: 1-17) of practitioners used lymphocyte-depleting agents as the first-line approach for the treatment of Banff grade 1B acute rejection. Eighteen percent (95% CI: 7-29) and 36% (95% CI: 8-65) of respondents reported that they would not use high-dose steroids for treating clinical and subclinical borderline rejections, respectively. Seventy percent (95% CI: 54-83) of respondents answered that there was no indication to assess histological response to treatment independent of the change in kidney function. LIMITATIONS: The limitations of this study are its limited sample size and the low representation of pediatric specialists. CONCLUSIONS: There is heterogeneity regarding the use of surveillance biopsies, treatment of borderline rejection, and modalities to monitor treatment response among transplant physicians. Our results illustrate the current state of practice patterns across Canada and can be used to inform the design of future trials.

CONTEXTE: Un des objectifs du Programme national de recherche en transplantation rénale du Canada (PNRTC) est de développer des traitements plus efficaces et moins toxiques en vue d'améliorer l'issue des greffes. Il est impératif de comparer ces nouvelles modalités aux pratiques cliniques existantes si l'on veut élaborer des stratégies de prise en charge thérapeutiques innovantes. Cependant, en contexte de greffe rénale, il n'existe aucune pratique standardisée pour la prise en charge thérapeutique du rejet aigu à médiation cellulaire (RAMC) provoqué par la cytotoxicité des lymphocytes T. OBJECTIF: Décrire le schéma de pratique des médecins canadiens en matière de diagnostic, de traitement et de monitorage du RAMC. TYPE D'ÉTUDE: Il s'agit d'une étude menée sous forme de sondage. PARTICIPANTS: Les chirurgiens et néphrologues en transplantologie impliqués dans la prise en charge du RAMC au Canada. MÉTHODOLOGIE: Nous avons préparé un sondage Web anonyme constitué de questions relatives au diagnostic et au monitorage du RAMC. Les répondants visés étaient les abonnés à la liste d'envoi du groupe de transplantation rénale de la Société canadienne de transplantation (SCT). Ils ont reçu le sondage à trois reprises entre juin et octobre 2016. RÉSULTATS: Les répondants, au nombre de 47, étaient en grande majorité des néphrologues transplantologues (97 %). Ils provenaient d'au moins 18 des 25 centres hospitaliers canadiens dans lesquels on pratique des greffes rénales (adultes ou pédiatriques). Vingt-huit pour cent (28 %) des répondants ont recours aux biopsies de surveillance pour évaluer le risque de rejet du greffon. Les stéroïdes administrés à fortes doses sont employés par la plupart des répondants pour traiter les rejets cliniques et infracliniques de stade 1A et 1B (classification de Banff). Les agents de déplétion des lymphocytes sont utilisés par 9 % (IC 95 % : 1-17) des praticiens comme approche thérapeutique de première ligne pour les rejets aigus de stade 1B de Banff. En matière de traitement des cas rejets limites cliniques et infracliniques, 18% (IC 95 % : 7-29) et 36 % (IC 95 % : 8-65) des répondants ont indiqués qu'ils n'emploieraient pas de stéroïdes à forte dose. Enfin, 70 % (IC 95 % : 54-83) des spécialistes sondés jugeaient qu'il n'y avait pas d'indication d'évaluer la réponse histologique au traitement indépendamment de la réponse au traitement en terme de fonction rénale. LIMITES DE L'ÉTUDE: Les résultats du sondage sont limités par le faible nombre de répondants et par la sous-représentation des spécialistes en pédiatrie. CONCLUSION: Chez les médecins sondés, on a constaté des différences dans trois aspects de la prise en charge de la greffe rénale : la fréquence du recours aux biopsies de surveillance, le traitement des cas limites de rejet et les modalités employées pour mesurer la réponse au traitement. Nos résultats témoignent de l'hétérogénéité actuelle des schémas de pratique au Canada et pourraient servir à orienter la conception d'études ultérieures.

Any place left for induction chemotherapy for locally advanced head and neck squamous cell carcinoma?

The issue of induction chemotherapy (ICT) interest in locoregionally advanced squamous cell cancer of the head and neck is a real epic that has been carried out over four phase III studies: PARADIGM, DECIDE, NCT01086826 and lastly the conclusive GORTEC 2007-02. With no significant benefit in overall survival of ICT, followed by concurrent chemoradiation over the standard chemoradiotherapy alone, in three of these studies, and a significant number of treatment-related deaths with the standard regimen docetaxel, cisplatin, and fluorouracil, ICT is no longer a hot topic. However, this strategy might still be useful in the aim of limiting the metastatic extension affecting up to 30% of patients: ICT is systematically associated with a reduced metastatic relapse even though the survival effect is never statistically significant when compared directly with concomitant radiochemotherapy. This review summarizes the major studies with their limits and discusses how the ICT could improve the patients' prognosis in the future.

[Pertuzumab and solid tumors: perspectives]. / Pertuzumab et tumeurs solides : perspectives.

Over the past decade, trastuzumab was the only available monoclonal anti-HER2 antibody for the treatment of HER2 positive breast and gastric cancer. Recently, pertuzumab added to docetaxel and trastuzumab showed dramatic overall survival improvement in first line treatment of HER2 positive metastatic breast cancer. Pertuzumab is the first approved monoclonal antibody in a new class of drugs called dimerization inhibitors. This agent was also approved in association with trastuzumab for neoadjuvant HER2-positive breast cancer treatment. However, pertuzumab development was not confined to breast cancer and in the present review, we will focus on biological rational, preclinical data and clinical trial results of pertuzumab in solid tumors excluding breast cancer.

Pertuzumab: development beyond breast cancer.

Pertuzumab (Perjeta®) represents the first monoclonal antibody in a new class of agents known as dimerization inhibitors. Pertuzumab was recently approved for the treatment of Human Epidermal Receptor 2 (HER2)-positive breast cancer in the metastatic and neo-adjuvant setting. This approval for first-line therapy for metastatic breast cancer was based on the results of a large randomized multicenter phase III trial showing a significant improvement in overall survival when pertuzumab was combined with trastuzumab and docetaxel in HER2-positive metastatic breast cancer. In the neoadjuvant setting, dual HER2 blockade by trastuzumab and pertuzumab improved the complete pathological response rate. However, pertuzumab development was not confined to breast cancer and in the present article, we focus on pertuzumab data for solid tumors other than breast cancer, and review the biological rationale for its use, the published pre-clinical and clinical evidence, as well ongoing trials.