Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program 'iTHER'

iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival. Keywords: Adolescent; Cancer; Child; Hereditary; Molecular biology; Molecular targeted therapy; Next-generation sequencing; Precision medicin

Impact of an Inner-City Smoke-Free Zone on Outdoor Smoking Patterns:A Before-After Study

INTRODUCTION: On September 2, 2019, Rotterdam’s first inner-city outdoor smoke-free zone encompassing the Erasmus MC, a large university hospital in the Netherlands, the Erasmiaans high school, the Rotterdam University of Applied Sciences and the public road in between, was implemented. AIMS AND METHODS: We aimed to assess spatiotemporal patterning of smoking before and after implementation of this outdoor smoke-free zone. We performed a before–after observational field study. We systematically observed the number of smokers, and their locations and characteristics over 37 days before and after implementation of the smoke-free zone. RESULTS: Before implementation of the smoke-free zone, 4098 people smoked in the area every weekday during working hours. After implementation, the daily number of smokers was 2241, a 45% reduction (p = .007). There was an increase of 432 smokers per day near and just outside the borders of the zone. At baseline, 31% of the smokers were categorized as employee, 22% as student and 3% as patient. Following implementation of the smoke-free zone, the largest decreases in smokers were observed among employees (–67%, p value .004) and patients (–70%, p value .049). Before and after implementation, 21 and 20 smokers were visibly addressed and asked to smoke elsewhere. CONCLUSIONS: Implementation of an inner-city smoke-free zone was associated with a substantial decline in the number of smokers in the zone and an overall reduction of smoking in the larger area. Further research should focus on optimizing implementation of and compliance with outdoor smoke-free zones. IMPLICATIONS: A smoke-free outdoor policy has the potential to denormalize and discourage smoking, support smokers who want to quit, and to protect people from secondhand smoke exposure. Implementation of an inner-city smoke-free zone encompassing a large tertiary hospital and two educational institutions was associated with a substantial decline in the number of smokers in the zone, as well as in the larger area. Voluntary outdoor smoke-free zones can help reduce the number of smokers in the area and protect people from secondhand smoke. There is a need to explore effectiveness of additional measures to further improve compliance

Een rookvrije omgeving in het belang van het kind

Achtergrond: het percentage rokers onder medewerkers van de verslavingszorg is hoger dan onder de Nederlandse bevolking. Voor een succesvolle behandeling van een tabaksverslaving is het van groot belang dat de behandelaar niet rookt. Verslavingszorg Noord Nederland (VNN) streeft ernaar rookvrij te zijn, en daarom richt dit onderzoek zich op het in kaart brengen van barrières die rokende medewerkers ervaren bij het stoppen met roken.Methode: in totaal hebben 39 medewerkers van VNN een vragenlijst ingevuld. Antwoorden van rokende en niet-rokende respondenten zijn met elkaar vergeleken, en verschillen tussen de antwoorden zijn getoetst met een Fisher’s exact test.Resultaten: van de respondenten geeft 41 % aan te roken, van wie ruim 56 % dagelijks. Rokende respondenten lijken de barrières om te stoppen met roken voornamelijk bij zichzelf (dus in de interne context) te zoeken en minder in de omgeving (de externe context).Conclusie: de resultaten van dit onderzoek laten zien dat rokende respondenten door hun verslaving een beperktere blik hebben op de potentiële barrières om te stoppen met roken. Het is dus belangrijk om rokende medewerkers bewust te maken van het feit dat ze door het eigen rookgedrag bij anderen de behoefte aan roken versterken of anderen kunnen aanzetten om te gaan roken.<br/

Smokers’ responses to being addressed when smoking in an outdoor voluntary smoke-free zone:An observational study

INTRODUCTION: Addressing smokers who smoke in a voluntary smoke-free area is vital to its successful implementation. Many people perceive barriers in addressing smokers due to fear of negative responses. Insights in actual responses are currently lacking. METHODS: This is an observational field study at the voluntary smoke-free zone surrounding the Erasmus MC and two schools in Rotterdam, the Netherlands. In the first month after implementing the zone, Erasmus MC representatives performed rounds to address smokers who were smoking inside the zone. Four people observed addressors for two weeks then they also addressed the smokers. Smokers were classified as employees, patients, students, or other. We noted whether smokers were addressed directly or indirectly, and their verbal and behavioral responses to being addressed. Differences between the responses of the groups were assessed using chi-squared tests. RESULTS: In all, 331 smokers were observed of whom 73% were addressed directly. Most verbal reactions were positive (46%) or neutral (18%). Employees were more likely to respond guiltily, whereas patients more often responded angrily than the others. After being addressed, the majority of smokers either extinguished their cigarette (41%) or left to continue smoking outside the smoke-free zone (34%). CONCLUSIONS: Most smokers showed a positive or neutral response when being addressed about smoking inside the smoke-free zone and the majority adapted their behavior to comply with the policy. These findings may help decrease barriers for those in doubt about addressing smokers that fail to comply with a smoke-free policy

Pediatric patients' views regarding smoke-free hospital grounds compared to those of adults:A survey study

INTRODUCTION: Children are important stakeholders in discussions about regulation of smoking and protection from secondhand smoke, but are rarely acknowledged as such. We explored the opinion of pediatric patients and other key stakeholders regarding the planned smoke-free zone around the Erasmus MC, a large university hospital in the Netherlands. METHODS: In 2019, we conducted a survey among pediatric patients and their parents, Erasmus MC employees, visitors, and adult patients, before implementation of the outdoor smoke-free zone, to assess their opinions on smoking and the planned smoke-free policy. Qualitative and quantitative data were collected and analyzed mostly using descriptive statistics and thematic analysis. RESULTS: In all, 91 parent-child dyads and 563 employees, visitors, patients and students filled in the questionnaires. Over 90% of children reported that they were regularly exposed to tobacco smoke, most often on the streets. Many underlined the exemplary role of healthcare providers, and 89% felt that nobody should be allowed to smoke near the hospital. Among parents, 89% were (very) positive towards the planned implementation of the smoke-free zone. In addition, 70% of adult patients, 81% of employees, 65% of visitors, 89% of students and 75% of ‘others’ were (very) positive about the new smoke-free policy. Smokers and former smokers generally were less positive about the policy. CONCLUSIONS: Children generally disapproved smoking around a hospital and felt that healthcare providers should be a good example concerning not smoking. The majority of adult patients, employees and visitors support a smoke-free zone surrounding the hospital, and virtually all pediatric patients and their parents do. Children should be acknowledged as important stakeholders in smoke-free policies and should be involved in planning and implementation

Smoke and Alcohol Free with EHealth and Rewards (SAFER) pregnancy study:a before-after study protocol

Despite existing interventions, tobacco smoking and alcohol consumption during pregnancy are common. The Smoke and Alcohol Free with EHealth and Rewards (SAFER) pregnancy intervention combines monthly group sessions, access to a web-based platform and incentives upon biochemically validated cessation for a maximum duration of 6 months to promote cessation of smoking and alcohol use before and during pregnancy. To inform development of the SAFER pregnancy intervention, two focus groups with the target population were held beforehand, with results reported here alongside the final SAFER pregnancy study protocol. In a before-after study we aim to include 66 women who are pregnant or have a wish to become pregnant and who smoke and/or consume alcohol (i.e. target population of the SAFER pregnancy intervention). The primary outcome measure is cessation of smoking and/or alcohol use at 34-38 weeks of gestation, or after six group sessions if women did not become pregnant during the study period. Secondary outcomes focus on the barriers and facilitators for implementation of the SAFER pregnancy intervention

Incentives for smoking cessation during pregnancy:an ethical framework

INTRODUCTION: Smoking during pregnancy increases the risk of morbidity and mortality of the mother and child. The inability of the unborn child to protect itself, raises the social and academic responsibility to protect the child from the harmful effects of smoking. Interventions including rewards ('incentives') for lifestyle changes are an upcoming trend and can encourage women to quit smoking. However, these incentives can, as we will argue, also have negative consequences, for example the restriction of personal autonomy and encouragement of smoking to become eligible for participation. To prevent these negative consequences, we developed an ethical framework that enables to assess and address unwanted consequences of incentive-based interventions whereby moral permissibility can be evaluated. METHODS: The possible adverse consequences of incentives were identified through an extensive literature search. Subsequently, we developed ethical criteria to identify these consequences based on the biomedical ethical principles of Beauchamp and Childress. RESULTS: Our framework consists of twelve criteria. These criteria concern (i) effectiveness, (ii) support of a healthy lifestyle, (iii) motivational for the target population, (iv) stimulating unhealthy behaviour, (v) negative attitudes, (vi) personal autonomy, (vii) intrinsic motivation, (viii) privacy, (ix) fairness, (x) allocation of incentives, (xi) cost-effectiveness, and (xii) health inequity. Based on these criteria, the moral permissibility of potential interventions can be evaluated. CONCLUSION: Incentives for smoking cessation are a response to the responsibility to protect the unborn child. But these interventions might have possible adverse effects. This ethical framework aims to identify and address ethical pitfalls in order to avoid these adverse effects

Identifying the needs for a web-based postpartum platform among parents of newborns and health care professionals: qualitative focus group study

Background: During the turbulent postpartum period, there is an urgent need by parents for support and information regarding the care for their infant. In the Netherlands, professional support is provided during the first 8 days postpartum and for a maximum of 8 hours a day. This care is delivered by maternity care assistants (MCAs). Despite the availability of this extensive care, a majority of women prefer to make use of a lesser amount of postpartum care. After this period, access to care is less obvious. Where parents are automatically offered care in the first 8 days after birth, they must request care in the period thereafter. To compensate for a possible gap in information transfer, electronic health (eHealth) can be a valuable, easily accessible addition to regular care. Objective: We explored the needs and preferred

The Value of Early Tumor Size Response to Chemotherapy in Pediatric Rhabdomyosarcoma

Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood. Results of clinical trials, with three-year event-free and overall survival as primary outcomes, often take 7 to 10 years. Identification of an early surrogate biomarker, predictive for survival, is therefore crucial. We conducted a systematic review to define the prognostic value of early tumor size response in children with IRSG group III rhabdomyosarcoma. The search included MEDLINE/EMBASE from inception to 18 November 2020. In total, six studies were included, describing 2010 patients, and assessed by the Quality in Prognosis Studies (QUIPS) instrument. Four studies found no prognostic value for tumor size response, whereas two studies reported a prognostic effect. In these two studies, the survival rate of patients with progressive disease was not separately analyzed from patients with stable disease, potentially explaining the difference in study outcome. In conclusion, our findings support that early progression of disease is associated with poorer survival, justifying adaptation of therapy. However, in patients with non-progressive disease, there is no evidence that the degree of response is a prognostic marker for survival. Because the vast majority of patients do not have progressive disease, early tumor size response should be reconsidered for assessment of treatment efficacy. Therefore, at present, early surrogate biomarkers for survival are still lacking