The LEGACy study: a European and Latin American consortium to identify risk factors and molecular phenotypes in gastric cancer to improve prevention strategies and personalized clinical decision making globally

Gastric cancer; Tumor microenvironment; PreventionCàncer gàstric; Microambient tumoral; PrevencióCáncer gástrico; Microambiente tumoral; PrevenciónBackground Gastric Cancer (GC) is the fourth most deadly cancer worldwide. Enhanced understanding of its key epidemiological and molecular drivers is urgently needed to lower the incidence and improve outcomes. Furthermore, tumor biology in European (EU) and Latin American (LATAM) countries is understudied. The LEGACy study is a Horizon 2020 funded multi-institutional research approach to 1) detail the epidemiological features including risk factors of GC in current time and 2) develop cost-effective methods to identify and integrate biological biomarkers needed to guide diagnostic and therapeutic approaches with the aim of filling the knowledge gap on GC in these areas. Methods This observational study has three parts that are conducted in parallel during 2019–2023 across recruiting centers from four EU and four LATAM countries: Part 1) A case-control study (800 cases and 800 controls) using questionnaires on candidate risk factors for GC, which will be correlated with clinical, demographic and epidemiological parameters. Part 2) A case-control tissue sampling study (400 cases and 400 controls) using proteome, genome, microbiome and immune analyses to characterize advanced (stage III and IV) GC. Patients in this part of the study will be followed over time to observe clinical outcomes. The first half of samples will be used as training cohort to identify the most relevant risk factors and biomarkers, which will be selected to propose cost-effective diagnostic and predictive methods that will be validated with the second half of samples. Part 3) An educational study, as part of our prevention strategy (subjects recruited from the general public) to test and disseminate knowledge on GC risk factors and symptoms by a questionnaire and informative video. Patients could be recruited for more than one of the three LEGACy studies. Discussion The LEGACy study aims to generate novel, in-depth knowledge on the tumor biological characteristics through integrating epidemiological, multi-omics and clinical data from GC patients at an EU-LATAM partnership. During the study, cost-effective panels with potential use in clinical decision making will be developed and validated.This work was funded by the European Union’s Horizon 2020 research and innovation program (Grant agreement No GA825832). The European Union will not be involved in the collection, analysis and interpretation of data, in writing future manuscripts or deciding to submit manuscripts for publication

International consensus on the management of metastatic gastric cancer:step by step in the foggy landscape: Bertinoro Workshop, November 2022

Background: Many gastric cancer patients in Western countries are diagnosed as metastatic with a median overall survival of less than twelve months using standard chemotherapy. Innovative treatments, like targeted therapy or immunotherapy, have recently proved to ameliorate prognosis, but a general agreement on managing oligometastatic disease has yet to be achieved. An international multi-disciplinary workshop was held in Bertinoro, Italy, in November 2022 to verify whether achieving a consensus on at least some topics was possible. Methods: A two-round Delphi process was carried out, where participants were asked to answer 32 multiple-choice questions about CT, laparoscopic staging and biomarkers, systemic treatment for different localization, role and indication of palliative care. Consensus was established with at least a 67% agreement. Results: The assembly agreed to define oligometastases as a “dynamic” disease which either regresses or remains stable in response to systemic treatment. In addition, the definition of oligometastases was restricted to the following sites: para-aortic nodal stations, liver, lung, and peritoneum, excluding bones. In detail, the following conditions should be considered as oligometastases: involvement of para-aortic stations, in particular 16a2 or 16b1; up to three technically resectable liver metastases; three unilateral or two bilateral lung metastases; peritoneal carcinomatosis with PCI ≤ 6. No consensus was achieved on how to classify positive cytology, which was considered as oligometastatic by 55% of participants only if converted to negative after chemotherapy. Conclusion: As assessed at the time of diagnosis, surgical treatment of oligometastases should aim at R0 curativity on the entire disease volume, including both the primary tumor and its metastases. Conversion surgery was defined as surgery on the residual volume of disease, which was initially not resectable for technical and/or oncological reasons but nevertheless responded to first-line treatment.</p

Promoter methylation of Wnt-antagonists in polypoid and nonpolypoid colorectal adenomas

BACKGROUND: Nonpolypoid adenomas are a subgroup of colorectal adenomas that have been associated with a more aggressive clinical behaviour compared to their polypoid counterparts. A substantial proportion of nonpolypoid and polypoid adenomas lack APC mutations, APC methylation or chromosomal loss of the APC locus on chromosome 5q, suggesting the involvement of other Wnt-pathway genes. The present study investigated promoter methylation of several Wnt-pathway antagonists in both nonpolypoid and polypoid adenomas. METHODS: Quantitative methylation-specific PCR (qMSP) was used to evaluate methylation of four Wnt-antagonists, SFRP2, WIF-1, DKK3 and SOX17 in 18 normal colorectal mucosa samples, 9 colorectal cancer cell lines, 18 carcinomas, 44 nonpolypoid and 44 polypoid adenomas. Results were integrated with previously obtained data on APC mutation, methylation and chromosome 5q status from the same samples. RESULTS: Increased methylation of all genes was found in the majority of cell lines, adenomas and carcinomas compared to normal controls. WIF-1 and DKK3 showed a significantly lower level of methylation in nonpolypoid compared to polypoid adenomas (p < 0.01). Combining both adenoma types, a positive trend between APC mutation and both WIF-1 and DKK3 methylation was observed (p < 0.05). CONCLUSIONS: Methylation of Wnt-pathway antagonists represents an additional mechanism of constitutive Wnt-pathway activation in colorectal adenomas. Current results further substantiate the existence of partially alternative Wnt-pathway disruption mechanisms in nonpolypoid compared to polypoid adenomas, in line with previous observations

Promoter methylation of Wnt-antagonists in polypoid and nonpolypoid colorectal adenomas.

BACKGROUND: Nonpolypoid adenomas are a subgroup of colorectal adenomas that have been associated with a more aggressive clinical behaviour compared to their polypoid counterparts. A substantial proportion of nonpolypoid and polypoid adenomas lack APC mutations, APC methylation or chromosomal loss of the APC locus on chromosome 5q, suggesting the involvement of other Wnt-pathway genes. The present study investigated promoter methylation of several Wnt-pathway antagonists in both nonpolypoid and polypoid adenomas. METHODS: Quantitative methylation-specific PCR (qMSP) was used to evaluate methylation of four Wnt-antagonists, SFRP2, WIF-1, DKK3 and SOX17 in 18 normal colorectal mucosa samples, 9 colorectal cancer cell lines, 18 carcinomas, 44 nonpolypoid and 44 polypoid adenomas. Results were integrated with previously obtained data on APC mutation, methylation and chromosome 5q status from the same samples. RESULTS: Increased methylation of all genes was found in the majority of cell lines, adenomas and carcinomas compared to normal controls. WIF-1 and DKK3 showed a significantly lower level of methylation in nonpolypoid compared to polypoid adenomas (p < 0.01). Combining both adenoma types, a positive trend between APC mutation and both WIF-1 and DKK3 methylation was observed (p < 0.05). CONCLUSIONS: Methylation of Wnt-pathway antagonists represents an additional mechanism of constitutive Wnt-pathway activation in colorectal adenomas. Current results further substantiate the existence of partially alternative Wnt-pathway disruption mechanisms in nonpolypoid compared to polypoid adenomas, in line with previous observations

Respectful leadership:Reducing performance challenges posed by leader role incongruence and gender dissimilarity

We investigate how respectful leadership can help overcome the challenges for follower performance that female leaders face when working (especially with male) followers. First, based on role congruity theory, we illustrate the biases faced by female leaders. Second, based on research on gender (dis-)similarity, we propose that these biases should be particularly pronounced when working with a male follower. Finally, we propose that respectful leadership is most conducive to performance in female leader–male follower dyads compared with all other gender configurations. A multi-source field study (N = 214) provides partial support for our hypothesis. While our hypothesized effect was confirmed, respectful leadership seems to be generally effective for female leaders irrespective of follower gender, thus lending greater support in this context to the arguments of role congruity rather than gender dissimilarity

Improving adaptive and cognitive skills of children with an intellectual disability and/or autism spectrum disorder: Meta-analysis of randomised controlled trials on the effects of serious games

The aim of this meta-analysis is to investigate the effectiveness of serious games on social and cognitive skills of children with an intellectual disability (ID) and/or autism spectrum disorder (ASD). Randomised controlled trials of the effectiveness of serious games were identified through a systematic search of PubMed, Web of Science, PsycINFO, and Embase, using keywords related to serious games and the target groups. Eleven studies with a total of 654 participants (mean age 4–11 years) were included. The methodological quality of the studies was assessed using the Cochrane risk of bias assessment tool V2. Serious games were associated with improved adaptive and cognitive skills of children with ID or ASD compared with controls, with a small effect size (g = 0.420, 95% confidence interval 0.130–0.710; p = .009; number needed to treat = 4.28), with moderate to high heterogeneity. Multiple influence analyses showed that zero heterogeneity could be achieved with exclusion of three studies, one by one, while retaining a significant effect size. Moderation analyses showed no significant differences between the skills examined, the type of controls, involvement of another person, duration of the intervention, or age of the children. These findings indicate that serious games are linked to improvements in adaptive and cognitive functioning of children with ID or ASD, but the association is not necessarily straightforward. Although more study is needed into the effective elements of these games, these results represent an important first step in implementing serious games proven to strengthen daily functioning and social participation of children with ID or ASD

The co-creation design process of ‘You &amp; I’: a serious game to support mentalizing and stress-regulating abilities in adults with mild to borderline intellectual disabilities

Interventions to support mentalizing abilities are relevant for all people to enhance social skills and well-being. For people with mild to borderline intellectual disabilities, learning mentalizing skills may be challenging, however, because of the abstract and complex nature of the construct. The application of serious games has the potential to teach and train in these skills and engage this target group in treatment. This study investigates the key elements of a design model for a serious game aimed at learning abstract skills, taking into account the needs and wishes of adults with mild to borderline intellectual disabilities. We first searched the literature for guidelines covering effective interventions and for game design elements with the potential to train in abstract skills and motivate this specific group. We then included co-researchers with mild to borderline intellectual disabilities in guiding the development of the serious game ‘You & I’. Here we describe application of the recommendations from the literature to the development of the game and the co-creation process. This process resulted in key elements described in a design model that provides more structured knowledge for future studies of teaching abstract skills using a serious game in this population

Self-reported support needs and available support resources for siblings (6-12 years) of children with intellectual disability and/or visual impairment in the Netherlands and Belgium: do they match?

Having a brother or sister with a disability can impact the well-being and mental health of their siblings. For example, in a recent meta-analysis it has been found that siblings of children with chronic health conditions ‘may be at increased risk of depression’ (Martinez et al., 2022). In order to gain understanding of the experiences of these siblings, several studies including interviews with siblings of children with chronic health conditions have been done (Mandleco &amp; Webb, 2015; Moyson &amp; Roeyers, 2012; Vella Gera et al., 2021). Based on these interviews, implications were made about the support needs of siblings. It has for example been concluded that siblings need support with dealing with the behaviour of their brother or sister, or will benefit from learning that they are not alone in their experiences (Mandleco &amp; Webb, 2015; Moyson &amp; Roeyers, 2012). In other studies, siblings were asked about their support needs directly. For example, one study investigated the support needs of siblings (age 12-14 years) of children with cancer through focus groups and one-on-one interviews with siblings and caregivers, resulting in 10 domains of need (Patterson et al., 2011). Another study used retrospective one-on-one interviews with adult siblings of persons with disabilities or chronic illness, focusing both on their childhood experiences and the support they missed (Hanvey et al., 2022). A third study used questionnaires and one-on-one interviews about online support needs with siblings (age 11-21 years) of children with chronic conditions (Joosten et al., 2019). However, no studies have been found in which school age (6-12 years) siblings of children with intellectual disability (ID) or visual impairment (VI) were interviewed directly about their support needs. Focusing on the other end, the support that is being offered to siblings, several systematic reviews about studied sibling interventions have been computed. For example in a recent systematic mixed-methods review it has been found that the researched sibling support programs can improve sibling well-being, although research methods are not always sound and accessibility could be improved (Wolff et al., 2022). Looking more into which resources are accessible, the available support sources for siblings of youth with chronic health conditions have recently been identified and analysed, finding that there are gaps in the available support (Nguyen et al., 2021). In order to offer support resources that match the support needs of siblings, more knowledge is needed about which interventions should be offered to which siblings and how (Wolff et al., 2022), Therefore, in the current study the support needs of siblings of children with intellectual disability (ID) and/or visual impairment (VI) will be investigated through one-on-one interviews with siblings between the age of six and twelve years old. Thematic analysis will be used to find themes of support needs, received support, and desired types of support. In addition, a systematic inventory of the available Dutch support resources for siblings in the Netherlands and Belgium will be made. Next, the available support will be linked to the self-reported support needs of siblings, by coding the support resources with a checkbox created based on the interview results. This study will provide the clinical field with an overview of support needs and available resources, and will point out which support needs still need to be met. The definition of support that will be used in this study is: ‘‘Supports are resources and strategies that aim to promote the development, education, interests, and personal well-being of a person and that enhance individual functioning’ (Luckasson et al., 2002, p. 151). Support needs are defined based on ‘felt needs’: “what the person wants or perceives as needed” (Thompson et al., 2009)