Cowden Syndrome

TARGET-VM is a modular open-label, signal seeking, phase II trial of targeted therapies for patients with vascular malformations. Patients with vascular malformations which are refractory to standard therapies, or in whom standard therapy is not appropriate, are potentially eligible for the clinical trial. Vascular malformations will be classified as slow-flow or fast-flow lesions using established clinical criteria. Genetic testing to identify causative variants in genes affecting the phosphoinositide 3-kinase (PI3K) signalling pathway for slow-flow vascular malformations or the Mitogen-Activated Protein Kinase (MAPK) signalling pathway for fast-flow vascular malformations must be performed using research protocols or commercial testing assays that are external to this clinical trial. The study consists of individual modules, each evaluating the clinical efficacy of 48 weeks of targeted therapy. The treatment modules are: 1. Module 1 - Treatment for slow-flow vascular malformations Eligible patients with slow-flow vascular malformations with an identified causative variant in the PI3K signalling pathway will receive alpelisib, an oral alpha-specific PI3-kinase inhibitor for a total duration of 48 weeks as monotherapy (treatment period), followed by 24 weeks of follow-up (follow-up period). 2. Module 2 - Treatment for fast-flow vascular malformations Eligible patients with fast-flow vascular malformations with an identified causative variant in the MAPK signalling pathway will receive mirdametinib, an investigational oral MEK inhibitor for a total duration of 48 weeks as monotherapy (treatment period), followed by 24 weeks of follow-up (follow-up period). TARGET-VM will be conducted only in Victoria, Australia.

Background: * RASopathies are a group of neurodevelopmental genetic conditions caused by mutations affecting components within the RAS-map kinase (RAS-MAPK) cellular signaling pathway. * Caregivers of children with a RASopathy are faced with numerous challenges related to the physical, cognitive, and behavioral symptoms associated with their child s condition. * The use of virtual interventions has been increasing over the past decade, which increase accessibility and are especially critical during times of physical distancing, such as due to COVID-19. * Similarly, Ecological Momentary Assessments (EMA) are being utilized more frequently in order to maximize ecological validity of results and minimize recall bias. * To our knowledge, no psychological interventions have been investigated targeting parenting stress among caregivers of a child with a RASopathy. Primary Objectives: * Internal Pilot Study: To assess the feasibility (e.g., enrollment and attrition) and acceptability (e.g., satisfaction) of an Acceptance and Commitment Therapy (ACT) coping intervention on parenting stress for caregivers of a child with a RASopathy * Randomized Controlled Trial (RCT): To compare Parental Stress Scale (PSS) changes from baseline to 8 weeks between the Immediate Intervention Arm and the Waitlist Control Arm Eligibility: * Caregiver (parent or legal guardian) of a child (\< 18 years) residing with them at least 50% of the time who has a diagnosis of RASopathy syndrome including NF1, Noonan Syndrome, Legius Syndrome, Cardiofaciocutaneous (CFC) syndrome, and Costello Syndrome, or another RASopathy * Access to necessary resources for participating in a technology-based intervention (i.e., computer, smartphone, internet access) or be willing to use an iPod provided by the study team * Must score a 15 or higher total score on modified questions from the PSS to indicate at least a moderate level of parenting stress * Ability to read and speak English Design: * This is an 8-week psychological intervention study that has two phases: the first, an internal pilot study, will enroll an initial, small cohort of caregivers (n = 8), all of whom will participate in the ACT intervention. (COMPLETE) * Due to the success of the internal pilot study (with specific benchmarks met), the second phase of this study will be an RCT comparing participants who receive the intervention immediately (Immediate Intervention Arm) with those in a control group (Waitlist Control Arm). Participants randomized to the Waitlist Control Arm will cross over to receive the intervention after the waitlist period. * The intervention for the RCT phase involves a baseline 90-minute coaching session and two follow-up coaching sessions with a therapist over video chat, followed by weekly prerecorded video modules that the participants can view at their convenience over the following 8 weeks. * Participants will complete measures of parenting stress, mindfulness, psychological flexibility, self-compassion, and perceptions of child well-being at baseline, the 8-week post-intervention assessment, and a 3-month follow-up assessment. Additionally, the study will use EMA whereby questions will be sent electronically at random times and days (once a day at varying times on 5 days a week) during weeks 0-8 (the first week will serve as baseline data for comparison) for the Immediate Intervention Arm and weeks 0-18 for the Waitlist Control Arm using the Catalyst mobile application by MetricWire software. * We plan to enroll 8 participants in the internal pilot phase and 56 participants in the RCT phase to account for the potential attrition of two caregivers from the intervention, for a total accrual target of 64 evaluable participants.

The purpose of this study is to examine the impact of new cancer genetic counseling models that aim to increase patient engagement with the genetics team. To do this, the study consists of two trials to evaluate two related interventions. The first trial is the EfFORT Trial, which evaluates a cascade genetic testing intervention. Cascade testing is the process of offering genetic testing to people who are at risk of having inherited a possibly harmful gene change that has been found in their family. The study will look at how often genetic testing occurs when healthcare providers have permission to reach out to family members to recommend genetic testing and to help those who are interested get tested. The study will look at whether this cascade testing intervention is practical and effective. The study would like to see how this approach of healthcare providers reaching out directly to family members compares with the usual approach of patients telling their family members about the recommendation to get genetic testing. The second trial is the STRIVE Trial, which evaluates an intervention designed to help patients who receive an uncertain result from genetic testing (also called a "variant of uncertain significance") stay connected with their genetics care team, and to help patients and their primary care providers stay up-to-date about the meaning of uncertain genetic test results. The study will look at whether an intervention that consists of a study online portal for patients with uncertain genetic test results and their primary care providers will help them to stay up-to-date on the meaning of uncertain genetic test results. The study would like to see how this intervention compares to the usual approach of encouraging patients to re-contact their genetics care team on their own about a year after getting genetic testing."

Cancer Predisposition Syndromes (CPS), caused by germline mutations in cancer predisposition genes (CPG) are heritable disorders associated with an increased risk of developing certain types of cancer. Knowledge of CPG will advance the understanding of tumorigenesis, improve patient care, and facilitate genetic counselling of patients and families. But the prevalence of CPS in Australian children with cancer and the psychosocial impact of germline sequencing to identify CPG have not been studied. The clinical benefit of family-based WGS in every new child with cancer compared with conventional predictive factors is currently unknown. By testing every child with newly diagnosed cancer the aim is to determine the utility of this approach and its impact on participants and families. The principal objective of the proposed multicentre prospective study is establish the clinical benefit and utility of family-based WGS to identify underlying CPS in every newly diagnosed child with cancer.

After collection of the non objection and verification of the eligibility criteria, a first clinical questionnaire will be completed by the participant and the prescribing physician to collect the main medical events including the history of malignant tumor pathologies until the date of inclusion in the study. Thereafter, an annual questionnaire will be sent to the participants to update the elements related to a tumor pathology. For the case of patients who have died or been lost to follow-up, only the information from the first clinical questionnaire will be collected from the data available from the prescribing physician without informing the relatives. However, the investigating center will have to check that these patients have not objected, during their lifetime, to the use of their data.

Through the CHARM Consortium (www.charmconsortium.ca), the investigators have shown that cell-free DNA (cfDNA) profiling can enable more frequent cancer surveillance from readily accessible blood collections. The investigators are now conducting a prospective, multi-center, randomized control trial of cfDNA testing of 1,000 HCS carriers from across Canada to 1) compare cancer detection rates with and without cfDNA testing, 2) assess cancer stage shift and clinical impact reducing mortality and morbidity cancers, and 3) assess impact of access to cfDNA results on patients' quality of life and psychological distress.

In this study, the investigators aim to compare a mobile health platform, known as a 'chatbot,' that leverages artificial intelligence and natural language processing to scale communication, to 'usual care' that patients would receive. This comparison will enable the investigators to determine if the chatbot system can improve rates of recommendation for genetic testing among patients at elevated risk of harboring a familial cancer syndrome in an all-Medicaid gynecology clinic. Furthermore, the investigators aim to evaluate facilitators of inequity in regard to patient access to and utilization of genetic testing services.

Study Description:\<TAB\> The RASopathies are a clinically defined group of disorders caused by pathogenic germline variants in genes encoding components of the Ras/mitogen-activated-protein kinase (Ras/MAPK) pathway. These disorders have overlapping clinical features due to Ras/MAPK dysfunction, including a predisposition to the development of certain malignancies. The aims of this prospective longitudinal cohort study are to determine the incidence of malignancy in patients with RASopathies and determine the underlying differences in those who develop tumors as compared to those who do not, in order to inform cancer screening recommendations. In addition, this longitudinal cohort study will provide a better understanding of non-tumor RASopathy manifestations. Objectives: Primary Objectives: * To establish a longitudinal cohort of participants with a clinical diagnosis of a RASopathy and/or a pathogenic germline variation in a Ras/MAPK pathway gene (excluding NF1). * To study the lifetime rates of cancer development in participants with a RASopathy. * To longitudinally characterize germline RASopathy-related tumor and non-tumor clinical manifestations. Secondary Objectives: * To create a biospecimen repository of carefully annotated tissue samples for use in subsequent etiologically oriented translational research projects. * To describe novel phenotypes associated with germline Ras/MAPK pathway genetic variation. Endpoints:\<TAB\> * Number of participants meeting enrollment criteria for inclusion in the RASopathy cohort. * Development of RASopathy-associated neoplasms in patients with RASopathies other than neurofibromatosis type 1 (NF1). * Longitudinal standardized quantitative evaluations of specific RASopathy manifestations.

The overall objective of this project is to refine and study Nest, a software platform that integrates genetic data into patient care, with a goal of improving adherence to recommended care and empowering patients and clinicians to utilize genetic information longitudinally. Nest stores structured genetic results in the electronic medical record (EMR) and provides an interface for clinicians to order guidelines-based, personalized care plans with automated charting. For patients, the mobile friendly platform serves as a secure tool to store results, understand risks and recommended care, adhere to care, and share results with at-risk relatives. To facilitate continuity of care, patients can share genetic results and care plans with other clinicians. For this application, the investigators propose two phases. During Phase 1, the investigators will pilot the EMR-integrated Nest platform to ensure that the intervention is feasible and acceptable to clinicians and patients. Phase 2 will test Nest efficacy to improve patient and clinician experiences and outcomes, including patient knowledge of cancer risks and recommended care, and will assess implementation outcomes to facilitate future dissemination. The investigators will leverage a team with complementary expertise in genomic data, business, software development, and care of young adults with cancer risk. This team has already successfully collaborated in development of a patient-facing intervention for adolescents and young adults (AYAs) with cancer risk syndromes, and now seeks to meet the critical need for integrated and coordinated care, crossing patients, clinicians, and health systems. The long-term goal of this application is to harness an EMR integrated platform to improve care and outcomes for AYAs with cancer risk syndromes, as an initial step toward genomic data integration for an ever-increasing array of conditions with clinical implications. Phase 1 Aims: Aim 1: Pilot Nest among 20 young adult hereditary cancer patients and up to 20 clinicians, refining implementation to ensure feasibility and acceptability. Our working hypothesis is that the Nest intervention will be feasible and acceptable to patients and clinicians. Phase 2 Aims: In Phase 2, the investigators will Implement the Nest intervention by conducting a randomized trial at a single large cancer center and its associated community-based satellites. Aim 1: Measure the impact of the Nest intervention on patient knowledge of cancer risk and recommended care, psychological distress, and information sharing with family and clinicians. Our working hypothesis is that patients assigned to the Nest intervention will have increased knowledge of cancer risks and recommended care, without increased psychological distress, and will have increased frequency of information sharing with family and other clinicians. Aim 2: Examine impact of the Nest intervention on clinician behavior, including guideline-concordant orders and referrals as well as EMR documentation. Our working hypothesis is that patients assigned to the Nest intervention will have higher rates of guidelines-concordant orders and referrals and Nest Clinical Decision Support (CDS) summaries in EMR documentation. Aim 3: Evaluate implementation outcomes, including patient and clinician utilization of Nest features, to facilitate future dissemination. The investigators will examine the frequency of utilization of Nest features, including patient access and sharing of information and clinician use of orders and documentation templates, to assess features that are most useful and/or in need of further refinement. Impact: At the completion of the proposed research, our expected outcomes are: to have a refined platform that results in increased knowledge, information sharing, and guidelines concordant care.

Background Kidney, prostate, bladder, testis and penile cancer account for 22% of cancers diagnosed in the United States and are responsible for 10% of cancer deaths each year in the U.S. Understanding the genes and gene pathways that cause genitourinary malignancies will provide the foundation for the development of targeted therapeutic agents for patients affected with these cancers. Since 1982 investigators in the Urologic Oncology Branch have been studying the genetic basis of urologic cancers. The identification of the genes for cancer of the kidney has led to the approval by the FDA of a number of new agents for patients with advanced disease. It is our goal to study the cancer gene pathways of genitourinary malignancies in order to further understand the cancer gene pathways that cause these diseases. Objectives Collection of benign and malignant tissue from patients with known or suspected cancer Collection of benign and malignant tissue from patients with rare inherited conditions associated with an increased risk for kidney cancer Determine the molecular genetic differences between normal and tumorigenic tissues Investigate the categories of genes/ biochemical pathways such as those that influence the cell cycle, angiogenesis, metabolic changes, and metastatic potential Examine protein expression and bioimmunoassays investigating potential genetic markers Investigate cellular/biochemical response to existing and novel therapeutic agents. Investigate quality of life in men who have prostate cancer Investigate molecular genetic basis of urologic malignancies Examine cell free DNA and circulating tumor DNA for cancer gene mutations Eligibility Patients with biopsy-proven malignant disease Patients suspected of having malignant disease Patients with known or suspected inherited urologic malignant disorder Family members (related by blood) of patients who have or are suspected of having an inherited genitourinary disorder or malignancy Family members of patients with a DNA variant Design Patients will be screened for eligibility in the Urologic Oncology Branch Clinic Blood and urine samples may be obtained Normal and malignant tissue may be collected from patients undergoing clinically indicated surgical procedures Basic scientific research will be performed on collected specimens Patients will have the option to be contacted if a result is detected that would affect their health and they will be given the opportunity to be evaluated and re-tested on an IRB approved protocol if available Germline and somatic whole genome exome sequencing may be performed