Anavatti, India

Canada-wide Implementation of a Virtual Sexual Health and Rehabilitation eClinic (SHAReClinic) for Prostate Cancer Patients and Their Partners

Detailed Description The considerable prevalence of sexual dysfunction (SD) after prostate cancer (PCa) treatment makes SD post-treatment a substantial health-related quality of life burden for patients and their partners. Research indicates that 40% to 75% of men suffer from SD post-PCa. Sixty percent of men experience significant distress in response to SD. Significant distress is also reported by partners and couples. Overall, patients cite sexual health concerns as the most significant unmet need following treatment for PCa. Accordingly, there is an existent need for equitable, timely, and affordable access to high-quality SD treatment for Canadian PCa patients and their partners. Unfortunately, none of the empirically-based, comprehensive interventions reported in the literature have been implemented into clinical settings in Canada. The lack of translation from research evidence to clinical implementation is common across healthcare provision. It is known that most research, even positive full-scale studies, do not result in practice-change or take years to do so. A key aspect contributing to this lack of knowledge translation is the complexity of transitioning an "experimental intervention" to "real world" clinical settings. In sexual healthcare in oncology, ineffective knowledge translation is ubiquitous and includes several unique complexities that impair the implementation, integration, and sustainability of empirically-based treatment. The recent advent of virtual care in healthcare offers an opportunity to address many of the barriers to implementing sexual recovery programs within PCa treatment facilities. Virtual care provides greater accessibility for patients not proximal to cancer centres, or who are unable to travel due to financial constraints or physical limitations. Encouragingly, examples of internet-delivered interventions exist for men with PCa and their partners. Schover and colleagues found that a digitally-based intimacy enhancement intervention was as effective as a brief in-person sex therapy intervention in improving sexual outcomes in couples after PCa. Although these advances in models of care provision are inspiring, the majority of Canadian PCa patients and their partners have yet to benefit from virtual care innovations. In an effort to advance evidence-based survivorship programming in the treatment of SD post-PC, a team of expert Canadian healthcare practitioners and patient/partner advocates developed the Sexual Health and Rehabilitation eClinic (SHAReClinic). SHAReClinic is a web-based, bio-psychosocial SD intervention specifically for patients/couples who have undergone treatment for PCa. A pilot study evaluating the acceptability and engagement of SHAReClinic achieved significant patient activity on the platform and 80% patient engagement at 1-year follow-up. Additionally, evaluation of the effectiveness of SHAReClinic showed non-inferior sexual health outcomes when compared to a "best practice" in-person sexual health clinic. Rationale Sexual dysfunction after PCa treatment has significant adverse impacts on patient/partner health-related quality of life. Few Cancer Centres in Canada offer comprehensive care for SD post-PCa treatment, resulting in significant barriers to care equity and access. SHAReClinic is established as effective virtual care programming for SD post-PCa. The goal of this research is to evaluate the SHAReClinic in 2 cancer centres currently using it as usual care and 9 cancer centres which has newly implemented SHAReClinic as part of their usual care. The SHAReClinic will be offered to 1. Newly diagnosed patients at who are scheduled to undergo active treatment for localized prostate cancer, 2. patients currently undergoing active treatment for prostate cancer and 3. patients who have undergone prostate cancer treatment within the last 6 months. Active treatment can include any of the following options surgical, radiation, and/or ADT. The SHAReClinic goals are to re-establish optimal sexual function, satisfaction and to support the maintenance of intimacy following prostate cancer treatment. These goals are addressed through two complementary components: 1) a bio-medical component (erectile rehabilitation), focused on the long term penile health or short-term erectile function as per patient preference, and 2) a psychological component (intimacy maintenance), involving the maintenance or restoration of couples' intimacy and sexual activity (penetrative or non-penetrative). Both physical and psychological factors can affect patients' sexual satisfaction after cancer treatment; resultantly, interventions should incorporate a bio-psychosocial approach to rehabilitation. Study Design This is a prospective observational evaluation of a virtual sexual health and rehabilitation intervention program. As part of patient standard care, facilitated web-based clinic visits will be provided to patients once before treatment, 6 weeks, 10 weeks, 4 months, 6 months and 12 months post cancer treatment. Patients who opt-in to the SHAReClinic will also be invited to register for this study. The study involves no additional requirements from patients, as all questionnaires (baseline, 6-weeks, 6 months, and 12 months) are completed as part of their enrolment in the SHAReClinic. Patients experience in the SHAReClinic involves the following: Upon registration, patients will be paired with a sexual health coach from their center and asked about their availability to receive a phone/video call from their sexual health coach. At the beginning of the first clinic visit, participants will be asked to complete a set of questionnaires. The questionnaires take around 10-15 minutes to complete. Patients are also asked to complete the same questionnaires at 6 week, 6 months and 12 months. The topics covered in each clinic visit vary and are based on the treatment schedules of the participants. A Q&A session on the web page will be available for participants to leave any questions or concerns regarding their sexual health, rehabilitation process and the content of the portal. Participants are free to request for a check-in call with their sexual health coach if they want to chat about their concerns by phone. Each clinic visit will last approximately 30 minutes. If participants miss their clinic visit, they will get a notification from the platform and then a reminder call from their sexual health coach. At the end of their final SHAReClinic clinic visit, participants will be asked to fill out a satisfaction questionnaire, including questions about the ease of access to the website, their experience with SHAReClinic portals and communication with their sexual health coach. The satisfaction questionnaire takes about 10 minutes to complete.

The Feasibility and Efficacy of Dose Timing (Morning vs Evening) of Temozolomide in the Treatment of Glioblastoma

TMZ-CHRONO is a randomized, multi-centre pilot trial evaluating the feasibility of chronotherapy (dose-timing) for temozolomide (TMZ) in IDH-wildtype glioblastoma (GBM). The body's biological functions follow a circadian rhythm. Chronotherapy is the deliberate timing of medications to enhance therapeutic benefit and/or minimize toxicity, and can be achieved by dose-timing treatments. There is evidence suggesting that cancer cells may react differently to chemotherapy based on the time of day they are exposed. In fact, researchers have already found that giving anti-cancer treatments at a particular time of the day works better in rectal and ovarian cancer. TMZ is a standard of care treatment for GBM, however there is currently no consensus or guideline with respect to the optimal timing of adjuvant TMZ administration. The study team recently conducted systematic review on TMZ chronotherapy in the treatment of glioma. With emerging evidence that TMZ timing may be important, it is paramount to conduct a large pragmatic randomized study to assess this claim in GBM. The current study is a minimal risk pilot trial to inform the development of a larger, pragmatic randomized clinical trial in the future. Prospective participants will be approached by their physician (or a member within the circle of care) during their routine clinic visit to begin the integrated verbal consent model process. The physician will explain that the patient is receiving standard of care treatment, with the only change being the timing of adjuvant TMZ (morning vs evening). The physician will then ask the patient for verbal consent to participate in this research study and document this consent in the patient's electronic medical record. Eligible and consenting patients will be randomized to one of two study arms (morning administration of TMZ, and evening administration of TMZ) in a 1:1 fashion using a permuted block design through the Ottawa Methods Centre. Randomization will be stratified by cancer centre [The Ottawa Hospital Cancer Centre (TOHCC) and the London Health Sciences Centre (LHSC); Canada]. The participants and investigators will not be blinded to treatment arm allocations. The primary aim of the study is to understand if taking TMZ at a prescribed time of day (morning/evening) is feasible in adults with GBM. The secondary aims of the study are to evaluate participant recruitment, safety, health-related quality of life, and changes in condition over time. Data is collected throughout the study at baseline, randomization, pre/post-TMZ cycles, and at 4-, 8-, 12-, and 24-weeks following randomization. The study team will continue to follow the participant conditions after TMZ completion for up to 5 years. This pilot trial is the first and necessary step to assess the feasibility of randomized treatment allocation, rate of pill diary completion, and metrics surrounding participant accrual. This will help determine the number of recruitment sites and expected duration of accrual for a future pragmatic, randomized clinical trial on chronotherapy of TMZ in IDH-wildtype GBM.

A Study to Assess the Efficacy and Safety of Induction Therapy With RO7790121 in Participants With Moderately to Severely Active Crohn's Disease

Exercise Preconditioning to Protect Against Dialysis-induced Cardiac Injury

This will be the first randomized crossover-controlled trial with two experimental conditions assessing the impact of exercise preconditioning in the HD population. If proven effective exercise preconditioning could be developed as a therapeutic option to reduce rates of heart failure in the dialysis population.

Evaluating the Efficacy of the Study Product on Overall Cognitive Function in Children

The investigational product, Kids Plus Multi & Omega dietary supplement contains a mixture of vitamins, minerals, and omega-3 fatty acids. Emerging evidence reports the positive effects of micronutrient supplementation on cognitive performance among school-aged children. However, there is still limited evidence on the efficacy of multiple micronutrient supplementation on other aspects of cognitive function in children. Therefore, the objective of this randomized, triple-blind placebo-controlled clinical trial is to evaluate the efficacy of Kids Plus Multi & Omega dietary supplement on cognitive function in children after 56 days of supplementation. Overall cognitive function as well as cognitive domains related to focus, memory, learning and cognitive flexibility will be assessed using the National Institutes of Health (NIH) Toolbox Cognition Battery.

The Dragon PLC Trial (DRAGON-PLC)

Primary liver cancer (PLC) is the third most common cause of cancer death worldwide. Surgical resection is the mainstay for a curative approach as contemporary chemotherapy and immune-based therapies only lead to a median survival of 10-14 months. A complete surgical resection increases the median survival to 42 months (range 32-52 months). However, PLC is mainly diagnosed at an advanced stage and >70% of PLC patients are ineligible for an immediate surgical approach. There are different reasons that make a patient ineligible for surgery, one important reason is the risk of liver failure after the surgery due to a small remnant liver. This study aims to improve the oncological, radiological and surgical strategy to allow more patients to undergo liver resection safely, to improve quality of life and to extend overall survival at acceptable costs. Adequate function of the future liver remnant (FLR) is a prerequisite for surgical resectability. This is necessary in order to avoid liver failure after surgery, a major cause of morbidity (38%) and mortality (27%). To mitigate this risk, regenerative strategies based on preoperative calculation of the FLR volume and function are essential. Patients with technically resectable disease but predicted insufficient FLR volume or function are referred to as primarily unresectable or potentially resectable (PU/PR). These patients can undergo strategies that capitalize on the regenerative capacity of the liver which aim to preoperatively increase the FLR volume and function in order to allow surgery. Many of the patients that are primarily unresectable due to an insufficient FLR can become ultimately and safely resectable after the induction of adequate FLR-hypertrophy by the current standard, portal vein embolisation (PVE). However, 25% of patients do not show sufficient FLR growth after PVE and are unable to safely undergo resection. A new approach has been developed to improve this. Combined portal and hepatic vein embolisation (PVE/HVE) has great promise in terms of increasing FLR growth, resection rate (RR), safety and potentially, overall survival. Establishing PVE/HVE as the new standard could result in increased survival and a better quality of life (QoL) for patients.

Weight-Bearing CT and Conventional Periprosthetic Distal Knee Fractures

Total knee arthroplasty is the most cost-effective and successful treatment for knee joints with end-stage osteoarthritis, with more than 58,000 TKA surgeries in Canada in 2021-2022.1 The prevalence of TKA surgeries is increasing per year and is projected to rise due to an ageing population and obesity problems.1 In addition to the primary surgery, more than 4,000 Canadians require revision TKA surgery per year; the TKA revision burden is estimated to reach $13 billion by 2030 as a consequence of a substantial increase of 149% in primary surgeries by 2030 in the United States.1-3 Revision surgery is more invasive than primary surgery and poses the risk of increasing patient mortality rates, especially for older adults.3 Thus, it is imperative for surgeons to make an appropriate radiographic diagnosis of implant fixation and/or fracture healing, but many cases remain challenging to diagnose.4 In the orthopaedic literature, there is no consensus on a reliable definition criterion for long-bone non-unions, making the standardization of diagnoses difficult; the lack of a trustworthy assessment for component fixation and fracture healing can lead to patients receiving sub-optimal care.5 This can also limit the collection of evidence supporting the use of specific implant components, surgical techniques, and post-operative activity guidelines. Moreover, comparing healing results of different clinical studies for long-bone non-unions can become problematic due to different criteria being used.5 Radiographic features associated with loosening such as radiolucencies are often only appreciable for the cement-bone interface, rather than the cement-implant interface which is the most common site of failure causing loosening.4 Failure to properly diagnose fracture non-union leaves patients in pain with substantial morbidity, while unnecessary surgery risks significant complication. Given the increasing rates of TKA and associated predictions of increasing revision burden,6 along with ongoing debates over the superiority of certain implants or surgical techniques, there is an unmet need for better fixation and bone healing assessment. Historically, radiostereometric analysis (RSA) has been the gold standard for measuring implant fixation.7 However, it remains a niche tool limited to clinical research because of its requirement for implanted marker beads and specialized equipment being accessible for a handful of labs in North America.7-8 Recently, multiple groups have developed approaches to perform RSA-like measurements using clinical CT scans for shoulder, hip, and knee replacements.9 The accuracy and precision of the "CT-RSA" methods are on par with conventional RSA and acceptable for clinical studies.10-15 It is predicted that there will be a greater uptake of CT-RSA than conventional RSA, but the technology is still in its infancy.9 The application of CT-RSA will undoubtedly be more inclusive as examinations can now be performed on patients who did not have marker beads implanted at the time of their original surgery, and CAD models of implants are not needed.16 Using a weight-bearing CT scanner is the most similar implementation of CT-RSA to conventional RSA, as exams can be acquired in unloaded and loaded positions. However, the availability of weight- bearing CT will always be lesser than conventional clinical CT scanners, even as more and more high volume orthopaedic centres are acquiring weight-bearing CT scanners. While some groups have implemented specialized loading devices to perform such scans with conventional CT,17 a more generalizable approach of simple internal-external leg rotations held in place with tape would ultimately offer the greatest potential uptake across centres. The results of this proposed study will demonstrate the ability to precisely measure displacements between bone segments under loading following periprosthetic fracture repair with weight-bearing CT and conventional CT scanners. These will be the first-ever measurements of distal femur periprosthetic fracture healing with weight-bearing CT-RSA. Demonstration of this will enable us to pursue future studies that are prospective in nature and may evaluate topics such as time to weight-bearing activities, different types of surgical reconstructions, and relationship between healing and bone quality/bone health. Other centres with access to weight-bearing CT will also benefit from this work. Consideration for the ability to perform similar measurements with conventional CT in place of weight-bearing CT will improve the generalizability of this approach and support it as a clinical diagnostic tool. For example, surgeons may better understand bone fragment motion over time and recommend appropriate postoperative activities for patients' weight-bearing tolerance. Therefore, the proposed study design will evaluate the ability to perform inducible displacement measurements following the surgical repair of distal femur periprosthetic fractures using both weight-bearing CT and conventional CT.

Caregiver Training to Support Children With Social Communication Challenges

Background Pediatric speech-language pathologists (SLPs) report that a substantial proportion of their caseloads now include children with diagnosed or suspected autism. This aligns with persistent increases in autism diagnoses worldwide and underscores the importance of effective, feasible, and resource-efficient support services. For children with diagnosed autism, or children with social communication challenges who may be waiting for diagnostic assessments, identifying effective services targeting language and social communication is particularly important because development of these skills is among the most important contributors to long-term outcomes in autistic children. Furthermore, supporting social communication aligns with parents' treatment priorities for their autistic children. SLPs provide early support services that focus on promoting engagement and communication within meaningful contexts. For young children, their parents are often their primary communication partners. Therefore, parent coaching interventions are commonly used by SLPs to support social communication development in young autistic children. Parent coaching interventions allow clinicians to capitalize on parents' expert knowledge of their child. These interventions increase the potential for children to generalize skills learned in sessions to their daily life, thus increasing treatment dosage without increasing the cost. Furthermore, by reducing the frequency of direct contact hours with the therapist, public systems can optimize resource use and make these interventions accessible to a greater number of parents. The past decade has seen an increase in the number of randomized control trials (RCTs) examining the efficacy of parent-delivered early interventions for autistic children; however, most were conducted in specialized research clinics that often do not reflect how treatment is offered by community SLPs. This can negatively impact the generalizability of the findings to real-world clinical practice. While explanatory trials determine the efficacy of an intervention (in a highly controlled setting), pragmatic trials determine the effectiveness of an intervention in a real-world context, that is, everyday clinical practice. Pragmatic RCTs embrace the complexity, unpredictability, and inconsistency inherent in routine clinical practice by including diverse patient populations and allowing flexibility and variability in how the intervention is delivered. Additionally, few clinical trials have included examination of for whom the intervention works (moderators of treatment outcome), why the intervention works (mediators of treatment outcomes), or how implementation processes could have impacted treatment effects. This leaves clinicians with limited information to effectively individualize and refine interventions to fit child, family, and system needs. One parent coaching intervention commonly used by SLPs is More Than Words® - The Hanen Program® for Parents of Autistic Children or Children Who May Benefit from Social Communication Support (MTW). In fact, a recent survey identified MTW as the preschool autism intervention program most widely used (61%) by SLPs in Ontario, Canada. The two existing RCTs on MTW involved university-based program delivery and report mixed findings that included positive effects in parents' responsiveness and aspects of social communication for some children. Non-randomized observational studies of the MTW program reported improved parent responsiveness, self-efficacy, and interaction style; and improved child language and social communication skills post-program. When asked about perceived outcomes, parents from community-delivered MTW programs highlighted the new strategies they learned, their child's growth in functional communication skills, overall improvement in their relationship with their child, and the social and professional support network they gained. Studies of parents' experiences participating in MTW suggests they value the program and the opportunity to connect with other parents, but seek improvements in navigating program content, the numerous forms associated with participation, parent-to-parent discussion, and the amount of individualized time with the SLP. Although these results are promising, as is the case for parent-delivered interventions more broadly, community-based RCTs of the MTW program are lacking, and little evidence exists for the mediators and moderators of effective MTW delivery in real-world practice. Pragmatic RCTs are needed to build this understanding. For a pragmatic RCT of the MTW program (and other parent coaching interventions) to be useful, it is critical to ensure that the methods used to evaluate treatment effects and mediators/moderators are not only sound but also ecologically valid and feasible for use in the community practice contexts in which the study is to be conducted. Given that real-world practice can be highly variable and unpredictable in ways that are outside of the control of the researcher, large-scale RCTs can be at risk for implementation failure without careful attention at the methodological planning stages. One solution is to first conduct a pragmatic methodological feasibility trial to identify and develop mitigation plans for possible issues in recruitment, retention, data collection, and analysis. A second associated solution is to employ principles of integrated knowledge translation, that is, ensure that co-construction and collaboration between researchers and community partners begins right from the planning stages. This can ensure that outcome measures selected are ideal from both a reliability, validity, and sensitivity perspective and practical for clinicians and families to use during real-world program delivery. In sum, for a full-scale pragmatic RCT to be successful and for results to be meaningful to end users, foundational work is needed that focuses on (a) systematic co-development of a comprehensive evaluation protocol, (b) testing of the acceptability and feasibility of the evaluation protocol within real-world community settings, and subsequently, (c) pilot testing of a pragmatic RCT protocol. Rationale With an overarching objective to conduct pragmatic RCTs of the MTW program, the investigators first needed a comprehensive evaluation protocol of the MTW program as implemented in community practice that would be both feasible for clinicians and families and sensitive enough to measure treatment effects and moderators and mediators of child and family outcomes. Therefore, the investigators partnered with program developers and expert SLPs from The Hanen Centre to co-construct a logic (causal) model of the MTW program that links specific program objectives with evaluation tools (outputs, outcomes) and procedures. In brief, key areas integrated during development of the logic model and evaluation plan included: (a) theories and research guiding MTW program development, (b) outcome measures and treatment mediators and moderators identified in previous research, (c) expert SLP views on MTW objectives and outcomes, and mediators and moderators affecting treatment responses, and (f) organizational structures, barriers, and facilitators for SLPs delivering the program. The result of this co-construction process was a logic model of the MTW program and an associated evaluation protocol with proposed outcome measures. The investigators recently completed the second aim, which was to assess the feasibility of the selected outcome measures and proposed evaluation procedure ("A Single Arm Feasibility Study of a Caregiver-Delivered Intervention for Preschool-Aged Children with Social Communication Challenges"). The following dimensions of feasibility were assessed: (a) recruitment capability, (b) feasibility, acceptability, and practicality of data collection and analysis procedures, and (c) preliminary effectiveness based on the selected outcome measures. A pragmatic, single-arm, pre-post methodological feasibility study design was employed to implement our co-constructed evaluation protocol during MTW programs delivered by community-based SLPs as a part of standard care in the Ontario Preschool Language Program (PSL), a publicly-funded service. In brief, the results revealed that of those approached, 45% of SLPs and 57% of parent-child dyads were willing to participate. None of the 21 enrolled parent-child dyads withdrew from the study; however, outcome measure completion ranged from 48-81%, with 4 dyads providing little to no data. SLPs viewed study methods and measures as acceptable and feasible and researcher coding of video-recorded outcome measures was reliable and practical. Preliminarily effectiveness analyses showed post-program gains in children's early communication skills and communicative participation by parent report, and in 10 of 11 child, parent, and dyadic joint engagement behaviours coded by the researchers. All parents agreed or strongly agreed that their child benefited from the MTW program and most reported increased self-efficacy in supporting their child's communication. Collectively, the results of the feasibility trial supported use of the investigators' co-constructed evaluation protocol in a future RCT of the MTW program. The current pilot RCT is the next step. The estimations of recruitment, retention, and adherence rates noted in the feasibility trial will provide valuable insights, allowing for observation of how new adjustments and procedures developed in response to these findings alter success in these components of the study procedures. This pilot RCT will also provide critical information on recruitment, retention, and data collection for the waitlist control group, which was not assessed in the previous study and for whom methodological uncertainties remain. Additionally, findings from the feasibility trial indicated that securing a sufficient number of community sites willing and able to randomize their patients was not feasible, as the program is already considered standard care despite limited definitive RCT data to support its use. Consequently, this pilot RCT has been designed to be as pragmatic as possible, aiming to simulate standard care while employing MTW program sessions specific to this study (i.e., sessions not already part of community SLPs' existing schedules). Objectives The objective is to gather data that will inform the decision on whether to conduct, and refine the design of, a larger definitive RCT. This will be done by evaluating the feasibility of recruitment, randomization, retention, and adherence of parent-child dyads and exploring potential trends in the preliminary effectiveness of the virtual MTW program through a pilot pragmatic randomized waitlist control trial. Methods The Virtual MTW Program in Ontario MTW is a 13-week parent-implemented program designed to enhance communication, play development, and parent-child interaction for children under 4 years of age who are autistic and/or have social communication challenges. MTW is delivered by SLPs certified by The Hanen Centre, a global not-for-profit organization based in Toronto that developed and routinely updates the program and trains SLPs in its delivery. Traditionally, MTW has been delivered in-person, but since the onset of the pandemic in 2020, a virtual version aimed at replicating the in-person experience was added. The program delivery model to be used in this study will be the virtual MTW program. Virtual delivery includes a group orientation session, a pre-program consultation appointment, eight 2½ hour group training sessions (typically with 6-8 parents per group), and three individual video feedback sessions. At the orientation session, the SLP provides an overview of the program and provides the parent with forms to complete (i.e., parent report of their child's communication, video consent form). At the pre-program consultation, the SLP conducts an informal assessment of the child's communication and records a video of the parent-child interaction. Parents and the SLP co-develop communication goals based on the child's social communication needs and ability. During group training sessions, parents learn support strategies to target goals (e.g., joining a child's idea in play, rather than directing the play). Group virtual education sessions include SLP-led didactic presentations, video examples, group discussions, and opportunities for practice (e.g., role play). During virtually delivered, individual video feedback sessions, parents demonstrate the use of communication facilitation strategies with their child, while the SLP records the interactions. The parent and SLP then review the videos together, analyze use of the strategies and how the child responded, and formulate plans to foster the development of new skills. In Ontario, parents who have concerns about their young child's speech-language development can self-refer for services through the Ontario Preschool Speech and Language (PSL) program, a publicly funded provincial program supporting over 60,000 children from birth through to entry into senior kindergarten annually. For children with diagnosed or suspected autism in the Ontario PSL program, one common standard of care includes offering the MTW program to families. Some Ontario families elect to pursue privately funded SLP services instead. Although some private SLPs in Ontario may deliver the MTW group program as a part of their private services, this is less common. For this pilot pragmatic RCT, registered SLPs employed by The Hanen Centre who routinely deliver MTW programs will deliver the program virtually according to their standard clinical delivery. For this study, recruitment of the parent-child participants and allocation to group program schedule will be independently conducted by the investigators Participant Recruitment and Sample Size Recruitment will be complete through community SLPs across Ontario who provide services to children under 4 years. As such, most children will be recruited through their SLP in the Ontario PSL; however, SLPs in private practice who support this age range will also be sources of recruitment. The investigators will contact SLPs via email, directly for those in private practice or through regional managers for those working within the PSL program. A study flyer will be shared with SLPs for them to facilitate the recruitment of eligible parent-child dyads from their caseload for the study. Families will then self-refer if interested in participating. Since pilot studies are not confirmatory trials and are hence not hypothesis driven, no formal sample size calculation will be carried out. Based on many literature studies, a sample size ranging from 12-35 is commonly recommended for conducting a pilot study. In the investigators' previous feasibility study, a recruitment rate of 57% was observed with 21 out of 37 parent-child dyads approached by SLPs enrolled in the study. There was no attrition; however, completion rates for pre-post outcome measures range from 60-70%. Based on these findings, the investigators aim to recruit 36 parent-child dyads for each of the two groups to target at minimum 15 complete datasets in each of the treatment and control groups. Eligibility Pre-Screening. SLPs will share the study flyer with potential participants whom they believe to be eligible. Interested families will then be pre-screened for eligibility. Either they will complete an eligibility screening survey (delivered using REDCap, a secure, online data collection platform) by following the survey link from the flyer or they will contact the Study Coordinator by email/phone and answer pre-screening questions over the phone with the study coordinator or other study team member. As a part of this screening, parents are asked to confirm they are available to attend group sessions on either Saturday mornings or Monday evenings (or both). Informed Consent. Families who screen eligible will be provided with a copy of the study consent form to download and review within the survey or will be sent a copy via email. A member of the research team will schedule a phone or Zoom call with the parent in which they will meet with a member of the research team to review the study information and consent form before e-signing it (in REDCap). Measures Feasibility Outcome Measures. To examine the primary research questions related to the feasibility of the proposed RCT method, the following areas will be evaluated. 1. Recruitment. The number of participants who complete and pass the screening survey will be recorded. The number of participants who enroll (sign the consent form) will also be recorded. 2. Retention: To assess retention in the MTW program, parent's attendance over the duration of the program will be recorded by the Hanen SLP delivering the program. Study withdrawal and loss to follow-up will also be recorded. 3. Randomization: The randomization method will be assessed by comparing the treatment and waitlist control groups pre-program to ensure no significant difference between them in the baseline measures including child's age, sex, or CFCS Level. 4. Adherence: Completion rates for each baseline and treatment outcome measure at each time point will be recorded for both groups 5. Fidelity: A SLP fidelity measure was developed for this pilot RCT, to assess the Hanen SLP's ability to implement the program components as intended. The individual items in this measure represent content that SLPs delivering the program attend to, but do not necessarily explicitly document. As such, the self-administered, session-specific checklists in this measure aim to document what the SLP covers when delivering the group and individual sessions (in accordance with the MTW Program Leader's Guide that manualizes program delivery). After each session, the SLP indicates Yes (2), Partly (1), or No (0) about their ability to complete each program component associated with that session, which will be used to generate an overall session fidelity percentage score (total score/ total possible score x 100). Demographic/Baseline Measures. These measures will be collected to describe sample characteristics, confirm group equivalence after randomization, and conduct exploratory mediator/moderator analyses. 1. Child and Family Questionnaire. This form was developed by the investigators to collect demographic information of the children and parents participating in this study. It includes details about the parent's relationship to the child, cultural and ethnic background, home language, education, and household income. For the child, it gathers information on age, sex assigned at birth, health conditions, developmental diagnoses, past or current interventions, and participation in an early learning environment. Additionally, it explores family history of speech, language, or learning difficulties. 2. Communication Function Classification System (CFCS). The CFCS is a valid and reliable tool used to classify a child's everyday communication abilities into one of five levels based on how they send and receive messages. The SLP assesses the child's current level of communication based on function not chronological age or developmental stage using the CFCS flow chart, which includes five levels ranging from Level I (Effective Sender and Receiver with unfamiliar and familiar partners) to V (Seldom Effective Sender and Receiver with familiar partners). As such, a lower level is indicative of greater effectiveness as a communicator. 3. MTW Social Communication Stage. The Social Communication Checklist is a Hanen Centre-developed MTW program form that is completed by SLPs in collaboration with parents. It is used to identify the stage that best describes the child's current communication skills according to stages addressed by MTW program and coined by The Hanen Centre as: Explorer, Requester, Early Communicator, and Partner. The number of checkmarks at each stage is tallied, with more checkmarks at higher stages indicative of better outcomes. The number of skills children gain at each stage from before to after the program will be counted. Treatment Outcome Measures. A variety of child and parent treatment outcome measures will be recorded at baseline (T1 for TG; T1 and T2 for WCG), post-program (T2 for TG and T3 for WCG) and after 3 months of receiving the intervention (T3 for TG and T4 for WCG). These measures are described in the Outcome Measures section of the trial registration. Following enrolment, the study coordinator will assign each parent-child dyad a unique study identification number, which will be linked to identifying information gathered through the consent process in a separate Master list. Baseline Demographic Information Collection. Parents will receive an email with a link to Child and Family Questionnaire (a REDCap survey) to collect demographic and baseline information about the child, parent, and family. Additionally, an investigator who is (or is supervised by) a registered SLP will conduct the parent-child appointment remotely at a time convenient for parents. The purpose of this appointment is threefold: (a) to ask parents about their child's involvement in an early learning environment (a demographic data point for the Child and Family Questionnaire that requires discussion), (b) to discuss and observe the child's communication abilities in order to determine their current level of communication function, and (c) to review instructions for the parents to video record interactions with their child during the study. A semi-structured interview guide will be followed to ensure all three components are completed, and the research team member will code responses on a REDCap survey linked to the Child and Family Questionnaire previously completed by the parent. Random Allocation. Once the above demographic/baseline information has been collected, parent-child dyads will be stratified according to their MTW group program availability (Saturdays and/or Mondays) in preparation for random allocation within these two strata. A maximum of 9 families can attend MTW program group sessions according to Hanen Centre requirements. As such, once 18 families enroll who are stratified into the same MTW group session day (Saturday or Monday), they will be randomly allocated to the TG (to receive the MTW intervention immediately) or the WCG (to receive the intervention after a 3-month waiting period). Given the relatively small sample size, blocked randomization stratified by session day availability will be employed. The randomization order will be generated in 3 blocks of 6 (3 TG and 3 WCG). To minimize the likelihood of more than three consecutive parent-child dyads being assigned to the same group, only 14 of the 20 possible block permutations will be used, with sequences TTWWWT, TWWWTT, WWWTTT, TTTWWW, WWTTTW, WTTTWW being eliminated. The study coordinator will use the following random sequence generator that follows these criteria for group allocation: https://www.online-python.com/GZQV5NHF6r. The same process will be repeated as each group of 18 families per stratum enroll. Depending on the rate and frequency of dyad recruitment, this means that overlapping Saturday and/or Monday MTW programs cohorts could occur during the study. Once randomly assigned to groups, the study coordinator will contact families to inform them of their start dates, along with their scheduled time frames for completing study activities. A spreadsheet containing the names and contract information of the parent-child dyads for the TG will be provided to the Hanen SLP assigned to deliver that program session so that clinical contact and planning can begin. The same information for the WCG will be provided to the Hanen SLP assigned to that session ~3 weeks prior to its start date so as to minimize clinician awareness of families' allocation to TG versus WCG, recognizing that it may not be possible to fully mask order from the Hanen SLPs. Outcome Measure Assessment Points. At each time point, parents will receive a reminder email that will include a link to the secure OneDrive folder specific to their family that will have a copy of two fillable PDF forms to be completed (FOCUS-34, CSBS-DP CQ) and instructions on how to record and upload their video interaction. Parents will collect 10-minute videotaped naturalistic interactions of themselves playing with their child and then upload them to their OneDrive folder. Included in the email will also be a link to the Parent and Services Evaluation (a REDCap survey), which includes questions about the past three months related to (a) parent's reported self-efficacy and (b) services and supports accessed for the child. MTW Program. Once the family starts the MTW program, they will not be contacted by the investigators until after the program ends. During the pre-program consultation, the Hanen SLP will record the child's MTW social communication stage. Throughout the program, the Hanen SLP will record parent attendance and complete the corresponding SLP fidelity checklist to record their own fidelity to treatment for that session. These data will be uploaded by the Hanen SLP to a secure OneDrive folder unique to that SLP. The study coordinator will then abstract the social communication stage, adherence, and SLP fidelity into a case report form that uses only de-identified numbers for the dyads before submitting the data for analysis. Video Coding. Following submission of all parent-child interaction videos, the video filenames will be de-identified by the study coordinator to mask both the group allocation and the time point of each video. Two trained and blinded research team members will code the JERI and Parent Fidelity from these video recordings, rating of each variable using REDCap forms. For all three measures, two coders will independently code 20% of videos to determine reliability using Cohen's Weighted Kappa. Planned Analyses Analyses will primarily use descriptive statistics and confidence interval (CI) estimation to evaluate the study procedures and outcomes. Descriptive statistics will be used to characterize feasibility outcomes and participant measures at baseline and Times 1-4. Continuous variables (e.g., CSBS Total Raw Score, FOCUS-34) will be expressed as means and standard deviations (M ± SD), while categorical variables (e.g., JERI variables, CFCS levels, self-efficacy) will be presented as frequencies and percentages. Descriptive and statistical analyses will be conducted using JASP (Version 0.19.0). A) Primary Feasibility Outcomes The summary below outlines the one overarching and five key progression criteria [hat will be evaluated using a traffic light system to determine whether a definitive RCT is feasible and what changes would be required (Green - RCT is feasible & no changes are needed, Amber - RCT is feasible following minor changes, Red - RCT is not feasible without major changes.) To assess baseline equivalences between the two groups, independent t-tests will be conducted in continuous measures and Fisher's exact test for categorical variables. Objective 1: To evaluate overall feasibility of study procedures (recruitment, retention, randomization, data collection, data management, follow-up) 1. Green: Each component of the study procedures runs smoothly without serious problems or obstructions that were able to stop the study. Study procedures are judged strongly feasible and suitable to proceed by the study team and community collaborators. 2. Amber: Study procedures are judged to be likely feasible by the study team and community collaborators, but minor problems in one or more components of the study procedures need to be amended before proceeding 3. Red: The study team and community collaborators identified major problems in one or more components of the study procedures that must be remedied in order for the study to be feasible and to be able to proceed Objective 2: To evaluate parent-child dyad recruitment rates 1. Green: 72 dyads are recruited (100%) within 9 months, with at least 30 dyads recruited within the first 4 months 2. Amber: 72 dyads are recruited but it takes longer than predicted (e.g.,12 months) 3. Red: Unable to recruit at least 36 (50%) dyads within 9 months Objective 3: To evaluate parent-child dyad retention through to study completion 1. Green: ≥ 80% dyads retained to study completion (< 20% dropped out) in both the Treatment and Waitlist Control groups 2. Amber: 60-79% dyads retained to study completion in both the Treatment and Waitlist Control groups 3. Red: < 60% dyads retained to study completion in either the Treatment or the Waitlist Control group Objective 4: To evaluate ability for randomization to yield baseline equivalence of groups 1. Green: Children in the Treatment and Control groups did not differ on baseline characteristics 2. Amber: Children in the Treatment and Control groups minimally differed in a few baseline characteristics 3. Red: Children in the Treatment and Control groups differed in multiple baseline characteristics Objective 5: To evaluate adherence to outcome data completion. 1. Green: ≥ 80% completion rate (< 20% missing data) for all outcome measures at the pre- and post-treatment data collection points; and ≥ 70% completion rate for all measures at follow up 2. Amber: 60-79% completion rate for one or more outcome measures at the pre- and post-treatment data collection points; and/or 50-69% completion rate for one or more measures at follow up 3. Red: < 60% completion rate for one or more outcome measures at the pre- and post treatment data collection points; and/or < 50% completion rate for one or more measures at follow up Objective 6. To evaluate SLP fidelity to treatment 1. Green: ≥80% of SLP sessions meet MTW fidelity standards (≥ 75% overall session fidelity percentage score) 2. Amber: 70-79% of SLP sessions meet MTW fidelity standards 3. Red: < 70% of SLP sessions meet MTW fidelity standards (B) Secondary (Exploratory) Outcomes Although this study is not designed or powered to detect statistical effects, repeated measures ANOVA will be used to explore preliminary effectiveness, that is, possible changes within each group (TG and WCG) over time according to the treatment outcome measures. Post-hoc pairwise comparisons will explore differences between specific time points and groups. Given sample size limitations, p-values will not be examined. Effect sizes for time, group, and interaction effects will be calculated using Eta Squared (η²). The effect sizes will be reported, with thresholds interpreted as small (η² ≥ 0.01), medium (η² ≥ 0.06), and large (η² ≥ 0.14). 95% CIs will also be reported for the effect sizes. The Intention-To-Treat principle will be followed for these analyses. Exploratory analyses aimed at identifying potential moderators and mediators of treatment effects will be conducted by combining data from the waitlist group after receiving the MTW program with the treatment group (maximum possible N=72). Potential moderators such child factors (e.g., age, functional communication level), parent factors (e.g., self-efficacy, level of education), and family context (e.g., household income, engagement in prior services, as well as mediators (e.g., parent self-efficacy, parent fidelity, early adoption of strategies) will be drawn from theoretically informed selection of variables including child factors and family context. Analyses will include visual inspection as well as examination of estimated effects, and 95% CIs.

A Study of 2 Doses of Ritlecitinib in People 12 Years of Age and Older With Alopecia Areata

Using Radiotherapy and Immunotherapy to Treat Advanced Liver Cancer Before Transplant

This is a pilot, open-label, single-arm, study evaluating the combination of locoregional radiotherapy (SBRT or Y90-RE) followed by Atezolizumab and Bevacizumab (AtezoBev) in patients with advanced liver cancer. The study aims to assess the feasibility of integrating immunotherapy with locoregional treatments and liver transplantation pathways. Disease Background: Hepatocellular carcinoma (HCC) is the most frequent type of liver cancer, globally the 6th most common cancer, 3rd leading cause of cancer-related deaths with a stage-dependent detrimental poor prognosis. In 2023 in Canada 4,700 patients were diagnosed with liver cancers with an overall 5 year survival of 45% (95%CI 42, 47). HCC is a well vascularized tumor and may complicate by invading the surrounding vascular structures. If this invasion is identified on imaging or pathology, this is called macrovascular invasion (MVI). In case of MVI, it is most commonly seen affecting the portal vein (PV) and less commonly the hepatic vein (HV), inferior vena cava (IVC) or hepatic artery (HA). With regard to localization of MVI of the PV and its branches, a classification (Vp1-Vp4) has been published to harmonize reporting and to facilitate the clinical decision-making process. As an additional comorbidity of an MVI affecting the PV, an adjacent portal vein tumor thrombus (PVTT) may further deteriorate the hepatic function. Overall MVI in HCC is detected in ~35% of patients at time of diagnosis6. In this subgroup of patients, a 3-year overall survival (OS) of 20% (95%CI 0.13, 0.26) has been reported. In general, for patients with HCC, numerous guidelines and recommendations for diagnostics, staging, and management are available and updated regularly including those from the 'European Association for the Study of the Liver' (EASL) and the 'American Association for the Study of Liver Diseases' (AASLD). Among most guidelines, the commonly recommended staging criteria is the Barcelona Clinic Liver Cancer (BCLC) classification. Clinical decision making for the optimal treatment is guided by the BCLC tumor stages. According to BCLC, HCC with MVI is classified as advanced disease (BCLC stage C). Liver Transplantation, Bridging and Downstaging: Liver transplantation (LT) is the standard treatment option for early to intermediate staged HCC, but patient selection remains challenging. LT not only removes all tumor tissue but also the surrounding pro-carcinogenic liver tissue, as ~90% of HCC develops in liver cirrhosis. LT listing guidelines - determining the patient selection process - consider MVI as exclusion criteria, due to high risk of recurrence and reduced OS after transplantation. At UHN since 2012 the provincial listing criteria ('Trillium Gift of Life Network') determine LT listing as follows: total tumor volume (TTV) ≤ 145cm3, alpha fetoprotein (AFP) ≤ 1000ug/L, diagnostic imaging (classified as 'Liver Imaging Reporting and Data System' 5) or otherwise biopsy proven HCC nodule, no evidence of macrovascular invasion, no evidence of extrahepatic spread and no mixed types with predominance of cholangiocarcinoma. Patients who are deemed eligible for LT undergo a standardized work-up and if no contraindications are identified, patients are being waitlisted until a donor organ becomes available. In patients who are waitlisted, the treatment concept called "bridging" involves performing therapies of HCC for the purpose of preventing or minimizing waitlist dropout due to disease progression. In patients who have tumor burden which is beyond LT criteria, "downstaging" is the process of reducing the tumor burden in order to achieve eligibility for transplantation. A published meta-analysis of 25 studies, which included patients who received downstaging therapies, demonstrated successful downstaging in 55.2% of patients, resulting in 31.5% who underwent LT and a 50.6% drop-out rate. The risk of hepatic decompensation was low (3.6%, 95%CI 2.0-6.3%). Patients with hepatocellular carcinoma with MVI which received a liver transplantation after downstaging demonstrated 5-years OS of 40-60%. This is a remarkable gain of OS compared to the overall 3-year OS of patients with MVI of 20%. Advanced Hepatocellular Carcinoma Treatment: For advanced HCC (e.g. with MVI), locoregional therapy (radiotherapy through transarterial radioembolization (TARE) or stereotactic body radiotherapy (SBRT); transarterial (chemo)embolization (TA(C)E) and systemic therapy options are available as standard of care (SOC). In the last years several advancements in the field immunotherapy have led to different available treatment options. Yang et al. have discussed the multiplex of available systemic treatments, which are ongoingly evolving. The BCLC currently recommends Atezolizumab plus Bevacizumab as a first line systemic treatment option. Atezolizumab (TECENTRIQ, Genentech, Inc., South San Francisco, CA) is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets PD-L1 and inhibits the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), both of which function as inhibitory receptors expressed on T cells. Bevacizumab (AVASTIN, Genentech, Inc., South San Francisco, CA) is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in vitro and in vivo assay systems. The combination of Atezolizumab plus Bevacizumab (AtezoBev) is considered the first-line systemic treatment option for unresectable HCC, becoming the SOC in Canada and has been shown to be superior compared to other available comparator treatment options with regard to overall survival. The IMRABVE150 trial assessed AtezoBev in patients with unresectable HCC. The median treatment duration of Atezolizumab was 8.4 months (IQR: 3.5-18.3) and Bevacizumab 7.0 months (IQR: 3.4-15.9). They have reported an objective response rate of 30% (95% CI 25, 35) (including complete response in 8% and partial response in 22%) and a disease control rate of 74%. In patients with a response, the duration of response was reported as 18.1 months (95%CI: 14.6-NE). Regarding safety, for AtezoBev a treatment-related grade 3 or 4 adverse event was reported in 43% of patients . The mostcommon events for grade 3 or 4 were hypertension, aspartate aminotransferase increase, proteinuria or platelet count decrease. Liver injury was very rare (occurring in <1%). Radiotherapy as a type of radiopharmaceutical therapy used to treat HCC, can be administered internally (radioembolization: TARE, or referred to as selective internal radiation therapy (SIRT)) or externally (SBRT, or external beam radiation therapy (EBRT)). Radioembolization consists of microspheres (of either glass or resin) which carry the radioactive isotope Yttrium-90, that are injected selectively into either the branches of the hepatic artery. The reasoning behind arterial administration is that the HCC lesion has preferential arterial blood supply, so the embolization is directed primarily and selectively to tumor tissue. Yttrium-90 radioembolization (Y90-RE) efficacy has been demonstrated in intermediate and advanced HCC, including those with PVTT. The type of microsphere used at UHN is the glass type, commercially known as TherasphereTM produced by Boston Scientific. The phase III SARAH trial was unable to show a superiority of Y90-RE vs Sorafenib with regard to OS with an acceptable safety profile. In the Y90-RE treatment arm of this study, macrovascular invasion was seen in 63%, predominantly affecting the main portal branches (46%, Vp3). This treatment resulted in a disease control rate of 68% with stable disease in 49%, partial response in 16% and complete response in 3%. In 41% of patients a grade≥3 adverse event was encountered with liver dysfunction accounting for 11% of events. Through refinement of application protocols and patient selection criteria, SBRT has gained an increasing role in the treatment of HCC. Whilst the BCLC 2022 guidelines do not mention SBRT, this treatment option has been endorsed by societal guidelines such as the AASLD. In a multi-institutional randomized control trial led by UHN compared patients on sorafenib vs. sorafenib plus SBRT. Nearly 75% of patients had MVI. Median PFS was improved with SBRT from of 9.2m vs. 5.5m (p < 0.01) with a trend towards improved OS. ≥3 grade treatment-related adverse events in 47% of patients treated with SBRT and sorafenib and was not significantly different from sorafenib alone. In a pivotal pilot study by O'Conner et al., SBRT as a bridging procedure has excellent post-transplant overall survival of 100%. Due to the different mechanisms, a synergistic effect of radiotherapy (SBRT or Y90-RE) and AtezoBev as potential combined treatment modalities can be postulated. Two published studies have demonstrated the feasibility and safety of the combination of these two treatment options in phase I trials for advanced HCC. Villalobos et al. assessed the subgroup of AtezoBev (n=10) with an objective response rate of 60% and an acceptable safety profile with 50% grade 3 adverse events (lymphocyte count). Yu et al. report on 10 patients with a complete response in 75% and partial response in 25%. Health Canada and Cancer Care Ontario approved radiotherapy, as well as AtezoBev, as standard of care treatment options for patients with advanced HCC. Data on the combination of radiotherapy (SBRT or Y90-RE) with AtezoBev as a downstaging protocol to achieve eligibility for LT in patients with advanced HCC is warranted. The novelty in this proposed study lies to explore the combination of two already standard of care treatment options to improve downstaging results and ultimately long-term OS. The investigators hypothesize that by administering a combination of radiotherapy and AtezoBev as a downstaging strategy, 60% of patients will be enlisted for LT and transplant them with acceptable outcomes (5-year overall survival (OS) of >60%). Study Design and Methodology: Patients with locally advanced HCC with MVI on imaging (Vp 1-3) (inclusion and exclusion criteria below), with no other contraindications for LT, can be considered for inclusion. Tumor biopsy is required to rule out poorly differentiated HCC (a contraindication for LT). Schema: Patients will be recruited from the surgical and medical oncology, transplant hepatology clinics at UHN at any time during their diagnostic workup. Patients will undergo a clinical liver biopsy to confirm diagnosis of HCC and exclude poorly differentiated disease. Clinical data including patients' baseline characteristics, demographics, disease history, tumor details, treatment details, blood test results, relevant pathology and scan results will be collected during the study (details in 'Data collection'). Participants enrolled in the study will receive locoregional radiotherapy (SBRT or Y90-RE) at the start of study as part of the study (due to a person participating in the study), under standard treatment protocol based on consensus decision from Multidisciplinary Rounds, which takes into account patient and disease factors. Storage, administration and treatment of Y90-RE will be done according to established treatment protocols and standard of care at UHN. SBRT will be planned and delivered according to institutional protocols at UHN, within the Radiation Medicine Program (RMP). Treatment will be delivered in 5 fractions, preferably every other day, with cone beam CT or MR guidance. Target volume will include the entirety of the tumor as delineated on multiphasic simulation CT and MR, including all macroscopic vascular tumor thrombus. Total treatment dose will be at the discretion of the treating radiation oncologist, but will consider underlying liver function, tumor volume, and organ at risk dose tolerances. In general, doses will range from 2750-5000cGy. Radiotherapy plans will be reviewed with the study PI in cases where there is risk of radiation to the porta hepatis. Organ at risk tolerance is prioritized over tumoral coverage to maximize safety. Adjunct medication including anti-emetics, proton pump inhibitors, and steroids may be prescribed at the discretion of the treatment radiation oncologist. Post radiotherapy assessment is generally performed at the one month visit to monitor resolution of any acute toxicities. Two to six weeks after radiotherapy, AtezoBev will be initiated as part of the study, as per standard treatment protocol. Administration of Atezolizumab and Bevacizumab will be performed according to SOC in approx. 21-days intervals. Clinical follow up during treatment will be done as per SOC in medical and surgical oncology clinics at UHN. 2-3 months after radiotherapy first re-staging (imaging (computed tomography (CT) or magnetic resonance imaging (MRI) abdomen and laboratory assessment) will be performed, which will be continued in 2-3-monthly intervals (as per SOC at UHN for patients undergoing treatment with AtezoBev). If the tumor burden at any time of this routine and clinically indicated visits meets LT listing criteria (absence of extrahepatic metastasis, alpha fetoprotein (AFP) <1000ng/mL, total tumor volume (TTV) <145cm3), the patient will be referred to the transplant clinic for evaluation of eligibility. If in three consecutive re-staging (9 months after starting treatment) no eligibility for transplant referral criteria is met, patients will be excluded from the study and will continue their treatment, as per SOC at UHN for the disease stage (second, thirds line systemic therapy, locoregional therapy - as indicated). If disease progression (locally or metastasis) or other LT-ineligible criteria as per SOC are detected the patient will complete the study enrollment and will be treated outside of this protocol as per SOC (will continue with second, third line therapies for advanced HCC. For patients who, within the 9 months of treatment, meet the LT eligibility criteria and are referred to LT clinic is for evaluation of eligibility, will then be worked up for liver transplantation as per SOC and if no contraindications present, waitlisted for transplantation. Evaluation for bridging treatment during the listing period occurs as per SOC. An up-to-date re-staging will be needed within four weeks of transplantation to confirm current status of the tumor burden. After LT, patients will be followed as per SOC. Clinical data will be collected for 5 years post-transplant for recurrence free survival (RFS) and OS. Study Aims, Objectives and Hypotheses: The primary aim is to investigate the downstaging efficacy of this multimodal treatment protocol for patients with advanced HCC with MVI within 20 patients who receive LT. The objective is to assess the number of patients enrolled which achieve eligibility for liver transplant waitlisting and subsequent LT. The investigators hypothesize that at least 60% will be waitlisted for LT after having received the combined treatment. Assuming a dropout rate from the waitlist of 30% (death, tumor progression, patient refusal etc.), it is expected 48 patients to be enrolled. Once 20 patients have undergone liver transplantation, no additional patients will be enrolled from the beginning of the trial. The secondary aim is to investigate the long-term oncological results of this treatment regimen. The objective is to determine the 5-year overall survival (OS) and recurrence free survival (RFS) in the proportion having received LT. The investigators hypothesize that the OS survival in this cohort will be >60% and the RFS <30%. Exploratory aims are to assess the: 1. Radiological response (on imaging): Objective response rate (ORR), Complete response (CR), Partial response (PR)) 2. Pathological response (on liver explant pathology): Percentage of viable tumor, Rate of complete pathological response, Rate of major pathological response (<10% viable tumor) 3. Biochemical response: Serum markers including alpha fetoprotein (AFP) 4. Rate of rejection of the liver transplant graft.