Browsing by Subject "Pediatric cancer"

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children and adolescents, is characterized by skeletal muscle features. The Ras-driven subset, which includes the embryonal (eRMS) and pleomorphic (pRMS) histologic subtypes, is an aggressive high risk subgroup with a 5-year survival rate of <30%. Recently the YAP oncoprotein, which is ordinarily silenced by the Hippo tumor suppressor pathway, was found to be highly upregulated in RMS tumors. However, the role of YAP in the Ras-driven subset was unknown.

In patient-derived Ras-driven eRMS cell lines, we suppressed YAP genetically via shRNAs. YAP suppression decreased cell proliferation, increased myogenic differentiation, and promoted apoptosis in vitro and in vivo in subcutaneous xenografts. Pharmacologic inhibition by the YAP-TEAD inhibitor verteporfin also decreased cell proliferation and tumor growth. In a genetically defined model of Ras-driven RMS, constitutively active YAPS127A can serve as the initial oncogenic alteration whereby YAPS127A is sufficient for senescence bypass in primary skeletal muscle myoblasts, but requires expression of hTERT and oncogenic Ras for tumorigenesis in vivo. Importantly these tumors are histologically consistent with human Ras-driven RMS.

To understand the impact of YAP signaling on cell stemness, we cultured eRMS cells as 3D spheres. These spheres are enriched in stem cell genes, as well as in YAP and Notch signaling. The Notch pathway is another developmental pathway that is also highly upregulated in eRMS and contributes to tumorigenesis. Using the spheres as a model, we uncovered a bidirectional signaling circuit between YAP and Notch that regulates stemness. Active Notch signaling upregulates YAP, and YAP in turn upregulates the Notch ligands JAG1 and DLL1 and the transcription factor RBPJ. This circuit controls expression of several stem cell genes including SOX2, which is functionally required for eRMS cell stemness. Silencing this circuit for therapeutic purposes may be challenging, since the inhibition of one node (for example pharmacologic Notch blockade) can be rescued by upregulation of another (constitutive YAP expression). Instead, dual inhibition of Notch and YAP is necessary. Supporting the existence of this circuit beyond a model system, nuclear Notch and YAP protein expression are correlated in human eRMS tumors, and YAP suppression in vivo decreases both Notch signaling and SOX2 expression. In preliminary studies, we also analyzed the differential effects of the three Ras isoforms on eRMS tumorigenesis, Ras-Notch, and Ras-YAP signaling, and developed a method to culture the alveolar RMS subtype as spheres. In conclusion, the YAP oncoprotein drives Ras-driven tumorigenesis by promoting cell growth, survival, and stemness, and through signaling interactions with the Notch pathway. This study also provides rationale for combination therapies targeting YAP and Notch for the treatment of Ras-driven RMS.

Problem and Purpose: Adolescents and young adults (AYAs) with cancer are a population with unique age-specific characteristics and often neglected therapeutic needs. Specifically, Korean AYAs with cancer reported greater level of stress that comes from unique cultural and societal characteristics, but there is a lack of support systems to help their healthy adjustment to the cancer diagnosis. Family communication allows family members to share thoughts and feelings openly and clearly with one another, particularly regarding stressful situations. Studies have shown the importance of family support and communication for maintaining psychological well-being in pediatric patients with cancer, yet despite its pivotal role, little attention has been paid to the parent-adolescent communication in the childhood cancer context. We conducted an integrative literature review on facilitators and barriers to parent-child communication in the childhood cancer context and found that most children, AYAs and their parents were struggling to engage in family communication because of their fear related to expected negative outcomes by sharing sensitive topics, such as emotional harms to each other. In addition, they were rarely aware of the potential benefits from engaging in family communication. However, we also found that there was a lack of research on parent-adolescent communication in the Korean childhood cancer context. This gap in the literature makes us to conduct these dissertation studies with aims of: (1) understanding the Korean parent-adolescent communication experiences in the childhood cancer context, and (2) exploring the potential benefits from engaging in parent-adolescent communication in the Korean childhood cancer context.

Methods: The overall dissertation studies were conducted in Korean. First, a qualitative descriptive design study with a sample of 10 AYAs with cancer and their parents was conducted to explore Korean adolescents’ and their parents’ experiences related to therapeutic and emotional communication in the childhood cancer context. Individual semi-structured interviews were conducted in Korean. The interview transcripts were translated and analyzed using a traditional content analysis, generating themes. Based upon the findings, we designed a cross sectional, descriptive, correlational design study to determine the relationship between engaging in parent-adolescent communication and use of positive coping in Korean AYAs, and the underlying mechanism. Data were collected from 144 AYAs aged 11-26, and their 73 parents, using a packet of self-administered questionnaires that included measures on sociodemographic and health history, parent-adolescent communication, family cohesion, hope, and uncertainty. The study obtained the needed institutional Review Board approvals from both Duke University and the Korean study site.

Results: From the first, qualitative descriptive design study with Korean adolescents with cancer and their parents, we developed the overarching core theme of “I cannot share my feelings” as a synthesis of three main themes that emerged: (1) restricted topics that I can share; (2) being closer but lacking depth; and (3) effects of restricted topics oncoping. Contrary to our expectation that participants would avoid communication related to the cancer diagnosis, they reported no challenges in communicating about treatment or day-to-day management routines; however, consistent with prior findings, they often experienced challenges in communicating about emotions due to a desire to protect one another. Furthermore, this family communication challenge resulted in creating serious risks for ineffective coping. Therefore, we conducted the next proposed study to determine the relationship between engaging in parent-adolescent communication and use of courageous coping. From this correlational, descriptive design study, we found a significant relationship between engaging in effective family communication and use of courageous coping (confrontive, optimistic, and supportant), regardless of AYA’s gender, age, cancer treatment status, and the level of symptom distress in both cases of mother and AYAs (0.26,p=0.0024, R2=0.07, medium effect), and a father and AYAs (0.25,p=0.0042, R2=0.06, medium effect). Next, we also revealed that the family cohesion was a significant mediator of the relationship between family communication and use of courageous coping in case of communicating with both a mother and a father. For example, the effect of communication with mother on use of courageous coping was reduced and no longer statistically significant, after controlling for family cohesion (Model 1, 0.11,p=0.2753, partial r2=0.01, very small effect). Last, this finding suggested that uncertainty directly influenced hope, and hope then fully mediated the impact of family cohesion on use of courageous coping among Korean AYAs with cancer when communicating with a mother. Whereas, hope only partially mediated the impact of family cohesion on the use of courageous coping among Korean AYAs when communicating with a father. Therefore, we revealed that uncertainty in illness and hope mediated the relationship between family cohesion and courageous coping in Korean AYAs with cancer.

Conclusion: Above all, in this dissertation study, we explored the Korean parent-adolescent communication experiences from the perspectives of Korean AYAs and their parents. The main finding from this study is that Korean adolescents with cancer and their parents struggle to share their emotional needs because of their fear related to the expected emotional harms and they hardly expect the benefits from engaging in family communication. The urgent needs to inform them of the benefits from engaging in family communication lead us to examine the relationship between engaging in parent-adolescent communication and use of courageous coping in the childhood cancer context. This study finding revealed the positive relationship between engaging in parent-adolescent communication and use of courageous coping among Korean AYAs and other mediating roles of family cohesion, uncertainty, and hope. This study highlighted the important role of family cohesion, decreased uncertainty, and increased hope in communicating with AYAs in the childhood cancer context to help their positive adjustment to cancer diagnosis by fostering their use of positive coping.

Implications: The current study helped us to be able to understand the family communication experiences of Korean AYAs and their parents in the childhood cancer context and provided directions to guide development of future family communication model and interventions. However, several limitations also exist and provide direction for future research. First, the future study need to employ a longitudinal design study to help clearer understanding of Korean family communication experiences and the relationship between engaging in family communication and use of courageous coping among Korean AYAs with cancer. Secondly, future study with bigger sample size are necessary. Finally, although this study was conducted targeting Korean AYAs living in Korea, the study findings will provide good implications to USA health care providers taking care of Korean AYAs, broadly other Asian AYAs from similar cultural backgrounds.

Caregivers of survivors of pediatric cancer face ongoing social, emotional and financial challenges that may result in enduring illness- and caregiving-related distress. After patients complete treatment there are challenges that persist. Indeed, emerging physical and cognitive "late effects," resulting from the disease and treatment, require families to adapt to a new normal state that may require significant long-term follow-up and care by the survivor and their primary caregiver. This study compares the psychological adjustment of caregivers of pediatric cancer survivors with caregivers of healthy children. In addition, this study evaluates individual factors, such as family functioning and coping style, which may be associated with poorer adjustment among caregivers of pediatric cancer survivors. Caregivers of pediatric cancer survivors (n = 64) and caregivers of healthy children (n = 64) were recruited during regularly scheduled clinic visits to complete questionnaires including a demographic and illness questionnaire and measures of psychosocial functioning. A series of multivariate analyses of covariance were conducted to assess for differences in caregiver distress by group. Caregivers of survivors reported significantly more child-specific parenting stress and somatization than caregivers of healthy children. Hierarchical regression modeling revealed that Escape-avoidance coping and Supportive family functioning predicted 25-40% of the variance in parenting-related psychological adjustment among caregivers of survivors. Caregivers of pediatric cancer survivors face unique challenges that contribute to ongoing distress, particularly related to the parenting role. This population may benefit from interventions aimed at reducing avoidance based coping and improving family functioning.