Gene therapy in sickle cell disease: Attitudes and informational needs of patients and caregivers.

BACKGROUND: Sickle cell disease (SCD) is an inherited blood disorder that results in serious morbidity and early mortality. Novel therapies for SCD, most notably genetic therapies (GTs) and HLA-mismatched donor hematopoietic cell transplantation, are in clinical trials. While potentially curative, these interventions are some of the most intensive treatments for SCD and are associated with serious and life-altering side effects, which may manifest several years after treatment. Little is known about knowledge, beliefs, and attitudes of individuals with SCD, or their caregivers, toward existing and these emerging therapies. METHODS: Patients with SCD at least 13 years of age (n = 66) and caregivers (n = 38) were surveyed about knowledge, attitudes, and beliefs surrounding treatments for SCD. RESULTS: Only 4.8% felt "extremely knowledgeable" about GT for SCD while the majority (63.4%) reported little knowledge. Overall, health literacy was low among respondents. Most respondents had a neutral attitude regarding the safety of GT for SCD, and whether it was a good treatment for the disorder (56.7% and 58.6%, respectively). Only a few respondents endorsed the idea that GT was "unsafe" or "not a good treatment" (5.8% and 4.8%, respectively). There was an association between increasing knowledge about GT and agreement that it is safe (p = .012) and a good treatment for SCD (p = .031). CONCLUSIONS: Given that very few patients with SCD feel knowledgeable about GT and a majority have neutral feelings about the safety and utility of this new approach, culturally appropriate patient-centered education is urgently needed as these treatments get regulatory approval and proceed to the clinic.

Impact of sleep, neuroendocrine, and executive function on health-related quality of life in young people with craniopharyngioma.

AIM: To examine the impact of clinical factors, cognitive deficits, and sleepiness on health-related quality of life (HRQoL) among young people with craniopharyngioma. METHOD: Seventy-eight patients (67% White; 41 males, 37 females; mean age 10y 8mo, SD 3y 11mo, range 6-20y) with craniopharyngioma were assessed for tumor extent and diabetes insipidus. All patients underwent overnight polysomnography and multiple sleep latency tests after surgical resection. Executive functioning was assessed using parent-reported measures. Patients and their parents completed measures of HRQoL. None had a history of previous radiation therapy. RESULTS: Path analysis was used to test hypothesized relations while controlling for demographic and disease characteristics. Analyses revealed poorer parent-reported HRQoL among young people with greater executive functioning symptoms (estimate -0.83; p<0.001). Direct and indirect effects were found among diabetes insipidus, executive functioning, and parent-reported HRQoL. Diabetes insipidus directly predicted greater global executive functioning impairment (estimate 5.15; p=0.04) and indirectly predicted lower HRQoL through executive functioning impairment (estimate -4.25; p=0.049). No significant effects were found between excessive daytime sleepiness, tumor hypothalamic involvement, diabetes insipidus, executive functioning, and patient-reported HRQoL. INTERPRETATION: These findings suggest that young people with craniopharyngioma presenting with diabetes insipidus may benefit from targeted neurocognitive and psychosocial screening to inform interventions. What this paper adds Children with craniopharyngioma and executive functioning impairment are more likely to have poorer health-related quality of life (HRQoL). Diabetes insipidus, a complication associated with surgery, predicted greater executive functioning impairment. Diabetes insipidus indirectly predicted lower parent-reported HRQoL through executive functioning impairment.

Predictors of narcolepsy and hypersomnia due to medical disorder in pediatric craniopharyngioma.

PURPOSE: Several studies describe sleep-wake disturbances in pediatric craniopharyngioma, but none have determined the prevalence or associated predictors of excessive sleepiness in this group after diagnosis and prior to post-operative observation or adjuvant radiotherapy. In this study, we report sleep-wake disturbances in children and adolescents with craniopharyngioma and associated clinical and treatment variables. METHODS: After surgery and prior to radiotherapy or observation, pediatric patients (n = 110) with craniopharyngioma ≥ 3 years old completed a baseline sleep clinic evaluation by a pediatric sleep specialist, polysomnography (PSG) and next-day multiple sleep latency test (MSLT). MSLT was limited to those ≥ 6 years old. Logistic regression models were used to determine the relationship between patient characteristics and the presence and type of hypersomnia. RESULTS: Amongst patients completing PSG and MSLT, 80% had polygraphic evidence of excessive daytime sleepiness. Hypersomnia due to medical condition was diagnosed in 45% and narcolepsy in 35%. Overweight or obese patients were more likely to be diagnosed with hypersomnia (P = 0.012) or narcolepsy (P = 0.009). Grade 2 hypothalamic involvement (HI) at diagnosis was associated with the diagnosis of narcolepsy (P = 0.0008). CONCLUSIONS: This study describes the prevalence and associated predictors of hypersomnia for patients with craniopharyngioma after surgical resection. HI was predictive of narcolepsy diagnosis, and a higher body mass index z-score was associated with hypersomnia due to medical condition and narcolepsy. We recommend that sleep assessment and intervention begin after surgical resection, especially in overweight or obese patients and those with extensive tumors.

Actigraphy versus Polysomnography to Measure Sleep in Youth Treated for Craniopharyngioma.

OBJECTIVE/BACKGROUND: Youth with craniopharyngioma are at increased risk for excessive daytime sleepiness and narcolepsy. Polysomnography (PSG) is the gold standard for diagnosing sleep disorders, but is time-intensive, costly, and does not offer an in vivo measure of typical sleep routine. We determined the sensitivity, specificity, and accuracy of actigraphy compared with PSG in measuring nocturnal sleep in pediatric craniopharyngioma. PARTICIPANTS: Fifty youth with craniopharyngioma (age 3-20 years) were assessed by overnight PSG and concurrent actigraphy after surgical resection and before proton therapy. METHODS: PSG and actigraphy data were synchronized utilizing an epoch-by-epoch comparison method. Sensitivity, specificity, and accuracy were calculated using measures of true wake, true sleep, false wake, and false sleep. Bland-Altman plots were conducted to further assess level of agreement. RESULTS: Actigraphy was 93% sensitive (true sleep [TS]) and 87% accurate (ability to detect TS and true wake) in measuring sleep versus wakefulness and was a reliable measure of sleep efficiency (SE) and sleep latency (SL). Specificity (true wake) was poor (55%) and total sleep time (TST) was underestimated by an average of 15.1 min. Wake after sleep onset (WASO) was overestimated by an average of 14.7 min. CONCLUSIONS: Actigraphy was highly sensitive and accurate and was a reliable measure of SE and SL. Although there were differences in TST and WASO measurements by actigraphy and PSG, our findings provide the basis for future studies on the use of actigraphy to monitor treatment response to wakefulness-promoting medications in youth with craniopharyngioma who demonstrate excessive daytime sleepiness.

Internalizing Symptoms and Their Impact on Patient-Reported Health-Related Quality of Life and Fatigue among Patients with Craniopharyngioma During Proton Radiation Therapy.

OBJECTIVE: The aim of this study was to describe fatigue, health-related quality of life (HRQOL) and brain tumor-associated symptoms after surgical resection and during proton radiotherapy, using latent class analysis (LCA), and to determine if there is class membership change among pediatric patients with craniopharyngioma. METHODS: For all patients (n = 92), demographic and disease-related/clinical variables were attained, and patient reported outcomes were collected prior to proton therapy, at week three, and at the completion of proton therapy. The mean scores for fatigue, HRQOL, and brain tumor symptoms were compared over time and profiles were identified. Factors that influenced profile status and transition probability were examined. RESULTS: Fatigue, HRQOL, and brain tumor symptoms improved over time during proton therapy; however, a subset remained in the lower profile, profile 1, associated with increased internalizing behaviors, compared to profile 2. CONCLUSIONS: Future study should explore the bidirectional relationship of sleep, worry and anxiety in the context of ongoing radiotherapy.

Parental Understanding of Their Child's Germline Genomic Testing: Intent of Disclosure to Their Child and Family.

Genomic testing is becoming increasingly common in the care of pediatric patients with cancer. Parental understanding of germline results and their intent and timing of results disclosure to their child and family may have significant implications on the family unit. The purpose of this study was to examine parental understanding of germline genomic results and plans for disclosure to their child and other relatives. Semi-structured interviews were conducted with 64 parents of children with cancer, approximately eight weeks after parents had received their child's results. Parents of children with negative results (n = 20), positive results (n = 15), or variants of uncertain significance (n = 29), were interviewed. Fifty-three parents (83%) correctly identified their child's results as negative, uncertain, or positive. Most parents had disclosed results to family members; however, only 11 parents (17%) acknowledged discussing results with their child. Most parents delayed disclosure due to the young age of their child at the time of testing. In summary, most parents appropriately described their child's germline genomic results, yet few discussed the results with their child due to age. Families should be followed with supportive counseling to assist parents in the timing and content of result disclosure to their children.

Parental Preferences Surrounding Timing and Content of Consent Conversations for Clinical Germline Genetic Testing Following a Child's New Cancer Diagnosis.

PURPOSE: Clinical genomic testing is increasingly being used to direct pediatric cancer care. Many centers are interested in offering testing of tumors and paired germline tissues at or near the time of cancer diagnosis. We conducted this study to better understand parent preferences surrounding timing and content of consent conversations for clinical germline genetic testing of their children with cancer as a part of real-time cancer care. PATIENTS AND METHODS: A seven-question survey developed by the Division of Cancer Predisposition and collaborators at St Jude Children's Research Hospital (St Jude) was distributed to members of the St Jude Patient Family Advisory Council, which included parents of childhood cancer survivors and bereaved parents whose children with cancer had died. Parents were asked to provide free text comments after each question. Qualitative methods were used to derive codes from parent comments, and survey results were depicted using descriptive statistics. RESULTS: The survey was completed by 172 parents. Ninety-three (54%) endorsed an approach for consent conversations ≥ 1 month after cancer diagnosis, whereas 58 (34%) endorsed an approach at 1-2 weeks and 21 (12%) at 1-2 days. Needing time to adjust to a new or relapsed cancer diagnosis and feeling overwhelmed were frequent themes; however, parents acknowledged the urgency and importance of testing. Parents desired testing of as many cancer-related genes as possible, with clinical utility the most important factor for proceeding with testing. Most parents (75%) desired germline results to be disclosed in person, preferably by a genetic counselor. CONCLUSION: Parents described urgency and benefits associated with germline testing, but desired flexibility in timing to allow for initial adjustment after their child's cancer diagnosis.

Knowledge Is Power: Benefits, Risks, Hopes, and Decision-Making Reported by Parents Consenting to Next-Generation Sequencing for Children and Adolescents with Cancer.

OBJECTIVES: To qualitatively describe parent perspectives of next-generation genomic sequencing (NGS) for their children with cancer, including perceived benefits, risks, hopes/expectations, and decision-making process when consenting or not consenting to NGS and prior to result disclosure. DATA SOURCES: Qualitative interviews were used. CONCLUSION: Altruism is an important factor in parents consenting to NGS testing, as well as making sense of their child's cancer and legacy building. Parents described realistic hopes and expectations associated with NGS participation. Although parents endorsed the likelihood of no medical benefit, those consenting to NGS felt there was no reason not to participate. Parents declining participation expressed avoidance of worry and parent guilt if a germline variant were to be disclosed. IMPLICATIONS FOR NURSING PRACTICE: As NGS evolves into a component of the routine diagnostic workup for pediatric cancer patients, genetic nurses play a role in conducting informed consent conversations and ensuring that patients and families have realistic hopes and expectations associated with NGS.