Implementing a behavioral physical activity program in children and adolescent survivors of childhood cancer: a pilot randomized controlled trial.

Purpose We aimed to document the acceptability (enrollment rate) and feasibility (phone call delivery rate) of implementing a behavioral PA intervention over 12 weeks, in addition to documenting its effects on patient-reported outcomes and physical functioning. This study also describes the costs of carrying out a behavioral PA intervention. A total of 40 participants were randomized in a 1:1 ratio. The tailored behavioral PA intervention was developed based on the most recent PA guidelines in pediatric oncology and on the COM-B framework to enact PA behavior changes. The prescription (frequency, intensity, time and type (FITT)) was adjusted each week during the weekly support calls. The control group did not receive the intervention. 26 males and 14 females (13.6 years old on average and 2.9 years post-cancer treatment on average) participated in our study. The acceptability rate was 90.9% and the feasibility rate was > 85%. We found that 85% improved PA frequency, 80% improved PA intensity, 100% improved PA time, and 50.0% achieved the recommended PA guidelines. No adverse events were reported over the duration of the intervention. Physical function improved with longer 6-minute walk distances in the intervention group (465.8 ± 74.5 m) than in the control group (398.7 ± 92.9 m) (p = 0.016). PROs scores for all participants were within the limits of the normal range. The estimated cost per participant of carrying out this intervention was USD $126.57. Our 12-week behavioral PA intervention, based on the COM-B framework, was found to be acceptable, feasible and safe in childhood cancer survivors. This study is an important step in the right direction to make exercise standard practice in pediatric oncology.

Determinants of Decision Regret Regarding Fertility Preservation in Adolescent and Young Adult Cancer Survivors: A Systematic Review.

Given recent advances in cancer therapeutics, there is a growing population of adolescent and young adult (AYA) cancer survivors navigating the physical and psychological consequences of cancer treatment. Fertility preservation (FP) conversations are of increasing importance for these survivors. Decision regret (DR) is a measure of distress or remorse following a health care decision, and it is a useful tool to evaluate the impact of a treatment on quality of life. The aim of this systematic review is to culminate existing literature focused on determinants of FP DR among AYA cancer survivors and to propose future interventions to reduce DR among AYA cancer survivors. An electronic database search was performed using PubMed, Web of Science, and APA PsycINFO for articles published before December 2023 using the following search criteria: PubMed: "Fertility Preservation"[Mesh] AND decision regret, APA PsycINFO and Web of Science: Fertility Preservation AND decision regret. Articles were organized into five categories that emerged after initial review. Nineteen articles that focused on DR and FP in AYA cancer survivors aged ≤40 and ≥12 years were included. Article results were categorized into five categories pertaining to determinants of FP DR: Unmet Informational and Emotional Needs, Need for Developmentally Appropriate Conversations, Insufficiency of Provider Training, Quality and Timeliness of Fertility Preservation Discussions, and Societal Barriers. These results highlight the need for improved patient and provider education on FP, such as future longitudinal studies focused on standardization of FP-related protocols and the impact of their implementation on DR, especially for AYA cancer survivors.

Physical activity and psychological support can replace "another pill" to manage cancer-related symptoms in children and adolescents diagnosed with cancer.

The management of cancer-related symptoms with nonpharmacological treatment has been proven effective, but more studies are still required to strengthen the scientific evidence. Given the state of the evidence, one might wonder about the perceptions of pediatric oncology experts, healthcare providers and CAM providers regarding the use of supportive care in pediatric oncology. Related to this important question, Mora et al. recently published an exploratory qualitative study entitled "Supportive care for cancer-related symptoms in pediatric oncology: a qualitative study among healthcare providers" in the BMC Complementary Medicine and Therapies Journal. The data generated by the authors provided new insights and perspectives to the current literature. However, their findings must be put into perspective to increase the scope of the original article and to highlight that physical activity and psychosocial interventions are powerful nonpharmacological interventions to manage cancer-related symptoms.

Assessment on the use of allopurinol to improve safety and efficacy of mercaptopurine in pediatric patients with Acute Lymphoblastic Leukemia and Lymphoma during maintenance therapy.

BACKGROUND: Mercaptopurine is an important component of acute lymphoblastic leukemia (ALL) and lymphoma (LLy) maintenance therapy. The 6-thioguanine nucleosides (6-TGN) are believed to be the primary contributor to myelosuppression and immunosuppressive effects, while 6-methylmercaptopurine (6-MMPN) is believed to be responsible for several toxicities including hepatotoxicity, pancreatitis, and hypoglycemia. Previous reports suggest the addition of allopurinol may reduce these toxicities. AIMS: To assess the use of allopurinol to improve both safety and efficacy of mercaptopurine in pediatric patients with ALL and LLy during maintenance therapy. Secondary objectives included evaluating patient tolerability and skewed metabolism. In addition, we also analyzed mercaptopurine daily dose reduction upon allopurinol initiation. METHODS AND RESULTS: The primary endpoint was time within goal ANC prior to and after initiation of allopurinol. Secondary endpoints included; improvement in selective toxicities (hepatotoxicity, pancreatitis, and hypoglycemia) and 6-MMPN to 6-TGN ratio prior to and after allopurinol initiation. In addition, an exploratory endpoint assessing mercaptopurine daily dose reduction prior to and after allopurinol initiation was included. Sixteen patients met inclusion criteria and 15 (94%) of which were included in this study. Median percent of maintenance days within goal ANC prior to and after initiation of allopurinol was 27.8 (IQR 22.6-44.9) and 41.6 (IQR 20.2-58.2) respectively. All patients experienced selective toxicities; 15 (100%) hepatotoxicity, 1 (7%) pancreatitis, and 3 (20%) hypoglycemia. Improvement of toxicities was seen in 13/15 (87%), 1/1 (100%), and 2/3 (67%) respectively. Average 6-MMPN:6-TGN ratio prior to allopurinol initiation was 304:1 and after, allopurinol initiation improved to 15:1, resulting in a 95% reduction. Average mercaptopurine dose prior to and after allopurinol initiation decreased by about 56% (63 to 28 mg/m2 /day). CONCLUSION: Results suggest that the use of allopurinol in pediatric patients with ALL and LLy receiving mercaptopurine during maintenance therapy is both safe and effective.

Behavioral physical activity intervention coupled with standard post-cancer directed treatment care to mitigate chronic pain in childhood cancer survivors: A protocol for a single-center, pilot randomized controlled trial.

Background: Long term survivors of childhood cancer have a high prevalence of chronic pain. Novel, multidisciplinary approaches to manage pain, are needed to allow for a reduction in the use of opioids for pain management. Physical activity is highly effective in managing chronic pain in children and adolescents, however, evidence about the combination of physical activity intervention and pain medications in chronic pain management in childhood cancer survivors is lacking. The aim of this study is to investigate the feasibility, acceptability and preliminary effects of a behavioral physical activity intervention integrated into standard post cancer directed treatment care to mitigate chronic pain in this unique population. Methods: This is a single site pilot randomized controlled trial of a 16-week physical activity intervention coupled with standard care. The primary aim is to assess the feasibility and acceptability of the physical activity intervention in childhood cancer survivors with chronic pain. Secondary aims include evaluating the differences in functional and psychosocial outcomes along with self-reported pain scores and cumulative dose of pain medications between the exercise group and standard cancer care group. The physical activity intervention is a home-based program structured to increase patients' physical activity behavior and to favor low intensity bodily movement using aerobic exercise and resistance training. Conclusions: This study will demonstrate that behavioral supportive measures like physical activity may be a novel means to improve cancer related chronic pain in young survivors of childhood cancer and decrease medication usage for pain along with improvement in functional and psychosocial outcomes.

Physical activity and physical fitness assessments in adolescents and young adults diagnosed with cancer: a scoping review.

PURPOSE: This scoping review describes the assessment methodologies for physical activity (PA) and physical fitness assessments used in studies focusing on adolescents and young adults (AYAs) diagnosed with cancer. METHODS: A search of the literature was conducted in PubMed, CINAHL, Web of Science, and Cochrane Library following the PRISMA-ScR statement. A total of 34 studies were included in this review. RESULTS: PA was primarily assessed via self-reported questionnaires (30/34) either completed in-person (n = 17) or online (n = 13) at different time points and different stages along the cancer trajectory (i.e., from diagnosis onward). A total of 9 studies conducted a physical fitness assessment. CONCLUSIONS: PA and physical fitness measurements are key when trying to describe outcomes, assess for associations, track changes, measure intervention adherence, and test intervention efficacy and effectiveness. Considerable heterogeneity across studies was reported limiting the generation of formal recommendations or guidance for researchers, healthcare providers, and policy makers.

Chronic pain in children and adolescents diagnosed with cancer: the challenge of mitigating the pain and the potential of integrating exercise into pain management.

BACKGROUND: Pain is one of the most common and distressing symptoms experienced by children and adolescents diagnosed with cancer. It is vital that children and adolescents receive adequate pain management early on in their cancer treatments to mitigate pain and cancer-related symptoms. Exercise training shows particular promise in the management of acute and chronic pain among children and adolescents diagnosed with cancer. METHODS: This position paper comes to outline the challenge of mitigating pain in children and adolescents diagnosed with cancer, and the potential benefits of integrating exercise training to the management of chronic pain in this population in need. RESULTS: Integrating exercise training into the care and pain management of children and adolescents diagnosed with cancer who have chronic pain would have the advantage of addressing several shortcomings of pain medication. Pain medication aims to temporarily manage or reduce pain; it does not have the potential to directly improve a patient's physical condition in the way that exercise training can. The current paucity of data available on the use of exercise training as a complementary treatment to pain medications to reduce chronic pain in children and adolescents diagnosed with cancer allows only for hypotheses on the effectiveness of this pain management modality. CONCLUSION: More research on this important topic is necessary and mitigating pain effectively while also reducing the use of opioid pain medication is an important goal shared by patients, their families, clinicians, and researchers alike. Future research in this area has great potential to inform clinical care, clinical care guidelines, and policy-making decisions for pain management in children and adolescents diagnosed with cancer who experience chronic pain.

Nutritional assessment and dietary intervention among survivors of childhood cancer: current landscape and a look to the future.

Over 85% of childhood cancer patients become long-term survivors. Still, cancer and its therapies are associated with a myriad of long-term complications such that childhood cancer survivors (CCS) endure excess disease burden, morbidity, and mortality throughout their lifetimes. Existing literature suggests that CCS maintain poor dietary intake and nutritional status. Thus, as childhood cancer cure rates continue to improve, the role of diet and nutrition in mitigating many of the most common adverse long-term health outcomes among CCS has gained significant interest. Herein we present an in-depth review of existing scientific literature evaluating dietary intake and nutrition status among CCS and its impact on treatment-related health complications; as well as contemporary intervention strategies aimed at overcoming distinctive barriers and improving deleterious lifestyle behaviors in this heterogeneous, at-risk population. Patient-specific, clinical, and systemic factors act as barriers to the timely conduct of comprehensive dietary/nutritional assessments and provision of tailored, risk-based recommendations. This Mini Review discusses the current state of the science, persisting research gaps, and opportunities for advancement of assessment and intervention strategies to address the unique needs of CCS. Search Strategy: We searched PubMed for peer-reviewed articles with the search terms "pediatric cancer," "pediatric malignancy," "pediatric oncology," "childhood cancer," "survivorship," "cancer late effects," "long-term follow-up," "body mass index," "nutritional status," "malnutrition," "body weight," "body weight changes," "body composition," "obesity," "overweight ", "Mediterranean diet," "DASH diet," "processed foods," "micronutrients," "antioxidants," "vitamin D," "calcium," "selenium," "zinc," "metabolic syndrome," "heart disease," "cardiovascular disease," "cardiometabolic disease," "hypertension," "hyperlipidemia," "HDL," "LDL," and "small dense LDL" from January 1, 1995, to July 21, 2023. We also selected relevant articles from our personal files and from reference lists of identified papers. We prioritized publications after 2013; however, commonly cited and highly regarded (defined by high citation count and journal impact factor) older publications were also included. Randomized controlled trials, observational studies, retrospective studies, meta-analysis, editorials, and review articles were included, whereas conference abstracts and case reports were excluded. We only searched for articles published in English, or those translated into English.

A scoping review to map the evidence of physical activity interventions in post-treatment adolescent and young adult cancer survivors.

PURPOSE: This scoping review describes and synthesizes previously reported data to document physical activity (PA) interventions in adolescents and young adult (AYA) cancer survivors and to explore whether PA interventions tested to date improve survivors' health outcomes. METHODS: A search of the literature was conducted in PubMed, CINAHL, EMBASE, Web of Science and Cochrane Library following the PRISMA-ScR statement. We included all original studies (n = 8) investigating PA interventions in AYA cancer survivors. RESULTS: This review showed that PA interventions were feasible and acceptable in AYA cancer survivors. PA interventions were individualized and mainly aerobic in nature. Studies examining the effects of PA interventions on survivors' health evaluated physical and mental health outcomes. CONCLUSIONS: Our scoping review maps the current evidence of PA interventions and highlights the paucity of data in this area of investigation, obviating how much work remains to be done to demonstrate the potential benefits of PA on AYA cancer survivors' health outcomes.

Long-term causes of death among pediatric patients with cancer.

BACKGROUND: The objectives of this study were to characterize the risk of death (1) from the primary cancer vs competing cause of death; and (2) from various causes of death vs the general poplation. The relative risk of death after a pediatric cancer diagnosis versus the general population and the risk of death from a primary cancer diagnosis versus competing causes of death. METHODS: This retrospective, population-based study used the Surveillance, Epidemiology, and End Results database (1980-2015) and included patients aged 0 to 19 years at the time of diagnosis. Observed deaths were calculated; the risk of death versus the general population was assessed with standardized mortality ratios (SMRs). Competing risk models for the cause of death were performed. RESULTS: There were 58,356 patients who were diagnosed, and the mortality rate was 22.8%. To assess causes of death, 6996 patients who died during the study period were included (45,580 total person-years at risk): 5128 (73%) died of their primary cancer, and 1868 (27%) died of a competing cause. Among all patients, the rate of death from the index cancer was higher than the rate of death from another cause within the first 5 years after diagnosis. The risk of death from a nonprimary cancer began to supersede the rate of death from the primary cancer 10 years after diagnosis for patients with germ cell tumors, lymphomas, and sarcomas. SMRs for the primary cancer were highest within the first 5 years after diagnosis for all cancers (SMRs, 100-50,000; P < .0001). The risk of death from competing causes (heart disease, suicide, and sepsis) was elevated (SMR, >100; P < .001). The risk of dying of heart disease was high, especially for patients with astrocytomas (SMR, 47.84; 95% confidence interval [CI], 27.87-76.59) and neuroblastomas (SMR, 98.59; 95% CI, 47.28-181.32). The risk of dying of suicide was high in most patients, particularly for those with osteosarcomas (SMR, 111.40; 95% CI, 2.82-620.69), Hodgkin lymphomas (SMR, 62.35; 95% CI, 34.89-102.83), and gonadal germ cell tumors (SMR, 28.97; 95% CI, 12.51-57.09). CONCLUSIONS: The cause of death for patients with gonadal germ cell tumors, lymphomas, and sarcomas is more commonly a secondary cancer or noncancerous cause than the primary disease; their risk of death from competing causes (heart disease, suicide, and sepsis) rises throughout life.

Successful Treatment of Relapsed Pediatric Acute Myeloid Leukemia Presenting as Central Nervous System Myeloid Sarcoma: A Single-Institution Case Series.

Relapsed acute myeloid leukemia presenting as an isolated central nervous system myeloid sarcoma (CNS MS) is very rare and generally entails poor outcomes. CNS MS treatment is not well defined and can include systemic chemotherapy, intrathecal chemotherapy, radiation therapy, or hematopoietic stem cell transplant. Thiotepa, vinorelbine, topotecan, and clofarabine (TVTC) has been successful for reinduction therapy in relapsed/refractory leukemia to induce remission before hematopoietic stem cell transplant. There is no published evidence of TVTC being utilized for CNS MS. In this series, we report 2 symptomatic patients with isolated CNS MS at relapse who demonstrated near complete resolution after reinduction with TVTC and additional intrathecal chemotherapy.

Opportunities for Growth: Evaluating the Feasibility of a Community Gardening Intervention Pairing Adolescent and Young Adult Cancer Survivors with Experienced Gardeners.

We evaluated the feasibility of a mentored gardening intervention for adolescent and young adult (AYA) cancer survivors in a hospital-based community garden as a way to improve diet and physical activity, using qualitative data to assess the challenges, facilitators, and areas for future programmatic improvement and replication. Over the course of growing season 2018, AYA cancer survivors tended a garden plot in a community garden under the mentorship of an experienced (master) gardener. AYA cancer survivors were successful in planting and harvesting vegetables from the garden in partnership with their mentors. Qualitative results and future directions for the project are discussed.

Genomic Characterization of Poorly Differentiated Neuroendocrine Carcinoma in a Pediatric Patient.

Primary neuroendocrine carcinomas (NEC) are rare tumors in children and young adults, resulting in a lack of standardized treatment approach. To refine the molecular taxonomy of these rare tumors, we performed whole exome sequencing in a pediatric patient with mediastinal NEC. We identified a somatic mutation in HRAS gene and LOH regions in NF2, MYO18B, and RUX3 genes. In addition, a germline heterozygous somatic variant in BRCA2 with LOH at that same position in the tumor tissue was also found. Our data provide valuable insight into the genomic landscape of this tumor, prompting further investigation of therapeutic targets.

MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia.

The outcome for pediatric acute lymphoblastic leukemia (ALL) patients who relapse is dismal. A hallmark of relapsed disease is acquired resistance to multiple chemotherapeutic agents, particularly glucocorticoids. In this study, we performed a genome-scale short hairpin RNA screen to identify mediators of prednisolone sensitivity in ALL cell lines. The incorporation of these data with an integrated analysis of relapse-specific genetic and epigenetic changes allowed us to identify the mitogen-activated protein kinase (MAPK) pathway as a mediator of prednisolone resistance in pediatric ALL. We show that knockdown of the specific MAPK pathway members MEK2 and MEK4 increased sensitivity to prednisolone through distinct mechanisms. MEK4 knockdown increased sensitivity specifically to prednisolone by increasing the levels of the glucocorticoid receptor. MEK2 knockdown increased sensitivity to all chemotherapy agents tested by increasing the levels of p53. Furthermore, we demonstrate that inhibition of MEK1/2 with trametinib increased sensitivity of ALL cells and primary samples to chemotherapy in vitro and in vivo. To confirm a role for MAPK signaling in patients with relapsed ALL, we measured the activation of the MEK1/2 target ERK in matched diagnosis-relapse primary samples and observed increased phosphorylated ERK levels at relapse. Furthermore, relapse samples have an enhanced response to MEK inhibition compared to matched diagnosis samples in xenograft models. Together, our data indicate that inhibition of the MAPK pathway increases chemosensitivity to glucocorticoids and possibly other agents and that the MAPK pathway is an attractive target for prevention and/or treatment of relapsed disease.

Wnt inhibition leads to improved chemosensitivity in paediatric acute lymphoblastic leukaemia.

While childhood acute lymphoblastic leukaemia (ALL) is now highly curable, the dismal prognosis for children who relapse warrants novel therapeutic approaches. Previously, using an integrated genomic analysis of matched diagnosis-relapse paired samples, we identified overactivation of the Wnt pathway as a possible mechanism of recurrence. To validate these findings and document whether Wnt inhibition may sensitize cells to chemotherapy, we analysed the expression of activated ß-catenin (and its downstream target BIRC5) using multiparameter phosphoflow cytometry and tested the efficacy of a recently developed Wnt inhibitor, iCRT14, in ALL cell lines and patient samples. We observed increased activation of ß-catenin at relapse in 6/10 patients. Furthermore, treatment of leukaemic cell lines with iCRT14 led to significant downregulation of Wnt target genes and combination with traditional chemotherapeutic drugs resulted in a synergistic decrease in viability as well as a significant increase in apoptotic cell death. Finally, pre-treatment of purified blasts from patients with relapsed leukaemia with the Wnt inhibitor followed by exposure to prednisolone, restored chemosensitivity in these cells. Our results demonstrate that overactivation of the Wnt pathway may contribute to chemoresistance in relapsed childhood ALL and that Wnt-inhibition may be a promising therapeutic approach.

Bilateral parotid gland enlargement and palpable nephromegaly in infant acute lymphoblastic leukemia: case report and review of the literature.

Acute lymphoblastic leukemia (ALL) in infants below 1 year of age accounts for 2.5% to 5% of childhood ALL. Most children with ALL present with fever, bruising, mucosal bleeding, bone pain, pallor, hepatosplenomegaly, and lymphadenopathy. Common sites of extramedullary involvement at diagnosis include liver, spleen, lymph nodes, brain, and testes. Nephromegaly has also been reported. We present a novel case of bilateral parotid enlargement along with bilateral palpable nephromegaly in a patient with newly diagnosed infant ALL. This unique presentation highlights the importance of considering ALL in the differential diagnosis of parotid enlargement especially when associated with abnormal blood counts.

Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia.

Relapsed childhood acute lymphoblastic leukemia (ALL) carries a poor prognosis, despite intensive retreatment, owing to intrinsic drug resistance. The biological pathways that mediate resistance are unknown. Here, we report the transcriptome profiles of matched diagnosis and relapse bone marrow specimens from ten individuals with pediatric B-lymphoblastic leukemia using RNA sequencing. Transcriptome sequencing identified 20 newly acquired, novel nonsynonymous mutations not present at initial diagnosis, with 2 individuals harboring relapse-specific mutations in the same gene, NT5C2, encoding a 5'-nucleotidase. Full-exon sequencing of NT5C2 was completed in 61 further relapse specimens, identifying additional mutations in 5 cases. Enzymatic analysis of mutant proteins showed that base substitutions conferred increased enzymatic activity and resistance to treatment with nucleoside analog therapies. Clinically, all individuals who harbored NT5C2 mutations relapsed early, within 36 months of initial diagnosis (P = 0.03). These results suggest that mutations in NT5C2 are associated with the outgrowth of drug-resistant clones in ALL.