Acral Skin Rash Caused by Altered Mercaptopurine Metabolism in Maintenance Therapy for B-Cell Acute Lymphoblastic Leukemia.

6-mercaptopurine is a mainstay of acute lymphoblastic leukemia treatment. It has a narrow therapeutic window, dictated by its metabolite, thioguanine and 6-methylmercaptopurine. Skin manifestations usually consist of mild facial rash or hypersensitivity exanthems. We report a child who developed a painful acral rash and mucositis while undergoing maintenance therapy for B-cell acute lymphoblastic leukemia without infectious or known drug etiology. Thiopurine metabolites were skewed toward 6-methylmercaptopurine. Two weeks after allopurinol was added and 6-mercaptopurine (6-MP) dose adjusted, the cutaneous manifestations and other constitutional symptoms resolved. We posit that the rash was because of 6-MP toxicity related to skewed metabolism, adding to the growing list of toxicity related to altered 6-MP metabolism.

Long-term outcomes of pediatric and young adult patients receiving radiotherapy for nonmalignant vascular anomalies.

BACKGROUND: Nonmalignant vascular anomalies (VA) comprise a heterogeneous spectrum of conditions characterized by aberrant growth or development of blood and/or lymphatic vessels and can cause significant morbidity. Little is known about outcomes after radiotherapy in pediatric and young adult patients with nonmalignant VA. METHODS: Thirty patients who were diagnosed with nonmalignant VA and treated with radiotherapy prior to 2017 and before the age of 30 were identified. Clinical and treatment characteristics and outcomes were recorded. RESULTS: Median age at first radiotherapy was 15 years (range 0.02-27). Median follow-up from completion of first radiotherapy was 9.8 years (range 0.02-67.4). Lymphatic malformations (33%), kaposiform hemangioendothelioma (17%), and venous malformations (17%) were the most common diagnoses. The most common indication for first radiotherapy was progression despite standard therapy and/or urgent palliation for symptoms (57%). After first radiotherapy, 14 patients (47%) had a complete response or partial response, defined as decrease in size of treated lesion or symptomatic improvement. After first radiotherapy, 27 (90%) required additional treatment for progression or recurrence. Long-term complications included telangiectasias, fibrosis, xerophthalmia, radiation pneumonitis, ovarian failure, and central hypothyroidism. No patient developed secondary malignancies. At last follow-up, three patients (10%) were without evidence of disease, 26 (87%) with disease, and one died of complications (3.3%). CONCLUSIONS: A small group of pediatric and young adult patients with nonmalignant, high-risk VA experienced clinical benefit from radiotherapy with expected toxicity; however, most experienced progression. Prospective studies are needed to characterize indications for radiotherapy in VA refractory to medical therapy, including targeted inhibitors.

Autoimmune Cytopenia as an Early and Initial Presenting Manifestation in Activated PI3 Kinase Delta Syndrome: Case Report and Review.

Activated PI3 kinase delta syndrome (APDS) is a combined immunodeficiency characterized by recurrent sinopulmonary infections, increased risk of herpesvirus infections, lymphoproliferation, autoimmunity, and increased risk of lymphoid malignancies. Gain-of-function mutations in PIK3CD and PIK3R1 result in increased phosphoinositide-3-kinase-delta activity which causes hyperactivation of lymphocytes and abnormal development and activation of T and B cells. Cytopenias are the most common autoimmune process occurring in patients with APDS and typically occur as a later manifestation of the disease. Here we present a female patient with an early autoimmune hemolytic anemia, hepatosplenomegaly, and frequent infections presenting in infancy, followed by development of significant lymphadenopathy before her diagnosis with APDS type 1. She had significant improvement in her infectious history with immunoglobulin replacement, and control of autoimmune hemolytic anemia with initiation of sirolimus after her diagnosis with APDS type 1. We utilize this case to review the literature on APDS and present the novel finding of early-onset autoimmune disease in the setting of APDS. Autoimmune cytopenias are seen in many primary immunodeficiencies, and workup of autoimmune cytopenias in young patients should include evaluation for underlying immune disorder.

Accelerated aging among childhood, adolescent, and young adult cancer survivors is evidenced by increased expression of p16INK4a and frailty.

BACKGROUND: Cellular senescence, measured by expression of the cell cycle kinase inhibitor p16INK4a , may contribute to accelerated aging in survivors of childhood, adolescent, and young adult cancer. The authors measured peripheral blood T-lymphocyte p16INK4a expression among pediatric and young adult cancer survivors, hypothesizing that p16INK4a expression is higher after chemotherapy and among frail survivors. METHODS: A cross-sectional cohort of young adult survivors and age-matched, cancer-free controls were assessed for p16INK4a expression and frailty. Newly diagnosed pediatric patients underwent prospective measurements of p16INK4a expression before and after cancer therapy. Frailty was measured with a modified Fried frailty phenotype evaluating sarcopenia, weakness, slowness, energy expenditure, and exhaustion. RESULTS: The cross-sectional cohort enrolled 60 survivors and 29 age-matched controls with a median age of 21 years (range, 17-29 years). The prospective cohort enrolled 9 newly diagnosed patients (age range, 1-18 years). Expression of p16INK4a was higher among survivors compared with controls (9.6 vs 8.9 log2 p16 units; 2-sided P = .005, representing a 25-year age acceleration in survivors) and increased among newly diagnosed patients from matched pretreatment to posttreatment samples (7.3-8.9 log2 p16 units; 2-sided P = .002). Nine survivors (16%) were frail and had higher p16INK4a expression compared with robust survivors (10.5 [frail] vs 9.5 [robust] log2 p16 units; 2-sided P = .055), representing a 35-year age acceleration among frail survivors. CONCLUSIONS: Chemotherapy is associated with increased cellular senescence and molecular age in pediatric and young adult cancer survivors. Frail survivors, compared with robust survivors, exhibit higher levels of p16INK4a , suggesting that cellular senescence may be associated with early aging in survivors.

Vincristine toxicity with co-administration of fluconazole during induction therapy for pediatric acute lymphoblastic leukemia.

BACKGROUND: Antifungal prophylaxis is recommended for patients with acute lymphoblastic leukemia (ALL) during high-risk periods such as induction; however, increased vincristine toxicities have been reported with the co-administration of triazole antifungals. We sought to determine whether vincristine-associated toxicities are higher among children with ALL concurrently given fluconazole prophylaxis compared to no prophylaxis. PROCEDURE: Using a retrospective cohort design, we reviewed records of pediatric patients treated for newly diagnosed ALL from 2003 to 2013. Patients were classified by fluconazole exposure during induction. The development of vincristine-associated toxicity and vincristine dose adjustment were the primary outcomes evaluated. The adjusted risk difference (RD) for vincristine-related toxicity associated with triazole exposure was determined. RESULTS: We identified 197 patients meeting inclusion criteria for evaluation, 160 (81%) of whom received fluconazole prophylaxis. Among patients receiving fluconazole, 36/160 (22%) developed vincristine toxicity compared to 7/37 (19%) among those not receiving prophylaxis (RD: 3%, 95% confidence interval [CI] -11 to 18%). Adjusting for patient age and race, no statistically significant increased risk for vincristine-associated toxicity with fluconazole exposure was observed (RD 5%, 95% CI -8 to 17%). An increased risk for vincristine-associated toxicity was independently associated with age 10 years or older (RD 19%, 95% CI 4-34%). CONCLUSION: Co-administration of fluconazole during induction therapy for pediatric ALL does not significantly increase the risk for vincristine-associated toxicities; however, patients 10 years or older are at an increased risk for toxicity independent of fluconazole exposure. Prophylaxis with fluconazole during induction therapy for pediatric ALL, if warranted, appears to be a safe clinical practice.

Eliciting the child's voice in adverse event reporting in oncology trials: Cognitive interview findings from the Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events initiative.

BACKGROUND: Adverse event (AE) reporting in oncology trials is required, but current practice does not directly integrate the child's voice. The Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) is being developed to assess symptomatic AEs via child/adolescent self-report or proxy-report. This qualitative study evaluates the child's/adolescent's understanding and ability to provide valid responses to the PRO-CTCAE to inform questionnaire refinements and confirm content validity. PROCEDURE: From seven pediatric research hospitals, children/adolescents ages 7-15 years who were diagnosed with cancer and receiving treatment were eligible, along with their parent-proxies. The Pediatric PRO-CTCAE includes 130 questions that assess 62 symptomatic AEs capturing symptom frequency, severity, interference, or presence. Cognitive interviews with retrospective probing were completed with children in the age groups of 7-8, 9-12, and 13-15 years. The children/adolescents and proxies were interviewed independently. RESULTS: Two rounds of interviews involved 81 children and adolescents and 74 parent-proxies. Fifteen of the 62 AE terms were revised after Round 1, including refinements to the questions assessing symptom severity. Most participants rated the PRO-CTCAE AE items as "very easy" or "somewhat easy" and were able to read, understand, and provide valid responses to questions. A few AE items assessing rare events were challenging to understand. CONCLUSIONS: The Pediatric and Proxy PRO-CTCAE performed well among children and adolescents and their proxies, supporting its content validity. Data from PRO-CTCAE may improve symptomatic AE reporting in clinical trials and enhance the quality of care that children receive.

A mindful self-compassion videoconference intervention for nationally recruited posttreatment young adult cancer survivors: feasibility, acceptability, and psychosocial outcomes.

PURPOSE: Young adult (YA) cancer survivors report substantial distress, social isolation, and body image concerns that can impede successful reintegration into life years after treatment completion. Mindful Self-Compassion (MSC) interventions focus on developing mindfulness and self-compassion for managing distress, hardships, and perceived personal inadequacies. An MSC intervention would be beneficial in supporting YA survivors' management of psychosocial challenges that arise in survivorship; however, a telehealth intervention modality is essential for reaching this geographically dispersed population. We conducted a single-arm feasibility study of an MSC 8-week videoconference intervention for nationally recruited YA survivors (ages 18-29). METHODS: The MSC intervention was group-based, 90-minute videoconference sessions, held weekly over 8 weeks, with audio-supplemented home practice. Feasibility and acceptability were assessed via attendance rate and an intervention satisfaction scale. Baseline to post-intervention changes in psychosocial outcomes (body image, anxiety, depression, social isolation, posttraumatic growth, resilience, self-compassion, mindfulness) were assessed using paired t tests and Cohen's d effect sizes. RESULTS: Thirty-four participants were consented and 25 attended a videoconference group. Feasibility was established with 84% attending at least six of the eight sessions, and intervention acceptability was high (M = 4.36, SD = 0.40, score range = 1-5). All psychosocial outcomes, except for resilience, demonstrated significant changes (p < 0.002), with medium to large effect sizes (Cohen's d > 0.5). CONCLUSION: YA survivors are interested in receiving an MSC videoconference intervention. Feasibility, acceptance, and potential psychosocial benefits of the intervention were demonstrated. Findings can be applied toward the design of an efficacy randomized controlled trial to improve quality of life for YA survivors in transition after cancer treatment.

DIAGNOSING AND MONITORING ENDOCRINE DYSFUNCTION, DIABETES, AND OBESITY IN A COHORT OF ADULT SURVIVORS OF CHILDHOOD CANCER.

OBJECTIVE: The 5-year survival rate for childhood cancer has increased to 80%, resulting in a growing population of adult survivors of childhood cancer (ASOCC). Long-term endocrine dysfunction is as high as 63% when screened in research protocols. The purpose of this study was to evaluate the prevalence of endocrine testing, endocrine dysfunction, diabetes, obesity, and endocrinologist visits outside of a research screening protocol. METHODS: A retrospective chart review was performed for 176 ASOCC who were diagnosed with cancer before age 18, followed at least 10 years, were now at least 18, and had survived to the time of chart review. RESULTS: After a mean follow-up of 15.2 years (range 10-21 years), 33.5% of ASOCC had endocrine dysfunction, excluding obesity and diabetes. These outcomes were more common in those with any radiation (64.8%, P<.0001) or cranial radiation (73.1%, P<.0001). Many subjects had never had certain endocrine tests. Over half (54.6%) of subjects were either overweight or obese. Glycated hemoglobin A1C (A1C) testing was rare, but when performed, 38.1% were abnormal. 71% of subjects had never seen an endocrinologist. Even among subjects with cranial radiation, 65.4% had either never seen an endocrinologist or had not seen one in the past 5 years. CONCLUSION: This cohort of ASOCC showed high rates of endocrine dysfunction, overweight or obesity, and diabetes in those who had been tested, combined with low rates of testing and endocrinology evaluation. Endocrinologists need to be aware of the endocrine risks in ASOCC, the need for long-term monitoring, and increase their collaboration with oncology. ABBREVIATIONS: A1C = glycated hemoglobin A1C ASOCC = adult survivors of childhood cancer BMI = body mass index COG = Children's Oncology Group EMR = electronic medical record FSH = follicle-stimulating hormone IGF-1 = insulin-like growth factor 1 LH = luteinizing hormone TSH = thyroid-stimulating hormone.

WHIM syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor CXCR4.

WHIM syndrome is a rare, autosomal dominant, immunodeficiency disorder so-named because it is characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (defective neutrophil egress from the BM). Gain-of-function mutations that truncate the C-terminus of the chemokine receptor CXCR4 by 10-19 amino acids cause WHIM syndrome. We have identified a family with autosomal dominant inheritance of WHIM syndrome that is caused by a missense mutation in CXCR4, E343K (1027G → A). This mutation is also located in the C-terminal domain, a region responsible for negative regulation of the receptor. Accordingly, like CXCR4(R334X), the most common truncation mutation in WHIM syndrome, CXCR4(E343K) mediated approximately 2-fold increased signaling in calcium flux and chemotaxis assays relative to wild-type CXCR4; however, CXCR4(E343K) had a reduced effect on blocking normal receptor down-regulation from the cell surface. Therefore, in addition to truncating mutations in the C-terminal domain of CXCR4, WHIM syndrome may be caused by a single charge-changing amino acid substitution in this domain, E343K, that results in increased receptor signaling.

An evaluation of POSSUM and P-POSSUM scoring in predicting post-operative mortality in a level 1 critical care setting.

BACKGROUND: POSSUM and P-POSSUM are used in the assessment of outcomes in surgical patients. Neither scoring systems' accuracy has been established where a level 1 critical care facility (level 1 care ward) is available for perioperative care. We compared POSSUM and P-POSSUM predicted with observed mortality on a level 1 care ward. METHODS: A prospective, observational study was performed between May 2000 and June 2008. POSSUM and P-POSSUM scores were calculated for all postoperative patients who were admitted to the level 1 care ward. Data for post-operative mortality were obtained from hospital records for 2552 episodes of patient care. Observed vs expected mortality was compared using receiver operating characteristic (ROC) curves and the goodness of fit assessed using the Hosmer-Lemeshow equation. RESULTS: ROC curves show good discriminative ability between survivors and non-survivors for POSSUM and P-POSSUM. Physiological score had far higher discrimination than operative score. Both models showed poor calibration and poor goodness of fit (Hosmer-Lemeshow). Observed to expected (O:E) mortality ratio for POSSUM and P-POSSUM indicated significantly fewer than expected deaths in all deciles of risk. CONCLUSIONS: Our data suggest a 30-60% reduction in O:E mortality. We suggest that the use of POSSUM models to predict mortality in patients admitted to level 1 care ward is inappropriate or that a recalibration of POSSUM is required to make it useful in a level 1 care ward setting.

The first step to integrating the child's voice in adverse event reporting in oncology trials: a content validation study among pediatric oncology clinicians.

PURPOSE: Children with cancer experience significant toxicities while undergoing treatment. Documentation of adverse events (AEs) in clinical trials is mandated by federal agencies. Although many AEs are subjective, the current standard is clinician reporting. Our long-term goal is to create and validate a self-report measure of subjective AEs for children aged 7 years and older that will inform AE reporting for the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). This content validation study aimed to identify which of the AEs in the current CTCAE should be included in a pediatric self-report measure. METHODS: We sought expert panel review and consensus among 187 pediatric clinicians from seven Children's Oncology Group institutions to determine which of the 790 AEs are amenable to child self-report. Two survey iterations were used to identify suitable AEs, and clinician agreement estimated by the content-validity ratio (CVR) was assessed. RESULTS: Response rates for surveys 1 and 2 were 72% and 67%, respectively. After the surveys, 64 CTCAE terms met the criteria of being subjective, relevant for use in pediatric cancer trials, and amenable to self-report by a child. The most frequent reasons for removal of CTCAE terms were that they relied on laboratory or clinical measures or were not applicable to children. CONCLUSION: The 64 CTCAE terms will be translated into child-friendly terms as the basis of the child-report toxicity measure. Ultimately, systematic collection of these data will improve care by enhancing the accuracy and completeness of treatment toxicity reports for childhood cancer.

Developing a Comprehensive Adolescent and Young Adult Cancer Program: Lessons Learned from 7 Years of Growth and Progress.

Purpose: Every year, nearly 100,000 adolescents and young adults (15-39 years, AYAs) are diagnosed with cancer in the United States and many have unmet physical, psychosocial, and practical needs during and after cancer treatment. In response to demands for improved cancer care delivery for this population, specialized AYA cancer programs have emerged across the country. However, cancer centers face multilevel barriers to developing and implementing AYA cancer programs and would benefit from more robust guidance on how to approach AYA program development. Methods: To contribute to this guidance, we describe the development of an AYA cancer program at the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center. Results: We summarize the evolution of UNC's AYA Cancer Program since it was established in 2015, offering pragmatic strategies for developing, implementing, and sustaining AYA cancer programs. Conclusion: The development of the UNC AYA Cancer Program since 2015 has generated many lessons learned that we hope may be informative to other cancer centers seeking to build specialized services for AYAs.

Anaplastic large cell lymphoma: an unusual presentation in a 7-year-old girl.

Anaplastic large cell lymphoma (ALCL) accounts for 10% to 30% of all childhood lymphomas and approximately 5% of all non-Hodgkin's lymphoma. ALCL is considered to be a T-cell non-Hodgkin's lymphoma that can be divided into two major groups with distinct genetic, immunophenotypic, and clinical behaviors. The first group consists of a spectrum of CD30+ T-cell lymphoproliferative disorders that include primary cutaneous ALCL (C-ALCL) and lymphomatoid papulosis. The second group is systemic ALCL (S-ALCL), which is further divided into two subgroups: anaplastic lymphoma kinase positive (ALK+) and ALK-negative. Between 30% and 60% of S-ALCL express ALK, which is usually the result of a t(2;5) translocation that correlates with onset in the first three decades of life, male predominance, and good prognosis. Although morphologically similar, ALK- ALCL shows varied clinical behaviors and immunophenotypes; is commonly seen in older age groups, with a peak incidence in the sixth decade of life with no preference as to sex; and has an overall poorer prognosis. We present a case of CD30+, ALK- S-ALCL in a 7-year-old girl.

A Quality Improvement Approach to Enhance LGBTQ+ Inclusivity in Pediatric Primary Care.

BACKGROUND: Lesbian, gay, bisexual, transgender, and queer (LGBTQ+) teens are at higher risk of illness as a result of bias but are less likely than peers to attend well visits. Medical organizations recommend improving care through staff education, visual cues, and routine inquiry of sexual orientation and gender identity (SO/GI) and pronouns. It is unknown how to do this confidentially in pediatrics. This quality improvement (QI) project aimed to confidentially collect and document SO/GI and pronouns early in at least 90% of teen acute care visits. METHODS: A diverse, representative QI team in a resident primary care clinic conducted a series of staff and clinician trainings to improve knowledge, then displayed welcoming signage and offered staff pronoun and rainbow pins. Multiple Plan-Do-Study-Act cycles developed methods of routine and private collection of SO/GI and pronouns. Outcome measures included proportion of teen acute visits with such documentation collected via weekly chart reviews. Process measures included staff/clinician preparedness, assessed by surveys. RESULTS: SO/GI and pronouns were documented in 0% of teen acute visits at baseline, 70% after 6 months, and 90% during the 20-week sustainment measurement phase. The proportion of staff and clinicians who felt prepared to provide care for LGB and transgender patients increased (53% to 68% for LGB, P = .07; and 30% to 57% for transgender, P = .002). CONCLUSIONS: QI methods can create protocols for confidential, sustainable SO/GI and pronoun collection from teens early in acute visits. This allows clinicians and staff to address patients appropriately and for clinicians to better meet their needs.

Functional Outcomes of Patella Fractures Treated With Anterior Plate Osteosynthesis at One Year.

OBJECTIVES: To evaluate the functional outcomes of patients with displaced patellar fractures treated with anterior plate constructs. DESIGN: Prospective cohort and retrospective clinical and radiographic assessment. SETTING: Level I Trauma Center. PATIENTS/PARTICIPANTS: Between 2014 and 2018, 18 patients who underwent operative intervention for an isolated, displaced patella fracture (OTA/AO 34C1-3) with a minimum of 1-year follow-up agreed to participate in the study. The mean follow-up was 19.5 ± 6.0 months. INTERVENTION: Patients were treated with 2.4 or 2.7-mm plates and supplemental screws or cerclage wires. MAIN OUTCOME MEASUREMENTS: Patients were evaluated with the Short Form-36 Survey and the Knee Injury and Osteoarthritis Outcome Scores and asked about symptomatic implants. The range of motion was assessed by goniometer. RESULTS: The cohort had no wound complications, infections, nonunion, loss of reduction, or implant failure. Active knee flexion was 131 ± 7 degrees. Five patients (28%) endorsed implant irritation. Only one patient (5.5%) underwent implant removal, which consisted of transverse screw removal alone. Twelve of the 14 patients (86%), who were previously employed, returned to work at 10 ± 7 weeks. All Knee Injury and Osteoarthritis Outcome Scores subscale scores and the Short Form-36 Survey scores for physical functioning, limitations due to physical health, limitations due to mental health, and social functioning were significantly lower than reference population norms (P < 0.05). CONCLUSIONS: Anterior plating provides reliable fixation for displaced patellar fractures and results in a low incidence of implant irritation. However, patients who had anterior fixation for displaced patella fractures continue to exhibit functional deficits at 1-year postoperatively. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Fatigue as marker of thrombocytopenia in childhood idiopathic thrombocytopenic purpura.

Patients with ITP are said to be normal apart from bleeding. Review of clinic notes for 27 children seen January-October, 2008 showed that 6 (22%) had a history of fatigue which resolved with improvement of platelet counts. While preliminary, our experience suggests that fatigue can be striking in children with ITP.