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Context The National Cancer Institute created the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to allow direct input on symptomatic adverse events (AEs) from adult patients in oncology trials. Objectives This study sought to determine the youngest age to complete the PRO-CTCAE, evaluated comprehension of PRO-CTCAE among adolescents, tested new items not currently in PRO-CTCAE, and tested a parent-proxy version. Methods From seven pediatric cancer hospitals, 51 adolescents (13–20 years) receiving cancer treatment participated, along with 40 parent proxies. We evaluated 55 AEs from the PRO-CTCAE library (97 questions) and seven new AEs not in PRO-CTCAE that assess symptom frequency, severity, interference, or presence. Questions were distributed across three forms to reduce burden. Cognitive interviews with retrospective probing were completed in age groups of 13–15 and 16–20 year olds. Proxies were interviewed independently. Results In general, the 16–20 year olds and the parent proxies were able to understand and complete the PRO-CTCAE and newly designed AE questions. Five PRO-CTCAE terms (bloating of the abdomen, anxiety, flashing lights in front of your eyes, hot flashes, and bed sores) and the wording of the questions about AE severity were challenging for a few adolescents and proxies. The 13–15 year olds had greater challenges completing the PRO-CTCAE. Conclusion This study extends use of the adult PRO-CTCAE for adolescents as young as 16 years and proposes new questions for seven new symptomatic AEs and a parent-proxy version of PRO-CTCAE. Additional testing of the new questions and alternative language for more challenging PRO-CTCAE items is recommended in adults.

Summary Background Sodium thiosulfate is an antioxidant shown in preclinical studies in animals to prevent cisplatin-induced hearing loss with timed administration after cisplatin without compromising the antitumour efficacy of cisplatin. The primary aim of this study was to assess sodium thiosulfate for prevention of cisplatin-induced hearing loss in children and adolescents. Methods ACCL0431 was a multicentre, randomised, open-label, phase 3 trial that enrolled participants at 38 participating Children's Oncology Group hospitals in the USA and Canada. Eligible participants aged 1–18 years with newly diagnosed cancer and normal audiometry were randomly assigned (1:1) to receive sodium thiosulfate or observation (control group) in addition to their planned cisplatin-containing chemotherapy regimen, using permuted blocks of four. Randomisation was initially stratified by age and duration of cisplatin infusion. Stratification by previous cranial irradiation was added later as a protocol amendment. The allocation sequence was computer-generated centrally and concealed to all personnel. Participants received sodium thiosulfate 16 g/m 2 intravenously 6 h after each cisplatin dose or observation. The primary endpoint was incidence of hearing loss 4 weeks after final cisplatin dose. Hearing was measured using standard audiometry and reviewed centrally by audiologists masked to allocation using American Speech-Language-Hearing Association criteria but treatment was not masked for participants or clinicians. Analysis of the primary endpoint was by modified intention to treat, which included all randomly assigned patients irrespective of treatment received but restricted to those assessable for hearing loss. Enrolment is complete and this report represents the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00716976. Findings Between June 23, 2008, and Sept 28, 2012, 125 eligible participants were randomly assigned to either sodium thiosulfate (n=61) or observation (n=64). Of these, 104 participants were assessable for the primary endpoint (sodium thiosulfate, n=49; control, n=55). Hearing loss was identified in 14 (28·6%; 95% CI 16·6–43·3) participants in the sodium thiosulfate group compared with 31 (56·4%; 42·3–69·7) in the control group (p=0·00022). Adjusted for stratification variables, the likelihood of hearing loss was significantly lower in the sodium thiosulfate group compared with the control group (odds ratio 0·31, 95% CI 0·13–0·73; p=0·0036). The most common grade 3–4 haematological adverse events reported, irrespective of attribution, were neutropenia (117 [66%] of 178 participant cycles in the sodium thiosulfate group vs 145 [65%] of 224 in the control group), whereas the most common non-haematological adverse event was hypokalaemia (25 [17%] of 149 vs 22 [12%] of 187). Of 194 serious adverse events reported in 26 participants who had received sodium thiosulfate, none were deemed probably or definitely related to sodium thiosulfate; the most common serious adverse event was decreased neutrophil count: 26 episodes in 14 participants. Interpretation Sodium thiosulfate protects against cisplatin-induced hearing loss in children and is not associated with serious adverse events attributed to its use. Further research is needed to define the appropriate role for sodium thiosulfate among emerging otoprotection strategies. Funding US National Cancer Institute.

OBJECTIVE: This case-control study compared substance use behaviors between Hispanic adolescent and young adult survivors of childhood cancers (cases) and a community sample of participants without cancer (controls). METHODS: A total of 100 cases (mean age at survey 19.9, SD=2.8), were matched 1-1 by ethnicity, age, and sex to controls (200 participants). Differences in self-reported prior 30-day use of tobacco, alcohol, binge drinking of alcohol, and marijuana were examined using conditional multivariable logistic regression. RESULTS: The odds of tobacco, alcohol, binge drinking, and marijuana use were significantly lower for cases than controls (all p’s

Background Adolescent and young adult (AYA) acute leukemia patients have inferior outcomes in comparison to their younger counterparts, related to higher risk disease and increased toxicity (Hochberg J, et al., BJH, 2013). AYA recipient age (≥13 years) vs children (ages 2-12 years) has been associated with increased acute and chronic graft versus host disease (GVHD) in matched sibling donor SCT (Qayed M, et al., BBMT, 2017). Objective To determine the association between recipient age (age ≥13 years vs age 2-12 years) and risk of acute grade II-IV and chronic GVHD following MUD SCT in acute leukemia recipients. Methods We reviewed all pediatric and young adult recipients receiving a MUD SCT enrolled on Children's Oncology Group clinical trials ASCT0431, AAML03P1, AAML0531, AAML1031 from 2004-present. Variables assessed included age at transplant, sex, race, performance score, leukemia type (ALL vs AML), remission (CR1 vs CR2), stem cell source, donor/recipient ABO, CMV, and sex matching, GVHD prophylaxis, year of transplant, time from diagnosis to transplant. Overall survival (OS), event-free survival (EFS), acute and chronic GVHD were assessed with Kaplan-Meier curves, cumulative incidence curves, and multivariable Cox proportional hazard models. Results Four-hundred eighty-six children and young adults underwent transplant on these trials, including 205 patients undergoing MUD SCT. For the MUD population, 8% were under age 2 years, 58% were age 2-12, and 34% were age 13-29. Seventy-one percent of patients had AML in CR1; 8% had ALL in CR1; 21% had ALL in CR2. Stem cell source included bone marrow (48%), peripheral blood stem cells (14%), and cord blood (38%). Complete HLA match in 60%, 1 allele HLA mismatch in 27%, 2+ HLA mismatches in 13%. Five-year OS and EFS rates (± standard error) for MUD were 48.4±3.8% and 44.6±3.6%, respectively. In multivariable analysis, older recipient age was associated with a significant increase in grade II-IV acute GVHD, hazard ratio or HR (95% CI) =2.03(1.28, 3.22) for age ≥13 vs age 2-12, p=0.004 (see Figure 1). HLA mismatches (≥2) were associated with grade II-IV acute GVHD, HR=2.35(1.30, 4.24) for ≥2 HLA mismatches vs matched, p=0.039 (see Figure 2). Older recipient age was not associated with chronic GVHD (p=0.83). However, significant association was found between chronic GVHD vs leukemia type and remission status (p=0.007; see Figure 3), with ALL in CR2 having more chronic GVHD than did AML in CR1 (HR=3.54(1.56, 8.03)). Acute GVHD, as expected, was a risk factor for the development of chronic GVHD (HR=2.18(1.03, 4.60), p=0.040). Conclusion Older recipient age (ages ≥13 years vs ages 2-12 years) was associated with significantly increased risk of grade II-IV acute GVHD in patients with acute leukemia following MUD SCT. Further evaluations of differential toxicity of AYA vs younger pediatric patients undergoing MUD SCT are underway.

The adolescent at the end of life poses a unique combination of challenges resulting from the collision of failing health with a developmental trajectory meant to lead to attainment of personal independence. Because virtually all spheres of the dying adolescent's life are affected, optimal palliative care for these young persons requires a multidisciplinary team whose members have a good understanding of their complementary roles and a shared commitment to providing well-coordinated care. Members of the team include the physician (to initiate and coordinate palliative care management); the nurse (to work collaboratively with the physician and adolescent, especially through effective patient advocacy); the psychologist (to assess and manage the patient's neurocognitive and emotional status); the social worker (to assess and optimize support networks); the chaplain (to support the adolescent's search for spiritual meaning); and the child life specialist (to facilitate effective communication in preparing for death). A crucial area for dying adolescents is medical decision making, where the full range of combined support is needed. By helping the young person continue to develop personal autonomy, the multidisciplinary team will enable even the dying adolescent to experience dignity and personal fulfillment.

Introduction: For many forms of cancers, survival improvement in the AYA population has lagged behind that of younger patients. One contributing factor could be differences in drug metabolism and tolerance of cancer treatment. Although previous studies have documented greater vincristine-related neurotoxicity (VRNT) in AYA vs. younger patients, comparative vincristine PK studies have yielded mixed results with no clear difference in PK related to age. One limitation of these studies is that age, rather than a more physiological assessment of developmental maturity, was used for the comparison. The primary aim of this study was to determine whether developmental differences in vincristine PK related to Tanner Stage could be detected in a sample of children and AYAs undergoing treatment for ALL. Our hypothesis was that vincristine PK would be related to Tanner Stage. Methods: From September 2014-March 2015, a purposeful sample of 30 patients with a diagnosis of ALL treated at Children9s Hospital of Los Angeles were recruited to this IRB-approved study either prior to starting Induction phase or during Maintenance phase. Tanner Stage was classified as ≤2 or ≥4, excluding Tanner Stage 3. Vincristine blood levels were obtained around the first dose during Induction or any single monthly dose during Maintenance at pre-specified time points: 0 min, 10 min, 30 min, 1 hour, 12 hour (Induction only), and 24 hours. For all patients, the vincristine dose was 1.5 mg/m 2 (max 2 mg). Vincristine levels were determined by high performance liquid chromatography. Mean vincristine clearance was compared using the independent T-test. Univariate and multivariate linear regression analysis via backward selection was performed using Tanner Stage, age, sex, BMI, fluconazole exposure, and treatment phase as predictors. P-values were two-sided with significance set at Results: The age range was 1-24 yrs ( 2 , respectively (p=0.71). As summarized in Tables 1 and 2, in both univariate and multivariate analyses no predictors, including Tanner Stage, were associated with vincristine clearance. Conclusions: In this pilot study, we were unable to detect an association between vincristine clearance and Tanner Stage. These data suggest that even when using a measure more reflective of physiological maturity than age, substantial developmental differences in vincristine clearance appear to be lacking. This calls into question the potential explanation of altered clearance for the increased VRNT observed in AYAs, and suggests that future investigations should be directed toward potential developmental differences in vincristine pharmacodynamics. Our data may have implications for understanding other differences in chemotherapy toxicity observed in AYAs. Disclosures No relevant conflicts of interest to declare.

Background/Purpose: The optimal management for typhlitis in pediatric oncology patients has not always been clear from the medical literature. Trends have varied between operative and nonoperative approaches. The aim of this study was to review the successful nonoperative management of these patients at our institution over the last decade to further clarify management guidelines for this difficult problem. Methods: Medical records of pediatric hematology and oncology patients up to 21 years of age with typhlitis diagnosed at the DeVos Children's Hospital from 1990 to 2000 were reviewed. Results: Twelve patients were included. Ten patients (83%) with computed tomography (CT) scans suggestive of the diagnosis were treated successfully nonoperatively. Management usually included bowel rest, antibiotics, and supplemental parenteral nutrition. Two patients (17%) in whom CT scans were not obtained underwent surgery for presumed appendicitis and pneumoperitoneum, respectively. Typhlitis was found incidentally. In the latter patient, the pneumoperitoneum resulted from a perforated jejunum caused by graft-versus-host disease. This patient died of septic complications and was the only mortality in the series (8%). Conclusions: Pediatric cancer patients with typhlitis can be treated carefully nonoperatively with bowel rest, antibiotics, and supplemental nutrition. Usual indications for surgery (ie, perforation, clinical deterioration) still should be used. The early use of CT scanning helps to facilitate the diagnosis and may provide the ability to differentiate typhlitis from other abdominal diseases for which surgery would be indicated. J Pediatr Surg 37:1151-1155. Copyright 2002, Elsevier Science (USA). All rights reserved.

OBJECTIVE: Juvenile xanthogranuloma (JXG) with systemic (extracutaneous) involvement is a rare histiocytic disorder in which significant morbidity and occasional deaths may occur. The objective of this study was to characterize the spectrum of anatomic involvement, associated clinical problems, and management considerations in children with systemic JXG. STUDY DESIGN: Two current cases and literature reports of 34 children with various forms of systemic JXG were analyzed with respect to age, clinical presentation, site(s) of involvement, therapy, and outcome. RESULTS: The median age of the 36 patients was 0.3 years (range, birth to 12 years). Symptoms were usually referable to bulky or infiltrative disease. Twenty patients had disease in two or more sites. Cutaneous lesions were present in fewer than half the patients. The most frequent extracutaneous sites of disease were the subcutaneous soft tissue (12); central nervous system (8); liver/spleen (8); lung (6); eye/orbit, oropharynx, and muscle (4 each); with three or fewer instances of disease in each of several other sites. Most patients were treated with excision or had spontaneous regression (some with organ involvement). However, 12 patients received treatment that included radiation or systemic chemotherapy. Survivors, some with long-term disabilities, included young children who had received radiation therapy to the brain, eye, skin, or heart. Two patients died of disease. CONCLUSIONS: Systemic JXG may involve varying numbers and combinations of extracutaneous sites. The extent of disease should be determined in patients with JXG who are suspected to have systemic involvement. In contrast to the cutaneous form, systemic JXG may be associated with significant complications requiring aggressive medical care. When feasible, surgical excision of lesions may be curative. Optimal treatment for symptomatic, unresectable disease is currently undefined but should be selected to minimize toxic effects in these children who are typically younger than 1 year old at presentation. (J P EDIATR 1996;129:227-37)

OBJECTIVE: To catalog and evaluate patterns of disease in families of children with pleuropulmonary blastoma (PPB). METHODS: Data have been collected since 1988 on 45 children with PPB and their families. All pathologic materials were centrally reviewed. Preliminary molecular genetic analyses were performed when possible. RESULTS: In 12 of 45 patients, an association was found between PPB and other dysplasias, neoplasias, or malignancies in the patients with or in their young relatives. The diseases found to be associated with PPB include other cases of PPB, pulmonary cysts, cystic nephromas, sarcomas, medulloblastomas, thyroid dysplasias and neoplasias, malignant germ cell tumors, Hodgkin disease, leukemia, and Langerhans cell histiocytosis. Abnormalities of the p53 tumor suppressor gene, Wilms tumor suppressor gene (WT1), and the putative second genetic locus for Wilms tumor (WT2) were not found in preliminary investigations. CONCLUSIONS: The occurrence of PPB appears to herald a constitutional and heritable predisposition to dysplastic or neoplastic disease in approximately 25% of cases. All patients with PPB and their families should be investigated carefully. Further research of this new family cancer syndrome may provide insight into the genetic basis of these diseases. (J P EDIATR 1996;128:220-4)

Mo1, LFA-1, and p150,95 are structurally related glycoproteins of the CD11/CD18 complex that are expressed on the membrane of human leukocytes. In the neutrophil, the surface expression of the CD11/CD18 complex is up-modulated (Mo1 greater than p150,95 much greater than LFA-1) by stimulatory factors that include calcium ionophore A23187, phorbol myristate acetate (PMA), and N-L-formyl-L-leucyl-L-phenylalanine (fMLP). Here, in an immunofluorescence analysis, we have examined CD11/CD18 glycoprotein expression by human monocytes, pulmonary alveolar macrophages (PAM, obtained by bronchoalveolar lavage), and breast milk macrophages (BMM) as compared to neutrophils before and after exposure to A23187 (1 microM), fMLP (0.1 microM), or PMA (0.1 microgram/ml) for 15 min at 37 degrees C. Unstimulated monocytes within unfractionated blood mononuclear cells kept at 4 degrees C (n = 13) expressed all three CD11/CD18 glycoproteins, and exposure to A23187 resulted in significant increases in the surface expression of Mo1 (median of 5.7-fold), LFA-1 (median of 2.1-fold), and p150,95 (median of 7.2-fold). Exposure to fMLP- or PMA-stimulated increases of lesser magnitude. CD11/CD18 expression by PAM (n = 9) was barely detectable and was unaffected by exposure to A23187. In contrast, BMM (n = 11) expressed all three CD11/CD18 glycoproteins (with considerable variability among specimens), but no increase was stimulated by A23187. These results demonstrate that monocytes, like neutrophils, have the capacity to respond to activating factors with an increase in CD11/CD18 glycoprotein expression; macrophage differentiation is accompanied by a loss (PAM) or retention (BMM) of CD11/CD18 expression that is unmodulated in response to activation.

CD11/CD18 leukocyte glycoprotein deficiency is a rare, inherited disorder of leukocyte function, manifested by recurrent severe bacterial infections. A deficiency in the expression of a family of leukocyte membrane glycoproteins (the CD11/CD18 glycoproteins) represents the molecular basis for this disease.