Despite complete resection, 20% -50% of pediatric craniopharyngiomas experience recurrence. Subtotal resection followed by radiation achieves comparable results. More effective therapies are needed. In tumor cell lines, prolonged exposure to interferon optimizes the anti-proliferative and anti-angiogenic effect. Conjugating proteins with poly-ethylene-glycol (PEG) lengthens the plasma half-life by reducing sensitivity to proteolysis, providing protracted activity. Stratum II of the PBTC-039 study proposed to estimate the sustained objective response rate (ORR=CR + PR) associated with PEGIntron/Sylatron in progressive/recurrent craniopharyngiomas post RT. Simon’s 2-stage design with 10% unacceptable and 35% desirable ORR required a total sample size of 19 (α=β=0.1). An interim analysis was planned after 11 patients and ≥2 objective responses within the first year were needed to expand accrual. 12 patients were enrolled 11, (5 males and 6 females) were eligible and evaluable. Median age at diagnosis was 7.0 years (range, 2.0–12.4) and at study entry was 20.5 years (6.1–25). Median number of cycles received was 6 (1–17). No grade 4 adverse events (AE) were reported. Grade 3 attributable AEs included decreased neutrophil count, nausea, fatigue, fever, headache and anorexia (n=1 each). No objective responses were observed. With a median follow-up 12.9 months (3.2 - 25.7), 5/11 patients have progressed at a median of 8.2 months (2.9–19.5). Other off-treatment reasons were AE, alternative therapy/withdrawal and not meeting weight criteria. PFS estimate at 1-year was 68.2% ± 14.5%. One patient remains on treatment. Although well tolerated, stratum II was permanently closed after interim analysis due to lack of objective responses.

PURPOSE:Proton therapy can allow for superior avoidance of normal tissues. A widespread consensus has been reached that proton therapy should be used for patients with curable pediatric brain tumor to avoid critical central nervous system structures. Brainstem necrosis is a potentially devastating, but rare, complication of radiation. Recent reports of brainstem necrosis after proton therapy have raised concerns over the potential biological differences among radiation modalities. We have summarized findings from the National Cancer Institute Workshop on Proton Therapy for Children convened in May 2016 to examine brainstem injury. METHODS AND MATERIALS:Twenty-seven physicians, physicists, and researchers from 17 institutions with expertise met to discuss this issue. The definition of brainstem injury, imaging of this entity, clinical experience with photons and photons, and potential biological differences among these radiation modalities were thoroughly discussed and reviewed. The 3 largest US pediatric proton therapy centers collectively summarized the incidence of symptomatic brainstem injury and physics details (planning, dosimetry, delivery) for 671 children with focal posterior fossa tumors treated with protons from 2006 to 2016. RESULTS:The average rate of symptomatic brainstem toxicity from the 3 largest US pediatric proton centers was 2.38%. The actuarial rate of grade ≥2 brainstem toxicity was successfully reduced from 12.7% to 0% at 1 center after adopting modified radiation guidelines. Guidelines for treatment planning and current consensus brainstem constraints for proton therapy are presented. The current knowledge regarding linear energy transfer (LET) and its relationship to relative biological effectiveness (RBE) are defined. We review the current state of LET-based planning. CONCLUSIONS:Brainstem injury is a rare complication of radiation therapy for both photons and protons. Substantial dosimetric data have been collected for brainstem injury after proton therapy, and established guidelines to allow for safe delivery of proton radiation have been defined. Increased capability exists to incorporate LET optimization; however, further research is needed to fully explore the capabilities of LET- and RBE-based planning.

BackgroundWe conducted a phase II study of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy (RT) to assess progression-free survival (PFS) in children with newly diagnosed diffuse intrinsic pontine gliomas (DIPG). Patients and methodsChildren 3-17 years with newly diagnosed DIPG were eligible. Capecitabine, 650mg/m(2)/dose BID (maximum tolerated dose [MTD] in children with concurrent radiation), was administered for 9weeks starting the first day of RT. Following a 2-week break, three courses of capecitabine, 1,250mg/m(2)/dose BID for 14 days followed by a 7-day rest, were administered. As prospectively designed, 10 evaluable patients treated at the MTD on the phase I trial were included in the phase II analyses. The design was based on comparison of the PFS distribution to a contemporary historical control (n=140) with 90% power to detect a 15% absolute improvement in the 1-year PFS with a type-1 error rate, =0.10. ResultsForty-four patients were evaluable for the phase II objectives. Capecitabine and RT was well tolerated with low-grade palmar plantar erythrodyesthesia, increased alanine aminotransferase, cytopenias, and vomiting the most commonly reported toxicities. Findings were significant for earlier progression with 1-year PFS of 7.21% (SE=3.47%) in the capecitabine-treated cohort versus 15.59% (SE=3.05%) in the historical control (P=0.007), but there was no difference for overall survival (OS) distributions (P=0.30). Tumor enhancement at diagnosis was associated with shorter PFS and OS. Capecitabine was rapidly absorbed and converted to its metabolites. ConclusionCapecitabine did not improve the outcome for children with newly diagnosed DIPG.

Background Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG. Methods Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course. BRAF aberrations in tumor tissue were determined by real-time polymerase chain reaction and fluorescence in situ hybridization. Results Thirty-eight eligible subjects were enrolled. Dose levels 1 and 2 (33 and 43 mg/m2/dose b.i.d.) were excessively toxic. DLTs included grade 3 elevated amylase/lipase (n = 1), headache (n = 1), mucositis (n = 2), and grades 2-3 rash (n = 6). At dose level 0 (25 mg/m2/dose b.i.d, the RP2D), only 3 of 24 subjects experienced DLTs (elevated amylase/lipase, rash, and mucositis). At the R2PD, the median (range) area under the curve (AUC0-∞) and apparent oral clearance of selumetinib were 3855 ng*h/mL (1780 to 7250 ng × h/mL) and 6.5 L × h-1 × m-2 (3.4 to 14.0 L × h-1 × m-2), respectively. Thirteen of 19 tumors had BRAF abnormalities. Among the 5 (20%) of 25 subjects with sustained partial responses, all at the RP2D, 4 had BRAF aberrations, 1 had insufficient tissue. Subjects received a median of 13 cycles (range: 1-26). Fourteen (37%) completed all protocol treatment (26 cycles [n = 13], 13 cycles [n = 1]) with at least stable disease; 2-year progression-free survival at the RP2D was 69 ± SE 9.8%. Conclusion Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.

STUDY QUESTION Does lower dose (<26 Gy) cranial radiation therapy (CRT) used for central nervous system prophylaxis in acute lymphoblastic leukemia (ALL) adversely affect sperm concentration or morphology? SUMMARY ANSWER CRT doses <26 Gy had no demonstrable adverse effect on sperm concentration or morphology. WHAT IS KNOWN ALREADY Treatment with alkylating agents produces oligospermia and azoospermia in some patients. No prior study has been large enough to evaluate the independent effects of alkylating agents and lower dose (<26 Gy) CRT on sperm concentration or morphology. STUDY DESIGN, SIZE, DURATION This cross-sectional study included male adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT and who enrolled in the St. Jude Lifetime Cohort Study (SJLIFE) from September 2007 to October 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS The inclusion criteria were males, ≥18 years of age, ≥10 years after diagnosis, treated at St. Jude Children's Research Hospital for ALL, and received alkylating agent chemotherapy. Semen analyses were performed on 173 of the 241 (78.1%) adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT. Cumulative alkylating agent treatment was quantified using the cyclophosphamide equivalent dose (CED). Log-binomial multivariable models were used to calculate relative risks (RRs) and 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE Compared to those without CRT, risk of oligospermia or azoospermia was not increased for CRT <20 Gy (P = 0.95) or 20-26 Gy (P = 0.58). Participants 5-9 years of age at diagnosis compared to those 0-4 years of age (RR = 1.30, 95% CI, 1.05-.61) or those treated with 8-12 g/m2 CED (RR = 2.06, 95% CI, 1.08-3.94) or ≥12 g/m2 CED (RR = 2.12, 95% CI, 1.09-4.12) compared to those treated with >0 to <4 g/m2 CED had an increased risk for oligospermia or azoospermia. LIMITATIONS, REASONS FOR CAUTION Our study relied on the results of one semen analysis. ALL survivors who did not participate in SJLIFE or who declined to submit a semen analysis may also have biased our results regarding the proportion with azoospermia or oligospermia, since those who provided a semen specimen were less likely to have previously fathered children compared to those who did not. The lower rate of previous parenthood among participants may have resulted in a higher observed frequency of azoospermia and oligospermia. WIDER IMPLICATIONS OF THE FINDINGS Treatment with <26 Gy CRT did not increase the risk of oligospermia or azoospermia, although a CED exceeding 8 g/m2 and an age at diagnosis of 5-9 years did increase risk of oligospermia and azoospermia. These findings can be used to counsel adult survivors of pediatric ALL. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Institutes of Health (grant numbers CA 21765, CA 195547, CA00874) and the American Lebanese Syrian Associated Charities (ALSAC). The authors have no competing interests to declare.

Background: Survivors of childhood non-Hodgkin lymphoma (NHL) are at increased risk for chronic health conditions. The objective of this study was to characterize health conditions, neurocognitive function, and physical performance among a clinically evaluated cohort of 200 childhood NHL survivors.Method: Chronic health and neurocognitive conditions were graded as per a modified version of the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) and impaired physical function defined as performance< 10th percentile of normative data. Multivariable regression was used to investigate associations between sociodemographic characteristics, therapeutic exposures, and outcomes.Results: Survivors were a median age of 10 years (range 1-19) at diagnosis and 34 years (range 20-58) at evaluation. Eighty-eight (44%) received radiation, 46 (23%) cranial radiation, and 69 (35%) high-dose methotrexate. Most prevalent CTCAE Grades 3-4 (severe life-threatening) conditions were obesity (35%), hypertension (9%), and impairment of executive function (13%), attention (9%), and memory (4%). Many had impaired strength (48%), flexibility (39%), muscular endurance (36%), and mobility (36%). Demographic and treatment-related factors were associated with the development of individual chronic diseases and functional deficits.Conclusions: Clinical evaluation identified a high prevalence of chronic health conditions, neurocognitive deficits, and performance limitations in childhood NHL survivors.

While relatively rare, non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) represent half of all pediatric soft tissue sarcomas. Despite risk-adapted multi-modality therapy, nearly half of patients with high risk features succumb to their disease, while long term survivors are often faced with significant treatment related morbidity. Here we report mature treatment outcomes and toxicities for pediatric and young adult patients with high grade NRSTS treated on a prospective trial employing limited margin radiotherapy. A total of 62 pediatric or young adult patients with high grade NRSTS requiring radiation were treated on an institutional review board approved prospective institutional study of 3D conformal or intensity-modulated external beam radiotherapy and/or interstitial brachytherapy using a 2-cm anatomically constrained margin. Median age at study enrollment was 15.3 years (range, 3 – 22 years). Adjuvant radiotherapy was provided to 72% of patients, while 18% and 10% were treated with perioperative or definitive irradiation, respectively. The most common histologies were synovial sarcoma (21%) and malignant peripheral nerve sheath tumor (18%). Gray's method was used to estimate cumulative incidence of local failure, the Kaplan-Meier product limit method was used to estimate survival, competing risk regression model was used to determine independent predictors of disease outcome, and toxicity was reported according to CTCAE v2.0 guidelines. With a median follow-up of all patients of 5.1 years (range, 0.2 – 10.9 years), nine patients experienced local failure. The 5-year overall cumulative incidence of local failure was 14.9% (95% CI = 7.3 – 25.2%), while cumulative distant failure incidence was 31.1% (95% CI = 19.9 – 43.0%). The 5 year Kaplan-Meier estimates for event free survival and overall survival was 50.6% (95% CI = 37.4 – 62.4%) and 67.9% (95% CI = 54.2 – 78.3%), respectively. Multivariable analysis indicated that age was the only independent predictor of local recurrence (P = 0.005). No grade 5 toxicity was observed, while grade 3 or 4 acute and late toxicities were reported for 13 (21%) and 12 (19%) patients, respectively. Delivery of limited margin radiotherapy using conformal external beam or brachytherapy provides a high rate of local tumor control with acceptable treatment related morbidity.

Children diagnosed with DIPG have a median survival of less than one year despite RT, the primary modality of therapy. PDGF pathway activation has been noted in tumor tissue analyzed from approximately 70 % of pediatric DIPG and 50% of HGG patients, suggesting that inhibition of this pathway may be of clinical benefit. Crenolanib is a highly selective antagonist of the PDGF pathway with in vitro IC50 of 35- and 185- fold lower than observed with dasatinib and imatinib, respectively. We used a rolling-6 design to study the MTD of once-daily crenolanib administered during and after local RT in children with newly diagnosed DIPG (Stratum A), and in recurrent/progressive HGG, including DIPG (Stratum B).We have completed accrual of 55 patients, 30 and 20 evaluable in Stratum A and B, respectively. Serum pharmacokinetic analyses were performed using non-compartmental techniques on all patients for samples collected on days 1 and 28 of course 1. Fifty evaluable patients were enrolled on the two strata and the maximum tolerated dosage (MTD) of 170 mg/m2has been established in each stratum. Dose limiting toxicities (DLTs) were primarily elevated liver enzymes in both strata (<15% of patients), and the most common Grade 3 toxicity seen on Stratum A was leukopenia that resolved with drug interruption. PFS and OS at 2 years were 8% (± 4.5%) and 22% (±7%) for Stratum A, and 5% (± 3.5%) and 30% (± 9%) for stratum B. The PK and current preliminary toxicity data indicate that crenolanib is well tolerated in children at doses slightly higher than the established MTD from Phase I trial in adults (280 mg/day).The spectrum of toxicities observed in children is similar to those observed in adults, though leukopenia is a novel toxicity.

Cediranib (AZD2171), an oral pan-vascular endothelial growth factor (VEGF) inhibitor, was evaluated in this phase I study to determine its toxicity profile, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics in children and adolescents with recurrent or refractory primary central nervous system (CNS) tumors.

BACKGROUNDWe sought to estimate the maximum tolerated or recommended phase 2 dose and describe the pharmacokinetics and toxicities of enzastaurin, an oral inhibitor of protein kinase Cβ, in children with recurrent central nervous system malignancies.METHODSEnzastaurin was administered continuously once daily at 3 dose levels (260, 340, and 440 mg/m(2)) and twice daily at 440 mg/m(2)/day. Plasma pharmacokinetics were evaluated following a single dose and at steady state. Inhibition of protein kinase C and Akt cell signaling in peripheral blood mononuclear cells was evaluated. Akt pathway activity was measured in pretreatment tumor samples.RESULTSThirty-three patients enrolled; 1 was ineligible, and 3 were nonevaluable secondary to early progressive disease. There were no dose-limiting toxicities during the dose-finding phase. Two participants receiving 440 mg/m(2) given twice daily experienced dose-limiting toxicities of grade 3 thrombocytopenia resulting in delayed start of course 2 and grade 3 alanine transaminase elevation that did not recover within 5 days. There were no grade 4 toxicities during treatment. The concentration of enzastaurin increased with increasing dose and with continuous dosing; however, there was not a significant difference at the 440 mg/m(2) dosing level when enzastaurin was administered once daily versus twice daily. There were no objective responses; however, 11 participants had stable disease >3 cycles, 7 with glioma, 2 with ependymoma, and 2 with brainstem glioma.CONCLUSIONEnzastaurin was well tolerated in children with recurrent CNS malignancies, with chromaturia, fatigue, anemia, thrombocytopenia, and nausea being the most common toxicities. The recommended phase 2 dose is 440 mg/m(2)/day administered once daily.

PTC299 is a novel, orally-bioavailable small molecule that selectively inhibits vascular endothelial growth factor receptor protein synthesis at the post-transcriptional level. Based on promising preclinical results, we conducted a pediatric phase I study to estimate the maximum tolerated dose, describe dose-limiting toxicities (DLT) and characterize the pharmacokinetic profile of PTC299 in children with recurrent CNS tumors. PTC299 was administered orally twice or three times daily, depending on the regimen. Four regimens were evaluated using the rolling 6 design, starting with 1.2 mg/kg/dose twice daily and escalating to 2 mg/kg/dose three times daily. Pharmacokinetic studies were performed during the first two courses. Twenty-seven children (14 male, median age 11.2, range 5.5–21 years) with recurrent brain tumors were treated; 21 were fully evaluable for toxicity assessment. Therapy was well-tolerated, and the only DLT was grade 3 hyponatremia. Grade three and grade four toxicities were uncommon in subsequent cycles. Median AUC 0–Tlast values at the 2 mg/kg were similar to those observed in adults. The study was terminated while patients were being treated at the highest planned dose, due to hepatotoxicity encountered in the ongoing adult phase I studies. No complete or partial responses were observed. Two patients with low-grade gliomas were noted to have minor responses, and at the time of the study’s closure, 5 children with low-grade gliomas had been on therapy for 8 or more courses (range 8–16). PTC299 was well-tolerated at the highest dose level tested (2 mg/kg/dose TID) in children with recurrent brain tumors and prolonged disease stabilization was seen in children with low-grade gliomas.

BACKGROUNDDiffuse intrinsic pontine glioma (DIPG) is associated with poor survival regardless of therapy. We used volumetric apparent diffusion coefficient (ADC) histogram metrics to determine associations with progression-free survival (PFS) and overall survival (OS) at baseline and after radiation therapy (RT).METHODSBaseline and post-RT quantitative ADC histograms were generated from fluid-attenuated inversion recovery (FLAIR) images and enhancement regions of interest. Metrics assessed included number of peaks (ie, unimodal or bimodal), mean and median ADC, standard deviation, mode, skewness, and kurtosis.RESULTSBased on FLAIR images, the majority of tumors had unimodal peaks with significantly shorter average survival. Pre-RT FLAIR mean, mode, and median values were significantly associated with decreased risk of progression; higher pre-RT ADC values had longer PFS on average. Pre-RT FLAIR skewness and standard deviation were significantly associated with increased risk of progression; higher pre-RT FLAIR skewness and standard deviation had shorter PFS. Nonenhancing tumors at baseline showed higher ADC FLAIR mean values, lower kurtosis, and higher PFS. For enhancing tumors at baseline, bimodal enhancement histograms had much worse PFS and OS than unimodal cases and significantly lower mean peak values. Enhancement in tumors only after RT led to significantly shorter PFS and OS than in patients with baseline or no baseline enhancement.CONCLUSIONSADC histogram metrics in DIPG demonstrate significant correlations between diffusion metrics and survival, with lower diffusion values (increased cellularity), increased skewness, and enhancement associated with shorter survival, requiring future investigations in large DIPG clinical trials.

PURPOSE:To estimate the maximum-tolerated dose (MTD), describe dose-limiting toxicities (DLTs), and characterize pharmacokinetic properties of MK-0752, a gamma secretase inhibitor, in children with refractory or recurrent CNS malignancies.PATIENTS AND METHODS:MK-0752 was administered once daily for 3 consecutive days of every 7 days at escalating dosages starting at 200 mg/m(2). The modified continual reassessment method was used to estimate the MTD. A course was 28 days in duration. Pharmacokinetic analysis was performed during the first course. Expression of NOTCH and hairy enhancer of split (HES) proteins was assessed in peripheral-blood mononuclear cells (PBMCs) before and following treatment with MK-0752.RESULTS:Twenty-three eligible patients were enrolled: 10 males (median age, 8.1 years; range, 2.6 to 17.7 years) with diagnoses of brainstem glioma (n = 6), ependymoma (n = 8), medulloblastoma/primitive neuroectodermal tumor (n = 4), glioblastoma multiforme (n = 2), atypical teratoid/rhabdoid tumor (n = 1), malignant glioma (n = 1), and choroid plexus carcinoma, (n = 1). Seventeen patients were fully evaluable for toxicity. No DLTs occurred in the three patients enrolled at 200 mg/m(2)/dose. At 260 mg/m(2)/dose, DLTs occurred in two of six patients, both of whom experienced grade 3 ALT and AST. There were no grade 4 toxicities; non-dose-limiting grade 3 toxicities included hypokalemia and lymphopenia. Population pharmacokinetic values (% coefficient of variation) for MK-0752 were apparent oral clearance, 0.444 (38%) L/h/m(2); apparent volume of distribution, 7.36 (24%) L/m(2); and k(a), 0.358 (99%) hr(-1).CONCLUSION:MK-0752 is well-tolerated in children with recurrent CNS malignancies. The recommended phase II dose using the 3 days on followed by 4 days off schedule is 260 mg/m(2)/dose once daily.

SummaryObjectivesTo estimate the prevalence of central precocious puberty (CPP) after treatment for tumours and malignancies involving the central nervous system (CNS) and examine repercussions on growth and pubertal outcomes.DesignRetrospective study of patients with tumours near and/or exposed to radiotherapy to the hypothalamus/pituitary axis (HPA).Patients and MeasurementsPatients with CPP were evaluated at puberty onset, completion of GnRH agonist treatment (GnRHa) and last follow‐up. Multivariable analysis was used to test associations between tumour location, sex, age at CPP, GnRHa duration and a diagnosis of CPP with final height <‐2SD score (SDS), gonadotropin deficiency (LH/FSHD) and obesity, respectively.ResultsEighty patients (47 females) had CPP and were followed for 11·4 ± 5·0 years (mean ± SD). The prevalence of CPP was 15·2% overall, 29·2% following HPA tumours and 6·6% after radiotherapy for non‐HPA tumours. Height <‐2SDS was more common at the last follow‐up than at the puberty onset (21·4% vs 2·4%, P = 0·005). Obesity was more prevalent at the last follow‐up than at the completion of GnRHa or the puberty onset (37·7%, 22·6% and 20·8%, respectively, P = 0·03). Longer duration of GnRHa was associated with increased odds of final height <‐2SDS (OR = 2·1, 95% CI 1·0–4·3) and longer follow‐up with obesity (OR = 1·3, 95% CI 1·1–1·6). LH/FSHD was diagnosed in 32·6%. There was no independent association between CPP and final height <‐2SDS, and LH/FSHD and obesity in the subset of patients with HPA low‐grade gliomas.ConclusionsPatients with organic CPP experience an incomplete recovery of growth and a high prevalence of LH/FSHD and obesity. Early diagnosis and treatment of CPP may limit further deterioration of final height prospects.

PURPOSE:To estimate the prevalence of and risk factors for growth hormone deficiency (GHD), luteinizing hormone/follicle-stimulating hormone deficiencies (LH/FSHD), thyroid-stimulatin hormone deficiency (TSHD), and adrenocorticotropic hormone deficiency (ACTHD) after cranial radiotherapy (CRT) in childhood cancer survivors (CCS) and assess the impact of untreated deficiencies. PATIENTS AND METHODS:Retrospective study in an established cohort of CCS with 748 participants treated with CRT (394 men; mean age, 34.2 years [range, 19.4 to 59.6 years] observed for a mean of 27.3 years [range, 10.8 to 47.7 years]). Multivariable logistic regression was used to study associations between demographic and treatment-related risk factors and pituitary deficiencies, as well as associations between untreated deficiencies and cardiovascular health, bone mineral density (BMD), and physical fitness. RESULTS:The estimated point prevalence was 46.5% for GHD, 10.8% for LH/FSHD, 7.5% for TSHD, and 4% for ACTHD, and the cumulative incidence increased with follow-up. GHD and LH/FSHD were not treated in 99.7% and 78.5% of affected individuals, respectively. Male sex and obesity were significantly associated with LH/FSHD; white race was significant associated with LH/FSHD and TSHD. Compared with CRT doses less than 22 Gy, doses of 22 to 29.9 Gy were significantly associated with GHD; doses ≥ 22 Gy were associated with LH/FSHD; and doses ≥ 30 Gy were associated with TSHD and ACTHD. Untreated GHD was significantly associated with decreased muscle mass and exercise tolerance; untreated LH/FSHD was associated with hypertension, dyslipidemia, low BMD, and slow walking; and both deficits, independently, were associated with with abdominal obesity, low energy expenditure, and muscle weakness. CONCLUSION:Anterior pituitary deficits are common after CRT. Continued development over time is noted for GHD and LH/FSHD with possible associations between nontreatment of these conditions and poor health outcomes.

10064 Background: Adult survivors of childhood NHL are at risk for chronic conditions likely underestimated by patient reported outcomes. Prevalence and severity based on direct clinical assessment are lacking. Methods: Clinical, laboratory, and performance-based evaluations were obtained on 200 adult survivors of pediatric NHL at St. Jude Children’s Research Hospital. Chronic conditions were graded per CTCAE criteria. Impaired physical function was defined as performance below the 10th percentile of normative data. Multivariable Poisson regression models were used to investigate associations [relative risk (RR), 95% confidence intervals (CI)] between patient characteristics, therapies, and clinical outcomes. Results: Survivors (66% male, 87% white) were a median age of 10 years (range 1-19) at diagnosis and 34 years (20-58) at evaluation. Forty-six (23%) received radiation to the brain, 69(35%) high dose methotrexate, and 161(81%) steroids. Most (93%) had ≥ 1 chronic condition, 77% ≥ 2 chronic conditions, and 50% a severe/life-threatening (grade 3-4) condition. Most prevalent were overweight/obesity (65%), cognitive impairment (46%), dyslipidemia (41%), and impaired fasting glucose (37%). Most prevalent grade 3-4 conditions were obesity (35%), hypertension (15%), and cognitive impairment (13%). Risk-based screening detected cardiomyopathy in 14(8.5%); 50% grades 3-4. There were 27 second cancers (61% grades 3-4) in 23(12%) survivors. Prevalence of abnormal body composition, measured by waist to height ratio and percent fat on dual-energy x-ray absorptiometry was 72%. Many had impaired aerobic (22%), strength (48%), muscular endurance (36%), flexibility (39%), and mobility (36%) assessments. Adjusting for ages at diagnosis and evaluation, race, and methotrexate, male sex (RR 1.2, CI 1.1-1.5), anthracycline ≥ 250mg/m2 (RR 1.3, CI 1.1-1.6), and radiation (RR 1.3, CI 1.1-1.6) were associated with having ≥ 2 chronic conditions. Non-white race (RR 1.6, CI 1.2-2.1) was associated with a grade 3-4 condition. Conclusions: Prospective systematic evaluation identified significant chronic conditions and performance limitations in adult survivors of childhood NHL.

BACKGROUND: Pre-clinical evaluation of vorinostat and isotretinoin demonstrated cytotoxicity in medulloblastoma (MB) and synergistic activity when combined with cisplatin. This study sought to evaluate the feasibility of combining vorinostat and isotretinoin with cytotoxic chemotherapy in young children with newly diagnosed brain tumors. METHODS: Eligible patients were less than 4 years of age with newly diagnosed medulloblastoma (MB) or supratentorial primitive neuroectodermal tumor (CNS-PNET). Localized desmoplastic MB was excluded. Treatment consisted of 3 induction cycles given every 21 days with vorinostat and isotretinoin(days 1-4), cisplatin(day 4), vincristine(days 4,11,18), cyclophosphamide(days 5-6), and etoposide(days 4-6); 3 consolidation cycles with carboplatin and thiotepa(days 1-2) with stem cell rescue(day 4); and 12 cycles of monthly maintenance therapy with vorinostat and isotretinoin. Patients with M0 MB received focal radiation therapy following consolidation therapy; others received radiation at the discretion of the treating physician. Craniospinal radiation was not allowed on protocol. RESULTS: 31 patients received treatment on study; 19 (61.3%) were male; 7 (22.6%) had spinal cord or cerebrospinal fluid metastasis at diagnosis. Diagnosis was MB for 20, other CNS-PNET for 11. 24/31 patients completed 3 cycles of induction therapy within the pre-specified feasibility endpoint of 98 days. Eight experienced disease progression on therapy. Twelve completed therapy, five continue on therapy, five discontinued study treatment without progression, and one died of pulmonary toxicity following second cycle of consolidation. Two-year Progression Free Survival and Overall Survival for the entire cohort were 64.4% (SE ±11.1%) and 75.6% (SE ±10.0%), respectively; 68.2% (SE ±12.8%) and 77.0% (SE ±11.1%) for MB. Frozen tumor was collected from 30/31 tumors. CONCLUSION: It is feasible to administer vorinostat with isotretinoin and chemotherapy to young children with newly diagnosed MB or CNS-PNET. This multimodality therapy regimen resulted in encouraging progression-free survival without craniospinal radiation in a high-risk group of young children. Genomic studies are planned.

BackgroundFemale survivors of central nervous system (CNS) tumors are at an increased risk for gonadal damage and variations in the timing of puberty following radiotherapy and alkylating agent‐based chemotherapy.ProcedureClinical and laboratory data were obtained from 30 evaluable female patients with newly diagnosed embryonal CNS tumors treated on a prospective protocol (SJMB 96) at St. Jude Children's Research Hospital (SJCRH). Pubertal development was evaluated by Tanner staging. Primary ovarian insufficiency (POI) was determined by Tanner staging and FSH level. Females with Tanner stage I–II and FSH > 15 mIU/ml, or Tanner stage III–V, FSH > 25 mIU/ml and FSH greater than LH were defined to have ovarian insufficiency. Recovery of ovarian function was defined as normalization of FSH without therapeutic intervention.ResultsMedian length of follow‐up post completion of therapy was 7.2 years (4.0–10.8 years). The cumulative incidence of pubertal onset was 75.6% by the age of 13. Precocious puberty was observed in 11.1% and delayed puberty in 11.8%. The cumulative incidence of POI was 82.8%, though recovery was observed in 38.5%.ConclusionsTreatment for primary CNS embryonal tumors may cause variations in the timing of pubertal development, impacting physical and psychosocial development. Female survivors are at risk for POI, a subset of whom will recover function over time. Further refinement of therapies is needed in order to reduce late ovarian insufficiency. Pediatr Blood Cancer 2015;62:329–334. © 2014 Wiley Periodicals, Inc.