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Background Off‐label drug prescribing is common in pediatric clinical medicine, though the extent and impact of this practice in pediatric oncology has not yet been characterized. Methods We completed a retrospective single‐institution cohort study evaluating prevalence, characteristics, and clinical outcomes of off‐label prescribing of 108 FDA‐approved targeted anticancer drugs in patients, Off‐label prescribing patterns and outcomes with targeted anticancer agents have not been previously described in pediatric oncology. In this analysis from a large pediatric cancer center, off‐label prescribing of FDA‐approved targeted therapies was common, increasing, encompassed a broad sample of targeted agents, and was tolerable.

Medulloblastoma outcomes have improved with craniospinal irradiation and chemotherapy, but such therapy has resulted in poor neurocognitive outcomes for young patients. Chemotherapy-only regimens with autologous transplant have been implemented with the intention of avoiding radiation. It is not yet known whether single or tandem transplantation is superior with respect to efficacy and/or safety.We performed a retrospective review of children with medulloblastoma treated at Dana-Farber Cancer Institute from 1996 to 2016 who received either single or tandem autologous transplantation after completion of induction chemotherapy. We compared safety and outcome data between the two groups.Among 23 patients, 12 received tandem transplants. Median follow-up was 6.4 years (IQR = 0.8-10.5). There was no statistically significant difference in 5-year EFS or OS between the single (70.7 ± 14%, 80.2 ± 13%) and tandem transplant groups (57.1 ± 15%, 79.6 ± 13%). Seven tandem transplant patients received subsequent radiation while only four required radiation in the single transplant group (p = .41). In the single transplant regimen, patients experienced longer antibiotic duration (p = .03) and LOS (p = .01) and a trend toward increased number of transfusions (p = .06). Four cases of veno-occlusive disease were reported in the single transplant group (p = .04).Outcomes were similar between regimens, but the single transplant regimen had more hepatic complications. These data suggest that tandem transplant regimens may have reduced toxicity compared to the single transplant regimen with similar outcome measures.

Background: Integratedbehavioral health models have been proposed as care delivery approaches to mitigate mental health disparities in primary care settings. However, these models have not yet been widely adopted or evaluated in pediatric oncology medical homes. Methods: We conducted a retrospective cohort study of 394 children with newly diagnosed cancer at Dana-Farber/Boston Children's Cancer and Blood Disorders Center (DF/BCH) from April 2013 to January 2017. Baseline sociodemographic characteristics and psychiatry utilization outcomes at 12 months following diagnosis were abstracted from the medical record. The severity of household material hardship (HMH), a concrete poverty exposure, at diagnosis and race/ethnicity were characterized by parent report using the Psychosocial Assessment Tool 2.0 (PAT). Associations between sociodemographic characteristics and receipt of psychiatry consultation were assessed with multivariable logistic regression models. Results: Among 394 children, 29% received a psychiatric consultation within 12 months postdiagnosis. Of these, 88% received a new psychiatric diagnosis, 76% received a psychopharmacologic recommendation, and 62% received a new behavioral intervention recommendation. In multivariable logistic regression adjusting for age, cancer diagnosis, and PAT total score, there was no statistically significant association between HMH severity or household income and psychiatry utilization. Children who identified as racial/ethnic minorities were significantly less likely to receive a psychiatry consultation (OR = 0.48, 95% CI = 0.27–0.84). Conclusions: In a pediatric oncology medical home with an integrated behavioral health model, socioeconomic status was not associated with disparate psychiatry utilization. However, there remained a profound racial/ethnic disparity in psychiatry utilization, highlighting the need for additional research and care delivery intervention.

BACKGROUND Many childhood cancersurvivors experience at least one late effect of treatment, and both late effects and persistent cancer-related worry can negatively impact quality of life in survivorship. Little is known about the prevalence or impact of parental worry about late effects early in treatment. This study evaluated parental perceived likelihood, impact, and worry about late effects of childhood cancer. PROCEDURE We surveyed 96 parents of pediatric cancer patients at Dana-Farber/Boston Children's Cancer and Blood Disorders Center within a year of diagnosis. Parents were asked about their experiences with late effects communication, general worry about late effects, and specific late effect worries. RESULTS Most (96%) parents valued information about late effects, and 93% considered late effects in their treatment decision-making. Yet, 24% could not recall receiving any information about late effects, and only 51% felt well prepared for potential late effects. Though only 20% of parents considered their child at high risk of experiencing late effects, 61% were extremely/very worried about late effects. Those who felt their child was at high risk of experiencing late effects were more likely to worry (OR = 4.7, P = 0.02). CONCLUSIONS Many parents feel inadequately informed about late effects of cancer treatment, and only one-fifth of parents consider late effects to be likely for their child. However, a majority of parents worry about late effects, including ones they think their child is unlikely to experience. Although some worry is anticipated, disproportionate worry may be mitigated by addressing both educational shortfalls and emotional concerns.

Pyruvate kinase deficiency (PKD) is a rare, autosomal recessive red blood cell enzyme disorder, which leads to lifelong hemolytic anemia and associated complications from the disease and its management.An international, multicenter registry enrolled 124 individuals younger than 18 years old with molecularly confirmed PKD from 29 centers. Retrospective and prospective clinical data were collected.There was a wide range in the age at diagnosis from 0 to 16 years. Presentation in the newborn period ranged from asymptomatic to neonatal jaundice to fulminant presentations of fetal distress, myocardial depression, and/or liver failure. Children5 years old were significantly more likely to be transfused than children12 to18 years (53% vs. 14%, p = .0006), which correlated with the timing of splenectomy. Regular transfusions were most common in children with two severe PKLR variants. In regularly transfused children, the nadir hemoglobin goal varied considerably. Impact on quality of life was a common reason for treatment with regular blood transfusions and splenectomy. Splenectomy increased the hemoglobin and decreased transfusion burden in most children but was associated with infection or sepsis (12%) and thrombosis (1.3%) even during childhood. Complication rates were high, including iron overload (48%), perinatal complications (31%), and gallstones (20%).There is a high burden of disease in children with PKD, with wide practice variation in monitoring and treatment. Clinicians must recognize the spectrum of the manifestations of PKD for early diagnostic testing, close monitoring, and management to avoid serious complications in childhood.

PURPOSE Siloed electronic medical data limits utility and accessibility. At the Dana-Farber/Boston Children's Cancer and Blood Disorders Center, cross-institutional data were inconsistent and difficult to access. To unify data for clinical operations, administration, and research, we developed the Pediatric Patient Informatics Platform ( PPIP), an integrated datamart harmonizing multiple source systems across two institutions into a common technology. PATIENTS AND METHODS Starting in 2009, user requirements were gathered and data sources were prioritized. Project teams, including biostatisticians, database developers, and an external contractor, were formed. Read-access to source systems was established. The 3-layer PPIP architecture was developed: STAGING, a near-exact copy of source data; INTEGRATION, where data were reorganized into domains; and, CONSUMPTION, where data were optimized for rapid retrieval. The diverse systems were integrated into a common IBM Netezza technology. Data filters were defined to accurately capture the Center's patients, and derived data items were created for harmonization across sources. An interactive online query tool, PPIP360, was developed using Microstrategy Analytics. RESULTS Driven by scientific objectives, the PPIP datamart was created, including 33,674 patients, 2,983 protocols, and 3.6 million patient visits from 14 source databases, 164 source tables, and 2,622 source data items. The PPIP360 has 605 data items and 33 metrics across 11 reports and dashboards. Dana-Farber and Boston Children's established a legal data-sharing agreement. The PPIP has supported hundreds of faculty, staff, and projects, including planning clinical trials and informing strategic planning. CONCLUSION The PPIP has successfully harmonized and integrated diagnostic, demographic, laboratory, treatment, clinical outcome, pathology, transplant, meta-protocol, and –omics data, for efficient, daily operational and research activities at Dana-Farber/Boston Children's Cancer and Blood Disorders Center, and future external sharing.

BACKGROUND Prognostic significance of IDH-mutation in glioma is incompletely understood in children and adolescents/young adults (YAs). We compared the clinico-genomic features, outcomes and prognostic factors observed in IDH-mutant gliomas across age groups. METHODS Clinical, histologic and molecular data of patients with IDH-mutant gliomas from 8 pediatric institutions (spanning twenty years) and adult patients from two institutions (from 2013–2019) were identified. Patients were grouped as pediatric (< 19y), YA (19y to < 40y) or older adult (≥ 40y). Genomic alterations, including somatic mutations and copy number variants, were captured with institutional next generation sequencing. Factors were compared across age categories using Fisher’s exact test or analysis-of-variance. Cox proportional-hazards regression tested factors for association with overall (OS) and progression-free survival (PFS). RESULTS Of 379 patients, 48(13%) were pediatric, 204(54%) YA and 127(33%) older adult. Histological subtype differed significantly by age group (p< 0.0001). YAs had higher rates of malignant transformation (p=0.01) and shorter time-from-diagnosis-to-malignant transformation (p=0.01) compared to other age groups. Analysis of genomic alterations revealed an age-related difference in distribution in ATRX mutations only (p=0.0018). Median PFS and OS for the entire cohort were 4.62 and 17.19 years. In univariate models, PFS differed by age group (p=0.0012), with YAs having the worst outcomes. Lack of MGMT methylation (p=0.024) predicted poorer OS. Upfront observant management was predictive of poorer PFS. Gene mutations were not associated with PFS. In multi-variable models, YAs had shorter PFS compared to pediatric (hazard ratio [HR]=2.03, p=0.01) and older adults (HR=1.59, p=0.003) after adjusting for histology, extent of resection, and initial therapy. Age at diagnosis was not associated with OS in multi-variable analysis. CONCLUSIONS Within our cohort, YA with IDH-mutant tumors progressed more quickly compared to their pediatric counterparts. Further study of YA patients with IDH-mutant glioma is critical to better define best practices for this group.

Background: Pyruvate kinase deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia. The spectrum of disease in PKD is broad, ranging from an incidentally discovered mild anemia to a severe transfusion-dependent anemia. Splenectomy partially ameliorates the anemia and reduces the transfusion burden in the majority of patients. Because hemoglobin poorly correlates with symptoms in PKD, transfusion requirements are typically used clinically to classify disease severity with those who are regularly transfused despite splenectomy recognized as the most severely affected subgroup. Aim: To compare demographics, complications, and laboratory results between the most severely-affected PKD patients (those that are splenectomized and regularly transfused) with non-regularly transfused splenectomized PKD patients. Methods: After ethics committee approval, patients were enrolled on the PKD Natural History Study, a prospective 30 site international study. All patients had molecularly confirmed PKD. Only splenectomized patients were included in the analysis. Transfusion frequency was observed over a 3-year period. Patients were divided into two groups based on transfusion frequency: the severe phenotype group was defined as those who receive regular transfusions (≥6 discrete red cell transfusion episodes per year) and the control group did not receive regular transfusions. Phenotype stability over the 3-year period was also assessed. Results: 154 splenectomized patients with PKD were included: 30 patients in the severe PKD phenotype group and 124 patients in the comparison PKD group. Results of the analysis comparing the two groups are described in the Table. Severely affected patients were more likely to be female (77% versus 51%, p=0.013), older at the time of splenectomy (median age: 5 versus 3.6, p=0.011), have iron overload (93% vs. 51%, p Conclusions: Patients with PKD who are regularly transfused despite splenectomy appeared to have similar rates of PKD-associated complications (except for iron overload) and similar relevant laboratory values and genotypes when compared to those who are not regularly transfused after splenectomy. The similarity observed between severe phenotype patients and comparison patients with PKD may result from a protective effect of transfusion (e.g. reduction of bone fractures and extramedullary hematopoiesis) or could suggest transfusion-dependence is an artificial signifier of disease severity, reflective of provider practices and patient symptoms rather than an actual distinct phenotype. Transfusion requirements in severe PKD appear to fluctuate significantly over time. Download : Download high-res image (830KB) Download : Download full-size image Disclosures Al-Samkari: Dova: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. van Beers: RR Mechatronics: Research Funding; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding. Barcellini: Agios: Consultancy, Other: Advisory board; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board; Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau. Eber: Agios Pharmaceuticals, Inc.: Consultancy. Glader: Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat: Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Kuo: Pfizer: Consultancy; Novartis: Consultancy, Honoraria; Celgene: Consultancy; Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy. Despotovic: Dova: Honoraria; Novartis: Research Funding; Amgen: Research Funding. Kwiatkowski: Celgene: Consultancy; Terumo: Research Funding; Apopharma: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Imara: Consultancy; Novartis: Research Funding. Thompson: Baxalta: Research Funding; Novartis: Consultancy, Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Ravindranath: Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Rothman: Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Verhovsek: Sickle Cell Awareness Group of Ontario: Membership on an entity's Board of Directors or advisory committees; Sickle Cell Disease Association of Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Haemoglobinopathy Association: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy. Kunz: Novartis: Membership on an entity's Board of Directors or advisory committees. Sheth: CRSPR/Vertex: Other: Clinical Trial Steering committee; Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy. London: United Therapeutics: Consultancy; ArQule, Inc: Consultancy. Grace: Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Context Bereaved parents provide an important perspective for improving care for patients and families throughout the illness and after a child's death. However, involvement of bereaved parents in research studies is fraught with concerns over inflicting psychological distress and issues with study recruitment. Data on research strategies to engage parents early in their bereavement are limited. Objectives To describe involvement of bereaved parents in the development of a comprehensive survey, examine the response rates with varying recruitment strategies and describe participation experiences of parent participants. Methods Parents of children who endured the death of their child from cancer six to 24 months prior were invited to complete a 195-item survey examining their early grief experience. Results Forty-nine of the 137 eligible parents from 36 different households completed the survey (response rate 36%). The respondents were predominantly white (N = 43; 88%), female (N = 32; 65%), and non-Hispanic (N = 43; 88%). The median length of time from child's death to survey completion was 11 months (range 7–26). Thirty parents (61%) indicated they were comfortable/very comfortable answering the survey, 40 (82%) answered that they experienced at least a little benefit from involvement, and 36 (73%) indicated they experienced at least some distress. Conclusion Some parents of children who died of cancer are willing to participate in research early in their bereavement, and although most experience some distress, they are comfortable answering questions about their experience and benefit from participation. Recruitment strategies including personal outreach may result in better response rates.

Diagnosis of pyruvate kinase deficiency (PKD), the most common cause of hereditary non-spherocytic haemolytic anaemia, remains challenging in routine practice and no biomarkers for clinical severity have been characterised. This prospective study enrolled 41 patients with molecularly confirmed PKD from nine North American centres to evaluate the diagnostic sensitivity of pyruvate kinase (PK) enzyme activity and PK:hexokinase (HK) enzyme activity ratio, and evaluate the erythrocyte PK (PK-R) protein level and erythrocyte metabolites as biomarkers for clinical severity. In this population not transfused for ≥90 days before sampling, the diagnostic sensitivity of the PK enzyme assay was 90% [95% confidence interval (CI) 77-97%], whereas the PK:HK ratio sensitivity was 98% (95% CI 87-100%). There was no correlation between PK enzyme activity and clinical severity. Transfusion requirements correlated with normalised erythrocyte ATP levels (r = 0·527, P = 0·0016) and PK-R protein levels (r = -0·527, P = 0·0028). PK-R protein levels were significantly higher in the never transfused [median (range) 40·1 (9·8-73·9)%] versus ever transfused [median (range) 7·7 (0·4-15·1)%] patients (P = 0·0014). The PK:HK ratio had excellent sensitivity for PK diagnosis, superior to PKLR exon sequencing. Given that the number of PKLR variants and genotype combinations limits prognostication based on molecular findings, PK-R protein level may be a useful prognostic biomarker of disease severity and merits further study.

[Figure: see text] BACKGROUND: More than 80% of children with cancer become long-term survivors, yet most survivors experience late effects of treatment. Little is known about how parents and physicians consider late-effects risks against a potential survival benefit when making treatment decisions. METHODS: We used a discrete choice experiment to assess the importance of late effects on treatment decision-making and acceptable trade-offs between late-effects risks and survival benefit. We surveyed 95 parents of children with cancer and 41 physicians at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center to assess preferences for 5 late effects of treatment: neurocognitive impairment, infertility, cardiac toxicity, second malignancies, and impaired growth and development. RESULTS: Each late effect had a statistically significant association with treatment choice, as did survival benefit (P < .001). Avoidance of severe cognitive impairment was the most important treatment consideration to parents and physicians. Parents also valued cure and decreased risk of second malignancies; physician decision-making was driven by avoidance of second malignancies and infertility. Both parents and physicians accepted a high risk of infertility (parents, a 137% increased risk; physicians, an 80% increased risk) in exchange for a 10% greater chance of cure. CONCLUSIONS: Avoidance of severe neurocognitive impairment was the predominant driver of parent and physician treatment preferences, even over an increased chance of cure. This highlights the importance of exploring parental late-effects priorities when discussing treatment options.

BACKGROUND Children with advanced cancer experience high symptom distress, which negatively impacts their health-related quality of life (HRQOL). To the authors' knowledge, the relationship between income and symptom distress and HRQOL is not well described. METHODS The Pediatric Quality of Life and Symptoms Technology (PediQUEST) multisite clinical trial evaluated an electronic patient-reported outcome system to describe symptom distress and HRQOL in children with advanced cancer via repeated surveys. The authors performed a secondary analysis of PediQUEST data for those children with available parent-reported household income (dichotomized at 200% of the Federal Poverty Level and categorized as low income [

Background Intraoperative electrocorticography (ECoG) has been utilized in patients with tumor-associated seizures; however, its effectiveness for seizure control remains controversial. Objective To evaluate clinical outcomes in pediatric patients undergoing lesionectomy with or without ECoG. Methods Patients undergoing brain tumor resection at Boston Children's Hospital were examined retrospectively (2005-2014). Inclusion criteria involved diagnosis of a supratentorial tumor, ≥2 unequivocal seizures, and ≥6 mo follow-up. Patients with isolated cortical dysplasia or posterior fossa tumors were excluded. Logistic regression models evaluated predictors of ECoG use, and the impact of ECoG, gross total resection, and focal cortical dysplasia with tumors on seizure freedom by Engel Class and anti-epileptic drug use (AED). Results A total of 119 pediatric patients were included (n = 69 males, 58%; median age, 11.3 yr). Forty-one patients (34.5%) had ECoG-guided surgery. Preoperative seizure duration and number and duration of AED use were significant predictors for undergoing ECoG. There were no differences in seizure freedom (Engel Class I) or improved Engel Score (Class I-II vs III-IV) in patients who did or did not have ECoG at 30 d, 6 mo, and 1, 2, or 5 yr. Patients undergoing ECoG required a greater number of AEDs at 6 mo (P = .01), although this difference disappeared at subsequent time intervals. Gross total resection predicted seizure freedom at 30 d and 6 mo postsurgery (P = .045). Conclusion This retrospective study, one of the largest evaluating the use of ECoG during tumor resection, suggests that ECoG does not provide improved seizure freedom compared to lesionectomy alone for children.

Context Although access to subspecialty pediatric palliative care (PPC) is increasing, little is known about the role of PPC for children with advanced heart disease (AHD). Objectives The objective of this study was to examine features of subspecialty PPC involvement for children with AHD. Methods This is a retrospective single-institution medical record review of patients with a primary diagnosis of AHD for whom the PPC team was initially consulted between 2011 and 2016. Results Among 201 patients, 87% had congenital/structural heart disease, the remainder having acquired/nonstructural heart disease. Median age at initial PPC consultation was 7.7 months (range 1 day–28.8 years). Of the 92 patients who were alive at data collection, 73% had received initial consultation over one year before. Most common indications for consultation were goals of care (80%) and psychosocial support (54%). At initial consultation, most families (67%) expressed that their primary goal was for their child to live as long and as comfortably as possible. Among deceased patients (n = 109), median time from initial consultation to death was 33 days (range 1 day–3.6 years), and children whose families expressed that their primary goal was for their child to live as comfortably as possible were less likely to die in the intensive care unit (P = 0.03) and more likely to die in the setting of comfort care or withdrawal of life-sustaining interventions (P = 0.008). Conclusion PPC involvement for children with AHD focuses on goals of care and psychosocial support. Findings suggest that PPC involvement at end of life supports goal-concordant care. Further research is needed to clarify the impact of PPC on patient outcomes.

Ependymoma is the third most common brain tumor in children, but there is a paucity of large studies with more than 10 years of follow-up examining the long-term survival and recurrence patterns of this disease. We conducted a retrospective chart review of 103 pediatric patients with WHO Grades II/III intracranial ependymoma, who were treated at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Chicago’s Ann & Robert H. Lurie Children’s Hospital between 1985 and 2008, and an additional 360 ependymoma patients identified from the Surveillance Epidemiology and End Results (SEER) database. For the institutional cohort, we evaluated clinical and histopathological prognostic factors of overall survival (OS) and progression-free survival (PFS) using the log-rank test, and univariate and multivariate Cox proportional-hazards models. Overall survival rates were compared to those of the SEER cohort. Median follow-up time was 11 years. Ten-year OS and PFS were 50 ± 5% and 29 ± 5%, respectively. Findings were validated in the independent SEER cohort, with 10-year OS rates of 52 ± 3%. GTR and grade II pathology were associated with significantly improved OS. However, GTR was not curative for all children. Ten-year OS for patients treated with a GTR was 61 ± 7% and PFS was 36 ± 6%. Pathological examination confirmed most recurrent tumors to be ependymoma, and 74% occurred at the primary tumor site. Current treatment paradigms are not sufficient to provide long-term cure for children with ependymoma. Our findings highlight the urgent need to develop novel treatment approaches for this devastating disease. Electronic supplementary material The online version of this article (doi:10.1007/s11060-017-2568-8) contains supplementary material, which is available to authorized users.

Purpose External beam radiation therapy to initial sites of disease may influence relapse patterns in high-risk neuroblastoma. However, the effect of systemic irradiation by use of total body irradiation (TBI) on anatomic patterns of relapse has not previously been investigated. Methods and Materials We retrospectively analyzed patients receiving definitive treatment of high-risk neuroblastoma with subsequent relapse in bony metastatic sites, with a date of relapse between January 1, 1997, and December 31, 2012. Anatomic sites of disease, defined by metaiodobenzylguanidine (MIBG) avidity, were compared at diagnosis and at first relapse. The Fisher exact test was performed to compare relapse in initially involved sites between patients treated with and without TBI. Results Seventy-four patients with a median age at diagnosis of 3.5 years (range, 0.3-15.3 years) had relapse in 227 sites of MIBG-avid metastatic disease, with a median time to relapse of 1.8 years. Of the 227 sites of first relapse, 154 sites (68%) were involved at diagnosis. When we compared relapse patterns in patients treated with and without TBI, 12 of 23 patients (52%) treated with TBI had relapse in ≥1 previously MIBG-avid site of disease whereas 40 of 51 patients (78%) treated without TBI had relapse in ≥1 previously MIBG-avid site of disease ( P =.03). Conclusions Patients treated with systemic irradiation in the form of TBI were significantly less likely to have relapse in prior sites of disease. These findings support further investigation into the role of radiopharmaceutical therapies in curative multimodality therapy.

Context Childhood cancer care is delivered by interprofessional health care teams; however, little is known about how parents perceive overall team-delivered care (TDC). Objectives We sought to describe parent perceptions of TDC and associated factors, including care rendered by individual clinicians, teamwork, information consistency, and patient and parent characteristics. Methods Cross-sectional surveys were distributed to parents of 104 children with recurrent/refractory cancer enrolled in a multisite symptom management trial. The primary outcome, TDC, was parent report of care quality delivered by the child's care team during the preceding three months. Likert-scaled items (excellent/very good/good/fair/poor) queried care quality delivered by individual clinicians, perceived teamwork, and other factors. Factors associated with parent perceptions of excellent TDC were identified using Fisher's exact test. Results Eighty-six parents (83%) responded. During the preceding three months, 63% (n = 54) of parents reported excellent TDC. However, only 47% (n = 40) described their care team's teamwork as excellent. Approximately one-quarter (24%) described care rendered by their child's oncologist as less-than-excellent. Among parents who reported psychosocial clinician involvement (71%; n = 60), only 43% described this care as excellent. Individually, excellent care from each clinician type (oncologist, psychosocial clinician, and primary nurse) was associated with excellent TDC (all P ≤ 0.001; no correction for multiple comparisons). Conclusion Among parents of children with advanced cancer, more than one-third report less-than-excellent TDC. In addition, less than half report excellent teamwork, and ratings of care rendered by individual clinicians are highly variable. Findings suggest that interventions are needed to enhance interprofessional teamwork in the care of children with advanced cancer.

Germline mutations in GATA2 are associated with an inherited predisposition to bone marrow failure (BMF), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). Hematopoietic stem cell transplantation (HSCT) remains the only curative therapy. However, patients may be at an increased risk for transplant-related toxicity (TRT) and transplant-related mortality (TRM) due to their underlying disease biology. We performed a retrospective case-control study of pediatric patients with BMF/MDS/AML with germline GATA2 mutations, comparing HSCT outcomes to randomly selected patients without germline GATA2 mutations and BMF/MDS (control A) and acute leukemia (control B). The 5-year overall and disease-free survival rates in the GATA2 cohort (65%, 51%) were similar to control A (58%, 49%) and B (45%, 43%) cohorts. In contrast, the 5-year event-free survival rate was significantly lower in the GATA2 cohort (7% ± 6%, 28% ± 10%, and 33% ± 8% for GATA2, A, and B, respectively), due to an increased number of unique TRTs. Specifically, neurologic toxicities occurred significantly more frequently in GATA2 patients than in the control groups, and post-HSCT thrombotic events occurred only in the GATA2 cohort. There was no difference in TRM, infections, or graft-versus-host disease across groups. The higher incidence of thrombotic and neurologic events specific to GATA2 patients warrants further investigation and has potential treatment ramifications.

BackgroundNUT midline carcinoma, renamed NUT carcinoma (NC), is an aggressive squamous cancer defined by rearrangement of the NUTM1 gene. Although a subset of patients can be cured, for the majority of patients the prognosis is grim. We sought to classify patients into risk groups based on molecular and clinicopathologic factors at the time of diagnosis.MethodsClinicopathologic variables and survival outcomes were extracted for a total of 141 NC patients from the NUT midline carcinoma Registry using questionnaires and medical records. Translocation type was identified by molecular analyses. Survival tree regression analysis was performed to determine risk factors associated with overall survival (OS).ResultsFor 141 patients, the median age at diagnosis was 23.6 years. Fifty-one percent had thoracic origin compared with 49% nonthoracic sites (41% head and neck, 6% bone or soft tissue, 1% other). The median OS was 6.5 months (95% confidence interval [CI] = 5.8 to 9.1 months). Most patients had the BRD4-NUTM1 fusion (78%), followed by BRD3-NUTM1 (15%) and NSD3-NUTM1 (6%). Survival tree regression identified three statistically distinct risk groups among 124 patients classified by anatomical site and genetics: group A is nonthoracic primary, BRD3-, or NSD3-NUT (n = 12, median OS = 36.5 months, 95% CI = 12.5 to not reported months); group B is nonthoracic primary, BRD4-NUT (n = 45, median OS = 10 months, 95% CI = 7 to 14.6 months); and group C is thoracic primary (n = 67, median OS = 4.4 months, 95% CI = 3.5 to 5.6 months). Only groups A and B had long-term (≥3 years, n = 12) survivors.ConclusionsWe identify three risk groups defined by anatomic site and NUT fusion type. Nonthoracic primary with non-BRD4-NUT fusion confers the best prognosis, followed by nonthoracic primary with BRD4-NUT. Thoracic NC patients, regardless of the NUT fusion, have the worst survival.

ObjectiveTo identify risk factors associated with nonmelanoma skin cancer (NMSC) occurrence and survival in children.Study designThis was a multicenter, retrospective, case-control study of patients 12months prior to diagnosis and 49% of patients were diagnosed with ≥2 skin cancers. At last follow-up, 5% (6 of 124) of patients with NMSC died. Voriconazole exposure was noted in 7 cases and associated with worse 3-year overall survival (P=.001).ConclusionsNMSC in children and young adults is often associated with a predisposing condition or iatrogenicexposure. High-risk patients should be identified early to provide appropriate counseling and management.

An international, multicenter registry was established to collect retrospective and prospective clinical data on patients with pyruvate kinase (PK) deficiency, the most common glycolytic defect causing congenital nonspherocytic hemolytic anemia. Medical history and laboratory and radiologic data were retrospectively collected at enrollment for 254 patients with molecularly confirmed PK deficiency. Perinatal complications were common, including anemia that required transfusions, hyperbilirubinemia, hydrops, and prematurity. Nearly all newborns were treated with phototherapy (93%), and many were treated with exchange transfusions (46%). Children age 5 years and younger were often transfused until splenectomy. Splenectomy (150 [59%] of 254 patients) was associated with a median increase in hemoglobin of 1.6 g/dL and a decreased transfusion burden in 90% of patients. Predictors of a response to splenectomy included higher presplenectomy hemoglobin (P 5 .007), lower indirect bilirubin (P 5 .005), and missense PKLR mutations (P 5 .0017). Postsplenectomy thrombosis was reported in 11% of patients. The most frequent complications included iron overload (48%) and gallstones (45%), but other complications such as aplastic crises, osteopenia/bone fragility, extramedullary hematopoiesis, postsplenectomy sepsis, pulmonary hypertension, and leg ulcers were not uncommon. Overall, 87 (34%) of 254 patients had both a splenectomy and cholecystectomy. In those who had a splenectomy without simultaneous cholecystectomy, 48% later required a cholecystectomy. Although the risk of complications increases with severity of anemia and a genotype-phenotype relationship was observed, complications were common in all patients with PK deficiency. Diagnostic testing for PK deficiency should be considered in patients with apparent congenital hemolytic anemia and close monitoring for iron overload, gallstones, and other complications is needed regardless of baseline hemoglobin. This trial was registered at www.clinicaltrials.gov as #NCT02053480.

Christopher J Centeno,1,2 John Pitts,1 Hasan Al-Sayegh,2 Michael D Freeman,3 1Centeno-Schultz Clinic, 2Regenerative Sciences, LLC., Broomfield, CO, 3Public Health Department, Oregon Health and Science University, Portland, OR, USA Introduction: This was a prospective case series designed to investigate treatment for anterior cruciate ligament (ACL) tears using an injection of autologous bone marrow concentrate. Methods: Consecutive adult patients presenting to a private outpatient interventional musculoskeletal and pain practice with knee pain, ACL laxity on exam, and magnetic resonance imaging (MRI) evidence of a grade 1, 2, or 3 ACL tears with less than 1 cm retraction were eligible for this study. Eligible patients were treated with an intraligamentous injection of autologous bone marrow concentrate, using fluoroscopic guidance. Pre- and postprocedural sagittal MRI images of the ACLs were analyzed using ImageJ software to objectively quantify changes between pre- and posttreatment scans. Five different types of measurement of ACL pixel intensity were examined as a proxy for ligament integrity. In addition pain visual analog scale (VAS) and Lower Extremity Functional Scale (LEFS) values were recorded at baseline and at 1 month, 3 months, 6 months, and annually postinjection. Objective outcomes measured were pre- to post-MRI measurement changes, as analyzed by the ImageJ software. Subjective outcomes measured were changes in the VAS and LEFS, and a self-rated percentage improvement. Results: Seven of ten patients showed improvement in at least four of five objective measures of ACL integrity in their postprocedure MRIs. In the entire study group, the mean gray value, median, raw integrated density, and modal gray value all decreased toward low-signal ACLs (P=0.01, P=0.02, P=0.002, and P=0.08), indications of improved ligament integrity. Seven of ten patients responded to the self-rated metrics follow up. The mean VAS change was a decrease of 1.7 (P=0.25), the mean LEFS change was an increase of 23.3 (P=0.03), and mean reported improvement was 86.7%. Conclusion: Based on this small case series, autologous bone marrow concentrate shows promise in the treatment of grade 1, 2, and possibly grade 3 ACL tears without retraction. Further investigation using a controlled study design is warranted. Keywords: anterior cruciate ligament injury, regenerative therapy, bone marrow concentrate, mesenchymal stem cells, knee instability

BACKGROUND: Although medical marijuana (MM) may have utility in the supportive care of children with serious illness, it remains controversial. We investigated interdisciplinary provider perspectives on legal MM use in children with cancer. METHODS: We sent a 32-item, cross-sectional survey to 654 pediatric oncology providers in Illinois, Massachusetts, and Washington characterizing MM practices, knowledge, attitudes, and barriers. Forty-eight percent responded; 44% (n = 288) were included in analyses. Providers were stratified by status as legally eligible to certify (ETC) for MM. We used Fisher’s exact and Wilcoxon rank tests and univariate and multivariate logistic regression models for group comparisons. RESULTS: The provider median age was 35 years (range 22–70 years); 33% were ETC (83 physicians; 13 Washington state advance practice providers). Thirty percent of providers received ≥1 request for MM in the previous month. Notably, only 5% of all providers knew state-specific regulations. ETC providers were more likely to know that MM is against federal laws (P < .0001). Whereas most providers (92%) reported willingness to help children with cancer access MM, in adjusted models, ETC providers were less likely to indicate approval of patient MM use by smoking, oral formulations, as cancer-directed therapy, or to manage symptoms (P < .005 for all). Forty-six percent of all providers cited the absence of standards around formulations, potency, or dosing to be the greatest barrier to recommending MM. CONCLUSIONS: Most pediatric oncology providers are willing to consider MM use in children with cancer and receive frequent inquiries. However, ETC providers endorse less favorable attitudes overall. The absence of standards is an important barrier to recommending MM.

Poverty is an important patient-reported outcome of therapy and a potential predictor of outcome disparities in pediatric cancer. We previously identified that nearly 30% of pediatric cancer families experience household material hardship (HMH), a concrete measure of poverty including food, energy, or housing insecurity, during the first 6 months of chemotherapy. We conducted a follow-up survey in a subcohort of these families at least 1 year off-therapy and found that 32% reported HMH in early survivorship. Persistently high concrete resource needs off-therapy may have significance for child health and quality of life, and thus represent targets for future investigation.

Literature on the relationship between depression and C-reactive protein (CRP), a biomarker of systematic inflammation, remains inconsistent. Insufficient adjustment for confounders and effect modifiers might be one explanation. We used the data of 6396 men and 6610 women aged 18 or older, who completed a depression screening and had blood collected as a part of the National Health and Nutrition Examination Survey, 2005-2010. Depression was measured using the 9-item depression scale of the Patient Health Questionnaire (PHQ-9). The odds ratios (ORs) of depression were 1.00 (reference), 1.89 (95% CI=0.77-4.67) and 3.41(1.25-9.25) respectively for men with low, intermediate and upper quartile of CRP. Adjustment for covariates, mainly body mass index, diminished the association among women, from 1.65(1.00-2.74) to 1.08(0.57-2.03) for intermediate, from 2.44 (1.43-4.16) to 1.05 (0.56-1.98) for upper quartile of CRP. Adjustment for the history of major medical illnesses changed ORs neither among men nor among women. The study concluded that CRP remained significantly associated with depression in a dose-response fashion among men but women after being adjusted for body weight. Abnormal body weight, both under and overweight, explained a substantial part of the relationship between CRP and depression among women.

Background The mortality pattern of individuals with impaired verbal memory (IVM) has not yet been well described. We sought to describe the risk of all-causes, as well as specific causes of death associated with IVM. Method We used the data of 4151 nationally representative adults ≥60 years old who participated in the third National Health and Nutrition Examination Survey, 1988–1994, and completed one non-contextual (i.e., word list memory) and one contextual delayed-recall tests (i.e., short story recall). The participants were passively followed up through 31 December 2006. We determined the hazard ratio of death from all-causes and specific cause through Cox proportional hazard regression. Results Severe and moderate IVM were present in 268 (6.5%) and 495 (11.9%) participants at baseline survey, and 2550 deaths occurred by the end of 18-year follow-up (median = 12 years). The medians of survival time adjusted for all-causes death were 6.17(95%CI: 5.50, 6.92), 9.50 (8.92, 10.25), and 13.17 (12.75, 13.58) years, respectively for the individuals with severe, moderate, and no IVM. Severe IVM was significantly associated with death from cardio-cerebral vascular diseases [hazard ratio = 1.70, 95%CI = (1.36–2.12)], stroke [2.60 (1.69–3.99)], and Alzheimer's disease [3.50 (1.40–8.76)]. The shortened survival time of the participants with IVM was mainly driven by the deaths of cerebral-cardiovascular diseases, which accounted for almost half of all deaths. Conclusion The predictability of memory scores to early cerebral-cardiovascular deaths demonstrated that central challenge among individuals with cognitive impairment was cardiovascular diseases management. Copyright © 2014 John Wiley & Sons, Ltd.

Background: Pyruvate Kinase (PK) deficiency is caused by mutations in the PKLR gene leading to chronic hereditary non-spherocytic hemolytic anemia. Diagnostic evaluation can be challenging with falsely normal PK enzyme activity levels in chronically transfused patients, in those with profound reticulocytosis, or in patients with mutations with unusual biochemical properties. Genetic testing can also be complex, as up to 20% of affected patients have new PKLR variants and up to 10% of patients have variants not routinely detected through exon sequencing. The phenotypic spectrum is broad, and biomarkers of clinical severity would be helpful for both prognosis and monitoring. Aims: To describe the correlation of PK enzyme activity, red cell PK (PK-R) protein level, and red cell metabolites [adenosine triphosphate (ATP), 2,3-diphosphoglycerate (2,3-DPG)] with clinical phenotype. To estimate the sensitivity of PK enzyme activity to diagnose PK deficiency in a cohort of patients with genetically confirmed PK deficiency. Methods: Blood samples were collected from a subset of 41 patients enrolled in the PK Deficiency Natural History Study, all with two confirmed PKLR mutations and no red cell transfusions for ≥3 months prior to the blood sample. PK and hexokinase (HK) enzyme activity testing were performed using standard biochemical assays (Beutler 1985) at the Stanford Red Blood Cell Special Studies Laboratory (normal ranges: PK activity: 3.2-6.5 EU/gm Hb, HK activity: 0.14-0.37 EU/gm Hb). Baseline PK-R protein was quantitated by antibody-based capture and detection using a Meso Scale assay and the signal normalized to a control sample without PK deficiency. ATP and 2,3-DPG concentrations (μg/ml) in blood were analyzed using qualified tandem mass spectrometry methods and then normalized for individual hemoglobin (Hb) values (ATP and 2,3-DPG concentrations were converted to g/dL and divided by Hb (g/dL)). Spearman correlation coefficients were calculated to estimate the correlation between continuous variables, and Wilcoxon rank-sum testing was used to assess the association of continuous and binary variables. Results: The median age was 25.3 years (range 1.4-60.4) and 80% of patients were splenectomized (Table). The mean PK enzyme activity level was 1.1 EU/gm Hb with 90% (37/41) of patients with low PK activity. Normal PK activity was observed in 4 patients, 3 of whom had high HK activity and a low PK/HK ratio (normal mean PK/HK ratio 15.6, range: 8.7-22.5), with a sensitivity of 98% (40/41) when both PK activity and PK/HK ratio were used together. There were no correlations between PK enzyme activity and clinical severity indicators, including transfusion status (p=0.3), splenectomy status (p=0.4), or post-splenectomy Hb (r=0.109). Normalized ATP levels were significantly correlated with normalized 2,3-DPG levels (r=0.93) and higher in ever transfused (median=0.0022, range=0.0011-0.0029) compared with never transfused patients (median=0.0012 , range=0.0008-0.0020), (p=0.004). PK-R protein level was inversely correlated with the total number of transfusions prior to enrollment (r= -0.53) and was higher in never transfused (median=40.1%, range=9.8-73.9%) compared with ever transfused patients (median=7.7%, range=0.4%-15.1%), (p=0.0014). Conclusions: In this cohort with a molecularly confirmed diagnosis, PK deficiency was detected by enzyme testing with 98% sensitivity by utilizing both the PK activity and the PK/HK ratio. Although these assays cannot distinguish between heterozygotes and affected patients, the combination of PK activity and the PK/HK ratio is useful as a screening test to determine which patients require genetic testing. There was no correlation between PK enzyme activity and clinical phenotype. PK-R protein and ATP levels were inversely correlated with clinical severity and may be a helpful marker of disease phenotype. Disclosures Al-Samkari: Agios: Consultancy, Research Funding; Moderna: Consultancy; Dova: Consultancy, Research Funding. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Thompson:bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Rothman:Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Kwiatkowski:Celgene: Consultancy; Terumo: Research Funding; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy. Kung:Agios Pharmaceuticals, Inc: Employment, Other: Stakeholder. Kosinski:Agios Pharmaceuticals, Inc: Employment, Other: Stakeholder. London:United Therapeutics: Consultancy; ArQule, Inc: Consultancy. Grace:Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background: Pyruvate kinase deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia. The spectrum of disease in PKD is broad, ranging from an incidentally discovered mild anemia to a severe transfusion-dependent anemia. Splenectomy partially ameliorates the anemia and reduces the transfusion burden in the majority of patients. Because hemoglobin poorly correlates with symptoms in PKD, transfusion requirements are typically used clinically to classify disease severity with those who are regularly transfused despite splenectomy recognized as the most severely affected subgroup. Aim: To compare demographics, complications, and laboratory results between the most severely-affected PKD patients (those that are splenectomized and regularly transfused) with non-regularly transfused splenectomized PKD patients. Methods: After ethics committee approval, patients were enrolled on the PKD Natural History Study, a prospective 30 site international study. All patients had molecularly confirmed PKD. Only splenectomized patients were included in the analysis. Transfusion frequency was observed over a 3-year period. Patients were divided into two groups based on transfusion frequency: the severe phenotype group was defined as those who receive regular transfusions (≥6 discrete red cell transfusion episodes per year) and the control group did not receive regular transfusions. Phenotype stability over the 3-year period was also assessed. Results: 154 splenectomized patients with PKD were included: 30 patients in the severe PKD phenotype group and 124 patients in the comparison PKD group. Results of the analysis comparing the two groups are described in the Table. Severely affected patients were more likely to be female (77% versus 51%, p=0.013), older at the time of splenectomy (median age: 5 versus 3.6, p=0.011), have iron overload (93% vs. 51%, p Conclusions: Patients with PKD who are regularly transfused despite splenectomy appeared to have similar rates of PKD-associated complications (except for iron overload) and similar relevant laboratory values and genotypes when compared to those who are not regularly transfused after splenectomy. The similarity observed between severe phenotype patients and comparison patients with PKD may result from a protective effect of transfusion (e.g. reduction of bone fractures and extramedullary hematopoiesis) or could suggest transfusion-dependence is an artificial signifier of disease severity, reflective of provider practices and patient symptoms rather than an actual distinct phenotype. Transfusion requirements in severe PKD appear to fluctuate significantly over time. Disclosures Al-Samkari: Dova: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. van Beers:RR Mechatronics: Research Funding; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding. Barcellini:Agios: Consultancy, Other: Advisory board; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board; Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau. Eber:Agios Pharmaceuticals, Inc.: Consultancy. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Kuo:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; Celgene: Consultancy; Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy. Despotovic:Dova: Honoraria; Novartis: Research Funding; Amgen: Research Funding. Kwiatkowski:Celgene: Consultancy; Terumo: Research Funding; Apopharma: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Imara: Consultancy; Novartis: Research Funding. Thompson:Baxalta: Research Funding; Novartis: Consultancy, Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Rothman:Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Verhovsek:Sickle Cell Awareness Group of Ontario: Membership on an entity's Board of Directors or advisory committees; Sickle Cell Disease Association of Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Haemoglobinopathy Association: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy. Kunz:Novartis: Membership on an entity's Board of Directors or advisory committees. Sheth:CRSPR/Vertex: Other: Clinical Trial Steering committee; Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy. London:United Therapeutics: Consultancy; ArQule, Inc: Consultancy. Grace:Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

BACKGROUND: TP53 mutations are rare across pediatric cancers. Recent work using CRISPR-Cas9 screens has demonstrated that MDM2 and MDMX are strong dependencies in a range of TP53-wildtype pediatric malignancies. Increased expression of MDM2 and MDMX is a common mechanism for suppressing p53 in pediatric malignancies and can occur by copy number gain or amplification, as has been reported in retinoblastoma and hepatoblastoma. In pediatric high-grade gliomas, activating PPM1D mutations drive p53 suppression, likely through MDM2 stabilization. ALRN-6924 is a novel, first-in-class, cell-permeating stapled peptide that disrupts the inhibitory interactions between MDM2/MDMX(MDM4) and p53. ALRN-6924 has been evaluated in two adult Phase I trials, with good tolerability and evidence of clinical activity across a range of cancer subtypes. Given the oncogenic roles of MDM2 and MDMX in pediatric malignancies, we developed a Phase I clinical trial designed to evaluate the tolerability, pharmacokinetics, and pharmacodynamic and antitumor activity of ALRN-6924. METHODS: This is a Phase I, open-label, investigator-initiated multicenter study of ALRN-6924 in children 1-21 years of age with relapsed/refractory cancer (NCT03654716). The primary objectives are to determine the recommended phase 2 dose, and to describe toxicities and pharmacokinetic parameters of ALRN-6924 in this population. The monotherapy arm consists of two cohorts: Cohort A for patients with TP53-wildtype solid tumors and lymphomas; and Cohort B for patients with retinoblastoma, or TP53-wildtype tumors that meet any of the following criteria: hepatoblastoma, malignant rhabdoid tumor, MDM2 or MDMX amplification, TET2 loss, or PPM1D activating mutations. Patients with CNS primary tumors are only eligible for Cohort B. In Cohorts A and B, patients receive ALRN-6924 intravenously on Days 1, 4, 8 and 11 of a 21-day cycle starting at a dose of 2.2 mg/kg. An expansion cohort for patients eligible for Cohort B will open following completion of monotherapy dose escalation. Patients with relapsed/refractory leukemias enroll to Cohort C and receive ALRN-6924 in combination with low-dose cytarabine on days 1, 8 and 15 of a 28-day cycle starting at a dose of 2.7 mg/kg. Pharmacokinetic sampling and pharmacodynamic testing (serum MIC-1 modulation) is required for all patients. Correlative biology studies will include evaluation of circulating tumor DNA for TP53 mutations in patients with solid tumors and serial assessment of leukemic blasts in patients with relapsed leukemia. Enrollment began in October 2018. Up to 69 patients will be enrolled. Citation Format: David S. Shulman, Kieuhoa T. Vo, Elizabeth Fox, Jodi A. Muscal, Loren D. Walensky, Yana Pikman, Kimberly Stegmaier, Alanna Church, Brian D. Crompton, Andrew E. Place, Susan N. Chi, Allison F. O'Neill, Junne Kamihara, Suzanne Ezrre, Cecilia Carlowicz, Dawn Pinchasik, Hasan Al-Sayegh, Clement Ma, Wendy B. London, Steven G. DuBois. A Phase I multicenter trial of the dual MDM2/MDMX inhibitor ALRN-6924 in children and young adults with relapsed/refractory pediatric cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT112.

Introduction The purpose of the present investigation is to report on detailed complications among a much larger group of 2372 orthopaedic patients treated with stem cell injections who were followed in a treatment registry for up to nine years. Methods All patients underwent an MSC-based, percutaneous injection treatment of an orthopaedic condition between December 2005 and September 2014 at one of 18 clinical facilities. Treated areas of the body included the knee, hip, ankle/foot, hand/wrist, elbow, shoulder, and spine. The patients were followed prospectively via enrollment in a treatment registry. Patients were followed prospectively at one, three, six and 12 months, and annually thereafter, using an electronic system, ClinCapture software. Results A total of 3012 procedures were performed on 2372 patients with follow-up period of 2.2 years. A total of 325 adverse events were reported. The majority were pain post-procedure (n = 93, 3.9 % of the study population) and pain due to progressive degenerative joint disease (n = 90, 3.8 % of the study population). Seven cases reported neoplasms, a lower rate than in the general population. The lowest rate of adverse events was observed among patients injected with BMC alone. Conclusion Lowest rate of adverse events was among those patients receiving BMC injections alone, but the higher rate of AEs for BMC plus adipose and cultured cells was readily explained by the nature of the therapy or the longer follow-up. There was no clinical evidence to suggest that treatment with MSCs of any type in this study increased the risk of neoplasm.

Background: Kaposiform lymphangiomatosis (KLA) is a rare, aggressive lymphatic malformation that can lead to significant morbidity and mortality (Croteau et al 2014). First described as a distinct entity from generalized lymphatic anomaly (GLA) in 2014, KLA is histologically defined by spindled "kaposiform" endothelial cells associated with abnormal proliferation of lymphatic vessels. High risk features include pleural/pericardial effusions and coagulopathy. Respiratory failure, infections, and hemorrhage are common causes of death. In the largest case series of patients with KLA (n=20), five-year survival was 51%. Mean interval between diagnosis and death was 2.75 years. In recent years, the oral agent sirolimus has been used to treat KLA as a single agent or in combination with steroids and vincristine. No update has been published about overall outcomes for patients since the more widespread use of sirolimus. Methods: We conducted a retrospective chart review of 44 patients with biopsy-proven KLA referred to the Vascular Anomalies Center at Boston Children's Hospital and Cincinnati Children's Hospital Medical Center between 1995 and 2018. Twenty patients were previously analyzed in a retrospective review. Patient data were gathered through the electronic medical record and and the Lymphatic Anomalies Registry. Response to treatment was defined by clinical assessment via extraction from the medical record, improvement in patient or parent-reported quality-of-life, improved coagulopathy, and decreased size of lesions on imaging. Toxicities were graded according to the NIH CTCAE grading scale. Clinical outcomes were evaluated up until July 2018. Results: Among 44 patients with KLA, the median age at onset of symptoms was 7 years (range=0-40.6 years). The median time from development of first symptoms to diagnosis of KLA was 16.4 months (range=0-12 years). Seventy-eight percent of patients had pleural or pericardial effusions at presentation (Figure 1). Anatomic involvement varied, with 65% of patients having bony involvement and 68% of patients having visceral disease. Bleeding was also common, with 14% of patients requiring transfusions of blood products. Twenty-four (56%) of 44 patients were treated with sirolimus. Of those 24 patients, 20 (83%) patients reported ever having a sustained response to sirolimus (>6 months) based on our criteria. Despite improvement in disease symptoms, there was no significant difference in overall survival between patients who were treated with sirolimus and those who were not (log-rank p=0.62; Figure 1). Of the 44 patients evaluated in our study, fourteen died. Nine of the patients did not receive sirolimus (they died prior to its use in treating vascular anomalies). Of the 5 patients who received sirolimus and subsequently died, one reported marked improvement in his quality of life, but died from a pneumothorax during chest tube placement for a pleural effusion. The other patient who responded died from respiratory failure after a period of non-adherence with taking sirolimus. The remaining three patients did not respond to sirolimus and died of multi-organ failure. Among the 14 patients who died, the median time from diagnosis to death was 2.2 years (range 0.2- 7.1 years). Among 24 patients treated with sirolimus, 16 (67%) patients were treated concurrently with either vincristine (n=10) and/or steroids (n=15). Eight patients had sustained response with sirolimus alone. Minimal side effects were observed; there was only one grade 3 thrombocytopenia that did not require cessation of sirolimus. Sixteen patients remained on sirolimus at last follow-up. Conclusions: Most patients treated with sirolimus report stabilization of their disease symptoms and improvement in quality of life. Sirolimus is well-tolerated and most patients who respond remain on sirolimus as a form of chronic therapy. However, overall mortality for KLA remains high, even for those patients treated with sirolimus. More research is needed to investigate possible risk factors for poor outcomes. Investigation regarding phenotype-genotype correlation for KLA is ongoing, with the hope of identifying additional treatment options. In our study, there was a gap of > 1 year between time of symptom onset and diagnosis of KLA, highlighting a need for increased awareness of this unique disease entity and prompt referral of patients to a center with expertise in vascular anomalies. Disclosures No relevant conflicts of interest to declare.

6085Background: NUT midline carcinoma (NMC) is a rare subtype of squamous cancer defined by rearrangement of the NUT gene. Due to its rarity and under-diagnosis, there are no existing models to cla...

Background Prior studies describing the treatment of symptomatic knee osteoarthritis with injections of bone marrow concentrate have provided encouraging results. The relationship between the cellular dose contained within the bone marrow concentrate and efficacy of the treatment, however, is unclear. In the present study we describe clinical outcomes for symptomatic knee osteoarthritis in relation to higher and lower cell concentrations contained within a bone marrow concentrate treatment protocol. Methods Data from an ongoing patient registry was culled to identify 373 patients that received bone marrow concentrate injections for the treatment of 424 osteoarthritic knee joints. The clinical scales for these patients were assessed at baseline and then tracked post-procedure at 1, 3, 6 and 12 months, and annually thereafter. Tracked outcomes included the numeric pain scale; a lower extremity functional questionnaire; an International Knee Documentation Committee scale; and a subjective improvement rating scale. Using pain and functional outcome measures, a receiver operating characteristic analysis was used to define an optimal clinical outcome threshold at which bone marrow nucleated cell count could be divided into either a lower or higher cell count group within a treatment protocol. Results The lower and higher cell count groups were defined using a threshold of 4 × 108 cells. There were 224 and 185 knee joints treated in the lower (≤4 × 108) and higher (>4 × 108) cell count groups respectively. Most joints were diagnosed with early stage knee osteoarthritis. Both the lower and higher cell count groups demonstrated significant positive results with the treatment for all of the pain and functional metrics. The higher cell count group reported lower post treatment numeric pain scale values, in comparison with the lower cell count group (1.6 vs. 3.2; P

Christopher J Centeno,1 Hasan Al-Sayegh,1 Jamil Bashir,1 Shaun Goodyear,2 Michael D Freeman3 1Centeno-Schultz Clinic, Broomfield, CO, USA; 2Forensic Research and Analysis, Portland, OR, USA; 3Department of Public Health and Preventive Medicine and Psychiatry, Oregon Health and Science University, Portland, OR, USA Introduction: Shoulder pain is a common musculoskeletal complaint in the general population. Bone marrow concentrate (BMC) injections offer promising potential as a minimally invasive approach for treatment of shoulder pain in degenerative disease. In this study, we investigated the clinical outcomes of the BMC injections for treatment of shoulder pain and disability due to osteoarthritis (OA) and rotator cuff tears in a treatment registry population. Methods: A total of 115 shoulders in 102 patients were treated with autologous BMC injections for symptomatic OA at the glenohumeral joint and/or rotator cuff tears. Data were collected for factors potentially influencing outcome, including age, sex, body mass index, and the type of condition treated (ie, OA or rotator cuff tear). Clinical outcomes were assessed serially over time using the disabilities of the arm, shoulder and hand score (DASH), the numeric pain scale (NPS), and a subjective improvement rating scale. Baseline scores were compared to the most recent outcome scores at the time of the analysis and adjusted for demographic differences. We reported comparisons of pre- and post-treatment scores, the differences between osteoarthritis and rotator cuff groups, and the predictive effects on the clinical outcomes. Results: At the most current follow-up assessment after treatment, the average DASH score decreased (improved) from 36.1 to 17.1 (P

Little is known about the cause-specific deaths among young suicide attempters from the general population, and the time window for intervention to reduce the elevated rate of death was unclear. We analyzed a nationally representative sample of young adults (17-39 years old) who participated in the third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) and were followed up with vital status through December 31, 2006. The history of attempted suicide was associated with an increased rate for all-cause death (HR = 1.52 [95% CI = 0.92-2.52]) with borderline statistical significance. Previous suicide attempters experienced a 3-fold (HR = 2.68[=1.01-7.09]) increased rate for cardiovascular diseases (CVD), and a 7-fold (HR = 7.10 [95% CI = 1.37-36.9]) increased rate of death due to completed suicide compared with non-attempters. The survival curves of the attempters declined rapidly for the first 3 years of follow-up, and the distance between curves remained consistent starting from the third year to the end of the follow-up. Prevention services should be tailored not only for suicide, but also for cardiovascular diseases among populations with suicidal tendency, and the service should be intensified within first 3 years after suicidal behaviors occur.

The published online version contains mistake in Acknowledgment Section. The author name "Steve Gorin, M.D." should have been "Steven Gorin, D.O, M.S.Ed.".

We conducted a retrospective cohort study of 125 pediatric oncology patients who died in 2010-2014 to explore how healthcare utilization, pediatric palliative care (PPC) receipt, and end-of-life care (EOLC) differed between patients enrolled in early phase clinical trials (EP) and those not enrolled (NEP). Baseline characteristics and healthcare utilization did not significantly differ between groups. EP patients received PPC consultation closer to death than NEP patients (median days before death = 58 [interquartile range = 16-84] vs. 85 [32-173]; P = 0.04). Our findings suggest that early phase trial enrollment does not substantially alter EOLC for children with advanced cancer but may contribute to later PPC engagement. Future studies should definitively assess the relationship between trial enrollment and PPC timing.

Introduction.We investigated the use of autologous bone marrow concentrate (BMC) with and without an adipose graft, for treatment of knee osteoarthritis (OA).Methods.Treatment registry data for patients who underwent BMC procedures with and without an adipose graft were analyzed. Pre- and posttreatment outcomes of interest included the lower extremity functional scale (LEFS), the numerical pain scale (NPS), and a subjective percentage improvement rating. Multivariate analyses were performed to examine the effects of treatment type adjusting for potential confounding factors. The frequency and type of adverse events (AE) were also examined.Results.840 procedures were performed, 616 without and 224 with adipose graft. The mean LEFS score increased by 7.9 and 9.8 in the two groups (out of 80), respectively, and the mean NPS score decreased from 4 to 2.6 and from 4.3 to 3 in the two groups, respectively. AE rates were 6% and 8.9% in the two groups, respectively. Although pre- and posttreatment improvements were statistically significant, the differences between the groups were not.Conclusion.BMC injections for knee OA showed encouraging outcomes and a low rate of AEs. Addition of an adipose graft to the BMC did not provide a detectible benefit over BMC alone.

Introduction: We investigated the efficacy and safety of autologous bone marrow concentrate (BMC) for the treatment of symptomatic hip osteoarthritis. Methods: Treatment registry data for 216 hips treated among 196 patients who underwent a BMC procedure for hip osteoarthritis (OA) were analyzed. Data regarding adverse events (AEs), subjective percentage improvement, Oxford Hip Scores (OHS), and numeric pain scale (NPS) scores were assessed and compared to baseline at 1, 3, 6 months, and annually after treatment. Results: The mean reported subjective percentage improvement across all 216 treated hips was 30.2%. The mean OHS change was 6.4 points improved (p

The mortality pattern of individuals with impaired verbal memory (IVM) has not yet been well described. We sought to describe the risk of all-causes, as well as specific causes of death associated with IVM.We used the data of 4151 nationally representative adults ≥60 years old who participated in the third National Health and Nutrition Examination Survey, 1988-1994, and completed one non-contextual (i.e., word list memory) and one contextual delayed-recall tests (i.e., short story recall). The participants were passively followed up through 31 December 2006. We determined the hazard ratio of death from all-causes and specific cause through Cox proportional hazard regression.Severe and moderate IVM were present in 268 (6.5%) and 495 (11.9%) participants at baseline survey, and 2550 deaths occurred by the end of 18-year follow-up (median = 12 years). The medians of survival time adjusted for all-causes death were 6.17 (95% CI: 5.50, 6.92), 9.50 (8.92, 10.25), and 13.17 (12.75, 13.58) years, respectively for the individuals with severe, moderate, and no IVM. Severe IVM was significantly associated with death from cardio-cerebral vascular diseases [hazard ratio = 1.70, 95% CI = (1.36-2.12)], stroke [2.60 (1.69-3.99)], and Alzheimer's disease [3.50 (1.40-8.76)]. The shortened survival time of the participants with IVM was mainly driven by the deaths of cerebral-cardiovascular diseases, which accounted for almost half of all deaths.The predictability of memory scores to early cerebral-cardiovascular deaths demonstrated that central challenge among individuals with cognitive impairment was cardiovascular diseases management.

Deficiency of clotting factors VIII (Hemophilia A) and IX (Hemophilia B) represent one of the most debilitating inherited groups of bleeding disorders. According to the most recent survey report from the World Hemophilia Federation, an estimated 178,500 patients suffer from hemophilia globally (143,000 Hemophilia A, 28,000 with Hemophilia B approximately). By most recent estimates from 2014 India has surpassed every country in the global database with a total of 17,470 patients with hemophilia ahead of USA with its 17,131 reported cases. Infectious disease and perinatal mortality take precedence for resource allocation in evolving economies like India, presenting an ongoing challenge for "rare" diseases like hemophilia. This study assesses the quality of hemophilia care at the SMS Medical School which is the flagship medical care center in the northwestern Indian city of Jaipur, the capital of the largest Indian state with an area of 0.34 million square kilometers and population of 68.55 million. Since the introduction of the free factor distribution in the fall of 2012, the program grew from a modest patient population size of 60 patients to a robust 700 plus patients within 4 years aided by the World Hemophilia Twinning program grant. A standardized self-administered questionnaire was administered to all the hemophilia patients seen at the outpatient comprehensive hemophilia program (CHP) at the SMS Medical College between February 1, 2016 and May 5, 2016. Two hundred patients met the inclusion criteria and participated in the study. One hundred eighty-seven (94%) and 13 (6) patients were diagnosed with hemophilia A and B respectively; 126 (63) had severe disease while 65 (33) had moderate and 9 (5) had mild hemophilia. In an expected male predominant sample (n=198 males [99.5]), the median age at the time of study was 12 years (range=1-53 years), and 144 (72) patients were from rural outskirts of the resource poor state visiting the tertiary care center for hemophilia care. Contrary to popular belief, only a minority 11% and 1% of patients identified themselves of the Muslim and Sindhi faith respectively, versus a majority 87% who followed Hinduism. Tenets of consanguinity and family size have often led to misunderstanding and stigmatization of the disease in the Asian subcontinent prior to this study thus far. Despite a majority 63% patients suffering from severe hemophilia, nearly half (44%) reported a delay of more than 6 months in diagnosis time from the first bleed. Remarkably, 96 % reported to know their diagnosis fully and 93% reported understanding that hemophilia is a genetically transmitted disorder but approximately 82.5 % did not know if they ever underwent testing for viral infections (H.I.V, Hepatitis B, C ) since their diagnosis . Nearly 45 % were offered genetic counseling services at some point during their care, a remarkable feat for a hemophilia program in a resource strapped environment. Inpatient stay for bleeds and complications in this predominantly severe mix of patients was encouragingly less than 1-5 days in 93% of the patients but despite free drug delivery program 79% families reported an out of pocket expense of more than 10,000 Indian rupees (INR; approximately 147 USD) during the hospital stay. This in a state where 65% of patients reported per capital household income less than 100,000 INR (1,485 USD) was particularly concerning. Nearly 18 % of the respondents identified themselves as below poverty (BPL) and enjoyed the benefits of free transportation under the governmental subsidies through a BPL card. Household income and below poverty status were not associated with hemophilia care outcomes (p-values Reported favorable patient satisfaction (86%) and continued access to free factor infusion services irrespective of socio economic status as demonstrated by this study, for a resource limited setting caring for over 600 hemophilia patients should be considered a success. New epidemiologic insights from this study will help researchers and clinicians alike to design care delivery models for hemophilia. Not only does this study reflect the power of international collaborations in remarkably improving services for such ignored debilitating diseases in the resource limited nations but also presents as a unique first quality assessment tool for the nation with the largest number of identified hemophilia patients in the world. Disclosures Parnes: Pfizer: Consultancy; Baxalta: Research Funding. Neufeld:Pfizer: Consultancy; baxalta: Consultancy, Research Funding.

Introduction: Germline mutations in GATA2 lead to myelodysplastic syndromes (MDS) and bone marrow failure (BMF). Stem cell transplantation (SCT) remains the only curative therapy. In our previously described cohort of pediatric MDS/BMF patients with GATA2 mutation we noted a high transplant related mortality (TRM), a low relapse rate and frequent toxicities including thromboses. We hypothesized that analogous to other inherited syndromes the underlying GATA2 mutation may contribute to increased toxicity. Methods: We performed a case control study of patients treated at our center in 2000-20014 comparing pediatric MDS/BMF patients with GATA2 mutations to MDS/BMF patients without the mutation (control A) and to patients with acute leukemia (ALL or AML) (control B). Controls were randomly selected and matched for age (0-10, 11-20), stem cell source (matched related donor (MRD), matched unrelated donor (MUD), mismatched unrelated donor (mmURD) or umbilical cord blood (UCB) and conditioning regimen. We assessed if the proportion of patients who experienced a) high grade transplant related toxicity (TRT) including: infections, organ toxicities, secondary malignancies, thrombotic events; b) acute (grade II-IV) or extensive chronic GVHD (cGVHD); and, c) TRM within 100 and 365 days from transplant day, differed between the investigational and control cohorts. All pairwise comparisons of these factors were performed using a one-sided Fisher's Exact test. We reported overall survival (OS), disease free survival (DFS) and event free-survival (EFS) (events: TRM, relapse, acute GVHD, cGVHD, secondary malignancy, thrombotic events using point estimates at 5 years post-transplant (± standard error). Results: 80 patients were analyzed: 15 GATA2, 25 control A and 40 control B. The diagnoses in the GATA2 vs. the control A cohort were: RCC (n=8 vs 9), RAEB/ RAEB-T/AML-MRC (n=4 vs 11), AML (n=2 vs 0), BMF (n=0 vs 1), aplastic anemia (n=0 vs 4) and ALL (n=1 vs 0). Control B patients had AML (n=20) or ALL (n=20). Monosomy 7 was the most common cytogenetic abnormality in the GATA2 cohort [(n=9 (60%)] vs. 9 (36%) and 3 (8%) in Control A and B. The median follow-up for the study population was 3 years (range=0.14-12.1). GATA2 patients were treated with the following conditioning regimens: cyclophosphamide (CY)/total body irradiation (TBI) +/-ATG (n=11), fludarabine/CY/TBI (n=2) and busulfan/CY (n=2) and transplanted using bone marrow from a MRD (n=3), MUD (n=5) and mmURD (n=3), or UCB (n=4). GVHD prophylaxis consisted of cyclosporine A (CSA)/MTX+/- prednisone (n=9) or CSA/ mycophenolate mofetil (n=3). Thrombotic events were seen only in the GATA2 cohort (p< 0.001). For all other toxicities 10 (67%) occurred in the GATA2 group vs. 7 (28%) in control A (p=0.019), and 8 (20%) in control B (p=0.0018)]. Other comparisons were not statistically significant. Secondary malignancy was rare, but 1 (6.7%) was observed in the GATA2 cohort vs. 1 (4%) and 2 (5%) in control A or B. Severe lung disease requiring lung transplant was observed in 2 (13.3%) of the GATA2 patients and in 0 (0%) and 1 (2.5%) in control A and B, respectively. Acute and cGVHD were seen in 5 (33.3%) and 5 (33%) in the GATA2 group vs. 5 (20%) and 8 (32%) in control A and 10 (25%), 9 (22.5%) in control B. TRM within 100 and 365 days occurred in 2 (13%), 3 (20%) in the GATA2 cohort and 2 (8%), 4 (16%) in control A and 2 (5%), 7 (17.5%) in control B. TRM was the most common cause of death within 365 days in all groups. Relapse rate was not different between groups. The 5-year OS in the GATA2 cohort was 65±13% compared to 58%±10% and 45%±8% for control A and B, respectively. The 5-year EFS were 7%±6%, 31%±11% and 33%±8% for cases, A, and B, respectively. The 5-year DFS was 51%±13% in the GATA2 group, 51% ±11% in control A, and 44%±8% in control B. Conclusions: Pediatric MDS/BMF patients with GATA2 mutations had a significantly higher rate of TRT and thromboses compared to those without themutation or pre-treated leukemia patients. The 5-year EFS was lower in the GATA2 patients, but 5-year OS and DFS was comparable across the groups. Toxicities observed, especially frequent thromboses appear unique to the GATA2 cohort and warrant specific treatment considerations in the future. Disclosures No relevant conflicts of interest to declare.