A nomogram of clinical and biologic factors to predict survival in children newly diagnosed with high-risk neuroblastoma: An International Neuroblastoma Risk Group project.

BACKGROUND: Long-term outcome remains poor for children with high-risk neuroblastoma (five-year overall survival [OS] ∼50%). Our objectives were to (a) identify prognostic biomarkers and apply them in a nomogram to identify the subgroup of ultra-high-risk patients at highest risk of disease progression/death, for whom novel frontline therapy is urgently needed; and (b) validate the nomogram in an independent cohort. METHODS: A total of 1820 high-risk patients (≥18 months old with metastatic neuroblastoma), diagnosed 1998-2015, from the International Neuroblastoma Risk Groups (INRG) Data Commons were analyzed in a retrospective cohort study. Using multivariable Cox regression of OS from diagnosis, a nomogram was created from prognostic biomarkers to predict three-year OS. External validation was performed using the SIOPEN HR-NBL1 trial cohort (n = 521), evidenced by receiver operating characteristic curves. RESULTS: The nomogram, including MYCN status (P < 0.0001), lactate dehydrogenase (LDH) (P = 0.0007), and presence of bone marrow metastases (P = 0.004), had robust performance and was validated. Applying the nomogram at diagnosis (a) gives prognosis of an individual patient and (b) identifies patients predicted to have poor outcome (three-year OS was 30% ± 5% for patients with a nomogram score of > 82 points; 58% ± 1% for those ≤82 points). Median follow-up time was 5.5 years (range, 0-14.1). CONCLUSIONS: In high-risk neuroblastoma, a novel, publicly available nomogram using prognostic biomarkers (MYCN status, LDH, presence of bone marrow metastases; https://neuroblastoma.shinyapps.io/High-Risk-Neuroblastoma-Nomogram/) has the flexibility to apply a clinically suitable and context-specific cutoff to identify patients at highest risk of death. This will facilitate testing urgently needed new frontline treatment options to improve outcome for these children.

Comparison of Outcomes of Myeloablative Allogeneic Stem Cell Transplantation for Pediatric Patients with Bone Marrow Failure, Myelodysplastic Syndrome and Acute Myeloid Leukemia with and without Germline GATA2 Mutations.

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.

Clinical spectrum of pyruvate kinase deficiency: data from the Pyruvate Kinase Deficiency Natural History Study.

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 = .007), lower indirect bilirubin (P = .005), and missense PKLR mutations (P = .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.

Sun exposure and protection practices in children after allogeneic hematopoietic stem cell transplantation: A Survey-Based Cross-Sectional Cohort Study.

BACKGROUND/OBJECTIVE: Pediatric hematopoietic stem cell transplantation (HSCT) patients are at an increased risk for skin cancers. Sun exposure is a significant modifiable environmental risk factor. While patient education on sun protection and avoidance behaviors with regular dermatology evaluations are crucial for pediatric HSCT patients, the real-life practice of these sun-protection recommendations in this patient population compared to their peers is unknown. METHODS: A survey-based cross-sectional cohort study was performed in pediatric HSCT patients seen at the Dana-Farber Cancer Institute and Boston Children's Hospital over a 1.5-year period compared with age/sex/Fitzpatrick skin phototype-matched healthy controls. Study participants were surveyed using the validated Glanz survey for pediatric sun protection behavioral research. RESULTS: Eighty-five pediatric HSCT patients and 85 controls completed the study. Pediatric HSCT patients more frequently used sunscreen, hats, umbrellas, and sunglasses and obtained full-body skin exams compared to controls. No difference was observed in sun exposure during hours of peak sun intensity, frequency of purposeful tanning, tanning bed use, and the number of painful sunburns received between pediatric HSCT patients and controls. CONCLUSIONS: Although pediatric HSCT patients practice more sun protection behaviors, they experienced harmful sunburns and intentional tanning behaviors at the same rate as their peers. Patient-directed counseling and strategies to improve patient adherence to optimal sun protection behaviors could have a significant impact on the dermatology quality of life in pediatric HSCT patients.

Response Evaluation Criteria in Solid Tumors (RECIST) following neoadjuvant chemotherapy in osteosarcoma.

BACKGROUND: In osteosarcoma, patient survival has not changed in over 30 years. Multiple phase II trials have been conducted in osteosarcoma using the Response Evaluation Criteria in Solid Tumors (RECIST) as a primary endpoint; however, none of these have revealed new treatment strategies. We investigated RECIST in newly diagnosed patients who received neoadjuvant chemotherapy proven to be beneficial. METHODS: Patients treated from 1986 to 2011 for newly diagnosed osteosarcoma with paired tumor imaging before and after adequate neoadjuvant chemotherapy were included in this retrospective study. Two radiologists performed independent, blinded (to image timing) RECIST measurements of primary tumor and lung metastases at diagnosis and post-neoadjuvant chemotherapy. Association between RECIST and histological necrosis and outcome were assessed. RESULTS: Seventy-four patients met inclusion criteria. Five-year overall survival and progression-free survival (PFS) were 77 ± 7% and 61 ± 8%, respectively. No patients had RECIST partial or complete response in the primary tumor. Sixty-four patients (86%) had stable disease, and 10 (14%) had progressive disease (PD). PD in the primary tumor was associated with significantly worse PFS in localized disease patients (P = 0.02). There was no association between RECIST in the primary tumor and necrosis. There were an insufficient number of patients with lung nodules ≥1 cm at diagnosis to evaluate RECIST in pulmonary metastases. CONCLUSIONS: PD by RECIST predicts poor outcome in localized disease patients. In bone lesions, chemotherapy proven to improve overall survival does not result in radiographic responses as measured by RECIST. Further investigation of RECIST in pulmonary metastatic disease in osteosarcoma is needed.

Nonmalignant late cutaneous changes after allogeneic hematopoietic stem cell transplant in children.

BACKGROUND: There are limited pediatric data on nonmalignant cutaneous changes, including autoimmune conditions and permanent alopecia, after hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We sought to characterize late cutaneous changes and associated risk factors after allogeneic HSCT in children. METHODS: A cross-sectional cohort study of pediatric HSCT recipients was performed at a single institution. All participants underwent a full skin examination. RESULTS: The median visit age was 13.8 years, with a median time post-HSCT of 3.6 years. Of 85 patients, 14% (n = 12) had vitiligo, 16% (n = 14) had psoriasis/sebopsoriasis, 25% (n = 21) had alopecia, and 6% (n = 5) had nail changes. Factors significantly associated with vitiligo included a history of chronic graft-versus-host disease (cGVHD), transplant indication of primary immunodeficiency, and younger age at transplant (<10 years of age). Fifty-two percent of patients with alopecia had androgenetic alopecia patterns. Factors significantly associated with alopecia included cGVHD, busulfan conditioning, and family history of early male pattern alopecia. All patients with nail changes had cGVHD. LIMITATIONS: The cross-sectional design did not allow time of onset identification. Histopathologic correlation was not performed. CONCLUSION: Pediatric HSCT recipients, particularly those with cGVHD, are at risk for developing nonmalignant late cutaneous changes.

Historical time to disease progression and progression-free survival in patients with recurrent/refractory neuroblastoma treated in the modern era on Children's Oncology Group early-phase trials.

BACKGROUND: Early-phase trials in patients with recurrent neuroblastoma historically used an objective "response" of measureable disease (Response Evaluation Criteria In Solid Tumors [RECIST], without bone/bone marrow assessment) to select agents for further study. Historical cohorts may be small and potentially biased; to the authors' knowledge, disease recurrence studies from international registries are outdated. Using a large recent cohort of patients with recurrent/refractory neuroblastoma from Children's Oncology Group (COG) modern-era early-phase trials, the authors determined outcome and quantified parameters for designing future studies. METHODS: The first early-phase COG trial enrollment (sequential) of 383 distinct patients with recurrent/refractory neuroblastoma on 23 phase 1, 3 phase 1/2, and 9 phase 2 trials (August 2002 to January 2014) was analyzed for progression-free survival (PFS), overall survival (OS), and time to disease progression (TTP). Planned frontline therapy for patients with high-risk neuroblastoma included hematopoietic stem cell transplantation (approximately two-thirds of patients underwent ≥1 hematopoietic stem cell transplantation); 13.2% of patients received dinutuximab. RESULTS: From the time of the patient's first early-phase trial enrollment (383 patients), the 1-year and 4-year PFS rates ( ± standard error) were 21% ± 2% and 6% ± 1%, respectively, whereas the 1-year and 4-year OS rates were 57% ± 3% and 20% ± 2%, respectively. The median TTP was 58 days (interquartile range, 31-183 days [350 patients]); the median follow-up was 25.3 months (33 patients were found to be without disease recurrence/progression). The median time from diagnosis to first disease recurrence/progression was 18.7 months (range, 1.4-64.8 months) (176 patients). MYCN amplification and 11q loss of heterozygosity were prognostic of worse PFS and OS (P = .003 and P<.0001, respectively, and P = .02 and P = .03, respectively) after early-phase trial enrollment. CONCLUSIONS: This recent COG cohort of patients with recurrent/refractory neuroblastoma is inclusive and representative. To the authors' knowledge, the current study is the first meta-analysis of PFS, TTP, and OS within the context of modern therapy. These results will inform the design of future phase 2 studies by providing a) historical context during the search for more effective agents; and, b) factors prognostic of PFS and OS after disease recurrence to stratify randomization. Cancer 2017;123:4914-23. © 2017 American Cancer Society.

A modified γ-retrovirus vector for X-linked severe combined immunodeficiency.

BACKGROUND: In previous clinical trials involving children with X-linked severe combined immunodeficiency (SCID-X1), a Moloney murine leukemia virus-based γ-retrovirus vector expressing interleukin-2 receptor γ-chain (γc) complementary DNA successfully restored immunity in most patients but resulted in vector-induced leukemia through enhancer-mediated mutagenesis in 25% of patients. We assessed the efficacy and safety of a self-inactivating retrovirus for the treatment of SCID-X1. METHODS: We enrolled nine boys with SCID-X1 in parallel trials in Europe and the United States to evaluate treatment with a self-inactivating (SIN) γ-retrovirus vector containing deletions in viral enhancer sequences expressing γc (SIN-γc). RESULTS: All patients received bone marrow-derived CD34+ cells transduced with the SIN-γc vector, without preparative conditioning. After 12.1 to 38.7 months of follow-up, eight of the nine children were still alive. One patient died from an overwhelming adenoviral infection before reconstitution with genetically modified T cells. Of the remaining eight patients, seven had recovery of peripheral-blood T cells that were functional and led to resolution of infections. The patients remained healthy thereafter. The kinetics of CD3+ T-cell recovery was not significantly different from that observed in previous trials. Assessment of insertion sites in peripheral blood from patients in the current trial as compared with those in previous trials revealed significantly less clustering of insertion sites within LMO2, MECOM, and other lymphoid proto-oncogenes in our patients. CONCLUSIONS: This modified γ-retrovirus vector was found to retain efficacy in the treatment of SCID-X1. The long-term effect of this therapy on leukemogenesis remains unknown. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01410019, NCT01175239, and NCT01129544.).

Rethinking childhood ependymoma: a retrospective, multi-center analysis reveals poor long-term overall survival.

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.

Cytomegalovirus Infection in Pediatric Hematopoietic Stem Cell Transplantation: Risk Factors for Primary Infection and Cases of Recurrent and Late Infection at a Single Center.

Cytomegalovirus (CMV) infection is a significant source of morbidity and mortality in allogeneic stem cell transplantation (SCT). We identified a cohort of 91 pediatric SCT patients at risk (defined as either donor and/or recipient seropositivity) for CMV infection at our institution. We retrospectively categorized at-risk SCT recipients as those who (1) were at risk of CMV infection in the post-SCT period, (2) had documented CMV infection before SCT, (3) experienced recurrence of post-SCT CMV viremia, or (4) experienced late post-SCT CMV viremia; categories were not mutually exclusive. We analyzed the impact of SCT-related factors on incidence of CMV infection and outcome, and we described the outcome of each of these cohorts. In univariate analysis, recipient CMV seropositivity, use of umbilical cord blood graft, and acute graft-versus-host disease (GVHD) predicted post-SCT CMV viremia, and the effects of acute GVHD (odds ratio, 4.018; 95% confidence interval, 1.032 to 15.643) and CMV seropositivity (odds ratio, 16.525; 95% confidence interval, 2.041 to 133.803) were confirmed in multivariate analysis. Patients with recurrence of post-SCT CMV viremia had a 50% all-cause mortality rate, compared with 12% in all 91 patients. Patients with pre-SCT CMV infection had a high incidence of post-SCT CMV infection but could successfully undergo SCT with antiviral prophylaxis and pre-emptive CMV treatment. All patients with late CMV infection had prior GVHD. Theses findings identify risk factors for post-SCT CMV infection and provide novel descriptions of childhood SCT recipients with pre-SCT, recurrent, and late CMV infection, which may contribute to risk stratification strategies for CMV at-risk patients in pediatric allogeneic SCT.

End-of-Life Care Patterns Associated with Pediatric Palliative Care among Children Who Underwent Hematopoietic Stem Cell Transplant.

Stem cell transplantation (SCT) is an intensive therapy offering the possibility of cure for life-threatening conditions but with risk of serious complications and death. Outcomes associated with pediatric palliative care (PPC) for children who undergo SCT are unknown. Therefore, we evaluated whether PPC consultation is associated with differences in end-of-life (EOL) care patterns for children who underwent SCT and did not survive. Medical records of children who underwent SCT at Boston Children's Hospital/Dana-Farber Cancer Institute for any indication from September 2004 to December 2012 and did not survive were reviewed. Child demographic and clinical characteristics and PPC consultation and EOL care patterns were abstracted. Children who received PPC (PPC group) were compared with those who did not (non-PPC group). Children who received PPC consultation (n = 37) did not differ from the non-PPC group (n = 110) with respect to demographic or clinical characteristics, except they were more likely to have undergone unrelated allogeneic SCT (PPC, 68%; non-PPC, 39%; P = .02) or to have died from treatment-related toxicity (PPC, 76%; non-PPC, 54%; P = .03). PPC consultation occurred at a median of .7 months (interquartile range [IQR], .4 to 4.2) before death. PPC consultations most commonly addressed goals of care/decision-making (92%), psychosocial support (84%), pain management (65%), and non-pain symptom management (70%). Prognosis discussions (ie, the likelihood of survival) occurred more commonly in the PPC group (PPC, 97%; non-PPC, 83%; P = .04), as did resuscitation status discussions (PPC, 88%; non-PPC, 58%; P = .002). These discussions also occurred earlier in the PPC group, for prognosis a median of 8 days (IQR, 4 to 26) before death compared with 2 days (IQR, 1 to 13) in the non-PPC group and for resuscitation status a median of 7 days (IQR, 3 to 18) compared with 2 days (IQR, 1 to 5) in the non-PPC group (P < .001 for both of the timing of prognosis and resuscitation status discussions). The PPC group was also was more likely to have resuscitation status documented (PPC, 97%; non-PPC, 68%; P = .002). With respect to patterns of care, compared with non-PPC, the PPC group was as likely to die in a medicalized setting (ie, the hospital) (PPC, 84%; non-PPC, 77%; P = .06) or have hospice care (PPC, 22%; non-PPC, 18%; P = .6). However, among children who died in the hospital, those who received PPC were more likely to die outside the intensive care unit (PPC, 80%; non-PPC, 58%; P = .03). In addition, the PPC group was less likely to receive intervention-focused care such as intubation in the 24 hours before death (PPC, 42%; non-PPC, 66%; P = .02) or cardiopulmonary resuscitation (PPC, 3%; non-PPC, 20%; P = .03) at EOL. Children who received PPC for at least a month were more likely to receive hospice care (PPC, 41%; non-PPC, 5%; P = .01). Children who underwent SCT and did not survive were likely to die in a medicalized setting, irrespective of PPC. However, PPC was associated with less intervention-focused care and greater opportunity for EOL communication and advance preparation. In the intense, cure-oriented SCT setting, PPC may facilitate advance care planning in this high-risk population.

Trajectory of Material Hardship and Income Poverty in Families of Children Undergoing Chemotherapy: A Prospective Cohort Study.

BACKGROUND: Poverty is correlated with negative health outcomes in pediatric primary care, and is emerging as a negative prognostic indicator in pediatric oncology. However, measures of poverty amenable to targeted intervention, such as household material hardship (HMH)--including food, energy, and housing insecurity--have not been described in pediatric oncology. We describe the trajectory of family reported HMH and income poverty at a pediatric oncology referral center in New England with high psychosocial supports. PROCEDURE: Single site, prospective cohort study including 99 English-speaking families of children receiving chemotherapy for primary cancer. Families completed face-to-face surveys at two time-points: (1) Within 30 days of child's diagnosis (T1) (N = 99, response rate 88%); (2) 6-months following diagnosis (T2) (N = 93, response rate 94%). HMH was assessed in three domains: food, energy, and housing insecurity. RESULTS: Twenty percent of families reported low-income (≤200% Federal Poverty Level) and at least one HMH prior to their child's diagnosis. At T2, 25% of families lost >40% annual household income secondary to treatment-related work disruptions, and 29% of families reported HMH despite utilization of psychosocial supports. CONCLUSIONS: Low-income and HMH are prevalent in a significant proportion of newly diagnosed pediatric oncology families at a large referral center. Despite psychosocial supports, the proportion of families experiencing unmet basic needs increases during chemotherapy to nearly one in three families. HMH provides a quantifiable and remediable measure of poverty in pediatric oncology. Interventions to ameliorate this concrete component of poverty could benefit a significant proportion of pediatric oncology families.

Newborn Screening for Sickle Cell Disease in Liberia: A Pilot Study.

BACKGROUND: In malaria-endemic countries in West Africa, sickle cell disease (SCD) contributes to childhood mortality. Historically, Liberia had regions wherein hemoglobin S and beta-thalassemia trait were mutually exclusive. Data on hemoglobinopathies in the Monrovia, the capital, are outdated and do not reflect urban migration. Updating the epidemiology of SCD is necessary to plan a public health and clinical agenda. Neither newborn screening (NBS) nor screening tools were available in country. This pilot study aimed to determine the feasibility of NBS using a South-South partnership and define the incidence of sickle cell trait (SCT) and SCD in Monrovia. PROCEDURE: This descriptive epidemiologic feasibility study collected dried blood spots from 2,785 consecutive newborns delivered at a hospital in Monrovia. Samples were analyzed by isoelectric focusing at a regional reference laboratory. Infants with SCD were referred for preventive care. RESULTS: SCT occurred in 10.31% of infants screened. SCD occurred in 33 infants screened [1.19% (95% confidence interval [CI]: 0.79-1.59%)] (FS: 28/33, FSB: 2/33, FSA: 2/33, FSX: 1/33). There were no infants with FSC phenotype observed. Nonsickling hemoglobin phenotypes "FC" and "F" were each present in three infants screened. Seventy-six percent of infants with SCD were brought to care, demonstrating the feasibility of our approach. CONCLUSIONS: The incidence of SCD and other hemoglobinopathies remains high in Liberia. Additional studies are needed to clarify sickle genotypes and identify the contribution of silent beta-thalassemia alleles. By developing regional partnerships, countries similar to Liberia can acquire current data to inform NBS as an important public health initiative toward improving child health.

Immobilization of nitrilase on bioinspired silica for efficient synthesis of 2-hydroxy-4-(methylthio) butanoic acid from 2-hydroxy-4-(methylthio) butanenitrile.

In this paper, a simple and effective method using sodium metasilicate as precursor and amine as additive was first reported to immobilize recombinant nitrilase, for efficient production of 2-hydroxy-4-(methylthio) butanoic acid from 2-hydroxy-4-(methylthio) butanenitrile. High immobilization recovery of enzyme activity (above 90 %) was achieved. The immobilized enzyme displayed better thermal stability, pH stability and shelf life compared to free nitrilase. Moreover, it showed excellent reusability and could be recycled up to 16 batches without significant loss in activity. 200 mM 2-hydroxy-4-(methylthio) butanenitrile was completely converted by the immobilized enzyme within 30 min, and the accumulation amount of 2-hydroxy-4-(methylthio) butanoic acid reached 130 mmol/g of immobilized beads after 16 batches. These encouraging results demonstrated the efficiency of the new technology for nitrilase immobilization, which has great potential in preparation of 2-hydroxy-4-(methylthio) butanoic acid.

Prevalence and impact of financial hardship among New England pediatric stem cell transplantation families.

Poverty is correlated with negative health outcomes in pediatric primary care and subspecialties; its association with childhood hematopoietic stem cell transplantation (HSCT) patterns of care and clinical outcomes is not known. We describe family-reported financial hardship at a primary referral center in New England and explore the relationship between measures of poverty and patterns of care and clinical outcomes. Forty-five English-speaking parents of children after allogeneic HSCT in the prior 12 months completed a 1-time survey (response rate 88%). Low-income families, defined as ≤200% federal poverty level (FPL), were compared with all others. Eighteen (40%) families reported pre-HSCT incomes ≤200% FPL. Material hardship, including food, housing, or energy insecurity was reported by 17 (38%) families in the cohort. Low-income families reported disproportionate transplantation-related income losses, with 7 (39%) reporting annual income losses of >40% compared with 2 (18%) wealthier families (P = .02). In univariate analyses, 11 (61%) low-income children experienced graft-versus-host disease (GVHD) of any grade in the first 180 days after HSCT compared with 2 (7%) wealthier children (P = .004). We conclude that low income and, in particular, material hardship, are prevalent in a New England pediatric HSCT population and represent targets for improvement in quality of life. The role of poverty in mediating GVHD deserves further investigation in larger studies that can control for known risk factors and may provide a targetable source of transplantation-associated morbidity.

Incidence and causes of hospital readmission in pediatric patients after hematopoietic cell transplantation.

Allogeneic (allo) and autologous (auto) hematopoietic cell transplantation (HCT) provide the potential to cure otherwise fatal diseases but they are resource-intense therapies. There is scant literature describing the burden of hospital readmission in the critical 6-month period of immunosuppression after HCT. We report the incidence, causes, and outcomes of readmission in the 6 months after day 0 of HCT and in the 30 days after hospital discharge. This study is an institutional review board-approved retrospective medical record review of children who underwent HCT at a single institution. Between January 1, 2008 and December 31, 2011, 291 children underwent HCT at our institute. Of these, 140 patients were excluded because they were not followed primarily at our institute for the first 6 months after transplantation, 14 patients were excluded because they died during their initial hospitalization, and 1 patient was excluded because the initial hospitalization was longer than 6 months. Of the remaining 136 patients, 63% had at least 1 readmission. Of the patients who underwent allo-HCT, 78% were readmitted, in contrast to 38% of auto-HCT patients (P < .001). For the 206 readmissions, the mean length of hospital stay was 10.7 days (range, 1 to 129). Seventy-two percent of auto-HCT patients were initially readmitted for fever, and 46% ultimately had a source identified. No risk factors for readmission were found in the auto-HCT group. Fifty-two percent of allo-HCT patients were readmitted for fever and 28% of these patients ultimately had an identified source. Gastrointestinal-related problems accounted for 30% of primary readmissions among allo-HCT patients. Patients with an unrelated donor had a trend towards increased rates of 30-day readmission (P = .06) and were more likely to have a second readmission (P = .002). Patients who were cytomegalovirus (CMV) positive before transplantation were more likely to be readmitted (P = .02). The majority of children who undergo HCT are readmitted during the critical 180 days after transplantation. Readmission is much more common among allo-HCT patients, in particular those with unrelated donors and CMV-positive serologies before transplantation. Fever is the most common cause of readmission in these patients, and serious infections are identified in a significant portion of patients. These findings and future research in this area will help improve both patient education and resource utilization.

Pediatric aplastic anemia and refractory cytopenia: A retrospective analysis assessing outcomes and histomorphologic predictors.

Pediatric acquired aplastic anemia (AA) is a bone marrow disorder that is difficult to distinguish from inherited bone marrow failure syndromes and hypocellular refractory cytopenia of childhood (RCC). Historically, patients with hypocellular RCC have been given the diagnosis of AA. To assess the clinical and histologic distinction between RCC and AA, we performed a retrospective analysis of 149 patients previously diagnosed with AA between 1976 and 2010. We evaluated event free survival (EFS), overall survival (OS), response rates to immunosuppressive therapy, treatment-related toxicities and clonal evolution. The 5-year EFS and OS were 50.8% ± 5.5% and 73.1% ± 4.7%, respectively. Patients with very severe AA had worse OS compared to patients with severe and moderately severe AA. Seventy-two patients had diagnostic pathology specimens available for review. Three pediatric hematopathologists reviewed and reclassified these specimens as AA, RCC or Other based on 2008 WHO Criteria. The concordance between pathologists in the diagnosis of AA or RCC was modest. RCC was associated with a trend toward improved OS and EFS and was not prognostic of immunosuppression therapy treatment failure. There was a low rate of clonal evolution exclusively associated with moderately severe AA. Our findings indicate that a diagnosis of RCC is difficult to establish with certainty and does not predict outcomes, calling into question the reproducibility and clinical significance of the RCC classification and warranting further studies.

Voriconazole phototoxicity in children: a retrospective review.

BACKGROUND: Voriconazole, an antifungal agent, is associated with various cutaneous reactions, including phototoxicity, accelerated photoaging, and skin cancer. Incidence and risk factors for these reactions in children have not been well described. OBJECTIVE: We sought to determine the incidence of and factors associated with phototoxic reactions and nonmelanoma skin cancer in pediatric patients treated with voriconazole. METHODS: This was a retrospective analysis of 430 pediatric patients treated with voriconazole between 2003 and 2013 at Boston Children's Hospital. RESULTS: Incidence of phototoxicity was 20% in all children treated with voriconazole and 47% in children treated for 6 months or longer. Factors associated with phototoxicity included white race, cystic fibrosis, cumulative treatment time, and cumulative dose. Four patients (1%) had nonmelanoma skin cancer; all experienced a phototoxic reaction during voriconazole treatment. Of those with phototoxicity, 5% were discontinued on voriconazole, 6% were referred to dermatology, and 26% received counseling about sun protection from their primary physician. LIMITATIONS: Our study is limited by its retrospective design and potential referral bias associated with a tertiary-care center. CONCLUSIONS: Voriconazole-associated phototoxicity is relatively common in children and may lead to nonmelanoma skin cancer. However, those with phototoxic reactions are often continued on therapy, rarely referred to dermatology, and infrequently counseled on sun protection.

Long-term outcome of 4,040 children diagnosed with pediatric low-grade gliomas: an analysis of the Surveillance Epidemiology and End Results (SEER) database.

BACKGROUND: Children with pediatric low-grade gliomas (PLGG) are known to have excellent 10-year survival rates; however the outcomes of adult survivors of PLGG are unknown. We identified patients diagnosed with PLGG diagnosed between 1973 and 2008 through the Surveillance Epidemiology and End Results (SEER) database to examine outcomes of adult survivors of PLGG. PROCEDURE: Four thousand and forty patients with either WHO grade I or II PLGG were identified and outcome data retrieved. Two analyses were performed to assess survival and risk of death from tumor. Competing risks analysis was conducted and cumulative incidence curves of death due to disease were generated. Cox proportional hazards regression was performed, with adjustment for non-disease death. Kaplan-Meier curves for overall cancer specific survival (OS) were also generated. RESULTS: The 20-year OS was 87% ± 0.8% and the 20-year cumulative incidence of death due to glioma was 12% ± 0.8%. The incidence of death after transition to adulthood (age greater than 22 years) was slightly lower, with 20-year cumulative incidence of disease death of 7% ± 1.8%. Year of diagnosis, age of diagnosis, histology, WHO grade, primary site, radiation, and degree of initial resection were prognostic in univariate analysis, while the administration of radiation was the greatest risk of death in multivariate analysis of OS (hazard ratio = 3.9). CONCLUSIONS: PLGGs are associated with an excellent long-term survival, with a low likelihood of PLGG related death in adult survivors. Treatment strategies for pediatric tumors should therefore aim for disease control during childhood and adolescence with an emphasis on minimizing long-term treatment induced toxicities.