A 9-year-old girl with blisters on the hands and face: An early presentation of variegate porphyria.

Variegate porphyria (VP) is a rare subtype of porphyrias characterized by dysfunction of enzymes in the heme biosynthesis pathway leading to an accumulation of porphyrins and their precursors. The resulting buildup can manifest as neuropsychiatric symptoms and photosensitive blistering eruptions on sun-exposed skin. We report a case of VP in a 9-year-old girl with many confounding medical factors that warranted alternative explanations for her cutaneous lesions. VP has been reported infrequently in the pediatric population and is associated with more severe neuropsychiatric outcomes compared to adult-onset disease.

Feasibility of a Pilot Home Phlebotomy Program for Pediatric Hematology/Oncology Patients During the COVID-19 Pandemic.

Medical care during the Coronavirus 2019 global pandemic required significant shifts in health care delivery systems. Telehealth was widely deployed but was of limited utility for patient populations who rely heavily on laboratory monitoring. This includes pediatric hematology and oncology patients. We report on the feasibility and successful implementation of a home phlebotomy program that has minimized disruption in care for this high-risk patient population. During the initial months of the COVID-19 outbreak, we completed 189 home phlebotomy visits for pediatric hematology and oncology patients. Patient and staff satisfaction with the program were high, and potential exposures to COVID were avoided.

Advanced stage anaplastic large cell lymphoma in children and adolescents: results of ANHL0131, a randomized phase III trial of APO versus a modified regimen with vinblastine: a report from the children's oncology group.

BACKGROUND: Optimal therapy for children and adolescents with advanced stage anaplastic large cell lymphoma (ALCL) is unknown. ANHL0131 examined whether a maintenance regimen including vinblastine compared to the standard APO (doxorubicin, prednisone, vincristine, methotrexate, 6-mercaptopurine) regimen would result in superior event-free survival. PROCEDURE: One hundred and twenty five eligible patients were enrolled. Induction was identical for both arms. Post induction patients were randomized to receive APO with vincristine every 3 weeks or a regimen that substituted vincristine with weekly vinblastine (APV). RESULTS: There was no difference between the patients randomized to the APO versus APV arms in either event free survival (EFS) or overall survival (OS) (three year EFS 74% vs. 79%, P = 0.68 and three years OS of 84% vs. 86%, P = 0.87, respectively). Patients in the APV arm required dose reduction secondary to myelosuppression and had a higher incidence of neutropenia as well as infection with neutropenia compared to those in the APO arm (P < 0.001, P = 0.019, respectively). CONCLUSIONS: Treatment with weekly vinblastine instead of every three week vincristine as part of multi-agent maintenance therapy did not result in improvement in EFS or OS. Weekly vinblastine was associated with increased toxicity. (ClinicalTrials.gov Identifier NCT00059839).

Lifestyle and metabolic syndrome in adult survivors of childhood cancer: a report from the St. Jude Lifetime Cohort Study.

BACKGROUND: Childhood cancer survivors (CCS) are at an increased risk of developing metabolic syndrome (MetSyn), which may be reduced with lifestyle modifications. The purpose of this investigation was to characterize lifestyle habits and associations with MetSyn among CCS. METHODS: CCS who were ≥ 10 years from diagnosis, aged > 18 years, and participating in the St. Jude Lifetime Cohort Study completed medical and laboratory tests and a food frequency questionnaire. The Third Report of the National Cholesterol Education Program Adult Treatment Panel criteria were used to classify participants with MetSyn. Anthropometric, food frequency questionnaire, and self-reported physical activity data were used to characterize lifestyle habits according to World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommendations. Those who met ≥ 4 of 7 recommendations were classified as having followed guidelines. Sex-stratified log-binomial regression models were used to evaluate associations between dietary/lifestyle habits and MetSyn, adjusted for age, age at cancer diagnosis, receipt of cranial radiotherapy, education, and household income. RESULTS: Among 1598 CCS (49.2% of whom were male, with a median age of 32.7 years [range, 18.9 years-60.0 years]), 31.8% met criteria for MetSyn and 27.0% followed WCRF/AICR guidelines. Females who did not follow WCRF/AICR guidelines were 2.4 times (95% confidence interval, 1.7-3.3) and males were 2.2 times (95% confidence interval, 1.6-3.0) more likely to have MetSyn than those who followed WCRF/AICR guidelines. CONCLUSIONS: Adherence to a heart-healthy lifestyle is associated with a lower risk of MetSyn among CCS. There is a need to determine whether lifestyle interventions prevent or remediate MetSyn in CCS.

Development of the just culture assessment tool: measuring the perceptions of health-care professionals in hospitals.

OBJECTIVES: Given the growing support for establishing a just patient safety culture in health-care settings, a valid tool is needed to assess and improve just patient safety culture. The purpose of this study was to develop a measure of individual perceptions of just culture for a hospital setting. METHODS: The 27-item survey was administered to 998 members of a health-care staff in a pediatric research hospital as part of the hospital's ongoing patient safety culture assessment process. Subscales included balancing a blame-free approach with accountability, feedback and communication, openness of communication, quality of the event reporting process, continuous improvement, and trust. The final sample of 404 participants (40% response rate) included nurses, physicians, pharmacists, and other hospital staff members involved in patient care. Confirmatory factor analysis was used to test the internal structure of the measure and reliability analyses were conducted on the subscales. RESULTS: Moderate support for the factor structure was established with confirmatory factor analysis. After modifications were made to improve statistical fit, the final version of the measure included 6 subscales loading onto one higher-order dimension. Additionally, Cronbach α reliability scores for the subscales were positive, with each dimension being above 0.7 with the exception of one. CONCLUSIONS: The instrument designed and tested in this study demonstrated adequate structure and reliability. Given the uniqueness of the current sample, further verification of the JCAT is needed from hospitals that serve broader populations. A validated tool could also be used to evaluate the relation between just culture and patient safety outcomes.

Long-term outcome and evaluation of organ function in pediatric patients undergoing haploidentical and matched related hematopoietic cell transplantation for sickle cell disease.

HLA-matched related donor (MRD) hematopoietic stem cell transplantation (HSCT) is a well-established therapy for patients with sickle cell disease (SCD); however, experience using alternative donors, including haploidentical donors, in HSCT for SCD is limited. We report the long-term outcomes of 22 pediatric patients who underwent related donor HSCT for SCD at St. Jude Children's Research Hospital, either a myeloablative sibling MRD HSCT (n = 14) or reduced-intensity parental haploidentical donor HSCT (n = 8). The median patient age was 11.0 ± 3.9 years in the MRD graft recipients and 9.0 ± 5.0 years in the haploidentical donor graft recipients. The median follow-up was 9.0 ± 2.3 years, with an overall survival (OS) of 93% and a recurrence/graft failure rate of 0%, for the MRD cohort and 7.4 ± 2.4 years, with an OS of 75%, disease-free survival of 38%, and disease recurrence of 38%, for the haploidentical donor cohort. We report the long-term hematologic response and organ function in patients undergoing MRD or haploidentical donor HSCT for severe SCD. Our data demonstrate long-term hematologic improvements after HSCT with sustained engraftment, and confirm that HSCT offers long-term protection from common complications of SCD, including stroke, pulmonary hypertension, acute chest, and nephropathy, regardless of donor source.

Successful allogeneic hematopoietic cell engraftment after a minimal conditioning regimen in children with relapsed or refractory solid tumors.

Children with relapsed or refractory solid tumors face dismal prognoses, and novel therapies are desperately needed. Allogeneic hematopoietic cell transplantation (HCT) offers potential for cell-based therapy, but the toxicity of myeloablation limits this approach in heavily pretreated patients. We sought to determine the feasibility of HCT in a cohort of 24 children with incurable solid tumors using human leukocyte antigen-matched sibling or unrelated donors and a minimal conditioning regimen. Before stem cell infusion, all patients received 3 daily doses of 30 mg/m(2) fludarabine followed by 2 Gy of total body irradiation. Hematopoietic cell recovery was rapid and reliable. Median time to neutrophil engraftment was 13.5 days for sibling donors and 12 days for unrelated donors. Donor lymphocyte infusions were used safely in 4 patients, all of whom had either improved chimerism or apparent tumor response. Graft-versus-host disease was comparable across donor sources and did not affect survival. Relapse remains a substantial barrier, although objective graft-versus-tumor effect was observed in several patients. Four patients with detectable disease before HCT achieved a complete response for at least 30 days after HCT, and two remain long-term survivors. Three patients were in complete response before HCT and remained in remission for 3, 6, and 74 months after HCT. Early disease response was associated with improved survival. Allogeneic HCT using this conditioning regimen offers a potential platform for novel immunotherapies.

Effects of conditioning regimens and T cell depletion in hematopoietic cell transplantation for primary immune deficiency.

This study analyzes the hematopoietic cell transplantation experience in patients with immune deficiency at a single institution. The objective is to comprehensively evaluate the short-term and long-term outcomes with various preparative regimens, donor grafts, and ex vivo manipulations to identify transplantation approaches that most likely favor early donor immune competency without generating excessive toxicity. Clinical outcomes were evaluated in 52 consecutive patients with immune deficiencies. Thirty-seven of the 52 patients (71%) survived with attenuation of their underlying disease. The use of a melphalan-based reduced-intensity conditioning preparative regimen and immunomagnetic CD3(+) T cell depletion techniques (when T cell depletion was indicated) were associated with improved event-free survival. Survivors who received a preparative regimen other than a melphalan-based reduced-intensity regimen suffered from therapy-related morbidities or chronic/recurrent infections. Our findings indicate that melphalan-based reduced-intensity conditioning regimens and immunomagnetic CD3(+) T cell depletion limit therapy-related toxicity, and demonstrate promising results for the early establishment of donor immune competency.

ALK+ anaplastic large cell lymphoma exhibits phosphatidylinositol-3 kinase/Akt activity with retained but inactivated PTEN--a report from the Children's Oncology Group.

BACKGROUND: ALK+ anaplastic large cell lymphoma (ALCL) is usually a disease of young patients. We investigated phosphatidylinositol-3 kinase (PI3K)/Akt pathway-associated factors in pediatric cases and cell lines. PROCEDURE: Patient materials consisted of tissue slides of ALK+/CD30+ ALCL from 33 patients treated on Pediatric Oncology Group protocols (9219, n = 8 and 9315, n = 25). Slides were examined by immunohistochemistry for phospho(p)-Akt and PTEN, the primary feedback regulator of the pathway, as well as for p27kip1 and stathmin-1. ALCL cell lines SUDHL-1 and Karpas-299 were examined for ALK, pALK, pAkt, p27/Kip1, PTEN, pPTEN, CD30, pSTAT3, and pSTAT5; ALK inhibition was performed using compound PF-2341066 and PTEN genes were sequenced. RESULTS: A majority of patients expressed pAkt, PTEN, and stathmin, with p27kip1 levels less than controls. Cell lines showed expression of ALK, pALK, pSTAT3, pSTAT5, CD30, pAkt, PTEN, and pPTEN, with p27 slightly less than positive controls, and germline PTEN DNA. There was evidence of phosphorylated PTEN (pPTEN) associated with inhibited function. Pharmacologic inhibition of activated ALK diminished pSTAT3, pSTAT5, and CD30 expression but not pAkt or pPTEN in cultured cell lines. CONCLUSION: We conclude that the PI3K/Akt pathway is activated in many, though not all, pediatric ALK+ ALCL. Our data suggest that activation of this pathway involves post-translational regulation of PTEN. Pharmacologic inhibition of activated ALK does not reduce modest levels of activated Akt as it does with the more abundant levels of activated STAT3 or STAT5. Future therapy of ALCL might, in selected patients, best combine agents inhibiting PI3K/Akt with those targeting ALK.

Detectable minimal residual disease before hematopoietic cell transplantation is prognostic but does not preclude cure for children with very-high-risk leukemia.

In patients with acute leukemia, detection of minimal residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) correlates with risk of relapse. However, the level of MRD that is most likely to preclude cure by HCT is unclear, and the benefit of further chemotherapy to reduce MRD before HCT is unknown. In 122 children with very-high-risk acute lymphoblastic leukemia (ALL; n = 64) or acute myeloid leukemia (AML, n = 58), higher MRD levels at the time of HCT predicted a poorer survival after HCT (P = .0019); MRD was an independent prognostic factor in a multivariate analysis (P = .0035). However, the increase in risk of death associated with a similar increment of MRD was greater in ALL than in AML, suggesting that a pretransplantation reduction of leukemia burden would have a higher impact in ALL. At any given MRD level, survival rates were higher for patients treated in recent protocols: the 5-year overall survival for patients with ALL was 49% if MRD was detectable and 88% if it was not and the corresponding rates for patients with AML were 67% and 80%, respectively. Although MRD before HCT is a strong prognostic factor, its impact has diminished and should not be regarded as a contraindication for HCT.

High success rate of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia.

We evaluated 190 children with very high-risk leukemia, who underwent allogeneic hematopoietic cell transplantation in 2 sequential treatment eras, to determine whether those treated with contemporary protocols had a high risk of relapse or toxic death, and whether non-HLA-identical transplantations yielded poor outcomes. For the recent cohorts, the 5-year overall survival rates were 65% for the 37 patients with acute lymphoblastic leukemia and 74% for the 46 with acute myeloid leukemia; these rates compared favorably with those of earlier cohorts (28%, n = 57; and 34%, n = 50, respectively). Improvement in the recent cohorts was observed regardless of donor type (sibling, 70% vs 24%; unrelated, 61% vs 37%; and haploidentical, 88% vs 19%), attributable to less infection (hazard ratio [HR] = 0.12; P = .005), regimen-related toxicity (HR = 0.25; P = .002), and leukemia-related death (HR = 0.40; P = .01). Survival probability was dependent on leukemia status (first remission vs more advanced disease; HR = 0.63; P = .03) or minimal residual disease (positive vs negative; HR = 2.10; P = .01) at the time of transplantation. We concluded that transplantation has improved over time and should be considered for all children with very high-risk leukemia, regardless of matched donor availability.

Safe and successful implementation of CPOE for chemotherapy at a children's cancer center.

Computerized prescriber order entry (CPOE) for medications has been implemented in only approximately 1 in 6 United States hospitals, with CPOE for chemotherapy lagging behind that for nonchemotherapy medications. The high risks associated with chemotherapy combined with other aspects of cancer care present unique challenges for the safe and appropriate use of CPOE. This article describes the process for safe and successful implementation of CPOE for chemotherapy at a children's cancer center. A core principle throughout the development and implementation of this system was that it must be as safe (and eventually safer) as existing paper systems and processes. The history of requiring standardized, regimen-specific, preprinted paper order forms served as the foundation for safe implementation of CPOE for chemotherapy. Extensive use of electronic order sets with advanced functionality; formal process redesign and system analysis; automated clinical decision support; and a phased implementation approach were essential strategies for safe implementation of CPOE. With careful planning and adequate resources, CPOE for chemotherapy can be safely implemented.

Six-month dietary changes in ethnically diverse, obese adolescents participating in a multidisciplinary weight management program.

This study's objective was to examine dietary and metabolic changes in obese adolescents who completed 6 months of participation in an outpatient multidisciplinary weight management program (N = 67). Participants (75% African American, 66% female, mean age = 13.7 years) completed 24-hour dietary recalls and underwent measurement of anthropometrics and fasting blood lipid parameters at baseline and after 6 months of participation. General linear models suggested that participants significantly reduced total energy, total fat, saturated fat, carbohydrate, sodium, and sugar intakes, and increased fiber and fruit and vegetable intake (P < .05). Gender-stratified models showed differences in fruit/vegetable intake, percentage calories from fat, sodium, and dietary cholesterol intakes by gender. Significant improvements in body mass index percentile and lipid profiles were also found, lending objective support to the dietary changes participants made. Findings suggest that participation in this multidisciplinary treatment helped participants make behaviorally based dietary changes, which were associated with improved dietary intakes and health status.

Safety and efficacy of high dose intravenous desferrioxamine for reduction of iron overload in sickle cell disease.

BACKGROUND: Patients with sickle cell disease (SCD) receiving chronic blood transfusions are at risk of developing iron overload and organ toxicity. Chelation therapy with either subcutaneous (SQ) desferrioxamine (DFO) or oral deferasirox is effective in preventing and reducing iron overload but poses significant challenges with patient compliance. Intravenous (IV) infusions of high dose DFO have been utilized in non-compliant patients with heavy iron overload in small case series. PROCEDURE: We review our experience of high dose IV DFO in 27 patients with SCD who had significant iron overload and were noncompliant with subcutaneous (SQ) DFO. All patients were treated in-hospital with DFO 15 mg/kg/hr IV for 48 hr every 2-4 weeks with a mean duration of 19.6 months. RESULTS: We observed a significant decrease in liver iron burden with high dose intermittent IV DFO. Histological examination of liver biopsies revealed a decrease in the grade of liver iron storage. Also there was significant improvement in liver enzymes (ALT, AST) after high dose IV DFO. No audiologic or ophthalmologic toxicity or acute or chronic pulmonary complications were observed. CONCLUSIONS: In our cohort of patients with SCD we observed a significant decrease in liver iron burden with high dose IV DFO. Our patients tolerated the therapy well without any major toxicity. This regimen is safe and may be an option for poorly compliant patients with significant iron overload.

Prevalence of the metabolic syndrome among obese adolescents enrolled in a multidisciplinary weight management program: clinical correlates and response to treatment.

OBJECTIVE: The aim of this study was to determine the prevalence of the metabolic syndrome at baseline and after 6 months of lifestyle modification among obese adolescents referred to a multidisciplinary weight management program. METHODS: A total of 165 obese adolescents were evaluated at baseline, and measurements were repeated in 57 subjects who completed 6 months of the program. Metabolic syndrome was defined as having three or more of the following: a body mass index (BMI) >97(th) percentile, hypertension, low high-density lipoprotein cholesterol (HDL-C), hypertriglyceridemia, and impaired fasting glucose (IFG). RESULTS: The prevalence of a BMI >97(th) percentile, hypertension, hypertriglyceridemia, low HDL-C, and IFG was 92.7, 54.5, 29.1, 26.7, and 2.4%, respectively. The prevalence of the metabolic syndrome at baseline was 30.3%. After 6 months of lifestyle modification, BMI z scores, percent body fat, total cholesterol, and low-density lipoprotein cholesterol (LDL-C) decreased significantly from baseline; however, there was no significant change in the number of subjects demonstrating >or=three criteria of the metabolic syndrome. CONCLUSIONS: Approximately one third of the study subjects met the criteria of the metabolic syndrome, emphasizing the growing concern for the future development of premature cardiovascular disease in this high-risk population. Our data suggest that new strategies for lifestyle modification may be needed to improve cardiovascular risk factors significantly among adolescents with obesity.

Evaluation of a 6-month multi-disciplinary healthy weight management program targeting urban, overweight adolescents: effects on physical fitness, physical activity, and blood lipid profiles.

This study evaluated preliminary physical fitness, physical activity, and blood lipid profile data obtained from overweight adolescents upon enrolling in a healthy weight management program and following 6 months of program participation. One hundred and sixty-eight participants (13.4+/-1.8 years, 37.9+/-8.3 kg/m(2), 59.5% female and 76.2% African-American) enrolled in the program. The intervention addressed factors related to nutrition, physical activity, and other behaviors related to weight management. Sixty-four participants (38.1%) completed 6 months of program participation. While there was no significant reduction in body mass or body mass index (BMI), BMI z-score was reduced by 1.2% (p < 0.05), cardiorespiratory fitness was increased by 10.8% (p = 0.001), body fat percentage was reduced by 2.6% (p = 0.001), total cholesterol was reduced by 7.2% (p < 0.001), and low density lipoprotein (LDL-C) was reduced by 8.4% (p < 0.001) at 6 months. Continued development and evaluation of programs designed to prevent and treat child and adolescent overweight is warranted to address this major public health issue.

Non-anaplastic peripheral t-cell lymphoma in childhood and adolescence: a Children's Oncology Group study.

BACKGROUND: Peripheral T-cell lymphomas (PTCL) other than anaplastic large cell lymphoma (ALCL) are rare in young patients. While a high proportion of adults with PTCL have poor risk disease, pediatric PTCL is not well characterized. This study examines the outcome of localized and advanced PTCL in pediatric patients treated in standardized fashion. PROCEDURE: We identified 20 pediatric patients diagnosed with PTCL whose tumor cells did not express CD30 and/or ALK, as determined by immunohistochemistry, between 1992 and 2000 on one of two treatment protocols for localized NHL (POG 9219) or advanced stage large cell lymphoma (POG 9315). All cases were centrally reviewed. RESULTS: The median age was 12.6 (range 0.7-16.9)-9 male and 11 female. Histological subtypes in the WHO Classification included PTCL, unspecified (12), extra-nodal NK/T-cell lymphoma of nasal type (4), subcutaneous panniculitis-like T cell lymphoma (1) and enteropathy-type T-cell lymphoma (1). Two cases exhibited both T-cell and histiocyte markers and were reclassified as histiocytic sarcoma per the WHO, although T-lineage remains possible. Of 10 patients with localized disease, only two relapsed and 9 survive. Of 10 patients with advanced disease, six relapsed and five (50%) survive. CONCLUSIONS: These results suggest that localized PTCL in children and adolescents is frequently cured with modern therapy, but that advanced stage cases may require novel therapy.

Liver biopsy results in patients with sickle cell disease on chronic transfusions: poor correlation with ferritin levels.

BACKGROUND: Chronic transfusions are effective in preventing stroke and other complications of sickle cell disease. The aim of this study was to determine whether serum ferritin levels correlated with liver iron content in sickle cell patients on chronic transfusion. PROCEDURE: Forty-four liver biopsy specimens from 38 patients with homozygous sickle cell anemia (HbSS) and one patient with sickle thalassemia receiving chronic transfusions were studied. Five patients underwent a second liver biopsy for follow up. Three ferritin measurements were used to calculate a mean for each patient. The association between serum ferritin levels and liver iron quantitation was measured using the Spearman rank correlation, and sensitivity and specificity were determined for selected threshold values of serum ferritin. RESULTS: Serum ferritin levels ranged from 515 to 6076 ng/ml, liver iron concentration ranged from 1.8 to 67.97 mg/g dry weight. The amount of iron per gram liver dry weight was moderately correlated with serum ferritin values (r = 0.46). The correlation of duration of transfusion with serum ferritin (r = 0.40) and with liver iron content (r = 0.41) also indicated moderate correlation. Liver biopsy results led to changes in the management after 29/44 (66%) of the biopsies. Serum ferritin >/=2500 ng/ml predicted high liver iron content (>/=7 mg/g), with a sensitivity of 62.5% and a specificity of 77.8%. CONCLUSION: We found a poor correlation between serum ferritin levels and liver iron content (LIC). Despite being on chelation therapy, many patients on chronic transfusion had high levels of liver iron. Measurement of LIC is highly recommended in these patients.

Happiness and time perspective as potential mediators of quality of life and depression in adolescent cancer.

BACKGROUND: Given the increase in 5- and 10-year survival rates of children and adolescents diagnosed with cancer, current psycho-oncology literature is focusing on finding correlates and predictors to their positive psychosocial adjustment. The purpose of this study was to evaluate two potential mediators to adolescent cancer survivors' quality of life (QOL) and depressive symptomology. PROCEDURE: Adolescent cancer survivors (N = 50; 50% males; mean diagnosis age, 13.7; mean age at study, 20.2) were surveyed, testing the mediation effects of their happiness (Subjective Happiness Scale) and past-negative time perspective (Zimbardo Time Perspective Inventory) on QOL (PedsQL 4.0) and depressive symptomology (CES-D). Independent variables included gender and treatment intensity. RESULTS: Happiness significantly mediated the relationship between treatment intensity in both depressive symptomology (beta = -0.65, P < 0.05, CI = -2.46, -6.41) and QOL (beta = 0.54, P < 0.05, CI = 3.66, 9.01). A past-negative time perspective significantly mediated the relationship between gender and depressive symptomology (beta = 0.60, P < 0.05, CI = 3.34, 9.78). Survivors' gender was not associated with happiness and treatment intensity was not associated with time perspective. CONCLUSIONS: Happiness may be a more direct predictor of QOL and depression than the intensity of treatment for cancer. Also, thinking negatively about one's past may be a more direct predictor of depressive symptomology than being female. Therefore, interventions that cultivate happiness and reframe time perspective may be effective ways to improve survivors' QOL and decrease depressive symptoms-regardless of gender and intensity of treatment protocol.