Treatment choice in pediatric immune thrombocytopenia (ITP) is arbitrary, because few studies are powered to identify predictors of therapy response. Increasingly, rituximab is becoming a treatment of choice in those refractory to other therapies.
The objective of this study was to evaluate univariate and multivariable predictors of platelet count response to rituximab. After local IRB approval, 565 patients with chronic ITP enrolled and met criteria for this study in the longitudinal, North American Chronic ITP Registry (NACIR) between January 2004 and October 2010. Treatment response was defined as a post-treatment platelet count ≥50,000/µl within 16 weeks of rituximab and 14 days of steroids. Treatment response data were captured both retrospectively at enrollment and then prospectively.
Eighty (14.2%) patients were treated with rituximab with an overall response rate of 63.8% (51/80). Univariate correlates of response to rituximab included the presence of secondary ITP and a positive response to steroids. In multivariable analysis, response to steroids remained a strong correlate of response to rituximab, OR 6.8 (95% CI 2.0–23.0, P = 0.002). Secondary ITP also remained a strong predictor of response to rituximab, OR 5.6 (95% CI 1.1–28.6, P =0.04). Although 87.5% of patients who responded to steroids responded to rituximab, 48% with a negative response to steroids did respond to rituximab.
In the NACIR, response to steroids and presence of secondary ITP were strong correlates of response to rituximab, a finding not previously reported in children or adults.
ITP; pediatric; rituximab; treatment
SCH 727965 is a novel drug in clinical development that potently and selectively inhibits CDK1, CDK2, CDK5, and CDK9. The activity of SCH 727965 was evaluated against the PPTP’s in vitro and in vivo panels.
SCH 727965 was tested against the PPTP in vitro panel using 96 hour exposure at concentrations ranging from 0.1 nM to 1.0 μM. It was tested against the PPTP in vivo panels at a dose of 40 mg/kg administered intraperitoneally twice weekly for 2 weeks and repeated at Day 21 with a total observation period of 6 weeks.
The median IC50 value for the cell lines was 7.5 nM, with less than 4-fold range between the minimum (3.4 nM) and maximum (11.2 nM) IC50 values. SCH 727965 demonstrated an activity pattern consistent with cytotoxicity for most of the cell lines. Forty-three xenograft models were studied and SCH 727965 induced significant delays in event free survival distribution compared to control in 23 of 36 (64%) evaluable solid tumor xenografts and in 3 of 7 ALL xenografts. SCH 727965 did not induce objective responses in the solid tumor panels and the best response observed was stable disease for one osteosarcoma xenograft. In the leukemia panel, there were two objective responses with a complete response observed in a single xenograft.
SCH 727965 shows an interesting pattern of activity suggesting its potential applicability against selected childhood cancers, particularly leukemias.
Preclinical Testing; Developmental Therapeutics; SCH 727965; Dinaciclib
Marked elevations of AFP and bHCG in serum or CSF may serve as surrogate diagnostic markers in lieu of histology for primary CNS mixed, malignant germ cell tumors. There is less information on the diagnostic sensitivity of bHCG assays in germinoma.
We report baseline serum and lumbar CSF bHCG values in 58 newly diagnosed, histologically confirmed germinoma patients gathered from 2 prospective clinical trials which required that patients have a normal AFP and bHCG ≤50 mIU/ml in serum and lumbar CSF.
The location of the primary tumors was: suprasellar(23); pineal(20); suprasellar/pineal(9) and other sites(6). The mean age of the study population was 13.5 (4.3–25.9) years. A total of 23(40%) patients had elevations of bHCG in either serum or CSF, 20(34.5%) of whom had only bHCG elevations in CSF. The patients bHCG profiles were divided into 4 categories: I (normal serum and lumbar CSF bHCG) - 35(60%); II (normal serum and elevated CSF bHCG) - 20(34.5%); III (elevated serum and CSF bHCG) - 2(3.5%) and IV (elevated serum and normal CSF bHCG) - 1(2%). The median CSF bHCG level was 7.7(2.5–16) in the 22 patients with abnormal CSF values and the lumbar value was higher than the serum value in 20 of 23(87%) patients with bHCG elevations.
Lumbar CSF was a more informative screen for bHCG than serum but the majority of patients (60%) had normal bHCG values at diagnosis. Until a more sensitive tumor marker for germinoma is devised, histologic confirmation remains the standard of care.
germinoma; bHCG; tumor markers; diagnosis
Abdominal aortic calcification (AAC), metabolic syndrome, and low bone mineral density (BMD) are risk factors for atherosclerotic disease and cardiovascular morbidity. We evaluated AAC in 662 adult survivors of childhood ALL (median age 31 years). AAC was present in 10% of subjects, metabolic syndrome in 36%, and low BMD in 29%. The adjusted odds ratio (OR) for AAC among women with metabolic syndrome was 2.3 (95% CL=1.0, 4.3). The OR for AAC in men with low BMD was 3.1 (95% CL=1.3, 7.3). A substantial proportion of adult survivors of childhood ALL have AAC and/or metabolic syndrome, suggestive of early atherosclerotic disease.
adverse late effects; bone mineral density; cancer; cardiovascular disease; epidemiology; metabolic syndrome
Acute myeloid leukemia (AML) remains a major therapeutic challenge in pediatric oncology even with intensified cytarabine (ara-C)-based chemotherapy. Therefore, new therapies are urgently needed to improve treatment outcome of this deadly disease. In this study, we evaluated antileukemic interactions between clofarabine (a second-generation purine nucleoside analog) and valproic acid (VPA, a FDA-approved agent for treating epilepsy in both children and adult and a histone deacetylase inhibitor), in pediatric AML.
In vitro clofarabine and VPA cytotoxicities of the pediatric AML cell lines and diagnostic blasts were measured by using MTT assays. The effects of clofarabine and VPA on apoptosis and DNA double strand breaks (DSBs) were determined by flow cytometry analysis and Western blotting, respectively. Active form of Bax was measured by Western blotting post immunoprecipitation.
We demonstrated synergistic antileukemic activities between clofarabine and VPA in both pediatric AML cell lines and diagnostic blasts sensitive to VPA. In contrast, antagonism between the two agents could be detected in AML cells resistant to VPA. Clofarabine and VPA cooperate in inducing DNA DSBs, accompanied by Bax activation and apoptosis in pediatric AML cells.
Our results document synergistic antileukemic activities of combined VPA and clofarabine in pediatric AML and suggest that this combination could be an alternative treatment option for the disease.
pediatric acute myeloid leukemia; clofarabine; valproic acid; histone deacetylase inhibitor; synergistic antileukemic interaction
Burkitt lymphoma (BL) is endemic in parts of Tanzania, but there is scant country or region level data about burden and trends of BL in Tanzania over the past three decades. Here, we update baseline epidemiology of BL in northern Tanzania using recent data.
Data for childhood BL diagnosed at six hospitals in Mara and Mwanza regions in northern Tanzania during 2000 – 2009 were compiled. Age, sex, and regional patterns were analyzed. Crude incidence rates of BL were calculated by sex, anatomic site, geographical region, and calendar year.
Among 944 cases, 549 (58%) were male (male/female case ratio 1.4:1). Among those with known anatomic site (92%), facial only tumors represented a large proportion of tumors in boys than girls (50% versus 36%, P<0.002). Tumors occurred at a younger mean age in boys than girls (6.8 versus 7.6 years, P<0.01). Crude BL incidence was 4.2 per 100,000, but varied by region (3.0 in Mwanza versus 6.8 in Mara, P=0.01), by district (from 1.4 to 22), by gender (5.0 in boys versus 4.0 in girls) and by age group (2.0 in 0–4, 7.8 in 5–9, and 3.1 in 10–15 years). BL incidence peaked in 2001 and decreased gradually thereafter.
Our results indicate that male sex, young age, and geographical characteristics are risk factors for BL in Tanzania. BL incidence declined with calendar year, but the significance of this finding is uncertain. Well-designed epidemiological studies of BL in Tanzania may shed light on environmental characteristics underlying these patterns.
Burkitt lymphoma; Malaria; Epstein Bar Virus; Epidemiology; Tanzania
Hodgkin lymphoma is highly curable but associated with significant late effects. Reduction of total treatment would be anticipated to reduce late effects. This aim of this study was to demonstrate that a reduction in treatment was possible without compromising survival outcomes.
Protocol P9426, a response-dependent and reduced treatment for low risk Hodgkin lymphoma (stages I, IIA, and IIIA1) was designed in 1994 based on a previous pilot project. Patients were enrolled from 10/15/1996 to 09/19/2000. Patients were randomized to receive or not receive Dexrazoxane and received 2 cycles of chemotherapy consisting of Doxorubicin, Bleomycin, Vincristine, and Etoposide. After 2 cycles, patients were evaluated for response. Those in complete response (CR) received 2550 cGy of involved field radiation therapy (IFRT). Patient with partial response or stable disease, received 2 more cycles of chemotherapy and IFRT at 2550 cGy.
There were 294 patients enrolled, with 255 eligible for analysis. The 8 year event free survival (EFS) between the Dexrazoxane randomized groups did not differ (EFS 86.8 + 3.1% with DRZ, and 85.7 + 3.3% without DRZ (p=0.70). Forty five percent of patients demonstrated CR after two cycles of chemotherapy. There was no difference in EFS by histology, rapidity of response, or number of cycles of chemotherapy. Six of the eight secondary malignancies in this study have been previously reported.
Despite reduced therapy and exclusion of most patients with Lymphocyte Predominant histology, EFS and overall survival are similar to other reported studies. The protocol documents that it is safe and effective to reduce therapy in low risk Hodgkin lymphoma based on early response to chemotherapy with rapid responding patients having the same outcome as slower-responding patients when given 50% of the chemotherapy.
Response-dependent; Hodgkin lymphoma; children and adolescents
The cognitive late effects experienced by many survivors of pediatric acute lymphoblastic leukemia (ALL) and brain tumors are well-established. The most commonly reported deficit is difficulty with attention. Problems with social functioning have also been identified, but their relationship with cognitive functioning is not well understood. This multi-site, cross-sectional study aimed to examine the impact of attention on social functioning.
469 survivors of ALL and brain tumors (55% ALL; 57% male) completed study procedures, including parent- and teacher-report measures of attention (Conners’ Rating Scales, Revised) and parent-report of social functioning (Social Skills Rating System) as part of their screening evaluation for a large clinical trial. Survivors were 12.1 years of age and 4.9 years from the end of treatment at the time of study.
Results revealed that survivors’ parent-reported attention problems were uniquely associated with their social functioning, relative to known demographic- and treatment-related risk factors. Teacher-reported attention problems, in contrast, were not, despite a significant correlation between the two. Deficits in intelligence and female gender were also significantly associated with poor social functioning.
Attention problems uniquely impact difficulties with social functioning in survivors of pediatric cancer. Future studies will need to further examine the relationship between attention and social functioning in survivors, particularly when assessed by teacher report.
childhood cancer survivors; attention problems; social functioning; late effects
In children with cancer, suboptimal nutrition states are common consequences of the disease and its treatment. These nutrition states have been attributed to a number of etiologies dependent on the patient’s tumor type and treatment, and are associated with increased morbidity and mortality. Interventions vary from psychosocial to pharmacological and surgical management. Further research is necessary to understand the epidemiology and etiology of these nutrition states. Of great importance is the development and implementation of effective interventions to optimize nutritional status among children with cancer during and after therapy.
nutrition; pediatric oncology; obesity; malnutrition; support care
Treatment of pediatric lymphocyte-predominant Hodgkin lymphoma (LPHL) is controversial but has typically consisted of both chemotherapy and radiation. Radiation therapy is associated with potential late effects in children and adolescents. We examined the impact of radiation therapy on long-term outcome of patients with LPHL treated on CCG-5942, a large pediatric cooperative group study of Hodgkin lymphoma.
Eighty-two patients with LPHL were registered on CCG-5942. Fifty-two patients (63%) received chemotherapy alone; 29 patients (35%) received chemotherapy followed by involved-field radiation therapy (IFRT).
The median follow-up of the LPHL patients is 7.7 years; 63 patients (77%) have > 5 years of follow-up. The 5-year event-free survival (EFS) and overall survival (OS) were 97% and 100%. Two relapses occurred, both in patients who did not receive IFRT. There were no significant differences in EFS or OS between patients who received or did not receive IFRT.
This subset analysis demonstrates the chemosensitivity of pediatric LPHL. Patients who had a complete response to chemotherapy had an excellent EFS and OS without the addition of radiotherapy.
Lymphocyte-Predominant Hodgkin Lymphoma
Rhabdoid tumors (also called atypical teratoid/rhabdoid tumor (AT/RT) in the brain), are highly malignant, poor prognosis lesions arising in the kidneys, soft tissues and central nervous system. Targeted therapy in this disease would benefit from advanced technologies detecting relevant actionable mutations.
Here we report on the evaluation of twenty-five tumors, all with known SMARCB1/INI1 alterations, for the presence of 983 different mutations in 115 oncogenes and tumor-suppressor genes using OncoMap, a mass spectrometric method of allele detection.
Other than mutations in SMARCB1, our results identified a single activating mutation in NRAS and complete absence of oncogenic mutations in all other genes tested.
The absence of mutations in canonical pathways critical for development and progression of adult cancers suggests that distinct mechanisms drive these highly malignant pediatric tumors. This may limit the therapeutic utility of available targeted therapies and require a refocusing toward developmental and epigenetic pathways.
Rhabdoid; AT/RT; targeted therapy; OncoMap
Malignant degeneration frequently arises from preexisting plexiform neurofibroma in patients with neurofibromatosis type 1 (NF1). Image guided biopsy for diagnostic purposes, such as with CT guidance, can be technically challenging in these patients, as CT cannot distinguish malignant from benign areas within the same tumor. Navigation with multi-modality (PET, CT, and ultrasound) image fusion facilitated the successful biopsy and diagnosis of angiosarcoma arising from a pelvic neurofibroma in a patient with NF1. Successful targeting assisted treatment selection in this case. This novel navigation technique may facilitate the otherwise difficult diagnosis of malignancy in patients with NF1. Pediatr Blood Cancer.
FDG-PET; image guided biopsy; malignant peripheral neural sheath tumor; neurofibromatosis type 1; plexiform neurofibroma
The purpose of this analysis is to explore whether the International Germ Cell Classification Consensus (IGCCC) tumor marker criteria, developed for adult males with metastatic malignant germ cell tumors (MGCT), are prognostic among pediatric patients and whether tumor marker data may be relevant in pediatric risk stratification.
The IGCCC was applied to 436 pediatric germ cell patients treated on Pediatric Intergroup Studies from 1990 to 1996. Multivariable Cox proportional hazards model identified prognostic variables; survival rates among IGCCC risk groups were compared using the log-rank test. Concordance and relative performance of IGCCC versus COG risk stratification was evaluated.
Applying the IGCCC, 21% of pediatric patients were good risk (GR), 35% intermediate risk (IR), and 44% poor risk (PR). Only modest concordance between IGCCC and COG stratification systems was noted (49%). Nonetheless, the IGCCC identified a group of PR patients who had significantly worse event-free survival (EFS) versus GR/IR patients (6-year EFS 80% vs. 91%), which was similar to the difference observed using the COG system (6-year EFS 77% vs. 90%). The IGCCC performed well within subgroups for which the IGCCC is not intended (prepubertal, female, and non-metastatic patients).
Applying the IGCCC system to pediatric patients produces a different stratification than does the application of the COG system, although both are prognostic. Development of a de novo pediatric prognostic classification is warranted.
germ cell tumors; International Germ Cell Classification; pediatric germ cell tumors; risk stratification; tumor markers
The objectives of this study were to evaluate factors that influence agreement between parent-proxy and child self-report of health-related quality of life (HRQL) in sickle cell disease. We hypothesized that the mental health of the parent, parental HRQL and child characteristics would affect agreement.
In a cross-sectional study of children with sickle cell disease, HRQL of the child and the parent’s HRQL and mental health were assessed. The effect of parent and child characteristics on agreement between parent-proxy and child self-report of HRQL were determined.
Rates of agreement between parent-proxy and child self-report of HRQL ranged between 42–49%. Parents with increased symptoms of distress had an increased odds of reporting a worse physical (Odds Ratio (OR) 1.12) and psychosocial HRQL (OR 1.10) compared to the child’s self-report. Severe sickle cell disease was associated with an increased odds of the parent reporting the child’s physical HRQL was worse, (OR 4.68) compared to the child’s self-report.
Greater symptoms of distress in the parent are associated with worse parent-proxy report of the child’s HRQL. Severe sickle cell disease is associated with greater disagreement between parent-proxy and child self-report of HRQL. These findings broaden our understanding of factors that influence proxy-reporting of a child’s HRQL.
sickle cell disease; health-related quality of life; family factors; well being
Sorafenib is an inhibitor of multiple kinases (e.g., VEGF receptors, PDGFR, FLT3, RET, BRAF, KIT) and is approved by FDA for treatment of two adult cancers. The activity of sorafenib was evaluated against the PPTP's in vitro and in vivo panels.
Sorafenib was evaluated against the PPTP in vitro panel using 96 hour exposure at concentrations ranging from 1.0 nM to 10.0 μM. It was tested against the PPTP in vivo panels at a dose of 60 mg/kg administered by oral gavage daily for 5 days per week, repeated for 6 weeks.
In vitro sorafenib demonstrated cytotoxic activity, with a median IC50 value of 4.3 μM. Twenty of 23 cell lines had IC50 values between 1.0 and 10.0 μM. A single cell line (Kasumi-1) with an activating KIT mutation had an IC50 value < 1.0 μM (IC50 = 0.02 μM). In vivo sorafenib induced significant differences in EFS distribution compared to control in 27 of 36 (75%) of the evaluable solid tumor xenografts and in 1 of 8 (12.5%) of the evaluable ALL xenografts. Sorafenib induced tumor growth inhibition meeting criteria for intermediate activity (EFS T/C) in 15 of 34 (44%) evaluable solid tumor xenografts. No xenografts achieved an objective response.
The primary in vitro activity of sorafenib was noted at concentrations above 1 μM, with the exception of a more sensitive cell line with an activating KIT mutation. The primary in vivo effect for sorafenib was tumor growth inhibition, which was observed across multiple histotypes.
Preclinical Testing; Developmental Therapeutics; tyrosine kinases
MLN4924 is an investigational first-in-class small molecule inhibitor of NEDD8-activating enzyme (NAE). NAE is an essential component of the NEDD8 conjugation pathway, controlling the activity of a subset of ubiquitin-proteasome system (UPS) E3 ligases, multiprotein complexes that transfer ubiquitin molecules to substrate proteins.
MLN4924 was tested against the PPTP in vitro panel using 96 hour exposure time at concentrations ranging from 1.0 nM to 10 μM. It was tested in vivo at a dose of 100 mg/kg [66 mg/kg for the acute lymphoblastic leukemia (ALL) xenografts] administered orally twice daily × 5 days. Treatment duration was 3 weeks.
The median relative IC50 for MLN4924 against the PPTP cell lines was 143 nM, (range 15 nM to 678 nM) with that for the Ewing panel being significantly lower (31 nM). MLN4924 induced significant differences in EFS distribution compared to control in 20 of 34 (59%) evaluable solid tumor xenografts. MLN4924 induced intermediate activity (EFS T/C values > 2) in 9 of the 33 evaluable xenografts (27%), including 4 of 4 glioblastoma xenografts, 2 of 3 Wilms tumor xenografts, 2 of 5 rhabdomyosarcoma xenografts, and 1 of 4 neuroblastoma xenografts. For the ALL panel, 5 of 8 evaluable xenografts showed intermediate activity for the EFS T/C measure. MLN4924 did not induce objective responses in the PPTP solid tumor or ALL panels.
MLN4924 showed potent activity in vitro and in vivo showed tumor growth inhibitory activity against a subset of the PPTP solid tumor and ALL xenografts.
Preclinical Testing; Developmental Therapeutics; MLN4924
Major professional organizations have called for psychosocial risk screening to identify specific psychosocial needs of children with cancer and their families and facilitate the delivery of appropriate evidence-based care to address these concerns. However, systematic screening of risk factors at diagnosis is rare in pediatric oncology practice. Subsequent to a brief summary of psychosocial risks in pediatric cancer and the rationale for screening, this review identified three screening models and two screening approaches (Distress Thermometer [DT], Psychosocial Assessment Tool [PAT]), among many more papers calling for screening. Implications of broadly implemented screening for all patients across treatment settings are discussed.
Specific cytogenetic clones might distinguish patients with unrecognized Fanconi anemia (FA) who present with acute myeloid leukemia (AML) from those with sporadic AML. Cytogenetic reports in literature cases of FA and AML were compared with de novo cases enrolled on CCG-2961. Gain of 1q, gain of 3q, monosomy 7, deleted 7q, gain of 13q, and deleted 20q were more frequent in FA AML; t(8;21), trisomy 8, t(9;11), t(6;9) and inversion 16 were exclusive to de novo AML cases. Observation of the FA AML cytogenetic clonal patterns should raise suspicion of an underlying leukemia predisposition syndrome and influence management.
Acute myelogenous leukemia; Fanconi anemia; cytogenetics; clones; sporadic AML
The objectives of this phase I study were to determine the maximum tolerated dose (MTD), toxicity profile and pharmacokinetics of a 24-hour continuous intravenous infusion of trabectedin administered to children and adolescents with refractory or relapsed solid tumors.
Patients between the ages of 4 and 16 years old with refractory solid tumors received trabectedin as a 24-hour infusion every 21 days. Dexamethasone and prophylactic growth factor support were administered with each cycle. Pharmacokinetic studies were conducted during cycle 1.
Patients (n=12) median (range) age 14.5 (8–16) years received trabectedin at 1.1 (n=3), 1.5 (n=6) or 1.7 (n=3) mg/m2. At the 1.5 mg/m2 dose level, one patient had dose limiting anorexia and fatigue. At 1.7 mg/m2, 2 patients experienced dose limiting toxicity, dehydration and gamma-glutamyl transpeptidase (GGT) elevation. Non-dose limiting toxicities included elevated serum transaminases, myelosuppression, nausea, emesis and fatigue. Plasma pharmacokinetic parameters were similar to historical data in adults. One partial response (PR) was observed in a patient with neuroendocrine carcinoma. Stable disease (SD) (≥6 cycles) was achieved in 3 patients (osteosarcoma n=2, desmoplastic small round cell tumor n=1).
The MTD of trabectedin in pediatric patients with refractory solid tumors is 1.5 mg/m2 IV over 24 hours every 21 days. Dexamethasone to ameliorate hepatic toxicity and prophylactic growth factor support are required.
trabectedin; phase I clinical trial; pediatrics; pharmacokinetics
Propranolol is a non-selective beta-adrenergic antagonist successfully used in a case of kaposiform hemangioendothelioma associated with Kasabach-Merritt phenomenon. We report eleven patients treated with propranolol for kaposiform hemangioendothelioma and the related variant tufted angioma, six of whom also had Kasabach-Merritt phenomenon. The varied responses to treatment, with only 36% responding in our series, demonstrate the need for further study of this medication before routine use for these indications.
propranolol; kaposiform hemangioendothlioma; tufted angioma; vascular tumor; Kasabach-Merritt; treatment
Desaturation of hemoglobin (Hb) in cerebral tissue, a physiologic marker of brain vulnerable to ischemic injury, can be detected non-invasively by transcranial oximetry. Absolute cerebral oximetry has not been studied in sickle cell disease (SCD), a group at very high risk of cerebral infarction in whom prevention of brain injury is key.
We measured absolute Hb saturation in cerebral tissue (SCTO2) in children with SCD using near-infrared spectrophotometry and investigated the contributions of peripheral Hb saturation (SPO2), hematologic measures, cerebral arterial blood flow velocity, and cerebral arterial stenosis to SCTO2. We also assessed the effects of transfusion.
We studied 149 children with SCD (112 HbSS/Sβ0; 37 HbSC/Sβ+). SCTO2 was abnormally low in 75% of HbSS/Sβ0 and 35% of HbSC/Sβ+ patients. SCTO2 (mean±SD) was 53.2±14.2 in HbSS/Sβ0 and 66.1±9.2% in SC/Sβ+ patients. SCTO2 correlated with age, sex, Hb concentration, reticulocytes, Hb F, and SPO2, but not transcranial Doppler arterial blood flow velocities as continuous measures. In multivariable models, SPO2, Hb concentration, and age were significant independent determinants of SCTO2. Cerebral vasculopathy was associated with ipsilateral cerebral desaturation. Transfusion increased SCTO2 and minimized the inter-hemispheric differences in SCTO2 due to vasculopathy.
Cerebral desaturation, a physiologic marker of at-risk brain, is common in SCD, more severe in HbSS/Sβ0 patients, and associated with peripheral desaturation, more severe anemia, and increasing age. Cerebral oximetry has the potential to improve the identification of children with SCD at highest risk of neurologic injury and possibly serve as a physiologic guide for neuroprotective therapy.
sickle cell disease; desaturation; hypoxemia; brain; risk factor; stroke
Pediatric acute lymphoblastic leukemia (ALL) therapies have been associated with many late effects, including obesity, hyperglycemia, and insulin resistance. Few data are available linking these abnormalities to specific risk factors present during ALL treatment.
Retrospective cohort study with prospective follow-up. Subjects had been diagnosed with ALL at ages 1–18 years and had been off chemotherapy for > 9 months. Oral glucose tolerance testing (OGTT) was performed and these results compared to demographic, treatment, and anthropomorphic data from medical records.
27 subjects (11 female) were evaluated. Mean (± SD) diagnosis age 5.7 ± 3.5 years, mean study age 11.3 ± 3.7 years, mean time off therapy 2.8 ± 1.5 years. Six subjects had transient hyperglycemia during ALL treatment. At study time, one subject had prediabetes; eight (29.6%) had insulin resistance. Insulin resistance was not predicted by glucose levels during treatment, cumulative steroid or asparaginase dose, or type of steroid received. Body mass index (BMI) for age correlated significantly with several measures of insulin resistance, including fasting insulin, HOMA index, Matsuda index and insulin AUC (p = 0.001 to 0.009). Waist-hip ratio and BMI at ALL diagnosis also correlated with insulin resistance, but these factors’ effects could not be separated from BMI at study time.
Variations in ALL therapy and presence of transient hyperglycemia do not appear to increase risk of glucose intolerance or insulin resistance in the first few years after completion of therapy. Elevated BMI strongly predicted insulin resistance in this study, as it does in the general population.
ALL; Hematology/Oncology; Pediatric Endocrinology
The ganglioside GD2 is an attractive target for immunotherapy of neuroectodermal tumors. We tested a unique bispecific antibody anti-CD3 × anti-GD2 (3F8BiAb) for its ability to redirect activated T cells (ATC) to target GD2-positive neuroblastomas.
ATC were generated from normal human peripheral blood mononuclear cells (PBMC) by stimulating the PBMC with OKT3 and expanding the T cells in the presence of interleukin 2 (IL-2) for 14 days. ATC were armed with 3F8BiAb (100 ng/106 cells) or Her2BiAb (50 ng/106 cells) prior to use. 3F8 BiAb were tested for its dual-binding specificity to GD2 expressed on cancer cell lines and CD3 expressed on ATC. 3F8BiAb-armed ATC were further tested ex vivo for their cytotoxicity against GD2 positive tumor targets and its ability to induce cytokine response upon binding to targets.
GD2 expression in neuroblastoma cells was confirmed by FACS analysis. Specific binding of 3F8BiAb to the tumor targets as well as to ATC was confirmed by FACS analysis. 3F8BiAb-armed ATC exhibited specific killing of GD2 positive neuroblastoma cell lines significantly above unarmed ATC (P < 0.001). GD2BiAb-armed ATC secreted significantly higher levels of Th1 cytokines and chemokines compared to unarmed ATC (P < 0.001).
These preclinical findings support the potential of a novel immunotherapeutic approach to target T cells to neuroblastoma.
bispecific antibody; GD-2; immunotherapy; neuroblastoma; T cells
Severe chronic active Epstein-Barr virus infection (CAEBV) in T or NK cells is a rare complication of latent EBV infection. CAEBV associated T-cell lymphoproliferative disease (LPD) consists of polyclonal lesions as well as aggressive lymphomas. Here we report such a patient. In addition, we show that this primary CAEBV associated T-cell lymphoma expresses CD70 and is sensitive to killing by CD70-specific T cells, identifying CD70 as a potential immunotherapeutic target for CAEBV-associated T-cell lymphoma.
EBV; CD70; Lymphoma; Immunotherapy