Sunil Desai

Advanced-Stage Large-Cell Lymphoma in Children and Adolescents: Results of a Randomized Trial Incorporating Intermediate-Dose Methotrexate and High-Dose Cytarabine in the Maintenance Phase of the APO Regimen: A Pediatric Oncology Group Phase III Trial

PURPOSE The Pediatric Oncology Group adopted a histology-based approach to non-Hodgkins lymphoma and treated patients with advanced large-cell lymphoma on a separate protocol (doxorubicin, vincristine, prednisone, 6-mercaptopurin, and methotrexate; APO regimen). In this study, we assessed the effects of an intense antimetabolite therapy alternating with APO on overall survival (OS) and event-free survival (EFS) and looked into biologic correlates. PATIENTS AND METHODS From December 1994 to April 2000, we enrolled 180 eligible pediatric patients with stage III/IV large-cell lymphoma (LCL); 90 patients were randomly assigned to the intermediate-dose methotrexate (IDM) and high-dose cytarabine (HiDAC) arm, 85 patients to the APO arm, and five patients directly to the APO arm by study design due to CNS involvement. Planned therapy duration was 12 months. RESULTS The 4-year EFS for all patients was 67.4% (SE, 4.2%), and OS was 80.1% (SE, 3.6%) without any significant difference between the two arms. The 4-year EFS and OS were 71.8% (SE, 6.1%) and 88.1% (SE, 4.4%), respectively, for patients with anaplastic large-cell lymphoma, and 63.8% (SE, 10.3%) and 70.3% (SE, 9.0%), respectively, for patients with diffuse large B-cell lymphoma. Only 11 patients required radiation (due to unresponsive bulky disease or CNS involvement). The IDM/HiDAC arm was associated with more toxicity. CONCLUSION The efficacy of incorporating IDM/HiDAC in the treatment plan of pediatric and adolescent patients with advanced-stage LCL was inconclusive as to its effect on EFS, regardless of the lymphoma phenotype. It cannot be excluded that with a higher number of patients, one treatment could prove superior and future studies will build on these data.

Hyaluronan Synthase 3 Variant and Anthracycline-Related Cardiomyopathy: A Report From the Children's Oncology Group

PURPOSE The strong dose-dependent association between anthracyclines and cardiomyopathy is further exacerbated by the co-occurrence of cardiovascular risk factors (diabetes and hypertension). The high morbidity associated with cardiomyopathy necessitates an understanding of the underlying pathogenesis so that targeted interventions can be developed. PATIENTS AND METHODS By using a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy by using the ITMAT/Broad CARe cardiovascular single nucleotide polymorphism (SNP) array to profile common SNPs in 2,100 genes considered relevant to de novo cardiovascular disease. RESULTS By using a matched case-control design (93 cases, 194 controls), we identified a common SNP, rs2232228, in the hyaluronan synthase 3 (HAS3) gene that exerts a modifying effect on anthracycline dose-dependent cardiomyopathy risk (P = 5.3 × 10(-7)). Among individuals with rs2232228 GG genotype, cardiomyopathy was infrequent and not dose related. However, in individuals exposed to high-dose (> 250 mg/m(2)) anthracyclines, the rs2232228 AA genotype conferred an 8.9-fold (95% CI, 2.1- to 37.5-fold; P = .003) increased cardiomyopathy risk compared with the GG genotype. This gene-environment interaction was successfully replicated in an independent set of 76 patients with anthracycline-related cardiomyopathy. Relative HAS3 mRNA levels measured in healthy hearts tended to be lower among individuals with AA compared with GA genotypes (P = .09). CONCLUSION Hyaluronan (HA) produced by HAS3 is a ubiquitous component of the extracellular matrix and plays an active role in tissue remodeling. In addition, HA is known to reduce reactive oxygen species (ROS) -induced cardiac injury. The high cardiomyopathy risk associated with AA genotype could be due to inadequate remodeling and/or inadequate protection of the heart from ROS-mediated injury on high anthracycline exposure.

Randomized trial of r-metHu granulocyte colony-stimulating factor in an intensive treatment for T-cell leukemia and advanced-stage lymphoblastic lymphoma of childhood: a Pediatric Oncology Group pilot study.

PURPOSE Contemporary chemotherapy has significantly improved the event-free survival (EFS) among patients with T-cell disease. However, myelosuppression has been a significant adverse effect of this approach. In this study, we assessed the impact of r-metHu granulocyte colony-stimulating factor (G-CSF) on the period of neutropenia, number of days of hospitalization, and delays in subsequent administration of chemotherapy in a cohort of patients with T-cell leukemia (T-ALL) or advanced stage lymphoblastic lymphoma (ASLL). PATIENTS AND METHODS This open-label, randomized trial incorporated r-metHuG-CSF into the induction and two consecutive continuation-therapy cycles of our intensive program for T-cell malignancies. In the induction phase, r-metHuG-CSF was given after two different combinations of chemotherapy, one of which included vincristine, prednisone, cyclophosphamide, and adriamycin and the other a continuous infusion of high-dose ara-C and L-asparaginase. In the two continuation-therapy cycles, r-metHuG-CSF was given following the combination of vincristine, adriamycin, prednisone, and 6-mercaptopurine (MP) and after continuous infusion of high-dose cytarabine (ara-C). RESULTS Fifty-six patients with T-ALL and 33 with ASLL were enrolled onto study from April 1994 to December 1995. Our data show no significant difference in number of days of absolute neutrophil count (ANC) less than 500/microL, hospitalizations, or delays in therapy in the induction phase. However, in the continuation-therapy phase the number of days of ANC less than 500/microL was significantly shorter (P = .017) on the G-CSF-arm without significantly affecting the number of days of hospitalizations or delays in therapy. CONCLUSION r-metHuG-CSF did not significantly affect the period of neutropenia, hospitalization, or delays in therapy in the induction phase, whereas in the two cycles of continuation therapy, it significantly shortened the period of neutropenia.

Prevalence of post-thrombotic syndrome following asymptomatic thrombosis in survivors of acute lymphoblastic leukemia.

Summary.  Background: Deep vein thrombosis (DVT) is a complication of treatment of acute lymphoblastic leukemia (ALL) in children but little is known about the long‐term outcomes of these DVT. Objective: To determine the incidence of post‐thrombotic syndrome (PTS) in (i) children with ALL diagnosed with asymptomatic DVT using radiographic testing and (ii) an unselected group of ALL survivors. Methods: Cross‐sectional study in two populations. Group I comprised children in the Prophylactic Antithrombin Replacement in Kids with ALL treated with L‐Asparaginase (PARKAA) study diagnosed with DVT by radiographic tests. Group II consisted of non‐selected childhood ALL survivors <21 years. PTS was assessed using a standardized scoring sheet. Results: Group I: 13 PARKAA patients (median age 12 years) were assessed, and 7 had PTS (54%; 95% CI, 25–81). All patients had collaterals, three also had increased arm circumference. Group II: 41 patients (median age 13 years) with a history of ALL were enrolled, and 10 had PTS (24%; 95% CI, 11–38). All patients had collaterals; five also had increased arm circumference. Conclusion: There is a high incidence of PTS in survivors of childhood ALL with radiographically diagnosed asymptomatic DVT. A significant proportion of ALL survivors develop PTS, indicating previously undiagnosed DVT.

Non-anaplastic peripheral T-cell lymphoma in childhood and adolescence: A Children’s Oncology Group Study

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.

Threshold Current of an Insulated Needle in the Intrathecal Space in Pediatric Patients

A threshold current of <1 mA has been suggested to be sufficient to produce a motor response to electrical stimulation in the intrathecal space. We designed this study to determine the threshold current needed to elicit motor activity for an insulated needle in the intrathecal space. Twenty pediatric patients aged 7.3 ± 3.9 yr scheduled for lumbar puncture were recruited. After sedation with propofol, patients were turned to the lateral position and an 18-gauge or 20-gauge introducer needle was placed at the L4-5 level through which an insulated 24-gauge Pajunck unipolar needle (with a Sprotte tip and stylet) was inserted. The needle was advanced into the intrathecal space as suggested by the presence of a “pop.” At this point, a nerve stimulator was attached to the insulated needle and the current was gradually increased until motor activity was evident. The needle hub was checked for cerebrospinal fluid. If cerebrospinal fluid was not present, the needle was advanced further until cerebrospinal fluid was present. The threshold current was retested. The mean current in the intrathecal space required to elicit a motor response was 0.6 ± 0.3 mA (range, 0.1–1 mA). In 19 patients, the twitches were observed at the L4-5 myotomes and 1 patient had twitches at L2. Twitches were observed unilaterally in 19 children and bilaterally in one child. This confirms the hypothesis that the threshold current in the intrathecal space is <1 mA and that it differs significantly from the threshold currents reported for electrical stimulation in the epidural space.

Comparison of the anticoagulant effect of a direct thrombin inhibitor and a low molecular weight heparin in an acquired antithrombin deficiency in children with acute lymphoblastic leukaemia treated with l‐asparaginase: an in vitro study

Thrombosis occurs in 37% of children with acute lymphoblastic leukaemia (ALL) and is related to an l‐asparaginase‐induced acquired antithrombin (AT) deficiency. The incidence dictates the need for anticoagulant prophylaxis. Direct thrombin inhibitors (DTI) are independent of AT for effect and may thus have advantages in this population. The objective of this study was to determine the interaction of an AT deficiency with the anticoagulant effects of a DTI and a low molecular weight heparin (LMWH). Plasma samples from children with ALL were pooled (mean AT 0·53 U/ml). LMWH 0·3 and 0·7 U/ml or melagatran 0·3 and 0·5 μmol/l were added to the pools, then divided and AT was added back to one aliquot. In additional experiments, AT was added to AT immuno‐depleted plasma. Endogenous thrombin generation capacity (ETGC) was assessed by the continuous method. In plasma with LMWH, there was a 66–88% decrease in ETGC in AT‐normalised samples compared with neat. Conversely, no significant difference in ETGC with or without AT added for melagatran was seen. Experiments with AT‐depleted plasma showed no effect of AT level on anticoagulant activity of DTI, but a significant relationship for LMWH. By contrast to LMWH, DTI provides a consistent anticoagulant response independent of AT levels in children with AT deficiency.

The treatment of pediatric Philadelphia positive (Ph+) leukemias in the imatinib era.

As the treatment of Philadelphia positive (Ph+) leukemias in the era of imatinib continues to evolve, the role of allogeneic hematopoietic cell transplantation (allogeneic‐HCT) in first remission is becoming more unclear.

Color flow Doppler ultrasonography can distinguish caudal epidural injection from intrathecal injection.

BACKGROUND:Color flow Doppler ultrasonography has been used to confirm caudal epidural injection, but its ability to detect accidental intrathecal injection is unknown. We hypothesized that, when using color flow Doppler, the injection of fluid into the epidural space would result in turbulent flow which would appear as a burst of color while intrathecal injection would show an absence of a color flow Doppler signal. METHODS:Two groups of pediatric patients (up to 6 years of age) were prospectively enrolled for this observational study during a 2-month period. One group (group E) consisted of patients suitable for elective surgery using caudal epidural analgesia, and the other (group I) included patients receiving lumbar puncture for intrathecal chemotherapeutic injection. After induction of general anesthesia and placement of the patient in the lateral position, an 8 MHz curved array probe (Sonosite TITAN, Bothell, WA) was applied to obtain a transverse image of the lumbar region (L1-L3). Real-time images using color flow Doppler were obtained and recorded during initial injections of 2 consecutive (20 seconds apart) aliquots of 0.1 mL/kg medication of local anesthetic (0.25% bupivacaine) or chemotherapy drugs (mixture of methotrexate, cytarabine, and hydrocortisone) at a rate of 0.5 to 1.0 mL/s. After obtaining the study images, the rest of the medication was injected in standard fashion. A blinded anesthesiologist later evaluated the recorded images to determine a positive or negative result (positive = presence of turbulence as illustrated by a medley of color; negative = no turbulence or color). Sensitivity, specificity, and positive and negative predictive values were calculated for those patients who had successful analgesia (group E) and intrathecal (group I) injections. RESULTS:Forty recorded images from 41 patients (group E, n = 21; group I, n = 20) were included in the analysis. The observed sensitivity, specificity, positive predictive value, and negative predictive values were all 100%. The lower 95% confidence limits were 0.832. CONCLUSION:In the context of this study, color flow Doppler could differentiate epidural from intrathecal injection into the caudal space of children up to 6 years of age using a 0.1 mL/kg injection volume and injection rate of 0.5 to 1.0 mL/s.

Clinical and Genetic Risk Prediction of Subsequent CNS Tumors in Survivors of Childhood Cancer: A Report From the COG ALTE03N1 Study

Purpose Survivors of childhood cancer treated with cranial radiation therapy are at risk for subsequent CNS tumors. However, significant interindividual variability in risk suggests a role for genetic susceptibility and provides an opportunity to identify survivors of childhood cancer at increased risk for these tumors. Methods We curated candidate genetic variants from previously published studies in adult-onset primary CNS tumors and replicated these in survivors of childhood cancer with and without subsequent CNS tumors (82 participants and 228 matched controls). We developed prediction models to identify survivors at high or low risk for subsequent CNS tumors and validated these models in an independent matched case-control sample (25 participants and 54 controls). Results We demonstrated an association between six previously published single nucleotide polymorphisms (rs15869 [ BRCA2], rs1805389 [ LIG4], rs8079544 [ TP53], rs25489 [ XRCC1], rs1673041 [ POLD1], and rs11615 [ ERCC1]) and subsequent CNS tumors in survivors of childhood cancer. Including genetic variants in a Final Model containing age at primary cancer, sex, and cranial radiation therapy dose yielded an area under the curve of 0.81 (95% CI, 0.76 to 0.86), which was superior ( P = .002) to the Clinical Model (area under the curve, 0.73; 95% CI, 0.66 to 0.80). The prediction model was successfully validated. The sensitivity and specificity of predicting survivors of childhood cancer at highest or lowest risk of subsequent CNS tumors was 87.5% and 83.5%, respectively. Conclusion It is possible to identify survivors of childhood cancer at high or low risk for subsequent CNS tumors on the basis of genetic and clinical information. This information can be used to inform surveillance for early detection of subsequent CNS tumors.