Veronique Dinand

Hodgkin's disease in Indian children: Outcome with chemotherapy alone

To assess the efficacy of chemotherapy alone, using four cycles of COPP alternating with four cycles of ABVD in all stages of childhood Hodgkins disease (HD).

Proliferative index and CD15 expression in pediatric classical Hodgkin lymphoma

This study was conducted to assess the clinical and prognostic significance of lack of CD15 expression, proliferative index (PI), and expression of tumor suppressor protein p53 in pediatric classical Hodgkin lymphoma (CHL).

Dengue fever causing febrile neutropenia in children with acute lymphoblastic leukemia: An unknown entity

Dengue fever is endemic in many parts of the world but it has not been described as a cause of febrile neutropenia. We describe here clinical features, laboratory values and outcome in 10 children with acute lymphoblastic leukemia (ALL) and with dengue fever as a cause of febrile neutropenia. These data are compared to an age-matched control population of 22 children with proven dengue infection without ALL. Except for fever in all patients and plethoric face in one patient, typical symptoms of dengue such as abdominal pain, myalgias, and headaches, were absent. Mean duration of hospital stay was 6.3±2.0 days in ALL patients vs. 5.0±2.0 in controls (p=0.096). Median platelet count was 13,000/cmm (range 1000-28,000) in cases vs. 31,500 (range 13,000-150,000) in controls (p=0.018). Mean time for recovery for platelet was 6.0±1.3days in ALL patients vs. 2.5±0.9days in controls (p<0.001). All 10 patients survived. In endemic areas, high suspicion of dengue fever should be maintained in children with ALL and febrile neutropenia although typical symptoms may be lacking. Platelet recovery may be significantly delayed.

Severe combined immunodeficiency caused by a new homozygous RAG1 mutation with progressive encephalopathy.

We describe an unusual case of severe combined immunodeficiency (SCID) with neutropenia and central nervous system (CNS) manifestations in which a novel RAG1 mutation was identified. A 15-month-old boy presented with failure to thrive, neutropenia and recurrent infections. He was diagnosed with T-B-NK+ SCID. He subsequently developed right partial seizures with ipsilateral hemiparesis and became comatose. Magnetic resonance imaging (MRI) of the brain revealed an inflammatory lesion in the left thalamus which later progressed to diffuse meningo-encephalitis on serial imaging. No CNS infection was documented. Genetic work-up in the child revealed a novel homozygous deleterious mutation in the RAG1 gene (c:2881T>C; p:I794T), for which both parents were heterozygous. He underwent a haploidentical bone marrow transplant without conditioning and died on day +35 with no improvement in his neurological status. The features of neutropenia and progressive encephalopathy could be linked to the novel genetic defect but more data is required to establish this conclusively.

Serum vascular endothelial growth factor-A levels during induction therapy in children with acute lymphoblastic leukemia

ObjectiveTo evaluate serum vascular endothelial growth factor (VEGF) levels in children with acute lymphoblastic leukemia (ALL) during the induction phase of chemotherapy.DesignProspective sudy.SettingHospital-based study over 18 months.Patients30 children with ALL and 17 healthy age- and sexmatched controls.InterventionSerum concentration of VEGF-A-165 isoform (s-VEGF) was measured by enzyme-linked immunoabsorbant assay at diagnosis and at the end of induction chemotherapy.Main outcome measuress-VEGF was compared with markers of tumor burden. Kinetics of s-VEGF was assessed in response to induction chemotherapy.ResultsMedian VEGF was significantly lower in untreated patients than in controls (17.0 vs. 42.6 pg/mL, P=0.004). s-VEGF levels were fairly correlated with WBC count (r=−0.56, P=0.004) and LDH (r=−0.52, P=0.02) at diagnosis. All patients but one were in morphologic remission at the end of induction. Median s-VEGF concentration on day 29/33 was significantly higher than on day 1 (44.2 pg/mL, P=0.009).ConclusionUntreated children with ALL have significantly lower s-VEGF concentration than controls. At the end of the induction therapy, s-VEGF increased to levels similar to controls. The role of ligand-receptor interaction between VEGF and VEGF receptors on leukemia cells needs to be further delineated.

Orbital myeloid sarcoma presenting as massive proptosis

A 10-year-old boy presented with right proptosis for 8 months. The eyeball was grossly pushed down, with diffuse corneal haze and non-reactive pupil. Systemic examination was normal. Previous investigations in another centre included a computerized tomography scan, which showed a well-defined enhancing retro-bulbar mass, a non-contributory fine needle aspiration cytology and a biopsy showing fibrocollagenous tissue with moderate lympho-monocytic infiltrate suggestive of non-specific inflammation. PET-CT scan revealed the presence of enlarged fluoro-deoxyglucose-avid cervical and mesenteric lymph nodes. Biopsy of the retro-bulbar mass was repeated in our centre. It showed fibrocollagenous and skeletal muscle tissue infiltrated by lymphoid follicles, dispersely lying lymphocytes and plasma cells, and admixed large atypical cells with vesicular nuclei, prominent nucleoli and scanty cytoplasm, strongly positive for myeloperoxidase, CD43 and CD99 immunohistochemistry. Hemogram was normal. Bone marrow aspiration/biopsy and CSF showed no evidence of acute myeloid leukemia. The child received chemotherapy in another centre and is in complete remission 6 months after completion.

Pediatric Hodgkin lymphoma presenting with pulmonary nodules and leukemoid reaction

An 8‐year‐old female presented with fever and severe pain in the hipbones and legs for 2½ months. Investigations revealed a leukemoid reaction and bilateral diffuse nodular opacities on chest X‐ray. Supraclavicular lymph node biopsy was diagnostic of Hodgkin lymphoma (HL), mixed cellularity. Both pulmonary nodules and leukemoid reaction being present in the same patient with HL has not been reported. Pediatr Blood Cancer 2010;55:193–195.

Plasma Epstein-Barr virus (EBV) DNA as a biomarker for EBV-associated Hodgkin lymphoma

ObjectivesTo assess plasma Epstein-Barr virus (EBV) DNA as a biomarker of tumour burden at diagnosis and during therapy in children with Hodgkin lymphoma.DesignCase-control study, with prospective follow-up of the Hodgkin lymphoma cohort (2007-2012).SettingPediatric Hematology Oncology unit of a tertiary care hospital in Delhi.PatientsThirty children with Hodgkin lymphoma and 70 sex and age-matched controls (benign lymphadenopathy 19, non-lymphoid malignancy 29, Burkitt lymphoma 5, healthy children 17).InterventionPositive EBV-staining on immunohistochemistry was defined as EBV-associated Hodgkin lymphoma. Plasma EBV real-time quantitative polymerase chain reaction (PCR) was tested at presentation, after first and last chemotherapy cycles, and on follow-up.Main outcome measuresPlasma EBV quantitative PCR was compared between cases and controls. Its kinetics was assessed during and after chemotherapy.ResultsResults: EBV quantitative PCR was positive in 19 (63%) Hodgkin lymphoma cases (range 500–430,000 copies/mL), with 87.5% accuracy (kappa=0.69) as compared with EBVimmunohistochemistry. Sensitivity and specificity of the quantitative PCR were 87.5% and 81.8%, respectively. Only boys showed positive EBV immunohistochemistry and/or quantitative- PCR positivity. All controls were quantitative-PCR negative. All quantitative-PCR positive cases with follow-up blood sample showed EBV clearance after the first cycle. A quantitative-PCR negative case in long-term remission became positive at relapse. EBV status did not influence survival.ConclusionPlasma EBV-DNA, detectable in EBV-associated Hodgkin lymphoma, becomes undetectable early after initiating therapy. It can be used as a biomarker of treatment response in EBV-associated Hodgkin lymphoma.

Unfavorable outcome in CD15 negative pediatric classical Hodgkin lymphoma

To the Editor: The letter of Barros et al. [1] raises interesting issues. In our study on pediatric Hodgkin lymphoma (HL), we found that lack of CD15 expression was independently associated with poor overall and poor failure-free survival (HL) [2]. Barros et al. reference to the study Petrella et al. [3] inwhich they have actually reported an unfavorable outcome of CD15 negative cases. Also, that study was done prior to when the distinction between classical HL and nodular lymphocyte predominant (LP) HL was described [4]. The latter is consistently CD15 negative, and has a significantly favorable outcome [5]. The report of Petrella et al. includes 11 cases of LP, which could have been either lymphocyte rich classical HL (one of the four classical HL subtypes) or nodular LP, and therefore cannot be compared with studies on CD15 negative classical HL. There are only two studies on classical HL which report CD15 negativity to be an independent prognostic factor for overall and disease-free/failure-free survival [2,6], while no prognostic significance is reported bymany studies, possibly due to the limited number of cases studied. TheGerman study included a large number of cases and is a good support for our findings, as they found a significant association between lack of CD15 expression and higher stages at diagnosis [6]. Other studies might confirm whether CD15 negative classical HL presents with unfavorable risk factors that would lead to a poorer survival. The significant association between CD15 negativity and p53 negativity reported in our paper refers to a total absence of p53 immunostaining, that is, absence of p53 overexpression. The same association was found between CD15 negativity and low p53 expression, with a cut-off value of 10% (P1⁄4 0.009; odds ratio 5.4, 95%confidence interval 1.4–22).Wild-type p53 protein is normally below the detection sensitivity of immunohistochemistry. P53 immunodetection in Reed-Sternberg cells is thought to be the result of accumulation of a non-functional p53 protein, due to mdm2 binding, rather than p53 mutation [7]. However, Chabay et al. have shown that p53 is functional as a transcriptional activator in more than half the pediatric HL cases studied [7]. In any case, the association between loss of CD15 antigen expression and lack of p53 overexpression is a purely statistical correlation, which might be verified in further studies. The significant cut-off value for p53 expression in Reed-Sternberg cells is still to be identified. Veronique Dinand, MD, PhD* Department of Pediatrics All India Institute of Medical Sciences New Delhi, India

Outcome of Pediatric Acquired Aplastic Anemia: A Developing World Experience

Introduction: Outcome data of children with acquired aplastic anemia (AA) are lacking from the developing world. Here, we describe the same from a centre in North India. Methods: Retrospective data regarding medical history, physical examination, complete blood count, bone marrow aspirate, and biopsy were retrieved for all children <18 years, with acquired AA admitted between January 2005 and June 2012. In addition, the outcome data after immunosuppressive therapy (IST) or bone marrow transplant (BMT) was obtained. Results: A total of 61 children were diagnosed with AA (Inherited-18 and acquired-43). Among 43 children with acquired AA, 3 had nonsevere and 40 had severe. One patient with nonsevere AA died of sepsis and 2 recovered spontaneously. Of the 40 remaining children with severe AA, 10 refused therapy and 3 died due to severe sepsis prior to any therapy. Five underwent upfront matched sibling donor BMT and one post-IST failure. Four year overall survival (OS) and event free survival (EFS) for children undergoing BMT was 100% and 80 ± 17.9, respectively. Out of 22 treated with IST, 20 were evaluable for response. Seventeen received one course and 3 received two course of IST. The overall response to IST was seen in 14/20 (70%). Only two achieved complete response while remaining 12 had partial response. The 4-year estimated OS and EFS for children treated with IST was 74.4 ± 12.1% and 65.6 ± 12.2. Conclusion: Outcomes for children with AA are encouraging in the developing world although barriers like sepsis and treatment abandonment remain. BMT offers faster and complete recovery.