Hemolysis in Early Infancy: Still a Cause of Cholestatic Neonatal Giant Cell Hepatitis.

Before the prophylactic use of anti-D antibodies in pregnancy, hemolytic anemia of the newborn was the most common cause of hyperbilirubinemia. Nowadays, given the rarity of hemolytic anemia of the newborn, hepatobiliary abnormalities, perinatal infections, and metabolic disorders have become the most common conditions in the differential diagnosis of neonatal cholestasis. Here, we report 3 instances of cholestatic giant cell hepatitis in 3 infants who had Coombs' positive hemolysis due to ABO incompatibility in 1, Rh incompatibility in another, and combined ABO and Rh incompatibility in the third. Although rare, cholestatic neonatal giant cell hepatitis associated with hemolysis still needs to be considered in patients with neonatal cholestasis. A marked elevation of aspartate aminotransferase over alanine aminotransferase can be a helpful clue to an early diagnosis.

Primary Lung Cribriform Adenocarcinoma With Squamoid Morules Harboring Somatic CTNNB1 Mutation in a Never-Smoked Healthy Adolescent.

Primary lung adenocarcinomas are rare in pediatric patients, and even rarer in patients without precedent malignancy or congenital malformation. Here we present the first reported case of primary lung cribriform adenocarcinoma with squamoid morules in a previously healthy adolescent female. Molecular testing identified CTNNB1 mutation in the tumor and excluded other common mutations in lung adenocarcinoma. Our case suggests molecular alterations to the same signaling pathway can lead to similar histomorphology regardless of the tissue of origin.

Acquired thrombotic thrombocytopenic purpura in children: a single institution experience.

OBJECTIVE: To describe the clinical features, treatment and prognosis of acquired thrombotic thrombocytopenic purpura (TTP) in children based on a single institution experience. METHODS: This study is a retrospective review of all 12 children with TTP seen at New York Medical College- Westchester Medical Center during a period of 15 y from 1993 to 2008. RESULTS: There were 7 females and 5 males with acquired TTP, with a median age of 13 (range, 6-17); and no cases of congenital TTP. The classic pentad of TTP (microangiopathic hemolytic anemia, thrombocytopenia, neurologic symptoms, renal dysfunction and fever) was seen in only three patients. Nine had renal involvement; eight had neurologic symptoms; and four had fever. All 12 patients had thrombocytopenia, anemia, and elevated LDH. Nine had idiopathic TTP. Three patients had one of the following underlying disorders: systemic lupus erythematosus, mixed connective tissue disorder, and aplastic anemia (post-bone marrow transplant on cyclosporine). ADAMTS13 level was decreased in 7 of 8 patients studied. Eight of 10 patients achieved remission with plasmapheresis alone. Two needed additional treatment before achieving remission. Two had one or more relapses, requiring immunosupressive treatment with vincrisine, prednisone, or rituximab. The patient with aplastic anemia died of pulmonary hypertension 5 y after bone marrow transplantation. All other 11 patients are alive and free of TTP for a median follow-up of 12 mo (range, 3-72 mo). CONCLUSIONS: Acquired pediatric TTP responds well to plasmapheresis. However, many patients do require additional treatment because of refractoriness to plasmapheresis or relapse. The clinical features, response to treatment, and relapse rate of pediatric TTP appear similar to those of adult TTP.

Urinary tract infections in pediatric oncology patients with fever and neutropenia.

The relevancy of the urinary tract as a source of infection during febrile neutropenia is not known. The authors sought to determine the frequency of urinary tract infections (UTIs) in pediatric cancer patients with febrile neutropenia. Urine was collected from a mid-stream void before the administration of antibiotics. Demographic, clinical, and laboratory data were collected. The frequency of UTI and usefulness of urinalysis and localizing signs in predicting UTI in pediatric cancer patients with fever and neutropenia were determined. Forty-five patients had 58 febrile neutropenic episodes eligible for study participation. No patient presented with localizing signs. The urinalysis was negative in 53 episodes and positive in 5 episodes. Four patients had 5 UTIs. The frequency of UTI was 8.6% (5 of 58 febrile neutropenia episodes). Four patients had bacteremia, none of whom had a UTI. The sensitivity, specificity, and negative predictive value of urinalysis was 40%, 94%, and 94%, respectively, and for localizing signs was undefined, 100%, and 91%, respectively. UTI is as common as bacteremia in the current pediatric cancer patients with fever and neutropenia. Urinalysis and urine culture should be obtained routinely as part of the diagnostic evaluation of patients with fever and neutropenia.

Hemophagocytic lymphohistiocytosis associated with necrotizing enterocolitis in premature newborns.

Hemophagocytic lymphohistiocytosis (HLH) is a systemic disease resulting from the excessive release of inflammatory cytokines by macrophages under prolonged antigenic stimulation. If untreated, it leads to multiorgan failure and death. Necrotizing enterocolitis (NEC) has not previously been associated with HLH. Here we report four preterm infants who were diagnosed with HLH associated with NEC. Two patients received chemotherapy and one survived. The other two infants succumbed to multiorgan failure. These results suggest that NEC may be a common clinical manifestation of HLH in premature neonates.

Managing incidentally diagnosed isolated factor VII deficiency perioperatively: a brief expert consensus report.

While isolated factor VII (FVII) deficiency is being more frequently diagnosed owing to improved preoperative screening procedures, there is no specific guideline for perioperative management of such patients. To complicate the issue, FVII activity levels seem to correlate less well with the risk of hemorrhage than the patient's past and family bleeding history do. We have devised expert consensus recommendations for managing such patients perioperatively, taking into consideration the personal and family bleeding history, the FVII activity level and the inherent bleeding risk of the procedure itself. We hope that clinicians will find this a useful tool in the decision-making process, thereby limiting the use of recombinant factor VIIa to those who need it most, and preventing possible thrombotic complications in those without a strong indication for its use.

Rituximab therapy to prevent relapse in chronic relapsing thrombotic thrombocytopenic purpura (TTP) in a child.

Our patient first developed thrombotic thrombocytopenic purpura (TTP) at age 10 years with an initial platelet count of 10,000/microL. She achieved remission with plasmapheresis (PE), but suffered 2 relapses in the next 2 years, each approximately 1 year from PE, with ADAMTS13 levels of <5%. Early in her third remission, with vincristine (weekly x 4 doses) and prednisone (for 2 weeks) her ADAMTS13 increased to 99% in 24 weeks, but decreased to <4% in the next 38 weeks. After 4 weekly doses of rituximab (375 mg/m(2)), her ADAMTS13 level reached 101% in 9 weeks and has remained consistently above 97% on bimonthly monitoring for more than a year. She remains in continuous clinical and hematologic remission with an ADAMTS13 level of 108% at 60 weeks from rituximab therapy and 124 weeks from her second relapse. This case report suggests that monitoring ADAMTS13 level at regular intervals in recurrent TTP may help us identify patients at risk for further relapse; and such a relapse may be prevented, or at least delayed with timely rituximab therapy, thus reducing morbidity from relapsed TTP and its treatment.

DNA damage response as a biomarker in treatment of leukemias.

Early assessment of cancer response to the treatment is of great importance in clinical oncology. Most antitumor drugs, among them DNA topoisomerase (topo) inhibitors, target nuclear DNA. The aim of the present study was to explore feasibility of the assessment of DNA damage response (DDR) as potential biomarker, eventually related to the clinical response, during treatment of human leukemias. We have measured DDR as reported by activation of ATM through its phosphorylation on Ser 1981 (ATM-S1981(P)) concurrent with histone H2AX phosphorylation on Ser139 (gammaH2AX) in leukemic blast cells from the blood of twenty patients, 16 children/adolescents and 4 adults, diagnosed with acute leukemias and treated with topo2 inhibitors doxorubicin, daunomycin, mitoxantrone or idarubicin. Phosphorylation of H2AX and ATM was detected using phospho-specific Abs and measured in individual cells by flow cytometry. The increase in the level of ATM-S1981(P) and gammaH2AX, varying in extent between the patients, was observed in blasts from the blood collected one hour after completion of the drug infusion with respect to the pre-treatment level. A modest degree of correlation was observed between the induction of ATM activation and H2AX phosphorylation in blasts of individual patients. The number of the studied patients (20) and the number of the clinically non-responding ones (2) was too low to draw a conclusion whether the assessment of DDR can be clinically prognostic. The present findings, however, demonstrate the feasibility of assessment of DDR during the treatment of leukemias with drugs targeting DNA.

Cleft palate, bilateral external auditory canal atresia, and other midline defects associated with Diamond-Blackfan anemia: case report.

Diamond-Blackfan anemia (DBA) is associated with congenital anomalies especially of the midline. When present, facial anomalies are reminiscent of Treacher-Collins syndrome, and both DBA and Treacher-Collins syndrome are disorders of ribosomal biogenesis. Herein, we describe a female infant with multiple midline defects associated with DBA and reaffirm the absence of RPS-19 mutations in DBA patients with facial anomalies.

Neuroblastoma masquerading as cervical lymphadenitis.

Cervical lymphadenitis is a common pediatric finding prompting medical evaluation. The most common etiologies are infectious and reactive. The location of the involved lymph node group may provide clues to the origin of the underlying pathologic process. We describe a 21-month-old boy with metastatic neuroblastoma who presented with classic findings of infectious lymphadenitis. Surgical intervention and careful examination of histopathology led to this unexpected diagnosis.

Recurrent immune thrombocytopenic purpura in children.

Recurrent immune thrombocytopenic purpura (ITP) is defined as the recurrence of ITP after at least 3 months of remission sustained without treatment. Among 340 children with ITP, 14 had recurrent ITP (4.1%). Ten were females. The initial course was acute in 8 patients and chronic in 6. The median time to recurrence was 33 months (range 4-120). Only 1 patient had a second recurrence. Twelve (86%) achieved complete (n = 10) or partial (n = 2) remission, two of them after splenectomy. One patient continued to require treatment at 10 months from recurrence. One child died of intracranial hemorrhage despite aggressive treatment including splenectomy and craniotomy.

The safety of central line placement prior to treatment of pediatric acute lymphoblastic leukemia.

BACKGROUND: Central venous lines are placed in children with acute lymphoblastic leukemia at diagnosis, despite significant cytopenias, to facilitate the administration of chemotherapy and blood sampling. The present study aimed to determine the safety of central line placement in these patients. METHODS: We reviewed the charts of 115 consecutive patients treated during a 10-year period. Data abstracted comprised age, gender, presenting and preoperative blood counts, type of central line, blood products transfused preoperatively, duration of neutropenia (absolute neutrophil count [ANC], <500/microl), treatment, and central line-associated complications. RESULTS: There were 66 male and 49 female patients with a median age of 4 years. Seventy-one patients were classified as standard-risk and 44 as high-risk. Respective median blood counts at diagnosis and prior to surgery were white cell count (microl), 4,200 and 5,550; hemoglobin (g/dl), 7.7 and 9.4; platelet count (microl), 63,000 and 72,000; and ANC (microl), 3,950 and 4,900. The median duration of neutropenia was 15 days in the standard-risk group and 18 days in the high-risk group. Thirty-eight patients were not transfused preoperatively. There were no episodes of bacteremia. Seven patients (7%) with life-ports experienced a complication: in four blood could not be aspirated, two ports needed realignment, and one a wound infection developed without dehiscence. Four patients (27%) with external lines had a complication: one each with line occlusion, accidental removal by patient, line rupture, and line leakage at insertion site. The complication rate between ports and external lines was different (P = 0.045). CONCLUSIONS: Central line placement prior to anti-leukemia treatment is safe. Most complications are mechanical and not due to leukemia, chemotherapy, or cytopenias.

GATA1 as a new target to detect minimal residual disease in both transient leukemia and megakaryoblastic leukemia of Down syndrome.

Acquired mutations in exon 2 of the GATA1 gene are detected in most Down syndrome (DS) patients with transient leukemia (TL) and acute megakaryoblastic leukemia (AMKL). We sought to determine if GATA1 mutations can be utilized as markers for minimal residual disease (MRD). GATA1 mutations were screened by SSCP analysis and sequenced. Using GATA1 mutation-specific primers, follow-up bone marrow samples from four patients were assayed by quantitative PCR. We show that molecular monitoring of GATA1 mutations is possible in Down syndrome patients with TL and AMKL, and GATA1 could be a stable marker for MRD monitoring.

Detection of central nervous system leukemia in children with acute lymphoblastic leukemia by real-time polymerase chain reaction.

Accurate detection of central nervous system (CNS) involvement in children with newly diagnosed acute lymphoblastic leukemia (ALL) could have profound prognostic and therapeutic implications. We examined various cerebrospinal fluid (CSF) preservation methods to yield adequate DNA stability for polymerase chain reaction (PCR) analysis and developed a quantitative real-time PCR assay to detect occult CNS leukemia. Sixty CSF specimens were maintained in several storage conditions for varying amounts of time, and we found that preserving CSF in 1:1 serum-free RPMI tissue culture medium offers the best stability of DNA for PCR analysis. Sixty CSF samples (30 at diagnosis and 30 at the end of induction therapy) from 30 children with ALL were tested for CNS leukemic involvement by real-time PCR using patient-specific antigen receptor gene rearrangement primers. Six of thirty patient diagnosis samples were PCR-positive at levels ranging from 0.5 to 66% leukemic blasts in the CSF. Four of these patients had no clinical or cytomorphological evidence of CNS leukemia involvement at that time. All 30 CSF samples drawn at the end of induction therapy were PCR-negative. The data indicate that real-time PCR analysis of CSF is an excellent tool to assess occult CNS leukemia involvement in patients with ALL and can possibly be used to refine CNS status classification.

Long-term outcome of chronic idiopathic thrombocytopenic purpura in children.

OBJECTIVES: Children with chronic idiopathic thrombocytopenic purpura (ITP) generally have a favorable outcome, but it is not known whether there are any prognostic factors to predict outcome. The objectives of this study were to assess the spontaneous remission rate and the prognostic significance of age, gender, initial platelet count, initial treatment, and response to treatment. METHODS: In this retrospective review of 62 consecutive children with chronic ITP, 37 were girls and 27 were 10 years of age or older (median age 9 years; range, 0.75-19). RESULTS: Thirty-five patients (56%) achieved spontaneous remission (remission without splenectomy), 30 of them (48%) within 4 years from diagnosis. Twenty-eight (45%) were complete remissions (platelet counts of >/=100,000) and 7 (11%) were partial remissions (50,000-99,000). There was no significant difference in the spontaneous remission rate between the younger (<10 years) and older children (55.8% vs. 57.1%, P = 0.95) or between boys and girls (56% vs. 56.7%, P = 0.98). Similarly, platelet count at initial diagnosis, initial therapy, or response to initial therapy did not have any prognostic significance. All 14 patients who underwent splenectomy achieved complete remission. CONCLUSIONS: More than 50% of children with chronic ITP achieve spontaneous remission. Age, gender, platelet count at initial diagnosis, initial treatment, and response to initial treatment do not have any prognostic significance toward the outcome of chronic ITP.

Clinical features and treatment outcomes of 79 infants with immune thrombocytopenic purpura.

BACKGROUND: To determine the clinical features and treatment outcomes of infants with immune thrombocytopenic purpura (ITP). METHODS: Retrospective analysis of 79 infant ITP patients treated from 1987 to 2002. The data abstracted comprised age, gender, clinical features, and treatment outcomes. A score test for the trend in the odds ratios was used to determine the risk of chronic ITP with advancing age. The infants were compared to a group of contemporaneous older children with regard to bleeding severity and incidence of chronic ITP. RESULTS: The 34 female and 45 male infants had a median age of 16 months. Seventy-four presented with purpura, four with viral illnesses, and one was asymptomatic. Eight percent had active mucosal bleeding. The median platelet count was 8,000/microl. Forty infants received intravenous immunoglobulin, nine intravenous anti-D immunoglobulin, six steroids, and seven were observed without treatment. Fifty-five (76%) responded to a single course of treatment. Only 9% of infants developed chronic ITP compared to 18% of children between the ages of 25 and 119 months and 47% of children 120 months or older (P<0.0005). CONCLUSIONS: Infants with ITP respond favorably to treatment and are less likely to develop chronic ITP compared to older children.

A pilot trial of tandem autologous peripheral blood progenitor cell transplantation following high-dose thiotepa and carboplatin in children with poor-risk central nervous system tumors.

This is a pilot study performed to determine the maximum tolerated number of courses of high-dose thiotepa and carboplatin with autologous peripheral blood progenitor cell (PBPC) transplantation in poor-risk pediatric central nervous system (CNS) tumor patients. Twelve patients were enrolled and a total of 24 PBPC transplants were performed. The median age was 7.7 years. All patients had CNS tumors: 4 relapsed CNS PNET, 2 high-risk PNET in first remission, 2 relapsed/progressive brainstem tumor, 2 relapsed/progressive anaplastic astrocytoma, 1 relapsed GBM, and 1 recurrent ependymoma. The regimen consisted of thiotepa 250 mg/m2/day x 3 days and carboplatin 400 mg/m2/day x 3 days. No toxic deaths occurred. All patients were hospitalized for a median duration of 17 days. The median number of CD34 cells infused was 5.4 x 10(6)/kg (2.1-29.7 x 10(6)/kg) per course. Median time to ANC > 0.5 x 10(9)/L was 9 days, and platelets > 20 x 10(9)/L was 13.5 days. Four patients came off protocol after only one course of PBPC (2 had tumor progression, 2 parental choice); 4 patients underwent two, and 4 patients three courses of PBPC. Major nonhematologic complications were mucositis that necessitated infusion of narcotics (11/24 courses), fever of unknown origin (12/24), documented infection (9/24), and hemorrhagic cystitis (3/24). TPN was administered during 22 of 24 courses with a median duration of 15 days. It isfeasible to administer 2-3 courses of tandem high-dose thiotepa and carboplatin with PBPC transplant with prompt engraftment and manageable toxicities in pediatric CNS tumor patients.

Use of vincristine and cyclosporine in childhood thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening hematologic disorder in children. Plasmapheresis, the standard therapy for TTP, is effective in achieving remission in most patients. However, some patients become either refractory to or dependent upon plasmapheresis. The authors report three such patients in whom the use of vincristine or vincristine plus cyclosporine resulted in permanent remission. A 12-year-old girl with TTP dependent on plasmapheresis for more than 5 months responded to vincristine with a decrease in the required frequency of plasmapheresis, but the addition of cyclosporine abrogated the need for further plasmapheresis. She subsequently developed serologic evidence of systemic lupus erythematosus. Two 15-year-old boys with TTP (one of them with underlying mixed connective tissue disease) became refractory to plasmapheresis after a brief initial response. The addition of vincristine in one patient and vincristine and cyclosporine in the second (with mixed connective tissue disease) led to complete remission. The authors' experience in this case study of three patients suggests that vincristine and cyclosporine are effective agents in the management of patients with TTP who do not achieve complete remission with plasmapheresis alone.