Inflammatory myofibroblastic tumor of the liver in children.

Inflammatory pseudotumors, now more aptly termed inflammatory myofibroblastic tumors (IMTs), are uncommon benign neoplasms, which have been reported in most organs and tissues in the body. Originally described and commonly found in the lung, they are also found in the liver of children and adults. We review the literature and analyze the features of the hepatic IMTs reported in children, along with a case report of a 15-month-old boy who had a persistent IMT in the liver and underwent surgical resection for the same following a trial of conservative management.

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.

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.

NSC114792, a novel small molecule identified through structure-based computational database screening, selectively inhibits JAK3.

BACKGROUND: Human or animals lacking either JAK3 or the common gamma chain (gammac) expression display severe combined immunodeficiency disease, indicating the crucial role of JAK3 in T-cell development and the homeostasis of the immune system. JAK3 has also been suggested to contribute to the pathogenesis of tumorigenesis. Recent studies identified activating JAK3 mutations in patients with various hematopoietic malignancies, including acute megakaryoblastic leukemia. Importantly, functional analyses of some of those JAK3 mutations have been shown to cause lethal hematopoietic malignancies in animal models. These observations make JAK3 an ideal therapeutic target for the treatment of various human diseases. To identify novel small molecule inhibitors of JAK3, we performed structure-based virtual screen using the 3D structure of JAK3 kinase domain and the NCI diversity set of compounds. RESULTS: We identified NSC114792 as a lead compound. This compound directly blocked the catalytic activity of JAK3 but not that of other JAK family members in vitro. In addition, treatment of 32D/IL-2Rbeta cells with the compound led to a block in IL-2-dependent activation of JAK3/STAT5 but not IL-3-dependent activation of JAK2/STAT5. Consistent with the specificity of NSC114792 for JAK3, it selectively inhibited persistently-activated JAK3, but failed to affect the activity of other JAK family members and other oncogenic kinases in various cancer cell lines. Finally, we showed that NSC114792 decreases cell viability by inducing apoptosis through down-regulating anti-apoptotic gene expression only in cancer cells harboring persistently-active JAK3. CONCLUSIONS: NSC114792 is a lead compound that selectively inhibits JAK3 activity. Therefore, our study suggests that this small molecule inhibitor of JAK3 can be used as a starting point to develop a new class of drugs targeting JAK3 activity, and may have therapeutic potential in various diseases that are caused by aberrant JAK3 activity.

MS-1020 is a novel small molecule that selectively inhibits JAK3 activity.

In order to identify Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling inhibitors, a cell-based high throughput screening was performed using a plant extract library that identified Nb-(alpha-hydroxynaphthoyl)serotonin called MS-1020 as a novel JAK3 inhibitor. MS-1020 potently inhibited persistently-active STAT3 in a cell type-specific manner. Further examination showed that MS-1020 selectively blocked constitutively-active JAK3 and consistently suppressed interleukin-2-induced JAK3/STAT5 signalling but not prolactin-induced JAK2/STAT5 signalling. Furthermore, MS-1020 affected cell viability only in cancer cells harbouring persistently-active JAK3/STATs, and in vitro kinase assays showed MS-1020 binds directly with JAK3, blocking its catalytic activity. Therefore, the present study suggested that this reagent selectively inhibits JAK3 and subsequently leads to a block in STAT signalling. Finally, MS-1020 decreased cell survival by inducing apoptosis via down-regulation of anti-apoptotic gene expression. These results suggest that MS-1020 may have therapeutic potential in the treatment of cancers harbouring aberrant JAK3 signalling.

A small-molecule compound identified through a cell-based screening inhibits JAK/STAT pathway signaling in human cancer cells.

Inappropriate activation of JAK/STAT signaling occurs with high frequency in human cancers and is associated with cancer cell survival and proliferation. Therefore, the development of pharmacologic STAT signaling inhibitors has therapeutic potential in the treatment of human cancers. Here, we report 2-[(3,5-bis-trifluoromethyl-phenyl)-hydroxy-methyl]-1-(4-nitro-phenylamino)-6-phenyl-1,2,4a,7a-tetrahydro-pyrrolo[3,4-b]-pyridine-5,7-dione (AUH-6-96) as a novel small-molecule inhibitor of JAK/STAT signaling that we initially identified through a cell-based high-throughput screening using cultured Drosophila cells. Treatment of Drosophila cells with AUH-6-96 resulted in a reduction of Unpaired-induced transcriptional activity and tyrosine phosphorylation of STAT92E, the sole Drosophila STAT homologue. In human cancer cell lines, AUH-6-96 inhibited both constitutive and interleukin-6-induced STAT3 phosphorylation. Specifically, in Hodgkin lymphoma L540 cells, treatment with AUH-6-96 resulted in reduced levels of tyrosine phosphorylated STAT3 and of the STAT3 downstream target gene SOCS3 in a dose- and time-dependent manner. In addition, AUH-6-96-treated L540 cells showed decreased expression of persistently activated JAK3, suggesting that AUH-6-96 inhibits the JAK/STAT pathway signaling in L540 cells by affecting JAK3 activity and subsequently blocking STAT3 signaling. Importantly, AUH-6-96 selectively affected cell viability only of cancer cells harboring aberrant JAK/STAT signaling. In support of the specificity of AUH-6-96 for inhibition of JAK/STAT signaling, treatment with AUH-6-96 decreased cancer cell survival by inducing programmed cell death by down-regulating the expression of STAT3 downstream target antiapoptotic genes, such as Bcl-xL. In summary, this study shows that AUH-6-96 is a novel small-molecule inhibitor of JAK/STAT signaling and may have therapeutic potential in the treatment of human cancers harboring aberrant JAK/STAT signaling.

Early recognition of renal toxicity of high-dose methotrexate therapy: a case report.

A 10-year-old boy with osteosarcoma and normal renal function manifested laboratory evidence of impending renal toxicity and extreme elevation of aspartate aminotrasferase and alanine aminotransferase within 2 hours after the completion of a 4-hour infusion of high-dose methotrexate (MTX) (12 g/m2), and went on to develop acute renal failure with life-threatening hyperkalemia 29 hours later. Although his renal function recovered completely with high-dose leucovorin, hemodialysis, charcoal hemoperfusion, and carboxypeptidase G2, we present this case to emphasize that signs of renal toxicity may be present as early as 2 hours after the completion of a 4-hour MTX infusion, and to suggest that monitoring for MTX toxicity should perhaps begin within a few hours after the completion of 4-hour MTX infusion.

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.

ABVE-PC and modified BEACOPP regimen in Indian children with Hodgkin lymphoma: Feasibility and efficacy.

AIMS: To study the toxicity of ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide) and modified-BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) in intermediate-risk and high-risk Hodgkin lymphoma patients. METHODS: High-risk patients received 4 cycles of modified-BEACOPP (m-BEACOPP) plus 4 cycles of ABVD. Intermediate-risk patients received 4 cycles of ABVE-PC plus 2 cycles of ABVD. RESULTS: From 2010 to 2014, 17 patients received 66 cycles of m-BEACOPP and 9 patients received 40 cycles of ABVE-PC. In the m-BEACOPP and ABVE-PC courses, respectively, significant thrombocytopenia (<50,000/mm(3)) occurred in 10.6% vs 0% of courses; anemia (Hb. <8 gm/dl) in 27.3% vs 15%; neutropenia (ANC<500/mm(3)) in 46.9% vs 32.5%; and febrile neutropenia in 33.3% vs. 22.5%. Only episode of documented infection (hepatic abscess) occurred in ABVE-PC. There were no episodes of sepsis, typhlitis or pneumonia in either group. All 26 patients are in remission with a median follow-up of 35 months (range, 17-61); and there have been no relapses. Two of 26 (7.7%) patients failed to achieve rapid early response after 2 cycles and complete remission after 4 cycles of chemotherapy; both achieved remission with more intensive regimens followed by radiation. The remaining 24 patients did not receive radiation therapy. CONCLUSIONS: Both m-BEACOPP and ABVE-PC regimens have acceptable toxicity; and thus can be used in most centres with optimum supportive care facilities. They offer promising response rate and relapse free survival without the need for radiation therapy in most patients; and thus may be considered for children with high-risk and intermediate-risk Hodgkin lymphoma.

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.

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.

Low-dose rasburicase in hematologic malignancies.

OBJECTIVE: To define the efficacy and safety of low-dose rasburicase in children from south India with hematologic malignancies. METHODS: This study is a retrospective analysis of data on 41 children with hematologic malignacies with laboratory evidence of tumor lysis syndrome (TLS) or clinical features indicating high risk for developing TLS. Patients were treated with rasburicase in doses of 0.1-0.15 mg/kg dose, repeated when necessary. RESULTS: Male : Female ratio was 32:9. Thirty-six children had laboratory evidence of TLS and 5 were at risk for TLS. Diagnoses were T-cell acute lymphoblastic leukemia (ALL), 19; Pre-B ALL, 17; B-non-Hodgkin lymphoma (NHL), 2; T-NHL, 2; and acute myeloid leukemia (AML), 1. Initial plasma uric acid (PUA): median, 8.5 mg/dl (range, 4.3 to 45.5). Six had creatinine levels of >2 mg/dl on admission; and 10 had peak PO4 levels of >10 mg/dl. Dose of rasburicase used: median, 0.12 mg/kg (range, 0.08-0.24). Median reduction of PUA at 6 h: 80 % (range 40 to 98 %). Twenty-seven needed only one dose; 12 needed 2 or 3 doses; and two needed 5 doses each. One child required dialysis. None of the children developed anaphylaxis or hemolysis and there were no deaths from TLS. CONCLUSIONS: Low-dose rasburicase (0.1-0.15 mg/kg) is safe and effective in reducing PUA in Indian children with lymphoid malignancies, and thus it may reduce the risk of renal failure from TLS.

Fetal-type hepatoblastoma and del(3)(q11.2q13.2).

Hepatoblastoma is a rare embryonal malignancy of children. Trisomies or gains of chromosomes 1q, 2, 8, and 20 and a der(4)t(1;4)(q12;q34) have been described in hepatoblastoma. Herein, we describe a stage I fetal-type hepatoblastoma associated with a del(3)(q11.2q13.2).

Trends in diagnosis and management of iron deficiency during infancy and early childhood.

Iron deficiency remains a public health challenge. The neurocognitive deficits that are associated with iron deficiency are most worrisome. Moreover, iron deficiency-associated elevated blood lead levels magnify the problem. Pediatricians must strive to prevent iron deficiency.

Origin of a central nervous system lymphoid neoplasm in an immunocompromised host with acute lymphoblastic leukemia.

We describe a case of relapsed pediatric pre-B acute lymphoblastic leukemia (ALL) with a simultaneous presentation of an intracerebral lymphoid mass. Cytogenetic, immunophenotypic and molecular analysis (immunoglobulin heavy chain and T-cell receptor gene rearrangements) revealed that the brain neoplasm was distinct from the relapsed leukemia. We discuss the etiology of this extremely rare event, and raise issues about the clonality of lymphoid neoplasms and the behavior of hematopoietic cells within the central nervous system (CNS).

Neurotoxicity of intrathecal methotrexate: MR imaging findings.

We report a case of intrathecal methotrexate neurotoxicity manifesting as left arm weakness and aphasia. Diagnostic imaging showed restricted diffusion and fluid-attenuated inversion recovery imaging findings were normal at presentation. Three weeks later, diffusion abnormalities resolved, and T2-weighted studies showed increased signal intensity of prolonged T2 changes in areas of prior restricted diffusion. We attribute the clinical and radiographic findings to cytotoxic edema secondary to intrathecal methotrexate.

Perioperative management in children with sickle cell disease undergoing laparoscopic surgery.

OBJECTIVE: The aim of this study was to evaluate our experience with laparoscopic surgery in children with sickle cell disease. METHODS: A retrospective chart review was performed to analyze the indication for surgery, perioperative management, surgical technique, complications, duration of hospitalization, and outcome. One pediatric surgeon performed all procedures. RESULTS: Thirteen children underwent laparoscopic surgery for the following indications: symptomatic cholelithiasis/cholecystitis in 9; recurrent splenic sequestration in 3; and hypersplenism/symptomatic cholelithiasis in 1. The 7 boys and 6 girls had a median age of 7.8 years. Patients undergoing splenectomy only were younger than those undergoing cholecystectomy (median age, 3.6 years versus 11.5 years, respectively). Four children underwent endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy because of common bile duct dilatation and stones. Twelve patients received packed red blood cell transfusions prior to surgery. The median operative time was 150 minutes, and the median hospitalization was 3 days. Four patients suffered postoperative complications (2 with acute chest syndrome, 1 with recurrent abdominal pain, and 1 with priapism). The patient with abdominal pain was found to have a retained stone in the common bile duct, which was retrieved via endoscopic retrograde cholangiopancreatography and sphincterotomy. All complications resolved with medical management. CONCLUSIONS: Laparoscopic surgery is safe in children with sickle cell disease. Meticulous attention to perioperative management, transfusion guidelines, and pulmonary care may decrease the incidence of acute chest syndrome.

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.