Recurrent Skin Langerhan Cell Histiocytosis Successfully Treated With Indomethacin Monotherapy.

Langerhans cell histiocytosis (LCH) often has a recurrent and refractory course despite multiagent treatment modalities. Common relapse treatments include intense or prolonged cytotoxic chemotherapy regimens. There are a few prior reports that the nonsteroidal anti-inflammatory drug indomethacin demonstrated activity against bone LCH. Here we report indomethacin as a successful treatment for a case of chronic skin LCH that failed multiple prior chemotherapy regimens. This experience supports the need for trials to investigate indomethacin as a treatment for LCH both in the relapsed or refractory setting as well as potential combination or maintenance therapy in newly diagnosed patients.

Whole exome sequencing identified sixty-five coding mutations in four neuroblastoma tumors.

Neuroblastoma is a pediatric tumor characterized by histologic heterogeneity, and accounts for ~15% of childhood deaths from cancer. The five-year survival for patients with high-risk stage 4 disease has not improved in two decades. We used whole exome sequencing (WES) to identify mutations present in three independent high-risk stage 4 neuroblastoma tumors (COA/UAB-3, COA/UAB -6 and COA/UAB -8) and a stage 3 tumor (COA/UAB-14). Among the four tumors WES analysis identified forty-three mutations that had not been reported previously, one of which was present in two of the four tumors. WES analysis also corroborated twenty-two mutations that were reported previously. No single mutation occurred in all four tumors or in all stage 4 tumors. Three of the four tumors harbored genes with CADD scores ≥20, indicative of mutations associated with human pathologies. The average depth of coverage ranged from 39.68 to 90.27, with >99% sequences mapping to the genome. In summary, WES identified sixty-five coding mutations including forty-three mutations not reported previously in primary neuroblastoma tumors. The three stage 4 tumors contained mutations in genes encoding protein products that regulate immune function or cell adhesion and tumor cell metastasis.

Pediatric Anaplastic Embryonal Rhabdomyosarcoma: Targeted Therapy Guided by Genetic Analysis and a Patient-Derived Xenograft Study.

Therapy for rhabdomyosarcoma (RMS) has generally been limited to combinations of conventional cytotoxic agents similar to regimens originally developed in the late 1960s. Recently, identification of molecular alterations through next-generation sequencing of individual tumor specimens has facilitated the use of more targeted therapeutic approaches for various malignancies. Such targeted therapies have revolutionized treatment for some cancer types. However, malignancies common in children, thus far, have been less amenable to such targeted therapies. This report describes the clinical course of an 8-year-old female with embryonal RMS having anaplastic features. This patient experienced multiple relapses after receiving various established and experimental therapies. Genomic testing of this RMS subtype revealed mutations in BCOR, ARID1A, and SETD2 genes, each of which contributes to epigenetic regulation and interacts with or modifies the activity of histone deacetylases (HDAC). Based on these findings, the patient was treated with the HDAC inhibitor vorinostat as a single agent. The tumor responded transiently followed by subsequent disease progression. We also examined the efficacy of vorinostat in a patient-derived xenograft (PDX) model developed using tumor tissue obtained from the patient's most recent tumor resection. The antitumor activity of vorinostat observed with the PDX model reflected clinical observations in that obvious areas of tumor necrosis were evident following exposure to vorinostat. Histologic sections of tumors harvested from PDX tumor-bearing mice treated with vorinostat demonstrated induction of necrosis by this agent. We propose that the evaluation of clinical efficacy in this type of preclinical model merits further evaluation to determine if PDX models predict tumor sensitivity to specific agents and/or combination therapies.

Phenotypes of allo- and autoimmune antibody responses to FVIII characterized by surface plasmon resonance.

Evidence of antibody isotype/subtype switching may provide prognostic value regarding the state of immune responses to therapeutic proteins, e.g. anti-factor VIII (FVIII) antibodies that develop in many hemophilia A patients, clinically termed "inhibitors". A sensitive, high- information-content surface plasmon resonance (SPR) assay has been developed to quantify IgG subtype distributions and the domain specificity of anti-drug antibodies. Plasma samples from 22 subjects with an allo- or auto-immune reaction to FVIII were analyzed. Pre-analytical treatment protocols were developed to minimize non-specific binding and specific matrix interference due to von Willebrand factor-FVIII interactions. The dynamic range for IgG quantification was 0.2-5 µg/ml (∼1-33 nM), allowing characterization of inhibitor-positive samples. Subtype-specific monoclonal antibodies were used to quantify the IgG subtype distribution of FVIII-specific antibodies. Most samples obtained from multiply-infused inhibitor subjects contained IgG4 antibodies. Several distinct phenotypes were assigned based on the IgG subtype distribution: IgG1, IgG4, IgG1 & IgG4, and IgG1, IgG2 & IgG4. An IgG1-only response was found in mild/moderate HA subjects during early FVIII infusions, and analysis of serial samples followed antibody class switching as several subjects' immune responses developed. Competition studies utilizing a recombinant FVIII-C2 domain indicated 40-80% of FVIII-specific antibodies in most samples were directed against this domain.

Chemotherapy medication errors in a pediatric cancer treatment center: prospective characterization of error types and frequency and development of a quality improvement initiative to lower the error rate.

BACKGROUND: Chemotherapy medication errors occur in all cancer treatment programs. Such errors have potential severe consequences: either enhanced toxicity or impaired disease control. Understanding and limiting chemotherapy errors are imperative. PROCEDURE: A multi-disciplinary team developed and implemented a prospective pharmacy surveillance system of chemotherapy prescribing and administration errors from 2008 to 2011 at a Children's Oncology Group-affiliated, pediatric cancer treatment program. Every chemotherapy order was prospectively reviewed for errors at the time of order submission. All chemotherapy errors were graded using standard error severity codes. Error rates were calculated by number of patient encounters and chemotherapy doses dispensed. Process improvement was utilized to develop techniques to minimize errors with a goal of zero errors reaching the patient. RESULTS: Over the duration of the study, more than 20,000 chemotherapy orders were reviewed. Error rates were low (6/1,000 patient encounters and 3.9/1,000 medications dispensed) at the start of the project and reduced by 50% to 3/1,000 patient encounters and 1.8/1,000 medications dispensed during the initiative. Error types included chemotherapy dosing or prescribing errors (42% of errors), treatment roadmap errors (26%), supportive care errors (15%), timing errors (12%), and pharmacy dispensing errors (4%). Ninety-two percent of errors were intercepted before reaching the patient. No error caused identified patient harm. Efforts to lower rates were successful but have not succeeded in preventing all errors. CONCLUSIONS: Chemotherapy medication errors are possibly unavoidable, but can be minimized by thoughtful, multispecialty review of current policies and procedures. Pediatr Blood Cancer 2013;601320-1324. © 2013 Wiley Periodicals, Inc.

Pretreatment and routine echocardiogram monitoring during chemotherapy for anthracycline-induced cardiotoxicity rarely identifies significant cardiac dysfunction or alters treatment decisions: a 5-year review at a single pediatric oncology center.

BACKGROUND: The widespread use of anthracycline chemotherapy has contributed to improved outcomes in children with cancer. The most feared complication of the anthracyclines is cardiotoxicity. Routine echocardiographic monitoring typically is used before, during, and after treatment to minimize cardiotoxicity. The ideal use of screening before and during chemotherapy remains uncertain. METHODS: This was a retrospective review of children who were treated at a single cancer treatment center over 5 years. The results of all echocardiograms and related clinical decisions were reviewed. RESULTS: In 356 patients who were identified for review (age range, 3 months to 22 years; mean age, 10 years; median age, 11 years), 991 echocardiograms were reviewed (average, 2.78 echocardiograms per patient; median, 2 echocardiograms per patient; mode, 1; maximum, 11 echocardiograms per patient). Nine abnormal echocardiograms were identified (2.5% of patients and 0.9% of echocardiograms performed). Four echocardiograms were performed during episodes of septic shock, 2 echocardiograms represented false-positive studies after repeat evaluation, and 1 echocardiogram demonstrated mild abnormality of function on the day of surgical resection of a large Wilms tumor. None of the 356 pretreatment echocardiograms altered treatment decisions. In 635 follow-up echocardiograms during treatment, cardiac defects were detected in 2 patients (0.5%). CONCLUSIONS: The routine use of echocardiograms to screen for anthracycline-induced cardiac damage before and during chemotherapy rarely identified significant cardiac damage to impact treatment decisions. Improved screening techniques with better discrimination and predictability are needed. Pediatric Oncology cooperative groups should consider a revision of standard monitoring protocols before and during treatment.

Venous thromboembolism in pediatric patients: epidemiologic data from a pediatric tertiary care center in Alabama.

Venous thrombosis is an infrequent but serious cause of hospitalization in children. The epidemiology and natural history remains incompletely defined, especially in geographically distinct regions of the United States. We thus evaluated thrombosis in a single children's hospital over a 3-year period. Of 41,906 hospitalizations, 92 children were identified for review. The incidence of thrombosis was 21.9 per 10,000 admissions (0.22%). Venous thrombosis was of equal incidence in African-American and white patients. Locations of thrombosis included deep venous (51%), pulmonary (21%), renal vein (8%), intrahepatic (8%), and intracranial (12%). Risk factors for thrombosis included central catheter (32%), malignancy (18%), systemic infection (21%), neurologic disability (9%), cardiac (4%), nephrotic syndrome (3%), and autoimmune (6%). Six of 92 patients (7%) had thrombophilia. Positive family history of venous thromboembolism (VTE) or thrombophilic disorder predicted an abnormal test. Treatment included low-molecular-weight heparin (n=53), coumadin (n=12), heparin (n=10), tissue plasminogen activator (n=6), argatroban (n=1), thrombectomy (n=2), inferior vena cava filter (n=2), and no treatment (n=23). Seventy-seven percent demonstrated resolution of the VTE, 14% had persistent or recurrent VTE, and 9% died. Causes of death were malignancy, prematurity, septicemia, and congenital heart disease. Venous thrombosis is a serious comorbidity in hospitalized children. In our population, African-Americans had an equal incidence of VTE as whites. Positive family history predicted thrombophilia.

Inhibitors of factor VIII in black patients with hemophilia.

BACKGROUND: Black patients with hemophilia A (factor VIII deficiency) are twice as likely as white patients to produce inhibitors against factor VIII proteins given as replacement therapy. There are six wild-type factor VIII proteins, designated H1 through H6, but only two (H1 and H2) match the recombinant factor VIII products used clinically. H1 and H2 are found in all racial groups and are the only factor VIII proteins found in the white population to date. H3, H4, and H5 have been found only in blacks. We hypothesized that mismatched factor VIII transfusions contribute to the high incidence of inhibitors among black patients. METHODS: We sequenced the factor VIII gene (F8) in black patients with hemophilia A to identify causative mutations and the background haplotypes on which they reside. Results from previous Bethesda assays and information on the baseline severity of hemophilia, age at enrollment, and biologic relationships among study patients were obtained from review of the patients' medical charts. We used multivariable logistic regression to control for these potential confounders while testing for associations between F8 haplotype and the development of inhibitors. RESULTS: Of the 78 black patients with hemophilia enrolled, 24% had an H3 or H4 background haplotype. The prevalence of inhibitors was higher among patients with either of these haplotypes than among patients with haplotype H1 or H2 (odds ratio, 3.6; 95% confidence interval, 1.1 to 12.3; P=0.04), despite a similar spectrum of hemophilic mutations and degree of severity of illness in these two subgroups. CONCLUSIONS: These preliminary results suggest that mismatched factor VIII replacement therapy may be a risk factor for the development of anti-factor VIII alloantibodies.

Group A streptococcal infection of an intramuscular venous malformation: a case report and review of the literature.

Intramuscular venous malformations are uncommon benign masses of vascular origin that can occur anywhere in the body. They can be small and clinically insignificant or can be large and violate tissue planes and viscera. Presentation is as variable as the extent of the lesions. They can be diagnosed as a result of local pain and swelling or as incidental findings. Rarely, venous malformations can get infected and present with fever or other more severe systemic symptoms. The literature is sparse regarding infection of intramuscular venous malformations. This case describes the presentation, diagnosis, and management of a patient with group A streptococcal infection of a previously undiagnosed intramuscularvenous malformation in a patient who presented to our pediatric emergency department.

The use of recombinant factor VIIa in a patient with Noonan syndrome and life-threatening bleeding.

OBJECTIVE: To present a case report of a patient with Noonan syndrome who developed life-threatening gastrointestinal bleeding shortly after cardiac surgery that was successfully treated with recombinant factor VIIa. DESIGN: Case report. SETTING: Pediatric intensive care unit of a children's hospital. PATIENT: Ten-month-old with Noonan syndrome and massive gastrointestinal bleeding resulting in severe hypovolemic shock. INTERVENTIONS: Recombinant factor VIIa was used in this patient's severe bleeding associated with Noonan syndrome after no other supportive measures were successful. MEASUREMENTS AND MAIN RESULTS: Recombinant Factor VIIa significantly decreased the patient's bleeding and allowed his hypovolemic shock to improve. Ultimately, the patient made a complete recovery. CONCLUSIONS: Noonan syndrome has a constellation of both cardiac and noncardiac malformations including an increased risk of bleeding, and recombinant factor VIIa is an important agent in the treatment of significant bleeding.

Successful use of recombinant factor VIIa for emergency fasciotomy in a patient with hemophilia A and high-titer inhibitor unresponsive to factor VIII inhibitor bypassing activity.

We report a patient with hemophilia A and high-titer factor VIII inhibitor who developed compartment syndrome of his forearm following trauma. Emergency fasciotomy was performed. Initial hemostatic treatment with factor VIII inhibitor bypassing activity (FEIBA) was unsuccessful. Bleeding was controlled with recombinant factor VIIa.

Idiopathic thrombocytopenic purpura: a 10-year natural history study at the childrens hospital of alabama.

Childhood idiopathic thrombocytopenic purpura (ITP) is a common disorder. However, single-institution, long-term, natural history data are limited. The objective of this paper is to review presenting features, response to therapy, and natural history of ITP treated at a single pediatric academic medical center. A retrospective chart review was made for all children (ages birth-18 years) diagnosed with ITP (ICD 287.3) and treated at the Childrens Hospital of Alabama/University of Alabama at Birmingham between 1993 and 2003. Four hundred nine patients were identified (49% male, 51% female; mean age: 5.85 years; range: 1 month-17 years). There was no seasonal variation of presentation. The mean platelet count was 19k (0-120k). Bone marrow aspiration (BMA) was performed in 72% but altered the diagnosis or therapy in no patient. Treatment consisted of corticosteroids in 256 (92% response), intravenous immunoglobulin (IVIG) in 125 (87% response), Win-Rho D in 58 (91% response), and no therapy in 71 (100% response). Response was defined as increase in platelet count to > 50k. There was no difference in response to any therapy. No patients died. One patient presented with a CNS hemorrhage at presentation, responded to therapy, and survived. Twenty-three of 409 patients (6%) experienced clinical bleeding requiring hospitalization or blood transfusion. Chronic ITP (persistence > 6 months) was noted in 99 patients (24%). Chronic patients presented at an older age (7.8 vs 5.2 years for acute only, p<0.001), and with higher platelet counts (27k vs 17k, p<0.001). The risk of chronic ITP was partially predicted by presenting platelet count > 50k and age > 10 years, or both; 50% of patients presenting with these features developed chronic ITP vs 24% overall rate. Splenectomy was curative in 30/31 (97%) patients. There was no postsplenectomy sepsis. Of 99 patients with chronic ITP, 25 responded to splenectomy, 37 resolved at a mean of 20.3 months after diagnosis (7-96 months), 36 had persistent mild thrombocytopenia (50k-125k), and 1 failed to respond to any treatment including splenectomy. Overall, 91% of cases resolved with therapy or observation. ITP is a common pediatric disease presenting at any age with low morbidity and mortality. Most cases can be managed by pediatricians without hematology referral. Several equally successful therapeutic options exist. Chronic cases present at an older age with higher platelet counts. Up to 50% of cases of chronic ITP will resolve with ongoing follow-up. The overall prognosis in childhood ITP is excellent.

Tailored chemotherapy for malignant lymphoma arising in the setting of posttransplant lymphoproliferative disorder after solid organ transplantation.

Posttransplant lymphoproliferative disorder is a clinical challenge. Traditional chemotherapy results in tumor response, but toxicity and transplant rejection limit survival. The authors treated seven patients with malignant lymphoma after organ transplant with chemotherapy tailored to individual patient response. Chemotherapy consisted of vincristine, cyclophosphamide, and prednisone, with or without doxorubicin (Adriamycin; Pharmacia & Upjohn, Peapack, NJ, U.S.A.), or the ProMACE-CytaBOM regimen. Six of seven patients (86%) showed a complete response to treatment, with five of seven (71%) alive disease-free at 9 to 72 months (mean 38.2) after treatment. The results show that chemotherapy tailored to individual patient response is a safe and effective therapy for malignant lymphoma arising in patients with posttransplant lymphoproliferative disorder.

Severe hypophosphatemia: a rare cause of intravascular hemolysis.

A 3-year-old child presented with severe hyperphosphatemia (phosphate 45 mg/dL) secondary to chronic enema use. Following aggressive correction of the hyperphosphatemia, hypophosphatemia ensued (phosphate 1.7 mg/dL). Concurrently, the patient developed severe intravascular hemolysis and RBC morphologic defects. The hemolysis and morphologic defects corrected with return to normal serum phosphate levels. Severe hypophosphatemia is a rare cause of intravascular hemolysis.