Severe Methotrexate Toxicity Following a Capizzi Cycle in an Obese Adolescent With Acute Lymphoblastic Leukemia and Hepatic Steatosis.

Methotrexate is a major component of pediatric leukemia treatment. While toxicities are common after high-dose methotrexate, escalating dose methotrexate (Capizzi methotrexate) is typically well-tolerated. We report an adolescent Hispanic female with pre-B acute lymphoblastic leukemia, preexisting obesity and hepatic steatosis who developed severe multiorgan failure following an escalating dose of methotrexate with delayed methotrexate excretion of 11 days. We identified one similar report in an obese adult; however, this case is the first to our knowledge involving a pediatric patient. With the rising incidence of obesity and associated comorbidities among children and adolescents with leukemia, attention to potential risks for this population is warranted.

Comprehensive characterization of patient-derived xenograft models of pediatric leukemia.

Patient-derived xenografts (PDX) remain valuable models for understanding the biology and for developing novel therapeutics. To expand current PDX models of childhood leukemia, we have developed new PDX models from Hispanic patients, a subgroup with a poorer overall outcome. Of 117 primary leukemia samples obtained, successful engraftment and serial passage in mice were achieved in 82 samples (70%). Hispanic patient samples engrafted at a rate (51/73, 70%) that was similar to non-Hispanic patient samples (31/45, 70%). With a new algorithm to remove mouse contamination in multi-omics datasets including methylation data, we found PDX models faithfully reflected somatic mutations, copy-number alterations, RNA expression, gene fusions, whole-genome methylation patterns, and immunophenotypes found in primary tumor (PT) samples in the first 50 reported here. This cohort of characterized PDX childhood leukemias represents a valuable resource in that germline DNA sequencing has allowed the unambiguous determination of somatic mutations in both PT and PDX.

Genomic profiling of subcutaneous patient-derived xenografts reveals immune constraints on tumor evolution in childhood solid cancer.

Subcutaneous patient-derived xenografts (PDXs) are an important tool for childhood cancer research. Here, we describe a resource of 68 early passage PDXs established from 65 pediatric solid tumor patients. Through genomic profiling of paired PDXs and patient tumors (PTs), we observe low mutational similarity in about 30% of the PT/PDX pairs. Clonal analysis in these pairs show an aggressive PT minor subclone seeds the major clone in the PDX. We show evidence that this subclone is more immunogenic and is likely suppressed by immune responses in the PT. These results suggest interplay between intratumoral heterogeneity and antitumor immunity may underlie the genetic disparity between PTs and PDXs. We further show that PDXs generally recapitulate PTs in copy number and transcriptomic profiles. Finally, we report a gene fusion LRPAP1-PDGFRA. In summary, we report a childhood cancer PDX resource and our study highlights the role of immune constraints on tumor evolution.

Cultural Variations of Areca Nut Utilization and Its Availability in San Antonio, Texas.

Unknown in the U.S., areca nut (AN) is the fourth most used psychoactive substance in the world and is associated with oral cancers. We investigated the availability of AN in San Antonio ethnic grocery stores and assessed AN practices in immigrant communities. Grocery stores were contacted to assess AN availability. A survey on AN knowledge and utilization were administered at four community sites with large immigrant populations. 13 of the 19 identified grocery stores carried AN. Most survey participants (n = 66) recognized AN. Most Southeast Asians and South Asians knew what AN is, knew someone who uses it, and knew where to buy it. Most South Asian participants knew its harmful effects. AN usage is associated with older age, male sex, and recent immigration. AN is widely available and utilized among immigrant populations in San Antonio. Further work is needed to raise AN awareness among healthcare workers.

Pediatric Solid Tumor Care and Multidisciplinary Tumor Boards in Low- and Middle-Income Countries in Southeast Asia.

PURPOSE: Pediatric solid tumors require coordinated multidisciplinary specialist care. However, expertise and resources to conduct multidisciplinary tumor boards (MDTBs) are lacking in low- and middle-income countries (LMICs). We aimed to profile the landscape of pediatric solid tumor care and practices and perceptions on MDTBs among pediatric solid tumor units (PSTUs) in Southeast Asian LMICs. METHODS: Using online surveys, availability of specialty manpower and MDTBs among PSTUs was first determined. From the subset of PSTUs with MDTBs, one pediatric surgeon and one pediatric oncologist from each center were queried using 5-point Likert scale questions adapted from published questionnaires. RESULTS: In 37 (80.4%) of 46 identified PSTUs, availability of pediatric-trained specialists was as follows: oncologists, 94.6%; surgeons, 91.9%; radiologists, 54.1%; pathologists, 40.5%; radiation oncologists, 29.7%; nuclear medicine physicians, 13.5%; and nurses, 81.1%. Availability of pediatric-trained surgeons, radiologists, and pathologists was significantly associated with the existence of MDTBs (P = .037, .005, and .022, respectively). Among 43 (89.6%) of 48 respondents from 24 PSTUs with MDTBs, 90.5% of oncologists reported > 50% oncology-dedicated workload versus 22.7% of surgeons. Views on benefits and barriers did not significantly differ between oncologists and surgeons. The majority agreed that MDTBs helped to improve accuracy of treatment recommendations and team competence. Complex cases, insufficient radiology and pathology preparation, and need for supplementary investigations were the top barriers. CONCLUSION: This first known profile of pediatric solid tumor care in Southeast Asia found that availability of pediatric-trained subspecialists was a significant prerequisite for pediatric MDTBs in this region. Most PSTUs lacked pediatric-trained pathologists and radiologists. Correspondingly, gaps in radiographic and pathologic diagnoses were the most common limitations for MDTBs. Greater emphasis on holistic multidisciplinary subspecialty development is needed to advance pediatric solid tumor care in Southeast Asia.

Paraneoplastic Galactorrhea in Childhood T-ALL: An Evaluation of Tumor-derived Prolactin.

T-cell acute lymphoblastic leukemia (T-ALL) comprises 15% of childhood leukemia. Although multiagent pulse chemotherapy has improved event-free survival in recent decades, the lack of reliable prognosticators and high rate of relapse remain a challenge. Described is a novel discovery of tumor-derived hyperprolactinemia in childhood T-ALL through a case associated with paraneoplastic galactorrhea. Prolactin production by tumor cells, although a rare phenomenon, is previously demonstrated in several adult cancers and 2 pediatric malignancies with unknown implications. This is the first report demonstrating tumor-derived prolactin in pediatric T-ALL and offers potential as a disease marker and therapeutic drug target.

Fertility Preservation Counseling for Pediatric and Adolescent Cancer Patients.

PURPOSE: Fertility preservation for children and young adults with cancer is an important part of comprehensive patient care. In 2013, the American Society of Clinical Oncology (ASCO) released updated clinical practice guidelines addressing fertility preservation. This study aimed to evaluate if pediatric oncologists were performing fertility preservation counseling, if the new guidelines were being adopted, and how reproductive endocrinologists can educate this patient population and their providers. METHODS: A cross-sectional study was performed from May 26, 2014, to August 26, 2014. An online survey addressing fertility preservation practice patterns was created and provided to the members of the Children's Oncology Group (COG). RESULTS: Thirty-five percent of the 234 respondents reported reading the new 2013 ASCO guidelines. Ninety-five percent of providers reported mentioning fertility preservation options prior to treatment, most commonly including referral to a reproductive endocrinologist (28%), and sperm banking (57%). The most commonly reported barrier to fertility preservation counseling was the cost of treatment. CONCLUSION: Fertility preservation counseling is being performed by pediatric oncology providers. Familiarity of the ASCO guidelines is limited, revealing that the established methods for fertility preservation in women--embryo and oocyte cryopreservation--may be offered less than experimental methods in this younger patient population. Such differences in apparent practice patterns highlight the need for more education for providers.

Prophylactic eculizumab for kidney transplantation in a child with atypical hemolytic uremic syndrome due to complement factor H mutation.

We present a case of successful deceased-donor kidney transplantation in a three-yr-old child with aHUS due to complement factor H mutation, using only prophylactic eculizumab treatment prior to transplant. She developed disease exacerbation in the immediate post-operative period despite having therapeutic eculizumab concentrations and evidence for complete complement pathway blockade. The patient responded well to additional doses of eculizumab and has maintained excellent graft function and disease control in the first year post-transplantation. The optimal dosing scheme for eculizumab in the perioperative period remains to be determined. More sensitive biomarkers of early disease activity are needed to improve disease monitoring. Finally, the duration of eculizumab therapy in patients with aHUS remains to be determined.

Burkholderia cepacia septicemia in a pediatric oncology patient: a pharmacotherapy challenge.

OBJECTIVE: To discuss pharmacotherapy challenges encountered during treatment of a pediatric oncology patient with Burkholderia cepacia septicemia. CASE SUMMARY: An 11-year-old male with a history of aplastic anemia presented to the emergency department with a 1-day history of cough and purulent nasal discharge 6 months after undergoing bone marrow transplant. Blood cultures obtained from the patient's Broviac catheter revealed gram-negative rods. Piperacillin/tazobactam and tobramycin were administered, but the patient worsened clinically, with fever and chills. B. cepacia was identified as the offending pathogen, and the therapy was changed to meropenem and ciprofloxacin, as piperacillin/ tazobactam and tobramycin are ineffective against Burkholderia spp. Intravenous trimethoprim/sulfamethoxazole, the drug of choice for Burkholderia spp. infections, was unavailable as it had been placed on national manufacturer backorder. The patient improved initially, but he later experienced recurrence of fever, and blood culture results were positive for Burkholderia spp. Infection was eradicated after removal of the central line and administration of ceftazidime and oral minocycline. DISCUSSION: Literature reveals few cases of B. cepacia in pediatric oncology patients, and to our knowledge, no cases have been reported in bone marrow transplant patients in the US. Burkholderia spp. is highly resistant to many antibiotics, and commonly used agents for the empiric treatment of febrile neutropenia are not active against this organism. This indicates that most oncology patients who present with this infection would not receive appropriate initial treatment. In addition, antibiotic therapy may need to be modified, based on drug availability. CONCLUSIONS: B. cepacia is an emerging multidrug-resistant pathogen that can produce severe infection in immunocompromised patients. It is pertinent to consider this organism in oncology patients who do not improve with standard therapy, as prompt use of correct pharmacotherapy is necessary to avoid serious morbidity as well as mortality in this population.

Epidemiologic mapping of Florida childhood cancer clusters.

BACKGROUND: Childhood cancer remains the leading cause of disease-related mortality for children. Whereas, improvement in care has dramatically increased survival, the risk factors remain to be fully understood. The increasing incidence of childhood cancer in Florida may be associated with possible cancer clusters. We aimed, in this study, to identify and confirm possible childhood cancer clusters and their subtypes in the state of Florida. METHODS: We conducted purely spatial and space-time analyzes to assess any evidence of childhood malignancy clusters in the state of Florida using SaTScan. Data from the Florida Association of Pediatric Tumor Programs (FAPTP) for the period 2000-2007 were used in this analysis. RESULTS: In the purely spatial analysis, the relative risks (RR) of overall childhood cancer persisted after controlling for confounding factors in south Florida (SF) (RR = 1.36, P = 0.001) and northeastern Florida (NEF) (RR = 1.30, P = 0.01). Likewise, in the space-time analysis, there was a statistically significant increase in cancer rates in SF (RR = 1.52, P = 0.001) between 2006 and 2007. The purely spatial analysis of the cancer subtypes indicated a statistically significant increase in the rate of leukemia and brain/CNS cancers in both SF and NEF, P < 0.05. The space-time analysis indicated a statistically significant sizable increase in brain/CNS tumors (RR = 2.25, P = 0.02) for 2006-2007. CONCLUSIONS: There is evidence of spatial and space-time childhood cancer clustering in SF and NEF. This evidence is suggestive of the presence of possible predisposing factors in these cluster regions. Therefore, further study is needed to investigate these potential risk factors.

Loss of INI1 expression defines a unique subset of pediatric undifferentiated soft tissue sarcomas.

Malignant rhabdoid tumor has traditionally been defined by its histologic phenotype. However, genetic investigations of malignant rhabdoid tumor have revealed a characteristic loss of or mutation in the INI1 gene on chromosome 22q. The occurrence and significance of soft tissue tumors meeting genetic criteria for malignant rhabdoid tumor but with an undifferentiated non-rhabdoid histology is poorly characterized. Seventeen undifferentiated sarcomas, lacking rhabdoid histology were identified either through the surgical pathology files of The Children's Hospital of Philadelphia (1980-2005) or in consultation. Immunohistochemistry for the INI1 protein showed a loss of nuclear expression within tumor cells in five of these cases. On histologic review, these five tumors had a featureless sheet-like architecture; four were small round blue cell tumors, and one showed focal spindling. Although they had variably prominent nucleoli, classic rhabdoid morphologic features were not identified in any of these cases at primary presentation. Additional immunohistochemistry showed a polyphenotypic profile. Four of the five tumors showed genetic abnormalities involving the INI1 gene by a combination of fluorescent in situ hybridization, reverse transcription-polymerase chain reaction, and/or mutational analysis. Patient ages ranged from 1 week to 5 years. Four patients were male, and one was female. Sites included two neck tumors, two extremity tumors, and one paraspinal tumor. Two patients are alive and well over 15 years from the time of diagnosis; the remaining four are alive and well but with less than 2 years follow-up. Thus, alterations of the INI1 gene with consequent loss of expression identified a population of undifferentiated sarcomas lacking classic rhabdoid morphology in young patients, with evidence of favorable survival. Whether these undifferentiated sarcomas represent a clinicopathologic entity distinct from classic malignant rhabdoid tumor requires further investigation.

Androgen and c-Kit receptors in desmoplastic small round cell tumors resistant to chemotherapy: novel targets for therapy.

PURPOSE: Desmoplastic small round cell tumor (DSRCT) is a highly fatal, mainly peritoneal cell origin cancer which predominantly affects young adult males. This predilection in young males led us to examine the role of androgen receptors (AR), testosterone, and growth factors in the biology of DSRCT. METHODS: Slides were prepared from 27 multi-institutional patients all with end-stage DSRCT. Slides were stained for AR, c-Kit, various growth factors, and drug resistance-associated proteins. Immunohistochemical (IHC) expression was scored semi-quantitatively. Western blot and MTT studies were performed to validate the IHC findings of over-expression of the AR and its functional status by stimulation of growth by dihydrotestosterone, respectively. Six patients with positive AR status were treated solely with combined androgen blockade (CAB) as used for prostate cancer. RESULTS: Twenty-two patients were male (81%) and five were female (19%) with a median age at diagnosis of 23. All patients had failed at least two prior multi-agent chemotherapy regimens and 44% had progressed after autologous stem cell transplant. DSRCT samples from 10 of 27 patients were >or=2+ IHC positive for AR (37%,P=0.0045) and 7 of 20 patients were >or=2+ IHC positive for c-Kit (35%, P=0.018). We found elevated IHC expression of GST-pi, MRP and thymidylate synthase in smaller subsets of patients. In vitro studies for AR by Western blot and stimulation of growth by dihydrotestosterone in MTT assays suggest that the AR in DSRCT cells is functional. Six patients with positive AR status were treated with CAB alone and three of six attained clinical benefit (1-PR, 1-MR, 1-SD) in a range of 3-4 months. The three patients who responded to CAB had normal testosterone levels before CAB, while the three who did not respond to CAB had baseline castrate levels of testosterone. CONCLUSIONS: DSRCT has significant IHC expression of AR and c-Kit in heavily pre-treated patients. The presence of significant AR expression in 37% suggests that these patients could possibly respond to CAB. The significance of c-Kit expression in 35% of DSRCT patients is unknown and warrants further investigation.

Cholesterol binding, efflux, and a PDZ-interacting domain of scavenger receptor-BI mediate HDL-initiated signaling.

The binding of HDL to scavenger receptor-BI (SR-BI) mediates cholesterol movement. HDL also induces multiple cellular signals, which in endothelium occur through SR-BI and converge to activate eNOS. To determine the molecular basis of a signaling event induced by HDL, we examined the proximal mechanisms in HDL activation of eNOS. In endothelial cells, HDL and methyl-beta-cyclodextrin caused comparable eNOS activation, whereas cholesterol-loaded methyl-beta-cyclodextrin had no effect. Phosphatidylcholine-loaded HDL caused greater stimulation than native HDL, and blocking antibody against SR-BI, which prevents cholesterol efflux, prevented eNOS activation. In a reconstitution model in COS-M6 cells, wild-type SR-BI mediated eNOS activation by both HDL and small unilamellar vesicles (SUVs), whereas the SR-BI mutant AVI, which is incapable of efflux to SUV, transmitted signal by only HDL. In addition, eNOS activation by methyl-beta-cyclodextrin was SR-BI dependent. Studies of mutant and chimeric class B scavenger receptors revealed that the C-terminal cytoplasmic PDZ-interacting domain and the C-terminal transmembrane domains of SR-BI are both necessary for HDL signaling. Furthermore, we demonstrated direct binding of cholesterol to the C-terminal transmembrane domain using a photoactivated derivative of cholesterol. Thus, HDL signaling requires cholesterol binding and efflux and C-terminal domains of SR-BI, and SR-BI serves as a cholesterol sensor on the plasma membrane.

Acute myocardial infarction in sickle cell anemia.

Cardiovascular dysfunction consistent with ischemia has been observed during episodes of painful crisis and following periods of heavy physical exertion in individuals with sickle cell disease. Similar findings have been observed in other individuals while taking the alpha-adrenergic agonist pseudoephedrine. However, acute myocardial infarction is extremely rare. The authors describe a case of sudden death in a child with sickle cell disease due to acute myocardial infarction and suggest that heavy exertional stress and use of pseudoephedrine may have precipitated the event.