Chatchawin Assanasen

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.

Epidemiologic mapping of Florida childhood cancer clusters

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.

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.

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 Childrens 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 patients 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.

Systemic juvenile xanthogranuloma: A case report and brief review

A 2-month-old child presented with a 4-week history of rapidly enlarging, nontender ‘bumps’ on her body. The lesions initially arose on the child’s scalp, and despite treatment topical mupirocin, began appearing on her trunk, limbs and face. The child had been born at term and was otherwise healthy. Physical examination revealed eight subcutaneous nodules of varying sizes involving the child’s scalp, eyelid, posterior shoulder, elbow, abdomen and leg. The scalp nodules exhibited haemorrhagic crusts, while the truncal nodules had a faint brown–yellow colour. The largest lesion was a firm, subcutaneous, nonmobile mass on the right forehead without overlying epidermal changes (Fig. 1). Histological examination of a biopsy taken from a nodule on the leg revealed a nodular and diffuse wedge-shaped infiltrate that extended into the subcutaneous tissue and surrounding adnexal structures (Fig. 2a). The infiltrate was composed of mononuclear cells with oval to slightly folded nuclei and moderate amphophilic cytoplasm (Fig. 2b). Some cells demonstrated a foamy to vacuolated cytoplasm. Immunohistochemistry yielded positive staining for CD68 (Fig. 2c), CD14 and CD4 with negative staining for CD1a and S100 (Fig. 2d), consistent with juvenile xanthogranuloma (JXG). Owing to the extent and severity of the lesions, a high suspicion for systemic involvement prompted haematology/ oncology and ophthalmology consultations. Ophthalmological examination was unremarkable. However, magnetic resonance imaging (MRI) of the brain/chest/abdomen revealed multiple pulmonary and hepatic nodules, confirming systemic JXG. After 6 weeks of chemotherapy (vinblastine and prednisolone), all cutaneous lesions had halted in growth, with some decreasing in size. Repeat MRI revealed partial response of pulmonary and hepatic lesions. Several months into therapy, vinblastinerelated toxicities led to a transition to cytarabine. After 1 year of therapy, only residual hepatic lesions remained, with involution of all pulmonary lesions and skin nodules, prompting discontinuation of treatment for observation. At 2 years off treatment, imaging and physical examination revealed no evidence of progression or relapse. Systemic JXG is a rare histiocytic disorder, presenting mostly in early infancy as cutaneous and/or subcutaneous nodules with additional involvement of two or more organ systems. Among the reported cases, 34.5% of patients presented at birth, with 71% of cases diagnosed within the first year of life. Skin nodules, commonly < 40 mm in diameter, can appear brown–yellow in colour, and are often confused with xanthomas or lipomas. Extracutaneous sites include the liver, spleen, lung, central nervous system (CNS) and eyes, resulting in organ-specific symptoms and laboratory abnormalities. Children with ≥ 2 cutaneous xanthogranulomas should undergo evaluation for systemic JXG to include Correspondence: Dr M. David Meyer, University of Texas Health Science Center at San Antonio, 3rd Floor, Grossman Building, 7979 Wurzbach Road, Mail node 7876, San Antonio, TX 78229, USA E-mail: meyermd@uthscsa.edu

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.

Associations between maternal factors during pregnancy and risk of acute lymphoblastic leukemia: Plausibility rules.

E pidemiologic studies evaluate and describe patterns and effects of specific conditions in defined populations. When reviewing epidemiologic descriptions it is often easy to attempt to attribute direct causality to the identified associations. Causation, however, may be inferred but often requires further judgment and interpretation of several other interconnected factors. In this issue of Pediatric Blood and Cancer, Yan et al. sought to identify perinatal risk factors in the development of pediatric acute lymphoblastic leukemia [1]. The authors reviewed 336 studies identifying 49 studies (33,751 cases and 82,457 controls) that were appropriate for further evaluation. Employing metaanalysis techniques, they evaluated possible associations between maternal factors during pregnancy including: maternal age, level of education, alcohol consumption, smoking, coffee consumption, and case birth order. The authors report evidence of associations between childhood ALL and birth order (firstborn vs. others, OR1⁄4 1.08, 95% CI1⁄4 1.00–1.16), childhood ALL and maternal education level (>high school vs. <high school, OR1⁄4 0.82, 95% CI1⁄4 0.77–0.86), and childhood ALL and evidence of smoking (ever vs. never, OR1⁄4 1.10, 95% CI1⁄4 1.02– 1.19). Their statistical analysis did not find any associations between childhood ALL and maternal age, alcohol consumption, or coffee consumption. Potential confounding factors in the study were identified using a directed acyclic graph (DAG). The DAG revealed that the quality of the studies evaluated by the Newcastle–Ottowa scale (NOS), the age and ethnicity of cases and controls were found to be potential confounders in the analysis of birth order and childhood ALL risk. Age and ethnicity of cases and controls were also found to be potential confounders in the analysis of childhood ALL risk and the level of maternal education. In the evaluation of smoking activity and childhood ALL risk the ethnic group and study quality (NOS) were found to be potential confounders. Further subgroup analysis highlighted ethno-national differences as confounders. Other limitations discussed by the authors include the limited number of studies and cases incorporated into the current analysis. The inferences derived from the analysis, however, retain some degree of controversy. The report of smoking and risk of childhood leukemia infers an association that many would consider biologically plausible. As the authors state, tobacco related products contain known hazardous substances while smoking-related diseases have increased in women correlating with the rise in maternal smoking rates. The deleterious effects of parental smoking have been described in other disease processes in relation to specific biologic susceptibilities [2]. However, other case-control studies have identified similarly limited associations between maternal smoking and childhood leukemia risk as well. Klimentopoulou et al reviewed a case-control and meta-analysis of the Greek Nationwide Registry for Childhood Hematological Malignancies concluding that the overall risk (OR1⁄4 1.03, 95% CI1⁄4 0.95–1.12) lacked any significant validity to support the inference without other additional factors [3]. Conversely, the plausibility of higher parental education levels (left on its own or as a proxy for socioeconomic status) inferring beneficial associations with childhood ALL risk is limited as best. The authors suggest that enhanced maternal self-awareness provided by cumulative education may confer protective behaviors. This hypothesis significantly challenges the nine criteria of strength, consistency, specificity, temporality, plausibility, coherence, analogy, experimental evidence, and biologic gradient described by Austin Bradford Hill used to assess the considerations for causality [4]. The association of birth order with the risk of childhood ALL may be the most intriguing, as it appears to support the infectious etiologic hypothesis of childhood leukemia. The authors suggest that birth order may confer immunologic advantage consistent with other hypotheses describing that the lack of exposures to infection in infancy may in turn enhance risk for inappropriate immunologic responses (i.e., leukemia) later in life [5]. Other theories gaining support, however, appear to suggest an alternative expectation that higher birth order may be related to other risk factors associated with childhood ALL. High birth weight and rapid fetal growth have been reported with strong correlation as risk factors for childhood leukemia [6,7]. Further evidence has identified IGF-1 and IGF-2 as possible etiologic agents. Clinically, unless other comorbidities exist, anecdotal observations by many obstetricians suggest that higher birth order correlates with ‘‘faster labors and bigger

Abstract A85: Challenges in developing pediatric cancer care in Southern Vietnam

Worldwide, cancer has superseded infection and heart disease as the leading cause of death. Generally viewed as a lesser public health priority in lower to middle income countries (LMIC), 60% of the children worldwide have limited access to effective cancer diagnosis, therapy and supportive care measures. As a result, relapse and treatment related toxicities with fatal outcomes contribute significantly to decreased survival rates compared to developed countries. Survival rates as low as 5% have been previously been reported in Vietnam. These reports utilized surveys based on face-to-face interviews that extrapolated incidence rates and survival data. Below the 17th parallel the region of southern Vietnam remains isolated with limited access to modern research collaborations and methodologies. Currently, Ho Chi Minh City provides the region9s primary pediatric oncology clinical setting. Three hospitals, Blood and Transfusion Hospital, Children9s Hospital #2, and Oncology Hospital provide care for the surrounding population of 40 million. Recognizing that the definitions of underserved populations have blurred in relation to global communities, the University of Texas Health Science Center at San Antonio (UTHSCSA) and the Kids with Cancer Foundation of Vietnam have collaborated to evaluate clinical and educational challenges to improving healthcare delivery in Vietnam. Faculty from UTHSCSA have travelled to southern Vietnam on multiple occasions to interact and help identify gaps in care and academic based infrastructure. Interviews with local hospital administrators, medical school educators, physicians, and nursing staff were undertaken. Local institutional data were also reviewed. Observerships in the United States for Vietnamese pediatric oncologists were also established focusing on establishing on-going mentorship, clinical education, and the development a regional leukemia treatment protocol. Demographics and clinical data were collected at Oncology Hospital in Ho Chi Minh City, Vietnam for pediatric cancer patients diagnosed from 2003 through 2012. 4534 pediatric oncology cases were identified. The breakdown of cases by classification were similar to USA statistics with the exception of brain tumors, which represented only 5% of cases. Survival statistics were analyzed for certain disease groups. Acute lymphoblastic leukemia (ALL) cases had a 66.2% 5 yr OS. Hodgkin Lymphoma cases had a 92% 5 yr OS. NHL cases had a 41% OS. Rhabdomyosarcoma cases had a 50% 5 yr OS. Wilms Tumor analysis noted 78.67% 5 yr OS. Hepatoblastoma analysis revealed 42.8% 2 yr OS and Osteosarcoma analysis revealed 13.58% 5 yr OS. While these survival rates were better than the previously reported 5% for the region, they are still below survival rates in Western developed countries. The pronounced successes in pediatric cancer survival have been well documented and owe a significant debt to the advent of cooperative groups and a focus on basic research. Specific barriers identified in southern Vietnam included: the lack of a cooperative group structure to provide common treatment regimens amongst institutions, the lack of a central cancer registry, the lack of knowledge of genetic variance and tumor phenoptypes in the population, limited basic science infrastructure and training, the underutilization of reference laboratories, and the inability to ship specimens outside of the country. Political pressure represents a strong influencing factor in how such data is utilized. Importantly, although there are a growing number of young and clearly highly capable physicians interested in pediatric cancer, there are no formal training programs specifically focused on childhood cancer. Citation Format: Chatchawin Assanasen, Vivienne Rebel, Gail Tomlinson. Challenges in developing pediatric cancer care in Southern Vietnam. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr A85.