Integrated genomic analysis reveals aberrations in WNT signaling in germ cell tumors of childhood and adolescence.

Germ cell tumors (GCTs) are neoplasms of the testis, ovary and extragonadal sites that occur in infants, children, adolescents and adults. Post-pubertal (type II) malignant GCTs may present as seminoma, non-seminoma or mixed histologies. In contrast, pre-pubertal (type I) GCTs are limited to (benign) teratoma and (malignant) yolk sac tumor (YST). Epidemiologic and molecular data have shown that pre- and post-pubertal GCTs arise by distinct mechanisms. Dedicated studies of the genomic landscape of type I and II GCT in children and adolescents are lacking. Here we present an integrated genomic analysis of extracranial GCTs across the age spectrum from 0-24 years. Activation of the WNT pathway by somatic mutation, copy-number alteration, and differential promoter methylation is a prominent feature of GCTs in children, adolescents and young adults, and is associated with poor clinical outcomes. Significantly, we find that small molecule WNT inhibitors can suppress GCT cells both in vitro and in vivo. These results highlight the importance of WNT pathway signaling in GCTs across all ages and provide a foundation for future efforts to develop targeted therapies for these cancers.

A 12-Year-old Girl With Chronic Pediculosis Infestation Presenting With Severe Iron Deficiency Anemia.

Iron deficiency is the leading etiology of anemia worldwide. Excessive cow's milk intake and menorrhagia are the most common etiologies in the pediatric population in the United States, with parasitic infections a more common cause in lower-resource countries. Here we present a case of a 12-year-old female in the midwestern United States with severe iron deficiency anemia (hemoglobin 4.7 g/dL) and chronic pediculosis infestation. Anemia resolved with transfusion, iron supplementation, and eradication of the parasite. We believe this is the only reported case of a child in the United States with severe iron deficiency anemia secondary to chronic severe lice infestation.

Dextromethorphan Administration on Day 0 and Day 7 for Secondary Prevention of Methotrexate-induced Neurotoxicity in Childhood Acute Lymphoblastic Leukemia: A Retrospective Case Series.

Acute lymphoblastic leukemia is the most common malignancy in children. Long-term survival exceeds 90%; however, therapy-induced toxicity remains a concern. Methotrexate neurotoxicity (MTX-NT) is common, often necessitating alterations in chemotherapy regimens. Dextromethorphan has been used as an abortive and prophylactic treatment for MTX-NT. The authors report a case series of 7 pediatric patients with acute lymphoblastic leukemia with prior episodes of MTX-NT given a single dose of dextromethorphan (1 to 2 mg/kg) on the day of MTX administration and 7 days later. No subsequent episodes of MTX-NT occurred after 40 intravenous and 81 intrathecal administrations. This specific regimen of secondary prophylaxis may prevent MTX-NT.

Improving Patient Experience of Care Providers in a Multispecialty Ambulatory Pediatrics Practice.

Patient experience is positively associated with superior medical outcomes, clinical quality, patient safety measures, physician job satisfaction, doctor-patient communication, and patient compliance with treatment recommendations. A concrete pediatrics-focused methodology for improving patient experience in a multispecialty ambulatory setting has not been described, nor has the impact on practice outcomes been assessed. The primary aim of this study was to improve patient experience care provider scores at a single multiclinic children's hospital in the Midwest to the 70th percentile in a 5-year period. The secondary aim sought to determine the impact of quality improvement efforts on practice growth, patient complaint rate, and provider/staff engagement. Patient experience was measured by returned Press-Ganey surveys. Interventions involved establishing infrastructure, promoting feedback and transparency, providing education, and transforming culture. Provider scores improved from the 19th to the 70th percentile within 5 years. Practice volume increased by 17.1%; patient complaint/grievance frequency decreased 33-fold; and provider/staff engagement did not appreciably change.

A multicenter study of patients with multisystem Langerhans cell histiocytosis who develop secondary hemophagocytic lymphohistiocytosis.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the presence of abnormal CD1a-positive (CD1a+ )/CD207+ histiocytes. Hemophagocytic lymphohistiocytosis (HLH) represents a spectrum of hyperinflammatory syndromes typified by the dysregulated activation of the innate and adaptive immune systems. Patients with LCH, particularly those with multisystem (MS) involvement, can develop severe hyperinflammation mimicking that observed in HLH. Nevertheless, to the authors' knowledge, little is known regarding the prevalence, timing, risk factors for development, and outcomes of children and young adults who develop HLH within the context of MS-LCH (hereafter referred to LCH-associated HLH). METHODS: To gain further insights, the authors conducted a retrospective, multicenter study and collected data regarding all patients diagnosed with MS-LCH between 2000 and 2015. RESULTS: Of 384 patients with MS-LCH, 32 were reported by their primary providers to have met the diagnostic criteria for HLH, yielding an estimated 2-year cumulative incidence of 9.3% ± 1.6%. The majority of patients developed HLH at or after the diagnosis of MS-LCH, and nearly one-third (31%) had evidence of an intercurrent infection. Patient age <2 years at the time of diagnosis of LCH; female sex; LCH involvement of the liver, spleen, and hematopoietic system; and a lack of bone involvement each were found to be independently associated with an increased risk of LCH-associated HLH. Patients with MS-LCH who met the criteria for HLH had significantly poorer 5-year survival compared with patients with MS-LCH who did not meet the criteria for HLH (69% vs 97%; P < .0001). CONCLUSIONS: Given its inferior prognosis, further efforts are warranted to enhance the recognition and optimize the treatment of patients with LCH-associated HLH.

Determination of Key Drivers of Patient Experience in a Midsize Pediatric Hematology-Oncology Ambulatory Clinic.

BACKGROUND: Patient perception of care is positively associated with better medical outcomes, clinician job satisfaction, and fewer malpractice claims and also has significant downstream economic impact for healthcare organizations. A sparse amount of data exists regarding provider and practice characteristics driving high levels of patient experience in the pediatric hematology-oncology (PHO) ambulatory setting. The aims of this study were to determine key drivers of high care provider ratings and of the likelihood of recommending our ambulatory PHO practice. METHODS: Patient experience was measured using the Consumer Assessment of Healthcare Providers and Systems Clinician & Group Survey (CG-CAHPS). The study outcomes were to determine the survey items most associated with top-box scores for "Rate This Provider" and for "Likelihood of Your Recommending Our Practice to Others." RESULTS: The survey items Explanations the care provider gave you about your problem or condition and Concern the care provider showed for your questions or worries were most strongly correlated with high provider ratings. How well the staff worked together to care for you and Friendliness/courtesy of nurse/assistant were most strongly correlated with the likelihood of recommending the practice. CONCLUSION: High provider ratings were most associated with the physician's ability to explain problems and conditions to families. Staff teamwork and nursing attitude were most associated with patient recommendations of the PHO practice. By identifying key drivers of high provider and practice ratings by patients in the PHO ambulatory setting, a targeted approach with a focus on physician-specific communication attributes, teamwork, and nursing attitude can be deployed to improve the patient experience.

EGF Receptor and mTORC1 Are Novel Therapeutic Targets in Nonseminomatous Germ Cell Tumors.

Germ cell tumors (GCT) are malignant tumors that arise from pluripotent embryonic germ cells and occur in children and young adults. GCTs are treated with cisplatin-based regimens which, while overall effective, fail to cure all patients and cause significant adverse late effects. The seminoma and nonseminoma forms of GCT exhibit distinct differentiation states, clinical behavior, and response to treatment; however, the molecular mechanisms of GCT differentiation are not fully understood. We tested whether the activity of the mTORC1 and MAPK pathways were differentially active in the two classes of GCT. Here we show that nonseminomatous germ cell tumors (NSGCT, including embryonal carcinoma, yolk sac tumor, and choriocarcinoma) from both children and adults display activation of the mTORC1 pathway, while seminomas do not. In seminomas, high levels of REDD1 may negatively regulate mTORC1 activity. In NSGCTs, on the other hand, EGF and FGF2 ligands can stimulate mTORC1 and MAPK signaling, and members of the EGF and FGF receptor families are more highly expressed. Finally, proliferation of NSGCT cells in vitro and in vivo is significantly inhibited by combined treatment with the clinically available agents erlotinib and rapamycin, which target EGFR and mTORC1 signaling, respectively. These results provide an understanding of the signaling network that drives GCT growth and a rationale for therapeutic targeting of GCTs with agents that antagonize the EGFR and mTORC1 pathways. Mol Cancer Ther; 17(5); 1079-89. ©2018 AACR.

Improving Patient Satisfaction in a Midsize Pediatric Hematology-Oncology Outpatient Clinic.

PURPOSE: The study of patient satisfaction is a rapidly emerging area of importance within health care. High levels of patient satisfaction are associated with exceptional physician-patient communication, superior patient compliance, reduced risk of medical malpractice, and economic benefit in the value-based purchasing era. To our knowledge, no previous reports have evaluated methods to improve the patient experience within the pediatric hematology-oncology (PHO) outpatient clinic. METHODS: Patient satisfaction was measured using returned Press-Ganey surveys at Blank Children's Hospital PHO outpatient clinic (UnityPoint Health). The aim of this study was to raise the overall patient satisfaction score to the 75th percentile and raise the care provider score (CP) to the 90th percentile nationally. After analyzing data from 2013, interventions were implemented in January 2014, including weekly review of returned surveys, review of goals and progress at monthly staff meetings, distribution of written materials addressing deficiencies, score transparency among providers, provider use of Web-based patient satisfaction training modules, devotion of additional efforts to address less satisfied demographics (new patient consultations), and more liberal use of service recovery techniques. RESULTS: In the PHO outpatient clinic, overall patient satisfaction improved from the 56th to 97th percentile. Care provider scores improved from the 70th to 99 th percentile. For new patients, overall satisfaction improved from the 27th to 92 nd percentile, and care provider scores improved from the 29th to 98 th percentile. CONCLUSION: Patient satisfaction was improved in a midsize PHO clinic by implementing provider- and staff-driven initiatives. A combination of minor behavioral changes among care providers and staff in conjunction with systems-related modifications drove improvement.

Neonatal eosinophilic gastroenteritis: possible in utero sensitization to cow's milk protein.

Rectal bleeding in neonates is an alarming sign that suggests a possible serious underlying condition, such as infection or bleeding disorder that would necessitate hospitalization and prompt intervention. We report a case of eosinophilic gastroenteritis caused by cow's milk protein allergy in a one-day- old infant, who presented with frankly bloody stools associated with massive gastrointestinal and peripheral blood eosinophilia prior to initiation of enteral feedings. The patient's outcome was favorable, with complete spontaneous recovery in one week, after a period of bowel rest, parenteral nutrition, and use of amino acid formula. The eosinophilia was also transient and gradually resolving by two months of age. Rectal bleeding secondary to allergic colitis caused by cow's milk sensitization may occur in neonates, and failure to appreciate this possibility may lead to inappropriate diagnostic or therapeutic intervention.

DNA methylation analysis reveals distinct methylation signatures in pediatric germ cell tumors.

BACKGROUND: Aberrant DNA methylation is a prominent feature of many cancers, and may be especially relevant in germ cell tumors (GCTs) due to the extensive epigenetic reprogramming that occurs in the germ line during normal development. METHODS: We used the Illumina GoldenGate Cancer Methylation Panel to compare DNA methylation in the three main histologic subtypes of pediatric GCTs (germinoma, teratoma and yolk sac tumor (YST); N = 51) and used recursively partitioned mixture models (RPMM) to test associations between methylation pattern and tumor and demographic characteristics. We identified genes and pathways that were differentially methylated using generalized linear models and Ingenuity Pathway Analysis. We also measured global DNA methylation at LINE1 elements and evaluated methylation at selected imprinted loci using pyrosequencing. RESULTS: Methylation patterns differed by tumor histology, with 18/19 YSTs forming a distinct methylation class. Four pathways showed significant enrichment for YSTs, including a human embryonic stem cell pluripotency pathway. We identified 190 CpG loci with significant methylation differences in mature and immature teratomas (q < 0.05), including a number of CpGs in stem cell and pluripotency-related pathways. Both YST and germinoma showed significantly lower methylation at LINE1 elements compared with normal adjacent tissue while there was no difference between teratoma (mature and immature) and normal tissue. DNA methylation at imprinted loci differed significantly by tumor histology and location. CONCLUSION: Understanding methylation patterns may identify the developmental stage at which the GCT arose and the at-risk period when environmental exposures could be most harmful. Further, identification of relevant genetic pathways could lead to the development of new targets for therapy.

Mutation in the type IB bone morphogenetic protein receptor Alk6b impairs germ-cell differentiation and causes germ-cell tumors in zebrafish.

Germ-cell tumors (GCTs), which arise from pluripotent embryonic germ cells, exhibit a wide range of histologic differentiation states with varying clinical behaviors. Although testicular GCT is the most common cancer of young men, the genes controlling the development and differentiation of GCTs remain largely unknown. Through a forward genetic screen, we previously identified a zebrafish mutant line, tgct, which develops spontaneous GCTs consisting of undifferentiated germ cells [Neumann JC, et al. (2009) Zebrafish 6:319-327]. Using positional cloning we have identified an inactivating mutation in alk6b, a type IB bone morphogenetic protein (BMP) receptor, as the cause of the zebrafish GCT phenotype. Alk6b is expressed in spermatogonia and early oocytes, and alk6b mutant gonads display impaired BMP signal transduction, altered expression of BMP target genes, and abnormal germ-cell differentiation. We find a similar absence of BMP signaling in undifferentiated human GCTs, such as seminomas and embryonal carcinoma, but not in normal testis or in differentiated GCTs. These results indicate a germ-cell-autonomous role for BMP signal transduction in germ-cell differentiation, and highlight the importance of the BMP pathway in human GCTs.