Jennifer Willert

A transcriptional response to Wnt protein in human embryonic carcinoma cells

BackgroundWnt signaling is implicated in many developmental decisions, including stem cell control, as well as in cancer. There are relatively few target genes known of the Wnt pathway.ResultsWe have identified target genes of Wnt signaling using microarray technology and human embryonic carcinoma cells stimulated with active Wnt protein. The ~50 genes upregulated early after Wnt addition include the previously known Wnt targets Cyclin D1, MYC, ID2 and βTRCP. The newly identified targets, which include MSX1, MSX2, Nucleophosmin, Follistatin, TLE/Groucho, Ubc4/5E2, CBP/P300, Frizzled and REST/NRSF, have important implications for understanding the roles of Wnts in development and cancer. The protein synthesis inhibitor cycloheximide blocks induction by Wnt, consistent with a requirement for newly synthesized β-catenin protein prior to target gene activation. The promoters of nearly all the target genes we identified have putative TCF binding sites, and we show that the TCF binding site is required for induction of Follistatin. Several of the target genes have a cooperative response to a combination of Wnt and BMP.ConclusionsWnt signaling activates genes that promote stem cell fate and inhibit cellular differentiation and regulates a remarkable number of genes involved in its own signaling system.

Combination of gemcitabine and docetaxel in the treatment of children and young adults with refractory bone sarcoma

The combination of gemcitabine and docetaxel has demonstrated promise in sarcomas diagnosed in adults. In the current study, the toxicity and efficacy of this combination were evaluated in pediatric sarcomas.

Zygomycetes infections in pediatric hematology oncology patients: a case series and review of the literature.

Fungi from the Zygomycetes class are increasingly recognized causes of infection in immunosuppressed children, but no comprehensive literature review and few case series have been published on the topic. A case series of 6 pediatric oncology patients with Zygomycetes infections cared for at our institution was constructed, and a concurrent search of the English language literature for Zygomycetes infections in children with oncologic disorders was undertaken. Our case series described 6 patients (5 male) between the ages of 2.5 and 19.5 years. One patient was diagnosed with rhinocerebral disease, 2 with rhinosinusitis, 2 with pulmonary involvement, and 1 with a gastrointestinal presentation. Five patients survived. Our literature review identified 82 cases from 61 studies. The mean subject age was 10.8 years (1.4 to 21.0 y). About 92.7% of all patients suffered from some form of leukemia, with 70.7% suffering from acute lymphoblastic leukemia. Overall, 58.5% of reported patients survived, with individuals with disseminated disease showing the worst prognosis (68.2% mortality) and those with cutaneous disease the best (14.3% mortality). Survival is increasingly reported in the literature, perhaps as a result of improved diagnostic capabilities, increased physician awareness and increased reliance on adjunctive surgical therapy.

Population Pharmacokinetics of Bevacizumab in Children with Osteosarcoma: Implications for Dosing

Purpose: To describe sources of interindividual variability in bevacizumab disposition in pediatric patients and explore associations among bevacizumab pharmacokinetics and clinical wound healing outcomes. Experimental Design: Before tumor resection, three doses of bevacizumab (15 mg/kg) were administered to patients (median age, 12.2 years) enrolled in a multi-institutional osteosarcoma trial. Serial sampling for bevacizumab pharmacokinetics was obtained from 27 patients. A population pharmacokinetic model was fit to the data, and patient demographics and clinical chemistry values were systematically tested as predictive covariates on model parameters. Associations between bevacizumab exposure and wound healing status were evaluated by logistic regression. Results: Bevacizumab concentration–time data were adequately described by a two-compartment model. Pharmacokinetic parameter estimates were similar to those previously reported in adults, with a long median (range) terminal half-life of 12.2 days (8.6 to 32.4 days) and a volume of distribution indicating confinement primarily to the vascular space, 49.1 mL/kg (27.1 to 68.3 mL/kg). Body composition was a key determinant of bevacizumab exposure, as body mass index percentile was significantly (P < 0.05) correlated to body-weight normalized clearance and volume of distribution. Furthermore, bevacizumab exposure before primary tumor resection was associated with increased risk of major wound healing complications after surgery (P < 0.05). Conclusion: A population pharmacokinetic model for bevacizumab was developed, which demonstrated that variability in bevacizumab exposure using weight-based dosing is related to body composition. Bevacizumab dosage scaling using ideal body weight would provide an improved dosing approach in children by minimizing pharmacokinetic variability and reducing likelihood of major wound healing complications. Clin Cancer Res; 20(10); 2783–92. ©2014 AACR.

Hodgkin's and Non-Hodgkin's Lymphomas Occurring in Two Brothers with Wiskott-Aldrich Syndrome and Review of the Literature

Approximately 13% of patients with Wiskott-Aldrich syndrome (WAS), a primary immune deficiency, develop malignant tumors, the predominant form being non-Hodgkins lymphoma. Previously, only 4 cases of Hodgkins lymphoma have been reported in WAS patients. Herein, we review the literature of WAS-related lymphomas and report 2 brothers with WAS who both developed lymphomas; one developed Epstein-Barr virus (EBV)-driven diffuse large B-cell lymphoma, and one developed EBV-negative classical Hodgkins lymphoma. In contrast to many of the previously reported lymphomas in WAS patients, these lymphomas were extensively evaluated by means of molecular, flow cytometric, and immunohistochemical methods. Both brothers died shortly after diagnosis, despite aggressive therapy. The occurrence of 2 distinct forms of lymphomas in these brothers underscores the interplay between genetic susceptibility and environmental exposure in lymphoma pathogenesis.

Prenatal diagnosis of fetal hepatoblastoma: case report and review of the literature.

Hepatoblastoma is the most common liver malignancy in childhood. The reported incidence is 11.2 cases per 1 million during the first year of life. Genetic predispositions include Beckwith-Wiedemann syndrome and familial polyposis. The prognosis depends on the extent of tumor spreading at the time of initial treatment, which typically includes chemotherapy and surgery. Imaging of hepatoblastoma has only rarely been reported prenatally. Here we report a recent case with a successful outcome and discuss issues of differential diagnosis and treatment.

When disclosing a serious diagnosis to a minor conflicts with family values.

An 11-year old Asian-Indian boy was recently discovered to have acute myelogenous leukemia. The pediatric hematologist-oncologist arranged a meeting to inform the parents about the diagnosis, prognosis and treatment. The physician planned to include the child in this process. However, the childs father, a computer programmer, made a request that his son should not be informed about the diagnosis of leukemia. The father asked that his son should be told that he has a severe infection and will require intensive treatment. The oncologist then informed the father that, as a physician, she has the responsibility to truthfully disclose the diagnosis to a patient, and she insisted on informing the child about the leukemia in an open and truthful manner.

The treatment of pediatric Philadelphia positive (Ph+) leukemias in the imatinib era.

As the treatment of Philadelphia positive (Ph+) leukemias in the era of imatinib continues to evolve, the role of allogeneic hematopoietic cell transplantation (allogeneic‐HCT) in first remission is becoming more unclear.

Temozolomide and radiation for aggressive pediatric central nervous system malignancies.

This study describes the outcomes of children treated with combinations of temozolomide and radiation therapy for various aggressive central nervous system malignancies. Their age at diagnosis ranged from 1 to 15 years. Patients with focal disease were treated with concomitant temozolomide (daily 75 mg/m2) and three-dimensional conformal radiotherapy in a dose that ranged from 50 to 54 Gy, followed by temozolomide (200 mg/m2/d × 5 days/month in three patients, 150 mg/m2 × 5 days/ month in one patient). Patients with disseminated disease were treated with craniospinal radiation (39.6 Gy) before conformal boost. One patient received temozolomide (200 mg/m2 × 5 days/month) before craniospinal radiation, and one patient received temozolomide (daily 95 mg/m2) concomitant with craniospinal radiation and a radiosurgical boost, followed by temozolomide (200 mg/m2 × 5 days/month). Three patients achieved a partial response during treatment, with two of these patients dying of progressive disease after treatment. One patient has no evidence of disease. Three patients achieved stable disease, with one of these patients dying of progressive disease after treatment. Toxicities observed included low-grade neutropenia, thrombocytopenia, and lymphopenia. The combination of temozolomide and radiotherapy appears to be well tolerated in a variety of treatment schemas for aggressive pediatric central nervous system malignancies. This information is of particular use in designing future studies, given the recent positive results in a randomized study examining the use of temozolomide concomitant with radiation in the treatment of adult glioblastoma.

Effects of a unique pediatric hematology–oncology palliative care program on medical decision-making and communication between healthcare providers and families: Results of a supportive care survey

Abstract Purpose The purpose of this study was to evaluate family satisfaction with an embedded pediatric hematology–oncology (Hem-Onc) palliative care program and its decision-making tool (DMT). A secondary aim was to identify factors that play an important role in family medical decision-making. Methods Families were asked to complete a self-administered questionnaire within 4 weeks of participating in a Supportive Care Team (SCT) conference and receiving a DMT. Results Twenty parents or guardians of pediatric Hem-Onc patients participated in the study. All of the patients had approached a major treatment-related change; all of the study participants had attended a SCT medical decision-making conference and received a DMT. The most important considerations to the study participants regarding treatment decisions were their childs quality of life, their childs chance of improving, perception of their childs wishes, and the hospital staffs advice. Of the people and services that were most useful in guiding medical decision-making, 100% reported that nurses, 95% reported physicians, and 90% reported the SCT helped guide treatment decisions. Ninety percent of those surveyed remembered receiving the DMT, found it to be clear and straightforward, and thought that it improved communication between the family and the healthcare providers. Conclusions These findings suggest an embedded pediatric Hem-Onc supportive care program (SCP) and use of a DMT facilitate effective communication between families and healthcare providers, and provide families with adequate decision-making support.