Background Existing therapies for recurrent or refractory histiocytoses, including Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Rosai-Dorfman disease (RDD), have limited effectiveness. We report our experience with using clofarabine as therapy in children with recurrent or refractory histiocytic disorders, including LCH (11 patients), systemic JXG (4 patients), and RDD (3 patients). Methods Patients treated with clofarabine for LCH, JXG, or RDD by Texas Children’s Hospital physicians or collaborators between May 2011 and January 2013 were reviewed for response and toxicity. Results Patients were treated with a median of 3 chemotherapeutic regimens prior to clofarabine. Clofarabine was typically administered at 25 mg/m2/day for five days. Cycles were administered every 28 days for a median of six cycles (range: 2–8 cycles). Seventeen of eighteen patients are alive. All surviving patients showed demonstrable improvement after 2–4 cycles of therapy, with eleven (61%) complete responses, four (22%) partial responses, and two patients still receiving therapy. Five patients experienced disease recurrence, but three of these subsequently achieved complete remission. All patients with JXG and RDD had complete or partial response at conclusion of therapy. Side effects included neutropenia in all patients. Recurring but sporadic toxicities included prolonged neutropenia, severe vomiting, and bacterial infections. Conclusion Clofarabine has activity against LCH, JXG, and RDD in heavily pretreated patients, but prospective multi-center trials are warranted to determine long-term efficacy, optimal dosing, and late toxicity of clofarabine in this population.
These data demonstrate that early lymphocyte recovery represents a significant prognostic indicator for osteosarcoma. Early identification and risk stratification therapy based on the ALC-14 threshold may improve outcomes and our knowledge of this disease.
MicroRNAs (miRs) have emerged recently as important regulators of gene expression in the cell. Frequently dysregulated in cancer, miRs have shed new light on molecular mechanisms of oncogenesis, and have generated substantial interest as biomarkers, and novel therapeutic agents and targets. Recently, a number of studies have examined miR biology in Ewing sarcoma. Findings indicate that alterations in miR expression in Ewing Sarcoma are widespread, involve both EWS/Ets oncogenic fusion-dependent and independent mechanisms, and contribute to malignant phenotypes. miRs with prognostic potential have been identified, and several preclinical studies suggest that miR manipulation could be therapeutically useful in this aggressive disease. These and future studies of miR biology stand to expand our understanding of Ewing sarcoma pathogenesis, and may identify new biomarkers and treatment options.
Ewing Sarcoma is an aggressive, oncofusion-driven, malignant neoplasm of bone and soft tissue affecting predominantly children and young adults. Seeking to identify potential novel therapeutic targets/agents for this disease, our previous studies uncovered microRNAs regulated by EWS/Fli1, the most common oncofusion, with growth modulatory properties. In the present study, we sought to identify EWS/Fli1-repressed, growth suppressive, microRNAs potentially amenable to replacement in Ewing Sarcoma cells. Eight microRNAs (143, 153, 184, 193b, 195, 203, 206 and 223) were selected for evaluation as EWS/Fli1-repressed and underexpressed in Ewing Sarcoma cells, and reported to be growth suppressive in other pediatric or/and adult cancers. The selected miRs, and appropriate non-targeting controls, were introduced into two different Ewing Sarcoma cell lines (A673 and SK-ES-1), and effects on growth were examined using a high and low-density growth assay. MiR-193b was growth inhibitory in both assays and cell lines. In subsequent analyses, we found that stable overexpression of miR-193b also inhibits anchorage-independent growth in both A673 and SK-ES-1 cells. We further show that miR-193b negatively regulates expression of the ErbB4 oncogene in A673 and SK-ES-1 cells, and that depletion of ErbB4 is itself inhibitory to anchorage-independent growth in the same cell lines. Together, our studies show that the EWS/Fli1-repressed miR-193b is growth suppressive in Ewing Sarcoma, and identify ErbB4 as a target gene and candidate mediator of this growth suppression.
Objectives Accurate metrics of provider activity within the electronic health record (EHR) are critical to understand workflow efficiency and target optimization initiatives. We utilized newly described, log-based core metrics at a tertiary cancer center during rapid escalation of telemedicine secondary to initial coronavirus disease-2019 (COVID-19) peak onset of social distancing restrictions at our medical center (COVID-19 peak). These metrics evaluate the impact on total EHR time, work outside of work, time on documentation, time on prescriptions, inbox time, teamwork for orders, and undivided attention patients receive during an encounter. Our study aims were to evaluate feasibility of implementing these metrics as an efficient tool to optimize provider workflow and to track impact on workflow to various provider groups, including physicians, advanced practice providers (APPs), and different medical divisions, during times of significant policy change in the treatment landscape. Methods Data compilation and analysis was retrospectively performed in Tableau utilizing user and schedule data obtained from Cerner Millennium PowerChart and our internal scheduling software. We analyzed three distinct time periods: the 3 months prior to the initial COVID-19 peak, the 3 months during peak, and 3 months immediately post-peak. Results Application of early COVID-19 restrictions led to a significant increase of telemedicine encounters from baseline <1% up to 29.2% of all patient encounters. During initial peak period, there was a significant increase in total EHR time, work outside of work, time on documentation, and inbox time for providers. Overall APPs spent significantly more time in the EHR compared with physicians. All of the metrics returned to near baseline after the initial COVID-19 peak in our area. Conclusion Our analysis showed that implementation of these core metrics is both feasible and can provide an accurate representation of provider EHR workflow adjustments during periods of change, while providing a basis for cross-vendor and cross-institutional analysis.
Wilms' tumor is the most common renal malignancy in children. In addition to staging, molecular risk stratification, such as loss of heterozygosity (LOH) in Chromosomes 1 and 16, is being increasingly used. Although genetic predisposition syndromes have been well-characterized in some Wilms' tumors, recent sequencing and biology efforts are expanding the classification of this malignancy. Here we present a case of siblings with remarkably similar presentations of bilateral Wilms' tumor at ∼12 mo of age. Thorough exam after the younger sibling was diagnosed did not reveal any signs to suggest one of the known Wilms' predisposition syndromes. Both were treated with standard therapies with good response and long-term sustained complete remission of 53 and 97 mo, respectively. Wholeexome sequencing was performed on a tumor sample from each patient and matched blood from one, revealing a shared truncation mutation of TRIM28 in all three samples with heterozygosity in the germline sample. TRIM28 loss has been recently implicated in early-stage Wilms' tumors with epithelioid morphology. These siblings expand the phenotype for presentation with multifocal disease with retained excellent response to standard therapy.
Key Points Constitutional mismatch repair deficiency syndrome should be considered in children with acute leukemia and characteristic skin lesions. The high mutation burden of CMMRD-related cancers contributes to treatment resistance, necessitating individualized treatment strategies.
Denys-Drash syndrome is a genetic disorder characterized by ambiguous genitalia, cryptorchidism, nephrotic syndrome, and a high predilection for Wilms tumor with intravascular invasion. We report a 5-year-old male with Denys-Drash syndrome who rapidly developed Wilms tumor with vascular invasion, subsequent saddle tumor embolus, and required emergent embolectomy. This case illustrates the rapid emergence of Wilms tumor in a patient with Denys-Drash syndrome and the importance of considering embolectomy over thrombolytic therapy for PE in this population, given a high likelihood of tumor embolus.
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