Langerhans cell histiocytosis: NACHO update on progress, chaos, and opportunity on the path to rational cures.

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts.

Clofarabine monotherapy in aggressive, relapsed and refractory Langerhans cell histiocytosis.

Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.

Management of nutritional iron deficiency anemia for young children in the emergency department.

BACKGROUND: Guidelines for young children with nutritional iron deficiency anemia (IDA) presenting to the emergency department (ED) are lacking, leading to variability in care. We aimed to standardize management of these patients through the development and implementation of an evidence-based algorithm using quality improvement methodology. PROCEDURE: Baseline data of the target population (n = 42; 60% male; median age 22.5 months, median hemoglobin 5.3 g/dl) identified variability across four key measures of clinical management: laboratory evaluation, therapy choice, therapy administration, and patient disposition. Literature review and consensus from pediatric hematology providers informed a draft algorithm that was refined in an iterative multidisciplinary process. From September 2020 to June 2021, we aimed to increase IDA management per the algorithm by ≥20% relative to baseline for the four key outcome measures using sequential Plan-Do-Study-Act (PDSA) cycles. Process measures focusing on provider communication/documentation and balancing measures involving efficiency and therapy-related adverse events were assessed concurrently. RESULTS: Thirty-five patients were evaluated among four PDSA cycles and shared similar characteristics as the baseline population. Improvements of ≥20% above baseline adherence levels or 100% adherence were achieved for all outcome measure across four PDSA cycles. Adherence to recommended laboratory evaluation improved from 43 (baseline) to 71%, therapy choice from 78 to 100%, therapy administration from 50 to 83%, and disposition from 85 to 100%. ED length of stay remained stable. CONCLUSIONS: Implementation of a standardized algorithm for young children with nutritional IDA in the ED increased adherence to evidence-based patient care.

Sinusoidal Obstruction Syndrome of the Liver Associated With 6-Mercaptopurine During Maintenance in a Child With T-cell Acute Lymphoblastic Leukemia.

Sinusoidal obstruction syndrome (SOS) of the liver is a complication of chemotherapy most often encountered with hematopoietic stem cell transplant due to high-dose conditioning regimens, but it can also occur with regimens outside of the transplant setting. Mild-to-moderate SOS is a well-described 6-thioguanine toxicity; however, it has rarely been reported as secondary to 6-mercaptopurine, a related thiopurine. This report details a case of a 10-year-old male with T-cell acute lymphoblastic leukemia who developed severe SOS during maintenance therapy with 6-mercaptopurine, and a review of the related literature.

Chlorhexidine gluconate (CHG) foam improves adherence, satisfaction, and maintains central line associated infection rates compared to CHG wipes in pediatric hematology-oncology and bone marrow transplant patients.

CHG-based hygiene methods are often a component of daily hygiene bundles to prevent central line-associated blood stream infections (CLABSIs) in pediatric hematology-oncology patients; however, adherence with 2% CHG wipes was inconsistent within our institution, risking infection for immunocompromised patients. A new 4% CHG foam method offers an alternative and is applied while bathing, as opposed to wipes used 1 h after bathing. An initial cohort of 24 high-risk oncology and bone marrow transplant (BMT) patients agreed to use 4% CHG foam in place of wipes, and then answered surveys to describe their experiences. Ninety-two percent preferred foam over wipes and were more likely to use the foam moving forward. CHG foam was then made available as an option to all patients in need of central line care upon admission to the hospital. Hygiene bundles in the electronic medical record were reviewed to measure baseline adherence rates. Random audits by nursing administration prospectively assessed CHG adherence. CLABSI data were collected prospectively with routine quality metric reports. Results were analyzed using run charts and u-charts, respectively. Hematology-Oncology unit adherence rates remained at a higher rate of adherence, and BMT unit adherence rates increased from an average of 55%-81.6% (p < 0.001). Primary CLABSIs remained rare events (average <1/1000 CVL days). On cost analysis, utilizing CHG foam results in an annual savings estimate of $40,000 for a 24-bed unit. In conclusion, 4% CHG foam provides a cost-effective and patient-preferred option for daily hygiene that maintains CLABSI preventative efforts.

A Novel Oncodental Collaborative Team: Integrating Expertise for Central Line-Associated Bloodstream Infection Prevention in Pediatric Oncology Patients.

PURPOSE: Pediatric oncology and bone marrow transplant patients are at high risk of infection, and limitations to dental expertise among medical providers render patients vulnerable to central line-associated bloodstream infections from oral pathogens. Traditionally, oral health maintenance relied on patients and bedside nurses; however, routine methods are often suboptimal to prevent central line-associated bloodstream infection in high-risk patients. Limited overlap of medical and dental expertise, and limited dental resources in typical oncology units, prevent optimal oral care for children with cancer, requiring novel solutions to better integrate specialties. METHODS: Here, we outline the creation of a novel Pediatric oncodental team to address oral-systemic infection prevention strategies for high-risk patients. RESULTS: Our oncology and dental teams created a systematic approach for increasing oral surveillance and treatment in select high-risk patients. Supervised pediatric dental residents participated in scheduled oncology rounds, and a permanent oral health educator with a background in dental hygiene was also hired as a dedicated dental professional within our oncology department. CONCLUSION: Our pediatric oncodental team aims to sustain optimal oral complication prevention strategies to reduce the risk of infection, provide education on the significance of the oral-systemic link in cancer care, and improve access and continuity of care.

A 14-Year-Old Female With Chest Mass, Shortness of Breath, and Hypertension.

BACKGROUND: A previously healthy 14-year-old girl was evaluated in the emergency department (ED) with 2 months of shortness of breath and fatigue. METHODS: She initially presented to her primary pediatrician, where a complete blood count was only significant for mild anemia, thyroid function tests were normal, and a chest x-ray revealed a chest mass. This prompted her primary pediatrician to order a computed tomography scan and refer to the ED. RESULTS: Her computed tomography scan confirmed a mediastinal mass versus necrotic lymphadenopathy. Her initial physical exam was unremarkable, except for hypertension. From the ED, she was admitted to the pediatric hospital medicine service. Infectious disease, oncology, and nephrology services were consulted to guide diagnostic evaluation. CONCLUSIONS: Eventually, during her hospitalization, further history and workup led to a definitive diagnosis.

K-Ras and p53 mouse model with molecular characteristics of human rhabdomyosarcoma and translational applications.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, with overall long-term survival rates of ∼65-70%. Thus, additional molecular insights and representative models are critical for identifying and evaluating new treatment modalities. Using MyoD-Cre-mediated introduction of mutant K-RasG12D and perturbations in p53, we developed a novel genetically engineered mouse model (GEMM) for RMS. The anatomic sites of primary RMS development recapitulated human disease, including tumors in the head, neck, extremities and abdomen. We confirmed RMS histology and diagnosis through Hematoxylin and Eosin staining, and positive immunohistochemical staining for desmin, myogenin, and phosphotungstic acid-Hematoxylin. Cell lines from GEMM tumors were established with the ability to engraft in immunocompetent mice with comparable histological and staining features as the primary tumors. Tail vein injection of cell lines had high metastatic potential to the lungs. Transcriptomic analyses of p53R172H/K-RasG12D GEMM-derived tumors showed evidence of high molecular homology with human RMS. Finally, pre-clinical use of these murine RMS lines showed similar therapeutic responsiveness to chemotherapy and targeted therapies as human RMS cell lines.

Pathogenicity and impact of HLA class I alleles in aplastic anemia patients of different ethnicities.

Acquired aplastic anemia (AA) is caused by autoreactive T cell-mediated destruction of early hematopoietic cells. Somatic loss of human leukocyte antigen (HLA) class I alleles was identified as a mechanism of immune escape in surviving hematopoietic cells of some patients with AA. However, pathogenicity, structural characteristics, and clinical impact of specific HLA alleles in AA remain poorly understood. Here, we evaluated somatic HLA loss in 505 patients with AA from 2 multi-institutional cohorts. Using a combination of HLA mutation frequencies, peptide-binding structures, and association with AA in an independent cohort of 6,323 patients from the National Marrow Donor Program, we identified 19 AA risk alleles and 12 non-risk alleles and established a potentially novel AA HLA pathogenicity stratification. Our results define pathogenicity for the majority of common HLA-A/B alleles across diverse populations. Our study demonstrates that HLA alleles confer different risks of developing AA, but once AA develops, specific alleles are not associated with response to immunosuppression or transplant outcomes. However, higher pathogenicity alleles, particularly HLA-B*14:02, are associated with higher rates of clonal evolution in adult patients with AA. Our study provides insights into the immune pathogenesis of AA, opening the door to future autoantigen identification and improved understanding of clonal evolution in AA.

Transient Abnormal Myelopoeisis and Mosaic Down Syndrome in a Phenotypically Normal Newborn.

Transient abnormal myelopoiesis (TAM) is a common and potentially fatal neonatal complication of newborn babies with Down syndrome (DS). Children born with mosaic DS are also at risk of developing TAM. However, due to their variable phenotypes, early identification of patients with mosaic DS may be difficult; thus, early diagnosis of TAM is just as challenging. In this report, we describe a case of a phenotypically normal newborn who presented with concerns for neonatal leukemia. The diagnosis of mosaic DS and TAM was confirmed with abnormal GATA1 mutation testing, highlighting the importance of early GATA1 mutation testing in newborn leukemia with high suspicion for TAM.

Recent Insights into Therapy Resistance in Osteosarcoma.

Osteosarcoma, the most common bone malignancy of childhood, has been a challenge to treat and cure. Standard chemotherapy regimens work well for many patients, but there remain minimal options for patients with progressive or resistant disease, as clinical trials over recent decades have failed to significantly improve survival. A better understanding of therapy resistance is necessary to improve current treatments and design new strategies for future treatment options. In this review, we discuss known mechanisms and recent scientific advancements regarding osteosarcoma and its patterns of resistance against chemotherapy, radiation, and other newly-introduced therapeutics.

Rosette-Forming Glioneuronal Tumor of the Fourth Ventricle in Children: Case Report and Literature Review.

BACKGROUND: Rosette-forming glioneuronal tumor (RGNT) of the fourth ventricle is a rare World Health Organization (WHO) grade I neoplasm. Gross total resection (GTR) is the treatment of choice, and there is no firm evidence supporting other treatment options when GTR is not feasible. CASE DESCRIPTION: We report a 6-year-old boy who, following an initial subtotal resection of a fourth ventricular RGNT, received an individualized chemotherapy protocol with vincristine, etoposide, and carboplatin for 3 cycles. The tumor was stable for 2 years after the completion of chemotherapy but then began to progress, at which point GTR was successfully performed. In addition, we completed a comprehensive literature review of RGNT cases. To date, a total of 104 cases have been reported, 33 of which are pediatric cases. Recurrence has been reported in only 7 cases of all ages (4 in the pediatric population). Radiotherapy has been used in several cases, but adjuvant chemotherapy has been reported only once following a recurrence. CONCLUSIONS: We report a case of chemotherapy administration as a first-line treatment for a subtotally resected RGNT. Chemotherapy may be considered as an adjuvant therapy option for RGNT when GTR cannot be achieved. Furthermore, increased incidence of recurrence in the pediatric population may suggest that the tumor biology of RGNT in children differs from that in adults.

DNA Encapsulation of Ten Silver Atoms Produces a Bright, Modulatable, Near Infrared-Emitting Cluster.

Photostability, inherent fluorescence brightness, and optical modulation of fluorescence are key attributes distinguishing silver nanoclusters as fluorophores. DNA plays a central role both by protecting the clusters in aqueous environments and by directing their formation. Herein, we characterize a new near infrared-emitting cluster with excitation and emission maxima at 750 and 810 nm, respectively that is stabilized within C(3)AC(3)AC(3)TC(3)A. Following chromatographic resolution of the near infrared species, a stoichiometry of 10 Ag/oligonucleotide was determined. Combined with excellent photostability, the cluster's 30% fluorescence quantum yield and 180,000 M(-1)cm(-1) extinction coefficient give it a fluorescence brightness that significantly improves on that of the organic dye Cy7. Fluorescence correlation analysis shows an optically accessible dark state that can be directly depopulated with longer wavelength co-illumination. The coupled increase in total fluorescence demonstrates that enhanced sensitivity can be realized through Synchronously Amplified Fluorescence Image Recovery (SAFIRe), which further differentiates this new fluorophore.