Dabrafenib and trametinib in Langerhans cell histiocytosis and other histiocytic disorders.

The standard treatment for Langerhans cell histiocytosis (LCH) is chemotherapy, although the failure rates are high. Since MAP-kinase activating mutations are found in most cases, BRAF- and MEK-inhibitors have been used successfully to treat patients with refractory or relapsed disease. However, data on long-term responses in children are limited and there are no data on the use of these inhibitors as first-line therapy. We treated 34 patients (26 with LCH, 2 with juvenile xanthogranuloma, 2 with Rosai-Dorfman disease, and 4 with presumed single site-central nervous system histiocytosis) with dabrafenib and/or trametinib, either as first line or after relapse or failure of chemotherapy. Sixteen patients, aged 1.3-21 years, had disease that was recurrent or refractory to chemotherapy, nine of whom had multisystem LCH with risk-organ involvement. With a median treatment duration of 4.3 years, 15 (94%) patients have sustained favorable responses. Eighteen patients, aged 0.2-45 years, received an inhibitor as first-line treatment. All of these have had sustained favorable responses, with a median treatment duration of 2.5 years. Three patients with presumed isolated central nervous system/pituitary stalk histiocytosis had stabilization or improvement of their disease. Overall, inhibitors were well tolerated. Five patients with single-system LCH discontinued therapy and remain off therapy without recurrence. In contrast, all four patients with multisystem disease who discontinued therapy had to restart treatment. Our data suggest that children suffering from histiocytoses can be treated safely and effectively with dabrafenib or trametinib. Additional studies are, however, needed to determine the long-term safety and optimal duration of therapy.

Scheduled administration of virus-specific T cells for viral prophylaxis after pediatric allogeneic stem cell transplant.

Infections with double-stranded DNA viruses are a significant cause of morbidity and mortality in pediatric patients following allogeneic hematopoietic stem cell transplantation (HSCT). Virus-specific T-cell therapies (VSTs) have been shown to be an effective treatment for infections with adenovirus, BK virus, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). To date, prophylactic regimens to prevent or mitigate these infections using conventional antiviral medications provide suboptimal response rates. Here we report on a clinical trial (NCT03883906) performed to assess the feasibility of rapid manufacturing and early infusion of quadrivalent VSTs generated from stem cell donors ("donor-derived VSTs") into allogeneic HSCT recipients with minimal or absent viremia. Patients were eligible to receive scheduled VSTs as early as 21 days after stem cell infusion. Twenty-three patients received scheduled VSTs. Twenty of 23 patients had no viremia at the time of infusion, while 3 patients had very low-level BK viremia. Two developed clinically significant graft-versus-host disease (GVHD), although this incidence was not outside of expected incidence early after HSCT, and both were successfully treated with systemic corticosteroids (n = 2). Five patients were deemed treatment failures. Three developed subsequent significant viremia/viral disease (n = 3). Eighteen patients did not fail treatment, 7 of whom did not develop any viremia, while 11 developed low-level, self-limited viremia that resolved without further intervention. No infusion reactions occurred. In conclusion, scheduled VSTs appear to be safe and potentially effective at limiting serious complications from viral infections after allogeneic transplantation. A randomized study comparing this scheduled approach to the use of VSTs to treat active viremia is ongoing.

Discrepancies between F-18-FDG PET/CT findings and conventional imaging in Langerhans cell histiocytosis.

BACKGROUND: Accurate risk stratification of Langerhans cell histiocytosis (LCH) is essential as management can range from conservative in single system, low risk for central nervous system (CNS) involvement lesions to intensive chemotherapy for multisystem or high-risk disease. Additionally, being able to differentiate metabolically active from inactive lesions is essential for both prognostic reasons and to avoid potentially unnecessary treatment. METHODS: A retrospective review was performed on all patients with histopathology-confirmed LCH at Cincinnati Children's Hospital Medical Center (CCHMC) between 2009 and 2019. RESULTS: One hundred seven positron emission tomography (PET)/computerized tomography (CT) images were included in the review. A discrepancy between PET/CT and conventional imaging occurred on 53 occasions. On 13 occasions, increased uptake was observed on PET in an area with no identifiable lesion on conventional imaging. On 40 occasions, lesions were found on conventional imaging where no increased uptake was observed on PET. On eight skeletal surveys, three other radiographs, four diagnostic CTs, five localization CTs, and one bone scan, no lesion was identified in an area with increased fluorodeoxyglucose (FDG) uptake. This occurred exclusively in bone. On nine skeletal surveys, one other radiograph, four diagnostic CTs, six localization CTs, 19 magnetic resonance imaging (MRI) scans, and one bone scan, a lesion was identified in a location without increased FDG uptake. This occurred in bone, CNS, and lungs. CONCLUSION: F-18-FDG PET/CT is vital in the evaluation of LCH lesions given its ability to detect LCH lesions not detectable on conventional imaging modalities, as well as its ability to distinguish metabolically active from inactive disease. MRI and diagnostic CT are still useful adjunctive tests for identification of CNS and lung lesions.

Implementing video visits into an orthopedic hip arthroscopy practice: a case study.

Telehealth videoconferencing has been shown to be feasible, cost-effective and safe in numerous fields of medicine. In an effort to increase access and improve the quality of care offered to patients we implemented a telehealth initiative allowing for remote orthopedic clinic visits at a major academic medical center. Here we report on our experience and early outcomes. A telehealth platform was launched for a single fellowship trained orthopedic surgeon at a major academic hospital in August 2018. New patients residing outside the metro area, all return patients and patients with an uncomplicated post-operative course were offered the option to complete patient encounters remotely via a telehealth platform. Each patient was offered a Patient Satisfaction Survey following video visit. Patient zip codes were used to estimate patient commutes. Ninety-six percent of patients agreed/strongly agreed with the statement 'I was satisfied with my Telehealth experience' while 51% agreed/strongly agreed with the statement 'This visit was just as good as a face to face visit'. In all, 94% of patients agreed/strongly agreed with the statement 'Having a telehealth visit made receiving care more accessible for me'. The median miles saved on commutes were 123.3 miles. The no show rate for telehealth visits was 8.2% versus 3.2% for in-person (P < 0.001). Telehealth video visits provided patients with a modality for completing orthopedic clinic visits while maintaining a high-quality care and patient satisfaction. Patient convenience was optimized with video visits with elimination of long commutes. Level of evidence: IV.

Outcomes after bloodstream infection in hospitalized pediatric hematology/oncology and stem cell transplant patients.

BACKGROUND: Pediatric hematology/oncology (PHO) patients receiving therapy or undergoing hematopoietic stem cell transplantation (HSCT) often require a central line and are at risk for bloodstream infections (BSI). There are limited data describing outcomes of BSI in PHO and HSCT patients. METHODS: This is a multicenter (n = 17) retrospective analysis of outcomes of patients who developed a BSI. Centers involved participated in a quality improvement collaborative referred to as the Childhood Cancer and Blood Disorder Network within the Children's Hospital Association. The main outcome measures were all-cause mortality at 3, 10, and 30 days after positive culture date; transfer to the intensive care unit (ICU) within 48 hours of positive culture; and central line removal within seven days of the positive blood culture. RESULTS: Nine hundred fifty-seven BSI were included in the analysis. Three hundred fifty-four BSI (37%) were associated with at least one adverse outcome. All-cause mortality was 1% (n = 9), 3% (n = 26), and 6% (n = 57) at 3, 10, and 30 days after BSI, respectively. In the 165 BSI (17%) associated with admission to the ICU, the median ICU stay was four days (IQR 2-10). Twenty-one percent of all infections (n = 203) were associated with central line removal within seven days of positive blood culture. CONCLUSIONS: BSI in PHO and HSCT patients are associated with adverse outcomes. These data will assist in defining the impact of BSI in this population and demonstrate the need for quality improvement and research efforts to decrease them.

Exploitation of the Apoptosis-Primed State of MYCN-Amplified Neuroblastoma to Develop a Potent and Specific Targeted Therapy Combination.

Fewer than half of children with high-risk neuroblastoma survive. Many of these tumors harbor high-level amplification of MYCN, which correlates with poor disease outcome. Using data from our large drug screen we predicted, and subsequently demonstrated, that MYCN-amplified neuroblastomas are sensitive to the BCL-2 inhibitor ABT-199. This sensitivity occurs in part through low anti-apoptotic BCL-xL expression, high pro-apoptotic NOXA expression, and paradoxical, MYCN-driven upregulation of NOXA. Screening for enhancers of ABT-199 sensitivity in MYCN-amplified neuroblastomas, we demonstrate that the Aurora Kinase A inhibitor MLN8237 combines with ABT-199 to induce widespread apoptosis. In diverse models of MYCN-amplified neuroblastoma, including a patient-derived xenograft model, this combination uniformly induced tumor shrinkage, and in multiple instances led to complete tumor regression.