The derivation and maintenance of human pluripotent stem cells (hPSCs) in stable naïve pluripotent states has a wide impact in human developmental biology. However, hPSCs are unstable in classical naïve mouse embryonic stem cell (ESC) WNT and MEK/ERK signal inhibition (2i) culture. We show that a broad repertoire of conventional hESC and transgene-independent human induced pluripotent stem cell (hiPSC) lines could be reverted to stable human preimplantation inner cell mass (ICM)-like naïve states with only WNT, MEK/ERK, and tankyrase inhibition (LIF-3i). LIF-3i-reverted hPSCs retained normal karyotypes and genomic imprints, and attained defining mouse ESC-like functional features, including high clonal self-renewal, independence from MEK/ERK signaling, dependence on JAK/ STAT3 and BMP4 signaling, and naïve-specific transcriptional and epigenetic configurations. Tankyrase inhibition promoted a stable acquisition of a human preimplantation ICM-like ground state via modulation of WNT signaling, and was most efficacious in efficiently reprogrammed conventional hiPSCs. Importantly, naïve reversion of a broad repertoire of conventional hiPSCs reduced lineage-primed gene expression and significantly improved their multilineage differentiation capacities. Stable naïve hPSCs with reduced genetic variability and improved functional pluripotency will have great utility in regenerative medicine and human disease modeling.

When pediatric, adolescent, and young adult patients present with a bone sarcoma, treatment decisions, especially after relapse, are complex and require a multidisciplinary approach. This review presents scenarios commonly encountered in the therapy of bone sarcomas with the goal of objectively presenting a consensus, multidisciplinary management approach. Little variation was found in the authors' group with respect to local control or systemic therapy. Clinical trials were universally prioritized in all settings. Decisions regarding relapse therapies in the absence of a clinical trial had very minor variations initially, but a consensus was reached after a literature review and discussion. This review presents a concise document and figures as a starting point for evidence‐based care for patients with these rare diseases. This framework allows prospective decision making and prioritization of clinical trials. It is hoped that this framework will inspire and focus future clinical research and thus lead to new trials to improve efficacy and reduce toxicity. Cancer 2017;123:2206–2218. © 2017 American Cancer Society.

Optimal treatment of rhabdomyosarcoma (RMS) requires multidisciplinary approach, incorporating chemotherapy with local control. Although current therapies are built on cooperative group trials, a comprehensive standard of care to guide clinical decision making has been lacking, especially for relapsed patients. Therefore, we assembled a panel of pediatric and adolescent and young adult sarcoma experts to develop treatment guidelines for managing RMS and to identify areas in which further research is needed. We created algorithms incorporating evidence-based care for patients with RMS, emphasizing the importance of clinical trials and close integration of all specialties involved in the care of these patients.

Background Even though virtually all Ewing sarcoma patients achieve a radiographic complete response, up to 30% of patients who present with localized disease and up to 90% of those who present with metastases suffer a metastatic relapse, highlighting our inability to identify patients with residual disease at the end of therapy. Up to 95% of Ewing sarcomas carry a driving EWS-ETS translocation which has an intronic breakpoint that is specific to each tumor, and we developed a system to quantitatively detect the specific breakpoint DNA fragment in patient plasma. Methods We used a long range multiplex PCR technique to identify tumor-specific EWS-ETS breakpoints in Ewing sarcoma cell lines, patient derived xenografts, and patient tumors, and this sequence was used to design tumor specific primer sets to detect plasma tumor DNA (ptDNA) by droplet digital PCR (ddPCR) in xenograft bearing mice and patients. Results Tumor specific breakpoint DNA fragments were detected in the plasma of xenograft bearing mice, and signal correlated with tumor burden during primary tumor growth, following surgical resection, and upon metastatic relapse. Furthermore, we were able to detect the specific breakpoint in plasma DNA obtained from 3 patients with Ewing sarcoma, and in 2 patients, we were able to detect ptDNA when there was radiographically undetectable disease present. Conclusions Use of ddPCR to detect tumor specific EWS-ETS fusion gene breakpoint ptDNA fragments can be developed into a highly personalized biomarker of relapse that can be optimized in animal studies for ultimate use in patients.

Allogeneic (allo-) hematopoietic stem cell transplant (HSCT) is curative for many nonmalignant pediatric disorders, including hemoglobinopathies, bone marrow failure syndromes, and immunodeficiencies. There is great success using HLA-matched related donors for these patients; however, the use of alternative donors has been associated with increased graft failure, graft versus host disease (GVHD), and transplant-related mortality (TRM). HSCT using alternative donors with post-transplantation cyclophosphamide (PT/Cy) for GVHD prophylaxis has been performed for hematologic malignancies with engraftment, GVHD, and TRM comparable to that seen with HLA-matched related donors. There are limited reports of HSCT in nonmalignant pediatric disorders other than hemoglobinopathies using alternative donors and PT/Cy. We transplanted eleven pediatric patients with life-threatening nonmalignant conditions using reduced intensity conditioning (RIC), alternative donors, and PT/Cy alone or in combination with tacrolimus and mycophenolate mofetil. We observed limited GVHD, no TRM, and successful engraftment sufficient to eliminate manifestations of disease in all patients. Allo-HSCT using alternative donors and PT/Cy shows promise for curing nonmalignant disorders; development of prospective clinical trials to confirm these observations is warranted.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is characterized by normal development followed by a sudden, rapid hyperphagic weight gain beginning during the preschool period, hypothalamic dysfunction, and central hypoventilation. [1][2][3] Without intervention, symptoms progress leading to substantial morbidity and mortality. [1][2][3] In addition, these patients display poorly characterized mood disorders, personality changes, and developmental regression, including loss of toilet-training, and behavior mimicking autism spectrum disorders. 1,2,[4][5][6] The etiology of ROHHAD is unknown and careful investigations have not revealed a genetic etiology. 2, 7-9 The association with neural crest tumors suggests an immune-mediated process resembling opsoclonus myoclonus ataxia syndrome. 2,5,7,10 Lymphocytic infiltration of the brain, 11, 12 presence of oligoclonal bands in the cerebrospinal fluid, 13 and response to immunomodulary therapy 5, 14 support an autoimmune process.High-dose cyclophosphamide (Hi-Cy) results in near total ablation of active lymphocytes without myeloablation, thereby "rebooting" the immune system, making it an efficacious and safe approach for selected patients with severe refractory autoimmune diseases. 5,15 We previously reported on a child with ROHHAD whose symptoms improved after Hi-Cy. 5 We now describe serial neuropsychological assessments of 2 consecutive, similarly treated abstract Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare, generally progressive, and potentially fatal syndrome of unclear etiology. The syndrome is characterized by normal development followed by a sudden, rapid hyperphagic weight gain beginning during the preschool period, hypothalamic dysfunction, and central hypoventilation, and is often accompanied by personality changes and developmental regression, leading to substantial morbidity and mortality. We describe 2 children who had symptomatic and neuropsychological improvement after high-dose cyclophosphamide treatment. Our experience supports an autoimmune pathogenesis and provides the first neuropsychological profile of patients with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation.

Background Outcomes for patients with oncologic disease and/or after hematopoietic stem cell transplant (HSCT) requiring intensive care unit admission have improved, but indications for and outcomes after extracorporeal membrane oxygenation (ECMO) support in this population are poorly characterized. Procedure We analyzed data from consecutive patients < 18 years with oncologic disease and/or after HSCT reported to a pediatric ECMO registry by nine pediatric centers in the United States between 2011 and 2018. Results We identified 18 ECMO patients with oncologic disease and/or HSCT, and 415 ECMO controls matched with a propensity score algorithm based on age, gender, race, severity of illness at admission, and reason for ECMO. The primary indication for ECMO was respiratory failure in 66.7% in the oncologic disease and/or HSCT group, and in 70.7% in the matched ECMO control group. Eleven of 18 patients survived to hospital discharge (61.1%), similar to the matched control group (60.8%), P = 0.979. Children with oncologic disease and/or HSCT had lower mean platelet counts during ECMO and received higher volumes of platelets compared with the control group, mean 14.6 mL/kg/day (standard deviations [SD], 9.8) versus mean 9.3 mL/kg/day (SD, 10.4), P = 0.001. Of the 11 surviving children with oncologic disease and/or HSCT, five sustained new neurologic disorders (45.5%) versus 45 of 222 (20.3%) in the control group, P = 0.061. Bleeding complications were similar in the two groups. Conclusions Outcomes of patients with oncologic disease and/or HSCT supported on ECMO in the current era are not significantly different compared with matched ECMO controls and are improved from previously published reports.

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