A retrospective analysis of recurrent pediatric ependymoma reveals extremely poor survival ind ineffectiveness of current treatments across central nervous locations and molecular subgroups. Tryggve Lundar MD, PhD1,2, Bernt Johan Due-Tønnessen MD,PhD1Radec Fric MD,PhD1Department of Neurosurgery, Oslo University Hospital1and University of Oslo2Correponding author:Tryggve LundarDepartment of NeurosurgeryOslo University HospitalPostboks 4950 Nydalen, Oslo, NorwayEmail: email@example.comTotal word count: 474Short running title: GTR can improve outcome after relapse of pediatric ependymomaKey words: Pediatric ependymoma, relapse, repeat surgical resection (GTR)Number of tables: 0Number of figures: 0Letter to the EditorPediatr Blood CancerDear Editor,RE: Ritzmann TA, Rogers HA, Paine SML, Storer LCD, Jacques TS, Chapman RJ, Ellison D, Donson AM, Foreman NK, Grundy RG.A retrospective analysis of recurrent pediatric ependymoma reveals extremely poor survival ind ineffectiveness of current treatments across central nervous locations and molecular subgroups.Pediatr Blood Cancer 2020;67:e28426https://doi.org/10.1002/pbc.28426Congratulations to the authors with their detailed analysis of further management and outcome in pediatric patients who experience recurrence within a few years after initial treatment for ependymomas.Initial treatment for posterior fossa ependymomas (PFE) is maximal surgical resection (Gross total resection-GTR; if possible) followed by local radiotherapy or chemotherapy in small children. For supratentorial ependymomas (STE) GTR is also recommended (if possible) with or without postoperative radiotherapy.The management at relapses is, however, without consensus. The authors confirm the grave prognosis for these children. In the beginning of the discussion they state: Although primary surgery and irradiation reduced relapse risk variability in different intracranial locations, once a patient recurred these interventions gave, at best, short-term benefits, confirming the need for better therapies.This of course true – better therapies are urgently needed. They point to the lack of consensus regarding treatment at relapse, but recent guidelines have recommended the use of reirradiation and further surgery. In the conclusion they underline that recurrent pediatric ependymoma is highly aggressive with extremely poor outcome.This negative statement, is to some extent, in conflict with the results given under 3.5.2. At relapse: GTR at first relapse was associated with sustained improved EFS (25% vs 0% 10-year survival).This statement is in accord with Vinchon et al1 : Total resection is the only curative treatment for RIE (recurrent intracranial ependymoma) and is often possible, especially when the initial resection was total.How often GTR is within reach at local relapes may be a difficult matter. We have, however, observed several patients who underwent GTR after recurrence, and are tumor-free today after many years of further follow-up(up to 27 years) without any additional treatment2. We recognize that these patients are few compared to the majority of pediatric ependymoma patients who do not grow-up to be well functioning adults. It is, however, important for these small patients and their caretakers to have a hope for cure even after relapse. The role of GTR if possible may be under-communicated.Kind regardsTryggve LundarBernt Johan Due-TønnessenRadek Fric
SUCCESSFUL USE OF CRUSHED FORMULATION OF DABRAFENIB AND TRAMETINIB IN A PEDIATRIC GLIONEURAL TUMORTania Mamdouhi1, Anshul Vagrecha2, Alan A. Johnson1,3, Carolyn Fein Levy1,2, Mark Atlas 1,2, Julie I. Krystal 1,2 1 Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY2 Department of Pediatrics, Division of Hematology/Oncology and Cellular Therapy, Cohen Children’s Medical Center, New Hyde Park, NY3 Department of Radiology, Division of Neuroradiology, Long Island Jewish Medical Center, New Hyde Park, NYCorresponding Author : Julie Krystal. Cohen Children’s Medical Center, 269- 01 76th Avenue, Suite 255, New Hyde Park, NY 11040. Jkrystal12@northwell.edu. Phone 718-470-3460. Fax 718-343-4642.Tables: 0Figures: 1Supporting Information Files : 0Short running title: Use of crushed formulation of dabrafenib and trametinibKeywords : Dabrafenib, Trametinib, BRAF, crushedData Availability: The data that support the findings of this study are available from the corresponding author upon reasonable request.
Multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 infection with clinical features of Kawasaki-like disease was reported in various pediatric centers in late April 2020. Currently, cases have increased throughout the world with a range of manifestations from less to greater severity. However, hemophagocytosis has not been described in patients with MIS-C. We describe two infants diagnosed with MIS-C who presented Macrophage Activation Syndrome (MAS) with hemophagocytosis documented in the bone marrow. MIS-C can be complicated with MAS, the key features for diagnosis are splenomegaly, hypofibrinogenemia, hypertriglyceridemia and bone marrow hemophagocytosis. Cytokine storm and MAS in MIS-C may represent part of the spectrum of the disease and HScore could be of value in order to give timely and aggressive treatment.
Unusual ovarian leukemic relapse in a girl with history of B cell lymphoblastic leukemiaACH Fung, KKY WongTo the editor:Extramedullary leukemic recurrence mostly occurs in the central nervous system and occasionally in the skin.  Here, we report an unusual case of a girl with relapsed lymphoblastic leukemia involving the ovary, presenting as a large pelvic mass.A 10-year-old girl with history of B cell lymphoblastic leukaemia treatment and in remission 1 year ago presented to oncology clinic with an enlarging pelvic mass for 2 months. Magnetic resonance imaging revealed a large lobulated solid heterogeneous pelvic mass (measuring 12cm in greatest dimension) with mass effect on pelvic organs (Figure 1a). Bone marrow aspirate at conventional site confirmed absence of lymphoblastic cells, which would have suggested leukaemia relapse. In view of the suspicion of a second primary tumour in the ovary with complication, exploratory laparotomy and left salpingo-oophorectomy were performed (Figure 1b). Histology showed diffuse infiltration of the ovary by B cell lymphoblastic leukaemia. Hematoxylin and eosin staining showed sheets of lymphoid cells with irregular nuclei. The tumour cells are positive for TdT, CD19, CD79a and CD34. (Figure 1c) She was well after operation. In view of extramedullary relapse, bone marrow aspirate was repeated after operation at anterior iliac spine which confirmed bone marrow relapse. She received treatment according to high risk protocol of CCCG Relapsed Acute Lymphoblastic Leukemia 2017 Study in Children .Acute lymphoblastic leukaemia (ALL) is responsible for one-third of childhood malignancy. Despite efforts in the treatment of ALL, 15-20% of patients developed relapse with highest risk immediately after cessation of treatment and diminishes with time.  Extramedullary involvement constitutes 2-5% of all relapses with the majority in the central nervous system. It seldom involves other sites, such as the eye, kidney, and omentum. Ovarian leukemic relapse is rarely reported in children with scarce case reports in the literature [4, 5] It is insidious and not usually detected until symptoms arise. Patient most commonly presents with lower abdominal pain or a palpable large abdominal mass.  Timely detection is important as it often coincides with marrow recurrence. Routine surveillance pelvic sonography is recommended for timely detection of pelvic extramedullary relapse. In patients with background of leukaemia presenting with an ovarian mass, a higher level of suspicion needs to be kept. In the absence of evidence in bone marrow relapse at conventional site, repeat marrow aspirate at another site would be warranted since this affect the choice of management. Previous reports shown that mainly chemotherapy had a beneficial effect, while neither local radiation nor extensive surgical resection of the leukaemic mass had any obvious effect on overall outcome . Operation could have been avoided if marrow relapse is confirmed at the time of ovarian mass detection. However, surgical excision was reported to have role in situation when bone marrow had good response but no signs of regression of ovarian mass. Reference1. Kim, J.W., et al., Ovarian and multiple lymph nodes recurrence of acute lymphoblastic leukemia: a case report and review of literature. Pediatr Surg Int, 2008. 24 (11): p. 1269-73.2. CCCG Relapsed Acute Lymphoblastic Leukemia 2017 Study in Children .https://ClinicalTrials.gov/show/NCT04224571.3. Berretta, R., et al., Isolated ovarian relapse of pre-B acute lymphoblastic leukemia: a case report. J Pediatr Adolesc Gynecol, 2009.22 (4): p. e65-8.4. Kantekure, K., et al., A unique case of relapsed B-acute lymphoblastic leukemia/lymphoma as an isolated omental mass. Case Rep Hematol, 2014. 2014 : p. 425163.5. Sava, C.N., et al., Unusual extramedullary relapses in a case of common B-cell acute lymphoblastic leukemia. Case report and review of literature. Rom J Morphol Embryol, 2019. 60 (1): p. 249-254.6. Turial, S., et al., Ovarian tumours: late extramedullary recurrence of acute leukaemia. Eur J Pediatr Surg, 2009.19 (3): p. 184-6.7. Lane, D.M. and R.L. Birdwell, Ovarian leukemia detected by pelvic sonography. A case report. Cancer, 1986. 58 (10): p. 2338-42.8. Pais, R.C., et al., Ovarian tumors in relapsing acute lymphoblastic leukemia: a review of 23 cases. J Pediatr Surg, 1991.26 (1): p. 70-4.9. Till, H., O. Muensterer, and U. Graubner, Laparoscopic adnexectomy of a persistent ovarian tumor in a girl with acute lymphoblastic leukemia relapse. Pediatr Hematol Oncol, 2003.20 (5): p. 417-20.
Background: Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy has been established as a novel treatment approach for peritoneal sarcomatosis. Despite promising clinical reports, there is still a lack of knowledge regarding optimal drug usage and local effects. Therefore, we intended to establish a murine animal model for further evaluation. Procedure: Alveolar rhabdomyosarcoma cells were xenotransplanted into NOD/LtSz-scid IL2Rγnullmice (n=100). The mice received a continuous intraperitoneal lavage with isotonic saline solution as control- or with cisplatin (30 or 60 mg/m2) as treatment group for 60 minutes at 37 or 42 °C (6 subgroups, each n=16). Tumor spread was documented by an adapted peritoneal cancer index and MRI (n=4). Tumor and tissue samples, harvested at the end of the perfusion, were evaluated regarding morphology, proliferation and apoptosis (H&E-, Ki-67-, Cleaved Caspase 3-staining, TUNEL-assay). Results: Extensive peritoneal sarcomatosis in over 91% of the cases was observed. HIPEC was feasible without acute side effects. Ki-67 staining revealed concentration- or temperature-dependent effects of cisplatin-based HIPEC on the tumors. While Cleaved Caspase-3 showed only sporadic apoptotic effects. TUNEL-assay detected concentration- or temperature-dependent apoptotic effects at the outer tumor surface. MRI scans confirmed the observed tumor dissemination. Conclusion: This is the first animal model for evaluation of HIPEC in pediatric RMS in mice. Cisplatin-based HIPEC had early effects on the proliferation whereas circumscribed apoptotic effects could be detected at the tumor surface. This model allows further insights on the possible efficiency of HIPEC in RMS. Further studies using other drug combinations and treatment will follow.
Background Previous studies have explored post-hematopoietic cell transplant (HCT) outcomes by race in adults; however, pediatric data addressing this topic are scarce. Procedure This retrospective registry study included 238 White (W) and 57 Black (B) children with hematologic malignancies (HM) receiving first allogeneic HCT between 2010 and 2019 in one of five Florida pediatric HCT centers. Results We found no differences between W and B children by transplant characteristics, other than donor type. There was a significant difference in use of HLA-mismatched donors (HLA-MMD) (53% W, 71% B, p=0.01). When comparing HLA-MMD use to fully HLA-matched donors, B had RR of 1.47 [95% CI 0.7-3] of receiving a mismatched unrelated donor (MMUD), RR of 2.34 [95% CI 1.2-4.4] of receiving a mismatched related donor (MMRD), and a RR of 1.9 [95% CI 0.99-3.6] of receiving a mismatched cord blood donor (MMCBD) HCT, respectively. There was no significant difference in the incidence of aGVHD (48% W, 35% B), p=0.1 or cGVHD (19% W 28% B, p=0.1), or primary cause of death. Overall 24-month survival was 61% [95% CI 54-68%] for W, and 60% [95% CI 38-68] for B children, log-rank p=0.72. While HLA matching improved survival in W children, the number of B children receiving HLA-matched HCT was too small to identify the impact of HLA matching on survival. Conclusions In this contemporary cohort of children with HM we found that B children were more likely to receive HLA-MMD transplants, but this did not adversely affect survival or GVHD rates.
Background – Loss of bone mineral is a common concomitant of the treatment of acute lymphoblastic leukemia (ALL) due mainly to chemotherapy, especially with corticosteroids. Osteopenia/osteoporosis may persist long into survivorship. Measurement of bone mineral density (BMD) by dual energy X-ray absorptiometry is limited to two-dimensionality and cannot distinguish trabecular from cortical bone. Methods – A sample of 74 subjects, more than 10 years from diagnosis, underwent peripheral quantitative computed tomography (pQCT) at metaphyseal (trabecular bone) and diaphyseal (cortical bone) sites in the radius and tibia. pQCT provides three-dimensional assessment of bone geometry, density and architecture. Results – Similarities of average values in multiple metrics with those in healthy subjects obscured deficits in both trabecular and cortical bone, as well as bone strength, revealed by Z scores using an ethnically comparable sample of healthy individuals. Connectivity, a measure of bone architecture and a surrogate measure of bone strength, was lower in females than males. Survivors of standard risk ALL had greater connectivity in and more compact trabecular bone than high risk survivors who had received more intensive osteotoxic chemotherapy. There were no statistically significant differences in any of the metrics at any of the sites between subjects who had or had not a history of fracture, cranial irradiation or use of a bisphosphonate. Conclusions – These long-term survivors of ALL have somehat compromised bone health, but data in comparable healthy populations are limited. Longitudinal studies in larger and more ethnically diverse cohorts will provide greater insight into bone health in this vulnerable population.
BACKGROUND: Workplace burnout can result in negative consequences for clinicians and patients. We assessed burnout prevalence and sources among pediatric hematology/oncology inpatient nurses, ambulatory nurses, physicians (MDs), and advanced practice providers (APPs) by evaluating effects of job demands and involvement in patient safety events (PSEs). METHODS: A cross-sectional survey (Maslach Burnout Inventory) measured emotional exhaustion, depersonalization, and reduced personal accomplishment. The NASA Task Load Index measured mental demand, physical demand, temporal demand, effort, and frustration. Relative weights analyses estimated the unique contributions of tasks and PSEs on burnout. Post-hoc analyses evaluated open-response comments for burnout factors. RESULTS: Burnout prevalence was 33%, 20%, 34% and 33% in inpatient nurses, ambulatory nurses, and MD, and APPs respectively (N=481, response rate 69%). Reduced personal accomplishment was significantly higher in inpatient nurses than MDs & APPs. Job frustration was the most significant predictor of burnout across all four cohorts. Other significant predictors of burnout included temporal demand (nursing groups & MDs) effort (inpatient nurses & MDs) and PSE involvement (ambulatory nurses). Open-response comments identified time constraints, lack of administrator support, insufficient institutional support for self-care, and inadequate staffing and/or turnover as sources of frustration. CONCLUSIONS: All four clinician groups reported substantial levels of burnout, and job demands predicted burnout. The body of knowledge on job stress and workplace burnout supports targeting organizational-level sources, versus individual-level factors, as the most effective prevention and reduction strategy. This study elaborates on this evidence by identifying structural drivers of burnout within a multidisciplinary context of pediatric hematology/oncology clinicians.
Background: Children with cancer diagnosis are overall at a higher risk of thrombosis. For a newly diagnosed bland thrombus, patients are commonly started on anticoagulants to prevent further extension and embolization of the clot. In the rare instance that a pediatric patient has a tumor thrombus, the role of anticoagulation is less clear. Procedure/Methods: Patients under 21 years of age with a finding of tumor thrombus on imaging from 2010-2020 at Texas Children’s Hospital were identified and their medical records were reviewed. Results: A total of 50 patients were identified. Most thrombi were incidental findings at diagnosis; however, there were two patients who presented with pulmonary embolism (PE). Inferior Vena Cava extension was noted in 36% of the patients and 24% patients had an intracardiac tumor thrombus. Hepatoblastoma (26%) was the most common malignancy associated with tumor thrombus. Anticoagulation was initiated in 10 patients (20%). Only 2 of these 10 patients showed response to anticoagulation. However, 40% (4/10) patients in the anticoagulation cohort were noted to have bleeding complications (p <.05). Conclusion: Children with intravascular extension of solid tumors were not commonly started on anticoagulation at the time of diagnosis, irrespective of the extent of tumor thrombus. Furthermore, we observed a significant trend toward higher incidence of bleeding complications after initiation of anticoagulation. There is inadequate evidence at this time to support routine initiation of anticoagulation in pediatric patients with intravascular extension of solid tumors.
Pancreatoblastoma (PBL) is a rare malignant epithelial neoplasm affecting typically young children. Signs related to advanced upper-abdominal tumor accompanied by elevated serum α-fetoprotein levels in a young child suggest PBL, however histopathological examination is required for diagnosis. The mainstay of treatment is a complete surgical resection. Inoperable and/or metastatic PBL may become amenable to complete, delayed surgery after neo-adjuvant chemotherapy. This manuscript presents the internationally consensus recommendations for the diagnosis and treatment of children with PBL, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the EU-funded PARTNER (Paediatric Rare Tumors Network – European Registry) project.
As part of the European Union-funded project designated PARTN-ER, the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) is continuously developing consensus recommendations in order to harmonize standard care for very rare solid tumors of children and adolescents. This paper presents the internationally recognized recommendations for the diagnosis and treatment of sex cord stromal tumors (SCST). The clinical approach to sex cord stromal tumors of the testis (TSCST) and ovary (OSCST) depends on histological differentiation and tumor stage. Virtually all TSCSTs present as localized non-metastatic tumors, with excellent prognosis after complete resection. In contrast, the prognosis of OSCSTs may be adversely affected by tumor spillage during surgery or presence of metastases. In these cases, cisplatin-based chemotherapy is recommended. Of note, some SCSTs may develop in the context of tumor predisposition syndromes e.g. DICER-1, so that specific follow-up is indicated. SCSTs should be diagnosed and treated according to standardized recommendations that include reference pathology, genetic testing for tumor predisposition syndromes in selected cases, and stratified adjuvant chemotherapy in patients with unfavorable risk profile. To ensure high quality of diagnosis and therapy, patients should be enrolled into prospective registries.
Background: The provision of Section 2302 of the 2010 Patient Protection and Affordable Care Act (ACA) allowed pediatric patients who are enrolled in Medicaid to receive hospice care concurrently with curative treatment (i.e., concurrent hospice care). Because it is a relatively new model of care and very little is known about the characteristics of children with cancer who receive it, the purpose of the current study was to compare demographic, health, and community characteristics of children who received standard hospice care versus concurrent hospice care. Procedure: This study was a retrospective, comparison study with national Medicaid files provided by the Center for Medicare and Medicaid Services (CMS). The sample included 1,685 pediatric patients under the age of 20 who were diagnosed with cancer, were enrolled in hospice between 2011 and 2013, and received standard hospice care (n= 1,008) or concurrent hospice care (n = 655). Results: Children of non-Caucasian race with multiple complex chronic conditions, mental/behavioral health problems technology dependence, and brain and orbital tumors, were more likely to be enrolled in concurrent care than in standard hospice care. The proportion of children enrolled in concurrent care versus standard hospice care was larger in rural areas, low-income communities, and in the Southern states. Conclusions: The enhanced uptake of concurrent care by traditionally underserved populations is promising. Concurrent hospice care, which allows for continued medical treatment and hospice care, could enhance access to hospice within these populations by offering a more blended model of care.
Background Outcomes of Ewing sarcoma (ES) in low and middle income countries lags behind the rest of the world owing to multiple tumoral, logistical and socio-economic factors. The data of outcomes and toxicity in these countries is sparse, especially in the adolescent and adult (AA) population and merits exploration Procedure This was a retrospective analysis of prospectively collected data of non-metastatic AA-ES patients, who received standard institutional combination chemotherapy regimen (EFT-2001) along with surgery or definitive radiotherapy. Various cohorts were analyzed for treatment-related toxicities, event- free survival (EFS) and overall survival (OS). Results There were 235 patients (primary safety cohort, PSC) with median age of 23 years. One hundred and ninety six were treatment naïve (primary efficacy cohort, PEC) and of these 119 had surgery. In PEC, at a median follow up of 36.4 months, estimated 5 year EFS and OS were 60.9% (95% CI 53.1% - 69.9%) and 84.5% (95% CI 77.7% - 91.9%), respectively. Of these, 158 complying with intended treatment, had an estimated 5 year EFS of 63.1% (95% CI 54.8%-72.6%). In multivariate analysis, good prognostic factors included longer symptom duration, ≥ 99% necrosis and treatment completion. Among PSC, grade 3-4 toxicities were febrile-neutropenia (50.6%), anemia (55.3%), peripheral neuropathy (15.7%), with 3 (1.3%) chemo-toxic deaths. Conclusions The outcomes of AA non-metastatic ES patients treated with EFT-2001 regimen were comparable to those reported by others, with acceptable toxicity and can be considered as standard-of-care, especially in LMICs.