Optimized peripheral blood progenitor cell mobilization for autologous hematopoietic cell transplantation in children with high-risk and refractory malignancies.

BACKGROUND: Autologous hematopoietic stem cell transplantation (aHSCT) using hematopoietic progenitor cells (HPCs) has become an important therapeutic modality for patients with high-risk malignancies. Current literature on standardized method for HPC apheresis in children is sparse and failure rate reported as high as 30%. PATIENTS/METHODS: A retrospective study of 125 pediatric patients with high-risk malignancies undergoing aHSCT in Western Australia between 1997 and 2016 was conducted. RESULTS: Mobilization was achieved by means of chemotherapy and granulocyte colony-stimulating factor (G-CSF). Patients underwent apheresis the day after CD34+ counts reached ≥20/µL and an additional dose of G-CSF. Peripheral arterial and intravenous lines were inserted in pediatric intensive care unit under local anesthetic and/or sedation, omitting the need for general anesthesia as well as facilitating an uninterrupted apheresis flow. Larger apheresis total blood volumes were processed in patients weighing ≤20 kg. The minimal dose of ≥2 × 106 CD34+ cells/kg was successfully collected in 98.4% of all patients. The optimal dose of 3-5 × 106 CD34+ cells/kg was collected in 96% of patients scheduled for a single aHSCT, 87.5% for tandem, and 100% for triple aHSCT. All HPC collections were completed in one apheresis session. Mobilization after ≤3 chemotherapy cycles and cycles including cyclophosphamide resulted in a significantly higher yield of CD34+ cells. CONCLUSION: Our approach to HPC mobilization by means of chemotherapy and single myeloid growth factor combined with optimal collection timing facilitated by continuous apheresis flow resulted in highly effective HPC harvest in children and adolescents with high-risk cancers.

Hematopoietic stem cell transplantation for children with acute myeloid leukemia in second remission: A report from the Australasian Bone Marrow Transplant Recipient Registry and the Australian and New Zealand Children's Haematology Oncology Group.

BACKGROUND: Approximately one-third of children with acute myeloid leukemia (AML) relapse, requiring re-treatment and allogeneic hematopoietic stem cell transplantation (HSCT). Although achieving second complete remission (CR2) prior to HSCT is desirable, once CR2 is attained, it is unclear if there is any benefit from further chemotherapy prior to HSCT. Moreover, although pre-HSCT minimal residual disease (MRD) has prognostic value in acute lymphoblastic leukemia, the benefit of MRD reduction after achieving CR prior to HSCT is less clear for AML. PROCEDURE: To address these questions, we analyzed data from pediatric transplant centers in Australia and New Zealand concerning relapsed childhood AML cases occurring between 1998 and 2013. Given the retrospective nature of our analysis and assay data available, we analyzed patients on the basis of measurable residual disease (MeRD) by any methodology, rather than MRD in the conventional sense. RESULTS: We observed improved overall survival (OS) in children receiving two chemotherapy cycles, compared to one cycle or three or more cycles pre-HSCT. Improved OS with two cycles remained significant for patients without MeRD after cycle 1. CONCLUSIONS: These data suggest that a second chemotherapy cycle pre-HSCT may improve survival by lowering disease burden. Prospective trials assessing strategies to reduce pre-HSCT MRD in relapsed childhood AML are warranted.

Immunogenicity and safety of single-dose, 13-valent pneumococcal conjugate vaccine in pediatric and adolescent oncology patients.

BACKGROUND: Children receiving immunosuppressive treatment for cancer are at high risk for invasive pneumococcal disease. The 13-valent pneumococcal conjugate vaccine (PCV13) can prevent pneumococcal disease in healthy children; however, there is an absence of literature regarding the benefit of PCV13 in immunocompromised children with cancer. METHODS: A prospective, open-label cohort study recruited children between ages 1 and 18 years who were receiving active immunosuppressive therapy (AIT) or were within 12 months after completing immunosuppressive therapy (CIT). Blood samples were taken before and 4 weeks after the administration of single-dose PCV13. Serotype-specific immunoglobulin G antibody titers were measured, and titers ≥0.35 µg/mL were considered protective. Solicited side effects were recorded in a 7-day diary after vaccination. RESULTS: Eighty-five children were recruited. At baseline, ≤50% had protective antibody titers against Streptococcus pneumoniae for 10 serotypes in the AIT group and for 8 serotypes in the CIT group. Postvaccination, ≥70% had protective antibody titers for 9 and 11 serotypes in the AIT and CIT groups, respectively. Both groups had comparable responses to PCV7 serotypes, whereas a significantly higher proportion in the CIT group achieved protective antibody titers to PCV13 serotypes. There was a low rate of serious adverse events (3.5%). CONCLUSIONS: A single-dose of PCV13 is safe and immunogenic in children diagnosed with cancer. All children who are receiving therapy for cancer should receive a single dose of PCV13 as soon as possible after diagnosis, regardless of prior PCV exposure. The current data support the recommendation for an additional dose of PCV13 after the completion of immunosuppressive therapy to provide additional protection against invasive pneumococcal disease. Cancer 2017;123:4215-4223. © 2017 American Cancer Society.

Deregulated expression of connective tissue growth factor (CTGF/CCN2) is linked to poor outcome in human cancer.

Connective tissue growth factor (CTGF/CCN2) has long been associated with human cancers. The role it plays in these neoplasms is diverse and tumour specific. Recurring patterns in clinical outcome, histological desmoplasia and mechanisms of action have been found. When CTGF is overexpressed compared to low-expressing normal tissue or is underexpressed compared to high-expressing normal tissue, the functional outcome favours tumour survival and disease progression. CTGF acts by altering proliferation, drug resistance, angiogenesis, adhesion and migration contributing to metastasis. The pattern of CTGF expression and tumour response helps to clarify the role of this matricellular protein across a multitude of human cancers.

Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group.

Medulloblastoma is curable in approximately 70% of patients. Over the past decade, progress in improving survival using conventional therapies has stalled, resulting in reduced quality of life due to treatment-related side effects, which are a major concern in survivors. The vast amount of genomic and molecular data generated over the last 5-10 years encourages optimism that improved risk stratification and new molecular targets will improve outcomes. It is now clear that medulloblastoma is not a single-disease entity, but instead consists of at least four distinct molecular subgroups: WNT/Wingless, Sonic Hedgehog, Group 3, and Group 4. The Medulloblastoma Down Under 2013 meeting, which convened at Bunker Bay, Australia, brought together 50 leading clinicians and scientists. The 2-day agenda included focused sessions on pathology and molecular stratification, genomics and mouse models, high-throughput drug screening, and clinical trial design. The meeting established a global action plan to translate novel biologic insights and drug targeting into treatment regimens to improve outcomes. A consensus was reached in several key areas, with the most important being that a novel classification scheme for medulloblastoma based on the four molecular subgroups, as well as histopathologic features, should be presented for consideration in the upcoming fifth edition of the World Health Organization's classification of tumours of the central nervous system. Three other notable areas of agreement were as follows: (1) to establish a central repository of annotated mouse models that are readily accessible and freely available to the international research community; (2) to institute common eligibility criteria between the Children's Oncology Group and the International Society of Paediatric Oncology Europe and initiate joint or parallel clinical trials; (3) to share preliminary high-throughput screening data across discovery labs to hasten the development of novel therapeutics. Medulloblastoma Down Under 2013 was an effective forum for meaningful discussion, which resulted in enhancing international collaborative clinical and translational research of this rare disease. This template could be applied to other fields to devise global action plans addressing all aspects of a disease, from improved disease classification, treatment stratification, and drug targeting to superior treatment regimens to be assessed in cooperative international clinical trials.

Connective tissue growth factor is expressed in bone marrow stromal cells and promotes interleukin-7-dependent B lymphopoiesis.

Hematopoiesis occurs in a complex bone marrow microenvironment in which bone marrow stromal cells provide critical support to the process through direct cell contact and indirectly through the secretion of cytokines and growth factors. We report that connective tissue growth factor (Ctgf, also known as Ccn2) is highly expressed in murine bone marrow stromal cells. In contrast, connective tissue growth factor is barely detectable in unfractionated adult bone marrow cells. While connective tissue growth factor has been implicated in hematopoietic malignancies, and is known to play critical roles in skeletogenesis and regulation of bone marrow stromal cells, its role in hematopoiesis has not been described. Here we demonstrate that the absence of connective tissue growth factor in mice results in impaired hematopoiesis. Using a chimeric fetal liver transplantation model, we show that absence of connective tissue growth factor has an impact on B-cell development, in particular from pro-B to more mature stages, which is linked to a requirement for connective tissue growth factor in bone marrow stromal cells. Using in vitro culture systems, we demonstrate that connective tissue growth factor potentiates B-cell proliferation and promotes pro-B to pre-B differentiation in the presence of interleukin-7. This study provides a better understanding of the functions of connective tissue growth factor within the bone marrow, showing the dual regulatory role of the growth factor in skeletogenesis and in stage-specific B lymphopoiesis.

Hepatic sinusoidal obstruction syndrome during chemotherapy for childhood medulloblastoma: report of a case and review of the literature.

Hepatic sinusoidal obstruction syndrome (HSOS), also known as veno-occlusive disease, is a well-recognized toxic complication after autologous and allogeneic hematopoietic stem cell transplant, during treatment of Wilms tumor and rhabdomyosarcoma associated with actinomycin-D, and during acute lymphoblastic leukemia therapy due to oral 6-thioguanine. However, its occurrence in the context of chemotherapy regimens for other childhood malignancies is rare. We report a 5-year-old girl with high-risk anaplastic medulloblastoma, who developed severe HSOS during her second cycle of maintenance chemotherapy, consisting of vincristine, cisplatin, and cyclophosphamide. She was treated with defibrotide with complete resolution of the HSOS. These findings and a review of the literature, highlight the occurrence of HSOS in children outside the established settings of hematopoietic stem cell transplantation, Wilms tumor, rhabdomyosarcoma, and acute lymphoblastic leukemia.

Morbidity in survivors of child and adolescent meningioma.

BACKGROUND: The extent of initial surgical resection has been identified as the strongest prognostic indicator for survival in child and adolescent meningioma. Given the paucity of data concerning long-term outcome, the authors undertook a meta-analysis to analyze morbidity in survivors of this disease. METHODS: Individual patient data were obtained from 19 case series published over the last 23 years through direct communication with the authors. Ordinal logistic regression models were used to assess the influence of risk factors on morbidity. RESULTS: Of 261 patients, 48% reported a completely normal life with no morbidity, and 25% had moderate/severe meningioma-associated morbidity at last follow-up. Multivariate analysis identified relapse as the only independent variable associated with an increased risk of morbidity (odds ratio, 4.02; 95% confidence interval, 2.11-7.65; P ≤ .001). Univariate analysis also revealed an increased risk for patients with neurofibromatosis (odds ratio, 1.90; 95% confidence interval, 1.04-3.48; P = .04). Subgroup analysis identified a higher incidence of morbidity among patients who had intracranial tumors with a skull base location compared with a nonskull base location (P ≤ .001). Timing at which morbidity occurred was available for 70 patients, with persistence of preoperative tumor-related symptoms in 67% and as a result of therapy in 20%. CONCLUSIONS: The majority of survivors of child and adolescent meningioma had no or only mild long-term morbidity, whereas 25% had moderate/severe morbidity, with a significantly increased risk in patients with relapsed disease. In the majority, morbidity occurred as a consequence of the tumor itself, justifying aggressive surgery to achieve gross total resection. However, for patients with neurofibromatosis and skull base meningioma, a more cautious surgical approach should be reserved.

Rapid update on childhood immune thrombocytopenic purpure.

Most childhood immune thrombocytopenic purpure is benign, self-limiting and requires no therapy. However, questions remain: (i) to treat or not; (ii) bone marrow examination or not; and (iii) admit to hospital or not. These questions have dominated the literature and we still need a prospective large multi-centre study of these issues to determine a useful bleeding score, quality of life measure and a measure of parental anxiety.

Chemotherapy increases amenability of surgical resection in congenital glioblastoma.

Brain tumors presenting in infancy, especially during the first 6 months of life, are often very large and highly vascular. It is generally accepted that gross total resection of the tumor affords the best outcome to the patient. However, tumor resection is frequently very challenging due to the risk of significant bleeding. We report two cases of congenital glioblastoma whose initial surgery was hampered by tumor hypervascularity and excessive blood loss, resulting in subtotal resection. Subsequent carboplatin-based chemotherapy led to a significant reduction in tumor size and vascularity, enabling safe gross total resection at second-look surgery. Based on these findings and a review of the literature, we recommend cytoreductive chemotherapy following diagnostic biopsy for infants presenting with large, highly vascular tumors, such as congenital glioblastoma, in lieu of aggressive upfront surgery, to increase the feasibility and facilitate safe gross total excision at second-look surgery.

Meningiomas in children and adolescents: a meta-analysis of individual patient data.

BACKGROUND: The epidemiological, prognostic, and therapeutic features of child and adolescent meningioma are poorly defined. Clinical knowledge has been drawn from small case series and extrapolation from adult studies. This study was done to pool and analyse the clinical evidence on child and adolescent meningioma. METHODS: Searches of PubMed, Medline, and Embase identified 35 case series of child and adolescent meningioma completed over the past 21 years. Individual patient data were obtained from 30 studies via direct communication with investigators. Primary outcomes were relapse-free survival (RFS) and overall survival. Prognostic variables were extent of initial surgery, use of upfront radiotherapy, age, sex, presence of neurofibromatosis, tumour location, and tumour grade. RFS and overall survival were analysed using Kaplan-Meier survival curves and multivariable Cox regression models. FINDINGS: From a total of 677 children and adolescents with meningioma, 518 were eligible for RFS analysis and 547 for overall survival analysis. Multivariable analysis showed that patients who underwent initial gross-total resection had better RFS (hazard ratio 0·16, 95% CI 0·10-0·25; p<0·0001) and overall survival (0·21, 0·11-0·39; p<0·0001) than those who had subtotal resection. No significant benefit was seen for upfront radiotherapy in terms of RFS (0·59, 0·30-1·16; p=0·128) or overall survival (1·10, 0·53-2·28; p=0·791). Patients with neurofibromatosis type 2 (NF2) had worse RFS than those without neurofibromatosis (2·36, 1·23-4·51; p=0·010). There was a significant change in overall survival with time between patients with NF2 compared with those without neurofibromatosis (1·45, 1·09-1·92; p=0·011); although overall survival was initially better for patients with NF2 than for those without neurofibromatosis, overall survival at 10 years was worse for patients with NF2. Patients with WHO grade III tumours had worse RFS than those with WHO grade I (3·90, 2·10-7·26; p<0·0001) and grade II tumours (2·49, 1·11-5·56; p=0·027). INTERPRETATION: Extent of initial surgical resection is the strongest independent prognostic factor for child and adolescent meningioma. No benefit for upfront radiotherapy was noted. Hence, aggressive surgical management, to achieve gross-total resection, is the initial treatment of choice. In the event of a subtotal resection, repeat resection is recommended to achieve maximum extirpation. Close observation is warranted for patients who have a subtotal resection or who have WHO grade III tumours. Patients without neurofibromatosis should have a minimum 10-year follow-up, whereas patients with NF2 should be considered a special risk category, necessitating life-long follow-up. FUNDING: None.

Double trouble: A case of fraternal twins with iron-refractory iron-deficiency anemia.

Iron-refractory iron-deficiency anemia (IRIDA) is a rare autosomal recessive disease that presents in childhood. We report the case of fraternal twins presenting with severe hypochromic microcytic anemia and hypoferritinemia. Two missense mutations affecting the TRMPSS6 gene were identified, consistent with IRIDA. Subsequent parenteral iron therapy improved clinical and blood parameters.

Pediatric meningioma: current approaches and future direction.

With improvement in leukemia therapy, central nervous system (CNS) tumors are the leading cause of cancer mortality in children and the most expensive of all human neoplasms to treat. Meningiomas are rare intracranial tumors in childhood and adolescence arising from arachnoid cell clonal outgrowth in the meninges. There have been no collaborative prospective therapeutic trials for pediatric meningioma because of its rarity, and the best evidence for management comes from retrospective case analyses and extrapolation from the treatment of adult meningioma. However this may not be ideal, because the underlying biology of adult and pediatric meningiomas seems to be different, as is the case for other CNS tumors. In addition, treatment of pediatric brain tumors requires consideration of long-term quality of life. This review reflects on what is currently known about pediatric meningiomas and opportunities for future directions.

Primary prophylaxis of venous thromboembolism in children.

Venous thromboembolism (VTE) is rare in children and young adolescents, and occurs predominantly in those with congenital heart disease in whom guidelines exist for VTE prophylaxis. For other paediatric patients, the rarity of the event makes writing an evidence-based clinical practice guideline difficult because each of the known risk factors contributes only a small increase in risk. Thrombophilia screening is controversial because few results assist with prediction of likely thrombosis and may not alter recommendations for prophylaxis. Recent publications highlight the importance of non-pharmacological prevention of VTE in children and adolescents undergoing surgery and the importance of liaison among surgeon, anaesthetist and haematologist. This annotation was written with the aim of collating current evidence for VTE prophylaxis and emphasising the need for further research in vulnerable subgroups.

Metabolic and Psychological Impact of a Pragmatic Exercise Intervention Program in Adolescent and Young Adult Survivors of Pediatric Cancer-Related Cerebral Insult.

PURPOSE: To assess metabolic function among adolescent and young adult (AYA) survivors of childhood cancer-related brain surgery or cranial irradiation (CRT) and to determine feasibility, safety, and metabolic as well as psychological impact of a 6-month exercise program in this cohort. METHODS: Twenty AYAs aged 15-23 years were recruited. All had completed cancer treatment by age 15.5 and were more than 1 year after end of treatment. Metabolic function was assessed at baseline (T1), after a 6-month non-intervention period (T2), and after the 6-month intervention (T3). Psychological assessments were performed at T1 and T3. Eight to 12 months after the program (T4), its lasting impact was assessed by questionnaire. The 6-month intervention consisted of small group-based, tailored, supervised exercise sessions combining resistance and aerobic exercise. Sessions were offered up to thrice per week and adherence defined as participation in ≥24 sessions. Flexibility was built into the design with an alternative home-based program offered to those who could not attend the gymnasium. RESULTS: Thirteen of the 20 recruited participants were adherent to the program. There was one fall during exercise, but no injury was sustained. Higher rates of metabolic impairment than would be expected in a healthy cohort were found at baseline both among brain tumor survivors and survivors of total body irradiation. Central adiposity reduced post-intervention (p = 0.014) and improvements in adaptive function were seen. Participants enjoyed the program, but work and study commitments limited attendance. CONCLUSION: AYA survivors of childhood brain tumors and CRT should be screened for metabolic and psychological well-being. Small group-based exercise is safe, feasible, and enjoyable for this cohort and may benefit them both metabolically and psychologically. TRIAL REGISTRATION: ACTRN12614000796684. Retrospectively registered July 28, 2014.

The case for DNA methylation based molecular profiling to improve diagnostic accuracy for central nervous system embryonal tumors (not otherwise specified) in adults.

Central nervous system primitive neuro-ectodermal tumors (CNS-PNETs), have recently been re-classified in the most recent 2016 WHO Classification into a standby catch all category, "CNS Embryonal Tumor, not otherwise specified" (CNS embryonal tumor, NOS) based on epigenetic, biologic and histopathologic criteria. CNS embryonal tumors (NOS) are a rare, histologically and molecularly heterogeneous group of tumors that predominantly affect children, and occasionally adults. Diagnosis of this entity continues to be challenging and the ramifications of misdiagnosis of this aggressive class of brain tumors are significant. We report the case of a 45-year-old woman who was diagnosed with a central nervous system embryonal tumor (NOS) based on immunohistochemical analysis of the patient's tumor at diagnosis. However, later genome-wide methylation profiling of the diagnostic tumor undertaken to guide treatment, revealed characteristics most consistent with IDH-mutant astrocytoma. DNA sequencing and immunohistochemistry confirmed the presence of IDH1 and ATRX mutations resulting in a revised diagnosis of high-grade small cell astrocytoma, and the implementation of a less aggressive treatment regime tailored more appropriately to the patient's tumor type. This case highlights the inadequacy of histology alone for the diagnosis of brain tumours and the utility of methylation profiling and integrated genomic analysis for the diagnostic verification of adults with suspected CNS embryonal tumor (NOS), and is consistent with the increasing realization in the field that a combined diagnostic approach based on clinical, histopathological and molecular data is required to more accurately distinguish brain tumor subtypes and inform more effective therapy.