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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.

Background Survivors of paediatric brain cancer and/or cranial radiotherapy (CRT) are at an increased risk of developing serious comorbidities. Established risk factors for chronic disease include central obesity, endothelial abnormalities and diminished fitness. Objectives Here we characterised anthropometry, body composition, bone mineral density (BMD), heart rate (HR), blood pressure (BP), endothelial function, muscular strength and endurance and aerobic fitness in adolescent and young adult (AYA) survivors. Methods Twenty survivors (10 male, 10 female; 20 ± 2 years) were compared with 19 matched controls. Muscular strength was assessed using three repetition maximum tests, while muscular endurance was determined as number of repetitions performed per minute. Peak oxygen uptake (VO2 peak) was assessed on a treadmill using a modified chronotropic protocol. Anthropometric measurements, HR and BP were taken using standard clinical protocols, while body composition and BMD were determined using dual X-ray absorptiometry (DXA). Endothelial function was measured using the flow mediated dilation technique. Results Survivors demonstrated deficits in muscular strength (latissimus dorsi pull-down, p = 0.020; bicep curl, p = 0.009), muscular endurance (squats, p = 0.012; sit-ups, p = 0.030; push-ups, p = 0.013), minute ventilation at peak exericse (p = 0.002) and VO2peak (L/min, p = 0.002; mL/kg/min, p = 0.008; mL/kg LBM/min, p = 0.010). Additionally, survivors had greater waist-to-hip ratios (p = 0.032), resting HR (p = 0.048) and higher percentage of total body (p = 0.017), central (p = 0.009) and peripheral (p = 0.032) fat. Lean body mass (p = 0.004) and BMD (p = 0.005) were lower in the survivor group. Conclusion AYA survivors of paediatric brain cancer and/or CRT exhibit altered body composition, increased resting HR and reduced BMD, muscular strength, muscular endurance and cardiorespiratory fitness compared to controls. [ABSTRACT FROM AUTHOR]

Influenza is associated with significant morbidity and mortality in children receiving therapy for cancer, yet recommendation for, and uptake of the seasonal vaccine remains poor. One hundred children undergoing treatment for cancer were vaccinated with the trivalent inactivated influenza vaccine according to national guidelines in 2010 and 2011. Influenza-specific hemagglutinin inhibition antibody titers were performed on blood samples taken prior to each vaccination and 4 weeks following the final vaccination. A nasopharyngeal aspirate for influenza was performed on all children who developed an influenza-like illness. Following vaccination, seroprotection and seroconversion rates were 55 and 43% for H3N2, 61 and 43% for H1N1, and 41 and 33% for B strain, respectively. Overall, there was a significant geometric mean fold increase to H3N2 ( GMFI 4.56, 95% CI 3.19-6.52, P < 0.01) and H1N1 ( GMFI 4.44, 95% CI 3.19-6.19, P < 0.01) strains. Seroconversion was significantly more likely in children with solid compared with hematological malignancies and in children <10 years of age who received a two-dose schedule compared to one. Influenza infection occurred in 2% of the vaccinated study population, compared with 6.8% in unvaccinated controls, providing an adjusted estimated vaccine effectiveness of 72% (95% CI −26-94%). There were no serious adverse events and a low reactogenicity rate of 3%. The trivalent inactivated influenza vaccine is safe, immunogenic, provides clinical protection and should be administered annually to immunosuppressed children receiving treatment for cancer. All children <10 years of age should receive a two-dose schedule. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]