The American Society of Pediatric Hematology/Oncology workforce assessment: Part 2-Implications for fellowship training.

The American Society of Pediatric Hematology/Oncology (ASPHO) solicited information from division directors and fellowship training program directors to capture pediatric hematology/oncology (PHO) specific workforce data of 6 years (2010-2015), in response to an increase in graduating fellows during that time. Observations included a stable number of physicians and advanced practice providers (APPs) in clinical PHO, an increased proportion of APPs hired compared to physicians, and an increase in training-level first career positions. Rapid changes in the models of PHO care have significant implications to current and future trainees and require continued analysis to understand the evolving discipline of PHO.

PAX genes in childhood oncogenesis: developmental biology gone awry?

Childhood solid tumors often arise from embryonal-like cells, which are distinct from the epithelial cancers observed in adults, and etiologically can be considered as 'developmental patterning gone awry'. Paired-box (PAX) genes encode a family of evolutionarily conserved transcription factors that are important regulators of cell lineage specification, migration and tissue patterning. PAX loss-of-function mutations are well known to cause potent developmental phenotypes in animal models and underlie genetic disease in humans, whereas dysregulation and/or genetic modification of PAX genes have been shown to function as critical triggers for human tumorigenesis. Consequently, exploring PAX-related pathobiology generates insights into both normal developmental biology and key molecular mechanisms that underlie pediatric cancer, which are the topics of this review.

Lack of prognostic significance of intratumoral angiogenesis in nonmetastatic osteosarcoma.

BACKGROUND: A need exists to stratify patients with nonmetastatic osteosarcoma into risk subcategories to administer risk-adapted therapy. Intratumoral angiogenesis determined at diagnosis may have a prognostic significance in this malignancy. PATIENTS AND METHODS: The authors performed a retrospective immunohistochemical study on archival pathologic material from patients with nonmetastatic osteosarcoma, excluding patients with purely chondroblastic tumors associated with hypovascularity of the cartilaginous stroma. Representative sections from the diagnostic biopsies were stained with a murine monoclonal antibody directed against CD34, an endothelial cell marker. Two pathologists unaware of the patients' long-term outcome counted microvessels in 10 microscopic fields from the most active areas of neovascularization. RESULTS: Between March 1988 and December 1996, 15 girls and 14 boys (median age 12.6 y, range 4.3-18.3) were identified. Seven patients had died of metastatic disease at a median of 3.4 years (range 0.8-7.4) after diagnosis; 22 were alive with no evidence of disease at a median follow-up of 6.8 years (range 2.7-11.4). There was no significant difference in the number of microvessels per field (pathologist 1, median 19 vs. 18.5; pathologist 2, median 15 vs. 10) between survivors or patients who died of metastatic disease. The correlation between the measurements of the two pathologists was excellent (correlation coefficient 0.87). CONCLUSIONS: Intratumoral neovascularization determined at diagnosis does not correlate with long-term outcome in patients with nonmetastatic osteosarcoma. A prospective study is necessary to confirm these results.

Fractionated cyclophosphamide and etoposide for children with advanced or refractory solid tumors: a phase II window study.

PURPOSE: Cyclophosphamide (CPA) has a broad spectrum of activity against solid tumors. Hepatic self-induction of the active metabolite 4-hydroxycyclophosphamide occurs after repeated administration. We evaluated the clinical efficacy of a window regimen that administers fractionated CPA in conjunction with etoposide (VP16) in children with advanced or refractory solid tumors. PATIENTS AND METHODS: Seventeen children with advanced (n = 12) or refractory (n = 5) solid tumors were entered onto this phase II window study. The treatment regimen consisted of intravenous (IV) CPA 500 mg/m(2)/d and IV VP16 100 mg/m(2)/d. Both drugs were administered daily by short infusions for 5 consecutive days. RESULTS: A total of 34 courses were administered, with a median of two courses per patient. The median interval between chemotherapy courses was 21 days (range, 17 to 35 days). Thirty-three courses were assessable for toxicity, and all patients were assessable for response. No life-threatening toxicities were observed. The incidence of grade 3 or 4 neutropenia was 94% and of fever and neutropenia 38%. Fever and neutropenia occurred after 12 of 26 courses without recombinant human granulocyte colony-stimulating factor (rhG-CSF) and after one of eight courses with rhG-CSF (P =. 09). Grade 3 or 4 thrombocytopenia occurred after 10 courses (29%). There were no positive blood cultures. One heavily pretreated patient developed a localized perirectal abscess that required drainage. There were 10 patients (59%) with partial responses, four (23.5%) with stable disease, and three with progressive disease. CONCLUSION: Fractionated IV CPA and VP16 over 5 days can be safely administered in children with advanced or refractory solid tumors and has notable antineoplastic activity.

Functional characteristics of neutrophils collected and stored after administration of G-CSF.

BACKGROUND: Granulocyte transfusion may be used in neutropenic patients with severe bacterial or fungal infections that are unresponsive to antibiotic therapy. However, the inability to store granulocyte concentrates limits their clinical usefulness. STUDY DESIGN AND METHODS: Neutrophil chemotaxis and NADPH oxidase activity and the integrity of the neutrophil NADPH oxidase system were examined after apheresis collection and during storage to 48 hours. Neutrophils were mobilized in vivo by G-CSF, collected by apheresis techniques, and stored in apheresis bags in the presence and absence of additional G-CSF. For all experiments, cells were further purified by standard techniques of dextran sedimentation and hypotonic RBC lysis. RESULTS: Neutrophil chemotaxis was preserved to 24 hours of storage but was not affected by the G-CSF added to storage units. The NADPH oxidase system was also preserved as a functioning complex, and both cytosolic proteins and membrane-associated proteins were normal to 48 hours. However, there were divergent responses by intact cells to activating stimuli and reduced oxidase activity in the cell-free system. G-CSF did not appear to significantly affect NADPH oxidase activity or NADPH oxidase system integrity during storage. CONCLUSION: Neutrophils collected after the administration of G-CSF retained functional and biochemical characteristics for at least 24 hours of storage, which suggests additional effects of G-CSF mobilization beyond enhancing PMN yields and the possibility of storage of these components after collection.

In vivo treatment with granulocyte colony-stimulating factor results in divergent effects on neutrophil functions measured in vitro.

We have studied the effects of granulocyte colony-stimulating factor (G-CSF) administration to normal individuals on a variety of functional and biochemical neutrophil characteristics that relate to host defense. G-CSF adversely affected neutrophil (polymorphonuclear leukocyte [PMN]) chemotaxis. While this could be partially explained by reduced assembly of neutrophil F-actin, we also recognized an elevated cytosolic calcium mobilization and a normal upregulation of neutrophil CD11b. G-CSF resulted in reduced PMN killing of Staphylococcus aureus with a 10:1 (bacteria:neutrophil) ratio and normal killing with a 1:1 ratio. In association with this, we demonstrated divergent effects on the respiratory burst of intact cells and divergent effects on the content of marker proteins for neutrophil granules. While G-CSF may have resulted in increased content of cytochrome b558 in the cell membrane, it did not alter the amounts of cytosolic oxidase components. After therapy, there was normal content of the azurophilic granule marker, myeloperoxidase, decreased content of the specific granule marker, lactoferrin, and normal content of lysozyme (found in both granules classes). Finally, G-CSF therapy markedly reduced the apoptotic rate of the isolated neutrophil. Therefore, considering disparate functional and biochemical activities, the real benefit of G-CSF therapy may lie in enhanced number and survival of neutrophils.

The effects of stem cell factor and granulocyte colony stimulating factor therapy on the activity of the neutrophil NADPH oxidase enzyme system.

BACKGROUND: To explore the effect of cytokine therapy on the NADPH oxidase in mature myeloid cells, we isolated neutrophils from patients receiving recombinant human granulocyte colony stimulating factor (G-CSF) and recombinant human stem cell factor (SCF) and evaluated oxidase activity. All patients had relapsed neoplastic disease and were at least 3 three weeks since the last course of chemotherapy or cytokine therapy. METHODS: Stimulus induced superoxide anion (O2-) production in response to PMA (200 ng/mL), fMLP (1 mumol/L), platelet activating factor (PAF, 2 mumol/L) priming of the fMLP induced response, and opsonized zymosan OZ (1 mg/mL) was measured. Polymorphonuclear leukocyte (PMN) subcellular components were prepared, after nitrogen cavitation, by separation on discontinuous sucrose gradients and NADPH oxidase activity was assessed in a SDS cell-free system. RESULTS: SCF had no effect on the activity of the neutrophil oxidase. Neutrophils isolated from patients treated with G-CSF and stimulated with PMA produced less (superoxide anion) O2- after therapy. PAF priming of the fMLP induced respiratory burst was also reduced after therapy with G-CSF. Subcellular NADPH oxidase activity was reduced before cytokine therapy commenced. This activity did not improve with cytokine treatment. CONCLUSIONS: It appears likely from this study that G-CSF therapy, with or without SCF, does not cause significant enhancement of neutrophil NADPH oxidase activity.

Intra-operative radiation therapy in pediatric neuroblastoma.

External beam irradiation (EBRT) has been shown to improve response rates and event-free survival in children with neuroblastoma and regional lymph node metastases. Irradiation during surgical exposure (intra-operative radiotherapy, IORT) with displacement of adjacent radiosensitive organs out of the treatment field allows for more precise delineation of the target volume and significantly reduces the amount of normal tissue exposed to irradiation. We have incorporated IORT into the treatment regimen of 24 children with neuroblastoma between the years of 1983-1991. IORT was directed to any residual tumor or the tumor bed; the median dose of radiation was 1,000 cGY, equivalent to 3,000 cGY of conventional EBRT. There were 11 males and 13 females. Two patients had stage II, 12 patients had stage III, and 10 patients had stage IV disease. Ten children received IORT for suspected recurrent or persistent neuroblastoma. Twelve patients were disease-free survivors following IORT with a median follow-up of 54 months. For those patients with stage III disease, seven children were disease-free survivors, while only three of 10 patients with stage IV disease survived (median follow-up 30 months). Disease-free Survival (DFS) correlated with the achievement of local tumor control in children with both stage III and IV neuroblastoma. There was limited morbidity and no episodes of obstructive uropathy were encountered. We conclude that IORT appears to be well tolerated and may have therapeutic benefit for a select group of patients with neuroblastoma. IORT merits future exploration by prospective study.