Leukapheresis in Pediatric Acute Leukemia with Hyperleukocytosis: A Single-Center Experience.

Hyperleukocytosis in pediatric acute leukemia is associated with increased morbidity and mortality and at present there is no consensus on the use of leukapheresis (LPH) for its management. Our aim was to review characteristics and outcomes of newly diagnosed leukemia patients with hyperleukocytosis (HL) comparing those who received LPH and those who did not. An IRB approved retrospective case control study reviewed data from a single institution over a 10 year period. At our institution, LPH was used in 8 of 62 (13%) patients with hyperleukocytosis with minimal complications. Mean leukocyte count in patients who received LPH versus those who did not was 498 k cells/mm3 and 237 k cells/mm3, respectively. Patients who had symptoms of neurologic (63 vs. 17%) or pulmonary leukostasis (75 vs. 17%) were more likely to have undergone leukapheresis. The time from presentation to the initiation of chemotherapy was not different between those who received LPH and those who did not (mean of 35 h vs. 34 h). There was one death in the LPH group, that was the result of neurologic sequelae of hyperleukocytosis and not LPH itself. The use of LPH in patients with hyperleukocytosis is safe, well tolerated and does not alter time to chemotherapy at our institution.

Disialoganglioside GD2 Expression in Pediatric Rhabdomyosarcoma: A Case Series and Review of the Literature.

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. Despite aggressive therapy, patients with metastatic or relapsed disease experience dismal outcomes and novel therapies are urgently needed. In this study, we evaluated expression of disialoganglioside (GD2), a cell surface antigen with therapeutic implication, in 16 RMS patient samples. Scoring revealed GD2 positivity in 25% of the samples. These data suggest that a small subset of RMS tumors express GD2, which may be a therapeutic target in these patients.

Complete Remission of an Extracranially Disseminated Anaplastic Pleomorphic Xanthoastrocytoma With Everolimus: A Case Report and Literature Review.

BACKGROUND: Surgical resection is the treatment of choice for pleomorphic xanthoastrocytoma, while chemotherapy and radiation therapy are typically used in patients with anaplasia, metastasis, or sometimes in subtotally resected cases, especially upon recurrence. Extracranial dissemination has been only rarely reported. We describe a five year old boy with the rare occurrence multiply recurrent and extracranially disseminated anaplastic pleomorphic xanthoastrocytoma. A complete resolution of his tumor was achieved for greater than two years thus far after administering everolimus. METHODS: We performed a comprehensive literature review of all pleomorphic xanthoastrocytoma cases; 359 cases were described, and 132 of these individuals were less than 18 years of age. RESULTS: Gross total resection was achieved in only 132 (36.7%) cases, while additional therapy was administered in 186 patients. Only four patients in additon to our own have been documented with extracranial dissemination (four of five in the pediatric population); two patients who succumbed to their disease underwent subtotal resection of the primary tumor. CONCLUSIONS: We report the first patient with extracranially disseminated anaplastic pleomorphic xanthoastrocytoma to be successfully maintained on everolimus as a single oral chemotherapy agent with complete resolution of the tumor. Pleomorphic xanthoastrocytoma can rarely disseminate extracranially in the pediatric population, hence pathologists and neuro-oncologists should be aware of this possibility.

Examining predictors and outcomes of fertility consults among children, adolescents, and young adults with cancer.

Infertility has a negative impact on quality of life among cancer survivors. Studies show establishing a fertility team results in improved patient satisfaction. A review of electronic medical records was performed to examine predictors of fertility referrals, interventions, and the impact of an opt-out consult mechanism. Findings show many patients, particularly those that are younger, are still not receiving fertility counseling despite the presence of a fertility team. Notably, patients were 3.6 times more likely to receive a consult after the opt-out. Strategies are needed to improve access to fertility related care, particularly in groups where consults are underutilized.

IL-6 and CXCL8 mediate osteosarcoma-lung interactions critical to metastasis.

Osteosarcoma (OS), a malignant tumor of bone, kills through aggressive metastatic spread almost exclusively to the lung. Mechanisms driving this tropism for lung tissue remain unknown, though likely invoke specific interactions between tumor cells and other cells within the lung metastatic niche. Aberrant overexpression of ΔNp63 in OS cells directly drives production of IL-6 and CXCL8. All these factors were expressed at higher levels in OS lung metastases than in matched primary tumors from the same patients. Expression in cell lines correlated strongly with lung colonization efficiency in murine xenograft models. Lentivirus-mediated expression endowed poorly metastatic OS cells with increased metastatic capacity. Disruption of IL-6 and CXCL8 signaling using genetic or pharmaceutical inhibitors had minimal effects on tumor cell proliferation in vitro or in vivo, but combination treatment inhibited metastasis across multiple models of metastatic OS. Strong interactions occurred between OS cells and both primary bronchial epithelial cells and bronchial smooth muscle cells that drove feed-forward amplification of IL-6 and CXCL8 production. These results identify IL-6 and CXCL8 as primary mediators of OS lung tropism and suggest pleiotropic, redundant mechanisms by which they might effect metastasis. Combination therapy studies demonstrate proof of concept for targeting these tumor-lung interactions to affect metastatic disease.

Osteosarcoma: Accelerating Progress Makes for a Hopeful Future.

Patients who develop osteosarcoma in 2017 receive treatment that remains essentially unchanged since the 1970s. Outcomes likewise remain largely unimproved. Large, collaborative, multinational efforts to improve therapy have evaluated strategies leveraging both cytotoxic intensification and immunomodulatory agents. While these have confirmed our capacity to conduct such trials, results have proved largely disappointing. This has motivated efforts to focus on the basic biology of osteosarcoma, where understanding remains poor but has improved significantly. Recent advances have identified characteristic genetic features of osteosarcoma, including profound chromosomal disruption, marked patient-patient heterogeneity, and a paucity of recurrent mutations. Analyses suggest genesis in early catastrophic genetic events, although the nature of the inciting events remains unclear. While p53 and Rb inactivation occurs in most osteosarcomas, the landscape of associated driver mutations has proved extensive. Few mutations recur with high frequency, though patterns continue to emerge that suggest recurrent alterations within specific pathways. Biological pathways implicated in osteosarcoma biology through genetic and other preclinical studies include PI3K/mTOR, WNT/ßcatenin, TGFß, RANKL/NF-κB, and IGF. Unfortunately, clinical studies evaluating targeted agents have to date yielded disappointing results, as have studies examining modern immunotherapeutics. It remains unclear whether this pattern of clinical failures exposes inadequacies of our preclinical models, unrealistic expectations for single-agent responses in heavily pretreated patients, or biology less relevant than suggested. Nearly all patients who succumb to osteosarcoma develop lung metastases, which exhibit marked chemoresistance. Much scientific effort has recently sought to enhance our mechanistic understanding of metastasis biology. This research has potential to reveal novel targets for preventing and treating metastasis and for uncovering key vulnerabilities of osteosarcoma cells. Efforts to implement drug development strategies that leverage clinical studies in veterinary patients have potential to accelerate the translation of novel experimental regimens toward human studies. These could reduce costs and development timelines, prioritize agents, and refine regimens prior to human clinical trials. The rise of philanthropic groups focused on osteosarcoma has enhanced cross-disciplinary and cross-institutional focus and provided much needed resources. Transformative new therapies will likely arise from collaborative, interdisciplinary efforts that extend our understanding of osteosarcoma's most basic inner workings.

Fertility counseling and preservation: considerations for the pediatric endocrinologist.

Infertility is a distressing consequence of numerous pediatric medical conditions and treatments. The field of pediatric fertility preservation has expanded rapidly over the past decade, and clinical guidelines emphasize the importance of discussing infertility risk and fertility preservation options with patients and families in a timely manner. Understanding the various mechanisms and presentations of fertility issues across diagnoses is imperative to provide counseling to patients and families, and identify individuals who may benefit from fertility preservation. The goals of this manuscript are to outline current fertility preservation options in pediatrics, review populations at-risk for infertility that are seen in pediatric endocrinology, and discuss other important issues related to fertility preservation including ethical considerations.