A pilot study evaluating the use of sirolimus in children and young adults with desmoid-type fibromatosis.

Deregulation of the mTOR pathway may play an important role in tumor biology when the APC/ß-catenin pathway is disrupted in desmoid-type fibromatosis (DT). A pilot study was conducted to determine whether sirolimus can block the mTOR pathway (primary aim) as well as determine whether it can safely be given in the preoperative setting, decrease tumor size/recurrence, and decrease tumor-associated pain in children and young adults (secondary aims) with DT. Nine subjects ages 5-28 years were enrolled from 2014 to 2017 across four centers. Sirolimus was feasible and was associated with a nonstatistically significant decrease in pS706K activation.

Chordoma of the Clivus and Acute Myeloid Leukemia: Is There a Connection?

Chordoma is a rare cancer in children and understanding the genesis of this tumor may contribute to treatment approaches. Evidence has proposed VDC/IE (vincristine, doxorubicin, cyclophosphamide/ifosfamide, etoposide) as a treatment option for young patients with chordoma to avoid the long-term effects of radiation therapy. We present a case of acute myeloid leukemia developing during treatment of localized chordoma of the clivus in a 20-month-old male. We propose a genomic relationship that may have contributed to the development of clival chordoma and acute myeloid leukemia without a latency period and advocate for genomic sequencing in children with chordoma before the initiation of systemic therapies.

Left Ventricular Metastasis in Neuroblastoma: A Case Report.

Neuroblastoma is the most common extracranial solid tumor in children. Most common sites of metastases from neuroblastoma are bone marrow, bone and lymph nodes, however cardiac metastasis is rarely seen. Metastatic cardiac tumors are 20 to 40 times more common than primary cardiac tumors. Mechanism of cardiac metastasis can be hematogenous, lymphatogenous, and direct extension/infiltration of tumor cells. Usually right heart metastasis is seen. Left ventricular metastatic tumor has never been reported with neuroblastoma.

Advances in therapy for pediatric sarcomas.

Pediatric sarcomas are relatively rare malignancies individually. As a group they are typically approached with combination chemotherapies in addition to local control. Fortunately, these malignancies have been approached through careful clinical trial collaboration to define risk groups and appropriately deliver local control measures and systemic therapies. Although local disease is typically approached with curative intent, therapy typically lasts over 6 months and has significant associated morbidities. It is more difficult to cure metastatic disease or induce sustained remissions. In this article, we discuss recent advances in the understanding of the disease process and highlight recent and future cooperative group trials in osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, nonrhabdomyosarcoma soft tissue sarcomas, and desmoid tumor as well as discuss promising therapeutic approaches such as epigenetics and immunotherapy.

Cell Cycle Checkpoints p16 and p21-Strong Predictors of Clinicopathologic Outcomes in High-Grade Osteosarcoma.

PURPOSE: In this study, we used a series of immunohistochemical measurements of 2 cell cycle regulators, p16 and p21, to evaluate their prognostic value, separately and in combination, for the disease outcomes. METHOD: A total of 101 patients with high-grade osteosarcoma were included in this study. Clinicopathologic data were collected, and immunohistochemistry for p16 and p21 was performed and interpreted by 3 independent pathologists. Statistical analysis was performed to assess the strength of each of these markers relative to disease outcome. RESULTS: Our results indicate that more than 90% expression (high) of p16 by immunohistochemistry on the initial biopsy has a strong predictive value for good histologic response to chemotherapy. The patients are also more likely to survive the past 5 years and less likely to develop metastasis than patients with less than 90% p16 (low) expression. The results for p21, on the other hand, show a unique pattern of relationship to the clinicopathologic outcomes of the disease. Patients with less than 1% (low) or more than 50% (high) expression of p21 by immunohistochemistry show a higher chance of metastasis, poor necrotic response to chemotherapy, and an overall decreased survival rate when compared with p21 expression between 1% and 50% (moderate). Our results also showed that the expression of p16 and combined p16 and p21 demonstrates a stronger predictive relationship to 5-year survival than tumor histologic necrosis and p21 alone. DISCUSSION: The results of this study, once proven to be reproducible by a larger number of patients, will be valuable in the initial assessment and risk stratification of the patients for treatment and possibly the clinical trials.

Investigating surface proteins and antibody combinations for detecting circulating tumor cells of various sarcomas.

Circulating tumor cells (CTCs) have gathered attention as a biomarker for carcinomas. However, CTCs in sarcomas have received little attention. In this work, we investigated cell surface proteins and antibody combinations for immunofluorescence detection of sarcoma CTCs. A microfluidic device that combines filtration and immunoaffinity using gangliosides 2 and cell surface vimentin (CSV) antibodies was employed to capture CTCs. For CTC detection, antibodies against cytokeratins 7 and 8 (CK), pan-cytokeratin (panCK), or a combination of panCK and CSV were used. Thirty-nine blood samples were collected from 21 patients of various sarcoma subtypes. In the independent samples study, samples were subjected to one of three antibody combination choices. Significant difference in CTC enumeration was found between CK and panCK + CSV, and between panCK and panCK + CSV. Upon stratification of CK+ samples, those of metastatic disease had a higher CTC number than those of localized disease. In the paired samples study involving cytokeratin-positive sarcoma subtypes, using panCK antibody detected more CTCs than CK. Similarly, for osteosarcoma, using panCK + CSV combination resulted in a higher CTC count than panCK. This study emphasized deliberate selection of cell surface proteins for sarcoma CTC detection and subtype stratification for studying cancers as heterogeneous as sarcomas.

Microfluidics-Enabled Isolation and Single-Cell Analysis of Circulating Tumor Cells.

Microfluidic platforms enable the enrichment and analysis of circulating tumor cells (CTCs), a potential biomarker for cancer diagnosis, prognosis, and theragnosis. Combined with immunocytochemistry/immunofluorescence (ICC/IF) assays for CTCs, microfluidics-enabled detection presents a unique opportunity to study tumor heterogeneity and predict treatment response, both of which can help cancer drug development. In this chapter, we detail the protocols and methods employed to fabricate and use a microfluidic device for the enrichment, detection, and analysis of single CTCs from the blood samples of sarcoma patients.

A Novel Palliative Care Peer Support Program for Adolescents and Young Adults: Survey and Factor Analytic Study.

Background: Palliative care literature indicates a dearth of programs addressing the psychosocial needs of adolescents and young adults (AYAs). Objectives: This study assessed patient-reported experiences of a palliative care peer support program, analyzed psychometric qualities of the program evaluation, and examined associations with quality-of-life scores to assess validity and potential impact on aspects of AYA quality of life. Design: This retrospective, cross-sectional study described self-reported Streetlight program evaluation and quality of life of AYA patients, exploratory factor analysis of survey responses, and analysis of associations with quality of life. Setting/Subjects: AYA participants (13-30) enrolled in the Streetlight program for at least six months were recruited during hospital admissions and clinic visits at UF Health Shands Hospital. Results: Participants' (n = 69) scores were high for Youth Quality of Life Instrument-Short Form (YQOL-SF) (82.6 of 100), and Streetlight evaluations (4.47 of 5). Patients endorsed themes of: high-quality friendships with volunteers, transformative impacts to wellbeing, and benefits to mental health and coping in open-ended responses. Analyses identified three factors explaining 61% of variance in Streetlight program evaluation responses: "Friendships and Support" (26%); "Coping, Family, and Providers" (20%); and "Diversion and Respect" (15%). Significant positive associations were found between Streetlight evaluation scores and YQOL-SF Belief in Self and Family factor scores, as well as between Streetlight evaluation Friendships and Support factor scores, and YQOL-SF total and factor-specific scores. Conclusions: Results suggest that the Streetlight program is a viable model to facilitate positive experiences, opportunities for socialization, and meaningful peer support for AYA patients.

"It Becomes a Family I'm a Part of We Get to Carry Each Other": Themes from Qualitative Interview of Patients Enrolled in an Inpatient Palliative Care Support Program for Adolescents and Young Adults.

Background: The pediatric palliative care literature provides little evidence regarding the lived experiences of adolescents and young adults (AYAs). Objectives: We sought to evaluate the aspects of a palliative care peer support program, which were most helpful to patients, and identify areas for improvement to better address their psychosocial needs. Design: This was a retrospective, cross-sectional study, which described self-reported Streetlight program evaluation using thematic analysis of interviews with AYAs. A total of 10 interviews was completed. Setting/Subjects: Thirty-three current and former Streetlight participants (13-30), enrolled in the Streetlight program for at least six months, were recruited during hospital admissions and clinic visits at UF Health Shands Hospital in the United States. Of the 33, 2 participants died before interviews could be conducted. A total of 10 interviews were conducted. Results: Thematic analysis of the 10 individuals identified 5 themes. They were (1) normalization of life in hospital, (2) mental health and instillation of hope, (3) companionship and connection, (4) diversity of volunteers, and (5) gratitude. Conclusions: Results suggest that AYAs who participated in a peer support, palliative care program benefitted from their exposure to volunteer social support. Addressing the need for continued study of this population provides opportunities to expand peer support, pediatric palliative care programs to other hospitals and care facilities.

External-beam radiotherapy for pediatric and young adult desmoid tumors.

BACKGROUND: To report long-term outcomes following radiotherapy for desmoid tumors in children and young adults and identify variables impacting local-regional control and treatment complications. PROCEDURE: From 1978 to 2008, 30 patients <30 years old were treated with radiotherapy for a pathologically confirmed desmoid tumor. The median age at radiotherapy was 23.7 years old (range, 10.3-29.9). Fifteen patients underwent definitive radiotherapy, 14 received radiotherapy after gross total resection, and 1 received preoperative radiotherapy. Sixteen patients received 1.8 Gy once daily and 14 received 1.2 Gy twice daily. Variables analyzed for prognostic value included gender, age at diagnosis, primary or recurrent presentation, age at radiotherapy, tumor site, tumor size, extent of resection, fractionation schedule, and radiotherapy dose. RESULTS: The actuarial 15-year overall survival and local-regional control rates were 96% and 55%, respectively. Local-regional control in patients <18 years old at the time of radiotherapy was 20% versus 63% in those 18-30 years old (P = 0.08). Local-regional control rates for tumors receiving ≥ 55 Gy and < 55 Gy were 79% and 30%, respectively (P = 0.02). No other factors had a statistically significant association with local-regional control by univariate analysis. Twelve of 30 patients experienced grade 3-4 complications, including pathologic fractures, impaired range of motion, pain, and in-field skin cancers. CONCLUSIONS: The role of radiotherapy in managing young patients with desmoid tumors remains unclear. Younger patient age is associated with inferior local-regional control following RT. In children and young adults, doses ≥55 Gy were associated with improved tumor control, but also lead to increased risk of complications.

Primary pulmonary artery sarcoma in the pediatric patient: Review of literature and a case report.

Primary pulmonary artery sarcoma (PAS) is extremely rare in children. Nevertheless, distinguishing primary PAS from pulmonary embolism is critical to a child's survival. Primary PAS is commonly misdiagnosed as a pulmonary embolism due to similar presenting symptoms and radiographic findings. However, compared to adults, pulmonary embolism is rare in children, especially in patients who do not have predisposing factors or hypercoagulable state. We present a child with primary PAS which mimicked pulmonary embolism on presentation but eventually was resected and is doing well 5 years after resection. In the absence of predisposing factors or hypercoagulable state, solid tumors such as primary PAS should be considered when assessing a pediatric patient with presumed pulmonary embolism.

GD2 chimeric antigen receptor modified T cells in synergy with sub-toxic level of doxorubicin targeting osteosarcomas.

Since the prognosis for children with high-risk osteosarcoma (OS) remains suboptimal despite intensive multi-modality therapies, there is a clear and urgent need for the development of targeted therapeutics against these refractory malignancies. Chimeric antigen receptor (CAR) modified T cells can meet this need by utilizing the immune system's potent cytotoxic mechanisms against tumor specific antigen targets with exquisite specificity. Since OS highly expresses the GD2 antigen, a viable immunotherapeutic target, we sought to assess if CAR modified T cells targeting GD2 could induce cytotoxicity against OS tumor cells. We demonstrated that the GD2 CAR modified T cells were highly efficacious for inducing OS tumor cell death. Interestingly, the OS cells were induced to up-regulate expression of PD-L1 upon interaction with GD2 CAR modified T cells, and the specific interaction induced CAR T cells to overexpress the exhaustion marker PD-1 along with increased CAR T cell apoptosis. To further potentiate CAR T cell killing activity against OS, we demonstrated that suboptimal chemotherapeutic treatment with doxorubicin can synergize with CAR T cells to effectively kill OS tumor cells.

Results of a Randomized, Double-Blinded, Placebo-Controlled, Phase 2.5 Study of Saracatinib (AZD0530), in Patients with Recurrent Osteosarcoma Localized to the Lung.

PURPOSE: Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. The Src pathway has been implicated in the metastatic behavior of osteosarcoma; about 95% of samples examined express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor that was evaluated in adults in Phase 1 studies. The primary goal of this study was to determine if treatment with saracatinib could increase progression-free survival (PFS) for patients who have undergone complete resection of osteosarcoma lung metastases in a double-blinded, placebo-controlled trial. Patients and Methods. Subjects with recurrent osteosarcoma localized to lung and who had complete surgical removal of all lung nodules were randomized within six weeks after complete surgical resection. Saracatinib, or placebo, was administered at a dose of 175 mg orally, once daily, for up to thirteen 28-day cycles. RESULTS: Thirty-seven subjects were included in the analyses; 18 subjects were randomized to receive saracatinib and 19 to receive placebo. Intent-to-treat analysis demonstrated a median PFS of 19.4 months in the saracatinib treatment group and 8.6 months in the placebo treatment group (p=0.47). Median OS was not reached in either arm. CONCLUSIONS: Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on OS, and Src inhibition alone may not be sufficient to suppress metastatic progression in osteosarcoma. There is a suggestion of potential clinical benefit as evidenced by longer PFS in patients randomized to saracatinib based on limited numbers of patients treated.

Clear cell sarcoma of the stomach.

Clear cell sarcoma (CCS) is a high grade soft tissue sarcoma with a distinct molecular profile. Gastrointestinal CCS is very rare and most reported cases are in adults. We describe a 10-year-old female with a 4-month history of anemia who later developed fever, weight loss and abdominal pain. She was subsequently found to have a large infiltrative gastric mass. A diagnosis of CCS was confirmed by molecular and cytogenetic studies. This case illustrates the necessity of a multimodal approach, particularly the use of molecular studies, in the diagnostic evaluation of rare tumors presenting in unusual sites.

Primary testicular presentation of ALK-1-negative anaplastic large cell lymphoma in a pediatric patient.

Anaplastic large cell lymphoma is a heterogeneous group of malignant non-Hodgkin lymphomas that occurs in up to 15% of all pediatric non-Hodgkin lymphomas. It is characterized by B-symptoms and involvement of extranodal sites such as skin, bone, and soft tissue. This brief report describes first reported case of pediatric primary testicular anaplastic large cell lymphoma in a 14-year-old boy. The presentation included acute testicular pain, fever, and vomiting. After chemotherapy and unilateral radical orchiectomy, patient continues in complete remission.

Emerging trends in immunotherapy for pediatric sarcomas.

While promising, immunotherapy has yet to be fully unlocked for the preponderance of cancers where conventional chemoradiation reigns. This remains particularly evident in pediatric sarcomas where standard of care has not appreciably changed in decades. Importantly, pediatric bone sarcomas, like osteosarcoma and Ewing's sarcoma, possess unique tumor microenvironments driven by distinct molecular features, as do rhabdomyosarcomas and soft tissue sarcomas. A better understanding of each malignancy's biology, heterogeneity, and tumor microenvironment may lend new insights toward immunotherapeutic targets in novel platform technologies for cancer vaccines and adoptive cellular therapy. These advances may pave the way toward new treatments requisite for pediatric sarcomas and patients in need of new therapies.

Radiation Treatment for Ewing Sarcoma Family of Tumors in Adult Patients: A Single Institution's Experience Over 40 Years.

PURPOSE/OBJECTIVES: To report prognostic factors and long-term outcomes in adults with Ewing sarcoma treated with definitive radiotherapy. MATERIALS AND METHODS: We reviewed patients 18 years old and above with nonmetastatic Ewing sarcoma treated with radiotherapy +/- chemotherapy or surgery. Outcomes were stratified by age (30 and above vs. younger than 30 y), soft tissue extension, tumor size (≥8.5 vs. <8.5 cm), tumor location, resection (yes vs. no), and treatment era (1970-1992 vs. 1993-2012). Toxicities were scored using the RTOG criteria. RESULTS: Fifty-five patients (21 women) were treated with radiotherapy. Average age at diagnosis: 26.7 years (38 patients below 30 vs. 17 patients 30 y and above). A total of 43 had soft tissue extension (78%). Median tumor size: 8.5 cm. Most tumors were in the pelvis (40%), followed by the lower (27%) and upper (24%) extremities. All but 1 patient received chemotherapy; 13 underwent resection. Median dose: 55 Gy. Median follow-up: 3.6 years; 17.5 years for living patients. The 5-year overall (OS) and cause-specific survival (CSS) rates were both 46%. OS and CSS rates were unaffected by age (P=0.97), tumor size (P=0.12), or tumor location (P=0.99). Soft tissue extension portended a significantly poorer prognosis for 5-year OS and CSS: 37% vs. 82% (with and without, respectively; P=0.04). Patients who underwent resection had improved 5-year OS and CSS: 77% vs. 37%, respectively (P=0.01). Patients treated after 1993 had improved 5-year OS: 58% vs. 37% (P=0.0264). CONCLUSIONS: Adult patients with Ewing sarcoma experience similar treatment outcomes regardless of age at diagnosis. Soft tissue extension represents a poor prognostic factor. Aggressive trimodality therapy achieved the highest OS and CSS.

Familiarity of pediatricians with different commercially available neonatal and infant formulas.

To assess the familiarity of pediatricians with commercially available formulas and their use for cow's milk protein allergy and colic, a list of formulas was generated by visiting several grocery stores. Pediatricians were ask to indicate their familiarity with these and other "specialized" formulas with regard to protein and carbohydrate sources, energy content, hypoallergenicity, and indication for infant colic. The participants answered an average of 46% of the questions correctly. Respondents were very familiar with 27% of the formulas, and unfamiliar with 35%. The highest score was 70%, and 10% of the responders correctly answered 65% or more of the questions. Fifty-one percent correctly identified the protein source of the formulas; 32% correctly identified the carbohydrate source. The energy content of the formulas was correctly identified by 54%. These data suggest that pediatricians have a poor understanding of the content and appropriate use of neonatal and infant formulas.