Publications by authors named "Sara M Federico"

25 Publications

  • Page 1 of 1

Induction Chemotherapy With an Anti-GD2 Monoclonal Antibody (Dinutuximab) and Cytokines in Children With Newly Diagnosed High-risk Neuroblastoma: A Case Series.

J Pediatr Hematol Oncol 2020 Nov 11. Epub 2020 Nov 11.

Department of Oncology, St Jude Children's Research Hospital.

Although outcomes for patients with high-risk neuroblastoma improved after the addition of a chimeric anti-GD2 monoclonal antibody (dinutuximab) as treatment for minimal residual disease, nearly half of these patients die of disease. Recent studies demonstrated efficacy of the combination of chemotherapy with anti-GD2 mAb in patients with relapsed or newly diagnosed disease. This retrospective case series describes 6 patients treated at St Jude Children's Research Hospital with an induction regimen containing dinutuximab and chemotherapy, followed by consolidation and postconsolidation therapy. The treatment was well tolerated with expected toxicities. All patients completed induction therapy and demonstrated a clinical response. Further studies are warranted.
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http://dx.doi.org/10.1097/MPH.0000000000001992DOI Listing
November 2020

Tailoring Therapy for Children With Neuroblastoma on the Basis of Risk Group Classification: Past, Present, and Future.

JCO Clin Cancer Inform 2020 10;4:895-905

Department of Pediatrics and Comer Children's Hospital, University of Chicago, Chicago, IL.

For children with neuroblastoma, the likelihood of cure varies widely according to age at diagnosis, disease stage, and tumor biology. Treatments are tailored for children with this clinically heterogeneous malignancy on the basis of a combination of markers that are predictive of risk of relapse and death. Sequential risk-based, cooperative-group clinical trials conducted during the past 4 decades have led to improved outcome for children with neuroblastoma. Increasingly accurate risk classification and refinements in treatment stratification strategies have been achieved with the more recent discovery of robust genomic and molecular biomarkers. In this review, we discuss the history of neuroblastoma risk classification in North America and Europe and highlight efforts by the International Neuroblastoma Risk Group (INRG) Task Force to develop a consensus approach for pretreatment stratification using seven risk criteria including an image-based staging system-the INRG Staging System. We also update readers on the current Children's Oncology Group risk classifier and outline plans for the development of a revised 2021 Children's Oncology Group classifier that will incorporate INRG Staging System criteria to facilitate harmonization of risk-based frontline treatment strategies conducted around the globe. In addition, we discuss new approaches to establish increasingly robust, future risk classification algorithms that will further refine treatment stratification using machine learning tools and expanded data from electronic health records and the INRG Data Commons.
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http://dx.doi.org/10.1200/CCI.20.00074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608590PMC
October 2020

A phase I trial of talazoparib and irinotecan with and without temozolomide in children and young adults with recurrent or refractory solid malignancies.

Eur J Cancer 2020 09 11;137:204-213. Epub 2020 Aug 11.

Departments of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Departments of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; The Departments of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA.

Background: Talazoparib combined with irinotecan and temozolomide demonstrated efficacy in a murine Ewing sarcoma model. Based on these data, we conducted a phase I trial of talazoparib and irinotecan with/without temozolomide in paediatric patients with recurrent/refractory solid malignancies.

Patients And Methods: Cohorts of 3-6 patients with recurrent/refractory solid malignancies received escalating doses of oral talazoparib and intravenous irinotecan (arm A) and oral talazoparib, oral temozolomide and intravenous irinotecan (arm B) in a 3 + 3 design. Talazoparib was administered on days 1-6, and intravenous irinotecan and oral temozolomide were administered on days 2-6, of a 21-day course. Serum for talazoparib and irinotecan pharmacokinetics was obtained during course 1. UGT1A1 polymorphism and Schlafen family member 11 (SLFN11) immunohistochemical staining were performed.

Results: Forty-one patients (20 males; median age, 14.6 years; 24 with recurrent disease) were evaluable for dose escalation. Twenty-nine and 12 patients were treated on arm A and arm B, respectively, for a total of 208 courses. The most common diagnosis was Ewing sarcoma (53%). The most common ≥grade III haematologic toxicities in arms A and B included neutropenia (78% and 31%, respectively) and thrombocytopenia (42% and 31%, respectively). In arms A and B, febrile neutropenia (24% and 14%, respectively) and diarrhoea (21% and 7%, respectively) were the most common ≥grade III non-hematologic toxicities. Six patients (Ewing sarcoma [5 patients] and synovial sarcoma [1 patient]) had a response (1 with a complete response, 5 with a partial response). The objective response rates were 10.3% (arm A) and 25% (arm B). Pharmacokinetic testing demonstrated no evidence of drug-drug interaction between talazoparib and irinotecan. UGT1A1 was not related to response. SLFN11 positivity was associated with best response to therapy.

Conclusions: The combination of talazoparib and irinotecan with/without temozolomide is feasible and active in Ewing sarcoma, and further investigation is warranted.
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http://dx.doi.org/10.1016/j.ejca.2020.06.014DOI Listing
September 2020

Phase I expansion cohort to evaluate the combination of bevacizumab, sorafenib and low-dose cyclophosphamide in children and young adults with refractory or recurrent solid tumours.

Eur J Cancer 2020 06 20;132:35-42. Epub 2020 Apr 20.

Department of Pediatrics, Children's Hospital Los Angeles, University of Southern California, Keck School of Medicine, Los Angeles, CA 90027, USA.

Background: Angiogenesis is critical for tumour growth and metastasis. Dual inhibition of vascular endothelial growth factors and platelet-derived growth factor receptors suppresses angiogenesis. This expansion cohort of a phase I study targeted angiogenesis with sorafenib, bevacizumab and low-dose cyclophosphamide in children and young adults with recurrent solid tumours.

Methods: An expansion cohort including patients with refractory or recurrent solid tumours was enrolled and received bevacizumab (15 mg/kg IV, day 1), sorafenib (90 mg/m po twice daily, days 1-21) and low-dose cyclophosphamide (50 mg/m po daily, days 1-21). Each course was 21 days. Toxicities were assessed using Common Terminology Criteria for Adverse Events, v3.0, and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. Serial bevacizumab pharmacokinetic (PK) studies were performed during course 1.

Results: Twenty-four patients (15 males; median age 14.5 yrs; range 1-22 yr) received a median of 6 courses (range 1-18). Twelve patients had a bone or soft tissue sarcoma. The most common grade III/IV non-haematologic toxicities were hypertension (N = 4), hand/foot rash (N = 3) and elevated lipase (N = 3). The most common grade III/IV haematologic toxicities were neutropenia (N = 7) and lymphopenia (N = 17). Three patients (2 synovial sarcoma, 1 rhabdoid tumour) achieved a partial response and 18 had stable disease. The progression-free survival at 3 and 6 months were 78.1% (95% confidence interval [CI] 60.6-95.6%) and 54% (95% CI 30.2-78.2%), respectively. Bevacizumab PKs in 15 patients was similar to published adult PK results.

Conclusions: Intravenous bevacizumab combined with oral sorafenib and low-dose cyclophosphamide was tolerated and demonstrated promising activity in a subset of childhood solid tumours.
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http://dx.doi.org/10.1016/j.ejca.2020.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958650PMC
June 2020

Longitudinal NK cell kinetics and cytotoxicity in children with neuroblastoma enrolled in a clinical phase II trial.

J Immunother Cancer 2020 03;8(1)

Oncology Department, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

Background: Natural killer (NK) cells are one of the main effector populations of immunotherapy with monoclonal antibody and cytokines, used in combination with chemotherapy to treat children with high-risk neuroblastoma on this phase II trial. However, the impact of chemoimmunotherapy on NK cell kinetics, phenotype, and function is understudied.

Methods: We prospectively examined NK cell properties from 63 children with newly diagnosed neuroblastoma enrolled in a phase II trial (NCT01857934) and correlated our findings with tumor volume reduction after 2 courses of chemoimmunotherapy. NK cell studies were conducted longitudinally during chemoimmunotherapy and autologous hematopoietic cell transplantation (autoHCT) with optional haploidentical NK cell infusion and additional immunotherapy.

Results: Chemoimmunotherapy led to significant NK cytopenia, but complete NK cell recovery reliably occurred by day 21 of each therapy course as well as after autoHCT. Haploidentical NK cell infusion elevated the NK cell count transiently during autoHCT. NK cell cytotoxicity increased significantly during treatment compared with diagnosis. In addition, NK cells maintained their ability to respond to cytokine stimulation in culture longitudinally. Unsupervised cluster analysis of CD56 NK cell count and tumor volume at diagnosis and after two courses of chemoimmunotherapy identified two patient groups with distinct primary tumor sizes and therapy responses.

Conclusion: After profound NK cytopenia due to chemoimmunotherapy, endogenously reconstituted NK cells exhibit enhanced NK cytotoxicity compared with pretherapy measurements. Our data suggest a relationship between CD56 expression and tumor size before and after two courses of chemoimmunotherapy; however, future studies are necessary to confirm this relationship and its predictive significance.

Trial Registration Number: NCT01857934.
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http://dx.doi.org/10.1136/jitc-2019-000176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206969PMC
March 2020

Clinical impact of post-induction resolution of pulmonary lesions in metastatic Ewing sarcoma.

Pediatr Blood Cancer 2020 04 15;67(4):e28150. Epub 2020 Jan 15.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Patients with metastatic Ewing sarcoma experience poor outcomes despite intensive systemic and local therapy. Early chemotherapy response of pulmonary metastases has been associated with prognosis in other pediatric malignancies. We reviewed the outcomes of patients with Ewing sarcoma and pulmonary metastases treated at our institution based on therapy received and early pulmonary response.

Materials And Methods: We retrospectively reviewed patients with newly diagnosed Ewing sarcoma and pulmonary metastases at St. Jude Children's Research Hospital between 1979 and 2015. Data obtained included demographic and treatment characteristics including chemotherapy, local control measures, whole lung irradiation (WLI) administration, autologous stem cell transplantation, and outcomes. Patients were evaluated for radiographic post-induction pulmonary complete response (CR). We estimated event-free survival (EFS) and overall survival (OS) and used Cox proportional hazards regression to examine the effects of clinical and treatment factors on outcomes.

Results: Fifty-four patients (median age, 12.9 years) were evaluated. Post-induction pulmonary CR was observed in 33 (61%) patients. WLI was delivered to 16 patients (4/33 with pulmonary CR and 12/21 with non-CR). At median 3.6 years follow-up, five-year EFS and OS were 30.8% ± 6.4% and 49.6% ± 7.1%, respectively. Post-induction pulmonary CR was associated with prolonged EFS (P < 0.001) but not improved OS (P = 0.065). Post-induction pulmonary CR was associated with a lower incidence of lung failure (P = 0.031).

Conclusions: Post-induction pulmonary CR is associated with improved EFS in patients with Ewing sarcoma who present with pulmonary metastases.
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http://dx.doi.org/10.1002/pbc.28150DOI Listing
April 2020

Impact of MYCN status on response of high-risk neuroblastoma to neoadjuvant chemotherapy.

J Pediatr Surg 2020 Jan 25;55(1):130-134. Epub 2019 Oct 25.

Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN; Division of Pediatric Surgery, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN. Electronic address:

Background/purpose: MYCN-amplification in neuroblastoma is associated with an aggressive clinical phenotype. We evaluated the association of MYCN amplification with tumor response to neoadjuvant chemotherapy.

Methods: Primary tumor response, assessed by percentage volume change on CT scan and degree of tumor resection, assessed by the operating surgeon, were retrospectively compared in 84 high-risk neuroblastoma patients. There were thirty-four (40%) with MYCN-amplified tumors and fifty (60%) with non-amplified tumors treated at our institution from 1999 to 2016. Metastatic disease response was assessed on MIBG scan by change in Curie score.

Results: MYCN-amplification was associated with a greater mean percentage reduction in primary tumor volume after neoadjuvant chemotherapy (72.27% versus 46.83% [non-amplified tumors], p = 0.001). The percentage of patients with a Curie score > 2 at diagnosis who then had a score ≤ 2 after neoadjuvant chemotherapy was not significantly different (8 [61.5%] and 8 [34.8%], respectively, p = 0.37). Twenty-eight (85.7%) patients with MYCN-amplification had ≥90% surgical resection compared to 45 (91.84%) patients with non-amplified tumors (p = 0.303).

Conclusions: MYCN-amplification in high-risk neuroblastoma was associated with a better response of the primary tumor to neoadjuvant chemotherapy, but not metastatic sites, than in patients with non-amplified tumors. This did not significantly impact the ability to resect ≥90% of the primary tumor/locoregional disease.

Type Of Study: Treatment Study LEVEL OF EVIDENCE: Level III.
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http://dx.doi.org/10.1016/j.jpedsurg.2019.09.067DOI Listing
January 2020

A Phase II Trial of Hu14.18K322A in Combination with Induction Chemotherapy in Children with Newly Diagnosed High-Risk Neuroblastoma.

Clin Cancer Res 2019 11 10;25(21):6320-6328. Epub 2019 Oct 10.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Purpose: We sought to evaluate whether combining a humanized antidisialoganglioside mAb (hu14.18K322A) with induction chemotherapy improves early responses and outcomes in children with newly diagnosed high-risk neuroblastoma.

Patients And Methods: We conducted a prospective nonrandomized, single-arm, two-stage, phase II clinical trial. Six courses of induction chemotherapy were coadministered with hu14.18K322A and followed with granulocyte-macrophage colony-stimulating factor (GM-CSF) and low-dose IL2. Consolidation was performed with a busulfan/melphalan preparative regimen. An additional course of hu14.18K322A was administered with parent-derived natural killer cells, when available, during consolidation. Hu14.18K322A, GM-CSF, IL2, and isotretinoin were then administered. Secondary outcomes included reduced tumor volume and semiquantitative I-metaiodobenzylguanidine scoring [i.e., Curie scores (CS)] at the end of induction.

Results: Forty-two patients received hu14.18K322A and induction chemotherapy. This regimen was well tolerated, with continuous-infusion narcotics adjusted to patient tolerance. Partial responses (PR) or better after the first two chemoimmunotherapy courses occurred in 32 patients [76.2%; 95% confidence interval (CI), 60.6-88.0]. This was accompanied by primary tumor volume reductions (median, -76%; range, -100% to 5%). Of 35 patients with stage IV disease who completed induction, 31 had end-of-induction CSs of 2 or less. No patients experienced progression during induction. Two-year event-free survival (EFS) was 85.7% (95% CI, 70.9-93.3).

Conclusions: Adding hu14.18K322A to induction chemotherapy produced early PR or better in most patients, reduced tumor volumes, improved CSs at the end of induction, and yielded an encouraging 2-year EFS. These results, if validated in a larger study, may change the standard of care for children with high-risk neuroblastoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825564PMC
November 2019

Sorafenib Population Pharmacokinetics and Skin Toxicities in Children and Adolescents with Refractory/Relapsed Leukemia or Solid Tumor Malignancies.

Clin Cancer Res 2019 12 27;25(24):7320-7330. Epub 2019 Aug 27.

Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Purpose: To determine the pharmacokinetics and skin toxicity profile of sorafenib in children with refractory/relapsed malignancies.

Patients And Methods: Sorafenib was administered concurrently or sequentially with clofarabine and cytarabine to patients with leukemia or with bevacizumab and cyclophosphamide to patients with solid tumor malignancies. The population pharmacokinetics (PPK) of sorafenib and its metabolites and skin toxicities were evaluated.

Results: In PPK analysis, older age, bevacizumab and cyclophosphamide regimen, and higher creatinine were associated with decreased sorafenib apparent clearance (CL/f; < 0.0001 for all), and concurrent clofarabine and cytarabine administration was associated with decreased sorafenib N-oxide CL/f ( = 7e-4). Higher bilirubin was associated with decreased sorafenib N-oxide and glucuronide CL/f ( = 1e-4). Concurrent use of organic anion-transporting polypeptide 1B1 inhibitors was associated with increased sorafenib and decreased sorafenib glucuronide CL/f ( < 0.003). In exposure-toxicity analysis, a shorter time to development of grade 2-3 hand-foot skin reaction (HFSR) was associated with concurrent ( = 0.0015) but not with sequential ( = 0.59) clofarabine and cytarabine administration, compared with bevacizumab and cyclophosphamide, and with higher steady-state concentrations of sorafenib ( = 0.0004) and sorafenib N-oxide ( = 0.0275). In the Bayes information criterion model selection, concurrent clofarabine and cytarabine administration, higher sorafenib steady-state concentrations, larger body surface area, and previous occurrence of rash appeared in the four best two-predictor models of HFSR. Pharmacokinetic simulations showed that once-daily and every-other-day sorafenib schedules would minimize exposure to sorafenib steady-state concentrations associated with HFSR.

Conclusions: Sorafenib skin toxicities can be affected by concurrent medications and sorafenib steady-state concentrations. The described PPK model can be used to refine exposure-response relations for alternative dosing strategies to minimize skin toxicity.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911639PMC
December 2019

Pain Outcomes After Celiac Plexus Block in Children and Young Adults with Cancer.

J Adolesc Young Adult Oncol 2018 12 16;7(6):666-672. Epub 2018 Aug 16.

Division of Anesthesiology, Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

The use of celiac plexus block (CPB) for abdominal pain has been extensively reported in adults. However, pediatric literature is limited to three single case reports and a series of three cases. This study evaluated the effectiveness of CPB in children and young adults (aged 8-20 years) with abdominal malignancies. Pain outcomes after CPB were evaluated in four children and young adults with cancer. Mean daily pain score (PS, 0-10) and morphine consumption (intravenous morphine equivalent daily [MED], mg/kg/day) before and after CPB were used to assess effectiveness. Mean daily PS reduced after CPB in all patients. In one patient, this reduction was sustained up to 6 months of follow-up, and analgesics were discontinued 1 week after CPB. The other three patients had limited survival (6, 16, and 37 days) after CPB. One patient had a PS of 0 over the last few days of life, but the MED was escalated from 0.74 before the block to 5.4 mg/kg/day at the end of life. In the other two patients, MED was lower during the first week after CPB than that before CPB (4.55 vs. 1.59 and 2.88 vs. 1.51 mg/kg/day, respectively). As these two patients had disease progression during their last days of life, the MED was increased to 4.75 and 263.9 mg/kg/day, respectively. Our results suggest that CPB may contribute to reducing PS and MED. We observed the use of CPB rather late in the disease trajectory.
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http://dx.doi.org/10.1089/jayao.2018.0035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302813PMC
December 2018

Treatment and secondary prophylaxis with ethanol lock therapy for central line-associated bloodstream infection in paediatric cancer: a randomised, double-blind, controlled trial.

Lancet Infect Dis 2018 08 5;18(8):854-863. Epub 2018 Jun 5.

Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA.

Background: Central line-associated bloodstream infections (CLABSIs) affect about 25% of children with cancer, and treatment failure is common. Adjunctive ethanol lock therapy might prevent treatment failure but high-quality evidence is scarce. We evaluated ethanol lock therapy as treatment and secondary prophylaxis for CLABSI in children with cancer or haematological disorders.

Methods: This randomised, double-blind, placebo-controlled superiority trial, with two interim futility and efficacy analyses (done when the first 46 and 92 evaluable participants completed study requirements), was done at two paediatric hospitals in the USA and Australia. Patients aged 6 months to 24 years, inclusive, with cancer or a haematological disorder and new CLABSI were eligible. Participants were randomly assigned (1:1) to receive either ethanol lock therapy (70% ethanol) or placebo (heparinised saline) for 2-4 h per lumen daily for 5 days (treatment phase), then for up to 3 non-consecutive days per week for 24 weeks (prophylaxis phase). The primary composite outcome was treatment failure, consisting of attributable catheter removal or death, new or persistent (>72 h) infection, or additional lock therapy during the treatment phase, and recurrent CLABSI during the prophylaxis phase. This trial is registered with ClinicalTrials.gov, number NCT01472965.

Findings: 94 evaluable participants were enrolled between Dec 14, 2011, and Sept 12, 2016, of whom 48 received ethanol lock therapy and 46 received placebo. The study met futility criteria at the second interim analysis. Treatment failure was similar with ethanol lock therapy (21 [44%] of 48) and placebo (20 [43%] of 46; relative risk [RR] 1·0, 95% CI 0·6-1·6; p=0·98). Some adverse events, including infusion reactions and catheter occlusion, were more frequent in the ethanol lock therapy group than in the placebo group. Catheter occlusion requiring thrombolytic therapy was more common with ethanol lock therapy (28 [58%] of 48) than with placebo (15 [33%] of 46; RR 1·8, 95% CI 1·1-2·9; p=0·012). Discontinuation of lock therapy because of adverse effects or patient request occurred in a similar proportion of participants in the ethanol lock therapy (nine [19%] of 48) and placebo groups (ten [22%] of 46; p=0·72).

Interpretation: Ethanol lock therapy did not prevent CLABSI treatment failure and it increased catheter occlusion. Routine ethanol lock therapy for treatment or secondary prophylaxis is not recommended in this population.

Funding: American Lebanese Syrian Associated Charities to St Jude Children's Research Hospital and an Australian Government Research Training Scholarship.
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http://dx.doi.org/10.1016/S1473-3099(18)30224-XDOI Listing
August 2018

FDG-PET CT in the evaluation of primary and secondary pancreatic malignancies.

Pediatr Blood Cancer 2018 10 11;65(10):e27115. Epub 2018 May 11.

Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee.

Purpose: Primary pancreatic carcinoma and pancreatic metastases are rare in the pediatric population. Pancreatoblastoma is the most common pancreatic malignant tumor in young children and solid-pseudopapillary tumor in teenagers. Pancreatic adenocarcinoma is extremely rare under the age of 40 and is usually associated with underlying genetic abnormalities. Secondary malignancies of the pancreas occur more frequently than primary pancreatic malignancies in children and are most commonly seen with non-Hodgkin lymphomas (NHL) and mesenchymal sarcomas. The purpose of this study was to characterize the metabolism of primary and secondary tumors of the pancreas in pediatric patients.

Materials And Methods: A retrospective analysis of all primary and secondary pancreatic malignancies imaged with 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) computed tomography (CT) was conducted.

Results: Three patients with primary pancreatic cancers were identified, one each with pancreatoblastoma, solid-pseudopapillary tumor, and adenocarcinoma. Each tumor showed elevated uptake of FDG. Metastatic disease in the pancreas was identified in 12 patients-five NHL (including three Burkitt lymphomas), six sarcomas (three osteosarcomas, two rhabdomyosarcomas, and one Ewing sarcoma family tumor), and one malignant rhabdoid tumor. Elevated but variable uptake of FDG was found in each of the tumors of patients with metastatic disease within the pancreas.

Conclusion: Both primary malignancies and metastatic disease within the pancreas, though very rare in children, adolescents, and young adults, are metabolically active and can be functionally characterized using FDG-PET CT.
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http://dx.doi.org/10.1002/pbc.27115DOI Listing
October 2018

A Pilot Trial of Humanized Anti-GD2 Monoclonal Antibody (hu14.18K322A) with Chemotherapy and Natural Killer Cells in Children with Recurrent/Refractory Neuroblastoma.

Clin Cancer Res 2017 Nov 22;23(21):6441-6449. Epub 2017 Sep 22.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Anti-GD2 mAbs, acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, combined with chemotherapy, cytokines, and haploidentical natural killer (NK) cells. Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40 mg/m/dose, days 2-5), GM-CSF, and IL2 with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4), and ifosfamide/carboplatin/etoposide (courses 5,6). Parentally derived NK cells were administered with courses 2, 4, and 6. Serum for pharmacokinetic studies of hu14.18K322A, soluble IL2 receptor alpha (sIL2Rα) levels, and human antihuman antibodies (HAHA) were obtained. Thirteen heavily pretreated patients (9 with prior anti-GD2 therapy) completed 65 courses. One patient developed an unacceptable toxicity (grade 4 thrombocytopenia >35 days). Four patients discontinued treatment for adverse events (hu14.18K322A allergic reaction, viral infection, surgical death, second malignancy). Common toxicities included grade 3/4 myelosuppression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK-cell infusions. The response rate was 61.5% (4 complete responses, 1 very good partial response, 3 partial responses) and five had stable disease. The median time to progression was 274 days (range, 239-568 days); 10 of 13 patients (77%) survived 1 year. Hu14.18K322A pharmacokinetics was not affected by chemotherapy or HAHA. All patients had increased sIL2Rα levels, indicating immune activation. Chemotherapy plus hu14.18K322A, cytokines, and NK cells is feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies of this approach are warranted in patients with relapsed and newly diagnosed neuroblastoma. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0379DOI Listing
November 2017

Orthotopic patient-derived xenografts of paediatric solid tumours.

Nature 2017 09 30;549(7670):96-100. Epub 2017 Aug 30.

Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Paediatric solid tumours arise from endodermal, ectodermal, or mesodermal lineages. Although the overall survival of children with solid tumours is 75%, that of children with recurrent disease is below 30%. To capture the complexity and diversity of paediatric solid tumours and establish new models of recurrent disease, here we develop a protocol to produce orthotopic patient-derived xenografts at diagnosis, recurrence, and autopsy. Tumour specimens were received from 168 patients, and 67 orthotopic patient-derived xenografts were established for 12 types of cancer. The origins of the patient-derived xenograft tumours were reflected in their gene-expression profiles and epigenomes. Genomic profiling of the tumours, including detailed clonal analysis, was performed to determine whether the clonal population in the xenograft recapitulated the patient's tumour. We identified several drug vulnerabilities and showed that the combination of a WEE1 inhibitor (AZD1775), irinotecan, and vincristine can lead to complete response in multiple rhabdomyosarcoma orthotopic patient-derived xenografts tumours in vivo.
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http://dx.doi.org/10.1038/nature23647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5659286PMC
September 2017

Assessment of Chemotherapy Response in Ewing Sarcoma.

Radiology 2016 11;281(2):647-649

Departments of Diagnostic Imaging * and.

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http://dx.doi.org/10.1148/radiol.2016160903DOI Listing
November 2016

A phase 1 study of oral ridaforolimus in pediatric patients with advanced solid tumors.

Oncotarget 2016 Dec;7(51):84736-84747

Department of Childhood and Adolescent Oncology, Gustave Roussy, University Paris-Sud, Villejuif, France.

Purpose: Ridaforolimus is an investigational, potent, selective mTOR inhibitor. This study was conducted to determine the recommended phase 2 dose (RP2D), maximum tolerated dose, safety, pharmacokinetics, and antitumor activity of oral ridaforolimus in children with advanced solid tumors.

Experimental Design: In this phase 1, multicenter, open-label study in children aged 6 to <18 years with advanced solid tumors, ridaforolimus was administered orally for 5 consecutive days/week in 28-day cycles until progression, unacceptable toxicity, or consent withdrawal. Dose started at 22 mg/m2 and increased to 28 mg/m2 and 33 mg/m2, followed by expansion at the RP2D.

Results: Twenty patients were treated; 18 were evaluable for dose-limiting toxicities. One dose-limiting toxicity (grade 3 increased alanine aminotransferase) occurred in 1 patient at 33 mg/m2. Dose escalation concluded at 33 mg/m2; the maximum tolerated dose was not determined. The most common treatment-related adverse events (frequency ≥40%) were manageable grade 1-2 stomatitis, thrombocytopenia, hypertriglyceridemia, increased alanine aminotransferase, fatigue, hypercholesterolemia, anemia, and increased aspartate aminotransferase. Ridaforolimus exposure at 28 mg/m2 and 33 mg/m2 exceeded adult target levels. The RP2D for oral ridaforolimus in children was defined as 33 mg/m2. Four patients received at least 4 cycles; 2 with pineoblastoma and diffuse intrinsic pontine glioma had stable disease for 12 and 46 cycles, respectively.

Conclusions: Ridaforolimus is orally bioavailable and well tolerated in children with advanced solid tumors. The RP2D (33 mg/m2, 5 days/week) exceeds the adult RP2D. The favorable toxicity and pharmacokinetic profiles may allow for combination therapy, a promising therapeutic option in pediatric malignancies.
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http://dx.doi.org/10.18632/oncotarget.12450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356695PMC
December 2016

Phase 1 study of dalotuzumab monotherapy and ridaforolimus-dalotuzumab combination therapy in paediatric patients with advanced solid tumours.

Eur J Cancer 2016 07 10;62:9-17. Epub 2016 May 10.

Department of Pediatric and Adolescent Oncology, Gustave Roussy, Univ. Paris-Sud, 114, rue Edouard Vaillant, 94805 Villejuif, France. Electronic address:

Aim: Dalotuzumab is a highly specific, humanised immunoglobulin G1 monoclonal antibody against insulin-like growth factor receptor 1. This multicenter phase 1 study (NCT01431547) explored the safety and pharmacokinetics of dalotuzumab monotherapy (part 1) and the combination of dalotuzumab with the mammalian target of rapamycin inhibitor ridaforolimus (part 2) in paediatric patients with advanced solid tumours.

Methods: Dalotuzumab was administered intravenously every 3 weeks starting at 900 mg/m(2) and escalating to 1200 and 1500 mg/m(2). Combination therapy included intravenous dalotuzumab at the defined single-agent recommended phase 2 dose (RP2D) and oral ridaforolimus 28 mg/m(2) daily (days 1-5), repeated weekly. Pharmacokinetic studies were performed to evaluate the mean serum trough dalotuzumab concentration, which guided the RP2D.

Results: Twenty-four patients were enrolled (part 1, n = 20; part 2, n = 4). No dose-limiting toxicities were observed in patients receiving dalotuzumab alone. One patient experienced dose-limiting stomatitis in the combination arm. Pharmacokinetic data showed dose-dependent increases in exposure (area under the curve from zero to infinity [AUC0-∞]) (87,900, 164,000, and 186,000 h*mg/ml for the 900, 1200, and 1500 mg/m(2) dose levels, respectively), maximum serum concentration (Cmax) (392, 643, and 870 mg/ml), and serum trough concentration (Ctrough) (67.1, 71.6, and 101 mg/ml). The mean half-life was 265, 394, and 310 h, respectively. Dalotuzumab pharmacokinetics were not affected by coadministration with ridaforolimus. One of six patients with Ewing sarcoma had confirmed partial response to dalotuzumab monotherapy at 900 mg/m(2). Time to response was 41 d, and progression occurred at 126 d.

Conclusion: Dalotuzumab was well tolerated in paediatric patients with advanced solid malignancies. The RP2D of dalotuzumab is 900 mg/m(2) (ClinicalTrials.gov identifier: NCT01431547, Protocol PN062).
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http://dx.doi.org/10.1016/j.ejca.2016.03.084DOI Listing
July 2016

Orbital Metastasis Is Associated With Decreased Survival in Stage M Neuroblastoma.

Pediatr Blood Cancer 2016 Apr 24;63(4):627-33. Epub 2015 Nov 24.

Department of Ophthalmology, University of TN Hamilton Eye Institute, Memphis, Tennessee.

Background: Approximately 30% of patients with metastatic (stage M) neuroblastoma present with periorbital ecchymosis from orbital osseous disease. Though locoregional disease is staged by imaging, the prognostic significance of metastatic site in stage M disease is unknown. We hypothesize that, compared to nonorbital metastasis, orbital metastasis is associated with decreased survival in patients with stage M neuroblastoma, and that periorbital ecchymosis reflects location and extent of orbital disease.

Procedure: Medical records and imaging from 222 patients with stage M neuroblastoma seen at St. Jude Children's Research Hospital between January 1995 and May 2009 were reviewed. Thirty-seven patients were <18 months of age at diagnosis and 185 were ≥18 months of age. Overall survival (OS) and 5-year survival (5YS) were compared for patients with and without orbital, calvarial and nonorbital osseous metastasis, and with and without periorbital ecchymosis (log-rank test). Associations of periorbital ecchymosis with orbital metastasis location/extent were explored (Fisher's exact test, t-test).

Results: In patients ≥18 months of age, only orbital metastasis was associated with decreased 5YS (P = 0.0323) and OS (P = 0.0288). In patients <18 months of age, neither orbital, calvarial, or nonorbital bone metastasis was associated with OS or 5YS. Periorbital ecchymosis was associated with higher number of involved orbital bones (P = 0.0135), but not location or survival.

Conclusions: In patients ≥ 18 months of age with stage M neuroblastoma, orbital metastatic disease is associated with decreased 5YS and OS. In future clinical trials, orbital disease may be useful as an imaging-based risk factor for substratification of stage M neuroblastoma.
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http://dx.doi.org/10.1002/pbc.25847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127440PMC
April 2016

A piece of my mind. Ditch the Scale.

Authors:
Sara M Federico

JAMA 2015 Nov;314(19):2025-6

Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee; and Department of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis.

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http://dx.doi.org/10.1001/jama.2015.5916DOI Listing
November 2015

Reply to: Radiation dose reduction thanks to split-bolus multi-1 detector computer tomography (MDCT) in children with non-thoracic neuroblastoma.

Pediatr Blood Cancer 2015 Oct 1;62(10):1867. Epub 2015 Jun 1.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, 38105.

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http://dx.doi.org/10.1002/pbc.25598DOI Listing
October 2015

The role of chest computed tomography (CT) as a surveillance tool in children with high-risk neuroblastoma.

Pediatr Blood Cancer 2015 Jun 13;62(6):976-81. Epub 2015 Jan 13.

Departments of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee; Departments of Pediatrics, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee.

Background: Standardization of imaging obtained in children with neuroblastoma is not well established. This study examines chest CT in pediatric patients with high-risk neuroblastoma.

Procedure: Medical records and imaging from 88 patients with high-risk neuroblastoma, diagnosed at St. Jude Children's Research Hospital between January, 2002 and December, 2009, were reviewed. Surveillance imaging was conducted through 2013. Ten patients with thoracic disease at diagnosis were excluded. Event free survival (EFS) and overall survival (OS) were estimated. Size specific dose estimates for CT scans of the chest, abdomen, and pelvis were used to estimate absolute organ doses to 23 organs. Organ dosimetry was used to calculate cohort effective dose.

Results: The 5 year OS and EFS were 51.9% ± 6.5% and 42.6% ± 6.5%, respectively. Forty-six (58.9%) patients progressed/recurred and 41 (52.6%) died of disease. Eleven patients (14%) developed thoracic disease progression/recurrence identified by chest CT (1 paraspinal mass, 1 pulmonary nodules, and 9 nodal). MIBG (metaiodobenzylguanidine) scans identified thoracic disease in six patients. Five of the 11 had normal chest MIBG scans; three were symptomatic and two were asymptomatic with normal chest MIBG scans but avid bone disease. The estimated radiation dose savings from surveillance without CT chest imaging was 42%, 34% when accounting for modern CT acquisition (2011-2013).

Conclusions: Neuroblastoma progression/recurrence in the chest is rare and often presents with symptoms or is identified using standard non-CT imaging modalities. For patients with non-thoracic high-risk neuroblastoma at diagnosis, omission of surveillance chest CT imaging can save 35-42% of the radiation burden without compromising disease detection.
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http://dx.doi.org/10.1002/pbc.25400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694045PMC
June 2015

Subsequent malignant neoplasms in pediatric patients initially diagnosed with neuroblastoma.

J Pediatr Hematol Oncol 2015 Jan;37(1):e6-e12

Departments of *Oncology §Biostatistics ∥Pathology, St Jude Children's Research Hospital †Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, TN ‡Department of Oncology, Duke University, Durham, NC.

Background: Most prior studies evaluating subsequent malignant neoplasms (SMNs) in patients with neuroblastoma are restricted to long-term survivors and/or their treatment exposures. This study investigates SMNs in patients diagnosed with neuroblastoma at our institution.

Methods: Records of 646 patients treated for neuroblastoma at St Jude Children's Research Hospital between 1961 and 2005 were reviewed. Data from patients with SMNs were analyzed and the 20- and 30-year cumulative incidence of SMNs and standardized incidence ratio were calculated.

Results: Twenty-one patients had a SMN. The 20- and 30-year cumulative incidences of a SMN were 2.6%±0.7% and 4.6%±1.1%, respectively. The standardized incidence ratio was 8.3 (95% confidence interval, 5.0-13.0). Five patients developed a SMN within 5 years from diagnosis. The median latency for the development of acute myeloid leukemia/myelodysplastic syndrome (n=4), sarcomas (n=7), and carcinomas (n=5) were 3.6, 9, and 24.2 years, respectively. Nine patients died from their SMN, including all with acute myeloid leukemia/myelodysplastic syndrome.

Conclusions: Patients with neuroblastoma have an increased risk of secondary neoplasia. Modification of risk-adapted therapies will likely alter the affected patient population and the incidence of SMNs. Future studies are necessary to link SMNs to treatment exposures and to evaluate the risk of SMNs beyond 30 years from diagnosis.
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http://dx.doi.org/10.1097/MPH.0000000000000148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266626PMC
January 2015

Targeting oxidative stress in embryonal rhabdomyosarcoma.

Cancer Cell 2013 Dec;24(6):710-24

Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In contrast, alveolar rhabdomyosarcomas (ARMS) have fewer genetic lesions overall and no known recurrently mutated cancer consensus genes. To identify therapeutics for ERMS, we developed and characterized orthotopic xenografts of tumors that were sequenced in our study. High-throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for ERMS.
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http://dx.doi.org/10.1016/j.ccr.2013.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904731PMC
December 2013

Clinical features and outcomes of young patients with head and neck non-rhabdomyosarcoma soft tissue sarcomas.

Head Neck 2015 Jan 12;37(1):76-83. Epub 2014 Feb 12.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Pediatrics University of Tennessee, College of Medicine, Memphis, Tennessee.

Background: The history, prognostic factors, and outcome of young patients with head and neck non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) have not been adequately characterized.

Methods: Medical records of 58 patients with head and neck NRSTS treated at St. Jude Children's Research Hospital were reviewed.

Results: The majority of tumors were ≤5 cm and high grade. Lymph node and/or distant metastases were present in 17% at presentation. Patients received a combination of surgery, chemotherapy, and radiotherapy. The 10-year event-free and survival rates were 53.1% ± 7.3% and 63.2% ± 7.1%, respectively. Features associated with inferior survival included high histologic grade (p = .006), tumor diameter >5 cm (p < .001), invasiveness (p < .001), and incomplete resection at diagnosis (p = .005).

Conclusion: Most head and neck NRSTS in young patients are small, high grade, and nonmetastatic. The outcome is poor compared to NRSTS at other anatomic sites. Innovative approaches to local control and improved systemic therapy are needed.
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http://dx.doi.org/10.1002/hed.23564DOI Listing
January 2015

Comparison of PET-CT and conventional imaging in staging pediatric rhabdomyosarcoma.

Pediatr Blood Cancer 2013 Jul 19;60(7):1128-34. Epub 2012 Dec 19.

Division of Solid Tumors, Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Background: Over the past decade, PET-CT has been used to assess rhabdomyosarcoma (RMS) in children. However, the role of PET-CT in staging RMS is unknown.

Procedure: Thirty subjects with RMS, median age 7.3 years, underwent PET-CT before therapy. PET-CTs and conventional imaging (CI) were independently reviewed by two radiologists and two nuclear medicine physicians to determine the presence of metastases. Accuracy, sensitivity, and specificity of PET-CT for detecting metastases were compared to CI using biopsy and clinical follow-up as reference standards. Maximum standardized uptake values (SUV(max)) of primary tumors, lymph nodes, and pulmonary nodules were measured.

Results: Primary tumors had an average SUV(max) of 7.2 (range, 2.5-19.2). Accuracy rates for 17 subjects with nodal disease were 95% for PET-CT and 49% for CI. PET-CT had 94% sensitivity and 100% specificity for nodal disease. Of seven pulmonary nodules detected by CI, three were not identified by PET-CT, two were indeterminate, and one was malignant with a SUV(max) (3.4) > twice that of benign nodules. Two subjects had bone disease; both were identified by PET-CT but only one by CI. Four subjects had bone marrow disease, two had positive PET-CTs but none had positive CI. Two subjects had soft tissue metastases detected by PET-CT but not CI.

Conclusions: PET-CT performed better than CI in identifying nodal, bone, bone marrow, and soft tissue disease in children with RMS. CI remains essential for detection of pulmonary nodules. We recommend PET-CT for staging of children with RMS. CI with Tc(99m) bone scan can be eliminated.
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http://dx.doi.org/10.1002/pbc.24430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266929PMC
July 2013