Publications by authors named "Michael S Isakoff"

22 Publications

  • Page 1 of 1

Genomic and Transcriptomic Analysis of Relapsed and Refractory Childhood Solid Tumors Reveals a Diverse Molecular Landscape and Mechanisms of Immune Evasion.

Cancer Res 2021 12 5;81(23):5818-5832. Epub 2021 Oct 5.

Translational Genomics Research Institute (TGen), Phoenix, Arizona.

Children with treatment-refractory or relapsed (R/R) tumors face poor prognoses. As the genomic underpinnings driving R/R disease are not well defined, we describe here the genomic and transcriptomic landscapes of R/R solid tumors from 202 patients enrolled in Beat Childhood Cancer Consortium clinical trials. Tumor mutational burden (TMB) was elevated relative to untreated tumors at diagnosis, with one-third of tumors classified as having a pediatric high TMB. Prior chemotherapy exposure influenced the mutational landscape of these R/R tumors, with more than 40% of tumors demonstrating mutational signatures associated with platinum or temozolomide chemotherapy and two tumors showing treatment-associated hypermutation. Immunogenomic profiling found a heterogenous pattern of neoantigen and MHC class I expression and a general absence of immune infiltration. Transcriptional analysis and functional gene set enrichment analysis identified cross-pathology clusters associated with development, immune signaling, and cellular signaling pathways. While the landscapes of these R/R tumors reflected those of their corresponding untreated tumors at diagnosis, important exceptions were observed, suggestive of tumor evolution, treatment resistance mechanisms, and mutagenic etiologies of treatment. SIGNIFICANCE: Tumor heterogeneity, chemotherapy exposure, and tumor evolution contribute to the molecular profiles and increased mutational burden that occur in treatment-refractory and relapsed childhood solid tumors.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-1033DOI Listing
December 2021

Phase II trial of gemcitabine and nab-paclitaxel in patients with recurrent Ewing sarcoma: A report from the National Pediatric Cancer Foundation.

Pediatr Blood Cancer 2020 07 9;67(7):e28370. Epub 2020 May 9.

Division of Pediatric Hematology-Oncology, Duke Children's Hospital and Health Center, Durham, North Carolina.

Background: The combination of gemcitabine and docetaxel is often used to treat patients with recurrent sarcoma. Nab-paclitaxel is a taxane modified to improve drug exposure and increase intratumoral accumulation and, in combination with gemcitabine, is standard therapy for pancreatic cancer. Applying the dosages and schedule used for pancreatic cancer, we performed a phase II trial to assess the response rate of gemcitabine and nab-paclitaxel in patients with relapsed Ewing sarcoma.

Procedure: Using a Simon's two-stage design to identify a response rate of ≥ 35%, patients received nab-paclitaxel 125 mg/m followed by gemcitabine 1000 mg/m i.v. on days 1, 8, and 15 of four-week cycles. Immunohistochemical analysis of archival tissue was performed to identify possible biomarkers of response.

Results: Eleven patients from four institutions enrolled, with a median age of 22 years (range, 14-27). Patients were heavily pretreated (median 3 prior regimens, range, 1-7). Thirty-five cycles were administered (median 2, range, 1-8). Accrual was stopped after 11 patients, due to only one confirmed partial response. Two other patients had partial responses after two cycles, but withdrew because of adverse effects or progression before confirmation of continued response. The predominant toxicity was myelosuppression, and four (36%) patients were removed due to hematologic toxicity despite pegfilgrastim and dose reductions. Expression of secreted protein, acidic and rich in cysteine (SPARC) and CAV-1 in archival tumors was not predictive of clinical benefit in this small cohort of patients.

Conclusions: In patients with heavily pretreated Ewing sarcoma, the confirmed response rate of 9% was similar to multi-institutional studies of gemcitabine and docetaxel.
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http://dx.doi.org/10.1002/pbc.28370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771264PMC
July 2020

Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort.

Eur J Cancer 2019 03 25;109:36-50. Epub 2019 Jan 25.

CDC MRC Clinical Trials Unit at UCL, London, UK.

Background: High-grade osteosarcoma is a primary malignant bone tumour mainly affecting children and young adults. The European and American Osteosarcoma Study (EURAMOS)-1 is a collaboration of four study groups aiming to improve outcomes of this rare disease by facilitating randomised controlled trials.

Methods: Patients eligible for EURAMOS-1 were aged ≤40 years with M0 or M1 skeletal high-grade osteosarcoma in which case complete surgical resection at all sites was deemed to be possible. A three-drug combination with methotrexate, doxorubicin and cisplatin was defined as standard chemotherapy, and between April 2005 and June 2011, 2260 patients were registered. We report survival outcomes and prognostic factors in the full cohort of registered patients.

Results: For all registered patients at a median follow-up of 54 months (interquartile range: 38-73) from biopsy, 3-year and 5-year event-free survival were 59% (95% confidence interval [CI]: 57-61%) and 54% (95% CI: 52-56%), respectively. Multivariate analyses showed that the most adverse factors at diagnosis were pulmonary metastases (hazard ratio [HR] = 2.34, 95% CI: 1.95-2.81), non-pulmonary metastases (HR = 1.94, 95% CI: 1.38-2.73) or an axial skeleton tumour site (HR = 1.53, 95% CI: 1.10-2.13). The histological subtypes telangiectatic (HR = 0.52, 95% CI: 0.33-0.80) and unspecified conventional (HR = 0.67, 95% CI: 0.52-0.88) were associated with a favourable prognosis compared with chondroblastic subtype. The 3-year and 5-year overall survival from biopsy were 79% (95% CI: 77-81%) and 71% (95% CI: 68-73%), respectively. For patients with localised disease at presentation and in complete remission after surgery, having a poor histological response was associated with worse outcome after surgery (HR = 2.13, 95% CI: 1.76-2.58). In radically operated patients, there was no good evidence that axial tumour site was associated with worse outcome.

Conclusions: In conclusion, data from >2000 patients registered to EURAMOS-1 demonstrated survival rates in concordance with institution- or group-level osteosarcoma trials. Further efforts are required to drive improvements for patients who can be identified to be at higher risk of adverse outcome. This trial reaffirms known prognostic factors, and owing to the large numbers of patients registered, it sheds light on some additional factors to consider.
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http://dx.doi.org/10.1016/j.ejca.2018.11.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506906PMC
March 2019

A phase II study of eribulin in recurrent or refractory osteosarcoma: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2019 02 30;66(2):e27524. Epub 2018 Oct 30.

Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.

Background: Patients with recurrent or refractory osteosarcoma have a poor prognosis with less than 30% surviving two years. Eribulin is a synthetic analog of halichondrin B, has a novel mechanism of action when compared with other microtubule inhibitors, and may have antitumor activity in osteosarcoma.

Methods: A prospective study was designed to assess the disease control success at four months and objective response rates in patients with recurrent or refractory osteosarcoma treated with eribulin. Eligible patients were between 12 and 50 years of age, had measurable tumor, and met standard organ function requirements. Patients were given eribulin 1.4 mg/m /dose on days 1 and 8 of each 3-week cycle for up to 24 months if there was no progressive disease. Response to therapy was assessed using RECIST 1.1 criteria after cycles 2 and 5 and every fourth cycle thereafter.

Results: Nineteen patients enrolled on the AOST1322 study. The median age of enrollment was 16 years (range, 12-25 years). Twelve patients were male and seven female. Eribulin was well tolerated, with neutropenia identified as the most common toxicity. The median progression-free survival was 38 days and no patients reached the four-month time point without progression. No objective responses were seen in any patient.

Conclusion: This study rapidly assessed the clinical activity of a novel agent in this patient population. Eribulin was well tolerated, but there were no patients who demonstrated objective response, and all patients had progression prior to four months.
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http://dx.doi.org/10.1002/pbc.27524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501793PMC
February 2019

Factors influencing survival after recurrence in osteosarcoma: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2019 01 25;66(1):e27444. Epub 2018 Sep 25.

Center for Cancer and Blood Disorders, Connecticut Children's Medical Center, Hartford, Connecticut.

Background: Despite drastic improvement in overall survival for pediatric patients with cancer, those with osteosarcoma have stable rates of survival since the 1980s. This project evaluates the effect of several variables on survival after first recurrence in patients with osteosarcoma.

Methods: Data from three prospective North American cooperative group trials for newly diagnosed osteosarcoma are included: INT-0133, POG-9754, and AOST0121. The analytic population for this study is all enrolled patients with first event-free survival (EFS) event of relapse. The primary outcome measure for this retrospective analysis was survival after recurrence (SAR).

Results: The analytic population consisted of N = 431 patients. SAR was statistically significantly associated with age at enrollment (<10 years, P = 0.027), presence of metastatic disease at diagnosis (localized, P < 0.0001), site of relapse (combination lung + bone, unfavorable, P = 0.005), and time to first relapse (2+ years, favorable, P < 0.0001) in multivariate analysis. Ethnicity, primary site of tumor, race, and sex were not significantly related to SAR.

Conclusions: Prolonged SAR in patients with relapsed osteosarcoma is associated with age, extent of disease at diagnosis, site of and time to relapse. Adolescent and young adult patients with osteosarcoma have shorter SAR than younger patients, consistent with studies showing decreased overall survival in this group. Although patients with primary metastatic disease have shorter SAR, there is a subset of patients who relapse greater than 2 years from initial diagnosis that will become survivors. Histological response was significantly associated with time to relapse, but was not predictive of SAR.
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http://dx.doi.org/10.1002/pbc.27444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249072PMC
January 2019

Consensus and controversies regarding the treatment of rhabdomyosarcoma.

Pediatr Blood Cancer 2018 Feb 14;65(2). Epub 2017 Sep 14.

Division of Pediatric Hematology/Oncology, University of Kentucky, Lexington, Kentucky.

Optimal treatment of rhabdomyosarcoma (RMS) requires multidisciplinary approach, incorporating chemotherapy with local control. Although current therapies are built on cooperative group trials, a comprehensive standard of care to guide clinical decision making has been lacking, especially for relapsed patients. Therefore, we assembled a panel of pediatric and adolescent and young adult sarcoma experts to develop treatment guidelines for managing RMS and to identify areas in which further research is needed. We created algorithms incorporating evidence-based care for patients with RMS, emphasizing the importance of clinical trials and close integration of all specialties involved in the care of these patients.
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http://dx.doi.org/10.1002/pbc.26809DOI Listing
February 2018

Treatment pathway of bone sarcoma in children, adolescents, and young adults.

Cancer 2017 Jun 21;123(12):2206-2218. Epub 2017 Mar 21.

Center for Cancer and Blood Disorders, Connecticut Children's Medical Center, Hartford, Connecticut.

When pediatric, adolescent, and young adult patients present with a bone sarcoma, treatment decisions, especially after relapse, are complex and require a multidisciplinary approach. This review presents scenarios commonly encountered in the therapy of bone sarcomas with the goal of objectively presenting a consensus, multidisciplinary management approach. Little variation was found in the authors' group with respect to local control or systemic therapy. Clinical trials were universally prioritized in all settings. Decisions regarding relapse therapies in the absence of a clinical trial had very minor variations initially, but a consensus was reached after a literature review and discussion. This review presents a concise document and figures as a starting point for evidence-based care for patients with these rare diseases. This framework allows prospective decision making and prioritization of clinical trials. It is hoped that this framework will inspire and focus future clinical research and thus lead to new trials to improve efficacy and reduce toxicity. Cancer 2017;123:2206-2218. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5485018PMC
June 2017

Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial.

Lancet Oncol 2016 Oct 25;17(10):1396-1408. Epub 2016 Aug 25.

Center for Cancer and Blood Disorders, Connecticut Children's Medical Center, Hartford, CT, USA.

Background: We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma.

Methods: EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m, doxorubicin 37·5 mg/m per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m) at 2·8 g/m per day with equidose mesna uroprotection, followed by etoposide 100 mg/m per day over 1 h on days 1-5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030.

Findings: Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6-76·6); 62·3 months (IQR 46·9-77·1) for the MAP group and 61·1 months (IQR 46·5-75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78-1·23]); hazards were non-proportional (p=0·0003). The most common grade 3-4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate.

Interpretation: EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting.

Funding: UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.
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http://dx.doi.org/10.1016/S1470-2045(16)30214-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052459PMC
October 2016

Pediatric phase I trial of oral sorafenib and topotecan in refractory or recurrent pediatric solid malignancies.

Cancer Med 2016 Feb 29;5(2):294-303. Epub 2015 Dec 29.

Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Targeted kinase inhibitors and camptothecins have shown preclinical and clinical activity in several cancers. This trial evaluated the maximum tolerated dose (MTD) and dose-limiting toxicities of sorafenib and topotecan administered orally in pediatric patients with relapsed solid tumors. Sorafenib was administered twice daily and topotecan once daily on days 1-5 and 8-12 of each 28-day course. The study utilized a standard 3 + 3 dose escalation design. Three dose levels (DL) were evaluated: (1) sorafenib 150 mg/m(2) and topotecan 1 mg/m(2) ; (2) sorafenib 150 mg/m(2) and topotecan 1.4 mg/m(2) ; and (3) sorafenib 200 mg/m(2) and topotecan 1.4 mg/m(2) . Pharmacokinetics were ascertained and treatment response assessed. Thirteen patients were enrolled. DL2 was the determined MTD. Grade 4 thrombocytopenia delaying therapy for >7 days was observed in one of six patients on DL2, and grade 4 neutropenia that delayed therapy in two of three patients on DL3. A patient with preexisting cardiac failure controlled with medication developed a transient drop in the left ventricular ejection fraction that improved when sorafenib was withheld. Sorafenib exposure with or without topotecan was comparable, and the concentration-time profiles for topotecan alone and in combination with sorafenib were similar. One objective response was noted in a patient with fibromatosis. We determined MTD to be sorafenib 150 mg/m(2) twice daily orally on days 1-28 combined with topotecan 1.4 mg/m(2) once daily on days 1-5 and 8-12. While these doses are 1 DL below the MTD of the agents individually, pharmacokinetic studies suggested adequate drug exposure without drug interactions. The combination had limited activity in the population studied.
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http://dx.doi.org/10.1002/cam4.598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735769PMC
February 2016

Rapid Protocol Enrollment in Osteosarcoma: A Report From the Children's Oncology Group.

Pediatr Blood Cancer 2016 Feb 16;63(2):370-1. Epub 2015 Sep 16.

Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.

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http://dx.doi.org/10.1002/pbc.25754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830388PMC
February 2016

Osteosarcoma: Current Treatment and a Collaborative Pathway to Success.

J Clin Oncol 2015 Sep 24;33(27):3029-35. Epub 2015 Aug 24.

Michael S. Isakoff, Center for Cancer and Blood Disorders, Connecticut Children's Medical Center, Hartford, CT; Stefan S. Bielack, Klinikum Stuttgart, Olgahospital, Stuttgart, Germany; Paul Meltzer, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; and Richard Gorlick, The Children's Hospital of Montefiore; Bronx, NY.

Osteosarcoma is the bone tumor that most commonly affects children, adolescents, and young adults. Before 1970, treatment primarily included surgical resection. However, the introduction of chemotherapy led to a dramatic improvement in prognosis for patients with localized osteosarcoma; long-term survival rates of less than 20% improved to 65% to 70% after the advent of multiagent chemotherapy regimens. Controversy concerning the ideal combination of chemotherapy agents ensued throughout the last quarter of the 20th century because of conflicting and often nonrandomized data. However, large cooperative group studies and international collaboration have demonstrated that the most effective regimens include the combination of high-dose methotrexate, doxorubicin, and cisplatin (MAP). The introduction of biologic agents such as muramyl tripeptide and the use of additional cytotoxic chemotherapy such as ifosfamide have not definitively improved the survival of patients with osteosarcoma. Collaborative efforts to increase understanding of the biology of osteosarcoma and the use of preclinical models to test novel agents will be critical to identify the path toward improving outcomes for patients. Once promising agents are identified, an international infrastructure exists for clinical trials. Herein, biologic, preclinical, and clinical trial efforts will be described along with future international collaborative strategies to improve outcomes for patients who develop this challenging tumor.
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http://dx.doi.org/10.1200/JCO.2014.59.4895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979196PMC
September 2015

Clinical features and outcomes of infants with Ewing sarcoma under 12 months of age.

Pediatr Blood Cancer 2015 Nov 14;62(11):1947-51. Epub 2015 Jul 14.

Department of Pediatrics, San Francisco School of Medicine, UCSF Benioff Children's Hospital, University of California, San Francisco, California.

Background: Ewing sarcoma peaks in incidence in adolescence. Infants <12 months old have rarely been reported. We aimed to compare clinical features, treatment, and survival of infants <12 months to those of older pediatric patients with Ewing sarcoma.

Procedure: We utilized the SEER database to identify patients <12 months of age diagnosed with Ewing sarcoma between 1973 and 2011. We used Fisher exact tests to compare clinical features and treatment modalities between these patients and patients aged 1-19 years. We used Kaplan-Meier methods to describe overall survival in these two groups.

Results: Of 1,957 patients in the cohort, 39 (2.0%) were diagnosed at <12 months of age. Infants had a different distribution of primary tumor sites, with lower extremity tumors under represented. Compared to older patients, infants were more likely to have soft tissue tumors (81.6% vs. 27.1%; P < 0.001); have primitive neuroectodermal tumor/Askin tumor (61.5% vs. 19.9%; P < 0.001); and have tumors <8 cm (81.0% vs. 53.2%; P < 0.014). Infants were less likely to receive radiation therapy (13.2% vs. 53.3%; P < 0.001). Infants were at increased risk for early death (P < 0.013 by Wilcoxon), though long-term overall survival was not different between age groups (P < 0.25 by log rank).

Conclusions: Ewing sarcoma is rare in infants, with different clinical presentations and treatment approaches. These patients appear to be at higher risk for early death, but long-term survival is similar to older pediatric patients.
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http://dx.doi.org/10.1002/pbc.25635DOI Listing
November 2015

A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer.

Pediatr Blood Cancer 2014 Apr 4;61(4):636-42. Epub 2013 Oct 4.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Division of Pediatric Hematology-Oncology, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts.

Background: Preclinical models show that an antiangiogenic regimen at low-dose daily (metronomic) dosing may be effective against chemotherapy-resistant tumors. We undertook a prospective, open-label, single-arm, multi-institutional phase II study to evaluate the efficacy of a "5-drug" oral regimen in children with recurrent or progressive cancer.

Procedure: Patients ≤21 years old with recurrent or progressive tumors were eligible. Treatment consisted of continuous oral celecoxib, thalidomide, and fenofibrate, with alternating 21-day cycles of low-dose cyclophosphamide and etoposide. Primary endpoint was to assess, within eight disease strata, activity of the 5-drug regimen over 27 weeks. Blood and urine angiogenesis markers were assessed.

Results: One hundred one patients were enrolled; 97 began treatment. Median age was 10 years (range: 191 days-21 years); 47 (49%) were female. Disease strata included high-grade glioma (HGG, 21 patients), ependymoma (19), low-grade glioma (LGG, 12), bone tumors (12), medulloblastoma/primitive neuroectodermal tumor (PNET, 8), leukemia (4), neuroblastoma (3), and miscellaneous tumors (18). Treatment was generally well tolerated; most common toxicities were hematologic. Twenty-four (25%) patients completed 27 weeks therapy without progression, including HGG: 1 (5%), ependymoma: 7 (37%), LGG: 7 (58%), medulloblastoma/PNET: 1, neuroblastoma: 1, and miscellaneous tumors: 7 (39%). Best response was complete response (one patient with medulloblastoma), partial response (12), stable disease (36), progressive disease (47), and inevaluable (1). Baseline serum thrombospondin levels were significantly higher in patients successfully completing therapy than in those who progressed (P = 0.009).

Conclusion: The 5-drug regimen was well tolerated. Clinical activity was demonstrated in some but not all tumor strata.
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http://dx.doi.org/10.1002/pbc.24794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4285784PMC
April 2014

Feasibility and dose discovery analysis of zoledronic acid with concurrent chemotherapy in the treatment of newly diagnosed metastatic osteosarcoma: a report from the Children's Oncology Group.

Eur J Cancer 2013 Jul 7;49(10):2384-91. Epub 2013 May 7.

University of California San Francisco, Benioff Children's Hospital, San Francisco, CA, United States.

Aim: Patients with metastatic osteosarcoma (OS) have a poor outcome with conventional therapies. Zoledronic acid (ZA) is a third-generation bisphosphonate that reduces skeletal-related events in many adult cancers, and pre-clinical data suggest a possible benefit in OS. This study assessed the maximum tolerated dose (MTD) and the feasibility of ZA when combined with chemotherapy in patients with metastatic OS.

Patients And Methods: Patients with a histological diagnosis of OS were eligible if they were <40 years of age, had initially metastatic disease and met organ function requirements. Treatment combined surgery and a conventional chemotherapy regimen. ZA was given concurrent with chemotherapy for a total of eight doses over 36 weeks. Three dose levels of ZA were tested: 1.2 mg/m(2) [max 2 mg], 2.3 mg/m(2) [max 4 mg] and 3.5 mg/m(2) [max 6 mg]. The MTD was determined during induction. Six patients were to be treated at each dose level, with an additional six patients treated with the MTD to help assess post-induction feasibility.

Results: Twenty-four patients (median age 13.5 years [range, 7-22]; 16 females) were treated. Five patients experienced dose-limiting toxicities (DLTs) during induction, including three patients treated with 3.5 mg/m(2). DLTs included hypophosphatemia, hypokalemia, hyponatremia, mucositis, limb pain and limb oedema. There were no reports of excessive renal toxicity or osteonecrosis of the jaw. The MTD was defined as 2.3 mg/m(2) (max 4 mg).

Conclusions: ZA can be safely combined with conventional chemotherapy with an MTD of 2.3 mg/m(2) (max 4 mg) for patients with metastatic osteosarcoma.
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http://dx.doi.org/10.1016/j.ejca.2013.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689577PMC
July 2013

Poor survival for osteosarcoma of the pelvis: a report from the Children's Oncology Group.

Clin Orthop Relat Res 2012 Jul 22;470(7):2007-13. Epub 2012 Feb 22.

Department of Hematology-Oncology, Connecticut Children's Medical Center, 282 Washington Street, Hartford, CT 06106, USA.

Background: The pelvis is an infrequent site of osteosarcoma and treatment requires surgery plus systemic chemotherapy. Poor survival has been reported, but has not been confirmed previously by the Children's Oncology Group (COG). In addition, survival of patients with pelvic osteosarcomas has not been compared directly with that of patients with nonpelvic disease treated on the same clinical trials.

Questions/purposes: First, we assessed the event-free (EFS) and overall survival (OS) of patients with pelvic osteosarcoma treated on COG clinical trials. We then asked whether patient survival compared with that of patients treated on the same clinical trials with nonpelvic disease. Finally, we asked whether patients with metastatic disease at initial diagnosis had worse survival.

Methods: We retrospectively reviewed data from 1054 patients with osteosarcoma treated in four studies between 1993 and 2005. Twenty-six of the 1054 patients (2.5%) had a primary tumor of the pelvis. At diagnosis, nine patients had metastatic disease. The minimum followup was 2 months (mean, 34 months; range, 2-102 months).

Results: Two of the nine patients with metastatic disease at diagnosis and five of the 17 with localized disease were alive at last contact. Estimates of the 5-year EFS for localized versus metastatic disease of the pelvis were 22% versus 23%. OS for patients with localized versus metastatic disease was 47% versus 22%. Patients with osteosarcoma in all other locations had a 5-year EFS of 57% and OS of 69%.

Conclusions: Our analysis confirms poor survival for patients with pelvic osteosarcoma. Survival with metastatic disease in the absence of a pelvic primary tumor is similar to that for localized or metastatic pelvic osteosarcoma. Improved surgical or medical therapy is needed, and patients with pelvic osteosarcoma may warrant alternate or experimental therapy.
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http://dx.doi.org/10.1007/s11999-012-2284-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369072PMC
July 2012

Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic leukemia.

Blood 2011 Dec 3;118(23):6043-9. Epub 2011 Oct 3.

Department of Pediatric Hematology-Oncology, Children's Memorial Hospital and Northwestern University Feinberg School of Medicine, Chicago, IL 60614-3394, USA.

The outcomes in children with refractory/relapsed (R/R) acute lymphoblastic leukemia (ALL) are dismal. The efficacy and safety of intravenous clofarabine 40 mg/m(2) per day, cyclophosphamide 440 mg/m(2) per day, and etoposide 100 mg/m(2) per day for 5 consecutive days in pediatric patients with R/R ALL was evaluated in this phase 2 study. The primary endpoint was overall response rate (complete remission [CR] plus CR without platelet recovery [CRp]). Among the 25 patients (median age, 14 years; pre-B cell ALL, 84%; ≥ 2 prior regimens: 84%; refractory to previous regimen: 60%), the overall response rate was 44% (7 CR, 4 CRp) with a 67.3-week median duration or remission censored at last follow-up. Most patients proceeded to alternative therapy, and 10 patients (40%) received hematopoietic stem cell transplantation. Six patients (24%) died because of treatment-related adverse events associated with infection, hepatotoxicity, and/or multiorgan failure. The study protocol was amended to exclude patients with prior hematopoietic stem cell transplantation after 4 of the first 8 patients developed severe hepatotoxicity suggestive of veno-occlusive disease. No additional cases of veno-occlusive disease occurred. The regimen offered encouraging response rates and sustained remission in R/R patients. Future investigation should include exploration of patient selection, dosing, and supportive care. This trial was registered at www.clinicaltrials.gov as #NCT00315705.
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http://dx.doi.org/10.1182/blood-2011-08-374710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3731655PMC
December 2011

Anti-insulin growth factor receptor therapy in Ewing sarcoma.

F1000 Med Rep 2009 Aug 17;1. Epub 2009 Aug 17.

The insulin-like growth factor (IGF) signal transduction pathway appears to play a key role in the development and proliferation of the Ewing sarcoma family of tumors. Integration of anti-IGF-1 receptor therapy into the standard treatment for these patients is a novel approach that will likely be incorporated into future treatment to determine whether such agents will improve the outcome for patients with this malignancy.
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http://dx.doi.org/10.3410/M1-62DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948310PMC
August 2009

A single-institution experience with treatment of severe acute chest syndrome: lack of rebound pain with dexamethasone plus transfusion therapy.

J Pediatr Hematol Oncol 2008 Apr;30(4):322-5

Division of Hematology/Oncology, Connecticut Children's Medical Center, Hartford, CT 06106, USA.

The use of corticosteroid therapy for the treatment of acute chest syndrome (ACS) in patients with sickle cell disease has been infrequently used owing to concerns for rebound pain. Here, we report a cohort of patients<21 years of age with sickle cell disease treated between January 2001 and June 2006 for severe ACS with both corticosteroids and transfusion therapy. We reviewed 53 episodes of severe ACS with an average hospital duration of 4.9 days. Only 1 patient out of 6 who were transferred to the intensive care unit required intubation. None of the ACS episodes resulted in death and none of the 4 readmissions after discharge were due to pain. There was no acute toxicity related to either corticosteroid or transfusion therapy.
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http://dx.doi.org/10.1097/MPH.0b013e3181647bb2DOI Listing
April 2008

Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation.

Proc Natl Acad Sci U S A 2005 Dec 21;102(49):17745-50. Epub 2005 Nov 21.

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Snf5 (Ini1/Baf47/Smarcb1), a core member of the Swi/Snf chromatin remodeling complex, is a potent tumor suppressor whose mechanism of action is largely unknown. Biallelic loss of Snf5 leads to the onset of aggressive cancers in both humans and mice. We have developed an innovative and widely applicable analytical technique for cross-species validation of cancer models and show that the gene expression profiles of our Snf5 murine models closely resemble those of human Snf5-deficient rhabdoid tumors. We exploit this system to produce what we believe to be the first report documenting the effects on gene expression of inactivating a Swi/Snf subunit in normal mammalian cells and to identify the transcriptional pathways regulated by Snf5. We demonstrate that the tumor suppressor activity of Snf5 depends on its regulation of cell cycle progression; Snf5 inactivation leads to aberrant up-regulation of E2F targets and increased levels of p53 that are accompanied by apoptosis, polyploidy, and growth arrest. Further, conditional mouse models demonstrate that inactivation of p16Ink4a or Rb (retinoblastoma) does not accelerate tumor formation in Snf5 conditional mice, whereas mutation of p53 leads to a dramatic acceleration of tumor formation.
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http://dx.doi.org/10.1073/pnas.0509014102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1308926PMC
December 2005
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