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  • American Association for Cancer Research (AACR)  (8)
  • 1
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 15 ( 2010-08-01), p. 4024-4030
    Abstract: Purpose: Osteosarcoma most commonly recurs in the lung. Based on preliminary data on the antitumor effects of granulocyte-macrophage colony stimulating factor (GM-CSF) in animal models, and promising phase I trials, we embarked on a feasibility study of inhaled GM-CSF in patients with first isolated pulmonary recurrence of osteosarcoma. Experimental Design: Forty-three eligible patients received inhaled GM-CSF at doses from 250 to 1,750 μg twice daily on alternate weeks. Following two cycles, patients underwent thoracotomy to resect tumor and analyze pulmonary nodules for expression of Fas/Fas ligand (Fas/FasL), and the presence of dendritic cells by immunostaining for CD1a, clusterin, and S100. Following surgery, patients received 12 additional cycles of therapy on alternating weeks or until progression. Event-free survival and survival, and feasibility of therapy delivery were evaluated. Results: Dose escalation to 1,750 μg twice daily was feasible with no dose-limiting toxicity. Mean scores for Fas/FasL in nodules from patients with bilateral recurrence who underwent unilateral thoracotomy pretreatment (using a scoring system of 0-3) were 1.3 and 0.88, respectively, compared with 0.78 and 0.62 in nodules resected following two cycles of therapy. Only 11 of 30 nodules postinhalation were positive for CD1a, 4 of 30 for S100, and 6 of 30 for clusterin. Event-free and overall survival at 3 years were 7.8% and 35.4%, respectively. Conclusions: Inhalation of GM-CSF at doses from 250 to 1,750 μg twice daily on alternate weeks was feasible with low toxicity. However, no detectable immunostimulatory effect in pulmonary metastases or improved outcome postrelapse was seen. Clin Cancer Res; 16(15); 4024–30. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 2
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 14 ( 2016-07-15), p. 3643-3650
    Abstract: Purpose: Flow cytometry and RT-PCR can detect occult Ewing sarcoma cells in the blood and bone marrow. These techniques were used to evaluate the prognostic significance of micrometastatic disease in Ewing sarcoma. Experimental Design: Newly diagnosed patients with Ewing sarcoma were enrolled on two prospective multicenter studies. In the flow cytometry cohort, patients were defined as “positive” for bone marrow micrometastatic disease if their CD99+/CD45− values were above the upper limit in 22 control patients. In the PCR cohort, RT-PCR on blood or bone marrow samples classified the patients as “positive” or “negative” for EWSR1/FLI1 translocations. The association between micrometastatic disease burden with clinical features and outcome was assessed. Coexpression of insulin-like growth factor-1 receptor (IGF-1R) on detected tumor cells was performed in a subset of flow cytometry samples. Results: The median total bone marrow CD99+CD45− percent was 0.0012% (range 0%–1.10%) in the flow cytometry cohort, with 14 of 109 (12.8%) of Ewing sarcoma patients defined as “positive.” In the PCR cohort, 19.6% (44/225) patients were “positive” for any EWSR1/FLI1 translocation in blood or bone marrow. There were no differences in baseline clinical features or event-free or overall survival between patients classified as “positive” versus “negative” by either method. CD99+CD45− cells had significantly higher IGF-1R expression compared with CD45+ hematopoietic cells (mean geometric mean fluorescence intensity 982.7 vs. 190.9; P & lt; 0.001). Conclusions: The detection of micrometastatic disease at initial diagnosis by flow cytometry or RT-PCR is not associated with outcome in newly diagnosed patients with Ewing sarcoma. Flow cytometry provides a tool to characterize occult micrometastatic tumor cells for proteins of interest. Clin Cancer Res; 22(14); 3643–50. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 3
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 22, No. 10 ( 2013-10-01), p. 1837-1843
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 22, No. 10 ( 2013-10-01), p. 1837-1843
    Abstract: Background: Hepatoblastoma is a rare pediatric liver tumor that has significantly increased in incidence over the last several decades. The International Agency for Research on Cancer (IARC) recently classified hepatoblastoma as a tobacco-related cancer. Parental alcohol use has shown no association. We examined associations between parental tobacco and alcohol use around the time of pregnancy and hepatoblastoma in a large case–control study. Methods: Maternal interviews were completed for 383 cases diagnosed in the United States during 2000–2008. Controls (n = 387) were identified through U.S. birth registries and frequency-matched to cases on birth weight, birth year, and region of residence. We used unconditional logistic regression to calculate ORs and 95% confidence intervals (CI) for associations between parental smoking and maternal drinking and offspring hepatoblastoma. Results: We found no association between hepatoblastoma and maternal smoking at any time (OR, 1.0; 95% CI, 0.7–1.4), within the year before pregnancy (OR, 1.1; 95% CI, 0.8–1.6), early in pregnancy (OR, 1.0; 95% CI, 0.7–1.6), or throughout pregnancy (OR, 0.9; 95% CI, 0.5–1.6). We observed marginally positive associations between hepatoblastoma and paternal smoking in the year before pregnancy (OR, 1.4; 95% CI, 1.0–2.0) and during pregnancy (OR, 1.4; 95% CI, 0.9–2.0). Maternal alcohol use was not associated with hepatoblastoma. Conclusion: Our results do not provide evidence for an etiologic relationship between maternal smoking or drinking and hepatoblastoma, and only weak evidence for an association for paternal smoking in the year before pregnancy. Impact: Our study provides limited support for hepatoblastoma as a tobacco-related cancer; however, it remains wise to counsel prospective parents on the merits of smoking cessation. Cancer Epidemiol Biomarkers Prev; 22(10); 1837–43. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036781-8
    detail.hit.zdb_id: 1153420-5
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  • 4
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 1828-1828
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 1828-1828
    Abstract: Infertility treatment is increasing rapidly in the U.S. A subset of infertility treatment, assisted reproductive technology (ART), has increased 150% between 1996 and 2005 and now accounts for over 1% of all births in the U.S. Parental infertility treatment has been hypothesized to be a risk factor for childhood cancer through potential effects on imprinting and methylation, but few studies have examined treatment as a risk factor for hepatoblastoma (HB). One recent study found a nine-fold increase in HB risk for those with reported or inferred parental infertility treatment. We examined case data from a case-control study of HB conducted through the Children's Oncology Group (COG). Only case data was used since the control series is not yet complete. Proportions of cases whose parents had used infertility services and exact 95% confidence intervals (CI) were constructed and compared to national data. National data were obtained from the 2002 National Survey of Family Growth (NSFG), the ART Surveillance Report 2002-2006, and the National Center for Health Statistics birth data 2002-2006. We also examined the relationship between Beckwith-Wiedemann Syndrome (BWS) and ART in our data set. We included cases of 312 cases HB diagnosed in the year 2000 or later to better match available national data. Among cases’ mothers, 12.5% (n = 39; 95% CI: 9.0-16.7) indicated they sought medical advice for fertility issues with the index child, which is similar to ever use of fertility services in the U.S. in 2002 (15.3% for those with at least one child). However, we found a higher proportion of cases conceived through ART (n =14, 4.8%; 95%CI: 2.7%-7.8%) compared to an overall prevalence of 1.2% in the US in 2002-2006. We further assessed the proportion of cases born after ART within strata of low birth weight, a strong risk factor for HB, and plurality to assess if the increase in ART use was due to either plurality or birth weight. Within each plurality strata the proportion of ART cases was similar for cases overall, those with low birth weight, and those with very low birth weight. Overall, the proportion of ART cases who were singletons did not appear to be elevated (observed: n = 4, 1.4% (95% CI: 0.4-3.5), national: 0.6%). We did, however, observe a higher than expected proportion of twins conceived through ART compared to national data (observed: n = 8, 50% (95% CI: 24.7-75.3), national: 16.4%). In addition, we found a high proportion of cases with reported BWS who were conceived through ART (n = 4, 33.3%; 95% CI: 9.9-65.1)). In conclusion, we found a possible excess of children conceived through ART among cases diagnosed with hepatoblastoma and within those cases diagnosed with BWS. This excess appears to be limited to twin pregnancies. These findings provide tentative evidence that there is an excess of children conceived through ART among HB cases. Supported by NIH CA111355, and the Children's Cancer Research Fund, Minneapolis, MN. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1828.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 16 ( 2014-08-15), p. 4200-4209
    Abstract: Despite successful primary tumor treatment, the development of pulmonary metastasis continues to be the most common cause of mortality in patients with osteosarcoma. A conventional drug development path requiring drugs to induce regression of established lesions has not led to improvements for patients with osteosarcoma in more than 30 years. On the basis of our growing understanding of metastasis biology, it is now reasonable and essential that we focus on developing therapeutics that target metastatic progression. To advance this agenda, a meeting of key opinion leaders and experts in the metastasis and osteosarcoma communities was convened in Bethesda, Maryland. The goal of this meeting was to provide a “Perspective” that would establish a preclinical translational path that could support the early evaluation of potential therapeutic agents that uniquely target the metastatic phenotype. Although focused on osteosarcoma, the need for this perspective is shared among many cancer types. The consensus achieved from the meeting included the following: the biology of metastatic progression is associated with metastasis-specific targets/processes that may not influence grossly detectable lesions; targeting of metastasis-specific processes is feasible; rigorous preclinical data are needed to support translation of metastasis-specific agents into human trials where regression of measurable disease is not an expected outcome; preclinical data should include an understanding of mechanism of action, validation of pharmacodynamic markers of effective exposure and response, the use of several murine models of effectiveness, and where feasible the inclusion of the dog with naturally occurring osteosarcoma to define the activity of new drugs in the micrometastatic disease setting. Clin Cancer Res; 20(16); 4200–9. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 6
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 12, No. 6 ( 2006-03-15), p. 1750-1759
    Abstract: Purpose: Evaluate the clinical safety, toxicity, immune activation/modulation, and maximal tolerated dose of hu14.18-IL2 (EMD 273063) in pediatric patients with recurrent/refractory neuroblastoma and other GD2-positive solid tumors. Experimental Design: Twenty-seven pediatric patients with recurrent/refractory neuroblastoma and one with melanoma were treated with a humanized anti-GD2 monoclonal antibody linked to human interleukin 2 (IL-2). Cohorts of patients received hu14.18-IL2, administered i.v. over 4 hours for three consecutive days, at varying doses. Patients with stable disease, partial, or complete responses were eligible to receive up to three additional courses of therapy. Results: Most of the clinical toxicities were anticipated and similar to those reported with IL-2 and anti-GD2 monoclonal antibody therapy and to those noted in the initial phase I study of hu14.18-IL2 in adults with metastatic melanoma. The maximal tolerated dose was determined to be 12 mg/m2/d, with agent-related dose-limiting toxicities of hypotension, allergic reaction, blurred vision, neutropenia, thrombocytopenia, and leukopenia. Three patients developed dose-limiting toxicity during course 1; seven patients in courses 2 to 4. Two patients required dopamine for hypotension. There were no treatment-related deaths, and all toxicity was reversible. Treatment with hu14.18-IL2 led to immune activation/modulation as evidenced by elevated serum levels of soluble IL-2 receptor α (sIL2Rα) and lymphocytosis. The median half-life of hu14.18-IL2 was 3.1 hours. There were no measurable complete or partial responses to hu14.18-IL2 in this study; however, three patients did show evidence of antitumor activity. Conclusion: Hu14.18-IL2 (EMD 273063) can be administered safely with reversible toxicities in pediatric patients at doses that induce immune activation. A phase II clinical trial of hu14.18-IL2, administered at a dose of 12 mg/m2/d × 3 days repeated every 28 days, will be done in pediatric patients with recurrent/refractory neuroblastoma.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 7
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 11 ( 2019-06-01), p. 3229-3238
    Abstract: Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centrosome and spindle maturation. Alisertib (MLN8237) is a potent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816). Patients and Methods: Alisertib (80 mg/m2/dose) was administered orally, daily for 7 days every 21 days. Pharmacogenomic (PG) evaluation for polymorphisms in the AURK gene and drug metabolizing enzymes (UGT1A1*28), and plasma pharmacokinetic studies (PK) were performed. Using a 2-stage design, patients were enrolled to 12 disease strata (10 solid tumor and 2 acute leukemia). Response was assessed after cycle 1, then every other cycle. Results: A total of 139 children and adolescents (median age, 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 μmol/L, exceeding the 1 μmol/L target trough concentration in 67% of patients. No correlations between PG or PK and toxicity were observed. Conclusions: Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single-agent alisertib was less than 5%.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 8
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2020
    In:  Clinical Cancer Research Vol. 26, No. 11_Supplement ( 2020-06-01), p. A55-A55
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 11_Supplement ( 2020-06-01), p. A55-A55
    Abstract: Background: Patients with intermediate-risk rhabdomyosarcoma (IR RMS) have approximately 60-70% chance of survival with current therapies. However, biomarkers of outcome and response to therapy are lacking for these patients. Circulating tumor DNA (ctDNA) has been shown to be prognostic in a wide range of cancer types, but it is unknown whether patients with IR RMS have detectable levels of ctDNA. Objective: To study ctDNA prevalence and prognostic impact in newly diagnosed IR RMS, we utilized two next-generation sequencing (NGS) approaches that detect the presence of somatic copy-number changes and oncogenic translocations. Methods: Cell-free DNA was extracted from serum samples obtained from patients with newly diagnosed IR RMS who enrolled on the COG studies ARST0531 and D9803, including patients with embryonal (ERMS) and alveolar (ARMS) histology subtypes. While both subtypes are characterized by frequent somatic copy-number variants (CNVs), ARMS is also defined by recurrent translocations. To detect CNVs, we performed ultra-low passage whole-genome sequencing (ULP-WGS). Translocations were detected with a validated custom hybrid capture assay (TranSS-Seq). Results: Serum samples were analyzed from 132 patients with IR RMS, including 75 with ERMS and 57 with ARMS. ctDNA was detected by CNVs in 70% (92/132) of IR RMS patients with similar detection rates in each histology: 65% (49/75) in ERMS and 75% (43/57) in ARMS. Among the ARMS samples sequenced, only 37% (18/49) were positive by TranSS-Seq. Furthermore, copy-number events resulting in amplifications of the somatic translocation frequently resulted in miscalculation of ctDNA content by the TranSS-Seq method. Estimates of event-free and overall survival were lower in patients with detectable ctDNA, though the differences were not statistically significant. Conclusion: Patients with IR RMS frequently have detectable levels of ctDNA that can be measured by NGS assays designed to detect somatic structural events. This study relied on previously banked serum samples and a relatively small retrospective analysis. These findings provide justification for our current efforts to utilize a large prospective study, COG ARST1431, to collect pretreatment and serial blood samples using procedures optimized for ctDNA assays. Sequencing of matched tumor samples is ongoing to understand the differences in sensitivity between ULP-WGS and TranSS-Seq for ctDNA detection in patients with ARMS. Citation Format: Samuel Abbou, David Hall, Donald A. Barkauskas, Kelly Klega, Anwesha Nag, Aaron R. Thorner, Mark Krailo, Steven Dubois, Douglas S. Hawkins, Brian D. Crompton. Circulating tumor DNA in newly diagnosed intermediate-risk rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A55.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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