16 results on '"Krailo, Mark"'
Search Results
2. Minimal adjuvant chemotherapy for children with hepatoblastoma resected at diagnosis (AHEP0731): a Children's Oncology Group, multicentre, phase 3 trial
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Katzenstein, Howard M, Langham, Max R, Malogolowkin, Marcio H, Krailo, Mark D, Towbin, Alexander J, McCarville, Mary Beth, Finegold, Milton J, Ranganathan, Sarangarajan, Dunn, Stephen, McGahren, Eugene D, Tiao, Gregory M, O'Neill, Allison F, Qayed, Muna, Furman, Wayne L, Xia, Caihong, Rodriguez-Galindo, Carlos, and Meyers, Rebecka L
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Hepatoblastoma ,Male ,Time Factors ,Pediatric Cancer ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Risk Assessment ,Risk Factors ,Clinical Research ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Chemotherapy ,Hepatectomy ,Oncology & Carcinogenesis ,Child ,Preschool ,Adjuvant ,Neoplasm Staging ,Cancer ,Pediatric ,Liver Neoplasms ,Age Factors ,Infant ,Evaluation of treatments and therapeutic interventions ,United States ,Progression-Free Survival ,Vincristine ,6.1 Pharmaceuticals ,Disease Progression ,Female ,Fluorouracil ,Patient Safety ,Cisplatin - Abstract
BackgroundHepatoblastoma treatment with curative intent requires surgical resection, but only about a third of newly diagnosed patients with hepatoblastoma have resectable disease at diagnosis. Patients who have upfront resection typically receive a total of 4-6 cycles of adjuvant chemotherapy post-surgery, with the combination of cisplatin, fluorouracil, and vincristine. We aimed to investigate whether event-free survival in children with hepatoblastoma who had complete resection at diagnosis could be maintained with two cycles of adjuvant chemotherapy.MethodsIn this Children's Oncology Group, multicentre, phase 3 trial, patients were enrolled in four risk groups on the basis of Evans surgical stage, tumour histology, and levels of α-fetoprotein at diagnosis to receive risk-adapted therapy. Here, we report on the low-risk stratum of the trial. Eligible patients were younger than 21 years and had histologically confirmed, stage I or II hepatoblastoma without 100% pure fetal stage I or small-cell undifferentiated histology; elevated serum α-fetoprotein level (>100 ng/mL); a complete resection at diagnosis; at least 50% Karnofsky (patients >16 years) or Lansky (patients ≤16 years) performance status; and had received no previous chemotherapy or other hepatoblastoma-directed therapy. Patients received two 21-day cycles of cisplatin, fluorouracil, and vincristine within 42 days of resection, consisting of cisplatin (100 mg/m2 per dose or 3·3 mg/kg per dose for children
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- 2019
3. Correction: Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Childrens Oncology Group
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Shulman, David, Klega, Kelly, Imamovic-Tuco, Alma, Clapp, Andrea, Nag, Anwesha, Thorner, Aaron, Van Allen, Eliezer, Ha, Gavin, Lessnick, Stephen, Gorlick, Richard, Janeway, Katherine, Leavey, Patrick, Mascarenhas, Leo, London, Wendy, Stegmaier, Kimberly, Hall, David, Krailo, Mark, Barkauskas, Donald, DuBois, Steven, Crompton, Brian, and Vo, Kieuhoa
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The authors have noticed that the final paragraph of the Results section contains errors in the number of patients involved. The correct number of patients is included in the text below. These errors do not affect the Figure referenced.In osteosarcoma, we focused on 8q gain as a specific biological feature of interest. Among the 41 patients with detectable ctDNA in the osteosarcoma cohort, 8q gain was detected in 73.2% (30/41). The 3-year EFS for patients with 8q gain (n = 30) in ctDNA was 60.0% (95% CI 40.5-75.0) compared to 80.8 (95% CI 42.4-94.9) in patients without 8q gain (n = 11) in ctDNA (p = 0.18; Fig. 3).
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- 2019
4. Ovarian Yolk Sac Tumors; Does Age Matter?
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Faure Conter, Cecile, Xia, Caihong, Gershenson, David, Hurteau, Jean, Covens, Al, Pashankar, Farzana, Krailo, Mark, Billmire, Deborah, Patte, Catherine, Fresneau, Brice, Shaikh, Furqan, Stoneham, Sara, Nicholson, James, Murray, Matthew, Frazier, Anne Lindsay, Murray, Matthew [0000-0002-4480-1147], and Apollo - University of Cambridge Repository
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Adult ,Ovarian Neoplasms ,Adolescent ,Age Factors ,Endodermal Sinus Tumor ,Infant, Newborn ,Infant ,Prognosis ,Young Adult ,Child, Preschool ,Humans ,Female ,Child ,Neoplasm Staging - Abstract
BACKGROUND: Whereas among pediatric oncologists, ovarian yolk sac tumor (O-YST) is considered a chemosensitive tumor, it is often cited as an adverse prognostic factor in adult women with ovarian germ cell tumors. METHODS: The Malignant Germ Cell International Consortium data set included 6 pediatric clinical trials (United States, United Kingdom, and France) and 2 adult gynecology clinical trials (United States). Any patient with an O-YST that was International Federation of Gynecology and Obstetrics stage IC or higher and treated with a platinum-based chemotherapy was eligible. Age was modeled as a continuous and a categorical variable (children, 0-10 years; adolescents, 11-17 years; and adults, ≥18 years). In addition, analyses to establish the optimal cut point for age were conducted. Tumors were coded as pure YST (YST +/- teratoma), mixed YST (YST + other malignant germ cell component), or putative YST ("mixed" germ cell tumor + alpha-fetoprotein >1000 ng/mL). Histology, stage (II/III vs IV), preoperative alpha-fetoprotein levels (10,000 ng/mL), and chemotherapeutic regimen (carboplatin vs cisplatin) were analyzed as covariates. RESULTS: Two hundred fifty-one patients (median age, 13 years; range, 0-38 years) were identified (78 children, 139 adolescents, and 34 adults). Histology was pure, mixed, and putative in 129, 56, and 66 cases, respectively. Twenty-six patients had stage IV disease, similarly distributed in the 3 age groups. Median follow-up was 5.8 years. The overall 5-year event-free survival and overall survival was 91% (95% confidence interval, 87%-94%) and 96% (92%-98%), respectively. Age did not affect risk of event or death, modeled either as a categorical or continuous variable. Analysis failed to identify an age cut point that affected risk. None of the other covariates investigated had a prognostic impact on event-free survival or overall survival. CONCLUSIONS: Ovarian yolk sac tumors have an excellent outcome across all age-groups. Age has no apparent impact on the probability of event or death, allowing pediatric and gynecologic oncologists to enroll patients onto joint pediatric and adult trials.
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- 2019
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5. Detection of Relapse by Tumor Markers Versus Imaging in Children and Adolescents With Nongerminomatous Malignant Germ Cell Tumors: A Report From the Children's Oncology Group
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Fonseca, Adriana, Xia, Caihong, Lorenzo, Armando J, Krailo, Mark, Olson, Thomas A, Pashankar, Farzana, Malogolowkin, Marcio H, Amatruda, James F, Billmire, Deborah F, Rodriguez-Galindo, Carlos, Frazier, A Lindsay, and Shaikh, Furqan
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Adult ,Male ,Pediatric Research Initiative ,Adolescent ,Clinical Sciences ,Oncology and Carcinogenesis ,Young Adult ,Rare Diseases ,Testicular Neoplasms ,Clinical Research ,Neoplasms ,Humans ,Clinical Trials ,Oncology & Carcinogenesis ,Child ,Preschool ,Retrospective Studies ,Cancer ,Ovarian Neoplasms ,Pediatric ,screening and diagnosis ,Tumor ,Prevention ,Neurosciences ,Infant ,Newborn ,4.1 Discovery and preclinical testing of markers and technologies ,Phase III as Topic ,Detection ,Neoplasm Recurrence ,Local ,Germ Cell and Embryonal ,Biomedical Imaging ,Female ,Biomarkers ,4.2 Evaluation of markers and technologies - Abstract
PurposeTo investigate relapse detection methods among children and adolescents with nongerminomatous malignant germ cell tumors (MGCTs) and to determine whether tumor markers alone might be sufficient for surveillance.MethodsWe retrospectively reviewed all patients enrolled in a phase III, single-arm trial for low-risk and intermediate-risk MGCTs. The method used to detect relapse was assessed based on case report forms, tumor markers, imaging, and pathology reports. Relapses were classified into one of two categories on the basis of whether they were (1) detectable by tumor marker elevation or (2) not detectable by tumor markers.ResultsA total of 302 patients were enrolled, and 284 patients had complete data for review. Seven patients had normal tumor markers at initial diagnosis, and none experienced a relapse. At a median follow-up of 5.3 years, 48 patients (16.9%) had experienced a relapse. After central review, 47 of 48 relapses (98%) were detected by tumor marker elevation. Of the 47 patients, 16 (33.3%) had abnormal tumor markers with normal/unknown imaging, 31 patients (64.6%) had abnormal tumor markers with abnormal imaging, and one patient (2.1%) had abnormal imaging with unknown marker levels at relapse.ConclusionTumor marker elevation is a highly sensitive method of relapse surveillance, at least among children and adolescents with tumor marker elevation at initial diagnosis. Eliminating exposure to imaging with ionizing radiation may enhance the safety of relapse surveillance in patients treated for MGCT.
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- 2019
6. Bias_Manuscript_SupplementaryMaterial – Supplemental material for Bias in retrospective analyses of biomarker effect using data from an outcome-adaptive randomized trial
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Lingyun Ji, McShane, Lisa M, Krailo, Mark, and Sposto, Richard
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FOS: Clinical medicine ,160807 Sociological Methodology and Research Methods ,humanities ,111599 Pharmacology and Pharmaceutical Sciences not elsewhere classified ,FOS: Sociology - Abstract
Supplemental material, Bias_Manuscript_SupplementaryMaterial for Bias in retrospective analyses of biomarker effect using data from an outcome-adaptive randomized trial by Lingyun Ji, Lisa M McShane, Mark Krailo and Richard Sposto in Clinical Trials
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- 2019
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7. Upfront window vincristine/irinotecan treatment of high-risk hepatoblastoma: A report from the Children's Oncology Group AHEP0731 study committee
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Katzenstein, Howard M, Furman, Wayne L, Malogolowkin, Marcio H, Krailo, Mark D, McCarville, M Beth, Towbin, Alexander J, Tiao, Greg M, Finegold, Milton J, Ranganathan, Sarangarajan, Dunn, Stephen P, Langham, Max R, McGahren, Eugene D, Rodriguez-Galindo, Carlos, and Meyers, Rebecka L
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Hepatoblastoma ,Male ,Adolescent ,Pediatric Cancer ,Oncology and Carcinogenesis ,Irinotecan ,Rare Diseases ,high-risk ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Hepatectomy ,Oncology & Carcinogenesis ,Child ,Preschool ,Cancer ,Pediatric ,Liver Neoplasms ,Infant ,Evaluation of treatments and therapeutic interventions ,Liver Transplantation ,metastatic ,Survival Rate ,Vincristine ,6.1 Pharmaceuticals ,Public Health and Health Services ,Camptothecin ,Female ,alpha-Fetoproteins - Abstract
BackgroundThe identification of new therapies for high-risk (HR) hepatoblastoma is challenging. Children's Oncology Group study AHEP0731 included a HR stratum to explore the efficacy of novel agents. Herein, the authors report the response rate to the combination of vincristine (V) and irinotecan (I) and the outcome of patients with high-risk hepatoblastoma.MethodsPatients with newly diagnosed metastatic hepatoblastoma or those with a serum α-fetoprotein (AFP) level 1 log10 ) decline in their AFP level. Responders were to receive 2 additional cycles of VI intermixed with 6 cycles of the combination of cisplatin, doxorubicin, 5-fluorouracil, and vincristine (C5VD). Nonresponders were to receive 6 cycles of C5VD alone.ResultsA total of 32 patients with a median age at diagnosis of 26 months (range, 11-159 months) were enrolled between September 2009 and February 2012. Fourteen of 30 evaluable patients were responders (RECIST and AFP in 6 patients, RECIST only in 3 patients, and AFP only in 5 patients). The median AFP decline after 2 cycles of VI for the entire group was 345,565 ng/mL (85% of the initial AFP). The 3-year event-free and overall survival rates were 49% (95% confidence interval, 30%-65%) and 62% (95% confidence interval, 42%-77%), respectively.ConclusionsThe VI combination appears to have substantial activity against HR hepatoblastoma. The ultimate impact of this regimen in improving the outcomes of children with HR hepatoblastoma remains to be determined. Cancer 2017;123:2360-2367. © 2017 American Cancer Society.
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- 2017
8. Assessment of extent of surgical resection of primary high-grade osteosarcoma by treating institutions: A report from the Children's Oncology Group
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Morris, Carol D, Teot, Lisa A, Bernstein, Mark L, Marina, Neyssa, Krailo, Mark D, Villaluna, Doojduen, Janeway, Katherine A, DuBois, Steven G, Gorlick, Richard G, and Randall, Robert Lor
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Adult ,surgical margins ,Adolescent ,Pediatric Cancer ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Bone Neoplasms ,Cohort Studies ,Young Adult ,Rare Diseases ,Clinical Research ,osteosarcoma ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,cooperative group trial ,Oncology & Carcinogenesis ,Child ,Preschool ,Retrospective Studies ,Cancer ,Pediatric ,Osteosarcoma ,Evaluation of treatments and therapeutic interventions ,Middle Aged ,Methotrexate ,Doxorubicin ,Patient Safety ,Cisplatin ,Neoplasm Grading ,6.4 Surgery - Abstract
BackgroundComplete surgical resection of primary tumors is critical for long-term control of high-grade osteosarcoma. Uniform assessment of the extent of surgical resection is important in clinical trials, though the accuracy of this reporting has been poorly studied.MethodsWe conducted a retrospective cohort study of patients 5-40 years of age with newly diagnosed high-grade resectable osteosarcoma treated as part of the AOST0331 clinical trial at Children's Oncology Group institutions. The extent of surgical resection of the primary tumor was graded as wide or radical by the treating institution. Central assessment of the extent of resection by two orthopedic oncologists was compared with institutional assessment by reviewing pathology and operative reports.ResultsWe included 956 patients who had data available for central review. The extent of resection reported by treating institutions was 536/956 (56%) radical and 420/956 (44%) wide. The extent of resection assessed by central review was 162/956 (17%) radical and 794/956 (83%) wide. The overall discordance rate for the cohort was 43%.ConclusionsInstitutional reports of radical resection in high-grade osteosarcoma significantly over-estimate the proportion of patients undergoing radical resection. This highlights the need for centralized review and improved accuracy of reporting of the extent of resection. J. Surg. Oncol. 2016;113:351-354. © 2016 Wiley Periodicals, Inc.
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- 2016
9. Assessing the Prognostic Significance of Histologic Response in Osteosarcoma: A Comparison of Outcomes on CCG-782 and INT0133-A Report From the Children's Oncology Group Bone Tumor Committee
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Bishop, Michael W., Chang, Yu-Chen, Krailo, Mark D., Meyers, Paul A., Provisor, Arthur J., Schwartz, Cindy L., Marina, Neyssa M., Teot, Lisa A., Gebhardt, Mark C., Gorlick, Richard, Janeway, Katherine A., and Chou, Alexander J.
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Adult ,Male ,Osteosarcoma ,Adolescent ,Infant ,Bone Neoplasms ,Induction Chemotherapy ,Prognosis ,Article ,Necrosis ,Treatment Outcome ,Child, Preschool ,Humans ,Female ,Child ,Biomarkers ,Proportional Hazards Models ,Retrospective Studies - Abstract
The prognostic value of histologic response for osteosarcoma may have changed with induction chemotherapy schedules over time. We hypothesized that the increased intensity of induction therapy provided on INT0133 compared to the Children's Cancer Group study CCG-782 would diminish the impact of histologic response on the risk of events after definitive surgery.Retrospective analysis was performed for patients aged22 with newly diagnosed nonmetastatic osteosarcoma enrolled on CCG-782 and INT0133. Clinical factors were evaluated for association with response and outcome. Good response was defined as5% viable tumor at resection. Associations of response, study, and postdefinitive surgery event-free survival (EFS-DS) were determined using Cox proportional hazard models. EFS-DS was estimated by Kaplan-Meier methodology.Data were available for 814 patients (206 CCG-782, 608 INT0133). For good responders, 10-year EFS-DS (±SE) was 75.4% ± 7.7% for CCG-782 and 70.8% ± 3.1% for INT0133. For poor responders, 10-year EFS-DS was 39.9% ± 4.9% for CCG-782 and 58.4% ± 3.1% for INT0133. Histologic response predicted outcome across studies (P0.0001). Significant interaction between study and histologic response was observed for EFS-DS (P = 0.011). Using proportional hazards regression, INT0133 poor responders had less risk of events compared to CCG-782 poor responders (relative hazard ratio (RHR) = 0.6:1), but good responders on INT0133 had a greater risk of events compared to CCG-782 good responders (RHR = 1.53:1).We observed an inverse relationship between the predictive value of tumor necrosis and intensity of induction therapy, raising questions about the true prognostic value of histologic response. This highlights the need for novel markers to develop strategies for treatment in future trials.
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- 2015
10. Tumoral TP53 and/or CDKN2A alterations are not reliable prognostic biomarkers in patients with localized Ewing sarcoma: a report from the Children's Oncology Group
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Lerman, Daniel M, Monument, Michael J, McIlvaine, Elizabeth, Liu, Xiao-qiong, Huang, Dali, Monovich, Laura, Beeler, Natalie, Gorlick, Richard G, Marina, Neyssa M, Womer, Richard B, Bridge, Julia A, Krailo, Mark D, Randall, R Lor, Lessnick, Stephen L, and Children's Oncology Group Ewing Sarcoma Biology Committee
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Male ,Pediatric Research Initiative ,Adolescent ,Pediatric Cancer ,Clinical Sciences ,Oncology and Carcinogenesis ,Bone Neoplasms ,outcomes ,Polymerase Chain Reaction ,Fluorescence ,Paediatrics and Reproductive Medicine ,Rare Diseases ,Clinical Research ,Ewing ,Genetics ,Humans ,Prospective Studies ,Oncology & Carcinogenesis ,Children's Oncology Group Ewing Sarcoma Biology Committee ,Child ,In Situ Hybridization ,Cyclin-Dependent Kinase Inhibitor p16 ,Neoplasm Staging ,Cancer ,Pediatric ,Tumor ,Human Genome ,Sarcoma ,Prognosis ,Survival Rate ,Mutation ,biomarker ,Female ,Tumor Suppressor Protein p53 ,Gene Deletion ,Biomarkers ,Ewing sarcoma ,Follow-Up Studies - Abstract
BackgroundA growing collection of retrospective studies have suggested that TP53 mutations and/or CDKN2A deletions have prognostic significance in Ewing sarcoma. We sought to evaluate these variables in patients with localized disease treated prospectively on a single Children's Oncology Group protocol.ProcedureOf the 568 patients enrolled on Children's Oncology Group protocol AEWS0031 (NCT00006734), 112 had tumor specimens of sufficient quality and quantity to allow for analysis of TP53 mutations status by DNA sequencing, and CDKN2A deletion by dual color fluorescent in situ hybridization.ResultsEight of 93 cases (8.6%) were found to have TP53 point mutations and 12 of 107 cases (11.2%) demonstrated homozygous CDKN2A deletion. Two cases were found to have an alteration in both genes. There was no significant difference in event-free survival of patients with TP53 mutations and/or CDKN2A deletions compared to patients with normal TP53/CDKN2A gene status, as demonstrated by log rank test (p = 0.58).ConclusionsAlthough previous retrospective studies suggest their significance, TP53 mutation and/or CDKN2A deletion are not reliable prognostic biomarkers in localized Ewing sarcoma.
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- 2015
11. Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: a report from the Children's Oncology Group
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DuBois, Steven G, Krailo, Mark D, Gebhardt, Mark C, Donaldson, Sarah S, Marcus, Karen J, Dormans, John, Shamberger, Robert C, Sailer, Scott, Nicholas, Richard W, Healey, John H, Tarbell, Nancy J, Randall, R Lor, Devidas, Meenakshi, Meyer, James S, Granowetter, Linda, Womer, Richard B, Bernstein, Mark, Marina, Neyssa, and Grier, Holcombe E
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Male ,Adolescent ,Pediatric Cancer ,Oncology and Carcinogenesis ,Bone Neoplasms ,Cohort Studies ,surgery ,Rare Diseases ,Clinical Research ,Ewing ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Oncology & Carcinogenesis ,Child ,propensity score ,Randomized Controlled Trials as Topic ,Cancer ,Pediatric ,Evaluation of treatments and therapeutic interventions ,Sarcoma ,radiation ,local control ,Multivariate Analysis ,Public Health and Health Services ,Female ,Patient Safety ,6.4 Surgery ,Ewing sarcoma - Abstract
BackgroundPatients with Ewing sarcoma require local primary tumor control with surgery, radiation, or both. The optimal choice of local control for overall and local disease control remains unclear.MethodsPatients with localized Ewing sarcoma of bone who were treated on 3 consecutive protocols with standard-dose, 5-drug chemotherapy every 3 weeks were included (n=465). Propensity scores were used to control for differences between local control groups by constructing multivariate models to assess the impact of local control type on clinical endpoints (event-free survival [EFS], overall survival, local failure, and distant failure) independent of differences in their propensity to receive each local control type.ResultsPatients who underwent surgery were younger (P=.02) and had more appendicular tumors (P
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- 2015
12. HER-2 expression is not prognostic in osteosarcoma; a Children's Oncology Group prospective biology study
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Gorlick, Sarah, Barkauskas, Donald A., Krailo, Mark, Piperdi, Sajida, Sowers, Rebecca, Gill, Jonathan, Geller, David, Randall, R. Lor, Janeway, Katherine, Schwartz, Cindy, Grier, Holcombe, Meyers, Paul A., Gorlick, Richard, Bernstein, Mark, and Marina, Neyssa
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Adult ,Male ,Pediatric Research Initiative ,Adolescent ,Receptor, ErbB-2 ,Clinical Sciences ,Oncology and Carcinogenesis ,Bone Neoplasms ,Article ,Immunoenzyme Techniques ,Paediatrics and Reproductive Medicine ,Young Adult ,ErbB-2 ,Rare Diseases ,Clinical Research ,osteosarcoma ,Biomarkers, Tumor ,Humans ,Prospective Studies ,Oncology & Carcinogenesis ,Neoplasm Metastasis ,Child ,Preschool ,Cancer ,Pediatric ,Osteosarcoma ,screening and diagnosis ,Tumor ,Her-2 ,human epidermal growth factor receptor ,Infant ,Prognosis ,4.1 Discovery and preclinical testing of markers and technologies ,Survival Rate ,Detection ,Child, Preschool ,immunohistochemistry ,Female ,Biomarkers ,Receptor ,Follow-Up Studies ,4.2 Evaluation of markers and technologies - Abstract
BackgroundSince the initial reports of human epidermal growth factor receptor 2 (HER-2) expression as being prognostic in osteosarcoma, numerous small studies varying in the interpretation of the immunohistochemical (IHC) staining patterns have produced conflicting results. The Children's Oncology Group therefore embarked on a prospective biology study in a larger sample of patients to define in osteosarcoma the prognostic value of HER-2 expression using the methodology employed in the initial North American study describing an association between HER-2 expression and outcome.ProcedureThe analytic patient population was comprised of 149 patients with newly diagnosed osteosarcoma, 135 with localized disease and 14 with metastatic disease, all of whom had follow up clinical data. Paraffin embedded material from the diagnostic biopsy was stained with CB11 antibody and scored by two independent observers. Correlation of HER-2 IHC score and demographic variables was analyzed using a Fisher's exact test and correlation with survival using a Kaplan-Meier analysis.ResultsNo association was found with HER-2 status and any of the demographic variables tested including the presence or absence of metastatic disease at diagnosis. No association was found between HER-2 status and either event free survival or overall survival in the patients with localized disease.ConclusionHER-2 expression is not prognostic in osteosarcoma in the context of this large prospective study. HER-2 expression cannot be used as a basis for stratification of therapy. Identification of potential prognostic factors should occur in the context of large multi-institutional biology studies.
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- 2014
13. Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group
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Womer, Richard B, West, Daniel C, Krailo, Mark D, Dickman, Paul S, Pawel, Bruce R, Grier, Holcombe E, Marcus, Karen, Sailer, Scott, Healey, John H, Dormans, John P, and Weiss, Aaron R
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Adult ,Pediatric Research Initiative ,Adolescent ,Pediatric Cancer ,Clinical Trials and Supportive Activities ,Clinical Sciences ,Oncology and Carcinogenesis ,Bone Neoplasms ,Drug Administration Schedule ,Young Adult ,Rare Diseases ,Clinical Research ,Ewing ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Ifosfamide ,Prospective Studies ,Oncology & Carcinogenesis ,Child ,Preschool ,Cyclophosphamide ,Etoposide ,Cancer ,Pediatric ,Infant ,Evaluation of treatments and therapeutic interventions ,Sarcoma ,Middle Aged ,Orphan Drug ,Vincristine ,Doxorubicin ,6.1 Pharmaceuticals - Abstract
PurposeChemotherapy with alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide cycles and primary tumor treatment with surgery and/or radiation therapy constitute the usual approach to localized Ewing sarcoma in North America. We tested whether chemotherapy intensification through interval compression could improve outcome.Patients and methodsThis was a prospective, randomized controlled trial for patients younger than 50 years old with newly diagnosed localized extradural Ewing sarcoma. Patients assigned to standard and intensified treatment were to begin chemotherapy cycles every 21 and 14 days, respectively, provided an absolute neutrophil count greater than 750×10(6)/L and a platelet count greater than 75×10(9)/L. Patients received vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1.2 g/m2) alternating with ifosfamide (9 g/m2) and etoposide (500 mg/m2) for 14 cycles, with filgrastim (5 mg/kg per day; maximum, 300 mg) between cycles. Primary tumor treatment (surgery, radiation, or both) was to begin at week 13 (after four cycles in the standard arm and six cycles in the intensified arm). The primary end point was event-free survival (EFS). The study is registered at ClinicalTrials.gov (identifier: NCT00006734).ResultsFive hundred eighty-seven patients were enrolled and randomly assigned, and 568 patients were eligible, with 284 patients in each regimen. For all cycles, the median cycle interval for standard treatment was 21 days (mean, 22.45 days); for intensified treatment, the median interval was 15 days (mean, 17.29 days). EFS at a median of 5 years was 65% in the standard arm and 73% in the intensified arm (P=.048). The toxicity of the regimens was similar.ConclusionFor localized Ewing sarcoma, chemotherapy administered every 2 weeks is more effective than chemotherapy administered every 3 weeks, with no increase in toxicity.
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- 2012
14. Body mass index (BMI) at diagnosis is associated with surgical wound complications in patients with localized osteosarcoma: a report from the Children's Oncology Group
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Hingorani, Pooja, Seidel, Kristy, Krailo, Mark, Mascarenhas, Leo, Meyers, Paul, Marina, Neyssa, Conrad, Ernest U., and Hawkins, Douglas S.
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Adult ,Male ,Osteosarcoma ,Young Adult ,Postoperative Complications ,Adolescent ,Child, Preschool ,Humans ,Female ,Child ,Article ,Body Mass Index - Abstract
Malnutrition is common at diagnosis and during treatment for sarcoma patients. Poor nutritional status is associated with increased risk of complications, particularly infections. We investigated the role of body mass index (BMI) on the incidence of surgical wound complications in patients with localized osteosarcoma treated on the Children's Oncology Group (COG) legacy trial, INT-0133.Patients considered in this report had localized osteosarcoma, enrolled on COG trial INT-0133, remained on protocol therapy to have definitive surgery 6-16 weeks after study entry, and had adequate height, weight, and surgical complication data for analysis. By protocol design, definitive surgical resection was planned for 10 weeks after induction chemotherapy. Wound complications within 30 days after definitive surgery were considered post-operative. BMI was calculated at the start of neoadjuvant chemotherapy and expressed as age- and gender-adjusted percentile. The incidence of wound complications was evaluated by logistic regression or Fisher's exact test.A total of 498 patients met criteria for analysis. Low BMI (≤10th percentile) was seen in 73 (14.7%), middle BMI (11th-94th percentile) in 382 (76.7%), and high BMI (≥95th percentile) in 43 (8.6%) patients. Wound infection or slough was seen in low BMI patients (OR = 2.0, P = 0.07) although the results did not reach statistical significance. Arterial thrombosis was more common in high BMI patients (OR = 9.4, P = 0.03).Abnormal BMI at the start of treatment for localized osteosarcoma is associated with increased risk of post-operative wound complications such as arterial thrombosis. Future studies should evaluate whether maintenance of age-appropriate BMI reduces the risk of surgical complications.
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- 2010
15. Striking Predictive Power For Relapse and Decreased Survival Associated With Detectable Minimal Residual Disease by IGH VDJ Deep Sequencing Of Bone Marrow Pre- and Post-Allogeneic Transplant In Children With B-Lineage ALL: A Subanalysis Of The COG ASCT0431/PBMTC ONC051 Study
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Michael A. Pulsipher, Christopher S Carlson, Krailo Mark, Donna A. Wall, Kirk R. Schultz, Nancy Bunin, Michael Kalos, Desmarias Cindy, David Williamson, Gastier-Foster Julie, Michael J. Borowitz, and Stephan A. Grupp
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Relapse prevention ,Biochemistry ,Minimal residual disease ,Surgery ,Leukemia ,medicine.anatomical_structure ,Internal medicine ,Cohort ,medicine ,Cumulative incidence ,Bone marrow ,business ,J-segment ,Preparative Regimen - Abstract
We previously reported strong power to predict relapse and lower event free survival (EFS) associated with the presence of minimal residual disease (MRD) > 0.1% detected in bone marrow (BM) both pre- and post-transplant by standardized multi-channel flowcytometry in children with ALL enrolled on a randomized phase III Children's Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial, ASCT 0431. We performed further analysis of this cohort to test whether the high level of sensitivity of MRD detection offered by deep-sequencing methods increases predictive power for relapse and event free-survival (EFS). Patients in the trial were children aged 1-21yrs who underwent TBI-based myeloablative HCT for high risk ALL in CR1 or CR2. BM samples were taken within 2 weeks of initiation of the preparative regimen (pre-HCT sample) and at 1,3, and 9-12 months after HCT. These samples were sent for central flow cytometry and banked. DNA was prepared from marrow specimens at each time point in a patient, and used as template in preparing IGH VDJ sequencing reactions. 20,000 B cell genomes were used as input for index specimen libraries, used to define IGH sequences greater than 5% frequency in the sample. For a large majority of patients the index sample was taken at diagnosis, prior to transplant, but in five patients this specimen was unavailable, so a specimen taken at relapse was used to define the tumor tagging sequences. 130 bp reads starting at the WGXG motif in the J segment and extending back across the CDR3 region into the V segment were collected in each library, to a coverage of at least 5X for the input genomes. Tumor tagging sequences were confidently identified in 64 patients. To assess MRD, we then prepared libraries from the equivalent of 100,000 B cell genomes at each time point during or after transplant, and screened the resulting data for the frequency of each tumor tracking sequence in the individual. The Kaplan-Meier estimate of EFS and the Gray estimate of cumulative incidence of relapse were calculated. Evidence of tumor in the pre-transplant sample had significantly increased 36-month cumulative incidence (CI) of relapse when compared with no evidence tumor (57% v. 4.4%; p=0.008). Similarly, evidence of tumor was associated with a significant increase in 36-month CI of relapse or death when compared with no evidence of tumor (70% v. 17%, p=0.0014; and 54% v. 17%, p=0.012). Evidence of tumor in the post-transplant sample (within 90 days of transplant) had significantly increased 36-month cumulative incidence (CI) of relapse when compared with no evidence tumor (75% v. 26%; p Conclusions Patients with no detectable leukemia by deep sequencing pre-HCT relapsed less that 5% of the time, a striking improvement compared to our previous ability to predict relapse with flow MRD (No detectable MRD by flow, 25% risk of relapse in the previous analysis). Detection of any tumor in the first 90 days after HCT by this method is also highly predictive of relapse and survival. Patients identified as high risk for relapse by this method may be candidates for interventions aimed at preventing relapse. Analysis including a direct comparison with flow MRD and post transplant chimerism, as well as definition of specific cut points for levels of disease detected by deep sequencing will be presented with this data. Disclosures: Carlson: Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties. Kalos:Novartis corporation: CART19 technology, CART19 technology Patents & Royalties; Adaptive biotechnologies: Member scientific advisory board , Member scientific advisory board Other. Cindy:Adaptive Biotechnologies: Employment. Williamson:Adaptive Biotechnologies: Employment. Grupp:Novatis: Research Funding.
- Published
- 2013
16. A report on the review of archived osteosarcoma and EWING sarcoma specimens at the Biopathology Center, BONE Sarcoma Committee, Children's Oncology Group
- Author
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Sonja Chen, Shenoy, Archana, Al-Ibraheemi, Alyaa, Bush, Jonathan, Davis, Jessica L., Grohar, Patrick, Binitie, Odion, Krailo, Mark D., Reed, Damon R., and Janeway, Katherine A.
- Subjects
Cancer Research ,Oncology - Abstract
11524 Background: The Children’s Oncology Group (COG) Biorepository at the Biopathology Center (BPC), Nationwide Children’s Hospital, Columbus, OH contains archived tumor specimens submitted for COG study protocols. The BPC repository is utilized for numerous biology study aims with the goal of improved understanding of tumor pathophysiology, and impacts future clinical trials design and patient care. BPC pathologists perform quality assurance (QA) reviews of archival material before biospecimens are released for study. Since QA reviews are not routinely included in the submission process into the BPC, the quality and utility of tissue is often unclear. Therefore, a pathology quality assurance review was conducted to explore the utility of future testing on banked formalin fixed paraffin embedded (FFPE) Ewing Sarcoma and Osteosarcoma specimens. Methods: The BPC staff retrieved archival tumor cases for review between 06/2020 and 1/2022. One hematoxylin and eosin-stained slide per FFPE tissue block was digitally scanned for whole slide image (WSI) analysis and uploaded with a de-identified pathology report on a virtual slide-viewing platform. Five board certified pediatric pathologists with sarcoma expertise (AA, JB, SC, AS, JD) designed a digital QA review form and performed reviews. The QA review data collection form included diagnosis, volume of viable tumor, decalcification techniques, ancillary molecular/cytogenetic studies and a comment box to include additional noteworthy information. Results: During the study period, of the 1379 digitally prepared cases, 486 case reviews were completed, totaling 1192 digital slides reviewed. Of the reviewed cases, 465 (95%) were concordant with the diagnosis and had variable volumes of viable tumor (scant to adequate), while 33 (7%) of cases had no viable tumor (extensive necrosis or no tumor on the slide) and 21 (4%) had an alternative diagnosis (e.g. tumor submitted as osteosarcoma, re-classified as a chondromyxoid fibroma). Of the reviewed concordant cases, 271 (58%) were consistent with OS, 187 (40%) were consistent with ES and 7 (2%) were consistent non-ES round cell sarcomas (e.g. BCOR or CIC- rearranged sarcomas). Conclusions: Over ninety percent of reviewed specimens passed QA review, whereas the remaining failed due to diagnostic discordance or lack of viable tumor. Among cases with diagnostic concordance, variable volumes of tumor were present, including cases with scant viable tumors. Although QA reviews are time consuming, these results suggest QA reviews at tissue submission could potentially improve tissue quality available and timeliness of sample delivery for research. In addition, it would provide an opportunity for follow-up with sites to request submission of higher quality specimens and mitigate storage of tissue without potential for future use.
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