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1
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Khan K, Kane K, Davison Z, Green D. Post-treatment late and long-term effects in bone sarcoma: A scoping review. J Bone Oncol 2025; 52:100671. [PMID: 40206491 PMCID: PMC11979976 DOI: 10.1016/j.jbo.2025.100671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 03/05/2025] [Accepted: 03/06/2025] [Indexed: 04/11/2025] Open
Abstract
Despite the fact that chemotherapy for bone sarcomas (e.g. Ewing sarcoma, osteosarcoma) has well-reported toxicities and that surgical intervention is frequently life altering, follow-up care to monitor for late and long-term effects beyond that of oncological surveillance in former patients is variable. Anecdotal evidence suggests that inconsistent follow-up means some former bone sarcoma patients are left to cope with post-treatment late and long-term effects with limited support. Here, we performed a scoping review to provide a more empirical identification of the knowledge gaps and to provide an overview of the peer reviewed academic literature reporting the late and long-term effects of treatment for bone sarcoma. JBI Scoping Review Network guidelines for charting, analysis and data extraction were followed. Literature searches were conducted in Medline (Ovid), Cochrane CENTRAL, EMBASE (Ovid), CINAHL, PsycINFO, Proquest and Web of Science (Clarivate Analytics) from March 2024 to September 2024. Paper titles and abstracts were screened by two independent reviewers followed by full text analysis by the lead researcher. Seventy-four peer reviewed articles were included in the analysis. Most studies were of a retrospective study design, some up to 20 years of follow-up and included chemotherapy, surgery and sometimes radiotherapy as the treatment modality. Our analysis identified secondary malignancies, cardio- and nephrotoxicity, lower bone mineral density and microarchitectural deterioration, cancer related fatigue and motor neuropathies as the major physical late and long-term effects requiring dedicated follow-up. In some cases, follow-up may need to span decades, especially given the increasing population of former patients. Our results form the evidence-based foundations for future work that might include late and long-term effect follow-up service mapping exercises and expanded clinical recommendations.
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Affiliation(s)
- Kaainat Khan
- Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom
| | | | - Zoe Davison
- Bone Cancer Research Trust, Leeds, United Kingdom
| | - Darrell Green
- Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom
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2
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Xie J, Mellado-Lagarde MM, Blankenship K, Ganguly D, Twarog NR, Bianski B, Kieffer M, Atkinson S, Sheppard H, Gartrell J, Cler S, Federico SM, Stewart EA, Tinkle CL, Shelat AA. The Combination of PARP and Topoisomerase 1 Inhibitors Improves Radiation Therapy for Ewing Sarcoma. Cancer Sci 2025. [PMID: 40069935 DOI: 10.1111/cas.70042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 02/17/2025] [Accepted: 02/25/2025] [Indexed: 04/02/2025] Open
Abstract
Although primary tumor control rates after surgery and/or radiation therapy (RT) are generally high in patients with Ewing sarcoma (EWS), those with unresectable tumors have failure rates approaching 30% and experience poorer outcomes. Additionally, although metastatic site irradiation is associated with improved survival, dose, and volume effects influence the long-term toxicity risk. Consequently, it is important to identify novel systemic agents to enhance the therapeutic ratio of RT. Given the reported DNA damage response deficits in EWS, we hypothesized that PARP inhibitors (PARPis) would preferentially potentiate radiation relative to standard-of-care (SOC) chemotherapeutics. We investigated primary and recurrent SOC drugs and PARPis with varied trapping potential in combination with radiation in EWS cell lines. At physiologically relevant concentrations, the strong PARP trapper talazoparib (TAL) potentiated radiation to a greater extent than did SOC or other PARPis, although the magnitude of the effect was modest. The radiosensitizing effect of TAL was mediated through the induction of DNA double-strand breaks, rather than through the catalytic inhibition of PARP1. Drug + RT combinations were further tested in vivo by using orthotopic xenograft models of EWS treated with image-guided fractionated radiation. The addition of RT to the combination of TAL plus irinotecan (IRN), a recently evaluated clinical regimen for relapsed pediatric solid tumors, significantly prolonged survival and reduced tumor burden in all EWS-treated mice. This triplet therapy (TAL + IRN + RT) was feasible and yielded responses in several patients with EWS and may represent a useful salvage strategy in recurrent or progressive disease.
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Affiliation(s)
- Jia Xie
- Department of Radiation Oncology, St. Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, USA
- Department of Chemical Biology and Therapeutics, SJCRH, Memphis, Tennessee, USA
| | | | | | - Debolina Ganguly
- Department of Chemical Biology and Therapeutics, SJCRH, Memphis, Tennessee, USA
| | - Nathaniel R Twarog
- Department of Chemical Biology and Therapeutics, SJCRH, Memphis, Tennessee, USA
| | - Brandon Bianski
- Department of Radiation Oncology, St. Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, USA
| | | | - Stefan Atkinson
- Department of Developmental Neurobiology, SJCRH, Memphis, Tennessee, USA
| | | | | | - Samuel Cler
- Department of Oncology, SJCRH, Memphis, Tennessee, USA
- Department of Developmental Neurobiology, SJCRH, Memphis, Tennessee, USA
| | | | - Elizabeth A Stewart
- Department of Oncology, SJCRH, Memphis, Tennessee, USA
- Department of Developmental Neurobiology, SJCRH, Memphis, Tennessee, USA
| | - Christopher L Tinkle
- Department of Radiation Oncology, St. Jude Children's Research Hospital (SJCRH), Memphis, Tennessee, USA
| | - Anang A Shelat
- Department of Chemical Biology and Therapeutics, SJCRH, Memphis, Tennessee, USA
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3
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Rezaeian AH, Wei W. Molecular signaling and clinical implications in the human aging-cancer cycle. Semin Cancer Biol 2024; 106-107:28-42. [PMID: 39197809 PMCID: PMC11625621 DOI: 10.1016/j.semcancer.2024.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 08/07/2024] [Accepted: 08/09/2024] [Indexed: 09/01/2024]
Abstract
It is well documented that aging is associated with cancer, and likewise, cancer survivors display accelerated aging. As the number of aging individuals and cancer survivors continues to grow, it raises additional concerns across society. Therefore, unraveling the molecular mechanisms of aging in tissues is essential to developing effective therapies to fight the aging and cancer diseases in cancer survivors and cancer patients. Indeed, cellular senescence is a critical response, or a natural barrier to suppress the transition of normal cells into cancer cells, however, hypoxia which is physiologically required to maintain the stem cell niche, is increased by aging and inhibits senescence in tissues. Interestingly, oxygen restriction or hypoxia increases longevity and slows the aging process in humans, but hypoxia can also drive angiogenesis to facilitate cancer progression. In addition, cancer treatment is considered as one of the major reasons that drive cellular senescence, subsequently followed by accelerated aging. Several clinical trials have recently evaluated inhibitors to eliminate senescent cells. However, some mechanisms of aging typically can also retard cancer cell growth and progression, which might require careful strategy for better clinical outcomes. Here we describe the molecular regulation of aging and cancer in crosstalk with DNA damage and hypoxia signaling pathways in cancer patients and cancer survivors. We also update several therapeutic strategies that might be critical in reversing the cancer treatment-associated aging process.
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Affiliation(s)
- Abdol-Hossein Rezaeian
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States.
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, United States.
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Bell A, Rangaswami A, Murphy P, Meng M, Raphael R, Wu N, Goldsby R. Subsequent Renal Cancer Among Childhood Cancer Survivors: Analysis of Surveillance, Epidemiology, and End Results. J Pediatr Hematol Oncol 2024; 46:e387-e392. [PMID: 38934569 PMCID: PMC11268548 DOI: 10.1097/mph.0000000000002910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 05/15/2024] [Indexed: 06/28/2024]
Abstract
Renal cancer, although still rare among individuals under 45 years of age, is on the rise in the general population. The risk and timing of subsequent renal cancer in survivors of childhood cancer is not well established. Using the SEER registry, we reported the incidence of subsequent malignant renal neoplasms after treatment for primary malignancy diagnosed under 20 years of age. We evaluated clinical characteristics, standardized incidence ratio (SIR), and Kaplan-Meier survival estimates. Fifty-three survivors developed subsequent renal cancer (54 total cases). Of these, 54.7% were female, 88.7% were white, and 13.2% were Hispanic. Mean ages at primary malignancy and subsequent renal cancer were 10.1 and 31.1 years, respectively. Forty-seven cases were second cancers, 6 were third, and 1 was fourth. For survivors of childhood cancer, the overall SIR for renal cancer was 4.52 (95% CI: 3.39-5.89). The 5-year overall survival rate after development of subsequent renal cancer was 73% (95% CI: 58%-83%). Renal cancer occurs 4.5 times more frequently in childhood cancer survivors than in the general population, necessitating long-term care considerations.
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Affiliation(s)
| | | | | | - Max Meng
- Urology, UCSF Benioff Children’s Hospitals, San Francisco, CA
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Lim H, Im M, Seo ES, Cho HW, Ju HY, Yoo KH, Cho SY, Kim JW, Lim DH, Sung KW, Lee JW. Tandem High-Dose Chemotherapy Increases the Risk of Secondary Malignant Neoplasm in Pediatric Solid Tumors. Cancer Res Treat 2024; 56:642-651. [PMID: 37997325 PMCID: PMC11016644 DOI: 10.4143/crt.2023.999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 11/23/2023] [Indexed: 11/25/2023] Open
Abstract
PURPOSE This study aimed to investigate the incidence and risk factors for secondary malignant neoplasms (SMN) in pediatric solid tumors, focusing on the effects of tandem high-dose chemotherapy (HDCT). MATERIALS AND METHODS Patients (aged < 19 years) diagnosed with or treated for pediatric solid tumors between 1994 and 2014 were retrospectively analyzed. The cumulative incidence of SMN was estimated using competing risk methods by considering death as a competing risk. RESULTS A total of 1,435 patients (413 with brain tumors and 1,022 with extracranial solid tumors) were enrolled. Seventy-one patients developed 74 SMNs, with a 10-year and 20-year cumulative incidence of 2.680±0.002% and 10.193±0.024%, respectively. The types of SMN included carcinoma in 28 (37.8%), sarcoma in 24 (32.4%), and hematologic malignancy in 15 (20.3%) cases. Osteosarcoma and thyroid carcinoma were the most frequently diagnosed tumors. Multivariate analysis showed that radiotherapy (RT) > 2, 340 cGy, and tandem HDCT were significant risk factors for SMN development. The SMN types varied according to the primary tumor type; carcinoma was the most frequent SMN in brain tumors and neuroblastoma, whereas hematologic malignancy and sarcomas developed more frequently in patients with sarcoma and retinoblastoma, respectively. CONCLUSION The cumulative incidence of SMN in pediatric patients with solid tumors was considerably high, especially in patients who underwent tandem HDCT or in those who received RT > 2,340 cGy. Therefore, the treatment intensity should be optimized based on individual risk assessment and the long-term follow-up of pediatric cancer survivors.
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Affiliation(s)
- Hana Lim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Minji Im
- Department of Pediatrics, CHA Gangnam Medical Center, CHA University School of Medicine, Seoul, Korea
| | - Eun Seop Seo
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee Won Cho
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hee Young Ju
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Keon Hee Yoo
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Yoon Cho
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong-Won Kim
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Do Hoon Lim
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ki Woong Sung
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ji Won Lee
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Corvest V, Marec-Bérard P, Lervat C, Pacquement H, Toulmonde M, Gentet JC, Laurence V, Cleirec M, Mansuy L, Bompas E, Castex MP, Taque S, Filhon B, Tabone MD, Verité C, Entz-Werle N, Saumet L, Guimard G, Pondrom M, Chevreau C, Flandrin J, Duranteau L, Rousset-Jablonski C, Brugières L, Jimenez M, Le Deley MC, Gaspar N, Fresneau B. Late toxicity comparison of alkylating-based maintenance regimen with cyclophosphamide (VAC) vs ifosfamide (VAI) in Ewing sarcoma survivors treated in the randomized clinical trial Euro-EWING99-R1 in France. Int J Cancer 2023; 152:1659-1667. [PMID: 36250317 PMCID: PMC10092329 DOI: 10.1002/ijc.34326] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 08/12/2022] [Accepted: 09/07/2022] [Indexed: 11/06/2022]
Abstract
In Euro-EWING99-R1 randomized trial, cyclophosphamide was shown to be noninferior to ifosfamide in the consolidation of standard-risk Ewing sarcoma (SR-EWS) after a common induction with VIDE (vincristine-ifosfamide-doxorubicin-etoposide). We present the results of the late effects analysis of VAC (vincristine-dactinomycin-cyclophoshamide) vs VAI (vincristine-dactinomycin-ifosfamide) conducted in Euro-EWING99-R1 French cohort. Of 267 French randomized patients, 204 were alive and free-of-relapse at 5-years including 172 with available long-term follow-up data concerning cardiac, renal and/or gonadal functions (sex-ratio M/F = 1.3, median age at diagnosis = 14 years): 84 randomized in VAC (median cumulative doses: cyclophosphamide = 9.7 g/m2 , ifosfamide = 59.4 g/m2 ) and 88 in VAI (ifosfamide = 97.1 g/m2 ). With a median follow-up of 10 years (range = 5-17), five late relapses and five second malignancies were recorded. The 10-year event-free survival among 5-year free-of-relapse survivors was similar between VAC and VAI (93% vs 95%, P = .63). We estimated the 10-year cumulative probabilities of cardiac and kidney toxicities at 4.4% (95% confidence interval [95% CI] = 1.1%-7.6%) and 34.8% (95% CI = 26.8%-42.0%), respectively. Cardiac toxicity cumulative probability was similar in both arms, whereas kidney toxicity was higher in VAI (at 10 years, 43.0% vs 25.7%, P = .02), resulting from significant difference in glomerular toxicity (31.1% vs 13.1%, P < .01). At 10 years, gonadal toxicity was observed in 27% and 28% of pubertal men and women, respectively, without significant difference between VAC and VAI. Kidney and gonadal toxicities represent major issues in Euro-EWING99-R1, with significantly higher risk of kidney toxicities with VAI, without significant gonadal toxicity reduction. These results support the need to limit cumulative doses of both alkylating agents and to use mixed regimen as in VIDE-VAC or VDC/IE (vincristine-doxorubicin-cyclophoshamide/ifosfamide-etoposide).
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Affiliation(s)
- Victoria Corvest
- Department of Children and Adolescents Oncology, Gustave Roussy, Villejuif, France
| | - Perrine Marec-Bérard
- Department of Oncology for Child and Adolescent, Centre Léon Bérard, Pediatric Oncology and Hematology Institute (IHOPe), Lyon, France
| | - Cyril Lervat
- Centre Oscar Lambret, Unité d'Oncologie Pédiatrique, Lille, France
| | | | - Maud Toulmonde
- Département d'Oncologie Médicale, Institut Bergonié, Unités Sarcomes et Phases Précoces, Bordeaux, France
| | - Jean-Claude Gentet
- Department of Pediatric Hematology, Immunology and Oncology, APHM - La Timone Children's Hospital, Marseille, France
| | - Valérie Laurence
- Medical Oncology, Adolescents and Young Adults Unit, Institut Curie, Paris, France
| | - Morgane Cleirec
- Service d'Oncologie Pédiatrique, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Ludovic Mansuy
- Department of Pediatric Hematology and Oncology, Nancy University Hospital, Vandœuvre-lès-Nancy, France
| | - Emmanuelle Bompas
- Department of Medical Oncology, Centre René Gauducheau, Nantes, France
| | | | - Sophie Taque
- Department of Pediatric Onco-Hematology, Rennes University Hospital, Rennes, France
| | - Bruno Filhon
- Department of Pediatric Hematology and Oncology, Rouen University Hospital, Rouen, France
| | - Marie-Dominique Tabone
- Service d'Hémato-Oncologie Pédiatrique, Hôpital Armand Trousseau - AP-HP, Sorbonne Université, Paris, France
| | - Cécile Verité
- Department of Pediatric and Adolescent Hematology and Oncology, Pellegrin Hospital, Bordeaux, France
| | - Natacha Entz-Werle
- Pédiatrie Onco-Hématologie, Hôpital Universitaire de Strasbourg, Strasbourg, France
| | - Laure Saumet
- Service d'Onco-Hématologie Pédiatrique, Hôpital Arnaud de Villeneuve, Montpellier, France
| | - Gregory Guimard
- Department of Paediatric Oncology/Hematology, CHU de Reims, American Hospital, Reims, France
| | - Morgane Pondrom
- Department of Pediatric Hemato-Oncology, Nice University Hospital, Nice, France
| | - Christine Chevreau
- Department of Medical Oncology, Institut Claudius Regaud IUCT-O, Toulouse, France
| | - Jennifer Flandrin
- Service de Gynécologie Adolescente et Jeune Adulte (GYNADO), Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Lise Duranteau
- Service de Gynécologie Adolescente et Jeune Adulte (GYNADO), Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Christine Rousset-Jablonski
- Département de Chirurgie, Centre Léon Bérard, INSERM U1290, RESearch in HealthcAre PErformance (RESHAPE), Lyon, France
| | - Laurence Brugières
- Department of Children and Adolescents Oncology, Gustave Roussy, Villejuif, France
| | - Marta Jimenez
- Research and Development Department, Unicancer, Paris, France
| | - Marie-Cécile Le Deley
- Unité de Méthodologie et Biostatistiques, Centre Oscar Lambret, Lille, France.,Université Paris-Saclay, UVSQ, Inserm, CESP, Villejuif, France
| | - Nathalie Gaspar
- Department of Children and Adolescents Oncology, Gustave Roussy, Villejuif, France
| | - Brice Fresneau
- Department of Children and Adolescents Oncology, Gustave Roussy, Villejuif, France.,Université Paris-Saclay, UVSQ, Inserm, CESP, Villejuif, France
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Shafqat S, Arana Chicas E, Shafqat A, Hashmi SK. The Achilles' heel of cancer survivors: fundamentals of accelerated cellular senescence. J Clin Invest 2022; 132:e158452. [PMID: 35775492 PMCID: PMC9246373 DOI: 10.1172/jci158452] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Recent improvements in cancer treatment have increased the lifespan of pediatric and adult cancer survivors. However, cancer treatments accelerate aging in survivors, which manifests clinically as the premature onset of chronic diseases, such as endocrinopathies, osteoporosis, cardiac dysfunction, subsequent cancers, and geriatric syndromes of frailty, among others. Therefore, cancer treatment-induced early aging accounts for significant morbidity, mortality, and health expenditures among cancer survivors. One major mechanism driving this accelerated aging is cellular senescence; cancer treatments induce cellular senescence in tumor cells and in normal, nontumor tissue, thereby helping mediate the onset of several chronic diseases. Studies on clinical monitoring and therapeutic targeting of cellular senescence have made considerable progress in recent years. Large-scale clinical trials are currently evaluating senotherapeutic drugs, which inhibit or eliminate senescent cells to ameliorate cancer treatment-related aging. In this article, we survey the recent literature on phenotypes and mechanisms of aging in cancer survivors and provide an up-to-date review of the major preclinical and translational evidence on cellular senescence as a mechanism of accelerated aging in cancer survivors, as well as insight into the potential of senotherapeutic drugs. However, only with time will the clinical effect of senotherapies on cancer survivors be visible.
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Affiliation(s)
| | - Evelyn Arana Chicas
- Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA
| | - Areez Shafqat
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Shahrukh K. Hashmi
- Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
- Clinical Affairs, Khalifa University, Abu Dhabi, United Arab Emirates
- Department of Medicine, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates
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Ewing Sarcoma of the 9th Rib Subsequent to Pediatric Leukemia: A Case Series. J Pediatr Hematol Oncol 2022; 44:e609-e611. [PMID: 35200228 DOI: 10.1097/mph.0000000000002282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 06/14/2021] [Indexed: 11/26/2022]
Abstract
Ewing sarcoma is an aggressive malignancy of bone and soft tissue that accounts for ∼2% of cases of childhood cancer. It has been rarely reported as a secondary neoplasm. Data from the Childhood Cancer Survivor Study has evaluated secondary sarcomas in 5-year survivors of childhood cancer. We report 2 pediatric patients in northeast Pennsylvania, who developed secondary Ewing sarcoma of the 9th rib within 5 years of primary childhood leukemia diagnoses.
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9
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Pedersen C, Rechnitzer C, Andersen EAW, Kenborg L, Norsker FN, Bautz A, Baad-Hansen T, Tryggvadottir L, Madanat-Harjuoja LM, Holmqvist AS, Hjorth L, Hasle H, Winther JF. Somatic Disease in Survivors of Childhood Malignant Bone Tumors in the Nordic Countries. Cancers (Basel) 2021; 13:cancers13184505. [PMID: 34572734 PMCID: PMC8467516 DOI: 10.3390/cancers13184505] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/02/2021] [Accepted: 09/03/2021] [Indexed: 01/18/2023] Open
Abstract
Simple Summary The treatment of osteosarcoma and Ewing sarcoma, the two major types of malignant bone tumors in children, has progressed considerably during the last decades, with more patients becoming long-term survivors. This improvement has resulted in an increasing number of patients with long-term adverse health consequences from the life-saving treatment. The aim of this study was to provide a detailed, comprehensive overview of somatic diseases that require hospitalization in long-term survivors of osteosarcoma and Ewing sarcoma. This study contributes new insights into the risk of somatic late effects in survivors of osteosarcoma and Ewing sarcoma which are urgently requested by pediatric oncologists, researchers, and by survivors and their families. The study provides an essential basis for the development of preventive intervention strategies and for optimal patient counseling and follow-up care, which all contribute to improving the health and quality of life in survivors. Abstract Survivors of malignant bone tumors in childhood are at risk of long-term adverse health effects. We comprehensively reviewed cases of somatic diseases that required a hospital contact in survivors of osteosarcoma and Ewing sarcoma. In a population-based cohort study, 620 five-year survivors of osteosarcoma (n = 440) or Ewing sarcoma (n = 180), diagnosed before the age of 20 years in Denmark, Finland, Iceland, and Sweden during 1943–2008, were followed in the national hospital registers. Overall rates of hospital contacts for any somatic disease and for 12 main diagnostic groups and 120 specific disease categories were compared with those in a matched comparison cohort (n = 3049) randomly selected from the national population registers. The rate of hospital contact for any somatic disease was 80% higher in survivors of malignant bone tumors than in comparisons and remained elevated up to 30 years after diagnosis. The rate of hospital contacts was higher after Ewing sarcoma (rate ratio (RR) 2.24; 95% confidence interval (CI) 1.76–2.85) than after osteosarcoma (RR 1.67; 95% CI 1.41–1.98). Elevated rates were observed for 11 main diagnostic groups, including infections, second malignant neoplasms, and diseases of the skin, bones, and circulatory, digestive, endocrine, and urinary systems. Survivors of malignant bone tumors in childhood are at increased risk of somatic diseases many years after diagnosis. This comprehensive study contributes new insight into the risk of late effects in survivors of osteosarcoma and Ewing sarcoma, which is an essential basis for optimal patient counseling and follow-up care.
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Affiliation(s)
- Camilla Pedersen
- Danish Cancer Society Research Center, 2100 Copenhagen, Denmark; (E.A.W.A.); (L.K.); (F.N.N.); (A.B.); (J.F.W.)
- Correspondence:
| | - Catherine Rechnitzer
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, 2100 Copenhagen, Denmark;
| | | | - Line Kenborg
- Danish Cancer Society Research Center, 2100 Copenhagen, Denmark; (E.A.W.A.); (L.K.); (F.N.N.); (A.B.); (J.F.W.)
| | - Filippa Nyboe Norsker
- Danish Cancer Society Research Center, 2100 Copenhagen, Denmark; (E.A.W.A.); (L.K.); (F.N.N.); (A.B.); (J.F.W.)
| | - Andrea Bautz
- Danish Cancer Society Research Center, 2100 Copenhagen, Denmark; (E.A.W.A.); (L.K.); (F.N.N.); (A.B.); (J.F.W.)
| | - Thomas Baad-Hansen
- Department of Orthopedic Surgery, Sarcoma Centre of Aarhus University Hospital, 8200 Aarhus, Denmark;
| | - Laufey Tryggvadottir
- The Icelandic Cancer Registry, 105 Reykjavik, Iceland;
- Faculty of Medicine, University of Iceland, 102 Reykjavik, Iceland
| | | | - Anna Sällfors Holmqvist
- Department of Clinical Sciences Lund, Lund University, 222 41 Lund, Sweden; (A.S.H.); (L.H.)
- Department of Pediatric Hematology and Oncology, Skane University Hospital, 221 85 Lund, Sweden
| | - Lars Hjorth
- Department of Clinical Sciences Lund, Lund University, 222 41 Lund, Sweden; (A.S.H.); (L.H.)
- Department of Pediatric Hematology and Oncology, Skane University Hospital, 221 85 Lund, Sweden
| | - Henrik Hasle
- Department of Pediatrics, Aarhus University Hospital, 8200 Aarhus, Denmark;
| | - Jeanette Falck Winther
- Danish Cancer Society Research Center, 2100 Copenhagen, Denmark; (E.A.W.A.); (L.K.); (F.N.N.); (A.B.); (J.F.W.)
- Department of Clinical Medicine, Faculty of Health, Aarhus University and University Hospital, 8200 Aarhus, Denmark
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Siddique A, Simonsick EM, Gallicchio L. Functional decline among older cancer survivors in the Baltimore longitudinal study of aging. J Am Geriatr Soc 2021; 69:3124-3133. [PMID: 34346072 DOI: 10.1111/jgs.17369] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 06/29/2021] [Accepted: 07/03/2021] [Indexed: 01/22/2023]
Abstract
BACKGROUND Evidence has begun to emerge indicating that cancer survivors experience accelerated aging. This study examines this phenomenon by evaluating trajectories of functional decline in older adults with a history of a cancer diagnosis relative to those without a history of cancer. METHODS Community dwelling healthy volunteers in the Baltimore Longitudinal Study of Aging were evaluated in the Clinical Research Unit of the National Institute on Aging Intramural Research Program. Between 2006 and 2019, 1728 men and women (aged 22-100) underwent clinical evaluation of functional status; 359 reported having a history of cancer. Longitudinal associations between self-reported cancer history and measures of functional decline were examined using generalized estimating equations. Additionally, time-to-event and Cox proportional hazards models were used to examine trajectories of decline. Where appropriate, age-stratified associations were examined, and models were adjusted for sex, body mass index, race, smoking status, education, and number of comorbid conditions. RESULTS Among all participants, a history of cancer was associated with 1.42 (95% CI 1.11-1.81) greater odds of weak grip strength. Among older participants (>65 years of age), those with a history of cancer had 1.61 (95% CI 1.28, 2.02) greater odds of slow gait speed and a 0.11 unit (95% CI 0.19-0.03) lower physical performance score than those with no cancer history. Time-to-event analysis showed that older individuals with a history of cancer experienced steeper decline in grip strength and gait speed than older adults with no history of cancer (p < 0.01). CONCLUSION Cancer survivors, especially older individuals, demonstrate greater odds of and accelerated functional decline, suggesting that cancer and/or its treatment may alter aging trajectories. Observational and intervention studies are needed for prevention, mitigation, and/or reversal of aging-related effects of cancer and its treatment.
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Affiliation(s)
- Arfan Siddique
- Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, Maryland, USA
| | - Eleanor M Simonsick
- National Institute on Aging, Intramural Research Program, Baltimore, Maryland, USA
| | - Lisa Gallicchio
- Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, Maryland, USA
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11
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Heitzeneder S, Sotillo E, Shern JF, Sindiri S, Xu P, Jones R, Pollak M, Noer PR, Lorette J, Fazli L, Alag A, Meltzer P, Lau C, Conover CA, Oxvig C, Sorensen PH, Maris JM, Khan J, Mackall CL. Pregnancy-Associated Plasma Protein-A (PAPP-A) in Ewing Sarcoma: Role in Tumor Growth and Immune Evasion. J Natl Cancer Inst 2020; 111:970-982. [PMID: 30698726 DOI: 10.1093/jnci/djy209] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 09/10/2018] [Accepted: 11/12/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Ewing sarcoma (EWS) manifests one of the lowest somatic mutation rates of any cancer, leading to a scarcity of druggable mutations and neoantigens. Immunotherapeutics targeting differentially expressed cell surface antigens could provide therapeutic benefit for such tumors. Pregnancy-associated plasma protein A (PAPP-A) is a cell membrane-associated proteinase produced by the placenta that promotes fetal growth by inducing insulinlike growth factor (IGF) signaling. METHODS By comparing RNA expression of cell surface proteins in EWS (n = 120) versus normal tissues (n = 42), we comprehensively characterized the surfaceome of EWS to identify highly differentially expressed molecules. Using CRISPR/Cas-9 and anti-PAPP-A antibodies, we investigated biological roles for PAPP-A in EWS in vitro and in vivo in NSG xenograft models and performed RNA-sequencing on PAPPA knockout clones (n = 5) and controls (n = 3). All statistical tests were two-sided. RESULTS EWS surfaceome analysis identified 11 highly differentially overexpressed genes, with PAPPA ranking second in differential expression. In EWS cell lines, genetic knockout of PAPPA and treatment with anti-PAPP-A antibodies revealed an essential survival role by regulating local IGF-1 bioavailability. MAb-mediated PAPPA inhibition diminished EWS growth in orthotopic xenografts (leg area mm2 at day 49 IgG2a control (CTRL) [n = 14], mean = 397.0, SD = 86.1 vs anti-PAPP-A [n = 14], mean = 311.7, SD = 155.0; P = .03; median OS anti-PAPP-A = 52.5 days, 95% CI = 46.0 to 63.0 days vs IgG2a = 45.0 days, 95% CI = 42.0 to 52.0 days; P = .02) and improved the efficacy of anti-IGF-1R treatment (leg area mm2 at day 49 anti-PAPP-A + anti-IGF-1R [n = 15], mean = 217.9, SD = 148.5 vs IgG2a-CTRL; P < .001; median OS anti-PAPP-A + anti-IGF1R = 63.0 days, 95% CI = 52.0 to 67.0 days vs IgG2a-CTRL; P < .001). Unexpectedly, PAPPA knockout in EWS cell lines induced interferon (IFN)-response genes, including proteins associated with antigen processing/presentation. Consistently, gene expression profiles in PAPPA-low EWS tumors were enriched for immune response pathways. CONCLUSION This work provides a comprehensive characterization of the surfaceome of EWS, credentials PAPP-A as a highly differentially expressed therapeutic target, and discovers a novel link between IGF-1 signaling and immune evasion in cancer, thus implicating shared mechanisms of immune evasion between EWS and the placenta.
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12
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Subsequent primary neoplasms among bone sarcoma survivors; increased risks remain after 30 years of follow-up and in the latest treatment era, a nationwide population-based study. Br J Cancer 2020; 122:1242-1249. [PMID: 32066914 PMCID: PMC7156510 DOI: 10.1038/s41416-020-0748-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 01/13/2020] [Accepted: 01/24/2020] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND The long-term risks and time trends of subsequent primary neoplasms (SPNs) among Ewing (ES) and osteosarcoma (OS) survivors are not fully understood. METHODS We performed a nationwide study of all ES and OS patients identified in the Swedish Cancer Registry from 1958 to 2015 with up to 58 years of follow-up. The risk of SPN was compared with that of the general population using standardised incidence ratios (SIRs) and absolute excess risks (AERs). RESULTS One hundred and fifteen SPNs were diagnosed among 1779 patients with ES or OS, yielding an overall SIR of 2.3 (95% confidence interval (CI), 1.9-2.7). The risk remained significantly increased in the latest treatment era (SIR2000-2015 2.0; 95% CI, 1.1-3.5). The highest absolute excess risks (AER) was due to breast cancer (AER 15.2/10,000 person-years; 95% CI, 5.0-29.8) followed by female genital malignancies (AER 9.5/10,000 person-years; 95% CI, 2.4-21.5). The excess breast cancer risk among ES survivors was noted also after 30 years of follow-up with 127 extra breast cancers/10,000 person-years (95% CI, 6.6-419). CONCLUSIONS Breast- and female genital malignancies contribute most to the excess risk of SPN among ES and OS survivors. Importantly, excess risks did not decline over calendar time or long-term follow-up.
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13
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Caruso J, Shulman DS, DuBois SG. Second malignancies in patients treated for Ewing sarcoma: A systematic review. Pediatr Blood Cancer 2019; 66:e27938. [PMID: 31347793 DOI: 10.1002/pbc.27938] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 07/07/2019] [Accepted: 07/10/2019] [Indexed: 01/16/2023]
Abstract
The therapies used to treat Ewing sarcoma are associated with a risk of second malignant neoplasm (SMN). We conducted a systematic review to pool available evidence on the risks, types, and outcomes after SMN. We obtained 52 articles that met inclusion criteria. Cumulative incidence rates of SMN ranged from 0.9 to 8.4% and 10.1 to 20.5% at 5 and 30 years after initial diagnosis. Of the 327 reported SMNs, 63.6% were solid tumors, although acute myeloid leukemia /myelodysplastic syndrome was the single most commonly diagnosed SMN, with generally poor outcomes. Patients treated for Ewing sarcoma are at substantial risk of SMN, with a broad range of reported secondary cancers.
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Affiliation(s)
| | - David S Shulman
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts
| | - Steven G DuBois
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts
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14
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Han S, Li Y, Li Y, Zhao M. Diagnostic efficacy of PET/CT in bone tumors. Oncol Lett 2019; 17:4271-4276. [PMID: 30944621 PMCID: PMC6444356 DOI: 10.3892/ol.2019.10101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 01/22/2019] [Indexed: 11/19/2022] Open
Abstract
Clinical value of PET/CT (positron emission tomography/computed tomography) in the diagnosis of malignant bone tumors (BT) was investigated. Fifty-four patients with BT were first diagnosed by ordinary CT and then by PET/CT. The diagnostic efficacy outcomes and diagnosis of malignant BT by clinical stage of the two methods for BT were observed and recorded, and the diagnostic value of PET/CT in the diagnosis of BT was evaluated. There were 14 cases of benign BT patients, 15 cases of stage I, 10 cases of stage II and 15 cases of stage III in malignant BT patients. The diagnostic coincidence rate of PET/CT was 92.59% and the diagnostic coincidence rate of CT was 72.22%, which showed that the diagnostic coincidence rate of PET/CT was significantly higher than that of CT (P<0.05). The sensitivity, negative predictive value and positive predictive value of PET/CT were 95.00, 85.71 and 95.00%, respectively, which were higher than those of CT (P<0.05). CT and PET/CT were used for the clinical staging and pathological diagnosis of malignant BT; the results showed that the diagnostic accuracy of PET/CT in the clinical stages of malignant BT was also significantly higher than that of CT (P<0.05). The diagnostic efficacy of PET/CT in BT is better than that in CT. PET/CT can diagnose the pathological properties of BT more accurately, and can also effectively diagnose the clinical stage of malignant BT and provide clinical diagnostic basis for follow-up procedures.
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Affiliation(s)
- Songhui Han
- Department of Intervention, Henan Province Luoyang Orthopedic Traumatological Hospital (Henan Provincal Orthopedic Hospital), Luoyang, Henan 471002, P.R. China
| | - Yanzhou Li
- Department of Intervention, Henan Province Luoyang Orthopedic Traumatological Hospital (Henan Provincal Orthopedic Hospital), Luoyang, Henan 471002, P.R. China
| | - Yuejing Li
- Department of Intervention, Henan Province Luoyang Orthopedic Traumatological Hospital (Henan Provincal Orthopedic Hospital), Luoyang, Henan 471002, P.R. China
| | - Min Zhao
- Department of Intervention, Henan Province Luoyang Orthopedic Traumatological Hospital (Henan Provincal Orthopedic Hospital), Luoyang, Henan 471002, P.R. China
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15
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Demoor-Goldschmidt C, de Vathaire F. Review of risk factors of secondary cancers among cancer survivors. Br J Radiol 2018; 92:20180390. [PMID: 30102558 DOI: 10.1259/bjr.20180390] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Improvements in cancer survival have made the long-term risks from treatments more important, in particular among the children, adolescents and young adults who are more at risk particularly due to a longer life expectancy and a higher sensitivity to treatments. Subsequent malignancies in cancer survivors now constitute 15 to 20% of all cancer diagnoses in the cancer registries. Lots of studies are published to determine risk factors, with some controversial findings. Just data from large cohorts with detailed information on individual treatments and verification of what is called "secondary cancers" can add some knowledge, because their main difficulty is that the number of events for most second cancer sites are low, which impact the statistical results. In this review of the literature, we distinguish second and secondary cancers and discuss the factors contributing to this increased risk of secondary cancers. The article concludes with a summary of current surveillance and screening recommendations.
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Affiliation(s)
- Charlotte Demoor-Goldschmidt
- CESP University, Paris-Sud, UVSQ, INSERM, Université Paris-Saclay, Villejuif, France.,Cancer and Radiation Team, Gustave Roussy, Villejuif, France.,Pediatric Oncology, Hematology, Immunology, CHU d'Angers, Angers, France
| | - Florent de Vathaire
- CESP University, Paris-Sud, UVSQ, INSERM, Université Paris-Saclay, Villejuif, France.,Cancer and Radiation Team, Gustave Roussy, Villejuif, France
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16
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Li X, Li W, Mo W, Yang Z. Acute lymphoblastic leukemia arising after treatment of Ewing sarcoma was misdiagnosed as bone marrow metastasis of Ewing sarcoma: A case report. Medicine (Baltimore) 2018; 97:e9644. [PMID: 29505001 PMCID: PMC5779770 DOI: 10.1097/md.0000000000009644] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
RATIONALE Both acute lymphoblastic leukemia (ALL) and Ewing sarcoma (ES) are small round cell tumors, and it is difficult to differential diagnose them because of overlapping clinical, radiographic, histologic, and immunophenotypic features. PATIENT'S CONCERNS A 5-year-old boy was admitted to our hospital because of pains in his left leg without obvious inducement and lameness worsening with walking over a two 2-month period. DIAGNOSES Based on the comprehensive analysis of radiography, magnetic resonance imaging (MRI), pathology biopsy and immunohistochemistry, the lesion was confirmed to be ES. INTERVENTIONS The patient received neoadjuvant chemotherapy with 2 cycles of VAC (vincristine 1 mg/m, adriamycin 50 mg/m, cyclophosphamide 800 mg/m) and 2 cycles of IE (ifosfamide 1.2 g/m, etoposide 70 mg/m, mesna 1.2 g/m) regimens. OUTCOMES After 16 months, the results of routine blood tests showed reduced hemoglobin levels and decreased platelet counts. In addition, blast-like cells were found in a peripheral blood smear. All of the results suggested that the patient should undergo bone marrow aspiration and biopsy, which showed blast-like cells similar to that observed in cases of ES. Thus, a diagnosis of bone marrow metastasis of ES was established. However, when combined with immunohistochemistry data and medical history, the patient was eventually diagnosed as ALL arising after treatment of ES. LESSONS When there was an abnormality in peripheral blood, it was easily misdiagnosed as bone marrow metastasis of ES after ES patient received neoadjuvant chemotherapy. We should jointly analyze bone marrow aspiration smear, bone marrow biopsy, immunohistochemistry, analysis of the medical history, even cytogenetic and molecular analysis for differential diagnosis.
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17
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Satyarth S, Parikh S, Anand A, Sawhney J, Panchal H, Patel A, Shah S. Acute Lymphoblastic Leukemia as Secondary Malignancy in a Case of Ewing's Sarcoma on Treatment. Indian J Med Paediatr Oncol 2017; 38:354-356. [PMID: 29200689 PMCID: PMC5686982 DOI: 10.4103/ijmpo.ijmpo_110_16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The survival of Ewing's sarcoma (ES) has improved due to advances in both local and systemic therapy. This has given rise to an increased detection of second malignant neoplasms which can be in the form of solid tumors and hematological malignancies. The most common hematological malignancies are acute myeloid leukemia/myelodysplastic syndrome. Acute lymphoblastic leukemia (ALL) is relatively uncommon in occurrence in this setting. Furthermore, the average refractory period for hematological malignancies varies from 3 to 5 years. We report a case of a young female who developed ALL while on adjuvant therapy for ES.
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Affiliation(s)
- Satyam Satyarth
- Department of Medical Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
| | - Sonia Parikh
- Department of Medical Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
| | - Asha Anand
- Department of Medical Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
| | - Jyoti Sawhney
- Department of Medical Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
| | - Harsha Panchal
- Department of Medical Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
| | - Apurva Patel
- Department of Medical Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
| | - Sandeep Shah
- Department of Medical Oncology, Gujarat Cancer Research Institute, Ahmedabad, Gujarat, India
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18
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Marina NM, Liu Q, Donaldson SS, Sklar CA, Armstrong GT, Oeffinger KC, Leisenring WM, Ginsberg JP, Henderson TO, Neglia JP, Stovall MA, Yasui Y, Randall RL, Geller DS, Robison LL, Ness KK. Longitudinal follow-up of adult survivors of Ewing sarcoma: A report from the Childhood Cancer Survivor Study. Cancer 2017; 123:2551-2560. [PMID: 28222219 DOI: 10.1002/cncr.30627] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2016] [Revised: 01/13/2017] [Accepted: 01/17/2017] [Indexed: 01/18/2023]
Abstract
BACKGROUND Ewing sarcoma survivors (ESSs) are at increased risk for treatment-related complications. The incidence of treatment-related morbidity and late mortality with aging is unknown. METHODS This study reports survival probabilities, estimated with the Kaplan-Meier method, and the cumulative incidence of cause-specific mortality and chronic conditions among ESSs in the Childhood Cancer Survivor Study who were treated between 1970 and 1986. Piecewise exponential models were used to estimate relative rates (RRs) and 95% confidence intervals (CIs) for these outcomes. Chronic conditions were graded with the Common Terminology Criteria for Adverse Events (version 4.03). RESULTS Among 404 5-year ESSs (median age at last follow-up, 34.8 years; range, 9.1-54.8 years), the 35-year survival rate was 70% (95% CI, 66%-74%). Late recurrence (cumulative incidence at 35 years, 15.1%) was the most common cause of death, and it was followed by treatment-related causes (11.2%). There were 53 patients with subsequent neoplasms (SNs; cumulative incidence at 35 years, 24.0%), and 38 were malignant (14.3% at 35 years). The standardized incidence ratios were 377.1 (95% CI, 172.1-715.9) for osteosarcoma, 28.9 (95% CI, 3.2-104.2) for acute myeloid leukemia, 14.9 (95% CI, 7.9-25.5) for breast cancer, and 13.1 (95% CI, 4.8-28.5) for thyroid cancer. Rates of chronic conditions were highest for musculoskeletal (RR, 18.1; 95% CI, 12.8-25.7) and cardiac complications (RR, 1.8; 95% CI, 1.4-2.3). Thirty-five years after the diagnosis, the cumulative incidences of any chronic conditions and 2 or more chronic conditions were 84.6% (95% CI, 80.4%-88.8%) and 73.8% (95% CI, 67.8%-79.9%), respectively. CONCLUSIONS With extended follow-up, ESSs' risk for late mortality and SNs does not plateau. Treatment-related chronic conditions develop years after therapy, and this supports the need for lifelong follow-up. Cancer 2017;123:2551-60. © 2017 American Cancer Society.
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Affiliation(s)
- Neyssa M Marina
- Department of Pediatrics, Stanford University and Lucile Packard Children's Hospital, Palo Alto, California
| | - Qi Liu
- School of Public Health, University of Alberta, Edmonton, Alberta, Canada
| | - Sarah S Donaldson
- Depratment of Radiation Oncology, Stanford University, Stanford, California
| | - Charles A Sklar
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Gregory T Armstrong
- Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Kevin C Oeffinger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - Jill P Ginsberg
- Department of Pediatric Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Tara O Henderson
- University of Chicago, Comprehensive Cancer Center, Pediatric Oncology, Chicago, Illinois
| | - Joseph P Neglia
- University of Minnesota/Masonic Cancer Center, Pediatrics, Minneapolis, Minnesota, Minnesota
| | | | - Yutaka Yasui
- Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - R Lor Randall
- Department of Orthopedic Surgery, Primary Children's Hospital and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - David S Geller
- Montefiore Medical Center-Moses Campus and Orthopedic Surgery, Children's Hospital at Montefiore, Bronx, New York
| | - Leslie L Robison
- Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Kirsten K Ness
- Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee
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19
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Ewing Sarcoma of the Bone With EWS/FLI1 Translocation After Successful Treatment of Primary Osteosarcoma. J Pediatr Hematol Oncol 2017; 39:6-9. [PMID: 27918348 DOI: 10.1097/mph.0000000000000721] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Although prognosis in patients with localized osteosarcoma has been dramatically improved by the introduction of multiple chemotherapy agents known as combination chemotherapy, there is growing concern about the development of secondary malignant neoplasms. We report the case of a 13-year-old girl in whom the diagnosis of Ewing sarcoma of bone localized on the shaft of left femur was made 2 years after successful treatment without radiotherapy for osteosarcoma of right proximal femur. EWS-FLI1 fusion gene was detected by reverse transcriptase-polymerase chain reaction. To our knowledge, this is the first case with Ewing sarcoma of the bone as a secondary malignant neoplasm developed in osteosarcoma survivor. We collected 15 cases, included this case, with secondary Ewing sarcoma family of tumor by utilizing the PubMed search and might consider the causes of this secondary cancer.
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20
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Umer M, Qadir I, Abbasi N, Das JK, Lassi ZS. Radiotherapy for localised Ewing’s sarcoma in children. Hippokratia 2016. [DOI: 10.1002/14651858.cd011105.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Masood Umer
- Aga Khan University Hospital; Department of Surgery; Stadium Road Karachi Pakistan 74800
| | - Irfan Qadir
- Aga Khan University Hospital; Department of Surgery; Stadium Road Karachi Pakistan 74800
| | - Nadeem Abbasi
- Aga Khan University Hospital; Department of Radiation Oncology; Stadium Road Karachi Pakistan 74800
| | - Jai K Das
- Aga Khan University Hospital; Division of Women and Child Health; Stadium Road PO Box 3500 Karachi Sind Pakistan
| | - Zohra S Lassi
- The University of Adelaide; The Robinson Research Institute; Adelaide South Australia Australia 5005
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21
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Foulon S, Brennan B, Gaspar N, Dirksen U, Jeys L, Cassoni A, Claude L, Seddon B, Marec-Berard P, Whelan J, Paulussen M, Streitbuerger A, Oberlin O, Juergens H, Grimer R, Le Deley MC. Can postoperative radiotherapy be omitted in localised standard-risk Ewing sarcoma? An observational study of the Euro-E.W.I.N.G group. Eur J Cancer 2016; 61:128-36. [DOI: 10.1016/j.ejca.2016.03.075] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Revised: 03/09/2016] [Accepted: 03/22/2016] [Indexed: 12/22/2022]
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22
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Chen Z, Wu J, Guo Q. Actein Inhibits Cell Proliferation and Migration in Human Osteosarcoma. Med Sci Monit 2016; 22:1609-16. [PMID: 27173526 PMCID: PMC4918520 DOI: 10.12659/msm.898483] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background Osteosarcoma is one of the most common malignant bone cancers worldwide. Although the traditional chemotherapies have made some progression in the past decades, the mortality of osteosarcoma in children and adolescent is very high. Herein, the role of actein in osteosarcoma was explored. Material/Methods Cell viability assay was performed in osteosarcoma cell lines 143B and U2OS. Colony formation analysis was included when cells were treated with different doses of actin. Cell cycle assay was conducted to further examine the role of actein. Cell apoptotic rate and the relative activities of caspase-3, caspase-8, and caspase-9 were detected in 143B and U2OS osteosarcoma cells. Moreover, transwell assays were used to explore the effects of actein on cell metastasis. Results Actein significantly inhibited osteosarcoma cell viability in a time- and dose-dependent manner. Actein also dramatically suppressed the colony formation ability in osteosarcoma143B and U2OS cells. It was revealed that osteosarcoma cells were arrested in G0/G1 phase in the cell cycle progression and induced to apoptosis by administration of actein. The activities of pro-apoptotic factors such as caspase-3 and caspase-9 were significantly increased by actein. Furthermore, administration of actein decreased cell migrated and invasive abilities in both 143B and U2OS cell lines. Conclusions Actein inhibits tumor growth by inducing cell apoptosis in osteosarcoma. The inhibitive roles of actein in cell proliferation, migration and invasion suggest that actein may serve as a potential therapeutic agent in the treatment of osteosarcoma.
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Affiliation(s)
- Zhi Chen
- Department of Emergency Medicine, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (mainland)
| | - Jingdong Wu
- Department of Emergency Surgery, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (mainland)
| | - Qinghao Guo
- Department of Emergency Surgery, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China (mainland)
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23
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Ning MS, Perkins SM, Borinstein SC, Holt GE, Stavas MJ, Shinohara ET. Role of radiation in the treatment of non-metastatic osseous Ewing sarcoma. J Med Imaging Radiat Oncol 2015; 60:119-28. [DOI: 10.1111/1754-9485.12389] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Accepted: 08/16/2015] [Indexed: 12/21/2022]
Affiliation(s)
- Matthew S Ning
- Department of Radiation Oncology; Vanderbilt University School of Medicine; Nashville Tennessee USA
| | - Stephanie M Perkins
- Department of Radiation Oncology; Washington University School of Medicine; Saint Louis Missouri USA
| | - Scott C Borinstein
- Department of Pediatrics; Division of Pediatric Hematology/Oncology; Vanderbilt University School of Medicine; Nashville Tennessee USA
| | - Ginger E Holt
- Department of Orthopedics; Vanderbilt University School of Medicine; Nashville Tennessee USA
| | - Mark J Stavas
- Department of Radiation Oncology; Vanderbilt University School of Medicine; Nashville Tennessee USA
| | - Eric T Shinohara
- Department of Radiation Oncology; Vanderbilt University School of Medicine; Nashville Tennessee USA
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24
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Demoor-Goldschmidt C, Fayech C, Girard P, Plantaz D. [Secondary cancers: Incidence, risk factors and recommendations]. Bull Cancer 2015; 102:656-64. [PMID: 25911942 DOI: 10.1016/j.bulcan.2015.03.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 03/23/2015] [Indexed: 01/22/2023]
Abstract
Cure rates for most childhood cancers and adolescents have made remarkable progress over the last thirty to forty years. The development of secondary malignancies has become an important question for these patients. The frequency is low, but the risk is significantly higher (between 3 and 10 times) and it is the leading cause of long-term mortality off relapse. In this literature review, we discuss the epidemiological aspect and the risk factors contributing to this increased risk, and conclude with a summary of current recommendations for screening and surveillance. We also discuss briefly the constitutional predisposing genetic contributions to other cancers.
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Affiliation(s)
- Charlotte Demoor-Goldschmidt
- Institut de cancérologie de l'Ouest, ICO-René Gauducheau, service de radiothérapie, boulevard J-Monod, 44800 Saint-Herblain, France; Faculté de médecine de Nantes, 44000 Nantes, France.
| | - Chiraz Fayech
- Institut Gustave-Roussy, service d'oncologie pédiatrique, rue Camille-Des-Moulins, 94805 Villejuif, France
| | - Pauline Girard
- CHU de Grenoble, hôpital Couple Enfant, clinique universitaire de pédiatrie, CS10217, 38043 Grenoble cedex, France
| | - Dominique Plantaz
- CHU de Grenoble, hôpital Couple Enfant, clinique universitaire de pédiatrie, CS10217, 38043 Grenoble cedex, France
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Thiagarajan A, Iyer NG. Radiation-induced sarcomas of the head and neck. World J Clin Oncol 2014; 5:973-981. [PMID: 25493233 PMCID: PMC4259957 DOI: 10.5306/wjco.v5.i5.973] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Revised: 08/28/2014] [Accepted: 10/16/2014] [Indexed: 02/06/2023] Open
Abstract
With improved outcomes associated with radiotherapy, radiation-induced sarcomas (RIS) are increasingly seen in long-term survivors of head and neck cancers, with an estimated risk of up to 0.3%. They exhibit no subsite predilection within the head and neck and can arise in any irradiated tissue of mesenchymal origin. Common histologic subtypes of RIS parallel their de novo counterparts and include osteosarcoma, chondrosarcoma, malignant fibrous histiocytoma/sarcoma nitricoxide synthase, and fibrosarcoma. While imaging features of RIS are not pathognomonic, large size, extensive local invasion with bony destruction, marked enhancement within a prior radiotherapy field, and an appropriate latency period are suggestive of a diagnosis of RIS. RIS development may be influenced by factors such as radiation dose, age at initial exposure, exposure to chemotherapeutic agents and genetic tendency. Precise pathogenetic mechanisms of RIS are poorly understood and both directly mutagenizing effects of radiotherapy as well as changes in microenvironments are thought to play a role. Management of RIS is challenging, entailing surgery in irradiated tissue and a limited scope for further radiotherapy and chemotherapy. RIS is associated with significantly poorer outcomes than stage-matched sarcomas that arise independent of irradiation and surgical resection with clear margins seems to offer the best chance for cure.
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DuBois SG, Krailo MD, Gebhardt MC, Donaldson SS, Marcus KJ, Dormans J, Shamberger RC, Sailer S, Nicholas RW, Healey JH, Tarbell NJ, Randall RL, Devidas M, Meyer JS, Granowetter L, Womer RB, Bernstein M, Marina N, Grier HE. Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: a report from the Children's Oncology Group. Cancer 2014; 121:467-75. [PMID: 25251206 DOI: 10.1002/cncr.29065] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2014] [Revised: 08/05/2014] [Accepted: 08/15/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND Patients 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. METHODS Patients 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. RESULTS Patients who underwent surgery were younger (P=.02) and had more appendicular tumors (P<.001). Compared with surgery, radiation had higher unadjusted risks of any event (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.18-2.44), death (HR, 1.84; 95% CI, 1.18-2.85), and local failure (HR, 2.57; 95% CI, 1.37-4.83). On multivariate analysis, compared with surgery, radiation had a higher risk of local failure (HR, 2.41; 95% CI, 1.24-4.68), although there were no significant differences in EFS (HR, 1.42; 95% CI, 0.94-2.14), overall survival (HR, 1.37; 95% CI, 0.83-2.26), or distant failure (HR, 1.13; 95% CI, 0.70-1.84) between local control groups. CONCLUSIONS In this large group of similarly treated patients, choice of the mode of local control was not related significantly to EFS, overall survival, or distant failure, although the risk of local failure was greater for radiation compared with surgery. These data support surgical resection when appropriate, whereas radiotherapy remains a reasonable alternative in selected patients.
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Affiliation(s)
- Steven G DuBois
- Department of Pediatrics, University of California-San Francisco (UCSF) School of Medicine and UCSF Benioff Children's Hospital, San Francisco, California
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27
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Dauda MA, Yakubu D, Mandong BM, Ojo EO. Sarcomas in Nigerian Children in Jos North Central Nigeria. AFRICAN JOURNAL OF MEDICINE AND MEDICAL SCIENCES 2014; 43:37-44. [PMID: 26689374 PMCID: PMC4682882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
BACKGROUND There is a growing concern about childhood sarcomas, with recent studies suggesting an increase in the frequency of childhood sarcomas in sub-Saharan Africa. This study was carried out to determine the pattern of childhood sarcomas in Jos, North Central Nigeria and to compare the data obtained with other previous related studies. METHODS Review of the Jos University Teaching Hospital cancer registry from January 2001 to December 2010. Data of all children (0-15 years) in the data base were retrieved for analysis. RESULTS Two hundred and ten histological diagnosis of malignancies were made in children over the period, with 81 cases (39%) being childhood Sarcomas. The sarcomas occurred predominantly in males (54%) with male/female ratio of 2:1. The minimum age was 2 months and the maximum age was 15 years. Soft tissue sarcoma (STS) was the most predominant group which accounted for 73 cases (90%) of all sarcomas seen. Rhabdomyosarcoma (RMS) was the most common STS, it accounted for 65 cases (89%) of the STS and 80% of all the sarcomas. This is followed by Kaposi Sarcoma (KS) accounting for 6.9% of STS. There were 8 cases of Osteosarcoma which accounted for 10% of all the sarcomas. Embryonal RMS predominated in the very young children while all other sarcomas affected the older children. Extremities were the sites of predilection for most of the sarcomas (36%). Seventeen (17) cases of the RMS were of superior prognostic group, 34 (54%) were of intermediate prognostic group while 24 cases (37%) were of poor prognostic group. CONCLUSION Childhood sarcomas are common in our environment and RMS is the single most common sarcoma while the non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) are rare.
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28
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Lee JS, DuBois SG, Boscardin WJ, Wustrack RL, Goldsby RE. Secondary malignant neoplasms among children, adolescents, and young adults with osteosarcoma. Cancer 2014; 120:3987-93. [DOI: 10.1002/cncr.28936] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Revised: 06/12/2014] [Accepted: 06/16/2014] [Indexed: 11/11/2022]
Affiliation(s)
- Jean S. Lee
- Department of Pediatrics, Benioff Children's Hospital; University of California at San Francisco; San Francisco California
| | - Steven G. DuBois
- Department of Pediatrics, Benioff Children's Hospital; University of California at San Francisco; San Francisco California
| | - W. John Boscardin
- Department of Biostatistics and Epidemiology; University of California at San Francisco School of Medicine; San Francisco California
| | - Rosanna L. Wustrack
- Department of Orthopedic Surgery; University of California at San Francisco School of Medicine; San Francisco California
| | - Robert E. Goldsby
- Department of Pediatrics, Benioff Children's Hospital; University of California at San Francisco; San Francisco California
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29
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Choi DK, Helenowski I, Hijiya N. Secondary malignancies in pediatric cancer survivors: perspectives and review of the literature. Int J Cancer 2014; 135:1764-73. [PMID: 24945137 DOI: 10.1002/ijc.28991] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Accepted: 02/13/2014] [Indexed: 02/03/2023]
Abstract
With continuing improvements in the successful treatment of pediatric malignancies, long term survivors of pediatric cancers and their providers are faced with new oncologic issues regarding long-term morbidities. As pediatric cancer survivors have matured into adulthood, the development of secondary malignancies has become a significant issue for these patients. Whether a consequence of treatment for the patient's original cancer, such as chemotherapy, ionizing radiation, or hematopoietic stem cell transplantation, secondary malignancies now present patients and providers with new challenges regarding treatment, surveillance and counseling. We review the major risk factors for secondary malignancies in pediatric cancer survivors, with particular emphasis on important molecular and cytogenetic risk factors, both inherited and acquired. We conclude with a discussion of recommendations for surveillance and counseling of these patients.
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Affiliation(s)
- Daniel K Choi
- Division of Hematology/Oncology/Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
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30
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Henderson TO, Ness KK, Cohen HJ. Accelerated aging among cancer survivors: from pediatrics to geriatrics. Am Soc Clin Oncol Educ Book 2014:e423-e430. [PMID: 24857133 DOI: 10.14694/edbook_am.2014.34.e423] [Citation(s) in RCA: 110] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
There are almost 14-million cancer survivors in the United States and the population is growing. Almost two-thirds of these survivors are age 65 or older. Given this, it is imperative to understand the impact of cancer and its therapies on the aging process. Childhood cancer survivors, diagnosed with cancer at age 21 or younger, particularly females, have rates of frailty similar to rates in older adults. This phenomenon appears to start early, suggesting an aging phenotype. Frailty among childhood cancer survivors increases risk for chronic disease and mortality. Adults diagnosed with cancer are faced with the effects of cancer and its therapies compounded by the issues of multiple morbidities that occur with the typical aging process. Intervention studies to date have focused on smoking cessation, diet, and exercise, as well as improving rates of late effects surveillance in childhood cancer survivors. No intervention studies have specifically addressed the issue of frailty or multiple morbidities in cancer survivors. Concerted efforts must continue to create and disseminate survivorship care plans to all cancer survivors.
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Affiliation(s)
- Tara O Henderson
- From the University of Chicago Comer Children's Hospital, Chicago, IL; St. Jude Children's Research Hospital, Memphis, TN; Duke University, Durham, NC
| | - Kirsten K Ness
- From the University of Chicago Comer Children's Hospital, Chicago, IL; St. Jude Children's Research Hospital, Memphis, TN; Duke University, Durham, NC
| | - Harvey Jay Cohen
- From the University of Chicago Comer Children's Hospital, Chicago, IL; St. Jude Children's Research Hospital, Memphis, TN; Duke University, Durham, NC
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31
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Kasahara Y, Iwabuchi H, Takachi T, Hosokai R, Yoshida S, Imamura M, Watanabe A, Umezu H, Hotta T, Ogose A, Imai C. Alveolar rhabdomyosarcoma after treatment of osteosarcoma. Pediatr Int 2013; 55:527-30. [PMID: 23910806 DOI: 10.1111/ped.12070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2011] [Revised: 08/31/2012] [Accepted: 02/01/2013] [Indexed: 12/01/2022]
Abstract
Secondary rhabdomyosarcoma (RMS) after treatment of osteosarcoma (OS) is rare. Reported here is the case of a metachronous RMS in the nasal cavity, developing 12 years after successful treatment of non-metastatic OS. The patient was diagnosed as having OS of the femur at 2 years of age. Chemotherapy for OS included doxorubicin (cumulative dose, 488 mg/m(2) ). No radiotherapy was given. There was no family history suggestive of cancer predisposition syndrome. At 14 years of age, alveolar RMS was diagnosed on histopathology. PAX3-FKHR fusion transcripts were detected on reverse transcription-polymerase chain reaction. Germline TP53 mutation was not seen on standard DNA sequencing. The occurrence of secondary sarcomas, in the Children's Cancer Survivor study conducted in North America, has been associated with high cumulative doses of anthracyclines, which may also have played a role in the development of RMS in the present case. In the future, novel molecular technologies might uncover genetic cancer predisposition in patients with metachronous cancers.
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Affiliation(s)
- Yasushi Kasahara
- Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
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Ouyang ZX, Li XA. Inhibitory effects of tamoxifen and doxorubicin, alone and in combination, on the proliferation of the MG63 human osteosarcoma cell line. Oncol Lett 2013; 6:970-976. [PMID: 24137447 PMCID: PMC3796417 DOI: 10.3892/ol.2013.1487] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Accepted: 07/10/2013] [Indexed: 12/02/2022] Open
Abstract
The present study aimed to compare the combined effect of tamoxifen (TAM) and doxorubicin (ADM) with the individual effects of TAM and ADM alone on the MG63 human osteosarcoma cell line. Estrogen receptor (ER) expression was detected in the MG63 cells using reverse transcription PCR. The morphological changes during the inhibition of cell growth were observed using an inverted microscope and a 3-(4, 5-dimethy1-2-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) colorimetric assay following the individual or combined addition of TAM and ADM. ERα and ERβ expression was detected in the MG63 cells. The typical apoptotic cell morphology was observed in all groups, with the exception of the control group. The MTT colorimetric analysis demonstrated that the rate of inhibition of cell proliferation in the combination group was significantly increased compared with that in the other groups (P<0.05). ERα and ERβ expression was detected in the MG63 human osteosarcoma cells. TAM and ADM alone were able to inhibit cell proliferation. The combination of TAM and ADM significantly enhanced the inhibitory effect, partly through the enhanced sensitivity of the cells to ADM by TAM, which caused the inhibition of cell proliferation and apoptosis.
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Affiliation(s)
- Zheng-Xiao Ouyang
- Department of Orthopaedics, Hunan Provincial Tumor Hospital and Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
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33
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Applebaum MA, Goldsby R, Neuhaus J, DuBois SG. Clinical features and outcomes in patients with secondary Ewing sarcoma. Pediatr Blood Cancer 2013; 60:611-5. [PMID: 22847990 PMCID: PMC3488141 DOI: 10.1002/pbc.24251] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2012] [Accepted: 06/13/2012] [Indexed: 12/20/2022]
Abstract
BACKGROUND Ewing sarcoma (EWS) is rarely diagnosed as a second malignancy. We sought to describe a cohort of patients with secondary EWS and investigate if patient characteristics and survival differ between patients with secondary and primary EWS. PROCEDURE Patients with EWS or peripheral primitive neuroectodermal tumor (PNET) reported to the Surveillance, Epidemiology, and End Results Program (SEER) database from 1973 to 2008 were evaluated based on primary or secondary tumor sequence. Overall survival was estimated by Kaplan-Meier methods and evaluated using the log-rank test. Competing risk analysis was used to describe risk of death due to malignancy rather than other causes. RESULTS Fifty-eight cases of secondary EWS were reported, accounting for 2.1% of all EWS cases. The median latency from primary malignancy to secondary EWS was 64 months (range 1-282 months). 12.1% of patients with secondary EWS received radiation to the site of secondary tumor during therapy for their primary malignancy. Patients with secondary EWS were more likely to have axial tumors (77.4% vs. 62.5%; P = 0.03) and smaller tumors (75.0% vs. 48.2% <8 cm; P = 0.001). Five-year overall survival from diagnosis was inferior for patients with secondary compared to primary EWS (34.3% vs. 52.2%; P = 0.002). However, patients with secondary tumors were less likely than those with primary EWS to die from their malignancy [hazard ratio 0.44; 95% confidence interval (CI) 0.23-0.85]. CONCLUSIONS Secondary EWS accounts for a minority of cases of EWS. Tumor size and site and patient survival differ among patients with primary and secondary EWS.
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Affiliation(s)
- Mark A. Applebaum
- Department of Pediatrics, University of California, San Francisco School of Medicine, San Francisco, California
| | - Robert Goldsby
- Department of Pediatrics, University of California, San Francisco School of Medicine, San Francisco, California
| | - John Neuhaus
- Department of Biostatistics, University of California, San Francisco School of Medicine, San Francisco, California
| | - Steven G. DuBois
- Department of Pediatrics, University of California, San Francisco School of Medicine, San Francisco, California
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34
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Marks AM, Packer RJ. A review of secondary central nervous system tumors after treatment of a primary pediatric malignancy. Semin Pediatr Neurol 2012; 19:43-8. [PMID: 22641075 DOI: 10.1016/j.spen.2012.02.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Despite remarkable strides in the treatment of pediatric malignancies over the last 50 years, long-lasting sequelae and secondary malignancies continue to plague this population. This article reviews the incidence, diagnosis, and etiology of secondary central nervous system tumors in the setting of a history of primary pediatric malignancy. Particular attention is paid to central nervous system tumors presenting after treatment of leukemia and primary brain tumors, as well as the role of treatment and underlying cancer predisposition syndromes in the risk of developing these secondary tumors.
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Affiliation(s)
- Asher M Marks
- Department of Hematology/Oncology, Children's National Medical Center, Washington, DC, USA
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35
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Li X, Guo Z, Sheng Q, Xue X, Liang X. Sequential elution of multiply and singly phosphorylated peptides with polar-copolymerized mixed-mode RP18/SCX material. Analyst 2012; 137:2774-6. [DOI: 10.1039/c2an35247h] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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36
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Termuhlen AM, Tersak JM, Liu Q, Yasui Y, Stovall M, Weathers R, Deutsch M, Sklar CA, Oeffinger KC, Armstrong G, Robison LL, Green DM. Twenty-five year follow-up of childhood Wilms tumor: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer 2011; 57:1210-6. [PMID: 21384541 PMCID: PMC4634648 DOI: 10.1002/pbc.23090] [Citation(s) in RCA: 133] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2010] [Accepted: 01/24/2011] [Indexed: 11/11/2022]
Abstract
BACKGROUND Treatment cures over 90% of children with Wilms tumor (WT) who subsequently risk late morbidity and mortality. This study describes the 25-year outcomes of 5-year WT survivors in the Childhood Cancer Survivor Study (CCSS). PROCEDURE The CCSS, a multi-institutional retrospective cohort study, assessed WT survivors (N = 1,256), diagnosed 1970-1986, for chronic health conditions, health status, health care utilization, socioeconomic status, subsequent malignant neoplasms (SMNs), and mortality compared to the US population and a sibling cohort (N = 4,023). RESULTS The cumulative incidence of all and severe chronic health conditions was 65.4% and 24.2% at 25 years. Hazard ratios (HR) were 2.0, 95% confidence interval (CI) 1.8-2.3 for grades 1-4 and 4.7, 95%CI 3.6-6.1 for grades 3 and 4, compared to sibling group. WT survivors reported more adverse general health status than the sibling group (prevalence ratio [PR] 1.7; 95%CI 1.2-2.4), but mental health status, socioeconomic outcome, and health care utilization were similar. The cumulative incidence of SMN was 3.0% (95%CI 1.9-4.0%) and of mortality was 6.1% (95%CI 4.7-7.4%). Radiation exposure increased the likelihood of congestive heart failure (CHF) (no doxorubicin-HR 6.6; 95%CI 1.6-28.3; doxorubicin ≤ 250 mg/m(2) -HR 13.0; 95%CI 1.9-89.7; doxorubicin >250 mg/m(2) -HR 18.3; 95%CI 3.8-88.2), SMN (standardized incidence ratio [SIR] 9.0; 95%CI 3.9-17.7 with and 4.9; 95%CI 1.8-10.6 without doxorubicin) and death. CONCLUSION Long-term survivors of WT treated from 1970 to 1986 are at increased risk of treatment related morbidity and mortality 25 years from diagnosis.
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Affiliation(s)
- Amanda M. Termuhlen
- Department of Pediatrics, University of Southern California, Miller Children's Hospital, Long Beach CA
| | - Jean M. Tersak
- Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - Qi Liu
- Department of Public Health Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Yutaka Yasui
- Department of Public Health Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Marilyn Stovall
- Department of Radiation Physics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Rita Weathers
- Department of Radiation Physics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Melvin Deutsch
- Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Charles A. Sklar
- Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Kevin C. Oeffinger
- Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Greg Armstrong
- Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN
| | - Leslie L. Robison
- Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN
| | - Daniel M. Green
- Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN
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Hagleitner MM, Hoogerbrugge PM, van der Graaf WTA, Flucke U, Schreuder HWB, te Loo DMWM. Age as prognostic factor in patients with osteosarcoma. Bone 2011; 49:1173-7. [PMID: 21893224 DOI: 10.1016/j.bone.2011.08.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2011] [Revised: 08/11/2011] [Accepted: 08/15/2011] [Indexed: 11/28/2022]
Abstract
Age at diagnosis is a well known prognostic factor in many different malignancies; its significance for patients with osteosarcoma is however controversial. To gain more insight in the prognostic role of age, we performed a retrospective study at our institute. We included 102 patients with de-novo osteosarcoma and formed three age groups to evaluate age specific survival rates: ≤ 14 years, 15-19 years and 20-40 years. Differences in outcome between patients aged 15-19 years treated at either the pediatric department or the adult department of oncology were evaluated. The 5-year overall survival rate (OSR) of the whole population was 53.5%±1.5%. OSR of 70.6%±0.8% was seen in patients ≤ 14 years old, 52.5%±1.1% in patients 15-19 years old and 33.3%±0.9% in the patients aged 20-40 years (p=0.01). Significant differences were observed with regard to stage at presentation (higher in older age groups), size of the tumor (larger in younger age groups) and histological response (more good responders in younger age groups). No significant difference was seen between outcomes of patients aged 15-19 years treated at the pediatric or adult oncology department. In conclusion, younger patients have a significantly better outcome than older patients.
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Affiliation(s)
- Melanie M Hagleitner
- Department of Pediatric Hematology and Oncology, Radboud University Nijmegen Medical Centre, 6500HB Nijmegen, The Netherlands.
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38
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Affiliation(s)
- Abby M Allen
- University of Alabama at Birmingham, Birmingham, AL 35233, USA.
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39
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Maule M, Scélo G, Pastore G, Brennan P, Hemminki K, Olsen JH, Tracey E, Pukkala E, Weiderpass E, Brewster DH, Tamaro S, Chia KS, Pompe-Kirn V, Kliewer EV, Tonita JM, Martos C, Jonasson JG, Merletti F, Boffetta P. Second malignancies after childhood noncentral nervous system solid cancer: Results from 13 cancer registries. Int J Cancer 2011; 129:1940-52. [DOI: 10.1002/ijc.26135] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2010] [Accepted: 03/28/2011] [Indexed: 11/06/2022]
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40
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Nagarajan R, Kamruzzaman A, Ness KK, Marchese VG, Sklar C, Mertens A, Yasui Y, Robison LL, Marina N. Twenty years of follow-up of survivors of childhood osteosarcoma: a report from the Childhood Cancer Survivor Study. Cancer 2011; 117:625-34. [PMID: 20922787 PMCID: PMC3025070 DOI: 10.1002/cncr.25446] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2009] [Revised: 04/13/2010] [Accepted: 04/14/2010] [Indexed: 11/11/2022]
Abstract
BACKGROUND Osteosarcoma survivors have received significant chemotherapy and have undergone substantial surgeries. Their very long-term outcomes (20 year) are reported here. METHODS The authors assessed the long-term outcomes of 733 5-year survivors of childhood osteosarcoma diagnosed from 1970 to 1986 to provide a comprehensive evaluation of medical and psychosocial outcomes for survivors enrolled in the Childhood Cancer Survivor Study (CCSS). Outcomes evaluated included overall survival, second malignant neoplasms (SMNs), recurrent osteosarcoma, chronic health conditions, health status (general and mental health and functional limitations), and psychosocial factors. Outcomes of osteosarcoma survivors were compared with general-population statistics, other CCSS survivors, and CCSS siblings. RESULTS Survivors had a mean follow-up of 21.6 years. The overall survival of children diagnosed with osteosarcoma who survived 5 years at 20 years from original diagnosis was 88.6% (95% confidence interval [CI], 86.6%-90.5%). The cumulative incidence of SMNs at 25 years was 5.4%, with a standardized incidence ratio of 4.79 (95% CI, 3.54-6.33; P<.01). Overall, 86.9% of osteosarcoma survivors experienced at least 1 chronic medical condition, and >50% experienced ≥2 conditions. Compared with survivors of other cancers, osteosarcoma survivors did not differ in their reported general health status (odds ratio [OR], 0.9; 95% CI, 0.7-1.2), but were more likely to report an adverse health status in at least 1 domain (OR, 1.9; 95% CI, 1.6-2.2), with activity limitations (29.1%) being the most common. CONCLUSIONS Childhood osteosarcoma survivors in this cohort did relatively well, considering their extensive treatment, but are at risk of experiencing chronic medical conditions and adverse health status. Survivors warrant life-long follow-up.
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Affiliation(s)
- Rajaram Nagarajan
- Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
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Abstract
Ewing's sarcoma (ES) is a rare tumor that is most common in children and young adults. Late effects of ES therapy include second cancers, a tragic outcome for survivors of such a young age. This paper will explore the frequencies and types of malignancies that occur after ES. Additionally, it will review how second malignancies have changed with the shift in treatment from high-dose radiation to chemotherapy regimens including alkylators and epipodophyllotoxins. The risk of additional cancers in ES survivors will also be compared to survivors of other childhood cancers. Finally, the possible genetic contribution to ES and second malignancies will be discussed.
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VEGF blockade decreases the tumor uptake of systemic oncolytic herpes virus but enhances therapeutic efficacy when given after virotherapy. Gene Ther 2010; 17:922-9. [PMID: 20508601 PMCID: PMC2900405 DOI: 10.1038/gt.2010.82] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Effective therapies for metastatic sarcomas remain elusive. Oncolytic viruses have shown promise as anticancer agents, but their access to metastatic sites following systemic delivery is low. As systemic delivery of small-molecule chemotherapy is enhanced by previous treatment with antiangiogenic agents because of changes in intravascular-to-tumor interstitial pressure, we sought to determine whether antiangiogenic pretreatment increases the antitumor efficacy of systemic virotherapy by increasing virus uptake into tumor. Virus biodistribution and antitumor effects were monitored in tumor-bearing mice given antihuman vascular endothelial growth factor (VEGF) or antimouse VEGFR2 before or after an intravenous (i.v.) injection of virus. Without pretreatment, the average virus titers in the tumor samples amplified 1700-fold over 48 h but were undetectable in other organs. After antiangiogenic treatment, average virus titers in the tumor samples were unchanged or in some cases decreased up to 100-fold. Thus, antiangiogenic pretreatment failed to improve the tumor uptake of systemic oncolytic herpes simplex virus (oHSV), in contrast to previously reported enhanced uptake of small molecules. Superior tumor control because of the combined effects of virus and anti-VEGF was seen most dramatically when anti-VEGF was given after virus. Our data suggest that i.v. oHSV can treat distant sites of disease and can be enhanced by antiangiogenic therapy, but only when given in the proper sequence.
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Current world literature. Curr Opin Pediatr 2010; 22:117-26. [PMID: 20068414 DOI: 10.1097/mop.0b013e32833539b5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Madanat-Harjuoja LMS, Malila N, Lähteenmäki P, Pukkala E, Mulvihill JJ, Boice JD, Sankila R. Risk of cancer among children of cancer patients - a nationwide study in Finland. Int J Cancer 2010; 126:1196-205. [PMID: 19728329 DOI: 10.1002/ijc.24856] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Cancer treatments have the potential to cause germline mutations that might increase the risk of cancer in the offspring of former cancer patients. This risk was evaluated in a population-based study of early onset cancer patients in Finland. Using the nationwide registry data, 26,331 children of pediatric and early onset cancer patients (diagnosed under age 35 between 1953 and 2004) were compared to 58,155 children of siblings. Cancer occurrence among the children was determined by linkage with the cancer registry, and the standardized incidence ratios (SIRs) were calculated comparing the observed number of cancers with that expected, based on rates in the general population of Finland. Among the 9,877 children born after their parent's diagnosis, cancer risk was increased (SIR 1.67; 95% CI 1.29-2.12). However, after removing those with hereditary cancer syndromes, this increase disappeared (SIR 1.03; 95% CI 0.74-1.40). The overall risk of cancer among the offspring of siblings (SIR 1.07; 95% CI 0.94-1.21) was the same as among the offspring of the patients with non hereditary cancer. Risk of cancer in offspring, born before their parents cancer diagnosis, was elevated (SIR 1.37, 95% CI 1.20-1.54), but removing hereditary syndromes resulted in a diminished and nonsignificant association (SIR 1.08, 95% CI 0.93-1.25). This study shows that offspring of cancer patients are not at an increased risk of cancer except when the patient has a cancer-predisposing syndrome. These findings are directly relevant to counseling cancer survivors with regard to family planning.
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Federman N, Bernthal N, Eilber FC, Tap WD. The multidisciplinary management of osteosarcoma. Curr Treat Options Oncol 2009; 10:82-93. [PMID: 19238553 DOI: 10.1007/s11864-009-0087-3] [Citation(s) in RCA: 101] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2009] [Accepted: 01/20/2009] [Indexed: 02/06/2023]
Abstract
Patients with suspected or confirmed osteosarcoma should be evaluated and treated at a comprehensive cancer center within a multidisciplinary sarcoma program that includes pediatric, medical and radiation oncologists, orthopedic and surgical oncologists, musculoskeletal pathologists, and radiologists. Successful treatment involves proper diagnosis, neoadjuvant and adjuvant multi-agent chemotherapy, and aggressive surgery with an emphasis toward limb-preserving procedures. Treatment of osteosarcoma should be undertaken within the framework of large cooperative group clinical trials for children, adolescents, and adults. Patients treated with osteosarcoma should be followed closely both for recurrence of disease and for development of late effects of the treatment of their cancer. The treatment of metastatic, recurrent and/or refractory disease is more controversial. Despite advances in systemic treatment, surgical technique, and supportive care, the overall outcome is still poor.
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Affiliation(s)
- Noah Federman
- Division of Pediatric Hematology/Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
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