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1.  Breast Imaging in Women Previously Irradiated for Hodgkin Lymphoma 
American journal of clinical oncology  2014;10.1097/COC.0000000000000025.
Women treated with mantle irradiation for Hodgkin Lymphoma (HL) are at an increased risk of developing breast cancer (BC). Current guidelines recommend screening breast magnetic resonance imaging (MRI) as an adjunct to mammography (M) in these patients. There are limited data, however, as to the impact of breast MRI on cancer detection rates. The aim of the current study is to evaluate the use of breast MRI in in survivors of HL treated and followed at a single institution.
We retrospectively reviewed 980 female patients treated with mantle irradiation for HL between 1961 and 2008. Records were reviewed to determine age at radiotherapy treatment, radiotherapy dose, breast imaging (including M and breast MRI), biopsy results if applicable, and incidence of BC.
118 patients had breast imaging performed at our institution. Median age at HL diagnosis was 28 years (range 10–69). Median radiotherapy dose was 36 Gy (range 20–45 Gy). Seventy-nine patients (67%) underwent M screening only, 1 (1%) breast MRI only, and 38 (32%) both M and breast MRI. Of these 38, 19 (50%) underwent 54 screening MRI studies (range per patient = 1–8), 13 (34%) underwent preoperative MRI for workup of BC, and 6 (16%) initiated screening MRI of the contralateral breast only after diagnosed with BC. Fifty-nine biopsies were performed: 47 were prompted by suspicious M findings only, 10 by palpable findings on physical examination, and 2 by suspicious breast MRI findings. Of the 47 biopsies prompted by M, 24 revealed malignant disease while 23 proved to be benign. All 10 biopsies performed by palpation were malignant. Both biopsies prompted by MRI findings were benign. With M, there were 34 true positive (TP) findings in 32 patients, 23 false positive (FP) findings, and 1 false negative (FN) finding. With screening MRI, there were 2 FP findings, one FN finding, and no TP findings.
The role of screening breast MRI in women previously irradiated for HL is evolving. Further education of patients and physicians is important to increase awareness of more sensitive breast cancer screening modalities in this high-risk population. Future studies are necessary to determine the appropriate integration of screening breast MRI into the ongoing follow up of these women.
PMCID: PMC4079764  PMID: 24390271
Hodgkin Lymphoma (HL); Breast Imaging; Breast Magnetic Resonance Imaging (MRI)
Post-operative radiation therapy (RT) is recommended for patients with rhabdomyosarcoma (RMS) having microscopic disease. Sometimes RT dose/volume is reduced or omitted in an attempt to avoid late effects, particularly in young children. We reviewed operative bed recurrences to determine if non-compliance with RT protocol guidelines, influenced local-regional control.
All operative bed recurrences among 695 Group II RMS patients on IRS I-IV were reviewed for deviation from RT protocol. Major/minor dose deviation was defined as > 10% or 6–10% of the prescribed dose (40–60 Gy), respectively. Major/minor volume deviation was defined as tumor excluded from the RT field or treatment volume not covered by the specified margin (pre-operative tumor volume and 2–5 cm margin), respectively. No RT was a major deviation.
Forty-six of 83 (55%) patients with operative bed recurrences did not receive the intended RT (39 major and 7 minor deviations). RT omission was the most frequent RT protocol deviation (19/46 – 41%), followed by dose (17/46 – 37%), volume (9/46 – 20%), dose and volume deviation (1/46 – 2%). Only 7 operative bed recurrences occurred on IRS IV (5% local-regional failure) with only 3 RT protocol deviations. 63 (76%) patients with a recurrence died of disease despite retrieval therapy, including 13 of 19 non-irradiated children.
Over half the operative bed recurrences were associated with non-compliance; omission of RT was the most common protocol deviation. Three-fourths of children die when local-regional disease is not controlled, emphasizing the importance of RT in Group II RMS.
PMCID: PMC4462166  PMID: 20646841
Rhabdomyosarcoma; Radiation Therapy; Group II; Protocol Compliance; Recurrence
3.  Curry-assisted diagnosis in the rheumatology clinic 
Oxford Medical Case Reports  2015;2015(6):297-299.
We report five cases of glucocorticoid-responsive mouth symptoms in polymyalgia rheumatica/giant cell arteritis (GCA); three cases of tongue pain exacerbated by hot/spicy food, a case of scalp pain made worse by eating hot/spicy food and a case of sore tongue as a presenting feature of GCA. These cases emphasize the importance of asking about mouth symptoms and changes in taste when evaluating patients with suspected GCA.
PMCID: PMC4455788  PMID: 26069840
4.  Recent advances in understanding and managing rhabdomyosarcoma 
F1000Prime Reports  2015;7:59.
Rhabdomyosarcoma is the most common childhood soft tissue sarcoma and the fourth most common pediatric solid tumor. For most patients, treatment consists of a multimodality approach, including chemotherapy, surgery, and/or radiotherapy. To guide treatment, patients with rhabdomyosarcoma are risk stratified based on a number of factors. These factors include clinical group, which depends largely on the extent of resection and nodal involvement, and stage, which takes into account tumor size, invasion, nodal involvement, and disease site. Histology of the tumor and age at diagnosis are also factored into risk stratification. Recent advances in understanding the biology of the disease have allowed for the further sub-classification of rhabdomyosarcoma. In addition, elucidation of additional clinical features associated with poor prognosis has allowed for better understanding of risk and provides more clarity regarding those patients who require more intensive therapy. Many areas of active investigation are ongoing, including the following: further delineation of the biological underpinnings of the various disease subtypes with the possibility of molecularly targeted therapy; a better understanding of clinical risk factors, including the evaluation and management of potentially involved lymph nodes; determination of the appropriate role of post-treatment imaging and assessment of response to therapy; and incorporation of advanced radiotherapeutic techniques, including conformal intensity-modulated photon and proton therapy.
PMCID: PMC4447051  PMID: 26097732
5.  RELAPSE AFTER TREATMENT OF PEDIATRIC HODGKIN LYMPHOMA: Outcome and Role of Surveillance After End of Therapy 
Pediatric blood & cancer  2013;60(9):1458-1463.
The outcome of treatment for pediatric Hodgkin lymphoma (HL) is excellent using chemotherapy and radiation. However, a minority of patients will relapse after treatment, but additional therapy achieves durable second remission in many cases. The optimal surveillance strategy after modern therapy for HL has not been well-defined.
We reviewed the outcomes of pediatric patients with HL treated between 1990 and 2006 to determine the primary event that led to the detection of relapse. We determined the probability of relapse detection by routine follow-up procedures, including history, physical examination, laboratory tests, and imaging, and determined the impact of each of these screening methods on the likelihood of survival after relapse.
Relapse occurred in 64 of 402 evaluable patients (15.9%) at a median of 1.7 years from the time of diagnosis. The majority of relapses (60%) were diagnosed at a routine visit, and patient complaint was the most common initial finding that led to a diagnosis of relapse (47% of relapses). An abnormal finding on physical examination was the primary event in another 17% of relapses, and imaging abnormalities led to the diagnosis in the remaining 36%. Laboratory abnormalities were never the primary finding. The method of detection of relapse and timing (whether detected at a routine visit or an extra visit) did not impact survival.
In pediatric Hodgkin lymphoma, most relapses are identified through history and physical examination. Frequent imaging of asymptomatic patients does not appear to impact survival and is probably not warranted.
PMCID: PMC4313350  PMID: 23677874
pediatric; childhood; Hodgkin lymphoma; relapse; surveillance; outcome
6.  The Cyclophosphamide Equivalent Dose as an Approach for Quantifying Alkylating Agent Exposure. A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2013;61(1):53-67.
Estimation of the risk of adverse long-term outcomes such as second malignant neoplasms and infertility often requires reproducible quantification of exposures. The method for quantification should be easily utilized and valid across different study populations. The widely used Alkylating Agent Dose (AAD) score is derived from the drug dose distribution of the study population and thus cannot be used for comparisons across populations as each will have a unique distribution of drug doses.
We compared the performance of the Cyclophosphamide Equivalent Dose (CED), a unit for quantifying alkylating agent exposure independent of study population, to the AAD. Comparisons included associations from three Childhood Cancer Survivor Study (CCSS)outcome analyses, receiver operator characteristic (ROC) curves and goodness of fit based on the Akaike’s Information Criterion (AIC).
The CED and AAD performed essentially identically in analyses of risk for pregnancy among the partners of male CCSS participants, risk for adverse dental outcomes among all CCSS participants and risk for premature menopause among female CCSS participants, based on similar associations, lack of statistically significant differences between the areas under the ROC curves and similar model fit values for the AIC between models including the two measures of exposure.
The CED is easily calculated, facilitating its use for patient counseling. It is independent of the drug dose distribution of a particular patient population, a characteristic that will allow direct comparisons of outcomes among epidemiological cohorts. We recommend the use of the CED in future research assessing cumulative alkylating agent exposure.
PMCID: PMC3933293  PMID: 23940101
late effects of cancer treatment; chemotherapy; long term survival; cyclophosphamide; alkylating agent; alkylating agent dose score
7.  Changes in Health Status Among Aging Survivors of Pediatric Upper and Lower Extremity Sarcoma: A Report from the Childhood Cancer Survivor Study (CCSS) 
To evaluate health status and participation restrictions in childhood extremity sarcoma survivors.
Members of the CCSS cohort with extremity sarcomas, who completed 1995, 2003 or 2007 questionnaires, were included.
Cohort Study of extremity sarcomas survivors.
Childhood cancer survivors diagnosed and treated between 1970–1986.
Not applicable.
Main Outcome Measure
Prevalence rates for poor health status in six domains and five sub-optimal social participation categories were compared by tumor location and treatment exposure with generalized estimating equations adjusted for demographic/personal factors and time/age.
Among 1094 survivors, median age at diagnosis 13 years (range 0–20), current age 33 years (range 10–53), 49% were male, 87.5% Caucasian, and 75% had lower extremity tumors. In adjusted models, when compared to upper extremity survivors, lower extremity survivors had increased risk of activity limitations but lower risk of not completing college. Compared to those who did not have surgery, those with limb-sparing (LS) and upper extremity amputations (UEA) were 1.6 times more likely to report functional impairment; while those with an above the knee amputation (AKA) were 1.9 times more likely to report functional impairment. Survivors treated with LS were 1.5 times more likely to report activity limitations. Survivors undergoing LS were more likely to report inactivity, incomes < $20,000, unemployment and no college degree. Those with UEA more likely reported inactivity, unmarried status and no college degree. Lastly, those with AKA more likely reported no college degree. Treatment with abdominal irradiation was associated with increased risk of poor mental health, functional impairment and activity limitation.
Treatment for lower extremity sarcomas is associated with a 50% increased risk for activity limitations; upper extremity survivors are at 10% higher risk for not completing college. Type of local control influences health status and participation restrictions. Both these outcomes decline with age.
PMCID: PMC3913046  PMID: 23380347
upper extremity; lower extremity; sarcoma; survivors; childhood cancer
8.  The zebrafish reference genome sequence and its relationship to the human genome 
Howe, Kerstin | Clark, Matthew D. | Torroja, Carlos F. | Torrance, James | Berthelot, Camille | Muffato, Matthieu | Collins, John E. | Humphray, Sean | McLaren, Karen | Matthews, Lucy | McLaren, Stuart | Sealy, Ian | Caccamo, Mario | Churcher, Carol | Scott, Carol | Barrett, Jeffrey C. | Koch, Romke | Rauch, Gerd-Jörg | White, Simon | Chow, William | Kilian, Britt | Quintais, Leonor T. | Guerra-Assunção, José A. | Zhou, Yi | Gu, Yong | Yen, Jennifer | Vogel, Jan-Hinnerk | Eyre, Tina | Redmond, Seth | Banerjee, Ruby | Chi, Jianxiang | Fu, Beiyuan | Langley, Elizabeth | Maguire, Sean F. | Laird, Gavin K. | Lloyd, David | Kenyon, Emma | Donaldson, Sarah | Sehra, Harminder | Almeida-King, Jeff | Loveland, Jane | Trevanion, Stephen | Jones, Matt | Quail, Mike | Willey, Dave | Hunt, Adrienne | Burton, John | Sims, Sarah | McLay, Kirsten | Plumb, Bob | Davis, Joy | Clee, Chris | Oliver, Karen | Clark, Richard | Riddle, Clare | Eliott, David | Threadgold, Glen | Harden, Glenn | Ware, Darren | Mortimer, Beverly | Kerry, Giselle | Heath, Paul | Phillimore, Benjamin | Tracey, Alan | Corby, Nicole | Dunn, Matthew | Johnson, Christopher | Wood, Jonathan | Clark, Susan | Pelan, Sarah | Griffiths, Guy | Smith, Michelle | Glithero, Rebecca | Howden, Philip | Barker, Nicholas | Stevens, Christopher | Harley, Joanna | Holt, Karen | Panagiotidis, Georgios | Lovell, Jamieson | Beasley, Helen | Henderson, Carl | Gordon, Daria | Auger, Katherine | Wright, Deborah | Collins, Joanna | Raisen, Claire | Dyer, Lauren | Leung, Kenric | Robertson, Lauren | Ambridge, Kirsty | Leongamornlert, Daniel | McGuire, Sarah | Gilderthorp, Ruth | Griffiths, Coline | Manthravadi, Deepa | Nichol, Sarah | Barker, Gary | Whitehead, Siobhan | Kay, Michael | Brown, Jacqueline | Murnane, Clare | Gray, Emma | Humphries, Matthew | Sycamore, Neil | Barker, Darren | Saunders, David | Wallis, Justene | Babbage, Anne | Hammond, Sian | Mashreghi-Mohammadi, Maryam | Barr, Lucy | Martin, Sancha | Wray, Paul | Ellington, Andrew | Matthews, Nicholas | Ellwood, Matthew | Woodmansey, Rebecca | Clark, Graham | Cooper, James | Tromans, Anthony | Grafham, Darren | Skuce, Carl | Pandian, Richard | Andrews, Robert | Harrison, Elliot | Kimberley, Andrew | Garnett, Jane | Fosker, Nigel | Hall, Rebekah | Garner, Patrick | Kelly, Daniel | Bird, Christine | Palmer, Sophie | Gehring, Ines | Berger, Andrea | Dooley, Christopher M. | Ersan-Ürün, Zübeyde | Eser, Cigdem | Geiger, Horst | Geisler, Maria | Karotki, Lena | Kirn, Anette | Konantz, Judith | Konantz, Martina | Oberländer, Martina | Rudolph-Geiger, Silke | Teucke, Mathias | Osoegawa, Kazutoyo | Zhu, Baoli | Rapp, Amanda | Widaa, Sara | Langford, Cordelia | Yang, Fengtang | Carter, Nigel P. | Harrow, Jennifer | Ning, Zemin | Herrero, Javier | Searle, Steve M. J. | Enright, Anton | Geisler, Robert | Plasterk, Ronald H. A. | Lee, Charles | Westerfield, Monte | de Jong, Pieter J. | Zon, Leonard I. | Postlethwait, John H. | Nüsslein-Volhard, Christiane | Hubbard, Tim J. P. | Crollius, Hugues Roest | Rogers, Jane | Stemple, Derek L.
Nature  2013;496(7446):498-503.
Zebrafish have become a popular organism for the study of vertebrate gene function1,2. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease3–5. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes6, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.
PMCID: PMC3703927  PMID: 23594743
9.  Risk of Salivary Gland Cancer Following Childhood Cancer: A Report From The Childhood Cancer Survivor Study 
To evaluate effects of radiotherapy, chemotherapy, cigarette smoking and alcohol consumption on the risk of second primary salivary gland cancer (SGC) in the Childhood Cancer Survivor Study (CCSS).
Standardized incidence ratios (SIR) and excess absolute risks (EAR) of SGC in the CCSS were calculated using incidence rates from Surveillance, Epidemiology and End Results population-based cancer registries. Radiation dose to the salivary glands was estimated based on medical records. Poisson regression was used to assess risks with respect to radiation dose, chemotherapy, smoking and alcohol consumption.
During the time period of the study, 23 cases of SGC were diagnosed among 14,135 childhood cancer survivors. The mean age at diagnosis of the first primary cancer was 8.3 years, and the mean age at SGC diagnosis was 24.8 years. The incidence of SGC was 39-fold higher in the cohort than in the general population (SIR=39.4; 95% CI: 25.4–7.8). The EAR was 9.8 per 100,000 person years. Risk increased linearly with radiation dose (excess relative risk=0.36 per gray; 95% CI: 0.06 to 2.5) and remained elevated after 20 years. There was no significant trend of increasing risk with increasing dose of chemotherapeutic agents, pack-years of cigarette smoking or alcohol intake.
While the cumulative incidence of SGC was low, childhood cancer survivors treated with radiation experienced significantly increased risk for at least two decades following exposure, and risk was positively associated with radiation dose. Results underscore the importance of long-term follow up of childhood cancer survivors for the development of new malignancies.
PMCID: PMC3500417  PMID: 22836059
10.  Absolute Risk Prediction of Second Primary Thyroid Cancer Among 5-Year Survivors of Childhood Cancer 
Journal of Clinical Oncology  2012;31(1):119-127.
We developed three absolute risk models for second primary thyroid cancer to assist with long-term clinical monitoring of childhood cancer survivors.
Patients and Methods
We used data from the Childhood Cancer Survivor Study (CCSS) and two nested case-control studies (Nordic CCSS; Late Effects Study Group). Model M1 included self-reported risk factors, model M2 added basic radiation and chemotherapy treatment information abstracted from medical records, and model M3 refined M2 by incorporating reconstructed radiation absorbed dose to the thyroid. All models were validated in an independent cohort of French childhood cancer survivors.
M1 included birth year, initial cancer type, age at diagnosis, sex, and past thyroid nodule diagnosis. M2 added radiation (yes/no), radiation to the neck (yes/no), and alkylating agent (yes/no). Past thyroid nodule was consistently the strongest risk factor (M1 relative risk [RR], 10.8; M2 RR, 6.8; M3 RR, 8.2). In the validation cohort, 20-year absolute risk predictions for second primary thyroid cancer ranged from 0.04% to 7.4% for M2. Expected events agreed well with observed events for each model, indicating good calibration. All models had good discriminatory ability (M1 area under the receiver operating characteristics curve [AUC], 0.71; 95% CI, 0.64 to 0.77; M2 AUC, 0.80; 95% CI, 0.73 to 0.86; M3 AUC, 0.75; 95% CI, 0.69 to 0.82).
We developed and validated three absolute risk models for second primary thyroid cancer. Model M2, with basic prior treatment information, could be useful for monitoring thyroid cancer risk in childhood cancer survivors.
PMCID: PMC3530689  PMID: 23169509
11.  Local Control with Reduced Dose Radiotherapy for Low-Risk Rhabdomyosarcoma: A Report from the Children’s Oncology Group D9602 Study 
To analyze the effect of reduced-dose radiotherapy on local control in children with low-risk rhabdomyosarcoma (RMS) treated on the COG D9602 study.
Methods and Materials
Patients with low-risk RMS were non-randomly assigned to receive radiotherapy doses dependent upon the completeness of surgical resection of the primary tumor (Clinical Group) and presence of involved regional lymph nodes. After resection most patients with microscopic residual and uninvolved nodes received 36 Gy, those with involved nodes received 41.4 to 50.4 Gy, and those with orbital primaries received 45 Gy. All patients received vincristine and dactinomycin, with cyclophosphamide added for patient subsets that had a higher risk of relapse in IRSG III and IV studies.
Three hundred forty-two patients were eligible for analysis; 172 received radiotherapy as part of their treatment. The cumulative incidence of local/regional failure was 15% in patients with microscopic involved margins when cyclophosphamide was not part of the treatment regimen and 0% when cyclophosphamide was included. The cumulative incidence of local/regional failure was 14% in patients with orbital tumors. Protocol-specified omission of radiotherapy in girls with Group IIA vaginal tumors (n=5) resulted in 3 failures for this group.
Compared to IRS III and IV results, reduced-dose radiotherapydoes not compromise local control for patients with microscopic tumor after surgical resection or with orbital primary tumors when cyclophosphamide is added to the treatment program. Girls with unresected non-bladder GU tumors require radiotherapy for post-surgical residual tumor in order to achieve optimal local control.
PMCID: PMC3305826  PMID: 22104356
Rhabdomyosarcoma; Radiotherapy; Low-risk; Local Control
12.  The effect of radiation therapy techniques (IMRT vs. 3DCRT) on outcome in patients with intermediate risk rhabdomyosarcoma enrolled in COG D9803—A report from Children’s Oncology Group 
To compare dosimetric parameters of intensity modulated radiation therapy (IMRT) and three-dimensional conformal radiation therapy (3DCRT) in patients with intermediate risk rhabdomyosarcoma (RMS), and to analyze their effect on local-regional control (LRC) and failure-free survival (FFS).
Methods and Materials
The study population consisted of 375 patients enrolled on Children’s Oncology Group protocol D9803, receiving IMRT or 3DCRT. Dosimetric data was collected from 179 patients with an available composite plan. Chi-square or Fisher’s exact tests were used to compare patient characteristics and radiotherapy (RT) parameters between the two groups. Time-to- event outcomes were estimated using the Kaplan-Meier method and compared using log-rank tests. Cox analysis was used to examine the effect of RT technique on FFS after adjusting for primary site and risk group.
The median follow-up time was 5.7 and 4.2 years for patients receiving 3DCRT and IMRT respectively. No differences in 5 year failure of LRC (18% vs. 15%) and FFS (72% vs. 76%) were noted between the two groups. Multivariate analysis revealed no association between RT technique and FFS. Patients with primary tumors in parameningeal (PM) sites were more likely to receive IMRT than 3DCRT. IMRT became more common during the later years of the study. Patients receiving IMRT were more likely to receive >50Gy, photon energy of ≤6MV, and >5 RT fields than those who received 3DCRT. There was improved coverage of the IMRT planning target volume (PTV) by the prescription dose compared to the 3DCRT with similar target dose heterogeneity.
IMRT improved target dose coverage when compared to 3DCRT, though an improvement in LRC or FFS could not be demonstrated in this population. Future studies comparing integral dose to non-target tissue and late RT toxicity between the two groups is warranted.
PMCID: PMC3154985  PMID: 21470795
Rhabdomyosarcoma; Intermediate risk; IMRT/3DCRT
13.  Risk Factors for Obesity in Adult Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Journal of Clinical Oncology  2011;30(3):246-255.
Many Childhood Cancer Survivor Study (CCSS) participants are at increased risk for obesity. The etiology of their obesity is likely multifactorial but not well understood.
Patients and Methods
We evaluated the potential contribution of demographic, lifestyle, treatment, and intrapersonal factors and self-reported pharmaceutical use to obesity (body mass index ≥ 30 kg/m2) among 9,284 adult (> 18 years of age) CCSS participants. Independent predictors were identified using multivariable regression models. Interrelationships were determined using structural equation modeling (SEM).
Independent risk factors for obesity included cancer diagnosed at 5 to 9 years of age (relative risk [RR], 1.12; 95% CI, 1.01 to 1.24; P = .03), abnormal Short Form–36 physical function (RR, 1.19; 95% CI, 1.06 to 1.33; P < .001), hypothalamic/pituitary radiation doses of 20 to 30 Gy (RR, 1.17; 95% CI, 1.05 to 1.30; P = .01), and paroxetine use (RR, 1.29; 95% CI, 1.08 to 1.54; P = .01). Meeting US Centers for Disease Control and Prevention guidelines for vigorous physical activity (RR, 0.90; 95% CI, 0.82 to 0.97; P = .01) and a medium amount of anxiety (RR, 0.86; 95% CI, 0.75 to 0.99; P = .04) reduced the risk of obesity. Results of SEM (N = 8,244; comparative fit index = 0.999; Tucker Lewis index = 0.999; root mean square error of approximation = 0.014; weighted root mean square residual = 0.749) described the hierarchical impact of the direct predictors, moderators, and mediators of obesity.
Treatment, lifestyle, and intrapersonal factors, as well as the use of specific antidepressants, may contribute to obesity among survivors. A multifaceted intervention, including alternative drug and other therapies for depression and anxiety, may be required to reduce risk.
PMCID: PMC3269951  PMID: 22184380
14.  Chemotherapy and thyroid cancer risk: A report from the Childhood Cancer Survivor Study 
While ionizing radiation is an established environmental risk factor for thyroid cancer, the effect of chemotherapy drugs on thyroid cancer risk remains unclear. We evaluated the chemotherapy-related risk of thyroid cancer in childhood cancer survivors, and the possible joint effects of chemotherapy and radiotherapy.
The study included 12,547 five-year survivors of childhood cancer diagnosed during 1970 through 1986. Chemotherapy and radiotherapy information was obtained from medical records, and radiation dose was estimated to the thyroid gland. Cumulative incidence and relative risks were calculated using life-table methods and Poisson regression. Chemotherapy-related risks were evaluated separately by categories of radiation dose.
Histologically confirmed thyroid cancer occurred in 119 patients. Thirty years after the first childhood cancer treatment, the cumulative incidence of thyroid cancer was 1.3% (95% CI, 1.0–1.6) for females and 0.6% (0.4–0.8) for males. Among patients with thyroid radiation doses ≤ 20 Gy, treatment with alkylating agents was associated with a significant 2.4-fold increased risk of thyroid cancer (95% CI, 1.3–4.5; P = 0.002). Chemotherapy risks decreased as radiation dose increased, with a significant decrease for patients treated with alkylating agents (P-trend = 0.03). No chemotherapy-related risk was evident for thyroid radiation doses >20 Gy.
Treatments with alkylating agents increased thyroid cancer risk, but only in the radiation dose range under 20 Gy, where cell sparing likely predominates over cell killing.
Our study adds to the evidence for chemotherapy agent-specific increased risks of thyroid cancer, which to date, were mainly thought to be related to prior radiotherapy.
PMCID: PMC3253948  PMID: 22028399
Thyroid cancer; second cancer; chemotherapy; radiation risk; cohort study
Maintaining excellent cure rates in pediatric Hodgkin lymphoma while minimizing toxicity.
To evaluate the efficacy of 4 cycles of vinblastine, Adriamycin, methotrexate, and prednisone (VAMP) in patients with favorable risk Hodgkin lymphoma who achieve a complete response after 2 cycles and do not receive radiotherapy.
Design, Setting, and Patients
Multi-institutional, unblinded, non-randomized single group phase II clinical trial to assess the need for radiotherapy based on early response to chemotherapy. Eighty-eight eligible patients with Hodgkin lymphoma stage I and II (< 3 nodal sites, no B symptoms, mediastinal bulk, or extranodal extension) enrolled between March 3, 2000 through December 9, 2008. Data frozen March 12, 2012.
Patients who achieved a complete response (n=47) after 2 cycles received no radiotherapy, and those with less than complete response (n=41) were given 25.5 Gy involved field radiotherapy.
Main Outcome Measures
2-year event-free survival was the primary outcome measure. A 2-year event-free survival of greater than 90% was desired, and 80% was considered to be unacceptably low.
Two-year event-free survival was 90.8% (95% CI, 84.7% – 96.9%); for patients who did not require radiotherapy it was 89.4% (95% CI, 80.8% – 98%), compared with 92.5% (95% CI, 84.5% – 100%) for those who did (P=0.61). Most common acute side effects were neuropathic pain (2% of patients), nausea/vomiting (3% of patients), neutropenia (32% of cycles), and febrile neutropenia (2% of patients). Nine patients (10%) were hospitalized 11 times (3% of cycles) for febrile neutropenia or non-neutropenic infection. Long term side effects after radiotherapy were asymptomatic compensated hypothyroidism in 9 patients (10%), osteonecrosis and moderate osteopenia in 2 patients each, subclinical pulmonary dysfunction in 12 patients (26%) and asymptomatic left ventricular dysfunction in 4 patients (5%). No second malignant neoplasms were observed.
Among patients with favorable risk Hodgkin lymphoma and a complete early response to chemotherapy, the use of limited therapy resulted in a high rate of 2-year EFS.
PMCID: PMC3526806  PMID: 22735430
16.  Local Control and Outcome in Children with Localized Vaginal Rhabdomyosarcoma: A Report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group 
Pediatric blood & cancer  2011;57(1):76-83.
The local control approach for girls with non-resected vaginal rhabdomyosarcoma (RMS) enrolled onto Intergroup RMS Study Group (IRSG)/Children’s Oncology Group (COG) studies has differed from that used at other primary sites by delaying or eliminating radiotherapy (RT) based on response achieved with chemotherapy and delayed primary resection.
We reviewed locoregional treatment and outcome for patients with localized RMS of the vagina on the two most recent COG low-risk RMS studies.
Forty-one patients with localized vaginal RMS were enrolled: 25 onto D9602 and 16 onto Subset 2 of ARST0331. Only four of the 39 with non-resected tumors received RT. The 5-year cumulative incidence of local recurrence was 26% on D9602, and the 2-year cumulative incidence of local recurrence was 43% on ARST0331. Increased local failure rates appeared to correlate with chemotherapy regimens that incorporated lower cumulative doses of cyclophosphamide. Estimated 5-year and 2-year failure free survival rates were 70% (95% CI: 46%, 84%) on D9602 and 42% (95% CI: 11%, 70%) on ARST0331, respectively.
To prevent local recurrence, we recommend a local control approach for patients with non-resected RMS of the vagina that is similar to that used for other primary sites and includes RT. We recognize that potential long-term effects of RT are sometimes unacceptable, especially for children less than 24 months of age. However, when making the decision to eliminate RT, the risk of local recurrence must be considered especially when using a chemotherapy regimen with a total cumulative cyclophosphamide dose of ≤ 4.8 g/m2.
PMCID: PMC3459820  PMID: 21298768
rhabdomyosarcoma; female; genitourinary; vagina; radiotherapy
17.  Rhabdomyosarcoma in Infants Less than One Year of Age: A Report from the Children’s Oncology Group 
Cancer  2011;117(15):3493-3501.
Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children, occurs less commonly in infants. Historically, poorer outcomes have been seen for infants diagnosed with RMS than for older children.
We analyzed the characteristics, treatment administered, outcomes, and patterns of failure for infants < 1 year of age with non-metastatic RMS who were treated with multimodal therapy on Intergroup Rhabdomyosarcoma Study (IRS) protocols IRS-IV, D9602, and D9803.
Seventy-six infants with non-metastatic RMS were treated on the 3 protocols from 1991 to 2005. Median age was 7.4 months (range 0.1–12 months). Tumor histology included embryonal (57%), alveolar (21%), and undifferentiated sarcoma/other (22%). Parameningeal primary site was less common in this infant cohort (3%) than for all patients treated on IRS-IV (25%). Estimated 5-year failure-free survival and overall survival (95% confidence intervals) are 57% (44%, 67%) and 76% (65%, 85%) for infants compared to 81% (79%, 83%) and 87% (85%, 89%) for ages 1–9 years. Twenty-three of 32 infants with treatment failure had local recurrence/progression with (n=3) or without (n=20) distant failure. The overall local failure rate was 30%. Median time to treatment failure was 13 months. FFS was worse for infants with Group III tumors and for those who received less than protocol recommended radiation therapy.
Infants with RMS appear to have worse outcomes than older patients, in part due to high rates of local failure. Concerns regarding morbidity in infants and reluctance to perform aggressive local control measures may lead to higher rates of local failure.
PMCID: PMC3140625  PMID: 21264837
pediatric; sarcoma; infant; radiotherapy; rhabdomyosarcoma
18.  Regional Nodal Involvement and Patterns of Spread Along In-transit Pathways in Children with Rhabdomyosarcoma of the Extremity: A Report from the Children's Oncology Group 
To evaluate the incidence and prognostic factors for regional failure, with attention to in-transit pathways of spread, in children with non-metastatic rhabdomyosarcoma (RMS) of the extremity.
Intergroup Rhabdomyosarcoma Studies III, IV-Pilot, and IV enrolled 226 children with RMS of the extremity. Failure at in-transit (epitrochlear/brachial and popliteal) and proximal (axillary/infraclavicular and inguinal/femoral) nodes were evaluated. Median follow-up for surviving patients is 10.4 years.
Fifty-five (24%) of 226 children had clinical or pathologic evidence of either in-transit and/or proximal lymph node involvement (LNI) at diagnosis. The actuarial 5-year risk of regional failure is 12%. The prognostic factors for poor regional control are female gender and LNI at diagnosis. In the 116 patients with a distal extremity primary tumor, 5% had in-transit LNI at diagnosis. The estimated 5-year incidences of in-transit and proximal nodal failure are 12% and 8%, respectively. The in-transit failure rate is 0% in patients who received radiation therapy and/or underwent lymph node sampling of the in-transit nodal site, but 15% in those who did not (p=0.07), although 5-year EFS did not differ between these two groups (64% vs. 55%, p=0.47).
The high incidence of regional involvement necessitates aggressive identification and treatment of regional lymph nodes in RMS of the extremity. In patients with distal extremity tumors, in-transit failures are as common as failures in more proximal regional sites. Patients who undergo complete lymph node staging with appropriate radiotherapy to the in-transit nodal site, if indicated, are at a slightly lower risk of in-transit failure.
PMCID: PMC3116031  PMID: 20542386
rhabdomyosarcoma; regional failure; in-transit nodes; radiation therapy; extremity
19.  Local therapy for rhabdomyosarcoma of the hands and feet: Is amputation necessary? A report from the Children's Oncology Group 
To evaluate the outcome of children with rhabdomyosarcoma (RMS) of the hand or foot treated with surgery and/or local radiotherapy (RT).
Forty-eight patients with non-metastatic RMS of the hand or foot were enrolled on Intergroup Rhabdomyosarcoma Study Group III, IV-Pilot, and IV. Patients received multi-agent chemotherapy with surgery and/or RT. Twenty-four patients (50%) underwent surgery without local RT, of whom 4 had complete resection and 20 had an amputation. The remaining 24 patients (50%) underwent local RT, of whom 2 required RT for microscopic residual disease following prior amputation. Median follow-up for surviving patients is 9.7 years.
Actuarial 10-year local control is 100%; 10-year event-free (EFS) and overall survival (OS) are 62% and 63%, respectively. Poor prognostic factors for recurrence include gross residual (Group III) disease and nodal involvement (p=0.01 and 0.05, respectively). More patients in the RT group had alveolar histology, Group III disease, and nodal involvement, as compared to the surgery group. There is no difference in 10-year EFS (57% vs. 66%) or OS (63% vs. 63%) between patients who underwent surgery or local RT. Among relapsing patients, there are no long-term survivors. No secondary malignancies have been observed.
Despite having high-risk features, patients treated with local RT achieved excellent local control. Complete surgical resection without amputation is difficult to achieve in the hand or foot. Therefore, we recommend either definitive RT or surgical resection which maintains form and function as primary local therapy rather than amputation in patients with hand or foot rhabdomyosarcoma.
PMCID: PMC3075377  PMID: 20646853
Rhabdomyosarcoma; local control; radiotherapy; amputation
Fertility and sterility  2011;95(6):1922-1927.e1.
To evaluate the effect of hypothalamic/pituitary radiation dose on the occurrence of first pregnancy
Retrospective cohort study of childhood cancer five-year survivors (CCS) diagnosed between 1970 and 1986 prior to 21 years of age at one of 26 North American pediatric cancer treatment centers
Self-administered questionnaire
3619 female CCS who participated in the Childhood Cancer Survivor Study and received no/scatter (≤ 0.1 Gy) radiation to the ovaries and 2081 female siblings (Sibs) of the participants
Main Outcome Measure(s)
Self-reported pregnancy events
As a group CCS were as likely to report being pregnant as Sibs (Hazard Ratio (HR), 1.07; 95% Confidence Interval (95%CI), 0.97 to 1.19). Multivariable models showed a significant decrease in the risk of pregnancy with HPT RT doses ≥ 22 Gy compared with those CCS receiving no HPT RT.
These results support the hypothesis that exposures of 22 to 27 Gy HPT RT may be a contributing factor to infertility among female CCS.
PMCID: PMC3080448  PMID: 21376314
childhood cancer survivor; hypothalamic irradiation; pituitary irradiation; alkylating agent; pregnancy
21.  Prognostic Significance and Tumor Biology of Regional Lymph Node Disease in Patients With Rhabdomyosarcoma: A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2011;29(10):1304-1311.
Regional lymph node disease (RLND) is a component of the risk-based treatment stratification in rhabdomyosarcoma (RMS). The purpose of this study was to determine the contribution of RLND to prognosis for patients with RMS.
Patients and Methods
Patient characteristics and survival outcomes for patients enrolled onto Intergroup Rhabdomyosarcoma Study IV (N = 898, 1991 to 1997) were evaluated among the following three patient groups: nonmetastatic patients with clinical or pathologic negative nodes (N0, 696 patients); patients with clinical or pathologic positive nodes (N1, 125 patients); and patients with a single site of metastatic disease (77 patients).
Outcomes for patients with nonmetastatic alveolar N0 RMS were significantly better than for patients with N1 RMS (5-year failure-free survival [FFS], 73% v 43%, respectively; 5-year overall survival [OS], 80% v 46%, respectively; P < .001). Patients with a single site of alveolar metastasis had even worse FFS and OS (23% FFS and OS, P = .01) when compared with patients with N1 RMS; however, the differences was not as large as the differences between patients with N0 RMS and N1 RMS. For embryonal RMS, there was no statistically significant difference in FFS or OS (P = .41 and P = .77, respectively) for patients with N1 versus N0 RMS. Gene array analysis of primary tumor specimens identified that genes associated with the immune system and antigen presentation were significantly increased in N1 versus N0 alveolar RMS.
RLND alters prognosis for alveolar but not embryonal RMS. For patients with N1 disease and alveolar histology, outcomes were more similar to distant metastatic disease rather than local disease. Current data suggest that more aggressive therapy for patients with alveolar N1 RMS may be warranted.
PMCID: PMC3083998  PMID: 21357792
22.  Resectable Pediatric Nonrhabdomyosarcoma Soft Tissue Sarcoma: Which Patients Benefit from Adjuvant Radiation Therapy and How Much? 
ISRN Oncology  2012;2012:341408.
It remains unclear which children and adolescents with resected nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) benefit from radiation therapy, as well as the optimal dose, volume, and timing of radiotherapy when used with primary surgical resection. This paper reviews the sparse literature from clinical trials and retrospective studies of resected pediatric NRSTS to discern local recurrence rates in relationship to the use of radiation therapy.
PMCID: PMC3316976  PMID: 22523704
23.  Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort 
Objectives To assess the incidence of and risks for congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities among adult survivors of childhood and adolescent cancers.
Design Retrospective cohort study.
Setting 26 institutions that participated in the Childhood Cancer Survivor Study.
Participants 14 358 five year survivors of cancer diagnosed under the age of 21 with leukaemia, brain cancer, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, kidney cancer, neuroblastoma, soft tissue sarcoma, or bone cancer between 1970 and 1986. Comparison group included 3899 siblings of cancer survivors.
Main outcome measures Participants or their parents (in participants aged less than 18 years) completed a questionnaire collecting information on demographic characteristics, height, weight, health habits, medical conditions, and surgical procedures occurring since diagnosis. The main outcome measures were the incidence of and risk factors for congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities in survivors of cancer compared with siblings.
Results Survivors of cancer were significantly more likely than siblings to report congestive heart failure (hazard ratio (HR) 5.9, 95% confidence interval 3.4 to 9.6; P<0.001), myocardial infarction (HR 5.0, 95% CI 2.3 to 10.4; P<0.001), pericardial disease (HR 6.3, 95% CI 3.3 to 11.9; P<0.001), or valvular abnormalities (HR 4.8, 95% CI 3.0 to 7.6; P<0.001). Exposure to 250 mg/m2 or more of anthracyclines increased the relative hazard of congestive heart failure, pericardial disease, and valvular abnormalities by two to five times compared with survivors who had not been exposed to anthracyclines. Cardiac radiation exposure of 1500 centigray or more increased the relative hazard of congestive heart failure, myocardial infarction, pericardial disease, and valvular abnormalities by twofold to sixfold compared to non-irradiated survivors. The cumulative incidence of adverse cardiac outcomes in cancer survivors continued to increase up to 30 years after diagnosis.
Conclusion Survivors of childhood and adolescent cancer are at substantial risk for cardiovascular disease. Healthcare professionals must be aware of these risks when caring for this growing population.
PMCID: PMC3266843  PMID: 19996459
24.  Risk of Second Primary Thyroid Cancer after Radiotherapy for a Childhood Cancer in a Large Cohort Study: An Update from the Childhood Cancer Survivor Study 
Radiation research  2010;174(6):741-752.
Previous studies have indicated that thyroid cancer risk after a first childhood malignancy is curvilinear with radiation dose, increasing at low to moderate doses and decreasing at high doses. Understanding factors that modify the radiation dose response over the entire therapeutic dose range is challenging and requires large numbers of subjects. We quantified the long-term risk of thyroid cancer associated with radiation treatment among 12,547 5-year survivors of a childhood cancer (leukemia, Hodgkin lymphoma and non-Hodgkin lymphoma, central nervous system cancer, soft tissue sarcoma, kidney cancer, bone cancer, neuroblastoma) diagnosed between 1970 and 1986 in the Childhood Cancer Survivor Study using the most current cohort follow-up to 2005. There were 119 subsequent pathologically confirmed thyroid cancer cases, and individual radiation doses to the thyroid gland were estimated for the entire cohort. This cohort study builds on the previous case-control study in this population (69 thyroid cancer cases with follow-up to 2000) by allowing the evaluation of both relative and absolute risks. Poisson regression analyses were used to calculate standardized incidence ratios (SIR), excess relative risks (ERR) and excess absolute risks (EAR) of thyroid cancer associated with radiation dose. Other factors such as sex, type of first cancer, attained age, age at exposure to radiation, time since exposure to radiation, and chemotherapy (yes/no) were assessed for their effect on the linear and exponential quadratic terms describing the dose–response relationship. Similar to the previous analysis, thyroid cancer risk increased linearly with radiation dose up to approximately 20 Gy, where the relative risk peaked at 14.6-fold (95% CI, 6.8–31.5). At thyroid radiation doses >20 Gy, a downturn in the dose–response relationship was observed. The ERR model that best fit the data was linear-exponential quadratic. We found that age at exposure modified the ERR linear dose term (higher radiation risk with younger age) (P < 0.001) and that sex (higher radiation risk among females) (P = 0.008) and time since exposure (higher radiation risk with longer time) (P < 0.001) modified the EAR linear dose term. None of these factors modified the exponential quadratic (high dose) term. Sex, age at exposure and time since exposure were found to be significant modifiers of the radiation-related risk of thyroid cancer and as such are important factors to account for in clinical follow-up and thyroid cancer risk estimation among childhood cancer survivors.
PMCID: PMC3080023  PMID: 21128798
25.  Randomized Phase II Window Trial of Two Schedules of Irinotecan With Vincristine in Patients With First Relapse or Progression of Rhabdomyosarcoma: A Report From the Children's Oncology Group 
Journal of Clinical Oncology  2010;28(30):4658-4663.
To compare response rates for two schedules of irinotecan with vincristine in patients with rhabdomyosarcoma at first relapse or disease progression.
Patients and Methods
Patients with first relapse or progression of rhabdomyosarcoma and an unfavorable prognosis were randomly assigned to one of two treatment schedules of irinotecan with vincristine: regimen 1A included irinotecan 20 mg/m2/d intravenously for 5 days at weeks 1, 2, 4, and 5 with vincristine 1.5 mg/m2 administered intravenously on day 1 of weeks 1, 2, 4, and 5; regimen 1B included irinotecan 50 mg/m2/d intravenously for 5 days at weeks 1 and 4 with vincristine as in regimen 1A. Disease response was assessed at week 6. Those with responsive disease continued to receive 44 weeks of multiagent chemotherapy that incorporated the assigned irinotecan-vincristine regimen.
Ninety-two eligible patients were randomly assigned (1A, 45; 1B, 47). Response could be assessed in 89 patients (1A, 42; 1B, 47). There were five complete responses and six partial responses on regimen 1A (response rate, 26%; 95% CI, 16% to 42%) and 17 partial responses on regimen 1B (response rate, 37%; 95% CI, 25% to 51%; P = .36). Neutropenia was less common on regimen 1A (P = .04). One-year failure-free and overall survival rates for regimen 1A were 37% (95% CI, 23% to 51%) and 55% (95% CI, 39% to 69%), respectively, and for 1B, they were 38% (95% CI, 25% to 53%) and 60% (95% CI, 44% to 72%).
There was no difference in the response rates between the two irinotecan-vincristine schedules. We recommend the shorter, more convenient regimen (1B) for further investigation.
PMCID: PMC2974343  PMID: 20837952

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