Second Malignant Neoplasms Research Articles

Text mining electronic hospital records to automatically classify admissions against disease: Measuring the impact of linking data sources

ObjectiveText and data mining play an important role in obtaining insights from Health and Hospital Information Systems. This paper presents a text mining system for detecting admissions marked as positive for several diseases: Lung Cancer, Breast Cancer, Colon Cancer, Secondary Malignant Neoplasm of Respiratory and Digestive Organs, Multiple Myeloma and Malignant Plasma Cell Neoplasms, Pneumonia, and Pulmonary Embolism. We specifically examine the effect of linking multiple data sources on text classification performance. MethodsSupport Vector Machine classifiers are built for eight data source combinations, and evaluated using the metrics of Precision, Recall and F-Score. Sub-sampling techniques are used to address unbalanced datasets of medical records. We use radiology reports as an initial data source and add other sources, such as pathology reports and patient and hospital admission data, in order to assess the research question regarding the impact of the value of multiple data sources. Statistical significance is measured using the Wilcoxon signed-rank test.A second set of experiments explores aspects of the system in greater depth, focusing on Lung Cancer. We explore the impact of feature selection; analyse the learning curve; examine the effect of restricting admissions to only those containing reports from all data sources; and examine the impact of reducing the sub-sampling. These experiments provide better understanding of how to best apply text classification in the context of imbalanced data of variable completeness. ResultsRadiology questions plus patient and hospital admission data contribute valuable information for detecting most of the diseases, significantly improving performance when added to radiology reports alone or to the combination of radiology and pathology reports. ConclusionOverall, linking data sources significantly improved classification performance for all the diseases examined. However, there is no single approach that suits all scenarios; the choice of the most effective combination of data sources depends on the specific disease to be classified.

Second Malignant Neoplasms and Cause of Death in Patients With Germ Cell Cancer

ImportancePatients given systemic treatment for testicular germ cell cancer (GCC) are at increased risk for a second malignant neoplasm (SMN). Previous studies on SMN and causes of death lacked information on the exact treatment applied or were based on patients receiving former treatment options.ObjectiveTo evaluate the treatment-specific risks for SMN and death in a nationwide population-based cohort of patients with GCC treated with current standard regimens.Design, Setting, and ParticipantsThis study examined a Danish nationwide cohort of 5190 men with GCC who entered the Danish Testicular Cancer database between January 1, 1984, and December 31, 2007. Treatment results were compared with a randomly sampled, age-stratified, population-based control group. Cases of gonadal and extragonadal primary were included in the nationwide cohort. The treatments were surveillance only; retroperitoneal radiotherapy (RT); bleomycin, etoposide, and cisplatin (BEP); or more than 1 line of treatment (MTOL).Main Outcomes and MeasuresCumulative incidence and hazard ratios (HRs) for SMN and death calculated by the Cox proportional hazards model were compared with those of age-matched controls.ResultsThe study population comprised 2804 patients with seminoma and 2386 with nonseminoma. The median follow-up was 14.4 years (interquartile range, 8.6-20.5 years). The 20-year cumulative incidence of SMN with death as a competing risk was 7.8% (surveillance), 7.6% (BEP), 13.5% (RT), 9.2% (MTOL), and 7.0% (controls). We found no increased risk for SMN after surveillance, while the HRs were 1.7 (95% CI, 1.4-2.0), 1.8 (95% CI, 1.5-2.3), and 3.7 (95% CI, 2.5-5.5), respectively, after BEP, RT, and MTOL. Mortality owing to non-GCC causes was decreased after surveillance, but increased by 1.3 times after BEP and RT and by 2.6 times after MTOL. Excess mortality due to SMN was found after BEP (HR, 1.6; 95% CI, 1.2-2.2), RT (HR, 2.1; 95% CI, 1.5-2.9), and MTOL (HR, 5.8; 95% CI, 3.6-9.6).Conclusions and RelevanceWe found no increased risk for SMN or death among patients undergoing surveillance only. The risks for SMN and death due to SMN were increased after BEP alone, RT alone, and MTOL. Approaches to define patients who might benefit from less intensive treatment are needed.

Development of Secondary Malignant Neoplasms in Pediatric Patients Diagnosed With Glioblastoma or Anaplastic Astrocytoma

Development of Secondary Malignant Neoplasms in Pediatric Patients Diagnosed With Glioblastoma or Anaplastic Astrocytoma

Incidence and risk factors for secondary malignancy in patients with neuroblastoma after treatment with 131I-metaiodobenzylguanidine

Several reports of second malignant neoplasm (SMN) in patients with relapsed neuroblastoma after treatment with 131I-MIBG suggest the possibility of increased risk. Incidence of and risk factors for SMN after 131I-MIBG have not been defined.This is a multi-institutional retrospective review of patients with neuroblastoma treated with 131I-MIBG therapy. A competing risk approach was used to calculate the cumulative incidence of SMN from time of first exposure to 131I-MIBG. A competing risk regression was used to identify potential risk factors for SMN.The analytical cohort included 644 patients treated with 131I-MIBG. The cumulative incidence of SMN was 7.6% (95% confidence interval [CI], 4.4–13.0%) and 14.3% (95% CI, 8.3–23.9%) at 5 and 10 years from first 131I-MIBG, respectively. No increase in SMN risk was found with increased number of 131I-MIBG treatments or higher cumulative activity per kilogram of 131I-MIBG received (p = 0.72 and p = 0.84, respectively). Thirteen of the 19 reported SMN were haematologic. In a multivariate analysis controlling for variables with p < 0.1 (stage, age at first 131I-MIBG, bone disease, disease status at time of first 131I-MIBG), patients with relapsed/progressive disease had significantly lower risk of SMN (subdistribution hazard ratio 0.3, 95% CI, 0.1–0.8, p = 0.023) compared to patients with persistent/refractory neuroblastoma.The cumulative risk of SMN after 131I-MIBG therapy for patients with relapsed or refractory neuroblastoma is similar to the greatest published incidence for high-risk neuroblastoma after myeloablative therapy, with no dose-dependent increase. As the number of patients treated and length of follow-up time increase, it will be important to reassess this risk.

Second malignancy risk among pediatric, adolescent, and young adult survivors of fusion-positive and fusion-negative sarcomas: Results from the SEER database, 1992 through 2012.

The current study builds on the hypothesis that cancer-predisposing germline mutations are less common among patients with fusion-positive (F+) sarcomas compared to those with fusion-negative (F-) sarcomas, resulting in a lower risk of developing second malignant neoplasms (SMNs) in those with F + sarcomas. Standardized incidence ratios (SIRs) for developing SMNs were evaluated in 4822 survivors of F + and 3963 survivors of F- sarcomas that were diagnosed between 1992 and 2012 in pediatric, adolescent, and young adult patients (aged birth-39 years) and reported in the Surveillance, Epidemiology, and End Results (SEER) database. Cox proportional hazards models (adjusted hazard ratio [aHR]) and competing risk methods (subhazard ratio [sHR]) were used to evaluate SMN risk in those with F- versus F + sarcomas while controlling for demographic and clinical variables. SMN risk was found to be nearly 2-fold greater among survivors of F + sarcomas (SIR, 1.86; 95% confidence interval [95% CI], 1.48-2.30) and nearly 3-fold greater among survivors of F- sarcomas (SIR, 2.89; 95% CI, 2.30-3.59) compared with the reference population. Although SMN types were noted to be similar between the fusion groups, the rate of any SMN was noted to be greater among survivors of F- sarcomas (aHR, 1.38 [95% CI, 1.01-1.89] and sHR, 1.27 [95% CI, 0.94-1.73]) when compared with survivors of F + sarcomas. The difference was most notable for solid tumor SMNs after index sarcomas were diagnosed between 2002 and 2012, for which rates of SMN were >2-fold greater among survivors of F- sarcomas (aHR, 2.31 [95% CI, 1.20-4.48] and sHR, 2.24 [95% CI, 1.13-4.43]). The findings of the current study highlight the increased SMN risk experienced by survivors of sarcoma and demonstrate higher SMN rates in survivors of F- sarcomas compared to those with a history of F + sarcomas. Cancer 2016;122:3492-3500. © 2016 American Cancer Society.

Abstract 3452: Antidepressant use and risk of central nervous system metastasis

Abstract CNS metastasis is the spread of a primary cancer to the CNS and occurs in up to 25% of cancer patients. Antidepressant therapy, used in 15-30% of cancer patients, affects the blood-brain barrier, potentially making patients more susceptible to CNS metastasis. This hypothesis is supported by an experimental study reporting increased CNS metastasis from breast cancer in mice receiving fluoxetine, an antidepressant in the class of selective serotonin reuptake inhibitors (SSRIs). However, no human studies have looked at this association. We conducted a case-control study to examine whether antidepressants, and specifically SSRIs, increased the relative odds of CNS metastasis. We identified cancer patients diagnosed with breast cancer, melanoma, and non-Hodgkin lymphoma (NHL) at one academic cancer center in Rochester, NY between 2005 and 2013. We ascertained 189 patients with CNS metastasis (cases) and 945 patients without CNS metastasis (controls). Cases of CNS metastasis were identified by the ICD-9 code 198.3 secondary malignant neoplasm of brain and spinal cord. Cases and controls were classified with regard to their antidepressant use based on medical chart review. Using multivariable logistic regression, we estimated the relative odds of CNS metastasis associated with ‘any antidepressant use’ (any antidepressant irrespective of class), ‘any SSRI use’ (SSRI use, nonexclusively), and ‘exclusive SSRI use’ (only SSRI use and no other class of antidepressant), all compared to ‘no antidepressant use’. Subset analyses were planned a priori for breast cancer and melanoma; subset analyses could not be conducted for NHL due to the small sample size. Both cases and controls had a median age of 53 years (range: 25-94 years and 15-89 years, respectively). The prevalence of ‘any antidepressant use’ was 28.6% in cases and 25.7% in controls, whereas SSRIs were used in 16.9% of cases and 15.6% of controls. Among all patients, ‘any SSRI use’ was not associated with CNS metastasis (odds ratio (OR) = 1.21; 95% confidence interval (CI) = 0.74, 1.97). However, among breast cancer patients, ‘any SSRI use’ was associated with a 1.73 times greater odds of CNS metastasis (95% CI = 0.75, 4.04). No consistent patterns of association were observed in the analyses of other cancer subsets or exposure measures. This was the first study to examine the association between antidepressant use and CNS metastasis. We did not observe clear patterns of association which may be due in part to the small sample size in many of our analyses. However, we believe that the increased odds in the breast cancer subset warrants further investigation as this is consistent with the animal research. Citation Format: Megan Herr, Nimish Mohile, Edwin van Wijngaarden, Edward Brown, David Q. Rich. Antidepressant use and risk of central nervous system metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3452.

SU‐F‐T‐502: FFF Beams, Jaw‐Tracking and Treatment Techniques: Out of Field Dose Considerations for Pediatric Radiation Therapy Delivery

Purpose:To compare the extended dose profile delivered by 3DCRT and VMAT techniques for flattened and flattening‐filter‐free(FFF) photon beams (6X, 6XFFF,10XFFF), with and without jaw‐tracking (JT) on Varian TrueBeam linac. The goal is to determine which treatment technique/modality will minimize the peripheral photon dose exposure (and ultimately minimize the risk of second malignant neoplasms (SMN)) in pediatric patients.Methods:3DCRT, VMAT, and jaw tracking VMAT (JTVMAT) plans with 6X, 6XFFF and 10XFFF x‐ray beams were created on a 30×60×22.5cm solid water phantom with a 551 cc PTV. The 3DCRT plans consisted of a 4FLD arrangement. The optimization objectives for the single‐arc VMAT plans was V95%Rx=98% to PTV and minimize dose to a 5cm diameter organ at risk (OAR). The OAR to PTV distance varied from 0–30cm along the long axis at 7.5cm depth. The dose to the center of the OAR was measured using a 0.6cc ion chamber.Results:Relative to the 6X flattened beam, the 10XFFF photon beam had the lowest dose in the penumbra and peripheral region (&gt;15 cm) region by up to 20% and 40%, respectively for all modalities (3DCRT, VMAT, JTVMAT). The 6XFFF beams only showed a dose reduction in the peripheral region (by up to 20%). JT did not significantly affect the peripheral dose for all modalities and energies.Conclusion:Treating pediatric patients with a 10XFFF beam is the most effective way to reduce photon scatter dose in both the penumbra and peripheral regions. However, the neutron dose contribution resulting from the 10MV beam still needs to be considered. For all modalities, 6XFFF was the next effective method to reduce peripheral photon doses. 3DCRT beams had the lowest peripheral doses for all energies compared to VMAT and JTVMAT, however previous publications have shown that this comes at the expense of PTV conformity and OAR sparing.

Risk factors for subsequent endocrine-related cancer in childhood cancer survivors

Long-term adverse health conditions, including secondary malignant neoplasms, are common in childhood cancer survivors. Although mortality attributable to secondary malignancies declined over the past decades, the risk for developing a solid secondary malignant neoplasm did not. Endocrine-related malignancies are among the most common secondary malignant neoplasms observed in childhood cancer survivors. In this systematic review, we describe risk factors for secondary malignant neoplasms of the breast and thyroid, since these are the most common secondary endocrine-related malignancies in childhood cancer survivors. Radiotherapy is the most important risk factor for secondary breast and thyroid cancer in childhood cancer survivors. Breast cancer risk is especially increased in survivors of Hodgkin lymphoma who received moderate- to high-dosed mantle field irradiation. Recent studies also demonstrated an increased risk after lower-dose irradiation in other radiation fields for other childhood cancer subtypes. Premature ovarian insufficiency may protect against radiation-induced breast cancer. Although evidence is weak, estrogen-progestin replacement therapy does not seem to be associated with an increased breast cancer risk in premature ovarian-insufficient childhood cancer survivors. Radiotherapy involving the thyroid gland increases the risk for secondary differentiated thyroid carcinoma, as well as benign thyroid nodules. Currently available studies on secondary malignant neoplasms in childhood cancer survivors are limited by short follow-up durations and assessed before treatment regimens. In addition, studies on risk-modifying effects of environmental and lifestyle factors are lacking. Risk-modifying effects of premature ovarian insufficiency and estrogen-progestin replacement therapy on radiation-induced breast cancer require further study.

Clinical features and long-term outcomes of bilateral Wilms tumor treated with Taiwan Pediatric Oncology Group protocols: A single center report.

Wilms tumor (WT) is rare in Asia. Treatment of bilateral WT is challenging, and the treatment outcome of bilateral WT is rarely reported in low incidence areas. We enrolled patients with bilateral WT registered in Chang Gung Memorial Hospital, Taoyuan, Taiwan, between January 1986 and June 2015. They were treated according to the Taiwan Pediatric Oncology Group (TPOG) protocols. The clinical features and long-term outcomes were analyzed. Six patients with histologically-proved bilateral WT were identified for analysis. One additional patient who was diagnosed with unilateral WT-associated intralobar nephrogenic rest, in addition to two small lesions in the contralateral kidney, was also included. There were total of three male patients and four female patients. The median follow-up period was 19 years (range 8-29 years). Five patients underwent initial biopsy and preoperative chemotherapy followed by surgery, whereas two patients underwent initial surgery followed by adjuvant chemotherapy. Local recurrence was found in two patients. The 8-year event-free survival and overall survival rates were 71.4% and 100%, respectively. Two patients developed advanced stage of chronic kidney disease, but none had been diagnosed with secondary malignant neoplasm. Other health issues such as hypertension, scoliosis and unspecified autoimmune disease were also found. The treatment outcome in this study is comparably superior to other western countries. However, survivors of bilateral WT still have many chronic health issues and thereby need individualized long-term medical care.

Second malignant neoplasm (SMN) in a cohort of early stage cancer survivors (ESCS) followed at Instituto Oncológico Henry Moore (IOHM) in the last 15 years.

e13057Background: The prolonged survival achieved when tumors are treated at early stages allows the diagnosis of a SMN in many patients during the follow up period.The following study aims to present the incidence of secondary tumors in a cohort of ESCS patients (Pt) followed at IOHM. Methods: A search of the IOHM database was carried out, looking for Pt that had been registered between 1/12/2000 and 1/6/2015 with early stage (0-I-II-III) tumors and had been followed for more than six months. Those with a SMN were identified. In all of these, the following was studied: Dx, detection (screening vs symptomatic), presentation (synchronic vs metachronic) and stage. Results: It was possible to find 12038 ESCS that met selection criteria. Population characteristics: Median age at Dx of primary tumor: 58 years (r 18-98y). Sex: male 4689 Pt (39%) / female 7335 Pt (61%). Median follow up was 40 months (r 6-183m). The table below shows primary tumors and most frequent SMN. In 476/556 Pt (86%), SMN was metachronic ...

Rate of second malignant neoplasm in a cohort of early stage uveal melanoma followed at Instituto Oncológico Henry Moore (IOHM) in the last 15 years.

9587Background: Uveal melanoma (UM) is a rare neoplasm with a 3.3% rate of second malignant neoplasm (SMN) according to the Collaborative Ocular Melanoma Study (COMS) (Diener-West m et al. Arch Oph...

Second malignancies in patients with neuroblastoma: A report from the International Neuroblastoma Risk Group Project.

10547Background: Radiation and chemotherapy exposure are associated with the development of second malignant neoplasms (SMN) in neuroblastoma survivors. However, whether the incidence of SMN has ch...

Neuroblastoma: A Tough Nut to Crack.

Neuroblastoma, an embryonal tumor arising from neural crest-derived progenitor cells, is the most common solid tumor in childhood, with more than 700 cases diagnosed per year in the United States. In the past several decades, significant advances have been made in the treatment of neuroblastoma. Treatment advances reflect improved understanding of the biology of neuroblastoma. Although amplification of MYCN was discovered in the early 1980s, our understanding of neuroblastoma oncogenesis has advanced in the last decade as a result of high-throughput genomic analysis, exome and whole-genome sequencing, genome-wide association studies, and synthetic lethal drug screens. Our refined understanding of neuroblastoma biology and genetics is reflected in improved prognostic stratification and appropriate tailoring of therapy in recent clinical trials. Moreover, for high-risk neuroblastoma, a disease that was uniformly fatal 3 decades ago, recent clinical trials incorporating autologous hematopoietic transplant and immunotherapy utilizing anti-GD2 antibody plus cytokines have shown improved event-free and overall survival. These advances have resulted in a growing population of long-term survivors of neuroblastoma. Examination of the late effects and second malignant neoplasms (SMNs) in both older generations of survivors and more recently treated survivors will inform both design of future trials and surveillance guidelines for long-term follow-up. As a consequence of advances in understanding of the biology of neuroblastoma, successful clinical trials, and refined understanding of the late effects and SMNs of survivors, the promise of precision medicine is becoming a reality for patients with neuroblastoma.

Age at Primary Malignancy Determines Survival in Adolescent and Young Adults That Develop a Secondary Thyroid Cancer.

Second malignancy status is a risk factor for death in adolescent and young adults (AYAs) (ages 15-39) with thyroid cancer (TC). This study investigates whether age at primary malignancy (PM) is an independent predictor of overall survival (OS) for AYA patients diagnosed with secondary TC who have survived ≥5 years from their PM. Surveillance, Epidemiology and End Results program (SEER) multiple-primary session (SEER-9 [1973-2010] and SEER-13 [1992-2010]) identified all secondary TCs in patients <40 years of age who were also 5-year survivors. Patients with a thyroid second malignant neoplasm (SMN) diagnosed as an AYA were categorized by age at PM (pediatric <15 years vs. AYA). Kaplan-Meier and Cox proportional analysis determined OS. Four hundred twenty-eight cases of secondary AYA TCs in 5-year cancer survivors were identified; 71 had a pediatric PM and 357 an AYA PM. Median OS after a pediatric PM was 35.76 years and 33.22 years after an AYA-PM (p = 0.023); only one death was due to TC. Race, site and stage of PM, marital status, and three or more independent PMs also influenced OS (all p < 0.05). However, TC characteristics, stage, and treatment did not affect OS. Cox regression demonstrated that patients with an AYA PM had a 5.84 relative risk of death (95% confidence interval [95% CI]: 1.81-18.91) compared to patients with a pediatric PM. Among AYAs who develop a TC as a second PM, OS is not affected by the TC. The OS for these patients is associated with their demographics and the characteristics of their PM: patients who are black, male, have three or more primary cancers, and a higher stage of their first malignancy are more likely to die. For AYA patients with thyroid SMNs, having a prior AYA PM (compared to a pediatric PM), Black race, and having three or more independent tumors predicted a decreased OS, independent of PM type or PM/SMN stage.

Effects of Radiotherapy on the Risk of Developing Secondary Malignant Neoplasms in Hodgkin's Lymphoma Survivors.

Extended follow-up of Hodgkin lymphoma (HL) survivors indicates that these patients are at high risk of secondary malignant neoplasms (SMNs) contributing to increased morbidity and mortality. This study examined the characteristics of HL survivors who developed SMNs with the aim to report any correlation with radiotherapy (RT) dose. In this retrospective multi-center cohort study of HL patients treated between 1990 and 2011 at three major teaching hospitals in Lebanon, classification was into two groups including those treated with combined modality (RT and chemotherapy-CHT) and those treated with CHT alone. Approval from the University Institutional Review Board (IRB) was obtained. Of the 112 patients evaluated, 52.7% (59) received the combined modality while 47.3% (53) received CHT alone. There were 6 cases of SMNs in the combined modality cohort and 5 cases in the CHT cohort. The mean RT dose in the combined modality cohort was 34.5 Gray (Gy) (SD ± 5.3). A statistically significant increase (1.5 fold) in the risk of developing SMNs was observed among patients who received a dose higher than 41 Gy compared to a dose between 20 to 30 Gy (OR= 1.5; 95% confidence interval= 0.674 to 3.339, p=0.012). The risk of SMNs was not significantly higher among patients who received extended field compared to involved field RT (p=0.964). This study showed that the risk of developing SMNs is higher among patients treated with RT dose greater than 31 Gy, independent of the RT type used.

Therapeutic radiation and the potential risk of second malignancies.

Radiation has long been associated with carcinogenesis. Nevertheless, it is an important part of multimodality therapy for many malignancies. It is critical to assess the risk of secondary malignant neoplasms (SMNs) after radiation treatment. The authors reviewed the literature with a focus on radiation and associated SMNs for primary hematologic, breast, gynecologic, and pediatric tumors. Radiation appeared to increase the risk of SMN in all of these; however, this risk was found to be associated with age, hormonal influences, chemotherapy use, environmental influences, genetic predisposition, infection, and immunosuppression. The risk also appears to be altered with modern radiotherapy techniques. Practitioners of all specialties who treat cancer survivors in follow-up should be aware of this potential risk. Cancer 2016;122:1809-21. © 2016 American Cancer Society.

Abstract A50: Mutational analysis of a mouse model of second malignant neoplasms

Abstract Purpose: Second malignant neoplasms (SMNs) are therapy-induced malignancies and severe late complications that develop in pediatric cancer survivors. Ionizing radiation (IR) is a known mutagen and can cause SMNs. The mutational landscape of fractionated IR-induced tumorigenesis is not well-characterized on a genome level and but may reveal biological mechanisms that specifically contribute the development of SMNs. To study the influence of clinically relevant radiation delivery and germline mutations in a tumor suppressor gene, we previously developed mouse models of SMNs by delivering focal, fractionated irradiation to wildtype and Nf1 mutant mice. Irradiated mice developed diverse malignancies replicating the sarcomas and carcinomas observed as SMNs in pediatric cancer survivors. The goal of this study is to characterize the mutational profile of tumors induced by ionizing radiation that models clinical radiotherapy and to determine whether germline Nf1 mutations independently influence the mutational landscape. Materials/Methods: Whole exome sequencing was performed on 25 IR-induced malignancies arising in wildtype and Nf1 mutant mice. Indexed paired-end libraries were prepared using the Agilent SureSelectXT Mouse All Exon kit and sequencing was performed using Illumina HiSeq2000 technology (Illumina, San Diego, CA, USA). Alignments and somatic variants were identified using established procedures. Each exome was sequenced to a minimum of 5 Gb. Results: 6,623 somatic mutations were identified, of which 4,633 were non-synonymous. Tumors had an average mutation rate of 265 total SNVs/sample. Most nucleotide substitutions were C -&amp;gt; T or G-&amp;gt; A transitions. We analyzed the immediately flanking sequence context for each somatic variant using non-negative matrix factorization, and extracted 3 stable and distinctive mutational signatures. These signatures are present in multiple types of radiation-induced histologies, are uniquely distinguishable from mutational signatures of other well-recognized mutagens such as UV, and are similarly present in tumors arising in wildtype mice as well as Nf1 mutant mice, suggesting that the IR mutational signature persists in genetic backgrounds either resistant or susceptible to IR-induced tumorigenesis. We compared copy number alterations between tumors from wildtype and Nf1 mutant mice, and found significant differences between genetic backgrounds. Conclusions: IR-induced malignancies possess distinguishable and unique mutational signatures characterized by base substitutions occurring in very specific and unique sequence contexts. This analysis suggests that IR and genetic background influence the mutational landscape of tumors in very specific and discrete ways that are distinguishable from other cancer-promoting processes. SMNs from pediatric cancer survivors may harbor distinctive mutational motifs, and continued studies are needed to examine this. This data also suggest that the mutational landscape may differ between malignancies from different germline mutations or genetic backgrounds in pediatric cancer survivors. From a clinical standpoint, defining distinct mutational mechanisms in SMNs may improve the ability to predict which pediatric cancer survivors are at greatest risk for SMN formation as well as enable the development of strategies to mitigate and manage this risk. Citation Format: Amy Sherborne, Philip Davidson, Katharine Yu, Alice Nakamura, Mamunur Rashid, Jean Nakamura. Mutational analysis of a mouse model of second malignant neoplasms. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A50.

Second neoplasms in survivors of childhood acute lymphoblastic leukemia treated with both chemotherapy and radiotherapy.

e293 Background: Second malignant neoplasms (SMNs) are a concern in survivors of childhood cancer. Chemotherapy forms the mainstay of treatment for acute lymphoblastic leukaemia, but radiotherapy is used in certain situations. As both chemotherapy and radiotherapy can be carcinogenic, patients treated with both modalities may be at a higher risk of SMNs. This study aims to investigate the incidence of SMNs in patients treated with both chemotherapy and radiotherapy. Methods: Children aged 16 years and below diagnosed with acute lymphoblastic leukaemia from 1993 to 2014 were identified in the Childhood Cancer Registry. Manual and electronic medical records were reviewed for information on demographics, management and SMNs. Results: A total of 64 patients treated with both chemotherapy and radiotherapy were identified. Seventeen (26.6%) were female and 47 (73.4%) were male. The median follow-up was 9.2 years (range, 1.1-22.0 years). The median age at diagnosis was 5.3 years, (range, 0.3-14.6 years). The median age at which radiotherapy was given was 6.6 years (range, 2.9-15.4 years). SMNs were noted in 3 of 64 (4.7%) patients. Two of 3 patients had a SMN within the radiation field (both cranial). The histological diagnoses were basal cell carcinoma and cerebral PNET. The remaining patient had an ovarian immature teratoma outside the radiation field. The latency period ranged from 8.3 years to 13.3 years (median 9.4 years) from date of diagnosis to development of SMN. The estimated 10-year cumulative incidence was 4.3%, 95% CI [0.01, 0.13] using a competing risks analysis. Radiotherapy data was available in 63 patients. Fifty-one of 63 (81.0%) received cranial irradiation, of which 3 (5.9%) also received spinal irradiation. Total body irradiation was performed in 20 of 63 (31.7%), and testicular irradiation in 17 of 63 (27.0%) patients. The orbit was targeted in 3 of 63 (4.8%) patients. Conclusions: Long term survivors of acute lymphoblastic leukaemia treated with both chemotherapy and radiotherapy may have a significant risk of second malignant neoplasms, which may occur years after the initial diagnosis.

Chronic medical conditions in adult survivors of retinoblastoma: Results of the Retinoblastoma Survivor Study.

Limited data are available regarding long-term morbidity in adult survivors of retinoblastoma (Rb). The Retinoblastoma Survivor Study is a retrospective cohort of adult survivors of Rb diagnosed between 1932 and 1994. Participants completed a comprehensive questionnaire adapted from the Childhood Cancer Survivor Study surveys. Chronic conditions were classified using the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 4.03). Multivariate Poisson regression was used to compare survivors of Rb with 2377 non-Rb controls, consisting of the Childhood Cancer Survivor Study sibling cohort and survivors with bilateral versus unilateral disease. Survivors of Rb (53.6% with bilateral disease) and non-Rb controls had a mean age of 43.3 years (standard deviation, 11 years) and 37.6 years (SD, 8.6 years), respectively, at the time of study enrollment. At a median follow-up of 42 years (range, 15-75 years), 86.6% of survivors of Rb had at least 1 condition and 71.1% had a severe/life-threatening (grade 3-4) condition. The adjusted relative risk (RR) of a chronic condition in survivors compared with non-Rb controls was 1.4 (95% confidence interval [95% CI], 1.3-1.4; P<.01); for a grade 3 to 4 condition, the RR was 7.6 (95% CI, 6.4-8.9; P<.01). Survivors were at an excess risk regardless of laterality. After stratifying by laterality and excluding ocular conditions and second malignant neoplasms (SMNs), only those with bilateral disease were found to be at an increased risk of any nonocular, non-SMN condition (RR, 1.2; 95% CI, 1.1-1.2) and for grade 3 to 4 nonocular, non-SMN conditions (RR, 1.7; 95% CI, 1.2-2.5). Survivors of Rb have an increased risk of chronic conditions compared with non-Rb controls. After excluding ocular conditions and SMNs, this excess risk was found to persist only for those with bilateral disease. Cancer 2016;122:773-781. © 2016 American Cancer Society.

Re-irradiation of the pelvis for a genitourinary second malignant neoplasm or a local recurrence after full-dose pelvic radiotherapy for a pelvic cancer: Experience in a high-volume cancer center.

494 Background: Re-irradiation (re-RT) with external beam RT following prior pelvic RT has not been reported, given both an absence of guidelines and concerns for toxicity. We sought to characterize bladder and bowel toxicities among patients treated with high-dose palliative re-RT for genitourinary secondary malignant neoplasms (SMN) or local recurrence (LR) following prior RT for pelvic cancer and to assess the response to re-RT with regard to palliation of symptoms. Methods: With IRB approval, the records of 28 consecutive patients with advanced pelvic malignancies given palliative re-RT between 2008-2014 were retrospectively analyzed. Descriptive analyses focused on toxicities and symptom control; responses were evaluated by two independent observers. Results: The cohort contained 27 males and 1 female. Initial cancers included 19 prostate, 4 ureteral, 2 bladder, 2 rectal and 1 penile carcinoma and 1 large cell lymphoma. Median initial RT dose was 63.5 Gy (range, 30-75.6 Gy; 8 unknown). The median time between initial RT and re-RT was 9.5 years (range, 0.2-32 years). At re-RT, there were 16 LRs and 12 SMNs including 14 bladder, 11 prostate, 3 ureteral and 1 penile cancers. Indications for re-RT were most commonly pain and bleeding. Given the severity of symptoms and bulk of disease at the time of re-RT, hypofractionated higher-dose RT was given. Median re-RT dose was 50 Gy (range, 27.5-66 Gy). For patients who received &lt; 60 Gy, the median daily re-RT dose was 250 cGy. Re-RT was well-tolerated; there were no grade 2-4 toxicities. After treatment, 24 patients (92%) had complete resolution of their symptoms. Relief was durable in 67% of patients. Median overall survival was 5.8 months (range, 0.3-38.9 months) and 89% of patients were followed until death. Median follow-up was 5.2 months (range, 0.23-30.2 months). Conclusions: This institutional series suggests that moderate- to high-dose re-RT with median cumulative doses ≥ 100 Gy may achieve successful palliation of pelvic symptoms without undue toxicity in patients previously treated with high-dose RT. These results require validation in a larger prospective cohort.