Corrigendum: Second malignant neoplasms within 5 years from first primary diagnosis in pediatric oncology patients in Canada: a population-based retrospective cohort study.

[This corrects the article DOI: 10.3389/fonc.2024.1376652.].

Second malignant neoplasms within 5 years from first primary diagnosis in pediatric oncology patients in Canada: a population-based retrospective cohort study.

Introduction: From the advancement of treatment of pediatric cancer diagnosis, the five-year survival rate has increased significantly. However, the adverse consequence of improved survival rate is the second malignant neoplasm. Although previous studies provided information on the incidence and risk of SMN in long term survivors of childhood cancer, there is still scarce information known for short term (< 5 years) prognosis. This study aims to assess the incidence, characteristics, management, and outcome of children who develop SMN malignancies within 5 years of diagnosis of their initial cancer. Method: This is a retrospective cohort study of early Second Malignant Neoplasms (SMN) in pediatric oncology patients. The Cancer in Young People - Canada (CYP-C) national pediatric cancer registry was used and reviewed pediatric patients diagnosed with their first cancer from 2000-2015. Results: A total of 20,272 pediatric patients with a diagnosis of a first malignancy were analyzed. Of them, 0.7% were diagnosed with a SMN within the first 5 years following their first cancer diagnosis. Development of a SMN impacted survival, shown by an inferior survival rate in the SMN cohort (79.1%) after three years compared to that of the non-SMN cohort (89.7%). Several possible risk factors have been identified in the study including the use of epipodophyllotoxins, exposure to radiation, and hematopoietic stem cell 169 transplant. Discussion: This is the first national study assessing the incidence, 170 characteristics, risk factors and outcome of early SMN in Canadian children 171 from age 0-15 from 2000-2015.

Individualized combination therapies based on whole-exome sequencing displayed significant clinical benefits in a glioblastoma patient with secondary osteosarcoma: case report and genetic characterization.

BACKGROUND: The incidence of osteosarcoma as a secondary neoplasm in glioblastoma patient is extremely rare. The genetic characteristic still remains unclear until now. CASE DESCRIPTION: We reported a 47-year-old female patient with multiple intracranial disseminations and infiltrations (splenium of the corpus callosum and lateral ventricular wall) of a rapid progressive glioblastoma underwent occipital craniotomy and total resection of all the enhancing lesions. Whole-exome sequencing and pathological examination revealed glioblastoma, IDH1 wild type, PTEN deficient, TERT mutated, NF1mutated, MGMT unmethylated. After surgery, the patient received combined therapeutic regimen of TTFields (tumor-treating fields) plus pembrolizumab plus temozolomide and TTFields plus everolimus, which displayed significant clinical benefits. During the combined therapeutic course, an extremely rare secondary malignant neoplasm occurred, femur MR and pathological detection of biopsy tissue demonstrated osteosarcoma. The result of whole-exome sequencing revealed 7 germline mutated genes (EPAS1, SETD2, MSH3, BMPR1A, ERCC4, CDH1, AR). Bioinformatic analysis showed the two germline mutations (MSH3 and ERCC4) induced deficiency in the DNA repair machinery, which resulting in the accumulation of mutations and may generate neoantigens contributing to the development of a secondary osteosarcoma in this case. CONCLUSION: Individualized combination therapies based on whole-exome sequencing displayed significant clinical benefits in this case. Germline MSH3 and ERCC4 mutation may induce a secondary osteosarcoma in glioblastoma patients.

Role of Radiation Therapy in Mortality among Adolescents and Young Adults with Lymphoma: Differences According to Cause of Death.

BACKGROUND: Despite its efficacy, emerging concerns exist regarding radiation therapy (RT)-associated toxicity in adolescent and young adult (AYA) lymphoma patients. Few long-term follow-up studies have examined the association between RT and outcomes. METHODS: Lymphoma patients aged 15-39 years were identified in the Surveillance, Epidemiology and End Results (SEER) database from 1992 to 2016. Mortality was assessed by comparing those with and without RT using the Fine-Gray competing risk model. Standardized mortality ratios (SMRs) were used to assess the relative risk of death compared with the general U.S. RESULTS: In total, 29,686 patients were included; 10,708 (36.07%) received RT. Cause-specific mortality was compared between patients with and without RT while considering other competing events, including death due to index cancer, second malignant neoplasms (SMNs), and noncancer causes. Patients with RT had a lower probability of death and crude 5-year cumulative incidence of death. Moreover, there were significantly lower SMRs in patients with RT than in patients without RT. Differences between the two groups were greatest for mortality due to hematological malignancies and infections. Additionally, in the RT cohort, the SMR for index-cancer-related death was highest in the first year after diagnosis and gradually decreased. Hematological malignancies and infections were the most common specific SMN and noncancer causes of death, respectively. CONCLUSIONS: RT did not increase mortality from index cancer, SMNs, or noncancer causes in AYA patients with lymphoid malignancies. The current analysis may serve as a reference for healthcare providers monitoring RT application for AYA lymphoid malignancy survivors.

Trends in the risk of second primary malignances after non-Hodgkin's lymphoma.

Patients with non-Hodgkin's lymphoma (NHL) have an increased risk of developing second primary malignances (SPMs). In the current study, we aimed to evaluate the trends and relative clinical variables of SPM risk among NHL survivors over the past four decades. Standardized incidence ratio (SIR) and cumulative incidence frequency (CIF) were assessed in patients diagnosed with first primary NHL between 1975-2016 from the Surveillance, Epidemiology, and End Results (SEER) database. As a result, the overall SIR was 1.13 for SPMs of all sites among NHL survivors. Risk factors included male patients, "other" races, chemotherapy and radiation, and younger age at the time of NHL diagnosis. The relative and cumulative risk for both hematological and solid second cancers after NHL increased over time, whereas the increasing trend was more remarkable for hematological malignances compared with solid tumors. For individual cancer sites, the trends of SIRs varied. A significantly increasing trend of SPM risk was observed in the group receiving chemotherapy and those younger than 40 years at the time of NHL diagnosis. Recent calendar years was not an independent risk factor after adjusting age, race, gender, and therapies in the multivariate Cox proportional hazard regression. To conclude, the current study showed that the relative and cumulative risk of developing SPMs significantly increased in patients diagnosed with NHL in recent years. The trend of SPM risk was associated with certain clinical and demographic variables, and might vary according to different cancer types.

Second malignant neoplasms in lymphomas, secondary lymphomas and lymphomas in metabolic disorders/diseases.

With inconsistent findings, evidence has been obtained in recent years that metabolic disorders are closely associated with the development of lymphomas. Studies and multiple analyses have been published also indicating that some solid tumor survivors develop a secondary lymphoma, whereas some lymphoma survivors subsequently develop a second malignant neoplasm (SMN), particularly solid tumors. An interaction between the multiple etiologic factors such as genetic factors and late effects of cancer therapy may play an important role contributing to the carcinogenesis in patients with metabolic diseases or with a primary cancer. In this review, we summarize the current knowledge of the multiple etiologic factors for lymphomagenesis, focusing on the SMN in lymphoma, secondary lymphomas in primary cancers, and the lymphomas associated to metabolic disorders/diseases, which have been received less attention previously. Further, we also review the data of coexistence of lymphomas and hepatocellular carcinoma (HCC) in patients with infection of hepatitis C virus and hepatitis B virus.

Risk of Second Malignant Neoplasm in Familial Non-Medullary Thyroid Cancer Patients.

Introduction: Survival rates in patients with non-medullary thyroid carcinoma (NMTC) are high, increasing the possibility to develop a second malignant neoplasm (SMN). Many studies investigated the relationship between increased risk of SMN in NMTC patients treated with radioiodine, but few data are available about the impact of family history (FH) of thyroid cancer on SMN risk. Purpose: To assess the risk of SMN in a large cohort of sporadic and familial NMTC using the standardized incidence ratio (SIR). Patients and methods: We studied 918 NMTC patients (73.9% female patients) followed for a median follow-up of 9 years. In 798/918 (86.9%) patients, NMTC was sporadic, while the remaining 120 (13.1%) were familial NMTC (FNMTC). Results: We identified 119/918 (13%) patients with SMN in association with NMTC. NMTCs had an increased risk of SMN when compared to the general population (SIR 2.1, 95% CI 1.7-2.5). The rate of SMN for all sites was significantly higher in familial compared to sporadic NMTC (20% versus 11.9%, p = 0.01), primarily driven by families with more than two affected members. The risk of SMN was remarkably higher for breast cancer, especially in familial cases (SIR 22.03, 95% CI 14.4-41.2) compared to sporadic cases (SIR:17, 95% CI 11.9-24.6). Conclusions: NMTC patients have a higher risk of SMN compared to the general population and this risk is much higher in patients with FNMTC. This observation raises the hypothesis that genetic risk factors for a first cancer may predispose to SMN, especially among individuals with familial clustering of the same or other tumors.

Second Malignant Neoplasms in Patients With Rhabdomyosarcoma.

OBJECTIVE: Rhabdomyosarcoma (RMS) is a rare malignant tumor. The main treatment modality is comprehensive with chemotherapy, radiotherapy, and surgery. With the advancement in recent decades, patient survival has been prolonged, and long-term complications are attracting increasing attention among both physicians and patients. This study aimed to present the survival of patients with RMS and analyze the risk factors for the development of a second malignant neoplasm (SMN). METHODS: The Surveillance, Epidemiology, and End Results (SEER) Program 18 registry database from 1973 to 2015 of the National Cancer Institute of the United States was used for the survival analyses, and the SEER 9 for the SMN analysis. RESULTS: The 5-, 10-, and 20-year overall survival rates of the patients with RMS were 45%, 43%, and 33%, respectively. The risk of SMN was significantly higher in patients with RMS compared to the general population (SIR=1.95, 95% CI: 1.44 - 2.57, p < 0.001). The risk of developing SMN was increased in multiple locations, including the bones and joints (SIR = 35.25) soft tissues including the heart (SIR = 22.5), breasts (SIR = 2.10), male genital organs (SIR = 118.14), urinary system (SIR = 2.36), brain (SIR = 9.21), and all nervous system organs (SIR = 8.59). The multivariate analysis indicated that RMS in the limbs and earlier diagnosis time were independent risk factors for the development of SMN. Patients with head and neck (OR = 0.546, 95% CI: 0.313 - 0.952, p = 0.033) and trunk RMS (OR = 0.322, 95% CI: 0.184 - 0.564. p < 0.001) and a later diagnosis time were less likely to develop SMN (OR = 0.496, 95% CI: 0.421 - 0.585, p < 0.001). CONCLUSION: This study describes the risk factors associated with the development of SMN in patients with RMS, which is helpful for the personalized screening of high-risk patients with RMS.

The Burden of Late Effects and Related Risk Factors in Adolescent and Young Adult Cancer Survivors: A Scoping Review.

Risk factors associated with late effects in survivors of adolescent and young adult (AYA) cancer are poorly understood. We conducted a systematic scoping review to identify cohort studies published in English from 2010-2020 that included: (1) cancer survivors who were AYAs (age 15-39 years) at diagnosis and (2) outcomes of subsequent malignant neoplasms (SMNs), chronic conditions, and/or late mortality (>5 years postdiagnosis). There were 652 abstracts identified and, ultimately, 106 unique studies were included, of which 23, 34, and 54 studies related to the risk of SMNs, chronic conditions, and mortality, respectively. Studies investigating late effects among survivors of any primary cancer reported that AYA cancer survivors were at higher risk of SMN, chronic conditions, and all-cause mortality compared to controls. There was an indication that the following factors increased risk: radiation exposure (n = 3) for SMNs; younger attained age (n = 4) and earlier calendar period of diagnosis (n = 3) for chronic conditions; and non-Hispanic Black or Hispanic (n = 5), low socioeconomic status (n = 3), and earlier calendar period of diagnosis (n = 4) for late mortality. More studies including the full AYA age spectrum, treatment data, and results stratified by age, sex, and cancer type are needed to advance knowledge about late effects in AYA cancer survivors.

Risk of radiation-induced second malignant neoplasms from photon and proton radiotherapy in paediatric abdominal neuroblastoma.

BACKGROUND AND PURPOSE: State-of-the-art radiotherapy modalities have the potential of reducing late effects of treatment in childhood cancer survivors. Our aim was to investigate the carcinogenic risk associated with 3D conformal (photon) radiation (3D-CRT), intensity modulated arc therapy (IMAT) and pencil beam scanning proton therapy (PBS-PT) in the treatment of paediatric abdominal neuroblastoma. MATERIALS AND METHODS: The risk of radiation-induced second malignant neoplasm (SMN) was estimated using the concept of organ equivalent dose (OED) for eleven organs (lungs, rectum, colon, stomach, small intestine, liver, bladder, skin, central nervous system (CNS), bone, and soft tissues). The risk ratio (RR) between radiotherapy modalities and lifetime absolute risks (LAR) were reported for twenty abdominal neuroblastoma patients (median, 4y; range, 1-9y) historically treated with 3D-CRT that were also retrospectively replanned for IMAT and PBS-PT. RESULTS: The risk of SMN due to primary radiation was reduced in PBS-PT against 3D-CRT and IMAT for most patients and organs. The RR across all organs ranged from 0.38 ± 0.22 (bladder) to 0.98 ± 0.04 (CNS) between PBS-PT and IMAT, and 0.12 ± 0.06 (rectum and bladder) to 1.06 ± 0.43 (bone) between PBS-PT and 3D-CRT. The LAR for most organs was within 0.01-1% (except the colon) with a cumulative risk of 21 ± 13%, 35 ± 14% and 35 ± 16% for PBS-PT, IMAT and 3D-CRT, respectively. CONCLUSIONS: PBS-PT was associated with the lowest risk of radiation-induced SMN compared to IMAT and 3D-CRT in abdominal neuroblastoma treatment. Other clinical endpoints and plan robustness should also be considered for optimal plan selection.

Clinical and molecular characterization of thyroid cancer when seen as a second malignant neoplasm.

BACKGROUND: Second malignant neoplasms (SMN) are among the most serious long-term adverse health conditions in cancer survivors. The aim of this study was to characterize clinical findings of patients who developed thyroid cancers as SMN, and to examine genomic alterations in thyroid cancer tissue. METHODS: Retrospective analysis of medical records from patients seen for management of thyroid cancer over 10-year period was performed. Clinical and pathologic data were retrieved from their medical charts. Tumor DNA and RNA were extracted from formalin-fixed, paraffin-embedded tissue and subjected to next-generation sequencing (NGS) using Ion Torrent Oncomine Focus Assay. Microfluidic digital polymerase chain reactions (PCRs) were performed using QIAcuity Digital PCR System to identify BRAF V600E mutations and RET/PTC fusions. RESULTS: Sixteen of 620 patients operated for thyroid cancer had history of previously diagnosed malignancy. Eight patients were male and eight patients were female, with a median age at diagnosis of 58.5 years (range, 4-78). Four patients had history of pediatric malignancy (PedCa), and 12 patients had a history of prior malignancy as an adult (AdCa). The latency periods for development of SMN in PedCa and AdCa patients were 10.8 (±5.2) years and 9.5 (±5.2) years, respectively. Histopathology revealed papillary thyroid cancers in 15 cases, and follicular thyroid cancer in 1 case. All tumors were classified as T1 or T2, and there were no patients presenting with metastases at the time of surgery. Genomic alterations were detected in 13/16 (81.2%) tumors including eight gene mutations (BRAF V600E (N = 4), RAS (N = 2), PI3CA (N = 2) and five gene fusions (RET/PTC1 (N = 4) and STRN/ALK (N = 1). In patients with PedCa and AdCa, mutations were detected in 1/4 (25%) and 7/12 (58.3%), respectively, p = 0.56; and fusions were detected in 3/4 (75%) and 2/12 (16.6%), respectively, p = 0.06. In patients with and without history of therapeutic irradiation, mutations were detected with the same frequencies (5/10 (50%), and 3/6 (50%), respectively, p = 1.0). Gene fusions were detected in patients with and without history of irradiation in 5/10 (55.5%) and 0/6 (0%), respectively, p = 0.09. CONCLUSIONS: Monitoring of cancer survivors for thyroid disorders allowed diagnosis of second thyroid cancers at early stages. Second thyroid cancers harbor genomic alterations that are typical for sporadic as well as for radio-induced thyroid cancers.

Racial/Ethnic Disparities on the Risk of Second Malignant Neoplasm Among Hodgkin Lymphoma Survivors.

BACKGROUND: Hodgkin lymphoma survivors are at risk for second malignant neoplasm (SMN). How race/ethnicity affects the risk remains unclear. METHODS: This retrospective cohort study included 22,415 patients diagnosed with primary Hodgkin lymphoma from January 1992 to December 2015 in 13 Surveillance, Epidemiology, and End Results-based registries and divided patients into four groups: non-Hispanic whites, non-Hispanic blacks, Hispanics, and Asian/others. Taking non-Hispanic whites as a reference, both the proportional subdistribution hazard (PSH) and the cause-specific hazard (CSH) methods were used to calculate the SMN hazard ratio for other racial/ethnic groups with and without considering the competing mortality risk. RESULTS: 1,778 patients developed SMN with a median follow-up of 11.63 years. In the adjusted PSH model, Hispanic, Asian/others, and non-Hispanic black patients had 26% (PSH, 0.74; 95% CI, 0.63-0.87), 20% (PSH, 0.80; 95% CI, 0.64-1.01), and 12% (PSH, 0.88; 95% CI, 0.75-1.03) decreased overall SMN hazard, respectively. Moreover, the PSH method revealed the racial/ethnic difference in the SMN risk in the skin, the respiratory system, and the endocrine system. These hazards were slightly higher and different with the use of the CSH approach. In addition to the aforementioned overall SMN and subtypes, adjusted CSH analysis also revealed the racial/ethnic disparities in the risk of subsequent female breast cancer, digestive cancer, and non-Hodgkin lymphoma. CONCLUSIONS: The subtype and SMN risk among Hodgkin lymphoma survivors varied by race/ethnicity. The use of CSH and PSH provides a dynamic view of racial/ethnic effects on SMN risk in Hodgkin lymphoma survivors.

Correlation between RB1germline mutations and second primary malignancies in hereditary retinoblastoma patients treated with external beam radiotherapy.

Retinoblastoma (Rb) results from biallelic inactivation of the RB1 gene. Hereditary Rb patients i. e germline carriers of a RB1 mutation also have a risk of developing subsequent malignant neoplasms (SMN) such as osteosarcomas. This SMN risk is maximized by external beam radiotherapy treatments (EBRT), which is why these treatments are now avoided. Nevertheless, EBRT is still a matter of great concern, as EBRT-treated patients are in their adulthood and SMNs remain the major cause of death for patients. To decipher the relationship between RB1 genotype and SMN development in EBRT treated patients, we conducted a retrospective study in a cohort of 160 irradiated hereditary Rbs with fully resolved RB1 mutational status. Median follow-up was 22 years [1-51] and median age of patients was 27 years old [7-53]. Among these 160 Rb patients, 120 did not develop any SMN (75%) and 40 developed SMNs (25%). The age at which EBRT is given (i.e. before or after the age of 12 months) was not correlated to SMN development (p = 0.6). We didn't find any difference in RB1 mutation type between patients with or without SMN, neither could we detect any linkage between mutation type and SMN location, SMN type and age at diagnosis. Interestingly, among 13 carriers of a RB1 low penetrance mutation, 3 of them developed sarcomas, a rare tumor that cannot be attributed to the general population. Our study cannot explain why a RB1 mutation leads or not to a SMN but demonstrated that EBRT patients with a low penetrance mutation remain at risk of SMN and should be cautiously monitored.

Low- and middle-income countries can reduce risks of subsequent neoplasms by referring pediatric craniospinal cases to centralized proton treatment centers.

Few children with cancer in low- and middle-income countries (LMICs) have access to proton therapy. Evidence exists to support replacing photon therapy with proton therapy to reduce the incidence of secondary malignant neoplasms (SMNs) in childhood cancer survivors. The purpose of this study was to estimate the potential reduction in SMN incidence and in SMN mortality for pediatric medulloblastoma patients in LMICs if proton therapy were made available to them. For nine children of ages 2 to 14 years, we calculated the equivalent dose in organs or tissues at risk for radiogenic SMNs from therapeutic and stray radiation for photon craniospinal irradiation (CSI) in a LMIC and proton CSI in a high-income country. We projected the lifetime risks of SMN incidence and SMN mortality for every SMN site with a widely-used model from the literature. We found that the average total lifetime attributable risks of incidence and mortality were very high for both photon CSI (168% and 41%, respectively) and proton CSI (88% and 26%, respectively). SMNs having the highest risk of mortality were lung cancer (16%), non-site-specific solid tumors (16%), colon cancer (5.9%), leukemia (5.4%), and for girls breast cancer (5.0%) after photon CSI and non-site-specific solid tumors (12%), lung cancer (11%), and leukemia (4.8%) after proton CSI. The risks were higher for younger children than for older children and higher for girls than for boys. The ratios of proton CSI to photon CSI of total risks of SMN incidence and mortality were 0.56 (95% CI, 0.37 to 0.75) and 0.64 (95% CI, 0.45 to 0.82), respectively, averaged over this sample group. In conclusion, proton therapy has the potential to lessen markedly subsequent SMNs and SMN fatalities in survivors of childhood medulloblastoma in LMICs, for example, through regional centralized care. Additional methods should be explored urgently to reduce therapeutic-field doses in organs and tissues at risk for SMN, especially in the lungs, colon, and breast tissues.

Impact of liver transplantation on the risk of second malignant tumors among hepatocellular carcinoma patients.

BACKGROUND: Population-based data on the development of second malignant neoplasms (SMNs) following the diagnosis of hepatocellular carcinoma (HCC) are uncommon. We evaluated this clinical vignette in HCC patients within the Surveillance, Epidemiology and End Results (SEER) database. METHODS: The SEER database (1973-2012) was queried using the SEER*Stat program to determine the clinico-pathological features of HCC patients with more than one year survival who developed SMNs. Standardized incidence ratios (SIRs) were calculated to determine the risk of each type of subsequent cancers. Relative risk was assessed to determine the impact of liver transplantation on the development of second malignant neoplasms. RESULTS: On SIR analysis, the following sites have an enhanced risk of developing an SMN following the diagnosis of HCC: tongue, anal canal, liver, lung, kidney, thyroid, non-Hodgkin lymphoma (both nodal and extra-nodal disease) and acute monocytic leukemia (P < 0.05 for all sites). A significantly higher RR was found for the development of lung cancer (RR = 2.096), thyroid cancer (RR = 3.045) and non-Hodgkin lymphoma (RR = 3.822) among patients who underwent liver transplantation compared to those who did not (P < 0.05). CONCLUSION: There is an excess risk for developing a number of SMNs among patients diagnosed with HCC.

Risk of Subsequent Primary Kidney Cancer After Another Malignancy: A Population-based Study.

BACKGROUND: Population-based data on the development of kidney cancer as a second malignant neoplasm following the diagnosis of other common malignancies are rare. This clinical scenario has been evaluated within the Surveillance, Epidemiology, and End Results (SEER) database. MATERIALS AND METHODS: The SEER-9 database (1973-2013) was queried using the SEER*Stat program to determine the standardized incidence ratios (SIRs) of kidney cancer development following each one of 10 common invasive malignancies (colorectal, breast, prostate, lung, thyroid, corpus uteri, urinary bladder, kidney/renal pelvis, cutaneous melanoma, and non-Hodgkin lymphoma). The following data were collected for patients with a second renal cancer: age at diagnosis of the second renal cancer; gender, race, and histology of the second primary renal cancer; SEER historic stage of the second primary renal cancer; and method of diagnostic confirmation of the second primary cancer. RESULTS: A total of 10,145 kidney cancers were observed. Elevated SIRs for kidney cancer were noted for all 10 evaluated malignancies in the initial 12 months after diagnosis. The SIRs remained elevated 12 to 59 months after diagnosis for all cancers except breast and prostate cancers. Increased risks persisted 60 to 119 months beyond diagnosis for renal cancer (SIR, 4.13), thyroid cancer (SIR, 2.30), and non-Hodgkin lymphoma (SIR, 1.40); and 120+ months for renal cancer (SIR, 3.60), thyroid cancer (SIR, 1.90), and non-Hodgkin lymphoma (SIR, 1.27). Increased kidney cancer risk after non-Hodgkin lymphoma was not related to radiation therapy. Papillary renal cell carcinoma has the highest SIRs for subsequent kidney cancers. CONCLUSION: Many common cancers are associated with an increased risk of kidney cancer development within the first 5 years after their diagnosis. Although this can be partly interpreted by increased rates of surveillance tests, radiotherapy effects, or genetic associations for some cancers, additional research is required to explain the persistently increased risk beyond 5 years associated with some cancers.

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.

BACKGROUND: 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. METHODS: 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. RESULTS: 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]). CONCLUSIONS: 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.

Biological measures to minimize the risk of radiotherapy-associated second cancer: A research perspective.

Purpose Second cancers are among the most serious sequelae for cancer survivors who receive radiotherapy. This article aims to review current knowledge regarding how the risk of radiotherapy-associated second cancer can be minimized by biological measures and to discuss relevant research needs. Results The risk of second cancer can be reduced not only by physical measures to decrease the radiation dose to normal tissues but also by biological means that interfere with the critical determinants of radiation-induced carcinogenesis. Requirements for such biological means include the targeting of tumor types relevant to radiotherapy-associated risk, concrete safety and efficacy evidence and feasibility and minimal invasiveness. Mechanistic insights into the process of radiation carcinogenesis provide rational approaches to minimize the risk. Five mechanism-based strategies are proposed herein based on the current state of knowledge. Epidemiological studies on the joint effects of radiation and lifestyle or other factors can provide evidence for factors that modify radiation-associated risks if deliberately controlled. Conclusions Mechanistic and epidemiological evidence indicates that it is possible to develop interventional measures to minimize the second cancer risk associated with radiotherapy. Research is needed regarding the critical determinants of radiation-induced carcinogenesis available for intervention and joint effects of radiation and controllable factors.

Minimally Invasive Adenocarcinoma of the Lung as Second Malignant Neoplasm Following Pediatric Rhabdomyosarcoma.

Primary pulmonary tumors are extremely rare in the pediatric population; however, sporadic cases of invasive pulmonary adenocarcinoma as a second malignant neoplasm (SMN) have been described in survivors of pediatric cancers. Pediatric patients with rhabdomyosarcoma (RMS) have a particularly increased risk of developing a SMN when compared to the general population, though pulmonary adenocarcinoma has not been previously described in a RMS patient. A 12-year-old female previously treated for stage IV pelvic RMS was found to have a left pulmonary nodule on surveillance computed tomography. The nodule was detected 4.25 years after the completion of treatment, which included resection, chemotherapy, and radiation to the abdomen and pelvis. Wedge resection of the pulmonary lesion was performed with negative margins. Histopathological examination revealed minimally invasive adenocarcinoma. Pulmonary adenocarcinoma may rarely present as a SMN in pediatric cancer survivors. The pathogenesis of this association is not yet entirely clear, but may include chemotherapy-induced mutagenesis and/or genetic predisposition. As pulmonary adenocarcinoma may present as a lung lesion radiographically indistinguishable from metastatic RMS, it should be considered in the differential diagnosis of any pediatric RMS survivor presenting with a new pulmonary nodule, especially in cases with late recurrence.