Second Malignant Neoplasms Research Articles

Childhood cancer survivors: Considerations for surgeons in the transition from pediatric to adult care

There are over 380,000 childhood cancer survivors (CCS) alive in the US, and the population is growing. CCS face significant long-term morbidity and mortality as a consequence of their cancer treatment and thus require lifelong, risk-based health care focused on surveillance and early intervention to minimize the impact of late effects and second malignant neoplasms (SMN). Surgeons play a critical role in the treatment of childhood cancer and the subsequent management of long-term health complications. In this review, we provide an overview of late effects associated with cancer surgeries, potential late effects that may require surgery as an adult, and cancer therapies that may impact future safe surgery and anesthesia. We also describe the barriers to successful transition from pediatric to adult health care for CCS and the importance of treatment summaries, surveillance guidelines, and survivorship care plans for surgeons caring for CCS.

Growth hormone treatment and risk of malignancy.

Growth hormone (GH) treatment has been increasingly widely used for children with GH deficiencies as the survival rate of pediatric patients with malignancies has increased. Both GH and insulin-like growth factor-I have mitogenic and antiapoptotic activity, prompting concern that GH treatment may be associated with tumor development. In this review, the authors examined the relationship between GH treatment and cancer risk in terms of de novo malignancy, recurrence, and secondary neoplasm. Although the results from numerous studies were not entirely consistent, this review of various clinical and epidemiological studies demonstrated that there is no clear evidence of a causal relationship between GH treatment and tumor development. Nonetheless, a small number of studies reported that childhood cancer survivors who receive GH treatment have a small increased risk of developing de novo cancer and secondary malignant neoplasm. Therefore, regular follow-ups and careful examination for development of cancer should be required in children who receive GH treatment. Continued surveillance for an extended period is essential for monitoring long-term safety.

Clinical assessment of the jaw-tracking function in IMRT for a brain tumor

Intensity-modulated radiotherapy (IMRT) improves dose conformity and saves critical organs. IMRT is widely used in cases of head and neck, prostate, and brain cancer due to the close location of the targets to critical structures. However, because IMRT has a larger amount of radiation exposure than 3 dimensional-conformal radiation therapy (3D-CRT), it has disadvantages such as increases in the low dose irradiation to normal tissues and in the accumulated dose for the whole volume due to leakage and transmission of the multi-leaf collimator (MLC). The increased accumulated dose and the larger low dose may increase the occurrence of secondary malignant neoplasms. For these reasons, the jaw-tracking function of the TrueBeam (Varian Medical Systems, Palo Alto, CA) was developed to reduce the leakage and the transmission dose of the MLC with linear accelerators. However, the change in the superficial dose has not been verified with a quantitative analysis of the dose reduction in a brain tumor. Therefore, in the present study, we intended to verify the clinical possibility of utilizing the jaw-tracking function for a brain tumor by comparing treatment plans and superficial doses. To accomplish this, we made three types of original treatment plans using Eclipse11 (Varian Medical Systems, Palo Alto, CA): 1) farther than 2 cm from the organs at risk (OAR); 2) within 2 cm of the OAR; and 3) intersecting with the OAR. Jaw-tracking treatment plans were also made with copies of the original treatment plan using Smart LMC Version 11.0.31 (Varian Medical Systems, Palo Alto, CA). A comparison between the original treatment plans and jaw-tracking treatment plans was performed using the difference of the mean dose and maximum dose to the OARs in cumulative Dose Volume Histogram (DVH). In addition, the dependencies of the effects of transmission and the scattering doses according to jaw motion were assessed through the difference in the surface doses. In the DVH comparison, a maximum dose difference of 0.4% was observed between the planning methods in the case of over 2 cm distance, and the maximum dose of 0.6% was obtained for within the 2 cm distance. For the case intersecting with the OAR, the maximum dose difference of 2.3% was achieved. According to these results, the differences in the mean doses and the maximum doses to the OARs ware larger when the OARs and the planning target volume (PTV) were closer. In addition, small differences in the surface dose measurements were observed. In the case of the inside field, the differences were under 2% of the prescription dose while the difference was under 0.1% in the case of the outside field. Therefore, treatment plans with the jaw-tracking function consistently affected the dose reduction for a brain tumor, and the clinical possibility could be verified as the surface dose was not increased.

Absolute Lymphocyte Counts at the End of Induction Is a Prognostic Indicator in Childhood Acute Lymphoblastic Leukemia

BACKGROUND: Recently, several studies have demonstrated that absolute lymphocyte counts (ALC) after induction therapy predicted treatment outcome. To address this issue, we here assessed the impact of the ALC at the end of induction therapy on outcomes in childhood ALL.METHODS: We reviewed 141 cases of pediatric ALL with 1-21 years of age treated on the Japan Association Childhood Leukemia Study group ALL-02 series of treatment trials between 2002 and 2013. Patients with Philadelphia chromosome-positive ALL were excluded. Variables retrospectively analyzed included ALC at several time points during remission induction, age at diagnosis, gender, initial white blood cell count (WBC), cytogenetics, immunological phenotype, stratified risk, treatment response for bone marrow (the percentage of blasts at day 15), and outcome. Events in the analysis of event-free survival (EFS) included induction failure, death, relapse and secondary malignant neoplasm. The comparison of categorical variables between groups was performed by chi-square test. The probability of EFS and overall survival (OS) were analyzed with the use of the Kaplan–Meier method and a stratified log-rank test. A multivariate analysis of survival was performed with the use of a Cox proportional-hazard model to evaluate the treatment effect with adjustment for stratification factors.RESULTS: The subjects included 121 of B-precursor ALL, 10 of T cell ALL, and 4 of acute mixed lineage leukemia/ acute unclassified leukemia. We found high WBC count at diagnosis (>100K/microL) and slow early responder for bone marrow at day 15 to be an unfavorable prognostic indicator, and also the ALC at the end of induction (day29) to be a statistically significant predictor of improved OS and EFS in our cohort. Patients with ALC ≥ 800/microL had a superior 5-year overall survival (100 ± 1.7% vs 88.1 ± 4.3 %, p=0.0001) and EFS (98.3 ± 1.7% vs 81.8 ± 5.0 %, p=0.0001). Multivariate analysis demonstrated that ALC at day29 was an independent, clinically significant predictor of improved EFS and OS after controlling WBC at diagnosis, gender, age at diagnosis, and cytogenetics. Multiple regression analysis adjusting for initial WBC count, peripheral blast counts at day8, and cytogenetics, also revealed an independent relationship (p=0.005) between treatment response (the percentage of blasts at day 15) and ALC at day29.CONCLUSIONS: ALC is a simple, statistically significant prognostic factor in childhood ALL that may refine current risk stratification algorithms. DisclosuresNo relevant conflicts of interest to declare.

Chronic Lymphocytic Leukemia-Associated Chromosomal Abnormalities and Risk of Secondary Malignancies

Introduction: Incidence of secondary malignant neoplasm in patients with chronic lymphocytic leukemia (CLL) is already established. Genetic predisposition has been considered to be a possible contributory factor for the preponderance of second cancers in this population. In the present study, we examined the frequency, characteristics, and clinical outcomes of secondary malignancies in patients with CLL based on their Interphase fluorescence in situ hybridization (FISH) panel.Methods: We reviewed the medical records of consecutive patients with CLL observed or treated at Ellis Fischel Cancer Center during the period from 2007-2014. We collected demographic data, CLL Rai stage, treatment history, Interphase fluorescence in situ hybridization (FISH) panel results and the presence of a secondary malignancy (skin cancers, solid tumors and hematologic malignancy excluding CLL transformation).Our aim was to investigate the association between secondary malignancy and chromosomal abnormalities and other risk factors using Chi2test for categorical variables and Wilcoxon rank-sum test for continuous variables. Cox proportional hazard models and logistic regression models were used to evaluate risk factors of developing secondary malignancy and overall survival.Results: We identified 142 CLL patients who were either observed (n=62) or had a history of treatment (n=80) for CLL. 67% were male and 33% were female. 85% of patients were Caucasians, 10% African Americans, and 5% other. Familial CLL was present in 6% of cases. 51% of patients were non-smokers. 5% of patients had cancers preceding the diagnosis of CLL (non-melanoma skin cancers=3, melanoma=1, Hodgkin’s lymphoma=1, Prostate=2). 28% of patients developed secondary malignancies after the diagnosis of CLL; among them non-melanoma skin cancers were the most common (78%), followed by cutaneous melanoma (9.5%) and papillary thyroid cancer (4.7%). Other malignancies included lung (2.3%), kidney (2.3%), prostate (2.3%) and ocular melanoma (2.3%). 12% patients had aggressive non-melanoma recurrent skin cancers that require multiple treatments along-with systemic therapy for progressive CLL.CLL-FISH panel at diagnosis was available in 98 patients. Among these patients,13q deletion was present in 45%. Within the 13q deletion group, secondary malignancy was noted in 50% during a median follow up of 7 years. All cases of papillary thyroid cancers were also present in 13q deletion. In contrast, 11q deletion was detected in 15% and trisomy 12 in 18% of patients with incidence of secondary malignancy 40% and 10%, respectively. No solid malignancy other than skin was identified in the 11q deletion and trisomy 12 groups. 17p deletion was present in 5% of cases and 60% of 17p deletion cases had secondary cancers (skin 80%). Normal FISH panel was present in 17% cases and 20% of normal FISH had secondary malignancy (solid 10%, skin 10%).The median overall survival time is 6 years for the entire cohort (IRQ: 3-9 years). Secondary malignancy was associated with worse overall survival (OS) (HR=0.57, 95% CI:0.33-0.98, p=0.04) compare to patients who did not have secondary malignancy. The risk of secondary malignancy is increased in patients with advanced age (OR=1.05, 95% CI:1.00-1.10, p=0.04) and in those who were treated with alkylating agent for CLL OR=6.62, 95% CI:2.08-21.03, p=0.001. However, there were no significant difference on risk of developing secondary malignancy based on specific chromosomal FISH result, Rai stage, smoking, family history and gender.Conclusion: Secondary malignancies are frequent in patients with detectable chromosome abnormality on FISH panel. However, the increased risk of secondary malignancy does not correlate with specific cytogenetic abnormality. Non melanoma skin cancers are exceedingly common in CLL patients and carries aggressive couse in progressive CLL patients. Larger studies are required to identify subtype of CLL based on integrated mutational and cytogenetic subgroup that are at increased risk of specific secondary malignancies. DisclosuresNo relevant conflicts of interest to declare.

Long-Term Outcome of Six Months Maintenance Chemotherapy for ALL in Children: An Extended Follow up Study of TCCSG L92-13

▪Maintenance therapy is a key component of ALL treatment. Although maintenance with 6-mercaptopurine (6-MP) and methotrexate (MTX) is generally less hemato-toxic, it occasionally causes severe complications such as infections, and too long maintenance is possibly associated with lower adherence. Thus, the duration of maintenance should be as short as possible, but excess shortening of maintenance therapy leads to high relapse incidence, as shown in our previous clinical trial, the Tokyo Children’s Cancer Study Group (TCCSG) L92-13 (1992 - 1995, n = 347). In this study, the shortened maintenance therapy to 6 months resulted in EFS of 59.5% at 5.5 years although OS was as good as 81.5%. Especially, higher relapse rate in standard-risk (SR) resulted in EFS of as low as 60.2% (Toyoda Y, et al. J Clin Oncol 2000). However, it should be noted that about 60% of ALL achieved continuous complete remission (CCR) with short maintenance therapy. Thus, to confirm long-term outcome of ALL with this short maintenance therapy, we conducted an extended follow up study of patients enrolled on the TCCSG L92-13.In the L92-13 trial, previously untreated children (15 years or younger) with ALL were enrolled, and were assigned to three risk groups, standard-risk (SR), high-risk (HR) and extremely high-risk (HEX), according to age at diagnosis, immunephenotype, sentinel cytogenetics and initial leukocyte count. All patients received four-drug induction, followed by consolidation therapy including re-induction. Maintenance therapy with daily 6-MP and weekly MTX was shortened to 6 months, and all treatment was discontinued at 12 months after diagnosis.The data was analyzed as of 2014 July. A median of follow up period of this extended study was 14.8 years, and the survival curve is shown in Figure 1A. Relapse was reported in 128 patients, with a median time of relapse was 1.8 years from diagnosis. EFS at 12 years for all patients was 58.7 +- 2.7% (59.2% for SR [n = 127], 57.8% for intermediate-risk [IR, n = 122], and 59.2% for high-risk [HR, n = 101]) and OS was 78.7 +- 2.2% (85.4% for SR, 80.0% for IR, and 69.0% for HR). Incidences of relapse and non-relapse mortality were 37.2 +- 2.6% and 3.2 +- 0.9%, respectively. Five patients (0 in SR group, 3 in HR group, and 2 in HEX group) developed secondary malignant neoplasms before relapse, which resulted in cumulative incidence of secondary malignancy of 0.9 +- 0.5% at 12 years.Patient gender was associated with the outcome, and female had better EFS (65.3 +- 3.7%) compared to male (52.2 +- 3.8%) (p = 0.04, Figure 1B). High-hyperdiploid (HHD) patients had relatively worse prognosis, with EFS of 50.0 +- 11.8%, although it is generally considered as good prognostic factor, and most of the relapsed HHD patients were salvaged and OS was 94.4 +- 5.4%.It is confirmed that 6 months maintenance therapy is insufficient for male, HHD, and standard risk patients. In contrast, most of patients who had been in first CR at previous analysis maintained CCR status. Our results demonstrate that short maintenance therapy can cure a substantial portion of ALL with extremely low non-relapse mortality, and that it may be possible to shorten the duration of maintenance therapy for female and non-HHD patients. This study provides precise information of leukemia biology and highlights the role of maintenance therapy. Ongoing molecular characterization of the cured patients will clarify the subset of patients who can be cured with short maintenance therapy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Dexrazoxane: a cardioprotectant for pediatric cancer patients receiving anthracyclines.

Anthracyclines are a fundamental part of many childhood cancer therapy regimens; however, the discovery of anthracycline-induced cardiotoxicity has raised concern and led to dose limitation. The cardiotoxicity of anthracyclines has resulted in an increased demand for cardioprotectants. Dexrazoxane is the only cardioprotectant that has proven efficacy in reducing cardiotoxic effects when given prior to the administration of anthracyclines. Currently, it is still considered an "off-label" use due to a paucity of data in the literature on dexrazoxane administration in children. Nevertheless, through evaluation of the available data, dexrazoxane is observed to be safe, tolerable, and efficacious in mitigating the cardiotoxic effects of anthracycline in children, without jeopardizing its antineoplastic activity or increasing the risk of developing secondary malignant neoplasms.

Second cancer risk in childhood cancer survivors treated with intensity-modulated radiation therapy (IMRT).

Treatment with radiotherapy (RT) is associated with an increased risk of second malignant neoplasms (SMNs) in childhood cancer survivors; it is unclear how treatment with intensity-modulated radiation therapy (IMRT) impacts this risk. We provide the first report of SMN risk in a cohort of childhood cancer survivors treated with IMRT. Retrospective review of patients ≤21 years of age treated with IMRT at Memorial Sloan Kettering Cancer Center between December 1998 and February 2009. Eligible patients survived at least 5 years from IMRT initiation. The risk of SMN was assessed via standardized incidence ratios (SIRs) and excess absolute risk (EAR). The cumulative incidence was estimated using methods for competing risks. Among 242 patients, six developed SMNs: four developed second solid cancers (all within the radiation field), and two developed myelodysplastic syndrome. Median time from IMRT initiation to a second solid cancer was 7.2 years (range, 6.8-9.5), with a 10-year cumulative incidence of 3.3% (95% confidence interval [CI], 1.0-7.8%), SIR of 11.4 (95% CI, 3.1-29.2) and EAR of 1.8 per 1,000 person-years (95% CI, -0.1 to 3.8). Longer follow-up is required to determine how the risk of SMN after IMRT compares to other modalities of radiation treatment, such as proton therapy. This study provides a preliminary report, which will serve as a baseline for future longitudinal analyses of SMN risk after IMRT. Pediatr Blood Cancer 2015;62:311-316. © 2014 Wiley Periodicals, Inc.

Validating Billing/Encounter Codes as Indicators of Lung, Colorectal, Breast, and Prostate Cancer Recurrence Using 2 Large Contemporary Cohorts

A substantial proportion of cancer-related mortality is attributable to recurrent, not de novo metastatic disease, yet we know relatively little about these patients. To fill this gap, investigators often use administrative codes for secondary malignant neoplasm or chemotherapy to identify recurrent cases in population-based datasets. However, these algorithms have not been validated in large, contemporary, routine care cohorts. To evaluate the validity of secondary malignant neoplasm and chemotherapy codes as indicators of recurrence after definitive local therapy for stage I-III lung, colorectal, breast, and prostate cancer. We assessed the sensitivity, specificity, and positive predictive value (PPV) of these codes 14 and 60 months after diagnosis using 2 administrative datasets linked with gold-standard recurrence status information: CanCORS/Medicare (diagnoses 2003-2005) and HMO/Cancer Research Network (diagnoses 2000-2005). We identified 929 CanCORS/Medicare patients and 5298 HMO/CRN patients. Sensitivity, specificity, and PPV ranged widely depending on which codes were included and the type of cancer. For patients with lung, colorectal, and breast cancer, the combination of secondary malignant neoplasm and chemotherapy codes was the most sensitive (75%-85%); no code-set was highly sensitive and highly specific. For prostate cancer, no code-set offered even moderate sensitivity (≤ 19%). Secondary malignant neoplasm and chemotherapy codes could not identify recurrent cancer without some risk of misclassification. Findings based on existing algorithms should be interpreted with caution. More work is needed to develop a valid algorithm that can be used to characterize outcomes and define patient cohorts for comparative effectiveness research studies.

Utility of bronchoalveolar lavage in cytology; a study at tertiary care hospital

Background: Numerous case reports have shown the advantage of using bronchoalveolar lavage (BAL) in cytologic diagnosis of primary and secondary malign ant neoplasm of the respiratory system. Aim: The aim of this study was to determine the usefulness of BAL in the diagnosis of malignant and non malignant lesions o f the lower respiratory tract. Material & Method: A retrospective analysis of 13 cases of BAL fluid r eceived at cytology department was analyzed for its utility in diagnosi ng and its usefulness for confirming the diagnosis. Result: From 13 cases 3 cases were found to be positive for mali gnant cells.Male to female ratio was 4:1. Age distr ibution varied between 18years to 80 years. Conclusion: BAL proved to be a valuable diagnostic tool in dete cting malignant and non malignant lesions.

Second malignancies in patients with neuroblastoma: the effects of risk-based therapy.

To investigate the incidence of second malignant neoplasms (SMN) for patients with neuroblastoma, we analyzed patients from the SEER database according to three treatment eras (Era 1: 1973-1989, Era 2: 1990-1996, and Era 3: 1997-2006) corresponding to the introduction of multi-agent chemotherapy, risk-based treatment, and stem cell transplant. The SEER database was mined for all patients with neuroblastoma or ganglioneuroblastoma. Cumulative incidence of SMN was calculated with death as a competing risk. A poisson regression model was used to estimate incidence rate ratios and 95% confidence intervals to compare the rates of SMN between patients in different Eras. The analytic cohort included 2,801 patients. Thirty-four patients developed a SMN, accounting for 1.2% of all patients. Of the patients who developed a SMN, 47.1% received radiation for their primary neuroblastoma. Fourteen of the SMN were carcinomas, and 10 were hematologic malignancies, with six cases of acute myelogenous leukemia. There was no difference in the incidence of SMN in Era 1 compared to Era 3 (P = 0.48). The cumulative incidence of SMN at 30 years for high-risk patients was 10.44% (95% CI 3.98-20.52%) compared to 3.57% (95% CI 1.87-6.12%) for non-high-risk patients (P < 0.001). This study showed no increase in the incidence of SMNs for children treated in the most recent treatment era as compared to earlier Eras. However, as the risk for developing SMN does not plateau, the number of SMNs will likely continue to rise in the cohort of patients treated after 1996. Comprehensive follow-up care for these survivors will be important.

Secondary malignant neoplasms after osteosarcoma: early onset and cumulative alkylating agent dose dependency.

To analyze the impacts of chemotherapeutic agent exposures on the development of secondary malignant neoplasms (SMP) after osteosarcoma. Of 132 patients who had been treated for high-grade extremity osteosarcoma from September 1992 to September 2008, 90 survivors were retrospectively reviewed. Fifty-eight of the survivors received a doublet of doxorubicin (ADR) and cisplatin (DDP), and 32 received a triplet of ADR, DDP, and ifosfamide (Ifos). On the basis of the dose distributions in the study cohort, the association between SMN and the cumulative dose of each agent was evaluated. After a mean of 13.1 years of follow-up, six SMNs were noted, three in each regimen. There were no SMNs among 42 patients who died of osteosarcoma. In Kaplan-Meier estimates, the triplet regimen group showed a higher cumulative incidence and shorter latency for SMNs than the doublet group (log rank P = 0.032). Fifteen years' cumulative incidence of SMNs in the triplet and doublet regimen group was 9.4 and 3.8%, respectively. In the independent t test, the mean latency to SMN in the triplet group (3.7 ± 1.3 years) was shorter than that in the double group (13.1 ± 2.8 years) (P = 0.017). In Cox regression, the alkylating agent score (AAS) [hazard ratio (HR) = 2.459, P = 0.015] and DDP (HR = 1.779, P = 0.046) showed a significant relationship with SMNs, whereas ADR (HR = 0.896, P = 0.664) and Ifos (HR = 3.694, P = 0.119) did not. AAS was also significant after adjusting for ADR and DDP (HR = 3.319, P = 0.020). High cumulative AAS is an independent risk factor for SMN and its early-onset development after osteosarcoma.

Second Cancer Risk in Childhood Cancer Survivors Treated With Intensity Modulated Radiation Therapy (IMRT)

Background Treatment with radiotherapy (RT) is associated with an increased risk of second malignant neoplasms (SMNs) in childhood cancer survivors; it is unclear how treatment with intensity-modulated radiation therapy (IMRT) impacts this risk. We provide the first report of SMN risk in a cohort of childhood cancer survivors treated with IMRT. Procedure Retrospective review of patients ≤21 years of age treated with IMRT at Memorial Sloan Kettering Cancer Center between December 1998 and February 2009. Eligible patients survived at least 5 years from IMRT initiation. The risk of SMN was assessed via standardized incidence ratios (SIRs) and excess absolute risk (EAR). The cumulative incidence was estimated using methods for competing risks. Results Among 242 patients, six developed SMNs: four developed second solid cancers (all within the radiation field), and two developed myelodysplastic syndrome. Median time from IMRT initiation to a second solid cancer was 7.2 years (range, 6.8–9.5), with a 10-year cumulative incidence of 3.3% (95% confidence interval [CI], 1.0–7.8%), SIR of 11.4 (95% CI, 3.1–29.2) and EAR of 1.8 per 1,000 person-years (95% CI, −0.1 to 3.8). Conclusions Longer follow-up is required to determine how the risk of SMN after IMRT compares to other modalities of radiation treatment, such as proton therapy. This study provides a preliminary report, which will serve as a baseline for future longitudinal analyses of SMN risk after IMRT. Pediatr Blood Cancer 2015;62:311–316. © 2014 Wiley Periodicals, Inc.

Secondary malignant neoplasms among children, adolescents, and young adults with osteosarcoma.

As patients with osteosarcoma become long-term survivors, increasing attention has turned to the burden of late effects. The goal of the current study was to describe the incidence, characteristics, and outcomes of secondary malignant neoplasms (SMNs) in this population. Patients aged birth to 40 years at time of primary diagnosis with osteosarcoma and reported to the Surveillance, Epidemiology, and End Results (SEER) program between 1973 and 2010 were eligible for inclusion in the cohort. Competing risks methods were used to estimate the cumulative incidence of SMNs and potential risk factors for developing an SMN. Standardized incidence ratios (SIR) and overall survival after an SMN were estimated. The SEER database included 3379 patients who were diagnosed with osteosarcoma as their first malignancy. Of these, 89 patients were diagnosed with an SMN. The cumulative incidence of any SMN was 2.1% (95% confidence interval [95% CI], 1.6%-2.7%) at 10 years, 4.0% (95% CI, 3.1%-5.1%) at 20 years, and 7.4% (95% CI, 5.6%-9.5%) at 30 years. The median time from the primary diagnosis to an SMN diagnosis was 6.0 years. The SIR for SMNs for survivors of osteosarcoma compared with the general population was 1.6 (95% CI, 1.0-2.5) for patients diagnosed with osteosarcoma from 1973 through 1985 and 4.7 (95% CI, 3.3-6.4) for patients diagnosed with osteosarcoma from 1986 through 2010, with a 34-fold increased risk of leukemia in this most recent era. The overall survival rate at 5 years for patients with SMNs after a diagnosis of osteosarcoma was 44.5%. Survivors of osteosarcoma are at an increased risk of developing SMNs compared with the baseline population, with an increased risk noted in patients treated in the more recent era.

Computed Tomography Correlation of Airway Disease With Bronchoscopy—Part II: Tracheal Neoplasms

This pictorial essay illustrates, describes, and correlates computed tomographic findings of tracheal neoplasms with fiberoptic bronchoscopy findings. Corresponding computed tomography (CT) and bronchoscopy findings of common primary tracheal neoplasms; squamous cell papilloma, papillomatosis, squamous cell carcinoma, adenoid cystic adenoma, non-Hodgkin׳s lymphoma, and a secondary malignant neoplasm of the trachea; and renal cell carcinoma were correlated.

Methodological extensions of meta-analysis with excess relative risk estimates: application to risk of second malignant neoplasms among childhood cancer survivors treated with radiotherapy.

Although radiotherapy is recognized as an established risk factor for second malignant neoplasms (SMNs), the dose response of SMNs following radiotherapy has not been well characterized. In our previous meta-analysis of the risks of SMNs occurring among children who have received radiotherapy, the small number of eligible studies precluded a detailed evaluation. Therefore, to increase the number of eligible studies, we developed a method of calculating excess relative risk (ERR) per Gy estimates from studies for which the relative risk estimates for several dose categories were available. Comparing the calculated ERR with that described in several original papers validated the proposed method. This enabled us to increase the number of studies, which we used to conduct a meta-analysis. The overall ERR per Gy estimate of radiotherapy over 26 relevant studies was 0.60 (95%CI: 0.30–1.20), which is smaller than the corresponding estimate for atomic bomb survivors exposed to radiation as young children (1.7; 95% CI: 1.1–2.5). A significant decrease in ERR per Gy with increase in age at exposure (0.85 times per annual increase) was observed in the meta-regression. Heterogeneity was suggested by Cochran's Q statistic (P < 0.001), which may be partly accounted for by age at exposure.

Current knowledge and future research directions in treatment-related second primary malignancies

Currently, 17–19% of all new primary malignancies occur in survivors of cancer, causing substantial morbidity and mortality. Research has shown that cancer treatments are important contributors to second malignant neoplasm (SMN) risk.In this paper we summarise current knowledge with regard to treatment-related SMNs and provide recommendations for future research. We address the risks associated with radiotherapy and systemic treatments, modifying factors of treatment-related risks (genetic susceptibility, lifestyle) and the potential benefits of screening and interventions. Research priorities were identified during a workshop at the 2014 Cancer Survivorship Summit organised by the European Organisation for Research and Treatment of Cancer.Recently, both systemic cancer treatments and radiotherapy approaches have evolved rapidly, with the carcinogenic potential of new treatments being unknown. Also, little knowledge is available about modifying factors of treatment-associated risk, such as genetic variants and lifestyle. Therefore, large prospective studies with biobanking, high quality treatment data (radiation dose–volume, cumulative drug doses), and data on other cancer risk factors are needed. International collaboration will be essential to have adequate statistical power for such investigations. While screening for SMNs is included in several follow-up guidelines for cancer survivors, its effectiveness in this special population has not been demonstrated. Research into the pathogenesis, tumour characteristics and survival of SMNs is essential, as well as the development of interventions to reduce SMN-related morbidity and mortality. Prediction models for SMN risk are needed to inform initial treatment decisions, balancing chances of cure and SMNs and to identify high-risk subgroups of survivors eligible for screening.

Increased risk of second malignant neoplasms (SMN) in young children with embryonal rhabdomyosarcoma (ERMS): Evidence for a cancer predisposition syndrome?

10042 Background: Germline TP53 mutations have been recently described in children with anaplastic EMRS, suggesting a possible association with Li-Fraumeni syndrome (LFS). In this population-based ...

Second malignant neoplasms in patients with Cowden syndrome with underlying germline PTEN mutations.

Patients with Cowden syndrome (CS) with underlying germline PTEN mutations are at increased risk of breast, thyroid, endometrial, and renal cancers. To our knowledge, risk of subsequent cancers in these patients has not been previously explored or quantified. We conducted a 7-year multicenter prospective study (2005 to 2012) of patients with CS or CS-like disease, all of whom underwent comprehensive PTEN mutational analysis. Second malignant neoplasms (SMNs) were ascertained by medical records and confirmed by pathology reports. Standardized incidence ratios (SIRs) for all SMNs combined and for breast, thyroid, endometrial, and renal cancers were calculated. Of the 2,912 adult patients included in our analysis, 2,024 had an invasive cancer history. Germline pathogenic PTEN mutations (PTEN mutation positive) were identified in 114 patients (5.6%). Of these 114 patients, 46 (40%) had an SMN. Median age of SMN diagnosis was 50 years (range, 21 to 71 years). Median interval between primary cancer and SMN was 5 years (range, <1 to 35 years). Of the 51 PTEN mutation-positive patients who presented with primary breast cancer, 11 (22%) had a subsequent new primary breast cancer and 10-year second breast cancer cumulative risk of 29% (95% CI, 15.3 to 43.7). Risk of SMNs compared with that of the general population was significantly elevated for all cancers (SIR, 7.74; 95% CI, 5.84 to 10.07), specifically for breast (SIR, 8.92; 95% CI, 5.85 to 13.07), thyroid (SIR, 5.83; 95% CI, 3.01 to 10.18), and endometrial SMNs (SIR, 14.08.07; 95% CI, 7.10 to 27.21). Patients with CS with germline PTEN mutations are at higher risk for SMNs compared with the general population. Prophylactic mastectomy should be considered on an individual basis given the significant risk of subsequent breast cancer.

Repair of ionizing radiation-induced DNA damage and risk of second cancer in childhood cancer survivors

The study's purpose was to assess whether individuals who developed a second malignant neoplasm (SMN) after treatment for a first malignant neoplasm (FMN) had a lower ability to repair DNA double-strand breaks (DSBs) using a bioassay with γH2AX intensity as a surrogate endpoint. In a case-control study nested in a cohort of childhood cancer survivors, lymphoblastoid cell lines (LCLs) were established from blood samples collected from 94 cases (SMN) and 94 matched controls (FMN). LCLs were irradiated with ionizing radiation (2 and 5 Gy) and γH2AX intensities measured 1, 3, 5 and 24h post-irradiation. Differences in mean γH2AX intensity between cases and controls were compared using Kruskal-Wallis tests. Generalized linear models for repeated measures and conditional logistic regressions for SMN risk estimates were performed. The mean baseline γH2AX intensity measured without irradiation was 9.1 [95% confidence interval (95% CI): 8.5-9.7] in the LCLs from cases and 6.4 (95% CI: 6.0-6.8) from controls (P < 0.001). Markedly higher γH2AX intensity, particularly at 1 h post-irradiation, was also found in the LCLs from the cases compared with the controls for all FMNs and for different types of FMN. Chemotherapy and radiation doses received by bone marrow and thymus for FMN treatment showed a non-significant effect on γH2AX intensity. This case-control study shows that higher baseline and post-irradiation levels of DNA DSBs, as measured by γH2AX intensity, are associated with the risk of SMN in childhood cancer survivors. Further investigations in a prospective setting are warranted to confirm this association.