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1.  Telomere Content and Risk of Second Malignant Neoplasm in Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study 
PURPOSE
Shorter constitutional telomere length has been associated with increased cancer incidence. Furthermore, telomere shortening is observed in response to intensive chemotherapy and/or ionizing radiation exposure. We aimed to determine if less telomere content was associated with treatment-related second malignant neoplasms (SMNs) in childhood cancer survivors.
EXPERIMENTAL DESIGN
Using a nested case-control design, 147 cancer survivors with breast cancer, thyroid cancer, or sarcoma developing after treatment for childhood cancer (cases) were matched (1:1) with childhood cancer survivors without a SMN (controls). Cases and controls were matched by primary cancer diagnosis, years since diagnosis, age at time of sample collection, years of follow up from childhood cancer diagnosis, exposure to specific chemotherapy agents, and to specific radiation fields. We performed conditional logistic regression using telomere content (TC) as a continuous variable to estimate odds ratios (ORs) with corresponding 95% confidence intervals (CI) for development of SMN. ORs were also estimated for specific SMN types, i.e., breast cancer, thyroid cancer, and sarcoma.
RESULTS
There was an inverse relationship between TC and SMN, with an adjusted OR of 0.3 per unit change in telomere length to single copy gene ratio (95% CI, 0.09–1.02, p=0.05). Patients with thyroid cancer SMN were less likely to have more telomere content (OR 0.04, 95% CI, 0.00–0.55, p=0.01), but statistically significant associations could not be demonstrated for breast cancer or sarcoma.
CONCLUSIONS
A relation between less telomere content and treatment-related thyroid cancer was observed, suggesting that shorter telomeres may contribute to certain SMNs in childhood cancer survivors.
doi:10.1158/1078-0432.CCR-13-2076
PMCID: PMC3944671  PMID: 24277454
telomere; second malignant neoplasm; risk; childhood cancer
2.  Physiologic Frailty As a Sign of Accelerated Aging Among Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study 
Journal of Clinical Oncology  2013;31(36):4496-4503.
Purpose
Frailty, a phenotype reported among 9.9% of individuals 65 years old and older (9.6% of women; 5.2% of men), has not been assessed among adult childhood cancer survivors (CCS). We estimated the prevalence of frailty and examined associations with morbidity and mortality.
Methods
Participants included 1,922 CCS at least 10 years from original cancer diagnosis (men, 50.3%; mean age, 33.6 ± 8.1 years) and a comparison population of 341 participants without cancer histories. Prefrailty and frailty were defined as two and ≥ three of the following conditions: low muscle mass, self-reported exhaustion, low energy expenditure, slow walking speed, and weakness. Morbidity was defined as grade 3 to 4 chronic conditions (Common Terminology Criteria for Adverse Events version 4.0). Fisher's exact tests were used to compare, by frailty status, percentages of those with morbidity. In a subset of 162 CCS who returned for a second visit, Poisson regression was used to evaluate associations between frailty and new onset morbidity. Cox proportional hazards regression was used to evaluate associations between frailty and death.
Results
The prevalence of prefrailty and frailty were 31.5% and 13.1% among women and 12.9% and 2.7% among men, respectively, with prevalence increasing with age. Frail CCS were more likely than nonfrail survivors to have a chronic condition (82.1% v 73.8%). In models adjusted for existing chronic conditions, baseline frailty was associated with risk of death (hazard ratio, 2.6; 95% CI, 1.2 to 6.2) and chronic condition onset (relative risk, 2.2; 95% CI, 1.2 to 4.2).
Conclusion
The prevalence of frailty among young adult CCS is similar to that among adults 65 years old and older, suggesting accelerated aging.
doi:10.1200/JCO.2013.52.2268
PMCID: PMC3871511  PMID: 24248696
3.  Neurocognitive Outcomes Decades After Treatment for Childhood Acute Lymphoblastic Leukemia: A Report From the St Jude Lifetime Cohort Study 
Journal of Clinical Oncology  2013;31(35):4407-4415.
Purpose
To determine rates, patterns, and predictors of neurocognitive impairment in adults decades after treatment for childhood acute lymphoblastic leukemia (ALL).
Patients and Methods
Survivors of childhood ALL treated at St Jude Children's Research Hospital who were still alive at 10 or more years after diagnosis and were age ≥ 18 years were recruited for neurocognitive testing. In all, 1,014 survivors were eligible, 738 (72.8%) agreed to participate, and 567 (76.8%) of these were evaluated. Mean age was 33 years; mean time since diagnosis was 26 years. Medical record abstraction was performed for data on doses of cranial radiation therapy (CRT) and cumulative chemotherapy. Multivariable modeling was conducted and glmulti package was used to select the best model with minimum Akaike information criterion.
Results
Impairment rates across neurocognitive domains ranged from 28.6% to 58.9%, and those treated with chemotherapy only demonstrated increased impairment in all domains (all P values < .006). In survivors who received no CRT, dexamethasone was associated with impaired attention (relative risk [RR], 2.12; 95% CI, 1.11 to 4.03) and executive function (RR, 2.42; 95% CI, 1.20 to 4.91). The impact of CRT was dependent on young age at diagnosis for intelligence, academic, and memory functions. Risk for executive function problems increased with survival time in a CRT dose-dependent fashion. In all survivors, self-reported behavior problems increased by 5% (RR, 1.05; 95% CI, 1.01 to 1.09) with each year from diagnosis. Impairment was associated with reduced educational attainment and unemployment.
Conclusion
This study demonstrates persistent and significant neurocognitive impairment in adult survivors of childhood ALL and warrants ongoing monitoring of brain health to facilitate successful adult development and to detect early onset of decline as survivors mature.
doi:10.1200/JCO.2012.48.2315
PMCID: PMC3842908  PMID: 24190124
4.  HIV risks vary according to type of sex work in a cross-sectional survey from Nagaland, India 
BMC Women's Health  2014;14(1):133.
Background
Human immunodeficiency virus (HIV) infection is a significant problem among female sex workers (FSWs) in Nagaland, India. Place of solicitation and sex vary considerably in this context. The aim of this study was to investigate the relationship between categories of sex work and HIV risks.
Methods
In 2009 a survey was undertaken among 417 FSWs in Dimapur, Nagaland using an interviewer-administered questionnaire and blood and urine samples. Using this data, we constructed a typology of sex work by combining usual place of solicitation and place of sex, and examined variations in demographics, sex work patterns, sexually transmitted infections (STIs) and HIV prevalence across typology categories. Binary logistic regression analyses were done to examine the association between category of sex work and HIV, STIs, and condom use.
Results
By combining place of solicitation with place of sex, seven distinct categories of sex work emerged. The largest category were women who usually solicited in a public place and had sex in a rented room or lodge (31.7%, n = 132). One-tenth of participants were HIV positive (10.3%) and 35.4% had at least one STI (reactive syphilis serology, gonorrhoea or chlamydia). FSWs who both solicited and entertained in a rented room or lodge (OR = 13.3; 95% CI 2.2, 81.5) and those who solicited by phone and had sex in a rented room or lodge (OR = 6.3; 95% CI 1.0, 38.0) were more likely to be HIV positive compared to home-based FSWs. Women who both solicited and entertained in public (OR = 6.7; 95% CI 1.6, 28.0) and who solicited in public and entertained in a rented room or lodge (OR = 2.5; 95% CI 1.1, 6.0) were more likely to test positive for an STI compared to home-based FSWs.
Conclusion
The results indicate that different categories of sex work are associated with different HIV and STI risk profiles. Local contextual understanding of the different types of sex work and the associated levels of risk assist NGOs to target their interventions more effectively and efficiently in order to reduce STI and HIV prevalence among FSWs and their clients.
doi:10.1186/s12905-014-0133-6
PMCID: PMC4240872  PMID: 25388946
HIV; Sex work; STI; India; Typology
5.  Injecting drug use in Manipur and Nagaland, Northeast India: injecting and sexual risk behaviours across age groups 
Harm Reduction Journal  2014;11(1):27.
Background
There is an HIV epidemic among people who inject drugs (PWID) in Manipur and Nagaland, Northeast India. Approximately one-third of PWID across these two states are aged below 25 years, yet until now there has been no systematic investigation of the differences between the younger and older PWID. We sought to profile differences in drug use and sexual practices across age groups and to examine whether age is associated with injecting and sexual risk behaviours.
Methods
We used combined cross-sectional survey data collected in 2009 from two surveys involving a total of 3,362 (male) PWID in eight districts of Manipur and Nagaland. All data were collected using interviewer-administered questionnaires.
Results
Compared to PWID aged 35 years or older, PWID aged 18 to 24 years were more likely share needles/syringes in both Manipur (OR =1.8) and Nagaland (OR =1.6). Compared to PWID aged 35 years or older, PWID aged 18 to 24 years were almost two times as likely to draw up drug solution from a common container at their last injection in Manipur (OR =1.8). In Nagaland, PWID aged 18 to 24 years were more likely to use condoms consistently with both casual (OR =3.1) and paid (OR =17.7) female sexual partners compared to PWID aged 35 years or older.
Conclusion
Risky injecting practices were more common among younger PWID in both Manipur and Nagaland, while unprotected sex was more common among older PWID in Nagaland. There is a clear need to focus public health messages across different age groups.
doi:10.1186/1477-7517-11-27
PMCID: PMC4210540  PMID: 25312004
Injecting drug use; HIV; Youth
6.  Modifiable Risk Factors and Major Cardiac Events Among Adult Survivors of Childhood Cancer 
Journal of Clinical Oncology  2013;31(29):3673-3680.
Purpose
To evaluate the relative contribution of modifiable cardiovascular risk factors on the development of major cardiac events in aging adult survivors of childhood cancer.
Patients and Methods
Among 10,724 5-year survivors (median age, 33.7 years) and 3,159 siblings in the Childhood Cancer Survivor Study, the prevalence of hypertension, diabetes mellitus, dyslipidemia, and obesity was determined, along with the incidence and severity of major cardiac events such as coronary artery disease, heart failure, valvular disease, and arrhythmia. On longitudinal follow-up, rate ratios (RRs) of subsequent cardiac events associated with cardiovascular risk factors and cardiotoxic therapy were assessed in multivariable Poisson regression models.
Results
Among survivors, the cumulative incidence of coronary artery disease, heart failure, valvular disease, and arrhythmia by 45 years of age was 5.3%, 4.8%, 1.5%, and 1.3%, respectively. Two or more cardiovascular risk factors were reported by 10.3% of survivors and 7.9% of siblings. The risk for each cardiac event increased with increasing number of cardiovascular risk factors (all Ptrend < .001). Hypertension significantly increased risk for coronary artery disease (RR, 6.1), heart failure (RR, 19.4), valvular disease (RR, 13.6), and arrhythmia (RR, 6.0; all P values < .01). The combined effect of chest-directed radiotherapy plus hypertension resulted in potentiation of risk for each of the major cardiac events beyond that anticipated on the basis of an additive expectation. Hypertension was independently associated with risk of cardiac death (RR, 5.6; 95% CI, 3.2 to 9.7).
Conclusion
Modifiable cardiovascular risk factors, particularly hypertension, potentiate therapy-associated risk for major cardiac events in this population and should be the focus of future interventional studies.
doi:10.1200/JCO.2013.49.3205
PMCID: PMC3804290  PMID: 24002505
7.  Incidental Detection of Late Subsequent Intracranial Neoplasms with Magnetic Resonance Imaging Among Adult Survivors of Childhood Cancer 
Purpose
Survivors of childhood cancer are at increased risk of developing subsequent neoplasms. In long term survivors of childhood malignancies treated with and without cranial radiation therapy (CRT), undergoing unenhanced magnetic resonance imaging (MRI) of the brain, we estimated detection of intracranial neoplasms.
Methods
To investigate neurocognitive outcomes, 219 survivors of childhood cancer underwent unenhanced screening MRI of the brain. 164 of the survivors had been treated for acute lymphoblastic leukemia (ALL) (125 received CRT), and 55 for Hodgkin lymphoma (HL) (none received CRT). MRI examinations were reviewed and systematically coded by a single neuroradiologist. Demographic and treatment characteristics were compared for survivors with and without subsequent neoplasms.
Results
Nineteen of the 219 survivors (8.7%) had a total of 31 subsequent intracranial neoplasms identified by neuroimaging at a median time of 25 years (range 12-46 years) from diagnosis. All neoplasms occurred after CRT, except for a single vestibular schwannoma within the cervical radiation field in a HL survivor. The prevalence of subsequent neoplasms after CRT exposure was 14.4% (18 of 125). By noncontrast MRI, intracranial neoplasms were most suggestive of meningiomas. Most patients presented with no specific, localizing neurological complaints. In addition to the schwannoma, six tumors were resected based on results of MRI screening, all of which were meningiomas on histologic review.
Conclusion
Unenhanced brain MRI of long-term survivors of childhood cancer detected a substantial number of intracranial neoplasms. Screening for early detection of intracranial neoplasms among aging survivors of childhood cancer who received CRT should be evaluated.
Implications for Cancer Survivors
The high prevalence of incidentally detected subsequent intracranial neoplasms after CRT in long-term survivors of childhood cancer and the minimal symptoms reported by those with intracranial tumors in our study indicate that brain MRI screening of long-term survivors who received CRT may be warranted. Prospective studies of such screening are needed.
doi:10.1007/s11764-014-0344-8
PMCID: PMC4119575  PMID: 24488818
Survivors of Childhood Cancer; Cranial Radiation Therapy; Subsequent Intracranial Neoplasms; Meningiomas
8.  Chemotherapy-related neuropathic symptoms and functional impairment in adult survivors of extracranial solid tumors of childhood: Results from the St. Jude Lifetime Cohort Study 
Objective
To ascertain prevalence of peripheral sensory and motor neuropathy; to evaluate impairments in relation to function.
Design
St. Jude Lifetime Cohort Study, a clinical follow-up study designed to evaluate adverse late effects in adult survivors of childhood cancer.
Setting
St. Jude Children’s Research Hospital (SJCRH).
Participants
Eligibility required treatment for an extracranial solid malignancy between 1962 and 2002, age ≥18 years, ≥10 years post-diagnosis, no history of cranial radiation. 531 survivors were included in the evaluation: median age 32 years, median time from diagnosis 25 years.
Interventions
Not applicable.
Main Outcome Measures
Primary exposure measures were cumulative doses of vinca-alkaloid and platinum-based chemotherapies. Survivors with scores ≥ 1 on the sensory subscale of the modified Total Neuropathy Score were classified with prevalent sensory impairment. Those with sex-specific Z-scores of ≤−1.3 for dorsiflexion strength were classified with prevalent motor impairment. Participants completed the 6-minute walk test (endurance), the timed up and go test (mobility), and the sensory organization test (balance).
Results
The prevalence of sensory and motor impairment was 20% and 17.5%, respectively. Vinca-alkaloid exposure was associated with an increased risk of motor impairment (adjusted odds ratio (OR)=1.66, 95% Confidence Interval (CI): 1.04–2.64) without evidence for a dose response. Platinum exposure was associated with increased risk of sensory impairment (adjusted OR= 1.62, 95% CI: 0.97–2.72) without evidence of a dose response. Sensory impairment was associated with poor endurance (OR=1.99, 95% CI: 0.99–4.00) and mobility (OR=1.65, 95% CI: 0.96–2.83).
Conclusion
Vincristine and cisplatin exposure may increase risk for long-term motor and sensory impairment, respectively. Survivors with sensory impairment are at increased risk for functional performance limitations.
doi:10.1016/j.apmr.2013.03.009
PMCID: PMC3929944  PMID: 23537607
Peripheral nervous system diseases; vincristine; cisplatin; neoplasm
9.  Radiation, Atherosclerotic Risk Factors and Stroke Risk in Survivors of Pediatric Cancer: a Report from the Childhood Cancer Survivor Study 
Background
The impact of childhood cranial radiation therapy (CRT) on stroke risk in adulthood, and the role of modifiable atherosclerotic risk factors, remains poorly defined. We assessed long-term incidence rates and stroke risk factors in survivors of childhood cancer followed by the Childhood Cancer Survivor Study (CCSS).
Patients and Methods
CCSS is a multi-institutional retrospective cohort study of 14,358 five-year survivors of childhood cancer and 4,023 randomly selected sibling controls with longitudinal follow up. Age-adjusted incidence rates of self-reported late-occurring (≥ 5 years after diagnosis) first-stroke were calculated. Multivariable Cox Proportional Hazards models were used to identify independent stroke predictors.
Results
During a mean follow-up of 23.3 years, 292 survivors reported a late-occurring stroke. The age-adjusted stroke rate per 100,000 person-years was 77 (95% Confidence Interval [CI] 62–96) compared to 9.3 (95% CI 4–23) for siblings. Treatment with CRT increased stroke risk in a dose dependent manner: hazard ratio (HR) 5.9 (95% CI 3.5–9.9) for 30–49 Gy CRT, and 11.0 (7.4–17.0) for 50+ Gy CRT. The cumulative stroke incidence in survivors treated with 50+ Gy CRT was 1.1% (95% CI 0.4–1.8) at 10 years post-diagnosis and 12% (95% CI 8.9–15.0) at 30 years. Hypertension (HTN) increased stroke hazard by 4-fold (95% CI 2.8–5.5) and in black survivors by 16-fold (95% CI 6.9–36.6).
Conclusion
Young adult pediatric cancer survivors have an increased stroke risk that is associated with CRT in a dose dependent manner. Atherosclerotic risk factors enhanced this risk and should be treated aggressively.
doi:10.1016/j.ijrobp.2013.03.034
PMCID: PMC3696633  PMID: 23680033
10.  Evaluation of Memory Impairment in Aging Adult Survivors of Childhood Acute Lymphoblastic Leukemia Treated With Cranial Radiotherapy 
Background
Cranial radiotherapy (CRT) is a known risk factor for neurocognitive impairment in survivors of childhood cancer and may increase risk for mild cognitive impairment and dementia in adulthood.
Methods
We performed a cross-sectional evaluation of survivors of childhood acute lymphoblastic leukemia (ALL) treated with 18 Gy (n = 127) or 24 Gy (n = 138) CRT. Impairment (age-adjusted score >1 standard deviation below expected mean, two-sided exact binomial test) on the Wechsler Memory Scale IV (WMS-IV) was measured. A subset of survivors (n = 85) completed structural and functional neuroimaging.
Results
Survivors who received 24 Gy, but not 18 Gy, CRT had impairment in immediate (impairment rate = 33.8%, 95% confidence interval [CI] = 25.9% to 42.4%; P < .001) and delayed memory (impairment rate = 30.2%, 95% CI = 22.6% to 38.6%; P < .001). The mean score for long-term narrative memory among survivors who received 24 Gy CRT was equivalent to that for individuals older than 69 years. Impaired immediate memory was associated with smaller right (P = .02) and left (P = .008) temporal lobe volumes, and impaired delayed memory was associated with thinner parietal and frontal cortices. Lower hippocampal volumes and increased functional magnetic resonance imaging activation were observed with memory impairment. Reduced cognitive status (Brief Cognitive Status Exam from the WMS-IV) was identified after 24 Gy (18.5%, 95% CI = 12.4% to 26.1%; P < .001), but not 18 Gy (8.7%, 95% CI = 4.4% to 15.0%; P = .11), CRT, suggesting a dose–response effect. Employment rates were equivalent (63.8% for 24 Gy CRT and 63.0% for 18 Gy CRT).
Conclusions
Adult survivors who received 24 Gy CRT had reduced cognitive status and memory, with reduced integrity in neuroanatomical regions essential in memory formation, consistent with early onset mild cognitive impairment.
doi:10.1093/jnci/djt089
PMCID: PMC3687368  PMID: 23584394
11.  Report on the International Colloquium on Cardio-Oncology (Rome, 12–14 March 2014) 
ecancermedicalscience  2014;8:433.
Cardio-oncology is a relatively new discipline that focuses on the cardiovascular sequelae of anti-tumour drugs. As any other young adolescent discipline, cardio-oncology struggles to define its scientific boundaries and to identify best standards of care for cancer patients or survivors at risk of cardiovascular events. The International Colloquium on Cardio-Oncology was held in Rome, Italy, 12–14 March 2014, with the aim of illuminating controversial issues and unmet needs in modern cardio-oncology. This colloquium embraced contributions from different kind of disciplines (oncology and cardiology but also paediatrics, geriatrics, genetics, and translational research); in fact, cardio-oncology goes way beyond the merging of cardiology with oncology. Moreover, the colloquium programme did not review cardiovascular toxicity from one drug or the other, rather it looked at patients as we see them in their fight against cancer and eventually returning to everyday life. This represents the melting pot in which anti-cancer therapies, genetic backgrounds, and risk factors conspire in producing cardiovascular sequelae, and this calls for screening programmes and well-designed platforms of collaboration between one key professional figure and another.
The International Colloquium on Cardio-Oncology was promoted by the Menarini International Foundation and co-chaired by Giorgio Minotti (Rome), Joseph R Carver (Philadelphia, Pennsylvania, United States), and Steven E Lipshultz (Detroit, Michigan, United States). The programme was split into five sessions of broad investigational and clinical relevance (what is cardiotoxicity?, cardiotoxicity in children, adolescents, and young adults, cardiotoxicity in adults, cardiotoxicity in special populations, and the future of cardio-oncology). Here, the colloquium chairs and all the session chairs briefly summarised what was said at the colloquium. Topics and controversies were reported on behalf of all members of the working group of the International Colloquium on Cardio-Oncology.
doi:10.3332/ecancer.2014.433
PMCID: PMC4039411  PMID: 24932213
cardio-oncology; antitumor therapies; cardiovascular sequelae; patients; survivors
12.  Restricted Access to the Environment and Quality of Life in Adult Survivors of Childhood Brain Tumors 
Journal of neuro-oncology  2012;111(2):195-203.
Background:
Survivors of pediatric brain tumors are at-risk for late effects which may affect mobility within and access to the physical environment. This study examined the prevalence of and risk factors for restricted environmental access in survivors of childhood brain tumors and investigated the associations between reduced environmental access, health-related quality of life (HRQOL), and survivors’ social functioning.
Methods:
In-home evaluations were completed for 78 brain tumor survivors and 78 population-based controls matched on age, sex, and zip-code. Chi-square tests and multivariable logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for poor environmental access and reduced HRQOL.
Results:
The median age of survivors was 22 years at the time of study. Compared to controls, survivors were more likely to report avoiding most dimensions of their physical environment, including a single flight of stairs (p<0.001), uneven surfaces (p<0.001), traveling alone (p=0.01), and traveling to unfamiliar places (p=0.001). Overall, survivors were 4.8 times more likely to report poor environmental access (95% CI, 2.0-11.5, p<0.001). In survivors, poor environmental access was associated with reduced physical function (OR=3.6, 95% CI, 1.0-12.8, p=0.04), general health (OR=6.0, 95% CI, 1.8-20.6, p=0.002), and social functioning (OR=4.3, 95% CI, 1.1-17.3, p=0.03).
Conclusions:
Adult survivors of pediatric brain tumors were more likely to avoid their physical environment than matched controls. Restricted environmental access was associated with reduced HRQOL and diminished social functioning. Interventions directed at improving physical mobility may have significant impact on survivor quality of life.
doi:10.1007/s11060-012-1001-6
PMCID: PMC3995451  PMID: 23143294
CNS malignancies; survivorship; quality of life; environmental access
13.  Renal Carcinoma After Childhood Cancer: A Report From the Childhood Cancer Survivor Study 
Adult survivors of childhood cancer are known to be at increased risk of subsequent malignancy, but only limited data exist describing the incidence and risk factors for secondary renal carcinoma. Among 14 358 5-year survivors diagnosed between 1970 and 1986, we estimated standardized incidence ratios (SIRs) for subsequent renal carcinoma and identified associations with primary cancer therapy using Poisson regression. Twenty-six survivors were diagnosed with renal carcinoma (median = 22.6 years from diagnosis; range = 6.3–35.7 years), reflecting a statistically significant excess (SIR = 8.0, 95% confidence interval [CI] = 5.2 to 11.7) compared with the general population. Highest risk was observed among neuroblastoma survivors (SIR = 85.8, 95% CI = 38.4 to 175.2) and, in multivariable analyses, with renal-directed radiotherapy of 5 Gy or greater (relative risk [RR] = 3.8, 95% CI = 1.6 to 9.3) and platinum-based chemotherapy (RR = 3.5, 95% CI = 1.0 to 11.2). To our knowledge, this is the first report of an association between cisplatin and subsequent renal carcinoma among survivors of childhood cancer.
doi:10.1093/jnci/djt014
PMCID: PMC3691945  PMID: 23515901
14.  Risk of Salivary Gland Cancer Following Childhood Cancer: A Report From The Childhood Cancer Survivor Study 
Purpose
To evaluate effects of radiotherapy, chemotherapy, cigarette smoking and alcohol consumption on the risk of second primary salivary gland cancer (SGC) in the Childhood Cancer Survivor Study (CCSS).
Methods
Standardized incidence ratios (SIR) and excess absolute risks (EAR) of SGC in the CCSS were calculated using incidence rates from Surveillance, Epidemiology and End Results population-based cancer registries. Radiation dose to the salivary glands was estimated based on medical records. Poisson regression was used to assess risks with respect to radiation dose, chemotherapy, smoking and alcohol consumption.
Results
During the time period of the study, 23 cases of SGC were diagnosed among 14,135 childhood cancer survivors. The mean age at diagnosis of the first primary cancer was 8.3 years, and the mean age at SGC diagnosis was 24.8 years. The incidence of SGC was 39-fold higher in the cohort than in the general population (SIR=39.4; 95% CI: 25.4–7.8). The EAR was 9.8 per 100,000 person years. Risk increased linearly with radiation dose (excess relative risk=0.36 per gray; 95% CI: 0.06 to 2.5) and remained elevated after 20 years. There was no significant trend of increasing risk with increasing dose of chemotherapeutic agents, pack-years of cigarette smoking or alcohol intake.
Conclusion
While the cumulative incidence of SGC was low, childhood cancer survivors treated with radiation experienced significantly increased risk for at least two decades following exposure, and risk was positively associated with radiation dose. Results underscore the importance of long-term follow up of childhood cancer survivors for the development of new malignancies.
doi:10.1016/j.ijrobp.2012.06.006
PMCID: PMC3500417  PMID: 22836059
15.  Increased Tricuspid Regurgitant Jet Velocity by Doppler Echocardiography in Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study 
Journal of Clinical Oncology  2013;31(6):774-781.
Purpose
To determine the prevalence of pulmonary hypertension, a late effect of cancer therapy not previously identified in aging survivors of childhood cancer, and associations with chest-directed radiation therapy (RT) and measures of current cardiac function, lung function, and exercise capacity.
Patients and Methods
Cross-sectional evaluation of 498 survivors at a median age of 38.0 years (range, 20.0 to 59.0 years) and a median of 27.3 years (range, 12.2 to 46.0 years) from primary cancer diagnosis was performed. Abnormal tricuspid regurgitant jet velocity (TRV) was defined as more than 2.8 m/s by Doppler echocardiography.
Results
Increased TRV was identified in 25.2% of survivors who received chest-directed RT and 30.8% of those who received more than 30 Gy. In multivariable models, increased TRV was associated with increasing dose of RT (1 to 19.9 Gy: odds ratio [OR], 2.09; 95% CI, 0.63 to 6.96; 20 to 29.9 Gy: OR, 3.46; 95% CI, 1.59 to 7.54; ≥ 30 Gy: OR, 4.54; 95% CI, 1.77 to 11.64 compared with no RT; P for trend < .001), body mass index more than 40 kg/m2 (OR, 3.89; 95% CI, 1.46 to 10.39), and aortic valve regurgitation (OR, 5.85; 95% CI, 2.05 to 16.74). Survivors with a TRV more than 2.8 m/s had increased odds (OR, 5.20; 95% CI, 2.5 to 11.0) of severe functional limitation on a 6-minute walk compared with survivors with a TRV ≤ 2.8 m/s.
Conclusion
A substantial number of adult survivors of childhood cancer who received chest-directed RT have an increased TRV and may have pulmonary hypertension as a result of both direct lung injury and cardiac dysfunction. Longitudinal follow-up and confirmation by cardiac catheterization are warranted.
doi:10.1200/JCO.2012.43.0702
PMCID: PMC3574270  PMID: 23295810
16.  IMAGING CHANGES IN VERY YOUNG CHILDREN WITH BRAIN TUMORS TREATED WITH PROTON THERAPY AND CHEMOTHERAPY 
PT promises to reduce side effects in children with brain tumors by sparing normal tissue when compared to 3-dimensional conformal or intensity-modulated radiation therapy. Information is lacking about the combined effects of PT and chemotherapy in young children. We describe imaging changes in eight very young children with localized brain tumors who received PT after chemotherapy. Mostly transient signal abnormalities and enhancement in brain parenchyma were observed by serial MR imaging that were consistent with radiation-induced effects on normal appearing tissue. Correlation with PT planning data revealed that the areas of imaging abnormality were located within or adjacent to the volume that received the highest radiation dose. Radiologists should be aware of these findings in children who receive PT after chemotherapy. In this report we describe the time course of these PT-related imaging findings and correlate with treatment and clinical outcomes.
doi:10.3174/ajnr.A3219
PMCID: PMC3573244  PMID: 22821924
17.  Phase II Trial of Erlotinib during and after Radiotherapy in Children with Newly Diagnosed High-Grade Gliomas 
Background: Epidermal growth factor receptor is overexpressed in most pediatric high-grade gliomas (HGG). Since erlotinib had shown activity in adults with HGG, we conducted a phase II trial of erlotinib and local radiotherapy (RT) in children with newly diagnosed HGG.
Methods: Following maximum surgical resection, patients between 3 and 21 years with non-metastatic HGG received local RT at 59.4 Gy (54 Gy for spinal tumors and those with ≥70% brain involvement). Erlotinib started on day 1 of RT (120 mg/m2 per day) and continued for 2 years unless there was tumor progression or intolerable toxicities. The 2-year progression-free survival (PFS) was estimated for patients with intracranial anaplastic astrocytoma (AA) and glioblastoma (GBM).
Results: Median age at diagnosis for 41 patients with intracranial tumors (21 with GBM and 20 with AA) was 10.9 years (range, 3.3–19 years). The 2-year PFS for patients with AA and GBM was 15 ± 7 and 19 ± 8%, respectively. Only five patients remained alive without tumor progression. Twenty-six patients had at least one grade 3 or 4 toxicity irrespective of association with erlotinib; only four required dose modifications. The main toxicities were gastrointestinal (n = 11), dermatologic (n = 5), and metabolic (n = 4). One patient with gliomatosis cerebri who required prolonged corticosteroids died of septic shock associated with pancreatitis.
Conclusion: Although therapy with erlotinib was mostly well-tolerated, it did not change the poor outcome of our patients. Our results showed that erlotinib is not a promising medication in the treatment of children with intracranial AA and GBM.
doi:10.3389/fonc.2014.00067
PMCID: PMC3978340  PMID: 24744992
erlotinib; epidermal growth factor receptor; high-grade glioma; pediatric; phase II; radiotherapy
18.  Fractures among long-term survivors of childhood cancer: A report from the Childhood Cancer Survivor Study 
Cancer  2012;118(23):5920-5928.
Background
Although reductions in bone mineral density are well-documented among children during treatment for cancer and among childhood cancer survivors, little is known about the long-term risk of fracture. The aim of this study was to ascertain the prevalence of and risk factors for fractures among individuals participating in the Childhood Cancer Survivor Study (CCSS).
Methods
Analyses included 7414 5+ year survivors of childhood cancer diagnosed between 1970-86 who completed the 2007 CCSS follow-up questionnaire and a comparison group of 2374 siblings. Generalized linear models stratified by sex were used to compare the prevalence of reported fractures between survivors and siblings.
Results
The median ages at follow-up among survivors and siblings were 36.2, (range: 21.2-58.8) and 38.1 years (range: 18.4-62.6), respectively with a median 22.7 years of follow-up after cancer diagnosis for survivors. Approximately 35% of survivors and 39% of siblings reported ≥1 fractures during their lifetime. The prevalence of fractures was lower among survivors than siblings, both in males (prevalence ratio=0.87, 95%CI=0.81-0.94, p<0.001) and females (prevalence ratio=0.94, 95%CI=0.86-1.04, p=0.22). In multivariable analyses, increasing age at follow-up, white race, methotrexate treatment and balance difficulties were associated with increased prevalence of fractures among female survivors (p=0.05). Among males, only smoking history and white race were associated with an increased prevalence of fracture (p<0.001).
Conclusions
Findings from this study indicate that the prevalence of fractures among adult survivors is not increased compared to that of siblings. Additional studies of bone health among aging female cancer survivors may be warranted.
doi:10.1002/cncr.27626
PMCID: PMC3439597  PMID: 22605509
19.  Mature Teratoma of the Petrous Bone with Extension into the Cerebellopontine Angle: Case Report 
Purpose Intracranial teratomas in children involving lateral structures such as the petrous portion of the temporal bone are very uncommon. The authors report a case of a petrous teratoma with significant extension into the cerebellopontine angle with brainstem compression.
Case Report An 11-year-old girl presented left-sided facial weakness. Computed tomography (CT) demonstrated a multiloculated lesion expanding the labyrinthine structures in the left petrous temporal bone including the vestibule, semicircular canals, and cochlea, with extension to the left cerebellopontine angle via the expanded left internal auditory canal. The tumor was resected via a transtemporal approach with no evidence of recurrence at nearly 2 years.
Conclusion Complete resection should be the primary treatment for these tumors to minimize the risk of recurrence. To the authors' knowledge, this is the first case report of a mature teratoma originating in the petrous bone with extension into the cerebellopontine angle.
doi:10.1055/s-0033-1349203
PMCID: PMC3836897  PMID: 24294566
mature teratoma; petrous; temporal bone; cerebellopontine angle; resection; child; pediatric
20.  Neurocognitive Function and CNS Integrity in Adult Survivors of Childhood Hodgkin Lymphoma  
Journal of Clinical Oncology  2012;30(29):3618-3624.
Purpose
Long-term survivors of childhood Hodgkin lymphoma (HL) are at risk for cardiopulmonary complications and CNS stroke, although neurocognitive function has not been previously examined. The aim of this study was to examine neurocognitive and brain imaging outcomes in adult survivors of childhood HL.
Patients and Methods
In all, 62 adult survivors (mean age, 42.2 years; standard deviation [SD], 4.77; mean age at diagnosis, 15.1 years; SD, 3.30) were identified by stratified random selection from a large cohort treated with either high-dose (≥ 30 Gy) thoracic radiation (n = 38) or lower-dose (< 30 Gy) thoracic radiation combined with anthracycline (n = 24). Patients underwent neurocognitive evaluations, brain magnetic resonance imaging (MRI), echocardiograms, pulmonary function tests, and physical examinations.
Results
Compared with national age-adjusted norms, HL survivors demonstrated lower performance on sustained attention (P = .004), short-term memory (P = .001), long-term memory (P = .006), working memory (P < .001), naming speed (P < .001), and cognitive fluency (P = .007). MRI revealed leukoencephalopathy in 53% of survivors, and 37% had evidence of cerebrovascular injury. Higher thoracic radiation dose was associated with impaired cardiac diastolic function (E/E′; ratio of peak mitral flow velocity of early rapid filling [E] to early diastolic velocity of the mitral annulus [E′]; P = .003), impaired pulmonary function (diffusing capacity of lungs for carbon monoxide [DLcocorr; P = .04), and leukoencephalopathy (P = .02). Survivors with leukoencephalopathy demonstrated reduced cognitive fluency (P = .001). Working memory impairment was associated with E/E′, although impaired sustained attention and naming speed were associated with DLcocorr. Neurocognitive performance was associated with academic and vocational functioning.
Conclusion
These results suggest that adult long-term survivors of childhood HL are at risk for neurocognitive impairment, which is associated with radiologic indices suggestive of reduced brain integrity and which occurs in the presence of symptoms of cardiopulmonary dysfunction.
doi:10.1200/JCO.2012.42.6841
PMCID: PMC3462045  PMID: 22949149
21.  Clinical Ascertainment of Health Outcomes among Adults Treated for Childhood Cancer: A Report from the St. Jude Lifetime Cohort Study 
Importance
Adult survivors of childhood cancer are known to be at risk for treatment-related adverse health outcomes. A large population of survivors has not been evaluated using a comprehensive systematic clinical assessment to determine the prevalence of chronic health conditions.
Objective
Following systematic exposure-based medical assessments of a large cohort of adult survivors of childhood cancer, determine the prevalence of adverse health outcomes and the proportion associated with treatment-related exposures.
Design, Setting, and Participants
Presence of health outcomes was ascertained among 1713 adult (median age 32 years, range 18-60) survivors of childhood cancer (median time from diagnosis 25 years, range 10-47) enrolled in the St. Jude Lifetime Cohort Study since 10/1/2007 and followed through 10/31/2012.
Main Outcome Measures
Age-specific cumulative prevalence of adverse outcomes by organ system and sex-adjusted attributable fraction percentages with 95% confidence intervals were calculated.
Results
Using clinical criteria, the crude prevalence of adverse health outcomes was highest for pulmonary [65.2%(95% CI, 60.4-69.8%)], auditory [62.1%(95% CI, 55.8-68.2%)], endocrine-reproductive [62.0%(95% CI, 59.5-64.6%)], cardiac [56.4(95% CI, 53.5-59.2%)] and neurocognitive [48.0%(95%CI, 44.9-51.0%)] function, whereas abnormalities impacting hepatic [13.0%(95% CI, 10.8-15.3%)], skeletal [9.6%(95% CI, 8.0-11.5%)], renal [5.0%(95% CI, 4.0-6.3%)] and hematopoietic [3.0%(95% CI: 2.1-3.9%)] function were less common. Attributable fractions were highest for endocrine-reproductive disorders [88.4%(95% CI, 80.1-93.3%)] to 100%, but considerably lower for conditions highly prevalent in the general population such as hypertension [9.3%(95%CI, −16.3-29.2%)], dyslipidemia [15.5%(95% CI, 10.2-20.5%)], and obesity [42.1%(95% CI, 34.4-48.9%)]. Among survivors at risk for adverse outcomes following specific cancer treatment modalities, the estimated cumulative prevalence at 50 years of age was 21.6%(95% CI, 19.3-23.9%) for cardiomyopathy, 83.5%(95% CI, 80.2-86.8%) for heart valve disorder, 76.8%(95% CI, 73.6-80.0%) for pituitary dysfunction, 81.3%(95% CI, 77.6-85.0%) for pulmonary dysfunction, 86.5%(95% CI, 82.3-90.7%) for hearing loss, 40.9%(95% CI, 32.0-49.8%) for breast cancer, 31.1%(95% CI, 27.3-34.9%) for Leydig cell failure, and 31.9%(95% CI, 28.0-35.8%) for primary ovarian failure. At age 45 years, the estimated cumulative prevalence of any chronic health condition is 95.2% (95% CI 94.8-98.6%) and 80% (95% CI 73.0-86.6%) for a serious, life-threatening or disabling chronic condition.
Conclusion and Relevance
Systematic risk-based medical assessments of adults treated for childhood cancer identified a substantial number of previously undiagnosed problems that are typically prevalent in an older population underscoring the need for ongoing health monitoring and intervention of this population.
doi:10.1001/jama.2013.6296
PMCID: PMC3771083  PMID: 23757085
Childhood cancer; late effects; long-term follow-up; health screening
22.  White matter integrity is associated with cognitive processing in patients treated for a posterior fossa brain tumor 
Neuro-Oncology  2012;14(9):1185-1193.
Children treated for posterior fossa tumors experience reduced cognitive processing speed and, after imaging, show damage to white matter (WM) tracts in the brain. This study explores relationships between white matter microstructure, assessed by fractional anisotropy (FA), and speed of cognitive processing using tract-based spatial statistics (TBSS). At 36 months after treatment with radiotherapy and chemotherapy, 40 patients completed an MRI examination and neuropsychological evaluation. Patients were matched with healthy control subjects based on age, sex, and race. Individual FA values were extracted from examinations for all voxels identified as having significant association between processing speed and FA using TBSS. The regions were labeled anatomically, and fiber tracts were grouped into larger fiber bundle categories based on their anatomical and functional associations. Analyses were performed between mean skeletal FA values in each of the fiber bundles and each of the cognitive processing scores controlling for age. Children 3 years after treatment for posterior fossa brain tumors demonstrate significantly lower processing speed associated with decreased FA, compared with their healthy peers. Commissural fibers in the corpus callosum were negatively affected by disease and therapy with detrimental consequence on patients' cognitive processing. Diffusion tensor imaging of the white matter tracts in the brain is relevant to determining potential mechanisms underlying clinically meaningful change in cognitive performance. Neuroprotective strategies are needed to preserve critical functions.
doi:10.1093/neuonc/nos154
PMCID: PMC3424215  PMID: 22898373
diffusion tensor imaging; FA; medulloblastoma; processing speed; TBSS
23.  Screening Adult Survivors of Childhood Cancer for Cardiomyopathy: Comparison of Echocardiography and Cardiac Magnetic Resonance Imaging 
Journal of Clinical Oncology  2012;30(23):2876-2884.
Purpose
To compare two-dimensional (2D) echocardiography, the current method of screening for treatment-related cardiomyopathy recommended by the Children's Oncology Group Guidelines, to cardiac magnetic resonance (CMR) imaging, the reference standard for left ventricular (LV) function.
Patients and Methods
Cross-sectional, contemporaneous evaluation of LV structure and function by 2D and three-dimensional (3D) echocardiography and CMR imaging in 114 adult survivors of childhood cancer currently median age 39 years (range, 22 to 53 years) exposed to anthracycline chemotherapy and/or chest-directed radiation therapy.
Results
In this survivor population, 14% (n = 16) had an ejection fraction (EF) less than 50% by CMR. Survivors previously undiagnosed with cardiotoxicity (n = 108) had a high prevalence of EF (32%) and cardiac mass (48%) that were more than two standard deviations below the mean of normative CMR data. 2D echocardiography overestimated the mean EF of this population by 5%. Compared with CMR, 2D echocardiography (biplane method) had a sensitivity of 25% and a false-negative rate of 75% for detection of EF less than 50%, although 3D echocardiography had 53% and 47%, respectively. Twelve survivors (11%) had an EF less than 50% by CMR but were misclassified as ≥ 50% (range, 50% to 68%) by 2D echocardiography (biplane method). Detection of cardiomyopathy was improved (sensitivity, 75%) by using a higher 2D echocardiography cutoff (EF < 60%) to detect an EF less than 50% by the reference standard CMR.
Conclusion
CMR identified a high prevalence of cardiomyopathy among adult survivors previously undiagnosed with cardiac disease. 2D echocardiography demonstrated limited screening performance. In this high-risk population, survivors with an EF 50% to 59% by 2D echocardiography should be considered for comprehensive cardiac assessment, which may include CMR.
doi:10.1200/JCO.2011.40.3584
PMCID: PMC3671529  PMID: 22802310
24.  NECROSIS AFTER CRANIOSPINAL IRRADIATION: RESULTS FROM A PROSPECTIVE SERIES OF CHILDREN WITH CNS EMBRYONAL TUMORS 
PURPOSE
Necrosis of the CNS is a known complication of craniospinal irradiation (CSI) in children with medulloblastoma and similar tumors. We reviewed the incidence of necrosis in our prospective treatment series.
METHODS AND MATERIALS
Between 1996 and 2009, 236 children with medulloblastoma (n = 185) or other CNS embryonal tumors (n=51) received post-operative CSI followed by dose-intense cyclophosphamide, vincristine, and cisplatin. Average-risk cases (n = 148) received 23.4 Gy CSI, 36 Gy posterior fossa, and 55.8 Gy primary; after 2003, the treatment was 23.4 Gy CSI and 55.8 Gy primary. All high-risk cases (n = 88) received 36–39.6 Gy CSI and 55.8 Gy primary. The primary site clinical target volume margin was 2-cm (pre-2003) or 1-cm (post-2003). With competing risk of death by any cause, we determined the cumulative incidence of necrosis.
RESULTS
With a median follow-up of 52 months (range, 4–163 months), eight cases of necrosis were documented. One death was attributed. The median time to the imaging evidence was 4.8 months and symptoms 6.0 months. The cumulative incidence at 5 years was 3.7% ± 1.3% (n = 236) for the entire cohort, and 4.4% ± 1.5% (n = 196) for infratentorial tumor location. The mean relative volume of infratentorial brain receiving high-dose irradiation was significantly greater for patients with necrosis compared to those without: ≥ 50 Gy (92.12% ± 4.58 vs. 72.89% ± 1.96, p = 0.0337), ≥ 52 Gy (88.95% ± 5.50 vs. 69.16% ± 1.97, p = 0.0275), and ≥ 54 Gy (82.28% ± 7.06 vs. 63.37% ± 1.96, p = 0.0488).
CONCLUSIONS
Necrosis in patients with CNS embryonal tumors is uncommon. When competing risks are considered, the incidence is 3.7% at 5 years. The volume of infratentorial brain receiving greater than 50, 52, and 54 Gy is predictive for necrosis.
doi:10.1016/j.ijrobp.2012.01.061
PMCID: PMC3529413  PMID: 22768993
necrosis; medulloblastoma; craniospinal irradiation; pediatrics
25.  Hospitalization Rates Among Survivors of Childhood Cancer in the Childhood Cancer Survivor Study Cohort 
Pediatric blood & cancer  2011;59(1):126-132.
Background
Chronic health conditions are common among long-term childhood cancer survivors, but hospitalization rates have not been reported. The objective of this study was to determine overall and cause-specific hospitalization rates among survivors of childhood cancer and compare rates to the U.S. population.
Procedure
The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort of 5+ year survivors of childhood malignancies treated at 26 participating centers. Self-reported hospitalizations from 10,366 survivors (diagnosed 1970–1986) were compared to U.S. population rates using age-and sex-stratified standardized incidence ratios (SIRs). Reasons for hospitalization were evaluated and associations between demographic, cancer and treatment-related risk factors with hospitalization were investigated.
Results
Survivors were, on average, 20.9 years from cancer diagnosis (SD: 4.6, range: 13–32) and 28.6 years of age (SD: 7.7, range: 13–51). Survivor hospitalization rates were 1.6 times the U.S. population (95% CI: 1.6; 1.7). Increased hospitalization rates were noted irrespective of gender, age at follow-up and cancer diagnosis, with highest SIRs noted among male (SIR=2.6, 95% CI: 2.2; 3.0) and female (SIR=2.7, 95% CI: 2.4; 3.1) survivors aged 45–54. Female gender, an existing chronic health condition and/or a second neoplasm, and prior treatment with radiation were associated with an increased risk of non-obstetrical hospitalization.
Conclusions
Survivors of childhood cancer demonstrate substantially higher hospitalization rates. Additional research is needed to further quantify the healthcare utilization and economic impact of treatment-related complications as this population ages.
doi:10.1002/pbc.24017
PMCID: PMC3359936  PMID: 22180128
childhood cancer; cancer survivor; hospitalization

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