Vincristine/irinotecan/temsirolimus upfront window treatment of high-risk hepatoblastoma: A report from the Children's Oncology Group AHEP0731 Study Committee.

BACKGROUND: Survival for children with metastatic hepatoblastoma (HB) remains suboptimal. We report the response rate and outcome of two courses of vincristine/irinotecan/temsirolimus (VIT) in children with high-risk (HR)/metastatic HB. PROCEDURES: Patients with newly diagnosed HB received HR window chemotherapy if they had metastatic disease or a serum alpha-fetoprotein (AFP) level less than 100 ng/mL. Patients received vincristine (days 1 and 8), irinotecan (days 1-5), and temsirolimus (days 1 and 8). Cycles were repeated every 21 days. Responders had either a 30% decrease using RECIST (Response Evaluation Criteria in Solid Tumors) criteria OR a 90% (>1 log10 decline) AFP decline after two cycles. Responders received two additional cycles of VIT intermixed with six cycles of cisplatin/doxorubicin/5-fluorouracil/vincristine (C5VD). Nonresponders received six cycles of C5VD alone. RESULTS: Thirty-six eligible patients enrolled on study. The median age at enrollment was 27 months (range: 7-170). Seventeen of 36 patients were responders (RECIST and AFP = 3, RECIST only = 4, AFP only = 10). The median AFP at diagnosis was 222,648 ng/mL and the median AFP following two VIT cycles was 19,262 ng/mL. Three-year event-free survival was 47% (95% confidence interval [CI]: 30%-62%), while overall survival was 67% (95% CI: 49%-80%). CONCLUSION: VIT did not achieve the study efficacy endpoint. Temsirolimus does not improve the response rate seen in patients treated with vincristine and irinotecan (VI) alone as part of the initial treatment regimen explored in this study. Additionally, AFP response may be a more sensitive predictor of disease response than RECIST in HB.

Small Cell Undifferentiated Histology Does Not Adversely Affect Outcome in Hepatoblastoma: A Report From the Children's Oncology Group (COG) AHEP0731 Study Committee.

PURPOSE: Small cell undifferentiated (SCU) histology in hepatoblastoma (HB) tumors has historically been associated with a poor prognosis. Tumors from patients enrolled on Children's Oncology Group (COG) study AHEP0731 underwent institutional and central pathologic review for identification of SCU histology. PATIENTS AND METHODS: Patients with SCU histology identified at the local treating institution who had otherwise low-risk tumors were upstaged to the intermediate-risk treatment stratum, whereas those only identified by retrospective central review were treated per the local institution as low-risk. Patients with otherwise intermediate- or high-risk tumors remained in that treatment stratum, respectively. Central review was to be performed for all tissue samples obtained at any time point. Treatment was per local review, whereas analysis of outcome was based on central review. RESULTS: Thirty-five patients had some elements (1%-25%) of SCU identified on central review of diagnostic specimens. All but two patient tissue sample retained nuclear INI1 expression. The presence of SCU histology did not correlate with age, alpha-fetoprotein level at diagnosis, or sex. The presence of SCU did not affect event-free survival (EFS). EFS at 5 years for patients with low-risk, intermediate-risk, and high-risk with SCU HB was 86% (95% CI, 33 to 98), 81% (95% CI, 57 to 92), and 29% (95% CI, 4 to 61), respectively, compared with EFS at 5 years for patients without SCU enrolled with low-risk, intermediate-risk, and high-risk of 87% (95% CI, 72 to 95), 88% (95% CI, 79 to 94), and 55% (95% CI, 32 to 74; P = .17), respectively. CONCLUSION: The presence of SCU histology in HB does not appear to adversely affect outcome. Future studies should be able to treat patients with SCU HB according to risk stratification without regard to the presence of SCU histology.

Doxorubicin in combination with cisplatin, 5-flourouracil, and vincristine is feasible and effective in unresectable hepatoblastoma: A Children's Oncology Group study.

BACKGROUND: The Children's Oncology Group (COG) adopted cisplatin, 5-flourouracil, and vincristine (C5V) as standard therapy after the INT-0098 legacy study showed statistically equivalent survival but less toxicity in comparison with cisplatin and doxorubicin. Subsequent experience demonstrated doxorubicin to be effective in patients with recurrent disease after C5V, and this suggested that it could be incorporated to intensify therapy for patients with advanced disease. METHODS: In this nonrandomized, phase 3 COG trial, the primary aim was to explore the feasibility and toxicity of a novel therapeutic cisplatin, 5-flourouracil, vincristine, and doxorubicin (C5VD) regimen with the addition of doxorubicin to C5V for patients considered to be at intermediate risk. Patients were eligible if they had unresectable, nonmetastatic disease. Patients with a complete resection at diagnosis and local pathologic evidence of small cell undifferentiated histology were also eligible for an assessment of feasibility. RESULTS: One hundred two evaluable patients enrolled between September 14, 2009, and March 12, 2012. Delivery of C5VD was feasible and tolerable: the mean percentages of the target doses delivered were 96% (95% CI, 94%-97%) for cisplatin, 96% (95% CI, 94%-97%) for 5-fluorouracil, 95% (95% CI, 93%-97%) for doxorubicin, and 90% (95% CI, 87%-93%) for vincristine. Toxicity was within expectations, with death as a first event in 1 patient. The most common adverse events were febrile neutropenia (n = 55 [54%]), infection (n = 48 [47%]), mucositis (n = 31 [30%]), hypokalemia (n = 39 [38%]), and elevated aspartate aminotransferase (n = 28 [27%]). The 5-year event-free and overall survival rates for the 93 patients who did not have complete resection at diagnosis were 88% (95% CI, 79%-93%) and 95% (95% CI, 87%-98%), respectively. CONCLUSIONS: The addition of doxorubicin to the previous standard regimen of C5V is feasible, tolerable, and efficacious, and this suggests that C5VD is a good regimen for future clinical trials.

Environmental Influences on Sleep in the California Teachers Study Cohort.

Only two-thirds of Americans meet the recommended 7 hours of sleep nightly. Insufficient sleep and circadian disruption have been associated with adverse health outcomes, including diabetes and cardiovascular disease. Several environmental disruptors of sleep have been reported, such as artificial light at night (ALAN) and noise. These studies tended to evaluate exposures individually. We evaluated several spatially derived environmental exposures (ALAN, noise, green space, and air pollution) and self-reported sleep outcomes obtained in 2012-2015 in a large cohort of 51,562 women in the California Teachers Study. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for sleep duration and latency. After adjusting for age, race/ethnicity, chronotype, use of sleep medication, and self-reported trouble sleeping, ALAN (per 5 millicandela (mcd)/m2 luminance, OR = 1.13, 95% CI: 1.07, 1.20) and air pollution (per 5 µg/m3 PM2.5, OR = 1.06, 95% CI: 1.04, 1.09) were associated with shorter sleep duration (<7 hours), and noise was associated with longer latency (>15 minutes) (per 10 decibels, OR = 1.05, 95% CI: 1.01, 1.10). Green space was associated with increased duration (per 0.1 units, OR = 0.41, 95% CI: 0.28, 0.60) and decreased latency (per 0.1 units, OR = 0.55, 95% CI: 0.39, 0.78). Further research is necessary to understand how these and other exposures (e.g., diet) perturb an individuals' inherited sleep patterns and contribute to downstream health outcomes.

Outdoor artificial light at night and risk of non-Hodgkin lymphoma among women in the California Teachers Study cohort.

BACKGROUND: Outdoor artificial light at night (ALAN) has been implicated in a growing number of adverse health outcomes. ALAN is believed to disrupt circadian rhythms and has been associated with increased inflammation, one of the hallmarks of cancer. We examined the association between outdoor ALAN and a cancer strongly associated with autoimmune and inflammatory conditions, non-Hodgkin lymphoma (NHL), in the prospective California Teachers Study cohort. METHODS: Outdoor ALAN was assigned to participant addresses at study baseline (1995-96) through use of the New World Atlas of Artificial Night Sky Brightness. Among 105,937 women followed from 1995 to 2015, linkage to the California Cancer Registry identified 873 incident cases of NHL. Age-stratified Cox proportional hazards models were used to calculate hazard ratios (HR) and 95 % confidence intervals (95 %CI) for overall NHL and the most common NHL subtypes; diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Multivariate analyses adjusted for previously reported subtype specific covariates (e.g. body mass index (BMI) for DLBCL). RESULTS: Compared to the lowest quintile, participants residing in the highest quintile of outdoor ALAN at baseline were more likely to develop NHL (HR = 1.32, 95 %CI = 1.07-1.63), and, in particular, DLBCL (HR = 1.87, 95 %CI = 1.16-3.02). The elevated risk for DLBCL remained statistically significant after adjusting for age, race/ethnicity, BMI, and socioeconomic status (DLBCL:HR = 1.87, 95 %CI = 1.16-3.02, NHL:HR = 1.32, 95 %CI = 1.07-1.63). There was no association between ALAN and FL or CLL/SLL. CONCLUSION: DLBCL risk was elevated among women residing in neighborhoods with greater outdoor ALAN. Future research in circadian disruption and DLBCL may clarify potential biological processes implicated in this association.

Association between rice consumption and risk of cancer incidence in the California Teachers Study.

PURPOSE: We evaluated the contribution of rice intake, a source of dietary arsenic, to cancer risk in a population of women with likely low arsenic exposure from drinking water and variable rice intake who participated in the California Teachers Study. METHODS: Rice consumption was categorized into quartiles (< 9.6, 9.7-15.6, 15.7-42.7, and ≥ 42.8 g/day). Multivariable-adjusted hazard ratios and 95% confidence intervals (95% CI) for incident cancer were estimated comparing rice consumption categories with bladder, breast, kidney, lung, and pancreatic cancer, with progressive adjustment for age, total calories, BMI, race, smoking status, physical activity, and cancer-specific covariates. RESULTS: The number of breast, lung, pancreatic, bladder, and kidney cancer cases was 7,351; 1,100; 411; 344; and 238, respectively. The adjusted hazard ratios (95% CI) comparing the highest versus lowest rice intake quartiles were 1.07 (1.00-1.15); 0.87 (0.72-1.04); 0.95 (0.66-1.37); 1.11 (0.81-1.52) and 1.07 (0.72-1.59) for breast, lung, pancreatic, bladder, and kidney cancers, respectively. Results were consistent when rice was modeled as a continuous variable and in analyses stratified by smoking status. CONCLUSION: Rice consumption was not associated with risk of kidney, lung or pancreatic cancer, except maybe a small excess risk for breast cancer and a small non-significant excess risk for bladder cancer, comparing the highest versus lowest quartile of rice intake. Due to lower consumption patterns in this cohort, future studies should involve populations for which rice is a staple food and use of an arsenic biomarker.

Insights from Adopting a Data Commons Approach for Large-scale Observational Cohort Studies: The California Teachers Study.

BACKGROUND: Large-scale cancer epidemiology cohorts (CEC) have successfully collected, analyzed, and shared patient-reported data for years. CECs increasingly need to make their data more findable, accessible, interoperable, and reusable, or FAIR. How CECs should approach this transformation is unclear. METHODS: The California Teachers Study (CTS) is an observational CEC of 133,477 participants followed since 1995-1996. In 2014, we began updating our data storage, management, analysis, and sharing strategy. With the San Diego Supercomputer Center, we deployed a new infrastructure based on a data warehouse to integrate and manage data and a secure and shared workspace with documentation, software, and analytic tools that facilitate collaboration and accelerate analyses. RESULTS: Our new CTS infrastructure includes a data warehouse and data marts, which are focused subsets from the data warehouse designed for efficiency. The secure CTS workspace utilizes a remote desktop service that operates within a Health Insurance Portability and Accountability Act (HIPAA)- and Federal Information Security Management Act (FISMA)-compliant platform. Our infrastructure offers broad access to CTS data, includes statistical analysis and data visualization software and tools, flexibly manages other key data activities (e.g., cleaning, updates, and data sharing), and will continue to evolve to advance FAIR principles. CONCLUSIONS: Our scalable infrastructure provides the security, authorization, data model, metadata, and analytic tools needed to manage, share, and analyze CTS data in ways that are consistent with the NCI's Cancer Research Data Commons Framework. IMPACT: The CTS's implementation of new infrastructure in an ongoing CEC demonstrates how population sciences can explore and embrace new cloud-based and analytics infrastructure to accelerate cancer research and translation.See all articles in this CEBP Focus section, "Modernizing Population Science."

Physical Activity, Hormone Therapy Use, and Stroke Risk among Women in the California Teachers Study Cohort.

BACKGROUND: Postmenopausal hormone therapy (HT) increases the risk of stroke. Here we evaluate whether leisure time physical activity (LTPA) can change stroke risk in women using HT, leveraging data from the California Teachers Study. METHODS: Female California educators without a prior history of stroke (n = 118,294) were followed from 1995 through 2015 for stroke end points. Based on statewide hospitalization data, 4,437 women had ischemic (n = 3,162; International Classification of Diseases [ICD]-9 433, 434, 436) or hemorrhagic (n = 1,275; ICD-9 430-432, excluding 432.1) stroke. LTPA and HT use were evaluated at 2 time points (baseline [1995-1996] and 10-year follow-up [2005-2006]). LTPA was assessed using American Heart Association (AHA) recommendations (>150 min/week moderate or >75 min/week strenuous physical activity). Using multivariable Cox proportional hazards models, we estimated the hazard ratios (HRs) and 95% CIs for the associations between HT use and concurrent LTPA with incident stroke. RESULTS: Compared to women who never used HT, stroke risk was highest among women who were current HT users and did not meet AHA recommendations for LTPA at the time of their HT use: HRbaseline 1.28 (95% CI 1.13-1.44); HR10-year follow-up 1.17 (95% CI 0.91-1.50). Based on the baseline questionnaire, current HT users who met AHA recommendations for LTPA in 1995-1996 still had elevated stroke risk in the 20-year follow-up (HR 1.22, 95% CI 1.08-1.37). However, among current HT users who met AHA recommendations for LTPA at the 2005-2006 follow-up questionnaire, stroke risk was not elevated (HR 1.01, 95% CI 0.80-1.29). Evaluation of the 2 time points in concert further demonstrated that meeting AHA recommendations for LTPA at the most recent follow-up time point was required to reduce HT-related stroke risk. CONCLUSION: Concurrent physical activity may attenuate the short-term increase in risk of stroke risk associated with HT use.

Using Marketing Automation to Modernize Data Collection in the California Teachers Study Cohort.

BACKGROUND: Like other cancer epidemiologic cohorts, the California Teachers Study (CTS) has experienced declining participation to follow-up questionnaires; neither the reasons for these declines nor the steps that could be taken to mitigate these trends are fully understood. METHODS: The CTS offered their 6th study questionnaire (Q6) in the fall of 2017 using an integrated, online system. The team delivered a Web and mobile-adaptive questionnaire to 45,239 participants via e-mail using marketing automation technology. The study's integrated platform captured data on recruitment activities that may influence overall response, including the date and time invitations and reminders were e-mailed and the date and time questionnaires were started and submitted. RESULTS: The overall response rate was 43%. Participants ages 65 to 69 were 25% more likely to participate than their younger counterparts (OR = 1.25; 95% CI, 1.18-1.32) and nonwhite participants were 28% less likely to participate than non-Hispanic white cohort members (OR = 0.72; 95% CI, 0.68-0.76). Previous questionnaire participation was strongly associated with response (OR = 6.07; 95% CI, 5.50-6.70). Invitations sent after 2 pm had the highest response (OR = 1.75; 95% CI, 1.65-1.84), as did invitations sent on Saturdays (OR = 1.48; 95% CI, 1.36-1.60). CONCLUSIONS: An integrated system that captures paradata about questionnaire recruitment and response can enable studies to quantify the engagement patterns and communication desires of cohort members. IMPACT: As cohorts continue to collect scientific data, it is imperative to collect and analyze information on how participants engage with the study.See all articles in this CEBP Focus section, "Modernizing Population Science."

Aspirin reduces long-term stroke risk in women with prior hypertensive disorders of pregnancy.

OBJECTIVE: To determine whether hypertensive disorders of pregnancy (HDP) increased long-term stroke risk in women in the California Teachers Study (CTS), a prospective cohort study, and whether aspirin or statin use modified this risk. METHODS: CTS participants ≤60 years of age at the time of enrollment in 1995 were followed up prospectively for validated stroke outcomes obtained via linkage with California hospital records through December 31, 2015. We calculated unadjusted and adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the primary outcomes of all stroke and stroke before 60 years of age among those with and without a history of HDP. We tested for interactions (p < 0.2) and performed stratified analyses to assess the risk of the primary outcomes in women with and without self-reported use of aspirin or statins. RESULTS: Of 83,749 women included in the analysis, 4,070 (4.9%) had HDP. Women with prior HDP had increased risk of all stroke (adjusted HR 1.3, 95% CI 1.2-1.4) but no increased risk of stroke before age 60 (adjusted HR 1.2, 95% CI 0.9-1.7). There was an interaction (p = 0.18) between aspirin use and HDP history on risk of stroke before age 60: nonusers of aspirin had higher risk (adjusted HR 1.5, 95% CI 1.0-2.1) while aspirin users did not (adjusted HR 0.8, 95% CI 0.4-1.7). This effect was not seen with statins. CONCLUSIONS: After controlling for comorbid conditions, women with prior HDP had increased long-term stroke risk, which was reduced by aspirin use. Randomized trials may be needed to assess whether long-term aspirin use could benefit selected women with a history of HDP.

Regular and low-dose aspirin, other non-steroidal anti-inflammatory medications and prospective risk of HER2-defined breast cancer: the California Teachers Study.

BACKGROUND: Regular users of aspirin may have reduced risk of breast cancer. Few studies have addressed whether risk reduction pertains to specific breast cancer subtypes defined jointly by hormone receptor (estrogen and progesterone receptor) and human epidermal growth factor receptor 2 (HER2) expression. This study assessed the prospective risk of breast cancer (overall and by subtype) according to use of aspirin and other non-steroidal anti-inflammatory medications (NSAIDs) in a cohort of female public school professionals in California. METHODS: In 1995 - 1996, participants in the California Teachers Study completed a baseline questionnaire on family history of cancer and other conditions, use of NSAIDs, menstrual and reproductive history, self-reported weight and height, living environment, diet, alcohol use, and physical activity. In 2005-2006, 57,164 participants provided some updated information, including use of NSAIDs and 1457 of these participants developed invasive breast cancer before January 2013. Multivariable Cox proportional hazards regression models provided hazard rate ratios (HRR) for the association between NSAID use and risk of invasive breast cancer as well as hormone receptor- and HER2-defined subtypes. RESULTS: Developing breast cancer was associated inversely with taking three or more tablets of low-dose aspirin per week (23% of participants). Among women reporting this exposure, the HRR was 0.84 (95% confidence interval (CI) 0.72-0.98) compared to those not taking NSAIDs and this was particularly evident in women with the hormone receptor-positive/HER2-negative subtype (HRR = 0.80, 95% CI 0.66-0.96). Use of three or more tablets of "other" NSAIDs was marginally associated with lower risk of breast cancer (HRR = 0.79, 95% CI 0.62-1.00). Other associations with NSAIDs were generally null. CONCLUSION: Our observation of reduced risk of breast cancer, among participants who took three or more tablets of low-dose aspirin weekly, is consistent with other reports looking at aspirin without differentiation by dose. This is the first report to suggest that the reduction in risk occurs for low-dose aspirin and not for regular-dose aspirin and only among women with the hormone receptor-positive/HER2-negative subtype. This preliminary study builds on previous knowledge and further supports the need for formal cancer chemoprevention studies of low-dose aspirin.

Graft-versus-Host Disease-Associated Vulvovaginal Symptoms after Bone Marrow Transplantation.

We conducted a retrospective review to assess the prevalence of graft-versus-host disease (GVHD)-associated gynecologic conditions among bone marrow transplantation (BMT) patients at City of Hope Medical Center. We calculated the associations among the estimated risks of various gynecologic complications, including vaginal stenosis, by performing chi-square tests and t-test statistics. Between 2010 and 2014, 180 patients were referred to the gynecologic clinic after their BMT. One hundred twenty-four patients (69%) had GVHD; among these patients, 51 (41%) experienced dyspareunia and 43 (35%) had vaginal stenosis. GVHD patients were significantly more likely to have vaginal stenosis (P < .0001), more likely to have used a vaginal dilator (P = .0008), and less likely to have urinary incontinence (UI) than those without GVHD (P < .001). There was no difference in developing pelvic organ prolapse (POP) in patients with or without GVHD (P = .4373). GVHD was a common complication after allogenic BMT. Patients with BMT were more likely to have vulvovaginal symptoms, such as dyspareunia and pelvic pain. Patients with GVHD are at high risk for vaginal stenosis requiring the use of a vaginal dilator. However, they are at low risk for developing UI and POP.