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Human immunodeficiency virus (HIV)-associated cognitive disorders (HAND) is characterized by impaired motor and intellectual functions, as well as mood disorders. Brain-derived neurotrophic factor and its receptor TrkB (or NTRK2) mediate the efficacy of antidepressant drugs. Genomic studies of BDNF/TrkB have implicated common single-nucleotide polymorphisms in the pathology of depression. In the current study, we investigated whether single-nucleotide polymorphisms (SNPs) (rs1212171, rs1439050, rs1187352, rs1778933, rs1443445, rs3780645, rs2378672, and rs11140800) in the NTRK2 has a functional impact on depression in HIV-positive subjects. We have utilized the Central Nervous System (CNS) HIV Antiretroviral Therapy Effects Research (CHARTER) cohort. Our methods explored the univariate associations of these SNPs with clinical (current and lifetime) diagnosis of depression via chi-square. The distribution of alleles was significantly different for African-Americans and Caucasians (non-Hispanic) for several SNPs, so our regression analyses included both “statistical controls” for race group and models for each group separately. Finally, we applied a method of simultaneous analysis of associations, estimating the mutually shared information across a system of variables, separately by race group. Our results indicate that there is no significant association between clinical diagnosis of major depression and these SNPs for either race group in any analysis. However, we identified that the SNP associations varied by race group and sex.

Background Breast cancer survivors are at increased risk for developing second primary cancers compared with the general population. Little is known about whether body mass index (BMI) increases this risk. We examined the association between BMI and second cancers among women with incident invasive breast cancer. Methods This retrospective cohort included 6481 patients from Kaiser Permanente Colorado and Washington of whom 822 (12.7%) developed a second cancer (mean follow-up was 88.0 months). BMI at the first cancer was extracted from the medical record. Outcomes included: 1) all second cancers, 2) obesity-related second cancers, 3) any second breast cancer, and 4) estrogen receptor–positive second breast cancers. Multivariable Poisson regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for second cancers associated with BMI adjusted for site, diagnosis year, treatment, demographic, and tumor characteristics. Results The mean age at initial breast cancer diagnosis was 61.2 (SD = 11.8) years. Most cases were overweight (33.4%) or obese (33.8%) and diagnosed at stage I (62.0%). In multivariable models, for every 5 kg/m2 increase in BMI, the risk of any second cancer diagnosis increased by 7% (RR = 1.07, 95% CI = 1.01 to 1.14); 13% (RR = 1.13, 95% CI = 1.05 to 1.21) for obesity-related cancers, 11% (RR = 1.11, 95% CI = 1.02 to 1.21) for a second breast cancer, and 15% (RR = 1.15, 95% CI = 1.04 to 1.27) for a second estrogen receptor–positive breast cancer. Conclusions We observed a statistically significant increased risk of second cancers associated with increasing BMI. These findings have important public health implications given the prevalence of overweight and obesity in breast cancer survivors and underscore the need for effective prevention strategies.

PURPOSE Mortality for patients with classical Hodgkin lymphoma (cHL) treated during an era characterized in the United States by widespread use of doxorubicin, bleomycin, vinblastine, and dacarbazine and diminishing use of radiotherapy is not well understood. PATIENTS AND METHODS We identified 20,007 individuals diagnosed with stage I/II (early) or III/IV (advanced) cHL between age 20 and 74 years treated with initial chemotherapy in US population-based cancer registries during 2000-2015 (follow-up through 2016). We used standardized mortality ratios (SMRs) to compare cause-specific relative mortality risk following cHL to that expected in the general population and estimated excess absolute risks (EARs; per 10,000 patient-years) to quantify disease-specific death burden. RESULTS We identified 3,380 deaths in the cHL cohort, including 1,321 (39%) not attributed to lymphoma. Overall, noncancer SMRs were increased 2.4-fold (95% CI, 2.2 to 2.6; observed, 559; EAR, 61.6) and 1.6-fold (95% CI, 1.4 to 1.7; observed, 473; EAR, 18.2) for advanced- and early-stage cHL, respectively, compared with the general US population. SMRs and EARs differed substantially by cause of death and cHL stage. Among the highest EARs for noncancer causes of death were those for heart disease (EAR, 15.1; SMR, 2.1), infections (EAR, 10.6; SMR, 3.9), interstitial lung disease (ILD; EAR, 9.7; SMR, 22.1), and adverse events (AEs) related to medications/drugs (EAR, 7.4; SMR, 5.0) after advanced-stage cHL and heart disease (EAR, 6.6; SMR, 1.7), ILD (EAR, 3.7; SMR, 13.1), and infections (EAR, 3.1; SMR, 2.2) after early-stage cHL. Strikingly elevated SMRs for ILD, infections, and AEs were observed < 1 year after cHL. Individuals age 60-74 years with advanced-stage cHL experienced a disproportionate excess of deaths as a result of heart disease, ILD, infections, AEs, and solid tumors. CONCLUSION Despite evolving cHL treatment approaches, patients continue to face increased nonlymphoma mortality risks from multiple, potentially preventable causes. Surveillance, early interventions, and cHL treatment refinements may favorably affect patient longevity, particularly among high-risk subgroups.

Objective To describe the scoring approach, considering interpretability, validity, and use, of a new patient-centered patient reported outcome (PRO), the Urinary Symptom Questionnaire for Neurogenic Bladder-Intermittent Catheter version (USQNB-IC). Design Subject matter experts (researchers, clinicians, a consumer, a psychometrician) classified USQNB-IC items. Profiles were then composed based on self-management decisions made by patients; patient management decisions made by clinicians; and research-oriented decisions made by investigators. Participants in an 18-month pilot study completed the USQNB-IC every week. Differences in decisions based on traditional 'total scores' and profiles were examined. Validity was defined based on alignment of scoring method with decisions. Setting A new set of patient-centered PROs enable monitoring and decision-making around urinary signs and symptoms among people with neurogenic bladder (NB). Participants Classifications USQNB-IC items by subject matter experts. Utility of the classifications and profiles that were created was assessed using weekly responses from the 6-month baseline period from 103 participants in a pilot study. Interventions Not applicable. Main outcome measures Classification of the 29 symptoms resulted in four categories with exchangeability within-category and nonexchangeability across categories. The burden of each symptom type is one approach to scoring the USQNB-IC. Five profiles, based on these categories, emerged based on, and supportive of, decisions to be made according to symptoms, representing a categorical approach to scoring the USQNB-IC. Results USQNB-IC items are not all exchangeable. Four symptom classifications comprise within-class exchangeable items. Five profiles emerged to summarize these items to promote decision-making and identification of change over time. Both ways to "score" the USQNB-IC are described and discussed. Conclusions "Profiling" promotes valid and interpretable decisions by patients and clinicians, based on a patient's urinary symptoms with the USQNB-IC cross-sectionally and longitudinally. Alternatively, four subsets of the 29 USQNB-IC symptoms can be used as continuous outcomes representing "burden" in clinical management or research.

It is common to create courses for the higher education context that accomplish content-driven teaching goals and then develop assessments (quizzes and exams) based on the target content. However, content-driven assessment can tend to support teaching- or teacher-centered instruction. Adult learning and educational psychology theories suggest that instead, assessment should be aligned with learning, not teaching, objectives. To support the alignment of assessments with instruction in higher education, the Assessment Evaluation Rubric (AER) was developed. The AER can be utilized to guide the development and evaluation/revision of assessments that are already used. The AER describes, or permits the evaluation of, four features of an assessment: its general alignment with learning goal(s), whether the assessment is intended to/effective as formative or summative, whether some systematic approach to cognitive complexity is reflected, and whether the assessment (instructions as well as results) itself is clearly interpretable. Each dimension (alignment, utility, complexity, and clarity) has four questions that can be rated as present/absent. Other rating methods can also be conceptualized for the AER’s 16 questions, depending on the user’s intent. Any instructor can use the AER to evaluate their own assessments and ensure that they—or new assessments in development—will promote learning and learner-centered teaching. As instructors shift from face-to-face toward virtual or hybrid teaching models, or as they shift online instruction (back) to face-to-face teaching, it creates an ideal opportunity to ensure that assessment is optimizing learning and is valid for instructional decision-making.

BACKGROUND: Mutually increased risks for thyroid and breast cancer have been reported, but the contribution of etiologic factors versus increased medical surveillance to these associations is unknown. METHODS: Leveraging large-scale US population-based cancer registry data, we used standardized incidence ratios (SIRs) to investigate the reciprocal risks of thyroid and breast cancers among adult females diagnosed with a first primary invasive, non-metastatic breast cancer (N=652,627) or papillary thyroid cancer (PTC) (N=92,318) during 2000–2017 who survived ≥1-year. RESULTS: PTC risk was increased 1.3-fold [N=1,434; SIR=1.32; 95% confidence interval (CI)=1.25–1.39] after breast cancer compared to the general population. PTC risk declined significantly with time since breast cancer (Poisson regression=P(trend)

OBJECTIVE: Test the effectiveness of intravesical Lactobacillus rhamnosus GG (LGG) to reduce the burden of urinary symptoms for individuals with spinal cord injury and disease (SCI/D) with neurogenic lower urinary tract dysfunction (NLUTD) who manage their bladders with intermittent catheterization (IC). DESIGN: A 3-phase study (6 months each in baseline; intervention; and washout).Participants self-managed following the Self-Management Protocol using Probiotics (SMP-Pro), completing the online Urinary Symptom Questionnaire for Neurogenic Bladder-IC version (USQNB-IC) weekly. SETTING: Nationwide (US). PARTICIPANTS: 96 adults and 7 children with SCI/D. INTERVENTIONS: In response to one or both of the SMP-Pro trigger urinary symptoms, "cloudier" or "foul smelling" urine, subjects self-administered using a clean urinary catheter an LGG+Normal Saline instillate once or twice in a 30-hour period. MAIN OUTCOME MEASURES: Change in USQNB-IC burden was adjusted individually according to the prior phase for four symptom types. Adjusted changes in burden between the intervention and washout phases were analyzed using one-sample t-tests. Holm correction was applied for the four types of symptoms: A, clinically actionable; B1, bladder function; B2, urine quality; and C, other. RESULTS: During the intervention phase, participants met SMP-Pro instillation criteria3.83 times on average (range 1 - 20). An average of 5.6 doses of LGG were instilled.For those who instilled at least once, burdens of type A and B2 symptoms were significantly improved at washout (both adjusted p

Study design Descriptive Psychometrics Study OBJECTIVES: Neurogenic lower urinary tract dysfunction (NLUTD), or "neurogenic bladder" is a common and disruptive condition for individuals with spinal cord injury (SCI) and disease (including multiple sclerosis, MS). Our team has developed patient-centered instruments of urinary symptoms specific to patients with NLUTD, across bladder management methods. Validity evidence is needed to support the use of two new instruments, Urinary Symptom Questionnaires for people with Neurogenic Bladder (USQNB) for those who manage their bladder with indwelling catheters (IDC), or who void (V). Setting Online surveys completed by individuals in the United States with NLUTD due to either SCI or MS who manage their bladder with indwelling catheters (SCI, n = 306; MS, n = 8), or by voiding (SCI, n = 103; MS, n = 383). A total of n = 381 USQNB-IDC respondents (five control groups), and 351 USQNB-V respondents (four control groups), contributed to our convergent and divergent validity evidence. Methods Data were collected online to estimate key aspects of psychometric validity (content, reflection of the construct to be measured; face, recognizability of the contents as representing the construct to be measured; structural, the extent to which the instrument captures recognizable dimensions of the construct to be measured). Divergent and convergent validity evidence was derived from multiple control groups, while evidence of criterion validity was derived from attribution of each item to their experience "with a UTI". Results Evidence of face, content, criterion, convergent, and divergent validity was compiled for each instrument. Conclusions The instruments demonstrate adequate, multi-dimensional, validity evidence to recommend their use for decision-making by patients, clinicians, and researchers.

Background: Disrupted sleep is common among nursing home patients with dementia and is associated with increased agitation, depression, and cognitive impairment. Detecting and treating sleep problems in this population are therefore of great importance, albeit challenging. Systematic observation and objective recordings of sleep are time-consuming and resource intensive and self-report is often unreliable. Commonly used proxy-rated scales contain few sleep items, which affects the reliability of the raters' reports. The present study aimed to adapt the proxy-rated Sleep Disorder Inventory (SDI) to a nursing home context and validate it against actigraphy. Methods: Cross-sectional study of 69 nursing home patients, 68% women, mean age 83.5 (SD 7.1). Sleep was assessed with the SDI, completed by nursing home staff, and with actigraphy (Actiwatch II, Philips Respironics). The SDI evaluates the frequency, severity, and distress of seven sleep-related behaviors. Internal consistency of the SDI was evaluated by Cronbach's alpha. Spearman correlations were used to evaluate the convergent validity between actigraphy and the SDI. Test performance was assessed by calculating the sensitivity, specificity, and predictive values, and by ROC curve analyses. The Youden's Index was used to determine the most appropriate cut-off against objectively measured sleep disturbance defined as

Previous studies have shown an overall decreased risk of second cancers among prostate cancer survivors, but this has not been comprehensively examined by race/ethnicity. We conducted a retrospective cohort study of 716,319 one-year survivors of prostate cancer diagnosed at ages 35–84 during 2000–2015 as reported to 17 US Surveillance, Epidemiology and End Results (SEER) registries. We estimated standardized incidence ratios (SIRs) for second primary non-prostate malignancies by race/ethnicity (non-Latino white, Black, Asian/Pacific Islander [API] and Latino), by Gleason, and by time since prostate cancer diagnosis. Poisson regression models were used to test heterogeneity between groups with the expected number as the offset. 60,707 second primary malignancies were observed. SIRs for all second cancers combined varied significantly by race/ethnicity: SIRwhite: 0.88 (95% confidence interval: 0.87–0.89), SIRLatino: 0.92 (0.89–0.95), SIRBlack: 0.97 (0.95–0.99), and SIRAPI: 1.05 (1.01–1.09) (p-heterogeneity

Background It is unclear whether the established association between cutaneous melanoma (CM) and lymphoid neoplasms (LNs) differs across LN subtypes. This study quantifies risk for developing CM after specific LNs and, conversely, for developing specific LNs after CM, as well as assessing clinical impact. Methods We identified a cohort of Caucasian adults (age 20-83 years) initially diagnosed with CM or LN, as reported to 17 US population-based cancer registries, 2000-2014. Standardized incidence ratios (SIRs) quantified second cancer risk. We assessed impact of second cancer development on risk of all-cause mortality using Cox regression. Results Among 151 949 one-or-more-year survivors of first primary LN, second primary CM risk was statistically significantly elevated after chronic lymphocytic leukemia/small lymphocytic lymphoma (SIR = 1.96, 95% confidence interval [CI] = 1.74 to 2.21), follicular lymphoma (SIR = 1.32, 95% CI = 1.09 to 1.58), and plasma cell neoplasms (SIR = 1.33, 95% CI = 1.07 to 1.63). Risks for these same subtypes were statistically significantly elevated among 148 336 survivors of first primary CM (SIR = 1.44, 95% CI = 1.25 to 1.66; SIR = 1.47, 95% CI = 1.21 to 1.77; SIR = 1.25, 95% CI = 1.06 to 1.47; respectively). Risk for CM was statistically significantly elevated after diffuse large B-cell lymphoma (SIR = 1.22, 95% CI = 1.02 to 1.45) and Hodgkin lymphoma (SIR = 1.75, 95% CI = 1.33 to 2.26), but the reciprocal relationship was not observed. There were no statistically significant associations between marginal zone lymphoma and CM. Among survivors of most LN subtypes, CM statistically significantly increased risk of death (hazard ratio [HR] range = 1.52, 95% CI = 1.25 to 1.85, to 2.46, 95% CI = 1.45 to 4.16). Among survivors of CM, LN statistically significantly increased risk of death (HR range = 1.75, 95% CI = 1.15 to 2.65, to 6.28, 95% CI = 5.00 to 7.88), with the highest risks observed for the most aggressive LN subtypes. Conclusions Heterogeneous associations between CM and specific LN subtypes provide novel insights into the etiology of these malignancies, with the mutual association between CM and certain LN suggesting shared etiology. Development of second primary CM or LN substantially reduces overall survival.

PURPOSE: Radiotherapy for ductal carcinoma (DCIS) is increasing, but the risks and benefits of the treatment remain uncertain. We aimed to investigate the relationship between radiotherapy for DCIS and risk of second non-breast cancers in a large US cohort. METHODS: We conducted a retrospective cohort study of 52,556 women in 12 U.S. population-based cancer registries diagnosed with first primary DCIS during 1992–2008 at age 25–79 years. We estimated relative risks (RRs), attributable risks (AR) and excess absolute risks (AER) of second non-breast cancers associated with radiotherapy using Poisson regression adjusted for age at and year of diagnosis, grade, hormonal therapy (yes/no or unknown), and time since diagnosis. RESULTS: Approximately half of the women (46.3%) received radiotherapy. Radiotherapy was associated with an increased risk of all second non-breast cancers combined (RR=1.17, 95% Confidence Interval [CI]1.08–1.28) and all in-field, radiation-related second cancers combined (RR=1.37, 95%CI:1.15–1.63), driven by second lung cancers (RR=1.33, 95CI:1.10–1.60) and non-CLL leukemia (RR=1.71, 95%CI:1.02–2.86). The estimated cumulative excess risk of all second non-breast cancers was 0.8% by 15 years after DCIS diagnosis. CONCLUSIONS: Radiotherapy was associated with an increased risk of second non-breast cancers. The specific excess of cancers at sites likely in/near the radiotherapy field suggests the findings are unlikely due exclusively to confounding, but further research into factors related to receipt of radiotherapy is needed. Our risk estimates can be used to help assess the balance of the risks and benefits of radiotherapy for DCIS and to inform clinical practice.

IMPORTANCE: Chest irradiation for childhood cancer is associated with increases in breast cancer risk. Growing evidence suggests that anthracyclines increase this risk, but the outcome of combined anthracycline use and radiotherapy has not been studied. OBJECTIVES: To evaluate breast cancer risk in childhood cancer survivors following radiotherapy and chemotherapy and assess whether risks varied by estrogen receptor (ER) status. DESIGN, SETTING, AND PARTICIPANTS: In a North American hospital-based nested case-control study, a retrospective cohort of 14 358 five-year survivors of childhood cancer, diagnosed from 1970 to 1986 and followed up through December 31, 2016, was analyzed. Cases (n = 271) were defined as women with subsequent breast cancer. Controls (n = 1044) were matched 4:1 to cases by age at first cancer and duration of follow-up (± 2 years). Data analysis was conducted from September 2017 to July 2018. EXPOSURES: Radiation dose to breast tumor site and ovaries and cumulative chemotherapy doses, including anthracyclines and alkylating agents. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) for subsequent breast cancer by ER status. RESULTS: A total of 271 women served as breast cancer cases (median age at first cancer diagnosis, 15 years [range, 3-20]; median age at breast cancer diagnosis, 39 years [range, 20-57]): 201 invasive (113 ER positive [ER+], 41 ER negative [ER–], and 47 unknown) and 70 in situ breast cancers. The OR for breast cancer increased with increasing radiation dose to the breast (OR per 10 Gy, 3.9; 95% CI, 2.5-6.5) and was similar for ER+ (OR per 10 Gy, 5.5; 95% CI, 2.8-12.6) and ER– (OR per 10 Gy, 4.8; 95% CI, 1.7-22.3) cancers. For women who received ovarian doses less than 1 Gy, the OR per 10 Gy to the breast was higher (OR, 6.8; 95% CI, 3.9-12.5) than for women who received ovarian doses greater than or equal to 15 Gy (OR, 1.4; 95% CI, 1.0-6.4). The OR for breast cancer increased with cumulative anthracycline dose (OR per 100 mg/m(2), 1.23; 95% CI, 1.09-1.39; P

Data on cause-specific mortality after lymphoplasmacytic lymphoma (LPL) and Waldenstrom macroglobulinaemia (WM) are lacking. We identified causes of death amongst 7289 adults diagnosed with incident first primary LPL (n = 3108) or WM (n = 4181) during 2000-2016 in 17 USA population-based cancer registries. Based on 3132 deaths, 16-year cumulative mortality was 23·2% for lymphomas, 8·4% for non-lymphoma cancers and 14·7% for non-cancer causes for patients aged

Background While radiotherapy is a major risk factor for thyroid cancer after childhood cancer, factors contributing to increased thyroid cancer risk after adulthood cancer remain unclear. Methods We evaluated second primary papillary thyroid cancer (PTC) risk among 3,175,216 ≥ 1-year adult survivors of non-thyroid malignancies from US population-based cancer registries (2000–2015), using standardized incidence ratios (SIRs). Because heightened surveillance may increase detection of indolent thyroid tumors and earlier detection of advanced tumors, we examined SIRs by PTC stage and time since first cancer (latency). Results SIRs for second primary PTC (N = 4333) were statistically-significantly 1.2–3.5-fold elevated overall and after 23/27 first cancer types evaluated, with generally similar risks for localized and regional/distant PTC. SIRs for regional/distant PTC (N = 1501) were highest after pancreatic (SIR = 3.7; 95% confidence interval [CI] = 1.9–6.5) and soft tissue (SIR = 4.2; 95%CI = 2.8–6.2) cancers, followed by melanoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, and larynx, kidney, and brain/central nervous system (SIRs = 2.0–2.9) cancers. SIRs typically decreased with increasing latency but remained statistically-significantly elevated for regional/distant-PTC ≥5 years after diagnosis of cancers of the rectum, pancreas, lung/bronchus, soft tissue, female breast, uterine corpus, prostate, and kidney, and after melanoma, Hodgkin lymphoma, CLL/SLL, and follicular lymphoma. Neither total nor regional/distant PTC were clearly associated with initial course of radiotherapy or chemotherapy. Conclusions PTC risk was elevated after a range of first primary adult cancers but was not clearly related to treatment. Although surveillance may contribute to elevated short-term risks of PTC, longer-term elevations in regional/distant PTC may be attributable to shared risk factors.

Excess sarcoma risks after childhood cancer are well established, but risks among young adulthood cancer survivors are poorly understood. Using US population-based cancer registry data, we compared bone and soft-tissue sarcoma risk vs the general population among 186 351 individuals who were diagnosed with nonsarcoma first primary malignancies at ages 20–39 years from 1975 to 2014 (follow-up through 2015) and survived at least 1 year. Bone sarcomas were rare (n = 50), but risk was statistically significantly elevated overall (2.9-fold) and greater than fivefold after Hodgkin lymphoma, non-Hodgkin lymphoma, and central nervous system tumors. Soft-tissue sarcomas were more common (n = 284) and risks were statistically significantly elevated approximately twofold overall and after melanoma and carcinomas of the breast, thyroid, and testis, and greater than fourfold after Hodgkin lymphoma and central nervous system tumors. Risks varied markedly by subtype, with the highest risks (greater than fourfold) for osteosarcoma and the soft-tissue subtypes of rhabdomyosarcoma and blood vessel and nerve sheath sarcomas. These data demonstrate elevated risk for sarcoma after a range of young adulthood cancers.

Infectious agents have been identified in the etiology of certain non-Hodgkin lymphoma (NHL) subtypes and solid tumors. The impact of this shared etiology on risk for second cancers in NHL survivors has not been comprehensively studied. We used US population–based cancer registry data to quantify risk of solid malignancies associated with infectious etiology among 127 044 adult 1-year survivors of the 4 most common NHL subtypes diagnosed during 2000 to 2014 (mean follow-up, 4.5-5.2 years). Compared with the general population, elevated risks for liver, stomach, and anal cancers were observed among diffuse large B-cell lymphoma (DLBCL) survivors (standardized incidence ratio [SIR], 1.85; 95% confidence interval [CI], 1.46-2.31; SIR, 1.51; 95% CI, 1.16-1.94; SIR, 3.71; 95% CI, 2.52-5.27, respectively) and marginal zone lymphoma (MZL; SIR, 1.98; 95% CI, 1.34-2.83; SIR, 2.78; 95% CI, 2.02-3.74; SIR, 2.36; 95% CI, 1.02-4.64, respectively) but not follicular lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma. Anal cancer risk was particularly elevated among DLBCL survivors with HIV (SIR, 68.34; 95% CI, 37.36-114.66) vs those without (SIR, 2.09; 95% CI, 1.22-3.34). The observed patterns are consistent with shared associations between these cancers and hepatitis C virus, Helicobacter pylori, and HIV, respectively. In contrast, risks for cervical and oropharyngeal/tonsil cancers were not elevated among survivors of any NHL subtype, possibly because of the lack of NHL association with human papillomavirus or population-wide screening practices (for cervical cancer). In summary, patterns of elevated second cancer risk differed by NHL subtype. Our results suggest shared infectious etiology has implications for subsequent cancer risks among DLBCL and MZL survivors, which may help inform surveillance for these survivors.

Background: Pancreatic cancer risk is elevated among testicular cancer (TC) survivors. However, the roles of specific treatments are unclear. Methods: Among 23 982 5-year TC survivors diagnosed during 1947–1991, doses from radiotherapy to the pancreas were estimated for 80 pancreatic cancer patients and 145 matched controls. Chemotherapy details were recorded. Logistic regression was used to estimate odds ratios (ORs). Results: Cumulative incidence of second primary pancreatic cancer was 1.1% at 30 years after TC diagnosis. Radiotherapy (72 (90%) cases and 115 (80%) controls) was associated with a 2.9-fold (95% confidence interval (CI) 1.0–7.8) increased risk. The OR increased linearly by 0.12 per Gy to the pancreas (P-trend

Descriptive epidemiological information on myeloproliferative neoplasms (MPNs) and myelodysplastic (MDS)/MPNs is largely derived from single institution and European population-based studies. Data obtained following adoption of the World Health Organization classification of haematopoietic neoplasms and JAK2 V617F mutation testing are sparse. Using population-based data, we comprehensively assessed subtype-specific MPN and MDS/MPN incidence rates (IRs), IR ratios (IRRs) and relative survival (RS) in the United States (2001-12). IRs were highest for polycythaemia vera (PV) (IR = 10·9) and essential thrombocythaemia (ET) (IR = 9·6). Except for ET and mastocytosis, overall IRs were significantly higher among males (IRRs = 1·4-2·3). All evaluable MPNs were associated with lower IRs among Hispanic whites than non-Hispanic whites (NHWs), with the exception of BCR-ABL1-positive chronic myeloid leukaemia (CML), chronic eosinophilic leukaemia (CEL) and juvenile myelomonocytic leukaemia. Except for CEL, Asians/Pacific Islanders had significantly lower MPN IRs than NHWs. ET, MPN-unclassifiable and CEL IRs were 18%, 19% and 60% higher, respectively, among blacks than NHWs. Five-year RS was more favourable for younger (60 years) than older individuals and for women compared with men, except for PV at older ages. RS was highest (90%) for younger PV and ET patients and lowest (20%) for older chronic myelomonocytic leukaemia and atypical BCR-ABL1-negative CML patients. Varying MPN and MDS/MPN incidence patterns by subtype support distinct aetiologies and/or susceptible populations. Decreased survival rates as compared to that expected in the general population were associated with every MPN subtype, highlighting the need for new treatments, particularly among older individuals.

CONSTRUCT: In this study we describe a multidimensional scaling (MDS) exercise to validate the curricular elements composing a new Mastery Rubric (MR) for a curriculum in evidence-based medicine (EBM). This MR-EBM comprises 10 elements of knowledge, skills, and abilities (KSAs) representing our institutional learning goals of career-spanning engagement with EBM. An MR also includes developmental trajectories for each KSA, beginning with medical school coursework, including residency training, and outlining the qualifications of individuals to teach and mentor in EBM. The development was not part of the validation effort, as our curriculum is focused at a single stage (undergraduate medical students).An MR comprises the desired KSAs for an entire curriculum, together with descriptions of a learner's performance and/or capabilities as they develop from novice to proficiency of the curricular target(s). The MR construct is intended to support curriculum development or refinement by capturing the KSAs that support the articulation of concrete learning goals; it also promotes assessment that demonstrates development in the target KSAs and encourages reflection and self-directed learning throughout the learner's career. Two other MRs have been published, and this is the first one specific to teaching and learning in medicine; this is also the first one created specifically to evaluate an existing curriculum.To validate the dispersion of the elements of the EBM curriculum, the nine clinical instructors in the EBM two-course curriculum completed an MDS exercise, rating the similarities of the 10 curricular elements. MDS is a mathematical approach to understanding relationships among concepts/objects when these relationships are difficult to quantify. Eliciting similarity ratings biased the responses toward the null hypothesis (that the elements are not different).MDS results suggested that the MR represents 10 different, although related, facets of the construct "evidence-based medicine." The results support the makeup of the MR-EBM, and its use to revise our EBM curriculum so that it is more closely aligned with this MR.An MR is a tool, and the MR-EBM that we describe can be useful to develop or evaluate a curriculum in EBM. The MR tool is particularly compatible with the objectives of training for EBM and practice and can be applied to create or evaluate a curriculum using any topical KSA framework. The MR-EBM we describe could be adopted or adapted to represent other institutional objectives for EBM training.

Background: The increasing incidence of estrogen receptor (ER)-positive breast cancer in the U.S. in concert with the aging population and improved survival have resulted in an increased number of women at risk of developing a second contralateral primary breast cancer. Results from randomized clinical trials have suggested a reduced risk of contralateral breast cancer among women taking tamoxifen or aromatase inhibitors. However, little is known about the duration of beneficial effects of endocrine therapy within the context of real life treatment scenarios, where gaps in treatment and varying durations of use may influence risk. Methods: We assessed contralateral breast cancer risk associated with adjuvant tamoxifen treatment among a cohort of 7,541 women, ages 24-85 years, who were members of Kaiser Permanente (KP) Northwest or Colorado, and were diagnosed with invasive breast cancer between 1990 and 2008 and remained at risk of contralateral breast cancer for at least one year. We also assessed risk in relation to aromatase inhibitor use, though statistical power was somewhat limited due to the relatively recent introduction of aromatase inhibitors in this older cohort. Use of tamoxifen, aromatase inhibitors and other treatments was ascertained from KP prescription and medical records. Relative risks (RR) and 95% confidence intervals (CI) were estimated using multivariable Poisson regression adjusting for study site, age at and year of diagnosis, stage at diagnosis, ER status, chemotherapy, and radiotherapy. Results: Over a median (range) of 6.3 (1.0-20.9) years of follow-up, 248 women developed contralateral breast cancer. Among patients surviving at least five years (n=4,668), 58% were prescribed tamoxifen with a median (range) duration of use of 4.2 (0.25-16.2) years. In models evaluating joint effects of tamoxifen duration and time since last use, we observed a statistically significant reduced risk of contralateral breast cancer among current tamoxifen users (RR=0.47, 95% CI: 0.30, 0.74) and among former users with 4+ years of tamoxifen (RR=0.39, 95% CI: 0.24, 0.63) as compared with women not treated with tamoxifen. Former users with 1-4 years of tamoxifen demonstrated a suggestive reduction in risk (RR=0.71, 95% CI: 0.45, 1.10), but there was no evidence of risk reduction for former users with Conclusions: Adjuvant tamoxifen and aromatase inhibitor therapy considerably reduce the risk of contralateral breast cancer. Furthermore, our data suggest that tamoxifen protects against contralateral breast cancer while women are being treated and that the protective effect appears to continue after cessation with longer durations of use. Citation Format: Gierach GL, Curtis RE, Pfeiffer RM, Mullooly M, Hoover RN, Nyante SJ, Feigelson HS, Glass AG, Berrington de Gonzalez A. Adjuvant endocrine therapy and risk of contralateral breast cancer among a cohort of U.S. women with breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-12-01.

A methodology for assessing the efficiency and economic viability of renewable gas generation and energy conversion to compliment residential PV is proposed and demonstrated for the 10,000 resident example community of Oak View in Huntington Beach, California. Renewable fuel production processes included in this work are (1) processing of community-produced organic fraction of municipal solid waste in an anaerobic digester, and (2) using solar generation paired with water electrolysis. Six pathways – three ending in natural gas pipeline injection and three ending in solid oxide fuel cell electricity production – were evaluated for each PV capacity scenario. The renewable fuel production potential based only upon waste from the studied community was determined to be 2400 MMBtu per year of renewable natural gas (RNG) from anaerobic digestion, and up to 28,500 MMBtu of hydrogen from electrolysis using only excess solar PV electricity. With current costs the levelized cost of energy (LCOE) for renewable fuel production is $40–203/MMBtu, depending upon the energy pathway and scale. The LCOE for renewable electricity production is $0.37–1.28/kWh. A combination of LCFS and tipping fees as low as $20 per ton can yield renewable fuel at $2 per MMBtu. Likewise, a tipping fee of $32 can lead to the production of renewable electricity at $0.18 per kWh. Using future costs, the unsubsidized cost of electricity can drop as low as $0.15 per kWh, and renewable fuel can be produced at $18 per MMBtu. If Low Carbon Fuel Credits exist in 2050, a tipping fee of less than $9 per ton can yield renewable fuel at $2 per MMBtu. On an energy basis, over 80% of the community electrical demand can be met through a combination of local solar PV, anaerobic digestion, and fuel cell operation (80% zero net electricity). In this scenario, solar PV meets 52% of the community electrical load, while excess solar production produces hydrogen that is passed through a fuel cell to meet 26% of the electrical load. The remaining 3% is met using RNG produced through anaerobic digestion using only organic waste from the studied community. This analysis indicates that the production of renewable fuel in the urban environment is currently not economically feasible but will become competitive with conventional energy in the future.

Importance Therapy-related myelodysplastic syndrome or acute myeloid leukemia (tMDS/AML) is a rare, usually fatal complication of chemotherapy, including certain alkylating agents, topoisomerase II inhibitors, and platinum compounds. With the introduction of new chemotherapeutic agents, expanded indications for established agents, and increased neoadjuvant and adjuvant chemotherapy, tMDS/AML risks in the modern age are poorly understood. Objectives To quantify tMDS/AML risk after chemotherapy for solid cancer among United States adults since 2000 and correlate tMDS/AML risk patterns with chemotherapy treatment practices. Design, Setting, and Participants A population-based cohort study was conducted using cancer registries from the Surveillance, Epidemiology, and End Results (SEER) Program and Medicare claims. Risk analyses included 1619 tMDS/AML cases among 700 612 adults (age, 20-84 years) who were diagnosed with first primary solid cancer during 2000 to 2013 (followed up through 2014), received initial chemotherapy, and survived 1 year or longer, as reported to SEER. Descriptive analyses were conducted of SEER records linked with Medicare claims for chemotherapy in 165 820 older adults (age, 66-84 years) receiving initial chemotherapy for a first primary solid cancer in 2000-2013. Data analysis was conducted from October 2017 to April 2018. Exposures Receipt of initial chemotherapy for solid cancer. Main Outcomes and Measures Second primary tMDS/AML. Results Based on 1619 tMDS/AML cases in the SEER database (mean [SD] age, 64.3 [12.2] years; 1148 [70.9%] female), tMDS/AML risks were statistically significantly elevated after chemotherapy for 22 of 23 solid cancers (all except colon). Relative risks ranged from 1.5 to greater than 10 and excess absolute risks from 1.4 to greater than 15 cases per 10 000 person-years compared with the general population. Overall survival following tMDS/AML diagnosis was poor (1270 of 1619 patients [78.4%] died; median overall survival, 7 months). For patients treated with chemotherapy at the present time, approximately three-quarters of tMDS/AML cases expected to occur within the next 5 years will be attributable to chemotherapy. In the SEER-Medicare database, use of known leukemogenic agents, particularly platinum compounds, in initial chemotherapy increased substantially since 2000, most notably for gastrointestinal tract cancers (esophagus, stomach, colon, and rectum; 10% in 2000-2001 to 81% during 2012-2013). Conclusions and Relevance Large-scale, United States population-based data demonstrate excess tMDS/AML risks following chemotherapy for nearly all solid tumor types, consistent with expanded use of known leukemogenic agents in the 21st century. Continued efforts to reduce treatment-related adverse events, particularly for solid cancer patients with favorable prognosis, are needed.

This population-based cohort study examines the association of radiotherapy for Hodgkin lymphoma with risk of ER-positive and ER-negative breast cancers using data from the US National Cancer Institute Surveillance, Epidemiology, and End Results database.

Although increased risk of acute myeloid leukemia (AML) has been observed after chemotherapy and radiotherapy, less is known about radiotherapy-related risks of specific AML subtypes and other specific myeloid neoplasms. We used the US population-based cancer registry data to evaluate risk of myeloid neoplasms among three cohorts of cancer survivors initially treated with radiotherapy only. We included 1-year survivors of first primary thyroid (radioiodine only, stages I–IV; N = 49 879), prostate (excluding stage IV; N = 237 439), or uterine corpus cancers (stage I–II; N = 16 208) diagnosed during 2000–2013. We calculated standardized incidence ratios (SIRs) and excess absolute risks (EARs). Thyroid cancer survivors had significantly elevated risks of total AML (SIR = 2.77, 95% CI: 1.99–3.76), AML with cytogenetic abnormalities (SIR = 3.90, 95% CI: 1.57–8.04), AML with myelodysplasia-related changes (SIR = 2.87, 95% CI: 1.05–6.25), and BCR-ABL1-positive chronic myelogenous leukemia (CML) (SIR = 5.38, 95% CI: 2.58–9.89). Irradiated prostate and uterine corpus cancer survivors were at elevated risk for total AML (SIR = 1.14, 95% CI: 1.03–1.27 and SIR = 1.77, 95% CI: 1.01–2.87, respectively), AML with cytogenetic abnormalities (SIR = 2.52, 95% CI: 1.84–3.37 and SIR = 7.21, 95% CI: 2.34–16.83, respectively), and acute promyelocytic leukemia (SIR = 3.20, 95% CI: 2.20–4.49 and SIR = 8.88, 95% CI: 2.42–22.73, respectively). In addition, prostate cancer survivors were at increased risk of BCR-ABL1-positive CML (SIR = 2.11, 95% CI: 1.52–2.85). Our findings support the importance of diagnostic precision in myeloid neoplasm classification since susceptibility following radiotherapy may vary by myeloid neoplasm subtype, thereby informing risk/benefit discussions in first primary cancer treatment.

Background We developed a Urinary Symptom Questionnaire for individuals with neurogenic bladder due to spinal cord injury (SCI) and spina bifida (SB) who manage their bladders with intermittent catheterization, the USQNB-IC. This project followed an approach to patient-centered patient reported outcomes development that we created and published in 2017, specifically to ensure the primacy of the patient’s perspective and experience. Participants Two sets of responses were collected from individuals with neurogenic bladder due to either SCI (n = 336) and SB (patients, n = 179; and caregivers of patients with NB, n = 66), and three sets of “controls”, individuals with neurogenic bladder who do not have a history of UTIs (n = 49) individuals with chronic mobility impairments (neither SCI nor SB) and without neurogenic bladder (n = 46), and those with no mobility impairment, no neurogenic bladder, and no history of UTIs (n = 64). Method Data were collected from all respondents to estimate these psychometric or measurement domains characterizing a health related PRO: Reliability (minimization of measurement error; internal consistency or interrelatedness of the items; and maximization of variability that is due to “true” difference between levels of the symptoms across patients), and validity (content, reflection of the construct to be measured; face, recognizability of the contents as representing the construct to be measured; structural, the extent to which the instrument captures recognizable dimensions of the construct to be measured; and criterion, association with a gold standard). Results Evidence from these five groups of respondents suggest the instrument has face, content, criterion, convergent, and divergent validity, as well as reliability. The items were all more descriptive of our patient (focus) groups and were only weakly endorsed by the control groups. Conclusions The instrument is unique in its emphasis on, and origination from, the lived experiences of patients with neurogenic bladder who use intermittent catheterization; this preliminary psychometric evidence suggests the instrument could be useful for research and in the clinic. These results justify further development of the instrument, including formal exploration of the scoring and estimation of responsivity of these items to clinical interventions as well as patient-directed self care.

Purpose Previous studies have reported that survivors of non-Hodgkin lymphoma (NHL) have an increased risk of developing cutaneous melanoma; however, risks associated with specific treatments and immune-related risk factors have not been quantified. Patients and Methods We evaluated second melanoma risk among 44,870 1-year survivors of first primary NHL diagnosed at age 66 to 83 years from 1992 to 2009 and included in the Surveillance, Epidemiology, and End Results-Medicare database. Information on NHL treatments, autoimmune diseases, and infections was derived from Medicare claims. Results A total of 202 second melanoma cases occurred among survivors of NHL, including 91 after chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 111 after other NHL subtypes (cumulative incidence by age 85 years: CLL/SLL, 1.37%; other NHL subtypes, 0.78%). Melanoma risk after CLL/SLL was significantly increased among patients who received infused fludarabine-containing chemotherapy with or without rituximab (n = 18: hazard ratio [HR], 1.92; 95% CI, 1.09 to 3.40; n = 10: HR, 2.92; 95% CI, 1.42 to 6.01, respectively). Significantly elevated risks also were associated with T-cell activating autoimmune diseases diagnosed before CLL/SLL (n = 36: HR, 2.27; 95% CI, 1.34 to 3.84) or after CLL/SLL (n = 49: HR, 2.92; 95% CI, 1.66 to 5.12). In contrast, among patients with other NHL subtypes, melanoma risk was not associated with specific treatments or with T-cell/B-cell immune conditions. Generally, infections were not associated with melanoma risk, except for urinary tract infections (CLL/SLL), localized scleroderma, pneumonia, and gastrohepatic infections (other NHLs). Conclusion Our findings suggest immune perturbation may contribute to the development of melanoma after CLL/SLL. Increased vigilance is warranted among survivors of NHL to maximize opportunities for early detection of melanoma.

Aim Aboriginal leaders concerned about high rates of alcohol use in pregnancy invited researchers to determine the prevalence of fetal alcohol syndrome (FAS) and partial fetal alcohol syndrome (pFAS) in their communities. Methods Population-based prevalence study using active case ascertainment in children born in 2002/2003 and living in the Fitzroy Valley, in Western Australia (April 2010–November 2011) (n = 134). Socio-demographic and antenatal data, including alcohol use in pregnancy, were collected by interview with 127/134 (95%) consenting parents/care givers. Maternal/child medical records were reviewed. Interdisciplinary assessments were conducted for 108/134 (81%) children. FAS/pFAS prevalence was determined using modified Canadian diagnostic guidelines. Results In 127 pregnancies, alcohol was used in 55%. FAS or pFAS was diagnosed in 13/108 children, a prevalence of 120 per 1000 (95% confidence interval 70–196). Prenatal alcohol exposure was confirmed for all children with FAS/pFAS, 80% in the first trimester and 50% throughout pregnancy. Ten of 13 mothers had Alcohol Use Disorders Identification Test scores and all drank at a high-risk level. Of children with FAS/pFAS, 69% had microcephaly, 85% had weight deficiency and all had facial dysmorphology and central nervous system abnormality/impairment in three to eight domains. Conclusions The population prevalence of FAS/pFAS in remote Aboriginal communities of the Fitzroy Valley is the highest reported in Australia and similar to that reported in high-risk populations internationally. Results are likely to be generalisable to other age groups in the Fitzroy Valley and other remote Australian communities with high-risk alcohol use during pregnancy. Prevention of FAS/pFAS is an urgent public health challenge.

To further understand the risk of stomach cancer after fractionated high-dose radiotherapy, we pooled individual-level data from three recent stomach cancer case-control studies. These studies were nested in cohorts of five-year survivors of first primary Hodgkin lymphoma (HL), testicular cancer (TC) or cervical cancer (CX) from seven countries. Detailed data were abstracted from patient records and radiation doses were reconstructed to the site of the stomach cancer for cases and to the corresponding sites for matched controls. Among 327 cases and 678 controls, mean doses to the stomach were 15.3 Gy, 24.7 Gy and 1.9 Gy, respectively, for Hodgkin lymphoma, testicular cancer and cervical cancer survivors, with an overall mean dose of 10.3 Gy. Risk increased with increasing radiation dose to the stomach cancer site (P < 0.001) with no evidence of nonlinearity or of a downturn at the highest doses (≥35 Gy). The pooled excess odds ratio per Gy (EOR/Gy) was 0.091 [95% confidence interval (CI): 0.036-0.20] with estimates of 0.049 (95% CI: 0.007-0.16) for Hodgkin lymphoma, 0.27 (95% CI: 0.054-1.44) for testicular cancer and 0.096 (95% CI: -0.002-0.39) for cervical cancer (P homogeneity = 0.25). The EOR/Gy increased with time since exposure (P trend = 0.004), with an EOR/Gy of 0.38 (95% CI: 0.12-1.04) for stomach cancer occurring ≥20 years postirradiation corresponding to odds ratios of 4.8 and 10.5 at radiation doses to the stomach of 10 and 25 Gy, respectively. Of 111 stomach cancers occurring ≥20 years after radiotherapy, 63.8 (57%) could be attributed to radiotherapy. Our findings differ from those based on Japanese atomic-bomb survivors, where the overall EOR/Gy was higher and where there was no evidence of an increase with time since exposure. By pooling data from three studies, we demonstrated a clear increase in stomach cancer risk over a wide range of doses from fractionated radiotherapy with the highest risks occurring many years after exposure. These findings highlight the need to directly evaluate the health effects of high-dose fractionated radiotherapy rather than relying on the data of persons exposed at low and moderate acute doses.

PHENOMENON: The purpose of “systematic” reviews/reviewers of medical and health professions educational research is to identify best practices. This qualitative paper explores the question of whether systematic reviews can support “evidence informed” teaching, and contrasts traditional systematic reviewing with a knowledge-translation approach to this objective.\ud APPROACH: Degrees of Freedom Analysis is used to examine the alignment of systematic review methods with educational research and the pedagogical strategies and approaches that might be considered with a decision-making framework developed to support valid assessment. This method is also used to explore how knowledge translation can be used to inform teaching and learning.\ud FINDINGS: The nature of educational research is not compatible with most (11/14) methods for systematic review. The inconsistency of systematic reviewing with the nature of educational research impedes both the identification and implementation of ‘best-evidence’ pedagogy and teaching. This is primarily because research questions that do support the purposes of review do not support educational decision-making. By contrast to systematic reviews of the literature, both a Degrees of Freedom Analysis (DOFA) and knowledge translation (KT) are fully compatible with informing teaching using evidence. A DOFA supports the translation of theory to a specific teaching or learning case, so could be considered a type of KT. The DOFA results in a test of alignment of decision options with relevant educational theory and KT leads to interventions in teaching or learning that can be evaluated. Examples of how to structure evaluable interventions are derived from a knowledge-translation approach that are simply not available from a systematic review.\ud INSIGHTS: Systematic reviewing of current empirical educational research is not suitable for deriving or supporting best practices in education. However, both “evidence-informed” and scholarly approaches to teaching can be supported as knowledge translation projects, which are inherently evaluable and can generate actionable evidence about whether the decision or intervention worked for students, instructors, and the institution. A Degrees of Freedom Analysis can also support evidence- and theory-informed teaching to develop an understanding of what works, why, and for whom. Thus, knowledge translation, but not systematic reviewing, can support decision-making around pedagogy (and pedagogical innovation) that can also inform new teaching and learning initiatives; it can also point to new avenues of empirical research in education that are informed by, and can inform, theory.

Purpose To determine whether prediagnostic body mass index (BMI) is associated with risk of second obesity-associated cancers in colorectal cancer (CRC) survivors, and whether CRC survivors have increased susceptibility to obesity-associated cancer compared with cancer-free individuals. Patients and Methods Incident first primary CRC cases (N = 11,598) were identified from five prospective cohort studies. We used Cox proportional hazards regression models to examine associations between baseline (prediagnostic) BMI and risk of second obesity-associated cancers (postmenopausal breast, kidney, pancreas, esophageal adenocarcinoma, endometrium) in CRC survivors, and compared associations to those for first obesity-associated cancers in the full cohort. Results Compared with survivors with normal prediagnostic BMI (18.5-24.9 kg/m2), those who were overweight (25-29.9 kg/m2) or obese (30+ kg/m2) had greater risk of a second obesity-associated cancer (n = 224; overweight hazard ratio [HR], 1.39; 95% CI, 1.01 to 1.92; obese HR, 1.47; 95% CI, 1.02 to 2.12; per 5-unit change in BMI HR, 1.12; 95% CI, 0.98 to 1.29). The magnitude of risk for developing a first primary obesity-associated cancer was similar (overweight HR, 1.18; 95% CI, 1.14 to 1.21; obese HR, 1.61; 95% CI, 1.56 to 1.66; per 5-unit change in BMI HR, 1.23; 95% CI, 1.21 to 1.24). Before diagnosis CRC patients were somewhat more likely than the overall cohort to be overweight (44% v 41%) or obese (25% v 21%). Conclusion CRC survivors who were overweight or obese before diagnosis had increased risk of second obesity-associated cancers compared with survivors with normal weight. The risks were similar in magnitude to those observed for first cancers in this population, suggesting increased prevalence of overweight or obesity, rather than increased susceptibility, may contribute to elevated second cancer risks in colorectal cancer survivors compared with the general population. These results support emphasis of existing weight guidelines for this high-risk group.

The use of Big Data--however the term is defined--involves a wide array of issues and stakeholders, thereby increasing numbers of complex decisions around issues including data acquisition, use, and sharing. Big Data is becoming a significant component of practice in an ever-increasing range of disciplines; however, since it is not a coherent "discipline" itself, specific codes of conduct for Big Data users and researchers do not exist. While many institutions have created, or will create, training opportunities (e.g., degree programs, workshops) to prepare people to work in and around Big Data, insufficient time, space, and thought have been dedicated to training these people to engage with the ethical, legal, and social issues in this new domain. Since Big Data practitioners come from, and work in, diverse contexts, neither a relevant professional code of conduct nor specific formal ethics training are likely to be readily available. This normative paper describes an approach to conceptualizing ethical reasoning and integrating it into training for Big Data use and research. Our approach is based on a published framework that emphasizes ethical reasoning rather than topical knowledge. We describe the formation of professional community norms from two key disciplines that contribute to the emergent field of Big Data: computer science and statistics. Historical analogies from these professions suggest strategies for introducing trainees and orienting practitioners both to ethical reasoning and to a code of professional conduct itself. We include two semester course syllabi to strengthen our thesis that codes of conduct (including and beyond those we describe) can be harnessed to support the development of ethical reasoning in, and a sense of professional identity among, Big Data practitioners.

Although elevated risks of pancreatic cancer have been observed in long-term survivors of Hodgkin lymphoma (HL), no prior study has assessed the risk of second pancreatic cancer in relation to radiation dose and specific chemotherapeutic agents.We conducted an international case-control study within a cohort of 19 882 HL survivors diagnosed from 1953 to 2003 including 36 cases and 70 matched controls.Median ages at HL and pancreatic cancer diagnoses were 47 and 60.5 years, respectively; median time to pancreatic cancer was 19 years. Pancreatic cancer risk increased with increasing radiation dose to the pancreatic tumor location (Ptrend = 0.005) and increasing number of alkylating agent (AA)-containing cycles of chemotherapy (Ptrend = 0.008). The odds ratio (OR) for patients treated with both subdiaphragmatic radiation (≥10 Gy) and ≥6 AA-containing chemotherapy cycles (13 cases, 6 controls) compared with patients with neither treatment was 17.9 (95% confidence interval 3.5-158). The joint effect of these two treatments was significantly greater than additive (P = 0.041) and nonsignificantly greater than multiplicative (P = 0.29). Especially high risks were observed among patients receiving ≥8400 mg/m(2) of procarbazine with nitrogen mustard or ≥3900 mg/m(2) of cyclophosphamide.Our study demonstrates for the first time that both radiotherapy and chemotherapy substantially increase pancreatic cancer risks among HL survivors treated in the past. These findings extend the range of nonhematologic cancers associated with chemotherapy and add to the evidence that the combination of radiotherapy and chemotherapy can lead to especially large risks.

Advances in Hodgkin lymphoma (HL) treatment have dramatically improved prognosis, with 5-year relative survival now over 80% in the United States (US) and Europe. However, subsequent malignancies, often occurring as late adverse effects of treatment, are a leading cause of morbidity and mortality

As the population of cancer survivors has increased and continues to age, the occurrence of second cancers has risen dramatically—from 9% of all cancer diagnoses in 1975–1979 to 19% in 2005–2009. The Childhood Cancer Survivor Study, a cohort of more than 14,000 childhood cancer survivors with detailed exposure data and long-term follow-up, has substantially contributed to our understanding of the roles of radiotherapy and chemotherapy in second cancer occurrence. In particular, dose-related risks have been demonstrated for second cancers of the breast, thyroid, central nervous system, gastrointestinal tract, and sarcomas following radiation. Cytotoxic chemotherapy—which has long been known to be leukemogenic—also appears to contribute to risk for a range of other second cancer types. Individuals who develop a second cancer are at particularly high risk for developing additional second cancers. A genome-wide association study of survivors of Hodgkin lymphoma who received radiotherapy identified a locus on chromosome 6q21 as being associated with second cancer risk, demonstrating that recent advances in genomics are likely to prove invaluable for elucidating the contribution of genetic susceptibility to second cancer etiology. Among adults, risk of second cancers varies substantially by type of first and second cancer, patient age, and prevalence of second cancer risk factors, including primary cancer treatments, environmental and lifestyle exposures, and genetic susceptibility. Further research is needed to quantify second cancer risks associated with specific etiologic factors and to identify the patients at highest risk of developing a second cancer to target prevention and screening efforts.

The aetiology of marginal zone lymphoma (MZL) is purported to differ by anatomic site. While this is supported by clinical series of single MZL sites, no population-based study has comprehensively assessed incidence patterns across sites. To gain insight into disease aetiology, we assessed MZL incidence by site using data from 18 U.S. Surveillance, Epidemiology and End Results (SEER) Program population-based registries. We calculated age-adjusted incidence rates (IRs) by sex, race, and calendar year. During 2001-2009, 4,081 (IR = 5·7/1,000,000 person-years) and 8,821 (IR = 12·3) individuals were diagnosed with nodal MZL and extranodal MZL, respectively. The most common extranodal sites were stomach (IR = 3·8), spleen (IR = 1·6), eye/adnexa (IR = 1·4), and lung, skin, and salivary glands (IRs = 0·9-1·0). We observed distinct age-specific patterns by MZL site, with IRs increasing steeply at younger ages and less prominently after mid-life at several sites, except skin. Gender and racial/ethnic disparities were also apparent across sites. Between 2001-2005 and 2006-2009, MZL IRs decreased significantly for gastric (-15%) and soft tissue (-28%) sites, whereas IRs increased significantly for lung (18%), skin (43%), and kidney/renal pelvis (116%). In combination, our findings support the contention that MZL is characterized by aetiological heterogeneity across sites and susceptibility is probably influenced by intrinsic characteristics and environmental exposures.

Background: It is unclear why systematic training in end-of-residency clinic handoffs is not universal. Purposes: We assessed Internal Medicine-Pediatrics (Med-Peds) residency program directors’ attitudes regarding end-of-residency clinic handoff systems and perceived barriers to their implementation. Methods: We surveyed all Med-Peds program directors in the United States about end-of-residency outpatient handoff systems. Results: Program directors rated systems as important (81.5%), but only 31 programs (46.3%) utilized them. Nearly all programs with (29/31 [93.5%]), and most programs without systems (24/33 [72.7%]) rated them as important. Programs were more likely to have a system if the program director rated it important (p = .049), and less likely if they cited a lack of faculty interest (p = .023) or difficulty identifying residents as primary providers (p = .04). Conclusions: Most program directors believe it important to formally hand off outpatients. Barriers to establishing handoff systems can...

As the life sciences have become more data intensive, the pressure to incorporate the requisite training into life-science education and training programs has increased. To facilitate curriculum development, various sets of (bio)informatics competencies have been articulated; however, these have proved difficult to implement in practice. Addressing this issue, we have created a curriculum-design and -evaluation tool to support the development of specific Knowledge, Skills and Abilities (KSAs) that reflect the scientific method and promote both bioinformatics practice and the achievement of competencies. Twelve KSAs were extracted via formal analysis, and stages along a developmental trajectory, from uninitiated student to independent practitioner, were identified. Demonstration of each KSA by a performer at each stage was initially described (Performance Level Descriptors, PLDs), evaluated, and revised at an international workshop. This work was subsequently extended and further refined to yield the Mastery Rubric for Bioinformatics (MR-Bi). The MR-Bi was validated by demonstrating alignment between the KSAs and competencies, and its consistency with principles of adult learning. The MR-Bi tool provides a formal framework to support curriculum building, training, and self-directed learning. It prioritizes the development of independence and scientific reasoning, and is structured to allow individuals (regardless of career stage, disciplinary background, or skill level) to locate themselves within the framework. The KSAs and their PLDs promote scientific problem formulation and problem solving, lending the MR-Bi durability and flexibility. With its explicit developmental trajectory, the tool can be used by developing or practicing scientists to direct their (and their team's) acquisition of new, or to deepen existing, bioinformatics KSAs. The MR-Bi is a tool that can contribute to the cultivation of a next generation of bioinformaticians who are able to design reproducible and rigorous research, and to critically analyze results from their own, and others', work.

Introduction: Advances in cHL treatment over the past 50 years have been fueled, in part, by recognition of long-term treatment-related complications that emerged after cure of cHL became a reality. While cHL-specific survival has continued to improve with time, premature death following diagnosis and treatment of cHL remains life-limiting. Most studies of cHL mortality have focused on long-term survivors and included patients treated with chemotherapy approaches and radiation techniques used in the past. Therefore, we sought to comprehensively quantify early and late cause-specific risks of death among U.S. adults with cHL treated with chemotherapy during a treatment era predominated by ABVD-based (doxorubicin, bleomycin, vinblastine, dacarbazine) chemotherapy. Methods: We used data from 17 cancer registry areas of the Surveillance, Epidemiology, and End Results Program to quantify risks of death among individuals diagnosed with early (I/II) or advanced (III/IV) stage cHL between ages 20-74 years and treated with initial chemotherapy during 2000-2015. We calculated standardized mortality ratios (SMRs) and 95% confidence intervals to compare cause-specific risk of death following cHL to that expected in the general U.S. population and estimated absolute excess risks (per 10,000 patient-years) to quantify disease-specific death burden. Results: Among 24,205 cHL patients, we assessed mortality among the 85% (n=20,491) treated with initial chemotherapy (37% of the 20,491 also received initial radiotherapy). With a mean follow-up of 6.7 years, we observed 3,230 deaths due to lymphoma (n=1,936), other neoplasms (n=273), noncancers (n=937), and unknown (n=84) causes. The risk of non-lymphoma deaths overall was significantly elevated 1.5- and 2.3-fold among adults diagnosed with early or advanced cHL, respectively, representing 20 (early stage) and 75 (advanced stage) excess deaths/10,000 patient-years. The most common causes of noncancer deaths were attributed to cardiovascular (n=284), respiratory (n=166), and infectious (n=119) diseases and accidents/falls/adverse events (n=121). The greatest increased risk of cardiovascular deaths was observed for heart disease 5 years after early and advanced stage cHL. Death from interstitial lung disease (ILD) significantly exceeded the expected rate by 14- and 24-fold in early and advanced stage cHL, respectively, most notably within the first year of diagnosis (SMRearly=90; SMRadvanced=128), with SMRs decreasing substantially after 1-year but remaining significantly increased in both stage groups. Patients were also prone to infection-related deaths irrespective of early (SMRearly=2.2) or advanced (SMRadvanced=3.9) cHL, both 1 year after diagnosis, with the greatest excesses occurring within the first year. Individuals with early (SMRearly=1.8) and advanced stage (SMRadvanced=4.2) disease had significantly elevated risks of death from adverse events (deaths coded as sequelae of drug, treatment, or other specified exposure), most notably 9-fold among both stage groups 1-4 years after diagnosis, and excesses persisted at >5-years among those with advanced stage cHL (SMRadvanced=9.1). Lung cancer accounted for the majority of solid tumor deaths among those with early (SMRearly=1.4) and advanced stage (SMRadvanced=1.9) cHL, with heightened risks beginning at >5 years among early stage cHL and at 1-4 years among advanced stage disease. Conclusion: Despite tailored treatment approaches in an ABVD-predominant era, risk of non-lymphoma deaths remains significantly elevated among cHL patients 20-74 years of age in the U.S., with early or advanced stage disease, and 1 year from diagnosis. Our data strongly support implementation of preventive and supportive measures following cHL diagnosis and continued refinement of treatment approaches to minimize premature deaths. Disclosures No relevant conflicts of interest to declare.

e19056 Background: LPL and WM are rare, indolent mature B-cell lymphomas. While recent studies reveal improving survival after LPL/WM, cause-specific mortality has not been comprehensively studied. Methods: We identified 6659 adults with first primary LPL (n = 2866) or WM (n = 3793) within 17 US population-based cancer registries from 2000 to 2015. Patients were followed for vital status (mean follow-up = 5.07 years), and causes of death were determined from death certificates. Standardized mortality ratios (SMRs) estimated relative risk of death compared to the general population. We estimated cumulative mortality and absolute excess risk (AER) per 10,000 person-years. Results: We observed 2826 deaths overall, of which 43%, 13%, and 42% were due to lymphoma, cancers excluding lymphoma, and non-malignant causes, respectively. There was a 20% higher risk of death due to non-malignant causes compared to the general population (n = 1194, SMR = 1.2, 95% confidence interval [CI] = 1.1 to 1.2). The most common non-malignant causes included infectious (n = 162, SMR = 1.8, 95% CI = 1.5 to 2.1, AER = 21.0), respiratory (n = 131, SMR = 1.2, 95% CI = 1.0 to 1.5, AER = 7.4), and digestive (n = 76, SMR = 1.9, 95% CI = 1.5 to 2.4, AER = 10.7) diseases. Cause-specific mortality varied by time since and age at LPL/WM diagnosis. Risks were highest in the first year after LPL/WM for non-malignant causes (SMR = 1.4, AER = 34.3), particularly infections (SMR = 2.4, AER = 34.4) and non-neoplastic hematologic diseases (SMR = 17.3, AER = 20.7). In contrast, risk of death due to cancers excluding lymphoma increased with time since diagnosis (SMR< 1y = 1.2, SMR≥5y = 1.7; AER< 1y = 15.1, AER≥5y = 60.0). Analyses by age, focused on AERs, showed generally similar risks across age groups (cancers excluding lymphoma: AER< 65= 26, AER65-75= 28, AER≥75= 31; non-malignant causes: AER< 65= 52, AER65-75= 66, AER≥75= 23). Cumulative mortality from non-malignant causes (23.7%) exceeded that from lymphoma (22.9%) beginning 9 years after LPL/WM diagnosis. Conclusions: Using population data, we identified areas to improve survivorship care of LPL/WM patients, particularly for non-malignant causes of death.

10053 Background: Breast cancer is a common late-effect for female childhood cancer survivors and chest radiotherapy is an established risk factor. Recent findings showed that treatment with anthracyclines also increases breast cancer risk. However, the risk from the combined effect of radiotherapy and anthracyclines is unknown. Methods: We conducted a matched case-control study of 271 subsequent breast cancer and 1044 controls nested within the CCSS - a North-American cohort of five-year survivors of childhood cancer, diagnosed from 1970-1986 and followed-up through 2016. Detailed treatment records were abstracted to estimate radiation dose (Gy) to the breast cancer location and ovaries and calculate cumulative chemotherapy doses (mg/m2). Multivariable conditional logistic regression was used to estimate Odds ratios (OR) and 95% confidence intervals (CI). Results: Breast cancer risk increased linearly with radiation dose to the breast (OR per 10Gy = 3.9, 95%CI:2.5-6.5) and decreased with increasing ovarian dose (p < 0.01). Adjusted for radiation dose, the highest quartile of dose (455+mg/m2) of anthracyclines was associated with a 3.8-fold increased risk of breast cancer (95%CI:1.8-8.2) compared to no anthracyclines. This risk increased with cumulative anthracycline dose (p-trend < 0.01) and was non-significantly higher for ER+ than ER- breast cancers. For a breast dose of 10+Gy, the OR was 19.1 (95%CI:7.6-48.0) with anthracyclines versus 9.6 (95%CI:4.4-20.7) without anthracyclines, compared to 0- < 1Gy breast dose and no anthracyclines (p-additive interaction = 0.04). Conclusions: The combination of anthracyclines and radiotherapy doses to the breast can markedly increase breast cancer risk compared to those who receive neither treatment. Our results can be used to inform risk management for childhood cancer patients treated in the past, as well as project potential breast cancer risk from current treatment protocols.

Background and objectivesHIV-infected patients are at risk for developing chronic kidney disease (CKD), defined by estimated glomerular filtration rate (eGFR) Design, setting, participants and measurementsA retrospective cohort study (2012-2016) was conducted in all HIV-infected patients seen in a federally qualified community health center in Houston, Texas. CKD prevalence and its association with HIV viral load and CD4 count were determined. The association of the change in eGFR over time and comorbidities was assessed using linear mixed models.ResultsOf 3714 HIV-infected patients analyzed, 153 (4.1%) had CKD. The prevalence of CKD in the different racial groups was 5.4% White, 4.0% African American, 2.8% Hispanic/Latino and 3.2% Asian. There was no difference in the rate of decline in kidney function in White vs. African American HIV infected patients with CKD. Compared with non-CKD patients, CKD patients were older, had lived longer with HIV infection, had lower CD4 cell counts, higher proportions of hypertension, hyperlipidemia, and cerebrovascular disease, and had significantly higher rates of eGFR deterioration represented by a median decrease of 26.5% from first to last follow-up eGFR (versus 0% change). Linear mixed modeling identified older age, male gender, White race, longer time with HIV infection, hypertension, history of kidney stones, cerebrovascular disease, autoimmune disease, increased potassium and total cholesterol levels, and being treated with combination ART as associated with a worsening eGFR over time.ConclusionThis study demonstrates a prevalence of CKD in HIV-infected patients of 4.1% and points to an important role for HIV medications and other common comorbidities in the genesis and progression of kidney disease. Importantly, CKD was not more prevalent in African Americans than in Whites, perhaps due to a low prevalence of IV drug abuse as inferred from the lower prevalence of HCV infection in this cohort.

Background: Urinary symptoms are common for people with neurogenic lower urinary tract dysfunction (NLUTD). No nonprescription approach has been proven safe and effective for self-management of urinary symptoms. Our objective was to describe the safety and tolerability of Lactobacillus rhamnosus GG ( LGG®) instilled intravesically for self-management of inflammatory urinary symptoms in adults and children with NLUTD due to spinal cord injury or disease (SCI/D) and who use intermittent catheterization (IC). Methods: A total of 103 individuals with SCI/D enrolled in an 18-month study consisting of three 6-month stages: baseline (weekly observation of urinary symptoms); intervention (self-instilled intravesical LGG® in response to more cloudy or foul-smelling urine); and washout (weekly observation of urinary symptoms). Urinary symptoms were assessed using the Urinary Symptom Questionnaire for people with neurogenic bladder using intermittent catheters (USQNB-IC). Safety was based on serious adverse events and adverse events (S/AEs) and trends in symptoms. Tolerability was defined as the independence of AE experience and willingness to use/pay for this intervention. Results: A total of 74 (77%) adults and 6 (86%) of children completed the study, of whom 64 instilled LGG® for a total of 357 instillations (range 1–41 per person). There were 59 S/AEs, 44% (26/59) of which were categorized as infectious genitourinary. There was no statistical relationship between S/AEs and use or dose of the intervention. Conclusions: One or two doses of self-instilled intravesical LGG® in response to more cloudy or foul-smelling urine was safe and well tolerated among this sample of adults and children with SCI/D who have NLUTD and use IC.

Following cancer radiotherapy, reconstruction of doses to organs, other than the target organ, is of interest for retrospective health risk studies. Reliable estimation of doses to organs that may be partially within or fully outside the treatment field requires reliable knowledge of the location and size of the organs, e.g., the stomach, which is at risk from abdominal irradiation. The stomach location and size are known to be highly variable between individuals, but have been little studied. Moreover, for treatments conducted years ago, medical images of patients are usually not available in medical records to locate the stomach. In light of the poor information available to locate the stomach in historical dose reconstructions, the purpose of this work was to investigate the variability of stomach location and size among adult male patients and to develop prediction models for the stomach location and size using predictor variables generally available in medical records of radiotherapy patients treated in the past. To collect data on stomach size and position, we segmented the contours of the stomach and of the skeleton on contemporary computed tomography (CT) images for 30 male patients in supine position. The location and size of the stomach was found to depend on body mass index (BMI), ponderal index (PI), and age. For example, the anteroposterior dimension of the stomach was found to increase with increasing BMI (≈0.25 cm kg(-1) m(2)) whereas its craniocaudal dimension decreased with increasing PI (≈-3.3 cm kg(-1) m(3)) and its transverse dimension increased with increasing PI (≈2.5 cm kg(-1) m(3)). Using the prediction models, we generated three-dimensional computational stomach models from a deformable hybrid phantom for three patients of different BMI. Based on a typical radiotherapy treatment, we simulated radiotherapy treatments on the predicted stomach models and on the CT images of the corresponding patients. Those dose calculations demonstrated good agreement between predicted and actual stomachs compared with doses derived from a reference model of the body that might be used in the absence of individual CT scan data.

Purpose To provide dosimetric data for an epidemiologic study on the risk of second primary esophageal cancer among breast cancer survivors, by reconstructing the radiation dose incidentally delivered to the esophagus of 414 women treated with radiation therapy for breast cancer during 1943-1996 in North America and Europe. Methods and Materials We abstracted the radiation therapy treatment parameters from each patient's radiation therapy record. Treatment fields included direct chest wall (37% of patients), medial and lateral tangentials (45%), supraclavicular (SCV, 64%), internal mammary (IM, 44%), SCV and IM together (16%), axillary (52%), and breast/chest wall boosts (7%). The beam types used were 60 Co (45% of fields), orthovoltage (33%), megavoltage photons (11%), and electrons (10%). The population median prescribed dose to the target volume ranged from 21 Gy to 40 Gy. We reconstructed the doses over the length of the esophagus using abstracted patient data, water phantom measurements, and a computational model of the human body. Results Fields that treated the SCV and/or IM lymph nodes were used for 85% of the patients and delivered the highest doses within 3 regions of the esophagus: cervical (population median 38 Gy), upper thoracic (32 Gy), and middle thoracic (25 Gy). Other fields (direct chest wall, tangential, and axillary) contributed substantially lower doses (approximately 2 Gy). The cervical to middle thoracic esophagus received the highest dose because of its close proximity to the SCV and IM fields and less overlying tissue in that part of the chest. The location of the SCV field border relative to the midline was one of the most important determinants of the dose to the esophagus. Conclusions Breast cancer patients in this study received relatively high incidental radiation therapy doses to the esophagus when the SCV and/or IM lymph nodes were treated, whereas direct chest wall, tangentials, and axillary fields contributed lower doses.