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Objectives Approximately 0.2% to 2.7% of children with congenital heart disease require a tracheostomy after cardiac surgery with the majority having single ventricle (SV) type heart lesions. Tracheostomy in SV patients is reported to be associated with high mortality. We hypothesized that short- and long-term survival of patients with SV heart disease would vary according to tracheostomy indication. Methods This is a single center, 20-year, retrospective review of all patients with SV heart disease who underwent tracheostomy. Demographic, cardiac anatomy, surgical, intensive care unit, and hospital course data were collected. The primary outcome was survival following tracheostomy. Secondary outcome was the completion of staged palliation to Fontan. Results In total, 25 patients with SV heart disease who underwent tracheostomy were included. Indications for tracheostomy included one or more of the following: tracheobronchomalacia (n = 8), vocal cord paralysis (n = 7), tracheal/subglottic stenosis (n = 6), primary respiratory insufficiency (n = 4), diaphragm paralysis (n = 3), suboptimal hemodynamics (n = 2), and other upper airway issues (n = 1). Survival at six months, one year, five years, and ten years was 76%, 68%, 63%, and 49%, respectively. Most patients completed Fontan palliation (64%). Patients who underwent tracheostomy for suboptimal hemodynamics and/or respiratory insufficiency had a higher mortality risk compared to those with indications of upper airway obstruction or diaphragm paralysis (hazard ratio 4.1, 95% confidence interval 1.2-13.7; P = .02). Conclusions Mortality risk varies according to tracheostomy indication in patients with SV heart disease. Tracheostomy may allow staged surgical palliation to proceed with acceptable risk if it was indicated for anatomic or functional airway dysfunction.

Survivorship focuses on individual's health and well-being. Assessing for cancer recurrence is a follow-up priority for survivors and providers. However, providers also emphasize the importance of assessing for adherence to ongoing treatment. Providers should also assess for sequelae of local-regional and systemic treatment. Assessing for mental health is important, as many cancer survivors experience anxiety or depression. Finally, survivors should be encouraged to have ongoing visits with their primary care to ensure screening for other health conditions. This article reviews the recommendations for survivorship and the level of evidence supporting each aspect of high-quality survivorship care.

Background: Burnout is well characterised in physicians and residents but not in paediatric cardiology fellows, and few studies follow burnout longitudinally. Training-specific fears have been described in paediatric cardiology fellows but also have not been studied at multiple time points. This study aimed to measure burnout, training-specific fears, and professional fulfilment in paediatric cardiology fellows with the attention to time of year and year-of-training. Methods: This survey-based study included the Professional Fulfillment Index and the Impact of Events Scale as well as an investigator-designed Fellow Fears Questionnaire. Surveys were distributed at three-time points during the academic year to paediatric cardiology fellows at a large Midwestern training programme. Fellow self-reported gender and year-of-training were collected. Descriptive analyses were performed. Results: 10/17 (59%) of fellows completed all surveys; 60% were female, 40% in the first-year class, 40% in the second-year class, and 20% in the third-year class. At least half of the fellows reported burnout at each survey time point, with lower mean professional fulfilment scores. The second-year class, who rotate primarily in the cardiac ICU, had higher proportions of burnout than the other two classes. At least half of fellows reported that they “often” or “always” worried about not having enough clinical knowledge or skills and about work–life balance. Conclusions: Paediatric cardiology fellows exhibit high proportions of burnout and training-specific fears. Interventions to mitigate burnout should be targeted specifically to training needs, including during high-acuity rotations.

We sought to evaluate local/regional recurrence rates after breast-conserving surgery in a cohort of patients enrolled in legacy trials of the Alliance for Clinical Trials in Oncology and to evaluate variation in recurrence rates by receptor subtype.Multiple randomized controlled trials have demonstrated equivalent survival between breast conservation and mastectomy, albeit with higher local/regional recurrence rates after breast conservation. However, absolute rates of local/regional recurrence have been declining with multi-modality treatment.Data from five Alliance for Clinical Trials in Oncology legacy trials that enrolled women diagnosed with breast cancer between 1997 and 2010 were included. Women who underwent breast-conserving surgery and standard systemic therapies (n=4,404) were included. Five-year rates of local/regional recurrence were estimated from Kaplan-Meier curves. Patients were censored at time of distant recurrence (if recorded as first recurrence), death, or last follow-up. Multivariable Cox proportional hazards models were used to identify factors associated with time to local/regional recurrence, including patient age, tumor size, lymph node status, and receptor subtype.Overall 5-year recurrence was 4.6% (95% CI=4.0-5.4%). Five-year recurrence rates were lowest in those with ER+ or PR+ tumors (Her2+ 3.4% [95% CI 2.0-5.7%], Her2- 4.0% [95% CI 3.2-4.9%]) and highest in the triple negative subtype (7.1% [95% CI 5.4-9.3%]). On multivariable analysis, increasing nodal involvement and triple-negative subtype were positively associated with recurrence (P0.0001).Rates of local/regional recurrence after breast conservation in women with breast cancer enrolled in legacy trials of the Alliance for Clinical Trials in Oncology are significantly lower than historic estimates. This data can better inform patient discussions and surgical decision-making.

The objective is to determine perspectives of general surgeons, plastic surgeons, and cancer navigators on factors contributing to breast cancer patients' decision for post-mastectomy reconstruction, especially for women facing financial hardship.We mailed Wisconsin general and plastic surgeons who performed5 breast cancer procedures annually a survey, including a postcard inviting cancer navigators to participate. Descriptive statistics summarize item responses. McNemar's chi-squared tests evaluated surgeons' perspectives of factors influencing reconstruction for all women compared to women facing financial hardship.Respondents include 70 general surgeons, 18 plastic surgeons, and 9 navigators. Respondents perceived preference-related factors as important, including "does not want more surgery" (85% reported it important overall and 77% for financial hardship women) and "reconstructed breast is not important to her" (77% vs. 61%). Surgeons perceived logistical factors were more important for women facing financial hardship, including "capacity to be away from work or home responsibilities for recovery" (30% reported important overall and 60% for financial hardship women), "concerned about out-of-pocket costs" (26% vs. 57%), and "frequent visits to complete reconstruction too burdensome" (27% vs. 49%).Our findings demonstrate Wisconsin surgeons and cancer navigators perceive logistical concerns influence reconstruction decisions for women facing financial hardship.

Socioeconomic disparities in post-mastectomy breast reconstruction exist. Key informants have suggested that finding providers who accept Medicaid insurance and longer travel time to a plastic surgeon are important barriers. Our objective was to assess the relationship between these factors and reconstruction for socioeconomically disadvantaged women in Wisconsin.We identified women 75 years of age with stage 0-III breast cancer who underwent mastectomy using the Wisconsin Cancer Reporting System. Women in the most disadvantaged state-based tertile of the Area Deprivation Index were included (n = 1809). Geocoding determined turn-by-turn drive time from women's address to the nearest accredited Commission on Cancer or National Accreditation Program for Breast Centers. Multivariable logistic regression determined the relationship between reconstruction, Medicaid, and travel time, controlling for patient factors known to impact reconstruction. Average adjusted predicted probabilities of receiving reconstruction were calculated.Most patients had early-stage breast cancer (51% stage 0/I) and 15.2% had Medicaid. 37% of women underwent reconstruction. Socioeconomically disadvantaged women with Medicaid (OR = 0.62, 95% CI 0.46-0.84) and longer travel times (OR = 0.99, 95% CI 0.99-1.0) were less likely to receive reconstruction. Patients with the lowest predicted probability of reconstruction were those with Medicaid who lived furthest from a plastic surgeon.Among socioeconomically disadvantaged women, Medicaid and travel remained associated with lower rates of reconstruction. Further work will explore opportunities to improve access to reconstruction for women with Medicaid. This is particularly challenging as it may require socioeconomically disadvantaged women to travel further to receive care.

Background Guidelines for follow-up after locoregional breast cancer treatment recommend imaging for distant metastases only in the presence of patient signs and/or symptoms. However, guidelines have not been updated to reflect advances in imaging, systemic therapy, or the understanding of biological subtype. We assessed the association between mode of distant recurrence detection and survival. Methods In this observational study, a stage-stratified random sample of women with stage II-III breast cancer in 2006-2007 and followed through 2016 was selected, including up to 10 women from each of 1217 Commission on Cancer facilities (n = 10 076). The explanatory variable was mode of recurrence detection (asymptomatic imaging vs signs and/or symptoms). The outcome was time from initial cancer diagnosis to death. Registrars abstracted scan type, intent (cancer-related vs not, asymptomatic surveillance vs not), and recurrence. Data were merged with each patient’s National Cancer Database record. Results Surveillance imaging detected 23.3% (284 of 1220) of distant recurrences (76.7%, 936 of 1220 by signs and/or symptoms). Based on propensity-weighted multivariable Cox proportional hazards models, patients with asymptomatic imaging compared with sign and/or symptom detected recurrences had a lower risk of death if estrogen receptor (ER) and progesterone receptor (PR) negative, HER2 negative (triple negative; hazard ratio [HR] = 0.73, 95% confidence interval [CI] = 0.54 to 0.99), or HER2 positive (HR = 0.51, 95% CI = 0.33 to 0.80). No association was observed for ER- or PR-positive, HER2-negative (HR = 1.14, 95% CI = 0.91 to 1.44) cancers. Conclusions Recurrence detection by asymptomatic imaging compared with signs and/or symptoms was associated with lower risk of death for triple-negative and HER2-positive, but not ER- or PR-positive, HER2-negative cancers. A randomized trial is warranted to evaluate imaging surveillance for metastases results in these subgroups.

Test the effectiveness of benchmarked performance reports based on existing discharge data paired with a statewide intervention to implement evidence-based strategies on breast re-excision rates.Breast-conserving surgery (BCS) is a common breast cancer surgery performed in a range of hospital settings. Studies have demonstrated variations in post-BCS re-excision rates, identifying it as a high-value improvement target.Wisconsin Hospital Association discharge data (2017-2019) were used to compare 60-day re-excision rates following BCS for breast cancer. The analysis estimated the difference in the average change preintervention to postintervention between Surgical Collaborative of Wisconsin (SCW) and nonparticipating hospitals using a logistic mixed-effects model with repeated measures, adjusting for age, payer, and hospital volume, including hospitals as random effects. The intervention included 5 collaborative meetings in 2018 to 2019 where surgeon champions shared guideline updates, best practices/challenges, and facilitated action planning. Confidential benchmarked performance reports were provided.In 2017, there were 3692 breast procedures in SCW and 1279 in nonparticipating hospitals; hospital-level re-excision rates ranged from 5% to50%. There was no statistically significant baseline difference in re-excision rates between SCW and nonparticipating hospitals (16.1% vs. 17.1%, P =0.47). Re-excision significantly decreased for SCW but not for nonparticipating hospitals (odds ratio=0.69, 95% confidence interval=0.52-0.91).Benchmarked performance reports and collaborative quality improvement can decrease post-BCS re-excisions, increase quality, and decrease costs. Our study demonstrates the effective use of administrative data as a platform for statewide quality collaboratives. Using existing data requires fewer resources and offers a new paradigm that promotes participation across practice settings.

Standard clinical practice and national guidelines dictate somatic testing of metastatic colorectal cancer (mCRC) tumors to guide appropriate therapy; however, previous studies suggest that not all patients are tested. The objective of this study was to investigate potential differences in testing for mCRC by demographic and clinical factors.We performed a retrospective review of de-identified patient data derived from electronic health records (EHRs) of 25,469 patients diagnosed with mCRC between the years 2013 and 2020. Our outcome was a receipt of the following tests: (a) biomarker testing (BRAF, KRAS, NRAS, MMR/MSI) and (b) next-generation sequencing (NGS). We interrogated our data using the machine-learning algorithm Classification and Regression Tree (CART), a unique approach to identifying combinations of, rather than individual demographic and clinical characteristics associated with receipt of testing.A total of 25,469 patients were identified with mCRC. Of these, 21,133 (83%) received either biomarker testing only (n = 12,485) or any testing (biomarker + NGS) (n = 8648). The proportion of patients who received any testing increased over calendar time for all age, race, and sex categories. Receipt of any testing was highest (90%) among younger and patients with better performance status, and there was no difference in receipt of any testing by race. The highest percentage of NGS testing was among those with better performance status,70 years old, commercial or other governmental program payers, and low comorbidity burden; however, those who were Black or Hispanic had a lower prevalence of NGS testing than those who were White.Considerable variations exist in somatic biomarker testing across subgroups of the population. Identification of genomic alterations can aid in determining targeted treatment and improving clinical outcomes; therefore, equitable use of these testing strategies, particularly NGS, is necessary.

Stress urinary incontinence (SUI) impacts ~1/3 of women over age 50. Negative publicity around PP meshes used in pelvic prolapse repair drives the need for identifying alternative biomaterials for SUI repair. Our study evaluated in vivo response to collagen sling implanted in an ovine model. Electrocompacted collagen threads were filament wound as slings and crosslinked in genipin. Collagen slings were implanted suburethrally mimicking the transvaginal tape technique. Main study groups were: Collagen sling (n = 3, 6 months) and PP sling (n = 3, 6 months). Collagen sling was also tested at 3-weeks (n = 1) to observe early-stage tissue response and 1-year (n = 2) to assess biomaterial longevity in a preliminary capacity. Collagen slings healed to a fibrous ligament texture at 6 months and maintained such texture to 1 year. Histological scoring indicated biocompatible responses to collagen slings with no adverse events. All study groups exhibited complete tissue ingrowth and interstitial de novo collagen deposition at all time points. Collagen threads induced orderly de novo collagen deposition that was aligned along long axes of threads. Tissue infiltrated collagen slings that were explanted at 6 and 12 months presented similar structural strength with native tissues such as vagina and fascia, and PP (Lynx) slings (p .05). With the limitation of low number of animals per time point in hindsight, this preliminary study justifies evaluation of collagen slings in a larger sample size of animals, particularly to assess persistence of ligamentous tissue response over longer durations than 1-year.

The population of older adults with cancer in the United States is rapidly increasing, which will have a substantial impact on the oncology and public health workforces across the cancer continuum, from prevention to end of life. Unfortunately, inequities in existing social structures that cause increased psychosocial stressors have led to disparities in the incidence of cancer and the morbidity and mortality of cancer for individuals from marginalized backgrounds. It is imperative that older adults, especially those from historically marginalized backgrounds, be adequately represented in all stages of cancer research to address health inequities. Continued efforts and progress toward achieving social justice and health equity require a deeper commitment to and better understanding of the impact of social determinants of health within the cancer domain. Undoubtedly, a more holistic and integrated view that extends beyond the biologic and genetic factors of health must be adopted for health entities to recognize the critical role of environmental, behavioral, and social determinants in cancer health disparities. Against this backdrop, this paper uses a life course approach to present a multifactorial framework for understanding and addressing cancer disparities in an effort to advance social justice and health equity for racially and ethnically diverse older adults.

ObjectiveTo explore the frequency of occurrence of extra-renal manifestations associated with monogenic kidney stone diseases.MethodsA literature review was conducted to identify genes that are well-established monogenic causes of nephrolithiasis. The Online Mendelian Inheritance in Man (OMIM) and Human Protein Atlas (HPA) databases were used to identify associated diseases and their properties. Disease phenotypes were ascertained using OMIM clinical synopses and sorted into 24 different phenotype categories as classified in OMIM. Disease phenotypes caused by the same gene were merged into a single gene-associated phenotype (GAP) unit such that one GAP encompasses all related disease phenotypes for a specific gene. We measured the total number of GAPs involving each phenotype category and determined the median phenotype category. Phenotype categories were classified as overrepresented or underrepresented if the number of GAPs involving them was higher or lower than the median, respectively. A chi-square test was conducted to determine whether the number of GAPs affecting a given category significantly deviated from the median.ResultsFifty-five genes were identified as monogenic causes of nephrolithiasis. All GAPs comprised at least one extra-renal phenotype category. The median phenotype category was part of 10 (18%) unique GAPs. A total of 6 significantly overrepresented (growth, skeletal, neurologic, abdomen/gastrointestinal, muscle, metabolic features) and 5 significantly underrepresented (mouth, voice, neck, immunology, neoplasia) phenotype categories were identified among our group of monogenic kidney stone diseases (pConclusionMonogenic nephrolithiasis is a multi-system disorder. Recognizing the extra-renal manifestations associated with monogenic causes of kidney stones is critical for earlier diagnosis and optimal prognosis in patients.

BackgroundCystine stone is a Mendelian genetic disease caused bySLC3A1orSLC7A9. In this study, we aimed to estimate the genetic prevalence of cystine stones and compare it with the clinical prevalence to better understand the disease etiology.MethodsWe analyzed genetic variants in the general population using the 1000 Genomes project and the Human Gene Mutation Database to extract allSLC3A1andSLC7A9pathogenic variants. All variants procured from both databases were intersected. Pathogenic allele frequency, carrier rate, and affected rate were calculated and estimated based on Hardy-Weinberg equilibrium.ResultsWe found that 9 uniqueSLC3A1pathogenic variants were carried by 26 people and 5 uniqueSLC7A9pathogenic variants were carried by 12 people, all of whom were heterozygote carriers. No homozygote, compound heterozygote, or double heterozygote was identified in the 1000 Genome database. Based on the Hardy-Weinberg equilibrium, the calculated genetic prevalence of cystine stone disease is 1 in 30,585.ConclusionThe clinical prevalence of cystine stone has been previously reported as 1 in 7,000, a notably higher figure than the genetic prevalence of 1 in 30,585 calculated in this study. This suggests that the etiology of cystine stone is more complex than what our current genetic knowledge can explain. Possible factors that may contribute to this difference include novel causal genes, undiscovered pathogenic variants, alternative inheritance models, founder effects, epigenetic modifications, environmental factors, or other modifying factors. Further investigation is needed to fully understand the etiology of cystine stone.

BackgroundCystinosis is a metabolic disease characterized by the accumulation of cystine most often presenting in an infantile nephropathic form caused by pathogenic variants in theCTNSgene. It is characterized by progressive loss of glomerular function leading to renal failure by the first decade of life, making early diagnosis crucial to improving outcomes. This study seeks to estimate the prevalence of cystinosis using a population genetics approach.MethodsThe Human Genome Mutation Database (HGMD) was used to identify known pathogenic variants inCTNS, and the 1000 Genomes (1KG) database was used to identifyCTNSvariants in a cohort representing a healthy population. These two databases were intersected to identify disease-causing variants and their carriers in the general population. The Hardy-Weinberg equilibrium was used to calculate expected carrier and affected rates for cystinosis.ResultsThe allele frequency for all disease-causing alleles was calculated to be 0.016. The predicted affected rate was calculated to be 0.00027 (approximately 1:3680), and the predicted carrier rate was 0.032 (approximately 1:30).ConclusionCompared to the reported clinical prevalence of between 1 in 100,000 to 1 in 200,000, the prevalence of cystinosis in this study was calculated to be 1 in 3,680. This significantly higher result may be due to the underdiagnosis of cystinosis or variable expressivity of variants presenting with a broad range of disease severity. These results support the proposal of newborn screening for early diagnosis and improved outcomes in infantile nephropathic cystinosis.

Perspective on this Article from A Large Prospective Study of SEP15 Genetic Variation, Interaction with Plasma Selenium Levels, and Prostate Cancer Risk and Survival

Introduction: Health-related quality of life in children who have undergone the Ross procedure has not been well characterised. The aim of this study was to characterise health-related quality of life in this cohort and compare to children with other CHD. Method: In this cross sectional, single-centre study, health-related quality of life was assessed in patients who underwent a non-neonatal Ross procedure using the Pediatric Quality of Life Inventory. Ross cohort scores were compared with healthy norms, patients with CHD requiring no surgical intervention or had curative surgery (Severity 2, S2) and patients who were surgically repaired with ≥1 surgical procedure and with significant residual lesion or need for additional surgery (Severity 3, S3). Associations between Pediatric Quality of Life Inventory score and patient factors were also examined. Results: 68 patients completed surveys. Nearly one-sixth of patients had overall scores below the cut-off for at-risk status for impaired health-related quality of life. There was no difference in overall health-related quality of life score between the Ross cohort and healthy children (p = 0.56) and S2 cohort (p = 0.97). Health-related quality of life was significantly higher in the Ross cohort compared to S3 cohort (p = 0.02). This difference was driven by a higher psychosocial health-related quality of life in the Ross cohort as compared to S3 cohort (p = 0.007). Anxiety scores were significantly worse in the Ross cohort compared to both S2 (p = 0.001) and S3 (p = 0.0017), respectively. Conclusion: Children who have undergone a Ross procedure report health-related quality of life equivalent to CHD not requiring therapy and superior to CHD with residual lesions. Despite these reassuring results, providers should be aware of potential anxiety among Ross patients.

Background: Prolonged effusions post-Fontan procedure are associated with morbidity. Fontan patients have higher pro-inflammatory cytokines in chest tube drainage compared to controls. Colchicine, an anti-inflammatory medication, decreases effusions in adults after cardiac surgery. We hypothesised that patients post-Fontan treated with colchicine would have decreased pro-inflammatory cytokine levels and shorter duration of chest tube drainage. Methods: This pilot clinical trial enrolled nine patients (intention to treat); five completed the protocol (per protocol). Post-operative Fontan patients 20 months to 5 years receiving colchicine were compared to a previously published control cohort (n = 25). Per protocol patients received 0.6 mg colchicine daily starting post-operative day 2, ending 1 day after chest tube removal. Chest tube samples were taken on days 1–4, 7 and 10, or until removal and analysed with a 17-cytokine Bio-Plex Assay. Descriptive statistics and basic univariate comparisons were made. Results: There was no difference in duration of chest tube drainage or length of stay between intention to treat patients and controls. Per protocol patients had shorter duration of chest tube drainage compared to controls (6 days [interquartile range 4.7–7], versus 10 days [7–11], p = 0.007) and shorter length of stay (7 days [5.5–9] versus 9 days [9–13], p = 0.005). Pro-inflammatory cytokines trended lower in per protocol patients. Conclusions: In this pilot cohort, patients who completed the colchicine protocol post-Fontan procedure had shortened duration of chest tube drainage and length of stay. A decrease of pro-inflammatory cytokines may contribute to the mechanism of this change. ClinicalTrials.gov: Colchicine in Postoperative Fontan Patients (CPFP); NCT03575572; https://clinicaltrials.gov/ct2/show/NCT03575572.

We investigate the search processes that dyads engage in when each human agent is responsible for one module of a complex task. Our laboratory experiment manipulates global vs. local incentives and low vs. high cross-modular interdependence. We find that dyads endogenously learn to coordinate their joint search efforts by engaging in parallel and sequential searches that, over time, give rise to coordinated repeated actions. Such collaborative search emerges despite complexity and misaligned incentives, and without a coordinating hierarchy.

Under-diagnosis of pediatric hypertension remains pervasive due to difficulty recognizing elevated systolic blood pressures (SBPs). We performed a retrospective review comparing recognition of and response to elevated SBPs ≥95th percentile before and after development of a clinical decision support tool (CDST) in an academic pediatric system. Of 44,351 encounters, 477 had elevated SBPs with documented recognition of an elevated SBP in 17.9% of encounters pre-CDST that increased to 33.7% post-CDST ( P = .001). Post-CDST, 75.5% of elevated SBPs had repeat measurement, with 90.8% of initially elevated SBPs normalizing to

Contains more detailed information on the individual cohorts contributing to the study and their genotyping results; Supplemental Tables 1 and 2

Supplementary Table 1 from Eighteen Insulin-like Growth Factor Pathway Genes, Circulating Levels of IGF-I and Its Binding Protein, and Risk of Prostate and Breast Cancer

Background: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer.Methods: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history.Results: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4–57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2–5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09).Conclusions: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles.Impact: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs. Cancer Epidemiol Biomarkers Prev; 24(7); 1121–9. ©2015 AACR.

Supplementary Methods and Tables

Supplementary Figure 1. Absolute Risk (With family history of prostate cancer)

Background: Genome-wide association studies have identified multiple genetic variants associated with susceptibility to prostate cancer (PrCa). In the two-stage Cancer Genetic Markers of Susceptibility prostate cancer scan, a single-nucleotide polymorphism (SNP), rs10486567, located within intron 2 of JAZF1 gene on chromosome 7p15.2, showed a promising association with PrCa overall (P = 2.14 × 10−6), with a suggestion of stronger association with aggressive disease (P = 1.2 × 10−7).Methods: In the third stage of genome-wide association studies, we genotyped 106 JAZF1 SNPs in 10,286 PrCa cases and 9,135 controls of European ancestry.Results: The strongest association was observed with the initial marker rs10486567, which now achieves genome-wide significance [P = 7.79 × 10−11; ORHET, 1.19 (95% confidence interval, 1.12-1.27); ORHOM, 1.37 (95% confidence interval, 1.20-1.56)]. We did not confirm a previous suggestion of a stronger association of rs10486567 with aggressive disease (P = 1.60 × 10−4 for aggressive cancer, n = 4,597; P = 3.25 × 10−8 for nonaggressive cancer, n = 4,514). Based on a multilocus model with adjustment for rs10486567, no additional independent signals were observed at chromosome 7p15.2. There was no association between PrCa risk and SNPs in JAZF1 previously associated with height (rs849140; P = 0.587), body stature (rs849141, tagged by rs849136; P = 0.171), and risk of type 2 diabetes and systemic lupus erythematosus (rs864745, tagged by rs849142; P = 0.657).Conclusion: rs10486567 remains the most significant marker for PrCa risk within JAZF1 in individuals of European ancestry.Impact: Future studies should identify all variants in high linkage disequilibrium with rs10486567 and evaluate their functional significance for PrCa. Cancer Epidemiol Biomarkers Prev; 19(5); 1349–55. ©2010 AACR.

Purpose: Variants at chromosomal loci 8q24 and 17q are established risk factors for prostate cancer. Many studies have confirmed the findings for risk, but few have examined aggressiveness and other clinical variables in detail. Additionally, Gleason score is typically used as a surrogate for the primary end point of prostate cancer mortality. We investigated whether the 8q24 and 17q risk variants are associated with clinical variables as well as prostate cancer mortality.Experimental Design: In the Physicians' Health Study (1,347 cases and 1,462 controls), the Dana-Farber Harvard Cancer Center Specialized Program of Research Excellence (Gelb Center; 3,714 cases), and the Fred Hutchinson Cancer Research Center King County Case-Control Studies (1,308 cases and 1,266 controls), we examined eight previously identified 8q24 and 17q risk variants for association with prostate cancer mortality in men of European ancestry. We considered associations with other surrogate markers of prostate cancer aggressiveness, such as Gleason score, pathologic stage, prostate-specific antigen at diagnosis, and age at diagnosis.Results: Six of the eight variants were confirmed as prostate cancer risk factors. Several variants were nominally associated with age at diagnosis; when totaling all alleles for single nucleotide polymorphisms significantly associated with risk, each additional allele decreased age at diagnosis by an average of 6 months in the Physicians' Health Study (P = 0.0005) and 4 months in the Dana-Farber Harvard Cancer Center Specialized Program of Research Excellence (Gelb Center) cohort (P = 0.0016). However, there were no statistically significant associations with prostate cancer mortality.Conclusions: Our results suggest that the 8q24 and 17q prostate cancer risk variants may influence age at diagnosis but not disease aggressiveness.

Background: A pressing clinical issue in prostate cancer is to distinguish which men will have an indolent or aggressive course of disease. Clinical variables such as Gleason grade and stage are useful predictors of lethal cancer; however, the low predictive values of the common Gleason scores, changes in grading over time, and earlier diagnosis of patients due to screening limits their clinical utility. Identifying genetic variants associated with lethal prostate cancer could inform clinical decision making.Methods: We conducted a genome-wide association study, comparing lethal prostate cancer cases to cases surviving at least 10 years beyond their initial diagnosis. Genotyping was done with the Affymetrix 5.0 chip [∼500,000 single nucleotide polymorphisms (SNP) and 1,483 copy number variants (CNV)] on DNA from participants in the Physicians' Health Study and Health Professionals Follow-up Study (196 lethal cases, 368 long-term survivors). After excluding SNPs and individuals based on quality control criteria, logistic regression assuming an additive model was done using the PLINK software.Results: No SNP reached genome-wide significance (P ≤ 1 × 10−7); however, three independent SNPs had P < 1 × 10−5. One top-ranked SNP replicated (P = 0.05) in an independent follow-up study. Although no CNV had genome-wide significance, 14 CNVs showed nominal association with prostate cancer mortality (P < 0.05).Conclusions: No variants were significantly associated at a genome-wide level with prostate cancer mortality. Common genetic determinants of lethal prostate cancer are likely to have odds ratios Impact: Genetic markers identified could provide biological insight to improve therapy for men with potentially fatal cancer. Larger studies are necessary to detect the genetic causes of prostate cancer mortality. Cancer Epidemiol Biomarkers Prev; 19(11); 2869–76. ©2010 AACR.

Supplementary Tables and Figures from Genome-wide Association Study of Prostate Cancer Mortality

Supplementary Table S1: Non-cancer diseases and traits included in the analysis and source of summary statistics Supplementary Table S2. Cancer-specific cumulative risks from SEER. Supplementary Table S3: Genetic correlations between cancers and 14 non-cancer traits