Contribution of Polygenic Risk to Hypertension Among Long-Term Survivors of Childhood Cancer.

BACKGROUND: Childhood cancer survivors experience significantly higher rates of hypertension which potentiates cardiovascular disease, but the contribution and relationship of genetic and treatment factors to hypertension risk are unknown. OBJECTIVES: To determine the contribution of a blood pressure polygenic risk score (PRS) from the general population and its interplay with cancer therapies to hypertension in childhood cancer survivors. METHODS: Using 895 established blood pressure loci from the general population, we calculated a PRS for 3572 childhood cancer survivors of European ancestry from Childhood Cancer Survivor Study (CCSS) original cohort, 1889 from CCSS expansion cohort, and 2534 from the St. Jude Lifetime Cohort (SJLIFE). Hypertension was assessed using National Cancer Institute criteria based on self-report of a physician diagnosis in CCSS and by blood pressure measurement in SJLIFE. RESULTS: In the combined sample of 7995 survivors, those in the top decile of the PRS had an odds ratio (OR) of 2.66 (95% CI=2.03-3.48) for hypertension compared to survivors in the bottom decile. The PRS-hypertension association was modified by being overweight/obese (per SD interaction OR=1.13; 95% CI=1.01-1.27) and exposure to hypothalamic-pituitary axis radiation (per SD interaction OR=1.18; 95% CI=1.05-1.33). Attributable fractions for hypertension to the PRS and cancer therapies were 21.0% and 15.7%, respectively, they jointly accounted for 40.2% of hypertension among survivors. CONCLUSIONS: A blood pressure PRS from the general population is significantly associated with hypertension among childhood cancer survivors and contributes to approximately one quarter of hypertension risk among survivors. These findings highlight the importance of screening for hypertension in all childhood cancer survivors, and identify higher risk subgroups.

Patient-reported outcomes in paediatric cancer survivorship: a qualitative study to elicit the content from cancer survivors and caregivers.

OBJECTIVES: Content elucidation for patient-reported outcomes (PROs) in paediatric cancer survivorship is understudied. We aimed to compare differences in the contents of five PRO domains that are important to paediatric cancer survivorship through semistructured interviews with paediatric cancer survivors and caregivers, and identified new concepts that were not covered in the item banks of the Patient-Reported Outcomes Measurement Information System (PROMIS). DESIGN: Semistructured interviews to collect qualitative PRO data from survivors and caregivers. SETTING: A survivorship care clinic of a comprehensive cancer centre in the USA. PARTICIPANTS: The study included 51 survivors (<18 years old) and 35 caregivers who completed interviews between August and December 2016. Content experts coded the transcribed interviews into 'meaningful concepts' per PROMIS item concepts and identified new concepts per a consensus. Frequencies of meaningful concepts used by survivors and caregivers were compared by Wilcoxon rank-sum test. RESULTS: For pain and meaning and purpose, 'Hurt a lot' and 'Purpose in life' were top concepts for survivors and caregivers, respectively. For fatigue and psychological stress, 'Needed to sleep during the day'/'Trouble doing schoolwork' and 'Felt worried' were top concepts for survivors, and 'Felt tired' and 'Felt distress'/'Felt stressed' for caregivers. Survivors reported more physically relevant contents (eg, 'Hard to do sport/exercise'; 0.78 vs 0.23, p=0.007) for pain, fatigue and stress, whereas caregivers used more emotionally relevant concepts (eg, 'Too tired to enjoy things I like to do'; 0.31 vs 0.05, p=0.025). Both groups reported positive thoughts for meaning and purpose (eg, 'Have goals for myself'). One (psychological stress, meaning and purpose) to eleven (fatigue) new concepts were generated. CONCLUSIONS: Important PRO contents in the form of meaningful concepts raised by survivors and caregivers were different and new concepts emerged. PRO measures are warranted to include survivorship-specific items by accounting for the child's and the caregiver's viewpoints.

Socio-demographic, Clinical, and Genetic Determinants of Quality of Life in Lung Cancer Patients.

Patient reported health-related quality of life (QOL) is a major component of the overall well-being of cancer patients, with links to prognosis. In 6,420 lung cancer patients, we identified patient characteristics and genetic determinants of QOL. Patient responses from the SF-12 questionnaire was used to calculate normalized Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. Further, we analyzed 218 single nucleotide polymorphisms (SNPs) in the p38 MAPK signaling pathway, a key mediator of response to cellular and environmental stress, as genetic determinants of QOL in a subset of the study population (N = 641). Trends among demographic factors for mean PCS and MCS included smoking status (PCS Ptrend < 0.001, MCS Ptrend < 0.001) and education (PCS Ptrend < 0.001, MCS Ptrend < 0.001). Similar relationships were seen for MCS. The homozygous rare genotype of MEF2B: rs2040562 showed an increased risk of a poor MCS (OR: 3.06, 95% CI: 1.05-8.92, P = 0.041). Finally, survival analysis showed that a low PCS or a MCS was associated with increased risks of five-year mortality (HR = 1.63, 95% CI: 1.51-1.77, HR = 1.23, 95% CI: 1.16-1.32, respectively) and there was a significant reduction in median survival time (Plog-rank < 0.001). These findings suggest that multiple factors contribute to QOL in lung cancer patients, and baseline QOL can impact survival.

Venous thrombosis following pancreaticoduodenectomy with venous resection.

BACKGROUND: Addition of en bloc segmental venous reconstruction (VR) to pancreaticoduodenectomy (PD) for venous involvement of pancreatic tumors increases the complexity of the operation and may increase complications. The long-term mesenteric venous patency rate and oncologic outcome has not been well defined. METHODS: Our prospective database was reviewed to assess 90-day postoperative outcomes for patients who underwent PD or PD + VR (September 2004-June 2016). Two independent observers reviewed CT scans to determine long-term vein patency. In patients with pancreatic ductal adenocarcinoma, the impact of VR on 5-year overall survival was assessed using multivariate Cox proportional hazards regression. Student's t-test was used to evaluate continuous variables and the chi-square test for categorical variables. RESULTS: Three hundred ninety-three patients underwent PD (51 PD + VR). Patients undergoing PD + VR had longer operations (561 ± 119 versus 433 ± 89 min, P < 0.00001) and greater blood loss (768 ± 812 versus 327 ± 423 cc, P < 0.00001). There was no difference in 90-day mortality, overall postoperative complication rates, complication severity grades, reoperation, readmission, or length of stay. 26.7% experienced venous thrombosis. Most thromboses occurred in the first year after surgery, but we also observed late thrombosis in 1 patient after 89-month follow-up. Among 135 patients with pancreatic ductal adenocarcinoma, survival was significantly longer in the PD-alone group (31.3 months [95% confidence interval: 22.9-40.0] versus 17.0 [95% confidence interval: 13.0-19.1], plog-rank = 0.013). CONCLUSIONS: PD + VR does not increase short-term morbidity, but venous thrombosis is frequent and can occur long after surgery. Survival is inferior when VR is required especially in the absence of neoadjuvant chemotherapy.

Determinants and prognostic value of quality of life in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Quality of life (QOL) is impaired in pancreatic cancer patients. Our aim was to investigate the determinants and prognostic value of QOL after diagnosis in a hospital-based cohort of racially/ethnically diverse patients with pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: QOL was prospectively assessed using the Short Form-12 in 2478 PDAC patients. The Physical Component Summary (PCS) and Mental Component Summary (MCS) were categorised into tertiles based on their distribution. Ordered logistic regression was adopted to compare the risk of having lower PCS and MCS by patient sociodemographic and clinical characteristics. The association of PCS and MCS with mortality was assessed by Cox regression. RESULTS: Compared with non-Hispanic whites, Hispanics were at significantly higher risk of having lower PCS (odds ratio [95% CI], 1.69 [1.26-2.26]; P < 0.001) and lower MCS (1.66 [1.24-2.23]; P < 0.001). Patients diagnosed with stage III (1.80 [1.10-2.94]; P = 0.02) and stage IV (2.32 [1.50-3.59]; P < 0.001) PDAC were more likely to have lower PCS than stage I patients. Other determinants of QOL included sex, age, drinking, smoking, education level, comorbidities and time since diagnosis. The low tertile of PCS (hazard ratio [95% CI], 1.94 [1.72-2.18]; P < 0.001) and MCS (1.42 [1.26-1.59]; P < 0.001) were each related to poor prognosis. Similar results were found for non-Hispanic whites as compared with African-Americans/Hispanics/others. CONCLUSION: QOL after diagnosis is a significant prognostic indicator for patients with PDAC. Multiple factors determine QOL, suggesting possible means of intervention to improve QOL and outcomes of PDAC patients.

D-mannose: a novel prognostic biomarker for patients with esophageal adenocarcinoma.

Metabolomic profiling is a promising approach to identify new biomarkers for cancer prognosis. However, the role of circulating metabolites as prognostic indicators in esophageal adenocarcinoma (EAC) has not been well explored. In this study, we aimed to evaluate the prognostic value of three serum metabolites, d-mannose, l-proline (LP), and 3-hydroxybutyrate (BHBA), which were significantly different between EAC patients and controls, identified through a global and targeted metabolite profiling. We measured the levels of d-mannose, LP, and BHBA in pretreatment serum from 159 EAC patients, using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) methods. A multivariable Cox model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association of these metabolites with recurrence and overall survival. We found that serum levels of d-mannose were significantly associated with recurrence and overall survival in EAC patients, whereas levels of LP and BHBA were not. Compared with patients with a low (first tertile) level of d-mannose, those with a high (second plus third tertiles) level had 49% reduced risk of recurrence (HR = 0.51; 95% CI: 0.29-0.91; P = 0.02), and 56% reduced risk of death (HR = 0.44; 95% CI: 0.25-0.77, P < 0.01). The significant association of high d-mannose levels with better prognosis was consistent among patients with early-stage and advanced-stage EAC. Our results suggest that serum level of d-mannose may be used as a novel prognostic biomarker for patients with EAC. Further studies in independent populations are warranted to confirm our findings.

Different dietary patterns and reduction of lung cancer risk: A large case-control study in the U.S.

Reducing lung cancer risk by modifying diet is highly desirable. We investigated whether different U.S. dietary patterns were associated with lung cancer risk. Dietary patterns were derived using exploratory factor analysis for 2139 non-small cell lung cancer (NSCLC) cases and 2163 frequency-matched controls. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Highest adherence (highest vs. lowest quintile) to the "Tex-Mex", "fruits and vegetables", and "American/Western" patterns was associated with a 55% reduced (OR = 0.45; 95% CI = 0.37-0.56; P < 0.001), 32% reduced (OR = 0.68; 95% CI = 0.55-0.85; P = 0.001), and 45% increased (OR = 1.45; 95% CI = 1.18-1.78; P < 0.001) risk of lung cancer, respectively. The effects were stronger for squamous cell carcinoma and ever smokers for the "fruits and vegetables" pattern, and stronger for other non-small cell lung cancer and never smokers for the "American/Western" pattern. Among six genome-wide association (GWA) studies-identified lung cancer susceptibility loci assessed, a variant (rs2808630) of the C-reactive protein gene modified the associations for the "fruits and vegetables" (P for interaction = 0.03) and "American/Western" (P for interaction = 0.02) patterns. Our study first showed that the "Tex-Mex" dietary pattern was associated with a reduced lung cancer risk. Also, the "fruits and vegetables" and "American/Western" patterns affected lung cancer risk, and the effects were further modified by host genetic background.

Glycemic Index, Glycemic Load, and Lung Cancer Risk in Non-Hispanic Whites.

BACKGROUND: Postprandial glucose (PPG) and insulin responses play a role in carcinogenesis. We evaluated the association between dietary glycemic index (GI) and glycemic load (GL), markers of carbohydrate intake and PPG, and lung cancer risk in non-Hispanic whites. METHODS: GL and GI were assessed among 1,905 newly diagnosed lung cancer cases recruited from the University of Texas MD Anderson Cancer Center (Houston, TX) and 2,413 healthy controls recruited at Kelsey-Seybold Clinics (Houston, TX). We assessed associations between quintiles of GI/GL and lung cancer risk and effect modification by various risk factors. ORs and 95% confidence intervals (CI) were estimated using multivariable logistic regression. RESULTS: We observed a significant association between GI [5th vs. 1st quintile (Q) OR = 1.49; 95% CI, 1.21-1.83; P(trend) <0.001] and lung cancer risk and GI(ac) (5th vs. 1st Q OR = 1.48; 95% CI, 1.20-1.81; P(trend) = 0.001) and lung cancer risk. We observed a more pronounced association between GI and lung cancer risk among never smokers (5th vs. 1st Q OR = 2.25; 95% CI, 1.42-3.57), squamous cell carcinomas (SCC; 5th vs. 1st Q OR = 1.92; 95% CI, 1.30-2.83), and those with less than 12 years of education (5th vs. 1st Q OR = 1.75; 95% CI, 1.19-2.58, P(interaction) = 0.02). CONCLUSION: This study suggests that dietary GI and other lung cancer risk factors may jointly and independently influence lung cancer etiology. IMPACT: Understanding the role of GI in lung cancer could inform prevention strategies and elucidate biologic pathways related to lung cancer risk.

Genetic Variants in the Wnt/ß-Catenin Signaling Pathway as Indicators of Bladder Cancer Risk.

PURPOSE: Genetic factors that influence bladder cancer risk remain largely unknown. Previous research has suggested that there is a strong genetic component underlying the risk of bladder cancer. The Wnt/ß-catenin signaling pathway is a key modulator of cellular proliferation through its regulation of stem cell homeostasis. Furthermore, variants in the Wnt/ß-catenin signaling pathway have been implicated in the development of other cancers, leading us to believe that this pathway may have a vital role in bladder cancer development. MATERIALS AND METHODS: A total of 230 single nucleotide polymorphisms in 40 genes in the Wnt/ß-catenin signaling pathway were genotyped in 803 bladder cancer cases and 803 healthy controls. RESULTS: A total of 20 single nucleotide polymorphisms were nominally significant for risk. Individuals with 2 variants of LRP6: rs10743980 were associated with a decreased risk of bladder cancer in the recessive model in the initial analysis (OR 0.76, 95% CI 0.58-0.99, p=0.039). This was validated using the bladder genome-wide association study chip (OR 0.51, 95% CI 0.27-1.00, p=0.049 and for combined analysis p=0.007). CONCLUSIONS: Together these findings implicate variants in the Wnt/ß-catenin stem cell pathway as having a role in bladder cancer etiology.