Carpal tunnel syndrome in mucopolysaccharidosis I: a registry-based cohort study.

AIM: To characterize carpal tunnel syndrome (CTS) in patients with mucopolysaccharidosis I (MPS I). METHOD: Data were included for patients with MPS I who had either nerve conduction examination that included a diagnosis of CTS or who had CTS release surgery. Although this represented a subset of patients with CTS in the MPS I Registry, the criteria were considered the most objective for data analysis. RESULTS: As of March 2016, 994 patients were categorized with either severe (Hurler syndrome) or attenuated (Hurler-Scheie or Scheie syndromes) MPS I. Among these, 291 had a CTS diagnosis based on abnormal nerve conduction (n=54) or release surgery (n=237). Median ages (minimum, maximum) at first CTS diagnosis were 5 years 2 months (10mo, 16y 2mo) and 9y 11mo (1y 8mo, 44y 1mo) for patients with severe and attenuated MPS I respectively. Most patients had their first CTS diagnosis after MPS I diagnosis (94%) and treatment (hematopoietic stem cell transplant and/or enzyme replacement therapy) (74%). For 11% of patients with attenuated disease, CTS diagnosis preceded MPS I diagnosis by a mean of 7 years 6 months. INTERPRETATION: CTS is a rare complication in pediatric patients and should alert medical care providers to the potential diagnosis of MPS I. Significant delays exist between diagnosis of CTS and MPS I for patients with attenuated disease. WHAT THIS PAPER ADDS: There are significant delays in diagnosing carpal tunnel syndrome (CTS) in patients with mucopolysaccharidosis I (MPS I). Enzyme replacement therapy or hematopoietic stem cell transplant do not prevent the development of CTS. Testing for CTS in patients with MPS I is recommended to prevent irreparable damage. CTS in pediatric patients should alert physicians to potential diagnosis of MPS I.

Vitamin D-binding protein, circulating vitamin D and risk of renal cell carcinoma.

Cell culture experiments suggest that vitamin D may inhibit renal carcinogenesis, but human studies of circulating 25-hydroxyvitamin D [25(OH)D], the accepted measure of vitamin D status, and kidney cancer have been null. Limited research has examined the role of circulating vitamin D-binding protein (DBP) in the association between 25(OH)D and disease risk, and it is unclear whether free 25(OH)D in circulation is a better measure of effective exposure, or if DBP may independently impact outcomes. We conducted a nested case-control analysis within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study to examine whether circulating DBP concentration was prospectively associated with risk of renal cell carcinoma, and whether it modified the association with 25(OH)D. Renal cell carcinoma cases (n = 262) were matched 1:1 to controls on age (±1 year) and date of blood collection (± 30 days). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) of renal cell carcinoma risk by quartiles of 25(OH)D, DBP and the molar ratio of 25(OH)D:DBP, a proxy for free circulating 25(OH)D. Men with higher DBP concentrations were at significantly decreased risk of kidney cancer (Q4 vs. Q1: OR = 0.17, 95% CI = 0.08-0.33; p-trend < 0.0001), a finding unchanged by adjustment for 25(OH)D. Although we observed no association with total 25(OH)D, we found slightly increased risk with higher levels of estimated free 25(OH)D [Q4 vs. Q1 of the 25(OH)D:DBP ratio, OR = 1.61, 95% CI = 0.95-2.73; p-trend = 0.09]. The strong protective association observed between higher circulating DBP concentration and kidney cancer risk requires replication but suggests a vitamin D-independent influence of DBP.

Soluble receptor for advanced glycation end products and risk of liver cancer.

UNLABELLED: Binding of advanced glycation end products (AGEs) to their receptor (RAGE) increases oxidative stress and inflammation and may be involved in liver injury and subsequent carcinogenesis. Soluble RAGE (sRAGE) may neutralize the effects mediated by the AGE/RAGE complex. Epidemiologic studies examining sRAGE or AGEs in association with liver cancer are lacking. We examined the associations between prediagnostic serum concentrations of sRAGE or Nϵ-(carboxymethyl)-lysine (CML)-AGE and hepatocellular carcinoma in a case-cohort study within a cohort of 29,133 Finnish male smokers who completed questionnaires and provided a fasting blood sample between 1985 and 1988. During follow-up beginning 5 years after enrollment through April 2006, 145 liver cancers occurred. Serum concentrations of sRAGE, CML-AGE, glucose, and insulin were measured in case subjects and 485 randomly sampled cohort participants. Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) were available in most cases and in a subset of the study population. Weighted Cox proportional hazards regression was used to calculate relative risks (RR) and 95% confidence intervals (CI) adjusted for age, years of smoking, and body mass index. sRAGE and CML-AGE concentrations were inversely associated with liver cancer. Further adjustment for glucose and insulin or exclusion of case subjects with chronic HBV or HCV did not change the associations. CONCLUSION: Our results support the hypothesis that sRAGE is inversely associated with liver cancer. The findings need confirmation, particularly in populations that include women and nonsmokers. (HEPATOLOGY 2013 ).

Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms and gastric cancer risk: a prospective study of men in Shanghai, China.

Isothiocyanates (ITC) in cruciferous vegetables may be chemopreventive against gastric cancer development. Glutathione S-transferases (GSTs) may modify the chemopreventive effect of ITC. The relationship between urinary total ITC and risk of gastric cancer was prospectively examined. Between 1986 and 1989, 18,244 middle-aged men in Shanghai, China were enrolled in a prospective study of diet and cancer and donated baseline urine and blood samples. Urinary ITC was quantified for 307 incident cases of gastric cancer that occurred during the first 16 years of follow-up, and 911 matched control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression methods. Seropositivity for antibodies to Helicobacter pylori and homozygous deletions of GSTM1 and GSTT1 were determined. Compared to the first tertile, ORs (95% CIs) of gastric cancer for the second and third tertiles of urinary total ITC were 0.83 (0.61-1.15) and 0.66 (0.47-0.94) (p(trend) = 0.02). A stronger protective effect of ITC against gastric cancer development was seen among men with homozygous deletion of GSTM1 (third tertile versus first tertile, OR = 0.50, 95% CI = 0.27-0.93) or GSTT1 (third tertile vs. first tertile, OR = 0.47, 95% CI = 0.25-0.88), and particularly with deletions of both GSTM1 and GSTT1 (second and third tertiles vs. first tertile, OR = 0.44, 95% CI = 0.21-0.93). In this cohort of Chinese men at high risk for gastric cancer, isothiocyanates may protect against the development of gastric cancer. The protection may be stronger for individuals genetically deficient in enzymes that metabolize these chemopreventive compounds.

Urinary total isothiocyanates and colorectal cancer: a prospective study of men in Shanghai, China.

Laboratory and epidemiologic evidence suggests that dietary isothiocyanates (ITCs) may have a chemopreventive effect on cancer. Humans are exposed to ITCs primarily through ingestion of cruciferous vegetables that contain glucosinolates, the precursors to ITCs. The association between urinary total ITC level and colorectal cancer risk was examined in a cohort of 18,244 men in Shanghai, China, with 16 years of follow-up. Urinary total ITCs were quantified on 225 incident cases of colorectal cancer and 1,119 matched controls. Odds ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated using logistic regression models. High levels of urinary total ITCs were associated with a reduced risk of colorectal cancer 5 years after baseline measurements of ITCs, whereas a statistically nonsignificant increase in the risk of colorectal cancer was observed for cases within 5 years of post-enrollment (OR, 1.93; 95% CI, 0.85-4.39 for the upper three quartiles of urinary ITCs versus the lowest quartile). The inverse ITC-colorectal cancer association became stronger with a longer duration of follow-up. Compared with the first quartile, ORs (95% CIs) for the second, third, and fourth quartiles of total ITCs in urine collected 10 or more years before cancer diagnosis were 0.61 (0.35-1.05), 0.51 (0.29-0.92), and 0.46 (0.25-0.83), respectively, for risk of colorectal cancer (P for trend = 0.006). The present study suggests that dietary ITCs may exert tumor inhibitory effects, especially during earlier stages of the multistage process of carcinogenesis.

Circulating 25-Hydroxyvitamin D and Prostate Cancer Survival.

BACKGROUND: Recent epidemiologic evidence suggests that higher circulating vitamin D does not protect against prostate cancer and, in fact, may increase the risk of developing this malignancy. However, few studies have examined the most clinically relevant outcome, prostate cancer mortality. METHODS: We examined prediagnostic serum 25-hydroxy-vitamin D (25(OH)D) and prostate cancer survival in a cohort of 1,000 cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. During 23 years of follow-up, 363 men died from their disease. Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of death from prostate cancer by season-specific quintile of 25(OH)D. Multivariable models were adjusted for age, physical activity, cigarettes per day, and family history of prostate cancer. RESULTS: Men with higher serum 25(OH)D were less likely to die from their prostate cancer (Q5 vs. Q1 HR, 0.72; 95% CI, 0.52-0.99; Ptrend = 0.006). This finding was independent of stage or grade at diagnosis and appeared restricted to men who survived longer (survived <3.3 years: Q5 vs. Q1 HR, 0.95; 95% CI, 0.61-1.50; Ptrend, 0.53; survived ≥3.3 years: Q5 vs. Q1 HR, 0.53; 95% CI, 0.34-0.85; Ptrend, 0.0002). CONCLUSIONS: In this population of men diagnosed with prostate cancer, higher serum 25(OH)D years prior to diagnosis was associated with longer prostate cancer survival. IMPACT: In light of inconsistent evidence regarding the role of vitamin D in the development of prostate cancer, the present findings regarding the most clinically relevant prostate cancer outcome, disease-specific mortality, could have important public health implications. Cancer Epidemiol Biomarkers Prev; 25(4); 665-9. ©2016 AACR.

Comparing metabolite profiles of habitual diet in serum and urine.

BACKGROUND: Diet plays an important role in chronic disease etiology, but some diet-disease associations remain inconclusive because of methodologic limitations in dietary assessment. Metabolomics is a novel method for identifying objective dietary biomarkers, although it is unclear what dietary information is captured from metabolites found in serum compared with urine. OBJECTIVE: We compared metabolite profiles of habitual diet measured from serum with those measured from urine. DESIGN: We first estimated correlations between consumption of 56 foods, beverages, and supplements assessed by a food-frequency questionnaire, with 676 serum and 848 urine metabolites identified by untargeted liquid chromatography mass spectrometry, ultra-high performance liquid chromatography tandem mass spectrometry, and gas chromatography mass spectrometry in a colon adenoma case-control study (n = 125 cases and 128 controls) while adjusting for age, sex, smoking, fasting, case-control status, body mass index, physical activity, education, and caloric intake. We controlled for multiple comparisons with the use of a false discovery rate of <0.1. Next, we created serum and urine multiple-metabolite models to predict food intake with the use of 10-fold crossvalidation least absolute shrinkage and selection operator regression for 80% of the data; predicted values were created in the remaining 20%. Finally, we compared predicted values with estimates obtained from self-reported intake for metabolites measured in serum and urine. RESULTS: We identified metabolites associated with 46 of 56 dietary items; 417 urine and 105 serum metabolites were correlated with ≥1 food, beverage, or supplement. More metabolites in urine (n = 154) than in serum (n = 39) were associated uniquely with one food. We found previously unreported metabolite associations with leafy green vegetables, sugar-sweetened beverages, citrus, added sugar, red meat, shellfish, desserts, and wine. Prediction of dietary intake from multiple-metabolite profiles was similar between biofluids. CONCLUSIONS: Candidate metabolite biomarkers of habitual diet are identifiable in both serum and urine. Urine samples offer a valid alternative or complement to serum for metabolite biomarkers of diet in large-scale clinical or epidemiologic studies.

Carotenoids, retinol, tocopherols, and prostate cancer risk: pooled analysis of 15 studies.

BACKGROUND: Individual studies have suggested that circulating carotenoids, retinol, or tocopherols may be associated with prostate cancer risk, but the studies have not been large enough to provide precise estimates of associations, particularly by stage and grade of disease. OBJECTIVE: The objective of this study was to conduct a pooled analysis of the associations of the concentrations of 7 carotenoids, retinol, α-tocopherol, and γ-tocopherol with risk of prostate cancer and to describe whether any associations differ by stage or grade of the disease or other factors. DESIGN: Principal investigators of prospective studies provided individual participant data for prostate cancer cases and controls. Risk by study-specific fifths of each biomarker was estimated by using multivariable-adjusted conditional logistic regression in matched case-control sets. RESULTS: Data were available for up to 11,239 cases (including 1654 advanced stage and 1741 aggressive) and 18,541 controls from 15 studies. Lycopene was not associated with overall risk of prostate cancer, but there was statistically significant heterogeneity by stage of disease, and the OR for aggressive disease for the highest compared with the lowest fifth of lycopene was 0.65 (95% CI: 0.46, 0.91; P-trend = 0.032). No other carotenoid was significantly associated with overall risk of prostate cancer or with risk of advanced-stage or aggressive disease. For retinol, the OR for the highest compared with the lowest fifth was 1.13 (95% CI: 1.04, 1.22; P-trend = 0.015). For α-tocopherol, the OR for the highest compared with the lowest fifth was 0.86 (95% CI: 0.78, 0.94; P-trend < 0.001), with significant heterogeneity by stage of disease; the OR for aggressive prostate cancer was 0.74 (95% CI: 0.59, 0.92; P-trend = 0.001). γ-Tocopherol was not associated with risk. CONCLUSIONS: Overall prostate cancer risk was positively associated with retinol and inversely associated with α-tocopherol, and risk of aggressive prostate cancer was inversely associated with lycopene and α-tocopherol. Whether these associations reflect causal relations is unclear.

Genome-wide association study of circulating vitamin D-binding protein.

BACKGROUND: Vitamin D status may influence a spectrum of health outcomes, including osteoporosis, arthritis, cardiovascular disease, and cancer. Vitamin D-binding protein (DBP) is the primary carrier of vitamin D in the circulation and regulates the bioavailability of 25-hydroxyvitamin D. Epidemiologic studies have shown direct DBP-risk relations and modification by DBP of vitamin D-disease associations. OBJECTIVE: We aimed to characterize common genetic variants that influence the DBP biochemical phenotype. DESIGN: We conducted a genome-wide association study (GWAS) of 1380 men through linear regression of single-nucleotide polymorphisms (SNPs) in the Illumina HumanHap500/550/610 array on fasting serum DBP, assuming an additive genetic model, with adjustment for age at blood collection. RESULTS: We identified 2 independent SNPs located in the gene encoding DBP, GC, that were highly associated with serum DBP: rs7041 (P = 1.42 × 10⁻²46) and rs705117 (P = 4.7 × 10⁻9¹). For both SNPs, mean serum DBP decreased with increasing copies of the minor allele: mean DBP concentrations (nmol/L) were 7335, 5149, and 3152 for 0, 1, and 2 copies of rs7041 (T), respectively, and 6339, 4280, and 2341, respectively, for rs705117 (G). DBP was also associated with rs12144344 (P = 5.9 × 10⁻7) in ST6GALNAC3. CONCLUSIONS: In this GWAS analysis, to our knowledge the first to examine this biochemical phenotype, 2 variants in GC--one exonic and one intronic--were associated with serum DBP concentrations at the genome-wide level of significance. Understanding the genetic contributions to circulating DBP may provide greater insights into the vitamin D binding, transport, and other functions of DBP and the effect of vitamin D status on health outcomes.

Urinary levels of cigarette smoke constituent metabolites are prospectively associated with lung cancer development in smokers.

Polycyclic aromatic hydrocarbons (PAH) are believed to be among the principal causative agents for lung cancer in smokers, but no epidemiologic studies have evaluated the relationship of PAH uptake and metabolism to lung cancer. In this study, we quantified prediagnostic urinary levels of r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), a validated biomarker of PAH uptake and metabolism, as well as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), and cotinine and its glucuronides (total cotinine), validated biomarkers of uptake of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and nicotine, respectively, in relation to lung cancer risk among current smokers in a nested case-control study within a cohort of 18,244 Chinese men in Shanghai, China. Urinary levels of PheT, total NNAL, and total cotinine were significantly higher in cases than controls (N = 476 matched pairs). ORs (95% confidence intervals) for lung cancer in the second, third, fourth, and fifth quintiles of PheT were 1.70 (1.00-2.88), 1.07 (0.62-1.84), 1.48 (0.86-2.53), and 2.34 (1.33-4.11), respectively, relative to the lowest quartile (P(trend) = 0.023) after adjustment for self-reported smoking intensity and duration and urinary total NNAL and total cotinine. This study also confirmed that urinary total NNAL and total cotinine are independently related to lung cancer risk.

Alcohol and tobacco use in relation to gastric cancer: a prospective study of men in Shanghai, China.

BACKGROUND: Epidemiologic findings of tobacco and alcohol use in relation to gastric cancer are inconsistent. Well-designed prospective studies examining their relationship are sparse. METHODS: The association between cigarette smoking/alcohol intake and gastric cancer risk was examined in a population-based prospective cohort of 18,244 middle-aged and older men in Shanghai, China, who were enrolled in the study during 1986-1989. After up to 20 years of follow-up, 391 incident gastric cancer cases were identified. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and corresponding 95% confidence intervals (95% CI). RESULTS: Ever smokers experienced a statistically significant increased risk of gastric cancer (HR, 1.59; 95% CI, 1.27-1.99) compared with nonsmokers after adjustment for alcohol intake and other confounders. Among nondrinkers, smokers experienced 80% increased risk of gastric cancer (HR, 1.81; 95% CI,1.36, 2.41). Conversely, heavy drinkers experienced a statistically significant increase in risk of gastric cancer (HR, 1.46; 95% CI, 1.05-2.04) among all subjects and a statistically nonsignificant 80% increased risk among never smokers. Further adjustment for Helicobacter pylori serology, serum levels of beta-carotene and vitamin C, and urinary level of total isothiocyanates in combination with glutathione S-transferase (GST) M1 and GSTT1 genotypes did not materially change the associations between smoking/alcohol consumption and gastric cancer risk. CONCLUSIONS: These results suggest that cigarette smoking and alcohol consumption may exert independent effects on the development of gastric cancer in this high-risk population. IMPACT: Modification of these lifestyle choices may reduce the incidence of gastric cancer.