Near patient anti-platelet response testing over time and gene analysis in patients admitted with acute coronary syndromes.

We sought to assess the relationships between platelet reactivity at different time points, CYP2C19*2 and ABCB1 status and clinical outcomes in patients with acute coronary syndromes (ACS). Anti-platelet response to clopidogrel was studied prospectively using the VerifyNow (VN) P2Y12 assay at the time of angiography and at 30 days post procedure in 151 patients admitted with ACS who underwent percutaneous coronary intervention (PCI). Troponin T levels were measured at angiography and 16-24 hour following PCI. DNA was extracted and the presence of CYP2C19*2 allele and ABCB1 polymorphisms were determined. Adverse cardiovascular and cerebral events (ACCE) were assessed at 12 months. High VN P2Y12 response at angiography was associated with a greater peri-procedural rise in troponin T, but not ACCE. However, VN P2Y12 response measured at 30 days was associated with ACCE (p = 0.017). CYP2C19*2 status was associated with higher VN P2Y12 response at angiography (p < 0.0001) and 30 days (p = 0.006) but not ACCE. Near-patient testing for clopidogrel response was associated with subsequent ACCE when performed 30 days following PCI, but not at angiography.

Elevated, combined serum free light chain levels and increased mortality: a 5-year follow-up, UK study.

AIMS: Abnormal serum free light chain (FLC) ratios are diagnostically important in almost all plasma cell disorders. However, absolute increases in polyclonal FLC levels are often discarded as inconsequential. Here we report an association between increased combined polyclonal FLC (cFLC: FLCκ plus FLCλ) concentrations and mortality. METHODS: 723 patients sent for 30 routine haematological assessments were enrolled. Patients with a confirmed monoclonal gammopathy were removed. The remaining 527 patients were followed up for up to 4.5 years. Statistical analysis was performed using SPSS (V.19). RESULTS: During follow-up, there were 99 deaths (18.8%). Kaplan-Meier survival analysis revealed 29% of these deaths occurred within the first 100 days (N=29). Multivariate analysis identified only cFLC >65 mg/l, albumin <33 g/l and  estimated glomerular filtration rate <30 ml/min/1.73 m(2) to be independently associated with mortality within 100 days and 4.5 years with, cFLC having the highest HR of 7.1. A simple risk stratification model based only on albumin and cFLC identified 86% mortality within 100 days and 62% over 4.5 years. CONCLUSIONS: Elevated cFLC is significantly associated with increased mortality and with albumin can be used to identify patients at risk of mortality at 4.5 years with high-risk patients detected within 100 days.

Associations between ultraviolet radiation, basal cell carcinoma site and histology, host characteristics, and rate of development of further tumors.

BACKGROUND: Patients with basal cell carcinoma (BCC) frequently develop further tumors during follow-up. OBJECTIVE: We sought to elucidate the relative effects of pattern of ultraviolet radiation exposure, and site and histologic type of the first tumor, on the rate of increase in BCC numbers. METHODS: We used negative binomial regression analysis to study the association of selected variables on the rate of increase in BCC numbers in 266 Caucasian patients who first presented with a tumor on the head/neck or trunk with nodular or superficial histology. RESULTS: Patients with an initial truncal BCC with superficial histology demonstrated significantly faster increases in BCC numbers than did patients with other site and histology combinations. CONCLUSIONS: These data indicate that site and histology define subsets of patients with BCC.

Polymorphism in the nuclear excision repair gene ERCC2/XPD: association between an exon 6-exon 10 haplotype and susceptibility to cutaneous basal cell carcinoma.

Cutaneous basal cell carcinoma (BCC) risk is mediated by interactions between ultraviolet radiation (UVR) and host factors, including DNA repair efficiency. We investigated the association between BCC risk and SNPs in exon 6 (c.466C > A, dbSNP238406:g.C > A; designated C/A156), exon 10 (c.932G > A, dbSNP1799793:g.G > A; designated G/A312), and exon 23 (c.2251A > C, dbSNP13181:g.A > C; designated A/C751) of the nucleotide excision repair gene, XPD (ERCC2; excision repair cross-complementing repair deficiency, complementation 2 [xeroderma pigmentosum D]). XPD genotype frequencies were not significantly different in 509 cases and 379 controls, although AA156 (odds ratio [OR]=0.61, 95% confidence interval [CI]=0.37-1.01, P=0.052) and AA312 (OR=0.65, 95% CI=0.40-1.05, P=0.08) were linked with reduced risk. A156-A312 and A156-A312-A751 haplotype frequencies however, were significantly lower in cases than controls (OR=0.12, 95% CI=0.05-0.31, P < 0.001; OR=0.10, 95% CI=0.03-0.33, P < 0.001). We confirmed the robustness of these findings by showing significant associations of the haplotypes with risk in two randomly selected equal sized groups of cases and controls and, using the false positive report probability (FPRP) approach (FPRP values < 0.001 and < 0.004, respectively). A156-A312 was similarly associated with reduced risk in subgroups, including cases with no family history of skin cancer, with only BCC on the head/neck, and those with a high rate of increase in BCC numbers. The association was not dependent on gender, age, or extent of UVR exposure. A156-A312 was found in 6.3% of controls and the corresponding risk haplotype, C156-G312 (OR=1.65, 95% CI=1.21-2.26, P=0.002) in 35.4% of controls. We interpret these data as showing that XPD SNP mediate susceptibility to BCC.

Polymorphisms in glutathione S-transferases and non-melanoma skin cancer risk in Australian renal transplant recipients.

Caucasian renal transplant recipients from Queensland, Australia have the highest non-melanoma skin cancer (NMSC) risk worldwide. Although ultraviolet light (UVR) exposure is critical, genetic factors also appear important. We and others have shown that polymorphism in the glutathione S-transferases (GST) is associated with NMSC in UK recipients. However, the effect of high UVR exposure and differences in immunosuppressive regimen on these associations is unknown. In this study, we examined allelism in GSTM1, GSTM3, GSTT1 and GSTP1 in 361 Queensland renal transplant recipients. Data on squamous (SCC) and basal cell carcinoma (BCC), UVR/tobacco exposure and genotype were obtained. Associations with both NMSC risk and numbers were examined using logistic and negative binomial regression, respectively. In the total group, GSTM1 AB [P = 0.049, rate ratio (RR) = 0.23] and GSTM3 AA (P = 0.015, RR = 0.50) were associated with fewer SCC. Recipients were then stratified by prednisolone dose (< or =7 versus >7 mg/day). In the low-dose group, GSTT1 null (P = 0.006, RR = 0.20) and GSTP1 Val/Val (P = 0.021, RR = 0.20) were associated with SCC numbers. In contrast, in the high-dose group, GSTM1 AB (P = 0.009, RR = 0.05), GSTM3 AB (P = 0.042, RR = 2.29) and BB (P = 0.014, RR = 5.31) and GSTP1 Val/Val (P = 0.036, RR = 2.98) were associated with SCC numbers. GSTM1 AB (P = 0.016) and GSTP1 Val/Val (P = 0.046) were also associated with fewer BCC in this group. GSTP1 associations were strongest in recipients with lower UVR/tobacco exposure. The data confirm our UK findings, suggesting that protection against UVR-induced oxidative stress is important in NMSC development in recipients, but that this effect depends on the immunosuppressant regimen.

Associations between UVR exposure and basal cell carcinoma site and histology.

While sunlight is critical in basal cell carcinoma (BCC) pathogenesis the relationship between exposure and tumor site and histology is unclear. We determined if tumor site (trunk or head/neck) or histology (nodular or superficial) is determined by exposure pattern. In 66 cases with truncal and 362 patients with head/neck BCC at first presentation, average hours exposure/year, intermittency score, childhood sunburning and skin type were not significantly associated with tumor site or histology. However, often sunbathing was associated with a five-fold increased risk of truncal BCC. Average sunbathing score was significantly greater in 22 cases with truncal compared with 325 cases with head/neck nodular tumors and also in 44 cases with superficial truncal compared with superficial head/neck BCC. Thus, sunbathing determined tumor site but not histology.

PTCH polymorphism is associated with the rate of increase in basal cell carcinoma numbers during follow-up: preliminary data on the influence of an exon 12-exon 23 haplotype.

After first presentation with a basal cell carcinoma (BCC), patients demonstrate interindividual diversity in the rate of development of further BCCs (number/year of follow-up). The mechanism for this variation is unknown. In this study, we evaluated whether PTCH variants mediate this phenomenon. We used negative binomial regression analysis to identify associations between BCC numbers/year and host characteristics, parameters of exposure to ultraviolet radiation (UVR), and PTCH exon 12(1686) C/T, intron 15(2560+9) G/C, and exon 23(3944) C/T genotypes and haplotypes in 279 BCC cases who presented with an initial tumor on the head/neck. PTCH genotypes were not significantly associated with BCCs/year, although cases with two copies of the C1686-C3944 haplotype developed significantly fewer BCCs/year than those without this haplotype (rate ratio = 0.44; 95% CI = 0.27-0.71). Cases with one copy of T1686-T3944 developed more BCCs/year (rate ratio = 2.46; 95% CI = 1.27-3.97) than those without the haplotype. We found no significant associations between BCCs/year and the other PTCH haplotypes studied. We reexamined the association of C1686-C3944 with BCCs/year in a model that included UVR exposure parameters (sunburning in childhood, sunbathing score, intermittency of exposure between 40 and 60 years of age, exposure in hours/year) and skin type, gender, and age at first presentation. The association between C1686-C3944 and BCCs/year remained significant (rate ratio = 0.44; 95% CI = 0.26-0.73 for two copies of the haplotype). The data show that allelic variation in PTCH contributes to the rate of development of BCC.

Combined effects of gender, skin type and polymorphic genes on clinical phenotype: use of rate of increase in numbers of basal cell carcinomas as a model system.

Patients with a basal cell carcinomas (BCC) have an increased risk of further tumors. We studied the individual and combined impact of gender, skin type and allelic genes cytochrome P450 (CYP2D6), vitamin D receptor (VDR), tumor necrosis factor-alpha, TNF-alpha) on the rate of increase in BCC numbers after first presentation. Individually, male gender, skin type 1, CYP2D6 EM, VDR TT and TNF-alpha GG were associated with more BCC/year (rate ratio (RR) 1.20-1.36) while RR for associations of combinations of two, three and four variables were greater than in their reference categories (RR 1.32-1.90, 2.20-2.84, 3.06-5.49, respectively). The data show that different factors mediate the numbers of BCC/year in males and females and, the individual contributions of variables to risk is modest.

The rate of increase in the numbers of primary sporadic basal cell carcinomas during follow up is associated with age at first presentation.

Basal cell carcinoma (BCC) patients demonstrate marked variation in tumour numbers and site. Previous studies also show an association between age at first BCC presentation and development of BCC on the trunk. In this study we have investigated the association between age at first presentation and the rate of development of truncal and non-truncal tumours in 747 patients with BCC. We used negative binomial regression analysis to show that increasing age at first presentation was associated with an increased rate of BCC development (rate ratio 1.01/year, 95% CI 1.01-1.02, P < 0.001). In particular, development of tumours was greater in cases aged 60.0-69.9, 70.0-79.9 and 80.0-89.9 years than in those 40.0-49.9 years (P = 0.05, 0.01 and 0.039, respectively). While few cases aged over 70 years of age first present with a truncal BCC, the numbers of BCC/year were greater than in those with a head/neck BCC. The data suggest different genetic factors mediate the appearance of BCC in patients of different ages particularly those aged above and below 60 years.