Donor-Derived Urothelial Carcinoma in Renal Transplant Recipients.

Cancer is a significant cause of morbidity and mortality in recipients of renal transplantation. The vast majority develop from recipient origins, whereas donor-derived malignancies are exceedingly rare. We report 2 cases of poorly differentiated donor-derived urothelial carcinoma (UC) in renal transplantation recipients. The first patient underwent a living-related-donor renal transplantation 24 years prior and presented with back pain, hematuria, and rising creatinine and was found to have a 14 cm mass in the renal allograft with regional lymphadenopathy and liver metastases. Pathology showed UC with small-cell differentiation. The second patient presented with hematuria and rising creatinine and was initially found to have muscle invasive bladder cancer seven years after a deceased donor renal transplantation. Nine months after radical cystectomy, a large 9 cm mass was found on his allograft, for which radical nephrectomy and excision of prior ileal conduit was performed. Pathology showed UC with sarcomatoid differentiation. Short tandem repeat (STR) genotyping confirmed donor-derived origins. Both patient tumors expressed PD-L1 suggesting an additional therapeutic avenue for these rare tumors.

Underutilization of Androgen Deprivation Therapy with External Beam Radiotherapy in Men with High-grade Prostate Cancer.

Multiple randomized trials have shown a survival benefit to long durations of androgen deprivation therapy (ADT) in patients with Gleason grade group (GG) 4-5 (ie, Gleason score 8-10) prostate cancer (PCa) undergoing definitive external beam radiotherapy (EBRT). We conducted a population-based retrospective study utilizing the complete Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database from 2008 to 2011, extracting PCa patients of non-Hispanic white (NHW) and African-American (AA) race diagnosed with GG 4-5PCa who received EBRT with or without concomitant ADT. Of 961 patients receiving definitive EBRT, 225 (23.4%) received no ADT, 297 (30.9%) received 1-6mo of ADT, 313 (32.6) received 7-23mo of ADT, and 126 (13.1%) received ≥24mo of ADT. On multinomial logistic regression after inverse probability treatment weighting to balance for differences in other covariates, AA men still had significantly lower odds of receiving 1-6mo of ADT versus no ADT compared with NHW men (odds ratios 0.519 [95% confidence interval, 0.384-0.700]). In conclusion, long-duration ADT is underutilized, with nearly 90% of patients with GG 4-5PCa receiving <24mo of concomitant ADT, and AA men are less likely to receive ADT than NHW men. PATIENT SUMMARY: In this report, we examined the utilization of concomitant androgen deprivation therapy (ADT) among men with high-grade prostate cancer undergoing definitive external beam radiotherapy. We found that long-duration ADT was underutilized overall; moreover, African-American men were less likely to receive concomitant ADT than non-Hispanic white men.

Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential.

BACKGROUND: Metastatic prostate cancer (PC) is highly lethal. The ability to identify primary tumors capable of dissemination is an unmet need in the quest to understand lethal biology and improve patient outcomes. Previous studies have linked chromosomal instability (CIN), which generates aneuploidy following chromosomal missegregation during mitosis, to PC progression. Evidence of CIN includes broad copy number alterations (CNAs) spanning > 300 base pairs of DNA, which may also be measured via RNA expression signatures associated with CNA frequency. Signatures of CIN in metastatic PC, however, have not been interrogated or well defined. We examined a published 70-gene CIN signature (CIN70) in untreated and castration-resistant prostate cancer (CRPC) cohorts from The Cancer Genome Atlas (TCGA) and previously published reports. We also performed transcriptome and CNA analysis in a unique cohort of untreated primary tumors collected from diagnostic prostate needle biopsies (PNBX) of localized (M0) and metastatic (M1) cases to determine if CIN was linked to clinical stage and outcome. METHODS: PNBX were collected from 99 patients treated in the VA Greater Los Angeles (GLA-VA) Healthcare System between 2000 and 2016. Total RNA was extracted from high-grade cancer areas in PNBX cores, followed by RNA sequencing and/or copy number analysis using OncoScan. Multivariate logistic regression analyses permitted calculation of odds ratios for CIN status (high versus low) in an expanded GLA-VA PNBX cohort (n = 121). RESULTS: The CIN70 signature was significantly enriched in primary tumors and CRPC metastases from M1 PC cases. An intersection of gene signatures comprised of differentially expressed genes (DEGs) generated through comparison of M1 versus M0 PNBX and primary CRPC tumors versus metastases revealed a 157-gene "metastasis" signature that was further distilled to 7-genes (PC-CIN) regulating centrosomes, chromosomal segregation, and mitotic spindle assembly. High PC-CIN scores correlated with CRPC, PC-death and all-cause mortality in the expanded GLA-VA PNBX cohort. Interestingly, approximately 1/3 of M1 PNBX cases exhibited low CIN, illuminating differential pathways of lethal PC progression. CONCLUSIONS: Measuring CIN in PNBX by transcriptome profiling is feasible, and the PC-CIN signature may identify patients with a high risk of lethal progression at the time of diagnosis.

Local Failure and Survival After Definitive Radiotherapy for Aggressive Prostate Cancer: An Individual Patient-level Meta-analysis of Six Randomized Trials.

BACKGROUND: The importance of local failure (LF) after treatment of high-grade prostate cancer (PCa) with definitive radiotherapy (RT) remains unknown. OBJECTIVE: To evaluate the clinical implications of LF after definitive RT. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data meta-analysis of 992 patients (593 Gleason grade group [GG] 4 and 399 GG 5) enrolled in six randomized clinical trials. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable Cox proportional hazard models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), and distant metastasis (DM)-free survival (DMFS) and LF as a time-dependent covariate. Markov proportional hazard models were developed to evaluate the impact of specific transitions between disease states on these endpoints. RESULTS AND LIMITATIONS: Median follow-up was 6.4 yr overall and 7.2 yr for surviving patients. LF was significantly associated with OS (hazard ratio [HR] 1.70 [95% confidence interval {CI} 1.37-2.10]), PCSS (3.10 [95% CI 2.33-4.12]), and DMFS (HR 1.92 [95% CI 1.54-2.39]), p < 0.001 for all). Patients who had not transitioned to the LF state had a significantly lower hazard of transitioning to a PCa-specific death state than those who transitioned to the LF state (HR 0.13 [95% CI 0.04-0.41], p < 0.001). Additionally, patients who transitioned to the LF state had a greater hazard of DM or death (HR 2.46 [95% CI 1.22-4.93], p = 0.01) than those who did not. CONCLUSIONS: LF is an independent prognosticator of OS, PCSS, and DMFS in high-grade localized PCa and a subset of DM events that are anteceded by LF events. LF events warrant consideration for intervention, potentially suggesting a rationale for upfront treatment intensification. However, whether these findings apply to all men or just those without significant comorbidity remains to be determined. PATIENT SUMMARY: Men who experience a local recurrence of high-grade prostate cancer after receiving upfront radiation therapy are at significantly increased risks of developing metastases and dying of prostate cancer.

Clonal diversity revealed by morphoproteomic and copy number profiles of single prostate cancer cells at diagnosis.

Tumor heterogeneity is prevalent in both treatment-naïve and end-stage metastatic castration-resistant prostate cancer (PCa), and may contribute to the broad range of clinical presentation, treatment response, and disease progression. To characterize molecular heterogeneity associated with de novo metastatic PCa, multiplatform single cell profiling was performed using high definition single cell analysis (HD-SCA). HD-SCA enabled morphoproteomic and morphogenomic profiling of single cells from touch preparations of tissue cores (prostate and bone marrow biopsies) as well as liquid samples (peripheral blood and bone marrow aspirate). Morphology, nuclear features, copy number alterations, and protein expression were analyzed. Tumor cells isolated from prostate tissue touch preparation (PTTP) and bone marrow touch preparation (BMTP) as well as metastatic tumor cells (MTCs) isolated from bone marrow aspirate were characterized by morphology and cytokeratin expression. Although peripheral blood was examined, circulating tumor cells were not definitively observed. Targeted proteomics of PTTP, BMTP, and MTCs revealed cell lineage and luminal prostate epithelial differentiation associated with PCa, including co-expression of EpCAM, PSA, and PSMA. Androgen receptor expression was highest in MTCs. Hallmark PCa copy number alterations, including PTEN and ETV6 deletions and NCOA2 amplification, were observed in cells within the primary tumor and bone marrow biopsy samples. Genomic landscape of MTCs revealed to be a mix of both primary and bone metastatic tissue. This multiplatform analysis of single cells reveals several clonal origins of metastatic PCa in a newly diagnosed, untreated patient with polymetastatic disease. This case demonstrates that real-time molecular profiling of cells collected through prostate and bone marrow biopsies is feasible and has the potential to elucidate the origin and evolution of metastatic tumor cells. Altogether, biological and genomic data obtained through longitudinal biopsies can be used to reveal the properties of PCa and can impact clinical management.

The Current Status and Future Role of the Phosphoinositide 3 Kinase/AKT Signaling Pathway in Urothelial Cancer: An Old Pathway in the New Immunotherapy Era.

The phosphoinositide 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a well studied signaling pathway that regulates diverse cellular functions including proliferation, metabolism, and transcription. Aberrant activation of this pathway has been implicated in multiple cancers. Genomic studies have shown that activating mutations in oncogenes as well as inactivating mutations in tumor suppressor genes are present across a variety of malignancies, including urothelial carcinoma. In bladder cancer, up to 40% of tumors exhibit constitutive activation of the PI3K/AKT/mTOR pathway. Current treatments for non-muscle-invasive disease confer a 5-year cancer-specific survival rate as high as 90%. However, patients with muscle-invasive, recurrent, or metastatic disease have a poor prognosis. Although the introduction of immune checkpoint inhibitors is certainly changing the therapeutic landscape and is a great addition to the platinum-based therapy that was the standard of care for the past 3 decades, it is anticipated that a great number of patients would fail to respond or their disease would progress with either chemotherapy or immunotherapy. Therefore, the use of agents that target members of the PI3K/AKT/mTOR pathway represent an attractive, alternative therapeutic strategy for patients with advanced urothelial carcinoma. In this review we describe the pathway, with a focus on the rationale for targeting the PI3K/AKT/mTOR pathway in patients with advanced urothelial carcinoma and considers the challenges that we face from the current clinical trials. Novel agents such as PI3K inhibitors and microRNA inhibitors that target this pathway might lead to durable responses especially when used in combination with chemotherapy or immune checkpoint inhibitors, however, toxicity remains an obstacle. Finally, in this review we discuss the importance of developing biomarkers to help select appropriate patients and identify optimal treatment options.

Essential Role of Lyn in Fibrosis.

Fibrotic disorders involve replacement of normal parenchyma with myofibroblasts, which deposit connective tissue, leading to obliteration of the function of the underlying organ. The treatment options are inadequate and reflect the fact that signaling targets in myofibroblasts are unknown. Here we identify the hyperactive Lyn signaling in myofibroblasts of patients with chronic pancreatitis-induced fibrosis. Lyn activation coexpress with markers of activated myofibroblasts, and is increased ~11-fold in chronic pancreatitis compared to normal tissue. Inhibition of Lyn with siRNA or INNO-406 leads to the substantial decrease of migration and proliferation of human chronic pancreatitis myofibroblasts in vitro, while leaving migration and proliferation of normal myofibroblasts only slightly affected. Furthermore, inhibition of Lyn prevents synthesis of procollagen and collagen in myofibroblasts in a mouse model of chronic pancreatitis-induced fibrosis. We conclude that Lyn, as a positive regulator of myofibroblast migration, proliferation, and collagen production, is a key target for preventing fibrosis.

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia of the Lung (DIPNECH): Current Best Evidence.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is recognized as a preneoplastic condition by the World Health Organization. We reviewed our experience with 30 patients and performed a systematic review of the English literature to collect best evidence on the clinical features and disease course in 169 additional patients. Some patients presented with one or more carcinoid tumors associated with multiple small pulmonary nodules on imaging studies and showed DIPNECH as a somewhat unexpected pathologic finding. Others presented with multiple small pulmonary nodules that raised suspicion of metastatic disease on imaging. A third subset was presented with previously unexplained respiratory symptoms. In most patients, DIPNECH was associated with a good prognosis, with chronological progression into a subsequent carcinoid tumor noted in only one patient and death attributed directly to DIPNECH in only two patients. There is no best evidence to support the use of octreotide, steroids, or bronchodilators in DIPNECH patients.

Src as the link between inflammation and cancer.

Although a causal link between chronic inflammation and cancer has been established, the exact molecular mechanism linking inflammation to cancer remains largely unknown. It was previously postulated that molecular switches responsible for cancer cell development, and for infiltration of inflammatory cells into cancer, were divided into a distinct set of intracellular proteins and signaling pathways. However, recent evidence suggests that both tumor cells and tumor-infiltrating immune cells utilize the same kinases, mostly that of Src family, to facilitate cancer development and progression. In the past few years several groups have found that Src activation both in cancer and inflammatory cells is mainly driven by pro-inflammatory cytokines within the tumor microenvironment. Here we evaluate the cross talks between Src kinase pathways in immune cells and cancer cells. We conclude that Src might serve as a critical mechanistic link between inflammation and cancer, mediating and propagating a cycle between immune and tissue cells that can ultimately lead to the development and progression of cancer.

Aged garlic extract supplemented with B vitamins, folic acid and L-arginine retards the progression of subclinical atherosclerosis: a randomized clinical trial.

OBJECTIVES: Previous studies demonstrated that aged garlic extract reduces multiple cardiovascular risk factors. This study was designed to assess whether aged garlic extract therapy with supplements (AGE+S) favorably affects inflammatory and oxidation biomarkers, vascular function and progression of atherosclerosis as compared to placebo. METHODS: In this placebo-controlled, double-blind, randomized trial (conducted 2005-2007), 65 intermediate risk patients (age 60+/-9 years, 79% male) were treated with a placebo capsule or a capsule containing aged garlic extract (250 mg) plus Vitamin B12 (100 microg), folic acid (300 microg), Vitamin B6 (12.5 mg) and l-arginine (100 mg) given daily for a 1 year. All patients underwent coronary artery calcium scanning (CAC), temperature rebound (TR) as an index of vascular reactivity using Digital Thermal Monitoring (DTM), and measurement of lipid profile, autoantibodies to malondialdehyde (MDA)-LDL, apoB-immune complexes, oxidized phospholipids (OxPL) on apolipoprotein B-100 (OxPL/apoB), lipoprotein (a) [Lp (a)], C-reactive protein (CRP), homocysteine were measured at baseline and 12 months. CAC progression was defined as an increase in CAC>15% per year and an increase in TR above baseline was considered a favorable response. RESULTS: At 1 year, CAC progression was significantly lower and TR significantly higher in the AGE+S compared to the placebo group after adjustment of cardiovascular risk factors (p<0.05). Total cholesterol, LDL-C, homocysteine, IgG and IgM autoantibodies to MDA-LDL and apoB-immune complexes were decreased, whereas HDL, OxPL/apoB, and Lp (a) were significantly increased in AGE+S to placebo. CONCLUSION: AGE+S is associated with a favorable improvement in oxidative biomarkers, vascular function, and reduced progression of atherosclerosis.

Prognostic value of number and site of calcified coronary lesions compared with the total score.

OBJECTIVES: This study sought to evaluate the long-term prognostic value of the number and sites of calcified coronary lesions and to compare the accuracy of number of calcified lesions with the extent of total calcium score. BACKGROUND: There is a strong relationship between mortality and total coronary artery calcium (CAC) score. It is not known whether the number of calcified lesions or their location influences outcome. METHODS: A total of 14,759 asymptomatic patients were referred for evaluation of CAC scanning using electron beam tomography. Univariable and multivariable Cox proportional hazards models were developed to estimate time to all-cause mortality at, on average, 6.8 years (n = 281). RESULTS: Risk-adjusted annual mortality was 0.19% (95% confidence interval 0.18% to 0.21%) for patients without any calcified lesions. For patients with >20 lesions, annual risk-adjusted mortality exceeded 2% per year. Mortality rates were significantly higher for left main lesions as compared to other coronary arteries with annual mortality rates of 1.3%, 2.1%, 9.2%, and 13.6% for 1 to 2, 3 to 5, and > or =6 lesions, respectively (p < 0.0001). For left main CAC scores of 0 to 10, 11 to 100, 101 to 399, and 400 to 999, annual risk-adjusted mortality was 0.33%, 0.81%, 1.73%, and 7.71%, respectively (p < 0.0001). All 4 patients with a CAC score of > or =1,000 in the left main died during follow-up. However, patients with more frequent calcified lesions also had higher CAC scores. Specifically, > or =81% of patients with >10 calcified lesions also had a CAC score > or =100. With exception, for patients with CAC scores > or =1,000, annual mortality was dramatically higher at 3.0% to 4.5% for those with 1 to 5 calcified lesions as compared with 1.1% to 2.0% for those with 6 or more lesions (p < 0.0001). CONCLUSIONS: We report that mortality rates increased proportionally with the number of calcified lesions. Although predictive information is contained in the number of calcified lesions, its added statistical value is minimal. With exception, patients with frequent lesions in the left main or those with a few large calcified lesions have a particularly high mortality risk.

Ethnic differences in the prognostic value of coronary artery calcification for all-cause mortality.

OBJECTIVES: The purpose of this study was to evaluate the prognostic value of coronary artery calcium (CAC), a known marker of subclinical atherosclerosis, in a large, ethnically diverse cohort of 14,812 patients for the prediction of all-cause mortality. BACKGROUND: Disparities in case fatality rates for heart disease among ethnic groups are well known. In 2001, rates of death from heart disease were 30% higher among African Americans (AA) than non-Hispanic whites (NHW). Some of this variability may be due to differing pathophysiological mechanisms and effects of underlying atherosclerosis. METHODS: Ten-year death rates from all causes (total deaths = 505) were compared using risk-adjusted Cox proportional hazards models in AA (n = 637), Hispanic (HS, n = 1,334), Asian (AS, n = 1,065), and NHW (n = 11,776) populations. RESULTS: Ethnic minority patients were generally younger (0.3 to 4 years), more often persons with diabetes (p < 0.0001), hypertensive (p < 0.0001), and female (p < 0.0001). The prevalence of CAC scores > or =100 was highest in NHW (31%) and lowest for HS (18%) (p < 0.0001). Overall survival was 96%, 93%, and 92% for AS, NHW, and HS, respectively, as compared with 83% for AA (p < 0.0001). When comparing prognosis by CAC scores in ethnic minorities as compared with NHW, relative risk ratios were highest for AA with CAC scores > or =400 exceeding 16.1 (p < 0.0001). Hispanics with CAC scores > or =400 had relative risk ratios from 7.9 to 9.0, whereas AS with CAC scores > or =1,000 had relative risk ratios 6.6-fold higher than NHW (p < 0.0001). CONCLUSIONS: Consistent with population evidence, AA with increasing burden of subclinical coronary artery disease were the highest-risk ethnic minority population. These data support a growing body of evidence noting substantial differences in cardiovascular risk by ethnicity.

Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients.

OBJECTIVES: The purpose of this study was to develop risk-adjusted multivariable models that include risk factors and coronary artery calcium (CAC) scores measured with electron-beam tomography in asymptomatic patients for the prediction of all-cause mortality. BACKGROUND: Several smaller studies have documented the efficacy of CAC testing for assessment of cardiovascular risk. Larger studies with longer follow-up will lend strength to the hypothesis that CAC testing will improve outcomes, cost-effectiveness, and safety of primary prevention efforts. METHODS: We used an observational outcome study of a cohort of 25,253 consecutive, asymptomatic individuals referred by their primary physician for CAC scanning to assess cardiovascular risk. Multivariable Cox proportional hazards models were developed to predict all-cause mortality. Risk-adjusted models incorporated traditional risk factors for coronary disease and CAC scores. RESULTS: The frequency of CAC scores was 44%, 14%, 20%, 13%, 6%, and 4% for scores of 0, 1 to 10, 11 to 100, 101 to 400, 401 to 1,000, and >1,000, respectively. During a mean follow-up of 6.8 +/- 3 years, the death rate was 2% (510 deaths). The CAC was an independent predictor of mortality in a multivariable model controlling for age, gender, ethnicity, and cardiac risk factors (model chi-square = 2,017, p < 0.0001). The addition of CAC to traditional risk factors increased the concordance index significantly (0.61 for risk factors vs. 0.81 for the CAC score, p < 0.0001). Risk-adjusted relative risk ratios for CAC were 2.2-, 4.5-, 6.4-, 9.2-, 10.4-, and 12.5-fold for scores of 11 to 100, 101 to 299, 300 to 399, 400 to 699, 700 to 999, and >1,000, respectively (p < 0.0001), when compared with a score of 0. Ten-year survival (after adjustment for risk factors, including age) was 99.4% for a CAC score of 0 and worsened to 87.8% for a score of >1,000 (p < 0.0001). CONCLUSIONS: This large observational data series shows that CAC provides independent incremental information in addition to traditional risk factors in the prediction of all-cause mortality.

Coronary calcium progression rates with a zero initial score by electron beam tomography.

BACKGROUND: A review of existing literature shows that for individuals with initial coronary calcium scores (CCS) of zero it would be reasonable to consider follow-up scanning no sooner than 3 years from the initial evaluation, however the data is very limited. In this study, we sought to determine the rate of new calcifications in patients initially presenting with a zero initial score on electron beam tomography (EBT). METHODS AND RESULTS: We evaluated 710 physician-referred participants (253 women and 448 men, mean age=56+/-9 years [range=29 to 93]) with no coronary artery calcium (CAC) at baseline electron beam tomography (EBT) scan. The participants underwent a follow-up scan at least 12 months apart. In our study, 248 (35%) were followed for 1-3 years, 256 (36%) for 3-5 years and 204 (29%) for >5 years, respectively. Overall, more than half of the individuals (62%) did not develop any CAC (score remained zero) in the interim period, whereas only 2% had CAC progression >50 during the follow-up. The overall median (interquartile range) and mean+/-S.D. change/year in these individuals was 0 (0-0.8) and 1+/-3, respectively. Only 11 (2%) had CAC progression/year of 11-50, whereas 3 (1%) had CAC change/year >50. It is interesting to note that even among individuals with long-term follow-up (>5 years), very few individuals (2%) had CAC progression >50. Individuals with follow-up 3-5 years did not have a significantly higher odds ratio for CAC change >10 (p=0.17) as compared to the reference group (follow-up of 1-3 years). All the other individuals who had a longer follow-up (>5 years) had a significantly higher likelihood of CAC progression >10 (OR=6.6, 95% CI=2.6-16.9, p<0.0001) compared to the reference group. CONCLUSION: In individuals with no detectable coronary calcium on an initial EBT scan, a repeat scan can be recommended no sooner than 5 years.

Prognostic significance of zero coronary calcium scores on cardiac computed tomography.

BACKGROUND: Most unexpected cardiovascular events occur in persons at intermediate risk of coronary artery disease (10%-20% 10-year risk). Coronary artery calcium (CAC) has been shown to be highly specific for atherosclerosis, occurring only in the intima of the coronary arteries. Evidence shows that elevated coronary calcium scores (CCSs) are predictive of future cardiovascular events, both independently of and incrementally to conventional cardiovascular risk factors. Several studies reported event rates of zero for those persons without CAC by cardiac computed tomography (CT). OBJECTIVES: We sought to evaluate the event rates in persons with negative calcium scores from the reported literature to establish whether these patients may be considered at low risk for hard cardiovascular events (myocardial infarction and death). METHODS: English-language studies from January 1, 1975, through February 1, 2007, were retrieved using MEDLINE and Current Contents databases, bibliographies, and expert consultation. RESULTS: Summary data show that in a total follow-up of 35,765 asymptomatic persons, 16,106 (45%) had scores of zero. Pooled sensitivity for CAC to detect a cardiovascular event was 98.1% [95% confidence interval (CI), 95.1%-99.9%], and negative predictive value was 99.9% (95% CI, 98.9%-100%). There were 48 hard events in this population, with an annual event rate of 0.027%. CONCLUSION: These large observational cohorts show that the absence of CAC by cardiac CT is associated with a low adverse event risk and therefore could be used as a tool to counsel patients about their risk of such events.

Ethnic differences of the presence and severity of coronary atherosclerosis.

BACKGROUND: Although cardiovascular risk factor levels are substantially different in Caucasians, African-American, Hispanics, and Asians, the relative rates of coronary heart disease in these groups are not consistent with these differences. The objective of the study is to assess the differences in the prevalence and severity of coronary artery calcification, as a measure of atherosclerosis, in these different ethnic groups. METHODS: Electron-beam tomography was performed in 16,560 asymptomatic men and women (Asians=1336, African-Americans=610, Hispanics=1256) aged >or=35 years referred by their physician for cardiovascular risk evaluation. The study population encompassed 70% males, aged 52+/-8 years. RESULTS: Caucasians were more likely to present with dyslipidemia (p<0.0001), while African-Americans and Hispanics had a higher prevalence of smoking, diabetes, and hypertension (all p<0.001). After adjustment for age, gender, risk factors, and treatment for hypercholesterolemia, compared with Caucasians, the relative risks for men having coronary calcification were 0.64 (95% CI: 0.48-0.86) in African-Americans, 0.88 (95% CI: 0.67-1.15) in Hispanics, and 0.66 (95% CI: 0.55-0.80) in Asians. After similar adjustments, the relative risks for women having coronary calcification, were 1.58 (95% CI: 1.13-2.19) for African-Americans, 0.84 (95% CI: 0.66-1.06) in Hispanics, and 0.71 (95% CI: 0.56-0.89) in Asian women. After adjusting for age and risk factors using multivariable analysis, African-American men were least likely to have any coronary calcium while African-American women had significantly higher OR of any calcification. Asian men and women had significantly lower OR of any calcification. There was no significant difference in prevalence or severity of atherosclerosis between Hispanics and Caucasians, in men or women. CONCLUSIONS: Our study results demonstrate significant difference in the presence as well as severity of calcification according to ethnicity, independent of atherosclerotic risk factors. Results from this study (physician referred) closely parallel the results from MESA (population based, measured risk factors). Ethnic specific data on the predictive value of differing coronary calcium scores are needed.

Diabetes and progression of coronary calcium under the influence of statin therapy.

BACKGROUND: Coronary artery calcium (CAC) is a sensitive marker for the detection of coronary heart disease (CHD). Coronary artery calcification can be accurately quantified using electron beam tomography (EBT). We sought to evaluate the progression of atherosclerosis in asymptomatic persons with type 2 diabetes and measure the influence of statin therapy on CAC progression. METHODS: We evaluated 163 asymptomatic patients with type 2 diabetes (120 men, 43 women). Patients were physician referred and underwent 2 consecutive EBT scans at least 1 year apart. Demographic data, risk factors for CHD, and medication use were collected. Patients with symptoms or known CHD were excluded. RESULTS: The mean age was 65 +/- 10 years. The mean CAC score at baseline was 651 +/- 414. Only 9 (6%) of 163 of participants had scores of 0 at baseline. The time between scans averaged 27 +/- 15 months. Patients not treated with statins demonstrated a median annual increase in CAC progression of 20% (4%-44%), whereas statin-treated patients demonstrated increase of 10% (4%-25%) (P = .0001). Hemoglobin A 1c was weakly associated with CAC progression. CONCLUSIONS: Asymptomatic diabetic patients show a high prevalence of atherosclerosis based on high frequency of coronary calcification. Statin therapy induced a 50% reduction in the rate of CAC progression. As rapid CAC progression has been associated with coronary events, EBT may serve as a noninvasive method for following atherosclerosis and response to therapy.