Aristolochic acid exposure in Romania and implications for renal cell carcinoma

Background: Aristolochic acid (AA) is a nephrotoxicant associated with AA nephropathy (AAN) and upper urothelial tract cancer (UUTC). Whole-genome sequences of 14 Romanian cases of renal cell carcinoma (RCC) recently exhibited mutational signatures consistent with AA exposure, although RCC had not been previously linked with AAN and AA exposure was previously reported only in localised rural areas. Methods: We performed mass spectrometric measurements of the aristolactam (AL) DNA adduct 7-(deoxyadenosin-N6-yl) aristolactam I (dA-AL-I) in nontumour renal tissues of the 14 Romanian RCC cases and 15 cases from 3 other countries. Results: We detected dA-AL-I in the 14 Romanian cases at levels ranging from 0.7 to 27 adducts per 108 DNA bases, in line with levels reported in Asian and Balkan populations exposed through herbal remedies or food contamination. The 15 cases from other countries were negative. Interpretation: Although the source of exposure is uncertain and likely different in AAN regions than elsewhere, our results demonstrate that AA exposure in Romania exists outside localised AAN regions and provide further evidence implicating AA in RCC

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Does the Extent of Carcinoma in Prostatic Biopsies Predict Prostate-Specific Antigen Recurrence? A Systematic Review

Context: The biologic potential of prostate cancer (pCA) is variable, and the ability to identify tumours that might cause morbidity and mortality is limited. Objective: This systematic review sought to establish whether measurement of tumour extent in biopsies provides additional prognostic information on the risk of disease progression. Evidence acquisition: A comprehensive 31-step search strategy was run in MEDLINE,EMBASE, and the Web of Knowledge (January 1990–July 2007) and supplemented by the hand-searching of references in retrieved articles and relevant journals to identify publications related to the measurement of the length of cancer in biopsies and biochemical or clinical recurrence or pCA death. Thirteen papers reporting on at least 100 patients were identified and included patients treated by watchful waiting or hormonal therapy (n = 1), radical prostatectomy (n = 11), or radiotherapy (n = 1). Only two studies reported on clinical progression or mortality. Sources of bias included patient selection and missing data resulting from the retrospective nature of the studies. Confounding factors included differences in biopsy strategies and measurement methods. Evidence synthesis: The percentage of cancer in biopsies (overall percentage or the greatest percentage in the most involved core) was an independent predictor of prostate-specific antigen (PSA) and clinical outcomes regardless of the form of treatment and was generally superior to simply counting the number of positive cores. The marked variability in study design, conduct, and reporting precluded meta-analysis of the data and precise risk estimation. Conclusions: Tumour quantitation is a promising prognostic tool in the assessment of risk of pCA progression. However, well-designed, population-based studies, controlling for confounding factors, are required to provide more accurate risk estimation and develop management strategies. This review highlights the need for new approaches in the assessment of pathologic prognostic factors to reach the level of evidence achieved in other areas of medical practice

Key clinical issues in renal cancer: a challenge for proteomics

Renal cancer has many clinical challenges which proteomics is ideally placed to address. The issues cover all aspects of the disease including diagnosis, prognosis, treatment selection and monitoring to detect metastatic disease. In all cases novel biomarkers would considerably help in clinical management and with the relative resistance to conventional chemotherapy and radiotherapy, a better understanding of the underlying pathogenesis may contribute to the much needed development of novel therapeutic targets and the better use of promising new anti-angiogenic treatments. This review briefly highlights some of the clinical issues and describes proteomics-based approaches generally, before focussing on reviewing the proteomic studies to date in this area