Background Effects of chronic cadmium exposure on liver disease and liver-related mortality are unknown. We evaluated the association of creatinine-corrected urinary cadmium levels with hepatic necroinflammation, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver-related mortality, and liver cancer mortality in the US general population. Methods We analyzed the relationship of individuals in the top quartile for urinary cadmium measured in 12,732 adults who participated in the Third National Health and Nutrition Examination Survey in 1988–1994 (NHANES III), and hepatic necroinflammation, NAFLD, and NASH. Associations between cadmium, liver-related mortality, and liver cancer mortality were evaluated in the NHANES III mortality follow-up study. Results The cutoffs for highest quartile of urinary cadmium per gram of urinary creatinine were 0.65 and 0.83 μg/g for men and women, respectively (P<0.001). After multivariate adjustment for other factors including smoking, the odds ratios [95 % confidence intervals (CI)] for hepatic necroinflammation, NAFLD, and NASH associated with being in the top quartile of cadmium levels by gender, were 2.21 (95 % CI, 1.64–3.00), 1.30 (95 % CI, 1.01–1.68) and 1.95 (95 % CI, 1.11–3.41) for men and 1.26 (95 % CI, 1.01–1.57), 1.11 (95 % CI, 0.88–1.41) and 1.34 (95 % CI, 0.72–2.50) for women, respectively. The hazard ratios for liver-related mortality and liver cancer mortality for both genders were 3.42 (95 % CI, 1.12–10.47) and 1.25 (95 % CI, 0.37–4.27). Conclusions Environmental cadmium exposure was associated with hepatic necroinflammation, NAFLD, and NASH in men, and hepatic necroinflammation in women. Individuals in the top quartile of creatinine-corrected urinary cadmium had over a threefold increased risk of liver disease mortality but not in liver cancer related mortality.

This trial confirms previous reports of a high rate of response to neoadjuvant therapy, but is the first to include small primary cancers and to show, in the context of a randomized trial, a reduction in the requirement for mastectomy. Until disease-free and overall survival data are available from the larger National Surgical Adjuvant Breast and Bowel Project (NSABP)-18 trial, such neoadjuvant treatment cannot be recommended outside of a clinical trial.

Background The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to determine the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection. Methods Multiplexed mutational profiling was performed using nucleic acids that were extracted from 200 resected ICC tumor specimens from 7 centers. The frequency of mutations was ascertained and the effect on outcome was determined. Results The majority of patients (61.5 %) had no genetic mutation identified. Among the 77 patients (38.5 %) with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5 %: IDH1 (15.5 %) and KRAS (8.6 %). Other genetic mutations were identified in very low frequency: BRAF (4.9 %), IDH2 (4.5 %), PIK3CA (4.3 %), NRAS (3.1 %), TP53 (2.5 %), MAP2K1 (1.9 %), CTNNB1 (0.6 %), and PTEN (0.6 %). Among patients with an IDH1-mutant tumor, approximately 7 % were associated with a concurrent PIK3CA gene mutation or a mutation in MAP2K1 (4 %). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (odds ratio 2.75), while KRAS-mutant tumors were more likely to be associated with R1 margin (odds ratio 6.51) (both P < 0.05). Although clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis. Conclusions Most somatic mutations in resected ICC tissue are found at low frequency, supporting a need for broad-based mutational profiling in these patients. IDH1 and KRAS were the most common mutations noted. Although certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly affect long-term prognosis.

BACKGROUND Surgery remains the only potentially curative option for patients with hepatocellular carcinoma (HCC) and fibrolamellar carcinoma (FLC). We sought to investigate the differences over time in surgically managed FLC compared with conventional HCC using population-based data. STUDY DESIGN Using SEER data, we identified 7,225 patients with surgically managed FLC or HCC from 1986 to 2008. We examined differences in clinicopathologic and surgical factors associated with long-term survival. RESULTS Of the 7,225 patients, the majority had HCC (n = 7,135; 99%) vs FLC (n = 90; 1%). Patients with FLC were younger (25 years vs 59 years) and more often were women (44% vs 27%) than patients with HCC (both p < 0.001). Regional disease was more common among patients with FLC (42.2%) vs patients with HCC (22.1%) (p < 0.001). More than one-third of patients with FLC (36.9%) were operatively managed with a hemi-hepatectomy compared with patients with HCC, who were more often managed with a liver transplant (p < 0.001). On univariable analysis, there was a marked difference in overall survival, with patients with FLC surviving a median of 75 months vs 43 months for HCC (hazard ratio [HR]: 0.59; p = 0.001). There was a marked difference in survival when patients were stratified by localized (FLC, 78 months vs HCC, 49 months; p = 0.012) vs regional disease (FLC, 46 months vs HCC, 23 months; p = 0.002. CONCLUSIONS Patients with FLC have many clinicopathologic features that are different from those of patients with HCC, including younger age and female sex. Despite a higher likelihood of advanced disease at the time of diagnosis, surgically treated FLC patients had better long-term outcomes than patients with conventional HCC.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the third leading cause of cancer death worldwide. Recurrence rates after curative intent treatment for HCC are high; 5-year disease-free survival ranges from only 19 to 81 %. There is no direct evidence to guide the optimal frequency and method of surveillance for recurrent HCC after curative intent treatment. In contrast, there is strong evidence supporting both primary screening for HCC in patients with chronic liver disease. After resection, HCC tends to recur locally, whereas the pattern after transplantation is more at extrahepatic sites. In theory, if an HCC recurrence is discovered early, more therapeutic options are available for treatment of the recurrent HCC. As such, close surveillance after curative intent therapy may have the potential to prolong survival. We herein review the available literature derived from primary surveillance of patients with cirrhosis, as well as data on postoperative surveillance of HCC patients. In aggregate, although data remain scarce, close surveillance with α-fetoprotein and cross-sectional imaging every 3-4 months for 3 years after curative intent therapy, followed by surveillance every 6-12 months thereafter, seems the most prudent approach to follow-up of patients with HCC in the postsurgical setting.

MK-0493 is a novel, potent, and selective agonist of the melanocortin receptor 4 (MC4R), one of the best-validated genetic targets and considered one of the most promising for the development of antiobesity therapeutics. An ad libitum energy-intake model was qualified with excellent reproducibility: the geometric mean ratio (GMR) with 95% confidence interval (CI) for total energy intake over a period of 24 h for 30 mg sibutramine/placebo was 0.82 (0.76, 0.88), and for 10 mg sibutramine/placebo it was 0.98 (0.91, 1.05). MK-0493 showed a small and marginally significant effect on 24-h energy intake, whereas 30 mg of sibutramine caused a significant reduction in total 24-h energy intake; specifically, the GMR (95% CI) for 30 mg sibutramine/placebo was 0.79 (0.74, 0.85). MK-0493 was associated with modest weight reduction from baseline but had only small, statistically insignificant effects relative to placebo after 12 weeks in a fixed-dose study and also after 18 weeks of stepped-titration dosing. We conclude that agonism of MC4R is not likely to represent a viable approach to the development of antiobesity therapeutics.

IntroductionAlthough a high frequency of androgen receptor (AR) expression in human breast cancers has been described, exploiting this knowledge for therapy has been challenging. This is in part because androgens can either inhibit or stimulate cell proliferation in pre-clinical models of breast cancer. In addition, many breast cancers co-express other steroid hormone receptors that can affect AR signaling, further obfuscating the effects of androgens on breast cancer cells.MethodsTo create better-defined models of AR signaling in human breast epithelial cells, we took estrogen receptor (ER)-α-negative and progesterone receptor (PR)-negative human breast epithelial cell lines, both cancerous and non-cancerous, and engineered them to express AR, thus allowing the unambiguous study of AR signaling. We cloned a full-length cDNA of human AR, and expressed this transgene in MCF-10A non-tumorigenic human breast epithelial cells and MDA-MB-231 human breast-cancer cells. We characterized the responses to AR ligand binding using various assays, and used isogenic MCF-10A p21 knock-out cell lines expressing AR to demonstrate the requirement for p21 in mediating the proliferative responses to AR signaling in human breast epithelial cells.ResultsWe found that hyperactivation of the mitogen-activated protein kinase (MAPK) pathway from both AR and epidermal growth factor receptor (EGFR) signaling resulted in a growth-inhibitory response, whereas MAPK signaling from either AR or EGFR activation resulted in cellular proliferation. Additionally, p21 gene knock-out studies confirmed that AR signaling/activation of the MAPK pathway is dependent on p21.ConclusionsThese studies present a new model for the analysis of AR signaling in human breast epithelial cells lacking ERα/PR expression, providing an experimental system without the potential confounding effects of ERα/PR crosstalk. Using this system, we provide a mechanistic explanation for previous observations ascribing a dual role for AR signaling in human breast cancer cells. As previous reports have shown that approximately 40% of breast cancers can lack p21 expression, our data also identify potential new caveats for exploiting AR as a target for breast cancer therapy.

Cholangiocarcinoma (CCA) is the second most common primary malignancy of the liver arising from malignant transformation and growth of biliary ductal epithelium. Approximately 50-70 % of CCAs arise at the hilar plate of the biliary tree, which are termed hilar cholangiocarcinoma (HC). Various staging systems are currently employed to classify HCs and determine resectability. Depending on the pre-operative staging, the mainstays of treatment include surgery, chemotherapy, radiation therapy, and photodynamic therapy. Surgical resection offers the only chance for cure of HC and achieving an R0 resection has demonstrated improved overall survival. However, obtaining longitudinal and radial surgical margins that are free of tumor can be difficult and frequently requires extensive resections, particularly for advanced HCs. Pre-operative interventions may be necessary to prepare patients for major hepatic resections, including endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography, and portal vein embolization. Multimodal therapy that combines chemotherapy with external beam radiation, stereotactic body radiation therapy, bile duct brachytherapy, and/or photodynamic therapy are all possible strategies for advanced HC prior to resection. Orthotopic liver transplantation is another therapeutic option that can achieve complete extirpation of locally advanced HC in judiciously selected patients following standardized neoadjuvant protocols.