Primary liver cancer, the most common histologic types of which are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), is the second leading cause of cancer death worldwide. While rising incidence of liver cancer in low-risk areas and decreasing incidence in some high-risk areas has been reported, trends have not been thoroughly explored by country or by histologic type. We examined liver cancer incidence overall and by histology by calendar time and birth cohort for selected countries between 1978 and 2007. For each successive 5-year period, age-standardized incidence rates were calculated from volumes V-IX of the Cancer Incidence in Five Continents electronic database (CI5plus) and the newly released CI5X (volume X) database. Wide global variations persist in liver cancer incidence. Rates of liver cancer remain highest in Asian countries, specifically Eastern and South-Eastern Asian countries. While rates in most of these high-risk countries have been decreasing in recent years, rates in India and several low-risk countries of Africa, Europe, the Americas, and Oceania have been on the rise. Liver cancer rates by histologic type tend to convey a similar temporal profile. However, in Thailand, France, and Italy, ICC rates have increased while HCC rates have declined. We expect rates in high-risk countries to continue to decrease, as the population seroprevalence of hepatitis B virus (HBV) continues to decline. In low-risk countries, targeted screening and treatment of the hepatitis C virus (HCV), treatment of diabetes and primary prevention of obesity, will be key in reducing future liver cancer incidence.

A small subpopulation of highly adaptable breast cancer cells within a vastly heterogeneous population drives cancer metastasis. Here we describe a function-based strategy for selecting rare cancer cells that are highly adaptable and drive malignancy. Although cancer cells are dependent on certain nutrients, e.g., glucose and glutamine, we hypothesized that the adaptable cancer cells that drive malignancy must possess an adaptable metabolic state and that such cells could be identified using a robust selection strategy. As expected, more than 99.99% of cells died upon glutamine withdrawal from the aggressive breast cancer cell line SUM149. The rare cells that survived and proliferated without glutamine were highly adaptable, as judged by additional robust adaptability assays involving prolonged cell culture without glucose or serum. We were successful in isolating rare metabolically plastic glutamine-independent (Gln-ind) variants from several aggressive breast cancer cell lines that we tested. The Gln-ind cells overexpressed cyclooxygenase-2, an indicator of tumor aggressiveness, and they were able to adjust their glutaminase level to suit glutamine availability. The Gln-ind cells were anchorage-independent, resistant to chemotherapeutic drugs doxorubicin and paclitaxel, and resistant to a high concentration of a COX-2 inhibitor celecoxib. The number of cells being able to adapt to non-availability of glutamine increased upon prior selection of cells for resistance to chemotherapy drugs or resistance to celecoxib, further supporting a linkage between cellular adaptability and therapeutic resistance. Gln-ind cells showed indications of oxidative stress, and they produced cadherin11 and vimentin, indicators of mesenchymal phenotype. Gln-ind cells were more tumorigenic and more metastatic in nude mice than the parental cell line as judged by incidence and time of occurrence. As we decreased the number of cancer cells in xenografts, lung metastasis and then primary tumor growth was impaired in mice injected with parental cell line, but not in mice injected with Gln-ind cells.

Background Marijuana has been reported to have several effects on the male reproductive system. Marijuana has previously been linked to reduced adult testosterone, however, a study in Denmark reported increased testosterone concentrations among marijuana users. This study was performed to estimate the effect of marijuana use on testosterone in U.S. males. Methods Data on serum testosterone, marijuana use and covariates for 1577 men from the 2011–2012 U.S. National Health and Nutrition Examination Survey (NHANES) were analyzed. Information on marijuana use was collected by a self-administered computer-assisted questionnaire. Serum testosterone was determined using isotope dilution liquid chromatography tandem mass spectrometry. The effects of marijuana use on serum testosterone concentrations were examined by frequency, duration, and recency of use. Adjusted means and 95% confidence intervals (CI) of serum testosterone across levels of marijuana use were estimated using multiple linear regression weighted by the survey weights. Results The majority (66.2%) of the weighted study population reported ever using marijuana with 26.6% reporting current marijuana use. There was no difference in serum testosterone between ever users (adjusted mean = 3.69 ng/mL, 95% CI: 3.46, 3.93) and never users (adjusted mean = 3.70 ng/mL, 95% CI: 3.45, 3.98) upon multivariable analysis. However, serum testosterone was inversely associated with time since last regular use of marijuana (p-value for trend = 0.02). When restricted to men aged 18 – 29 years, this relationship strengthened (p-value for trend < 0.01) and serum testosterone was also inversely associated with time since last use (p-value for trend < 0.01), indicating that recency of use, and not duration or frequency, had the strongest relationship with testosterone levels. Discussion Serum testosterone concentrations were higher in men with more recent marijuana use. Studies are needed to determine the extent to which circulating testosterone concentrations mediate the relationship of marijuana use to male reproductive outcomes.

Given the distinct time-trends and age-specific patterns of testicular cancer in men aged ≥50 years, additional investigation of risk factors for these tumors is warranted.