Effect of socioeconomic status on hepatocellular carcinoma incidence and stage at diagnosis, a population-based cohort study.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) incidence is increasing worldwide and cirrhosis is the most important risk factor predominantly caused by chronic viral hepatitis infection. We studied the impact of socioeconomic status (SES) on HCC incidence and stage at diagnosis among viral hepatitis cases. METHODS: A population-based retrospective cohort study was conducted through the Ontario Cancer Registry linked data. Incidence rates were calculated using person-time methodology. Association between SES (income quintile) and HCC incidence was assessed using proportional-hazards regression. The impact of SES on HCC stage was investigated using logistic regression. RESULTS: Among 11 350 individuals diagnosed with viral hepatitis between 1991 and 2010, a crude HCC incidence rate of 21.4 cases per 1000 person-years was observed. Adjusting for age, gender, urban/rural residence and year of viral hepatitis diagnosis, a significant association was found between SES and HCC incidence, with an increased risk among individuals in the lowest three income quintiles (incidence rate ratio, IRR = 1.235; 95% CI: 1.074-1.420; IRR = 1.183; 95% CI: 1.026-1.364; IRR = 1.158; 95% CI: 1.000-1.340 respectively). No significant association between SES and HCC incidence was found after additionally adjusting for risk factors associated with HCC. However, HCC risk factors such as cirrhosis and HIV are associated with SES. Furthermore, no association was found between SES and HCC stage. CONCLUSIONS: The association between SES and HCC incidence is likely because of differences in risk factors across income quintiles. Investigating how SES affects HCC incidence facilitates an understanding of which populations are at elevated risk for HCC.

Assessing adolescent immunization options for pertussis in Canada: A cost-utility analysis.

BACKGROUND: Adolescent tetanus, diphtheria and pertussis (Tdap) immunization helps prevent pertussis infection. Timing of Tdap receipt represents an important facet of successful adolescent pertussis immunization. Potential strategies for timing of vaccine administration are each associated with different benefits - including disease prevention - and costs. The objective of this study was to assess the cost-utility of adolescent pertussis immunization strategies in Canada. METHODS: A cost-utility analysis was conducted using a pertussis disease history-simulating Markov model, with adolescents (beginning at age 10 years) as the cohort of interest. The model assessed three Tdap vaccination strategies: (1) immunization of 10 year olds, (2) removal of adolescent vaccination, and (3) immunization of 14 year olds (status quo). The analysis was conducted from a healthcare payer perspective and used a lifetime time horizon. Primary outcomes included life years, quality-adjusted life years (QALYs), health system costs, and an incremental cost-effectiveness ratio (ICER). Costs and outcomes were discounted at 1.5 percent annually. Deterministic and probabilistic sensitivity analyses were performed to assess parameter uncertainty. RESULTS: The current recommended adolescent immunization strategy (at age 14) resulted in an average of 40.4432 expected QALYs and $26.28 per individual. This strategy was dominated by immunization at 10 years and no immunization. Compared to no immunization, immunizing adolescents at age 10 had an ICER of $74,899 per QALY. Results were most sensitive to the incidence of pertussis and the utility of moderate or severe pertussis. At a cost-effectiveness threshold of $50,000/QALY, removal of adolescent vaccination represented the most cost-effective strategy in 78% of simulations. CONCLUSION: Analysis assumes a policy context where immunization of pregnant women is recommended. Findings suggest that alternate adolescent Tdap vaccine strategies - either immunization of 10 year olds, or removal of the adolescent vaccine - are more cost-effective than the current practice of immunizing 14 year olds.

Effects of socioeconomic status on esophageal adenocarcinoma stage at diagnosis, receipt of treatment, and survival: A population-based cohort study.

The incidence of esophageal adenocarcinoma (EAC) is increasing worldwide and has overtaken squamous histology in occurrence. We studied the impact of socioeconomic status (SES) on EAC stage at diagnosis, receipt of treatment, and survival. A population-based retrospective cohort study was conducted using Ontario Cancer Registry-linked administrative health data. Multinomial logistic regression was used to examine the association between SES (income quintile) and stage at EAC diagnosis and EAC treatment. Survival times following EAC diagnosis were estimated using Kaplan-Meier method. Cox proportional-hazards regression analysis was used to examine the association between SES and EAC survival. Between 2003-2012, 2,125 EAC cases were diagnosed. Median survival for the lowest-SES group was 10.9 months compared to 11.6 months for the highest-SES group; the 5-year survival was 9.8% vs. 15.0%. Compared to individuals in the highest-SES group, individuals in the lowest-SES category experienced no significant difference in EAC treatment (91.6% vs. 93.3%, P = 0.314) and deaths (78.9% vs. 75.6%, P = 0.727). After controlling for covariates, no significant associations were found between SES and cancer stage at diagnosis and EAC treatment. Additionally, after controlling for age, gender, urban/rural residence, birth country, health region, aggregated diagnosis groups, cancer stage, treatment, and year of diagnosis, no significant association was found between SES and EAC survival. Moreover, increased mortality risk was observed among those with older age (P = 0.001), advanced-stage of EAC at diagnosis (P < 0.001), and those receiving chemotherapy alone, radiotherapy alone, or surgery plus chemotherapy (P < 0.001). Adjusted proportional-hazards model findings suggest that there is no association between SES and EAC survival. While the unadjusted model suggests reduced survival among individuals in lower income quintiles, this is no longer significant after adjusting for any covariate. Additionally, there is an apparent association between SES and survival when considering only those individuals diagnosed with stage 0-III EAC. These analyses suggest that the observed direct relationship between SES and survival is explained by patient-level factors including receipt of treatment, something that is potentially modifiable.

Selective inhibition of histone deacetylases sensitizes malignant cells to death receptor ligands.

Evasion of death receptor ligand-induced apoptosis represents an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (that we propose be named droxinostat) was identified as a chemical sensitizer to death receptor stimuli, decreasing the expression of the caspase-8 inhibitor FLIP. However, the direct targets of droxinostat were unknown. To better understand the mechanism of action of droxinostat and highlight new strategies to restore sensitivity to death receptor ligands, we analyzed changes in gene expression using the Connectivity Map after treating cells with droxinostat. Changes in gene expression after droxinostat treatment resembled changes observed after treatment with histone deacetylase (HDAC) inhibitors. Therefore, we examined the effects of droxinostat on HDAC activity and showed that it selectively inhibited HDAC3, HDAC6, and HDAC8 and that inhibition of these HDACs was functionally important for its ability to sensitize cells to death ligands. Thus, we have identified a selective HDAC inhibitor and showed that selective HDAC inhibition sensitizes cells to death ligands, thereby highlighting a new mechanism to overcome resistance to death receptor ligands.

Inhibition of the sodium potassium adenosine triphosphatase pump sensitizes cancer cells to anoikis and prevents distant tumor formation.

Normal epithelial cells undergo apoptosis upon detachment from the extracellular matrix, a process termed "anoikis." However, malignant epithelial cells with metastatic potential resist anoikis and can survive in an anchorage-independent fashion. Molecules that sensitize resistant cells to anoikis will be useful chemical probes to understand this pathway. To identify novel anoikis sensitizers in anoikis-resistant PPC-1 prostate adenocarcinoma cells, a library of 2,000 off-patent drugs and natural products was screened for their ability to preferentially induce cell death in suspension over adherent culture conditions. This screen identified five members of the family of cardiac glycosides as anoikis sensitizers, including ouabain, peruvoside, digoxin, digitoxin, and strophanthidin. We conducted further studies with ouabain to discern the mechanism of cardiac glycoside-induced anoikis sensitization. Ouabain initiated anoikis through the mitochondrial pathway of caspase activation. In addition, ouabain sensitized cells to anoikis by inhibiting its known target, the Na(+)/K(+) ATPase pump, and inducing hypoosmotic stress. Resistance to anoikis permits cancer cells to survive in the circulation and facilitates their metastasis to distant organs, so we tested the effects of Na(+)/K(+) ATPase inhibition on distant tumor formation in mouse models. In these mouse models, ouabain inhibited tumor metastases but did not alter the growth of subcutaneous tumors. Thus, we have identified a novel mechanism to sensitize resistant cells to anoikis and decrease tumor metastasis. These results suggest a potential mechanism for the observed clinical reduction in metastasis and relapse in breast cancer patients who have undergone treatments with cardiac glycosides.

Anoikis resistance and tumor metastasis.

As a barrier to metastases, cells normally undergo apoptosis after they lose contact with their extra cellular matrix or their neighbouring cells. This cell death process has been termed "anoikis". Tumour cells that acquire malignant potential have developed mechanisms to resist anoikis and thereby survive after detachment from their primary site and while travelling through the lymphatic and circulatory systems. Defects in the death receptor pathway of caspase activation, such as the over-expression of the caspase-8 inhibitor FLIP, can render cells resistant to anoikis. Likewise, roadblocks in the mitochondrial pathway, such as over-expression of the Bcl-2 family of anti-apoptotic proteins, can also confer resistance to anoikis. This review will focus on the roles of the death receptor and mitochondrial pathways in anoikis and anoikis resistance and how targeting defects in these pathways can restore sensitivity to anoikis and serve as the basis for therapeutic adjuncts that prevent metastasis.