The advancements in cancer therapy have improved the clinical outcomes of cancer patients in recent decades. However, advanced cancer therapy is expensive and requires good health care systems. For kidney cancer, no studies have yet established an association between clinical outcome and health care disparities. We used the mortality-to-incidence ratio (MIR) for kidney cancer as a marker of clinical outcome to compare World Health Organization (WHO) country rankings and total expenditures on health/gross domestic product (e/GDP) using linear regression analyses. We included 57 countries based on data from the GLOBOCAN 2012 database. We found that more highly developed regions have higher crude and age-standardized rates of kidney cancer incidence and mortality, but a lower MIR, when compared to less developed regions. North America has the highest crude rates of incidence, but the lowest MIRs, whereas Africa has the highest MIRs. Furthermore, favorable MIRs are correlated with countries with good WHO rankings and high e/GDP expenditures (p < 0.001 and p = 0.013, respectively). Kidney cancer MIRs are positively associated with the ranking of health care systems and health care expenditures.

Cisplatin-based chemotherapy is the first-line therapy for bladder cancer. However, cisplatin resistance has been associated with the recurrence of bladder cancer. Previous studies have shown that activation of FGFR and HER2 signaling are involved in bladder cancer cell proliferation and drug resistance. Smoking is the most common etiologic risk factor for bladder cancer, and there is emerging evidence that smoking is associated with cisplatin resistance. However, the underlying mechanism remains elusive. Acrolein, a highly reactive aldehyde, is abundant in tobacco smoke, cooking fumes, and automobile exhaust fumes. Our previous studies have shown that acrolein contributes to bladder carcinogenesis through the induction of DNA damage and inhibition of DNA repair. In this study, we found that acrolein induced cisplatin resistance and tumor progression in both non–muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) cell lines RT4 and T24, respectively. Activation of HER2 and FGFR3 signaling contributes to acrolein-induced cisplatin resistance in RT4 and T24 cells, respectively. Furthermore, trastuzumab, an anti-HER2 antibody, and PD173074, an FGFR inhibitor, reversed cisplatin resistance in RT4 and T24 cells, respectively. Using a xenograft mouse model with acrolein-induced cisplatin-resistant T24 clones, we found that cisplatin combined with PD173074 significantly reduced tumor size compared with cisplatin alone. These results indicate that differential molecular alterations behind cisplatin resistance in NMIBC and MIBC significantly alter the effectiveness of targeted therapy combined with chemotherapy. This study provides valuable insights into therapeutic strategies for cisplatin-resistant bladder cancer.

The mortality-to-incidence ratio (MIR) is associated with the clinical outcome of cancer treatment. For several cancers, countries with relatively good health care systems have favorable MIRs. However, the association between lung cancer MIR and health care expenditures or rankings has not been evaluated. We used linear regression to analyze the correlation between lung cancer MIRs and the total expenditures on health/gross domestic product (e/GDP) and the World Health Organization (WHO) rankings. We included 57 countries, for which data of adequate quality were available, and we found high rates of incidence and mortality but low MIRs in more developed regions. Among the continents, North America had the highest rates of incidence and mortality, whereas the highest MIRs were in Africa, Asia, Latin America, and the Caribbean. Globally, favorable MIRs correlated with high e/GDP and good WHO ranking (regression coefficient, −0.014 and 0.001; p = 0.004, and p = 0.014, respectively). In conclusion, the MIR for lung cancer in different countries varies with the expenditure on health care and health system rankings.

The mortality-to-incidence ratio (MIR) is associated with the clinical outcomes of different types of cancer as well as the ranking of health care systems. However, the association between MIRs for testicular cancer and health care disparities, including differences in expenditures and health system rankings, has not yet been reported. We used the Spearman’s rank correlation coefficient (CC) to analyze the correlation between testicular cancer MIRs and both total expenditures on health/gross domestic product (e/GDP) and the World Health Organization’s (WHO) health system rankings. After screening the data for quality and missing information, 57 countries were chosen for analysis. Generally, developed countries and regions had relatively high rates of incidence/mortality, but with a favorable MIR. Among the continents, Europe had the highest incidence rates, whereas the highest MIRs were in Africa. Globally, favorable testicular cancer MIRs were observed in countries with both a high e/GDP and a good WHO ranking (R² = 0.325, p < 0.001 and CC = −0.568, p < 0.001; R² = 0.367, p < 0.001 and CC = 0.655, p < 0.001, respectively). In conclusion, the MIR for testicular cancer varies in countries and regions based on both their total health expenditure and their health care system ranking.

Cisplatin-based chemotherapy is the first-line therapy for bladder cancer. However, cisplatin resistance has been associated with the recurrence of bladder cancer. Previous studies have shown that activation of FGFR and HER2 signaling are involved in bladder cancer cell proliferation and drug resistance. Smoking is the most common etiologic risk factor for bladder cancer, and there is emerging evidence that smoking is associated with cisplatin resistance. However, the underlying mechanism remains elusive. Acrolein, a highly reactive aldehyde, is abundant in tobacco smoke, cooking fumes, and automobile exhaust fumes. Our previous studies have shown that acrolein contributes to bladder carcinogenesis through the induction of DNA damage and inhibition of DNA repair. In this study, we found that acrolein induced cisplatin resistance and tumor progression in both non–muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) cell lines RT4 and T24, respectively. Activation of HER2 and FGFR3 signaling contributes to acrolein-induced cisplatin resistance in RT4 and T24 cells, respectively. Furthermore, trastuzumab, an anti-HER2 antibody, and PD173074, an FGFR inhibitor, reversed cisplatin resistance in RT4 and T24 cells, respectively. Using a xenograft mouse model with acrolein-induced cisplatin-resistant T24 clones, we found that cisplatin combined with PD173074 significantly reduced tumor size compared with cisplatin alone. These results indicate that differential molecular alterations behind cisplatin resistance in NMIBC and MIBC significantly alter the effectiveness of targeted therapy combined with chemotherapy. This study provides valuable insights into therapeutic strategies for cisplatin-resistant bladder cancer.

Supplementary Figure from Cigarette Smoke Containing Acrolein Contributes to Cisplatin Resistance in Human Bladder Cancers through the Regulation of HER2 Pathway or FGFR3 Pathway