Kazuhiro Yanagihara

A history of smoking is inversely correlated with the incidence of gemcitabine-induced neutropenia

BACKGROUND Smoking may affect the efficacy of chemotherapy and the incidence of adverse events. We investigated the correlation between smoking history and gemcitabine-induced neutropenia. PATIENTS AND METHODS Data on smoking history and incidence of grade 3-4 neutropenia were retrospectively gathered for 103 chemo-naive patients treated with gemcitabine monotherapy (59 patients with pancreatic, 41 with hepatobiliary and three with other cancers). RESULTS There was a significantly higher incidence of grade 3-4 neutropenia among patients without a history of smoking (55.7%) than among those with a history of smoking (including current and ex-smokers; 23.6%) [odds ratio (OR) 0.244, 95% confidence interval (CI) 0.105-0.569; P < 0.001]. After adjustment for age, gender, platelet and baseline neutrophil counts, history of surgery for primary cancer, creatinine concentration, hemoglobin concentration, aspartate aminotransferase concentration, alanine aminotransferase concentration and total bilirubin concentration, logistic regression analysis identified a history of smoking as an independent inverse predictor of gemcitabine-induced neutropenia (OR 0.188, 95% CI 0.057-0.618; P = 0.006). CONCLUSION Patients without a history of smoking may be at higher risk of developing gemcitabine-induced neutropenia. The mechanism underlying this phenomenon is unclear at this point.

Fas signal and cancer progression.

The Fas/FasL system has been demonstrated with respect to its capacity to induce cellular apoptosis [1]. However, Zhang et al. reported that Fas signaling did not inhibit the growth of 3LL cells in vitro, but it promoted lung cancer growth in vivo [2]. Such tumor-promoting effects of the Fas signal were not observed in FasL-deficient mice and in immunecompetent mice following inoculation with domain-negative Fas-overexpressing 3LL cells. Furthermore, myeloid-derived suppressor cells (MDSCs) and Foxp3 regulatory T cells accumulated in tumor tissues made by Fas-overexpressing 3LL cells, but not domain-negative Fasoverexpressing 3LL cells. Fas ligation induced 3LL lung cancer cells to produce the proinflammatory factor prostaglandin (PG)E 2 via the p38 pathway activation. 3LL cell-derived PGE 2 resulted in Fas ligation-induced MDSC chemoattraction. Moreover, administration of cyclooxygenase (COX)-2 inhibitor could significantly reduce MDSC accumulation in the Fasoverexpressing tumor in vivo. Therefore, Zhang et al. demonstrated that Fas signal can promote lung cancer growth by recruiting MDSCs via cancer cell-derived PGE 2 , and provided a new mechanistic explanation for the role of inflammation in cancer progression and immune escape [2]. Upregulation of COX-2 expression could be responsible for chronic inflammation-related cancer promotion [3]. Furthermore, nitric oxide (NO)-donating nonsteroidal anti-inf lammatory drugs (NSAIDs) have been reported to inhibit Wnt, NF-kB, inducible NO synthase and COX-2 in human colon cancer cells [3,4] resulting in inhibition of carcinogenesis of colonic adenoma and cancer progression [3,5]. MDSCs that were isolated from peripheral blood of metastatic renal cell carcinoma patients, but not from healthy donors, were capable of suppressing antigen-specific T-cell responses in vitro through the secretion of reactive oxygen species and NO upon interaction with cytotoxic T lymphocytes [6]. These findings suggest that Fas overexpression and MDSC accumulation may promote cancer growth under chronic inflammation, and NO-donating NSAIDs may play a key role in clinical application for Fas-related c ancer progression in cancer patients. Research Highlights