Impact of chrono-radiotherapy on the prognosis and treatment-related toxicity in patients with locally advanced nasopharyngeal carcinoma: A multicenter propensity-matched study.

The timing of radiotherapy (RT) delivery has been reported to affect both cancer survival and treatment toxicity. However, the association among the timing of RT delivery, survival, and toxicity in locally advanced nasopharyngeal carcinoma (LA-NPC) has not been investigated. We retrospectively reviewed patients diagnosed with LA-NPC who received definitive RT at multiple institutions. The median RT delivery daytime was categorized as morning (DAY) and night (NIGHT). Seasonal variations were classified into the darker half of the year (WINTER) and brighter half (SUMMER) according to the sunshine duration. Cohorts were balanced according to baseline characteristics using propensity score matching (PSM). Survival and toxicity outcomes were evaluated using Cox regression models. A total of 355 patients were included, with 194/161 in DAY/NIGHT and 187/168 in WINTER/SUMMER groups. RT delivered during the daytime prolonged the 5-year overall survival (OS) (90.6% vs. 80.0%, p = 0.009). However, the significance of the trend was lost after PSM (p = 0.068). After PSM analysis, the DAY cohort derived a greater benefit in 5-year progression-free survival (PFS) (85.6% vs. 73.4%, p = 0.021) and distant metastasis-free survival (DMFS) (89.2% vs. 80.8%, p = 0.051) in comparison with the NIGHT subgroup. Moreover, multivariate analysis showed that daytime RT was an independent prognostic factor for OS, PFS, and DMFS. Furthermore, daytime RT delivery was associated with an increase in the incidence of leukopenia and radiation dermatitis. RT delivery in SUMMER influenced only the OS significantly (before PSM: p = 0.051; after PSM: p = 0.034). There was no association between toxicity and the timing of RT delivery by season. In LA-NPC, the daytime of radical RT served as an independent prognostic factor. Furthermore, RT administered in the morning resulted in more severe toxic side effects than that at night, which needs to be confirmed in a future study.

Therapeutic hyperthermia regulates complement C3 activation and suppresses tumor development through HSPA5/NFκB/CD55 pathway in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is endemic in Southern China and Southeast Asia. Hyperthermia is widely used in combination with chemotherapy and radiotherapy to enhance therapeutic efficacy in NPC treatment, but the underlying anti-tumor mechanisms of hyperthermia remain unclear. Complement C3 has been reported to participate in the activation of immune system in the tumor microenvironment, leading to tumor growth inhibition. In this study, we aimed to explore the effect and mechanisms of hyperthermia and investigate the functional role of complement C3 in NPC hyperthermia therapy (HT). The serum levels of complement C3 before and after hyperthermia therapy in patients with NPC were analyzed. NPC cell lines SUNE1 and HONE1 were used for in vitro experiment to evaluate the function of complement C3 and HT on cell proliferation and apoptosis. SUNE1 xenograft mouse model was established and tumor-bearing mice were treated in water bath at a constant temperature of 43°C. Tumor samples were collected at different time points to verify the expression of complement C3 by immunohistochemical staining and western blot. The differential expressed genes after hyperthermia were analyzed by using RNA sequencing. We found that complement could enhance hyperthermia effect on suppressing proliferation and promoting apoptosis of tumor cells in NPC. Hyperthermia decreased the mRNA expression of complement C3 in tumor cells, but promoted the aggregation and activation circulating C3 in NPC tumor tissue. By using in vitro hyperthermia-treated NPC cell lines and SUNE1 xenograft tumor-bearing mice, we found that the expression of heat shock protein 5 (HSPA5) was significantly upregulated. Knockdown of HSPA5 abrogated the anti-tumor effect of hyperthermia. Moreover, we demonstrated that hyperthermia downregulated CD55 expression via HSPA5/NFκB (P65) signaling and activated complement cascade. Our findings suggest that therapeutic hyperthermia regulates complement C3 activation and suppresses tumor development via HSPA5/NFκB/CD55 pathway in NPC.

Fangchinoline exerts anticancer effects on colorectal cancer by inducing autophagy via regulation AMPK/mTOR/ULK1 pathway.

Autophagy has become a promising target for cancer therapy. Fangchinoline (Fan) has been shown to exert anticancer effects in some types of cancers. However, the anticancer effects on colorectal cancer (CRC) and the underlying mechanisms have never been elucidated. More specifically, regulation of autophagy in CRC by Fan has never been reported before. In the present study, Fan was found to induce apoptosis and autophagic flux in the CRC cell lines HT29 and HCT116, which was reflected by the enhanced levels of LC3-II protein and p62 degradation, and the increased formation of autophagosomes and puncta formation by LC3-II. Meanwhile, combination with the early-stage autophagy inhibitor 3-methyladenine (3-MA) but not the late-stage autophagy inhibitor chloroquine (CQ) further increased Fan-induced cell death, which suggested the cytoprotective function of autophagy induced by Fan in both HT29 and HCT116 cells. Moreover, Fan treatment demonstrated a dose- and time-dependently increase in the phosphorylation of AMPK and decrease in the phosphorylation of mammalian target of rapamycin (mTOR) and ULK1, leading to the activation of the AMPK/mTOR/ULK1 signaling pathway. Furthermore, in the HT29 xenograft model, Fan inhibited tumor growth in vivo. These results indicate that Fan inhibited CRC cell growth both in vitro and in vivo and revealed a new molecular mechanism involved in the anticancer effect of Fan on CRC, suggesting that Fan is a potent autophagy inducer and might be a promising anticancer agent.

Cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion for the treatment of gastric cancer: A single-centre retrospective study.

AIM: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemoperfusion (HIPEC) is the treatment regime most likely to achieve prolonged survival in patients with peritoneal carcinomatosis from gastroenteric cancer. To date, few publications have focused on the treatment of patients with gastric cancer alone. Several controversies remain unsolved, including the safety and effectiveness of the CRS-HIPEC combination regime, particularly in cases where HIPEC is used as adjuvant treatment after CRS. Therefore, in the current study, we aimed to evaluate the safety and effectiveness of CRS combined with HIPEC in patients with gastric cancer. METHOD: Data from 231 patients with a median age of 55.1 years treated with the CRS-HIPEC combination regime between January 2009 and December 2014 were retrospectively reviewed. All patients underwent the combination therapy (mean of 2.4 cycles per patient, range, 1 to 4 cycles). RESULTS: Median overall survival was 37.0 months, with 1-, 2- and 3-year survival rates recorded as 83.4%, 68.5%, and 38.7%, respectively. The serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199) were significantly decreased after combination therapy in the completeness of cytoreduction (CCR)-0 and CCR-1 groups, while no significant changes observed in marker levels were observed in the CC ≥2 group. The post-operative morbidity and mortality rates were 6.9% and 0.9%, respectively. Multivariate analysis revealed low TNM tumour stage, ascites condition and CCR score as independent predictors for better survival. CONCLUSION: In view of the acceptable morbidity and mortality rates we propose that CRS combined with HIPEC presents an effective and safe treatment modality for patients with gastric cancer, especially in cases where optimal cytoreduction is achieved before the HIPEC procedure.