Primary lesion radiotherapy during first-line icotinib treatment in EGFR-mutated NSCLC patients with multiple metastases and no brain metastases: a single-center retrospective study.

BACKGROUND: The most frequent mode of progression in the majority of non-small cell lung cancer (NSCLC) patients treated with  Epidermal growth factor - receptor tyrosine kinase inhibitors (EGFR-TKIs) is failure to respond to treatment at the primary lesion, suggesting that concurrent radiotherapy (CRT) to the primary lesion (CPRT) during first-line treatment with EGFR-TKI may be a novel therapeutic approach with a potential of additional benefit for metastatic NSCLC. Therefore, this study investigated the progression-free survival (PFS) and safety of CPRT during first-line icotinib treatment in NSCLC patients with EGFR mutations. METHODS: EGFR-mutant NSCLC patients diagnosed with limited multiple metastases were treated with first-line icotinib. The decision to treat the primary lesions with radiation largely depended on the patient's preference. The study endpoints included PFS, toxicity, progression pattern, and acquisition of the T790M mutation. RESULTS: The median PFS in the CPRT and Non-CPRT groups was 13.6 and 10.6 months (hazard ratio [HR] 0.23, 95% confidence interval [CI] 0.15-0.37, P < 0.001). Subgroup analysis showed that the results were statistically significant with 14.7 and 11.5 months for the 19del mutation (HR 0.20, 95% CI 0.10-0.40, P < 0.001) and 12.9 and 9.9 months for the L858R mutation (HR 0.25, 95% CI 0.13-0.48, P < 0.001). There were no reports of interstitial pneumonia associated with treatment at grade 4 or above. Patients who received CPRT during first-line icotinib treatment had the potential to decrease the primary lesion progression (P < 0.05) without increasing newly metastatic lesions (P > 0.05). The proportion of acquired T790M mutations was 26.7% and 45.7% in both groups (P > 0.05). CONCLUSION: This study suggests that CPRT is a viable option for patients with EGFR-sensitive mutations in NSCLC with limited multiple metastases during first-line icotinib treatment, which can significantly improve PFS with acceptable toxicities. Data on progression patterns and T790M mutations suggest the need to further investigate the benefits of radiation treatment from a molecular perspective.

Rhodium/Chiral-Diene-Catalyzed Switchable Asymmetric Divergent Arylation of Enone-Diones.

A rhodium/chiral diene catalytic system is reported for the reaction of enone-diones and arylboronic acids that allows the switchable synthesis of chiral bicyclic products and acyclic products in a controlled manner. The production of bicyclic products containing four contiguous stereocenters is assumed to proceed through the enantioselective arylrhodation of enone-diones with Cs2CO3, forming a rhodium-enolate intermediate, followed by desymmetrization of the diastereotopic diones via aldol cyclization with quantitative diastereoselection and excellent enantiomeric excess. The production of acyclic products is assumed to proceed through the enantioselective hydroarylation of enone-diones with excellent enantiomeric excess in which the aldol cyclization is significantly inhibited by the choice of Et3N as a base. The selectivity for bicyclic products (via tandem arylation-aldol cyclization) and acyclic products (via hydroarylation) is rationalized by the proposed model.

Hydroxychloroquine induced lung cancer suppression by enhancing chemo-sensitization and promoting the transition of M2-TAMs to M1-like macrophages.

BACKGROUND: Lysosome-associated agents have been implicated as possible chemo-sensitizers and immune regulators for cancer chemotherapy. We investigated the potential roles and mechanisms of hydroxychloroquine (HCQ) in combination with chemotherapy in lung cancer treatment. METHODS: The effects of combined treatment on non-small cell lung cancer (NSCLC) were investigated using cell viability assays and animal models. The influence of HCQ on lysosomal pH was evaluated by lysosomal sensors and confocal microscopy. The effects of HCQ on the tumour immune microenvironment were analysed by flow cytometry. RESULTS: HCQ elevates the lysosomal pH of cancer cells to inactivate P-gp while increasing drug release from the lysosome into the nucleus. Furthermore, single HCQ therapy inhibits lung cancer by inducing macrophage-modulated anti-tumour CD8+ T cell immunity. Moreover, HCQ could promote the transition of M2 tumour-associated macrophages (TAMs) into M1-like macrophages, leading to CD8+ T cell infiltration into the tumour microenvironment. CONCLUSIONS: HCQ exerts anti-NSCLC cells effects by reversing the drug sequestration in lysosomes and enhancing the CD8+ T cell immune response. These findings suggest that HCQ could act as a promising chemo-sensitizer and immune regulator for lung cancer chemotherapy in the clinic.

Associations between FAS rs2234767 and FASL rs763110 polymorphisms and the risk of lung cancer: a meta-analysis of 39,736 subjects.

BACKGROUND: Previous studies have investigated the associations between the common polymorphisms in FAS/FASL genes and lung cancer risk; however, the results remain inconsistent and inconclusive. Hence, we performed a meta-analysis to reassess the relationships between FAS rs2234767 and FASL rs763110 polymorphisms and the risk of lung cancer. METHODS: Eligible studies retrieved by an electronic search were pooled to calculate the strength of the associations using the odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: A total of 13 case-control studies involving 39,736 subjects (9,237 cases and 10,838 controls on FAS rs2234767 and 8,957 cases and 10,704 controls on FASL rs763110) were included in the meta-analysis. The results showed a significant association between FAS rs2234767 polymorphism and increased risk of lung cancer (A vs G: OR =1.07, 95% CI =1.01-1.13; AA vs GG: OR =1.23, 95% CI =1.06-1.43; AA vs GA + GG: OR =1.24, 95% CI =1.08-1.43). Similar association was also observed in Asian population (AA vs GA + GG: OR =1.30, 95% CI =1.01-1.67) and in the studies with large sample size (A vs G: OR =1.07, 95% CI =1.00-1.14; AA vs GG: OR =1.30, 95% CI =1.07-1.58). However, no significant association between FASL rs763110 polymorphism and lung cancer risk was found other than in the Asian population (CC vs TC + TT: OR =1.35, 95% CI =1.01-1.80). CONCLUSION: The meta-analysis indicated that FAS rs2234767 polymorphism was significantly associated with an increased risk of lung cancer and FASL rs763110 polymorphism may not contribute to susceptibility to lung cancer other than in Asian population.

Cyclooxygenase-2 polymorphisms and bladder cancer risk: a meta-analysis based on case-control studies.

The current meta-analysis incorporating 15 case-control studies involving 4,138 cases and 4,269 controls was performed on the basis of a systematical search in electronic databases for a more precise estimation on the associations of three common polymorphisms -765 G>C (rs20417), -1195G>A (rs689466) and +8473 C>T (rs5275) in Cyclooxygenase-2 (Cox-2) gene with the susceptibility to bladder cancer. The results showed that there was a significant association between rs5275 polymorphism and bladder cancer risk (C vs. T; OR=0.84; CC vs. TT: OR=0.76), especially among Chinese (CC vs. TC+TT: OR=0.48) and American (C vs. T; OR=0.83; TC vs. TT: OR=0.73; CC+TC vs. TT: OR=0.73). and the rs20417 polymorphism was significantly associated with an increased risk of bladder cancer among Chinese (C vs. G: OR=1.46; GC vs. GG: OR=1.49; CC+GC vs. GG: OR=1.51) and Indian (GC vs. GG: OR=1.63; CC+GC vs. GG: OR=1.46), but a reduced risk among American (C vs. G: OR=0.81; GC vs. GG: OR=0.76; CC+GC vs. GG: OR=0.76). Additionally, we found that the rs689466 polymorphism was associated with a decreased risk of bladder cancer in Indian (GA vs. GG: OR=0.68; AA vs. GG: OR=0.39).The present meta-analysis suggests that Cox-2 rs5275 polymorphism may contribute to the risk of bladder cancer, particularly among Chinese and American. The rs20417 polymorphism may play a protective role in the development of bladder cancer in Indian and Chinese but act as a risk factor among American, while the rs689466 polymorphism was more likely to be associated with a decreased risk of bladder cancer in Indian.