Chinese Medicine Prolongs Overall Survival of Chinese Patients with Advanced Gastric Cancer: Treatment Pattern and Survival Analysis of a 20-Year Real-World Study.

OBJECTIVE: To describe the treatment patterns and survival status of advanced gastric cancer (AGC) in China in the past two decades, and objectively evaluate the impact of standardized Chinese medicine (CM) treatment on the survival of AGC patients. METHODS: This multicenter registry designed and propensity score analysis study described the diagnosis characteristics, treatment-pattern development and survival status of AGC from 10 hospitals in China between January 1, 2000 and July 31, 2021. Overall survival (OS) was evaluated between non-CM cohort (standard medical treatment) and CM cohort (integrated standard CM treatment ≥3 months). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to adjust any difference in average outcomes for bias. RESULTS: A total of 2,001 patients histologically confirmed locally advanced and/or metastasis stomach and gastroesophageal junction adenocarcinoma were enrolled. Among them, 1,607 received systemic chemotherapy, 215 (10.74%) accepted molecular targeted therapy, 44 (2.2%) received checkpoint inhibitor therapy, and 769 (38.43%) received CM. Two-drug regimen was the main choice for first-line treatment, with fluoropyrimidine plus platinum as the most common regimen (530 cases, 60.09%). While 45.71% (16 cases) of patients with HER2 amplification received trastuzumab in first-line. The application of apatinib increased (33.33%) in third-line. The application of checkpoint inhibitors has increased since 2020. COX analysis showed that Lauren mixed type (P=0.017), cycles of first-line treatment >6 (P=0.000), CM (P=0.000), palliative gastrectomy (P=0.000), trastuzumab (P=0.011), and apatinib (P=0.008) were independent prognostic factors for the OS of AGC. After PSM and IPTW, the median OS of CM cohort and non-CM cohort was 18.17 and 12.45 months, respectively (P<0.001). CONCLUSIONS: In real-world practice for AGC in China, therapy choices consisted with guidelines. Two-drug regimen was the main first-line choice. Standardized CM treatment was an independent prognostic factor and could prolong the OS of Chinese patients with AGC. (Registration No. NCT02781285).

Clinical significance of circulating tumour cells and tumour marker detection in the chemotherapeutic evaluation of advanced colorectal cancer.

AIM: Systemic chemotherapy combining biological targeted therapies is the standard therapy for patients with metastatic colorectal cancer (mCRC), but effective markers are needed to identify clinical responders. Circulating tumour cells (CTCs) have been associated with prognosis in patients with mCRC. This study aimed to explore the relationship between CTC number and the clinical response of patients with advanced CRC. METHOD: Epithelial cell adhesion molecule-independent enrichment and CD45- fluorescence in situ hybridization immunofluorescence were used to detect peripheral blood CTCs in 79 patients with advanced CRC. Fisher's exact test and Spearman's rank correlation coefficient were used to analyse the correlation between CTC number and efficacy of chemotherapy. Kaplan-Meier and Cox regression analyses were used to evaluate progression-free survival (PFS). RESULTS: Among the evaluable patients, CTCs were significantly correlated with clinical response (r =4.891, p = 0.031). High CTC numbers were associated with a poor treatment response (r = -0.250, p = 0.027). Dynamic decrease in CTC number was associated with clinical response (p = 0.046). High baseline CTC number and carcinoembryonic antigen levels were prognostic factors for unfavourable PFS in multivariable analysis [hazard ratio (HR) = 3.30, p = 0.011 and HR = 2.04, p = 0.044, respectively]. Compared with the CTC-positive group, the CTC-negative group showed superior PFS (median PFS 15.53 vs. 9.43 months, p = 0.041) among CRC patients receiving first-line treatment. CONCLUSION: CTC number is a feasible biomarker for predicting outcomes in mCRC patients receiving systemic chemotherapy.

Chemotherapy-induced intestinal inflammatory responses are mediated by exosome secretion of double-strand DNA via AIM2 inflammasome activation.

Chemotherapies are known often to induce severe gastrointestinal tract toxicity but the underlying mechanism remains unclear. This study considers the widely applied cytotoxic agent irinotecan (CPT-11) as a representative agent and demonstrates that treatment induces massive release of double-strand DNA from the intestine that accounts for the dose-limiting intestinal toxicity of the compound. Specifically, "self-DNA" released through exosome secretion enters the cytosol of innate immune cells and activates the AIM2 (absent in melanoma 2) inflammasome. This leads to mature IL-1ß and IL-18 secretion and induces intestinal mucositis and late-onset diarrhoea. Interestingly, abrogation of AIM2 signalling, either in AIM2-deficient mice or by a pharmacological inhibitor such as thalidomide, significantly reduces the incidence of drug-induced diarrhoea without affecting the anticancer efficacy of CPT-11. These findings provide mechanistic insights into how chemotherapy triggers innate immune responses causing intestinal toxicity, and reveal new chemotherapy regimens that maintain anti-tumour effects but circumvent the associated adverse inflammatory response.

Co-expression of Lgr5 and CXCR4 characterizes cancer stem-like cells of colorectal cancer.

Therapies designed to target cancer stem cells (CSCs) in colorectal cancer (CRC) may improve treatment outcomes. Different markers have been used to identify CSCs or CSC-like cells in CRC, but the enrichment of CSCs using these markers has yet to be optimized. We recently reported the importance of Lgr5-positive CRC cells in cancer growth. Here, we studied the possibility of using Lgr5 and CXCR4 as CSC markers for CRC. We detected high Lgr5 and CXCR4 levels in stage IV CRC specimens. Both high Lgr5 and CXCR4 levels were associated with poor prognosis in stage IV CRC patients. In vitro, Lgr5+CXCR4-, CXCR4+Lgr5- and Lgr5+CXCR4+ cells were purified in human CRC cell lines and examined for their CSC properties. We found that compared to the unsorted cells, CXCR4+Lgr5-, Lgr5+CXCR4-, and Lgr5+/CXCR4+ cells showed significantly greater cancer mass after subcutaneous transplantation, greater tumor sphere formation, higher resistance to chemotherapy, and higher incidence of tumor formation after serial adoptive transplantation into NOD/SCID mice. Taken together, our data suggest that the combined use of Lgr5 and CXCR4 may facilitate the enrichment of CSCs in CRC, and that treating Lgr5+/CXCR4+ CRC cells may improve the outcome of CRC therapy.

Role of Lgr5-positive cells in colorectal cancer.

The molecular regulation of the growth of colorectal cancer (CRC) cells is not completely understood. Here, we report expression of Lgr5, a stem cell marker for the intestine and hair follicle, in some of the CRC cells in the patients. To determine the role of Lgr5-positive cells in the tumorigenesis of CRCs, we prepared an adeno-associated virus (AAV) that carries diphtheria toxin fragment A (DTA) under the control of Lgr5 promoter (AAV-pLgr5-DTA). Transduction of several CRC cell lines with this virus selectively killed Lgr5-positive cells, resulting in significant inhibition of the CRC cell growth in vitro and in vivo. Thus, our data highlight a potential role of Lgr5-positive cells in the tumorigenesis of CRCs, and suggest that treating these Lgr5-positive cells in CRCs may substantially improve the outcome of CRC therapy.

FBXL5 inhibits metastasis of gastric cancer through suppressing Snail1.

BACKGROUND/AIMS: The Snail family of transcription factors controls epithelial to mesenchymal transition (EMT), a process associated with tumorigenesis originated from epithelial cells. Snail1 is a member from Snail family and upregulation of Snail1 has been detected in gastric cancer (GC), suggesting a potential role of Snail1 in GC metastasis. We have recently reported that FBXL5 regulates cortactin by inducing its ubiquitylation and subsequent proteasomal degradation, resulting in inhibition of metastasis of GC. However, a role of FBXL4 in regulation of other EMT-associated proteins is not unknown. METHODS: The levels of FBXL5 and Snail1 as well as their relationship were determined in GC specimen. Co-immunoprecipitation (IP) was performed to detect the interaction between Snail1 and FBXL5 in GC cells. The effects on Snail1 by FBXL5 were examined by overexpression of depletion of FBXL5 in GC cells. The invasiveness of the FBXL5-modified GC cells was examined in both scratch wound healing assay and transwell matrix penetration assay. RESULTS: FBXL5 also physiologically interacted with Snail1. FBXL5 inhibited Snail1 to suppress GC cell invasiveness. CONCLUSION: FBXL5 negatively regulates several EMT-enhancing factors. FBXL5 is an attractive novel target for inhibiting invasion and metastasis of GC cells.

Meta-analysis comparing the safety and efficacy of metastatic colorectal cancer treatment regimens, capecitabine plus irinotecan (CAPIRI) and 5-fluorouracil/leucovorin plus irinotecan (FOLFIRI).

The relative efficacy and safety of first-line metastatic colorectal cancer (mCRC) treatment regimens, capecitabine with irinotecan (CAPIRI) and 5-fluorouracil/leucovorin plus irinotecan (FOLFIRI), are not well defined. We identified and subsequently examined seven independent, randomized controlled clinical trials, performing a meta-analysis to compare these two treatment regimens. Using Medline, EMBASE, Cochrane Library (CENTRAL), and the American Society of Clinical Oncology Annual Meeting to search available literature until February 2014, we identified seven studies comparing safety and efficacy of CAPIRI and FOLFIRI in mCRC patients. These studies were pooled and evaluated for rates of progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and diarrhea. CAPIRI and FOLFIRI demonstrated similar efficacy outcomes, though CAPIRI was associated with a higher incidence of diarrhea. CAPIRI and FOLFIRI are equally effective options for first-line treatment of mCRC.

FBXL5 targets cortactin for ubiquitination-mediated destruction to regulate gastric cancer cell migration.

Cortactin, an actin-interacting protein, is implicated in cytoskeletal architecture and often amplified in several types of cancer including gastric adenocarcinomas. Downregulation of cortactin decreases cell migration and invasion. However, how to regulate cortactin in gastric cancer remains largely unknown. Here, we report that FBXL5 interacts with and targets cortactin for ubiquitylation and subsequent proteasomal degradation. Furthermore, we showed that FBXL5-induced cortactin degradation is mediated by extracellular regulated signal kinase (ERK). Serine phosphorylation sites mutant, cortactinS405A/S418A, prevent FBXL5-induced cortactin degradation. Moreover, CortactinS405A/S418A exhibited stronger effects in promoting gastric cancer cell migration when compared to wild-type cortactin. Taken together, our data suggested a novel molecular mechanism for the negative regulation of cortactin by FBXL5 in gastric cancer cells migration.

Analysis of UGT1A1*28 genotype and SN-38 pharmacokinetics for irinotecan-based chemotherapy in patients with advanced colorectal cancer: results from a multicenter, retrospective study in Shanghai.

BACKGROUND: The UGT1A1*28 polymorphism, although closely linked with CPT-11-related adverse effects, cannot be used alone to guide individualized treatment decisions. However, CPT-11 dosage can be adjusted according to measured SN-38 pharmacokinetics. Our study is designed to investigate whether there is a relationship between SN-38 peak or valley concentrations and efficacy or adverse effects of CPT-11-based chemotherapy. We retrospectively studied 98 patients treated with advanced colorectal cancer in various UGT1A1*28 genotype groups (mainly (TA)6/(TA)6 and (TA)6/(TA)7 genotypes) treated with CPT-11 as first-line chemotherapy in Shanghai. METHODS: One hundred and sixty-four advanced colorectal cancer patients were enrolled. To understand differences in genotype expression, the frequency of UGT1A1*28 thymine-adenine (TA) repeats in TATA box arrangement was assessed by PCR with genomic DNA extracted from peripheral blood. For ninety-eight cases with the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes treated with CPT-11 as first-line chemotherapy, the plasma concentration of SN-38 was detected by HPLC 1.5 and 49 h after CPT-11 infusion. Efficacy and adverse effects were observed subsequently, and the relationship between SN-38 plasma concentration and efficacy or adverse effects within genotype groups, as well as differences in efficacy and adverse effects between (TA)6/(TA)6 and (TA)6/(TA)7 genotypes were analyzed statistically. RESULTS: One hundred and fourteen patients (69.51 %) were identified with the (TA)6/(TA)6 genotype, forty-eight patients (29.27 %) with the (TA)6/(TA)7 genotype, and two patients (1.22 %) with the (TA)7/(TA)7 genotype. The average peak and valley concentrations of SN-38 after CPT-11 infusion and plasma bilirubin average levels before and after CPT-11 treatment in the (TA)6/(TA)7 genotype group were all higher than those in (TA)6/(TA)6 group, and the difference was statistically significant (p = 0.00). Stepwise regression analysis showed that SN-38 peak and valley concentration was correlated with PFS in the (TA)6/(TA)6 genotype. In the (TA)6/(TA)7 group, SN-38 peak concentration was correlated with CPT-11 starting dose and OS, valley concentration correlated with plasma bilirubin levels before CPT-11 treatment, delayed diarrhea, and OS. For the (TA)6/(TA)6 genotype, mPFS of the SN-38 peak concentration >43.2 ng/ml subgroup was significantly longer than that of ≤43.2 ng/ml subgroup (8.0 ± 0.35 vs. 6.5 ± 0.79 months, χ (2) = 17.18, p = 0.00) with a relatively high incidence of Grade I/II° myelosuppression; for the (TA)6/(TA)7 genotype, there was no significant difference in mOS between the SN-38 valley concentration >16.83 ng/ml and ≤16.83 subgroups (17.3 ± 0.45 vs. 18.8 ± 0.50 months, χ (2) = 1.38, p = 0.24), but the former had a higher incidence of Grade III/IV° mucositis and delayed diarrhea. For 2 (TA)7/(TA)7 cases, although 25 % dose reduction of CPT-11, which is calculated according to body surface area, Grade IV° bone marrow suppression and Grade III° delayed diarrhea still occurred after CPT-11 treatment, though both adverse effects resolved and did not recur again after a 50 % dose reduction. CONCLUSION: The (TA)6/(TA)6 genotype and (TA)6/(TA)7 genotype accounted for the most, and (TA)7/(TA)7 genotype only account for a very small portion of advanced colorectal cancer patients in Shanghai. For the (TA)6/(TA)6 genotype, CPT-11 dosage can be increased gradually to improve efficacy for patients with SN-38 peak concentration ≤43.2 ng/ml after CPT-11 infusion; and for (TA)6/(TA)7 genotype patients, CPT-11 dosage may be lowered appropriately to reduce serious adverse effects such as bone marrow suppression and delayed diarrhea without affecting the efficacy for those with SN-38 valley concentration >16.83 ng/ml. For (TA)7/(TA)7 genotype patients, adverse effects should be closely observed after treatment even if CPT-11 dosage has been reduced.