The value of circulation tumor DNA in predicting postoperative recurrence of colorectal cancer: a meta-analysis.

PURPOSE: Surgical resection is the primary treatment for patients with nonmetastatic colorectal cancer (CRC). However, even after undergoing radical resection procedure, 30-50% of patients will still experience relapse. Circulation tumor DNA (ctDNA), deriving from tumor cells, is shed into the bloodstream and is a potential predictive biomarker of recurrence in CRC. This meta-analysis was performed to identify the clinical value of ctDNA in predicting the recurrence of CRC patients in post-operative. METHODS: PubMed, Embase, The Cochrane Library, and Web of Science were comprehensively searched to identify the studies that reported the function of ctDNA for predicting recurrence in CRC patients. The eligible studies were pooled to calculate the relative risk (RR) of recurrence in ctDNA positive and negative groups. The data of ctDNA on recurrence-free survival (RFS) were extracted and computed in hazard ratio (HR) and 95% confident interval (CI). Subgroup analyses were also performed. RESULTS: A total of 7 studies including 424 patients were included and analyzed in our meta-analysis. The results showed that pooled RR was 4.65 (95%CI: 2.68-8.08, P < 0.05), indicating ctDNA positive could predict the recurrence of CRC after curative surgical. The pooled HR demonstrated strong connection between ctDNA positive and RFS in patients with CRC (HR = 9.14, 95%CI: 4.02-20.75, P < 0.05). CONCLUSION: Evidence from the meta-analysis suggested that ctDNA is a promising potential biomarker for predicting postoperative recurrence of CRC. Given the inherent limitations of this study, we look forward to more well-designed clinical studies to validate and update this analysis in the future.

Qici Sanling decoction suppresses bladder cancer growth by inhibiting the Wnt/Β-catenin pathway.

Context: Bladder cancer, which has high recurrence, is one of the most deadly cancers in the world. Astragalus propinquus Schischkin (Fabaceae) and Sagittaria sagittifolia L. (Alismataceae) are important herbs reported to be effective in cancer therapy. Objective: The efficacy of QCSL (Qici Sanling decoction) in bladder cancer treatment was examined. Materials and methods: T24 cells were injected into the flanks of nude mice and the mice were randomly divided into five groups: control; 20 mg/kg XAV-939 (an inhibitor of the WNT/ß-catenin pathway); QCSL (100, 200, or 400 mg/kg). After 7 weeks, the mice were anaesthetised using isoflurane and the xenografts were excised to perform further experiments. Results: Both XAV-939 (tumour volume: 379.67 ± 159.92 mm3) and QCSL (796.18 ± 101.6 mm3) dramatically suppressed tumour growth comparing with control group (3612.12 ± 575.03 mm3). XAV-939 and QCSL treatments decreased cell proliferation from 56.3 ± 0.05% to 29.02 ± 0.07% and 37.51 ± 0.04%, respectively. In agreement, more infiltration of immune cells and pyknotic cells upon XAV-939 (apoptosis rates: 43.92 ± 0.03%) and QCSL (34.57 ± 0.04%) treatment comparing with control group (15.59 ± 0.03%) were observed. Furthermore, TUNEL staining of xenograft tumours illustrated more apoptotic cells upon XAV-939 and QCSL treatment. Mechanistically, XAV-939 and QCSL treatments significantly inhibited WNT/ß-catenin pathway in T24 xenograft tumours. Discussion and conclusions: Our findings give new insights into the role of QCSL in bladder cancer and explore potential mechanisms contributing to the therapeutic effects of QCSL in bladder cancer.

Inhibition of polypyrimidine tract-binding protein 3 induces apoptosis and cell cycle arrest, and enhances the cytotoxicity of 5- fluorouracil in gastric cancer cells.

BACKGROUND: Human polypyrimidine tract binding protein 3 (PTBP3) was first discovered in 1999 and has been well characterised as a differentiation regulator. However, its role in human cancer has rarely been reported. Our previous study revealed increased PTBP3 protein level in gastric cancer tissues. Downregulation of PTBP3 suppressed the proliferation and differentiation of gastric cancer cells in vivo. METHODS: PTBP3 mRNA levels in human gastric cancer and adjuvant non-tumour tissues were detected. Apoptosis and 5-FU effect were determined in PTBP3-silenced gastric cancer cells. Underlying molecular mechanisms were investigated. RESULTS: MRNA expression of PTBP3 was upregulated in gastric cancer tissues, especially in those at an advanced stage. PTBP3 silencing led to apoptosis, under which modulation of PTB and thereby switch of Bcl-x pre-mRNA splicing pattern might be an important mechanism. Further research found that inhibition of PTBP3 expression enhanced the chemosensitivity of gastric cancer cells towards 5-FU treatment. This was mediated by reduced expression of histone deacetylase 6 (HDAC6), which further inhibited the phosphorylation of Akt and the expression of thymidylate synthase (TYMS), the critical determinant of 5-FU cytotoxicity. CONCLUSIONS: PTBP3 might serve as a biomarker of gastric cancer or potential target for anti-cancer therapy.

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).

Construction of anoikis-related lncRNAs risk model: Predicts prognosis and immunotherapy response for gastric adenocarcinoma patients.

Background: Anoikis acts as a programmed cell death that is activated during carcinogenesis to remove undetected cells isolated from ECM. Further anoikis based risk stratification is expected to provide a deeper understanding of stomach adenocarcinoma (STAD) carcinogenesis. Methods: The information of STAD patients were acquired from TCGA dataset. Anoikis-related genes were obtained from the Molecular Signatures Database and Pearson correlation analysis was performed to identify the anoikis-related lncRNAs (ARLs). We performed machine learning algorithms, including Univariate Cox regression and Least Absolute Shrinkage and Selection Operator (Lasso) analyses on the ARLs to build the OS-score and OS-signature. Clinical subgroup analysis, tumor mutation burden (TMB) detection, drug susceptibility analysis, immune infiltration and pathway enrichment analysis were further performed to comprehensive explore the clinical significance. Results: We established a STAD prognostic model based on five ARLs and its prognostic value was verified. Survival analysis showed that the overall survival of high-risk score patients was significantly shorter than that of low-risk score patients. The column diagrams show satisfactory discrimination and calibration. The calibration curve verifies the good agreement between the prediction of the line graph and the actual observation. TIDE analysis and drug sensitivity analysis showed significant differences between different risk groups. Conclusion: The novel prognostic model based on anoikis-related lncRNAs we identified could be used for prognosis prediction and precise therapy in gastric adenocarcinoma.

Acacetin exerts antitumor effects on gastric cancer by targeting EGFR.

Background: Gastric cancer (GC) is a common malignant tumor with a poor prognosis. Combination treatments may prolong the survival of patients with GC. Acacetin, which is a flavonoid, exerts potent inhibitory effects on several types of cancer cells; however, the mechanisms of action remain poorly understood. Methods: Network pharmacology and RNA sequencing were used to predict the targets of acacetin, which were then verified by drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and molecular docking. The biological functions of acacetin in MKN45 and MGC803 cells were investigated using TUNEL assays, crystal staining and colony formation assays. The pathways affected by acacetin were verified through reverse experiments. The in vivo antitumor efficacy of acacetin was assessed in a subcutaneous xenotransplanted tumor model. Results: In this study, we identified EGFR from more than a dozen predicted targets as a protein that directly binds to acacetin. Moreover, acacetin affected the level of phosphorylated EGFR. In vitro, acacetin promoted the apoptosis of GC cells. Importantly, EGFR agonists reversed the inhibitory effects of acacetin on the STAT3 and ERK pathways. In vivo, acacetin decreased the protein levels of pEGFR in tumors, resulting in increased GC xenograft tumor regression without obvious toxicity. Conclusion: Our findings highlight EGFR as one of the direct targets of acacetin in GC cells. Acacetin inhibited the phosphatase activity of EGFR in vitro and in vivo, which played a role in the antitumor effects of acacetin. These studies provide new evidence for the use of acacetin as a potential reagent for the treatment of GC.

Prognostic Implications of LRP1B and Its Relationship with the Tumor-Infiltrating Immune Cells in Gastric Cancer.

BACKGROUND: Recent studies have shown that low-density lipoprotein receptor-related protein 1b (LRP1B), as a potential tumor suppressor, is implicated in the response to immunotherapy. The frequency of LRP1B mutation gene is high in many cancers, but its role in gastric cancer (GC) has not been determined. METHODS: The prognostic value of LRP1B mutation in a cohort containing 100 patients having received radical gastrectomy for stage II-III GC was explored. By analyzing the data of LRP1B mRNA, the risk score of differentially expressed genes (DEGs) between LRP1B mutation-type and wild-type was constructed based on the TCGA-STAD cohort. The infiltration of tumor immune cells was evaluated by the CYBERSORT algorithm and verified by immunohistochemistry. RESULTS: LRP1B gene mutation was an independent risk factor for disease-free survival (DFS) in GC patients (HR = 2.57, 95% CI: 1.28-5.14, p = 0.008). The Kaplan-Meier curve demonstrated a shorter survival time in high-risk patients stratified according to risk score (p < 0.0001). CYBERSORT analysis showed that the DEGs were mainly concentrated in CD4+ T cells and macrophages. TIMER analysis suggested that LRP1B expression was associated with the infiltration of CD4+ T cells and macrophages. Immunohistochemistry demonstrated that LRP1B was expressed in the tumor cells (TCs) and immune cells in 16/89 and 26/89 of the cohort, respectively. LRP1B-positive TCs were associated with higher levels of CD4+ T cells, CD8+ T cells, and CD86/CD163 (p < 0.05). Multivariate analysis showed that LRP1B-positive TCs represented an independent protective factor of DFS in GC patients (HR = 0.43, 95% CI: 0.10-0.93, p = 0.042). CONCLUSIONS: LRP1B has a high prognostic value in GC. LRP1B may stimulate tumor immune cell infiltration to provide GC patients with survival benefits.

Identifying HER2 from serum-derived exosomes in advanced gastric cancer as a promising biomarker for assessing tissue HER2 status and predicting the efficacy of trastuzumab-based therapy.

PURPOSE: This study aimed to evaluate the clinical relevance of exosomal HER2 (Exo HER2) level in assessing the tissue HER2 status and predicting the efficacy of trastuzumab treatment. METHODS: In this prospective study, patients with advanced gastric cancer (AGC) from three hospitals between August 2016 to November 2020 were enrolled. The Exo HER2 level was detected by enzyme-linked immunosorbent assay. Receiver operating characteristic curve (ROC) was drawn referring to the HER2 tissue status to assess the diagnostic value of Exo HER2. Cox proportional hazards regression and logistic regression were used to evaluate the association between Exo HER2 and progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients who received trastuzumab-based first-line therapy. RESULTS: In this study, 242 patients with advanced or metastatic gastric adenocarcinoma were registered. Of these, 238 AGC patients were eligible for evaluating serum-derived exosome HER2 diagnostic value, including 114 HER2-positive. Finally, 64 were eligible for efficacy analysis. The area under the ROC curve was 0.746. The optimal cutoff value for diagnosing tissue HER2-positive status was 729.95 ng/ml, with a sensitivity of 66.7% and a specificity of 74.2%. In 64 patients treated with trastuzumab, higher baseline Exo HER2 level indicated better prognosis. 844 ng/ml and 723 ng/ml were the right cutoffs for distinguishing the population with superior PFS (hazard ratio [HR] = 0.41, P = 0.017) and OS (HR = 0.30, P < 0.001), respectively. CONCLUSION: Serum exosomal HER2 level might serve as an effective biomarker for assessing tissue HER2 status in AGC and screening the potential patients who might benefit from anti-HER2 therapy.

Can Natural Products be Used to Overcome the Limitations of Colorectal Cancer Immunotherapy?

Colorectal cancer (CRC) is a common cancer of the digestive system that endangers human health. Immunotherapy is widely used in the treatment of patients with cancer. Some patients with dMMR/MSI-H CRC benefit from treatments that use immune checkpoint inhibitors, but most CRC patients are not sensitive to immunotherapy. Furthermore, internal resistance and immune escape lead to a reduced immunotherapy response. Therefore, the development of an effective combination therapy to improve the response rate to immunotherapy is a goal of cancer research. Natural products are potential candidates for comprehensive cancer treatments due to their wide range of immunomodulatory effects through multifactorial underlying mechanisms. In this review, we summarize the challenges in the treatment of CRC and assess the immunomodulatory effects of natural products and their active components. Our work suggests that natural products represent potential options for combined CRC immunotherapy.

New insights into natural products that target the gut microbiota: Effects on the prevention and treatment of colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignant carcinomas. CRC is characterized by asymptomatic onset, and most patients are already in the middle and advanced stages of disease when they are diagnosed. Inflammatory bowel disease (IBD) and the inflammatory-cancer transformation of advanced colorectal adenoma are the main causes of CRC. There is an urgent need for effective prevention and intervention strategies for CRC. In recent years, rapid research progress has increased our understanding of gut microbiota. Meanwhile, with the deepening of research on the pathogenesis of colorectal cancer, gut microbiota has been confirmed to play a direct role in the occurrence and treatment of colorectal cancer. Strategies to regulate the gut microbiota have potential value for application in the prevention and treatment of CRC. Regulation of gut microbiota is one of the important ways for natural products to exert pharmacological effects, especially in the treatment of metabolic diseases and tumours. This review summarizes the role of gut microbiota in colorectal tumorigenesis and the mechanism by which natural products reduce tumorigenesis and improve therapeutic response. We point out that the regulation of gut microbiota by natural products may serve as a potential means of treatment and prevention of CRC.

Acacetin inhibits invasion, migration and TGF-ß1-induced EMT of gastric cancer cells through the PI3K/Akt/Snail pathway.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a pivotal cellular phenomenon involved in tumour metastasis and progression. In gastric cancer (GC), EMT is the main reason for recurrence and metastasis in postoperative patients. Acacetin exhibits various biological activities. However, the inhibitory effect of acacetin on EMT in GC is still unknown. Herein, we explored the possible mechanism of acacetin on EMT in GC in vitro and in vivo. METHODS: In vitro, MKN45 and MGC803 cells were treated with acacetin, after which cell viability was detected by CCK-8 assays, cell migration and invasion were detected by using Transwell and wound healing assays, and protein expression was analysed by western blots and immunofluorescence staining. In vivo, a peritoneal metastasis model of MKN45 GC cells was used to investigate the effects of acacetin. RESULTS: Acacetin inhibited the proliferation, invasion and migration of MKN45 and MGC803 human GC cells by regulating the expression of EMT-related proteins. In TGF-ß1-induced EMT models, acacetin reversed the morphological changes from epithelial to mesenchymal cells, and invasion and migration were limited by regulating EMT. In addition, acacetin suppressed the activation of PI3K/Akt signalling and decreased the phosphorylation levels of TGF-ß1-treated GC cells. The in vivo experiments demonstrated that acacetin delayed the development of peritoneal metastasis of GC in nude mice. Liver metastasis was restricted by altering the expression of EMT-related proteins. CONCLUSION: Our study showed that the invasion, metastasis and TGF-ß1-induced EMT of GC are inhibited by acacetin, and the mechanism may involve the suppression of the PI3K/Akt/Snail signalling pathway. Therefore, acacetin is a potential therapeutic reagent for the treatment of GC patients with recurrence and metastasis.

Acupuncture improves chemotherapy-induced neuropathy explored by neurophysiological and clinical outcomes - The randomized, controlled, cross-over ACUCIN trial.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is recognized as the second commonest side effect after chemotherapy. Besides neurological deficits and pain, it is a potential reason for terminating chemotherapy. Effective curative treatments of neurodegeneration are lacking. Hitherto, no randomized controlled study used nerve conduction studies (NCS), the gold standard diagnostic tool for peripheral neuropathy, as the primary outcome parameter for evaluating acupuncture for CIPN, which can also measure structural changes. METHODS: The study was carried out at the HanseMerkur Center for TCM at the University Medical Center, Hamburg-Eppendorf. Sixty patients with CIPN were included in the study after physical examination, subjective evaluation and quantitative evaluation by NCS. Subsequently, the patients were randomly assigned to Group 1 (30 patients), which received, in the first period, needle acupuncture and to Group 2 (30 patients), which was assigned to the waiting list in the first period. Group 1 received a standard 10-week bilateral treatment of ST34 (Liangqiu), EX-LE12 (Qiduan) and EX-LE8 (Bafeng). After 14 weeks, both groups were re-evaluated. Using a cross-over design, the patients of Group 2 received the same treatment procedure as Group 1 in the first period. Patients of Group 1 were assigned to the waiting list for the second period. After 28 weeks both groups were re-evaluated. Wilcoxon test was used as a pre-test to rule out carryover effects and to test for differences between acupuncture and the waiting list. Group assignment was not exposed to the statistician and the neurologist. RESULTS: Sural sensory nerve amplitude, and sural nerve conduction velocity, were significantly improved (p < 0.01, effect size (f) 0.55 and 0.49) compared to measurements in the waiting period. Change of NCS of the tibial nerve did not significantly differ in group comparison. Patients reported subjective improvement during acupuncture treatment superior to the waiting period for burning pain, cramps, numbness, frequency of symptoms (all p < 0.01) and unsteadiness of gait (p < 0.05). On physical examination, blind walking, heel-to-toe walking, distal pallhypesthesia (both p < 0.01), and the neuropathy deficit score (p < 0.05) were significantly improved during acupuncture treatment compared to the waiting period. CONCLUSION: Acupuncture can enhance structural regeneration in CIPN as measured by NCS, which is manifested in subjective improvement and neurological findings.

Effects of traditional Chinese medicine collaborative model (TCMCM) combined with adjuvant chemotherapy on IIIb and IIIc gastric cancer: a protocol for a randomized controlled trial.

BACKGROUND: Metastasis and/or recurrence can decrease the survival time of gastric cancer patients undergoing radical operation. Among them, those with stage IIIb and IIIc are especially at a high risk of metastasis and recurrence. The traditional Chinese medicine collaborative model (TCMCM) has been used in the treatment of cancer; however, its effects have not been systematically evaluated. This study is designed to evaluate whether TCMCM can decrease adverse effects after chemotherapy and reduce the recurrence and metastasis of stage IIIb and IIIc gastric cancer. METHODS/DESIGN: This prospective, multicenter, randomized, open-label trial will recruit 260 patients with stage IIIb and IIIc gastric cancer who undergo radical surgery for D2 lymphadenectomy. The patients will be randomly assigned to receive usual adjuvant chemotherapy and TCMCM (intervention group) in a 1:1 ratio. Patients in the intervention group will receive an oral traditional Chinese formula, auricular acupressure, and acupoint therapy. All participants will receive usual adjuvant chemotherapy. The primary outcome is a 3-year disease-free survival rate. Secondary outcomes include quality of life, side effects caused by chemotherapy, and safety-related measures. Assessments will be performed during the screening period, at 4 and 8 cycles after adjuvant chemotherapy, and 9, 12, 18, 24, 30, and 36 months after randomization. Adverse events will be recorded. In addition, biological samples will be collected for mechanism analysis. DISCUSSION: This will be the first clinical trial to evaluate the effects of TCMCM on disease-free survival (DFS) and quality of life in patients with stage IIIb and IIIc gastric cancer. Our results may be used to standardize TCMCM. We will also perform a larger-scale clinical trial in the future. TRIAL REGISTRATION: ClinicalTrials.gov NCT03607656 . Registered on 1 July 2018. The final protocol version is V1.1.

METTL3 promotes colorectal carcinoma progression by regulating the m6A-CRB3-Hippo axis.

BACKGROUND: Colorectal carcinoma (CRC) is the third most common cancer and second most common cause of cancer-related deaths worldwide. Ribonucleic acid (RNA) N6-methyladnosine (m6A) and methyltransferase-like 3 (METTL3) play key roles in cancer progression. However, the roles of m6A and METTL3 in CRC progression require further clarification. METHODS: Adenoma and CRC samples were examined to detect m6A and METTL3 levels, and tissue microarrays were performed to evaluate the association of m6A and METTL3 levels with the survival of patients with CRC. The biological functions of METTL3 were investigated through cell counting kit-8, wound healing, and transwell assays. M6A epitranscriptomic microarray, methylated RNA immunoprecipitation-qPCR, RNA stability, luciferase reporter, and RNA immunoprecipitation assays were performed to explore the mechanism of METTL3 in CRC progression. RESULTS: M6A and METTL3 levels were substantially elevated in CRC tissues, and patients with CRC with a high m6A or METTL3 levels exhibited shorter overall survival. METTL3 knockdown substantially inhibited the proliferation, migration, and invasion of CRC cells. An m6A epitranscriptomic microarray revealed that the cell polarity regulator Crumbs3 (CRB3) was the downstream target of METTL3. METTL3 knockdown substantially reduced the m6A level of CRB3, and inhibited the degradation of CRB3 mRNA to increase CRB3 expression. Luciferase reporter assays also showed that the transcriptional level of wild-type CRB3 significantly increased after METTL3 knockdown but not its level of variation. Knockdown of YT521-B homology domain-containing family protein 2 (YTHDF2) substantially increased CRB3 expression. RNA immunoprecipitation assays also verified the direct interaction between the YTHDF2 and CRB3 mRNA, and this direct interaction was impaired after METTL3 inhibition. In addition, CRB3 knockdown significantly promoted the proliferation, migration, and invasion of CRC cells. Mechanistically, METTL3 knockdown activated the Hippo pathway and reduced nuclear localization of Yes1-associated transcriptional regulator, and the effects were reversed by CRB3 knockdown. CONCLUSIONS: M6A and METTL3 levels were substantially elevated in CRC tissues relative to normal tissues. Patients with CRC with high m6A or METTL3 levels exhibited shorter overall survival, and METTL3 promoted CRC progression. Mechanistically, METTL3 regulated the progression of CRC by regulating the m6A-CRB3-Hippo pathway.

Basic Characteristics, Status, and Challenges of Integrative Oncology in China.

Integrative oncology has developed for about 20 years in some countries; however, integrative oncology is still a relative new term for most China's oncologists. Thus, it is essential to summarize the experience and expertise, share details of differing existing models and discuss future perspectives to help define and guide practice in integrative oncology in China. This study presents a summary of the basic characteristics, status, and challenges of integrative oncology in China, and also reports on China's integrative physicians' service delivery, clinical practice and research patterns of integrative oncology by an online national survey, including 405 oncologists. It is easy for cancer patients to access to integrative therapies in China. Public funding is sufficient for integrative oncology in China, and services are often provided through general hospitals and academic hospitals. Most (95.3%) of oncologists showed a positive attitude toward the development of integrative oncology. More than half (55.6%) of the oncologists worried about the influence on integrative oncology of COVID-19, especially for routine treatment, follow-up and holding seminars. We found that integrative oncology in China has swiftly developed in recent years. However, we suggest that standard diagnosis and treatment patterns and national professional guidelines should be set up as soon as possible.

TP53 mutation and MET amplification in circulating tumor DNA analysis predict disease progression in patients with advanced gastric cancer.

BACKGROUND: Gastric cancer (GC) is a heterogeneous disease that encompasses various molecular subtypes. The molecular mutation characteristics of circulating tumor DNA (ctDNA) in advanced gastric cancer (AGC), especially the clinical utility of TP53 mutation and MET amplification in ctDNA need to be further explored. OBJECTIVES: The aim of this study was mainly to assess the clinical utility of TP53 mutation and MET amplification in ctDNA as biomarkers for monitoring disease progression of AGC. PATIENTS AND METHODS: We used multigene NGS-panel technology to study the characteristics of ctDNA gene mutations and screen the key mutant genes in AGC patients. The Kaplan-Meier method was used to calculate the survival probability and log-rank test was used to compare the survival curves of TP53 mutation and MET amplification in ctDNA of AGC patients. The survival time was set from the blood test time to the follow-up time to observe the relationship between the monitoring index and tumor prognosis. RESULTS: We performed mutation detection on ctDNA in 23 patients with AGC and identified the top 20 mutant genes. The five most frequently mutated genes were TP53 (55%), EGFR (20%), ERBB2 (20%), MET (15%) and APC (10%). TP53 was the most common mutated gene (55%) and MET had a higher frequency of mutations (15%) in our study. Kaplan-Meier analysis showed that patients with TP53 mutant in ctDNA had shorter overall survival (OS) than these with TP53 wild (P < 0.001). The Allele frequency (AF) of TP53 mutations in patient number 1 was higher in the second time (0.94%) than in the first time (0.36%); the AF of TP53 mutations in patient number 16 was from scratch (0∼0.26%). In addition, the AF of TP53 mutations in patients who survive was relatively low (P = 0.047). Simultaneously, Kaplan-Meier analysis showed that patients with MET amplification also had shorter OS than these with MET without amplification (P < 0.001). CONCLUSION: TP53 and MET are the two common frequently mutant genes in ctDNA of AGC patients.TP53 mutation and MET amplification in ctDNA could predict disease progression of AGC patients.

CircRNA_0084927 promotes colorectal cancer progression by regulating miRNA-20b-3p/glutathione S-transferase mu 5 axis.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related death worldwide. The 5-year survival rate of patients with early-stage CRC could reach 90%, but it is very low in patients with advanced-stage CRC. Recent studies have shown that circular RNAs play important roles in regulating the migration and invasion of CRC cells. AIM: To elucidate the role of circRNA_0084927 (circ_0084927) in the migration and invasion of CRC cells and its underlying mechanism. METHODS: Clinical tissue samples and cells were collected, and the expression of circ_0084927 was detected by quantitative polymerase chain reaction (qPCR). The diagnostic performance of circ_0084927 was assessed by receiver operating characteristic curve analysis. The role of circ_0084927 in CRC cell proliferation, migration, and invasion was determined using cell counting kit-8 assay, wound healing assay, and transwell assay, respectively. The regulatory relationship among circ_0084927, miRNA-20b-3p (miR-20b-3p), and glutathione S-transferase mu 5 (GSTM5) was identified using databases, luciferase reporter assay, qPCR, and Western blot analysis. AKT-mTOR signaling was also verified after circ_0084927 knockdown or miR-20b-3p mimic treatment. RESULTS: The expression of circ_0084927 was significantly increased in CRC tissues and cells, and it was higher in advanced-stage CRC compared with early-stage CRC. The area under the curve (AUC) of circ_0084927 was 0.806 [95% confidence interval (CI): 0.683-0.896]. In addition, the AUC was 0.874 (95%CI: 0.738-0.956) in patients with advanced-stage CRC and 0.713 (95%CI: 0.555-0.840) in those with early-stage CRC. Knockdown of circ_0084927 inhibited the migration and invasion of HCT116 cells. Moreover, circ_0084927 was found to act as a sponge of miR-20b-3p. MiR-20b-3p activation reduced the circ_0084927 level, whereas miR-20b-3p inhibition increased the circ_0084927 level. But the effect was not found after circ_0084927 mutation. In addition, miR-20b-3p expression in CRC patients was also reduced and negatively correlated with circ_0084927 expression. The function of circ_0084927 in HCT116 cells with circ_0084927 knockdown was rescued by miR-20b-3p. Moreover, GSTM5 expression was significantly decreased after overexpressing miR-20b-3p or inhibiting circ_0084927, but its expression was rescued when circ_0084927 and miR-20b-3p were both inhibited. Finally, AKT-mTOR signaling was markedly regulated by circ_0084927 and miR-20b-3p. CONCLUSION: The expression of circ_0084927 is significantly increased in CRC and higher in advanced-stage CRC than in early-stage CRC. Moreover, circ_0084927 potentially regulates CRC cell migration and invasion via the miR-20b-3p/GSTM5/ AKT/mTOR pathway.

[Survival time of advanced gastric cancer patients treated with integrated traditional Chinese and Western medicine therapy].

BACKGROUND: Advanced gastric cancer has a low survival rate while traditional Chinese medicine (TCM) therapy has effects in inhibiting tumor growth, lengthening survival time and improving the quality of life. OBJECTIVE: To analyze the effects of integrated traditional Chinese and Western medicine therapy on the survival time and quality of life of advanced gastric cancer patients. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: A total of 95 advanced gastric cancer patients were enrolled and divided into comprehensive group (48 cases) and control group (47 cases). The patients in the comprehensive group from the First Department of Oncology, Longhua Hospital, were treated with TCM therapy and chemotherapy based on the gastric cancer treatment guidelines made by the First Department of Oncology of Longhua Hospital, and the patients in the control group from Renji Hospital and Ruijin Hospital in Shanghai were treated with chemotherapy only. MAIN OUTCOME MEASURES: The survival time in the two groups were observed and compared. The Karnofsky score, body weight, the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) score, response rate and chemotherapy-related adverse events in the comprehensive group were observed. RESULTS: The estimated median survival time in the comprehensive group was 16.12 months, longer than 9.64 months in the control group (P<0.05). The scores of function and symptom of EORTC QLQ-C30 in the comprehensive group decreased, while the overall health status increased, and the results indicated that the quality of life of the patients in the comprehensive group was improved. In the comprehensive group, the body weight after treatment was higher than that before treatment (P=0.037), while there was no difference in Karnofsky scores between that before and after treatment (P=0.061). All the patients in the comprehensive group were assessable. The complete response rate was 0, 3 cases had a partial response, 34 cases had stable disease, and 11 cases had disease progression. The overall response rate was 6.25% (3/48), and the disease control rate was 77.08% (37/48). No patient withdrew because of severe adverse events and there was no chemotherapy-related death. CONCLUSION: Integrated traditional Chinese and Western medicine can prolong the survival time and improve the quality of life of advanced gastric cancer patients, and enhance the comprehensive effects.

[Clinical study on survival benefit for elderly patients with resected stage II or III colorectal cancer based on traditional Chinese medicine syndrome differentiation and treatment].

BACKGROUND: The incidence of colorectal cancer is high among the elderly. Traditional Chinese medicine (TCM) has been widely used in the treatment for colorectal cancer of old people. However, controlled trials with large sample size evaluating the effect of TCM are rare. OBJECTIVE: This research aimed to evaluate the survival benefit of using TCM syndrome differentiation treatment for elderly patients with stage II or III colorectal cancer. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: A total of 78 patients over 70 with resected stage II or III colorectal cancer were selected from the First Department of Oncology, Longhua Hospital of Shanghai University of Traditional Chinese Medicine, and Department of Anorectal Surgery, Changhai Hospital of Second Military Medical University. Patients were assigned to either integrated treatment group or Western medicine group by their own wills. MAIN OUTCOME MEASURES: Cox regression analysis was performed to determine all the potential factors which may affect prognosis such as gender, primary site, pathological type, TNM stage, chemotherapy period, radiotherapy and TCM therapy. RESULTS: A total of 78 cases were included in this study with 37 cases in integrated treatment group and 41 cases in Western medicine group. Cox regression analysis suggested that the TNM stage (P=0.001) and TCM therapy (P=0.021) were independent prognostic factors. The hazard ratio [Exp(ß)] of TCM therapy was 0.393, and 95% confidence interval (CI) was 0.178-0.870. Median disease-free survival (DFS) of Western medicine group was 41.293 months. DFS of integrated treatment group did not reach the median at the time of analysis. There was significant difference between the two groups (P=0.012). The 1-, 2-, 3-, 4-, and 5-year DFS rates of Western medicine group were 87.7 %, 69.6%, 63.4%, 46.5%, and 29.6%, respectively. The 1-, 2-, 3-, 4-, and 5-year DFS rates of integrated therapy group were 100%, 86.3%, 74.6%, 74.6%, and 74.6%, respectively. CONCLUSION: TCM syndrome differentiation and treatment is important for improving the prognosis of stage II or III colorectal cancer in elderly patients. Integrated treatment shows benefit for reducing relapse and metastasis rates, and prolonging survival for elderly patients. The influence of integrated treatment needs to be further evaluated.

[Survival benefit of an herbal formula for invigorating spleen for elderly patients with gastric cancer].

BACKGROUND: Gastric cancer is one of the most common malignant tumors. Traditional Chinese medicine (TCM) has been widely used in treatment of gastric cancer, but still lacking large sample controlled trial to evaluate its efficacy. OBJECTIVE: To analyze the prognostic factors of 220 elderly patients with gastric cancer, and to further study the efficacy of an herbal formula for invigorating spleen and it modifications based on syndrome differentiation of TCM in treatment of gastric cancer in elderly patients and the influence on prognosis. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: A total of 220 elderly patients aged 65 years or over with gastric cancer from Longhua Hospital of Shanghai University of Traditional Chinese Medicine, and Renji Hospital and Ruijin Hospital of Shanghai Jiao Tong University Medical College were prospectively enrolled. All patients were assigned to either traditional Chinese herbal medicine (TCHM) group (89 cases) or non-TCHM group (131 cases). Patients in the TCHM group were treated with an herbal formula for invigorating spleen plus chemotherapy, while patients in the non-TCHM group were only treated with chemotherapy. MAIN OUTCOME MEASURES: Univariate and Cox regression analyses were performed to determine all the potential prognostic factors. Kaplan-Meier curves were used to assess the differences in survival time between TCHM group and non-TCHM group after stratification for TNM stage, surgery or chemotherapy. RESULTS: The 220 eligible patients were histologically confirmed adenocarcinoma of the stomach from 2001 to 2007. Eighty-nine cases in the TCHM group received three or more months of TCHM treatment, and 131 cases in the non-TCHM group did not receive TCHM treatment. Cox regression analysis suggested that the TNM stage, radical resection, three or more treatment cycles of chemotherapy, and TCHM treatment were independent prognostic factors (P<0.01). The patients receiving TCHM treatment demonstrated better prognosis than the other prognostic factors in multivariate analysis; the odds ratio [Exp(beta)] of overall group was 0.322, and 95% confidence interval (CI) was from 0.212 to 0.489. Median overall survival of TCHM group was 41.129 months, and one-, three-, and five-year survival rates were 85.2%, 55.6% and 45.7% respectively. Median overall survival of non-TCHM group was 17.195 months, and one-, three-, and five-year survival rates were 63.9%, 26.9% and 21.9% respectively. In stratification analysis of stage for 96 patients who did not accepted radical resection or suffered from recurrence and metastasis (36 cases in the TCHM group, and 60 cases in the non-TCHM group), Cox regression analysis suggested that three or more treatment cycles of chemotherapy and TCHM treatment were independent prognostic factors for improving survival respectively (P<0.01). The hazard ratio [Exp(beta)] of TCHM in stratification for late stage was 0.421, and 95% confidence interval was from 0.255 to 0.693. Median overall survivals were 17.819 months for TCHM group and 8.548 months for non-TCHM group. In stratification analysis of surgery and chemotherapy for 102 patients with Ib-IV (M0) who accepted radical resection (R0 resection) and three or more treatment cycles of chemotherapy (33 cases in the TCHM group, and 69 cases in the non-TCHM group), the disease-free survival and overall survival did not reach the median at the time of analysis. In the TCHM group, one-, three-, and five-year disease-free survival rates were 97.0%, 59.9% and 50.4%, and one-, three-, and five-year survival rates were 100.0%, 74.1% and 61.4%, respectively. In the non-TCHM group, one-, three-, and five-year disease-free survival rates were 82.6%, 51.1% and 51.1%, and one-, three-, and five-year survival rates were 86.9%, 55.6% and 55.6%, respectively. CONCLUSION: The herbal formula for invigorating spleen has an important value for improving the prognosis of elderly patients with gastric cancer. This herbal formula show survival benefit for advanced gastric cancer in elderly patients. The influence of TCHM on disease-free survival and overall survival of postoperative gastric cancer in elderly patients need to be further evaluated.