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.

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).

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.

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.

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.

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.

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.

[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.

Survival analysis of 272 patients with pancreatic cancer undergoing combined treatment.

BACKGROUND: In China, traditional Chinese herbal medicine (TCHM) has been widely used for pancreatic cancer. This retrospective, matched case-control study aimed to assess factors affecting the survival time of patients with pancreatic cancer. METHODS: From 2004 to 2012, a total of 411 patients with pathologically confirmed pancreatic cancer were enrolled, and 272 patients were matched and divided into TCHM and non-TCHM groups (control group) based on received TCHM or not. The match was according to gender, age of onset, radiotherapy, and chemotherapy. Both groups received comprehensive treatments, the TCHM group simultaneously received the TCHM spleen-invigorating compound for more than 3 months. The Cox model was used for prognostic factor analysis and the Kaplan-Meier method for estimating median overall survival (OS) and disease-free survival (DFS). RESULTS: In 130 patients with advanced pancreatic cancer, COX analysis showed the Karnofsky Performance Scale (KPS; P = .000), radiotherapy (P = .003), and TCHM (P = .001) were independent prognostic factors for OS, with median OS of 12.7 and 9.9 months in TCHM and non-TCHM groups, respectively (hazard ratio [HR] = 0.520; 95% confidence interval [CI] = 0.353-0.766; P = .033). In 142 patients undergoing radical surgery, KPS (P = .000) and TCHM (P = .000) were independent prognostic factors for OS and DFS, median OS was 23.8 and 12.4 months in TCHM and non-TCHM groups, respectively (HR = 0.373; 95% CI = 0.251-0.554; P = .000), and the median DFS was 21.5 and 10.2 months in TCHM and non-TCHM groups, respectively (HR = 0.352; 95% CI = 0.237-0.522; P = .000). CONCLUSIONS: KPS was an important prognostic factor of pancreatic cancer. Spleen-invigorating compounds could have an effect on improving the prognosis of pancreatic cancer patients.

Survival benefit of traditional chinese herbal medicine (a herbal formula for invigorating spleen) in gastric cancer patients with peritoneal metastasis.

Objective. We evaluated the efficiency of traditional Chinese herbal medicine (a compound herbal formula for invigorating spleen) as a complementary and alternative therapy for gastric cancer patients with peritoneal metastasis. Methods. Between 2001 and 2012, 93 gastric cancer patients with peritoneal metastasis were enrolled in this study. The effect of traditional Chinese herbal medicine on their long-term outcome was investigated. Kaplan-Meier method was used to assess the difference in survival time, and Cox proportional hazards regression analysis was performed to identify independent prognostic factors. Result. First-line palliative chemotherapy plus traditional Chinese herbal medicine was performed in 47 patients and the other 46 patients received chemotherapy alone. The overall survival was different between patients with and without traditional Chinese herbal medicine (12.0 versus 10.5 months; P = 0.046). According to the Cox proportional hazard model, first-line chemotherapy cycle (hazards ratio [HR] = 0.527; 95% CI = 0.323~0.860) and TCHM (hazards ratio [HR] = 0.644; 95% CI = 0.481~0.992) were selected as independent prognostic factors for survival. Conclusion. The results suggest that traditional Chinese herbal medicine could improve the prognosis of the gastric cancer patients with peritoneal metastasis.