Efficacy of immune checkpoint inhibitors combined with bevacizumab in MSS/pMMR advanced colorectal cancer after first-line treatment failure.

Objective: To investigate the effects of a PD-1 inhibitor combined with a bevacizumab monoclonal antibody on tumor immune cells in patients with first-line treatment failure in MSS/pMMR advanced colorectal cancer. Methods: Control group consisted of 50 patients treated with the FOLFIRI combined with Bevacizumab regimen. The experimental group consisted of 60 patients treated with the Sintilimab combined with Bevacizumab regimen. By comparing the expression levels of CD8+ T lymphocytes, TAMs, and CAFs before and after treatment, short-term efficacy after treatment, and adverse drug reactions between the two groups, we comprehensively evaluated the impact of Sintilimab combined with Bevacizumab on patients with MSS/pMMR advanced colorectal cancer who failed first-line treatment. Results: There was a statistically significant difference in the percentage of CD8+ T lymphocytes, TAMs, and CAFs before and after treatment between the two groups (P<0.05);Immunohistochemical scoring of CD8+ T lymphocytes, TAMs, and CAFs showed significant differences between the groups post-treatment (P<0.05). The experimental group demonstrated statistically significant differences in immunohistochemical scoring of CD8+ T lymphocytes, TAMs, and CAFs before and after treatment (P<0.05). There was a statistically significant difference in the therapeutic effect between the two groups of tumors (P<0.05). The experimental group had greater PFS, mPFS, ORR, and DCR than did the control group. There was no statistically significant difference in the occurrence rate of drug-related adverse reactions after treatment between the two groups (P>0.05). The results of the Cox proportional hazards model analysis indicate that age, gender, and group are independent risk factors affecting MSS/pMMR advanced colorectal cancer patients treated with second-line therapy in this study. Patients aged ≤60 years, male patients, and those in the experimental group showed better treatment responses in this study. Conclusion: By administering immune checkpoint inhibitors in combination with bevacizumab to patients with advanced colorectal cancer with MSS/pMMR disease for whom first-line treatment failed, not only did the patients' prognosis improve, but the adverse drug reactions were also safe and controllable.

Corrigendum: Comparison of clinical safety and feasibility between reduced-port laparoscopic radical gastrectomy and conventional laparoscopic radical gastrectomy: A retrospective study.

[This corrects the article DOI: 10.3389/fsurg.2022.995194.].

Comparison of clinical safety and feasibility between reduced-port laparoscopic radical gastrectomy and conventional laparoscopic radical gastrectomy: A retrospective study.

Background: Traditional open gastric cancer surgery has evolved from porous to reduced-hole, single-hole, or even natural cavity surgery to laparoscopic surgery, due to the continuous development of minimally invasive concepts and medical technologies, as well as awareness for the concept of rapid recovery. Conventional laparoscopic radical gastrectomy is quite mature in age at the moment, but how to progress to minimally invasive surgery without increasing the difficulty of surgery while ensuring clinical safety and feasibility is worth further investigation. Therefore, the clinical safety and feasibility of reduced port laparoscopic radical gastrectomy were assessed in this study. Methods: Information on the clinical data of patients undergoing laparoscopic radical gastric cancer surgery in a single centre between May 2020 and May 2022 was collected, and a total of 232 patients were included in this study according to the study protocol design. The clinical data of 232 patients with gastric cancer treated by two different surgical methods, namely, reduced port laparoscopic surgery (RPLS) or conventional laparoscopic surgery (CLS), were retrospectively analysed. The intraoperative indices, postoperative pathological indices, and short-term postoperative complications (within 30 days) of the two different surgical methods were evaluated, as well as the surgical methods' feasibility and short-term postoperative recovery effect. Results: There was no significant difference between the general data of patients with RPLS and CLS (P > 0.05). Compared with CLSG, the operation time, digestive tract reconstruction time and lymph node dissection time of RPLSG are shorter. The intraoperative blood loss was less, and the incision was minimally invasive (P < 0.05). In the short-term postoperative effect, the level of white blood cell count on the first day, the time of getting out of bed, the time of removing drainage tube, the time of hospitalization and the VAS of pain on the first, third and fifth days after operation, RPLSG was obviously superior to CLSG (P < 0.05). There was no significant difference between RPLSG and CLSG in terms of pathological indices (P > 0.05). Conclusions: The treatment of gastric cancer with RPLS has good safety, feasibility and short-term postoperative effects, which is in line with the implementation of the modern concept of rapid rehabilitation surgery.

Total laparoscopic versus laparoscopic-assisted transabdominal posterior mediastinal digestive tract reconstruction in the treatment of Siewert II adenocarcinoma of the esophagogastric junction: A retrospective study.

Background: The method of operation and the range of resection for Siewert II adenocarcinoma of the esophagogastric junction (AEG) remain controversial. This study aims to evaluate the safety, feasibility, and short-term postoperative effect of total laparoscopic versus laparoscopic-assisted transabdominal posterior mediastinal digestive tract reconstruction in the treatment of Siewert II AEG. Methods: Total laparoscopic or laparoscopic-assisted gastrointestinal reconstruction through abdominal posterior mediastinum was performed in 108 patients with Siewert II AEG from October 2017 to February 2019. This study evaluated the loss of intraoperative blood, the number of lymph nodes, the marginal of the tumor, short-term postoperative complications (within 30 days), the rate of survival at follow-up, and the economic cost, feasibility, and effect of short-term postoperative recovery for patients who received these two operations. Result: There were no significant differences in general data between the total laparoscopic group and the laparoscopic-assisted group (P > 0.05). However, the total laparoscopic group cost more time on the surgical procedure and digestive tract reconstruction, lost less intraoperative blood, and had more mediastinal lymph nodes compared with the laparoscopic-assisted group (P < 0.05). The total laparoscopic group was significantly better than the laparoscopic-assisted group compared with the short-term postoperative recovery indexes, such as the first exhaust time, the first defecation time, the first fluid time, the first semi-fluid diet time, the postoperative hospital stay, and other postoperative recovery indexes (P < 0.05). In addition, there were no significant differences in postoperative complications, postoperative pathological indexes, the recurrence rate, and mortality between the total laparoscopic group and laparoscopic-assisted group (P > 0.05). Conclusions: The safety, feasibility, and short-term effect of total laparoscopic transabdominal posterior mediastinal digestive tract reconstruction in the treatment of Siewert II AEG were better than those for the laparoscopic-assisted group.

Efficacy and Safety of Apatinib for Elderly Patients with Advanced or Metastatic Gastric Cancer After Failure of at Least First-Line Chemotherapy: A Multi-Center, Single-Arm, Phase II Study.

BACKGROUND: Apatinib improves progression-free survival and overall survival with an acceptable safety profile in Chinese patients with chemotherapy-refractory advanced or metastatic gastric cancer. However, the efficacy and safety of apatinib are unclear for elderly patients. This study was undertaken to prospectively investigate the efficacy and safety of apatinib for elderly patients with unresectable advanced or metastatic gastric cancer, who experienced progression to at least one lines of chemotherapy. METHODS: This open-label, single-arm, phase II study enrolled patients aged ≥60 years with advanced gastric cancer, who experienced progression to one or more lines of chemotherapy at five centers in China. Patients received apatinib in an oral dose of 500mg or 250mg daily according to the research physicians' decision. The primary end point was progression-free survival, and the secondary end points were objective response rate, disease control rate, overall survival, and safety. RESULTS: Forty-eight patients were enrolled between June 2017 and September 2019. The median age was 65.5 years (range 60-80 years). Twenty-seven patients (56.3%) started treatment with an initial dose of 500 mg and 21 patients (43.7%) with 250 mg. The median progression-free survival and overall survival were 3.00 months (95% confidence interval, 2.17-3.84) and 8.10 months (95% confidence interval, 4.35-11.85), respectively. The objective response rate and disease control rate assessed by the investigators were 16.7% and 72.9%, respectively. The common side effects were fatigue (58.3%), hypertension (47.9%), abdominal pain (33.3%), proteinuria (29.2%), leukopenia (22.9%), and neutropenia (20.8%). Hypertension (22.9%) was the major grade 3/4 toxicity. CONCLUSION: These data suggest that apatinib is effective and relatively tolerable for elderly patients with unresectable advanced or metastatic gastric cancer who have received at least first-line chemotherapy.

Prognostic significance of pre- and post-operative tumour markers for patients with gastric cancer.

BACKGROUND: In clinical practice, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 are the most common markers measured before and after surgery for gastric cancer (GC). However, which pre- or post-operative combined tumour markers (CEA and CA19-9) have more prognostic value remains unclear. METHODS: Consecutive patients undergoing a resection for GC at the Fujian Medical University Union Hospital were included as a discovery database between January 2011 and December 2014. The prognostic impact of pre- and post-operative tumour markers was evaluated using Kaplan-Meier log-rank survival analysis and multivariable Cox regression analysis. The results were then externally validated. RESULTS: A total of 735 and 400 patients were identified in the discovery cohort and in the validation cohort, respectively. Overall survival rates decreased in a stepwise manner in association with the number of pre- and post-operative positive tumour markers (both P < 0.001). Multivariable analysis revealed that the number of pre-operative positive tumour markers was an independent prognostic factor (P < 0.05). For patients with abnormal pre-operative tumour markers, normalisation of tumour markers after surgery is an independent prognostic protective factor (hazard ratio (HR) = 0.618; 95% confidence interval (CI) = 0.414-0.921), and patients with both positive post-operative tumour markers had double the risk of overall death (HR = 2.338; 95% CI = 1.071-5.101). Similar results were observed in the internal validation and external validation cohorts. CONCLUSION: Pre-operative tumour markers have a better discriminatory ability for post-operative survival in GC patients than post-operative tumour markers, and the normalisation of tumour markers after surgery was associated with better survival.

A comparison between triplet and doublet chemotherapy in improving the survival of patients with advanced gastric cancer: a systematic review and meta-analysis.

BACKGROUND: Chemotherapy can improve the survival of patients with advanced gastric cancer. However, whether triplet chemotherapy can further improve the survival of patients with advanced gastric cancer compared with doublet chemotherapy remains controversial. This study reviewed and updated all published and eligible randomized controlled trials (RCTs) to compare the efficacy, prognosis, and toxicity of triplet chemotherapy with doublet chemotherapy in patients with advanced gastric cancer. METHODS: RCTs on first-line chemotherapy in advanced gastric cancer on PubMed, Embase, and the Cochrane Register of Controlled Trials and all abstracts from the annual meetings of the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology conferences up to October 2018 were searched. The primary outcome was overall survival, while the secondary outcomes were progression-free survival (PFS), time to progress (TTP), objective response rate (ORR), and toxicity. RESULTS: Our analysis included 23 RCTs involving 4540 patients and 8 types of triplet and doublet chemotherapy regimens, and systematic review and meta-analysis revealed that triplet chemotherapy was superior compared with doublet chemotherapy in terms of improving median OS (HR = 0.92; 95% CI, 0.86-0.98; P = 0.02) and PFS (HR = 0.82; 95% CI, 0.69-0.97; P = 0.02) and TTP (HR = 0.92; 95% CI, 0.86-0.98; P = 0.02) and ORR (OR = 1.21; 95% CI, 1.12-1.31; P < 0.0001) among overall populations. Compared with doublet chemotherapy, subgroup analysis indicated that OS improved with fluoropyrimidine-based (HR = 0.80; 95% CI, 0.66-0.96; P = 0.02), platinum-based (HR = 0.75; 95% CI, 0.57-0.99; P = 0.04), and other drug-based triplet (HR = 0.79; 95% CI, 0.69-0.90; P = 0.0006) chemotherapies while not with anthracycline-based (HR = 0.70; 95% CI, 0.42-1.15; P = 0.16), mitomycin-based (HR = 0.81; 95% CI, 0.47-1.39; P = 0.44), taxane-based (HR = 0.91; 95% CI, 0.81-1.01; P = 0.07), and irinotecan-based triplet (HR = 1.01; 95% CI, 0.82-1.24; P = 0.94) chemotherapies. For different patients, compared with doublet chemotherapy, triplet chemotherapy improved OS (HR = 0.89; 95% CI, 0.81-0.99; P = 0.03) among Western patients but did not improve (HR = 0.96; 95% CI, 0.86-1.07; P = 0.47) that among Asian patients. CONCLUSIONS: Compared with doublet chemotherapy, triplet chemotherapy improved OS, PFS, TTP, and ORR in patients with advanced gastric cancer in the population overall, and improved OS in Western but not in Asian patients.

Clinicopathological Characteristics and Prognoses of Elderly Gastric Cancer Patients after R0 Resection: A Multicenter Study in China.

The number of elderly gastric cancer (GC) patients has been rapidly increasing worldwide, but inadequate understanding regarding elderly GC patients has led to the paucity of appropriate treatment decisions. Our study evaluates clinicopathological characteristics and prognoses of elderly GC patients after R0 resection. Overall, 1877 consecutive GC patients who underwent R0 gastrectomy at four centers were enrolled. We divided patients into three groups according to age: young, middle, and elderly. We then analyzed clinicopathological characteristics and prognoses. Compared to the middle-aged group, the elderly group had a higher male-to-female ratio and number of patients with cardiac GC, trend of more advanced pathological stage, lower ratio of poor to moderate tumor grade, and fewer patients who received adjuvant chemotherapy or chemoradiotherapy. Moreover, 5 yr disease-free survival and overall survival rates of elderly patients were significantly less than those of middle-aged patients. A Cox analysis of middle-aged and elderly patients revealed that age and adjuvant chemotherapy were independent prognostic factors. Adjuvant chemotherapy improved long-term survival of elderly patients with stage III cancer. Elderly GC patients who underwent R0 resection had unique characteristics and poor long-term survival. We found that subjects should be stratified into the three aforementioned age groups when analyzing survival rates of GC patients. In addition, reasonable adjuvant treatment is recommended for elderly patients.

Novel fluoropyrimidine-based chemotherapy for advanced well-differentiated neuroendocrine tumors: a clinical update.

INTRODUCTION: Patients with advanced well-differentiated neuroendocrine tumors (NETs) who have bulky and/or symptomatic and/or rapidly progressive disease require chemotherapy treatment. AREAS COVERED: This review summarizes the accumulating evidence for treatment with fluorouracil-based chemotherapy in well-differentiated NETs. The main clinical studies, toxicity and predictors of fluorouracil- based chemotherapy regimens in well-differentiated NETs are discussed, along with the current issues, future research directions and therapeutic prospects. EXPERT OPINION: Somatostatin analogs may control symptoms of hormone excess and tumor growth in patients with well-differentiated metastatic NETs, and biological therapies may improve progression-free survival for these patients. However, chemotherapy leads to higher objective response rates and symptom control by reducing tumor bulk. The low response rate and significant toxicities of conventional chemotherapy regimens limit their widespread use. Fortunately, some novel fluoropyrimidine-based treatment including fluorouracil, capecitabine, or S-1 based chemotherapy with or without antiangiogenic agents have been investigated in recent years. These treatments showed significant efficacy and less toxicity in pancreatic and non-pancreatic metastatic well-differentiated NETs. Additionally, non-pancreatic well-differentiated NETs have also achieved similar tumor response or survival comparable to pancreatic NETs. Moreover, some predictors of response to these treatment regimens have been evaluated.

Relationship between Topoisomerase II Alpha Overexpression and Prognosis in Chinese Gastric Cancer Patients.

The aim of this study was to investigate topoisomerase II alpha (TOP2α) overexpression and its association with clinicopathological features and prognosis in gastric cancer (GC) patients. All selected GC patients at Affiliated Hospital of Qinghai University and Cancer Hospital, Chinese Academy of Medical Sciences, between December 2009 and December 2011, had formalin-fixed and paraffin-embedded tumor tissues. The patients received a telephone follow-up or in-/outpatient review, and their clinicopathological features and prognoses were analyzed. Also, the relationship between TOP2α expression and postoperative chemotherapy in GC patients was estimated. The results of the study showed that TOP2α overexpression correlated with location of tumor, depth of invasion, and pTNM stage. Moreover, it was associated with lower 5-year overall survival (OS) in noncardia GC patients younger than 60 years, with multivariate analysis demonstrating that it was an independent prognostic factor for these patients. Univariate analysis and multivariate analysis showed that TOP2α overexpression was associated with worse 5-year OS in noncardia GC patients ≤ 60 years receiving postoperative chemotherapy. TOP2α overexpression exhibited associations with location of tumor, depth of invasion, pTNM stage, and postoperative chemotherapy, making it a potential target for early diagnosis of GC patients. In addition, TOP2α overexpression was shown to be a predictor of 5-year OS in both noncardia GC patients ≤ 60 years and noncardia GC patients ≤ 60 years and receiving postoperative chemotherapy.

Association of HER2 status with prognosis in gastric cancer patients undergoing R0 resection: A large-scale multicenter study in China.

AIM: To determine whether the positive status of human epidermal growth receptor 2 (HER2) can be regarded as an effective prognostic factor for patients with gastric cancer (GC) undergoing R0 resection. METHODS: A total of 1562 GC patients treated by R0 resection were recruited. HER2 status was evaluated in surgically resected samples of all the patients using immunohistochemical (IHC) staining. Correlations between HER2 status and clinicopathological characteristics were retrospective analyzed. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard model, stratified by age, gender, tumor location and tumor-node-metastasis (TNM) stage, with additional adjustment for potential prognostic factors. RESULTS: Among 1562 patients, 548 (positive rate = 35.08%, 95%CI: 32.72%-37.45%) were HER2 positive. Positive status of HER2 was significantly correlated with gender (P = 0.004), minority (P < 0.001), tumor location (P = 0.001), pathological grade (P < 0.001), TNM stage (P < 0.001) and adjuvant radiotherapy (74.67% vs 23.53%, P = 0.011). No significant associations were observed between HER2 status and disease free survival (HR = 0.19, 95%CI: 0.96-1.46, P = 0.105) or overall survival (HR = 1.19, 95%CI: 0.96-1.48, P = 0.118) using multivariate analysis, although stratified analyses showed marginally statistically significant associations both in disease free survival and overall survival, especially among patients aged < 60 years or with early TNM stages (I and II). Categorical age, TNM stage, neural invasion, and adjuvant chemotherapy were, as expected, independent prognostic factors for both disease free survival and overall survival. CONCLUSION: The positive status of HER2 based on IHC staining was not related to the survival in patients with GC among the Chinese population.

Cross-talk between EPAS-1/HIF-2α and PXR signaling pathway regulates multi-drug resistance of stomach cancer cell.

EPAS-1/HIF-2α (Endothelial PAS domain-containing protein 1/hypoxia-inducible transcription factors 2α) is a transcription factor expressed in a wide range of human cancers, including stomach cancer. Although EPAS-1 has been studied for years, its function in oncogenic transformation processes needs to be further investigated. In this study, we found that EPAS-1 would promote the growth of stomach cancer cell line BGC-823. Our results revealed that EPAS-1 interacts with Pregnane X Receptor (PXR), a nuclear receptor that regulates multiple genes' transcription involved in multi-drugs resistance (MDR) process. Protein-protein interaction between EPAS-1 and PXR was identified by co-immunoprecipitation and GST-pull down assays. By this interaction, EPAS-1 recruited PXR to its response elements in promoter/enhancer regions of CYP3A4, a PXR target gene. Over-expression of EPAS-1 increased the expression of PXR responsive genes, enhanced the proliferation of BGC-823 cells and boosted the resistance of BGC-823 cells against the cytotoxicity of chemotherapeutic drugs, e.g. Mitomycin C and Paclitaxel. Reduction of EPAS-1 level via its siRNA disrupted the proliferation, and enhanced the susceptibility of BGC-823 cells to those chemotherapeutic drugs. Our findings suggested that EPAS-1 and PXR may cooperatively participate in development and especially MDR process of stomach cancer. These findings may contribute to more effective targeted drugs discovery for the stomach cancer therapy.