Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

BACKGROUND: The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. METHODS: Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m 2 docetaxel, 80 mg/m 2 oxaliplatin, 200 mg/m 2 calcium levofolinate, 2600 mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 21 (72.4%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2-89.2%), 78.8% (95% CI, 65.1-95.5%), and 70.9% (95% CI, 54.8-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3-93.1%) and 96.9% (95% CI, 84.3-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. CONCLUSIONS: The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.

Serum miR-191 and miR-425 as Diagnostic and Prognostic Markers of Advanced Gastric Cancer Can Predict the Sensitivity of FOLFOX Chemotherapy Regimen.

PURPOSE: miR-191 and miR-425 have been proved to be highly expressed in gastric carcinoma (GC). However, little research has been done on their clinical value in serum of patients with advanced GC. In addition, it is not clear whether they can be used as markers for the response and prognosis of GC patients treated with oxaliplatin combined with 5-fluorouracil and FOLFOX chemotherapy. PATIENTS AND METHODS: A total of 230 patients with advanced GC admitted to our hospital were selected as the study objects, all of whom received FOLFOX chemotherapy regimen. Another 100 cases of healthy subjects were included. QRT-PCR was employed to detect the serum expression of miR-191 and miR-425 in patients. RESULTS: Compared with the healthy subjects, the serum expressions of miR-191 and miR-425 in GC patients were significantly upregulated, which were correlated with differentiation degree and TNM staging, respectively. According to the ROC curve, the AUC of miR-191 and miR-425 for GC diagnosis was 0.937 and 0.901, respectively, while the AUC for differentiation degree diagnosis was 0.854 and 0.822, and that for TNM staging diagnosis was 0.860 and 0.829, respectively. The predictive AUC of miR-191 and miR-425 for chemosensitivity was 0.868 and 0.835, respectively, with a combined predictive AUC of 0.935. Low differentiation degree, high TNM staging, high miR-191 and high miR-425 expressions were independent risk factors for chemotherapy insensitivity. Differentiation degree, TNM staging, chemotherapy effect, miR-191 and miR-425 were independent influencing factors for the prognosis of GC patients. CONCLUSION: Up-regulated expression of miR-191 and miR-425 in the serum of patients with advanced GC are effective biomarkers for the diagnosis, chemotherapy and prognosis evaluation of GC.

Evaluation of PAX8 expression promotes the proliferation of stomach Cancer cells.

BACKGROUND: PAX8 was not only a mitotic factor, but identified as a transcription factor involved in the prognosis of human tumor patients. Elucidating the function of PAX8 on the pathology of stomach cancer was meaningful. RESULTS: PAX8 was found to be upregulated in primary stomach cancer tissue and the TCGA stomach cancer dataset. Interestingly, SOX13 and PAX8 showed consistent expression patterns, and the combined high PAX8 and SOX18 expression induced a worse prognosis of stomach cancer patients. SOX13 was further identified as a transcription factor of PAX8, and further affect Aurora B and Cyclin B1 expression, two cell cycle related factors of the downstream of PAX8, including. Furthermore, PAX8 depletion inducted G1-phase arrest and the decrease of EdU incorporation, cell viability and colony formation can be rescued by SOX13 overexpression. CONCLUSIONS: SOX13 participated in the elevated expression of PAX8, which promote the proliferation of stomach cancer cells. Therefore, SOX13 mediated PAX8 expression was recognized as a tumor-promoting role in stomach cancer.

Lymph Node Ratio as an Alternative to the Number of Metastatic Lymph Nodes for the Prediction of Esophageal Carcinoma Patient Survival.

BACKGROUND: The prognostic value of metastatic lymph node ratio (LNR) is still controversial in esophageal cancer. AIM: This study aimed to compare the impact of AJCC N staging system (pN) and LNR on the prediction of long-term survival of patients with esophageal carcinoma. METHODS: A total of 496 patients were retrospectively analyzed who underwent esophageal resection at Henan Tumor Hospital from January 2006 to December 2010. The Kaplan-Meier method and log-rank test were used to estimate survival curves. Univariate and multivariate analyses were performed to compare prognostic factors for long-term survival. The difference between pN and LNR with overall survival (OS) was compared by receiver operating characteristic (ROC) curve and area under the curve (AUC). RESULTS: The 1-, 3-, 5-year overall survival rates of 496 patients were 73.6, 47.1 and 34.2 %, respectively. Univariate analyses showed that diseased region, tumor length, depth of tumor invasion, pN and LNR affected the prognosis, and multivariate analyses demonstrated that depth of tumor invasion, pN and LNR were independent risk factors. Among the three significant variables verified by multivariate analyses, LNR was the best for inadequately staged patients (<12 examined LNs). ROC analyses showed that compared with pN (AUC = 0.579, p = 0.037), LNR (AUC = 0.680, p = 0.002) had better predictive value (z = 2.275, p = 0.029). CONCLUSIONS: LNR has greater prognostic value than pN for esophageal squamous cell carcinoma, especially for patients with <12 LNs removed.

Clinical observation and therapeutic evaluation of intravenous pump of recombinant human endostatin combined with TP regimen in treating patients with advanced ovarian cancer.

OBJECTIVES: To observe the curative effects and adverse reactions of recombinant human (rh)-endostatin injection combined with a TP regimen for treating patients with advanced ovarian cancer. METHODS: Fifty-four patients with pathologically confirmed ovarian cancer were randomly divided into a combined treatment (intravenous pump of rh-endostatin + TP regimen) group and a control (single chemotherapy) group, twenty-seven patients in each group. All patients were given a conventional CT examination. The level of vascular endothelial growth factor (VEGF), the size of tumor before treatment, after 2 cycles and after 4 cycles of treatment were determined for the comparison of curative effects and adverse reactions. RESULTS: The effective rate was 37.0% (10/27) and disease control rate was 63.0% (17/27) in the combined treatment group after 2 cycles of treatment. The effective rate was 25.9% (7/27) and disease control rate was 63.0% (17/27) in the control group. The comparison between these two groups showed no significant differences (P > 0.05). The effective rate was 63.0% (17/27) and disease control rate was 92.6% (25/27) in the combined treatment group after 4 cycles of treatment. The effective rate was 29.6% (8/27) and disease control rate was 63.0% (17/27) in the control group. The effective rate and disease control rate between these two groups after 4 cycles of treatment showed significant differences (P < 0.05). The incidences of cardiovascular toxicity, myelosuppression, sore muscles and joints, alopecia and gastrointestinal reaction was not significantly different between two groups (P > 0.05). CONCLUSION: The pump delivery of rh-endostatin can down-regulate the expression of VEGF in ovarian cancer and has the better curative effect and slighter adverse reactions.

Phosphorylated insulin-like growth factor-1 receptor expression predicts poor prognosis of Chinese patients with gastric cancer.

Previous studies have established the role of phosphorylated form of insulin-like growth factor type 1 receptor (p-IGF1R) as a good candidate for tumor biomarker. The aims of this study were to investigate p-IGF1R expression status in gastric cancer (GC) specimens and to clarify its clinical significance. A total of 78 GC patients treated with radical resection were enrolled in this study. Immunohistochemistry was used to detect p-IGF1R and phosphatase and tensin homolog deleted on chromosome ten (PTEN) protein expression in paired tumor and adjacent normal tissues. Results showed a higher level of p-IGF1R protein expression in tumor tissues than that in normal tissues, and the rate of p-IGF1R protein high/moderate expression in GC and normal tissues was 52.6% (41/78) and 6.4% (5/78), respectively (p < 0.001). In contrast, PTEN protein expression was downregulated in GC, as compared with normal tissues (negative/low expression 49/78 vs. 8/78, p < 0.001). Moreover, PTEN protein downregulation was consistent with p-IGF1R upregulation. Overexpression of p-IGF1R protein was associated with lymph metastasis, clinical stage, and adverse 3-year progression-free survival (PFS). Survival analysis and Cox proportional hazards model revealed that p-IGF1R overexpression was an independent factor in predicting PFS for GC patients, apart from lymph metastasis. In conclusion, p-IGF1R is highly expressed in GC, which may be a novel biomarker to predict the clinical outcome of GC patients.

Clinical observation and therapeutic evaluation of Rh-endostatin combined with DP regimen in treating patients with advanced esophageal cancer.

OBJECTIVE: To observe the curative effects of rh-endostatin combined with DP regimen in treating patients with advanced esophageal cancer and analyze the correlation of CT perfusion (CTP) parameters and the expression of vascular endothelial growth factor (VEGF). METHODS: Twenty patients with esophageal cancer confirmed pathologically were randomly divided into combined treatment (rh-endostatin+DP regimen) group and single chemotherapy group, 10 patients in each group, respectively. All patients were given conventional CT examination and CTP imaging for primary tumor. The level of VEGF, the size of tumor and CTP parameters (BF, BV, PS and MTT) before treatment and after 2 cycles of treatment were determined for the comparison and the correlation between CTP parameters and VEGF expression was analyzed. RESULTS: the therapeutic effect of rh-endostatin+DP regimen group was superior to single chemotherapy group. VEGF level after treatment in rh- endostatin +DP regimen group was obviously lower than single chemotherapy group (P<0.01). The expression of VEGF had positive correlation with BF and BV but negative correlation with MTT. Compared with treatment before for rh-endostatin +DP regimen group, BF, BV and PS decreased while MTT increased after treatment (P<0.05). However, there were no significant differences between treatment before and after treatment in single chemotherapy (P>0.05). CONCLUSIONS: Rh-endostatin can down-regulate the expression of VEGF in esophageal cancer, change the state of hypertransfusion and high permeability of tumor vessels and had the better curative effect and slighter adverse reactions when combined with chemotherapy.

MicroRNA-146a rs2910164 G/C polymorphism and gastrointestinal cancer susceptibility: a meta-analysis based on East Asian population.

OBJECTIVE: The relationship between microRNA (miR-146a) rs2910164G/C polymorphism and gastrointestinal cancer susceptibility is not consistent with each other of the published articles. The aim of this meta-analysis was to acquire a more precise effect of the association between the miR-146a rs2910164 G/C polymorphism and gastrointestinal cancer. MATERIALS AND METHODS: Through searching of the MedLine, Embase, China National Knowledge Infrastructure, and Wanfang databases. Case-control or cohort studies about the relationship between miR-146a rs2910164 G/C polymorphism and gastrointestinal cancer susceptibility were screened and included in this meta-analysis. Quantitative data synthesis was conducted for the associations of miR-146a rs2910164 G/C polymorphism and gastrointestinal cancer risk by statistical software STATA-11.0. RESULTS: Ten studies including 6473 gastrointestinal cancer patients and 7923 controls were identified and included in this meta-analysis. For recessive genetic model (CC vs. CG + GG), people with CG or GG is associated with the susceptibility of gastrointestinal cancer compared with genotype of CC (R = 0.73, 5% confidence interval [CI]: 0.55-0.97, [P = 0.03]); But for dominant model (CC + CG vs. GG) and homozygous model (CC vs. GG), no association of the miR-146a rs2910164G/C polymorphism and gastrointestinal cancer susceptibility were found (dominant: Odds ratio [OR] =0.94, 95% CI: 0.82-1.03, [P = 0.37]; homozygous: OR = 0.85, 95% CI: 0.71-1.03, [P = 0.10]). Sub-group analysis, for homozygous model, people with GG genotype had increased risk of developing colorectal cancer (OR = 0.77, 95% CI: 0.64-0.93, [P = 0.008]). CONCLUSION: No significant association between miR-146a rs2910164G/C polymorphism and gastrointestinal cancer susceptibility was found in this meta-analysis. But for homozygous model, people with GG genotype may have increased risk of developing colorectal cancer.

Molecular mechanism of indirubin-3'-monoxime and Matrine in the reversal of paclitaxel resistance in NCI-H520/TAX25 cell line.

BACKGROUND: Multidrug resistance (MDR) is a main reason for paclitaxel (TAX) treatment failure. Indirubin-3'-monoxime (IRO) and Matrine are traditional Chinese medicines, which may reverse the resistance of tumor cells to some chemotherapy drugs, but the relationship between paclitaxel resistance and Matrine is still unclear. The aim of this study was to explore the potential molecular mechanism of IRO and Matrine in reversal of TAX resistance. METHODS: In this study, MTT assay was used to measure the non-cytotoxic dosage of IRO and Matrine on NCI-H520/TAX25 cells and determine the reversal extent of TAX resistance under non-toxic doses. In addition, RT-PCR and Western blotting were used to evaluate the mRNA expression and the protein level of survivin, Oct-4, and Sox-2 in NCI-H520/TAX25 cells using semi-quantitative methods. RESULTS: There was no obvious inhibition on sensitive cell strains and drug-resistant strains, when the final concentration was at lest 4 µmol/L for IRO and 100 µmol/L for Matrine. So 4 µmol/L of IRO and 100 µmol/L of Matrine were considered as the reversal dosage. When 4 µmol/L of IRO or 100 µmol/L of Matrine were used together with TAX, the sensitivity to TAX increased evidently in NCI-H520/TAX2 cells; the reversal rate of IRO and Matrine was about 1.92 (43.56/22.6 nmol/L) and 1.74 (43.56/25.0 nmol/L), respectively. The mRNA expression and the protein level of survivin, Oct-4, and Sox-2 in NCI-H520/TAX25 decreased significantly (P < 0.05) after addition of IRO or Matrine in TAX treatment, compared to that of TAX treatment alone. CONCLUSION: The decrease in both mRNA expression and protein level of survivin, Oct-4, and Sox-2 might be the molecular mechanism, by which IRO and Matrine mediate the reversal of TAX resistance.

[The study of anti-tumor effect of Tetrandrine combined with Nedaplatin on human liver cancer cell line 7402].

OBJECTIVE: To study the anti-tumor effect of Tetrandrine (Tet) combined with Nedaplatin (Nap) on the human liver cancer cell line 7402, and explore its mechanism. METHODS: Human liver cancer line 7402 was treated by Tet and Nap in various concentrations respectively or in combination in vitro,and then the cell growth was assayed by MTT method, periodic return changes were observed by aridine orange (AO)-/ethidiumbromide (EB) fluorescent staining, DNA gel eledtophoresis and flow cytometry, and the expression of apoptosis-related genes were analyzed by immunohistochemical staining method. RESULTS: Compared with Tet or Nap individual drug groups, Tet combined with Nap obviously increased the inhibitatory rate and apoptosis rate of the human liver cancer cell line 7402. The cell cycle distribution was altered and ratio of S phase and G2/M phase cell increased following the treatment with Tet combined with Nap, with Bcl-2 gene expression down-regulated, and BAX gene expression up-regulated. CONCLUSION: Tet combined with Nap can obviously increase apoptosis-inducing effect, and its mechanism may be regulating cell cycle and increasing apoptosis-inducing effect which is regulated by several genes.