The Durable Effect of Pyrotinib Plus Trastuzumab and Chemotherapy in HER2-Positive Gastric Cancer With Brain Metastases: A Case Report and Literature Review.

Gastric cancer (GC) is a disease with macromolecular phenotypic heterogeneity and poor prognosis, especially for metastatic GC (mGC). Chemotherapy is the first choice for second-line treatment. However, the benefits of second-line chemotherapy are limited, so there is an urgent need for new treatment regimens to improve patient outcomes. A 65-year-old man with mGC was HER-2 positive. Standard trastuzumab, combined with chemotherapy, was given in the first-line therapy and progression-free survival (PFS) was 8 months. Second-line treatment with pyrotinib in combination with trastuzumab and chemotherapy yielded a PFS of 20 months, in sharp contrast to a median survival of 2.9-6.2 months for a majority of advanced GC patients. This case provides a meaningful reference for the second-line treatment of mGC patients with HER-2 positive. This case also provides valuable information on the response to pyrotinib plus trastuzumab of patients with brain metastases and a better understanding of dual target combination therapy applications in the future.

Effects of the Notch1 signaling pathway on human lung cancer A549 cells.

PURPOSE: To evaluate the effects of the Notch1 signaling pathway on human lung cancer A549 cells. MATERIALS AND METHODS: A549 cells were transfected with recombinant plasmids. Cell proliferation was detected by MTT assay. A tumor-bearing mouse model was established for intratumoral gene injection. Apoptosis-related factors were detected by immunohistochemical assay. Caspase-8, caspase-3, caspase-9, PI3K, pAkt and pSTAT3 expressions were detected by Western blotting. RESULTS: Compared with A549-GFP and A549 cells, A549-ICN cell growth in mice decelerated, tumor volume significantly reduced (p < 0.01), and survival time significantly increased (p < 0.05). Cyclin E and phosphorylated Rb protein expressions were significantly down-regulated. Compared with control, apoptosis-related protein Bcl-2 expression in tumors injected with Notch1 gene was significantly inhibited. After Deltex1 transfection, A549 cell proliferation decelerated, growth was significantly inhibited (p < 0.05), and survival time was significantly extended (p < 0.05). Cyclin E and mutant p53 protein expressions in tumors were down-regulated, phosphorylated Rb expression was almost completely inhibited, and Bcl-2 expression was significantly inhibited. TNF-α-related apoptosis-inducing ligand (TRAIL) inhibited A549-ICN cell growth time- and dose-dependently. After treatment for 24 h or longer, TRAIL induced apoptosis of more A549-ICN cells. Cleaved caspase-3 and cleaved caspase-9 were detected only in A549-ICN cells after 6 h of 40 ng/mL TRAIL treatment, but cleaved caspase-8 was not detected. Combining Notch1 signal with TRAIL inhibited PI3K, phosphorylated Akt and phosphorylated STAT3 expressions. CONCLUSION: The Notch1 signaling pathway may inhibit A549 cell growth in vitro and in vivo by regulating cell cycle-related and anti-apoptotic protein expressions. Notch1 activation also suppressed A549 cell apoptosis by inhibiting the PI3K/pAkt pathway and activating the caspase-3 pathway in cooperation with TRAIL.

Role of the stromal cell derived factor-1/CXC chemokine receptor 4 axis in the invasion and metastasis of lung cancer and mechanism.

BACKGROUND: Lung cancer is the most common tumor, and has the highest incidence and mortality rates among all malignant tumors. Since stromal cell derived factor-1 (SDF-1) and CXC chemokine receptor 4 (CXCR4) are specific to binding sites, they are more important than other members of the families for tumor invasion and metastasis. We herein aimed to investigate the role of the axis of chemokine SDF-1 and its receptor CXCR4 in the invasion and metastasis of lung cancer. METHODS: Sixty clinical non-small cell lung cancer (NSCLC) tissue samples were collected. The CXCR4 expressions in cancer, paracancerous and normal lung tissues were detected by immunocytochemical assay and PCR. Cells with CXCR4 overexpression (CXCR4-A549) were constructed. After induction with SDF-1, CXCR4-A549 and A549 cells were subjected to in vitro chemotaxis and invasion assays. Their proliferation and apoptosis were detected by flow cytometry. The activities of phosphoinositide 3-kinase/protein kinase B (AKT) and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK)-related signaling pathways were detected by Western blot. The downstream signaling molecules that may be activated by SDF-1/CXCR4 were analyzed. The expressions of vascular endothelial growth factor-C and matrix metalloproteinase-2 were detected by Western blot and PCR. A mouse model was established by subcutaneous inoculation of lung cancer cells. The effects of up-regulated CXCR4 expression on the migration of lung cancer cells in vitro and their tumorigenesis and metastasis in vivo were assessed. RESULTS: There was no expression in normal or paracancerous tissues. The expression of CXCR4 mRNA in lung cancer tissues was 83.3% (50/60). The expressions of CXCR4 in lung squamous cell carcinoma and adenocarcinoma were similar (P>0.05). The expression of CXCR4 was 76.9% (10/13) in highly differentiated carcinoma, 82.1% (23/28) in moderately differentiated carcinoma and 84.2% (16/19) in lowly differentiated carcinoma (P>0.05). The expression of CXCR4 was 72.7% (8/11) in TNM stage I patients, 83.9% (26/31) in stage II patients, and 88.9% (16/18) in stage III patients, with significant correlations. After up-regulation of CXCR4, the invasion ability of CXCR4-A549 cells was increased 1.62-fold (P<0.05). ERK and AKT were significantly phosphorylated 30 min after SDF-1 treatment. The tumorigenic rates of six mice inoculated with CXCR4-A549 and A549 cells were both 100%, with the average tumor weights of (4.37±0.96 g) and (3.24±1.16 g) respectively (P<0.05). In the CXCR4-A549 group, metastatic tumors clearly formed in the lungs of 6 mice, but only 2 mice in the A549 group had tumor cell invasion. CONCLUSIONS: SDF-1/CXCR4 played a key role in the invasion and metastasis of lung cancer. The interaction between SDF-1α and CXCR4 activated a series of downstream molecules by activating ERK and AKT.

[Chronomodulated chemotherapy of oxaliplatin, 5-fluorouracil and folinic acid for advanced gastric cancer].

OBJECTIVE: The combination of oxaliplatin (L-OHP), 5-fluorouracil (5-Fu) and folinic acid (FA), being one of the effective regimens for advanced gastric cancer, is used in form of chronomodulated chemotherapy for advanced gastric cancer to investigate its efficacy and safety. METHODS: Twenty-six patients received a 4-day chronomodulated infusion of L-OHP, 5-Fu and FA. L-OHP (25 mg.m(-2).d(-1)) infused from 10:00 am to 22:00 pm, and followed by 5-Fu (600 mg.m(-2).d(-1)) and FA (300 mg.m(-2).d(-1)) from 22:00 pm to 10:00 am for 4 days using a multichannel programmable pump, every 2 weeks as an cycle for at least 2 cycles. RESULTS: Twenty-six patients with previously untreated advanced gastric cancer were eligible. Two complete and 13 partial remissions were observed with an overall response rate of 57.7%. Stable disease was observed in 6 patients (23.1%) and progressive disease in five (19.2%). Four of these patients underwent surgery. The median remission time was 3.5 months and time to tumor progression (TTP) was 4.5 months. The median overall survival time was 8 months. A total of 80 cycles were given without any grade 4 toxicity observed, but grade 3 thrombocytopenia (1.3%) and mucositis (1.3%) in one patient, two grade 3 neutropenia (2.5%) and nausea/vomiting (2.5%) in 2. CONCLUSION: Chronomodulated intravenous chemotherapy of oxaliplatin, 5-fluorouracil and folinic acid is effective and safe in the treatment of advanced gastric cancer.