Survival Benefit and Genetic Profile of Pemetrexed as Initial Chemotherapy in Selected Chinese Patients With Advanced Lung Adenocarcinoma.

Objective: This study investigated survival in selected Chinese patients with advanced lung adenocarcinoma who received initial chemotherapy with pemetrexed. We also explored the relationship between genetic biomarkers and pemetrexed efficacy. Methods: We retrospectively collected patients (n = 1,047) enrolled in the Chinese Patient Assistance Program from multiple centers who received pemetrexed alone or combined with platinum as initial chemotherapy and continued pemetrexed maintenance therapy for advanced lung adenocarcinoma from November 2014 to June 2017. The outcomes were duration of treatment (DOT) and overall survival (OS). Clinical features were analyzed for their influence on the treatment effect and prognosis. Next-generation sequencing (NGS) was performed to identify genetic biomarkers associated with the efficacy of pemetrexed. Results: The median DOT was 9.1 months (95% CI: 8.5-9.8), and the median OS was 26.2 months (95% CI: 24.2-28.1). OS was positively correlated with DOT (r = 0.403, P < 0.001). Multivariable analysis showed that smoking status and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were independently associated with DOT; smoking status, ECOG PS, targeted therapy, and EGFR/ALK/ROS1 status were independently associated with OS. NGS in 22 patients with available samples showed genes with high mutation rates were: TP53 (54.5%), EGFR (50.0%), MYC (18.2%), and PIK3CA (13.6%). When grouped based on progression-free survival (PFS) reported in the PARAMOUNT study, the DOT > 6.9 months set was associated with PIK3CA, ALK, BRINP3, CDKN2A, CSMD3, EPHA3, KRAS, and RB1 mutations, while ERBB2 mutation was observed only in the DOT ≤ 6.9 months set. Conclusion: This study shows that initial chemotherapy with pemetrexed is an effective regimen for advanced lung adenocarcinoma in selected Chinese patients. There is no specific genetic profile predicting the benefit of pemetrexed found by NGS. Biomarkers predicting the efficacy of pemetrexed need further exploration.

[Down-regulation of TopI by RNA interference reduces the drug-sensitivity of small cell lung cancer cell lines to topotecan].

OBJECTIVE: To investigate the expressions of TopI gene in small cell lung cancer cell line H446, and explore the influence of TopI on the chemosensitivity of the cell line to topotecan (TPT). METHODS: Western blot was performed to detect the TopI expression in H446 cells. Lipofectamine 2000 was used for the transient transfection of H446 cells by siRNA, and the transfection efficacy was detected. TopI mRNA was analyzed by quantitative RT-PCR and TopI protein was detected by Western blot to selected effective siRNA. The drug-sensitivity to topotecan (TPT) was evaluated by MTT assay. RESULTS: TopI gene was expressed in H446 cells. Lipofectamine 2000 mediated the siRNA effectively (88.67%). Compared with its parental cells, RT-PCR results showed that TopI mRNAs in transfected cells were reduced by (95.7 +/- 1.6)%, (90.8 +/- 1.6)%, (96.1 +/- 2.7)% and (96.3 +/- 1.8)%, respectively, and decreased significantly at protein level. By MTT assay, the inhibition rate of TPT to H446 cells transfected by siRNA was lower than that of control group at same concentrations (P < 0.01). CONCLUSION: siRNAs can silence the expression of TopI and decrease the drug-sensitivity of H446 cells to TPT.

[Low dose-intensity docetaxel monotherapy for patients with anthracycline-resistant metastatic breast cancer in poor physical status].

OBJECTIVE: To evaluate the efficacy and safety of a weekly schedule of low dose-intensity docetaxel monochemotherapy for patients with anthracycline-resistant metastatic breast cancer (MBC) in poor physical status. METHODS: Thirty MBC patients who were previously exposed to anthracycline treatment received docetaxel alone at a dose of 30 mg/m2 on D1, D8 and D15, repeated every 4 weeks for a maximum of 6 cycles. RESULTS: Of the 30 evaluable patients, 2 (6.7%) achieved a complete response, and 9 (30.0%) a partial response, with an overall objective response rate of 36.7% (95% CI: 20.5%-53.9%). The most common adverse event was hematologic toxicity. After an average follow-up of 15.0 months, the median time to progression (TTP) was 8. 5 months and the median overall survival (OS) had not reached yet at the end of follow-up. CONCLUSION: The weekly low dose-intensity docetaxel monochemotherapy is effective and well-tolerated in patients with anthracycline-resistant metastatic breast cancer in poor physical status.

[Expression and significance of DNA topoisomerase I (topo I) in small cell lung cancer].

OBJECTIVE: To investigate the expression and its significance of DNA topoisomerase I (Topo I) in small cell lung cancer (SCLC). METHODS: Topo I expression was detected by immunohistochemical S-P technique on 50 cases of SCLC and 12 cases of normal lung tissues. RESULTS: The total positive rate of Topo I in normal lung tissue was 25.0% (3/12) and 78.0% (39/50) in SCLC. The expression of Topo I does not correlate with age, gender, smoking, tumor size and tumor site (P > 0.05), but significantly correlated with lymph node metastasis and clinical stage (P <0.05). CONCLUSION: High Topo I expression is a rationale indication of Topo I inhibitor treatment of malignancies. It should be possible to predict anti-tumor drug sensitivity by assessment of Topo I expression and help to improve the therapeutic efficacy for cancer patients.

[Expression and significance of integrin alpha5, beta1 and E-CD in patients with non-small cell lung carcinoma].

OBJECTIVE: To investigate the relationship between the expressions of integrin alpha5 beta1 and E-CD, and clinicopathological characteristics and prognosis of patients with non-small cell lung carcinoma (NSCLC). METHODS: The expression of integrin alpha5 beta1 and E-CD were analyzed in 53 NSCLC and 12 control specimens by immunohistochemical assay. RESULTS: The expression of integrin alpha5 beta1 was significantly higher in NSCLC (58.5%) than that in normal lung tissue (16.7%), and also positively related with pathological characteristics (P = 0.021), lymph node metastasis (P = 0.006), and clinical stage (P = 0.002). The 3-year survival rate in NSCLC group was significantly lower than that in control group (22.3% vs 40.6% , P = 0.041). The positive expression of E-CD in NSCLC and control group was 32.1% and 91.7%, respectively, and negatively correlated with pathological characteristics (P = 0.010) and lymph node metastasis (P = 0.002). The 3-year survival rate in control group was 19.9%, lower than that in NSCLC group (41.2%, P > 0.05), but the difference is not significant. CONCLUSION: The overexpression of integrin alpha5 beta1 may contribute to lymph node metastasis and play an inverse role, while E-CD may be a beneficial prognostic factor in patients with NSCLC.

Clinical comparative investigation of efficacy and toxicity of cisplatin plus gemcitabine or plus Abraxane as first-line chemotherapy for stage III/IV non-small-cell lung cancer.

PURPOSE: The purpose of this study was to observe the clinical efficacy and toxicity of cisplatin in combination with gemcitabine or Abraxane as first-line chemotherapy for stage III/IV non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 200 patients with advanced NSCLC, which was confirmed by pathology or cytology, were enrolled into our research by reviewing previous complete and retrievable medical records data of our hospital. A total of 100 patients were treated with gemcitabine (1,000 mg/m2, day 1 and day 8) in combination with cisplatin (75 mg/m2, days 1-3; GP group) and another 100 patients were treated with Abraxane (260 mg/m2, day 1) in combination with cisplatin (75 mg/m2, days 1-3; TP group). Twenty-one days were required to complete one cycle; at least two cycles were completed by each group. RESULTS: For the 100 patients in the GP group, the effective response rate (RR) was 27%, the disease control rate (DCR) was 63%, and the median progression-free survival (PFS) time was 8 months. For the 100 patients in the TP group, the RR was 52%, the DCR was 75%, and the median PFS was 20 months. There was significant difference in RR (P<0.001), but no significant difference in DSR and PFS (P>0.05). Common treatment-related adverse events were hematologic toxicity and gastrointestinal reaction. Hematologic toxicity mainly included decreased white blood cells and platelets. The differences between the two groups were statistically significant (P<0.05). Gastrointestinal reaction mainly included nausea and vomiting. There was no statistical significance between them (P=0.805). For the 85 patients with squamous carcinoma in the TP group, the RR was 60%, the DCR was 78%, and the median PFS was 7.5 months. For the 85 patients with squamous carcinoma in the GP group, the RR was 36%, the DCR was 62%, and the median PFS was 18.5 months. There was significant difference in RR (P=0.024), but no significant difference in DSR and PFS (P>0.05). For the 115 patients with adenocarcinoma in the TP group, the RR was 47%, the DCR was 73%, and the median PFS was 8 months. For the 115 patients with adenocarcinoma in the GP group, the RR was 20%, the DCR was 64%, and the median PFS was 20.5 months. There was significant difference in RR (P=0.003), but no significant difference in DCR and PFS (P>0.05). CONCLUSION: The efficacy of cisplatin in combination with Abraxane is better than that with gemcitabine in the treatment of NSCLC, and the treatment has less risk of hematologic toxicity.

[Effectiveness and safety of rhIL-11 in the treatment of chemotherapy-induced thrombocytopenia].

OBJECTIVE: To investigate the effectiveness, safety and possible mechanism of recombinate human interleukin 11 (rhIL-11) in the treatment of chemotherapy-induced thrombocytopenia. METHODS: Thirty-four patients (totally 76 cycles) with chemotherapy-induced thrombocytopenia received subcutaneous injection of rhIL-11 at the dose of 25 microg.kg(-1).d(-1) for 4 to 16 days. Serum IL-11 level was measured by ELISA, and IL-11 R alpha expression was detected by RT-PCR. RESULTS: The mean baseline platelet count before chemotherapy was (135.0 +/- 54.3) x 10(9)/L for the 1st cycle and (259.4 +/- 64.5) x 10(9)/L for the 2nd cycle. The time to administer rhIL-11 was 7 to 16 days (median 12 days) in the 1st cycle and 4 to 10 days (median 6 days) in the 2nd, respectively (P < 0.05). The duration of post-chemotherapy platelet count below 50 x 10(9)/L was 7 to 13 days (median 10 days) for the 1st cycle and 3 to 8 days (median 5 days) for the 2nd, respectively (P < 0.05). Platelet count reached 300 x 10(9)/L or above in 30 chemotherapy cycles. The maximum platelet count was found to appear at D10 to D 17 (median D14), and negatively correlated with the pre-chemotherapy serum IL-11 level after administration of rhIL-11. Major adverse reactions included edema, headache, muscle and joint pain. CONCLUSION: rhIL-11 is effective and safe for the treatment of chemotherapy-induced thrombocytopenia, with a relatively slow but sustained effect on the recovery of platelet count. Pre-chemotherpy serum IL-11 level might predict the efficacy of rhIL-11.

Study on interleukin-18 gene transfer into human breast cancer cells to prevent tumorigenicity.

To study the effect of interleukin-18 gene transfection on the tumorigenesis of breast cancer cell line Bacp37, human breast cancer cell line Bcap37 were transfected with Lipofectamine and selected by G418. The biological expression of rhIL-18 was tested by RT-PCR and ELISA method; nude mice were injected with Bcap37 cell with or without the hIL-18 gene. The hIL-18 cDNA was successfully integrated into Bcap37 cell; 126.3+/-4.5 pg hIL-18 secreted by one million transduced cells in 24 hours. Nude mice injected with IL-18 gene engineered Bcap37 cell had no tumor growth. These findings indicated that human breast cancer cells were successfully modified by the gene of IL-18 cytokine; the IL-18 gene engineered Bcap37 cells secreted hIL-18 and lost their tumorigenicity. The Bcap37 cells transduced with IL-18 gene may be used as breast cancer vaccine.

Optimal timing of radiotherapy with alternating/sequential radio-chemotherapy for limited-stage small cell lung cancer.

OBJECTIVE: To investigate the optimal timing of radiotherapy with alternating/sequential radio-chemotherapy for limited-stage small cell lung cancer (LS-SCLC). METHODS: 91 patients with LS-SCLC were retrospectively analyzed and divided into two groups according to the number of chemotherapy cycles before radiotherapy. If the patient received radiotherapy after 3 cycles or fewer cycles of chemotherapy, classification was into the early group, if not, into the late group. All patients received 6 cycles of standard chemotherapy (EP/EC) and conventional radiotherapy (56 gy~ 60 gy/28 f ~30 f). RESULTS: The response rate (RR) of the early and late groups were 85.7% and 81.6%, respectively, with no significant difference (p>0.05). In contrast, the progression-free survival (PFS) in the early group was better than that in the late group (11.8 months vs 9.86 months), and the difference was significant (p<0.05). There was no significant difference between two groups in adverse reactions, which gastrointestinal irritation and bone marrow suppression being the most common (p>0.05). CONCLUSIONS: Radiotherapy after 3 cycles or fewer cycles of chemotherapy does not bring significant benefits for RR of patients with LS-SCLC, but it could significantly prolong their PFS without increase in adverse reactions.

Twist1 correlates with poor differentiation and progression in gastric adenocarcinoma via elevation of FGFR2 expression.

AIM: To explore the correlation between Twist-related protein (Twist)1, fibroblast growth factor receptor (FGFR)2 and gastric adenocarcinoma differentiation and progression. METHODS: We evaluated Twist1 and FGFR2 in 52 gastric adenocarcinoma samples by immunohistochemistry and quantitative real time polymerase chain reaction, and analyzed the correlation between Twist1, FGFR2 and cancer differentiation. We also detected Twist1 and FGFR2 expression in gastric adenocarcinoma cell lines, and evaluated Twist1 influence on FGFR2 expression. In addition, we studied the role of FGFR2 in Twist1-promoted cancer progression, including proliferation, invasion and epithelial-mesenchymal transition (EMT). RESULTS: Twist1 and FGFR2 were detected in almost all the gastric adenocarcinoma samples. Twist1 (P = 0.0213) and FGFR2 (P = 0.0310) mRNA levels had a significant association with gastric adenocarcinoma differentiation. Moreover, Twist1 and FGFR2 expression in poorly differentiated cells (SNU-1 and SNU-16) was notably higher than in well-differentiated cells (MKN-7 and MKN-28). In poorly differentiated gastric adenocarcinomas, FGFR2 mRNA level was significantly positively correlated with Twist1 mRNA level (P = 0.004). Twist1 was proved to promote FGFR2 by regulating Twist1 expression by knockdown and overexpression. Additionally, Twist1 could induce proliferation, invasion and EMT in gastric cancer; of these, FGFR2 was required for invasion and EMT, rather than proliferation. CONCLUSION: Twist1 and FGFR2 are highly associated with differentiation of gastric adenocarcinoma; Twist1 can facilitate invasion and EMT in gastric adenocarcinoma via promotion of FGFR2 expression.

Clinical impact and reliability of carbonic anhydrase XII in the differentiation of malignant and tuberculous pleural effusions.

OBJECTIVE: To assess the practical utility of pleural fluid carbonic anhydrase XII (CAXII) quantification for differential diagnosis of effusions. MATERIALS AND METHODS: Fluid was collected prospectively from fifty patients presenting with lymphocytic pleural effusions for investigation and CAXII was quantified by ELISA. RESULTS: Pleural fluid CAXII concentrations were significantly higher in lung cancer patients (n=30) than in tuberculous controls (n=20). The sensitivity and specificity of this biomarker were 60%and 75%, respectively. CAXII measurement was not inferior to cytological examination in the diagnosis and exclusion of pleural effusions from lung cancer patients (sensitivity 60% vs. 57%; specificity 75% vs. 100%; positive predictive value 77%; negative predictive value 54%). In patients with negative cytology, it offered a sensitivity of 54%. CONCLUSIONS: Pleural fluid CAXII is elevated in pleural effusions from lung cancer patients. Measurement of CAXII may be used in the future as a valuable adjunct to cytology in the diagnostic assessment of patients with pleural effusions related to lung cancer, especially when cytological examination is inconclusive.

Biweekly oxaliplatin in combination with continuous infusional 5-fluorouracil and leucovorin (modified FOLFOX-4 regimen) as first-line chemotherapy for elderly patients with advanced gastric cancer.

OBJECTIVE: The aim of the study was to assess the toxicity and the clinical activity of biweekly oxaliplatin (OXA) in combination with continuous infusional 5-fluorouracil (5-FU) and leucovorin (LV) administered every 2 weeks (modified FOLFOX-4 regimen) in elderly patients with advanced gastric cancer (AGC). PATIENTS AND METHODS: A total of 44 previously untreated AGC patients aged 65 or older were treated with OXA 85 mg m-2 on day 1, LV 200 mg m-2 as a 2-hour infusion followed by a 22-hour infusion of 5-FU 1000 mg m using a multichannel programmable pump, repeated for 2 consecutive days every 2 weeks. RESULTS: All patients were assessable for toxicity and 40 patients for response. Median age was 69 years (65-83). The response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria was 52.5% (95% confidence interval: 44.6%-68.0%) with 3 complete responses, 18 partial responses, 11 stable diseases, and 8 progressions. Median time to progression was 6.5 months and median overall survival was 10.0 months. Toxicity was generally mild. Grade 3 hematologic toxicities of neutropenia, anemia, and thrombocytopenia were in 6.8%, 2.3%, and 4.5% of the patients, respectively. No grade 4 hematologic toxicities occurred. Grade 1 peripheral neuropathy was a common event (34.1%), whereas grade 3 peripheral neuropathy was recorded in only 1 (2.3%) patient. An acute hypersensitivity reaction was observed in 1 patient during administration. CONCLUSION: The modified FOLFOX-4 regimen is an active and well-tolerated chemotherapy for elderly patients aged > or =65 years with AGC. OXA may occasionally cause mild hypersensitivity.