Intratumoral injection of dendritic cells overexpressing interleukin­12 inhibits melanoma growth.

The present study aimed to investigate the antitumor effects of an intratumoral injection of dendritic cells (DCs) overexpressing interleukin-12 (IL­12) on melanoma. DCs, isolated from mouse spleen, were gene­modified using an IL­12 overexpression vector. Melanoma B6 cells were injected into C57BL/6 mice to generate tumors. Thereafter, DCs overexpressing IL­12 were injected into the tumors, and tumor volume was subsequently measured. Pathological changes in tumor tissue were detected by hematoxylin and eosin staining. The expression of interleukin-4 (IL­4) and IL­12 in tumors was measured by enzyme­linked immunosorbent assay, real­time PCR and western blotting. DCs were successfully isolated and a lentivirus vector expressing IL­12 was constructed. After intratumoral injection of phosphate­buffered saline (control group), tumor cells exhibited malignant growth; whereas tumors injected with DCs (DC group) or DCs + empty vector (DC + vector group) exhibited a small amount of inflammatory cell infiltration and limited areas of tissue necrosis. In contrast, tumors injected with DCs overexpressing IL­12 (DC + IL­12 group) displayed severe tissue necrosis, loss of cell structure, and inflammatory cell infiltration. Compared with the control group, the tumor volumes were significantly lower in the DC, the DC + vector and the DC + IL­12 groups, while the expression of IL­12 and IL­4 in the tumors was significantly higher. Importantly, the most marked changes in tumor volume and IL­12 and IL­4 expression were in the DC + IL­12 group, which were significantly greater than those in tumors treated with unmodified DCs. Hence, intratumoral injection of DCs overexpressing IL­12 exerted strong antitumor effects in melanoma, and biotherapy with DCs overexpressing IL­12 is a potential treatment strategy for melanoma.

Biosimilar candidate IBI305 plus paclitaxel/carboplatin for the treatment of non-squamous non-small cell lung cancer.

BACKGROUND: Bevacizumab is a monoclonal antibody (mAb) against vascular endothelial growth factor (VEGF) and used for treatments of various cancers. Due to the high costs of bevacizumab treatments, a biosimilar provides an affordable alternative therapy for cancer patients. METHODS: In this randomized, double-blind, multicenter, phase 3 study, locally advanced, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor were enrolled and randomized (1:1) into IBI305 or bevacizumab groups. Patients received 6 cycles of paclitaxel/carboplatin plus IBI305 or bevacizumab 15 mg/kg intravenously followed by IBI305 or bevacizumab 7.5 mg/kg maintenance until disease progression, unacceptable toxicity or death. The primary endpoint was confirmed objective response rate (ORR) by an independent radiological review committee (IRRC) and secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety. RESULTS: A total of 450 NSCLC patients were enrolled (224 in IBI305 group and 226 in bevacizumab group). ORRs were 44.3% for IBI305 and 46.4% for bevacizumab, and the ORR ratio was 0.95 (90% CI: 0.803 to 1.135), within the predefined equivalence margin of 0.75 to 1.33. No significant difference in PFS (7.64 vs. 7.77 m, P=0.9987) was observed between the 2 groups. Serious adverse events (AEs) occurred in 33.5% (75/224) of patients in the IBI305 group and 37.6% (85/226) in the bevacizumab group. AEs ≥ grade 3 were similar in the IBI305 and bevacizumab groups [84.4% (189/224) vs. 89.8% (203/226), P=0.085]. CONCLUSIONS: IBI305 is similar to bevacizumab in terms of efficacy and safety. TRIAL REGISTRATION: Clinicaltrials.org Identifier: NCT02954172. Registered on 3 November 2016. Https://clinicaltrials.gov/.

UNC0638, a G9a inhibitor, suppresses epithelial­mesenchymal transition­mediated cellular migration and invasion in triple negative breast cancer.

Triple-negative breast cancer (TNBC) is associated with an aggressive clinical history, high risk of recurrence and metastasis, and shorter patient survival due to lack of targeted therapy. In the present study, UNC0638, a chemical G9a inhibitor, was identified to suppress TNBC cell invasion and migration in vitro at a non­cytotoxic concentration. In addition, UNC0638 reduced the size and number of the tumorsphere and decreased anchor­independent colony formation in the two TNBC cell lines. Evaluation of the underlying mechanism revealed that the suppressive effect of UNC0638 is associated with modulation of epithelial­mesenchymal transition through enhancing E­cadherin promoter activities and restoring its expression. Thus, the current data indicates that UNC0638 may be developed as a chemotherapeutic agent to effectively treat metastatic cancers, including TNBC.

An insertion/deletion polymorphism within the promoter of EGLN2 is associated with susceptibility to colorectal cancer.

OBJECTIVE: To investigate the association between susceptibility to colorectal cancer (CRC) and a 4-bp insertion/deletion polymorphism (rs10680577) in the proximal promoter of the EGLN2 gene. METHOD: The first step in genotyping EGLN2 was PCR, then the PCR products were separated using 7% nondenaturing polyacrylamide gel electrophoresis and visualized by silver staining according to the final product band location and quantity to determine the genotype of the sample. The final count was done by two different pathologists. RESULT: In the codominant model, compared with the ins/ins genotype, subjects with the heterozygous ins/del or homozygous del/del genotype had a significantly increased risk of CRC (adjusted OR = 1.45, p<0.0001 and OR = 2.44, p = 0.0001, respectively). Each additional copy of the 4-bp deletion allele conferred a significantly increased risk of CRC (OR = 1.47, 95% CI 1.28-1.66, p<0.0001). In the stratification analysis, we further proved that the association was more prominent in TNM stage III and IV cancer compared with stage I and II (adjusted OR = 1.43, 95% CI 1.07-1.93, p for heterogeneity = 0.02). CONCLUSIONS: Our study provided initial evidence that the insertion/deletion polymorphism rs10680577 may play a functional role in the development of CRC in the Chinese population.

Cod skin peptide reduces chemotherapy-induced toxicity in gastric cancer patients.

BACKGROUND AND OBJECTIVES: The present study was conducted to evaluate the effect of cod skin peptide (CSPE) on chemotherapy-induced toxicity in gastric cancer patients. METHODS AND STUDY DESIGN: A cohort of 60 gastric cancer patients for chemotherapy was randomly divided into two groups (n=30 per group), who were orally treated with either supplemental CSPE or placebo apart from chemotherapy. The hematologic and gastrointestinal toxicities experienced by the patients, as well as their Karnofsky Performance Status (KPS) as an index of quality of life was evaluated. RESULTS: Leukocyte counts and haemoglobin levels were significantly reduced in the group treated with peptide (p<0.05), while gastrointestinal toxicity was not affected (p>0.05). KPS consists of 11 categories of quality of life, and the score denoted in deciles ranges from 100 (asymptomatic, normal function) to 0 (death). The KPS score is used to evaluate a cancer patient's ability to function at work and home, the severity of symptoms, and the patient's need for personal and medical care. Treatment with CSPE significantly improved the quality of life of patients, as indicated by increased KPS scores (p<0.05). CONCLUSIONS: CSPE can potentially be considered as a food supplement that can be used to improve the quality of life of cancer patients.

Randomized phase III trial of amrubicin/cisplatin versus etoposide/cisplatin as first-line treatment for extensive small-cell lung cancer.

BACKGROUND: Extensive-disease small-cell lung cancer (ED-SCLC) is characterized by rapid progression and relapse, despite high initial response rates to chemotherapy. The primary objective of this trial was to demonstrate the non-inferiority of amrubicin and cisplatin (AP) combination therapy compared with the standard first-line regimen of etoposide and cisplatin (EP) for previously untreated ED-SCLC in a Chinese population. When non-inferiority was verified, the objective was switched from non-inferiority to superiority. METHODS: From June 2008 to July 2010, 300 patients were enrolled and randomly assigned at a 1:1 ratio to AP and EP groups. AP-treated patients received cisplatin (60 mg/m(2), day 1) and amrubicin (40 mg/m(2), days 1-3) once every 21 days. EP-treated patients received cisplatin (80 mg/m(2), day 1) and etoposide (100 mg/m(2), days 1-3) once every 21 days. Treatment was continued for four to six cycles, except in cases of progressive disease or toxicity, and patient refusal. RESULTS: Median overall survival (OS) for AP vs. EP treatment was 11.8 vs. 10.3 months (p = 0.08), respectively, demonstrating non-inferiority of AP to EP (AP group: 95% confidence interval for hazard ratio 0.63-1.03 months). Median progression-free survival and overall response rates for AP vs. EP groups were 6.8 vs. 5.7 months (p = 0.35) and 69.8% vs. 57.3%, respectively. Drug-related adverse events in both groups were similar, with neutropenia being the most frequent (AP 54.4%; EP 44.0%). Leukopenia, pyrexia, and fatigue were more prevalent in the AP group, but all were clinically reversible and manageable. CONCLUSIONS: AP therapy demonstrated non-inferiority to EP therapy, prolonging OS for 1.5 months, but this difference was not statistically significant; thus we propose AP as a promising treatment option for ED-SCLC in China. TRIAL REGISTRATION: This trial was registered on 10 April 2008 (ClinicalTrials.gov NCT00660504).

CD243 gene polymorphism significantly associated with breast cancer susceptibility.

We aimed to obtain a summary risk estimate for CD243 gene polymorphism associated with breast cancer. A total of nine case-control studies, including 5,073 cancer patients and 7,498 control subjects, were pooled in our fixed effects meta-analysis of the association between CD243 gene polymorphism and risk of breast cancer. All data were analyzed by using Stata software (version 12.0). We found significant risk effects under TT vs. TC + CC genetic model [odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.01-1.18, P = 0.516], but not in other comparisons. Stratifying the pooled data by ethnicity and source of controls revealed that the association between the T allele and an increased risk of breast cancer was more pronounced among Asians (TT vs. CC: OR = 1.26, 95 % CI = 1.02-1.57, P = 0.720; TT vs. TC + CC: OR = 1.31, 95 % CI = 1.07-1.61, P = 0.708) and hospital-based studies (TT vs. CC: OR = 1.25, 95 % CI = 1.02-1.53, P = 0.877; TT vs. TC + CC: OR = 1.27, 95 % CI = 1.05-1.53, P = 0.540). No notable heterogeneity was indicated across studies. Our meta-analysis demonstrates that CD243 gene polymorphism may act as a predisposition factor for breast cancer, particularly in Asian populations.

Vascular endothelial growth factor gene polymorphism (-634G/C) and breast cancer risk.

The aim of this meta-analysis was to assess if the -634G/C polymorphism represents a predisposition factor for the risk of breast cancer. We included eight published case-control studies, in which a total of 6,175 cancer cases and 6,421 cancer-free controls were included. Pooled ORs and 95 % CIs were calculated by the fixed effects model to evaluate the association of the -634G/C polymorphism and breast cancer risk. When all studies were pooled, we did not find statistical evidence of any significant association with overall breast cancer risk (ORBB vs. bb = 1.00, 95 % CI = 0.93-1.07, P = 0.999; ORBB + Bb vs. bb = 1.00, 95 % CI = 0.95-1.05, P = 0.999; ORBB vs. Bb + bb = 1.03, 95 % CI = 0.96-1.09, P = 0.984; ORallele B vs. allele b = 1.01, 95 % CI = 0.97-1.05, P = 0.998; ORBb vs. bb = 0.99, 95 % CI = 0.92-1.06, P = 0.992). In further stratified analyses by ethnicity and control source, no significant association was revealed. This study suggests that the -634G/C polymorphism does not appear to represent a risk factor for breast cancer.

A multicentre randomised trial comparing weekly paclitaxel + S-1 with weekly paclitaxel + 5-fluorouracil for patients with advanced gastric cancer.

PURPOSE: This study aimed to compare the efficacy and toxicity of weekly paclitaxel plus S-1 with weekly paclitaxel plus 5-fluorouracil in treating advanced gastric cancer as first line regimen. The primary end-point was disease control rate (DCR). METHODS: Patients with advanced or recurrent gastric cancer were randomly assigned to an experimental arm or a control arm. The experimental arm's dosage schedule was paclitaxel 60 mg/m2 (intravenous infusion) on days 1, 8 and 15 and S-1 80-120 mg/d (oral administration) on days 1-14. Control arm patients were given the same paclitaxel, combined with 5-fluorouracil 500 mg/m2 (continuous intravenous infusion) on days 1-5; and leucovorin 20 mg/m2 (intravenous infusion) on days 1-5. All schedules were repeated every 28 d. RESULTS: A total of 240 patients were enrolled and equally randomised into two arms. The overall response rate and DCR of the experimental arm was non-inferior to that of the control arm both in the per-protocol set and the full analysis set. The secondary end-point median progression-free survival (PFS) of the experimental and control arms was 153 and 129 d, with the hazard ratio of 0.641 (95% CI: 0.473-0.868, P = 0.004). The hazard ratio of the time to treatment failure of the two arms was 1.449 (95% CI: 0.705-2.980, P = 0.229). The six-month PFS rates of both arms were similar (31.3% versus 31.8%, P = 0.94). Cox regression analysis indicated that only treatment regimen and age were independent predictive factors for PFS. The most common adverse events were haematological and gastrointestinal. The rates of grade 3-4 adverse events were not significantly different between the two study arms and were mostly lower than 5%. CONCLUSION: Weekly paclitaxel combined with S-1 is an active and well-tolerated regimen, supporting the view that S-1 can be an alternative for infusional 5-fluorouracil for advanced gastric cancer.

Safety analysis of weekly paclitaxel plus S-1 versus paclitaxel plus 5-fluorouracil/calcium folinate as first-line therapy in advanced gastric cancer: a multicenter open random phase II trial.

PURPOSE: To report the results of a safety analysis from a phase II trial comparing administration of weekly paclitaxel plus S-1 (TS) versus paclitaxel plus 5-fluorouracil (5-FU)/calcium folinate (LV) (TLF) as first-line therapy for advanced gastric cancer. METHODS: Patients (n = 240) with previously untreated advanced gastric cancer were randomly assigned to receive either TS or TLF in a 28-day cycle for six cycles. RESULTS: The clinical features of both sets of patients were similar, with the exception of the incidence of prior chemotherapy (P>0·05). Most treatment-related adverse events occurred at similar rates in both treatment arms. However, patients receiving TS experienced an increase in all-grade especially grade 3/4 neutropenia, with an incidence of 43·7% in the TS arm and 16·3% in the TLF arm, respectively (P<0·05). Other severe adverse events were infrequent and not significantly different between the groups. CONCLUSION: The safety and tolerance of weekly paclitaxel plus S-1 or 5-FU/LV is well in untreated advanced gastric cancer patients.

[A phase II prospective randomized controlled trial of weekly paclitaxel combined with S-1 or fluorouracil for advanced gastric carcinoma].

OBJECTIVE: To evaluate the efficacy and safety of weekly paclitaxel combined with S-1 or fluorouracil in the first line treatment of advanced gastric carcinoma. METHODS: Two hundred and forty patients with untreated advanced gastric carcinoma were randomized into two arms, patients in the experimental arm were given paclitaxel and S-1, while those in the control arm received paclitaxel and fluorouracil. The regimen of experimental arm was paclitaxel 60 mg/m(2) by intravenous infusion, day 1, 8, 15; S-1 80 - 120 mg/day given by oral administration, day 1 - 14. The regimen of control arm was fluorouracil 500 mg/m(2) by intravenous infusion continuously, day 1 - 5; CF 20 mg/m(2) by intravenous infusion, day 1 - 5. The regimens in both arms were repeated every 28 days. The efficacy and safety of both arms were assessed. RESULTS: Two hundred and twenty-eight patients were analyzed in the full analysis set, and 192 patients were analyzed in per-protocol set (experimental arm 100 patients, control arm 92 patients). The overall response rates of experimental and control arms were 50.0% and 28.3% (P = 0.002), and the disease control rates were 82.0% and 70.7% (P = 0.064), respectively. The primary endpoints of experimental arm were non-inferior to that of the control arm. The secondary endpoint of experimental arm in terms of median progression free survival was significantly better than that of control arm (5 months versus 4 months, P = 0.006). The experimental arm had a higher incidence of grade III-IV bone marrow suppression than the control arm, but the incidence of fever in both arms was not significantly different. CONCLUSIONS: Oral administration of S-1 is an alternative option of venous infusional fluorouracil. Weekly paclitaxel combined with S-1 is a safe regimen and has a promising efficacy.