A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study).

PURPOSE: To compare the efficacy and safety of high-dose vitamin C plus FOLFOX ± bevacizumab versus FOLFOX ± bevacizumab as first-line treatment in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Between 2017 and 2019, histologically confirmed patients with mCRC (n = 442) with normal glucose-6-phosphate dehydrogenase status and no prior treatment for metastatic disease were randomized (1:1) into a control (FOLFOX ± bevacizumab) and an experimental [high-dose vitamin C (1.5 g/kg/d, intravenously for 3 hours from D1 to D3) plus FOLFOX ± bevacizumab] group. Randomization was based on the primary tumor location and bevacizumab prescription. RESULTS: The progression-free survival (PFS) of the experimental group was not superior to the control group [median PFS, 8.6 vs. 8.3 months; HR, 0.86; 95% confidence interval (CI), 0.70-1.05; P = 0.1]. The objective response rate (ORR) and overall survival (OS) of the experimental and control groups were similar (ORR, 44.3% vs. 42.1%; P = 0.9; median OS, 20.7 vs. 19.7 months; P = 0.7). Grade 3 or higher treatment-related adverse events occurred in 33.5% and 30.3% of patients in the experimental and control groups, respectively. In prespecified subgroup analyses, patients with RAS mutation had significantly longer PFS (median PFS, 9.2 vs. 7.8 months; HR, 0.67; 95% CI, 0.50-0.91; P = 0.01) with vitamin C added to chemotherapy than with chemotherapy only. CONCLUSIONS: High-dose vitamin C plus chemotherapy failed to show superior PFS compared with chemotherapy in patients with mCRC as first-line treatment but may be beneficial in patients with mCRC harboring RAS mutation.

Mutation profiling in chinese patients with metastatic colorectal cancer and its correlation with clinicopathological features and anti-EGFR treatment response.

An increasing number of studies reveal the significance of genetic markers in guiding target treatment and refining prognosis. This retrospective observational study aims to assess the mutation profile of metastatic colorectal cancer (mCRC) in Chinese population with the help of MassARRAY® technique platform and OncoCarta™ Panel.322 Chinese patients with mCRC who received clinical molecular testing as part of their standard care were investigated. 80 patients received cetuximab palliative treatment. 238 common hot-spot mutations of 19 cancer related genes in the OncoCarta™ Panel were tested.44 mutations in 11 genes were detected in 156 cases (48.4%). At least one mutation was identified in 38.5% (124/322) of all tested cases, two concomitant mutations in 9.0% (29/322) and three mutations in 3 cases (<1%). KRAS was the most frequently mutated gene (34.8%), followed by PIK3CA (9.6%), NRAS (4.3%), BRAF (3.4%), EGFR (2.5%) and HRAS (1.2%). Less frequent mutations were detected in PDGFRA, RET, AKT1, FGFR1, and ERBB2. Co-mutation of RAS family subtypes was observed in 5 patients, and KRAS and BRAF concurrent mutation in 1 patient. KRAS, NRAS, BRAF and PIK3CA mutations had association with some clinicopathological features statistically. Patients identified as wild-type in all 19 genes had better objective response rate when treated with cetuximab.The clinical molecular testing with OncoCarta™ Panel supplemented the limited data of mCRC in Chinese population, and offered a clearer landscape of multiple gene mutational profile in not only clinically prognostic KRAS, NRAS, BRAF and PIK3CA genes, but also less frequent mutated genes. Knowledge of these multiple gene mutation patterns may give clues in exploring interesting accompanying co-occurrence relationship or mutually exclusive relationship between mutated genes, as well as in predicting benefit of all-wild-type patients from anti-EGFR treatment.

The Efficacy of Adjuvant FOLFOX6 for Patients With Gastric Cancer after D2 Lymphadenectomy: A Propensity Score-matched Analysis.

Adjuvant 5-fluorouracil, folinic acid, and oxaliplatin (FOLFOX6) are widely used for treating resected gastric cancer in clinics in China, but only few clinical trials have investigated its efficacy. Using propensity score matching, we evaluated the efficacy of adjuvant FOLFOX6 following D2 lymphadenectomy. Patients who received adjuvant FOLFOX6 following D2 lymphadenectomy (FOLFOX6, n = 113) or D2 lymphadenectomy only (surgery-only, n = 512) between 1998 and 2007 at our center were propensity score-matched; we identified a balanced 1:2 cohort, with 96 patients in the FOLFOX6 group and 192 patients in the surgery-only group. The overall survival (OS) was estimated using the Kaplan-Meier method; factors affecting survival were identified by Cox regression models. A nomogram incorporating independent prognosticators was constructed for predicting the 3-, 5-, and 7-year OS, and bootstrap validation was performed. The median follow-up was 9.3 years, and the 7-year OS was 52.1% in the FOLFOX6 group and 43.8% in the surgery-only group (P = 0.04), with an adjusted hazard ratio of 0.69 (95% confidence interval = 0.49-0.98). A prognostic nomogram was generated with the identified significant prognosticators (adjuvant FOLFOX6, number of total harvested nodes, the interaction effect between these two variables, tumor size, T and N stage). Internal validation of the nomogram revealed good predictive abilities, with a bootstrap-corrected concordance index of 0.70. Adjuvant FOLFOX6 following D2 lymphadenectomy is associated with survival benefit in resected gastric cancer. Receiving adjuvant FOLFOX6 can be developed into a nomogram with other independent prognosticators to refine OS prediction and estimation of benefit from adjuvant FOLFOX6 for resected gastric cancer.

Neuroprotective Effects of Icariin on Brain Metabolism, Mitochondrial Functions, and Cognition in Triple-Transgenic Alzheimer's Disease Mice.

AIMS: This study investigated the neuroprotective properties of icariin (an effective component of traditional Chinese herbal medicine Epimedium) on neuronal function and brain energy metabolism maintenance in a triple-transgenic mouse model of Alzheimer's disease (3 × Tg-AD). METHODS: 3 × Tg-AD mice as well as primary neurons were subjected to icariin treatment. Morris water maze assay, magnetic resonance spectroscopy (MRS), Western blotting, ELISA, and immunohistochemistry analysis were used to evaluate the effects of icariin administration. RESULTS: Icariin significantly improved spatial learning and memory retention in 3 × Tg-AD mice, promoted neuronal cell activity as identified by the enhancement of brain metabolite N-acetylaspartate level and ATP production in AD mice, preserved the expressions of mitochondrial key enzymes COX IV, PDHE1α, and synaptic protein PSD95, reduced Aß plaque deposition in the cortex and hippocampus of AD mice, and inhibited ß-site APP cleavage enzyme 1 (BACE1) expression. Icariin treatment also decreased the levels of extracellular and intracellular Aß1-42 in 3 × Tg-AD primary neurons, modulated the distribution of Aß along the neurites, and protected against mitochondrial fragmentation in 3 × Tg-AD neurons. CONCLUSIONS: Icariin shows neuroprotective effects in 3 × Tg-AD mice and may be a promising multitarget drug in the prevention/protection against AD.

Biocompatibility of Mn0.4Zn0.6Fe2O4 Magnetic Nanoparticles and Their Thermotherapy on VX2-Carcinoma-Induced Liver Tumors.

Malignant tumors are the most serious threat to human health. Much research has focused on revealing the characteristics of this disease and developing methods of treatment. Because tumor cells are more sensitive to heat than normal cells, thermotherapy for the treatment of tumors has attracted much attention. In this paper, we presented functional Mn-Zn ferrite nanoparticles with the molecular composition of Mn0.4Zn0.6Fe2O4 as the magnetic response material for the thermotherapy. The suggested Mn-Zn ferrite nanoparticles were with a self-regulation temperature of 43 degrees C which was ideal for tumor thermotherapy. The biocompatibility and anti-tumor effect of this material were well investigated. It was found that the Mn0.4Zn0.6Fe2O4 nanoparticles have no hemolysis activity, no genotoxic effects and cytotoxicity. Its Median Lethal Dose (LD50) arrived at 6.026 g/kg and it did not induce any abnormal clinical signs in laboratory animals. Moreover, the suggested nanoparticles can increase the inhibitory ratio of weight and volume of tumors, cause tumor tissues necrosis and show the therapeutic effect on the xenograft live cancers in vivo. Based on these results, we could envision the valuable application of the Mn0.4Zn0.6Fe2O4 nanoparticles for the practical thermotherapy.

A study on the preparation and characterization of plasmid DNA and drug-containing magnetic nanoliposomes for the treatment of tumors.

PURPOSE: To explore the preparation and characterization of a novel nanosized magnetic liposome containing the PEI-As(2)O(3)/Mn(0.5)Zn(0.5)Fe(2)O(4) complex. METHODS: Mn(0.5)Zn(0.5)Fe(2)O(4) and As(2)O(3)/Mn(0.5)Zn(0.5)Fe(2)O(4) nanoparticles were prepared by chemical coprecipitation and loaded with PEI. The PEI- As(2)O(3)/Mn(0.5)Zn(0.5)Fe(2)O(4) complex was characterized using transmission electron and scanning electron microscopy, X-ray diffraction, energy dispersive spectrometry, and Fourier transform infrared spectroscopy. Cell transfection experiments were performed to evaluate the transfect efficiency. Magnetic nanoliposomes were prepared by rotatory evaporation and their shape, diameter, and thermodynamic characteristics were observed. RESULTS: Mn(0.5)Zn(0.5)Fe(2)O(4) and PEI-As(2)O(3)/Mn(0.5)Zn(0.5)Fe(2)O(4) nanoparticles were spherical, with an average diameter of 20-40 nm. PEI-As(2)O(3)/Mn(0.5)Zn(0.5)Fe(2)O(4) was an appropriate carrier for the delivery of a foreign gene to HepG2 cells. Energy dispersive spectrometry results confirmed the presence of the elements nitrogen and arsenic. Nanoliposomes of approximately 100 nm were observed under a transmission electron microscope. Upon exposure to an alternating magnetic field, they also had good magnetic responsiveness, even though Mn(0.5)Zn(0.5)Fe(2)O(4)was modified by PEI and encased in liposomes. Temperatures increased to 37°C-54°C depending on different concentrations of PEI-As(2)O(3)/Mn(0.5)Zn(0.5)Fe(2)O(4)and remained stable thereafter. CONCLUSION: Our results suggest that PEI-As(2)O(3)/Mn(0.5)Zn(0.5)Fe(2)O(4) magnetic nanoliposomes are an excellent biomaterial, which has multiple benefits in tumor thermotherapy, gene therapy, and chemotherapy.

Arterial embolization hyperthermia using As2O3 nanoparticles in VX2 carcinoma-induced liver tumors.

BACKGROUND: Combination therapy for arterial embolization hyperthermia (AEH) with arsenic trioxide (As(2)O(3)) nanoparticles (ATONs) is a novel treatment for solid malignancies. This study was performed to evaluate the feasibility and therapeutic effect of AEH with As(2)O(3) nanoparticles in a rabbit liver cancer model. The protocol was approved by our institutional animal use committee. METHODOLOGY/PRINCIPAL FINDINGS: In total, 60 VX(2) liver-tumor-bearing rabbits were randomly assigned to five groups (n = 12/group) and received AEH with ATONs (Group 1), hepatic arterial embolization with ATONs (Group 2), lipiodol (Group 3), or saline (Group 4), on day 14 after tumor implantation. Twelve rabbits that received AEH with ATONs were prepared for temperature measurements, and were defined as Group 5. Computed tomography was used to measure the tumors' longest dimension, and evaluation was performed according to the Response Evaluation Criteria in Solid Tumors. Hepatic toxicity, tumor necrosis rate, vascular endothelial growth factor level, and microvessel density were determined. Survival rates were measured using the Kaplan-Meier method. The therapeutic temperature (42.5°C) was obtained in Group 5. Hepatotoxicity reactions occurred but were transient in all groups. Tumor growth was delayed and survival was prolonged in Group 1 (treated with AEH and ATONs). Plasma and tumor vascular endothelial growth factor and microvessel density were significantly inhibited in Group 1, while tumor necrosis rates were markedly enhanced compared with those in the control groups. CONCLUSIONS: ATON-based AEH is a safe and effective treatment that can be targeted at liver tumors using the dual effects of hyperthermia and chemotherapy. This therapy can delay tumor growth and noticeably inhibit tumor angiogenesis.

Novel microbial transformation of resibufogenin by Absidia coerules.

Resibufogenin is one of the major active components of the Chinese medicine ChanSu. In this paper, microbial transformation of resibufogenin by Absidia coerules AS 3.3382 was investigated and five metabolites were isolated and identified as 5beta-hydroxy-resibufogenin (2), 3-epi-resibufogenin (3), 3alpha-hydroxy-15-oxo-14alphaH-bufa-20, 22-dienolide (4), 3alpha,14alpha,15beta-trihydroxy-bufa-20, 22-dienolide (5) and 3-epi-15beta-hydroxy-bufalin (6). Among them, 4-6 are novel compounds, and compound 3 is a major transformed product. The cytotoxicities of the compounds against Bel-7402 and Hela cells were investigated, and our result suggested that 14,15-OH configuration was directly related to the cytotoxicities of bufadienolides.

[Efficacy of FORFIRI regimen on oxaliplatin-based chemotherapy-failed advanced colorectal cancer].

BACKGROUND AND OBJECTIVE: Irinotecan (CPT-11), oxaliplatin, 5-fluorouracil (5-FU) and capecitabine are main active agents for advanced colorectal cancer. FORFIRI regimen is recommended for the patients who were treated with oxaliplatin plus 5-FU or capecitabine previously. This study was to investigate the efficacy and safety of FORFIRI regimen in treating advanced colorectal cancer failing to prior oxaliplatin-based chemotherapy, and analyze the impacts of clinical factors on the responses. METHODS: A total of 90 patients with advanced colorectal adenocarcinoma, who had received prior adjuvant FOLFOX6 regimen and progressed within 12 months after the completion of therapy or had no response to prior FOLFOX6/CapeOX regimen as first-line therapy, were treated with FORFIRI regimen. The efficacy and adverse events were observed. RESULTS: Of the 81 evaluable patients, two achieved complete remission, 20 achieved partial remission and 34 had stable disease. The overall response rate was 27.2% and disease control rate was 69.1%. The median time to progression was 6.8 months (95% CI, 4.9-8.8 months) and median overall survival time was 18.8 months (95% CI, 17.5-20.2 months). The main adverse events time were nausea, vomiting, neutropenia, alopecia, fatigue, impaired liver function, oral mucositis and diarrhea. Grade III adverse events included alopecia in 15 patients (16.7%), vomiting in 10 patients (11.1%), nausea in eight patients (8.9%), neutropenia in five patients (5.6%), impaired liver function in two patients (2.2%) and oral mucositis in two patients (2.2%). CONCLUSION: FOLFIRI regimen is effective and well-tolerated as salvage therapy for advanced colorectal cancer failing to prior FOLFOX6/CapeOX regimen, and thus can be used widely.

Nanosized As2O3/Fe2O3 complexes combined with magnetic fluid hyperthermia selectively target liver cancer cells.

AIM: To study the methods of preparing the magnetic nano-microspheres of Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) complexes and their therapeutic effects with magnetic fluid hyperthermia (MFH). METHODS: Nanospheres were prepared by chemical co-precipitation and their shape and diameter were observed. Hemolysis, micronucleus, cell viability, and LD(50) along with other in vivo tests were performed to evaluate the Fe(2)O(3) microsphere biocompatibility. The inhibition ratio of tumors after Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) injections combined with induced hyperthermia in xenograft human hepatocarcinoma was calculated. RESULTS: Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) particles were round with an average diameter of 20 nm and 100 nm as observed under transmission electron microscope. Upon exposure to an alternating magnetic field (AMF), the temperature of the suspension of magnetic particles increased to 41-51 degrees C, depending on different particle concentrations, and remained stable thereafter. Nanosized Fe(2)O(3) microspheres are a new kind of biomaterial without cytotoxic effects. The LD(50) of both Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) in mice was higher than 5 g/kg. One to four weeks after Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) complex injections into healthy pig livers, no significant differences were found in serum AST, ALT, BUN and Cr levels among the pigs of all groups (P > 0.05), and no obvious pathological alterations were observed. After exposure to alternating magnetic fields, the inhibition ratio of the tumors was significantly different from controls in the Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) groups (68.74% and 82.79%, respectively; P < 0.01). Tumors of mice in treatment groups showed obvious necrosis, while normal tissues adjoining the tumor and internal organs did not. CONCLUSION: Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) complexes exerted radiofrequency-induced hyperthermia and drug toxicity on tumors without any liver or kidney damage. Therefore, nanospheres are ideal carriers for tumor-targeted therapy.

Using thermal energy produced by irradiation of Mn-Zn ferrite magnetic nanoparticles (MZF-NPs) for heat-inducible gene expression.

One of the main advantages of gene therapy over traditional therapy is the potential to target the expression of therapeutic genes in desired cells or tissues. To achieve targeted gene expression, we developed a novel heat-inducible gene expression system in which thermal energy generated by Mn-Zn ferrite magnetic nanoparticles (MZF-NPs) under an alternating magnetic field (AMF) was used to activate gene expression. MZF-NPs, obtained by co-precipitation method, were firstly surface modified with cation poly(ethylenimine) (PEI). Then thermodynamic test of various doses of MZF-NPs was preformed in vivo and in vitro. PEI-MZF-NPs showed good DNA binding ability and high transfection efficiency. In AMF, they could rise to a steady temperature. To analyze the heat-induced gene expression under an AMF, we combined P1730OR vector transfection with hyperthermia produced by irradiation of MZF-NPs. By using LacZ gene as a reporter gene and Hsp70 as a promoter, it was demonstrated that expression of a heterogeneous gene could be elevated to 10 to 500-fold over background by moderate hyperthermia (added 12.24 or 25.81 mg MZF-NPs to growth medium) in tissue cultured cells. When injected with 2.6 or 4.6 mg MZF-NPs, the temperature of tumor-bearing nude mice could rise to 39.5 or 42.8 degrees C, respectively, and the beta-gal concentration could increase up to 3.8 or 8.1 mU/mg proteins accordingly 1 day after hyperthermia treatment. Our results therefore supported hyperthermia produced by irradiation of MZF-NPs under an AMF as a feasible approach for targeted heat-induced gene expression. This novel system made use of the relative low Curie point of MZF-NPs to control the in vivo hyperthermia temperature and therefore acquired safe and effective heat-inducible transgene expression.