Laparoscopic hepatectomy for hepatocellular carcinoma in patients with clinically significant portal hypertension: a systematic review and meta-analysis.

OBJECTIVE: To compare the effects of laparoscopic hepatectomy (LH) on the short-term and long-term outcomes in hepatocellular carcinoma (HCC) patients with and without clinically significant portal hypertension (CSPH). METHODS: A systematic literature search of the PubMed, EMBASE, and Cochrane databases was performed for articles published from inception to March 1, 2023. Meta-analysis of surgical and oncological outcomes was performed using a random effects model. Data were summarized as mean difference and risk ratio with 95% confidence intervals. RESULTS: Five cohort studies with a total of 310 HCC patients were included (CSPH 143; Non-CSPH 167). In terms of surgical outcomes, estimated blood loss and the length of hospital stay were significantly lower in the Non-CSPH group than in the CSPH group. There were no significant differences between the two groups regarding other surgical outcomes, including the operative time, ratio of conversion to open surgery, and overall complication rate. In addition, there were also no significant differences between the two groups regarding the oncological outcomes, such as 1-, 3-, and 5-year overall survival. CONCLUSIONS: HCC patients with and without CSPH who underwent LH had comparable surgical and oncological outcomes. LH is a safe and effective treatment for HCC patients with CSPH under the premise of rational screening of patients.

Robotic versus laparoscopic liver resection for liver malignancy: a systematic review and meta-analysis of propensity score-matched studies.

OBJECTIVE: How different surgical procedures, including the robotic-assisted liver resection (RLR) and laparoscopic liver resection (LLR), can affect the prognosis of patients with liver malignancies is unclear. Thus, in this study, we compared the effects of RLR and LLR on the surgical and oncological outcomes in patients with liver malignancies through propensity score-matched cohort studies. METHODS: The PubMed, Embase, and Cochrane databases were searched using Medical Subject Headings terms and keywords from inception until May 31, 2023. The quality of the included studies was assessed using the Newcastle-Ottawa quality assessment scale. The mean difference with 95% confidence interval (95% CI) was used for analysis of continuous variables; the risk ratio with 95% CI was used for dichotomous variables; and the hazard ratio with 95% CI was used for survival-related variables. Meta-analysis was performed using a random-effects model. RESULTS: Five high-quality cohort studies with 986 patients were included (370 and 616 cases for RLR and LLR, respectively). In terms of surgical outcomes, there were no significant differences in the operation time, conversion rate to open surgery, overall complication rate, major complication rate, and length of hospital stay between the RLR and LLR groups. In terms of oncological outcomes, there were no significant differences in the 5-year overall survival and disease-free survival between the two groups. CONCLUSION: Surgical and oncological outcomes are comparable between RLR and LLR on patients with liver malignancies. Therefore, the benefits of applying RLR in patients with liver malignancies need to be further explored.

CT radiomics model for predicting the Ki-67 proliferation index of pure-solid non-small cell lung cancer: a multicenter study.

Purpose: This study aimed to explore the efficacy of the computed tomography (CT) radiomics model for predicting the Ki-67 proliferation index (PI) of pure-solid non-small cell lung cancer (NSCLC). Materials and methods: This retrospective study included pure-solid NSCLC patients from five centers. The radiomics features were extracted from thin-slice, non-enhanced CT images of the chest. The minimum redundancy maximum relevance (mRMR) and least absolute shrinkage and selection operator (LASSO) were used to reduce and select radiomics features. Logistic regression analysis was employed to build predictive models to determine Ki-67-high and Ki-67-low expression levels. Three prediction models were established: the clinical model, the radiomics model, and the nomogram model combining the radiomics signature and clinical features. The prediction efficiency of different models was evaluated using the area under the curve (AUC). Results: A total of 211 NSCLC patients with pure-solid nodules or masses were included in the study (N=117 for the training cohort, N=49 for the internal validation cohort, and N=45 for the external validation cohort). The AUC values for the clinical models in the training, internal validation, and external validation cohorts were 0.73 (95% CI: 0.64-0.82), 0.75 (95% CI:0.62-0.89), and 0.72 (95% CI: 0.57-0.86), respectively. The radiomics models showed good predictive ability in diagnosing Ki-67 expression levels in the training cohort (AUC, 0.81 [95% CI: 0.73-0.89]), internal validation cohort (AUC, 0.81 [95% CI: 0.69-0.93]) and external validation cohort (AUC, 0.78 [95% CI: 0.64-0.91]). Compared to the clinical and radiomics models, the nomogram combining both radiomics signatures and clinical features had relatively better diagnostic performance in all three cohorts, with the AUC of 0.83 (95% CI: 0.76-0.90), 0.83 (95% CI: 0.71-0.94), and 0.81 (95% CI: 0.68-0.93), respectively. Conclusion: The nomogram combining the radiomics signature and clinical features may be a potential non-invasive method for predicting Ki-67 expression levels in patients with pure-solid NSCLC.

Expression profiles of lncRNAs, miRNAs, and mRNAs during the proliferative phase of liver regeneration in mice with liver fibrosis.

The role of lncRNAs in the regeneration of fibrotic liver is unclear. To address this issue, we established a 70% hepatectomy model of liver fibrosis in mice, used high-throughput sequencing technology to obtain the expression profiles of lncRNAs, miRNAs, and mRNAs, and constructed a lncRNA-miRNA-mRNA regulatory network. A total of 1329 lncRNAs, 167 miRNAs, and 6458 mRNAs were differentially expressed. On this basis, a lncRNA-miRNA-mRNA ceRNA regulatory network consisting of 38 DE lncRNAs, 24 DE miRNAs, and 299 DE mRNAs was constructed, and a transcription factor (TF) - mRNA regulatory network composed of 20 TFs and 98 DE mRNAs was built. Through the protein network analysis, a core protein interaction network composed of 20 hub genes was derived. Furthermore, Xist/miR-144-3p/Cdc14b and Snhg3/miR-365-3p/Map3k14 axes in the ceRNA regulatory network were verified by Real-Time quantitative PCR. Therefore, we concluded that these new insights may further our understanding of liver regeneration.

Integrated analysis of lncRNA/circRNA-miRNA-mRNA in the proliferative phase of liver regeneration in mice with liver fibrosis.

BACKGROUND: Non-coding RNAs play important roles in liver regeneration; however, their functions and mechanisms of action in the regeneration of fibrotic liver have not been elucidated. We aimed to clarify the expression patterns and regulatory functions of lncRNAs, circRNAs, miRNAs, and mRNAs in the proliferative phase of fibrotic liver regeneration. METHODS: Based on a mouse model of liver fibrosis with 70% hepatectomy, whole-transcriptome profiling was performed using high-throughput sequencing on samples collected at 0, 12, 24, 48, and 72 h after hepatectomy. Hub genes were selected by weighted gene co-expression network analysis and subjected to enrichment analysis. Integrated analysis was performed to reveal the interactions of differentially expressed (DE) lncRNAs, circRNAs, miRNAs, and mRNAs, and to construct lncRNA-mRNA cis- and trans-regulatory networks and lncRNA/circRNA-miRNA-mRNA ceRNA regulatory networks. Real-Time quantitative PCR was used to validate part of the ceRNA network. RESULTS: A total of 1,329 lncRNAs, 48 circRNAs, 167 miRNAs, and 6,458 mRNAs were differentially expressed, including 812 hub genes. Based on these DE RNAs, we examined several mechanisms of ncRNA regulatory networks, including lncRNA cis and trans interactions, circRNA parental genes, and ceRNA pathways. We constructed a cis-regulatory core network consisting of 64 lncRNA-mRNA pairs (53 DE lncRNAs and 58 hub genes), a trans-regulatory core network consisting of 103 lncRNA-mRNA pairs (18 DE lncRNAs and 85 hub genes), a lncRNA-miRNA-mRNA ceRNA core regulatory network (20 DE lncRNAs, 12 DE miRNAs, and 33 mRNAs), and a circRNA-miRNA-mRNA ceRNA core regulatory network (5 DE circRNAs, 5 DE miRNAs, and 39 mRNAs). CONCLUSIONS: These results reveal the expression patterns of lncRNAs, circRNAs, miRNAs, and mRNAs in the proliferative phase of fibrotic liver regeneration, as well as core regulatory networks of mRNAs and non-coding RNAs underlying liver regeneration. The findings provide insights into molecular mechanisms that may be useful in developing new therapeutic approaches to ameliorate diseases that are characterized by liver fibrosis, which would be beneficial for the prevention of liver failure and treatment of liver cancer.

Anchoring grassland sustainability with a nature-based small burrowing mammal control strategy.

Over the last 40 years, a burrowing mammal eradication policy has been prevalent on the Qinghai-Tibetan Plateau (QTP). This policy is based on similar burrowing mammal eradication programs in other areas and is justified on the assumptions that burrowing mammals compete with livestock for forage and contribute to grassland degradation. However, there is no clear theoretical or experimental evidence supporting these assumptions. This paper synthesizes the ecological functioning of small burrowing mammals in natural grasslands and discusses the irrationality and consequences of burrowing mammal eradication for sustainable livestock grazing and grassland degradation. Past burrowing mammal eradication efforts have failed because increased food availability for the remaining rodents and reduced predator populations led to rapid population rebounds. Herbivores differ in diet, and there is clear evidence that burrowing mammals, especially plateau zokors Myospalax baileyi, have a different diet than livestock. In QTP meadows, burrowing mammal eradication induces a shift towards plant communities with fewer species preferred by livestock and more species preferred by burrowing mammals. Thus, eradicating burrowing mammals has the opposite effect, a reduction in livestock preferred vegetation. We suggest that the policy of poisoning burrowing mammals needs to be reconsidered and revoked as soon as possible. We argue that incorporating density-dependent factors such as predation and food availability are essential for maintaining a low burrowing mammal density. For degraded grasslands, we suggest that the optimal sustainable approach is to decrease the intensity of livestock grazing. Lower grazing induces changes in vegetation structure and plant species composition that increases predation on burrowing mammals and decreases the abundance of plants preferred by burrowing mammals. Such a nature-based grassland management system maintains the density of burrowing mammals at a low stable density while minimizing human management and interventions.

Laparoscopic versus open repeat hepatectomy for recurrent hepatocellular carcinoma: a systematic review and meta-analysis of propensity score-matched cohort studies.

OBJECTIVE: The effectiveness of laparoscopic repeat hepatectomy (LRH) versus open repeat hepatectomy (ORH) on recurrent hepatocellular carcinoma (RHCC) is unclear. We compared the surgical and oncological outcomes of LRH and ORH in patients with RHCC with a meta-analysis of studies based on propensity score-matched cohorts. METHODS: A literature search was conducted on PubMed, Embase, and Cochrane Library with Medical Subject Headings terms and keywords until 30 September 2022. The quality of eligible studies was evaluated with the Newcastle-Ottawa Scale. Mean difference (MD) with a 95% CI was used for the analysis of continuous variables; odds ratio (OR) with 95% CI was used for binary variables; and hazard ratio with 95% CI was used for survival analysis. A random-effects model was used for meta-analysis. RESULTS: Five high-quality retrospective studies with 818 patients were included; 409 patients (50%) were treated with LRH and 409 (50%) with ORH. In most surgical outcomes, LRH was superior to ORH: less estimated blood loss, shorter operation time, lower major complication rate, and shorter length of hospital stay (MD=-225.9, 95% CI=[-360.8 to -91.06], P =0.001; MD=66.2, 95% CI=[5.28-127.1], P =0.03; OR=0.18, 95% CI=[0.05-0.57], P =0.004; MD=-6.22, 95% CI=[-9.78 to -2.67], P =0.0006). There were no significant differences in the remaining surgical outcomes: blood transfusion rate and overall complication rate. In oncological outcomes, LRH and ORH were not significantly different in 1-year, 3-year, and 5-year overall survival and disease-free survival. CONCLUSIONS: For patients with RHCC, most surgical outcomes with LRH were superior to those of ORH, but oncological outcomes with the two operations were similar. LRH may be a preferable option for the treatment of RHCC.

Laparoscopic versus open hepatectomy for intrahepatic cholangiocarcinoma: Systematic review and meta-analysis of propensity score-matched studies.

OBJECTIVE: To compare the effects of laparoscopic hepatectomy (LH) versus open hepatectomy (OH) on the short-term and long-term outcomes of patients with intrahepatic cholangiocarcinoma (ICC) through a meta-analysis of studies using propensity score-matched cohorts. METHODS: The literature search was conducted in PubMed, Embase, and Cochrane Library databases until August 31, 2022. Meta-analysis of surgical (major morbidity, the length of hospital stay, 90-day postoperative mortality), oncological (R0 resection rate, lymph node dissection rate) and survival outcomes (1-, 3-, and 5-year overall survival and disease-free survival) was performed using a random effects model. Data were summarized as relative risks (RR), mean difference (MD) and hazard ratio (HR) with 95% confidence intervals (95% CI). RESULTS: Six case-matched studies with 1054 patients were included (LH 518; OH 536). Major morbidity was significantly lower (RR = 0.57, 95% CI = 0.37-0.88, P = 0.01) and the length of hospital stay was significantly shorter (MD = -2.44, 95% CI = -4.19 to -0.69, P = 0.006) in the LH group than in the OH group, but there was no significant difference in 90-day postoperative mortality between the 2 groups. There were no significant differences in R0 resection rate, lymph node dissection rate, 1-, 3-, and 5-year overall survival or disease-free survival between the LH and OH groups. CONCLUSIONS: LH has better surgical outcomes and comparable oncological outcomes and survival outcomes than does OH on ICC. Therefore, laparoscopy is at least not inferior to open surgery for intrahepatic cholangiocarcinoma.

Oncological outcomes of anatomic versus non-anatomic resections for small hepatocellular carcinoma: systematic review and meta-analysis of propensity-score matched studies.

BACKGROUND: Primary liver cancer is the second-most commonly occurring cancer and has resulted in numerous deaths worldwide. Hepatic resection is of two main types, i.e., anatomic resection (AR) and non-anatomic resection (NAR). The oncological outcomes of hepatocellular carcinoma (HCC) patients after AR and NAR are still considered controversial. Therefore, we aimed to compare the impact of AR and NAR on the oncological outcomes of HCC patients with tumor diameters ≤ 5 cm using the propensity score matching method and research-based evidence. METHOD: A systematic literature search was conducted. The main outcomes were disease-free survival (DFS), overall survival (OS), intrahepatic recurrence rate, and extrahepatic metastasis rate. Relative risk (RR) was calculated from forest plots and outcomes using random-effects model (REM). RESULT: AR significantly improved DFS at 1, 3. and 5 years after surgery, compared to NAR (RR = 1.09, 95% CI = 1.04-1.15, P = 0.0003; RR = 1.16, 95% CI = 1.07-1.27, P = 0.0005; RR = 1.29, 95% CI = 1.07-1.55, P = 0.008). However, both of the difference in DFS at 7 years and OS at 1 and 3 years after AR versus that after NAR were not statistically significant. Nevertheless, the long-term OS associated with AR (5, 7, and 10 years) was superior to that associated with NAR (RR = 1.12, 95% CI = 1.03-1.21, P = 0.01; RR = 1.19, 95% CI = 1.04-1.36, P = 0.01; RR = 1.18, 95% CI = 1.05-1.34, P = 0.008). The difference in the intrahepatic recurrence rate after AR versus that after NAR was not statistically significant, but the extrahepatic metastasis rate after AR was significantly lower than that observed after NAR (RR = 0.61, 95% CI = 0.40-0.94, P = 0.03). CONCLUSION: Therefore, AR should be the preferred surgical approach for HCC patients with tumor diameters ≤ 5 cm. TRIAL REGISTRATION: PROSPERO registration number CRD42022330596.

Laparoscopic versus open liver resection for hepatocellular carcinoma in elderly patients: Systematic review and meta-analysis of propensity-score matched studies.

BACKGROUND: The outcomes of elderly (≥65 years) patients with hepatocellular carcinoma (HCC) after laparoscopic liver resection (LLR) vs open liver resection (OLR) are debated. We compared the surgical and oncological outcomes after LLR and OLR in elderly HCC patients based on matched cohort studies that performed propensity score matching (PSM). METHODS: A computer search of the PubMed, Embase, and Cochrane databases until January 31, 2022, was conducted using a combination of Medical Subject Heading (MeSH) terms and other terms. The Newcastle-Ottawa literature evaluation scale was used for quality assessment of the included studies that met the inclusion criteria and none of the exclusion criteria. The postoperative LLR and OLR markers after PSM were summarized. RESULTS: Seven matched cohort studies were included. There were 1346 patients after PSM, of which 673 (50%) underwent LLR and 673 (50%) underwent OLR. All studies were of high quality. For surgical outcomes, the length of surgery was longer in the LLR group than in the OLR group (RR = 29.47, 95% CI = 26.55-32.39, P < 0.00001), but the length of hospitalization was significantly shorter (RR = -1.05,95% CI = -1.24 to -0.86, P < 0.00001), and the incidence of total postoperative complications and severe complications were significantly fewer (RR = 0.69,95% CI = 0.60-0.79, P < 0.00001; RR = 0.49,95% CI = 0.35-0.71, P = 0.0001, respectively). There were no significant differences in overall survival or disease-free survival between the two groups (HR = 0.87, 95% CI = 0.63-1.21, P = 0.41; HR = 0.87, 95% CI = 0.69-1.08, P = 0.20, respectively). CONCLUSIONS: In elderly patients with HCC, LLR was associated with better surgical outcomes than OLR, but there was no significant difference in oncological outcomes. LLR should be the preferred surgical method for elderly patients with HCC.

RNA-seq transcriptome profiling of liver regeneration in mice identifies the miR-34b-5p/phosphoinositide-dependent protein kinase 1 axis as a potential target for hepatocyte proliferation.

Characterized by compensatory hyperplasia dependent on hepatocyte proliferation, the liver will initiate regeneration after partial hepatectomy (PH) and acute or chronic injuries. A variety of genes and noncoding RNAs play pivotal roles in these cell proliferation and growth processes. However, it is still unclear how competition endogenous RNAs (ceRNAs) modulate cellular activities during each phase of liver regeneration, and the specific mechanisms of posttranscriptional gene expression regulation in hepatocyte proliferation remain to be elucidated. To investigate the mechanism of liver regeneration through RNA-seq profiling and to determine the role of miR-34b-5p/PDK1 on hepatocyte proliferation, we established a 2/3 PH mouse model for whole transcriptome profiling based on high-throughput sequencing techniques. We subsequently constructed a lncRNA-miRNA-mRNA ceRNA regulatory network through integrative analyses of RNA interactions. Finally, plasmid transfection in NCTC 1469 cells, dual luciferase reporter gene assay, quantitative real-time PCR, western blotting, Cell Counting Kit-8, and EdU-DNA synthesis cell proliferation assay were used to demonstrate the role of the miR-34b-5p/PDK1 axis in hepatocyte proliferation in vitro. A total of 1443 mRNAs (962 up, 481 down), 48 miRNAs (35 up, 13 down), and 1955 lncRNAs (986 up, 969 down) were identified as significantly differentially expressed. We then successfully constructed a ceRNA regulatory network consisting of 7 lncRNAs, 15 miRNAs, and 347 mRNAs based on the predicted inverse interactions among ceRNAs. Additionally, miR-34b-5p/PDK1 was predicted to be closely related to hepatocyte proliferation. We further demonstrated that miR-34b-5p could bind specifically to the 3'-untranslated region (3'-UTR) of PDK1 using the dual luciferase reporter assay. Ectopic overexpression of miR-34b-5p significantly reduced the mRNA and protein expression of PDK1, while it markedly inhibited the proliferation of mouse NCTC 1469 cells in vitro. In contrast, knocking down miR-34b-5p exhibited the inverse effects on PDK1 expression and hepatocyte proliferation. Through analyzing the ceRNA network during mouse liver regeneration, this study reveals that miR-34b-5p can inhibit hepatocyte proliferation through negatively regulating PDK1 and may be a potential pharmacological intervention target.

Nitrogen deposition magnifies destabilizing effects of plant functional group loss.

Terrestrial ecosystems are under threat by the co-occurring biodiversity loss and nitrogen (N) deposition. Awareness is growing that the stabilizing effects of plant diversity on productivity depend on environmental context, but it remains unknown about how the loss of plant functional groups and N deposition interactively influence species richness and community stability. Here we carried out an eight-year experiment of plant functional groups removal and N addition experiment in subalpine meadow. We found that the removal of plant functional groups and N addition interactively affected averaged plant species richness and community stability. Without N addition, the absence of forbs, but not other functional groups, significantly decreased average species richness and community stability through decreasing species asynchrony (i.e., asynchronous dynamics among species under fluctuating conditions). Under N addition, the absence of forbs, grasses and legumes all led to significant declines in average species richness, causing a decrease in community stability by decreasing species asynchrony, among which the absence of forbs had the greatest negative effects on community stability. Moreover, N addition reinforced the destabilizing effects caused by the loss of functional groups. Our findings show that the diverse forbs maintain plant community stability through asynchronous dynamics among species, especially under N deposition scenario. Therefore, we suggest that conservation and restoration of plant communities and their stability would benefit from a functional-group specific strategy by considering the largely ignored forb species, while helps guide conservation management efforts to reduce temporal variability for ecosystem service in the face of uncertain species extinction and N deposition scenarios.

RGBT Tracking via Noise-Robust Cross-Modal Ranking.

Existing RGBT tracking methods usually localize a target object with a bounding box, in which the trackers are often affected by the inclusion of background clutter. To address this issue, this article presents a novel algorithm, called noise-robust cross-modal ranking, to suppress background effects in target bounding boxes for RGBT tracking. In particular, we handle the noise interference in cross-modal fusion and seed labels from the following two aspects. First, the soft cross-modality consistency is proposed to allow the sparse inconsistency in fusing different modalities, aiming to take both collaboration and heterogeneity of different modalities into account for more effective fusion. Second, the optimal seed learning is designed to handle label noises of ranking seeds caused by some problems, such as irregular object shape and occlusion. In addition, to deploy the complementarity and maintain the structural information of different features within each modality, we perform an individual ranking for each feature and employ a cross-feature consistency to pursue their collaboration. A unified optimization framework with an efficient convergence speed is developed to solve the proposed model. Extensive experiments demonstrate the effectiveness and efficiency of the proposed approach comparing with state-of-the-art tracking methods on GTOT and RGBT234 benchmark data sets.

Selective Vascular Endothelial Growth Factor Receptor Inhibitors Provide Limited Benefits for Metastatic Colorectal Cancer: A Meta-Analysis.

BACKGROUND: Metastatic colorectal cancer (mCRC) is one of the most common and deadly cancers worldwide. For most patients diagnosed with mCRC and managed with 5-fluorouracil (5-FU)/leucovorin plus oxaliplatin (FOLFOX), the median survival time is still less than 2 years. Small molecule selective vascular endothelial growth factor receptor (VEGFR) inhibitors have been demonstrated to have strong anti-tumour activity in various cancer models. OBJECTIVE: To demonstrate the efficacy and safety of selective VEGFR inhibitors in the management of mCRC. METHODS: A comprehensive search in PubMed, EMBASE, Web of Science, Ovid MEDLINE, Google Scholar, Springer and Cochrane Central databases was performed for randomized controlled trials (RCTs) focusing on the effect of selective VEGFR inhibitors on mCRC. The primary outcome measures were progression-free survival (PFS) rates, overall survival (OS) rates, complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rates (ORRs), disease control rates (DCRs) and adverse effect (AE) rates. The dates of the included studies ranged from the inception of the database to January 15, 2020. RESULTS: Twenty-two RCTs were included. A total of 9362 patients met the inclusion criteria. Compared with placebo, selective VEGFR inhibitors significantly increased the PFS rate, SD, PR and DCR, reduced PD, caused more treatment-emergent adverse events (TEAEs), hypertension, hand-foot skin reaction, diarrhoea, fatigue, and thrombocytopaenia and increased aspartate aminotransferase(AST) concentration. There was no significant difference between selective VEGFR inhibitors and placebo regarding OS rate, CR, ORR, proteinuria, hyperbilirubinaemia or alkaline phosphatase(ALP) concentration. Additionally, compared with FOLFOX4+placebo, FOLFOX4+ selective VEGFR inhibitors, clearly reduced PD, and caused more 3-4 AEs, serious AEs, hypertension, hand-foot syndrome, diarrhoea, nausea, vomiting, decreased appetite, dehydration, fatigue, dizziness, neutropaenia and thrombocytopaenia. For PFS rate, OS rate, CR, PR, SD, ORR, abdominal pain, peripheral sensory neuropathy, asthaenia, anaemia and hypokalaemia rates, there was no significant difference between FOLFOX4+ selective VEGFR inhibitors and FOLFOX4+placebo. However, compared with FOLFOX4+bevacizumab, FOLFOX4+selective VEGFR inhibitors, led to increased hypertension, neutropaenia, fatigue, thrombocytopaenia and asthaenia. There is no clear difference between FOLFOX4+selective VEGFR inhibitors and FOLFOX4+ bevacizumab with regard to PFS rate, OS rate, CR, PR, SD, PD, ORR, diarrhoea, nausea, vomiting, peripheral neuropathy and abdominal pain rates. Selective VEGFR inhibitors+cetuximab increased PFS and PR and reduced PD compared to cetuximab, but there was no statistical difference between the two groups for OS and SD. CONCLUSION: Compared with placebo or cetuximab, selective VEGFR inhibitors alone or combined with cetuximab seemed to be more efficacious for mCRC respectively; however, the effects were not better than FOLFOX4 alone or when combined with bevacizumab for mCRC. Additionally, selective VEGFR inhibitors were not as safe as placebo or FOLFOX4 alone or in combination with bevacizumab in mCRC.

[Effects of sub-micro emulsion composition on cellular disposition of incorporated lipophilic drug].

OBJECTIVE: To investigate the effects of sub-micro emulsion composition on cellular uptake and disposition of incorporated lipophilic drug. METHODS: Sub-micro emulsions containing 10 % oil, 1.2 % lecithin and 2.25 % glycerol were prepared, and the fluorescent agent coumarin 6 was used as a model drug. The effects of oil types, co-surfactants and cationic lipid on uptake and elimination kinetics of 6-coumarin in HeLa cells were studied. The uptake mechanism of sub-micro emulsions was further investigated. RESULTS: Oil type and Tweens had no influence on the cellular uptake. Modifications of surfactants with Span series increased the cellular influx, among which Span 20 with hydrophilic-lipophilic balance (HLB) value of 8.6 was the best enhancer. The intracellular drug level reached up to (46.09 ± 1.98)ng/µg protein which had significant difference with control group [(38.54 ± 0.34)ng/µg protein]. The positively charged emulsions significantly increased the uptake rate constant and elimination rate constant which were 4 times and 1.5 times of those in anionic groups, respectively. The uptake enhancement was also observed in cationic emulsions, cellular concentrations at plateau were (42.73 ± 0.84)ng/µg protein, which was about 3 times of that in anionic emulsions [(15.71 ± 0.74)ng/µg protein], when extracellular drug concentration kept at 100 ng/ml. Cationic emulsions delivered the payload mainly by direct drug transfer to contacted cells, while the negative ones depended on both drug passive diffusion and clathrin-mediated endocytosis of drug containing oil droplets which accounted for 20% of the intracellular drug. CONCLUSION: Interfacial characteristic of sub-micro emulsions such as co-surfactants HLB as well as zeta potentials can influence lipophilic drug both in cellular uptake and elimination.