Tumor-derived extracellular vesicles delivering TNF-α promotes colorectal cancer metastasis via the NF-kB/LAMB3/AKT axis by targeting SNAP23.

Accumulating evidence have demonstrated that cytokines are enriched in tumor-derived extracellular vesicles (EVs) and widely involved in tumorigenesis of various types of carcinomas, including colorectal cancer (CRC). Nevertheless, the functions of cytokines in EVs secreted from colorectal cancer cells remain largely unknown. In the present study, we found that TNF-α was elevated in EVs from CRC patient serum samples and CRC cell lines, of which the expression was associated with aggressive features of colorectal cancer. EV TNF-α secretion is dependent on synaptosome-associated protein 23 (SNAP23). Functional experiments revealed that EV TNF-α promotes CRC cell metastasis via the NF-κB pathway by targeting SNAP23. Mechanistically, SNAP23 was transcriptionally upregulated by EV TNF-α/NF-κB axis to enhance the expression of laminin subunit beta-3 (LAMB3), thereby activating the PI3K/AKT signaling pathway and consequently facilitate CRC progression. Based on our findings, we could conclude that EV TNF-α plays an oncogenic role in CRC progression through SNAP23, which in turn promotes EV TNF-α secretion, suggesting that EV TNF-α/SNAP23 axis may serve as a diagnostic biomarker and potential therapeutic target for CRC.

Novel biomarkers to predict treatment response and prognosis in locally advanced rectal cancer undergoing neoadjuvant chemoradiotherapy.

PURPOSE: To identify genes associated with treatment response and prognosis for locally advanced rectal cancer (LARC) patients receiving neoadjuvant chemoradiotherapy (NCRT). METHODS: In our cohort, gene expression profiles of 64 tumor biopsy samples before NCRT were examined and generated. Weighted gene co-expression network analysis was performed to identify gene modules. External validation datasets included GSE3493, GSE119409, and GSE133057. The expression of candidate genes was evaluated using immunohistochemistry (IHC). TIMER was used to assess immune infiltration. RESULTS: We identified and validated the capability to predict the treatment response of CCT5 and ELF1 using our data and external validation datasets. The trends of survival differences of candidate genes in the GSE133057 dataset were similar to our cohort. High levels of CCT5 and ELF1 expression were associated with NCRT resistance and poor prognosis. Furthermore, the expression of CCT5 and ELF1 were also assessed in 117 LARC patients' samples by the IHC method. Based on IHC results and Cox analysis, the risk score model with CCT5 and ELF1 was constructed and performed well. The risk score was an independent prognostic factor for progression-free survival and overall survival in LARC patients and was then used to build nomogram models. The underlying mechanisms of CCT5 and ELF1 were explored using gene set enrichment analysis. The underlying pathway including apoptosis, cell cycle, and other processes. CCT5 and ELF1 expressions were significantly correlated with immune cell infiltration. CONCLUSION: CCT5 and ELF1 were determined as biomarkers for treatment response and prognosis in LARC patients. The risk score model and nomograms helped predict treatment response and survival outcomes for LARC patients undergoing NCRT.

Necessity of external iliac lymph nodes and inguinal nodes radiation in rectal cancer with anal canal involvement.

BACKGROUND AND PURPOSE: We aimed to explore the necessity of the external iliac lymph nodes (EIN) along with inguinal nodes (IN) region in clinical target volume (CTV) for rectal carcinomas covering the anal canal region. MATERIALS AND METHODS: This research premise enrolled 399 patients who had primary low rectal cancer detected below the peritoneal reflection via magnetic resonance imaging (MRI) and were treated with neoadjuvant radiotherapy (NRT), without elective EIN along with IN irradiation. We stratified the patients into two groups based on whether the lower edge of the rectal tumor extended to the anal canal (P group, n = 109) or not (Rb group, n = 290). Comparison of overall survival (OS), locoregional recurrence-free survival (LRFS), disease-free survival (DFS), as well as distant metastasis-free survival (DMFS) were performed via inverse probability of treatment weighting (IPTW) along with multivariable analyses. We compared the EIN and IN failure rates between the two groups via the Fisher and Gray's test. RESULTS: P group showed a similar adjusted proportion along with five-year cumulative rate of EIN failure compared with the Rb group. The adjusted proportion and five-year cumulative rate of IN failure in the P group was higher in comparison to the Rb group. There were no remarkable differences in the adjusted five-year OS, DFS, DMFS or LRFS between the two groups. Anal canal involvement (ACI) exhibited no effect on OS, LRFS, DFS, or DMFS. CONCLUSIONS: During NRT for rectal cancer with ACI, it may be possible to exclude the EIN and IN from the CTV.

Tumour-associated macrophage-derived DOCK7-enriched extracellular vesicles drive tumour metastasis in colorectal cancer via the RAC1/ABCA1 axis.

BACKGROUND: Metastasis accounts for the majority of deaths among patients with colorectal cancer (CRC). Here, the regulatory role of tumour-associated macrophages (TAMs) in CRC metastasis was explored. METHODS: Immunohistochemical (IHC) analysis of the TAM biomarker CD163 was conducted to evaluate TAM infiltration in CRC. Transwell assays and an ectopic liver metastasis model were established to evaluate the metastatic ability of tumour cells. RNA sequencing (RNA-seq) and liquid chromatography-mass spectrometry (LC-MS) were applied to identify the differentially expressed genes and proteins in CRC cells and in TAM-derived extracellular vesicles (EVs). Cholesterol content measurement, a membrane fluidity assay and filipin staining were performed to evaluate cholesterol efflux in CRC cells. RESULTS: Our results showed that TAM infiltration is positively correlated with CRC metastasis. TAMs can facilitate the migration and invasion of MC-38 and CT-26 cells via EVs. According to the RNA-seq data, TAM-EVs increase cholesterol efflux and enhance membrane fluidity in CRC cells by regulating ABCA1 expression, thus affecting the motility of CRC cells. Mechanistically, DOCK7 packaged in TAM-EVs can activate RAC1 in CRC cells and subsequently upregulate ABCA1 expression by phosphorylating AKT and FOXO1. Moreover, IHC analysis of ABCA1 in patients with liver-metastatic CRC indicated that ABCA1 expression is significantly greater in metastatic liver nodules than in primary CRC tumours. CONCLUSIONS: Overall, our findings suggest that DOCK7 delivered via TAM-EVs could regulate cholesterol metabolism in CRC cells and CRC cell metastasis through the RAC1/AKT/FOXO1/ABCA1 axis. DOCK7 could thus be a new therapeutic target for controlling CRC metastasis.

Mitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFß1-mediated tumor progression.

Although nontumor components play an essential role in colon cancer (CC) progression, the intercellular communication between CC cells and adjacent colonic epithelial cells (CECs) remains poorly understood. Here, we show that intact mitochondrial genome (mitochondrial DNA, mtDNA) is enriched in serum extracellular vesicles (EVs) from CC patients and positively correlated with tumor stage. Intriguingly, circular mtDNA transferred via tumor cell-derived EVs (EV-mtDNA) enhances mitochondrial respiration and reactive oxygen species (ROS) production in CECs. Moreover, the EV-mtDNA increases TGFß1 expression in CECs, which in turn promotes tumor progression. Mechanistically, the intercellular mtDNA transfer activates the mitochondrial respiratory chain to induce the ROS-driven RelA nuclear translocation in CECs, thereby transcriptionally regulating TGFß1 expression and promoting tumor progression via the TGFß/Smad pathway. Hence, this study highlights EV-mtDNA as a major driver of paracrine metabolic crosstalk between CC cells and adjacent CECs, possibly identifying it as a potential biomarker and therapeutic target for CC.

Particle radiotherapy in the era of radioimmunotherapy.

Radiotherapy (RT) is one of the key modalities for cancer treatment, and more than 70% of tumor patients will receive RT during the course of their disease. Particle radiotherapy, such as proton radiotherapy, carbon-ion radiotherapy (CIRT) and boron neutron capture therapy (BNCT), is currently available for the treatment of patients Immunotherapy combined with photon RT has been successfully used in the clinic. The effect of immunotherapy combined with particle RT is an area of interest. However, the molecular mechanisms underlying the effects of combined immunotherapy and particle RT remain largely unknown. In this review, we summarize the properties of different types of particle RT and the mechanisms underlying their radiobiological effects. Additionally, we compared the main molecular players in photon RT and particle RT and the mechanisms involved the RT-mediated immune response.

Prognostic value of mesorectal package area in patients with locally advanced rectal cancer following neoadjuvant chemoradiotherapy: A retrospective cohort study.

Background: The aim of this study is to explore the most effective inflammation, magnetic resonance imaging (MRI), and nutrition markers for survival and pathology complete response (pCR) in patients with locally advanced rectal cancer (LARC). Methods: A total of 278 patients with LARC undergoing neoadjuvant chemoradiotherapy (NCRT) and radical surgery from 2016 to 2019 were included. The X-tile method was used to select the optimal cutoff points for the mesorectal package area (MPA), advanced lung cancer inflammation index (ALI), prognostic nutritional index (PNI), systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) scores. Cox regression analysis was used to identify risk factors of disease-free survival (DFS). To discover pCR risk factors, logistic regression analysis was employed. A predictive nomogram for DFS was constructed. Results: According to the least absolute shrinkage and selection operator analysis, the MPA was the only significant predictor for the DFS in patients with LARC. Kaplan-Meier (K-M) analysis demonstrated that groups with higher MPA, PNI, SII, NLR, MLR, and ALI score had improved DFS (all P < 0.05). Receiver operating characteristic (ROC) analysis revealed that the MPA and PNI could accurately predict the pCR in patients with LARC after NCRT. The MPA score and NLR score were found to be independent predictors of DFS after NCRT using Cox regression analysis. Logistical regression analysis demonstrated that the MPA score, PNI score, and pre-NCRT cN stage were all independent predictors of pCR in patients with LARC after NCRT. Recursive partitioning analysis and time-independent ROC curve analysis demonstrated that MPA score was the most important predictor of pCR and prognosis in patients with LARC after NCRT. Conclusions: MPA was identified as the most effective marker for MRI, and the prognostic value was further confirmed by time-ROC analysis. More intense adjuvant treatment could be considered for lower-MPA score patients with LARC after NCRT. Obesity in the pelvis encourages the understanding of the prognosis prediction of patients with LARC after NCRT.

LncRNAs Associated with Chemoradiotherapy Response and Prognosis in Locally Advanced Rectal Cancer.

BACKGROUND: There are only limited studies on the long non-coding RNAs (lncRNAs) associated with neoadjuvant chemoradiotherapy (NCRT) response and prognosis of locally advanced rectal cancer (LARC) patients. This study identified lncRNAs associated with NCRT response and prognosis in CRC patients and explored their potential predictive mechanisms. METHODS: The study subjected the LncRNA expression profiles from our previous gene chip data to LASSO and identified a four-lncRNA signature that predicted NCRT response and prognosis. A Cox regression model was subsequently performed to identify the prognostic risk factors. The function of LINC00909, the lncRNA with the most powerful predictive ability, was finally identified in vivo and in vitro using CRC cell lines. RESULTS: A comparison of the relative lncRNA expression of NCRT-responsive and non-responsive patients revealed four hub lncRNAs: DBET, LINC00909, FLJ33534, and HSD52 with AUC = 0.68, 0.73, 0.73, and 0.70, respectively (all p < 0.05). COX regression analysis further demonstrated that DBET, LINC00909 and FLJ33534 were associated with the DFS in CRC patients. The expression of the four lncRNAs was also significant in LARC patients who had not undergone NCRT (all p < 0.05). A risk score model was subsequently constructed based on the results of the multivariate COX analysis and used to predict NCRT response and prognosis in the CRC and LARC patients. The expression and prognosis of DBET, LINC00909 and FLJ33534 in the CRC tissues were further validated in the R2 platform and Oncomine database. Notably, overexpression of the LINC00909 increased the cell line resistance to the 5-FU and radiotherapy in vivo and in vitro. CONCLUSION: DBET, LINC00909, and FLJ33534 are potential novel biomarkers for predicting NCRT response and prognosis in CRC patients. In particular, LINC00909 is an effective oncogene in CRC that could be used as a novel therapeutic target to enhance NCRT response.

Development and Validation of a Robust Pyroptosis-Related Signature for Predicting Prognosis and Immune Status in Patients with Colon Cancer.

BACKGROUND: Pyroptosis has been confirmed as a type of inflammatory programmed cell death in recent years. However, the prognostic role of pyroptosis in colon cancer (CC) remains unclear. METHODS: Dataset TCGA-COAD which came from the TCGA portal was taken as the training cohort. GSE17538 from the GEO database was treated as validation cohorts. Differential expression genes (DEGs) between normal and tumor tissues were confirmed. Patients were classified into two subgroups according to the expression characteristics of pyroptosis-related DEGs. The LASSO regression analysis was used to build the best prognostic signature, and its reliability was validated using Kaplan-Meier, ROC, PCA, and t-SNE analyses. And a nomogram based on the multivariate Cox analysis was developed. The enrichment analysis was performed in the GO and KEGG to investigate the potential mechanism. In addition, we explored the difference in the abundance of infiltrating immune cells and immune microenvironment between high- and low-risk groups. And we also predicted the association of common immune checkpoints with risk scores. Finally, we verified the expression of the pyroptosis-related hub gene at the protein level by immunohistochemistry. RESULTS: A total of 23 pyroptosis-related DEGs were identified in the TCGA cohort. Patients were classified into two molecular clusters (MC) based on DEGs. Kaplan-Meier survival analysis indicated that patients with MC1 represented significantly poorer OS than patients with MC2. 13 overall survival- (OS-) related DEGs in MCs were used to construct the prognostic signature. Patients in the high-risk group exhibited poorer OS compared to those in the low-risk group. Combined with the clinical features, the risk score was found to be an independent prognostic factor of CC patients. The above results are verified in the external dataset GSE17538. A nomogram was established and showed excellent performance. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that the varied prognostic performance between high- and low-risk groups may be related to the immune response mediated by local inflammation. Further analysis showed that the high-risk group has stronger immune cell infiltration and lower tumor purity than the low-risk group. Through the correlation between risk score and immune checkpoint expression, T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) was predicted as a potential therapeutic target for the high-risk group. CONCLUSION: The 13-gene signature was associated with OS, immune cells, tumor purity, and immune checkpoints in CC patients, and it could provide the basis for immunotherapy and predicting prognosis and help clinicians make decisions for individualized treatment.

Distribution and Antibiotic Resistance Patterns of Pathogenic Bacteria in Patients With Chronic Cutaneous Wounds in China.

Background: To determine the distribution and antimicrobial susceptibility pattern of pathogenic bacteria in patients with chronic cutaneous wounds on a national scale. Methods: A retrospective study was conducted using the data recorded between January 1, 2018 and January1, 2020 in 195 hospitals across China. After screening the data, 815 patients with chronic wounds were finally analyzed. The data collected included information about the patients' general condition and local cutaneous wound assessments, especially microbial culture and antibiotic susceptibility tests. The analyses were performed using SPSS Version 26. Results: The study included 815 patients (290 [35.6%] females; 63 [50-74] years). The most common causes of chronic cutaneous wounds were diabetes (183, 22.5%), infection (178, 21.8%), and pressure (140, 17.2%). Among these, 521(63.9%) samples tested yielded microbial growth, including 70 (13.4%) polymicrobial infection and 451 (86.6%) monomicrobial infection. The positive rate of microbial culture was highest in wound tissue of ulcers caused by infection (87.6%), followed by pressure (77.1%), diabetes (68.3%), and venous diseases (67.7%). Bates-Jensen wound assessment tool (BWAT) scores >25 and wounds that lasted for more than 3 months had a higher positive rate of microbial culture. BWAT scores >25 and wounds in the rump, perineum, and feet were more likely to exhibit polymicrobial infection. A total of 600 strains were isolated, of which 46.2% (277 strains) were Gram-positive bacteria, 51.3% (308 strains) were Gram-negative bacteria, and 2.5% (15 strains) were fungi. The most common bacterial isolates were Staphylococcus aureus (29.2%), Escherichia coli (11.5%), Pseudomonas aeruginosa (11.0%), Proteus mirabilis (8.0%), and Klebsiella pneumoniae (5.8%). The susceptibility tests showed that 116 cultured bacteria were Multidrug resistant (MDR) strains. The resistance rates of S. aureus were 92.0% (161/175) to penicillin, 58.3% (102/175) to erythromycin, and 50.9% (89/175) to clindamycin. Vancomycin was the most effective antibiotic (0% resistance rate) against all Gram-positive bacteria. Besides, the resistance rates of E. coli were 68.1% (47/69) to ampicillin, 68.1% (47/69) to ciprofloxacin, 60.9% (42/69) to levofloxacin. However, all the isolated Gram-negative bacteria showed low resistance rates to tigecycline (3.9%) and amikacin (3.6%). Conclusions: The distribution of bacteria isolated from chronic cutaneous wounds varies with the BWAT scores, causes, duration, and the location of wounds. Multidrug resistance is a serious health issue, and therefore antibiotics used in chronic wounds must be under strict regulation. Our findings may help clinicians in making informed decisions regarding antibiotic therapy.

Development and validation of risk and prognostic nomograms for bone metastases in Chinese advanced colorectal cancer patients.

BACKGROUND: Bone metastases (BM) from colorectal cancer (CRC) are often accompanied by extraosseous metastases, resulting in a dismal prognosis. The present study aimed to determine the risk factors for BM in metastatic CRC (mCRC) and the prognostic factors for CRC patients with BM. METHODS: The study was based on a training cohort of 214 mCRC patients (of which, 101 patients had BM) from our center, and a validation cohort of 511 mCRC patients (of which, 173 patients had BM) from another institute. Risk and prognostic nomograms for BM were developed using univariate and multivariate analyses. The goodness of fit, discrimination, and calibration performance of the nomograms were assessed by R2, concordance statistics (C-statistics), and the calibration curve. The results were internally validated using bootstrap resampling in the training cohort, and externally validated in the validation cohort. RESULTS: The novel BM risk nomogram comprised seven variables [degree of tumor differentiation, N-stage, serum alkaline phosphatase (ALP), lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), liver metastasis, and lung metastasis]. It showed good performance, with an R2 of 0.447 and a C-statistic of 0.846 [95% confidence interval (CI), 0.793 to 0.898] in the training cohort, and an R2 of 0.325 and a C-statistic of 0.792 (95% CI, 0.750 to 0.834) in the validation cohort. The optimal cutoff value to identify individuals at low or high risk was 56% probability, with a sensitivity of 71.3% and a specificity of 89.4%. The prognostic nomogram included five factors (tumor differentiation, number of extra-BM organs, number of BM lesions, ALP, and LDH), and had an R2 of 0.284 and a C-statistic of 0.723 (95% CI, 0.657 to 0.789) in the training set. This nomogram was externally validated in the validation cohort, with an R2 of 0.182 and a C-statistic of 0.682 (95% CI, 0.638 to 0.726). CONCLUSIONS: The developed and validated risk and prognostic nomograms showed good performance for predicting the occurrence of BM in mCRC as well as the prognosis of CRC patients with BM. The risk nomogram can be used as a cost-effective preliminary screening tool prior to bone scanning.

LncRNA MIR17HG promotes colorectal cancer liver metastasis by mediating a glycolysis-associated positive feedback circuit.

Glycolysis plays a crucial role in reprogramming the metastatic tumor microenvironment. A series of lncRNAs have been identified to function as oncogenic molecules by regulating glycolysis. However, the roles of glycolysis-related lncRNAs in regulating colorectal cancer liver metastasis (CRLM) remain poorly understood. In the present study, the expression of the glycolysis-related lncRNA MIR17HG gradually increased from adjacent normal to CRC to the paired liver metastatic tissues, and high MIR17HG expression predicted poor survival, especially in patients with liver metastasis. Functionally, MIR17HG promoted glycolysis in CRC cells and enhanced their invasion and liver metastasis in vitro and in vivo. Mechanistically, MIR17HG functioned as a ceRNA to regulate HK1 expression by sponging miR-138-5p, resulting in glycolysis in CRC cells and leading to their invasion and liver metastasis. More interestingly, lactate accumulated via glycolysis activated the p38/Elk-1 signaling pathway to promote the transcriptional expression of MIR17HG in CRC cells, forming a positive feedback loop, which eventually resulted in persistent glycolysis and the invasion and liver metastasis of CRC cells. In conclusion, the present study indicates that the lactate-responsive lncRNA MIR17HG, acting as a ceRNA, promotes CRLM through a glycolysis-mediated positive feedback circuit and might be a novel biomarker and therapeutic target for CRLM.

Androgen Receptor, Although Not a Specific Marker For, Is a Novel Target to Suppress Glioma Stem Cells as a Therapeutic Strategy for Glioblastoma.

Targeting androgen receptor (AR) has been shown to be promising in treating glioblastoma (GBM) in cell culture and flank implant models but the mechanisms remain unclear. AR antagonists including enzalutamide are available for treating prostate cancer patients in clinic and can pass the blood-brain barrier, thus are potentially good candidates for GBM treatment but have not been tested in GBM orthotopically. Our current studies confirmed that in patients, a majority of GBM tumors overexpress AR in both genders. Enzalutamide inhibited the proliferation of GBM cells both in vitro and in vivo. Although confocal microscopy demonstrated that AR is expressed but not specifically in glioma cancer stem cells (CSCs) (CD133+), enzalutamide treatment significantly decreased CSC population in cultured monolayer cells and spheroids, suppressed tumor sphere-forming capacity of GBM cells, and downregulated CSC gene expression at mRNA and protein levels in a dose- and time-dependent manner. We have, for the first time, demonstrated that enzalutamide treatment decreased the density of CSCs in vivo and improved survival in an orthotopic GBM mouse model. We conclude that AR antagonists potently target glioma CSCs in addition to suppressing the overall proliferation of GBM cells as a mechanism supporting their repurposing for clinical applications treating GBM.

Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer.

BACKGROUND: Mounting evidence has demonstrated the vital importance of tumor-associated macrophages (TAMs) and exosomes in the formation of the premetastatic niche. However, the molecular mechanisms by which tumor-derived exosomal miRNAs interact with TAMs underlying premetastatic niche formation and colorectal cancer liver metastasis (CRLM) remain largely unknown. METHODS: Transmission electron microscopy and differential ultracentrifugation were used to verify the existence of exosomes. In vivo and in vitro assays were used to identify roles of exosomal miR-934. RNA pull-down assay, dual-luciferase reporter assay, etc. were applied to clarify the mechanism of exosomal miR-934 regulated the crosstalk between CRC cells and M2 macrophages. RESULTS: In the present study, we first demonstrated the aberrant overexpression of miR-934 in colorectal cancer (CRC), especially in CRLM, and its correlation with the poor prognosis of CRC patients. Then, we verified that CRC cell-derived exosomal miR-934 induced M2 macrophage polarization by downregulating PTEN expression and activating the PI3K/AKT signaling pathway. Moreover, we revealed that hnRNPA2B1 mediated miR-934 packaging into exosomes of CRC cells and then transferred exosomal miR-934 into macrophages. Interestingly, polarized M2 macrophages could induce premetastatic niche formation and promote CRLM by secreting CXCL13, which activated a CXCL13/CXCR5/NFκB/p65/miR-934 positive feedback loop in CRC cells. CONCLUSIONS: These findings indicate that tumor-derived exosomal miR-934 can promote CRLM by regulating the crosstalk between CRC cells and TAMs. These findings reveal a tumor and TAM interaction in the metastatic microenvironment mediated by tumor-derived exosomes that affects CRLM. The present study also provides a theoretical basis for secondary liver cancer.

Dose escalation of preoperative short-course radiotherapy followed by neoadjuvant chemotherapy in locally advanced rectal cancer: protocol for an open-label, single-centre, phase I clinical trial.

INTRODUCTION: Preoperative radiotherapy followed by total mesorectal excision with adjuvant chemotherapy has been recommended as the preferred treatment method for locally advanced rectal cancer (LARC). Similar rates of local control, survival and toxicity were observed in preoperative long-course chemoradiotherapy (LCRT) (45-50.4 Gy in 25-28 fractions) and in short-course radiotherapy (SCRT) with 25 Gy over five fractions. Both regimens lower the local recurrence rates compared with that of surgery followed by postoperative radiotherapy. With the simplicity and lower cost of SCRT, a growing number of patients have been receiving SCRT as preoperative radiotherapy. However, the currently established SCRT (25 Gy over five fractions) followed immediately by surgery resulted in poor downstaging and sphincter preservation rate. The pathological complete response (pCR) rate is also markedly lower with SCRT than with LCRT (0.7%vs16%). Several studies recommended SCRT with delayed surgery for more than 4 weeks with expectation of improved pathological outcomes and fewer postoperative complications. While a number of clinical trials demonstrated a persistently better overall local control with SCRT than with LCRT, overall survival advantage has not been observed. Since survival is mainly depended on distant metastases, efforts should be made towards more effective pathological response and systemic treatment. Given the apparent advantages of SCRT, we aimed to establish a dose escalation of SCRT and sequential modified FOLFOX6 (mFOLFOX6) as preoperative therapy for LARC with objectives of achieving an optimal balance of safety, cost effectiveness and clinical outcome, and to support further investigation of this regimen in a phase II/III setting. METHODS: In this phase I study, three dose levels (6Gy×5F, 7Gy×5F, 8Gy×5F to gross tumour volume, while keeping the rest of irradiated volume at 5Gy×5) of SCRT followed by four cycles of mFOLFOX6 chemotherapy as neoadjuvant therapy will be tested by using the traditional 3+3 design. The pCR rate, R0 resection rate, sphincter preservation rate and treatment related toxicity will be assessed. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of Fujian Medical University Union Hospital (No. 2017YF020-02) and all participants provided written informed consent. Results from our study will be disseminated in international peer-reviewed journals. All study procedures were developed in order to assure data protection and confidentiality. TRIAL REGISTRATION NUMBER: NCT03466424; Pre-results.

Omega-3 polyunsaturated fatty acid supplementation and non-alcoholic fatty liver disease: A meta-analysis of randomized controlled trials.

BACKGROUND: Clinical trials examining the therapeutic benefit of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on nonalcoholic fatty liver disease (NAFLD) have reported inconsistent results. We performed a meta-analysis of randomized controlled trials (RCTs) examining the effect of ω-3 PUFA supplementation on NAFLD, and provide substantial evidence on whether ω-3 PUFA supplementation has a favorable effect for treating NAFLD. METHODS: We searched the PubMed, Cochrane Library, Springer Link, China National Knowledge Infrastructure (CNKI), Wanfang, and Chinese Scientific and Technological Journal (VIP) databases for RCTs on oral ω-3 PUFA supplementation in patients with NAFLD. The data were pooled; meta-analyses were conducted using random-effect or fixed-effect models. RESULTS: Eighteen studies involving 1424 patients were included. We found a significant benefit for ω-3 PUFAs vs control for liver fat, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase, triglycerides, insulin resistance, and glucose. However, there was significant interstudy heterogeneity. Subgroup and regression analyses showed no significantly clear methodologic discrepancy. Publication bias and serious adverse events were not detected. CONCLUSIONS: Our meta-analysis suggests that ω-3 PUFA supplementation may decrease liver fat and hepatic enzyme parameters. However, more large-scale, well-designed RCTs are needed to confirm the effect of ω-3 PUFA supplementation on these parameters.