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Adding irinotecan to neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC) increases the pathologic complete response (pCR) rate but brings more toxicities. Robust biomarkers to predict response to irinotecan-based nCRT are extremely necessary for selecting the right patients. Our previous study suggests that patient-derived tumor organoids (PDTOs) sensitivity to chemoradiotherapy matches patient responses. In this study, we investigated whether PDTOs sensitivity to irinotecan can predict complete response (CR) and survival. Eligible patients receiving irinotecan-based nCRT between April 5, 2017 and December 11, 2020 were enrolled in the training cohort (n = 91) for response prediction and survival analysis. Patients receiving nCRT between February 21, 2021 and September 17, 2021 were included in the validation cohort (n = 27). Predictive performances of irinotecan organoid size ratio (OSR) for CR or pCR were evaluated. The irinotecan-sensitive groups had higher response rates compared with the insensitive groups (training cohort: 71.8% vs 24.4%, P

In the simulation of discontinuous block systems, the discrete element method (DEM) has better computational efficiency and convergence than the finite element method (FEM). When several DEM particles are bonded together with parallel bonds (the bonded particle model, BPM), various shapes and block fractures can be simulated. The main aim of the BPM is to simulate a continuous material in which the stress distribution is continuous. Since the existing stress result for a single particle is an average value over the particle’s area, stress results do not exist in the area between particles. In this paper, the stress value for a single two-dimensional DEM particle is deduced. A stress recovery procedure with a linear stress function for a triangular element generated by the centroids of three bonded particles is proposed. In this way, the recovered stress field for the whole mesh composed of all triangular elements is continuous. A stress gradient exists in the whole mesh. This can also provide more accurate stress values for judging a fracture inside a block. Symmetrical and asymmetrical models are simulated by the BPM and FEM. Similar to the FEM results, the recovered stress results for the BPM can describe the stress distribution in the simulated continuous blocks. For the model with the theoretical stress solution, the recovered result and the theoretical solution coincide well.

Discontinuous deformation analysis (DDA) has been widely applied for the simulation of block systems that have many discontinuous surfaces. The penalty method is utilized to ensure that there are no penetrations between blocks. A linear polynomial function for displacement leads to a constant stress for a block, which cannot precisely describe the stress field within the block. Therefore, a high-order polynomial displacement function and a fine mesh are always used to improve the precision of the stress field. However, these means are not practical for simulating block systems that have many contacts. In this paper, the contact-stress-based stress recovery methods are proposed for DDA. High-precision solutions for the contact stresses on the boundaries of the blocks are utilized. The first-order Gaussian point of a block is the block’s centroid, where the constant stress obtained via DDA is of higher precision. The high-precision solutions for the stresses are utilized in the least squares method to recover a single block’s inner stress field. The proposed methods enhance the resolution of the stress field inside a single block without increasing the computational effort in the main iterative process for displacement in DDA. Numerical examples are simulated using both the finite element method (FEM) with a fine mesh and the proposed DDA program. The recovered DDA results can accurately describe the distribution of the stresses in a single block and, in some areas, have the same precision as the FEM results. Moreover, the precision of the proposed methods improves as the gradient of the contact stress on the boundary decreases.

e15598 Background: 5-FU-based regimens are the mainstay treatment for colorectal cancer. However, the limited response rate to 5-FU-based regimens hampered the increase in the treatment efficacy of locally advanced rectal cancer. During the drug screening in the rectal cancer organoid biobank (n = 106), we found out that more than half of the organoids that were resistant to 5-FU monotherapy and sensitive to irinotecan maintained sensitive status to the treatment of 5-FU combined with irinotecan (combination-sensitive), while a quite proportion of them turn to become remarkably resistant to 5-FU plus irinotecan (combination-resistant). Some studies suggested the mechanism of 5-FU-based resistance was associated with the activation of some oncogenic pathways. However, the mechanism of the addition of 5-FU promoting the resistance to irinotecan is still unclear. Methods: To investigate the relationship between the combination-resistant organoids and corresponding patient responses, we collected patient clinical responses and survival outcomes. RNA sequencing and ATAC sequencing were performed to identify differential genes and their enrichment pathways. Moreover, small molecule inhibitors were used to try to reverse the resistance induced by 5-FU. Results: Twenty-one organoids showed sensitivity to irinotecan and resistance to 5-FU. Among them, 8 organoids (38.1%) were combination-resistant and 13 organoids (61.9%) showed sensitivity to combination treatment. Combination-resistant organoids corresponding patients had worse pathologic tumor regression grades (pTRGs) distribution (8/8, 100% had TRGs of 2-3 versus 100% had TRGs of 0-1 in combination-sensitive patients; p < 0.05) and disease-free survival (DFS) rates (HR:11.57, 95% IC:1.025-130.5; p = 0.0047) than patients whose organoids were combination-sensitive. Combination-resistant organoids had higher expression of Ki-67 and CD44 and reduced cleaved-caspase 3 in the combination treatment group and 5-FU group compared with the irinotecan group and control. Furthermore, we identified hedgehog pathway activation after adding 5-FU to irinotecan in combination-resistant organoids through RNA sequencing and ATAC sequencing. GANT-61, an inhibitor of the hedgehog pathway, increased sensitivity to the combination of 5-FU and irinotecan in combination-resistant organoids. Conclusions: We found that organoids which are sensitive to irinotecan turn to become resistant to 5-FU combined with irinotecan. Moreover, corresponding patients had worse responses and a lower DFS rate. The hedgehog pathway is activated in these organoids after the addition of 5-FU to irinotecan, and GANT-61 could reverse the resistance caused by 5-FU. However, more organoid-associated trials with large-scale patients are warranted to reverse the 5-FU-based resistance in the future.

Background and Aim A debate exists over whether using preoperative transarterial chemoembolization for patients with hepatocellular carcinoma before liver transplantation. Numerous studies have been investigating on this, but there is still no unanimous conclusion about the effect of preoperative transarterial chemoembolization. We conducted the meta-analysis of all available studies to systematically evaluate the influence of preoperative transarterial chemoembolization on liver transplant. Methods A systematic search was performed by two authors (Si TF. and Guan RY.) through PubMed, Embase, Cochrane, and Science Citation Index Expanded, combined with Manual Retrieval and Cited Reference Search. The searching cut-off date was 2016/07/31, and all the data obtained were statistically analyzed using Review Manager version 5.1 software (Copenhagen, The Nordic Cochrane Center, The Cochrane Collaboration, 2011) recommended by Cochrane Collaboration. Results The study showed that there was no difference between the experimental group and the control group on perioperative mortality (RR = 1.10, 95% confidence interval (CI) = [0.49–2.48], P = 0.82) or biliary complications (RR = 0.96, 95%CI = [0.66–1.39], P = 0.83). Preoperative transarterial chemoembolization had no obvious effect on improving overall survival (HR = 1.05, 95%CI = [0.65–1.72], P = 0. 83) but would result in a higher rate of vascular complications (RR = 2.01, 95%CI = [1.23–3.27], P = 0.005) and a reduction of disease free survival (HR = 1.66, 95%CI = [1.02–2.70], P = 0.04). Subgroup analysis also revealed that patients from transarterial chemoembolization group in Asia had a much lower overall survival rate (HR = 2.65, 95%CI = [1.49–4.71], P = 0.0009) compared with the control group. Conclusions Considering the possible adverse impacts on liver transplantation and the variation in sensitivity to transarterial chemoembolization, clinicians should be more cautious when considering transarterial chemoembolization as the bridging therapy for patients in the waiting list.

Objectives Guillain‐Barré syndrome (GBS) is a type of acute autoimmune disease, which occurs in peripheral nerves and their roots. There is extensive evidence that suggests many immune‐associated genes have essential roles in GBS. However, the associations between immune genes and GBS have not been sufficiently examined as most previous studies have only focused on individual genes rather than their entire interaction networks. Materials and methods In this study, multiple levels of data including immune‐associated genes, GBS‐associated genes, protein‐protein interaction (PPI) networks and gene expression profiles were integrated, and an immune or GBS‐directed neighbour co‐expressed network (IOGDNC network) and a GBS‐directed neighbour co‐expressed network (GDNC network) were constructed. Results Our analysis shows the immune‐associated genes are strongly related to GBS‐associated genes whether at the interaction level or gene expression level. Five immune‐associated modules were also identified which could distinguish between GBS and normal samples. In addition, functional analysis indicated that immune‐associated genes are essential in GBS. Conclusions Overall, these results highlight a strong relationship between immune‐associated genes and GBS existed and provide a potential role for immune‐associated genes as novel diagnostic and therapeutic biomarkers for GBS.

Objective: We aimed to systematically evaluate the influence of preoperative transarterial chemoembolization (TACE) for resectable hepatocellular carcinoma (HCC) on long-term prognosis and perioperative safety. Materials and methods: Databases including PubMed, Embase, Cochrane, Wanfang, CNKI, VIP data were searched, combined with Manual Retrieval and Cited Reference Search to collect the published randomized controlled trial (RCT) about the influence of pre-TACE for curative resection of HCC. The searching cutoff date was 2016/02/25, all the data obtained were statistically analyzed using RevMan5.2 software recommended by Cochrane Collaboration. Results: A total of 5 RCT including 430 (pre-TACE group: 212, surgery alone group: 218) patients were included. The results of meta-analysis showed that: there was no difference between the 2 groups on overall survival (OS) rate [HR 1.25, 95%CI (0.92–1.68)], disease free survival (DFS) rate [HR 0.95 (0.76–1.19)], perioperative mortality rate [OR 0.70 (0.22–2.30)], or blood loss [SMD 0.07 (−0.14–0.29)], whereas the subgroup analysis revealed that pre-TACE would result in longer operation time [SMD 0.31 (0.06–0.57)], higher postoperative morbidity rate [OR 1.90 (1.02–3.53)] and combined resection rate of perihepatic organs [OR 5.46 (2.73–11.78)] in subgroup with mean tumor diameter >5cm. Conclusions: According to our study, pre-TACE treatment cannot improve the long-term prognosis of resectable HCC. With the growth of the tumor diameter, especially when it is over 5cm, it might add difficulties to surgery and affect the perioperative safety.

Glioblastomas (GBMs) and lower-grade gliomas (LGGs) are the most common malignant brain tumors. Despite extensive studies that have suggested that there are differences between the two in terms of clinical profile and treatment, their distinctions on a molecular level had not been systematically analyzed. Here, we investigated the distinctions between GBM and LGG based on multidimensional data, including somatic mutations, somatic copy number variants (SCNVs), gene expression, lncRNA expression and DNA methylation levels. We found that GBM patients had a higher mutation frequency and SCNVs than LGG patients. Differential mRNAs and lncRNAs between GBM and LGG were identified and a differential mRNA-lncRNA network was constructed and analyzed. We also discovered some differential DNA methylation sites could distinguish between GBM and LGG samples. Finally, we identified some key GBM- and LGG-specific genes featuring multiple-level molecular alterations. These specific genes participate in diverse functions; moreover, GBM-specific genes are enriched in the glioma pathway. Overall, our studies explored the distinctions between GMB and LGG using a comprehensive genomics approach that may provide novel insights into studying the mechanism and treatment of brain tumors.

A debate exists over whether using preoperative transarterial chemoembolization for patients with hepatocellular carcinoma before liver transplantation. Numerous studies have been investigating on this, but there is still no unanimous conclusion about the effect of preoperative transarterial chemoembolization. We conducted the meta-analysis of all available studies to systematically evaluate the influence of preoperative transarterial chemoembolization on liver transplant.A systematic search was performed by two authors (Si TF. and Guan RY.) through PubMed, Embase, Cochrane, and Science Citation Index Expanded, combined with Manual Retrieval and Cited Reference Search. The searching cut-off date was 2016/07/31, and all the data obtained were statistically analyzed using Review Manager version 5.1 software (Copenhagen, The Nordic Cochrane Center, The Cochrane Collaboration, 2011) recommended by Cochrane Collaboration.The study showed that there was no difference between the experimental group and the control group on perioperative mortality (RR = 1.10, 95% confidence interval (CI) = [0.49-2.48], P = 0.82) or biliary complications (RR = 0.96, 95%CI = [0.66-1.39], P = 0.83). Preoperative transarterial chemoembolization had no obvious effect on improving overall survival (HR = 1.05, 95%CI = [0.65-1.72], P = 0. 83) but would result in a higher rate of vascular complications (RR = 2.01, 95%CI = [1.23-3.27], P = 0.005) and a reduction of disease free survival (HR = 1.66, 95%CI = [1.02-2.70], P = 0.04). Subgroup analysis also revealed that patients from transarterial chemoembolization group in Asia had a much lower overall survival rate (HR = 2.65, 95%CI = [1.49-4.71], P = 0.0009) compared with the control group.Considering the possible adverse impacts on liver transplantation and the variation in sensitivity to transarterial chemoembolization, clinicians should be more cautious when considering transarterial chemoembolization as the bridging therapy for patients in the waiting list.