Background:Mucinous adenocarcinoma (MAC) is a peculiar histological subtype of colorectal cancer (CRC) with distinct medical, disease-related, and genetic characteristics. The prognosis of MAC is generally poorer less favorable compared to non-specific adenocarcinoma (AC), but the prognostic indicator of MAC is rare. Therefore, this study aims to identify potential biomarkers and construct a prognostic model to better predict patient outcomes in MAC. Methods:We conducted differential genes expression investigation, weighted gene co-expression network analysis (WGCNA), and least absolute shrinkage and selection operator (LASSO)-Cox regression model using RNA sequencing (RNA-seq) data from The Cancer Genome Atlas (TCGA) to pinpoint hub genes. Then, the hub genes were used to construct a prognostic model for MAC. Kaplan-Meier survival, receiver operating characteristic (ROC), and Cox regression analysis were used to assess the prognostic utility of the model. The potential biological function of the hub gene was examined using gene set enrichment analysis (GSEA). Results:Four hub genes, FAM174B, CREB3L1, SPDEF, and RAP1GAP, were identified between MAC and AC by differential genes expression analysis, WGCNA, and LASSO regression analysis. The prognostic signature model was constructed based on these four hub genes, which could divide MAC into low- and high-risk groups. The overall survival (OS) was notably lower in the high-risk group compared to the low-risk group (P=0.007). The area under the curves (AUCs) for 1-, 3-, and 5-year OS were 0.61 [95% confidence interval (CI): 0.73-0.49], 0.69 (95% CI: 0.76-0.63), and 0.77 (95% CI: 0.83-0.71), respectively. We also found that FAM174B expression was closely related to the OS of MAC (P=0.02). Further, the expression of FAM174B was positively correlated with MAC's Mucin type O-glycan biosynthesis. Finally, it was indicated that FAM174B was positively correlated with the critical molecules of mucus formation, MUC5AC (P=0.004, r=0.33), MUC5B (P<0.001, r=0.43), and MUC2 (P<0.001, r=0.39). Conclusions:We have developed and validated a four-gene prognostic model to predict the survival of MAC. Additionally, we found that FAM174B might correlate with mucin production in MAC.

Neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC). Mucinous adenocarcinoma (MAC) is a potential poor prognosis subgroup of rectal cancer. However, the predictive value of MAC in NCRT treatment of LARC is controversial. A comprehensive literature search of PubMed, Embase, and the Cochrane Library was performed. All studies examining the effect of MAC on CRT response in LARC were included. Outcomes of MAC were compared with non-specific adenocarcinoma (AC) by using random-effects methods. Data were presented as odds ratios (ORs) with 95

Objective The repair of great toe donor site defect after wrap‐around flap transfer is still controversial. The bilobed superficial circumflex iliac artery perforator (SCIP) flap can improve the aesthetics of the great toe while maintaining its function. Thus, this study aimed to report our experience in the reconstruction of big toe donor site defects with the bilobed SCIP flap and describe the clinical outcomes. Methods This study was a retrospective trial. From May 2017 to May 2020, 13 patients with the great toe donor site defect after wrap‐around flap transfer were included in this study. The average age of the patients was 44 years (range, 23–60 years). All patients received free bilobed SCIP flaps to reconstruct the donor site defect of the great toe. Relevant clinical features were recorded preoperatively. The thickness and design of the SCIP flap and the harvesting layer of the flap were measured during the operation. The survival rate of flaps and skin grafts and the incidence of infection were recorded after operation. At follow‐up, donor site complications and postoperative outcomes were evaluated. Results In all cases, the SCIP flap covering the donor site of the great toe survived. All patients were followed up for 24–40 months (mean, 30.5 months). The average thickness of the SCIP flap was 0.38cm. All SCIP flaps were harvested from the superficial fascial layer except for three obese patients. The thin SCIP flap had a bilobed design with no further defatting procedures. Postoperatively, the great toe‐nail flap donor site regained its original appearance without bloating or flap necrosis. There was a hidden linear scar in the groin donor site, which did not affect hip joint movement. All patients were satisfied with the aesthetics of the surgical site. Conclusion The SCIP flap with bilobed design for repairing the donor defect of the great toe after wrap‐around flap transfer is a kind of surgical method with excellent contour, meeting the requirements of function and aesthetics.

新辅助化疗(NACT)是指针对潜在可根治切除的肿瘤患者,以消除微转移、降低肿瘤分期和手术难度、改善术后局部复发和远处转移等为目的,在肿瘤手术切除或放疗之前,先予以全身化疗,待手术或放疗之后继续完成全程化疗的综合方案.结肠癌是最常见的癌症之一,肿瘤根治性切除联合术后辅助化疗是临床潜在可根治切除结肠癌的主要治疗方式.虽然这种治疗模式较前显著改善了患者的预后,但术后局部复发和远处转移仍是患者最主要的致死因素.近年来NACT方案开始被引入局部进展期结肠癌和原发灶可切除的肝转移患者等潜在可根治切除结肠癌患者的治疗.然而,结肠癌患者是否适合NACT及其方案的选择还存在较大的争议.笔者就局部进展期结肠癌、可切除结肠癌肝转移等在NACT中的进展与争议,以及影像学检查对NACT的作用作一综述.

Abstract Background: Up to 30% colorectal carcinoma (CRC) are inherited tendency. Lynch syndrome (LS) which is caused by mismatch repair (MMR) genes germline mutation, is the most prevalent form of hereditary CRC. Ethnical and regional differences would lead to diverse characteristics of LS. However, Studies of LS from China are few and with relatively small sample sizes. Method: Immunohistochemistry (IHC) testing for MMR deficiency (dMMR) is advocated to preliminarily screen LS in recent guidelines. This single center retrospective study from central China performed IHC to prescreen dMMR and analyze the patterns and characteristics of dMMR CRCs. Results: 12.0% (180/1505) CRCs had dMMR status in this study, they had the universal features such as younger diagnostic age, more proximal colon location, more poorly differentiated with an excess of mucinous type, advanced pT stage and lower pN stage (all P ＜ 0.05), but had larger tumor size and less perineural invasion (all P ＜ 0.05) compared with proficiency MMR CRCs, which were not reported before. Moreover, PMS2 deficiency (8.7%) was common in this study which was different from studies in Western. MLH1/PMS2, isolated PMS2, MSH2/MSH6 and isolated MSH6 were the most common deficiency patterns, and the MSH2/MSH6 subtype had the most often family history. Conclusion: This study demonstrated dMMR CRCs from central China had the similar general characteristics as reported studies, but had larger tumor size and less perineural invasion which were not reported before. What’s more, PMS2 deficiency (8.7%) was common in this study which was different from studies in Western.

Clinical and Translational MedicineVolume 13, Issue 4 e1246 LETTER TO THE EDITOROpen Access Colorectal mucinous adenocarcinoma indicates a meaningful subtype: A whole genome sequencing study Yunhua Xu, Yunhua Xu The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorXiguang Chen, Xiguang Chen The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorYuqiao Chen, Yuqiao Chen Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, P. R. ChinaSearch for more papers by this authorXiaofeng Wu, Xiaofeng Wu The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorQing Fang, Qing Fang The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorXiangwen Tan, Xiangwen Tan The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorShuxiang Li, Shuxiang Li The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorQiulin Huang, Qiulin Huang The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorXuyu Zu, Corresponding Author Xuyu Zu [email protected] The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, P. R. China Correspondence Shuai Xiao, The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected] Kai Fu, Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P. R. China. Email: [email protected] Xuyu Zu, The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected]Search for more papers by this authorKai Fu, Corresponding Author Kai Fu [email protected] Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, P. R. China Correspondence Shuai Xiao, The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected] Kai Fu, Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P. R. China. Email: [email protected] Xuyu Zu, The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected]Search for more papers by this authorShuai Xiao, Corresponding Author Shuai Xiao [email protected] orcid.org/0000-0003-0830-2188 The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. China Correspondence Shuai Xiao, The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected] Kai Fu, Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P. R. China. Email: [email protected] Xuyu Zu, The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected]Search for more papers by this author Yunhua Xu, Yunhua Xu The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorXiguang Chen, Xiguang Chen The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorYuqiao Chen, Yuqiao Chen Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, P. R. ChinaSearch for more papers by this authorXiaofeng Wu, Xiaofeng Wu The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorQing Fang, Qing Fang The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorXiangwen Tan, Xiangwen Tan The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorShuxiang Li, Shuxiang Li The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorQiulin Huang, Qiulin Huang The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. ChinaSearch for more papers by this authorXuyu Zu, Corresponding Author Xuyu Zu [email protected] The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, P. R. China Correspondence Shuai Xiao, The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected] Kai Fu, Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P. R. China. Email: [email protected] Xuyu Zu, The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected]Search for more papers by this authorKai Fu, Corresponding Author Kai Fu [email protected] Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, P. R. China Correspondence Shuai Xiao, The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected] Kai Fu, Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P. R. China. Email: [email protected] Xuyu Zu, The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected]Search for more papers by this authorShuai Xiao, Corresponding Author Shuai Xiao [email protected] orcid.org/0000-0003-0830-2188 The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Institute of Clinical Medicine, Hengyang Medical School, University of South China, Hengyang, P. R. China The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, P. R. China Correspondence Shuai Xiao, The First Affiliated Hospital, Department of Gastrointestinal Surgery, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected] Kai Fu, Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P. R. China. Email: [email protected] Xuyu Zu, The First Affiliated Hospital, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, P. R. China. Email: [email protected]Search for more papers by this author First published: 26 April 2023 https://doi.org/10.1002/ctm2.1246 Yunhua Xu Xiguang Chen contributed equally to this work. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Dear Editor, Colorectal cancer (CRC) is a common lethal gastrointestinal tumour. Mucinous adenocarcinoma (MAC) is a special histological subtype of CRC, which characterized by abundant extracellular mucin.1 MAC has distinct characteristics compared with the commonest subtype, non-specific adenocarcinoma (AC), including clinicopathologic factors, molecular features, therapy response, and prognosis.2-5 However, since the molecular mechanisms differences between the MAC and AC are still unclear, all of the current treatment guidelines rarely notice their distinction.6, 7 To illustrate these issues, we firstly performed RNA-sequencing on 40 samples comprising 15 MACs, 15 ACs, and 10 normal colorectal tissues, which were collected from our central (hereinafter referred as USC set). The baseline feature of CRC cases is appeared in Table S1. Through the clinicopathological features analysis, we found MAC had a more proximal colon location (p < .05) and larger tumour size (p < .05). In addition, MAC showed a higher pT stage and more frequent dMMR tendency (Table 1). Then, the TCGA-COAD transcriptome and clinical data (referred as TCGA set) were also downloaded and analyzed. Through analyzing TCGA clinical data, we got a similar result: no significant difference in other items except dMMR (Table S2). TABLE 1. The baseline characteristics of MAC and AC patients. AC (cases) MAC (cases) p Value Sex Female 12 8 Male 3 7 .245 Age (years) 62.00 ± 8.08 61.00 ± 13.62 .809 Location Proximal 4 11 Distal 8 2 Rectal 3 2 .029 Size (cm) 5.10 ± 1.64 7.07 ± 2.27 .011 pT stage 0-2 4 1 3-4 11 14 .330 pN stage N0 13 12 N+ 2 3 1.000 MMR status pMMR 12 10 dMMR 1 3 NA 2 2 .541 MVI/PNI status Absent 14 13 Present 1 2 1.000 Abbreviations: AC, adenocarcinoma; dMMR, deficient of MMR; EMT, epithelial-mesenchymal transition; GEO, Gene Expression Omnibus; GSEA, Gene Set Enrichment Analysis; MAC, mucinous adenocarcinoma; MMR, mismatch repair gene; MSI, microsatellite instability; MSS, microsatellite stable; MVI/PNI, microvascular invasion/perineural invasion; MYC, MYC Proto-Oncogene; NA, not available; pMMR, proficient of MMR; SM, supplementary material; TCGA, The Cancer Genome Atlas; TGF, transforming growth factor; TTN, Titin; USC, University Of South China. To elucidate the genome characteristic between MAC and AC, we analyzed the TCGA-COAD mutation data. Results showed that the mutation atlas of them was notably different. In the AC group, APC (74.6%) had the highest mutation frequency followed by TP53 (59.0%), TTN (49.4%) (Figure 1A). While in the MAC group, TTN (72.4%), APC (65.5%), and KRAS (46.6%) are the most mutated genes (Figure 1B). Additionally, we observed a high mutation frequency of BRAF, whereas TP53 was rare in MAC (Figure 1A, B). Additionally, comparing the common 10 mutant genes, we found only the mutation rate of TTN, RYR2, and OBSCN were distinctly different (Figure 1C). In addition, we observed that the integral genome alteration frequency of MAC is higher than AC (Figure 1D). Finally, we compared the fraction genome alteration of the above three genes. Although the mutation rate of these genes was higher in MAC, the fraction genome alteration was lower in MAC, and each gene had a unique mutational feature (Figure 1E). FIGURE 1Open in figure viewerPowerPoint The mutation signature of adenocarcinoma (AC) and mucinous adenocarcinoma (MAC). (A and B) The genomic landscape shows the top 15 mutated genes among AC, MAC. (C) The comparison of common 10 genes mutations in AC and MAC. The values in brackets indicate the statistical value in the mutation frequency of each gene between the two groups. Each column denotes an individual tumour, and each row represents the individual genes. The mutation rate of each gene in all samples was shown in right. (D) The comparison of the integral genome alteration frequency among AC, MAC. (E) The fraction genome altered of TTN, RYR2, and OBSCN. Colours indicate the type of genetic alterations as indicated in the legend. To study the transcriptomics features of MAC and AC, we performed differentially expressed genes (DEGs) analysis in TCGA and USC sets, respectively. In the TCGA set, we found thousands of DEGs between tumour and normal tissue (Figure 2A,B), and hundreds of DEGs between MAC and AC (Figure 2C). In the USC set, we got similar results (Figure 2D–F). The distribution of DEGs was shown as the ternary plot. The variation was apparent among transcriptional properties of different subtypes (Figure 2G,H). Finally, differences and similarities of DEGs for the TCGA and USC datasets are summarized in Figure 2I. Furthermore, we synthesize intersection DEGs of MAC versus AC in USC and TCGA set and performed functional enrichment analysis to uncover the potential gene functions. Through GO, KEGG, cancer hallmarks, and Reactome analysis, we found the gene functions of these DEGs were correlated with symporter activity, and metabolism-related molecules and pathways (SM1, Figure S1). FIGURE 2Open in figure viewerPowerPoint The analysis of differentially expressed genes (DEGs) among adenocarcinoma (AC), mucinous adenocarcinoma (MAC), and normal samples in TCGA and USC datasets. (A–C) The volcano plot of DEGs in AC versus Normal, MAC versus Normal, MAC versus AC samples in TCGA datasets. (D–F) The volcano plots of DEGs in AC versus Normal, MAC versus Normal, MAC versus AC samples in USC datasets. Red triangles indicate up-regulated genes, and green triangles indicate down-regulated genes as the legend. (G and H) The ternary plot of DEGs among AC, MAC, and Normal samples in TCGA and USC datasets. Genes more inclined to normal samples were marked in red, genes tend to AC samples were labeled in blue, and genes prone to MAC samples were tagged in yellow. (I) The 9-quadrant diagram of the distribution of common DEGs between TCGA and USC datasets. In 2011, Weinberg et al. summarized 10 cancer hallmarks, which become the cornerstone of tumour characteristic study.8 Thus, we analyzed the 10 hallmarks differences between AC and MAC. Results showed that evading growth suppressors and inducing angiogenesis appeared a marked weak activity. Nevertheless, reprogramming energy metabolism and tumour-promoting inflammation were highly expressed. Unfortunately, we didn't observe a hallmark that was significantly different between MAC and AC (SM1, Figure S2A,C). In addition, we found some genes played an important role in multiple hallmarks, while others played the exclusive roles in single hallmark (SM1, Figure S2B,D). According to Sadanandam et al. reported that CRCs could be classified into five cell phenotypes, which had distinct therapy response.9 We analyzed the cell subtype differences of MAC and AC both in TCGA and USC sets. Result showed that the samples of two datasets were well classified into five cell subtypes (Figure S3A,C), and the proportion of each subtype was different (Figure S3B,D). The Goblet-like group accounted for the largest proportion in the MAC, followed by Stem-like, and Ta was the least. On the contrary, the predominant cell subtype of AC was the Ta group, and the other four subtypes are relatively evenly distributed (Figure S3). The consensus molecular subtype (CMS) is a new and important classification system for CRC.10 We also explored the association between CMS and MAC, and results showed that there was good consistency between subtype prediction and template features of TCGA and USC set (Figure 3A, D). The signal feature of each subtype was also studied. Results showed that the CMS1 group has obvious MSI characteristics, and the CMS2 group has distinct MSS, MYC, and cell cycle features, and differentiation signal was visible in CMS3, while TGF-Beta and EMT signal was prominent in CMS4 (Figure 3B, E). Our results showed that AC group was enriched in CMS2 and CMS4 subtypes, and MAC group was enriched in CMS3 and CMS4 subtypes, especially in CMS3 (Figure 3C, F). FIGURE 3Open in figure viewerPowerPoint The consensus molecular subtype (CMS) subtype comparative analysis between mucinous adenocarcinoma (MAC) and adenocarcinoma (AC). (A and D) The CMS heatmap of top differentially expressed genes (DEGs) with shades of blue for down-regulation and red for up-regulation in TCGA and USC datasets. (B and E) The heatmap of pathways activity of each CMS subtype with shades of blue for low and red for high activity in TCGA and USC datasets. (C and F) The pie chart for each CMS subtype of AC and MAC samples in TCGA and USC datasets, respectively. Previous studies indicated MAC was correlated with poor chemotherapy response and prognosis. To better understand the underlying molecular mechanisms, we analyzed GEO dataset of CRC drug resistance (GSE83129). GSEA was carried out to acquire the enriched pathway by our sequencing results and drug resistance dataset. Six shared GOBP pathways were enriched in MAC and chemotherapy non-responder group (Figure 4A,B). The common genes interaction among these six GOBP pathways are shown in Figure 4C. We further found six intersection genes in GOBP①/GOBP③(Figure 4D), and 15 intersection genes in GOBP④/GOBP⑤ (Figure 4E). These 21 evolved drug-resistant gene clusters might confer chemotherapy resistance to MAC. FIGURE 4Open in figure viewerPowerPoint GSEA analysis of USC dataset and colorectal cancer (CRC) drug resistance dataset GSE83129. GSEA analysis showed the differentially enriched pathway in the mucinous adenocarcinoma (MAC)/adenocarcinoma (AC) samples and OXA_Responder/Non-responder samples. (A) The upset plot showed the intersection pathways of MAC/AC samples and OXA_Responder/Non-responder samples. (B) Shared enriched GO pathway by GSEA analysis. (C–E) Venn plots of the intersection of genes enriched in GO pathways. OXA, oxaliplatin. In conclusion, this whole genome sequencing study preliminarily revealed the molecular and functional characteristics of MAC, as well as potential clinical value, which indicated that MAC tend to metabolic and mesenchymal phenotypes, contributing to worse prognosis and chemotherapy resistance. ACKNOWLEDGEMENTS This work was supported by the Clinical Medical Technology Innovation Project of Hunan Province (grant number: 2020SK51815), the Scientific Research Fund Project of Hunan Provincial Health Commission (grant numbers: 20201919 and 202104010105), and Natural Science Foundation of Hunan Province (grant number: 2022JJ30538). CONFLICT OF INTEREST STATEMENT The authors declare no conflicts of interest. Supporting Information Filename Description ctm21246-sup-0001-SuppMat.docx22.1 KB Supporting Information ctm21246-sup-0002-SuppMat.docx25.5 KB Supporting Information ctm21246-sup-0003-SuppMat.doc2.2 MB Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1Hugen N, Brown G, Glynne-Jones R, de Wilt JHW, Nagtegaal ID. Advances in the care of patients with mucinous colorectal cancer. Nat Rev Clin Oncol. 2016; 13(6): 361- 369. doi:10.1038/nrclinonc.2015.140 2Luo C, Cen S, Ding G, Wu W. Mucinous colorectal adenocarcinoma: clinical pathology and treatment options. Cancer Commun (Lond). 2019; 39(1): 13. doi:10.1186/s40880-019-0361-0 3Bong J-W, Gim J-A, Ju Y, et al. Prognosis and sensitivity of adjuvant chemotherapy in mucinous colorectal adenocarcinoma without distant metastasis. Cancers (basel). 2022; 14(5): 1297. doi:10.3390/cancers14051297 4Zhang Y, Chen Y, Huang J, et al. Mucinous histology is associated with poor prognosis in locally advanced colorectal adenocarcinoma treated with postoperative first-line adjuvant chemotherapy: a systematic review and meta-analysis. Eur J Surg Oncol. 2022; 48(10): 2075- 2081. doi:10.1016/j.ejso.2022.06.024 5Zhang J, Xie X, Wu Z, et al. Mucinous adenocarcinoma predicts poor response and prognosis in patients with locally advanced rectal cancer: a pooled analysis of individual participant data from 3 prospective studies. Clin Colorectal Cancer. 2021; 20(4): e240- e248. doi:10.1016/j.clcc.2021.06.004 6Ott C, Gerken M, Hirsch D, et al. Advanced mucinous colorectal cancer: epidemiology, prognosis and efficacy of chemotherapeutic treatment. Digestion. 2018; 98(3): 143- 152. doi:10.1159/000487710 7Benson AB, Venook AP, Al-Hawary MM, et al. NCCN guidelines insights: colon cancer, version 2.2018. J Natl Compr Canc Netw. 2018; 16(4): 359- 369. doi:10.6004/jnccn.2018.0021 8Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144(5): 646- 674. doi:10.1016/j.cell.2011.02.013 9Sadanandam A, Lyssiotis CA, Homicsko K, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med. 2013; 19(5): 619- 625. doi:10.1038/nm.3175 10Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015; 21(11): 1350- 1356. doi:10.1038/nm.3967 Volume13, Issue4April 2023e1246 FiguresReferencesRelatedInformation

Flavonoids have been shown to be beneficial in a variety of inflammatory and metabolic diseases because of their anti-inflammatory and antioxidant properties. However, previous epidemiological studies have only demonstrated a negative correlation between flavonoid intake on inflammatory markers, and the optimal intake of dietary flavonoids and subclasses in terms of dietary anti-inflammatory efficacy remains undetermined. This study was based on 3 cycles (2007–2010, 2017–2018) of the National Health and Nutrition Examination Survey and the corresponding expanded flavonoid database. Weighted multiple linear regression was used to assess linear relationships between flavonoid intake and Dietary inflammation index (DII). Smoothed curve fit and a generalized additive model were used to investigate the nonlinear relationships and threshold effects, the 2-tailed linear regression model was used to find potential inflection points. A total of 12,724 adults were included in the study. After adjusting for potential confounders, flavonoid intake was significantly associated with DII, with the strongest negative association effect for flavonols (−0.40 [−0.45, −0.35]). In subgroup analyses stratified by sex, race, age, body mass index, education levels, and diabetes, flavonol intake maintained a significant negative linear correlation with DII. In addition, we found significant nonlinear relationships (L-shaped relationships) and threshold effects between total flavonoids, flavan-3-ols, and flavanols and DII, with inflection points of 437.65 mg/days, 157.79 mg/days, and 46.36 mg/days, respectively. Our results suggest a threshold for the dietary anti-inflammatory capacity of flavonoid intake in U.S. adults.

Purpose: Postoperative adjuvant chemotherapy followed surgery is the standard management for localized advanced colorectal carcinoma (CRC). Mucinous adenocarcinoma (MAC) is a peculiar histological subtype of CRC, but the prognosis of MAC patients is controversial. The objective of this study is to assess the implication of MAC in survival of patients treated with surgery and firs-line adjuvant chemotherapy. Methods: Studies describing outcomes for advanced MAC and non-specific adenocarcinoma (AC) of CRC patients treated with first-line postoperative adjuvant chemotherapy followed surgery were searched in PubMed, Embase, Medline, EBSCO, Wiley, and Cochrane Library (January 1963eAugust 2021). Hazard ratios (HRs) of overall survival (OS), disease-free survival (DFS) and cancer-specific survival (CSS) for MAC to AC were extracted. Random-effects model was used for calculating the pooled HRs and 95% confidence interval (CI). Results: This meta-analysis is comprised of 8 studies involving a total of 124,303 CRC patients treated with first-line adjuvant chemotherapy followed surgery. The pooled HR for MAC was 1.23 (95% CI, 1.07-1.41, p < 0.01, I-2 = 80%), and the DFS (HR, 2.95, 95% CI, 1.22-7.14) of MAC patients were significantly poorer than AC patients. Similar results were also observed in stage III and FOLFOX regimen subgroups. Conclusion: MAC was a risk factor for prognosis of localized advanced CRC patients treated with postoperative first-line adjuvant chemotherapy. Thus, the role of first-line adjuvant chemotherapy regimens should be further studied in these MAC patients.

Ferroptosis is an iron-dependent mode of cell death. It can occur through two major pathways, exogenous (or transporter-dependent) and endogenous (or enzyme-regulated) pathways are activated by biological or chemical inducers, and glutathione peroxidase activity is inhibited, which causes intracellular iron accumulation and lipid Peroxidation. Ferroptosis is closely related to the pathological process of many diseases. How to intervene in the occurrence and development of related diseases by regulating ferroptosis has become a hot research topic. At present, studies have shown that ferroptosis is found in common diseases such as tumors, inflammatory diseases, bacterial infections, pulmonary fibrosis, hepatitis, inflammatory bowel disease, neurodegenerative diseases, kidney injury, ischemia-reperfusion injury and skeletal muscle injury. This article reviews the characteristics and mechanism of ferroptosis, and summarizes how ferroptosis participates in the pathophysiological process in various systemic diseases of the body, which may provide new references for the treatment of clinical diseases in the future.

Background Endoscopy biopsy (EB) is the standard diagnostic method for colorectal cancer (CRC), whereas its accuracy and efficiency in mucinous adenocarcinoma (MAC) initial diagnosis is unclear. Methods The initial EB and postoperative specimen (PS) pathological diagnosis of MAC from two centers were retrospectively collected and analyzed. The accuracy and efficiency of initial EB compared with PS pathological diagnosis were analyzed. The potential factors which would affect the initial EB diagnosis of MAC were analyzed. Results 280 and 78 eligible cases were enrolled in this study from two centers respectively. The initial EB diagnosis accuracy for MAC were 84.62% and 83.33%. However, among the cases of PS diagnosis with MAC, the diagnostic efficiency of initial EB was only 36.49% and 32.50% respectively. Lower tumor differentiation and more EB number were associated with an increased probability for the EB diagnosis of MAC, but only tumor differentiation was an independent diagnositic factor for EB in the two cohorts. Conclusions The accuracy of initial EB with MAC is high, but the diagnostic efficiency was extremely low. Tumor differentiation and EB number were associated with the diagnosis efficiency of MAC before surgery.