Features of synchronous and metachronous dual primary gastric and colorectal cancer

BACKGROUND Studies evaluating the characteristics of dual primary gastric and colorectal cancer(CRC)(DPGCC)are limited.AIM To analyze the clinicopathologic characteristics and prognosis of synchronous and metachronous cancers in patients with DPGCC.METHODS From October 2010 to August 2021,patients with DPGCC were retrospectively reviewed.The patients with DPGCC were divided into two groups(synchronous and metachronous).We compared the overall survival(OS)between the groups using Kaplan-Meier survival methods.Univariate and multivariate analyses were performed using Cox’s proportional hazards model to identify the independent prognostic factors for OS.RESULTS Of the 76 patients with DPGCC,46 and 30 had synchronous and metachronous cancers,respectively.The proportion of unresectable CRC in patients with synchronous cancers was higher than that in patients with metachronous cancers(28.3%vs 3.3%,P=0.015).The majority of the second primary cancers had occurred within 5 years.Kaplan-Meier survival analysis showed that the patients with metachronous cancers had a better prognosis than patients with synchronous cancers(P=0.010).The patients who had undergone gastrectomy(P<0.001)or CRC resection(P<0.001)had a better prognosis than those who had not.In the multivariate analysis,synchronous cancer[hazard ratio(HR)=6.8,95%confidence interval(95%CI):2.0-22.7,(P=0.002)]and stage III-IV gastric cancer(GC)[HR=10.0,95%CI:3.4-29.5,(P<0.001)]were risk prognostic factor for OS,while patients who underwent gastrectomy was a protective prognostic factor for OS[HR=0.2,95%CI:0.1-0.6,P=0.002].CONCLUSION Regular surveillance for metachronous cancer is necessary during postoperative follow-up.Surgical resection is the mainstay of therapy to improve the prognosis of DPGCC.The prognosis appears to be influenced by the stage of GC rather than the stage of CRC.Patients with synchronous cancer have a worse prognosis,and its treatment strategy is worth further exploration.

Effect of BRAF mutation on the prognosis for patients with colorectal cancer undergoing cytoreductive surgery for synchronous peritoneal metastasis

Background:KRAS/BRAF mutations(mutKRAS/mutBRAF)are unfavorable prognostic factors for colorectal cancer(CRC)metastases to the liver and lungs.However,their effects on the prognosis for patients with synchronous peritoneal metastasis(S-PM)of CRC after cytoreductive surgery(CRS)and hyperthermic intraperitoneal chemotherapy(HIPEC)are controversial.In the study,we aimed to determine the effects of mutKRAS/mutBRAF on the prognosis for patients with S-PM who received CRS.Methods:A total of 142 patients diagnosed with S-PM between July 2007 and July 2019 were included in this study.The demographics,mutKRAS/mutBRAF status,overall survival(OS),and progression-free survival(PFS)of the patients were evaluated.The Kaplan–Meier method and log-rank test were used to estimate the difference in survival between groups.Results:Among 142 patients,68(47.9%)showed mutKRAS and 42(29.5%)showed mutBRAF.The median OS values were 8.4 and 34.3 months for patients with mutBRAF and BRAF wild-type,respectively(P<0.01).However,KRAS status was not significantly associated with median OS(P=0.76).Multivariate analysis revealed carcinoembryonic antigen,CRS,HIPEC,and mutBRAF as independent predictors for OS.Based on these findings,a nomogram was constructed.The C-index was 0.789(95%confidence interval,0.742–0.836),indicating good predictive ability of the model.Furthermore,the 1-and 2-year survival calibration plots showed good agreement between the predicted and actual OS rates.The area under curves of the 1-and 2-year survival predictions based on the nomogram were 0.807 and 0.682,respectively.Additionally,mutBRAF was significantly associated with lower PFS(P<0.001).Conclusions:mutBRAF is an independent prognostic risk factor for S-PM.The established nomogram predicted the OS of patients with CRC having S-PM with high accuracy,indicating its usefulness as a valuable prognostic tool for the designated patient cohort.

Dynamic heterogeneity of colorectal cancer during progression revealed clinical risk-associated cell types and regulations in single-cell resolution and spatial context

Background:Tumor heterogeneity is contributed by tumor cells and the microenvironment.Dynamics of tumor heterogeneity during colorectal cancer(CRC)progression have not been elucidated.Methods:Eight single-cell RNA sequencing(scRNA-seq)data sets of CRC were included.Milo was utilized to reveal the differential abundance of cell clusters during progression.The differentiation trajectory was imputed by using the Palantir algorithm and metabolic states were assessed by using scMetabolism.Three spatial transcription sequencing(ST-seq)data sets of CRC were used to validate cell-type abundances and colocalization.Cancer-associated regulatory hubs were defined as communication networks affecting tumor biological behaviors.Finally,quantitative reverse transcription polymerase chain reaction and immunohistochemistry staining were performed for validation.Results:TM4SF1t,SOX4t,and MKI67t tumor cells;CXCL12t cancer-associated fibroblasts;CD4t resident memory T cells;Treg;IgAt plasma cells;and several myeloid subsets were enriched in stage IV CRC,most of which were associated with overall survival of patients.Trajectory analysis indicated that tumor cells from patients with advanced-stage CRC were less differentiated,when metabolic heterogeneity showed a highest metabolic signature in terminal states of stromal cells,T cells,and myeloid cells.Moreover,ST-seq validated cell-type abundance in a spatial context and also revealed the correlation of immune infiltration between tertiary lymphoid structures and tumors followed by validation in our cohort.Importantly,analysis of cancer-associated regulatory hubs revealed a cascade of activated pathways including leukocyte apoptotic process,MAPK pathway,myeloid leukocyte differentiation,and angiogenesis during CRC progression.Conclusions:Tumor heterogeneity was dynamic during progression,with the enrichment of immunosuppressive Treg,myeloid cells,and fibrotic cells.The differential state of tumor cells was associated with cancer staging.Assessment of cancer-associated regulatory hubs suggested impaired antitumor immunity and increased metastatic ability during CRC progression.

克罗恩病患者的病耻感及影响因素的调查研究

目的克罗恩病因其无法治愈及肠道症状特点,不可避免地影响了患者生活,并可能导致病耻感。本研究旨在调查克罗恩病患者病耻感的现状及影响因素。方法采用便利抽样的方法,于2020年10月至2021年3月对广州市某三级甲等医院消化内科病房的146例克罗恩病患者进行问卷调查。采用自行设计的一般资料问卷、社会影响量表(Social Impact Scale,SIS)、炎症性肠病自我效能量表(Inflammatory Bowel Disease-Self-Eficacy Scale,IBD-SES)及社会支持评定量表(Social Support Rating Scale,SSRS)分别对克罗恩病患者的一般资料、病耻感现状、自我效能和社会支持水平进行调查。采用多重线性回归分析对克罗恩病患者病耻感的影响因素进行分析。结果克罗恩病患者病耻感得分为(58.14±10.74)分,处于中等水平。85.6%(125/146)的克罗恩病患者存在中重度的病耻感。多重线性回归分析结果显示,患者感知到的社会公众对疾病的了解情况、家庭人均月收入、年龄、自我效能为克罗恩病患者病耻感的影响因素,可解释病耻感总变异的52%。结论绝大部分克罗恩病患者存在中重度的病耻感。感知到的社会公众对疾病的了解少、家庭人均月收入低、年龄≥40岁、自我效能低的克罗恩病患者表现出更高程度的病耻感。

Evidence challenging the causal role of gut microbiota in inflammatory bowel diseases

Recently,Bourgonje et al.[1]investigated the antibody epitope repertoire in patients with inflammatory bowel diseases(IBD)[1].Using the high-throughput phage-display immunoprecipitation sequencing(PhIP-Seq)method,they made several significant findings,including elevated antibody reactivities against bacterial flagellins in patients with Crohn’s disease(CD)and the effectiveness of the antibody epitope pattern in differentiating between CD/ulcerative colitis and healthy controls[1].

Aquaporin 9 is involved in CRC metastasis through DVL2-dependent Wnt/β-catenin signaling activation

Background:Aquaporin 9(AQP9)is permeable to water or other small molecules,and plays an important role in various cancers.We previously found that AQP9 was related to the efficacy of chemotherapy in patients with colorectal cancer(CRC).This study aimed to identify the role and regulatory mechanism of AQP9 in CRC metastasis.Methods:The clinical significance of AQP9 was analysed by using bioinformatics and tissue microarray.Transcriptome sequencing,Dual-Luciferase Reporter Assay,Biacore,and co-immunoprecipitation were employed to demonstrate the regulatory mechanism of AQP9 in CRC.The relationship between AQP9 and CRC metastasis was verified in vitro and in vivo by using real-time cell analysis assay,high content screening,and liver metastasis models of nude mice.Results:We found that AQP9 was highly expressed in metastatic CRC.AQP9 overexpression reduced cell roundness and enhanced cell motility in CRC.We further showed that AQP9 interacted with Dishevelled 2(DVL2)via the C-terminal SVIM motif,resulting in DVL2 stabilization and the Wnt/b-catenin pathway activation.Additionally,we identified the E3 ligase neural precursor cell expressed developmentally downregulated 4-like(NEDD4L)as a modulator regulating the ubiquitination and degradation of AQP9.Conclusions:Collectively,our study revealed the important role of AQP9 in regulating DVL2 stabilization and Wnt/β-catenin signaling to promote CRC metastasis.Targeting the NEDD4L–AQP9–DVL2 axis might have therapeutic usefulness in metastatic CRC treatment.

Knowledge-embedded spatio-temporal analysis for euploidy embryos identification in couples with chromosomal rearrangements

Background:The goal of the assisted reproductive treatment is to transfer one euploid blastocyst and to help infertile women giving birth one healthy neonate.Some algorithms have been used to assess the ploidy status of embryos derived from couples with normal chromosome,who subjected to preimplantation genetic testing for aneuploidy(PGT-A)treatment.However,it is currently unknown whether artificial intelligence model can be used to assess the euploidy status of blastocyst derived from populations with chromosomal rearrangement.Methods:From February 2020 to May 2021,we collected the whole raw time-lapse videos at multiple focal planes from in vitro cultured embryos,the clinical information of couples,and the comprehensive chromosome screening results of those blastocysts that had received PGT treatment.Initially,we developed a novel deep learning model called the Attentive Multi-Focus Selection Network(AMSNet)to analyze time-lapse videos in real time and predict blastocyst formation.Building upon AMSNet,we integrated additional clinically predictive variables and created a second deep learning model,the Attentive Multi-Focus Video and Clinical Information Fusion Network(AMCFNet),to assess the euploidy status of embryos.The efficacy of the AMCFNet was further tested in embryos with parental chromosomal rearrangements.The receiver operating characteristic curve(ROC)was used to evaluate the superiority of the model.Results:A total of 4112 embryos with complete time-lapse videos were enrolled for the blastocyst formation prediction task,and 1422 qualified blastocysts received PGT-A(n=589)or PGT for chromosomal structural rearrangement(PGT-SR,n=833)were enrolled for the euploidy assessment task in this study.The AMSNet model using seven focal raw time-lapse videos has the best real-time accuracy.The real-time accuracy for AMSNet to predict blastocyst formation reached above 70%on the day 2 of embryo culture,and then increased to 80%on the day 4 of embryo culture.Combing with 4 clinical features of couples,the AUC of AMCFNet with 7 focal points increased to 0.729 in blastocysts derived from couples with chromosomal rearrangement.Conclusion:Integrating seven focal raw time-lapse images of embryos and parental clinical information,AMCFNet model have the capability of assessing euploidy status in blastocysts derived from couples with chromosomal rearrangement.