AbstractBackgroundLynch syndrome (LS) is an autosomal‐dominant disorder that increases the risk of many cancers. To identify novel or rare pathogenic variants of MMR genes associated with LS, especially in Chinese pedigrees.MethodsOne four‐generation Chinese Han family from northeast China with 29 members was enrolled. Clinical diagnosis of LS was established in this family, according to Amsterdam II. The proband and some relatives of the family were subjected to immunohistochemical analysis of MMR protein, microsatellite instability (MSI) testing, whole‐exome sequencing, and Sanger sequencing.ResultsNine patients with 19 primary cancers were found in this family, with a wide spectrum of synchronous and metachronous cancers, including digestive, reproductive, respiratory, urinary, and other systems. In addition, one member of this family is found to have both thyroid and lung cancers, which have been reported only once in LS patients before but have not been considered extracolonic in the LS spectrum. The immunohistochemical analysis of the mother of the proband showed loss of MSH2 and MSH6 protein, and consistently, high microsatellite instability (MSI‐H) was confirmed in LS patients. Furthermore, whole‐exome sequencing identified a nonsense variant in MSH2, MSH2:NM_000251:c.351G > A(p.W117*), in all three tested LS patients (II‐1, III‐1, and III‐4), but not in healthy relatives IV‐1 in this family. This result is further verified by Sanger sequencing.ConclusionUncover a rare nonsense variant in MSH2 gene, which contributes to LS of this family. The clinicopathological characteristics of LS in this family include common simultaneous or heterogeneous multiple primary cancers, a broad tumor spectrum, and a younger age with the continuation of genetic algebra.

The emergence of drug resistance and metastasis has long been a difficult problem for cancer treatment. Recent studies have shown that cancer stem cell populations are key factors in the regulation of cancer aggressiveness, relapse and drug resistance. Cancer stem cell (CSC) populations are highly plastic and self-renewing, giving them unique metabolic, metastatic, and chemotherapy resistance properties. N6-methyladenosine (m6A) is the most abundant internal modification of mRNA and is involved in a variety of cell growth and development processes, including RNA transcription, alternative splicing, degradation, and translation. It has also been linked to the development of various cancers. At present, the important role of m6A in tumour progression is gradually attracting attention, especially in the tumour stemness regulation process. Abnormal m6A modifications regulate tumour metastasis, recurrence and drug resistance. This paper aims to explore the regulatory mechanism of m6A in CSCs and clinical therapy, clarify its regulatory network, and provide theoretical guidance for the development of clinical targets and improvement of therapeutic effects.

Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly disease that has an increasing death rate but no effective treatment to now. Although biological and immunological hallmarks of PDAC have been frequently reported recently, early detection and the particularly aggressive biological features are the major challenges remaining unclear. In the current study, we retrieved multiple scRNA-seq datasets and illustrated the genetic programs of PDAC development in genetically modified mouse models. Notably, the transcription levels of Id1 were elevated specifically along with the PDAC development. Pseudotime trajectory analysis revealed that Id1 was closely correlated with the malignancy of PDAC. The gene expression patterns of human PDAC cells were determined by the comparative analysis of the scRNA-seq data on human PDAC and normal pancreas tissues. ID1 levels in human PDAC cancer cells were dramatically increased compared to normal epithelial cells. ID1 deficiency in vitro significantly blunt the invasive tumor-formation related phenotypes. IPA analysis on the differentially expressed genes suggested that EIF2 signaling was the core pathway regulating the development of PDAC. Blocking EFI2 signaling remarkably decreased the expression of ID1 and attenuated the tumor-formation related phenotypes. These observations confirmed that ID1 was regulated by EIF2 signaling and was the critical determinator of PDAC development and progression. This study suggests that ID1 is a potential malignant biomarker of PDAC in both mouse models and human and detecting and targeting ID1 may be a promising strategy to treat or even rescue PDAC.

Gastrointestinal tumor is a common malignancy that is dangerous to human health. Some of the patients exhibit familial hereditary syndromes; however, the molecular genetics of hereditary gastrointestinal tumors remain unclear. Here, a Chinese family including 21 people was investigated. Among them, three cases were respectively diagnosed with gastric cancer, colon cancer, and liver cancer; one case was diagnosed with cystic ovarian. Whole-exome sequencing (WES) and Sanger sequencing were applied to identify the pathogenic mutation of four patients. A novel frameshift mutation in exon 49 (c.7141_7151del) of ataxia telangiectasia mutated (ATM) gene was detected in three patients with gastric cancer, colon cancer, and cystic ovarian but absent in patient with liver cancer. This mutation was co-segregated with the disease phenotype and was predicted to be pathogenic. The deletion mutation in the ATM gene led to a frameshift mutation of the bases after ATM, ultimately causing the protein code to terminate at 2,401st amino acids (p.N2381fs). Our results detected a novel mutation of ATM in a family with hereditary gastrointestinal tumors and expanded the mutation spectrum of ATM gene. Taken together, these findings provide vital information about the possible detection of tumor occurrence and progression, contributing towards hereditary cancer prevention and screening.Abbreviations: ATM: Ataxia telangiectasia mutated; InDels: Insertions and deletions; NCCN: National Comprehensive Cancer Network; SNVs: Single nucleotide variations; WES: Whole-exome sequencing

Clinical reports indicate that gastric cancer (GC) has a high mortality rate, but its pathological mechanism remains poorly understood. This work integrated bioinformatics analysis with experimental verification to explore novel biomarkers of gastric cancer. First, weighted gene coexpression network analysis was applied to screen significant genes correlated with GC development. Gene set enrichment analysis was also used to unearth the most relevant biological functions of significant genes. As a result, we discovered homeobox C9 ( HOXC9 ) as a novel oncogene in GC, primarily through negatively regulating immune response. High expression of HOXC9 predicted a poor prognosis in GC patients, and knocking down HOXC9 efficiently enhanced the interferon‐gamma (IFNγ)‐dependent apoptosis in two GC cell lines as well as organoids from patients. Furthermore, cleaved caspase‐3/7 and phosphorylated signal transducer and activator of transcription 1 (p‐STAT1) were also significantly enhanced in HOXC9 knockdown cells and organoids treated with IFNγ. Mechanistically, we found that HOXC9 inhibited the death‐associated protein kinase 1 ( DAPK1 ) and its downstream retinoic acid‐inducible gene‐I ( RIG1 ) to generate GC IFNγ resistance. In summary, we identified and confirmed that HOXC9 generates IFNγ resistance in GC by inhibiting the DAPK1/RIG1/p‐STAT1 axis.

Tumor progression involves invasion, migration, metabolism, autophagy, exosome secretion, and drug resistance. Cargos transported by membrane vesicle trafficking underlie all of these processes. Rab GTPases, which, through coordinated and dynamic intracellular membrane trafficking alongside cytoskeletal pathways, determine the maintenance of homeostasis and a series of cellular functions. The mechanism of vesicle movement regulated by Rab GTPases plays essential roles in cancers. Therefore, targeting Rab GTPases to adjust membrane trafficking has the potential to become a novel way to adjust cancer treatment. In this review, we describe the characteristics of Rab GTPases; in particular, we discuss the role of their activation in the regulation of membrane transport and provide examples of Rab GTPases regulating membrane transport in tumor progression. Finally, we discuss the clinical implications and the potential as a cancer therapeutic target of Rab GTPases.

Tumor progression involves invasion, migration, metabolism, autophagy, exosome secretion, and drug resistance. Cargos transported by membrane vesicle trafficking underlie all of these processes. Rab GTPases, which, through coordinated and dynamic intracellular membrane trafficking alongside cytoskeletal pathways, determine the maintenance of homeostasis and a series of cellular functions. The mechanism of vesicle movement regulated by Rab GTPases plays essential roles in cancers. Therefore, targeting Rab GTPases to adjust membrane trafficking has the potential to become a novel way to adjust cancer treatment. In this review, we describe the characteristics of Rab GTPases; in particular, we discuss the role of their activation in the regulation of membrane transport and provide examples of Rab GTPases regulating membrane transport in tumor progression. Finally, we discuss the clinical implications and the potential as a cancer therapeutic target of Rab GTPases.

目的 探索腹腔镜直肠癌根治术治疗高龄患者的疗效.方法 选择2017年5月—2018年5月期间收治的100例高龄直肠癌患者为试验对象,采用数据库随机分为对照组和观察组,各50例,分别进行开腹手术治疗、腹腔镜直肠癌根治术治疗,随后对比两组各项指标.结果 观察组CA199(25.65±3.19)U/mL、CEA(4.36±1.65)ng/mL、AFP(5.17±1.33)ng/mL、CRP(5.19±1.22)mg/L、 并发症发生率(4.00％)、淋巴结转移数目(5.96±0.57)枚、淋巴结清扫数目(10.31±1.39)枚、手术时间(48.95±5.69)min、切口大小(2.37±0.17)cm、开始进食时间(12.19±5.85)h、肠鸣音恢复时间(29.37±5.52)h、 肛门排气时间(10.18±2.52)d、腹胀持续时间(3.49±0.35)d均优于对照组(P<0.05).结论 对高龄直肠癌患者实施腹腔镜直肠癌根治术治疗效果显著,可发挥操作简便、安全性高、疗效高、术后并发症少、恢复快等特点,更利于病情康复,加速胃肠道功能恢复,降低手术风险,改善预后.

目的 探究中低位直肠癌患者接受腹腔镜治疗的效果.方法 将中低位直肠癌患者150例,以双盲法进行随机分组,时间为2017年1月-2019年1月,对照组实施开腹手术治疗,试验组则实施腹腔镜手术治疗,分析两组中低位直肠癌患者肛门排气时间、住院时间、手术出血量、手术用时、淋巴结清扫数、并发症发生情况的差异.结果 试验组中低位直肠癌患者的肛门排气时间(1.98±0.75)d、住院时间(5.56±1.19)d、手术出血量(56.89±20.12)ml、手术用时(137.89±35.85)min均低于对照组肛门排气时间(3.71±1.12)d、住院时间(3.71±1.12)d、手术出血量(122.67±56.87)mL、手术用时(180.36±45.71)min,差异有统计学意义(t值分别为11.1150,7.0933,9.4435,6.3314,P值均<0.05);试验组淋巴结清扫数(11.23±0.75)个与对照组淋巴结清扫数(11.30±0.82)个相比,无统计学意义(t值=0.5455,P值>0.05);试验组中低位直肠癌患者的并发症发生率(5.33％),相较于对照组并发症发生率(21.33％),明显更低,差异有统计学意义(χ2值=8.3077,P值<0.05).结论 中低位直肠癌患者接受腹腔镜手术治疗,可较好将淋巴结清除,效果好,且可缩短患者的治疗和康复时间,减少其手术出血量,安全有效.

目的 研究中性粒细胞/淋巴细胞比值(NLR)与结直肠癌病理因素及预后的关系,为临床预测结直肠癌预后提供依据.方法 回顾性分析2013年1月至2016年1月中国医科大学附属第四医院收治的120例可手术结直肠癌患者的临床资料,收集患者入院2 d的血常规资料,计算NLR.对患者进行随访,随访截至2019年3月30日,采用受试者工作特征(ROC)曲线分析术前NLR对可手术结直肠癌患者死亡率的预测价值.分析NLR与结直肠癌病理特征及预后的关系,采用Cox分析影响结直肠癌患者全因死亡的危险因素.结果 截至随访结束,本组120例患者中有10例失访,随访成功率91.7％(110/120).中位随访时间为55个月.110例中死亡37例,存活73例.ROC曲线显示,NLR预测死亡的最佳临界点为3.1,此时的灵敏度为65.2％,特异度为74.4％.将3.1作为NLR的临界值,将110例患者分为NLR升高组(NLR>3.1)40例和NLR降低组(NLR≤3.1)70例.NLR升高组的年龄、恶性肿瘤家族史比例、肿瘤部位在结肠者及TNM分期为Ⅲ期的比例高于NLR降低组,差异有统计学意义.logistic回归分析显示肿瘤部位为结肠(OR=1.325,95％CI=1.104～2.654,P=0.042)、TNM分期高(OR=1.674,95％CI=1.233～5.987,P=0.032)是术前NLR升高的独立危险因素.NLR升高组的生存率较NLR降低组显著降低,差异有统计学意义(P<0.05).Cox多因素回归分析显示,术前NLR(OR=1.725,95％CI=1.124～6.674)、TNM分期(OR=1.835,95％CI=1.324～8.417)、年龄(OR=1.129,95％CI=1.054～2.215)、肿瘤分化程度(OR=1.378,95％CI=1.114～3.699)、脉管侵犯(OR=1.341,95％CI=1.097～3.241)是结直肠癌患者死亡率的独立影响因素(P<0.05).结论 术前NLR是结直肠癌死亡率的独立影响因素,可用于预测结直肠癌患者预后,NLR升高患者的预后不良.

This meta-analysis aimed to assess the diagnostic efficiency of blood-based septin 9 (SEPT9) methylation assay for the detection of colorectal cancer (CRC). Studies were searched in the Springer, Wiley, Cochrane Library, PubMed, Ovid, Embase, Web of Science, China BioMedicine, Wanfang and China National Knowledge Infrastructure databases until July 2017. Methodological quality assessment was performed based on the guidelines of the Quality Assessment of Diagnostic Accuracy Studies. According to 1/3 and 2/3 algorithms, the meta-analyses for the diagnostic effect of SEPT9 in CRC were compared with healthy subjects and subjects with polyps, adenoma, and non-CRC, respectively. The random effects model was applied and publication bias was evaluated. The included 29 studies comprised 10,486 subjects (3202 patients with CRC and 7284 controls). In comparison with healthy subjects, the pooled sensitivity with 95% confidence intervals (CIs) of SEPT9 methylation for the diagnosis of CRC was 0.74 (95% CI: 0.61–0.84) in the 1/3 algorithm group, whereas the specificity was 0.96 (95% CI: 0.95–0.97) in the 2/3 algorithm group. Additionally, positive likelihood ratio was less than 10 and negative likelihood ratio more than 0.1 in the 2/3 algorithm group for patients with CRC vs. polyps and adenoma. The P value of Deeks’ funnel plot was 0.36, suggesting that there was no publication bias. SEPT9 methylation can be used to diagnose CRC in healthy individuals under the 2/3 algorithm. The determination of SEPT9 methylation does not distinguish well between CRC and polyps or adenoma.

目的 探讨术前血清CEA和CA19-9水平在胃癌根治术后复发转移及预后中的应用价值.方法 应用电化学发光法检测136例胃癌患者术前静脉血清CEA和CA19-9水平,分析CEA和CA19-9水平与患者临床病理学参数、术后复发转移和预后的关系.采用Kaplan-Meier法(log-rank检验)进行生存分析.结果 136例胃癌患者中术后复发转移67例.术前血清CEA阳性率为48.5％(66/136),CA19-9阳性率为43.4％ (59/136).CEA阳性与T分期、TNM分期、淋巴结转移及脉管浸润有关(P=0.011、P=0.018、P=0.021、P=0.024),CA19-9阳性与T分期和淋巴结转移有关(P=0.018、P=0.045).CEA阳性组和CA19-9阳性组术后复发转移率分别为60.6％ (40/66)和61.0％ (36/59),CEA阴性组和CA19-9阴性组术后复发转移率分别为38.6％ (27/70)和40.3％ (31/77),CEA阳性组和CA19-9阳性组术后复发转移率分别明显高于CEA阴性组和CA19-9阴性组(P=0.010、P=0.016).Kaplan-Meier生存分析显示CEA阳性组和CA19-9阳性组术后无瘤生存时间明显短于CEA阴性组和CA19-9阴性组(P=0.003、P=0.007).结论 术前血清CEA和CA19-9水平检测在胃癌术后复发转移和预后判断中具有重要价值,术前联合检测血清CEA和CA19-9水平有助于提高胃癌术后复发转移和预后的预测.

We investigated the effects of perioperative blood transfusion in the prognosis of hereditary and sporadic colon cancer. There are 1075 colon cancer patients, including 936 sporadic colon cancer and 139 with hereditary colon cancer undergoing surgery at our hospital. All patients underwent 10 years of follow-up. In the sporadic group, mortality, local recurrence rate and distant metastases rate of transfused patients were significantly higher than non-transfused patients. The 10-year survival rates were significantly lower in patients receiving blood transfusions compared to non-transfused patients. In the hereditary group, mortality was higher in transfused patients compared to non-transfused patients.

Objective]To discuss the surgical indications and the treatment results of traumatic diaphragmatic hernia(TDH)and traumatic diaphragmatic injury (TDI)treated by abdominal operation[.Methods]Retrospective analy‐sis of 16 patients with treatment of TDH and TDI underwent abdominal surgery was conducted in terms of causes , clinical manifestation ,preoperative examination ,surgical approach selection and the result of surgical treatment .[Re‐sults]Sixteen cases were included in the group :14 males ,2 females ;13 left ,1 right ,2 double;all cases combined with united injury ,11 cases combined with traumatic shock .8 cases examined by X‐ray ,5 diagnosed ;16 cases examined by computed tomography ,135 diagnosed ;2 cases examined by thoracoscopy ,both with diaphragm injury ;16 cases were treated by abdominal diaphragm repair ,15 cases cured ,3 cases with complications ,2 cases with incision infection ,1 case with inflammatory intestinal obstruction and 1 case died of multiple organ failure[.Conclusion]Most of TDI and TDH could be repaired by abdominal operation so as to treat bleeding of the abdominal organs timely ,and the double side of diaphragm could be examined to avoid the misdiagnosis and missed diagnosis .Meanwhile the abdominal opera‐tion could reduce the effect of respiratory and circulatory system caused by open chest operation ,and will be benefit to postoperative discharge of phlegm and rehabilitation .

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Background The purpose of this research was to evaluate the therapeutic effects and prognostic factors of transanal local excision (TAE) for rectal cancer. Methods We retrospectively analyzed 116 cases that underwent TAE for rectal cancer from 1995 to 2008. A Cox regression analysis was used to analyze prognostic factors. Results The survival times for the patients were from 14 to 160.5 months (median time, 58.5 months). The 5-year and 10-year overall survival rates were 72% and 53%, respectively. In all 16 cases experienced local recurrence (13.8%). Pathological type, recurrence or metastasis, and depth of infiltration (T stage) were the prognostic factors according to the univariate analysis, and the latter two were independent factors affecting patient prognosis. For patients with T1 stage who underwent adjuvant radiotherapy, there was no local recurrence; for those in T2 stage, the local recurrence rate was 14.6%. In addition, there was no difference between the patients who received radiotherapy and those who did not (T1: P = 0.260, T2: P = 0.262 for survival rate and T1: P = 0.480, T2: P = 0.560 for recurrence). Conclusions The result of TAE for rectal cancer is satisfactory for T1 stage tumors, but it is not suitable for T2 stage tumors.

A number of tumor markers had been reported to be useful in detecting free cancer cells in the peritoneal cavity and predict peritoneal recurrence in gastric cancer patients. The objective of this study was to compare the clinical impact of different tumor markers in peritoneal lavage fluid using the real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) technique and to screen the most effective ones from them. The peritoneal lavage fluid of 116 patients with gastric cancer was sampled at laparotomy. After RNA extraction and reverse transcription, real-time quantitative polymerase chain reaction (PCR) was performed using the primers and probes for carcinoembryonic antigen (CEA), cytokeratin-20, matrix metalloproteinase-7 (MMP-7), carbohydrate antigen 125, and transforming growth factor-beta-1. Among the 116 patients, 45 (38.8%) were confirmed to have peritoneal recurrence. Any of the PCR-positive results of the five tumor markers could predict peritoneal recurrence in the univariate analysis (P < 0.001). In the multivariate analysis, the PCR results of CEA (P = 0.003) and MMP-7 (P = 0.028) were found to be independent prognostic factors. A real-time quantitative RT-PCR analysis of the CEA and MMP-7 transcripts in peritoneal lavage fluid could effectively predict peritoneal recurrence in advanced gastric cancer patients who underwent a potentially curative resection.

OBJECTIVE: This meta-analysis was performed to evaluate the role of toll-like receptor 4 (TLR-4) in colorectal carcinogenesis. METHODS: The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched from inception through November 1st, 2013 without language restrictions. Odds ratios (ORs) or standardized mean differences (SMD) with their 95% confidence intervals (CI) were calculated. RESULTS: Fourteen case-control studies met the inclusion criteria for this meta-analysis. A total of 1,209 colorectal cancer (CRC) cases and 1,218 healthy controls were involved in this meta-analysis. Two common polymorphisms (299 A>G and 399 C>T) in the TLR-4 gene, TLR-4 mRNA and protein expression were assessed. Our meta-analysis results revealed that the TLR-4 399 C>T polymorphism might increase the risk of CRC (allele model: OR = 1.77, 95%CI = 1.32 ∼ 2.36, P<0.001; dominant model: OR = 1.83, 95%CI = 1.32 ∼ 2.52, P<0.001; respectively). However, we found no correlation between the TLR-4 299 A>G polymorphism and CRC risk (all P>0.05). A subgroup analysis by ethnicity suggested that TLR-4 genetic polymorphisms were associated with an increased risk of CRC among Asians (allele model: OR = 1.50, 95%CI = 1.19 ∼ 1.88, P = 0.001; dominant model: OR = 1.49, 95%CI = 1.16 ∼ 1.92, P = 0.002; respectively), but not among Caucasians and Africans (all P>0.05). Furthermore, our results showed that TLR-4 mRNA and protein levels in CRC patients were higher than those in healthy controls (TLR-4 mRNA: SMD = 2.51, 95%CI = 0.98 ∼ 4.05, P = 0.001; TLR-4 protein: OR = 4.75, 95%CI = 1.16 ∼ 19.36, P = 0.030; respectively). CONCLUSION: Our findings provide empirical evidence that TLR-4 may play an important role in colorectal carcinogenesis. Thus, TLR-4 is a promising potential biomarker for the early diagnosis of CRC.

Objective To investigate the familial incidence of multiple primary carcinoma in Chinese hereditary nonpolyposis colorectal cancer patients (HNPCC) in Northeast China.Methods By family line investigation,multiple primary carcinoma (MPC) spectrum' s characteristics of 509 patients in 85 families registered in strict conformity with the HNPCC Amsterdam criteria Ⅱ were analyzed retrospectively.Results Of the 85 HNPCC families,multiple primary carcinoma developed in 55 patients in 25 families,among them 45 patients had metachronous carcinoma in 17 families,16 patients had synchronous carcinoma occurred in 12 families,6 patients with both synchronous carcinoma and metachronous carcinoma in 4 families.Conclusions Multiple primary carcinoma developed in significantly high incidence in Northeast China in Chinese hereditary nonpolyposis colorectal cancer patients,the most common MPC are colorectal cancer and endometrial cancer.

The aim of the present study was to determine whether allogeneic red blood cell transfusions showed a deleterious effect and what might be preoperative risk factors for blood transfusion in patients with TNM stage II colon cancer. Total 470 patients who fulfilled inclusion criteria were selected for a further 10-year follow-up study. We found that there were statistical significance between non-transfused and transfused group in mortality (P=0.018), local recurrence (P=0.000) and distant metastasis (P=0.040). Local recurrence and distant metastasis between 1 to 3 units and more than 3 units group did not show any significant differences. There was no difference in survival rate between non-transfused and 1 to 3 units group (log rank =0.031, P=0.860). The difference between different blood transfusion volume in transfused patients was found (78.77% vs 63.83%, P=0.006). Meanwhile, the significant difference of survival rate was existed between non-transfused group and more than 3 units group (84.83% vs 63.83%, P=0.002). Univariate analysis showed the following 3 variables to be associated with an increased risk of allogeneic blood transfusions: preoperative CEA level (P<0.05), location of tumor (P<0.01) and diameter of tumor (P<0.01). Multivariate analysis revealed that location of tumor and diameter of tumor are two independent factors for requirement of perioperative transfusions. Therefore, allogeneic transfusion increase the postoperative tumor mortality, local recurrence and distant metastasis in patients with stage II colon cancer. The postoperative tumor mortality, local recurrence and distant metastasis were not associated with the blood transfusion volume. The blood transfusion volume was associated with the survival rate. Location of tumor and diameter of tumor were the independent preoperative risk factors for blood transfusion.