Clonal hematopoiesis:a shared risk factor for cardiovascular diseases and tumors

Clonal hematopoiesis(CH)is a clonally expanded population of hematopoietic stem cells carrying somatic mutations that differentiate through multilineage hematopoiesis to form terminally differentiated mature hematopoietic cells carrying markers of the clonal mutation.Genes integral to critical cellular processes such as epigenetic regulation,DNA damage response,and inflammation frequently carry these mutations.Clonal hematopoiesis becomes increasingly prevalent with age and is associated with an increased risk of hematological tumors and some nonhematological conditions.Recent insights have revealed that the mutations driving CH are not only implicated in hematologic neoplasms but also possess the potential to influence cardiovascular pathogenesis.Here,we reviewed up-to-date findings about the roles of CH in cardiovascular diseases and tumors and explored the clinical significance of CH,as well as look forward to future related studies,so as to provide valuable references for future research and clinical practice.

Classification of submucosal tumors in the gastrointestinal tract

This review is part two of three, which will present an update on the classification of gastrointestinal submucosal tumors. Part one treats of the diagnosis and part three of the therapeutic methods regarding gastrointestinal submucosal tumors. In the past there has been some confusion as to the classification of gastrointestinal submucosal tumors. Changes in classifications have emerged due to recent advances in mainly immunohistochemistry and electron microscopy. The aim of this paper is to update the reader on the current classification. Literature searches were performed to find information related to classification of gastrointestinal submucosal tumors. Based on these searches the twelve most frequent submucosal tumor types were chosen for description of their classification. The factors that indicate whether tumors are benign or malignant are mainly size and number of mitotic counts. Gastrointestinal stromal tumors are defined mainly by their CD117 positivity. In the future, there should be no more confusion between gastrointestinal stromal tumors and other types of submucosal tumors.2007 The WJG Press. All rights reserved.

Combined hepatocellular and cholangiocarcinoma originating from the same clone:a pathomolecular evidence-based study

Background:Combined hepatocellular and cholangiocarcinoma(CHC) is a unique subtype of liver cancer comprising both hepatocellular carcinoma(HCC) and intrahepatic cholangiocarcinoma(ICC);however,its cellular origin remains unclear.The purpose of this study was to investigate the clinicopathologic features and the clonal relationship between HCC and ICC in 34 patients with CHC.Methods:The clinicopathologic features and prognosis of the 34 CHC patients were compared with those of 29 patients with separated HCC and ICC(5HC).Loss of heterozygosity(LOH) at 10 highly polymorphic microsatellite markers was detected in 16 CHC and 10 SHC tissues for determination of the clonal origin of CHC.Expression of hepatocyte markers[hepatocyte paraffin 1(Hep Par 1) and glypican 3(GPC3)]and cholangiocyte markers[cytokeratin(CK)7 and 19]in tumor tissues was examined by immuno histochemical analysis.Results:In the 16 CHC specimens,the difference in LOH patterns between HCC and ICC was less than 30%,suggesting the same clonal origin of HCC and ICC.Consistent with this finding,immunohistochemical analysis revealed that hepatocyte markers(Hep Par 1 and GPC3) and cholangiocyte markers(CK7 and CK19) were simultaneously expressed in both the HCC and ICC components in 52.9%of CHC specimens,suggesting that the two components shared a similar phenotype with hepatic progenitor cells(HPCs).On the contrary,in all 10 SHC cases,the difference in LOH patterns between the HCC and ICC components was greater than 30%,suggesting different clonal origins of HCC and ICC.Overall survival and disease-free survival were shorter for patients with CHC than for patients with SHC(P < 0.05).Conclusions:Our results suggest that the HCC and ICC components of CHC may originate from the same clone,having the potential for dual-directional differentiation similar to HPCs.CHC tended to exhibit the biological behaviors of both HCC and ICC,which may enhance the infiltrative capacity of tumor cells,leading to poor clinical outcomes for patients with CHC.

Endosonographic surveillance of 1-3 cm gastric submucosal tumors originating from muscularis propria

AIM To observe the natural course of 1-3 cm gastric submucosal tumors originating from the muscularis propria(SMTMPs).METHODS By reviewing the computerized medical records over a period of 14 years(2000-2013), patients with 1-3 cm gastric SMTMPs who underwent at least two endoscopic ultrasound(EUS) examinations were enrolled. Tumor progression was defined as a ≥ 1.2 times enlargement in tumor diameter observed during EUS surveillance. All patients were divided into stationary and progressive subgroups and further analyzed. We also reviewed the patients in the progressive subgroup again in 2016.RESULTS A total of 88 patients were studied, including 25 in the progressive subgroup. The mean time of EUS surveillance was 24.6 mo in the stationary subgroup and 30.7 mo in the progressive subgroup. Risk factors for tumor progression included larger tumor size and irregular border. Initial tumor size > 14.0 mm may be considered a cut-off size for predicting tumor progression. Seventeen patients underwent surgery, of whom 13 had gastrointestinal stromal tumors(GISTs) and 4 had leiomyomas. Tumor progression was found only in patients with GISTs. All of the tumors exhibited benign behaviors without metastasis until 2016.CONCLUSION Most 1-3 cm gastric SMTMPs(71.6%) are indolent. Tumor progression was found only in GISTs, and it is a good predictor for differentiating GISTs from leiomyomas. Predictors of tumor progression include larger tumor size(> 14.0 mm) and irregular border.

Identification of portal vein tumor thrombus with an independent clonal origin in hepatocellular carcinoma via multi-omics data analysis

Objective: Multiple mechanisms underlying the development of portal vein tumor thrombus(PVTT) in hepatocellular carcinoma(HCC) have been reported recently. However, the origins of PVTT remain unknown. Increasing multi-omics data on PVTTs in HCCs have made it possible to investigate whether PVTTs originate from the corresponding primary tumors(Ts).Methods: The clonal relationship between PVTTs and their corresponding primary Ts was investigated using datasets deposited in public databases. One DNA copy number variations dataset and three gene expression datasets were downloaded for the analyses.Clonality analysis was performed to investigate the clonal relationship between PVTTs and Ts from an individual patient.Differential gene expression analysis was applied to investigate the gene expression profiles of PVTTs and Ts.Results: One out of 19 PVTTs had no clonal relationship with its corresponding T, whereas the others did. The PVTTs with independent clonal origin showed different gene expression and enrichment in biological processes from the primary Ts. Based on the unique gene expression profiles, a gene signature including 24 genes was used to identify pairs of PVTTs and primary Ts without any clonal relationship. Validation in three datasets showed that these types of pairs of PVTTs and Ts can be identified by the 24-gene signature.Conclusions: Our findings show a direct evidence for PVTT origin and consolidate the heterogeneity of PVTTs observed in clinic.The results suggest that PVTT investigation at a molecular level is clinically necessary for diagnosis and treatment.

Collision tumor of the rectum: A case report of metastatic gastric adenocarcinoma plus primary rectal adenocarcinoma

Collision tumors are thought to arise from the accidental meeting and interpenetration of two independent tumors. We report here a highly unusual case of a 61-year old man who had a unique tumor that was composed of a metastatic adenocarcinoma from the stomach to the rectum, which harbored a collision tumor of primary rectal adenocarcinoma. The clonalities of the two histologically distinct lesions of the rectal mass were confirmed by immunohistochemical and molecular analysis. Although histologic examination is the cornerstone in pathology, immunohistochemical and molecular analysis can provide evidence regarding whether tumors originate from the same clone or different clones. To the best of our knowledge, this is the fi rst reported case of such an occurrence.

Discrimination of clonal origin patterns for molecular pathological diagnosis of RHCC/MHCC

Objective:The high post-operative recurrence of hepatocellular carcinoma(RHCC)and multinodular hepatocellular carcinoma(MHCC)seriously limit the surgical efficacy of HCC.Theoretically,RHCC/MHCC arise from either residual tumor cells or novel clone-derived tumor cells which have a great impact on designing personalized therapies and the evaluation of clinical long-term outcome.

Profiling of hepatocellular carcinoma neoantigens reveals immune microenvironment and clonal evolution related patterns

Objective: Neoantigens derived from tumor-specific genomic alterations have demonstrated great potential for immunotherapeutic interventions in cancers. However, the comprehensive profile of hepatocellular carcinoma(HCC) neoantigens and their complex interplay with immune microenvironment and tumor evolution have not been fully addressed.Methods: Here we integrated whole exome sequencing data, transcriptome sequencing data and clinical information of 72 primary HCC patients to characterize the HCC neoantigen profile, and systematically explored its interactions with tumor clonal evolution, driver mutations and immune microenvironments.Results: We observed that higher somatic mutation/neoantigen load was associated with better clinical outcomes and HCC patients could be further divided into two subgroups with distinct prognosis based on their neoantigen expression patterns. HCC subgroup with neoantigen expression probability high(NEP-H) showed more aggressive pathologic features including increased incidence of tumor thrombus(P=0.038), higher recurrence rate(P=0.029),more inclined to lack tumor capsule(P=0.026) and with more microsatellite instability sites(P=0.006). In addition,NEP-H subgroup was also characterized by higher chance to be involved in tumor clonal evolution [odds ratio(OR)=46.7, P<0.001]. Gene set enrichment analysis revealed that upregulation of MYC and its targets could suppress immune responses, leading to elevated neoantigen expression proportion in tumor cells. Furthermore, we discovered an immune escape mechanism that tumors could become more inconspicuous by evolving subclones with less immunogenicity. We observed that smaller clonal mutation clusters with higher immunogenicity in tumor were more likely to involve in clonal evolution. Based on identified neoantigen profiles, we also discovered series of neoantigenic hotspot genes, which could serve as potential actionable targets in future.Conclusions: Our results revealed the landscape of HCC neoantigens and discovered two clinically relevant subgroups with distinct neoantigen expression patterns, suggesting the neoantigen expression should be fully considered in future immunotherapeutic interventions.

Histological origin of pseudomyxoma peritonei in Chinese women:Clinicopathology and

AIM:To investigate the histological origin of pseudomyxoma peritonei(PMP)in Chinese women.METHODS:The clinical and pathological data were reviewed for 35 women with PMP,and specimens of the peritoneal,appendiceal and ovarian lesions of each patient were examined using the PV-6000 immunohistochemistry method.Antibodies included cytokeratin(CK)7,CK20,mucin(MUC)-1,MUC-2,carbohydrate antigen(CA)-125,estrogen receptor(ER),and progesterone receptor(PR).RESULTS:Abundant colloidal mucinous tumors were observed in the peritoneum in all 35 cases.Thirty-one patients had a history of appendectomy,28 of whom had mucinous lesions.There was one patient with appendicitis,one whose appendix showed no apparent pathological changes,and one with unknown surgical pathology.Ovarian mucinous tumors were found in 24 patients.The tumors were bilateral in 13 patients,on the right-side in nine,and on the left side in two.Twenty patients had combined appendiceal and ovarian lesions;16 of whom had undergone initial surgery for appendiceal lesions.Four patients had undergone initial surgery for ovarian lesions,and relapse occurred in these patients at 1,11,32 and 85 mo after initial surgery.Appendi-ceal mucinous tumors were found in each of these four patients.Thirty-three of the 35 patients showed peritoneal lesions that were positive for CK20 and MUC-2,but negative for CK7,MUC-1,CA125,ER and PR.The expression patterns in the appendix and the ovary were similar to those of the peritoneal lesions.In one of the remaining two cases,CK20,CK7 and MUC-2 were positive,and MUC-1,CA125,ER and PR were negative.The ovaries were not resected.The appendix of one patient was removed at another hospital,and no specimen was evaluated.In the other case,the appendix appeared to be normal during surgery,and was not resected.Peritoneal and ovarian lesions were negative for CK20,MUC-2,CK7,MUC-1,CA125,ER and PR.CONCLUSION:Most PMP originated from the appendix.Among women with PMP,the ovarian tumors were implanted rather than primary.For patients with PMP,appendectomy should be performed routinely.The ovaries,especially the right ovaries should be explored.

11例孤立性纤维性肿瘤的临床病理分析

目的 探讨孤立性纤维性肿瘤(SFT)的临床病理、免疫表型和预后。方法 收集11例SFT患者的临床及病理资料,行HE染色及免疫组化检测,总结其临床及影像学表现、组织学形态、免疫表型特征及预后,并结合相关文献进行复习。结果 11例患者中,男性9例,女性2例,年龄25~85岁。影像学均表现为结节状软组织肿块。肿瘤最大径3.5~30 cm,切面实性,部分有完整包膜。肿瘤细胞呈卵圆形或梭形、短梭形,疏密不均,可见薄壁鹿角形血管。部分病例细胞轻-中度异型,偶见奇异形核。免疫组化结果显示,所有肿瘤均表达CD34,8例STAT6核阳性。目前手术完整切除仍是SFT的首选治疗方法。本组10例患者获得随访,其中8例无病生存,1例死亡患者原因不详,1例术后复发仍带瘤生存。结论 SFT具有相对独特的病理组织学和分子遗传学改变,发生于胸膜外者生物学行为更具侵袭性。具有恶性组织学特征者具有较高的局部复发和转移率,因此正确的诊断对于治疗和患者管理具有重要意义。

AFP、CEA、CA724、CA125联合胃蛋白酶原检测对早期胃癌的诊断价值

目的探讨甲胎蛋白(AFP)、癌胚抗原(CEA)、癌抗原72-4(CA724)和癌抗原12-5(CA125)联合胃蛋白酶原(PG)在胃癌患者早期中的诊断及预后评估中的价值。方法选取2017年2月至2019年2月确诊的96例胃癌患者作为观察组,106例胃炎患者作为良性组,108例体检的健康受试者作为对照组。分析比较不同组别的血清AFP、CEA、CA724、CA125和PG之间的数据差异和阳性检出率。采用受试者工作特征(ROC)曲线、曲线下面积(AUC),评价这些标志物对胃癌的诊断价值。结果CEA、CA125在观察组中的平均水平明显高于良性组和对照组(P<0.05)。观察组的CA724、PGⅠ和PGR(PGⅠ/PGⅡ)水平显著低于其他2组(P<0.05),PGⅡ则与其他2组差异无统计学意义(P>0.05)。在阳性检出率方面,观察组CEA、CA125、CA724和PGR阳性检出率高于良性组和对照组(P<0.05)。联合检测观察组的阳性检出率高于良性组和对照组(P<0.05)。在针对不同标志物的单一诊断中,CEA、CA724、PGI和PGR表现出较高的AUC值,而联合检测这些标志物的AUC值为0.773,显示出更高的诊断性能。结论本研究强调了CEA、CA125、CA724和PGR在早期胃癌诊断中的重要性,特别是其在肿瘤患者和非肿瘤患者之间的显著差异。联合检测这些标志物显示出更高的诊断性能,为早期胃癌筛查和诊断提供了有力的支持,有望在临床实践中广泛应用。

中药常山、蜀漆古今文献考证

目的探究常山、蜀漆的基原、产地、性味归经、功效、毒性特点,以期为常山、蜀漆的研究与合理应用提供参考。方法以第5版中华医典数据库、读秀数据库、中医智库在线古籍数据库为检索范围,考证常山、蜀漆的基原、产地、性味归经、功效、毒性,同时结合现代文献研究进行分析。结果发现常山、蜀漆别名较多,分布广泛,喜阴凉湿润环境,以四川产量最大,质量最优。常山的性味与归经在历代古籍中未发现明显变化,但蜀漆性味记载存在分歧,且归经论述较少,未得统一。古籍载常山、蜀漆功效多为截疟、涌吐,现代药理研究发现两者还具有抗球虫、抗肿瘤、解热、降压、抗流感病毒等药理作用。但因两者均存在一定毒性,为保证安全用药,传统多通过炮制及配伍进行减毒存效,现代多从其活性成分本身的结构修饰及致毒机理实现减毒增效。结论古今文献梳理发现常山及蜀漆,除截疟外还具有抗肿瘤等多种药理活性,研发前景良好,但囿于其存在一定的毒性,制约了其临床应用,传统临床多通过炮制、配伍减毒存效,现代学者尝试通过结构修饰和改变给药途径减毒增效,为其减毒增效提供了新的思路和方向。

基于“君火以明,相火以位”防治恶性肿瘤

通过梳理古代文献阐明君火、相火的生理功能、病理变化以及“君火以明,相火以位”的含义,并结合恶性肿瘤生物学发病机制,分析“君火以明,相火以位”与恶性肿瘤发生发展的相关性,提出君火不明是肿瘤产生之基,相火妄动为肿瘤形成之始,痰瘀内生为肿瘤发展之渐,君相两衰为肿瘤进展之终。基于此,认为临床防治恶性肿瘤应节欲畅志以明君火,引火归元以敛相火,化痰祛瘀以消瘤体,潜阳培土以复正气。

Applied Value of Monitoring Serum Hepcidin in Differential Diagnosis of Infection versus Tumor Fevers

The applied value of serum hepcidin in differential diagnosis of infection fevers versus tumor fevers was explored.A total of 432 fever patients were selected according to the domestic fever of unknown origin（FUO） diagnostic criteria from our hospital between June 2010 and November 2013.Venous blood samples were taken on the day 1,5,10 after admission.The infection group（98 cases） and the tumor group（50 cases） were set up based on the clinical and laboratory findings.ELISA was used to determine the serum hepcidin and IL-6 levels.SPSS 13.0 was used for statistical analysis.Hepcidin showed obvious descending trend on the 10 th day in both the bacterial infection group（66 cases） and the virus infection group（32 cases）,and the descending trend was similar to that of inflammatory indexes such as procalcitonin（PCT）,hypersensitive C-reactive protein（h-CRP）,erythrocyte sedimentation rate（ESR）,white blood cell（WBC）,and ferritin.Serum hepcidin showed no obvious differences in the tumor group on the day 1,5,10 after admission.In the infection groups,serum hepcidin was positively correlated with IL-6（r=0.687,P=0.000） and CRP（r=0.487,P=0.026）,but had a poor correlation with blood sedimentation,ferritin,PCT and WBC（P〉0.05）.Monitoring dynamic changes of hepcidin and related inflammatory factors in patients with fever is expected to be used for clinical identification of infection fever and tumor fever.

Molecular genetics of ependymoma

Brain tumors are the leading cause of cancer death in children,with ependymoma being the third most common and posing a significant clinical burden.Its mechanism of pathogenesis,reliable prognostic indicators,and effective treatments other than surgical resection have all remained elusive.Until recently,ependymoma research was hindered by the small number of tumors available for study,low resolution of cytogenetic techniques,and lack of cell lines and animal models.Ependymoma heterogeneity,which manifests as variations in tumor location,patient age,histological grade,and clinical behavior,together with the observation of a balanced genomic profile in up to 50% of cases,presents additional challenges in understanding the development and progression of this disease.Despite these difficulties,we have made significant headway in the past decade in identifying the genetic alterations and pathways involved in ependymoma tumorigenesis through collaborative efforts and the application of microarray-based genetic(copy number) and transcriptome profiling platforms.Genetic characterization of ependymoma unraveled distinct mRNA-defined subclasses and led to the identification of radial glial cells as its cell type of origin.This review summarizes our current knowledge in the molecular genetics of ependymoma and proposes future research directions necessary to further advance this field.

多发性骨髓瘤的克隆异质性与克隆演变

多发性骨髓瘤(MM)是血液系统恶性肿瘤,即使患者在治疗后达到深度缓解,最终仍会复发,这可能与克隆异质性和克隆演变有关。克隆异质性是MM的特征,在骨髓微环境和抗肿瘤治疗的选择压力下,亚克隆遵循不同的进化模式发生演变,如分支进化模式、线性进化模式、中性进化模式等,克隆演变贯穿于MM各个阶段,推动着MM的发生、耐药及复发。该文对MM克隆异质性、克隆演变及临床意义进行综述,以期为临床治疗决策提供新思路。

分子遗传学技术在多结节肺癌诊断中的应用现状

多原发肺癌(MPLC)指患者有两个或以上原发肺结节的肺癌,不同结节组织学类型相似的MPLC极易与肺内转移癌(IM)相互误诊,两种诊断的治疗方案和预后差异化明显,目前对于MPLC仍没有诊断的金标准。基于肿瘤的异质性,分子遗传学检测肿瘤的克隆性起源对MPLC的诊断具有重要的参考价值,分子遗传学技术的不断发展使得分子遗传学检测的覆盖范围有所差异,对MPLC的诊断也有所影响。本文针对不同分子遗传学技术在MPLC诊断中的应用做了综述。

New strategy to distinguish clonal origin of RHCC/MHCC between intrahepatic metastasis and multicentric occurrence

Hepatocellular carcinoma (HCC) is a kind of malignancy with high potential of metastasis and multicentric occurrence. The treatment of recurrent hepatocellular carcinoma (RHCC) and multinodular hepatocellular carcinoma (MHCC) is always a nodus because of the diverse clonal origin of RHCC/MHCC. Theoretically, the RHCC/MHCC can originate from intrahepatic metastasis (IM type) or multicentric occurrence (MO type). Our previous study proposed that there are at least 6 subtypes of clonal origin patterns in RHCC. RHCC and MHCC with different clonal origins have variant biological behaviors, clinical prognosis as well as treatment strategy. Generally speaking, patients with IM type HCC have a poorer prognosis compared with those with MO type HCC. Therefore, it is essential to emphasize the distribution of the clonal origin in HCC in order to determine the choice of clinical treatment. Undoubtedly, the detection of clonal origin pattern will become a promising breakthrough in the molecular pathological diagnosis of HCC. We should attach more attention to the establishment of a standardized molecular pathological clonal origin detection method and a new stratification of clinical treatment choice for RHCC/MHCC in future.

王邦才治疗消化道恶性肿瘤术后经验介绍

介绍王邦才教授治疗消化道恶性肿瘤术后的临床经验。王邦才教授认为,消化道恶性肿瘤术后病机以虚实夹杂为特点,脾胃虚损为本,痰、瘀、浊、毒内蕴为标。基于补、通二法,强调脾胃分治扶正气、通补阳明除壅逆、身心同调畅情志,灵活运用化湿运脾、温阳健脾、甘润胃阴、通腑泄浊、活血通络等治法,随法施药。

细胞角蛋白7与细胞角蛋白20联合检测在鉴别卵巢及胃肠道来源性肿瘤中的诊断价值

目的检测细胞角蛋白7(CK7)与细胞角蛋白20(CK20)在卵巢上皮性肿瘤中的表达,探讨其于卵巢胃肠道来源性肿瘤的诊断意义。方法采用免疫组织化学方法检测CK7与CK20的表达。结果CK7-/CK20+表达所占比例最高,且在卵巢原发性肿瘤与胃肠道来源肿瘤中差异显著,具有统计学意义。结论CK7与CK20联合检测能有效鉴别卵巢原发性肿瘤与胃肠道来源的卵巢转移肿瘤。