Molecular targets and mechanisms of different aberrant alternative splicing in metastatic liver cancer

Metastasis remains a major challenge in the successful management of malignant diseases.The liver is a major site of metastatic disease and a leading cause of death from gastrointestinal malignancies such as colon,stomach,and pancreatic cancers,as well as melanoma,breast cancer,and sarcoma.As an important factor that influences the development of metastatic liver cancer,alternative splicing drives the diversity of RNA transcripts and protein subtypes,which may provide potential to broaden the target space.In particular,the dysfunction of splicing factors and abnormal expression of splicing variants are associated with the occurrence,progression,aggressiveness,and drug resistance of cancers caused by the selective splicing of specific genes.This review is the first to provide a detailed summary of the normal splicing process and alterations that occur during metastatic liver cancer.It will cover the role of alternative splicing in the mechanisms of metastatic liver cancer by examining splicing factor changes,abnormal splicing,and the contribution of hypoxia to these changes during metastasis.

Liver-first approach of colorectal cancer with synchronous hepatic metastases: A reverse strategy

Recently, there has been a change in the strategy of how synchronous colorectal hepatic metastases are attributed to the development of more valuable protocols of chemotherapy and radiotherapy for neoadjuvant treatment of colorectal neoplasms and their hepatic metastases. There is a consensus that patients with synchronous colorectal hepatic metastases have lower survival than those with metachronous colorectal hepatic metastases. Currently, controversy remains concerning the best approach is sequence in a patient with colorectal cancer and synchronous hepatic metastases resection. To obtain a better patient selection, the authors have suggested the initial realization of systemic chemotherapy in the circumstance of patients with colorectal tumor stage Ⅳ, since these patients have a systemic disease. The rationale behind this liver-first strategy is initially the control of synchronous hepatic metastases of colorectal carcinoma, which can optimize a potentially curative hepatic resection and longstanding survival. The liver-first strategy procedure is indicated for patients with colorectal hepatic metastases who require downstaging therapy to make a curative liver resection possible. Thus, the liver-first strategy is considered an option in cases of rectal carcinoma in the early stage and with limited or advanced synchronous colorectal hepatic metastases or in case of patients with asymptomatic colorectal carcinoma, but with extensive liver metastases. Patients undergoing systemic chemotherapy and with progression of neoplastic disease should not undergo hepatic resection, because it does not change the prognosis and may even make it worse. To date, there have been no randomized controlled trials on surgical approach of colorectal synchronous hepatic metastases, despite the relatively high number of available manuscripts on this subject. All of these published studies are observational, usually retrospective, and often non-comparative. The patient selection criteria for the liver-first strategy should be individualized, and the approach of these patients should be performed by a multidisciplinary team so its benefits will be fully realized.

Current surgical management of pancreatic endocrine tumor liver metastases

BACKGROUND: The management of metastatic disease in pancreatic endocrine tumors (PETs) demands a multidisciplinary approach and the cooperation of several medical specialties. The role of surgery is critical, even when a radical excision cannot always be achieved. DATA SOURCES: A PubMed search of relevant articles published up to February 2011 was performed to identify current information about PET liver metastases regarding diagnosis and management, with an emphasis on surgery. RESULTS: The early diagnosis of metastases and their accurate localization, most commonly in the liver, is very important. Surgical options include radical excision, and palliative excision to relieve symptoms in case of failure of medical treatment. The goal of the radical excision is to remove the primary tumor bulk and all liver metastases at the same time, but unfortunately it is not feasible in most cases. Palliative excisions include aggressive tumor debulking surgeries in well-differentiated carcinomas, trying to remove at least 90% of the tumor mass, combined with other additional destructive techniques such as hepatic artery embolization or chemoembolization to treat metastases or chemoembolization to relieve symptoms in cases of rapidly growing tumors. The combination of chemoembolization and systemic chemotherapy results in better response and survival rates. Other local destructive techniques include ethanol injection, cryotherapy and radiofrequency ablation. CONCLUSION: It seems that the current management of PETs can achieve important improvements, even in advanced cases.

Clinicopathologic risk factors and prognostic evaluation in hepatocellular carcinoma recurrence after surgery

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Update on surgical treatment of pancreatic neuroendocrine neoplasms

Pancreatic neuroendocrine neoplasms(PNENs) are rare and account for only 2%-4% of all pancreatic neoplasms. All PNENs are potential(neurendocrine tumors PNETs) or overt(neuroendocrine carcinomas PNECs) malignant,but a subset of PNETs is low-risk. Even in case of low-risk PNETs surgical resection is frequently required to treat hormone-related symptoms and to obtain an appropriate pathological diagnosis. Low-risk PNETs in the body and the tail are ideal for minimallyinvasive approaches which should be tailored to the individual patient. Generally,surgeons must aim for parenchyma sparing in these cases. In high-risk and malignant PNENs,indications for tumor resection are much wider than for pancreatic adenocarcinoma,in many cases due to the relatively benign tumor biology. Thus,patients with locally advanced and metastatic PNETs may benefit from extensive resection. In experienced hands,even multi-organ resections are accomplished with acceptable perioperative morbidity and mortality rates and are associated with excellent long term survival. However,poorly differentiated neoplasms with high proliferation rates are associated with a dismal prognosis and may frequently only be treated with chemotherapy. The evidence on surgical treatment of PNENs stems from reviews of mostly singlecenter series and some analyses of nation-wide tumor registries. No randomized trial has been performed to compare surgical and non-surgical therapies in potentially resectable PNEN. Though such a trial would principally be desirable,ethical considerations and the heterogeneity of PNENs preclude realization of such a study. In the current review,we summarize recent advances in the surgical treatment of PNENs.

Rational Operation for Primary Gastric Carcinoma with Liver Metastasis

OBJECTIVE To investigate the prognosis of advanced gastric carcinoma patients with liver metastasis,and provide a foundation for rational opera- tions. METHODS The operations and prognosis of 102 primary gastric carci- noma patients with liver metastasis were studied retrospectively. RESULTS In gastric carcinoma patients with H1 metastasis who under- went a resection operation,the 6-month,1-and 2-year post-operative sur- vival rates were 61%,42%and 7%.There was a statistically significant dif- ference in survival between resected and non-resected patients(P=0.000) In gastric carcinoma cases with H2 metastasis,resection operations resulted in 54%,16%and 8%respective survival rates,with no significant difference compared to patients not receiving a resection(P=0.132).Gastric carcinoma patients with H3 metastasis who received a resection operation showed 25%,13%and 0%respective survivals with no significantly better prognosis compared to the non-resected cases(P=0.135).There was no statistical y significant difference in survival between the cases with or without peritoneal metastasis(P=0.152). CONCLUSION A resection operation provides a better prognosis for gas- tric carcinoma patients with H1 metastasis independent of peritoneal metas- tasis,but resection has no benefit for gastric carcinoma cases with H2 or H3 metastasis.Peritoneal metastases are not the significant influencing factor for the prognosis of gastric cancer with liver metastasis.

Current status of surgical management of patients with gastroenteropancreatic neuroendocrine neoplasms

Neuroendocrine neoplasms(NENs)of the gastroenteropancreatic system are rare and heterogeneous tumours,yet with increasing prevalence.The most frequent primary sites are the small intestine,rectum,pancreas,and stomach.For a localized disease,surgical resection with local lymph nodes is usually curative with good overall and disease free survival.More complex situation is the treatment of locally advanced lesions,liver metastases,and,surprisingly,small asymptomatic tumours of the rectum and pancreas.In this review,we focus on the current role of surgical management of gastroenteropancreatic NENs.We present surgical approach for the most frequent primary sites.We highlight the role of endoscopic surgery and the watch-and-wait strategy for selected cases.As liver metastases pose an important clinical challenge,we present current indications and contraindications for liver resection and a role of liver transplantation for metastatic NENs.

手术治疗胃癌肝转移的预后分析

目的:探讨手术治疗胃癌肝转移的预后因素。方法:对25例患者临床病理特征及生存应用多元分析其与预后的关系。结果:20例行同时性肝切除,5例行异时性肝切除,1、3、5年生存率分别为84.0%,28.0%,21.0%。肝转移灶数目(孤立和多灶),转移灶分布(单叶和多叶),肝切除方式,原发灶组织学类型,淋巴结转移及脉管瘤栓与预后相关,多元分析显示多灶肝转移,原发灶淋巴结转移、脉管瘤栓是其预后独立危险因素。结论:对出现孤立转移灶、原发灶无淋巴结转移且无脉管瘤栓的胃癌肝转移患者应手术切除以获得更好的预后。

结直肠癌肝转移患者预后的多因素分析

背景与目的:影响结直肠癌肝转移预后的因素仍未明确,本文旨在探讨影响结直肠癌肝转移预后的相关临床病理因素。方法:选择中山大学肿瘤防治中心1996年1月至2000年12月收治的197例结直肠癌肝转移患者,分析临床病理因素与预后的关系。根据Cox回归模型的结果计算预后指数(prognosticindex,PI),并根据PI值将患者分为不同的危险组,比较各组的生存率。结果:全组总的1、3、5年生存率分别为59.04%、17.73%、11.48%。单因素分析显示,有无肝外病变、原发灶切除、肝转移瘤切除、肿瘤大体类型、血清CEA水平、肝转移瘤数目、大小、分布与结直肠癌肝转移的预后有关;多因素分析显示,肝转移瘤切除、血清CEA水平、肝转移瘤数目和大小与预后有关。根据PI值将患者分为高危组、中危组和低危组,3组的生存率两两间存在显著性差异(P<0.05)。结论:肝转移瘤切除、血清CEA水平、肝转移瘤数目和大小是影响结直肠癌肝转移预后的的重要因素,对于可行肝转移灶切除的患者应积极手术治疗,以提高患者的生存率;PI值可用于结直肠癌肝转移患者的预后估计。

胃癌患者术后端粒长度变化与预后观察

目的 分析原发性胃癌组织中的端粒长度变化与患者术后预后的关系。 方法 以琼脂糖DNA杂交检测58例手术切除的原发性胃癌与邻近胃组织中端粒限制性内切酶片段(TRF)的长度,并观察术后患者的临床状况及生存期。 结果 发现原发性胃癌组织中的平均TRF长度均比相应邻近胃组织缩短。其中原发性胃癌有14例TRF缩短,5例TRF延长;且在胃癌中TRF的这种异常状态与肿瘤的大小、转移、临床病理分期及患者的生存率相一致。 结论 TRF长度不仅参与了胃癌的发生与发展,而且也为胃癌的诊断及预后判断提供了一种新的手段。

近、远端胃癌临床病理特点分析(附428例报告)

目的 进一步探讨近、远端胃癌的临床病理特点。方法 收集和分析了 118例近端胃癌 (PGC)的临床和病理资料 ,并与同期 3 10例远端胃癌 (DGC)患者的相关资料进行比较。结果 近端胃癌的发生率较低 ,临床分期多数为Ⅲ期和Ⅳ期 ,病理组织学类型以低分化、未分化及粘液腺癌为多 ,手术类型中全胃切除术及联合脏器切除术占较高比例 ,断端癌残留及淋巴结转移率显著增高 ,伴有食管受累的患者其淋巴结转移的阳性率大大增加 ;随访 5年生存率 ,PGC组显著低于DGC组。手术后并发症及手术死亡率两组间的差异无显著性意义。结论 临床晚期癌多、食管容易受累及病理组织学分化差是近端胃癌预后差的重要原因。

新TNM分期系统对评价手术切除肝癌预后的意义

背景与目的2002年国际抗癌联盟对原第5版肝癌TNM(以下简称TNM5)分期进行了修订,提出了新的第6版TNM(以下简称TNM6)分期标准,目前应用TNM6分期评估手术切除肝癌患者预后的报道较少。本研究探讨TNM6分期对评价手术切除肝癌预后的价值及TNM6分期在我国临床应用的可行性和合理性。方法根据我院1993年1月至1998年12月施行的478例肝细胞肝癌切除病例资料和随访结果,分别按TNM5分期及TNM6分期进行生存分析,比较各期的生存率,并将TNM5分期和TNM6分期作相互比较,分析TNM6分期的优缺点。结果按TNM5分期标准各期病例数分别为Ⅰ期12例(2.5%),Ⅱ期224例(46.8%),ⅢA期95例(19.9%),ⅢB期8例(1.7%)和ⅣA期139例(29.1%);各期患者5年生存率分别为81.8%、41.5%、17.0%、0.0%和10.2%。Ⅰ期与Ⅱ期、ⅢB与ⅣA期患者生存率无统计学差异;Ⅱ、ⅢA、ⅢB期患者间在预后上有显著差别。按TNM6分期标准各期病例数分别为Ⅰ期234例(48.9%),Ⅱ期41例(8.6%),ⅢA期96例(20.1%),ⅢB期88例(18.4%)和ⅢC期19例(4.0%);各期患者5年生存率分别为43.3%、20.2%、13.1%、13.0%和0。Ⅰ期与Ⅱ期患者生存率有统计学差异,Ⅱ期、ⅢA期与ⅢB期患者互相之间生存率均无显著差异。结论肝癌TNM6分期较TNM5分期有重要进步,参数较少,且简便易用,但仍有一定局限性,临床应用于预后估计还不十分准确,并不完全适用于我国绝大多数合并肝硬化的肝癌患者。

150例胃癌手术治疗预后因素分析

目的 对 15 0例胃癌手术治疗预后因素的分析 ,探讨合理的胃癌根治性切除术式。方法 对 1987-1997年间收治的 15 0例胃癌行根治性切除术 10 0例 ,姑息性切除术 43例 ;采用AJCC胃癌TNM分期 ,分析其影响预后的因素。结果 全组术后 3、5、10年生存率分别为 44.7%、40 %、2 7%;根治性切除组和姑息性切除组分别为 6 0 .0 %、5 6 .0 %、42 .9%及 9.3%、7.0 %、0 .0 %,两组术后 3、5、10年生存率对比差异极显著 ,P值均〈0 .0 0 0 1;根治性切除组中切缘癌残留占 2 %,D≤N占 6 4%。结论 胃癌根治性切除术是影响本组胃癌手术治疗预后的关键因素 ,胃癌姑息切除、切缘癌残留及D≤N等可能为影响胃癌手术治疗预后的负面因素。

胃癌D2式淋巴结清除术的临床研究

目的:分析D2式淋巴结清除术对胃癌患者的预后、手术并发症和死亡率的影响。方法:对217例胃癌手术患者进行前瞻性研究,随机分成对照组(108例胃癌患者进行D0/D1式淋巴结清除术)和实验组(109例胃癌患者进行D2式淋巴结清除术),术后病理确诊分期,对比两组的有效率和不良反应发生率。结果:本组患者不同分期的5年生存率实验组:对照组分别为Ⅰ期90%(27/30)∶87.8%(29/33),P=0.878;Ⅱ期89.7%(35/39)∶47.2%(17/36),P=0.003;Ⅲ期52%(13/25)∶18.2%(4/22),P=0.008,Ⅳ期6.6%(1/15)∶5.8%(1/17),P=0.474。D2∶D0/D1术后总并发症发生率分别为27.5%∶21.3%,P=0.302,其中D0/D1、D2的手术死亡率均为0。结论:胃癌的D2式广泛性淋巴结清除术是安全的,能够显著地改善Ⅱ～Ⅲ期胃癌患者的预后。

高级别上皮内瘤变及早期胃癌内镜与外科治疗在随访及经济指标中评估研究

目的探讨内镜与外科手术治疗高级别上皮内瘤变及早期胃癌术后残胃及吻合口黏膜改变、费用及治疗时间、随访复发情况。方法收集25例内镜治疗及100例外科手术治疗患者,分别从术后黏膜改变状态(充血、糜烂、溃疡、伴随胆汁反流)、治疗费用与时间、术后随访复发情况3方面评估,利用SPSS 16.0统计软件进行统计。结果外科手术术后黏膜明显充血者87.0%,糜烂36.0%,溃疡9.0%,伴随胆汁反流高达48.0%,内镜组除手术瘢痕外无明显术后黏膜炎性改变(P<0.001);外科手术组平均花费为(3.56±1.12)万元,平均住院时间(20±9)天,内镜治疗组平均费用(0.57±0.42)万元,平均治疗时间(5±2)天(P<0.001);外科组随访中见1例复发,内镜治疗组无复发(P>0.05)。结论内镜切除治疗高级别上皮内瘤变不仅能显著改善术后黏膜状态、降低治疗费用、缩短恢复时间,而且具有与外科手术类似良好预后。

进展期胃癌新辅助化疗的临床疗效观察

目的评价进展期胃癌新辅助化疗的疗效及对预后的影响。方法回顾性分析45例确诊进展期胃癌患者通过新辅助化疗后再行手术治疗的疗效及预后,并与60例同期收治的未经新辅助化疗的胃癌手术患者进行对照。结果新辅助化疗组临床有效率RR(CR+PR)为68.9%(31/45),其中CR 6.7%(3例),PR 62.2%(28例),SD 28.9%(13例),PD 2.2%(1例),术后1例在病理水平达到完全缓解(pCR),缓解率为2.2%(1/45)。不良反应主要为Ⅰ及Ⅱ度白细胞减少、恶心、脱发、呕吐及黏膜炎,其中Ⅲ及Ⅳ级的白细胞减少及胃肠道反应6例(13.3%),无严重感染和死亡病例。新辅助化疗组手术根治性切除率为84.4%,对照组的手术根治性切除率为66.7%,两者差异有统计学意义(P<0.05)。与对照组比较,新辅助化疗组的术后生存期明显延长(P<0.05),且两组术后并发症无明显差异。结论手术切除较为困难或根治率低的局部晚期胃癌患者,术前配合新辅助化疗,可显著提高胃癌切除率,并且最终可明显提高胃癌患者的术后生存期。

胃癌患者腹腔内游离癌细胞检测及其相关因素与预后

目的:探讨胃癌患者腹腔内游离癌细胞形成的相关因素。方法:对114例胃癌患者在手术中对肿瘤未行侵入性操作前予以腹腔冲洗液细胞学检测,分析腹腔游离癌细胞的产生与浆膜受侵、淋巴结转移、临床分期及病理分型等因素的相关性并对所有患者进行3年的追踪回访。结果:114例胃癌腹腔冲洗液细胞学阳性率为39·47%(45/114),淋巴结转移、临床病理分期、肿瘤病理类型与腹腔冲洗液细胞学阳性显著相关,P<0·01,腹腔游离癌细胞阳性者预示术后不佳。3年内,腹腔游离癌细胞阳性组45例患者无1例生存。结论:腹腔脱落癌细胞形成微转移性,是胃癌术后腹腔复发及转移的主要危险因素之一。肿瘤浸润深度,淋巴结转移及TNM分期与腹腔游离癌细胞呈正相关。术中检测游离癌细胞有助于评价病期、手术效果,并为辅助治疗提供依据。

肝细胞生长因子及其受体c-Met表达与胃癌肝转移的相关性

目的:探讨肝细胞生长因子及其受体c-Met的表达及临床病理因素与胃癌肝转移的关系。方法:应用免疫组化方法检测HGF和及其受体c-Met在胃癌和肝转移癌组织中的表达情况,通过对比两者在原发癌和肝转移癌组织中的不同表达状态,探讨二者及临床病理因素与胃癌肝转移发生的关系。结果:实验组与对照组胃癌组织中HGF呈阳性表达率分别为68%和60%,两组比较差异具有统计学意义。实验组与对照组胃癌组织中c-Met呈阳性表达率分别为86%和68%,两组比较差异具有统计学意义。胃癌患者的淋巴结转移、HGF表达、c-Met表达与胃癌肝转移有关;而浸润深度、分化程度与胃癌肝转移无关。原发癌和肝转移癌HGF表达一致性分析存在显著差异。原发癌和肝转移癌c-Met表达一致性分析无显著差异。结论:HGF和c-Met的高表达与胃癌肝转移机制有关,对于c-Met表达程度的评估可能成为预测胃癌肝转移有价值的预后指标。

早期外科手术干预对腹腔镜胃癌根治术后胃肠道瘘患者预后的影响

目的探讨早期外科手术干预对腹腔镜胃癌根治术后胃肠道瘘患者预后的影响。方法回顾性分析1 031例腹腔镜胃癌根治术患者中发生胃肠道瘘的35例患者的临床资料。其中19例急诊全麻下行开腹置管引流的患者作为手术治疗组,16例经原腹腔引流管置入套管冲洗引流的患者作为保守治疗组,比较两组的治疗结果。结果手术治疗组治愈率为94.7%,保守治疗组治愈率为81.3%,差异无统计学意义(P>0.05)。手术治疗组瘘口愈合时间为(24.58±2.52)天,保守治疗组为(26.44±2.19)天,差异有统计学意义(P<0.05)。手术治疗组平均住院时间为(42.95±2.61)天,保守治疗组为(45.56±3.20)天,差异有统计学意义(P<0.05)。手术治疗组平均住院费用为(9.63±1.61)万元,保守治疗组为(11.13±1.20)万元,差异有统计学意义(P<0.05)。结论早期外科手术干预相对于传统保守治疗可缩短腹腔镜胃癌根治术后胃肠道瘘患者瘘口愈合时间及住院时间,减少住院费用,改善预后。

40例胃癌肝转移的手术治疗及预后

目的分析胃癌肝转移患者的手术治疗效果及影响预后的冈素,以探讨其手术指征。方法回顾性分析2010年1月1日至2012年1月1日于我院胃肠外科行原发灶+肝转移灶切除的40例胃癌合并肝转移患者的临床资料,分析其手术效果并用Log—rank检验及Cox风险比例模型分别对胃癌肝转移患者的主要临床病理因素与预后的关系进行单因素和多凶素分析。结果 40例患者均顺利完成手术,其中行R0切除30例,R1切除10例,无R2切除者。术后并发症发生率为15.0%(6/40),无术后大出血及死亡病例。1年、2年及3年总生存率分别为37.5%(15/40)、10.0%(4/40)、0,中位生存期为10.5个月。单因素分析显示原发灶病理类型、原发胃癌侵犯浆膜、胃周淋巴结转移、血管癌栓、神经侵犯、转移灶分布、转移灶直径、肝转移类型、肝切除方式和手术根治程度与预后相关。多因素分析显示原发胃癌侵犯浆膜、血管癌栓、神经侵犯、转移灶直径和手术根治程度为预后的独立影响因素。结论原发胃癌未侵犯浆膜、无血管癌栓、无神经侵犯、肝转移灶直径<5 cm和R0切除者可能是胃癌肝转移行原发灶+肝转移灶切除术的受益人群,亦可能是较佳的手术适应证。