Lynch综合征相关结直肠癌临床研究进展

Lynch综合征（LS）是由于错配修复（MMR）基因突变,继而引发肿瘤的一种常染色体显性遗传性疾病,在临床上主要表现为微卫星不稳定性（MSI）。遗传性结直肠癌最常见的病因就是LS。随着分子诊断技术地不断提高,通过对LS分子检测实现LS相关结直肠癌的精准诊疗,逐渐成为临床关注的焦点。在我国,LS相关结直肠癌虽有较好的预后,但进一步提高LS家族史患者的筛查和随访策略仍是重要任务。此外,利用LS的免疫学特性来指导其治疗和预防是许多学者面临的一项新挑战。笔者就LS相关结直肠癌的流行病学、临床病理特征、筛查诊断和治疗及预防等新进展进行综述。     

Development of minimal residual cancer cell research

Micrometastases of cancer cells occur during the early stages of cancer or from minimal residual cancer cells with metastatic potential. Recent progress in measuring methods has enabled the detection of minimal residual cancer cells in areas such as circulating tumor cells (CTCs) in peripheral blood, disseminated tumor cells in bone marrow, and free tumor cells in lymph nodes and the peritoneal cavity. Recently, it has been reported that the phenotypes of CTCs are closely related to cancer stem cells, and thus they may be of interest as new biomarkers in cancer patients. The usefulness of CTCs as predictive markers for recurrence and prognosis was demonstrated in patients with breast and colorectal cancer. Progress in the early diagnosis of the therapeutic effects of chemotherapy combined with molecular targeted drugs has also been enhanced by the detection of CTCs. Furthermore, individualized, limited surgery based on sentinel node navigation surgery has been performed not only in patients with breast cancer but also in those with gastric cancer. The clinical significance of free tumor cells in the peritoneal cavity of colorectal cancer patients has also become an area of interest. These developments in minimal residual cancer cell research may lead to a new metastatic cascade concept and novel approaches to cancer therapy.     

环状RNA的功能及其在结直肠癌中的研究进展

环状RNAs(circRNAs)是一种具有共价闭合环状的长链非编码RNA。circRNAs广泛存在于真核细胞并且结构稳定。circRNAs可作为微小RNAs(miRNAs)的分子海绵参与基因转录后调控,也可与多种蛋白相互作用,调控基因转录及蛋白翻译等。越来越多的研究表明,circRNA与结直肠癌的发生、发展密切相关,有望为结直肠癌的诊断和治疗提供新的分子标志物和靶点。本文从circRNAs的形成、生物学功能以及在结直肠癌疾病中的研究进展等方面进行简要综述,以期为结直肠癌早期诊断和治疗提供新靶点。     

Sporadisches und hereditäres Karzinom von Kolon und Rektum

In recent years, there have been major advances regarding the understanding of the pathogenesis of sporadic and hereditary colorectal cancer on the basis of molecular research. The clinical implications of this knowledge differ for the sporadic and hereditary forms. In sporadic colorectal cancer, gene mutations occur in colorectal cells but not as germline mutations. Even though molecular data currently do not influence the clinical management of this form of colorectal cancer, promising molecular approaches exist for the assessment of prognosis, early detection, prevention, and therapy. Germline mutations are the cause of hereditary colorectal cancers, in which molecular methods have a major impact on diagnosis and therapy. Prophylactic surgery is accepted for patients with familial adenomatous polyposis (FAP), but not for patients with hereditary non-polyposis colorectal cancer (HNPCC), the second main form of hereditary colorectal cancer. Further studies will have to clarity this issue.     

Predictive molecular diagnosis and preventive surgical treatment of hereditary colorectal carcinoma: a new field of interest for surgical research]

Colorectal cancer is one of the most frequent cancers in the Western hemisphere. It seems to be well established that colorectal tumors develop as a result of an accumulation of inherited and/or acquired somatic mutational events in tumor suppressor genes and oncogenes. An increasing understanding of the molecular basis of the most prevalent colorectal cancer syndromes, such as hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP), is reflected by modifications in diagnosis and therapy. Therefore, strategies have been developed for predictive molecular diagnosis and preventive surgical treatment of colorectal cancer syndromes. In the future surgical research will participate in research and development in the field of molecular diagnosis of colorectal cancer and will then evaluate the clinical management concepts as a result.     

结直肠癌分子标志物临床检测中国专家共识

结直肠癌是目前我国发病率及死亡率最高的恶性肿瘤之一。随着精准医疗理念及对肿瘤相关分子标志物研究的逐年深入,合理的检测及应用结直肠癌相关分子标志物已经成为目前临床实践的重要部分。为了提高临床医师对结直肠癌分子标志物的了解及应用,中国临床肿瘤学会(CSCO)结直肠癌专家委员会组织相关领域专家,根据近年的国内外临床研究及实际诊疗经验,经专家组反复修改讨论,撰写了结直肠癌分子标志物临床检测的专家共识,旨在为临床医师提供参考及指导,为结直肠癌患者提供更加精准、有效的治疗。     

Molecular biology of colorectal cancer and clinical consequences for colorectal cancer syndromes

Because of the accomplishments in biotechnical research in the past few decades our knowledge about the molecular mechanisms of carcinogenesis has grown rapidly. Colorectal cancer has been one of the most intensively investigated tumor entities, and it seems to be well established that colorectal tumor growth is associated with an accumulation of acquired somatic mutational events in tumor suppressor genes and oncogenes. Recent progress in our understanding of the molecular basis of the most prevalent colorectal cancer syndromes, such as hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP), is reflected by modifications in diagnosis and therapy. Identification and characterization of the causative genes for these colorectal cancer syndromes have enabled precise presymptomatic detection of mutations in individuals who bear an a priori risk of about 50% of developing colorectal cancer. Genotype-phenotype correlations might further increase the clinical management of hereditary colorectal cancer. Even though developments in cancer research are restricted to the minority of individuals with hereditary cancer syndromes, growing knowledge about the effect of low penetrance variations in tumor suppressor genes may affect the diagnosis and therapy of sporadic colorectal cancer. Received: 10 December 1997 / Accepted: 18 June 1998     

New molecular markers for bladder cancer detection

PURPOSE OF REVIEW: Bladder cancer continues to be one of the most common genitourinary malignancies. The mainstay of diagnosis remains cystoscopic visualization with transurethral biopsy or resection. As over two-thirds of bladder tumors recur, vigilant surveillance is required. Due to the invasiveness and expense of frequent cystoscopies and the lack of sensitivity of urinary cytology, especially for low-grade superficial lesions, novel molecular markers have been investigated as a means to detect bladder cancer noninvasively. RECENT FINDINGS: As our understanding of the pathogenesis of urothelial neoplasia improves, coupled with recent advances in molecular biological techniques, an array of new approaches to the diagnosis of bladder cancer has emerged. Several urine-based markers have been tested against the standard of urinary cytology with promising results. However, lack of standardization of technique and heterogeneity of bladder cancer itself may hinder the widespread dissemination of these diagnostic aids. SUMMARY: A host of new molecular markers based on the pathogenesis of bladder cancer have been investigated, such as telomerase, survivin, and multitarget fluorescence in situ hybridization, which may eventually improve detection and management of urothelial malignancies. By improving the sensitivity of urinary cytology for low-grade superficial lesions and detecting recurrent disease noninvasively early in its course, these new molecular markers might someday allow changes in the way bladder cancer is diagnosed and followed. At the present time, however, no single molecular marker provides 100% accuracy. Perhaps panels utilizing the most promising of these markers may alter bladder cancer detection and management policy.     

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??The progress and controversy on precision medicine of colorectal cancer YAO Hong-wei??ZHANG Zhong-tao. Department of General Surgery??Beijing Friendship Hospital??Capital Medical University ?? National Clinical Research Center for Digestive Diseases??Beijing 100050??China
Corresponding author: Zhang Zhongtao??E-mail??zhangzht@
medmail.com.cn
Abstract The main treatment of colorectal cancer is still surgical and comprehensive treatment. The eighth edition of AJCC colorectal cancer staging??recommended MSI??KRAS??NRAS and BRAF testing with high level of "evidence-based medicine" evidence. The diagnosis and treatment of colorectal cancer has changed from the traditional population based care to personalized precision medicine. The traditional distinction of left- and right-sided colon cancer is based on anatomy??embryology and symptomatology. And based on molecular pathology and immune environment??the sideness of colon cancer has gained a new definition from the development of precision medicine??and become one of the key factors to consider how to choose the targeted therapy and prognosis evaluation. The consensus molecular subtypes of colorectal cancer has been published for several years??but it is still controversial how to give more specific clinical maneuverability. Precision medicine of colorectal cancer will re-plan the cancer classification??prevention and screening??diagnosis and treatment??outcome prediction??and prognosis evaluation. Surgeons should welcome the era of precision medicine for colorectal cancer.     

结直肠癌肝转移分子机制的研究新进展

结直肠癌是最常见的恶性肿瘤之一,其致死率很高.大约1/3的结直肠癌患者发生同时性或异时性肝转移,而且发生肝转移的患者预后一般较差,因此研究结直肠癌肝转移的机制非常重要.近年来关于结直肠癌肝转移分子机制的研究越来越多,本文主要对其中一些分子机制的研究进行归纳总结,希望能对结直肠癌肝转移患者的诊治和预防提供新思路.     

Molecular markers for detection, surveillance and prognostication of bladder cancer

Many markers for the detection of bladder cancers have been tested and almost all urinary markers reported are better than cytology with regard to sensitivity, but they score lower in specificity. Currently molecular and genetic changes play an important role in the discovery of new molecular markers for detection, prognostication and surveillance. The purpose of this review is to highlight the most important urinary molecular biomarker developments that have been studied and reported recently. In the current review we have summarized the most recent and relevant published reports on molecular urinary markers. The results of this review show that the first generation of urinary markers did not add much to urinary cytology. The current generation of markers is better, but additional clinical trials are needed. Our knowledge of molecular pathways in bladder cancer is growing and new methods of marker development emerge, but the perfect marker is still to be found. Currently, there are not clinically usable molecular markers that can guide us in diagnosis or surveillance, nor guide us in lowering the frequency of urethrocystoscopy in bladder cancer.     

从临床研究和数据收集的角度看结直肠外科的发展方向

得益于近年来微创外科技术的发展、围手术期综合治疗策略和临床研究的进步,我国的结直肠外科也得到了快速发展。但对比我国与欧美发达国家的结直肠癌诊疗现状可以发现,西方发达国家的结直肠外科的专科化建设和规范化诊疗已经非常成熟,结直肠癌的多学科诊疗模式业已规范化运行。尽管我国东部沿海地区的高水平结直肠癌诊疗中心与西方国家相比已几乎无差距,但由于我国幅员辽阔且地区发展不平衡,结直肠外科的标准化手术以及规范化治疗理念仍有待普及。我国结直肠外科领域要寻求新的发展和突破,就要进一步开展更高质量的临床研究。笔者结合已参与和开展的国际国内临床研究经验,认为应该从以下两点对临床研究进行质量控制:(1)研究的结构化培训和质量控制;(2)数据库的建立和管理。总之不能仅将注意力集中于结直肠外科手术本身,更要完成向研究型医生、研究型学科的转变,培养开展数据收集和临床研究的理念,增强临床研究的科研意识,将高质量的数据收集和临床研究融入到日常临床实践的工作中。这样才能从根本上提高中国结直肠外科的综合实力,有效开展基于我国结直肠疾病现状的外科相关临床研究,并获得基于我国患者人群研究结果的高级别循证医学证据,形成我国结直肠外科诊断治疗相关的指南,用于指导我国结直肠疾病患者的外科临床实践,这也必将是中国结直肠外科发展的新方向。     

精准医学在结直肠癌诊治中的共识与争议

结直肠癌的治疗目前仍以手术切除和综合治疗为主,随着AJCC第8版结直肠癌分期系统的更新,将MSI、KRAS、NRAS、BRAF等分子检测进行了基于高级别“循证医学”证据的重点推荐,结直肠癌已经从传统的基于“群体化”诊治进入了精准的“个体化”医疗。传统的左、右半结肠癌是根据胚胎学、解剖学以及症状学等进行区分,在分子病理学指标及免疫环境检测的基础上,其已经从精准医学的发展中获得了新的定义,成为考虑如何选择靶向治疗和判断预后的关键因素之一。结直肠癌的共识分子亚型已经发布,但如何赋予其更具体的临床可操作性,目前尚存争议。结直肠癌“精准医学”将重新规划癌肿分类、预防筛查、诊断治疗、疗效预测、评估预后等各个临床实践节点,外科医师应该以积极的心态迎接结直肠癌“精准医学”时代的来临。     

The preoperative assessment and postoperative surveillance of patients with colon and rectal cancer

Many advances have been made in the field of colorectal cancer follow-up since the pioneering efforts of Wangensteen and others with second-look operations in the 1950s. The understanding of the biology and natural history of colorectal malignancy has been advanced. Diagnostic methods for detection of recurrent disease have also advanced tremendously with CEA monitoring, immunoscintigraphy. CT, MRI, and PET imaging. As has been discussed in this article, however, no strategy of postoperative follow-up has been shown unequivocally to produce improved survival benefit or cure rate. It is quite possible that benefit will be shown, but well-controlled trials will be required. Cost considerations will likely prove important, because the rate of detection of curable disease will likely.be low. Quality of life issues will also be important in such trials. Better treatment and outcome ol recurrent disease would provide a strong rationale for vigorous postoperative surveillance. New recommendations are currently evolving [54]. Early diagnosis seems likely to enhance the curability of both local and distant relapses and second primary tumors. Furthermore, there may be a survival and quality of life advantage that results from the early institution of chemotherapy, even for those tumors found to be inoperable [55]. In devising a plan for follow-up in patients, it is important to recognize the anatomic and temporal patterns of recurrence as well as their relationships to the initial tumor staging. Although there is little proof that the identification of recurrent disease in follow-up programs increases the likelihood of resectability, cure, or prolonged survival, many physicians have witnessed successful treatment of recurrent colorectal cancer. These anecdotal experiences, the unproven belief that follow-up is beneficial, and traditions imparted during training are among the likely motivating factors for most physicians caring for colorectal cancer patients.     

Referral guidelines for colorectal cancer--do they work?

AIMS AND METHODS: Urgent referral guidelines for patients with suspected colorectal cancer were introduced in 2000. In a district general hospital, we prospectively assessed the effect of these guidelines on the number of urgent referrals received and the number found to have cancer. RESULTS: Over the first year, 180 urgent referrals were received of whom 95 (55%) fitted the guidelines. Of these 95 patients, 24 (25%) had colorectal cancer. Conversely, only 2 of the 85 patients (2%) who did not fit the guidelines had colorectal cancer. During the same time period, a total of 145 new cancers were identified within the district of which 119 (82%) were in patients who had not been urgently referred to out-patients as suspected colorectal cancer. DISCUSSION: The guidelines are effective in that patients who fit them have a significant chance of having colorectal cancer. However, the majority of cancers are identified outside the new system. Efforts to reduce delays in diagnosis need to recognise that many patients do not have features which fit published referral criteria. Improved support for general practitioners and better access to specialist services are required to reduce delays in diagnosis.     

Hereditary colorectal cancer without associated polyadenomatosis

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant condition in which affected individuals develop colorectal cancer or extracolonic cancer, most commonly endometrial, at an early age. Recent advances in molecular genetics have led to the identification of a germline mutation of DNA mismatch-repair genes to be responsible for the majority of HNPPC cases. Since clinical screening of gene carriers can help to prevent cancer, it is important to devise strategies applicable to this syndrome. Recommendations for current management, especially screening and surgical treatment are under study, as they have not yet been clearly established. This paper reviews the clinical presentation, the molecular genetic diagnosis and therapeutic approaches of this syndrome including the controversies concerning prophylactic colectomy for cancer or gene carriers.     

Early detection of colorectal cancer using high-magnification chromoscopic colonoscopy

BACKGROUND: Endoscopic techniques aimed at early detection of colorectal cancer (CRC) and its precursors, permitting targeted in vivo luminal treatments, have been developed by the Japanese since the early 1990s. The introduction of this new technology to the UK (i.e. magnification endoscopes) may permit earlier and more accurate diagnosis. According to Japanese data, magnification chromoscopy can be used to predict histology and invasive depth of cancer, and help in the detection of flat and depressed colonic lesions. Flat and depressed lesions are not purely Japanese phenomena: they exist with a similar incidence in the UK. METHODS: A Medline search was performed for the years 1955-2001 using the following medical subject headings and search methodology: colorectal cancer and colonoscopy or aberrant crypt foci or molecular kinetics or flat/depressed lesions or chromoscopy. RESULTS AND CONCLUSION: Early CRC, in the form of flat or depressed lesions, can be difficult to detect using conventional colonoscopic techniques and penetrate the colonic mucosa deeply. The implications of detecting these lesions in relation to current approaches to the prevention of CRC are profound.     

遗传性非息肉病性结直肠癌家系临床及分子遗传学分析

目的探讨总结遗传性非息肉病性结直肠癌(hereditary nonpolyposis colorectal cancer,HNPCC)的临床和分子生物学特征,提高临床诊断和治疗水平。方法分析总结温州地区12个HNPCC家系临床病理特征。用显微切割、微卫星不稳定性分析、免疫组织化学、直接DNA测序法,检测HNPCC患者肿瘤组织微卫星不稳定性状态,错配修复基因hMHL1和hMSH2蛋白水平表达及hMHL1和hMSH2基因种系突变。结果12个家系32例患者中,患第1癌的中位年龄45．2岁;75．0％的患者在50岁以前发病;51．1％的肿瘤位于脾曲近侧结肠,34．4％为多原发结直肠癌,53．1％为组织分化差的癌,68．8％为Dukes A、B期。12个家系中6个家系伴有7例肠外肿瘤患者;19例健在患者生存1～28年,13例死亡患者平均生存期6．4年。9例患者肿瘤组织均表现高度微卫星不稳定性,其中5例患者表现hMSH2或hMLH1蛋白失表达(5／9);5个家系中3个家系存在hMH;1或hMSH2突变(3／5),其中有2个新发现的突变。结论HNPCC有特定的临床病理特征;检测错配修复基因hMHL1和hMSH2序列对HNPCC家系的成员具有指导价值;微卫星不稳定性和错配修复蛋白失表达是HNPCC的重要特征,可作为测序前的筛选手段。     

定量RT-PCR方法检测大肠癌外周血CEAmRNA方法及临床应用

目的：介绍定量巢式反转录聚合酶链反应（Nested-RT-PCR)检测大肠癌外周血CEAmRNA方法及其临床应用,提高大肠癌及其转移的早期诊断率,方法：用竞争性Nested-RT-PCR方法检测了10例大肠癌患者术前和术后外周血CEAmRNA并进行定量。结果：成功建立了定量Nested-RT-PCR技术检测CEAmRNA方法。10例标本中8例为阳性,并且随着治疗的进展,CEAmRNA的量也逐渐变化。结论：定量巢式反转录聚合酶链反应检测技术检测大肠癌患者外周血CEAmRNA的方法稳定可靠,可进行量化,对大肠癌及大肠癌术后转移的早期诊断有重要意义。     

Carbonic anhydrase IX and the future of molecular markers in renal cell carcinoma

The use of carbonic anhydrase IX as a promising molecular marker in RCC is described by authors from Los Angeles, who discuss the promise that molecular markers hold to improve diagnosis, staging, treatment, surveillance and survival of patients with RCC. There is a whole range of new treatments being introduced in the management of metastatic renal cancer. The use of VEGF-targeted therapy has particular importance, especially as it has a strong genetically linked rationale for its potential success in this area. Authors from the USA show that substantial clinical activity has been reported in initial clinical trials. In prostate cancer, drugs targeting microtubules, such as taxanes, have already been introduced clinically, and their success has received widespread attention. A new group of drugs, the epothilones, have similar but not identical binding properties to microtubules, and authors from the USA describe how they have shown activity in hormone-refractory prostate cancer, and are moving to phase III testing.