结直肠癌免疫治疗的研究及前景展望

结直肠癌是发病率高的消化系恶性肿瘤.手术加放化疗,一直以来未能显著提高患者术后5年生存率,约1/3的患者最终死于结直肠癌远处转移.肿瘤免疫治疗近年来越来越受到广泛关注,已成为研究热点.免疫治疗运用现代生物高科技技术,主要通过提高患者自身机体免疫系统的抗肿瘤能力来控制和杀伤肿瘤细胞,成为继手术、放疗和化疗之后的第4种肿瘤治疗模式.本文系统阐述了肿瘤免疫治疗的类型及不同类型在结直肠癌中的应用进展情况,指出不同免疫治疗方法的优势和缺点,特别讨论了结直肠癌炎症微环境、放疗和化疗与免疫治疗的关系.免疫治疗在不久的将来有可能成为结直肠癌个体化治疗的重要方式.     

转移性结直肠癌靶向治疗的研究进展

结直肠癌,尤其是转移性结直肠癌（mCRC）是最常见的恶性肿瘤之一,并是导致患者死亡的重要原因。近年靶向治疗的成功应用为mCRC的系统治疗提供了广阔前景。本文旨在对近年mCRC靶向治疗的临床进展作一综述。     

2019年结直肠癌领域治疗进展

2019年,结直肠癌领域的进展主要集中在围手术期的治疗模式以及姑息治疗中的免疫治疗和靶向治疗,本文将根据今年大型会议的报道以及重要期刊上的文献作为基础,梳理2019年在结直肠癌治疗领域的进展。     

PD-1抗体/PD-L1抗体在结直肠癌治疗中的应用现状及展望

结直肠癌是第二大最常见的肿瘤死亡原因。免疫治疗逐渐成为结直肠癌手术切除等常规治疗方式以外的另一种治疗方法。目前对抗PD-1/抗PD-L1药物疗效及不良反应的报道各不相同。本文将从PD-1信号通路及其阻断剂、PD-1/PD-L1抗体在结直肠癌中的临床应用、结直肠癌患者对免疫治疗的抵抗、PD-1/PD-L1抗体治疗的不良反应、预测PD-1/PD-L1抗体治疗疗效的生物学标志物等方面进行综述。     

免疫联合靶向药物治疗微卫星稳定型转移性结直肠癌的研究进展

结直肠癌(CRC)是常见的恶性肿瘤,且发现时多处于中晚期,晚期CRC仍以化疗为主。随着对CRC研究的不断深入,靶向治疗、免疫治疗等多种治疗方式也在不断进步。对于微卫星高度不稳定型CRC,免疫治疗在一线、后线、辅助及新辅助治疗方面均取得了突破。然而,绝大多数CRC属于微卫星稳定(MSS)型,免疫治疗的表现不尽如人意,目前的研究方向多将免疫治疗与靶向治疗、化疗、局部治疗等相结合作为突破方向。本文将对免疫联合靶向药物治疗MSS型CRC的研究现状和热点问题进行梳理和综述。     

贝伐单抗靶向治疗结直肠癌的临床研究进展

分子靶向治疗已成为结直肠癌治疗的有效策略。最近，血管生成抑制疗法日益成熟，针对血管内皮生长因子（VEGF）的重组人源化单克隆抗体贝伐单抗（bevacizumab，商品名：Avastin，阿瓦斯丁^TM）成为结直肠癌治疗研究的热点。美国食品药品管理局（FDA）于2004年批准贝伐单抗为晚期结直肠癌的一线用药，     

microRNA与结直肠癌关系的研究进展

结直肠癌的发病是一个多因素、多步骤的演进过程,基因表达异常在其中起重要作用.近年研究发现多种microRNA（miRNA）在结直肠癌中表达异常,可能参与了肿瘤的发生、发展过程,有望成为结直肠癌早期诊断、临床分期、个体化治疗、靶向治疗和预后评估的分子标记物.本文就近年来有关miRNA与结直肠癌天系的研究进展作一综述.     

结直肠癌的免疫治疗进展

近年来,随着全直肠系膜切除术（TME）的推广,新的化疗药如草酸铂、开普拓等的应用,结直肠癌的疗效有了一定的提高,免疫治疗也逐渐成为肿瘤综合治疗的重要组成部分。现就结直肠癌的免疫治疗综述如下。     

结直肠癌的免疫检查点阻断治疗

结直肠癌是常见的恶性肿瘤之一,总体预后相对较差。对转移性结直肠癌患者而言,探索更有效的治疗方法显得尤为重要。免疫治疗,特别是免疫检查点抑制剂,是近几年研究的热点,在黑色素瘤、肺癌等疾病中取得了较好的疗效。本文将重点阐述抗肿瘤免疫在结直肠癌中的作用,以及各种免疫检查点抑制剂在结直肠癌中应用的最新进展。     

中山医院结直肠癌MDT讨论治疗策略分析

目的分析结直肠癌多学科诊疗团队（MDT）讨论后制定的治疗策略。 方法回顾性分析2010年7月至2019年2月复旦大学附属中山医院进行MDT讨论的结直肠癌患者的临床资料,对MDT讨论结果进行统计分析。 结果结直肠癌MDT总计为1 953例结直肠癌患者进行4 535人次讨论制定个体化治疗方案。其中,553例患者肝转移灶和111例患者肺转移灶被认为可切除。另有261位最初不可切除的结直肠癌肝转移患者,在接受系统化疗联合分子靶向以及介入等综合治疗后,转化为可切除,建议接受肝转移灶切除手术。实际上总计772位结直肠癌患者接受肝转移灶切除,其中同时性肝转移患者有581例,而接受结直肠癌原发灶和肝转移灶同步切除的患者有248例。肝切除手术中仅有87例患者（11.3%）实施解剖性肝切除,绝大多数实施非解剖性肝切除。肝转移灶切除手术中联合射频消融的有62例（8.0%）。术后病理提示R1切除的有18位（2.3%）。 结论复杂结直肠癌病例推荐行MDT讨论。扩展手术适应证、应用二步肝切除术、联合射频消融等局部毁损治疗可以扩大肝转移灶手术的适应人群。初始无法手术切除的患者,如状况耐受,建议给予强烈的个体化转化治疗,争取转化后手术切除。     

Irinotecan therapy and molecular targets in colorectal cancer： A systemic review

Irinotecan is the second line chemotherapy for advanced stage colorectal cancer （CRC） after failure of first line chemotherapy with oxaliplatin and 5-fluorouracil. The aim of this review is to analyse the data on irinotecan as second line chemotherapy for advanced CRC and the potential roles of the molecular markers, p53 and vascular endothelial growth factor （VEGF） in the management of advanced CRC. Thus, the English literature from 1980 to 2008 concerning irinotecan, p53, VEGF and CRC was reviewed. On review, Phase Ⅱ and Ⅲ clinical trials showed that irinotecan improves pain-free survival, quality of life, 1-year survival, progression-free survival and overall survival in advanced CRC. p53 and VEGF were expressed in CRC and had a predictive power of aggressive clinical behaviour in CRC. Irinotecan sensitizes p53 wild type, mutant and null cells to Fas- mediated cell apoptosis in CRC cells. Wild type p53 cells were more sensitive to irinotecan than mutated p53. Irinotecan has an anti-VEGF effect inhibiting endothelial cell proliferation, increasing apoptosis and reducing microvascular density which is only limited by irinotecan toxicity levels. To conclude, irinotecan improves the patient＇s quality of life and the survival rates of patients with advanced CRC. p53 and VEGF status of the patients＇ tumour is likely to affect the responsiveness of CRC to irinotecan. It is recommended that studies of the expression of these molecular markers in relation to chemoresponsiveness of irinotecan should be carried out for better management of patients with advanced CRC.     

The management of colorectal liver metastases: Expanding the role of hepatic resection in the age of multimodal therapy

Colorectal cancer (CRC) caused nearly 204,000 deaths in Europe in 2004. Despite recent advances in the treatment of advanced disease, which include the incorporation of two new cytotoxic agents irinotecan and oxaliplatin into first-line regimens, the concept of planned sequential therapy involving three active agents during the course of a patient's treatment and the integrated use of targeted monoclonal antibodies, the 5-year survival rates for patients with advanced CRC remain unacceptably low. For patients with colorectal liver metastases, liver resection offers the only potential for cure. This review, based on the outcomes of a meeting of European experts (surgeons and medical oncologists), considers the current treatment strategies available to patients with CRC liver metastases, the criteria for the selection of those patients most likely to benefit and suggests where future progress may occur.     

DFMO: targeted risk reduction therapy for colorectal neoplasia

Strategies to decrease intracellular polyamine levels have been studied for their efficacy in reducing colorectal cancer (CRC) risk. A successful strategy combined agents that decreased polyamine synthesis by inhibiting ornithine decarboxylase with difluoromethylornithine (DFMO), and increased cellular export of polyamines by activating the spermidine/spermine acetyl transferase with non-steroidal anti-inflammatory drugs (NSAIDs). A Phase III trial treating resected adenoma patients with DFMO plus sulindac demonstrated marked reduction of metachronous adenomas, advanced adenomas and multiple adenomas compared to placebo. This combination regimen was well-tolerated, however there was a non-significant excess of cardiovascular events in the treatment arm compared to placebo as well as modest ototoxicity. Targeting this therapy to people at elevated risk of CRC, and employing clinical and genetic predictors, should improve patient benefit and reduce the risk of side effects to improve the acceptability of this strategy.     

Dendritic cell-based cancer immunotherapy for colorectal cancer

Colorectal cancer(CRC) is one of the most common cancers and a leading cause of cancer-related mortality worldwide. Although systemic therapy is the standard care for patients with recurrent or metastatic CRC, the prognosis is extremely poor. The optimal sequence of therapy remains unknown. Therefore, alternative strategies, such as immunotherapy, are needed for patients with advanced CRC. This review summarizes evidence from dendritic cell-based cancer immunotherapy strategies that are currently in clinical trials. In addition, we discuss the possibility of antitumor immune responses through immunoinhibitory PD-1/PD-L1 pathway blockade in CRC patients.     

Clinicopathologic characteristics of Chinese hereditary non‐polyposis colorectal cancer

OBJECTIVE: The aim of the present study was to examine the clinicopathologic characteristics of Chinese patients with hereditary non‐polyposis colorectal cancer (HNPCC) and those with suspected (atypical) HNPCC. METHODS: Personal and family cancer histories were obtained by reviewing the charts and interviewing the proband and participating relatives. Families were identified and classified into three groups by either the Amsterdam or Japanese criteria for HNPCC. Clinical characteristics including onset, localization, stage of colorectal cancer (CRC), tumor multiplicity, survival and mucinous histology were evaluated. RESULTS: Ninety‐eight subjects comprising 92 CRC patients and six extracolonic cancer patients from 13 typical and 19 non‐typical HNPCC kindreds were enrolled. There were 53 patients with CRC, one with both CRC and extracolonic cancer and five with extracolonic cancer in the typical HNPCC group, and in the atypical group there were 38 patients with CRC and one with extracolonic cancer. The average onset age of typical HNPCC and atypical HNPCC was 48 and 50 years, respectively, without statistical difference. There were no statistical differences in sex, pathological type, stage, site distribution of the tumor or survival between typical HNPCC and atypical HNPCC groups. There were 11.1% (6/54) metachronous CRC in the typical HNPCC group, and 7.9% (3/38) metachronous and 2.6% (1/38) synchronous CRC in the atypical HNPCC group. CONCLUSION: The Amsterdam criteria are important, but inappropriate for the establishing the clinical diagnosis of HNPCC in Chinese patients, with some atypical families that did not fulfil all the Amsterdam criteria probably possessing similar clinicopathogical features and genetic alterations. It seems that HNPCC should be considered in some suspected cases.     

阿司匹林在结直肠癌防治中的意义

阿司匹林作为基础抗凝药物,在心血管疾病中已得到广泛应用。近20年来,随着结直肠癌发病率和死亡率的逐年升高,阿司匹林在结直肠癌患者中的应用和影响也逐渐受到关注。一些回顾性的临床研究发现规律服用阿司匹林的结直肠癌患者肿瘤特异生存率更高,且远隔转移率更低。在现有的抗结直肠癌药物(5－Fu、奥沙利铂、伊立替康和靶向药物)之外,阿司匹林是否也可能作为一种抗肿瘤药物应用于结直肠癌的预防和治疗一直成为学术界关注的热点问题。本文回顾了阿司匹林与结直肠癌相关的临床研究,尝试客观的分析阿司匹林在结直肠癌预防和辅助治疗中的作用及其局限性,以期为临床治疗和研究提供借鉴。     

Bevacizumab plus infusional 5-fluorouracil, leucovorin and irinotecan for advanced colorectal cancer that progressed after oxaliplatin and irinotecan chemotherapy： A pilot study

AIM： To evaluate the combination of bevacizumab with infusional 5-fluorouracil （5-FU）, leucovorin （LV） and irinotecan （FOLFIRI） in patients with advanced colorectal cancer （CRC） pretreated with combination regimens including irinotecan and oxaliplatin. METHODS： Fourteen patients （median age 56 years） with advanced CRC, all having progressed after oxaliplatin- and irinotecan-based combination chemotherapy, were enrolled in this study. Patients were treated with 2 h infusion of irinotecan 150 mg/m2 on d 1, plus bevacizumab 5 mg/kg iv infusion for 90 min on d 2, and iv injection of LV 20 mg/m2 followed by a bolus of 5-FU 400 mg/m2 and then 22 h continuous infusion of 600 mg/m2 given on two consecutive days every 14 d. RESULTS： The median number of cycles of chemotherapy was six （range 3-12）. The response rate was 28.5%, one patient had a complete response, and three patients had a partial response. Eight patients had stable disease. The median time to progression was 3.9 mo （95% CI 2.0-8.7）, and the median overall survival was 10.9 mo （95% CI 9.6-12.1）. Grade 3/4 neutropenia occurred in five patients, and two of these developed neutropenic fever. Grade 3 hematuria and hematochezia occurred in one. Grade 2 proteinuria occurred in two patients. However, hypertension, bowel perforation or thromboembolic events did not occur in a total of 90 cycles. CONCLUSION： Bevacizumab with FOLFIRI is well tolerated and a feasible treatment in patients with heavily treated advanced CRC.     

Clinical characteristics of patients with sporadic colorectal cancer and primary cancers of other organs

Most cancer patients often neglect the possibility of secondary cancer. Colorectal cancer (CRC) is the third leading cause of cancer death in Taiwan. It is important to be aware of the clinical characteristics of double cancer in CRC patients for early diagnosis and treatment. We retrospectively analyzed 1,031 CRC patients who underwent surgical treatment at the Department of Surgery of Kaohsiung Medical University Hospital between January 1998 and December 2004. Among these patients, CRC was accompanied by cancer of other organs in 17 patients (1.65%), either synchronously or metachronously. Therefore, we describe our experience regarding the location of CRC, the clinical symptoms and signs of these patients, the TNM stage, histology, phase, association with other malignancies, interval between cancers and clinical outcomes. Of the 17 patients in whom CRC was accompanied by primary cancer of other organs, there were four synchronous and 13 metachronous multiple cancer patients. Our patient group comprised six men and 11 women with ages ranging from 47 to 88 years (median age, 66 years). The most common location of CRC was the sigmoid colon. Six gastric cancers (35.2%) and six breast cancers (35.2%) were associated with primary CRC. The remaining six second primary cancers were one lung cancer, one thyroid cancer, one cervical cancer, one ovarian cancer, one skin cancer, and one urinary bladder cancer. Of the 13 metachronous multiple cancer patients, eight patients developed subsequent CRC after primary cancers of other organs, whereas two patients developed a subsequent second primary cancer after CRC. The intervals between the development of metachronous multiple cancers ranged from 2 to 19 years. In this retrospective analysis, breast and gastric cancer patients were at increased risk of developing subsequent secondary CRC. Careful attention should always be paid to the possibility of secondary CRC in treating these cancer patients. Cancer patients with hematochezia or gastrointestinal symptoms/signs should be evaluated for the possibility of second primary CRC during their regular follow-up.     

Immunotherapy for colorectal cancer

The incidence of colorectal cancer(CRC)is on the rise,and the prognosis for patients with recurrent or metastatic disease is extremely poor.Although chemotherapy and radiation therapy can improve survival rates,it is imperative to integrate alternative strategies such as immunotherapy to improve outcomes for patients with advanced CRC.In this review,we will discuss the effect of immunotherapy for inducing cytotoxic T lymphocytes and the major immunotherapeutic approaches for CRC that are currently in clinical trials,including peptide vaccines,dendritic cell-based cancer vaccines,whole tumor cell vaccines,viral vector-based cancer vaccines,adoptive cell transfer therapy,antibody-based cancer immunotherapy,and cytokine therapy.The possibility of combination therapies will also be discussed along with the challenges presented by tumor escape mechanisms.     

Immunotherapy in human colorectal cancer: challenges and prospective

Human colorectal cancer(CRC) is the third most commonly diagnosed malignancies and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although new chemotherapeutic regimen improves survival rates, therapy with better efficacy and less adverse effects is drastically needed. Immunotherapy has been investigated in human CRC for decades with limited success. However, recent developments of immunotherapy, particularly immune checkpoint inhibitor therapy, have achieved promising clinical benefits in many types of cancer and revived the hope for utilizing such therapy in human CRC. In this review, we will discuss important immunological landscape within the CRC microenvironment and introduce immunoscore system to better describe immunophenotyping in CRC. We will also discuss different immunotherapeutic approaches currently utilized in different phases of clinical trials. Some of those completed or ongoing trials are summarized. Finally, we provide a brief prospective on the future human CRC immunotherapy.