卵巢癌的免疫治疗

卵巢癌作为妇女死亡的重要因素,一直受到人们的关注.手术和化学治疗目前都不能达到令人满意的效果.随着免疫学的进展,卵巢癌的免疫治疗将成为临床治疗的可选择手段之一.卵巢癌免疫治疗可分为预防性和治疗性免疫两种,同时还可分为腹腔内与全身两种给药方式.本文对卵巢癌的免疫治疗目前的一些进展,临床试验结果及发展中的一些问题与探索进行了综述.     

Immunotherapy in cervix cancer

The treatment approach to cervix cancer has remained unchanged for several decades and new therapeutic strategies are now required to improve outcomes, as the prognosis is still poor. In the last years, a better understanding of HPV tumor–host immune system interactions and the development of new therapeutics targeting immune checkpoints generated interest in the use of immunotherapy in cervix cancer. Preliminary phase I–II trials demonstrated the efficacy, the duration of responses and the manageable safety of this approach. Currently, many phase II and III studies are ongoing in both locally advanced and metastatic cervical cancer, assessing immunotherapy as a single agent or in combination with chemotherapy and radiotherapy. We reviewed the published data and the therapeutic implications of the most promising novel immunotherapeutic agents under investigation in cervix cancer.     

Immunotherapy opportunities in ovarian cancer

Ovarian cancer is responsible for the majority of gynecologic cancer deaths and despite the highest standard of multimodality therapy with surgery and cytotoxic chemotherapy, long-term survival remains low. With compelling evidence that epithelial ovarian cancer is an immunogenic tumor capable of stimulating an antitumor immune response, renewed efforts to develop immune therapies to augment the efficacy of traditional therapies are underway. Current immunotherapies focus on varied modes of antitumor vaccine development, particularly with the use of dendritic cell vaccines, effective methods for adoptive T-cell transfer and combinatorial approaches with immune modulatory therapy subverting natural tolerance mechanisms or boosting effector mechanisms. Additional combinatorial approaches include the use of cytokines and/or chemotherapy with immune therapy.     

Immunotherapy in ovarian,endometrial and cervical cancer: State of the art and future perspectives

The tumors of the female genital tract represent a leading cause of morbidity and mortality among women worldwide. Substantial progresses have been made in ovarian cancer, with the increasing knowledge about BRCA mutated tumors and the recent development of PARP inhibitors, and in cervical cancer, thanks to extensive screening and widespread of vaccination against Human Papilloma Virus. Nevertheless many needs remain unmet, advanced stage diseases are still incurable and cervical and endometrial carcinoma, as well as platinum-resistant ovarian carcinoma, can certainly be classifiable among the cancers with poor sensitivity to conventional chemotherapy. Immunotherapy, including a number of approaches, checkpoint inhibitors, adoptive cellular transfer, vaccines, has experienced a remarkable growth in the last few years and it is already an available option in melanoma, lung and renal malignancies. We reviewed the main findings about the immune microenvironment in ovarian, endometrial and cervical cancer with a special focus on the clinical data, the therapeutic implications and the most promising novel agents.     

Role of cytoreductive surgery in recurrent ovarian cancer

Cytoreductive surgery is well established in patients with primary ovarian cancer. The benefit of surgery in patients with recurrent ovarian cancer remains a controversial matter. There is a large heterogeneity in surgical results published in the literature, possibly caused by infrastructure, surgeons’ philosophy and belief in adding various surgical skills. This might also be a result of different preoperative selection procedures. Further questions to be addressed are the definition of surgical end points and whether there are predictive factors for a successful surgery. The surgical end point in recurrent ovarian cancer should be complete resection. Predictive factors could help identify patients in whom complete resection is possible.     

食管癌的免疫治疗

肿瘤进展通常与免疫抑制或癌细胞逃避免疫监视相关.免疫治疗可提高免疫系统识别和清除肿瘤细胞的能力,且对正常组织影响轻微,是目前晚期食管癌研究的热点.食管癌的免疫治疗方法主要包括免疫检查点抑制剂、过继细胞免疫治疗、肿瘤疫苗和抗体治疗.目前大量临床试验正在进行中,以评价免疫治疗在食管癌中的作用.以Pembrolizumab和Nivolumab为代表的免疫检查点抑制剂在晚期食管癌治疗中已取得初步成功,为食管癌患者改善预后和生命质量带来希望.未来还需要对肿瘤异质性、疗效预测靶点、免疫治疗耐受等影响免疫治疗疗效的问题展开进一步的研究.     

Immunotherapy in gastrointestinal cancer: Recent results,current studies and future perspectives

The new therapeutic approach of using immune checkpoint inhibitors as anticancer agents is a landmark innovation. Early studies suggest that immune checkpoint inhibition might also be effective in patients with gastrointestinal cancer. To improve the efficacy of immunotherapy, different strategies are currently under evaluation. This review summarises the discussion during the European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Translational Research Meeting in Mainz in November 2014 and provides an update on the most recent results of immune therapy in gastrointestinal cancers. Knowledge of potential relationships between tumour cells and their microenvironment including the immune system will be essential in gastrointestinal malignancies. In this context, the density of T cell infiltration within colorectal cancer metastases has been associated with response to chemotherapy, and a high expression of programmed cell death ligand 1 (PD-L1) in advanced gastric cancer has been related with poor prognosis. Effective targets might include neo-antigens encoded from genes carrying tumour-specific somatic mutations. Tailored immunotherapy based on such mutations could enable the effective targeting of an individual patient’s tumour with vaccines produced on demand. Other strategies considering checkpoint inhibitors have shown efficacy by targeting cytotoxic T-lymphocyte-associated protein 4 and PD-1 or PD-L1. DNA mismatch repair-deficient tumours appear to be potentially the best candidates for these therapies. Finally, the combination of oncolytic viruses with immunotherapy might boost antitumour activity as well. Further evaluation of these promising immunological therapeutic approaches will require large prospective clinical studies.     

上皮源性卵巢癌干细胞的研究进展

肿瘤干细胞(cancer stem cells,CSCs)是肿瘤组织内具有自我更新能力以及无限增殖和多向分化潜能的一群细胞,对化疗药物耐受.卵巢癌干细胞(epithelial ovarian cancer stem cells,EOCSCs)在卵巢癌的发生发展、侵袭转移和耐药复发过程中都起到了重要作用.传统的肿瘤细胞减灭术联合顺铂、紫杉醇全身化疗对减小肿瘤体积,缓解临床症状具有一定的作用,但治疗后残留的EOCSCs能够短时间内重建肿瘤组织,是卵巢癌复发和难治的根本原因.深入了解EOCSCs的生物学特性,探索EOCSCs的发生发展机制,研究针对EOCSCs的靶向治疗药物,是抗肿瘤治疗的关键.     

胃癌的免疫治疗

胃癌免疫治疗主要包括细胞因子疗法、单克隆抗体疗法、肿瘤疫苗等方法.基因免疫疗法是当前研究的热点,研究发现,Gbl-b基因在调节机体抗肿瘤免疫方面发挥着重要作用,Cbl-b蛋白与胃癌淋巴转移密切相关.通过沉默T淋巴细胞Cbl-b基因从而增强机体的抗肿瘤免疫有望在晚期胃癌治疗上取得良好的效果.     

BRCA1 mutation testing for Japanese patients with ovarian cancer in breast cancer screening

From February 1996 to April 1998, 2967 women received screening for breast cancer in the gynecologic ambulatory practice of the Hokkaido University Hospital. In 116 Japanese women with epithelial ovarian cancer, mutation analysis of BRCA1 exon 11 in genomic DNA was performed by the stop codon (SC) assay and DNA sequence analysis. Clinicopathological factors were also investigated in these patients. The aim of this study was to examine the advantages of performing BRCA1 mutation testing for ovarian cancer patients during breast cancer screening. We achieved a high detection rate (6.0) of patients with germline mutations in BRCA1. The high frequencies of breast ovarian cancer syndrome, serous adenocarcinoma, high histological grades, advanced FIGO stages, and breast cancer as double cancer were found to be characteristic of ovarian cancer with germline mutations in BRCA1. These characteristics may assist physicians in selecting BRCA1 mutation testing for ovarian cancer patients. The mean age at diagnosis of ovarian cancer was 51.0 and 51.2 years in the groups with and without mutation, respectively, and no difference was found in age at diagnosis. All of the nine living female mutation carriers were offered the options of increased surveillance or prophylactic surgery, and all chose the former. We have performed breast cancer screening and/or ovarian cancer screening every 6 months for these carriers. This may allow another advantage in establishing a relationship of mutual trust with a patient from a series of responsible follow-ups.     

Pazopanib in ovarian cancer

The majority of women with ovarian cancer present with advanced disease, and ultimately relapse following primary surgery and platinum-taxane chemotherapy. Despite recent advances in the development of targeted agents in ovarian cancer, survival rates remain poor. The promising activity of bevacizumab, a VEGF receptor inhibitor, has stimulated research on the use of additional anti-angiogenic agents in ovarian cancer. Pazopanib, an oral tyrosine kinase inhibitor, targets VEGF receptor-1, -2 and -3, platelet-derived growth factor receptor-α and -β and c-kit; resulting in the inhibition of angiogenesis and tumor proliferation. Early phase studies have demonstrated promising efficacy and tolerability. To date, there has been one Phase III trial of pazopanib in ovarian cancer, demonstrating a progression-free survival benefit in women treated with maintenance pazopanib following primary surgery and systemic therapy. This article summarizes the preclinical and clinical data of pazopanib in ovarian cancer, highlighting future research options for this agent.     

凋亡抑制蛋白与卵巢癌化疗耐药

卵巢癌是严重威胁妇女健康的恶性肿瘤之一,其病死率在妇科肿瘤中占第一位.化疗耐药是导致其治疗失败、病死率居高不下的重要原因.已有的研究表明,抗凋亡机制在肿瘤细胞发生、发展及化疗耐药中起重要作用.凋亡抑制蛋白(IAPs)是重要的细胞凋亡调节因子,在细胞凋亡中起关键作用.本文主要综述IAPs与卵巢癌化疗耐药的相关进展.     

免疫治疗在卵巢癌中的应用研究进展

卵巢癌的临床早期症状不明显,筛查手段有限,就诊时常处于晚期阶段,5年生存率仅30%~45%,严重威胁着女性健康。免疫治疗尤其是免疫检查点抑制剂治疗因其持久的抗肿瘤效应已被批准用于晚期或复发性的多种类型癌症的治疗。目前免疫治疗的一些研究进展为卵巢癌患者的临床管理提供了新的机遇与挑战。     

Epigenetic biomarkers in epithelial ovarian cancer

Ovarian cancer is the most lethal gynecological malignancy and the 5th leading cause of cancer death in women. Women with ovarian cancer are typically diagnosed at late stage, when the cancer has spread into the peritoneal cavity and complete surgical removal is difficult. The 5-year survival time for patients diagnosed at this stage is 30%, in contrast to a 5-year survival of 90% for patients diagnosed at early stage. Cancer screening and early detection have the potential to greatly decrease the mortality and morbidity from cancer. The emerging field of epigenetics offers a valuable opportunity to identify cancer-specific DNA methylation changes that can be used in the clinic to improve early-stage diagnosis and better predict response in treated patients.     

胆道肿瘤的免疫治疗

胆道肿瘤（BTC）侵袭性强,早期诊断率仅为10％。研究显示,吉西他滨联合顺铂方案现已成为晚期 BTC 的标准一线化疗方案,但疗效仍不满意。免疫细胞的浸润以及免疫相关的微环境可以抑制多种不同类型的肿瘤。研究发现,肿瘤浸润性 CD8＋细胞毒 T 细胞和 CD4＋T 细胞数量与 BTC 的预后密切相关,提示 BTC 的免疫治疗可能是一种新的手段。     

Survivin与卵巢癌关系的Meta分析

目的:应用Meta分析方法评估国内外有关卵巢癌组织中Survivin的表达及其临床意义。方法:通过计算机检索PubMed、CNKI等数据库全面检索国内外已发表的相关文献,最终进入系统评价的有13篇病例对照研究。应用Stata 11.0进行Meta分析,计算OR及95%CI。结果:表明Survivin的表达在卵巢癌组与卵巢良性肿瘤组,卵巢癌组与卵巢正常组织组,临床Ⅰ-Ⅱ组与临床Ⅲ-Ⅳ组,中、高分化组与低、未分化组的差异有统计学意义(P<0.05);Survivin淋巴结转移组与淋巴结未转移组的表达差异无统计学意义(P>0.05)。结论:Survivin的高表达可能在卵巢癌的发生发展中起重要作用。     

代谢组学在卵巢癌研究中的应用

卵巢癌是女性生殖器常见的三大恶性肿瘤之一,致死率居妇科恶性肿瘤首位。随着分子生物学的发展,肿瘤标志物已经成为恶性肿瘤诊断的常用方法之一。代谢组学是近年来出现的一种新的系统生物学研究手段,在药物代谢分析、恶性肿瘤的早期诊断等方面取得了新进展。本文就代谢组学的概念及发展,研究方法及在卵巢癌早期诊断、分型、分期中的应用进行综述。     

PSCA在卵巢癌组织中的表达及意义

目的：研究PSCA蛋白在卵巢癌组织中的表达及意义。方法：采用免疫组化SP法检测PSCA蛋白在115例卵巢癌组织、17例交界性囊腺瘤及20例良性囊腺瘤中的表达,并分析其与临床病理特征的相关性。结果：PSCA蛋白在上皮性卵巢癌、交界性囊腺瘤、良性囊腺瘤标本中阳性表达率分别为53.0％、35.3％、15.0％,三者比较差异有统计学意义（P＜0.05）。PSCA蛋白在卵巢癌组织中的表达与年龄无关（P＞0.05）。PSCA蛋白的表达与卵巢癌FIGO分期以及组织分化程度相关（ P＜0.05）。结论：PSCA蛋白的表达与卵巢癌的恶性程度及预后相关。     

卵巢癌中紫杉醇耐药机制与克服耐药策略的研究进展

化疗耐药是卵巢癌复发的主要原因,严重影响患者的预后。紫杉醇是卵巢癌化疗的一线用药之一,因此,有关紫杉醇耐药的机制和克服耐药的策略得到了广泛而深入的研究。本文简要介绍了近年来有关紫杉醇耐药和克服耐药策略的研究进展。