PD-1/PD-L1抑制剂治疗晚期卵巢癌的研究进展

卵巢癌是妇科恶性肿瘤中常见的类型之一,由于其早期无明显症状,患者就诊时已为晚期。目前晚期卵巢癌的标准治疗主要是以铂类为基础的化疗,但大多数患者会出现复发或耐药后进展等。因此,临床迫切需要新的治疗方法以改善晚期卵巢癌患者的预后。近年来,随着对肿瘤免疫学及分子生物学的不断深入研究,免疫治疗作为一种新兴的治疗肿瘤的方式,为晚期卵巢癌患者提供了新的治疗方向。本文将对晚期卵巢癌免疫治疗的临床研究现状进行综述。     

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.     

腹腔热灌注治疗在晚期卵巢癌中的临床研究进展

卵巢癌是3大常见妇科恶性肿瘤之一，预后差，病死率高。尽管多年来在卵巢癌治疗方面的研究取得了一定进展，但卵巢癌患者的总生存率仍在30%左右徘徊不前。全身化疗是临床治疗晚期卵巢癌的主要方式，尽管对大多数患者有效，但复发率很高。近年来，腹腔热灌注化疗（hyperthemicimmprionalcemdherap，HIFC）在晚期卵巢癌治疗中的应用受到了越来越多的关注。大量文献报道，HIPEC 可缩小卵巢癌的原发病灶，缩短化疗疗程，有效控制腹水及降低肿瘤标记物的水平，以及减少术中出血，在提高晚期卵巢癌患者生存率、缓解临床症状和减少复发等方面具有明显优势。本文就腹腔热灌注治疗在晚期卵巢癌中的研究进展进行综述。     

MTT法在卵巢外腹膜乳头状浆液性癌化疗中的应用

卵巢外腹膜乳头状浆液性癌（extraovarianpert－tonealserouspapillarycarcinomaEPSPC）是原发于腹膜表面、双侧卵巢正常或仅表面有微小浸润、组织学形态相似于卵巢乳头状浆液性癌的恶性肿瘤［1］。常被误诊为晚期卵巢癌腹腔广泛转移。其治疗多采用手术、化疗及免疫治疗等综合措施，但其手术成功率较低，故化疗在本病的治疗中占有重要地位。目前本病尚无统一的规范化疗方案，本研究采用MTT法对本病化疗药物进行敏感性预测，拟为临床用药个体化提供依据。材料与方法临床资料：本组收集临床诊为“卵巢癌”而病理结果证实为卵巢外腹膜浆液…     

从三焦膜腠理论探析晚期卵巢癌-腹膜转移及中医维持治疗

卵巢癌在妇科三大恶性肿瘤中致死率最高，腹膜转移-肠梗阻-死亡是晚期卵巢癌主要转归模式。中医药维持治疗晚期卵巢癌疗效确切，但理论基础尚需进一步完善。本文溯本求源，在三焦-膜腠理论指导下，结合临床体会，提出卵巢癌-腹膜转移的三焦定位，及三焦功能失调在卵巢癌发生及转移中的作用，并提出疏利三焦气机、和调脏腑气血，清化伏毒是中医维持治疗卵巢癌的主要策略，从三焦-膜腠系统角度丰富了卵巢癌中医理论，为卵巢癌治疗提供新思路。     

免疫疗法在卵巢癌治疗中的应用进展

卵巢癌是女性生殖系统常见的恶性肿瘤之一,发病率仅次于宫颈癌、子宫体癌,位居第三.近年来其病死率也一直居高不下.手术联合化疗是目前治疗卵巢恶性肿瘤的主要方法,但仍然存在着较高的复发率以及易产生耐药等诸多问题,总体临床预后不佳.因此,为了改善卵巢癌的临床结局,研究新的治疗措施便成为当下研究的重点.免疫治疗,尤其是免疫检查点抑制剂治疗,作为卵巢癌的一种新型治疗方法,近年来受到广泛关注.本文将对免疫治疗新技术在卵巢癌患者中的应用和研究进行综述.     

晚期上皮性卵巢癌靶向治疗的研究进展

上皮性卵巢癌目前治疗以手术联合化疗为主,但随着疾病的进展大多数患者不可避免会复发。近年来,靶向治疗在晚期上皮性卵巢癌的多线治疗中取得了突破性进展,多项研究提示以多腺苷二磷酸核糖聚合酶抑制剂和抗血管生成药物为主的靶向药物用于维持治疗能显著性延缓复发并改善患者的生存预后,此外,用于多线治疗后复发患者的单药治疗也初显疗效。虽然免疫检查点抑制剂单药治疗效果有限,但联合其他靶向或化疗药物可不同程度提高免疫活性。全文主要针对晚期上皮性卵巢癌靶向治疗和免疫治疗的研究进展进行综述。     

放疗联合免疫治疗在不可切除局部晚期及晚期肺癌中的应用进展

局部晚期及晚期肺癌患者死亡率高，既往治疗多采用放化疗联合的综合治疗，免疫治疗的加入显著改善 了疗效。放疗可通过诱导肿瘤细胞免疫原性死亡、刺激肿瘤细胞自身抗原释放、增加抗原呈递等机制，与免疫治疗 产生协同杀灭肿瘤细胞的作用。放疗与免疫治疗在肺癌中联合应用的相关临床研究陆续开展，其安全性及有效性 得到了验证。本文就放疗联合免疫治疗在不可切除局部晚期及晚期肺癌中的应用进行综述，为局部晚期及晚期肺 癌患者治疗方式的选择提供参考。     

基于肿瘤免疫微环境联合免疫治疗卵巢癌的研究进展

卵巢癌在女性生殖道恶性肿瘤中致死率最高,既往的标准治疗是手术加化疗,近几年以聚腺苷二磷酸核 糖聚合酶抑制剂为主的靶向治疗延长了部分患者的生存期,但仍然会面临耐药及复发。近年免疫治疗发展迅速,然 而已有的临床研究表明单一的免疫治疗在卵巢癌中疗效有限。肿瘤免疫微环境中免疫抑制性网络,在卵巢癌的发 生发展中起着重要作用,深入探索其机制有助于制定卵巢癌免疫治疗策略。本文综述了肿瘤免疫微环境与卵巢癌 的相互作用,针对免疫微环境,免疫治疗联合化疗和靶向治疗,以及过继细胞治疗等治疗方式的研究进展,为卵巢癌 得到长期持久的个性化治疗提供理论依据。     

药物选择 剂量 分割 顺序对放疗联合免疫治疗晚期非小细胞肺癌疗效的影响

非小细胞肺癌(non-small cell lung cancer，NSCLC)约占肺癌总数的85%，53%的患者在确诊时即为晚期。近年来，免疫检查点抑制剂(immune checkpoint inhibitors，ICIs)在晚期肿瘤治疗中效果显著。放疗在晚期NSCLC主要用于局部姑息治疗。研究显示免疫治疗协同放疗治疗晚期NSCLC与单独放疗或免疫治疗相比，可改善患者的无进展生存(progression-free survival，PFS)和总生存(overall survival，OS)，且不增加3级以上不良反应发生率。但ICIs的选择、放疗剂量、分割方式及联合治疗顺序仍未完全阐明。本文就免疫治疗联合放疗在晚期NSCLC中的临床研究进展作一综述，为临床选择提供参考。      

HE4在上皮性卵巢癌中的表达情况及其与临床特征及预后的关系分析

目的 探讨HE4在上皮性卵巢癌中的表达情况及其与临床特征及预后的关系.方法 选取150例上皮性卵巢癌患者和72例良性卵巢疾病患者,采用酶联免疫吸附法(ELISA)检测并比较150例上皮性卵巢癌患者和72例良性卵巢疾病患者的血清HE4水平;采用免疫组织化学法(IHC)检测150例上皮性卵巢癌患者癌组织和相应癌旁正常组织中HE4的表达情况,分析其与上皮性卵巢癌临床特征的关系;随访36个月,记录并分析HE4表达与上皮性卵巢癌患者生存情况的关系.结果 上皮性卵巢癌患者的血清HE4水平明显高于良性卵巢疾病患者,上皮性卵巢癌组织中HE4蛋白的阳性表达率明显高于癌旁正常组织,差异均有统计学意义(P﹤0.01);肿瘤直径﹥3 cm、低分化、Ⅲ～Ⅳ期、有淋巴结转移的上皮性卵巢癌组织的HE4蛋白的阳性表达率分别高于肿瘤直径≤3 cm、中高分化、Ⅰ～Ⅱ期、无淋巴结转移的癌组织,差异均有统计学意义(P﹤0.05);随访36个月,HE4蛋白阳性表达的上皮性卵巢癌患者的生存率低于阴性表达的患者,差异有统计学意义(P﹤0.05).结论 HE4是上皮性卵巢癌的良好肿瘤标志物,与肿瘤的良、恶性鉴别及临床特征有密切的关系,对上皮性卵巢癌患者的早期诊断及预后有一定的价值.     

卵巢癌患者血液高凝状态临床研究进展

卵巢癌患者的静脉血栓发生率远高于其他妇科肿瘤,约20%以上的卵巢癌患者存在高凝状态。肿瘤可导致血液高凝状态,而凝血功能的过度激活也极大地促进肿瘤的进展,是影响患者预后的重要因素。近年来,高凝状态逐渐成为卵巢癌研究领域的新热点,本文将对卵巢癌患者高凝状态的形成机制、临床意义及相关治疗进展进行综述。     

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for treatment of ovarian cancer

Hyperthermic intraperitoneal chemotherapy (HIPEC), a strategy combining maximal cytoreductive surgery and maximal regional chemotherapy, has been applied to treat ovarian cancer resulting in long-term survival rates in selected patients. However, the status of HIPEC in ovarian cancer remains an experimental procedure, given the many variables among the data and trials reviewed, to enable us to derive strong conclusions about its role from this overview. In this review we discuss treatment with HIPEC in patients with ovarian cancer and future prospective of its use in clinical setting. HIPEC is an effective tool in the treatment of selected patients with peritoneal carcinomatosis from ovarian cancer. Unfortunately, due to the lack of randomised trials, the evidence of HIPEC is very limited. Future randomised studies are awaited to define the role and clinical impact of HIPEC in ovarian cancer.     

Clinical significance of RCAS1 as a biomarker of ovarian cancer

Expression of RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) is associated with advanced disease of various malignancies including ovarian cancer. Proteolytic cleavage of RCAS1 at extracellular domains (ectodomain shedding) yields soluble RCAS1. Although RCAS1 can induce apoptosis in normal peripheral lymphocytes, its clinical significance and biologic function in ovarian cancer patients are unclear. Here, we evaluated serum RCAS1 concentrations to clarify its clinical significance and biologic activity in ovarian cancer. Via ELISA, we measured serum RCAS1 concentrations in samples from 75 healthy blood donors and 97 patients, 36 with ovarian benign tumor and 61 with ovarian cancer. We correlated via statistical means the RCAS1 values with patients' clinicopathologic variables. We assessed inhibition of growth of K562 cells, which express the putative RCAS1 receptor, via WST-1 assay of serum samples to clarify RCAS1's biologic activity. Ovarian cancer patients had significantly higher serum RCAS1 concentrations than did healthy blood donors and ovarian tumor patients (P<0.05). RCAS1 level was significantly different according to histologic subtype for both ovarian tumor and cancer patients (P=0.0266 and 0.0074, respectively). RCAS1 values were also significantly associated with response to treatment (P<0.001). The WST-1 assay showed that patients' serum induced K562 cell growth inhibition, but this effect partially recovered after immunodepletion of RCAS1 (P=0.0074). RCAS1 may be a biomarker of ovarian cancer by virtue of its ability to predict results of treatment and inhibit immune cell growth.     

MicroRNA‐135a‐3p as a promising biomarker and nucleic acid therapeutic agent for ovarian cancer

Ovarian cancer is the most lethal gynecologic malignancy. Recently, several molecularly targeted anticancer agents have been developed for ovarian cancer; however, its prognosis remains extremely poor. The development of molecularly targeted therapy, as well as companion diagnostics, is required to improve outcomes for patients with ovarian cancer. In this study, to identify microRNAs (miRNAs) involved in the progression of ovarian cancer we analyzed serum miRNAs in patients with ovarian cancer using miRNA array and quantitative RT‐PCR and examined the anticancer properties of miRNA expression in ovarian cancer cells. In patients with ovarian cancer, high amount of miR‐135a‐3p in serum samples was significantly associated with favorable clinical prognosis. The amount of miR‐135a‐3p was significantly decreased in patients with ovarian cancer compared with patients with ovarian cysts or normal ovaries. In SKOV‐3 and ES‐2 human ovarian cancer cells, enhanced expression of miR‐135a‐3p induced drug sensitivity to cisplatin and paclitaxel and suppressed cell proliferation and xenograft tumor growth. These findings suggest that miR‐135a‐3p may be considered as a biomarker and a therapeutic agent in ovarian cancer.     

Tumour-associated immune responses and isolated carcinoembryonic antigen and alpha feto-protein levels related to survival in ovarian cancer patients.

The presence of a tumour-associated immune response in 37 patients with ovarian cancer as assessed by blastogenesis (lymphocyte transformation) evoked by ovarian cancer cell extracts, has been correlated with survival following the test. The difference in these responses is unlikely to be accounted for on the basis of general impairment of cell-mediated immuno-competence. Serum carcinoembryonic antigen (CEA) was also determined in 27 ovarian cancer patients to assess its prognostic significance. Raised CEA levels and absence of blastogenic response to tumour cell extract during relapse are associated with a worse prognosis but neither of these parameters are significant in remission. Possible applications of these findings to the clinical management of ovarian cancer patients are discussed. Serum alpha feto-protein levels measured by radioimmunoassay were not found to be raised in any of the 32 ovarian cancer patients in whom it was measured.     

卵巢癌血清相关miRNAs的筛选及其临床意义

背景与目的：卵巢癌预后较差,发现时通常是晚期,需找寻与卵巢癌发生、发展相关的诊治方法。该研究检测miRNA在上皮性卵巢癌患者术前外周血清及良性卵巢肿瘤患者外周血清中表达情况的差异,筛选差异有统计学意义的miRNA并分析其与上皮性卵巢癌患者临床病理特征、预后等的关系。方法：定制研究相关的48种miRNA表达谱芯片,通过TaqMan低密度微阵列芯片,筛选出有统计学意义的miRNA。采用实时荧光定量聚合酶链反应(real-time fluorescent quantitative polymerase chain reaction,RTFQ-PCR)法验证筛选的miRNA在卵巢良、恶性肿瘤患者血清中的表达情况,选择具有统计学意义的miRNA行大样本验证并分析其与肿瘤分期、组织病理及预后等的关系。结果：通过TaqMan低密度微阵列芯片筛选和RTFQ-PCR验证,发现miR-125b在上皮性卵巢癌患者血清中的表达高于良性肿瘤患者(P=0.039),miR-125b在早期患者中的表达量高于晚期患者(P=0.003),术后无残余肿瘤患者表达量高于术后有残余肿瘤患者(P=0.013)。血清miR-125b高表达有利于卵巢癌患者无进展生存期(progression-free survival,PFS)延长(P=0.003),但对总生存期(overall survival,OS)无明显影响(P=0.069)。结论：miR-125b在上皮性卵巢癌的发生、发展中起着关键作用,与患者预后相关,是预测卵巢癌复发的潜在基因,但在肿瘤不同期别的表达情况发生变化,在早期作用比较明显,在晚期或肿瘤残余较多的患者表达较不明显,其作用机制有待进一步研究。     

Serum folate receptor alpha as a biomarker for ovarian cancer: Implications for diagnosis,prognosis and predicting its local tumor expression

Folate receptor alpha (FRA) is a GPI‐anchored glycoprotein and encoded by the FOLR1 gene. High expression of FRA is observed in specific malignant tumors of epithelial origin, including ovarian cancer, but exhibits very limited normal tissue expression, making it as an attractive target for the ovarian cancer therapy. FRA is known to shed from the cell surface into the circulation which allows for its measurement in the serum of patients. Recently, methods to detect the soluble form of FRA have been developed and serum FRA (sFRA) is considered a highly promising biomarker for ovarian cancer. We prospectively investigated the levels of sFRA in patients clinically suspected of having malignant ovarian tumors. A total of 231 patients were enrolled in this study and analyzed for sFRA as well as tumor expression of FRA by immunohistochemistry. High sFRA was predominantly observed in epithelial ovarian cancer patients, but not in patients with benign or borderline gynecological disease or metastatic ovarian tumors from advanced colorectal cancers. Levels of sFRA were highly correlated to clinical stage, tumor grade and histological type and demonstrated superior accuracy for the detection of ovarian cancer than did serum CA125. High sFRA was significantly associated with shorter progression‐free survival in both early and advanced ovarian cancer patients. Finally, tumor FRA expression status was strongly correlated with sFRA levels. Taken together, these data suggest that sFRA might be a useful noninvasive serum biomarkers for future clinical trials assessing FRA‐targeted therapy.     

Cell-free 59 kDa immunoreactive integrin-linked kinase: a novel marker for ovarian carcinoma.

PURPOSE: We reported that the expression of integrin-linked kinase (ILK) is up-regulated in ovarian carcinomas and that ovarian cancer cells have high expression of ILK. In this study, we have examined the expression of cell-free 59 kDa immunoreactive (ir)ILK in the serum and peritoneal fluid (PTF) of patients with ovarian cancer and evaluated its potential as a serum biomarker for early-stage screening and for monitoring clinical status of patients after chemotherapy treatment. EXPERIMENTAL DESIGN: Thirty-six serum specimens, including normal (n = 6), benign (n = 6), borderline (n = 4), grade 1 (n = 5), grade 2 (n = 5), and grade 3 (n = 10), were evaluated for the expression of irILK by Western blotting. The expression of irILK was evaluated in PTF (n = 10) and peritoneal washings from women with benign ovarian cysts (n = 4). In addition, tissue-conditioned medium obtained from the cultures of primary ovarian tumors (n = 9) was examined for the presence of irILK. Finally, the potential of serum irILK as a biomarker for ovarian cancer screening was evaluated by comparison with cancer antigen 125 (CA 125) concentrations in cancer patients before and after chemotherapy. RESULTS: irILK expression was present in normal serum and in serum of patients with benign ovarian tumors. irILK expression was 6-9-fold higher in the serum of patients with grade 1, grade 2, and grade 3 ovarian cancer than in the serum of healthy volunteers and patients with benign ovarian tumors (P < 0.01). Enhanced expression of irILK in the serum of ovarian cancer patients correlated with the concentration of CA 125. High expression of irILK was present in all 10 PTF tested. Tissue-conditioned medium prepared from malignant ovarian tumors had 4-fold more irILK expression than conditioned medium obtained from borderline and benign tumors (P < 0.01). irILK expression in serum of cancer patients was reduced to basal normal levels after six cycles of Taxol/carboplatin and was consistent with the change of CA 125 levels before and after chemotherapy. CONCLUSIONS: These data suggest that irILK is an ovarian tumor-associated antigen and implicates its potential not only as a biomarker for early-stage screening but also as a marker for monitoring the clinical condition of patients after treatment.     

Loss of trimethylation at lysine 27 of histone H3 is a predictor of poor outcome in breast, ovarian, and pancreatic cancers

Methylation of lysine 27 on histone H3 (H3K27) by the EZH2 complex is an epigenetic mark that mediates gene silencing. EZH2 is overexpressed in many cancers and correlates with poor prognosis in both breast and prostate cancers. However, the status of H3K27 methylation and its clinical implication in cancer patients have not been reported. We thus examined trimethylation of H3K27 (H3K27me3) by immunohistochemistry and its association with clinical variables and prognosis in breast, ovarian, and pancreatic cancers. We found that H3K27me3 expression was significantly lower in breast, ovarian and pancreatic cancers than in normal tissues (62% in breast cancer vs. 88% in normal breast tissue, P = 0.001; 38.4% in ovarian cancer vs. 83.3% in normal ovarian tissue, P < 0.05; and 26% in pancreatic cancer vs. 89% in normal pancreatic tissue, P < 0.001). H3K27me3 expression showed significant prognostic impact in breast, ovarian and pancreatic cancers in univariate survival analyses. In all three cancer types, patients with low expression of H3K27me3 had significantly shorter overall survival time when compared with those with high H3K27me3 expression. In a multivariate model, H3K27me3 expression was an independent prognostic value for overall survival in all three cancer types. These results suggest that H3K27me3 expression is a prognostic indicator for clinical outcome in patients with breast, ovarian, and pancreatic cancers.