The impact of lymph node dissection and adjuvant chemotherapy on survival: A nationwide cohort study of patients with clinical early-stage ovarian cancer

IntroductionTo establish the impact of lymph node dissection and chemotherapy on survival in patients with early-stage epithelial ovarian cancer (EOC).MethodsAll Dutch patients with International Federation of Gynaecology and Obstetrics (FIGO) stage I–IIA and IIIA1 EOC between 2000 and 2012 were included. Data concerning age, stage, tumour grade, histological subtype, hospital type, lymph node dissection, adjuvant chemotherapy and survival were extracted from the Netherlands Cancer Registry.ResultsOf 3658 patients included, 1813 (49.6%) had lymph nodes removed. Relative survival of patients with lymph node dissection (including those with lymph node metastases) was significantly better than that of patients without, also after correcting for stage, tumour grade, histology and age (89% and 82%, respectively; relative excess risk [RER], 0.64; 95% confidence interval [CI]: 0.52–0.78). There was a positive correlation between the number of removed lymph nodes and overall survival (after excluding patients with lymph node metastases). Of patients with stage I–IIA EOC who had ≥10 lymph nodes removed, there was no difference in relative survival between those who received chemotherapy and those who did not (RER, 0.51; 95% CI: 0.15–1.64). This was also true for a subgroup of patients with high-risk features (stage IC and IIA and/or tumour grade 3 and/or clear cell histology [RER, 0.90; 95% CI: 0.46–1.99]).ConclusionAdequate dissection of at least 10 but preferably ≥20 lymph nodes should be standard procedure for the staging of early-stage EOC. Adjuvant chemotherapy after an adequate lymph node dissection does not seem to contribute to a better relative survival.     

VEGF及其受体在上皮性卵巢癌组织中的表达及预后

目的 研究血管内皮生长因子（VEGF）及其受体血管内皮生长因子受体1（VEGFR1）、血管内皮生长因子受体2（VEGFR2）在上皮性卵巢癌中表达及临床预后意义。方法 采用SP免疫组化法检测139例不同卵巢组织VEGF及其受体VEGFR1、VEGFR2的表达及在上皮性卵巢癌组织中的共表达情况,并结合临床资料进行统计分析。结果 VEGF及其受体VEGFR1、VEGFR2在上皮性卵巢癌组织中的染色强度明显高于良性卵巢肿瘤及正常卵巢组织;并且VEGF及其受体在上皮性卵巢癌组织中的表达与临床分期、腹水量的差异均具有统计学意义（χ^2=4．207,P＝0．034;χ^2=7．432,P＝0．007）;在相关分析中高表达的VEGF与VEGFR2（r＝0．316,P＜0．05）、VEGFR1与VEGFR2（r＝0．415,P＜0．05）均存在相关性;VEGF及其受体三者共高表达较非共高表达患者的5年生存率差异具有统计学意义（χ^2＝4．043,P＝0．044）。结论 高表达和共表达VEGF及其受体VEGFR1和VEGFR2的患者可能存在较差预后,并且三者共表达及高表达可作为一项指导临床应用抗肿瘤血管生成药物（ Bev）靶向治疗的疗效预测分子。     

紫杉醇+铂类新辅助化疗方案治疗EOC的疗效及其对ERCC1与BRCA1表达的影响

目的：观察紫杉醇+铂类(TP/TC)新辅助化疗方案对原发性上皮性卵巢癌(EOC)患者的治疗效果及其对切除修复交叉互补基因1(ERCC1)与Bcl-2结合抗凋亡基因1(BRCA1)表达的影响。方法将我院2012年1月至2013年1月收治的32例肿瘤细胞减灭术前行TP/TC新辅助化疗的EOC患者作为观察组,41例肿瘤细胞减灭术前未化疗的EOC患者作为对照组,采用免疫组化技术检测两组患者病理组织中的ERCC1与BRCA1基因表达,并进行比较。结果观察组和对照组缓解(RR)率分别为65.63%(21/32)、60.98%(25/41),2年存活率分别为81.25%(26/32)、80.49%(33/41),差异均无统计学意义(P>0.05);观察组患者的ERCC1阳性率为100.00%(32/32),其中阳性高表达率为68.75%(22/32);BRCA1阳性率为81.25%(26/32),其中阳性高表达率为21.88%(7/32),两种基因阳性率和阳性高表达率均高于对照组[82.93%(34/41)、31.71%(13/41);53.66%(22/41)、2.44%(1/41)],差异均有统计学意义(P<0.05)。结论 TP/TC新辅助化疗方案对EOC患者ERCC1与BRCA1表达有明显影响,新辅助化疗可导致患者耐药率升高,因此建议新辅助化疗应有选择性。     

Risk factors for lymph node metastasis in apparent early-stage epithelial ovarian cancer: implications for surgical staging

Objectives

The extent of lymphadenectomy to be performed in apparent early-stage epithelial ovarian cancer (EOC) is not well defined. We evaluated the patterns of lymphatic spread in apparent early-stage EOC and risk factors for lymph node metastasis, as these have potential implications for clinical decision making.

Methods

All cases of apparent early-stage EOC diagnosed at our institution between January 1994 and December 2003 were retrospectively identified. Apparent early-stage EOC was defined as gross disease that appeared confined to the pelvis without abdominal spread at the time of initial exploration. Demographics, pathologic findings, staging procedures performed, and clinical impression at surgery were analyzed. Patterns of lymph node positivity and risk factors associated with upstaging were assessed.

Results

One hundred and ninety patients with apparent early-stage EOC undergoing primary surgical staging met criteria for inclusion. All patients had at least some pathologic assessment of lymph nodes, with 115 having both bilateral pelvic and paraaortic lymphadenectomy performed. After review of pathology and operative reports, the final FIGO staging within the cohort was 54 IA (28.4%), 10 IB (5.3%), 51 IC (26.8%), 1 IIA (0.5%), 4 IIB (2.1%), 37 IIC (19.5%), 8 IIIA (4.2%), 25 IIIC (13.2%). Overall 25/190 (13%) had lymph nodes metastasis as follows: 8 (32%) had positive pelvic nodes, 12 (48%) had positive paraaortic nodes, and 5 (20%) had both positive pelvic and paraaortic lymph nodes. Significant risk factors for lymph node metastasis included bilateral vs. unilateral primary lesion (26.8% vs. 7.5%, p < 0.001), positive cytologic washings vs. negative (22.4% vs. 9.1%, p = 0.012), ascites vs. no ascites (28.2% vs. 9.3%, p = 0.002), serous vs. other histology (28% vs. 9%, p = 0.001), grade 1 vs. grade 2 vs. grade 3 disease (2.7% vs. 1.9% vs. 23.2%, p < 0.001), and preoperative CA 125 levels of > 35 vs. ≤ 35 U/ml (22.4% vs.0% p = 0.006). No patients with mucinous cancers (n = 29) had lymph node metastases. Patterns of LN metastases were largely independent of laterality of primary lesions: among those with unilateral lesions and positive nodes (n = 10), 5 (50%) had ipsilateral lymph node involvement, 4 (40%) had bilateral involvement, and 1 (10%) had isolated contralateral lymph nodes positive.

Conclusions

Complete surgical staging in EOC patients with gross disease confined to the ovaries and pelvis should include bilateral pelvic and paraaortic lymphadenectomy.Even in patients with unilateral lesions, lymph node metastases are commonly bilateral. Bilateral ovarian lesions, positive cytology, presence of ascites, high grade histology, and serous histology are risk factors for lymph node involvement. This information may be helpful in counseling patients presenting for consideration of re-staging after unexpected findings of malignancy.     

MMP-1-PAR1 axis mediates LPA-induced epithelial ovarian cancer (EOC) invasion

Objectives

MMP-1 is over-expressed in many cancers, with high expression often associated with poor survival. In the present study, we examined the expression of MMP-1 in EOC and its role in EOC invasion. Moreover, we evaluated the role of a newly identified MMP-1-protease activated receptor (PAR)-1 axis in LPA-induced EOC invasion.

Methods

MMP-1 and PAR1 mRNA expression in EOC cell lines was determined by real time PCR. MMP-1 mRNA expression in 96 normal and carcinoma ovarian tissue specimens was analyzed using a TissueScan real time PCR array. MMP-1 concentration in conditioned medium was measured by MMP-1 ELISA. PAR1 protein expression was detected by Western blotting. Cell invasion was evaluated by in vitro Matrigel invasion assay.

Results

In ovarian tumor tissues more MMP-1 expression was observed than in normal ovarian tissues (p < 0.05), and its expression correlated with tumor grade (grade 3 > grade 2 > grade 1). Human recombinant MMP-1 as well as serum free conditioned medium containing high levels of MMP-1 from DOV13 and R182 cells significantly promoted DOV13 cell invasion (p < 0.05), implicating a direct role of MMP-1 in EOC invasion. Moreover, MMP-1 induced DOV13 invasion was significantly blocked by PAR1 siRNA silencing. Furthermore, MMP-1 and PAR1 were both significantly induced by LPA (20 μM), and siRNA silencing of MMP-1 and PAR1 both significantly reduced LPA's invasion-promoting effect in DOV13 cells (p < 0.05).

Conclusions

Our results suggest that the MMP-1-PAR1 axis is involved in EOC invasion and at least partially mediates LPA-induced EOC invasion. Therefore, blocking MMP-1 or PAR1 may represent a new therapeutic option for metastatic EOC.     

吉西他滨+卡铂对比泰素(TB)治疗复发卵巢上皮癌的临床疗效观察

目的研究吉西他滨+卡铂治疗复发性上皮性卵巢癌的疗效和毒性。方法实验组:27例复发性上皮性卵巢癌应用吉西他滨1000mg/m2,第一、八天静脉滴注,曲线下面积=5,第一天静脉滴注。对照组:31例复发性上皮性卵巢癌应用紫杉醇175mg/m2,第一天静脉滴注,卡铂曲线下面积=5。第一天静脉滴注。每21天为一个疗程,坚持化疗3~12个疗程。分析两组之间的治疗效果以及毒副反应,探讨两组肿瘤患者的生活质量情况。结果实验组总有效率为77.8%,其中完全有效(26.0%),部分有效(51.9%),中位无进展生存4.2个月(2~10个月);对照组ORR为48.4%,其中完全有效(12.9%),部分有效(35.5%),位无进展生存为2.8个月(2~13个月),两组有显著差异。两组毒副反应均为骨髓抑制,对照组还以过敏反应为显著,导致4例终止疗程。对照组较实验组明显加剧其毒副反应,差异有显著意义。在肿瘤患者的生活质量评分中,实验组81.5%>50分,而对照组只有35.5%,差异有显著性。结论在治疗复发性复发性上皮性卵巢癌中,吉西他滨+卡铂较紫杉醇方案更为有效,安全性更高,毒副反应更轻,对患者的生活质量影响更少。     

Methylation Status and Immunohistochemistry of BRCA1 in Epithelial Ovarian Cancer

Background: Cancer initiation and progression are controlled by genetic and epigenetic events. One epigeneticprocess which is widely known is DNA methylation, a cause of gene silencing. If a gene is silenced the protein whichit encodes will not expressed. Objectives: 1. Identify the methylation status of BRCA1 in patients with epithelialovarian cancer (EOC)and assess BRCA1 protein expression in tumor tissue. 2. Examine whether BRCA1 genemethylation and BRCA1 protein are associated with survival of epithelial ovarian cancer patients. Methods: Thestudy design was a prospective-cohort study, conducted at Sardjito hospital, Yogyakarta, Indonesia. Results:A total of 69 cases were analyzed in this study. The data showed that the methylation status of BRCA1 in EOCwas positive in 89.9%, with clear protein expression of BRCA1 in 31.9%. Methylation status and expression ofBRCA1 were not prognosticators of EOC patients. Menarche, CA125 level, clinical stage and residual tumorwere independent factors for prognosis.     

细胞减灭术加腹腔热灌注化疗治疗卵巢癌腹膜转移癌的临床研究

目的 研究细胞减灭术（CRS）加腹腔热灌注化疗（HIPEC）治疗卵巢癌腹膜转移癌的疗效及安全性。方法 46例晚期（A组,FIGO Ⅲc/Ⅳ期,n=16和复发性,B组,n=30）卵巢癌腹膜癌患者接受了CRS+HIPEC治疗,分析其临床资料,主要终点指标为总生存期,次要指标为安全性。结果 A、B两组患者的中位总生存期（OS）分别为74.0月和57.5月（P=0.68）。腹膜癌指数（PCI）≤20（n=24）和＞20（n=22）的中位OS分别为76.6和38.5月（P=0.01）。CC 0~1分和CC 2~3分的中位OS分别为79.5和24.3月（P=0.00）。对复发性卵巢癌腹膜癌患者来说,铂类敏感型和耐药型患者的中位OS分别为6 5 . 3 和2 0 . 0 月（P=0.05）。无围手术期死亡病例,5例患者出现术后并发症。多因素分析显示,CC 0~1分、术后化疗≥6周期为改善生存的独立预后因素。结论 CRS+HIPEC可延长卵巢癌腹膜癌患者的总生存期,安全可行。