吉西它滨在上皮性卵巢癌中的研究发展

手术和化疗是治疗上皮性卵巢癌的两大主要治疗手段,满意的肿瘤细胞减灭术是化疗成功的关键。上皮性卵巢癌复发率高达80％,化疗耐药是本病复发的根本原因。吉西他滨于2006年由美国食品药品监督管理局（FoodandDrugAdministration,FDA）批准用于停铂治疗半年后复发的卵巢癌患者的新化疗药物。本文聚焦该药近年来在上皮性卵巢癌中的应用及研究进展,现综述如下。     

Platelet microparticles: Detection and assessment of their paradoxical functional roles in disease and regenerative medicine

There is increasing research on and clinical interest in the physiological role played by platelet microparticles (PMPs). PMPs are 0.1–1-μm fragments shed from plasma membranes of platelets that are undergoing activation, stress, or apoptosis. They have a phospholipid-based structure and express functional receptors from platelet membranes. As they are the most abundant microparticles in the blood and they express the procoagulant phosphatidylserine, PMPs likely complement, if not amplify, the functions of platelets in hemostasis, thrombosis, cancer, and inflammation, but also act as promoters of tissue regeneration. Their size and structure make them instrumental in platelet–cell communications as a delivery tool of platelet-borne bioactive molecules including growth factors, other signaling molecules and micro (mi)RNA. PMPs can therefore be a pathophysiological threat or benefit to the cellular environment when interacting with the blood vasculature. There is also increasing evidence that PMP generation is triggered during blood collection, separation into components, and storage, a phenomenon potentially leading to thrombotic and inflammatory side effects in transfused patients. Evaluating PMPs requires strict pre-analytical and analytical procedures to avoid artifactual generation and ensure accurate assessment of the number, size repartitioning, and functional properties. This review describes the physical and functional methods developed for analyzing and quantifying PMPs. It then presents the functional roles of PMPs as markers or triggers of diseases like thrombosis, atherosclerosis, and cancer, and discusses the possible detrimental immunological impact of their generation in blood components. Finally we review the potential function of PMPs in tissue regeneration and the prospects for their use in therapeutic strategies for human health.     

G蛋白耦联受体30(GPR30)在上皮性卵巢癌中的表达与增殖相关基因c-fos、cyclinD1表达的相关性

目的:探索新型雌激素受体G蛋白耦联受体30(G protein coupled receptor 30,GPR30)在人上皮性卵巢癌发生发展中的作用。方法:采用免疫组织化学SP法检测30例上皮性卵巢癌组织中GPR30、增殖相关基因c-fos和cyclinD1的表达,并以9例良性卵巢肿瘤、4例正常卵巢组织作对照。结果:GPR30在上皮性卵巢癌的表达水平(80.0%)显著高于良性卵巢肿瘤(44.4%)和正常卵巢组织(25.0%)(P<0.01;P<0.05)。GPR30和c-fos的表达与上皮性卵巢癌的病理类型、FIGO分期有关,在浆液性囊腺癌、FIGOⅢ-Ⅳ期的表达水平显著升高(P<0.05)。未见cyclinD1的表达与上皮性卵巢癌临床病理参数的关系(P>0.05)。上皮性卵巢癌中GPR30与c-fos、cyclinD1的表达具有正相关性(P<0.01;P<0.05)。结论:GPR30可能通过c-fos、cyclinD1促进卵巢癌增殖,参与上皮性卵巢癌的发生、发展。     

miR-99a promotes proliferation targeting FGFR3 in human epithelial ovarian cancer cells

MiRNAs have been reported as important regulators in normal physiological processes, human cancer, and even their roles as therapeutic targets have been proposed. In epithelial ovarian cancer (EOC), the expression of miRNAs is reported to remarkably deregulate, showing that miRNAs are involved in the initiation and progression of this disease. In this study, we found that miR-99a was obviously decreased in EOC tissues, serums and cell lines SKOV-3. Importantly, fibroblast growth factor receptor 3 (FGFR₃), predicted to be one target gene of miR-99a using computational algorithms, was higher in expression in EOC cells. Subsequently, FGFR₃ was proved to be direct target of miR-99a by dual luciferase assay. Furthermore, overexpression of miR-99a dramatically suppressed expression level of FGFR₃ at both mRNA and protein levels, proving FGFR₃ to be inversely correlated with miR-99a. Finally, overexpression of miR-99a could significantly inhibit EOC cell proliferation in vitro by decreasing the expression of FGFR₃ which also reduced the EOC cell growth after siRNA knockdown. Conclusively, miR-99a expression was remarkably downregulated in serums, tissues and cell and suppresses EOC cell proliferation by targeting FGFR₃, suggesting miR-99a as a prospective prognosis marker and potential tumor suppressor for EOC therapeutics.     

Diagnostic performance of the biomarkers HE4 and CA125 in type I and type II epithelial ovarian cancer

Objective

To evaluate the diagnostic performance of HE4 and CA125 in patients presenting with suspicious malignant ovarian cysts. We especially wanted to investigate the levels of HE4 and CA125 with regard to the gene and histology-unifying model of type I and type II epithelial ovarian cancer (EOC).

Methods

Plasma from 373 women presenting with a suspicious malignant ovarian cyst was collected prior to surgery. Histology, grade, and stage were determined according to FIGO-classification. HE4 and CA125 were analyzed using ELISA, and the markers were evaluated for significance separately and in combination. Receiver operating curves, the area under the curve, sensitivity and specificity were estimated.

Results

The combination of HE4 and CA125 resulted in the best diagnostic power in comparing benign tumors to EOC (ROC AUC 0.93, sensitivity 94.4% at 75% specificity) for type II. Diagnostic power in type I (ROC AUC 0.79, sensitivity 61.9% at 75% specificity) was less impressive. In particular, mucinous benign vs. malignant tumors could not significantly be separated by the dual marker combination. Impressively high ROC AUC 0.99 was found for the late stage type II EOC with 100% sensitivity at 75% specificity.

Conclusions

HE4 and CA125 have a good ability to diagnose the more aggressive type II tumors but a poor diagnostic ability when patients are presenting with slow-growing type I in the early stage. Our results support the hypothesis that EOC should be looked upon as several different diseases, and that we lack biomarkers for sub-groups of EOC.     

卵巢癌患者术后早期血清CA125、CEA和TSGF的动态监测

目的:研究上皮性卵巢癌(EOC)患者经手术治疗后机体糖类抗原CA125、癌胚抗原(CEA)、恶性肿瘤相关物质群(TSGF)变化情况,初步探讨其联合检测在疗效预测及预后判断中的临床价值。方法:选取健康对照71例(正常对照组)及我院住院卵巢上皮癌患者71例(卵巢癌组),分别检测其术前、术后静脉血中CA125、CEA和TSGF水平,并对检测结果进行比较。结果:卵巢癌组患者术前血清TSGF、CA125、CEA水平均高于正常对照组,差异有统计学意义(P<0.05～0.01)。同术前比较,卵巢癌患者术后7、15、30dCA125、CEA和TSGF水平变化明显(P<0.05～0.01),CA125和CEA在术后30d左右接近正常水平,TSGF在术后15d左右接近正常。结论:手术前、后动态监测EOC患者血清CA125、CEA和TSGF的变化情况,有助于判断疗效,监测复发或转移。     

KLK10蛋白在上皮性卵巢癌中的表达及意义

目的：探讨KLK10蛋白在上皮性卵巢癌中的表达及临床意义。方法：应用免疫组化法检测10例上皮性卵巢良性、12例交界性和45例恶性肿瘤中KLK10蛋白的表达，分析KLK10表达与上皮性卵巢癌临床病理及生存状态的关系。结果：（1）在上皮性卵巢良性、交界性和恶性肿瘤组织中KLK10表达的阳性率分别为10％、58.33％和86．67％，3组间阳性率和阳性级别比较差异均有统计学意义（P〈0．05）；（2）KLK10表达的阳性率和表达强度在晚期组高于早期组，中低分化组高于高分化组，有淋巴结转移组高于无淋巴结转移组，生存时间〈5年组高于≥5年组，各组间比较差异均有统计学意义（P〈0．05）。结论：（1）KLK10蛋白在上皮性卵巢良性、交界性和恶性肿瘤细胞中表达的阳性率和表达强度呈逐渐升高。（2）KLK10蛋白在上皮性卵巢癌中的表达与临床分期、病理分级、淋巴结转移和5年生存率有关。     

Primary-care-based episodes of care and their costs in a three-month follow-up in Finland

Objective To explore patient characteristics, resource use, and costs related to different episodes of care (EOC) in Finnish health care.

Design Data were collected during a three-month prospective, non-randomized follow-up study (Effective Health Centre) using questionnaires and an electronic health record.

Setting Three primary health care practices in Pirkanmaa, Finland.

Subjects Altogether 622 patients were recruited during a one-week period. Inclusion criteria: the patient had a doctor’s or nurse’s appointment on the recruiting day and agreed to participate. Exclusion criteria: patients visiting a specialized health guidance clinic for pregnant women, children, and mothers.

Main outcome measures Patient characteristics, resource use, and costs based on the ICPC-2 EOC classification.

Results On average, the patients had 1.22 EOCs during the three months. Patient characteristics and resource use differed between the EOC chapters. Chapter L, “Musculoskeletal”, had the most episodes (17%). The most common (8%) single EOC was “upper respiratory infection”. The mean cost of an episode (COE) was €389.56 (standard error 61.11) and the median COE was €165.00 (interquartile range €118.46–288.56) during the three-month follow-up. The most expensive chapter was K, “Circulatory”, with a mean COE of €909.85. The most expensive single COE was in chapter K, €32 545.56. The most expensive 1% of the COEs summed up covered 36% of the total COEs.

Conclusion Patient characteristics, resource use, and costs differed between the ICPC-2 chapters, which could be taken into account in service planning and pricing. Future studies should incorporate more specific diagnoses, larger data sets, and longer follow-up times.

• Key points

• The most common episodes were under the ICPC-2 “Musculoskeletal” chapter, but the highest mean and single-episode costs were related to the “Circulatory” chapter.

• The mean (median) cost of episodes that started in primary care was €390 (€165) during the three-month follow-up.

• Patient characteristics, resource use, and costs differed significantly between the ICPC-2 chapters. The most expensive 1% of the episodes covered 36% of the total costs of all the episodes.

     

Possible Epithelial Ovarian Cancer Association with HPV18 or HPV33 Infection

The present study was conducted to investigate the prevalence of HPV infection in epithelial ovarian cancer (EOC) in Hunan province. DNA samples were collected from paraffin embedded ovarian tissue from 322 patients with EOC, 99 with ovarian benign tumors and 199 normal persons. The polymerase chain reaction and direct sequencing were used to identify the HPV types in the samples. The relationship between the infection of human papillomavirus (HPV) and the epithelial ovarian carcinoma (EOC) was investigated combined with clinical data. The prevalence of HPV18 and HPV33 in EOC group and benign group was higher than in the normal group. HPV18 and HPV33 may play a role in the development of both EOC and ovarian benign tumor and may participate in the development of EOC with traditional risk factors, family history and abortion, possibly exerting synergistic effects.     

Midkine as a potential diagnostic marker in epithelial ovarian cancer for cisplatin/paclitaxel combination clinical therapy

The paclitaxel/cisplatin combination therapy commonly is used as the first-line treatment for advanced ovarian cancer patients. Midkine (MK), known as a novel tumor biomarker, has been elevated in the serum of patients with epithelial ovarian cancer (EOC). In this study, we aimed to detect the expression of MK in EOC tissues and evaluate clinical value of MK in diagnosis and therapy of EOC. We perform immunohistochemistry analysis to detect MK in EOC sample with postoperative platinum/paclitaxel combination therapy, we found that 71.4% (85 in 119 samples) of these samples were MK positive (> 10% of the cells were stained), and the expression of MK was significantly associated with disease histology (P = 0.038) as well as differentiation grade (P < 0.001). Moreover, MK positive samples show much more sensitive to cisplatin/paclitaxel combination therapy, compared with MK negative samples (P = 0.029). Those results indicated that MK expression might correlate with paclitaxel and/or cisplatin cytotoxicity in clinical therapy of EOC. Then, we evaluated the sensitivity to cisplatin and paclitaxel in 5 ovarian cancer cell lines (ES2, A2870, HO-8910, SKOV3 and SW626), and ES2, the highest MK expression among those cell lines, show the most sensitive to paclitaxel and cisplatin. Further, we confirmed this correlation between MK and paclitaxel and/or cisplatin cytotoxicity with the gain- and lost- of function. Finally, we demonstrated that MK enhanced the cytotoxicity of paclitaxel and/or cisplatin by accumulated cisplatin and paclitaxel through inhibited the expression of multidrug resistance-associated protein 3 (MRP3). In conclusion, MK could be an effective biomarker in diagnosis and therapy of EOC, especially for the drug selection at the time of initial diagnosis.