Lidija Beketić-Orešković

Prognostic Significance of Carbonic Anhydrase IX (CA-IX), Endoglin (CD105) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in Breast Cancer Patients

The aim of this study was to examine the prognostic significance of carbonic anhydrase IX (CA-IX), an endogenous marker for tumor hypoxia; endoglin (CD105), a proliferation-associated and hypoxia-inducible glycoprotein and 8-hydroxy-2′-deoxyguanosine (8-OHdG), an oxidative DNA lesion, in breast cancer patients. Immunohistochemical expressions of CA-IX, CD105 and 8-OHdG, analyzed on paraffin-embedded tumor tissues from forty female breast cancer patients, were used to assess their prognostic implication on overall survival (OS) and relapse-free survival (RFS). Patients with high CA-IX expression (above cut-off value) had a higher occurrence of relapse (P = 0.002). High CA-IX expression was significantly associated with shorter RFS (P < 0.001, hazard ratio (HR) 0.21) and shorter OS (P < 0.001, HR 0.19). Lymph node negative patients with high CA-IX expression had worse RFS (P = 0.031, HR 0.14) and OS (P = 0.005, HR 0.05). Patients with grade I&II tumors and high CA-IX expression showed shorter RFS (P = 0.028, HR 0.28) and OS (P = 0.008, HR 0.20). Worse OS (P = 0.046, HR 0.28) was found in subgroup of patients with grade II tumors and high CA-IX expression. Among all three markers, only high CA-IX expression was strong independent prognostic indicator for shorter OS (HR 4.14, 95% CI 1.28–13.35, P = 0.018) and shorter RFS (HR 3.99, 95% CI 1.38–11.59, P = 0.011). Elevated expression of CA-IX was an independent prognostic factor for decreased RFS and OS and a significant marker for tumor aggressiveness. CD105 had week prognostic value; whereas, 8-OHdG, in this study, did not provide sufficient evidence as a prognostic indicator in breast cancer patients.

Thrombosis following ovarian hyperstimulation syndrome

Abstract The aim of this review is to analyse the pathophysiology and complications of thrombosis in conjuction with ovarian hyperstimulation syndrome (OHSS) following ovulation induction and to suggest practical guidelines usefull for the prevention and treatment. Although the incidence of thrombosis varies from 0.2% among in vitro fertilization (IVF) cycles and up to 10% for severe cases of the syndrome, it represents the most dangerous complication of OHSS. Different changes in haemostatic markers have been found to create a state of hypercoagulability, but no single standard test is available to estimate the state of thrombosis. The role of markers for thrombophilia is controversial. Thromboses are mostly venous (67–75%) involving upper limbs and neck, then arterial (25–33%) which are mainly intracerebral. The predominant sites of venous thromboembolism in the upper part of the body may be explained by higher concentrations of estrogens drained through lymphatic ducts from ascites and by compression of rudimentary branchyal cysts. Once early diagnosis is established, it is crucial to use an anticoagulant treatment with heparin proceeded with thromboprophylaxis. However, identification of patients at risk and preventive measures of OHSS are the best means in reducing the risk of thrombosis after ovarian stimulation. Chinese abstract 本综述的目的是分析促排卵导致的卵巢过度刺激综合征（OHSS）并发血栓形成的病理生理学特征与并发症，并针对其预防与治疗提出实用的临床指南。虽然体外受精治疗中血栓形成的发生率介于0.2∼10%之间，它却是OHSS最危险的并发症。现已发现了多种造成高凝状态的凝血标志物，但还没有单一的检验标准用于评估血栓形成的状态。关于标志物在血栓形成倾向中所起的的作用存在争议。血栓多为静脉血栓（67∼75%），包括上肢与颈部；而动脉血栓（25∼33%）多位于大脑内部。静脉血栓多位于身体上部，可能是由于腹水中较高浓度的雌激素经淋巴管排出，及残留囊肿的加压作用。一旦早期诊断确立，重要的是应用抗凝血剂治疗及肝素预防血栓。但是，鉴定高危患者与预防OHSS的发生是降低卵巢刺激后血栓风险的最好办法。

Dopamine agonists in prevention of ovarian hyperstimulation syndrome

Abstract The aim of this review is to analyze the efficacy of different dopamine agonists in the prevention of ovarian hyperstimulation syndrome (OHSS). Cabergoline, quinagolide and bromocriptine are the most common dopamine agonists used. There are wide clinical variations among the trials in the starting time (from the day of human chorionic gonadotrophin (hCG) to the day following oocyte retrieval); the duration of the treatment (4–21 days), the dose of cabergoline (0.5 mg or 0.25 mg orally) and in the regimens used. At present, the best known effective regimen is 0.5 mg of cabergoline for 8 days or rectal bromocriptine at a daily dose of 2.5 mg for 16 days. Dopamine agonists have shown significant evidences of their efficacy in the prevention of moderate and early-onset OHSS (9.41%), compared with a placebo (21.45%), which cannot be confirmed for the treatment of late OHSS. It would be advisable to start with the treatment on the day of hCG injection or preferably a few hours earlier. The use of dopamine agonists should be indicated in patients at high risk of OHSS, as well as in patients with a history of previous OHSS even without evident signs of the syndrome. Chinese abstract 这篇综述的目的是分析不同的多巴胺受体激动剂在预防卵巢过度刺激综合征（OHSS）中的疗效。卡麦角林，喹高利特和溴隐亭是最常见的多巴胺受体激动剂。在本研究的开始阶段，卡麦角林的使用时间（从HCG日至取卵日4天-21天不等），使用剂量（0.5mg或0.25mg口服）和使用方案等临床因素变化很大。目前，最有效的方案是卡麦角林每天0.5mg口服8天，或者直肠给药0.25mg每天，使用16天。多巴胺受体激动剂有显著地预防中度和早发性卵巢过度刺激综合征(9.41%)的疗效，与对照组（21.45%）相比较，发病率显著降低，但是其治疗晚期OHSS的效果尚不确定。目前，多建议在HCG注射的当日开始使用，提前几个小时效果可能更好。多巴胺受体激动剂应当对具有高OHSS发生风险的患者以及之前有OHSS史,甚至没有发病迹象的患者也可以使用。

Fertility preservation with ovarian stimulation protocols prior to cancer treatment

Abstract: An increasing trend towards later childbearing has been reported recently in many developed countries. Although the incidence of reproductive age in women who have delayed pregnancy with cancer is 10%, they may be concerned regarding the preservation of ovarian function due to advanced fertile age and with the impact of cancer treatment on later fertility. Among multiple strategies controlled, ovarian stimulation for embryo or oocyte cryopreservation is currently the most established method for fertility preservation. It is important to choose the appropriate ovulation induction protocol prior to oncologic treatment, because most of these patients have only the chance of a single cycle to conceive. Current treatment protocols offer a minimal time delay until oncologic treatment is commenced. In urgent settings, random-start ovarian stimulation represents a new technique which provides a significant advantage by decreasing the total time of the treatment, because it may be started irrespective of the phase of the cycle without compromising oocyte yield and maturity before cancer treatment. However, in patients with oestrogen-sensitive cancers stimulation, protocols using letrozole are currently preferred over tamoxifen regimens, and therefore, it may be highly advisable to use letrozole with gonadotrophins routinely as a safe, effective and novel protocol of ovulation induction.

Follicular progesterone elevations with ovulation induction for IVF.

Abstract The purpose of this review is to analyse the sources and effects of follicular progesterone elevations during ovarian stimulation, with the underlying mechanisms and preventive strategies on the in vitro fertilisation pregnancy outcome. In the early follicular phase, a flare-up effect of gonadotrophin releasing hormone (GnRH) agonists and incomplete luteolysis in GnRH antagonist regimens can result in significant elevations of progesterone. In the late follicular phase, progesterone elevations in GnRH analogue cycles are the result of the ovarian stimulation itself, driven by high follicle stimulating hormone dosage, estradiol levels, the number of follicles and oocytes. It seems that progesterone elevations (> or = 1.5 ng/mL or 4.77 nmol/L) have a detrimental effect on the outcome of pregnancy, accelerating the endometrial maturation. The most appropriate choice to avoid the negative effects of follicular progesterone elevations is to cancel fresh embryo transfer and to transfer frozen–thawed embryos in natural cycles. To prevent follicular phase elevations it might be preferable to use milder stimulation protocols, earlier trigger of ovulation in high responders and single-blastocyst transfer on day 5. The optimal GnRH analogue protocols during the entire stimulation period appear to be the long agonist as well as “long” and long GnRH antagonist regimens. Chinese abstract 这篇综述的目的是分析促排卵期间卵泡黄体激素的来源和作用，体外受精妊娠结局的机制及预防策略。在早卵泡期，促性腺激素释放激素（gonadotrophin releasing hormone，GnRH）激动剂的扳机效应和GnRH拮抗剂中不完整的黄体溶解效应会导致孕激素的升高。在晚卵泡期，GnRH类似物周期孕激素升高是促排卵本身，高卵泡刺激激素用量，雌二醇水平，卵泡和卵母细胞的数量驱动的结果。 孕激素升高似乎（>或=1.5ng/mL或4.77 nmol / L的）对妊娠结局产生不良影响，加速子宫内膜成熟。避免卵泡黄体激素升高的负面影响， 最合适的选择是取消新鲜胚胎移植，而在自然周期移植解冻的胚胎。为避免卵泡期卵泡黄体激素升高，可以使用温和的刺激方案，对高反应者进行较早的排卵诱发，并在第5天进行单个囊胚移植。在整个刺激周期最佳的GnRH类似物方案似乎是长激动剂“长”和长GnRH拮抗剂方案。

Apoptosis regulator Bcl-2 is an independent prognostic marker for worse overall survival in triple-negative breast cancer patients

Background: The objective of this study was to examine the prognostic significance of carbonic anhydrase IX (CAIX), an endogenous marker for tumor hypoxia; the cellular tumor antigen p53; and the apoptosis regulator Bcl-2, in triple-negative breast cancer (TNBC) patients. Methods: Immunohistochemically determined expression of CAIX, p53, Bcl-2 and proliferation factor Ki-67, analyzed in 64 paraffin-embedded TNBC tissue samples, was used to assess their relation to clinicopathological variables and prognostic implications for overall survival (OS). Results: Bcl-2 expression was negatively correlated with histological grade of tumor, while expression of p53 was positively correlated with the same clinical variable (p = 0.036 and p = 0.033, respectively). The p53 expression was also positively correlated with tumor size (p = 0.010). Survival analysis showed that patients with high Bcl-2 expression (above cutoff value determined by receiver operator characteristic [ROC] curve analysis) had shorter OS (p = 0.020). The same was observed for patients with tumors larger than 5 cm (p = 0.034) or positive lymph nodes (p = 0.004). Among all 3 examined markers, multivariate analysis showed that only Bcl-2 expression was a strong independent prognostic indicator for decreased OS (hazard ratio [HR] = 15.16, 95% confidence interval [95% CI], 2.881-79.727, p = 0.001). Conclusions: Elevated expression of Bcl-2 was an independent prognostic factor for poorer OS in TNBC and as such a significant marker for tumor aggressiveness.