Slavko Orešković

Involvement of PTCH gene in various noninflammatory cysts

Constitutional hemizygous inactivation of PTCH, the Shh signaling pathway gene that moderates the signal, manifests itself as nevoid basal cell carcinoma syndrome or Gorlin syndrome, a condition variably characterized by a number of developmental disorders and malformations, and by predisposition to some malignancies, basal cell carcinoma in particular. Loss of heterozygosity for the PTCH region was found several years ago in the epithelial lining of odontogenic keratocysts, the cyst type with highly increased incidence in nevoid basal cell carcinoma syndrome. This finding confirmed the expectations that the gene responsible for the syndrome would have a decisive role in the genesis of these cysts even when they are not syndrome related. Suggestive temporal distribution of Shh signaling, recently observed during tooth development, lead us to investigate PTCH association with dentigerous cysts, the other major noninflammatory cyst of odontogenic origin. We report here that PTCH appears to be inactivated in dentigerous cysts, suggesting that it is responsible for their genesis as well. More generally, if our similar observations of incomplete heterozygosity in this region for dermoid cysts can be interpreted as loss of heterozygosity, PTCH alterations may prove to be a necessary, and perhaps the initiating event, in formation and growth of various noninflammatory cysts. This would be consistent with our view that local PTCH inactivation can, under favorable circumstances, lead to persistent though not by itself truly aggressive cell proliferation.

Role of the hedgehog/patched signaling pathway in oncogenesis a new polymorphism in the PTCH gene in ovarian fibroma

Abstract: We compared the expression of target genes of Hedgehog/Patched signaling in ovarian fibromas and ovarian dermoids. We noted that high levels of SHH appear almost regularly, especially in dermoids, usually accompanied by increased expression of SMO. GLI overexpression does not coincide with that of PTCH. Loss of heterozygosity findings in the PTCH locus and increased expression of several genes in the pathway strongly suggest that the pathway is involved in both ovarian fibroma and dermoids.

Hyperthermic modulation of resistance to cis-diammine-dichloroplatinum(II) in human larynx carcinoma cells

The aim of the present study was to examine the effect of hyperthermia on cisplatin resistance in two sublines of human larynx carcinoma HEp2 cells. Hyperthermia was tumouricidal for both parental and cisplatin resistant cells, but cisplatin resistant cells were more sensitive to the heat at 43 and 44 degrees C. In combined cisplatin-hyperthermia treatment, heat chemosensitization was observed for parental, as well as for cisplatin resistant cells. At 42 degrees C, and at 43 degrees C, the thermal enhancement ratio (TER) for cisplatin toxicity was higher in resistant than in parental cells. The heating at 42 degrees C decreased the resistance factors in CA3 and CK2 cells from 2.2 and 3.5 to 1.8 and 2.2 respectively. At 43 degrees C, the resistance factors were decreased to 1.7 for CA3 cells and 2.0 for CK2 cells. The heating at 43 degrees C increased intracellular platinum accumulation in all cell lines examined. This effect was more pronounced in resistant, than in parental cells, causing complete reversal of the reduced platinum accumulation found at 37 degrees C in resistant cells. In conclusion, the resistance to cisplatin was partially reversed by hyperthermia in CA3 and CK2 cells. Increased drug accumulation was one of the mechanisms involved in hyperthermic potentiation of cisplatin toxicity and partial reversal of cisplatin resistance in human larynx carcinoma HEp2 cells.

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。

Macroprolactinemia: new insights in hyperprolactinemia

Hypersecretion of prolactin by lactotroph cells of the anterior pituitary may lead to hyperprolactinemia in physiological, pathological and idiopathic conditions. Most patients with idiopathic hyperprolactinemia may have radiologically undetected microprolactinomas, but some may present other causes of hyperprolactinemia described as macroprolactinemia. This condition corresponds to the predominance of higher molecular mass prolactin forms (big-big prolactin, MW > 150 kDa), that have been postulated to represent prolactin monomer complexed with anti-prolactin immunoglobulins or autoantibodies. The prevalence of macroprolactinemia in hyperprolactinemic populations between 15–46% has been reported. In the pathophysiology of macroprolactinemia it seems that pituitary prolactin has antigenicity, leading to the production of anti-prolactin autoantibodies, and these antibodies reduce prolactin bioactivity and delay prolactin clearance. Antibody-bound prolactin is big enough to be confined to vascular spaces, and therefore macroprolactinemia develops due to the delayed clearance of prolactin rather than increased production. Although the clinical symptoms are less frequent in macroprolactinemic patients, they could not be diff erentiated from true hyperprolactinemic patients, on the basis of clinical features alone. Although gel filtration chromatography (GFC) is known to be the gold standard for detecting macroprolactin, the polyethylene glycol precipitation (PEG) method has off ered a simple, cheap, and highly suitable alternative. In conclusion, macroprolactinemia can be considered a benign condition with low incidence of clinical symptoms and therefore hormonal and imaging investigations as well as medical or surgical treatment and prolonged follow-up are not necessary.

Maternal immune system adaptation to pregnancy - a potential influence on the course of diabetic retinopathy

BackgroundProgression of diabetic retinopathy occurs at least temporarily during pregnancy. Although the cause of this progression is not entirely understood, the immune phenomenon and chronic inflammation may play a significant role. During pregnancy in order to avoid fetus rejection, certain components of the immune system that are knowingly implicated in the pathogenesis of diabetic retinopathy are activated including generalized leukocyte activation and an increase in certain cytokine plasma levels. Activated leukocytes with up regulated adhesion molecules have an increased potential to bind to the endothelium cells of blood vessels. Leukocyte-endothelial interaction and the consequent leukostasis with capillary occlusion, ischemia and vascular leakage have a substantial role in the development of diabetic retinopathy. Furthermore, certain increased cytokines are known to cause blood-retinal-barrier breakdown whilst others promote angiogenic and fibrovascular proliferation and thereby can also be implicated in the pathogenesis of this diabetic complication.Presentation of the hypothesisWe hypothesized that the activation of the immune system during gestation may have an influence on the course of retinopathy in pregnant diabetic women.Testing the hypothesisWe suggest two prospective follow up studies conducted on women with type 1 diabetes mellitus. The first study would include a group of non-pregnant women and a group of diabetic women undergoing normal pregnancy matched for age and duration of diabetes. In the second study pregnant women would be divided into two groups: one with normal pregnancy and the other with preeclampsia. The procedure and data collection in both studies will be identical: a complete ophthalmological examination, glycaemic control, blood pressure measurement and venous blood samples for the determination of plasma levels of cytokines (TNF-alpha, IL-1beta, IL-6, IL-8) and adhesion molecules (ICAM-1, VCAM-1).Implications of the hypothesisConsidering the present assumption, the gestational immune activation could be suggested as a potential risk factor for the development and progression of retinopathy in diabetic women. A better understanding of immunomodulatory effects of pregnancy on diabetic retinopathy pave the way for further investigations of the mechanism of its pathogenesis and could be essential for novel approaches to the treatment of this serious sight threatening complication of diabetes mellitus.

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。

Outcome and efficacy of a transobturator polypropylene mesh kit in the treatment of anterior pelvic organ prolapse

To report the efficacy and complications of anterior pelvic organ prolapse (POP) repair with mesh placed through the transobturator route (Perigee system; AMS, Minnetonka, MN, USA).

Prevalence of gestational diabetes mellitus according to IADPSG and NICE criteria

To investigate the impact of the International Association of Diabetic Pregnancy Study Group (IADPSG) diagnostic criteria on the prevalence of gestational diabetes mellitus (GDM) and overt diabetes as compared with the UK National Institute for Health and Care Excellence (NICE) criteria, and to evaluate the prevalence of maternal and perinatal outcomes among pregnant women with fasting plasma glucose (FPG) levels of 5.1–5.5 mmol/L.

Fertility preservation options in breast cancer patients

Abstract The purpose of this review is to analyse current options for fertility preservation in young women with breast cancer (BC). Considering an increasing number of BC survivors, owing to improvements in cancer treatment and delaying of childbearing, fertility preservation appears to be an important issue. Current fertility preservation options in BC survivors range from well-established standard techniques to experimental or investigational interventions. Among the standard options, random-start ovarian stimulation protocol represents a new technique, which significantly decreases the total time of the in vitro fertilisation cycle. However, in patients with oestrogen-sensitive tumours, stimulation protocols using aromatase inhibitors are currently preferred over tamoxifen regimens. Cryopreservation of embryos and oocytes are nowadays deemed the most successful techniques for fertility preservation in BC patients. GnRH agonists during chemotherapy represent an experimental method for fertility preservation due to conflicting long-term outcome results regarding its safety and efficacy. Cryopreservation of ovarian tissue, in vitro maturation of immature oocytes and other strategies are considered experimental and should only be offered within the context of a clinical trial. An early pretreatment referral to reproductive endocrinologists and oncologists should be suggested to young BC women at risk of infertility, concerning the risks and benefits of fertility preservation options. Chinese abstract 本文旨在分析目前针对年轻乳腺癌患者生殖力保护的选择方法。由于癌症治疗技术的进步及延迟生育，越来越多的乳腺癌似乎应将其生殖力保护视为一项重要的问题。目前乳腺癌幸存者生殖力保护的选择范围囊括了完善的标准技术及实验性或临床性干预研究。标准方法中，随机启动卵巢刺激方案作为一项新技术可显著降低体外受精周期的总体时长。然而，目前对于雌激素敏感的肿瘤患者，使用芳香化酶抑制剂刺激方案优于接受他莫昔芬治疗。胚胎和卵母细胞冻存被认为是当今乳腺癌患者生殖力保护最成功的技术。由于应用GnRH激动剂的远期疗效尚存争议，且考虑其安全性和有效性，目前将化疗期间应用GnRH激动剂视为患者生殖力保护的实验性方法。卵巢组织冻存、卵母细胞体外成熟技术及其他技术都处于实验性阶段，且仅处于临床试验范围内。对于存在不孕不育风险的年轻乳腺癌患者，在权衡生殖力保护方法利弊后，应给予早期及时转至生殖内分泌专家和肿瘤学专家进行诊治。