Platinum-resistance in ovarian cancer cells is mediated by IL-6 secretion via the increased expression of its target cIAP-2

Ovarian carcinoma patients are initially responsive to platinum-based therapy, but eventually become refractory to treatment due to the development of platinum chemoresistance. Elevated levels of interleukin-6 (IL-6) in the sera and ascites of these patients predict poor clinical outcome. Our goal was to analyze the interaction between cisplatin and cisplatin-resistant ovarian cancer cells, and to identify means of circumventing platinum resistance. We studied ovarian carcinoma cell lines and cells drawn from ovarian carcinoma patients. Gene array analyses were performed on ovarian carcinoma cells upon treatment with cisplatin, and the results were validated by ELISA and Western blotting (WB). Cytotoxicity assays were performed on anti-IL-6 Ab-, IL-6-, and cellular inhibitor of apoptosis 2 (cIAP-2) siRNA-treated cells, following cisplatin addition. Our results revealed a highly significant increase in IL-6 and cIAP-2 mRNA and protein levels upon treatment with cisplatin. WB analysis of cisplatin-treated cells exhibited decreased cIAP-2 expression level following anti-IL-6 Ab addition. Furthermore, IL-6 by itself, significantly increased cIAP-2 levels in ovarian carcinoma cells. Finally, cytotoxicity assays showed sensitization to cisplatin following the addition of IL-6 and cIAP-2 inhibitors. In conclusion, cisplatin treatment of ovarian carcinoma cells upregulates IL-6 and cIAP-2 levels while their inhibition significantly sensitizes them to cisplatin. Here, we present cIAP-2 as a novel inducer of platinum resistance in ovarian carcinoma cells, and suggest an axis beginning with an encounter between cisplatin and these cells, mediated sequentially by IL-6 and cIAP-2, resulting in cisplatin resistance. Consequently, we propose that combining IL-6/cIAP-2 inhibitors with cisplatin will provide new hope for ovarian carcinoma patients by improving the current treatment.     

Patient-controlled epidural analgesia for labor pain: effect on labor, delivery and neonatal outcome of 0.125% bupivacaine vs 0.2% ropivacaine

The objective was to evaluate the influence of patient-controlled epidural analgesia (PCEA) using low doses of bupivacaine vs. ropivacaine, on labor pain, motor blockade, progression of labor, delivery and neonatal outcome. This randomized double blind study included 565 parturients. All received a 5-mL/h infusion and PCEA (5-mL boluses with a 20-min lockout, maximum volume 20 mL/h) of either 0.125% bupivacaine (n = 313: 165 nulliparous, 148 parous) or 0.2% ropivacaine (n = 252: 113 nulliparous, 139 parous). Pain score, lower limb motor block, sensory levels, local analgesic doses required, hemodynamic parameters, side effects and complications were assessed. Obstetric variables included cervical dilation at epidural insertion, incidence of ruptured membranes and their duration, use of oxytocin, fetal heart rate changes, duration of labor, mode and outcome of delivery, and use of invasive and non-invasive fetal monitoring. Neonatal characteristics included birth weight, Apgar scores, umbilical artery pH, serum bilirubin, hypoglycemia, need for assisted ventilation, sepsis or sepsis study, feeding difficulties and respiratory distress syndrome. Ropivacaine 0.2% was equianalgesic with 0.125% bupivacaine, but produced less motor block (P < 0.0001). There were no significant differences, however, in duration of labor, delivery type or neonatal outcome.     

Pulmonary complications following endotracheal intubation for anesthesia in breech extraction

A 28-year-old, healthy pregnant patient developed bilateral pneumothorax, subcutaneous emphysema, pneumomediastinum, pneumoretroperitoneum and pneumoperitoneum following endotracheal intubation and manual ventilation during general anesthesia for breech extraction. It is likely that positive-pressure ventilation was the cause for this very rare combination of complications. Early recognition and treatment may prevent such a catastrophe.     

Similar incidence of hypotension with combined spinal-epidural or epidural alone for knee arthroplasty

BACKGROUND: We hypothesized that the incidence of hypotension during total knee replacement (TKR) surgery is lower in patients given combined spinal-epidural (CSE) anesthesia vs those receiving epidural anesthesia alone. METHODS: In a prospective study, 80 American Society of Anesthesiologists I-II patients (aged 40-80 yr), undergoing elective TKR surgery were randomly assigned to either CSE anesthesia (CSE, n = 40) or epidural anesthesia alone (Epidural, n = 40). Hemodynamic measurements included oscillometric mean arterial blood pressure (MAP), heart rate (HR), and cardiac index (CI) as determined by thoracic bioimpedance; systemic vascular resistance (SVR) was calculated. Our primary endpoint (outcome) was the number of hypotension episodes (defined as MAP < 70 mmHg). RESULTS: Using univariate analysis, we found no differences between the groups in regards to MAP, HR, CI, or SVR during the perioperative period. The incidence of hypotension was similar in both groups (two patients in each group), as was the incidence of bradycardia (12 patients in CSE, 7 in Epidural; P = 0.2). There were no differences between groups in other hemodynamic measurements including CI and calculated SVR. Analgesia supplementation with fentanyl was more frequently required in the Epidural group (20 vs 6 patients - P = 0.03). CONCLUSION: Combined spinal-epidural anesthesia and epidural anesthesia alone during TKR surgery are associated with the same incidence of hypotension with statistically and clinically similar hemodynamic responses.     

Recurrent molar pregnancies associated with clomiphene citrate and human gonadotropins

A 34-year-old patient, gravida 7, para 0, with three consecutive spontaneous abortions followed by four recurrent molar pregnancies is described. The patient conceived only with clomiphene citrate or human gonadotropin treatment. The occurrence of molar pregnancies succeeded spontaneous abortions with one remaining pregnancy progressing to gestational trophoblastic disease. The role of clomiphene citrate and human gonadotropins in the pathogenesis of this disease is discussed.     

Activity of compound G2 isolated from alfalfa roots in experimental dermatophyte infection.

Compound G2 isolated from alfalfa roots was applied topically to skin lesions of guinea pigs experimentally infected with the dermatophyte Trichophyton mentagrophytes var. granulare. After 12 to 15 applications, 80% of the infected lesions were cured, as judged by clinical and microbial criteria, compared with 20% of the untreated lesions which healed spontaneously (P less than 0.01).     

Improved regional left ventricular function after successful satellite cell grafting in rabbits with myocardial infarction

OBJECTIVE: To evaluate whether satellite cells injected into infarct areas in rabbits remain viable during 6 weeks follow-up and can improve cardiac function as assessed by echocardiography. METHODS: Myocardial infarction was induced in 16 New Zealand white rabbits, by ligation of the marginalis sinistra artery. Tissue from gluteus muscle biopsies was dissected into small pieces and cultured. Within 2-3 weeks the cells were expanded by 2-3 orders of magnitude and were fluorescent labeled. Single cell pellets for resuspension at >10(6)/1 ml were directly injected into the infarct areas in 8 rabbits. In 8 additional rabbits, 1 ml saline was injected (control). Regional left ventricular function was assessed weekly by 2-D echocardiography until animals were sacrificed. Analysis was performed blind and independently by two experienced echocardiographers, based on the American Society of Echocardiography scheme. RESULTS AND DISCUSSION: Six treated and five control rabbits completed the study. One week after the artery occlusion, left ventricular function scoring did not differ between groups, mean 8.7+/-1.6 vs 8.3+/-1.9 (P=0.74). At 6 weeks post-injection, echocardiographic score was significantly better in the treated group, mean 2.6+/-0.9 vs 6.9+/-2.1 (P=0.002). The treated group showed significant gradual segmental improvement between the first week up to week 6. After sacrifice, macro and microscopic transmural areas showed typical changes of myocardial infarction. Histochemical staining identified viable grafted cells in high density 6 weeks post-transplantation in all grafted hearts. CONCLUSION: Autologous satellite cells (skeletal myofiber), can be successfully grafted into rabbit hearts following myocardial infarction and may induce improved regional left ventricular function.     

Preserving fertility when choosing chemotherapy regimens – the role of gonadotropin-releasing hormone agonists

Introduction: The late effects of cancer treatment have recently gained a worldwide ubiquitous interest among reproductive endocrinologists, oncologists, and all health care providers. Despite many publications on this subject, there are many equivocal issues necessitating summary. The case for and against using GnRH-agonist for fertility preservation is summarized with the rationale that preventing ovarian failure may be better than treating it.

Areas covered: We searched Medline in the last 10 years using terms: ‘fertility preservation’, ‘female chemotherapy’, ‘Gonadotropin-releasing hormone (GnRH) analogues’, ‘GnRH agonists’ ‘gonadotoxicity’, and ‘cancer treatment’. We included mainly publications from the past 7 years, but did not exclude previous, commonly referenced publications. Here, we summarize the various methods available for fertility preservation and minimizing chemotherapy induced gonadotoxicity.

Expert opinion: Until now, 20 studies (15 retrospective and 5 randomized controlled trial) have reported on 2038 patients treated with GnRH-a in parallel to chemotherapy, showing a significant decrease in premature ovarian failure (POF) rate in survivors versus 8 studies reporting on 509 patients, with negative results. Patients treated with GnRH-a in parallel to chemotherapy preserved their cyclic ovarian function in 91% of cases as compared to 41% of controls, with a pregnancy rate of 19 – 71% in the treated patients. Furthermore, over 10 recent meta-analyses have concluded that GnRH-a are beneficial and may decrease the risk of POF in survivors. Because most of the methods involving ovarian or egg cryopreservation are not yet clinically established and unequivocally successful, these young patients deserve to be informed with all the various modalities to minimize gonadal damage and preserve ovarian function and future fertility. Combining the various modalities for a specific patient may increase the odds of preservation of future fertility.