A double-blind, randomised, parallel group, multinational, multicentre study comparing a single dose of ondansetron 24 mg p.o. with placebo and metoclopramide 10 mg t.d.s. p.o. in the treatment of opioid-induced nausea and emesis in cancer patients

Nausea and emesis are common side effects of opioid drugs administered for pain relief in cancer patients. The aim of this study was to compare the anti-emetic efficacy and safety of ondansetron, placebo and metoclopramide in the treatment of opioid-induced nausea and emesis (OIE) in cancer patients. This was a multinational, multicentre, double-blind, parallel group study in which cancer patients who were receiving a full opioid agonist for cancer pain were randomised to receive one of oral ondansetron 24 mg once daily, metoclopramide 10 mg three times daily, or placebo. Study medication was started only if the patient experienced nausea and/or emesis following opioid administration. Efficacy and safety assessments were made over a study period of 24 h from the time of the first dose of anti-emetics/placebo. The study was terminated prematurely because of the difficulties in recruiting patients satisfying the stringent entry criteria. Ninety-two patients were included in the intent-to-treat population: 30 patients received placebo, 29 patients ondansetron and 33 patients metoclopramide. There was no statistically significant difference between the groups in the proportion achieving complete control of emesis (33% of patients on placebo, 48% on ondansetron and 52% on metoclopramide) or complete control of nausea (23% of patients on placebo, 17% on ondansetron and 36% on metoclopramide). Rescue anti-emetics were required in 8 of 33 patients on metoclopramide, 4 of 29 on ondansetron, and 3 of 30 on placebo. The incidence of adverse events was very low and similar in all treatment groups. Neither ondansetron 24 mg once daily nor metoclopromide 10 mg t.d.s. given orally was significantly more effective than placebo in the control of OIE in cancer patients.     

Bone marrow microvascular density and angiogenic growth factors in multiple myeloma.

There is evidence that angiogenesis plays an important role in the progression of multiple myeloma (MM). Hepatocyte growth factor (HGF) and tumor necrosis factor-alpha (TNF-alpha) are cytokines that potently stimulate angiogenesis. We evaluated the microvascular density (MVD) of bone marrow biopsies (after immunostaining with anti-CD34 antibodies) and serum levels of HGF and TNF-alpha in 43 patients with newly diagnosed MM. Twenty-four of these patients reached a plateau phase after treatment and were reevaluated for MVD, HGF and TNF-alpha. MVD values and serum levels of HGF and TNF-alpha were elevated in newly diagnosed MM patients in comparison with healthy controls. Pre-treatment MVD, HGF and TNF-alpha increased with advancing stage of MM disease. In patients reaching the plateau phase, a significant reduction in MVD, HGF and TNF-alpha levels occurred. A positive correlation was noted between pre-treatment MVD and serum levels of TNF-alpha and lactic dehydrogenase but not with HGF. However, HGF strongly correlated with beta2-microglobulin (beta2M), TNF-alpha and lactate dehydrogenase (LDH). We conclude that angiogenesis in MM, as expressed by the bone marrow MVD and the serum levels of angiogenic molecules such as HGF and TNF-alpha, increases with advancing clinical stage and decreases after effective chemotherapy.     

Gender Differences in the Clinical Characteristics and Atrioventricular Nodal Conduction Properties in Patients With Atrioventricular Nodal Reentrant Tachycardia

Gender Differences in Patients With AVNRT. Introduction: The detailed electrophysiological characteristics of the gender differences associated with atrioventricular nodal reentrant tachycardia (AVNRT) have not been clarified. This study investigated the gender‐related electrophysiological differences in a large series of patients undergoing radiofrequency catheter ablation. Methods and Results: A total of 2,088 consecutive AVNRT patients (men/women 869/1,219) who underwent catheter ablation were enrolled in this study. We evaluated the gender differences in their electrophysiological characteristics. Women had a significantly younger age of onset, higher incidence of multiple jumps, shorter AH interval, atrial effective refractory period (ERP), anterograde fast pathway ERP, anterograde slow pathway ERP, and retrograde slow pathway ERP, and longer ventricular ERP than men. The incidence of baseline ventriculoatrial dissociation was lower in women than in men. Women needed less isoproterenol/atropine to induce AVNRT. No gender differences in the radiation exposure time, procedure time, complication rate, acute success rate, or second procedure rate were noted. Both typical and atypical AVNRT were more predominant in women. In the patients with atypical AVNRT, there was no significant gender difference in incidence of baseline ventriculoatrial dissociation; however, the retrograde slow pathway ERP was significantly shorter in women than in men. Women of premenopausal age (≤50 years old) had a significantly higher incidence of anterograde multiple jumps and a retrograde jump phenomenon, and a shorter anterograde slow pathway ERP and retrograde slow pathway ERP than those of women over 50 years old. Conclusion: Gender differences in the anterograde and retrograde AV nodal electrophysiology were noted in the patients with AVNRT. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1114‐1119)     

Overexpression of mouse IsK protein fused to green fluorescent protein induces apoptosis of human astroglioma cells

Intracellular K(+) plays an important role in controlling ion homeostasis for maintaining cell volume and inhibiting activity of pro-apoptotic enzymes. Cytoplasmic K(+) concentration is regulated by K(+) uptake via Na(+) -K(+) -ATPase and K(+) efflux through K(+) channels in the plasma membrane. The IsK (KCNE1) protein is known to co-assemble with KCNQ1 (KvLQT1) protein to form a K(+) channel underlying the slowly activating delayed rectifier K(+) outward current which delays voltage activation. In order to further study the activity and cellular localization of IsK protein, we constructed a C-terminal fusion of IsK with EGFP (enhanced green fluorescent protein). Expression of the fusion protein appeared as clusters located in the plasma membrane and induced degeneration of both transiently or stably transfected cells.     

Epithelial NF-kappaB activation promotes urethane-induced lung carcinogenesis

Chronic inflammation is linked to carcinogenesis in several organ systems. In the lungs, NF-kappaB, a central effector of inflammatory responses, is frequently activated in non-small-cell lung cancer, but its role in tumor promotion has not been studied. Several lines of evidence indicate that ethyl carbamate (urethane)-induced lung tumor formation, a prototypical mouse model of multistage lung carcinogenesis, is potentiated by inflammation. We found that mouse strains susceptible to lung tumor formation (FVB, BALB/c) exhibited early NF-kappaB activation and inflammation in the lungs after urethane treatment. However, a resistant strain (C57B6) failed to activate NF-kappaB or induce lung inflammation. In FVB mice, we identified urethane-induced NF-kappaB activation in airway epithelium, as well as type II alveolar epithelial cells and macrophages. Using an inducible transgenic mouse model (FVB strain) to express a dominant inhibitor of NF-kappaB specifically in airway epithelial cells, we found that urethane-induced lung inflammation was blocked and tumor formation was reduced by >50%. Selective NF-kappaB inhibition resulted in increased apoptosis of airway epithelial cells at 2 weeks after urethane treatment in association with a marked reduction of Bcl-2 expression. These studies indicate that NF-kappaB signaling in airway epithelium is integral to tumorigenesis in the urethane model and identify the NF-kappaB pathway as a potential target for chemoprevention of lung cancer.     

From the Cover: Peptide antagonism as a mechanism for NK cell activation

Inhibition of natural killer (NK) cells is mediated by MHC class I receptors including the killer cell Ig-like receptor (KIR). We demonstrate that HLA-C binding peptides can function as altered peptide ligands for KIR and antagonize the inhibition mediated by KIR2DL2/KIR2DL3. Antagonistic peptides promote clustering of KIR at the interface of effector and target cells, but do not result in inhibition of NK cells. Our data show that, as for T cells, small changes in the peptide content of MHC class I can regulate NK cell activity.     

内毒素耐受THP-1细胞中糖皮质激素受体-α在炎症反应中的作用

目的:应用脂多糖(Lipopolysaccharide,LPS)刺激人单核细胞白血病细胞系THP-1细胞,模拟体外脓毒症模型,了解单核细胞系统在产生内毒素耐受时,糖皮质激素受体-α(Glucocorticoid receptor-α,GR-α)在转录水平上的表达。方法:用无血清培养基培养人THP-1细胞,将细胞随机分为4组(A、B、C、D),分别用不同浓度LPS刺激THP-1细胞24 h后,再改变LPS浓度刺激上述各组细胞24 h,分别提取RNA和蛋白质,以逆转录聚合酶链反应(RT-PCR)检测GR-α的mRNA表达,用西部印迹法(Western Blotting)检测NF-κB蛋白质表达,以酶联免疫吸附试验(ELISA)检测培养液中肿瘤坏死因子-α(TNF-α),白细胞介素1β(IL-1β),白细胞介素10(IL-10)水平。结果:A、B、C、D组GR-αmRNA与-βactin比值,NF-κB蛋白与GAPDH比值差异有统计学意义(P<0.01),在受到LPS刺激时,GR-αmRNA与NF-κB蛋白的表达负相关(r=0.816,P<0.01)。结论:内毒素耐受的THP-1细胞GR-α表达上调,这可能在THP-1细胞的内毒素耐受时炎症反应的发生起到重要作用。     

Weekly administration of topotecan–paclitaxel as second-line treatment in ovarian cancer

Purpose To investigate the weekly administration of topotecan combined with paclitaxel in pretreated advanced ovarian cancer patients; our objectives were to determine efficacy, toxicity and survival Methods The chemotherapy agents, topotecan and paclitaxel were administered on a weekly basis for 3 consecutive weeks, every 28 days. The plan was to give three courses (each course included three once-weekly infusions). The dose of topotecan was 1.75 mg/m² and of paclitaxel 70 mg/m². Results From January 2004 until January 2006, 45 patients were enrolled in this multicenter trial; 44 patients were evaluable for response and toxicity. The median age was 60 years old (range 39–82 years) and performance status was 0–2. Thirty-nine patients were in stage III and 5 in stage IV. All patients had been pretreated with carboplatin or cisplatin in combination with paclitaxel. Complete and partial responses were seen in 39% of the patients, stable disease in 43% and progressive disease in 18%; median survival time was 9 months, range 2–24+ months, (95% CI: 7.9–10.2). There was a notable absence of grade 3 toxicity except for neutropenia in 11% of the patients. Conclusion The combination of topotecan and paclitaxel administered on a weekly basis is a well-tolerated chemotherapy schedule. The response rate of 39% is quite high for patients with pretreated ovarian cancer.     

Bacterial colonization of chronic leg ulcers: current results compared with data 5 years ago in a specialized dermatology department

Background In nearly every chronic wound different bacteria species can be detected. Nevertheless, the presence of such microorganisms is not necessarily obligatory associated with a delayed wound healing. But from this initially unproblematic colonization an infection up to a sepsis can arise in some patients. The aim of our clinical investigation was to analyse the spectrum of microbial colonization of patients with a chronic leg ulcer in our specialized dermatological outpatient wound clinic, and to compare them with the results of comparable data already collected 5 years ago. Objectives In our retrospective investigation the results of bacteriological swabs were documented in 100 patients with a total of 107 chronic leg ulcers. All patients visited the specialized wound outpatient clinic, Department of Dermatology, University of Essen in Germany. Methods A total of 60 patients were female, 40 were male. The mean age was 65 years. Altogether a total of 191 bacterial isolates and 25 different bacterial species could be identified. Results The most often detected species were Staphylococcus aureus (n = 60), Pseudomonas aeruginosa (n = 36) as well as Proteus mirabilis (n = 17). In 10 patients (10%) we identified a colonization with methicillin resistant S. aureus (MRSA). Merely in 6 patients the taken swabs were sterile. Five years ago a comparable investigation was already carried out in our wound outpatient clinic. At that time we could detect in particular more frequent MRSA (21.5% vs. 10%) and rarely P. aeruginosa (24.1% vs. 33.6%). Conclusion The results of our investigation demonstrate the current spectrum of the bacterial colonization in patients with chronic leg ulcers in a university dermatological wound centre in comparison to the last 5 years. In our institution we were able to demonstrate a shift of the detected bacterial species from gram‐positive in direction to gram‐negative germs. Beside the already known problems with MRSA, in future therapeutic strategies in patients with chronic leg ulcers the increasing amount of gram‐negative bacteria and especially of P. aeruginosa should considered.     

Translational screening platform to evaluate chemotherapy in combination with focal therapy for retinoblastoma

Retinoblastoma is the most common pediatric eye cancer. It is currently treated with a limited number of drugs, adapted from other pediatric cancer treatments. Drug toxicity and relapse of the disease warrant new therapeutic strategies for these young patients. In this study, we developed a robust tumoroid-based platform to test chemotherapeutic agents in combination with focal therapy (thermotherapy) – a treatment option widely used in clinical practice – in accordance with clinically relevant trial protocols. The model consists of matrix-embedded tumoroids that retain retinoblastoma features and respond to repeated chemotherapeutic drug exposure similarly to advanced clinical cases. Moreover, the screening platform includes a diode laser (810 nm, 0.3 W) to selectively heat the tumoroids, combined with an on-line system to monitor the intratumoral and surrounding temperatures. This allows the reproduction of the clinical settings of thermotherapy and combined chemothermotherapy treatments. When testing the two main drugs currently used in clinics to treat retinoblastoma in our model, we observed results similar to those clinically obtained, validating the utility of the model. This screening platform is the first system to accurately reproduce clinically relevant treatment methods and should lead to the identification of more efficient drugs to treat retinoblastoma.