[Comparative evaluation of vertigo in patients after stapedotomy and stapedectomy]. / Posztoperatív vertigo vizsgálata stapedotomián és stapedectomián átesett betegeknél.

INTRODUCTION AND AIM: The reason of gradually developing conductive hearing loss in otosclerotic patients is the ossification of the stapes footplate to the surrounding bony structures and the therapy of stapes fixation is mainly surgical. In stapedotomy the footplate of the stapes is fenestrated with laser and microdrill in a diameter of 0.8 mm, whereas in stapedectomy there is complete removal of the footplate followed by the reconstruction of the ossicular chain. In the early postoperative period, temporary vertigo is frequently recorded which significantly influences the recovery. METHOD: In the Department of Otorhinolaryngology, University of Pécs both stapedectomy and stapedotomy were performed on a daily basis between 01.02.2010 and 15.03.2012. Our study focused on comparing the degree of postoperative vertigo after the two types of surgery. We hypothesized that the smaller fenestration of the stapes footplate during stapedotomy limits exposure to the inner ear reducing the severity of dizziness. Vertigo was evaluated subjectively with a retrospective questionnaire and objectively with static posturography. RESULTS: On the 1st postoperative day, significantly fewer patients reported vertigo in the stapedotomy group and with significantly lower intensity. Results of the questionnaire regarding the later postoperative period showed no significant differences between the groups. Based on the analysis of the posturography test results, no significant difference was detected between the postoperative stability of the two groups. Results of the questionnaire and the posturography showed no correlation. Posturography test results did not confirm the presence of subjective vertigo. CONCLUSION: Many factors may play a role in the development of vertigo after stapes surgery, but the type of intervention does not influence it. Orv Hetil. 2017; 158(38): 1503-1511.

The combination of trastuzumab and pertuzumab administered at approved doses may delay development of trastuzumab resistance by additively enhancing antibody-dependent cell-mediated cytotoxicity.

Although the recently concluded CLEOPATRA trial showed clinical benefits of combining trastuzumab and pertuzumab for treating HER2-positive metastatic breast cancer, trastuzumab monotherapy is still the mainstay in adjuvant settings. Since trastuzumab resistance occurs in over half of these cancers, we examined the mechanisms by which treatment of intrinsically trastuzumab-resistant and -sensitive tumors can benefit from the combination of these antibodies. F(ab')2 of both trastuzumab and pertuzumab were generated and validated in order to separately analyze antibody-dependent cell-mediated cytotoxicity (ADCC)-based and direct biological effects of the antibodies. Compared to monotherapy, combination of the two antibodies at clinically permitted doses enhanced the recruitment of natural killer cells responsible for ADCC, and significantly delayed the outgrowth of xenografts from intrinsically trastuzumab-resistant JIMT-1 cells. Antibody dose-response curves of in vitro ADCC showed that antibody-mediated killing can be saturated, and the two antibodies exert an additive effect at sub-saturation doses. Thus, the additive effect in vivo indicates that therapeutic tissue levels likely do not saturate ADCC. Additionally, isobole studies with the in vitro trastuzumab-sensitive BT-474 cells showed that the direct biological effect of combined treatment is additive, and surpasses the maximum effect of either monotherapy. Our results suggest the combined therapy is expected to give results that are superior to monotherapy, whatever the type of HER2-positive tumor may be. The combination of both antibodies at maximum clinically approved doses should thus be administered to patients to recruit maximum ADCC and cause maximum direct biological growth inhibition.

V-ATPase inhibition overcomes trastuzumab resistance in breast cancer.

The HER2 oncogene targeting drug trastuzumab shows remarkable efficacy in patients overexpressing HER2. However acquired or primary resistance develops in most of the treated patients why alternative treatment strategies are strongly needed. As endosomal sorting and recycling are crucial steps for HER2 activity and the vacuolar H⁺-ATPase (V-ATPase) is an important regulator of endocytotic trafficking, we proposed that targeting V-ATPase opens a new therapeutic strategy against trastuzumab-resistant tumor cells in vitro and in vivo. V-ATPase inhibition with archazolid, a novel inhibitor of myxobacterial origin, results in growth inhibition, apoptosis and impaired HER2 pro-survival signaling of the trastuzumab-resistant cell line JIMT-1. This is accompanied by a decreased expression on the plasma membrane and accumulation of HER2 in the cytosol, where it colocalizes with endosomes, lysosomes and autophagosomes. Importantly, microscopic analysis of JIMT-1 xenograft tumor tissue of archazolid treated mice confirms the defect in HER2-recycling which leads to reduced tumor growth. These results suggest that V-ATPase inhibition by archazolid induces apoptosis and inhibits growth of trastuzumab-resistant tumor cells by retaining HER2 in dysfunctional vesicles of the recycling pathway and consequently abrogates HER2-signaling in vitro as well as in vivo. V-ATPase inhibition is thus suggested as a promising strategy for treatment of trastuzumab-resistant tumors.

The real face of juvenile polyposis syndrome.

Colorectal cancers are mostly sporadic; some cases of familial clustering and autosomal dominant conditions are also known to occur. Juvenile polyposis syndrome (JPS) is an autosomal dominant condition caused by the mutation of the SMAD4 or the BMPR1A genes. JPS is characterized by hamartomatous polyps developing in the upper and lower intestine. Contradicting previous studies, many of these polyps can go through malignant transformation.This paper reports the case of a male patient who was continuously treated for juvenile polyposis. During the eighteen years of treatment, more than hundred polyps were endoscopically removed from his gastrointestinal tract. The patient's care was interrupted for eight years due to insufficient compliance. He was subsequently referred to our Department of Gastroenterology in severe clinical condition caused by metastatic colorectal cancer. He died after a short palliative therapy at the age of 31. His first-degree accessible relatives were further examined for juvenile polyposis syndrome. Several gastrointestinal polyps of different histological origin were observed in the deceased patient's brother, who subsequently had to undergo a left lateral hemicolectomy. Genetic analyses revealed mutations of the BMPR1A gene in the clinically affected brother, the brother's daughter, and in the deceased proband's daughter.Indebt genetic analyses helped customize and deliver care to a very specific group of individuals. We were able to identify potential family members on whom preventive care and treatment could be focused and simultaneously prevented unnecessary clinical and invasive procedures on those who were healthy. Furthermore, these analyses helped prevent future unnecessary trauma or distress on the analyzed family.

Fontolizumab in moderate to severe Crohn's disease: a phase 2, randomized, double-blind, placebo-controlled, multiple-dose study.

BACKGROUND: The safety and efficacy of fontolizumab, a humanized anti-interferon gamma antibody, was investigated in patients with Crohn's disease (CD). Elevated gut mucosal levels of interferon gamma, a key cytokine involved in the inflammatory process of CD, are associated with disease symptoms. METHODS: A total of 201 patients with Crohn's Disease Activity Index (CDAI) scores between 250 and 450 were randomized to receive an initial intravenous dose of 1.0 or 4.0 mg/kg fontolizumab or placebo, followed by up to 3 subcutaneous doses of 0.1 or 1.0 mg/kg fontolizumab or placebo every 4 weeks. Clinical response at day 29, the primary efficacy endpoint, was defined as a decrease in the CDAI of at least 100 points from baseline levels. RESULTS: Of 201 patients, 135 (67%) completed the study. Day 29 response rates were similar in all treatment groups (31%-38%). At subsequent timepoints a significantly greater proportion of patients in the 1.0 mg/kg intravenous / 1.0 mg/kg subcutaneous fontolizumab group had clinical response and significantly greater improvement in the CDAI score compared with patients who received placebo. All fontolizumab groups had significant improvement in C-reactive protein levels. The overall frequency of adverse events was similar in all groups (58%-75%); most events were related to exacerbation of CD. There was a low frequency (5.2%) of neutralizing antibodies to fontolizumab. CONCLUSIONS: Although a strong clinical response to fontolizumab was not observed, significant decreases in C-reactive protein levels suggest a biological effect. Fontolizumab was well tolerated, and further studies to assess its efficacy are warranted.

Efficacy and safety of infliximab induction therapy in Crohn's Disease in Central Europe--a Hungarian nationwide observational study.

BACKGROUND: Infliximab (IFX) has proven to be an effective addition to the therapeutic arsenal for refractory, fistulizing, and steroid dependent Crohn's disease (CD), with efficacy in the induction and maintenance of clinical remission of CD. Our objective in this study is to report the nationwide, multicenter experience with IFX induction therapy for CD in Hungary. METHODS: During a 6-year-period, beginning in 2000, a total of 363 CD patients were treated with IFX as induction therapy (5 mg/kg IFX infusions given at week 0, 2 and 6) at eleven centers in Hungary in this observational study. Data analysis included patient demographics, important disease parameters and the outcome of IFX induction therapy. RESULTS: Three hundred and sixty three patients (183 women and 180 men) were treated with IFX since 2000. Mean age was 33.5 +/- 11.2 years and the mean duration of disease was 6.7 +/- 6.1 years. The population included 114 patients (31.4%) with therapy-refractory CD, 195 patients (53.7%) with fistulas, 16 patients (4.4%) with both therapy-refractory CD and fistulas, and 26 patients (7.2%) with steroid dependent CD. Overall response rate was 86.2% (313/363). A higher response rate was observed in patients with shorter disease duration (p = 0.05, OR:0.54, 95%CI:0.29-0.99) and concomitant immunosuppressant therapy (p = 0.05, OR: 2.03, 95%CI:0.165-0.596). Concomitant steroid treatment did not enhance the efficacy of IFX induction therapy. Adverse events included 34 allergic reactions (9.4%), 17 delayed type hypersensitivity (4.7%), 16 infections (4.4%), and 3 malignancies (0.8%). CONCLUSION: IFX was safe and effective treatment in this cohort of Hungarian CD patients. Based on our experience co-administration of immunosuppressant therapy is suggested in patients receiving IFX induction therapy. However, concomitant steroid treatment did not enhanced the efficacy of IFX induction therapy.

(-)Deprenyl-N-oxide, a (-)deprenyl metabolite, is cytoprotective after hypoxic injury in PC12 cells, or after transient brain ischemia in gerbils.

BACKGROUND AND AIMS: (-)-Deprenyl (selegiline) possesses cyto-protective effect in a much lower concentration, than it is needed to inhibit MAO-B activity. In permanent MCA occlusion stroke model in rats, the infarct volume and the number of apoptotic neurons in the penumbra region were decreased by low concentration (-)deprenyl treatment. Augmented Bcl-2 protein expression was documented as the responsible factor of this effect. The stabilization of mitochondrial membrane and diminished ROS production are the further possible consequences of (-)deprenyl treatment. It is not clear however that (-)deprenyl, or its metabolites are the acting neuroprotective molecules in the hypoxic/ischemic conditions. We report here the possible cyto-protective effect of deprenyl-N-oxide (DNO), a recently synthesized (-)deprenyl metabolite. METHODS: DNO in a very low dose (10(-5,-8,-12) M) was tested in PC12 cell culture after hypoxia and in gerbils after transient occlusion of bilateral common carotid artery. In PC12 culture the cell death was visualized by PI staining. The level of reactive oxygen species was measured by the Cerium method, and the mitochondrial membrane integrity was labeled by JC1 staining. Apoptotic neurons were counted on formaldehyde fixed gerbil brain slices after TUNEL and caspase-3 immune-staining - NIKON/BIORAD confocal microscopy was used for the quantitative analysis. RESULTS: DNO treatment significantly decreased the frequency of cell death in PC12 cultures after hypoxia, increased the mitochondrial transmembrane potential (DeltaY(m)) and decreased the ROS production. In the CA2 regions of gerbil hippocampus, we found significantly less apoptotic neurons than in the untreated controls. CONCLUSION: Transient hypoxia or ischemia induced cell damage could be diminished by DNO. This (-)deprenyl metabolite is an active cell protective molecule.

A family with two consecutive nonsense mutations in BMPR1A causing juvenile polyposis.

We describe a novel germline mutation of BMPR1A in a family with juvenile polyposis and colon cancer. This mutation consists of two consecutive substitutions (735-6 TG>AT) that cause two nonsense mutations (Y245X, G246X), inherited in an autosomal dominant fashion, on one parental chromosome. This mutation caused protein truncation, and represents a novel case of consecutive nonsense mutations in human disease.

Visualization of mitochondrial membrane potential and reactive oxygen species via double staining.

Quantitative and qualitative analysis of both generated reactive oxygen species (ROS) and mitochondrial membrane potential cannot be detected simultaneously. We here introduce a simple, new double staining method. We have successfully used this for several years utilizing cerium for ROS detection and JC-1 staining to assess the mitochondrial membrane potential. The resultant signals on laser confocal images can be localized in the same cells and can easily quantify them. We used a confocal microscope along with our new, combined staining method to both visualize mitochondrial membrane potential (DeltaPsim) and imaged ROS. These were quantified by JC-1 staining and by cerium ions with reflectance in a method modified in our laboratory. To test this double labeling technique we used PC 12 cells subjected to 1 h hypoxia and 24h re-oxygenization. We are able to produce a quantitative analysis of red/green signals of JC-1 that reflected the energy state of the cells. Cerium reflectance correlates with the amount of ROS release in the same cells. Significant differences have been calculated after hypoxia and re-oxygenation in both modality of the cell staining. The red/green ratio was 18.2+/-9.3 (n=30) in normoxic cells versus 1.65+/-0.9 (n=30) in the hypoxia/re-oxygenation group (p<0.05). In the same randomly selected cells the average cerium reflectance signal intensity was 2.5+/-1.2 (n=30) in the control group while 5.8+/-3.1 (n=30) in the hypoxia/re-oxygenation group (p<0.05). This assay, by characterizing hypoxic injury and re-oxygenization induced ROS production, offers a qualitative and quantitative method to detect the consequences of oxidative stress in experimental conditions and to detect different cell protective strategies.

[Bilateral cancer of the male breast--a case report]. / Kétoldali férfi emlorák--esetismertetés.

Authors give account of a rare diagnosis in connection with their male patient treated with breast cancer. They review about their case, than look over the risk factors and treatment of male breast cancer. Authors underline the importance of examinations, and the possibility of the rare diagnoses.