The Safety of Local Hormonal Treatment for Vulvovaginal Atrophy in Women With Estrogen Receptor-positive Breast Cancer Who Are on Adjuvant Aromatase Inhibitor Therapy: Meta-analysis.

Atrophic vaginitis is a relatively common adverse effect of aromatase inhibitors used as an adjunctive treatment for breast cancer. Vaginal estrogen therapy is a treatment option, but the safety of its use in estrogen receptor-positive breast cancer remains understudied. The aim of our study was to determine the safety of local hormonal treatment of vulvovaginal atrophy in women treated with aromatase inhibitors. Our meta-analysis was based on a systematic search of the literature and selection of high-quality evidence. The safety of local hormonal therapy of vaginal atrophy in women on aromatase inhibitors were summarized using calculators built by the authors; heterogeneity was assessed by the Cochrane Q test and I2 values. Several types of bias were assessed; publication bias was calculated by a funnel plot and the Egger regression. Eleven studies fulfilled the inclusion criteria for our study. After 8 weeks of local hormonal treatment, there was no change in the serum levels of luteinizing hormone and estradiol, whereas sex hormone binding globulins were low, and follicle stimulating hormone was almost doubled compared with the baseline. Adverse effect rates of vaginal discharge, facial hair growth, urinary tract or yeast infection, and vaginal or vulvar itching and/or irritation did not show significant changes in the sensitivity analysis, with exception of a single trial. Current evidence suggests that vaginal estrogen administration in postmenopausal women with a history of breast cancer is not associated with systemic absorption of sex hormones and may provide indirect evidence for the safety of their use.

Relationship between socio-demographic characteristics and vocal fold nodules, polyps and oedema.

The aim of our study was to compare socio-demographic characteristics of vocal fold nodules, polyps and oedema. The study included patients diagnosed for the first time with vocal fold nodules, polyps and oedema at the Communication Disorders Care Center of Clinic for Otorhinolaryngology and Maxillofacial Surgery in Clinical Center of Serbia, Belgrade. Diagnosis was made on the basis of symptoms, clinical otorhinolaryngological and phoniatric examination and endovideolaryngostroboscopic findings. A self-administered questionnaire was used to collect the following data: socio-demographic status, exposure to occupational noise and air pollution, occupational voice demands, health habits, symptoms of the present voice problems and voice problems in the family. By multivariate logistic regression analyses, nodules and oedema were more frequent in women than men in comparison with polyps (p < 0.001). Patients with nodules and polyps were younger than those with oedema (p < 0.001). Patients with nodules were more frequently lecturers, singers and actors compared with polyp patients (p = 0.006), had occupational voice demands more frequently than patients with oedema (p = 0.037) and were less frequently smokers than patients with polyps (p = 0.043) and those with oedema (p < 0.001). Patients with oedema were more frequently current smokers than patients with nodules and those with polyps (p < 0.001). Hoarseness as the main symptom was more frequent among patients with nodules than among patients with polyps (p = 0.040) and those with oedema (p = 0.001).Voice problems in the family was more frequently reported by oedema patients than by patients with polyps (p = 0.005). These findings are in agreement with majority of previous studies and may be of help in investigations on the aetiology of the disease.

Effects of different preprocessing algorithms on the prognostic value of breast tumour microscopic images.

The purpose of this study was to improve the prognostic value of tumour histopathology image analysis methodology by image preprocessing. Key image qualities were modified including contrast, sharpness and brightness. The texture information was subsequently extracted from images of haematoxylin/eosin-stained tumour tissue sections by GLCM, monofractal and multifractal algorithms without any analytical limitation to predefined structures. Images were derived from patient groups with invasive breast carcinoma (BC, 93 patients) and inflammatory breast carcinoma (IBC, 51 patients). The prognostic performance was indeed significantly enhanced by preprocessing with the average AUCs of individual texture features improving from 0.68 ± 0.05 for original to 0.78 ± 0.01 for preprocessed images in the BC group and 0.75 ± 0.01 to 0.80 ± 0.02 in the IBC group. Image preprocessing also improved the prognostic independence of texture features as indicated by multivariate analysis. Surprisingly, the tonal histogram compression by the nonnormalisation preprocessing has prognostically outperformed the tested contrast normalisation algorithms. Generally, features without prognostic value showed higher susceptibility to prognostic enhancement by preprocessing whereas IDM texture feature was exceptionally susceptible. The obtained results are suggestive of the existence of distinct texture prognostic clues in the two examined types of breast cancer. The obtained enhancement of prognostic performance is essential for the anticipated clinical use of this method as a simple and cost-effective prognosticator of cancer outcome.

Translation of the Medical Fear Survey to Serbian: psychometric properties.

BACKGROUND: Medical Fear Survey (MFS) is an instrument designed for measuring fear of medical and related treatments. OBJECTIVE: Aim of the present study was MFS translation into Serbian, measurement of its psychometric properties and MFS validation using other Blood-injury-injections and related stimuli instruments that have been translated from English into Serbian. METHOD: After obtaining permission from the author of the original MFS, double forward translation from English to Serbian and backward translation to English were conducted in ten steps, according to International Society for Pharmacoeconomics and Outcomes Research (ISPOR) guidelines. Reliability, factorial analysis and concurrent validation of Serbian version of MFS were conducted on a sample of 485 medical or pharmacy students at University of Kragujevac, Serbia. RESULTS: Serbian version of MFS showed high internal consistency with a Cronbach's alpha 0.968 and good temporal stability after testing-and-retesting (Spearman's correlation coefficient 0.838, and intraclass correlation coefficient 0.877). Factorial analysis confirmed the same five factors demonstrated in the original English version: fear of mutilated bodies (10 items), fear of blood (11 items), fear of injections and blood draws (9 items), fear of sharp objects (10 items), and fear of medical examinations and physical symptoms (10 items). The total score of MFS correlated significantly with the total scores of Injection Phobia Scale-Anxiety (Spearman's correlation coefficient 0.391, p <0.001), Blood/Injection Fear Scale (Spearman's correlation coefficient 0.502, p <0.001) and Medical Avoidance Survey (Spearman's correlation coefficient 0.396, p <0.001). CONCLUSIONS: Serbian version of the 50-item MFS showed similar psychometric properties as the original English version of this scale, with the same factorial structure. It could be used for measurement of fear of medical and related treatments in Serbian socio-cultural milieu, preferably self-administered. Hippokratia 2016, 20(1): 44-49.

The influence of CYP2C8*3 on carbamazepine serum concentration in epileptic pediatric patients.

The aim of the present study was to investigate the distribution of CYP2C8 variants *3 and *5, as well as their effect on carbamazepine pharmacokinetic properties, in 40 epileptic pediatric patients on carbamazepine treatment. Genotyping was conducted using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and allele-specific (AS)-PCR methods, and steady-state carbamazepine plasma concentrations were determined by high performance liquid chromatography (HPLC). The CYP2C8 *3 and *5 polymorphisms were found at frequencies of 17.5 and 0.0%, respectively. After dose adjustment, there was a difference in daily dose in CYP2C8*3 carriers compared to non carriers [mean ± standard deviation (SD): 14.19 ± 5.39 vs. 15.46 ± 4.35 mg/kg; p = 0.5]. Dose-normalized serum concentration of carbamazepine was higher in CYP2C8*3 (mean ± SD: 0.54 ± 0.18 vs. 0.43 ± 0.11 mg/mL, p = 0.04), and the observed correlation between weight-adjusted carbamazepine dose and carbamazepine concentration after dose adjustment was significant only in CYP2C8*3 non carriers (r = 0.52, p = 0.002). However, the population pharmacokinetic analysis failed to demonstrate any significant effect of CYP2C8 *3 polymorphism on carbamazepine clearance [CL L/h = 0.215 + 0.0696*SEX+ 0.000183*DD]. The results indicated that the CYP2C8*3 polymorphism might not be of clinical importance for epilepsy treatment in pediatric populations.

The prognostic role of interleukin-8 (IL-8) and matrix metalloproteinases -2 and -9 in lymph node-negative untreated breast cancer patients.

PURPOSE: To investigate the relationships, if any, between interleukin (IL) -8/matrix metalloproteinase (MMP)-2/ MMP-9 and other prognostic variables in lymph node-negative untreated breast cancer patients, and to determine the prognostic value of these potential biomarkers. METHODS: The study included 135 patients with known clinicopathological parameters. IL-8, MMP-2 and MMP-9 levels were determined by ELISA in primary tumor tissue lysates. RESULTS: There were no significant relationships between IL-8/MMP-2/MMP-9 expression and available clinicopathological parameters (patient age, menopausal status, tumor size and tumor grade). Estrogen receptor (ER)- patients had higher levels of both IL-8 and MMP-9 (p=0.006 and p=0.04, respectively) compared to ER+ patients; there was a significant negative correlation between ER and IL-8 (p=0.02). MMP-9 expression was significantly higher in patients with higher levels of IL-8 (p<0.001) and there was a significant positive correlation between IL-8 and MMP-9, as well as between progesterone receptor (PR) and MMP-2 (p<0.001 and p=0.05, respectively). PR+ patients had higher levels of MMP-2 than PR- patients (p=0.03). Among the investigated biomarkers, only IL-8 had a statistically significant prognostic value in terms of relapse free survival (RFS) (p<0.001). Patients with higher levels of IL-8 had worse prognosis. CONCLUSIONS: Expression of IL-8 and consequently expression of MMP-9 could be hormonally regulated in breast cancer. IL-8 could be a marker of more aggressive, ER- breast cancer phenotype. Different expression of MMP-2 and MMP-9 regarding differential hormonal receptor expression could indicate distinct mechanisms of their regulation. It seems that IL-8 is a strong and independent unfavorable prognostic parameter in node-negative breast cancer. Node-negative patients with higher levels of IL-8 should be treated with adjuvant, especially IL-8 targeted therapy.

Factors influencing carbamazepine pharmacokinetics in children and adults: population pharmacokinetic analysis.

OBJECTIVE: The aim of the present study was to build population pharmacokinetic models for the clearance of carbamazepine (CBZ) in two separate populations of Serbian patients with epilepsy, children and adults. METHODS: Analysis was performed using 114 and 53 steady-state concentrations of CBZ collected from 98 children and 53 adult epileptic patients, respectively. Mean values of total body weight and age were 31 ± 13 kg and 8 ± 3 years in the population of children, and 67 ± 13 kg and 32 ± 15 years in the population of adults. The one-compartment model with first order elimination and without absorption was used from the PREDPP (Prediction for Observation Population Pharmacokinetics) library of NONMEM software. RESULTS: The derived final models of CBZ clearance were similar in the target populations. The most important factors which affected typical mean value of CBZ clearance in both populations studied were age of the patients and total daily dose; the CBZ clearance linearly followed increase of these factors. However, the influence of the patients' age was almost 3.4 times higher in the pediatric population than that in adults while the influence of total daily dose of CBZ is similar. On the other hand, final model in the adult population revealed also influence of concomitant therapy with phenobarbital (PB). The magnitude of this effect was +1.61 l h-1. The pharmacokinetic models obtained were validated in groups of 18 children and 13 adults with epilepsy. CONCLUSIONS: The derived models describe well CBZ clearance in terms of Serbian pediatric and adult epileptic patient characteristics, offering a basis for rational individualization of CBZ dosage regimens.

Factors influencing valproate pharmacokinetics in children and adults.

OBJECTIVE: The aim of the present study was to build population pharmacokinetic models for the clearance of valproate (VPA) in 2 separate populations of Serbian patients with epilepsy, children and adults. METHODS: Analysis was performed using 65 and 63 steady-state concentrations of VPA collected from 58 children and 60 adult epileptic patients, respectively. Mean values for total body weight and age were 27.07 ± 13.08 kg and 7.21 ± 3.63 years in the pediatric population, and 69.67 ± 15.60 kg and 33.97 ± 16.41 years in the adult population. The one-compartment model with first order elimination and without absorption was used from the PREDPP (Prediction for Observation Population Pharmacokinetics) library of NONMEM software. RESULTS: The derived final models show that VPA clearance increased with total body weight of patients in both populations. However, the carbamazepine comedication was the main determinant of the final model in children whereas phenobarbitone comedication was the most important factor in the adult population. The magnitudes of these effects were +0.159 lh-1 and +0.539 lh-1 for carbamazepine and phenobarbitone, respectively. A significant decrease in interindividual and intraindividual variability was observed in the target populations. The pharmacokinetic models obtained were validated in groups of 15 epileptic patients, each showing good predictive performance of the model. CONCLUSIONS: The derived models describe well VPA clearance in terms of characteristics of Serbian pediatric and adult epileptic patients, offering a basis for rational individualization of VPA dosage regimens.

Population pharmacokinetics of tacrolimus in kidney transplant patients.

OBJECTIVE: The purpose of this study was to derive population pharmacokinetics (PPK) model of tacrolimus clearance, identify and describe factors that influence it in Serbian kidney transplant patients. METHODS: Population pharmacokinetics analysis was performed using nonlinear mixed-effects model (NONMEM) program from Serbian adult kidney transplant patients receiving triple immunosuppressive therapy, including oral tacrolimus. Details of drug dosage history, sampling time and tacrolimus concentration in 63 patients (44 males and 19 females), 27 - 57 years old (age mean 40.88 +/- 7.01 years) were collected retrospectively. Effects of several covariates on tacrolimus clearance were tested: total body weight, gender, age, posttransplantation days, hemoglobin count, CRP, alanine aminotransferase/aspartate aminotransferase, total daily dose of tacrolimus, co-medication with cotrimoxasole, omeprazole, mycophenolate mofetil and prednisone (> 25 mg). RESULTS: Typical mean value of tacrolimus clearance, estimated by the base model (without covariates), in our population was 1.03 l h-1. The final model showed that tacrolimus clearance increased with total daily dose and concomitant administration of high-dose prednisone (> 25 mg). The magnitude of prednisone effect was + 1.16 l h-1. Final model was validated in a group of 17 patients, showing good predictive performance. CONCLUSIONS: The derived model describes well tacrolimus clearance in terms of characteristics of Serbian kidney transplant patients, offering basis for rational individualization of tacrolimus dosing regimens.

Population pharmacokinetics of lamotrigine in patients with epilepsy.

OBJECTIVE: The purpose of this study was to derive a population pharmacokinetics (PPK) model of lamotrigine clearance as well as to identify and describe factors that influence it in Serbian patients with epilepsy. METHODS: A total of 40 steady-state serum concentrations from 38 adult and pediatric patients with epilepsy, collected during routine therapeutic drug monitoring, were used for the analysis. To determine the influence of different covariates on the estimate of lamotrigine clearance we built a non-linear mixed-effects one-compartment model with the first order elimination and without absorption. RESULTS: Typical mean value of lamotrigine clearance, estimated by the base model (without covariates), in our population was 1.15 l h-1. The final model showed that lamotrigine clearance increased with total body weight, daily dose and concomitant administration of carbamazepine, and decreased with concomitant administration of valproate. The magnitude of carbamazepine and valproate effect was +1.13 l h-1 and -1 l h-1, respectively. The final model was validated in a group of 15 epileptic patients, showing good predictive performance. CONCLUSIONS: The derived model describes well lamotrigine clearance in terms of characteristics of Serbian patients, offering basis for rational individualization of lamotrigine dosing regimens.

[What do we need to help laryngectomized speeking?].

Multidisciplinary approach in rehabilitation of laryngectomized patients is the basic of esophageal voice and speech establishing. Well trained and dedicated stuff is cornerstone for such helpless patients. Communication Disorders Care Center and Laryngectomized Patients Society are minimal administrative precautions in organized community. Modern technology implementation gives us objective evaluation of therapy effects, that is 84% of successful treatment in our daily work.

[Imaging of larynx: diagnostic value of computed tomography and magnetic resonance imaging].

Computed tomography (CT) and magnetic resonance imaging (MRI) are enabling more precise diagnosis and treatment planning in patiensts with diseases of the larynx. The aim of this article is to describe the role of these methods in assessment of the laringeal diseases and key local anatomic characteristics important for spread of the disease. CT and MRI have a valuable contribution to the staging of the tumors due to the possibility to show the relationship to the ventricular complex, involvement of the subumucosal spaces, defining craniocaudal and anterposterior extension, laringeal cartilage invasion, as well as regional lymph node metastases.

[MR diagnostic value in assessing laryngeal tumor].

AIMS: To evaluate diagnostic accuracy of pretreatment surgical magnetic resonance images (MRI) in assessment of patients with tumors of the larynx. MATERIALS AND METHODS: The study included 12 patients, 11 men and 1 women, age 61,4 years. All patients underwent laryngeal endoscopy and biopsy followed by MRI. The biopsy confirmed that all patient had squamous-cell carcinoma. The MRI images were evaluated for presence in supraglottic, glottic or subglottic region, invasion of submucosal space, cartilage, extension to extralaryngeal tissue, presence of regional lymph nodes in regions I to VII. Imaging data were compared to surgical findings. RESULTS: In 11 patients (92%) the tumor was supraglottic and glotic region and in 1 (8%) subglottic. None of them had tumor only in one region. Paraglottic ivasion was seen in 9 (75%) and preepiglottic in 2 (50%) patients. Paraglottic and preepiglotic invasion in the same time was seen in 3 (25%) patients. 7 (58%) patients had normal vocal cord mobility, 3 (25%) mobility was unilateral and 2 (17%) had no vocal cord mobility. Cartilage invasion has not been seen in present study. All patients had billateral limphadenopathy region II-IV. Extension to extralaryngeal tissue was absent. These findings were confirmed on surgery with high diagnostic accuracy. CONCLUSION: MRI has been shown to be a reliable method for presurgical assessment of patients with tumor of the larynx.

Nonvibrating segment predicting glottis carcinoma.

Endovideolaryngostroboscopy is the obliged evaluation tool in our everyday practice. Standardized protocol in management of broad spectrum of vocal pathology is useful in clinical, scientific and educational evaluation of patient from the first interview till the end of the treatment. Using of contemporary computerised multidimensional analysis of stroboscopic image we are approaching to optimum evaluation of any kind of interpersonal communication disorder. There were 66 patients in prospective clinical study of correlation between suspect endovideolaryngostroboscopic findings and histo-pathology verification of glottis carcinoma. Asymmetric and irregular vibrations with absent mucosal wave or absent vibrations of one part or of the whole vocal fold was improved as carcinoma in 85% of patients. The most frequent diagnosis was Ca planocellularae invasivum G2 NG 2, with subsequent open chordectomy. In every case of hoarseness longer more than 14 days, endovideolaryngostroboscopy is the golden standard for evaluating the need for microlaryngoscopy and biopsy.

[Hearing damage caused by noise].

INTRODUCTION: Noise is most common profession risk, as well as risk from environment, for hearing loss. Top limit for industrial noise is 85 dB. OBJECTIVES: Aim of our study was to determined all number of recognized professional diseases in our country, as well as to see which of industries are with highest prevalence of professional hearing damage caused by noise. MATERIALS AND METHOD: We use an cohort study for analyzing patient histories which were hospitalised in the Institute of occupational health. All of them have recognized professional disease hearing loss. In order to be recognized as cases of a professional hearing damage, all of them had to satisfy all legal requirements. RESULTS: Average age of patients with professional damage of cochlear nerve was 50 y. They have high total time period as well as exposed time period. In 2003 and 2004 there was highest number of detected and recognized cases of such professional diseases. More than half of examined patients had lesion between 30 and 40 percent following tables of F. S. Most of them were metal and mining industry workers. CONCLUSION: Following results of the study we can conclude that regular medical examinations of workers in all industries are necessary, specially in metal and mining industry. It is also needed to use personal protection items and to provide appropriate medical education of both workers and the management staff of said industries in order to prevent this kind of profession disease.

[Laser surgery of supraglottic laryngeal carcinoma].

The limited excision addresses small superficial lesions affecting free edge of the epiglottis, the aryepiglottic fold or the superior edge of the arytenoid. The median supraglottic laryngectomy excluding the pre-epiglottic space addresses small superficial T1 lesions of the endolaryngeal epiglottis. The incision line extends to the pre-epiglottic space but does not aim at removing the pre-epiglottic space entirely. The pharyngo-epiglottic folds, aryepiglottic folds, and ventricular folds are preserved. The median supraglottic laryngectomy including the pre-epiglottic space addresses T1 and T2 lesions of the endolaryngeal epiglottis. The entire pre-epiglottic space is removed as far as possible. Depending on extent of the lesion, the resection can include one or two ventricular bands and the aryepiglottic folds. The lateral supraglottic laryngectomy addresses lesions affecting the three folds or T1 and T2 lesions of the aryepiglottic fold. The procedure removes free edge of the epiglottis ipsilateral to the lesion, the area of the three folds and the aryepiglottic fold. The resection can include the inner wall and anterior angle of the pyriform sinus, the entire ventricular fold and the arytenoid (provided it is mobile).

[Functional results of treatment of early carcinoma in the glottic region of the larynx].

Early stage glottic cancer can be successfully treated with open surgery, LASER surgery or radiotherapy. During this treatment the physician obviously has to bear in mind principles of oncological radicality, but also, none the less, the preservation of all the functions of the larynx, and especially the preservation of voice quality. The aim of the study is to compare, in a specifically designed prospective study, the method of treatment with the functional results of basic characteristics of spoken voice of patients with early stage cancer of the glottis region. Then, based on the analysis of the results, to try and determine the most successful method of treatment. The first study group consisted of 72 patients operated using transoral laser microsurgery; the second study group consisted of 75 patients operated using open surgery; and the third study group consisted of 74 patients treated with radiotherapy. The voice quality is much better after laser chordectomy compared to open surgery chordectomy with reconstruction. Furthermore, the functional results of voice quality, after a laser chordectomy, are worse when compared to the group of patients treated with radiotherapy. Taking into account all objective and subjective phoniatric parameters, we determined that there is no crucial difference in the voice quality of patients operated using laser chordectomy and patients primarily treated with radiotherapy. From a functional point of view these two methods are superior to open surgery chordectomy.

[Laser surgery of malignant tumors of the glottic region of the larynx].

The Nomenclature Committee of the European Laryngological Society taken the personal classification used by various members were analyzed and integrated into a common format. Thus, a new classification (Remacle et al., 2000) end next modification (Remacle et al., 2007) in was proposed and accepted by the members. This nomenclature takes into account both the histological and anatomical extent of surgery, and groups it into several categories. Subepithelial cordectomy--excision of the epithelium and the superficial layer of the lamina propria. Subligamentous cordectomy--excision of the epithelium, Reinke's space, and vocal ligament is undertaken. Transmuscular cordectomy--resection consists of the epithelium, lamina propria, and part of the vocal fold muscle, and may extend from the vocal process to the anterior commissure. Total or complete cordectomy--excision extends from the vocal process to the anterior commissure. Anteriorly, the incision is made at the anterior commissure. Type Va extended cordectomy--includes the anterior commissure and contralateral vocal fold, if necessary. In type Vb extended cordectomy, the excision is extended to remove part or all of the arytenoids. The posterior arytenoids mucosa is preserved. In Type Vc extended cordectomy, the whole of the ventricle and the ventricular fold is removed together with the vocal fold. In Type Vd extended cordectomy, surgery is extended inferiorly to include the subglottic mucosa. Type VI cordectomy--Anterior billateral cordectomy in this operation surgical intervention is focused on anterior commissure, therefore some authors name it commissurectomy.

[Bilateral vocal paralysis phonosurgery in adults].

Ordinary clinical manifestation of the patient with bilateral vocal fold paralysis is inability of abducting the cords with a result of narrowing the glottic space, causing inspiratory stridor and mild dysphonia. Such patients can be life threatened due to narrowing airway. Some kind of surgery has to be performed on these patients in order to enlarge the airway. When we treat patients with OPG, the most reasonable way is to gradually enlarge airway at glotic level and there are several surgical methods for achieving this. The least agresive and the safest procedures are posterior transversal cordectomy (PTC) or medial arytenoidectomy (MA), after which we can perform extended versions of some of these methods or combination of both. Bilateral vocal fold paralysis has to be diagnostically different from stenosis of posterior commissure, even though the procedures such as medial arytenoidectomy, posterior transversal cordectomy and total arytenoidectomy can be performed in both cases. The patients have to be explained that the aim of the procedure is to enlarge airway to the detriment of voice quality and voice capabilities.