Volume 21. Volume 21, Number 3, pp October/December 2015

Transcription

1 Volume 21 October/December 2015 Number 4 Volume 21, Number 3, pp October/December 2015

2 241 Objavljen je peti broj E-biltena informativno-stručnog elektronskog glasila Univerzitetskog kliničkog centra u Sarajevu (UKCS) The fifth issue of E-newsletter informative and professional electronic media University Clinical Center Sarajevo (UCCS) ISSN (ONLINE) Elektronsko glasilo /// Godina 1 /// Broj 5 /// Decembar ME BROJA /// TEME BROJA /// TEME BROJA /// TEME BROJA /// TEME BROJA /// TEME BROJA // PRVA ŠKOLA PEDIJATRIJSKOG ULTRAZVUKA NERACIONALNA UPOTREBA ANTIBIOTIKA JE ŠTETNA I NACIONALNI KONGRES O OSTEOPOROZI

3 242 New ICU - Central Medical Building - Clinical Center University of Sarajevo Nova Intenzivna njega - Klinički Centar Univerziteta u Sarajevu

4 New Central Medical Building - University Clinical Center Sarajevo Novi Centralni Medicinski Blok - Univerzitetski klinički centar u Sarajevu 243

5 Medical Journal

6 Medical Journal PUBLISHER: Institute for Research and Development University Clinical Center Sarajevo Sarajevo, Bolnička 25 Bosnia and Herzegovina For publisher: Sebija Izetbegović, MD, PhD General Manager UCCS AIMS AND SCOPE The Medical Journal is the official quarterly journal of the Institute for Research and Development of the University Clinical Center Sarajevo and has been published regularly since It is published in the languages of the people of Bosnia and Herzegovina i.e. Bosnian, Croatian and Serbian as well as in English. The Medical Journal aims to publish the highest quality materials, both clinical and scientific, on all aspects of clinical medicine. It offers the reader a collection of contemporary, original, peer-reviewed papers, professional articles, review articles, editorials, along with special articles and case reports. Copyright: the full text of the articles published in the Medical Journal can be used for educational and personal aims i.e. references cited upon the authors permission. If the basic aim is commercial no parts of the published materials may be used or reproduced without the permission of the publisher. Special permission is available for educational and non-profit educational classroom use. Electronic storage or usage: except as outlined above, no parts of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means without prior written permission from the Publisher. All rights reserved Institute for Research and Development UCCS. Notice: the authors, editor and publisher do not accept responsibility for any loss or damage arising from actions or decisions based on information contained in this publication; ultimate responsibility for the treatment of patients and interpretation of published materials lies with the medical practitioner. The opinions expressed are those of the authors and the inclusion in this publication of materials relating to a specific product, method or technique does not amount to an endorsement of its value or quality, or of the claims made by its manufacturer. EDITORIAL OFFICE Address: Medical Journal, Institute for Research and Development, University Clinical Center Sarajevo Sarajevo, Bolnička 25, Bosnia and Herzegovina, Phone: ; institutnir@bih.net.ba Web. Technical secretariat: svjetlana.barosevcic@kcus.ba Editor-in-Chief: mdilic@bih.net.ba SUBSCRIPTION Annual subscription rates: Bosnia and Herzegovina 50; Europe 80; and other 100. Editor-in-Chief Mirza Dilić Editorial Board Sebija Izetbegović, Enra Suljić-Mehmedika, Ismet Gavrankapetanović, Safet Guska, Almira Hadžović-Džuvo, Adnan Kapidžić, Abdulah Kučukalić, Mehmed Kulić, Benjamin Kulovac, Bakir Mehić, Nermina Obralić, Lilijana Oruč, Amer Ovčina, Asja Prohić, Svjetlana Radović, Senija Rašić, Mustafa Hiroš, Secretary International Advisory Board Kenan Arnautović (USA), Raffaele Bugiardini (Italy), Erol Ćetin (Turkey), Maria Dorobantu (Romania), Oktay Ergene (Turkey), Zlatko Fras (Slovenia), Dan Gaita (Romania), Mario Ivanuša (Croatia), Steen Dalby Kristensen (Denmark), Mimoza Lezhe (Albania), Mario Marzilli (Italy), Milica Medić- Stojanovska (Serbia), Davor Miličić (Croatia), Fausto Pinto (Portugal), Mihailo Popovici (Moldova), Marcella Rietschel (Germany), Nadan Rustemović (Croatia), Georges Saade (Lebanon), Petar Seferović (Serbia), Dragan Stanisavljević (Slovenia), Panos Vardas (Greece), Gordan Vujanić (UK), Jose Zamorano (Spain) English language revision Svjetlana Baroševčić Medical Journal is Indexed in EBSCO publishing USA SUPPLEMENTS, REPRINTS AND CORPORATE SALES For requests from industry and companies regarding supplements, bulk articles reprints, sponsored subscriptions, translation opportunities for previously published material, and corporate online opportunities, please contact; institutnir@bih.net.ba PRINT Eurografika Zvornik Printed on acid-free paper. TECHNICAL EDITOR Eurografika CIRCULATION 500 copies Member of National Journals Networks of the European Society of Cardiology

7 Content Medical Journal (2015) Vol. 21, No. 4 Original article Effects of antipsychotics treatment on nitric oxide levels in schizophrenia Amra Memić, Abdulah Kučukalić, Jasminko Huskić, Lilijana Oruč Negative emotional states and quality of life in women with breast cancer Nada Vaselić, Milka Šajinović, Mira Spremo, Tatjana Marković-Basara Frequency of anxiety and anxiety disorders among medical students during education Ifeta Ličanin, Belma Paralija, Delila Čengić, Ismana Šurković, Amira Redžic Significance of protective colostomy in preventing complications in low rectal anastomosis Jugoslav Đeri, Milan Simatović, Nebojša Trkulja, Nenad Lalović Difficulties and risks in treatment of hepatitis C viral infection among opiate addicts in substitution treatment Rasema Okić, Samir Kasper, Sabina Mađar Screening for the presence of silent myocardial ischemia using perfusion scintigraphy in patients with diabetes mellitus Miran Hadžiahmetović, Elma Kučukalić-Selimović, Šejla Cerić, Damir Čelik, Selma Agić, Majla Ćibo, Željka Raič-Gotovac, Amela Begić Ablation therapy with i-131 at thyroid cancer Rubina Alimanović-Alagić, Mevludin Mekić, Nermina Bešlić, Amra Skopljak-Beganović, Šejla Cerić Professional article Length of hospital stay in patients treated for bronchiolitis at the Pediatric Clinic in Sarajevo Ganimeta Bakalović, Jovana Panić, Amra Džinović, Selma Dizdar, Amina Selimović Glomerular filtration rate and proteinuria in children with cyanotic congenital heart disease Admir Hadžimuratović, Senka Mesihović-Dinarević, Emina Hadžimuratović Review article Evaluation of dermoscopic findings and follow up for patients with dysplastic nevi Hana Helppikangas, Samra Šoškić, Emina Kasumagić-Halilović Viral load as a predictor during and after peg interferon alfa-2a therapy in chronic hepatitis B Arben Vishaj, Tritna Kalo, Salih Ahmeti, Bahrije Halili Case report Hemorrhagic pancreatitis as a rare complication after surgery of choledochal cysts type 1 in a six year old girl Verica Mišanović, Fedžat Jonuzi, Duško Anić, Asmir Jonuzi, Selma Dizdar, Semra Rahmanović Surgical dilemmas during abdominal aortic aneurysm repair in the presence of horseshoe kidney Amel Hadžimehmedagić, Haris Vranić, Nermin Granov, Slavenka Štraus, Ljiljana Hećo Multiple capillary hemangioma with fast-flow arteriovenous malformation in the right hand Sanela Salihagić Instructions to authors Uputstva autorima

8 Medical Journal (2015) Vol. 21, No. 4, Original article Effects of antipsychotics treatment on nitric oxide levels in schizophrenia Uticaj antipsihotika na nivo nitričnog oksida kod shizofrenije Amra Memić 1*, Abdulah Kučukalić 1, Jasminko Huskić 2, Lilijana Oruč 1 1 Clinic of Psychiatry, University Clinical Centre Sarajevo, Bolnička 25, Sarajevo, Bosnia and Herzegovina; 2 Institute of Physiology and Biochemistry, Faculty of Medicine, Čekaluša 90, Sarajevo, Bosnia and Herzegovina *Corresponding author ABSTRACT Schizophrenia is a complex disorder, which affects around 1% of the population. After many years of research nitric oxide is still the focus of many studies. Insufficiency of nitric oxide is associated with the pathology of schizophrenia. Authors confirmed that antipsychotic show the low level of oxidants in schizophrenia. Thus, the aim of the present study was to analyze the level of nitric oxide in patients with schizophrenia to understand the role of nitric oxide and the effects of typical and atypical antipsychotics on nitric oxide levels in this complex psychiatric disorder. Over two year period 50 patients with schizophrenia from the Psychiatric Clinic of the University Clinical Center Sarajevo (UCCS), and 50 healthy controls, were recruited. The diagnosis assigned according to DSM-IV diagnostic criteria was confirmed by SCID 1. The concentration of NO in blood was done with measurement of nitrate and nitrite using colorimetric Greiss reaction. The serum NO levels in the group of patients with schizophrenia (35.8±3.37) were significantly higher than in the control group (15.545±0.87). In that regard, the important fact is that antipsychotics may influence the results of nitric oxide level. The nitric oxide level was higher in the group of patients on atypical antipsychotics ±0.44 as compared to the level in group of patient on typical ± There was no statistically significant difference (p>0.05). We cannot confirm that that there is a significant difference between effects of atypical and typical antipsychotics, but atypical antipsychotics may influence the significant increase in antioxidant effect in respect to typical antipsychotics. Key words: nitric oxide, schizophrenia, atypical antipsychotic, typical antipsychot INTRODUCTION Schizophrenia is a complex disorder, which affects around 1% of the population. This psychiatric disorder is manifested with different symptoms and the course and outcome of the disease are different between patients. Until today, ethiopathology of schizophrenia has still remained unclear. Heterogeneity and complexity of the etiology of schizophrenia as well as neuropathology remain the most challenging problem of biological psychiatry. The main hypothesis about the etiology of schizophrenia are gene expression (1), prenatal SAŽETAK Shizofrenija je kompleksan poremećaj, koji zahvata oko 1% stanovništva. Nakon mnogo godina istraživanja nitrični oksid je i dalje u fokusu mnogih studija. Nedostatak nitričnog oksida je povezana sa patologijom shizofrenije. Autori su potvrdili uticaj antipsihotika na nizak nivo oksidanata kod shizofrenije. Dakle, cilj ovog istraživanja bio je analizirati nivo nitričnog oksida kod shizofrenije da bi shvatili ulogu nitričnog oksida i efekat tipičnih i atipičnih antipsihotika na nivo nitričnog oksida u ovom kompleksnom psihijatrijskom poremećaju. U periodu od dvije godine 50 pacijenata sa shizofrenijom na Psihijatrijskoj klinici, UCCS i 50 zdravih kontrola je bilo regrutovano. Dijagnoza je dodijeljena prema DSM-IV dijagnostičkim kriterijima. Koncentracija NO u krvi je određena uz mjerenje nitrata i nitrita pomoću Greiss kolorimetrijske reakcije. Nivo NO kod pacijenata sa shizofrenijom (35.8 ± 3.37) bio je znatno veći nego kod kontrolne grupe ( ± 0.87). U tom kontekstu važna je činjenica da antipsihotici mogu utjecati na rezultate nivoa nitričnog oksida. Nivo nitričnog oksida bio je veći u grupi pacijenata na atipičnim antipsihoticima ± 0.44 u odnosu na nivo u grupi pacijenata na tipičnim antipsihoticima ± 0.028, razlika nije statistički značajna (p>0.05). Ne možemo potvrditi signifikantnu razliku između efekta atipičnih i tipičnih antipsihotika, ali atipični antipsihotici možda utiču na značajniji porast antioksidativnog dejstva u odnosu na tipične antipsihotike. Ključne riječi: nitrični oksid, shizofrenija, atipični antipsihotici, tipični antipsihotici and perinatal brain damage, including neurodevelopment theory, the neurodegenerative theory (2) of brain and neurotransmitters imbalance or dysfunction within several neurotransmitter systems when we talk about the predisposing factors that determine the tendency to develop the disorder. The precipitating factors were psychosocial such as social, cultural and interpersonal factors (3,4). One of the main neurotransmitters is glutamate which impairment of neurochemical balance is in connection with one of the leading hypothesis of developing of schizophrenia. Today, the hypothesis of glutamate added to the dopaminergic hypothesis of schizophrenia (5,6). Also, glutamate is a

9 248 A. MemiĆ et al. key cell of new psychopharmacological agents in the treatment of this disease in the future. Glutamate system is rare because it requires a key receptor for glutamate with it and co-transmitter to function. It is N-methyl-D-aspartate receptor (NMDA). The significant fact is that the activation of NMDA receptors with synaptic release of glutamate can start the synthesis of nitric oxide from L-arginine ( oxidative L-arginine way ) which is assumed to have an important role in the activation of excitatory amino acids in the development process, learning and memory but also in toxic damage of CNS associated with free radicals (7,8). Research findings have indicated the possible pathophysiology role of nitric oxide (NO) in schizophrenia and some other psychiatric disorder. The activation of NMDA is responsible to stimulation enzyme neuronal nitric oxide synthase, which catalyzes the oxidation of L-arginine into L-citrulline and NO (9). NO is a simple membrane permeable gas. Line activation of the following NO-cyclic guanosine monophosphates, involved in the modulation of glutamate and dopamine release, leads neurotransmitters in the pathophysiology of schizophrenia. Irregularities in this line of activation are still unclear, but, and possible new drugs target in a future that act downstream NMDA-NO for example - could bypass the problem of the downregulation of those receptors (10). After many years of research nitric oxide is still the focus of many studies. Insufficiency of nitric oxide is associated with the pathology of schizophrenia. All are closer toward the new molecule nitric oxide donor, which would be significant in the treatment of these diseases (11,12,13). Authors confirmed that antipsychotic show the low level of oxidants in schizophrenia (7). Patients with schizophrenia under antipsychotics show higher levels of nitric oxide (14,15,16), but some of the study shows the opposite results (17,18). Improvement of clinical symptoms can lead to normalization of nitric oxide level. Increased nitric oxide in patients under treatment indicates a possible fact of activation of nitrergic pathway by antipsychotic. We wanted to show the impact of antipsychotic drugs on the nitric oxide level. In this study we analyzed the level of nitric oxide in patients with schizophrenia to understand the role of nitric oxide and the effects of typical and atypical antipsychotics on nitric oxide levels in this complex psychiatric disorder. MATERIALS AND METHODS The research was a prospective clinical study. Over two year period 50 patients with schizophrenia from the Psychiatric Clinic of the UCSS, and 50 healthy controls, were recruited. The diagnosis assigned according to DSM-IV diagnostic criteria was confirmed by Structured Clinical Interview (SCID 1). To assess the presence of positive and negative psychopathology symptoms, Positive and Negative Syndrome Scale was also applied to each patient. Exclusion criteria from the study were: subject who decline participation and subjects under 18 and over 68 years of age. The research was approved by the Ethics Committee of the UCCS. Investigation and determination of clinical, test and laboratory parameters was carried out along with all other routine procedures as part of the treatment and monitoring of patients during their hospitalization at the Psychiatric Clinic of the UCCS, therefore there was no violation of ethical principles of working with patients. Patients confirmed their voluntary participation by signing an informed consent. All identification data was anonymous and permanently protected under regulations protecting identification data. The concentration of NO in blood was done with measurement of nitrate and nitrite using colorimetric Greiss reaction (19). The concentration of NO in serum was determined by conversion of nitrate (NO 3) to nitrite (NO 2) using elemental zinc and colorimetric measurement of nitrite (NO 2) (µmol/l). We took 1 ml of blood, added 8 mg of elemental zinc solved in 0.4 ml of deionized water, and then added ml 5% CH3COOH (acetic acid) and tilled 2 ml of deionized water. We mixed the sample for 5 min using vortex at room temperature and centrifuged it for 2.5 min at 700 rpm. We took 1 ml of supernatant and 1 ml of Greiss reagent and mixed it for 10 min in vortex at room temperature. After 10 min of mixing we measured light absorption (optical density) with spectrophotometer at 546 nm. The concentration of nitrate and nitrite was sensed from a standard curve with known concentrations of NaNO2 (1.56 µmol 100 µmol). As a blank test we used distilled water in which we added Griess reagent. Results are presented in tables and charts by number of cases, percentage, mean, standard deviation and range of values. Statistical analysis was carried out using Student s t test and analysis of variance (ANOVA) after determination of normal distribution of tested variables by Shapiro-Wilk test. The confidence level of all mentioned test was 95%. Analysis was carried out using statistical package for biomedical studies MedCalc v12.7. RESULTS Demographic data of the study is reported in Table 1. Out of the total number of patients (N=50), most of them were females. Within the baseline sample female patients were presented in 35 to 70% of cases, mostly single in 26 to 52% of cases or married in 21 to 42% of cases. According to employment structure, majority of patients were unemployed in 29 or 58% of cases or retired in 12 to 24% of cases, with only 9 to 18% of currently employed patients. Based on education level majority of patients were with secondary school degree 32 to 64%, and only small number of them were with high school degree (2 to 4%) or university degree (5 to 10%). Analysis by Chi square test and Student t-test showed a significant difference in the employment structure and education level between the two groups (p<0.05), but not in respect to other demographic data (p>0.05). Table 1 Demographic data. Gender Marital status Employment Education N Male Female Married Single Divorced Employed Unemployed Retired Grammar school High school education College education University degree %

10 Effects of antipsychotics treatment on nitric oxide levels in schizophrenia 249 In majority of cases the course of disease was either intermittent (15 to 30%) or progressive (16 to 32%) with the lowest number of patients with first time hospitalization (6 to 12%). Table 2 shows that the mean age of patients in our sample was 38.4±12.5 years with the youngest patient aged 20 and the oldest aged 68 years. The average age of schizophrenia onset was at 28±7.7 years, with the earliest occurrence of the disease at the age of 18 and the latest at the age of 49. The average duration of the episode prior to hospitalization was 32.5±35.4 days with the shortest duration of 5 and a maximum of 150 days. Average nitric oxide level in the baseline sample was 0.05±0.03 with values ranging from 0.02 to 0.17 which was also presented in Table 2. The serum NO levels in the group of patients with schizophrenia (35.8±3.37) were significantly higher than in the control group (15.545±0.87). Table 2 Mean values of the observed parameters. Mean Std. error Std. deviation Minimum Maximum Age Age of disease onset Episode duration prior to hospitalization Nitric oxide (NO) level Figure 1 shows that before admission the antipsychotic treatment was received by 28 to 56% of patients. Current medications for 34 to 68% of patients are typical antipsychotics (Haloperidol -24 or 48% or Fluphenazine - 10 or 20%), whereas 16 to 32% of patients receive atypical antipsychotics (Olanzapine - 11 to 22% and Risperidone - 5 to 10%). Figure 1 NO level based on type of antipsychotics before and during admission. Figure 2 NO level based on typical and atypical antipsychotics. Figure 2 shows that although the nitric oxide level was higher in the group of patients on atypical antipsychotics ±0.44 (range to 0.173) as compared to the level in the group of patient on typical antipsychotics ± (range 0.02 to 0.117), the difference was not statistically significant (p>0.05). Figure 3 NO level based on type of antipsychotics. Figure 3 shows that on average highest NO values were observed in patients on olanzapine ± 0.48 (range to 0.173) and the lowest in the group of patients on fluphenazine ± 0.11 (range to 0.057) with no statistically significant differences. DISCUSSION The pathophysiology of schizophrenia is qualified by abnormalities of several neurotransmitters including dopamine and glutamate (20,21). Until today some of the aberrations in this neurotransmission pathways have still remained unclear, so in this study we tried to understand the role of nitric oxide in schizophrenia by analyzing possible difference in nitric oxide level between schizophrenia and healthy controls group and nitric oxide level based on type of antipsychotics. In our study we tried to understand the effect of nitric oxide in patients with schizophrenia by comparison of nitric oxide levels between patients receiving typical and atypical antipsychotics, and healthy control group. Our results showed that nitric oxide levels in schizophrenia (35.8±3.37) were significantly higher than in the healthy control (15.545±0.87). We found increased in total nitric oxide levels in patient groups which is in line with the results of so many studies (14, 15, 16, 22, 23). This study showed that patients with schizophrenia under antipsychotics had higher nitric oxide level than healthy controls. These results are inconsistent with some of the studies (17,18,24). The possible reason for these results it the fact that the mean duration of schizophrenia could be a main factor for the nitric oxide levels, which is in connection with adaptive mechanisms. Some of the studies found decreased nitric oxide level in the first episode of the disease (25). Decreased nitric oxide levels in the first episode of schizophrenia were found in the study conducted by Das et al. (26). An important fact for determining the stage of schizophrenia is the level of nitric oxide. In that regard the important fact is that antipsychotics may influence the results of nitric oxide level. We also evaluated the effects of typical and atypical antipsychotics on nitric oxide level in schizophrenia. Our results showed the higher nitric oxide levels in patients with schizophrenia as compared to healthy control, and also that nitric oxide level was higher in the group of patients on atypical antipsychotics than in the group of patients on typical antipsychotics, but the difference was not statistically significant (p>0.05). Some of the studies reported the higher nitric oxide level in patients on antipsychotic treatment but with no differences between

11 250 A. MemiĆ et al. typical and atypical antipsychotics (27,28). The study of Noto et al. (29) shows the risperidone increased nitric oxide activity. Our results indicate that typical and atypical antipsychotic may normalize free radical metabolism. Determination of nitric oxide after admission to the hospital and at the end of treatment would be important, as well as over a long period of illness. Possible limitations of our study could be the fact that we did not examine the correlation between nitric oxide and the course and outcome of the disease. CONCLUSION Our findings of higher nitric oxide level in schizophrenia confirmed the pathophysiological role of nitric oxide in schizophrenia and effects of antipsychotics on nitric oxide level. We could not confirm that there was a significant differences between effects of atypical and typical antipsychotics, but the fact that patients on atypical antipsychotics showed higher nitric oxide level then patients on typical antipsychotics once again determined the significance thereof. Atypical antipsychotics may increase the stronger antioxidant effect as compared to typical antipsychotics. Our findings could point to the fact that nitric time induced by the use of antipsychotic drugs gives reason to believe that this time could be significant for new psychopharmacological agents in the treatment of schizophrenia. Conflict of interest: none declared. REFERENCES 1. Käkelä J, Panula J, Oinas E, Hirvonen N, Jääskeläinen E, Miettunen J. Family history of psychosis and social, occupational and global outcome in schizophrenia: a meta-analysis. Acta Psychiatr Scand. 2014;130: Hardy J, Gwinn-Hardy K. Genetic classification of primary neurodegenerative disease. Science. 1998;282: Tsuang M. Schizophrenia: genes and environment. Biol Psychiatry. 2000;47(3): Cannon TD, van Erp TG, Bearden CE, Loewy R, Thompson P, Toga AW et al. Early and late neurodevelopmental influences in the prodrome to schizophrenia: a contributions of genes, environment and their interactions. Schizophr Bull. 2003;29(4): Timms AE, Dorschner MO, Wechsler J, Choi KY, Kirkwood R, Girirajan S et al. Support for the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia from exome sequencing in multiplex families. JAMA Psychiatry. 2013;70: Hu W, MacDonald ML, Elswick DE, Sweet RA. The glutamate hypothesis of schizophrenia: evidence from human brain tissue studies. Ann. N.Y. Acad. Sci. 2014; 1338: Humphries C, Mortimer A, Hirsch S, de Belleroche J. NMDA receptor mrna correlation with antemortem cognitive impairment in schizophrenia. Neuroreport. 1996;7: Mohn AR, Gainetdinov RR, Caron MG, Koller BH. Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell. 1999; 98: Jaffrey SR, Snyder SH. Nitric oxide: a neural messenger. Annu Rev Cell Dev Biol. 1995;11: Oliveira JP, Zuardi AW, Hallak JE. Role of nitric oxide in patients with schizophrenia - a systematic review of the literature. Curr Psychiatry Rev. 2008;4: Pitsikas N. The role of nitric oxide donors in schizophrenia: Basic studies and clinical applications. Eur J Pharmacol. 2015; pii: S (15) Sanna MD, Monti M, Casella L, Roggeri R, Galeotti N, Morbidelli L. Neuronal effects of a nickel-piperazine/no donor complex in rodents. Pharmacol Res. 2015; 99: Tsai MC, Liou CW, Lin TK, Lin IM, Huang TL. Changes in oxidative stress markers in patients with schizophrenia: the effect of antipsychotic drugs. Psychiatry Res. 2013;209: Akyol O, Herken H, Uz E, Fadillioğlu E, Unal S, Söğüt S, et al. The indices of endogenous oxidative and antioxidative processes in plasma from schizophrenic patients. The possible role of oxidant/antioxidant imbalance. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26: Zoroglu SS, Herken H, Yurekli M et al. The possible pathophysiological role of plasma nitric oxide and adrenomedullin in schizophrenia. J Psychiatr Res. 2002;36: Yanik M, Vural H, Tutkun H et al. Is the arginine-nitric oxide pathway involved in the pathogenesis of schizophrenia? Neuropsychobiology. 2003;47: Peluso ET, Blay SL. Public stigma and schizophrenia in São Paulo city. Rev Bras Psiquiatr. 2011;33(2): Tuominen HJ, Tiihonen J, Wahlbeck K. Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2005;72: Grees LC, Wagner DA, Glogowski J. Analysis of nitrate, nitrite and 15N nitrate in biological fluids. Anal Biochem. 1982;126: Bressan RA, Pilowsky LS. Glutamatergic hypothesis of schizophrenia. Rev Bras Psiquitr. 2003;25(3): Thornberg SA, Saklad SR. A review of NMDA receptors and the phencyclidine model of schizophrenia. Pharmacotherapy. 1996;16: Taneli F, Piridar S, Akdeniz F, Uyanik BS, Ari Z. Serum nitric oxide metabolite levels and the effect of antipsychotic therapy in schizophrenia. Arch Med Res. 2004;35: Djordjević VV, Stojanović I, Stanković-Ferlez D, Ristić T, Lazarević D, Cosić V, et al. Plasma nitrite/nitrate concentrations in patients with schizophrenia. Clin Chem Lab Med. 2010;48(1): Kim YK, Lee BH, Park SH. Decreased plasma nitric oxide metabolite levels in schizophrenia. Psychiatry Invest. 2006;3: Ramirez J, Garnica R, Boll MC, Montes S, Rios C. Low concentration of nitrite and nitrate in the cerebrospinal fluid from schizophrenic patients: a pilot study. Schizophr Res. 2004;68: Das I, Khan NS, Puri BK, Hirsch SR. Elevated endogenous nitric oxide synthase inhibitor in schizophrenic plasma may reflect abnormalities in brain nitric oxide production. Neurosci Lett. 1996;215(3): Minutolo G, Petralia A, Dipasquale S, Aguglia E Nitric oxide in patients with schizophrenia: the relationship with the severity of illness and the antipsychotic treatment. Expert Opin Pharmacother. 13(14): Zhang XY1, Zhou DF, Shen YC, Zhang PY, Zhang WF, Liang J, Chen da C, Xiu MH, Kosten TA, Kosten TR Effects of risperidone and haloperidol on superoxide dismutase and nitric oxide in schizophrenia. Neuropharmacology. 62(5-6): Noto C, Ota VK, Gadelha A, Noto MN, Barbosa DS et al. Oxidative stress in drug naïve first episode psychosis and antioxidant effects of risperidone. J Psychiatr Res. 2015;68: Reprint requests and correspondence: Amra Memić, MD, PhD Clinic of Psychiatry University Clinical Centre Sarajevo Bolnička 25, Sarajevo Bosnia and Herzegovina Phone: amramemic@yahoo.com

12 Medical Journal (2015) Vol. 21, No. 4, Original article Negative emotional states and quality of life in women with breast cancer Negativna emocionalna stanja i zadovoljstvo životom žena sa karcinomom dojke Nada Vaselić 1*, Milka Šajinović 2, Mira Spremo 3, Tatjana Marković-Basara 3 1 Faculty of Philosophy, University of Banja Luka, Bulevar vojvode Petra Bojovića 1A, Banja Luka, Bosnia and Herzegovina, 2 ZU Dr Šajinović, Carice Milice 26, Banja Luka, Bosnia and Herzegovina, 3 Clinic of Psychiatry, University Clinical Center of Republika Srpska, Dvanaest beba, Banja Luka, Bosnia and Herzegovina *Corresponding author ABSTRACT Most of the women with breast cancer experience negative emotional states, such as stress, anxiety and depression, throughout all the phases and types of treatment. The level of these states differs individually, and it affects perceived quality of life. The aim of the research was to determine experienced levels of negative emotional states in patients diagnosed with breast cancer, and to examine the correlation between negative emotional states, and quality of life of the examinees. The sample included 86 outpatients who visited the policlinic for regular ultrasound and mammography checkups, and who were divided into two groups: clinical, consisting of women with breast cancer, who come for postoperative follow-up (n=32, 37.2%), and comparative group, including women with no health problems, whose reason for visit was of the preventive nature (n=54, 62.8%). We used socio-demographic questionnaire, depression, anxiety and stress scale - DASS-21, and Temporal satisfaction with life scale - TSWLS. Results show that women with breast cancer after the surgery and treatment usually get back to their activities and do not differ from the women without breast cancer regarding negative emotional states. This indicates the importance of the early detection of the problem, introduction of the efficient treatment, and providing adequate social support. Conclusion: the estimation of the psychological state and needs of the breast cancer patients is important in order to offer adequate support and help concerning the different reactions in specific phases of the illness and treatment. Key words: anxiety, depression, stress, breast cancer SAŽETAK Većina žena oboljelih od karcinoma dojke susreće se sa negativnim emocionalnim stanjima kao što su stres, anksioznost i depresija u svim fazama i vrstama tretmana. Nivo ovih stanja je individualan i održava se na zadovoljstvo životom. Cilj ovog istraživanja je utvrditi nivo negativnih emocionalnih stanja kod pacijentkinja sa dijagnostikovanim karcinomom dojke i njhovu povezanost sa zadovoljstvom životom ispitivanih žena. Uzorkom je obuhvaćeno 86 ispitanica koje su u ambulantnom tretmanu i dolaze na redovne kontrole. Podijeljen je u dvije grupe - kliničku, kojom su obuhvaćene žene sa karcinomom dojke, koje dolaze radi praćenja postoperativnog toka, (n=32, 37.2%) i komparativnu grupu koju čine žene sa urednim nalazom, a ljekaru se javljaju radi prevencije (n=54, 62.8%). U istraživanju je korišten upitnik sociodemografskih podataka, Skala temporalnog zadovoljstva životom (Temporal satisfaction with life scale TSWLS) i Upitnik o negativnim emocionalnim stanjima (Depression Anxiety and Stress Scale-DASS). Rezultati istraživanja pokazuju da se žene sa karcinomom dojke nakon provedene terapije i liječenja uglavnom vraćaju svojim aktivnostima i ne razlikuju se u pogledu negativnih emocionalnih stanja od žena sa urednim nalazima dojke. Navedeno ukazuje na značaj ranog otkrivanja bolesti, uvođenja efikasne terapije i pružanja odgovarajuće socijalne podrške. Zaključak: procjena psihološkog stanja i potreba pacijentkinja oboljelih od karcinoma dojke je važna radi pružanja adekvatne podrške i pomoći, u zavisnosti od različitih oblika reagovanja u specifičnim fazama bolesti i tretmana. Ključne riječi: anksioznost, depresija, stres, karcinom dojke INTRODUCTION In modern time, women are demanded to be actively enroled in numerous aspects of life. Challenges of everyday living, as well as various life events lead to stress of different intensity. Chronic stress causes exhaustion, immunity deficiency, and subsequently many types of illnesses, including breast cancer as rather frequent illness. Confronting the malignant tumor diagnosis is a stressful life event. Reaction to stress manifests not only through emotions, but also through thoughts, behaviours and relations with others. Informing the patient about the malignancy marks the beginning of the psychological crisis and is a state of brief psychological confusion in which a person is not capable to overcome psychological issues regarding the newly created circumstances of the diagnosis of severe illness, using the existing coping mechanisms (1). Early diagnostics and treatment of breast cancer prolongs life expectancy. However, women who suffer from this illness can experience several negative emotional states, such as stress, depression and anxiety, which can significantly affect the course of treatment (2). The incidence of psychological problems in women

13 252 N.Vaselić et al. with breast cancer is 33% during diagnosing, 15% one year after the diagnosis is made, and about 45% after the relapse of illness (3). In women with breast cancer, number of depressed is estimated to vary from 1.5% to 50% (4), anxious from 20% to 50% (5). Depression and anxiety are frequently correlated in women with breast cancer, and a lot of women suffer from symptoms of both types of disorders, about 11% to 16% of them (6,7). Women with more severe symptoms of depression and anxiety usually experience more side effects of the medications, and cope worse with those side effects, which can lead to lower quality of life (8,9). Symptoms of anxiety and depression reduce the capability of women to seek support when they need it the most (10,11). Furthermore, negative emotional states significantly increase the mortality risk in women with breast cancer (12). Diagnosing the illness is an important life event, that can lead to dramatic changes in the relationships, family roles, and can influence the psychological health of patients and their families (13,14). Factors linked to depression vary in different researches. Some studies find correlation between depression and psychosocial factors, such as marital status (divorce), lower education, lower income, while other results don t support these findings (15). Pain and physical damage connected to illness, correlate with depression (16). Furthermore, pain can predict the depression in patients with breast cancer (17). Fatigue, which is common physical symptom in patients with malignancy, can be the sign of progression of the illness, but also the side effect of radio or chemotherapy is frequently linked to depression (18,19). Mastectomy, a surgical removal of all or part of the breast, usually leaves scars and causes disfigurement, which can lead to perceiving oneself as less appealing and feminine and thus lead to depression (20). Helplessness/hopelessness is often recognised in patients with depression, and can negatively affect coping with malignancy (21). Life satisfaction or quality of life can be defined as one s perception of himself in a specific cultural, social and environmental context (22). Besides the objective factors, such as social, economic and political ones, the quality of life is affected by the subjective perception and estimate of physical, material, social and emotional wellbeing, personal growth and purposeful activity. Relation of objective and subjective quality of life is not linear, namely changes in objective factors do not cause the change in subjective component of life satisfaction (23,24). Many researches confirm that the level of perceived subjective quality of life is generally positive and stable. Researches also show that even the people who had experienced negative and traumatic life events report about the satisfying and positive subjective quality of life. The aim of the research was to determine the experienced levels of negative emotional states in patients diagnosed with breast cancer, and to examine the correlation between negative emotional states and quality of life of the examinees. MATERIALS AND METHODS The sample of the study was a convenience sample. It included 86 outpatients who visited the policlinic for regular checkups, and who were divided into two groups - clinical, consisting of women with breast cancer, who come for postoperative follow-up (n=32, 37.2%), and comparative group, comprising women with no health problems, whose reason for visit was of the preventive nature (n=54, 62.8%). The participants were from 30 to 73 years of age (57% under the age of 50 and 43% older than 50). Regarding the family status, most of the examinees were married, 58 of them (67.4%). There were 9 single participants (10.5%), 12 divorced (14%) and 7 widows (8.1%). Most of the participants were employed, 48 (55.8%), 24 (27.9%) of them were unemployed, and 14 were retired (16.3%). Instruments: we used self reporting scales: Depression Anxiety and Stress Scale DASS 21, constructed by Lovibond PF & Lovibond SH, 1995 (25). Temporal satisfaction with life scale TSWLS, constructed by Pavota, Dienera and Suha, addapted version by Penezić (26). Sociodemographic questionnaire created for the purpose of our research in order to collect data about marital and working status, family, etc. RESULTS The results were obtained from 86 examinees who visited a physician for a breast checkup, for prevention or for the reason of the postoperative follow-up. In majority of the participants families, 57% of them, one or more family members was diagnosed with severe somatic illness. Table 1 Life satisfaction differences between the groups. Past life satisfaction Present life satisfaction Future life satisfaction Group N M SD Results show that there is no statistically significant difference between clinical and comparative group, concerning past and present life satisfaction, nor in the expectancies about the future life satisfaction. The largest difference, but still statistically insignificant, was found regarding expectations of the future life satisfaction between the participants not diagnosed with breast cancer (M=2.39, SD=1.12) and participants with malignancy (M=2.84, SD=1.32, t=- 1.69, p=.09) in a way that examinees with breast cancer had more positive future life expectations then women from the comparative group. The other scores are presented in Table 1. Anxiety Depression Stress Group N Using t-test of independent samples, we compared levels of negative emotional states (depression, anxiety and stress) in a group of healthy women and in women with malignancy. There were no statistically significant differences between the groups on any of the subscales, as shown in Table 2. F Sig Sig t t df do Sig. (2-tailed) Table 2 Difference in negative emotional states between the groups. M SD F Sig. (2-tailed)

14 Negative emotional states and quality of life in women with breast cancer 253 Table 3 Correlation between life satisfaction and negative emotional states for the entire sample. Past life satisfaction Present life satisfaction Future life satisfaction When examining the entire sample, we observed that life satisfaction tended to negatively correlate with negative emotional states. There was a negative and low, but statistically significant correlation, between the past life satisfaction and depression in participants (r=0.29, p<.01). The higher the level of life satisfaction in present was negative emotional states were less experienced. The highest correlation was obtained between life satisfaction and depression (r=-0.42, p<.01), followed by stress (r=-0.33, p<.01) and anxiety (r=-0.29, p<.01). Expectations about life satisfaction in future in the same way correlated with the experience of distress. The more positive expectations from future was, the lower were levels of depression (r=-0.34, p<.01), stress (r=-0.28, p<.01), and anxiety (r=-0.26, p<.05) (Table 3). The same tendencies was found in the observation of the clinical group only, with one difference regarding the correlation of past life satisfaction which was mostly correlated with anxiety (r=-.39, p<.05). The results for other domains of life satisfaction and negative emotional states are presented in Table 4. Past life satisfaction Present life satisfaction Future life satisfaction DISCUSSION Anxiety ** -.262* Anxiety -.394* -.413* -.492** Depression -.299** -.420** -.343** Depression * -.440* Stress ** -.282** Table 4 Life satisfaction and negative emotional states in the clinical group. Stress ** -.496** Psychological problems among patients with breast cancer correlate with depression and depressive disorders, anxiety and anxiety disorders, anger, low self-esteem, and low emotional support (27). Assessing negative emotional states and quality of life in patients with malignancies, enables us to choose adequate therapeutic procedure, which can increase life expectancy, and at the same time provide better quality of life. Fears and worries about possible relapse of illness and lethal outcome, changes of body image that diminishes sense of femininity, sexuality and attractiveness are factors that make a ground for psychological distress (28) even years after diagnosing and treatment. Our research included 86 outpatients who visit policlinic for regular breast ultrasound and mammography checkups (women with no health problems) and for postoperative follow-up (the clinical group, that consisted of women with breast cancer). Life satisfaction largely depends on the number of stressful events, problems with self perception (body image), sexual relations, financial issues, anxious and depressive preoccupations (29). Numerous studies in clinical literature show the presence of increased anxiety in patients with malignancy (30). The period after finishing the treatment is the transitional period when women transform from the role of patient to the role survivor (31). Women in our sample could fall into second category, since they did not significantly differ from the general population. Anxiety is more frequent at the beginning of the treatment, and is linked to side effects of medicines and fear of relapse. Patients with malignancy can experience anxiety differently in different phases of illness while diagnosing, waiting for results, during treatment, or expecting relapse. Anxiety that is linked to malignant tumor can increase feeling of pain, cause insomnia, nausea and vomitting, and on psychological level, decrease in perceived quality of life. Study of Ashbury et al. (32) shows that 77% patients suffer from anxiety during the first two years of treatment. On the other hand, anxiety after diagnosing malignancy does not have to be pathological, but it is important to understand it s nature in the population of patients with malignancy, as it can slow the treatment process (33,34). Anxiety level is lower in people that have positive perception of satisfaction and meaning of life. Our results show, that the more positive expectations of future were, the lower were the levels of negative emotional states (table 3), which was found in similar studies (35). Somatic processes can provoke physiologially caused anxiety. Pain, asthenia, nausea, respiratory difficulties, and medications such as interferon, corticosteroids and morphine, are all linked to anxiety (36). Considering that our examinees are currently in a phase of a good remission, their levels of anxiety are lower, and do not differ significantly from the general population. Even though there are far less studies about anxiety in patients with malignancy than those on depression, disabling effects of anxiety can be the component of depressive reactions. However, diagnosis of breast cancer and its treatment causes stress which emphasizes the need for clinicians to adequatly identify pshychological consequences, such as depression, anxiety and stress. Early diagnose and treatment of depression in patients with breast cancer, not only enhances their life satisfaction, but also increases their chance of survival (37). Depression is often underestimated regarding women with breast cancer, and its incidence varies between 10% and 25% (38,39). It has been confirmed that the depression is highest while diagnosing (40), and it has been noticed, during follow-ups, and that the psychological needs of women with breast cancer have been frequently neglected (41). CONCLUSION The results of this research contribute to better understanding and recognizing the psychological problems in women with breast cancer. Results show that women with breast cancer, after the surgery and treatment, usually get back to their activities and do not differ from women without breast cancer regarding negative emotional states. This indicates the importance of early detection of the problem, introduction of the efficient treatment, and providing adequate social support. These findings can help the experts in the area of oncology, clinical and health psychology in a way that they implement psychological interventions and counseling during the diagnosing, treatment and rehabilitation of women with breast cancer. The subject is very important considering that the incidence

15 254 N.Vaselić et al. of malignancies in general, and especially breast cancer, increases, and that there is need to engage psychologists and similar professionals in everyday oncological practice. The question of psychological state estimation and needs of patients with breast cancer opens very important ethical questions, and offering adequate support and assistance demands excellent estimate of psychological state and needs that are supposed to be different in different phases of illness and treatment. Conflict of interest: none declared. REFERENCES 1. Vlajković J. (1992). Životne krize i njihovo prevazilaženje. Beograd: Nolit. 2. Institute of Medicine. Cancer care for the whole patient: Meeting psychosocial health needs. Washington, DC: The National Academies Press Burgess C, Comelius V, Love S, Graham J, Richards M, Ramirez A. Depression and anxiety in women with early breast cancer: Five-year observational cohort study. BMJ. 2005;330(7493): Trask P. 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16 Medical Journal (2015) Vol. 21, No. 4, Original article Frequency of anxiety and anxiety disorders among medical students during education Učestalost anksioznosti i anksioznih poremećaja kod studenata medicine u toku školovanja Ifeta Ličanin 1*, Belma Paralija 2, Delila Čengić 3, Ismana Šurković 3, Amira Redžic 4 1 Psychiatric Clinic, University Clinical Center Sarajevo, Bolnička 25, Sarajevo, Bosnia and Herzegovina; 2 Clinic of Pulmonary Disease, University Clinical Center Sarajevo, Bosnia and Herzegovina; 3 Clinic of Endocrinology, University Clinical Center Sarajevo, Bolnička 25, Sarajevo, Bosnia and Herzegovina, 4 Faculty of Medicine, University of Sarajevo, Čekaluša 90, Sarajevo, Bosnia and Herzegovina *Corresponding author ABSTRACT Introduction: mental health of university students is the area with increasing concern around the world due to the fact that this population is prone to depression, anxiety and stress. Anxiety disorders are one of the most common mental health problems among faculty students. Furthermore, it is known that medical students show greater prevalence of anxiety symptoms compared with other population groups and peers. Goals: to examine the prevalence of anxiety in the population of faculty students, and to determine whether there are differences in its appearance between the sexes and years of study. Material and methods: the study sample consisted of 201 students of the Sarajevo University Medical School, of which 63.2% were women. Anxiety is determined using Hamilton s inventory for anxiety and sociodemographic scale. Results and discussion: out of the total sample 46.8% of respondents showed signs of anxiety. The average score at the Hamilton anxiety scale amounted to 15.1±10.6 with a median of 12. Hamilton scale mean score for females (17.3±11.2) has been proven statistically significantly higher than male respondents with an average score of 11.3±8.3. With regard to the year of study anxiety score was higher in students of the first three years, 19.2±9.3 (range 5-37) compared to students on the last three years of the study 12.5±10.6 (range 0-47) with statistically significant difference (p<0.05). Conclusion: medical studies are high risk area for mental health problems. Female students show greater risk for anxiety, which declines over the course of the study. Key words: anxiety, medical students, mental health SAŽETAK Uvod: mentalno zdravlje univerzitetskih studenata je oblast za koju raste zabrinutost širom svijeta s obzirom da je ova populacija sklona depresiji, anksioznosti i stresu. Anksiozni poremećaji su jedan od najčešćih psihičkih problema na fakultetima. Također, poznato je da studenti medicine pokazuju veću prevalencu simptoma anksioznosti u usporedbi sa ostalom populacijom i vršnjacima. Ciljevi istraživanja: da se ispita učestalost anksioznosti u populaciji studenata, da se odredi da li ima razlika među spolovima, godinama studija- dobi. Ispitanici i metode: uzorak studije su činili 201 student Medicinskog fakulteta Univerziteta u Sarajevu od kojih je 63.2% ženskog spola. Kao instrumenti istraživanja korištena je Hamiltonova skala anksioznost i upitnik za sociodemografske karakteristike. Rezultati i diskusija: 46.8% od ukupnog broja ispitanika je pokazalo znakove anksioznosti. Prosječan skor na Hamiltonovoj skali anksioznosti je iznosio 15.1±10.6 uz medijanu od 12. Dokazan je statitstički signifikantno veći prosječni skor Hamiltonove skale kod ispitanika ženskog (17.3±11.2) u odnosu na ispitanike muškog spola sa prosječnim skorom od 11,3±8,3. S obzirom na godinu studija anksioznost je u prosjeku bila viša kod studenata prve tri godine tj. 19.2±9.3 (raspon 5-37) u odnosu na studente zadnje tri godine studija 12.5±10.6 (raspon 0-47) uz statistički signifkantnu razliku (p<0.05). Zaključak: studiji medicine je područje visokog rizika za mentalno zdravlje. Ženski spol pokazuje veći rizik za pojavu anskioznosti kod naših studentica, a anksioznost tokom studija opada. Ključne riječi: anksioznost, studenti medicine, mentalno zdravlje INTRODUCTION Anxiety is an emotional state characterized by a feeling of unease, agitation and tension, anticipation of potential dangers, as well as many physiological changes. It is a universal experience, so the anxiety and anxiety disorders are among the most common psychological and health problems with a prevalence of up to 20 to 30%. Stress in students across the world shows a worrying increasing trend (1). Mental health of university students is the area with increasing concern around the world because this population is prone to depression, anxiety and stress due to factors such as academic pressure, obstacles to the achievement of the objectives, changes in environment, changes in life in terms of the transition from school to the university and the transition from the student to the educated doctor (2). Furthermore, it is known that medical students have shown greater prevalence of anxiety symptoms compared with the rest of the population groups and peers (3). One dose of anxiety can be beneficial to students, but in a certain amount above this dose, it can be painful, paralyzing, and block the flow of thoughts and actions (4). Survey conducted in 2008 (Associated Press and MTV) showed

17 256 I. Ličanin et al. that 80% of respondents frequently or occasionally experience daily stress. From this group 34% of respondents felt depressed at some point in the last three months, whereas in 13% anxiety or depression was diagnosed and 9% seriously considered suicide during the past year (5). Medical students are overloaded with the huge amount of information that needs to be memorized in a short period of time (6). This can lead to feelings of disappointment because of the inability to handle with all the information at once and to achieve success during the test period. Many students struggle with the thought that they have the capacity to meet the demands of the medical curriculum (7). Each year of medical studies has been associated with its specific challenges (8). During the process of transformation from an insecure student to educated doctor students are faced with number of emotions. During the transition into the clinical environment in the third year of education, students can experience a loss of control that can be reflected in an increase in anxiety level. Studies suggest that mental health deteriorates after the students start with the study and remain at low level during the whole education (9). Many studies have shown the presence of anxiety among medical students, especially those in the first year of study, because then starts academic stressors such as sudden and huge volume of information overload, reduction of leisure time and the start of the evaluation in the form of exams and assignments (10). Female medical students have stronger reaction in form of anxiety then male (11). Gender differences in anxiety have been found both among doctors in training and young doctors, which is a reflection of epidemiological studies that anxiety is more common in women than in men (12) Goal To examine the prevalence of anxiety among the students of the Sarajevo Medical School and to establish whether there is a difference in the prevalence of anxiety in relation to sex, age, and academic year (the first three years compared to the last three years of education). MATERIALS AND METHODS The sample consisted of the University of Sarajevo Medical School students (n=201). The study was conducted during the second semester of the school year 2014/15 at the University of Sarajevo Medical School. Questionnaires were distributed to students with explanations regarding the objectives of the study and necessary instructions for proper filling out the questionnaire, after which the participants started voluntary and independent completing of the questionnaire for a maximum of 15 minutes. Respondents were guaranteed privacy and anonymous participation. The research contained the survey which examined the sociodemographic characteristics of respondents, while the second part of the questionnaire related to the Hamilton anxiety scale. The survey on the socio-demographic data included the information on gender, age, as well as data related to the study: years of study and number of repeated years. Hamilton anxiety scale (Hamilton Rating Scale for Anxiety, HAM-A) is the most widely used scale for anxiety symptoms. The analysis was conducted using statistical software IBM SPSS Statistics v21.0 (Chicago, Illinois, USA). The results are presented in tables and charts by number of cases, percentage, mean (X) with a standard deviation (SD) and standard error of arithmetic mean, median and range of values. Student s t and chi-square test at a confidence level of 95% or p <0.05 were used to test the differences. RESULTS The total sample included 201 respondents, of which 127 (63.2%) were females and 74 (36.8%) males. The average age of the subjects was 24.7±3.9 years, with the youngest respondent aged 18 and the oldest aged 38 years. The largest number of respondents was 24 years of age. The study sample had the highest number of sixth year students (56 or 27.9%) and the lowest number of the second year students (22 or 10.9%). Based on the distribution in the first and last three years of the study, smaller number of respondents in the first three years of education (77 or 38.3%) was noticed as compared to sixth year students (124 or 61.7%). Table 1 Mean anxiety score of respondents by the Hamilton scale. X SEM Median SD Minimum Maximum HAM - A Table 2 Anxiety score according to HAM-A (normal range 0-13, mild 14-17, moderate and severe depression with 25 or more points). HAM - A Normal range Mild anxiety Moderate anxiety Severe anxiety Total The average score on the Hamilton anxiety scale amounted to 15.1±10.6 with a median of 12 ranging from 0 to 47. According to the anxiety assessment criteria based on the HAM-A majority of subjects had a score corresponding to the normal range - without anxiety (107 or 53.2% of cases). Mild anxiety was observed in 20 (10%) and medium and severe anxiety in 37 (18.4%) respondents. In summary, 107 (53.2%) students did not show any signs of anxiety, while 94 students (46.8%) showed some of the symptoms. HAM - A HAM - A Normal range Mild Moderate Severe N % N % N % N % N % Gender Male Female N % Table 3 Comparison of anxiety score (according to the Hamilton scale) based on the severity of anxiety symptoms between males and females. TOTAL χ2=16.503; p=0.001 Total

18 Frequency of anxiety and anxiety disorders among medical students during education 257 Comparison according to the degree of anxiety based on the HAM-A shows statistically significant difference in relation to gender (p<0.05) with a higher number of males in the normal range and a higher number of females with moderate and severe anxiety. Table 4 Comparison of anxiety score (according to the Hamilton scale) based on the severity of anxiety symptoms among the students of first three years and students of the last three years of the study. HAM - A HAM - A This same relation can be observed in a comparison by category of anxiety where students of the last three years are significantly over-represented with normal range of values or without anxiety, and the students of the first three years in all three categories with present anxiety and statistically significant difference (p<0.05). DISCUSSION Normal range Mild Moderate Severe TOTAL χ2=31.544; p= N % N % N % N % N % Year of study I - III IV - VI Total In this study we wanted to examine the presence of anxiety, specifically symptoms of anxiety, among the students of the Sarajevo Medical School. For the purpose of statistical analysis 201 students were selected, of which 63.2% were females. The average age of subjects was 24.7 years with a standard deviation of 3.9 years, ranging from years. Survey conducted in Egypt included a total of 164 students from the Medical School of which 50% were females. The average age of subjects was 20.1 years with a standard deviation of 2.5 years, ranging from 18 to 25 years of age (13). A study conducted in Brazil involved a total of 232 students, of whom 62.5% were women, with an average age of 23.4 and standard deviation of 2.7 years, ranging from 18 to 30 years (14). Based on this we can conclude that the research carried out in Egypt and Brazil had substantially similar sample of respondents, also the male - female subjects ratio was similar to the ratio in our study, while the average age at the Sarajevo Medical School was a little bit higher than the average age of the students from Alexandria and Rio. The total sample included students from all educational years. The first year of the study included 12.4% of respondents, the second year 10.9%, the third 14.9%, the fourth 16.9%, and the fifth 16.9% of respondents. The largest number of respondents (27.9%) was registered at the sixth year of the study. The respondents were further divided into two groups; the first included the students in the first three years of the study, which amounted to 38.3% of the total sample, and the second group of students in the last three years of the study or 61.7% of the total sample. The study conducted in Brazil tested a total of 110 students from the first study year (73.8%) and 122 students from the sixth study year (62.56%). Our research results showed that 46.8% of respondents showed some signs of anxiety. The average score on the Hamilton anxiety scale amounted to 15.1±10.6 with a median of 12 ranging from 0 to 47. The study conducted in Egypt revealed that 43.9% of students showed signs of anxiety (according to Beck Anxiety Inventory). In the Brazil study, 30.9% of participants showed signs of anxiety (also according to Beck anxiety inventory). Comparing these results with those obtained in our study we could determine that the percentage of anxiety among students was similar, although it was higher at the Sarajevo Medical School, but with no significance. However, compared with other studies such as those in Greece, where the presence of anxiety was 10.4%, in the US 15.2% or 24% in the UK (13,15) we can conclude that anxiety in our students was much more represented. Why was that so? The answer to this question lies in the economic and social turmoil which is the source of majority of the population stress. Also, a disorganized educational system and the lack of services to deal with the mental health of students have great influence on the increased presence of anxiety. Comparison of the average values of the Hamilton scale score showed that female respondents had statistically significant higher scores with an average of 17.3±11.2 as compared to the male respondents with an average score of 11.3±8.3. In other words 55.9% of female respondents showed signs of anxiety as compared to 31.1% of male respondents with signs of anxiety. Also, a higher percentage of women showed signs of moderate (19.7%) and severe anxiety (26%) as compared to men where these percentages were 16.2% for moderate anxiety and 5.4% for severe anxiety. These results correspond to epidemiological studies according to which the anxiety is more prevalent in females. Also, the research conducted at the Federal University of Rio Grande de Sul (UFRGS) has shown that women are in a higher percentage (26.6%) more anxious than men (12.5%). Based on the years of education, anxiety was higher in students of the first three years 19.2±9.3 (range 5-37) as compared to students in the last three years of study -12.5±10.6 (range 0-47) with the statistically significant difference (p<0.05). Also, the students from the first three years of the study had higher percentage of moderate (32.5%) and severe anxiety (27.3%) than students in the last three years (9.7% moderate and 12.9% severe anxiety). A study conducted in Brazil compared the anxiety of students at the first and sixth year of the study. The results of this study showed that the anxiety on average was higher among first-year students (8.61±7.66) as compared to the sixth year students (4.99±5.36). Although our study included students from all study years and comparison between the first three study years and the last three study years, the results we obtained are comparable with those obtained in the Brazilian study. The reason is that the present study tried to prove that anxiety during studies is declining, as was evident in our results and the results of the Brazilian study. Measured by GAD-7 scale higher scores with statistically significant difference (p<0.05) was noted among the students of the first three years -6.6±4.8 (range 0-20) as compared to students in the last three years -5.7±4.8 (range 0-21). These results were merged with the results obtained by the Hamilton test for anxiety, by which

19 258 I. Ličanin et al. symptomatology of anxiety disorders could be determined as well as its decrease during the study. It is assumed that the higher prevalence of anxiety among the students at the beginning of the study is related to several factors: a higher level of physical and mental demands that is originally imposed by exam, family expectations, expectations of students as freshmen who usually fantasize and idealize environment and the subsequent difficulties in dealing with student life and finally the need for adapting to new world of relationships, and commitments. During the study we observed a progressive adaptation to all the listed factors of influence during the study. Also, students accepted their role of medical students, partly by identifying themselves with certain role models - for example, teachers or other higher grade students. Furthermore the students developed an individual approach to patients after positive and negative interactions with each other; they were introduced to their colleagues and sympathized with them, acting towards significant decline of initial anxiety registered in the first years of the study (16). CONCLUSION Out of the total sample 46.8% of respondents showed signs of anxiety. The difference in frequency of anxiety in females as compared to males was statistically significant Statistically significant difference was demonstrated in the incidence of anxiety among students of the first three years of the study as compared to students of the last three study years. 4. Brandtner M, Bardagi M. Sintomatologia de depressao e ansiedade em estudantes de uma universidade privada. Rio Grande do Sul. 2009;2: Anxiety and Depression Association of America. [Online] 6. Carveth JA, Gesse T, Moss N. Survival strategies for nurse-midwifery students. J Nurse Midwifery. 1996;41(1): Yusoff MS, Abdul Rahim AF, Baba AA, Ismail SB, Mat Pa MN, Esa AR. Prevalence and associated factors of stress, anxiety and depression among prospective medical students. Asian J Psychiatr. 2013;6(2): KBS, Guimaraes. Estresse e a formacao medica:implicacoes na saude mental dos estudantes. ASIS: Universidade Estadual Paulista Ahmed I, Banu H, Al-Fageer R, Al-Suwaidi R. Cognitive emotions: depression and anxiety in medical students and staff. J Crit Care. 2009;24(3):e Eller T, Aluoja A, Vasar V, Veldi M. Symptoms of anxiety and depression in Estonian medical students with sleep problems. Depress Anxiety. 2006;23(4): Rizvi AH, Awaiz M, Ghanghro Z, Jafferi MA, Aziz S. Pre-examination stress in second year medical students in a government college. J Ayub Med Coll Abbottabad. 2010;22(2): Al-Adawi SS. A comparative study of perceived stress among female medical and non-medical university students in Dammam. Sultan Qaboos Univ Med J. 2010;10(3): Mancevska S, Bozinovska L, Tecce J, Pluncevik-Gligoroska J, Sivevska-Smilevska E. Depression and anxiety and substance use in medical students in the Republic of Macedonia. Bratisl Lek Listy. 2008;109(12): Tjia J, Givens JL, Shea JA. Factors associated with undertreatment of medical study depression. J Am Coll Health. 2005;53(5): Yusoff MB, Rahim AFA, Yaacob MJ. The prevalence of final year medical students with depressive symptoms and its contributing factors. 2011; 18: Dahlin ME, Runeson B. Burnout and psychiatric morbidity among medical students entering clinical training: a three year perspective questionnaire and interview-based study. BMC Med Educ. 2007;7:6. Conflict of interest: none declared. REFERENCES 1. S1. Sax LJ. Health trends among college freshmen. J Am Coll Health. 1997;45(6): Bilgel N, Bayram N. The prevalence and socio-demographic correlations of depression, anxiety and stress among a group of university students. Soc Psychiatry Psychiatr Epidemiol. 2008;43(8): Dyrbye LN, Thomas MR, Shanafelt TD. Systematic review of depression, anxiety, and other indicators of psychological distress among US and Canadian medical students. Acad Med. 2006;81: Reprint requests and correspondence: Ifeta Ličanin, MD, PhD Psychiatric Clinic University Clinical Center Sarajevo Bolnička 25, Sarajevo Bosnia and Herzegovina Phone: licaninifeta@hotmail.com

20 Medical Journal (2015) Vol. 21, No. 4, Original article Significance of protective colostomy in preventing complications in low rectal anastomosis Značaj protektivne ileostome u prevenciji komplikacija kod niskih kolorektalnih anastomoza Jugoslav Đeri 1*, Milan Simatović 1, Nebojša Trkulja 1, Nenad Lalović 2 1 Department of General and Abdominal Surgery, University Clinical Center Banja Luka, Dvanaest beba, Banja Luka, Bosnia and Herzegovina; 2 Department of Surgery, University Hospital Foča, Studentska 5, Foča, Bosnia and Herzegovina *Corresponding author ABSTRACT The protective ileostomy is a procedure that is now increasingly used after creating low colorectal anastomosis, and after rectal cancer resection. The protective ileostomy to a lesser extent affects the prevention of dehiscence colorectal anastomosis, but it has much greater significance in reducing the severity of complications after anastomosis dehiscence. Colorectal anastomosis is a very specific procedure in digestive surgery in the formation and healing but also in complication development. Anastomotic healing is a complex process depending on many interrelated factors. However, both creation and closure of stoma are accompanied by certain complications. This study analyzed 126 patients with anastomoses created in the lower and middle third of the rectum, i.e. up to 10 cm from the anocutaneous line. The first group included 42 patients with protective ileostomy created after low colorectal anastomosis. The second group included 84 patients to whom protective ileostoma was not created after low colorectal anastomosis. The study followed frequency of complications in the two observed groups and the role of protective ileostomy in reducing the severity of complications. Key words: protective ileostomy, rectal cancer, colorectal anastomosis complications SAŽETAK Protektivna ileostoma je procedura koja se danas sve više koristi nakon kreiranja niske kolorektalne anastomoze, a poslije resekcije karcinoma rektuma. Protektivna ileostoma u manjoj mjeri utiče na sprečavanje dehiscencije kolorektalanih anastomoza, ali ona ima mnogo veći značaj u smanjenju težine komplikacije nakon dehiscencije anastomoze. Kolorektalna anastomoza je veoma specifična procedura u digestivnoj hirurgiji kako u formiranju, zarastanju tako i u nastanku komplikacija. Zarastanje anastomoze je složen proces koji zavisi od više međusobno povezanih faktora. Međutim i samo kreiranje kao i zatvaranje stome praćeni su određenim komplikacijama. U ovoj studiji posmatrana su 126 bolesnika kod kojih je anastomoza kreirana u donjoj i srednjoj trećini rektuma tj. do 10 cm od anokutane linije. Prva grupa je obuhvatala 42 bolesnika, kod kojih je nakon niske kolorektalne anastomoze kreirana protektivna ileostoma. Druga grupa je obuhvatala 84 bolesnika, kod kojih nakon niske kolorektalne anastomoze nije bila kreirana protektivna ileostoma. U studiji su praćene učestalost komplikacija u posmatrane dvije grupe i uloga protektivne ileostome u smanjenju težine komplikacija. Ključne riječi: protektivna ileostoma, karcinom rektuma, komplikacije kolorektalne anastomoze INTRODUCTION The incidence of postoperative complications in the colon and rectum is on average higher than in other abdominal organs. They threaten the patient s life, and often require emergency surgery with prolonged, complex and very expensive treatment. One of the major complications of the rectum is loosening seams on colorectal anastomosis and anastomotic dehiscence (1). Anastomosis failures are more common in low anterior resection of the rectum than in other resection of the colon and rectum. Dehiscence can occur from 3 to 45 days after surgery, although it is usually manifested between the fifth and eighth day (2). A number of factors may cause dehiscence of colorectal anastomosis. These may be technical factors such as surgical technique, traumatic operation, the tensions anastomoses, the existence of obstruction distal to the anastomosis, and inadequate preoperative preparation of the patient (3). The incidence of complications can be significantly reduced by using certain preoperative, intraoperative and postoperative procedures. Implementation of intraoperative prevention measures is the most important measure for preventing anastomotic dehiscence. There are number of intraoperative prevention measures such as adequate surgical technique, adequate anesthesia, properly created anastomosis, but it is believed that one of the most important preventive measures is creation of protective ileostomy (4). The first application of ileostomy dates back to the nineteenth century, and over time the technique of ileostomy creation and application had changed and improved (5). Nowadays, there are number of indications for the creation of bipolar ileostomy but it has lately been increasingly used routinely in order to protect the low colorectal and coloanal anastomosis (6).

21 260 J. Đeri et al. Although there are opposing views regarding the role of a loop ileostomy in protecting low colorectal anastomosis dehiscence its role is undoubtedly significant in reducing severity of complications and mortality rate in patients in which dehiscence have already occured (7). The main objective of this study was to determine whether protective ileostomy prevented the emergence of dehiscence at low colorectal anastomosis and to determine complications after low colorectal anastomosis dehiscence in patients with loop ileostomy and in patients without protective ileostomy. MATERIALS AND METHODS The study was designed as a retrospective-prospective study. It included 126 patients divided into two groups. The first group included 42 patients with protective ileostomy created after low colorectal anastomosis. The second group included 84 patients to whom protective ileostoma was not created after low colorectal anastomosis. Both groups of patients were similar in age and sex. Data for the study, such as gender, age, operating results, and complications were used from the medical records, operating protocols, and clinical examination of patients treated at the Clinic of General and Abdominal Surgery of the University Clinical Center Banja Luka. Given that the Institution in which the study was conducted did not have any official protocol related to implementation of the preoperative neoadjuvant therapy, the study was carried out on a small number of patients at discretion of the oncology consilium, and was not the subject of the observation study. Surgical techniques in both groups of patients were identical and included resection of low rectal excision, sharp thermocauter and ligasure, under direct visual control outside the visceral fascia covering the rectum and mesorectum. It was done in high ligation and resection of the lower mesenteric vessels. At the same time adequate hemostasis was made using ligatures spororesorptinog suture material and ligasure. In both groups of patients with rectal tumors at the distance of 10 cm from anocutane lines total mesorectal excision was performed, i.e. removing the entire mesorectum to provide preparation of smooth and glossy surface. Resection in most cases was done using linear TA stapler. In a small number of patients resection of the rectum was performed using a low anterior resection stapler (contour). The anastomosis was created by using mechanical circular stapling devices (staplers). All patients who were likely for loop ileostomy, were informed about this additional procedure prior to the operation, and their approval was required. The final decision about the need to create protective ileostomy was brought during the operation. The decision depended on the existence of factors which could threaten the anastomosis as well as from the opinion of the surgeon. Anastomosis protection was performed for the majority of coloanal anastomosis by creating a protective ileostomy. For creation of a loop ileostomy standard surgical technique was applied. Protective ileostomy was created in the lower right quadrant of the abdomen, on the line connecting the front upper belly button and pelvic bulge. RESULTS All patients from the study were divided into two study groups: study group A, which included 42 patients who underwent protective ileostomy, and study group B, which included 84 patients who did not undergo loop ileostomy. Table 1 shows that anastomosis dehiscence in patients who had built in stoma occurred in 9.5% of cases, whereas in patients who had this type of stoma built in, complications occurred in 11.9% of cases. Table 1 Comparative overview of the number of patients with dehiscence anastomoses in groups A and B. Dehiscence anastomosis Yes No Total Group A N % 4 9, , Group B N % 10 11, , Comparison of anastomotic dehiscence frequency in the two groups of patients using the Kruskal-Wallis test showed a level of significance (P) (Table 2). Since the calculated value was P> 0.01 it could be concluded that there was no statistically significant difference between the groups, with a confidence level of 99%, i.e. it could be concluded that the incidence of anastomotic dehiscence did not depend on whether patients had built-in ileostomy or not. Table 2 The incidence of dehiscence in group A and group B using Kruskal-Wallis test. Group With stoma Without stoma Total χ 2 test (hi square test) Df (number of degree of free choice) Asymp.sig. (level of significance) P N (number of samples) Mean Rank (middle ranking) With regard to severity of complications, in 7.1% of the total number of group A patients there was no need for reoperation after anastomotic dehiscence. In group B, in 5.95% of patients there was no need for reintervention. In 2.4% of patients with implanted stoma, or 4.8% of patients with built in stoma, reintervention was necessary. In 3.6% of patients who had built in stoma complications resulted in death, and in patients who had installed stoma, not a single case of death was registered (Table 3). Table 3 Frequency of reinterventions and deaths in patients with dehiscence in group A and B. Without repetitive operation after dehisc. Repetitive operation after dehisc. Mortality rate N % with dehisc % entire group If we take into account only the patients in which anastomotic dehiscence occurred after built in stoma, in 75% of them there was no need for reintervention, whereas in 25% of cases reintervention was needed but with no cases of death registered. In patients who had built in stoma, and where astomosis dehiscence occurred in 50% of cases reintervention was necessary and 60% of the cases ended in N % with dehisc % entire group

22 Significance of protective colostomy in preventing complications in low rectal anastomosis 261 death after reintervention. Comparison of types of complications that occurred in these two groups of patients using the Kruskal-Wallis test showed a level of significance (P) 0.001, which means that types of complications statistically significantly differed, at the level of reliability of 99% (Table 4). Table 4 Severity of complications using the Kruskal-Wallis test. DISCUSSION χ2 test (hi square test) df (number of degree of free choice) Asymp. sig. (significance level) P **Significance level of 99% 11,051 Colorectal anastomosis dehiscence is one of the most common and most serious complications in surgery of the digestive system, often with fatal outcome. Despite great advances in surgical technique, preoperative and postoperative care of patients the incidence of dehiscence at low colorectal anastomosis is still large (8). It is now moving at an average of 3-25%. The reasons for these variations are numerous factors, such as the selection of patients, a variety of surgical techniques, postoperative care, and others. Since the low anterior resection of the rectum become the method of choice in the treatment of rectal cancer, the impact of anastomotic dehiscence on morbidity and mortality occupy a great deal of attention. Due to high percentage of colorectal anastomosis dehiscence its prevention and complications control has been widely considereds. Therefore, to protect the low colorectal anastomosis, and prevent serious and sometimes fatal consequences of dehiscence, protective ileostomy, a procedure that is now more routinely used, is applied. Nowadays it is not easy to evaluate patients with probability of dehiscence or which patients will benefit from the application of protective ileostomy (9). Literature review did not result in finding any published prospective study related to the exact role of a loop ileostomy in protecting the low colorectal anastomosis. Therefore, the decision to create loop ileostomy for protecting the low colorectal anastomosis still largely depends on personal knowledge and experience of the surgeon. However, creating a loop ileostomy not only excludes the risk of colorectal anastomosis dehiscence, but is also significant for reducing complications and facilitate the treatment of patients with peritoneal (10,11). This study did not show significant difference in the incidence of respiratory failure in patients with the created loop ileostomy, in patients without protective ileostomy, and after low anterior resection. The incidence of dehiscence in patients with created loop ileostomy was 9.5%, while the incidence of dehiscence in patients without loop ileostomy was 11.9%. Gastinger et al. obtained similar results. In their study, 2729 patients received a protective stoma after low anterior resection. The protective ileostomy was created in 881 patients. Anastomotic dehiscence was in a similar percentage in both groups of patients. In those with protective stoma it was 14.2% and in those without a protective ileostomy dehiscence was 14.5%. However, the need for surgical intervention was significantly lower in patients with loop ileostomy and it amounted to 3.6%, whereas in patients without stoma it was 10.1%. Also, the percentage of mortality was significantly lower in patients with ileostomy 1 0,001** (0.9%) as compared to patients without stoma (2%) (12). Shiomi et al. conducted a retrospective study on 329 patients in five cancer centers in Japan. The aim of this study was to investigate risk factors for anastomotic dehiscence. Emergency surgical reoperation after dehiscence was required in patients with protecting ileostomy and in patients without protective ileostomy. The total percentage of anastomotic dehiscence was 10%. The study indicated that there was no significant difference in the incidence of dehiscence in patients with loop ileostomy and in those without loop ileostomy. The protective ileostomy had no connection with the easing anastomoze. However, this study also showed that there was a significant difference in the need for reintervention in these two groups of patients. In patients with a protective stoma percentage of reintervention was 11.1%, while the percentage of patients without stoma requiring reintervention was approximately 54%. This indicates that the application of protective stoma significantly mitigate the consequences of dehiscence and the need for urgent surgical reintervention (13). Our study, conducted at the Department of General and Abdominal Surgery on 126 patients, did not prove that protective ileostomy influenced the prevention of anastomotic dehiscence, or that it could significantly reduce the incidence of anastomosis dehiscence after low anterior resection. Nevertheless, some authors found that the protective ileostomy could significantly affect the reduction of colorectal anastomosis dehiscence. Mattheissen et al. conducted a study including 234 patients with rectal cancer. The aim of the study was to assess the incidence of anastomotic dehiscence and the intraoperative assessment for creating a loop ileostomy. They found that the use of loop ileostomy could significantly reduce the incidence of anastomotic dehiscence in patients with low colorectal anastomosis and progress of TME, and its use was fully justified. The incidence of dehiscence in patients with a created loop ileostomy after low anastomosis was about 10%. In patients after low anterior resection, in which protective ileostomy was not created, the incidence of dehiscence was 28% (14). Similar results on the positive implementation of protective ileostomy were shown by Dutch surgeon Peeters in his study of 924 patients. The study included patients verified for low rectal cancer resection with total mesorectal excision. Anastomotic dehiscence after low anterior resection was present in 107 patients (11.6%). The study showed that the application of protective stoma was significantly associated with a lower rate of dehiscence. The correlation between patients without stoma and anastomotic dehiscence was significant in both genders. Also, in patients with anastomotic dehiscence who had a protective ileostomy created, surgical reintervention was required in a considerably smaller number of patients. In this case, the application of the stoma has been fully supported (15). In the first group of patients without a protective ileostomy dehiscence was diagnosed in 10 of 84 patients. In 5 patients a milder complications were reported relating to emerged discharge of intestinal contents in the abdominal drain, fever and occasional abdominal pain. Severe complications with signs of peritoneal irritation, high febrile and even early signs of septic state were reported in 5 patients with dehiscence or in 50% of cases and the reinstatement surgery was required. In the second group of 42 patients with loop ileostomy dehiscence occurred in 4 patients. Three patients developed mild complications and received a successful conservative treatment. The need for new

23 262 J. Đeri et al. surgical intervention was required in only one out of 4 patients with peritoneal or in 25% of the cases. Also, mortality rate in the first group of patients without ileostomy and in whom dehiscence occurred, was approximately 30%. Due to complications 5 patients with respiratory failure required surgical treatment, with fatal outcome in 3 patients. In the second group of patients with the protective stoma and occurrence of dehiscence, there was no mortality. Similar ratio was showed in the study conducted at the Surgical Clinic of the St Spiridon Hospital. The study followed 75 patients who underwent surgery in the period from 2004 to They underwent low anterior resection of the rectum with total mesorectal excision. They analyzed the early postoperative period with all the complications that occurred in both groups of patients, as in patients with a protective stoma and patients without protective stoma. The obtained results showed that the protective ileostomy significantly reduces the risk of serious complications in case of anastomotic dehiscence (16). The beneficial effect on the reduction of stoma complications and mortality rate was confirmed in their study Gastinger et al., where the need for surgical intervention was significantly lower in patients with loop ileostomy (3.6%), whereas in patients without stoma it was 10.1%. Also, the percentage of mortality was significantly lower in patients with ileostomy (0.9%) as compared to patients without stoma (2%) (12). Chud at al. conducted a study to determine the necessity of creating a routine loop ileostomy. The study was designed to evaluate early morbidity, mortality and hospital stay in patients who underwent surgery for rectal cancer with and without protective stoma. The study was conducted in the period from 2001 to 2008, and included 256 patients divided into two groups. Group A in which anastomosis was not created after ileostomy, and group B with created ileostomy. There were 12 patients with dehiscence in group A and 3 patients with dehiscence in group B. Three cases of mortality were registered in group A were 3 deaths, whereas there was no mortality cases in group B, and all patients with peritoneal were successfully conservatively treated and released home on the twenty-fifth day. Complications of loop ileostomy occurred in a milder form and were usually treated out of hospital. Creating an ileostomy is useful and safe and is recommended as a routine procedure at low rectal cancer (17). Kohler et al. conducted a study on 190 patients with low resection of the rectum. Total of 31 patients underwent ultra low resection of the rectum due to low localization of the tumor. In these patients, due to low anterior, resection was done manually and a protective ileostomy was created. In patients with a loop ileostomy there was no need for new surgical intervention, and there were no cases of mortality (18). The advantage of protective ileostomy is that in cases of partial anastomotic dehiscence it prevents passage chairs at the site of dehiscence and thus offers the possibility of spontaneous anastomosis healing without the need for surgical reintervention. It also enables the oral nutrition of patients, which is very important for improving general condition of the patient and the healing of anastomosis. CONCLUSION This study showed that protective ileostomy created in patients after low anterior resection did not prevent development of dehiscence anastomosis. The study further showed that in the group without protective ileostomy dehiscence occurred in 11.9% of patients, whereas in the group with loop ileostomy dehiscence occurred in 9.5% of patients. However, creating a loop ileostomy after resection of rectal cancer reduced the severity of complications and the need for surgical reintervention, and protective ileostomy also significantly reduced mortality rate. Conflict of interest: none declared. REFERENCES 1. Montedori A, Cirocchi R, Farinella E, Sciannameo F, Abraha I. Covering ileo-or colostomy anterior resection for rectal carcinoma. Cochrane Database Syst Rev. 2010;(5). 2. Matthiessen P, Hallböök O, Andersson M, Rutegård J, Sjödahl R. Risk factors for anastomotic leakage after anterior resection of the rectum. Colorectal Dis. 2004;6(6): Stevović D. Colorectal anastomosis crijeva. Medicinska book Belgrade 1983; Konishi T, Watanabe T, Kishimoto J, Nagawa H. Risk factors for anastomotic leakage after surgery for colorectal cancer: results of a prospective surveillance. J Am Coll Surg. 2006;3: Franks K. Colectomy or ressection of the large intestine for malignat disease. 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Stoma -related complications are more frequent after transverse colostomy than loop ileostomy: a prospective randomized clinical trial. Br J Surg. 2001;88(3): Gastinger I, Marusch F, Steinert R, Wolff S, Koeckerling F, Lippert H; Working Group Colon/Rectum Carcinoma. Protective defunctioning stoma in low anterior resection for rectal carcinoma. Br J Surg. 2005;92(9): Shiomi A, Ito M, Saito N, Ohue M, Hirai T, Kubo Y, Moriya Y. Diverting stoma and rectal cancer surgery. A retrospective study of 329 patients from Japanese cancer centers. Int J Colorectal Dis. 2011;26(1): Matthiessen P, Hallböök O, Andersson M, Rutegård J, Sjödahl R. Risk factors for anastomotic leakage after anterior resection of the rectum. Colorectal Dis. 2004;6(6): Peeters KC, Tollenaar RA, Marijnen CA, Klein Kranenbarg E, Steup WH, Wiggers T, Rutten HJ, van de Velde CJ; Dutch Colorectal Cancer Group. Risk factors for anastomotic failure after total mesorectal excision of rectal cancer. Br J Surg. 2005;92(2): Radu I, Anitei G, Scripcariu V, Dragomir C. Low anterior resection of the rectum with total excision mesorectal - immediate results]. Rev Med Chir Soc Med Nat Iasi. 2011;115(2): Chude GG, Rayate NV, Patris V, Koshariya M, Jagad R, Kawamoto J, Lygidakis NJ. Defunctioning, loop ileostomy with low anterior resection for distal rectal cancer: should we make an ileostomy as a routine procedure? A prospective randomized suudy. Hepatogastroenterology. 2008;55(86-87): Köhler A, Athanasiadis S, Ommer A, Psarakis E. Long-term results of low anterior resection with anastomosis intersphincteric in carcinoma of the upper one-third of the rectum: analysis of 31 patients. Dis Colon Rectum. 2000;43(6): Reprint requests and correspondence: Jugoslav Đeri, MD, MSc Department of General and Abdominal Surgery University Clinical Center Banja Luka Dvanaest beba, Banja Luka, RS, Bosnia and Hercegovina djeri@blic.net

24 Medical Journal (2015) Vol. 21, No. 4, Original article Difficulties and risks in treatment of hepatitis C viral infection among opiate addicts in substitution treatment Poteškoće i rizici u liječenja hepatitis C virusne infekcije među opijatskim ovisnicima na supstitucionoj terapiji Rasema Okić 1*, Samir Kasper 2, Sabina Mađar 1 1 Institute for Alcoholism and Substance Abuse of Canton Sarajevo, Bolnička 25, Sarajevo, Bosnia and Herzegovina; 2 Institution for Addiction Diseases of Zenica-Doboj Canton, Dr. Abdulaziza Aska Borića 28, Zenica, Bosnia and Herzegovina *Corresponding author ABSTRACT Introduction: hepatitis C (HCV) infection has a high prevalence among those addicted to psychoactive substances (PAS). Respondents inclusion in treatment requires a multidisciplinary approach by psychiatrists-addictologists, gastroenterologist and virologists, but also education and motivation of respondents for the treatment. Goal: the aim of this study was to evaluate the total number of respondents who tried to enter the anti-hcv program, and the outcome of their treatment. Materials and methods: the study included a total of 304 opiate addicts on methadone substitution therapy (240 respondents) and Suboxone (64) from the Institution for fight Against Addiction Diseases of Zenica-Doboj Canton. Used materials: form for treated addicts (Pompidou), Short Symptom Inventory BSI-scale and hepatitis markers tests. Inclusion criteria for AVT were: stable psychological status, negative heroin tests for more than six months and optimal dose of methadone (40-60mg), or Suboxone (4-8mg). Results: at the time of the testing by BSI on current psychological symptoms and discomfort the mean of 44.52±33.59 was obtained. At the time of the testing minor mental problems were experienced by 23% of respondents while 13% of respondents had moderate and considerable problems. The AVT included 16 respondents. The treatment was completed by six respondents; six of them were in the treatment and four at preparation stage. Among those who have completed treatment, four of them (genotype II) had good therapeutic effect. Conclusion: inclusion of opiate addicts in AVT in our region is still a pioneering endeavor. Particularly important is the therapeutic support to the respondent s decision to make better use of opiate substitution treatment programs, as starting point for the HCV infection treatment. Key words: opiate addiction, substitution therapy, chronic hepatitis C SAŽETAK Uvod: HCV infekcija ima visoku prevalencu među ovisnicima o psihoaktivnim supstancama (PAS). Ovisnost o PAS je rijetko usamljeni poremećaj, već udružena sa drugim psihičkim poremećajima. Ulazak u liječenje zahtijeva multidisciplinaran pristup psihijatara-adiktologa, gastroenterologa i infektologa, te edukaciju i motivaciju pacijenata za ovaj tretman. Cilj ovog rada je evaluirati ukupan broj pacijenata koji su pokušali ući u anti HCV program i ishod njihovog liječenja. Materijali i metode: ispitanici su opijatski ovisnici, ukupno 304 na supstitucionoj terapiji Metadonom (240 pacijenta) i Suboxonom (64) Zavoda za bolesti ovisnosti Zeničko-Dobojskog kantona. Korišteni materijali su: Obrazac liječenih ovisnika (Pompidou), Kratki inventar simptoma- BSI skala za procjenu psihopatologije i testovi na hepatitis markere. Kriteriji za uključenje u AVT su: da su pacijenti u psihičkoj stabilizaciji, heroin negativni duže od šest mjeseci, a optimalne doze metadona su 40-60mg odnosno na Suboxonu 4-8 mg. Rezultati: u vrijeme samog testiranja BSI procjenom trenutnih psihičkih simptoma i nelagode dobijena aritmetička sredina je 44.52± Manje psihičke smetnje u času testiranja je imalo 23% pacijenata, a 13% ispitanika je imalo umjerene i prilične psihičke smetnje. U proces AVT ukupno je bilo ili je uključeno 16 pacijenata. Tretman su završilo šest pacijenta, šest je u toku tretmana, a četiri su u pripremi. Među onima koji su završili tretman, njih četiri (genotip II) je imalo dobar terapijski učinak. Zaključak: uključivanje opijatskih ovisnika na AVT na našim prostorima je još uvijek pionirski poduhvat. Od posebne važnosti je terapijski suport pacijentove odluke da bolje iskoriste programe opijatske supstitucione terapije, a kao polazište za liječenje HCV infekcije. Ključne riječi: opijatska ovisnost, supstituciona terapija, hronični hepatitis C INTRODUCTION Users of psychoactive substances are more prone to infections than others due to a decrease in body resistance. Even those who are involved in the program of opiate substitution treatment (OST) carry with them a whole range of somatic impairments with leading problems of the liver, skin, blood vessels etc. All of these diseases can be transmitted by blood transfusions and blood products, by unsterile needles among intravenous addicts, by shared dialyzer in dialysis centers, by transplanted organs, promiscuous sexual behavior without protection, through the open wound on the skin and mucous membranes, tattoos and piercings, vertically from mother to child

25 264 R. Okić et al. during birth and by sharing cutlery and/or means for personal hygiene (1). Hepatitis virosa C (HCV) is insidious, asymptomatic disease, which in 75-90% of cases progress to chronic hepatitis and in 20-25% of cases progress to liver cirrhosis. It happens that HCV is associated with hepatocellular carcinoma, which causes high mortality among cancer patients (1). All this reduces the quality of life and shortens the life of these persons. Patients who are in comorbid relation with mental disorders and PAS abuse have an increased risk for HCV infection. Furthermore, psychiatric disorders are more common during antiviral treatment and may be associated with the use of interferon, but also the primary psychiatric disorders (2). Depression, as one of the most important psychiatric side effects of alpha interferon therapy can be treated acutely or even better prevented by antidepressants treatment (2). A significant number of respondents on opiate substitution therapy (Methadone, Suboxone) are never considered to enter the program for Hepatitis C treatment because of their style of life; irresponsible, without collaborators in the treatment, with poor response and generally poor motivation for hepatitis C treatment (3). This is why we have established important criteria as a guide for selection of patients for inclusion in the interferon therapy. However, we encounter a series of obstacles, which are often traditional in nature, primarily stigma related to drug users compared to the rest of the population, followed by infectious disease they have, but also their interest and motivation for treatment. In the world, the interferon therapy is not carried out only among drug users in substitution treatment, but also among active drug users, drug users with psychiatric co-morbidity, and even with HIV co-infection (4,5). In our country, the interferon therapy has been implemented for the last three years, while the largest number of patients was referred from two of the Institutes for addiction diseases, in Sarajevo (32) and Zenica (16) respectively. All respondents were on substitution treatment by methadone or suboxone and stable in the program (abstinent from heroin for more than six months). MATERIALS AND METHODS The sample consists of 304 opiate addicts in substitution treatment at the Institute for Addiction Diseases of Zenica-Doboj Canton. Out of the total sample, 240 were on methadone substitution therapy and 64 on suboxone treatment. Methadone doses were between 40-60mg and suboxone from 4 to 8mg. In the total sample there were 33.34% of HCV positive patients. The inclusion criteria for AVT were the following: that the patient was HCV positive, stable in the program (negative on heroin for more than 6 months), that the doses of methadone were from 40-40mg and suboxone between 4 and 8mg; to have collaborator in the treatment, that they achieved a certain mental stabilization assessed by BSI scale, involved in the motivational group and acquire adequate motivation for the treatment of infectious diseases. Afterwards, a review and consultation with a hepatologist followed. RESULTS The average age of respondents in OST was 31 years, dominated by men in the sample (92%), with an average methadone dose of 56.5 mg, or suboxone dose of 6 mg. In the total sample there was 33.34% of HCV positive addicts, which was well below the European average. On the MINI test and BSI scale psychiatric comorbidity was significantly represented and dominated by antisocial personality disorder, followed by anxiety and depression, and panic disorder. BSI scale assessed current mental state with moderate to considerable mental problems in 13% of cases. Table 1 Basic characteristics of the respondents. Age Gender The result we obtained on the M.I.N.I. test was interpreted as the total sum of the results achieved in the test, where the lower limit was 190 points. Accordingly there were no psychopathological deviations. Score above 190 indicated the presence of one or more psychiatric disorders. On BSI scale we observed the presence/absence of the current level of psychological symptoms and discomfort where the results ranged from a minimum of 0 to maximum 212 points and the average result achieved in the study was 156. N DISCUSSION Mean methadone dose Mean suboxone dose Hepatitis C Table 3 Brief Symptom Inventory - BSI. % Not at all Mild Moderate Significant Severe Total ±7.9 years Male 92.0% Female 8.0% 56.5±25.19 mg 6 mg Positive 33.34% Negative 62.16% Never tested 4.50% Table 2 Means of results on M.I.N.I. and BSI scale. M.I.N.I. test BSI N Mean±SD ± ±33.59 SEM Minimum Table 4 Possibilities for involvement in AVT and monitoring of respondents - Comparison between Sarajevo and Zenica. Total number of patients on OST Indications and motivation for AVT Diagnostically processed Total included in AVT Discontinued AVT Completed program Currently in AVT In preparation for AVT Zenica Sarajevo This study showed a high prevalence of psychiatric disorders, but the prevalence of HCV infection was significantly lower than in other European countries, even in relation to the Institute for Addiction of Sarajevo Canton, where the prevalence was above 50%. Number of respondents enrolled in AVT was 32 of the total number of Maximum

26 Difficulties and risks in treatment of hepatitis C viral infection among opiate addicts in substitution treatment 265 patients on substitution (424). The complete program of therapy was completed by 22 patients. There are currently there 6 patients under treatment, while 4 patients discontinued the therapy (3 arbitrarily and in one case treatment was discontinued due to behavior problems). However, the criteria established by infectious diseases specialists and hepathologists in our region for the AVT significantly narrowed the field of action and made it difficult to differentiate drug addicts for treatment. Addictologists must motivate respondents for treatment, assess their suitability, socio-economic features, safety and efficacy of care, as well as monitor current mental state and therefore the quality of life (5). The PAS addicts must be treated in a multidisciplinary environment using standard combination of antiviral therapy, in spite of certain difficulties in accessing management and treatment characteristics (6). Large prospective cohort study was conducted at Ethos and involved 415 addicts with a history of intravenous drug use and chronic HCV infection at the OST treatment in public health institutions. After antiviral therapy similar susceptibility and response to interferon therapy was achieved as with other non-addicted population despite injection drug use. Younger age and adherence are better predictors of response to HCV treatment (7). HCV infection is only modestly treated in our setting among drug addicts and/or in case of acute psychiatric disorders. Although prospective and controlled data in the world during recent years show that if provided with interdisciplinary treatment, these patients did not differ from the general population sample. Moreover, depression as one of the most acute psychiatric side effects of alpha interferon therapy can be acutely treated or even prevented by antidepressant treatment. Other, less frequent complications such as mania, psychotic symptoms or delirium require individual psychiatric intervention (2). We must be honest and say that only a minority of drug users with HCV infection get a chance to start anti-hcv treatment. We need new models of therapeutic approaches to overcome rigid barriers. Actually these dual, simultaneous treatments provided by the infectious disease specialists and addictologists can be an effective model to overcome barriers to treatment and improve the response, as well as outcome, among respondents who are involved in OST programs (8). Developing modified, directly supervised therapeutic interventions (MDNT) for the treatment of hepatitis C has proved to be very successful, when drug addicts with psychiatric comorbidity are successfully treated in an easily accessible clinic for the treatment of hepatitis C. Thus, the availability of services and easier access, with support at all health care levels is of great importance for the treatment of a large number of HCV positive drug users (9). Despite the high prevalence of hepatitis C among drug users, HCV evaluation and acceptance of treatment are still very low among these patients, which also apply to institutions that deal with addiction and their relation to the HCV treatment. Only integrative care between specialists working in OST programs and the clinics for liver diseases can provide good treatment outcome (10). In Amsterdam (Netherlands) they have gone so far to perform a DUTCH-C project that included the active drug and alcohol addicts and potential other mental disorders. They have collaborated in the project with specialists of different disciplines in order to motivate addicts, provide them optimum care and cooperated with all specialist in disciplines required. It was concluded that these patients could be successfully treated only with available integrative approach to the above high risk population (11). Some countries have programs of heroin substitution treatment, this study followed respondents treated with heroin and HIV coinfection. We followed their socioeconomic characteristics and quality of life. Also, we consulted clinics which assessed how much supportive care and assistance these patients required. Of the total number of respondents (66) 62% achieved SVR. From baseline 64% of respondents treated with heroin achieved SVR. Also during antiviral therapy 71% of respondents used heroin, while even 80% had some other psychiatric disorders. What is most important is that the implementation of HCV treatment in integrative primary database within the OST and individual supportive strategy allows equally successful treatment in the population of active drug users in comparison with the general population (5). Respondents with involvement in some of substitution programs want to make better use of the above mentioned programs - as an opportunity and a starting point for the treatment of HCV infection. The use of antidepressants is necessary in this highly vulnerable population, which requires the use of integrative model of care for these patients (12). The importance of close relationship between OST centers with infectious disease centers was indicate in a pilot study conducted in Norway, in which 17 respondents with HCV genotype 3 was treated for 24 weeks. In order to optimize the compliance, the treatment was implemented at clinics for infectious diseases in cooperation with OST center. All injections were given in the OST center, but adequate psychological support to patients was also provided. The compliance was 100%, all responded to therapy, and the SVR was 16 (94%). This was another confirmation that antiviral therapy for opiate addicts should be implemented in close cooperation between addictologists and hepatologists (13). Current limitations for administration is the criteria that the patients are stable and at optimal doses of substituents and excluded from current psychological disturbances, severely narrows the field of action for addictologists, infectious disease specialist and hepatologists. The possibility of including the unstable addicts in the program of substitution, as well as psychologically destabilized, with intensive monitoring and psychiatric support would significantly increase the number patients involved in AVT and provided the possibility for better treatment (14). CONCLUSION Addiction on psychoactive substances is usually associated with some other mental disorders, whereas drug addicts have a high prevalence of HCV infection. Treatment of addiction, accompanying mental disorders, and antiviral therapy are essential in this highly vulnerable population. However, treatment requires a multidisciplinary approach and integrated care of addictologists, infectious disease specialists and hepatologists. From the addictology point of view it is necessary to involve drug addicts in the treatment and motivate them for AVT. On the other hand, infectious diseases specialists and hepathologists in our region should also expand the indications in the field on addicts who are not included in the

27 266 R. Okić et al. substitution program, treated for comorbid psychological problems, or have some other addictions, e.g. alcoholism. It is time to change the rules. Conflict of interest: none declared. REFERENCES 1. S.Krkić-Dautović, Priručnik za multidisciplinarni pristup prevenciji zloupotrebe psihoaktivnih supstanci, Sarajevo Schaefer M, Sarkar R, Diez-Quevedo C. Management of mental healih problems prior to and during treatment of hepatitis C virus infection in respondents with drug addiction. Clin. Infest Dis. 2013;57(Suppl 2): Neukam K, Mira JA, Gilabert I, Claro E, Vázquez MJ, Cifuentes C, et al. Efficacy of chronic hepatitis C therapy pegylated interferonand ribavirin in respondents on methadone maintenance treatment. Eur J Clin Microbiol Infect Dis. 2012;31(6): Litwin AH, Harris KA Jr, Nahvi S, Zamor PJ, Soloway IJ, Tenore PL, et al. Successful treatment of chronic hepatitis C with pegylated interferon in combination with ribavirin in a methadone maintenance treatment program. J Subst Abuse Treat. 2009:37(1): Brunner N, Senn O, Rosemann T, Falcato L, Brugmann P. Hepatitis C treatment for multimorbid respondents with substance use disorder in a primary care-based integrated treatment centre: a retrospektive analysis Eur J. Gastroenterol Hepatol. 2013; 25(11): Zanini B, Benini F, Pigozzi MG, Furba P, Giacò E, Cinquegrana A, et al. Addicts with chronic hepatitis C: difficult to reach, manage ot treat? World J Gastroenterol. 2013; 19(44): Grebely J, Alavi M, Micallef M, Dunlop AJ, Balcomb AC, Phung N, et al. Treatment for hepatitis Cvirus infection among people who inject drugs attending opioid substitution treatment and community health clinics: The ETHOS Study. Addiction doi: /add Stein MR, Soloway IJ, Jefferson KS, Roose RJ, Arnsten JH, Litwin AH. Concurrent group treatment for hepatitis C: implementationand outcames in a methadone maintenance treatment program J. Subst Abuse Treat. 2012;43(4): Bruce RD, Eiserman J, Acosta A, Gote C, Lim JK, Altice FL. Developing a modified directly observed therapy intervention for hepatitis C treatment in a methadonemaintenance program: implications for program replication. Am J Drug Alcohol Abuse. 2012;38(3): Martinez AD, Dimova R, Marks KM, Beeder AB, Zeremski M, Kreek MJ, et al. Integrated internist-addiction medicine medicine-hepatology model for hepatitis C management for individuals on methadone maintenance. J Viral Hepat. 2012;19(1): Lindenburg CE, Lambers FA, Urbanus AT, Schinkel J, Jansen PL, Krol A, et al. Hepatitis C testing and treatment among active drug users in Amsterdam: results from the DUTCH-C project. Eur J Gastroenterol Hepatol. 2011;23(1): Rosedale MT, Strauss SM. How persoms with chronic hepatitis C in residential substance abuse treatment programs think about depression and interferon therapy. 13. Kroock AL, Stokka D, Heger B, Nygaard E. Hepatitis C treatment of opioid dependants receiving maintenance treatment: results of a Norwegian pilot study. Eur Addict Res. 2007;13(4): Sylvestre DL, Clements BJ. Adherence to hepatitis C treatment in recovering heroin users maintained on methadone. Eur J Gstroenterol Hepatol. 2007;19(9): Reprint requests and correspondence: Rasema Okić, MD, PhD Institute for Alcoholism and Substance Abuse of Canton Sarajevo Bolnička Sarajevo Bosnia and Herzegovina Phone: r.okic@bih.net.ba

28 Medical Journal (2015) Vol. 21, No. 4, Original article Screening for the presence of silent myocardial ischemia using perfusion scintigraphy in patients with diabetes mellitus Skrining na prisustvo tihe ishemije miokarda upotrebom metode perfuzione scintigrafije kod dijabetičara Miran Hadžiahmetović 1*, Elma Kučukalić-Selimović 1, Šejla Cerić 1, Damir Čelik 2, Selma Agić 1, Majla Ćibo 3, Željka Raič-Gotovac 4, Amela Begić 1 1 Clinic of Nuclear Medicine, University Clinical Centre Sarajevo, Bolnička 25, Sarajevo, Bosnia and Herzegovina; 2 Clinic of Physiotherapy and Rehabilitation, University Clinical Centre Sarajevo, Bolnička 25, Sarajevo, Bosnia and Herzegovina; 3 Heart Center, University Clinical Center Sarajevo, Bolnička 25, Sarajevo, Bosnia and Herzegovina; 4 Clinic of Heart Disease and Rheumatism, University Clinical Centre Sarajevo, Bolnička 25, Sarajevo, Bosnia and Herzegovina. *Corresponding author ABSTRACT Introduction: coronary heart disease is a late complication of diabetes mellitus and one of the most common causes of death in more than half of patients with this disease. According to the recommendation of the European and the American Association of Diabetes Mellitus, guidelines for detection of coronary disease in diabetes melituss, a perfusion scintigraphy is one of the leading non-invasive method for detection of silent myocardial ischemia. Materials and methods: the study included a total of 80 patients, of which 40 were from the selective population of patients with diabetes mellitus who were treated for/controlled the disease progression. The control group included 40 patients who did not suffer from diabetes but from other diseases requiring the same diagnostic procedure. The analysis included the following data: medical history, stress test treadmill, i.e. cycle ergometer finding, myocardial perfusion scintigraphy and angiography. Results: findings of myocardial perfusion scintigraphy were positive in 87.5% of patients with diabetes mellitus. The sensitivity of myocardial perfusion scintigraphy (SN) in diabetic patients was 90.3% and specificity of the test (SP) 55.6%. The most common localization of ischemia (88.9%) was in the inferior wall of the heart. Coronarographically 38 patients without diabetes mellitus (94.8%) had positive findings, while the remaining 2 patients without diabetes mellitus (5.2%) had negative result. Conclusion: the results show that myocardial perfusion scintigraphy associated with ergometer findings can be used in the examination of diabetic patients with myocardial ischemia. Perfusion scintigraphy is a powerful tool in selecting patients for coronary angiography. Key words: ergometer stress test, myocardial perfusion scintigraphy, coronary angiography, silent myocardial ischemia, diabetes mellitus SAŽETAK Uvod: koronarna bolest je jedna od kasnih komplikacija dijabetes melitusa i predstavlja jedan od najčešćih uzroka smrti u više od pola oboljelih od ove bolesti. Prema preporuci evropskog i američkog udruženja za dijabetes melitus, smjernicama za detekciju koronarnih oboljenja kod dijabetes melituss-a, perfuziona scintigrafija je jedna od vodećih neinvazivnih metoda za detekciju tihe ishemije miokarda. Ispitanici i metode: u studiju je uključeno ukupno 80 pacijenata, od čega 40 pacijenata selektivne populacije oboljelih od dijabetes melitusa koji su se liječili/ kontrolisali stanja napredovanja bolesti. Kontrolnu grupu predstavlja 40 pacijenata koji nisu oboljeli od dijabetes melitusa već od druge bolesti koja je zahtijevala iste dijagnostičke procedure. Analizom su obuhvaćene slijedeće varijable: anamnestički podaci, test opterećenja - tredmil, odnosno ergometrijski nalaz, nalaz perfuzione scintigrafije miokarda i nalaz koronarografije. Rezultati istraživanja: nalaz perfuzione scintigrafije miokarda je bio pozitivan u 87.5% pacijenata sa dijabetes melitus-om. Senzitivnost perfuzione scintigrafije miokarda (SN) u dijabetičara iznosi 90.3%, odnosno, specifičnost testa (SP) iznosi 55.6%. Najčešča lokalizacija ishemije je bila na inferiornom zidu srca i iznosi 88,9%. Koronarografski 38 pacijenata bez dijabetes melitusa (94.8%) je imalo pozitivan nalaz, dok preostalih 2 pacijenta bez dijabetes melitusa (5.2%) su imali negativan nalaz. Zaključak: prikazani rezultati pokazuju da pefuziona scintigrafija miokarda udružena sa ergometrijskim nalazom može da se koristi pri kontroli pacijenata sa ishemijom miokarda kod dijabetičara. Perfuziona scintigrafija je moćan alat u odabiru pacijenata za koronarografiju. Ključne riječi: ergometrijski stres test, perfuziona scintigrafija miokarda, koronarografija, tiha ishemija miokarda, dijabetes melitus. INTRODUCTION Silent ischaemia is defined as the occurrence of myocardial ischemia in the absence of pain. Dysfunction of the endothelial cells of the arteries is more and more evident as an important factor in the formation of cardiovascular disease associated with diabetes mellitus (1,2). Cohn et al. proposed general classification of silent ischemic heart disease (3). 1. Patients who have never had angina but have risk factors for developing coronary heart disease; 2. Patients after myocardial infarction and then have the presence

29 268 M. HadŽiahmetoviĆ et al. of silent ischemia, which is diagnosed exercise test or 24-hour continuous electrocardiogram, 3. Patients who had recognized the symptoms of coronary disease, and in addition, episodes of silent ischemia. According to another classification, there are two types of this phenomenon. Type 1 is less common and occurs in patients with coronary artery disease who have angina. Type 2 occurs in patients with stable angina pectoris, unstable, or Prinzmetal s angina. Diagnostic methods for early detection of silent myocardial ischemia due to the increased risk of silent myocardial ischemia in patients with diabetes mellitus are of great medical importance. The methods used for detection are: 24-hour ambulatory electrocardiogram, echocardiography stress test, stress test, myocardial perfusion scintigraphy and coronary arteriography (3). Objective The aim was to examine the findings of myocardial perfusion scintigraphy in detection of myocardial ischemia in diabetic patients, and to compare them with coronary angiography as the gold standard. MATERIALS AND METHODS The study was conducted at the Clinic of Nuclear Medicine, University Hospital for Heart Disease and Rheumatism, Heart Center and Clinic of Endocrinology and Metabolic Disease, University Clinical Centre Sarajevo over the period of one year. The study was retrospective, clinical, diagnostic and analytical. As a source of data we used the existing medical documentation. The analysis included the following variables: medical history, test load on a treadmill or cycle ergometer finding, perfusion scintigraphy and angiography. The study included a total of 80 patients, of which 40 were from the selective population / patients treated for diabetes mellitus / controlled state of the disease progression. The control group included 40 patients who did not suffer from diabetes but from other diseases requiring the same diagnostic procedure. Criteria for inclusion in the study were as follows: - Patients of both sexes over 18 years of age; - Patients with diabetes; - Patients with family history of diabetes, cardiac or vascular disease; - Patients who have already had certain invasive or non-invasive heart procedures. The exclusion criteria were the following: - Patients with severe chronic heart failure; - Patients with severe hypertension; - Patients with renal failure; - Patients with respiratory disease (COPD); - Patients with skeletal defects. We used the existing medical records as data source. The analysis included the following data: medical history, test load on a treadmill or cycle ergometer findings, angiography and perfusion scintigraphy findings. a) load test on the treadmill Patients from the Clinic of Heart Disease and Rheumatism were examined by Bruce Treadmill Tests. Tests were carried out on the GE Marquette Series 2000 Treadmill device. The finding was considered positive in cases of depression or downstream of the sloping ST segment more than 1mm for 80 msec after the J point in at least 3 of the drain. The finding was considered negative if ischemic changes were not present in cardiac load of 85% of aerobic capacity. The finding was considered unacceptable if the patient was interrupted in the performance of the test before reaching 85% of aerobic capacity, and when ECG did not show signs of ischemia. b) myocardial perfusion scintigraphy The myocardial perfusion scintigraphy was conducted at the Clinic of Nuclear Medicine in two steps which included recording of the heart during load and after 3 hours rest. For the implementation of the procedures the clinical protocol was used. Siemens E.CAM Dual-Head 180 gamma camera was used. The method of quantification was done with QPS 3.1 software using an iterative reconstruction algorithm for data evaluation. The model of 20 myocardial segments was used for assessing the condition of the patient. c) coronary angiography For the procedure angiography machine Siemens Artis Zee Floor was used. Reading images (findings) was done with OsiriX software. Stenosis of 70% of the reduced lumen diameter was regarded as significant. Statistical analysis The database was developed in Microsoft Office Excel 2010 with data entered from paper documents. After checking the integrity of the data, the statistical analysis was performed in the IBM SPSS Statistics in for Windows. Testing of normality of continuous numerical data distribution was carried out by the inspection of histograms, quantile diagrams and through formal testing by the Kolmogorov-Smirnov test. The analysis of categorical variables was performed using Pearson s χ²test or Fisher s exact probability test. Analysis of normally distributed continuous characteristics was performed by using Independent Sample T test, while nonparametric distributed numerical variables were analyzed using the Mann-Whitney U test for independent samples. Threshold of statistical significance is set to the conventional level is α= Measures of diagnostic accuracy (validity, predictive value, likelihood ratio) are shown shown by analysis of the ROC curve (Receiver Operating Characteristic). RESULTS Out of the total number of diabetic patients (n = 40), 28 (70.0%) were males and 12 (30.0%) females. Out of the total number of non-diabetic patients (n = 40), 26 (65.0%) were males and 14 (35.0%)

30 Screening for the presence of silent myocardial ischemia using perfusion scintigraphy in patients with diabetes mellitus 269 females. There was no statistically significant difference in the frequency of male and female sex between the groups [χ2 (1)=0.228, P<0.05]. On average, female diabetic patients were older (X=63.50, SD=6.86) as compared to female patients without diabetes (X=58.71, SD=13:23). This difference was not statistically significant [t(24)=1.128, P> 0.05]. Figure 1 Gender structure of respondents. On average, male diabetic patients were older (X=60.39, SD=8.96) as compared to non-diabetic male patients (X=58.42, SD=8.38). This difference was not statistically significant [t(52)=0.833, P> 0.05]. Out of the total number of patients with diabetes (n = 40), 8 (20.0%) underwent a percutaneous transluminal coronary angioplasty (PTCA), whereas 32 (80.0%) did not. Out of the total number of patients without diabetes (n=40), 19 (47.5%) underwent the PTCA, while slightly over half of patients (21 or 52.5%) did not undergo the PTCA. There was a statistically significant difference in the frequency of the PTCA between diabetics and non-diabetics (20.0% vs. 47.5%). More than expected, non-diabetics had the PTCA done as compared to diabetics [χ2 (1)=6.765; P<0.01]. This difference between nondiabetics and diabetics was significant for the male (57.1% vs. 8.3%; P=0.009), but not for the female sex (42.3% vs. 25.0%; P>0.05). Out of the total number of diabetes patients (n=40), 16 (40.0%) had acute myocardial infarction (AMI) while the remaining 24 (60.0%) did not have it. Out of the total number of non-diabetic patients (n=40), 27 (67.5%) had AIM, while the remaining 13 (32.55) did not have it. (64.3% vs. 16.7%; P = 0.014), but not for the male sex (69.2% vs. 50.0%; P> 0.05). Out of the total number of patients with diabetes (n = 40), 24 (60.0%) had angina pectoris while the remaining 16 (40.0%) did not have it. Out of the total number of patients who were not diabetics (n = 40), 17 (42.5%) had angina pectoris, while the remaining 23 (57.5%) did not have it. There was no statistically significant difference in the frequency of angina pectoris between diabetics and non-diabetics (60.0% vs. 42.5%) [χ2 (1) = 2.452; P <0.05]. Out of the total number of patients with diabetes (n = 40), all patients had sinus rhythm. Out of the total number of patients without diabetes (n = 39), one patient (2.6) had nodal rhythm, while the remaining 38 (97.4%) patients had sinus rhythm. There was no statistically significant difference in the incidence of sinus rhythm between diabetics and non-diabetics (100.0% vs. 97.4%) [χ2 (1) = 1.039; P <0.05]. Patients with diabetes (n = 37) on average had ejection fraction EF (%) 48.43% (2.82) and the minimum EF amounted to 20.00%, while the maximum was 86.00%. Patients who did not have diabetes (n = 39) on average had the ejection fraction EF (%) 47.62% (2.63) and the minimum EF amounted to 15.00%, while the maximum was 91.00%. There was no statistically significant difference in mean ejection fraction (EF%) between diabetics and non diabetics [t (74) = 0.212, P <0.05]. Out of the total number of patients with diabetes (n = 40), 33 patients or 82.5% were positive for ergonomics, while the remaining 7 (17.5%) had a negative result. Out of the total number of patients without diabetes (n = 40), 31 patients or 77.5% had positive ergonomics findings, while the remaining 9 (22.5%) had negative result. The sensitivity of the test (SN) in diabetic patients was 87.1%. The specificity of the test (SP) was 33.3%. Positive predictive value (PPV) was 81.8%, i.e. the probability that a diabetic with a positive exercise testing actually had silent myocardial ischemia was 81.8% and negative predictive value (NPV) was 42.9%, i.e. the probability that a diabetic with a negative exercise testing actually had silent myocardial ischemia was 42.9%. The sensitivity of the test (SN) in non diabetics was 78.4%. The specificity of the test (SP) was 50.0%. The positive predictive value (PPV) was 96.7%, i.e. the likelihood that non diabetic patients with positive exercise testing actually had silent myocardial ischemia was 96.7% and negative predictive value (NPV) was 11.1%, i.e. the probability that a non-diabetics with a negative exercise testing actually had silent myocardial ischemia was 11.1%. d) perfusion scintigraphy Figure 2 Acute myocardial infarction by group of respondents. There was a statistically significant difference in the incidence of AMI between diabetics and non-diabetics (40.0% vs. 67.5%), respectively. Non-diabetics were more than expected had the AIM compared to diabetics [χ2 (1) = 6.084; P <0.05]. This difference between non-diabetics and diabetics was significant for the female Out of the total number of patients with diabetes (n=40), 32 (80.0%) were positive for perfusion scintigraphy, while the remaining 8 (20.0%) had a negative result. Out of the total number of patients without diabetes (n=40), 38 (95.0%) had positive angiography findings, while the remaining 2 patients (5.0%) had a negative result. Out of the total valid sample with diabetes infection (n=36), localization of silent ischemia was most often inferior, in 39.0% of patients. Out of the total number of patients who without diabetes (n=38), localization of silent ischemia was most often inferior, in 29 (31.9%) patients.

31 270 M. HadŽiahmetoviĆ et al. Figure 3 Findings of perfusion scintigraphy for the studied groups. There was a statistically significant difference in the frequency of positive perfusion scintigraphy findings between the diabetics and non-diabetics (80.0% vs. 95.0%) [χ2 (1) = 4.114; P <0.05]. The sensitivity of the test (SN) in diabetic patients was 90.3%. The specificity of the test (SP) was 55.6%. The positive predictive value (PPV) was 87.5%, i.e. the probability that a diabetic with a positive perfusion scintigraphy test actually had silent myocardial ischemia was 87.5%, and negative predictive value (NPV) was 62.5%, i.e. the probability that a diabetic with negative perfusion scintigraphy findings actually did not have silent myocardial ischemia was 62.5%. Positive likelihood ratio (LR +) was 2.03, i.e. the relationship between the likelihood of obtaining a positive test for the actual suffering and the likelihood of obtaining a positive test in the absence of disease was Negative likelihood ratio (LR) was 0.17, i.e. the relationship between the probability of obtaining negative test with sick patients and probability of obtaining negative test in the absence of disease was 00:17. The sensitivity of the test (SN) in non diabetics was 97.4%. The specificity of the test (SP) was 50.0%. The positive predictive value (PPV) was 97.4%, i.e. the probability of non-diabetics with a positive test for perfusion scintigraphy to actually have silent myocardial ischemia was 97.4% and negative predictive value (NPV) was 50.0%, i.e. the probability of non-diabetics with negative perfusion scintigraphy findings to actually not having silent myocardial ischemia was 50.0%. Positive likelihood ratio (LR +) was 1.95, i.e. the relationship between the likelihood of obtaining a positive test for the actual sufferers and the likelihood of obtaining a positive test in the absence of disease was Negative likelihood ratio (LR) was 0.05, i.e. the relationship between the probability of obtaining negative test with actual sufferers and probability of obtaining negative test in the absence of disease was e) results of coronary angiograms Out of the total number of patients with diabetes (n = 40), 31 (77.5%) had positive angiography findings, while the remaining 9 (22.5%) had a negative result. Out of the total number of patients without diabetes (n = 39), 38 (94.8%) had positive angiography findings, while the remaining 2 patients (5.2%) had a negative result. There was a statistically significant difference in the frequency of positive angiography findings between diabetics and non-diabetics (77.5% vs. 94.8%). Non diabetics more than expected had positive angiography finding as compared to diabetics [χ2 (1) = 7.099; P = 0.014]. Figure 4 Coronary angiography findings in the studied groups. DISCUSSION According to the study, the sensitivity of perfusion scintigraphy in relation to coronary angiography as the gold standard was 90.3% and specificity of perfusion scintigraphy was 55.6%. Semi structured data coincide with the results of world research. Prevalence and predictors of abnormal myocardial perfusion stress test in asymptomatic patients with diabetes mellitus type 2 was shown in a study where perfusion scintigraphy had a high prevalence of positive findings. Other laboratory findings such as smoking, alcohol consumption etc. had a great influence as independent predictors of abnormal SPECT (4). Restrictions that may arise due to diseases that limit the exercise test may be replaced by pharmacological stress test. The standard exercise testing will identify patients with no significant proximal or multivessel heart disease as well as damage left coronary artery. At the same time standard exercise testing would not recognize the disease in patients with one-vessel coronary artery disease as well as obstruction of a lower degree (5). Localization of myocardial ischemia on exercise testing coincides with other authors. The most common localization is the inferior wall of the heart, which is difficult to diagnose and anticipate heart attacks. In the second study, the limitations of myocardial perfusion scintigraphy in patients suffering from diabetes mellitus showed that perfusion scintigraphy ergometer associated with the stress test might be used as a method of detecting the silent myocardial ischaemia (6,7,8). The sensitivity of the test was 97.4%, whereas the specificity was 50.0%. The method of scintigraphy can detect pathological changes at cellular level before development of anatomical changes that can be detected by coronography (9,10,11). Miloradović et al. came to a conclusion that the improvement in function after revascularization occurred in a significant number of dysfunctional segments of the left ventricle. This method seems to be very useful in assessing the real live segments in a patient with a poor prognosis (12). Using the g-spect studies quantification wall motion of the heart and its disorders as well as the ejection fraction increases the sensitivity of the stress-rest test, especially in patients with triplevessel heart disease in which diffuse increase subendocardial flow may cause a worsening of ventricular function without focal perfusion defect (11). Coronary angiography confirmed perfusion scintigraphy associated with an ergometric stress test, which correlates with research conducted by other authors.

32 Screening for the presence of silent myocardial ischemia using perfusion scintigraphy in patients with diabetes mellitus 271 The study conducted by Baškot et al. was performed to determine the localization of culprit lesion using MPI in cases of angiographically detected coronary narrowing 75% of at least one coronary artery. The conclusion was that DipyEX MPI with 2 created indicators SRS and ISRS significantly increases the sensitivity, specificity and accuracy in the determination and localization of culprit lesions in patients undergoing elective PCI (5). Mortality caused by heart failure in patients with diabetes mellitus without known cerebrovascular disease was the same as in patients without diabetes and known coronary patients (13). The number of men was higher than the number of women. The observed difference was not significant between the groups. Patients who had diabetes mellitus and heart disease were older than patients who did not have diabetes mellitus. Ejection fraction was lower in diabetics than in nondiabetics. The very ejection fraction was not statistically significant. Majority of non-diabetics had PTCA as compared to diabetics. Diabetic patients had a smaller number of acute myocardial infarction in relation to the non diabetic. This explains the constant control of the diabetic condition, and more attention paid to the condition of their hearts. In a comparative study, 328 patients were randomized to PTCA or medical therapy. After 6 months, 82% of patients underwent MPI and were followed the next 6 years. Mortality rate for PTCA was 20% for those with a reversible defect as opposed to 7% for those without a reversible defect (P = 0.03). Multivariate analysis as strong predictors of mortality showed diabetes, smoking and reversible defect on MPI (12). CONCLUSION Male patients with silent myocardial ischemia and diabetes mellitus are more frequent than female patients with the same disease due to the fact that diabetes occurs earlier in males than in females. Myocardial ischemia in women is diagnosed at later stage and thus women diagnostic procedures are performed at a later stage. Non-diabetics more often experienced the chest pain or had acute myocardial infarction than diabetics given that those were possible diabetes related complications and as such were more frequently monitored and controlled in diabetics. Angiography is necessary to confirm diagnosis of silent myocardial ischemia in diabetic patients. For evaluation and re-evaluation of the condition after surgical or minimally invasive heart surgeries, perfusion scintigraphy is the method of choice. Conflict of interest: none declared. REFERENCES 1. Shah S, Win Z, Al-Nahhas A. Multiorgan dysfunctions in diabetic patients: the role of functional imaging. Minerva endocrinologica. 2009;34(3): Scholte AJ, Roos CJ, van Werkhoven JM. Function and anatomy: SPECT-MPI and MSCT coronary angiography. EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2010;6 Suppl G:G94-g Cohn PF. Asymptomatic coronary artery disease. Pathophysiology, diagnosis, management. Modern concepts of cardiovascular disease. 1981;50(10): Scholte AJ, Schuijf JD, Kharagjitsingh AV, Dibbets-Schneider P, Stokkel MP, van der Wall EE, et al. Prevalence and predictors of an abnormal stress myocardial perfusion study in asymptomatic patients with type 2 diabetes mellitus. European journal of nuclear medicine and molecular imaging. 2009;36(4): Branislav B, Igor I, Dragan K, Slobodan O, Nenad R, Miodrag Z. Nuclear Cardiology In the Era of the Interventional Cardiology Smanio PE, Carvalho AC, Tebexreni AS, Thom A, Rodrigues F, Meneghelo R, et al. Coronary artery disease in asymptomatic type-2 diabetic women. A comparative study between exercise test, cardiopulmonary exercise test, and dipyridamole myocardial perfusion scintigraphy in the identification of ischemia. Arquivos brasileiros de cardiologia. 2007;89(5):263-9, Hendel RC, Abbott BG, Bateman TM, Blankstein R, Calnon DA, Leppo JA, et al. The role of radionuclide myocardial perfusion imaging for asymptomatic individuals. Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology. 2011;18(1): Dorbala S, Di Carli MF, Delbeke D, Abbara S, DePuey EG, Dilsizian V, et al. SNMMI/ ASNC/SCCT guideline for cardiac SPECT/CT and PET/CT 1.0. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2013;54(8): Sprynger M. Evaluation, severity and prognostic significance of silent myocardial ischaemia in vascular patients. Acta chirurgica Belgica. 2003;103(3): Lima RdSL, Fonseca LMBd. Pesquisa de viabilidade miocárdica. Radiologia Brasileira. 2010;43:V-VI. 11. Myocardial perfusion scintigraphy. Myocardial Perfusion Scintigraphy: CRC Press; p Galassi AR, Marza F, Azzarelli S, Tomasello SD. Role of Stress Myocardial Scintigraphy in the Evaluation of Incompletely Revascularized Post-PCI Patients. International journal of molecular imaging. 2011;2011: Peix A. Usefulness of nuclear cardiology techniques for silent ischemia detection in diabetics. MEDICC review. 2013;15(1):33-6. Reprint requests and correspondence: Miran Hadžiahmetović, MD Clinic of Nuclear Medicine University Clinical Centre Sarajevo Bolnička Sarajevo Bosnia and Herzegovina miran1989@gmail.com

33 Medical Journal (2015) Vol. 21, No. 4, Original article Ablation therapy with i-131 at thyroid cancer Ablativna terapija sa i-131 kod karcinoma štitne žlijezde Rubina Alimanović-Alagić I*, Mevludin Mekić 2, Nermina Bešlić 1, Amra Skopljak-Beganović 3, Šejla Cerić 1 1 Clinic of Nuclear Medicine, University Clinical Centre Sarajevo, Bolnička 25, Sarajevo, Bosnia and Herzegovina; 2 Clinic of Cardiology and Rheumatology, University Clinical Centre Sarajevo, Bolnička 25, Sarajevo, Bosnia and Herzegovina; 3 Department for Medical Physics and Radiation Safety, University Clinical Centre Sarajevo, Bolnička 25, Sarajevo, Bosnia and Herzegovina *Corresponding author ABSTRACT Thyroid cancer represents one of the major medical and social problem of our time. Ablatition with radioactive iodine (I-131) is a therapy for follicular and papillary thyroid carcinoma. The aim of this study was to represent and to evaluate our experience with ablation therapy of thyroid cancer over one year period. The study included 103 patients after total thyroidectomy. All patients were hospitalized at the Nuclear Medicine Clinic of the University Clinical Center Sarajevo. This was a single centre, nonrandomized, open-label, parallel groups, drug interaction, one year study. We analyzed postoperative ablation of 103 patients with I-131 mci, 78 patients diagnosed with papillary thyroid carcinoma and 25 patients with follicular thyroid carcinoma. There were 73 female and 30 male included in the study. Age of patients varied from 17 to 75 years. Due to total thyroidectomy and lack of levotiroxine therapy all patients had high TSH. Blood test in both therapeutic groups showed decrease of TSH (from 46.5 to >100 miu/ml), Tg (from < 0.1 to > 500 ng/ml), and elevated ATGL values (from 1.3 to 2509 IU/ml). This study demonstrates that the dose (specific activity of I-131 administered) required to achieve ablation is a high dose of approximately 100 mc or higher, and, in terms of successful remnant ablation, lower doses are not as beneficial. We used conventional doses of 1.85 GBq to 7.4 GBq (50 to 200 mci). Key words: thyroid cancer, radioactive iodine (I-131), ablation dose SAŽETAK Karcinomi štitnjače kao oboljenje predstavljaju jedno od glavnih medicinskih i socijalnih problema našeg vremena. Ablacija radioaktivnim jodom (I-131) je način terapije kod folikularnog i papilarnog karcinoma štitnjače. Cilj ovog istraživanja predstavlja vlastita iskustava ablacijom kod terapija karcinoma štitnjače u razdoblju od godinu dana. U istraživanju je sudjelovalo 103 bolesnika nakon totalne tireoidektomije. Studija je predstavljala interakciju lijekova, rađena u jednom centru, kao nerandomizirana, otvorena, u dvije paralelne skupine, jednu godinu ablativnom terapijom I-131 na bolničkom pacijentima na Kilinici za nuklearnu medicinu-radioterapijskom odjelu u Univezitetskom Kliničkom centru u Sarajevu. Analizirali smo postoperativnu ablativnu terapiju sa I-131 bolesnika, i to 78 pacijenata sa papilarnim karcinomom štitnjače i 25 pacijenata sa folikularnim karcinomom štitnjače. U studiji je bilo 73 žena i 30 muškaraca. Starost pacijenata je varirala između 17 do 75 godina godina starosti. Nakon totalne tireoidektomije i bez terapije levotiroxin tableta kod svih bolesnika bio je visok TSH. U terapeutskom testu putem krvi smanjene su TSH vrijednosti (od 46,5 do> 100 miu / ml), Tg (s <0,1 do> 500 ng / ml), i povišene ATGL (od 1,3 do 2509 IU / ml). Ovom studiom smo pokazali da je potrebna visoka ablativna doza aktivnosti 100 mci I-131 u terapiji u smislu uspješne ablacije preostalog tkiva, dok niže doze nisu korisne. Koristili smo konvencionalne doze I-131 aktivnosti od 1,85 GBq do 7,4 GBq (50 do 200 mci). Ključne riječi: karcinom štitnjače, radioaktivni jod (I-131), ablativna doza INTRODUCTION The thyroid has two lobes. A thin piece of tissue - isthmus connects the two lobes. The thyroid makes thyroid hormone. The thyroid follicular cells make thyroid hormone (1). This hormone affects heart rate, blood pressure, body temperature, and weight. For example, too much thyroid hormone makes your heart race, and too little makes you feel very tired. Cancer begins in cells, the building blocks that make up tissues. Tissues make up the thyroid and other organs of the body. Normal thyroid cells grow and divide to form new cells as the body needs them. When normal cells grow old or get damaged, they die, and new cells take their place. Sometimes, this process goes wrong. New cells form when the body does not need them, and old or damaged cells do not die as they should. The buildup of extra cells often forms a mass of tissue called a nodule (2). It may also be called a growth or tumor. Treatment options for people with thyroid cancer are: Surgery Thyroid hormone treatment Radioactive iodine therapy External radiation therapy Chemotherapy The usual treatment for papillary thyroid cancer is surgery, thyroid hormone treatment, and radioactive iodine therapy. External radiation

34 Ablation therapy with i-131 at thyroid cancer 273 therapy and chemotherapy are not often used for people with papillary thyroid cancer (3). The treatment depends mainly on the type of thyroid cancer (papillary, follicular, medullary, or anaplastic. It also depends on the size of the nodule, your age, and whether the cancer has spread (4,5). Radioactive iodine therapy with I-131 is a treatment for papillary or follicular thyroid cancer. It kills thyroid cancer cells and normal thyroid cells that remain in the body after surgery. People with medullary or anaplastic thyroid cancer usually do not receive I-131 therapy. These types of thyroid cancer rarely respond to I-131 therapy (6,7). Picture of the front and the back of the thyroid. ( Diseases of the thyroid cancer represent one of the major medical and social problem of our time. Radioactive iodine (RAI) treatment with I-131 is a type of internal radiotherapy. After total thyroidectomy, a patient is treated with I-131 targeted treatment, in order to kill any cancer cells that may have been left behind for some types of thyroid cancer (papillary or follicular) (8). Thyroid tissue has a unique ability to take up iodine from blood. Like iodine, radioiodine is taken up and concentrated in thyroid follicular cells because they have a membrane sodium-iodide transporter. Compared with normal thyroid follicular cells, thyroid cancer cells have reduced expression of the transporter, which may account for the low 131-I uptake in thyroid cancer tissue (9,10). RAI (I-131) causes acute thyroid-cell death by emission of short path-length (1 to 2 mm) beta rays. The uptake of 131-I by thyroid tissue can be visualized by scanning to detect the gamma radiation that is also emitted by the isotope. 131-I must be taken up by thyroid tissue to be effective (11,12). Main types of cancer for I-131 treatment are follicular and papillary thyroid cancer. The radioactive iodine circulates through the body in the bloodstream then kills the cancer cells. Analyze differentiated thyroid carcinoma (DTC) in patients staged as pathological related to the DTC patients staged as pt1-pt4, with (TNM stages I, II,III and IV). Depending on the stage and PHD findings depends on access to further treatment and dose is given for therapeutic purposes (13). Although treatments with 131-I are generally safe, RAI produces radiation so patients must do their best to avoid radiation exposure to others, particularly to pregnant women and young children. The amount of radiation exposure markedly decreases as the distance from the patient increases. Depending on dose of I-131 given, patients may have to stay isolated in the hospital for about 2 to 4 days avoid exposing other people to radiation, especially if there are young children living in the same home. RAI with I-131, should never be used in a patient who is pregnant or nursing. This protects the baby who would otherwise receive radioactive milk and the mother s breasts which concentrate RAI. Breastfeeding must be stopped at least 6 weeks before administration of I-131 treatment and should not be restarted after administration of RAI, but can be safely done after future pregnancies. Also, pregnancy should be put off until at least 6 12 months after I-131 RAI treatment since the ovaries are exposed to radiation after the treatment and to ensure that thyroid hormone levels are normal and stable prior to pregnancy. I-131 will be eliminated from the body over the next several weeks after it is given. The majority of I-131 will be eliminated from the human body in 3 5 days, through natural decay, and through excretion in sweat and urine. Smaller amounts will continue to be released over the next several weeks, as the body processes thyroid hormones created with the I-131. For this reason, it is advised to regularly clean toilets, sinks, bed sheets and clothing used by the person who received the treatment. Patients may also be advised to wear slippers or socks at all times, and keep themselves physically isolated from others. This minimizes accidental exposure by family members, especially children. For RAI therapy to be most effective, patients must have high levels of thyroid-stimulating hormone (TSH) in the blood (14). This substance stimulates thyroid tissue (and cancer cells) to take up radioactive iodine. If the thyroid has been removed, one way to raise TSH levels is to not take thyroid hormone pills for several weeks. This causes very low thyroid hormone levels (a condition known as hypothyroidism), which in turn causes the pituitary gland to release more TSH. This intentional hypothyroidism is temporary, but it often causes symptoms like tiredness, depression, weight gain, constipation, muscle aches, and reduced concentration. This drug is given daily for 3 days, with the RAI therapy. Instructions to reduce exposure to others after I-131 treatment. Duration depends on the given dose of I-131 (15). The aim of the study: Our own experiences with ablation therapy with I-131 mci on patients with thyroid cancer (follicular and papillary) over a period of 12 months. MATERIALS AND METHODS The study included 103 patients after total thyroidectomy. This was a single centre, nonrandomized, open-label, parallel groups, drug interaction study one year with ablation therapy with I-131 conducted on patients hospitalized at the Clinic of Nuclear Medicine, Radiotherapy Department, of the University Clinical Centre Sarajevo. We analyzed postoperative ablation of 103 patients with I-131 mci, 78 patients diagnosed with papillary thyroid carcinoma and 25 patients with follicular thyroid carcinoma. In general, RAI is a safe and effective treatment for the thyroid disorders mentioned above (10,14). Loss of taste and dry mouth due to salivary gland damage may be seen. The use of lemon drops, vitamin C or sour stimulation to potentially decrease the exposure of the salivary glands to RAI is controversial and should be discussed with your physician. It is important to say that once you have been treated with RAI, regular medical follow-up is lifelong. All patients were examined by the Internist who informed them

35 274 R. Alimanović-Alagić et al. about the therapy. Prior to treatment the following was assessed: personal history and physical status, laboratories, appropriate blood tests, EKG exam, internal medicine specialist examination, ultrasound examination of residual part of the thyroid gland. Therapy with levotiroxin tablets was excluded four weeks earlier and patients were put on diet. The following blood tests were done: TSH hormone, Titer Antibodies: Tg and ATGL. Afterwards, ablative doses from 1.85 GBq to 7.4 GBq (50 to 200 mci) of I -131 in the form of a capsule was administered to patient. 72 hours after the treatment the scintigraphy of the entire body was performed. 2-3 months after discharge from hospital, patients were requested to return and had their hormone status checked. The most effective therapy is when patients have the high levels of thyroid-stimulating hormone (TSH) in the blood. This substance stimulates thyroid tissue (and cancer cells) to take up radioactive iodine. Anti-thyroglobulin antibodies (ATGL) are commonly identified in patients with differentiated follicular cell-derived thyroid cancer. When present, they interfere with the measurement of thyroglobulin (Tg), which is the primary biochemical marker used for disease surveillance, creating challenges in monitoring patients for residual or recurrent disease. The persistence of anti-tg antibodies, especially if levels are rising, may indicate persistent, recurrent, or progressive thyroid cancer. In contrast, declining anti-tg antibody levels may indicate reduced tumor burden or the absence of disease (16). After the surgery, total thyroidectomy, PHD test, hormone values and antibody depend on access to further treatment and dose is given in therapeutic treatments. Figure 3 Types of thyroid cancer. After total thyroidectomy and lack of levotiroxine therapy all patients had high TSH. Blood test in both therapeutic grousp showed decrease of TSH (from 46.5 to >100 miu/ml), Tg (from < 0.1 to > 500 ng/ml), and elevated ATGL values (from 1,3 to 2509 IU/ml). Figure 4 Values of TSH hormon. RESULTS We analyzed a total of 103 patients with I-131 for ablation of a postoperative thyroid remnant. 73 female and 30 male were included in the study. We treated 78 patients with papillary thyroid carcinoma and 25 patients with follicular thyroid carcinoma. Patients were from 17 to 75 years old, with an average of 51 years. Figure 5 Values of Tg. Figure 1 Sex distribution. Figure 6 Values of ATGL. Figure 2 Age distribution. Figure 7 Ablative dose activity with I-131 mci

36 Ablation therapy with i-131 at thyroid cancer 275 This study presented our first experience and we showed that recommended dose activity (specific activity of I-131 administered) required to achieve ablation was a dose of approximately 100 mci, and that lower doses were not common and recommended in our institution. DISCUSSION Postoperative ablation of functioning thyroid tissue has become established in the management of differentiated thyroid cancer as the long-term risk of recurrence and death is reduced. This beneficial effect results from the destruction of potentially malignant cells or occult multifocal disease that may occur in up to 30% of patients with papillary tumors. Furthermore, the specificity of thyroglobulin as a tumor marker is increased and the sensitivity of subsequent whole body scans seems improved because residual thyroid tissue may compete with recurrent or metastatic thyroid cancer cells for radioiodine uptake. Indeed, it has been demonstrated that patients with successful ablation of remnant thyroid tissue have a better prognosis than those with unsuccessful ablation (disease-free survival of 87% versus 49% after 10 years, while thyroid cancer-related survival was 93% versus 78%).This suggests that it is important to achieve complete ablation as soon as possible after diagnosis in order to ensure the best possible prognosis for a patient (3). The objective of the study was to determine, in patients with differentiated thyroid cancer (DTC) who appeared to be free of disease after surgery and ablative treatment, but who had positive serum TgAb, the value of performing DxWBS and obtaining serum Tg under stimulated Tg conditions (10). Anti-thyroglobulin antibodies are commonly identified in patients with differentiated follicular cell-derived thyroid cancer (16). Caglar suggests that remnant thyroid tissue in patients with lowrisk, well-differentiated thyroid cancer after total thyroidectomy can be ablated with 800 MBq of I-131. The success rate is not different from that obtained with 3700 MBq I-131 (17). Postoperative ablation of functioning thyroid tissue has become established in the management of differentiated thyroid cancer as the long-term risk of recurrence and death is reduced. This beneficial effect results from the destruction of potentially malignant cells or occult multifocal disease. Most studies used a high dose of MBq ( mci) (18,19,20). CONCLUSION In the both therapeutic groups there was normalization of the hormonal status, subjective and objectives parameters, at the control examinations, already after three months and six months follow-up. The side effects did not appear in any of the therapeutic groups, which demonstrated the safe application. Postoperative ablation of functioning thyroid tissue has become established in the management of differentiated thyroid cancer as the long-term risk of recurrence and death is reduced. We conclude that after increasingly meticulous near-total surgery and careful patient selection, the available data continue to favor higher doses of radioiodine (1.85 GBq to 7.4 GBq (50 to 200 mci) for remnant ablation, especially after near-total thyroidectomy. 72 hours after the treatment, the scintigraphy of the entire body was performed. 2-3 months after discharge from the hospital, patient were requested to return and had their hormone status checked. Our findings suggest that patients with differentiated thyroid cancer can be treated with doses of I-131 according to the percentage of neck uptake of postoperative total body scan, with high complete ablation rates, and without exposure to higher dose levels of I-131. Conflict of interest: none declared. REFERENCES 1. Guyton AC, Hall JE. Textbook of Medical Physiology. 10th Ed. Philadelphia: W.B. Saunders Company. 2000; Hegedus L. The thyroid Nodule. N Eng J Med. 2004;351: O Neill, CJ, Oucharek J, Learoyd D, Sidhu SB. Standard and emerging therapies for metastatic differentiated thyroid cancer. The Oncologist. 2010;15(2): Miller BS, Doherty GM. An examination of recently revised differentiated thyroid cancer guidelines. Current Opinion in Oncology. 2011;23(1): Jonklaas J, Cooper DS, Ain KB, Bigos T, Brierley JD, Haugen BR, et al. Radioiodine therapy in patients with stage I differentiated thyroid cancer. Thyroid. 2010;20(12): Robbins, Jacob, Schneider, Arthur B. Thyroid cancer following exposure to radioactive iodine. Reviews in Endocrine and Metabolic Disorders. 2010;1(3): Pagano L, Klain M, Pulcrano M, Angellotti G, Pasano F, Salvatore M, Lombardi G, Biondi B. Follow-up of differentiated thyroid carcinoma. Minerva Endocrinol. 2004; 29: Verburg FA, de Keizer B, Lips CJ, Zelissen PM, de Klerk JM. Prognostic significance of successful ablation with radioiodine of differentiated thyroid cancer patients. Eur J Endocrinol. 2005;152: American Thyroid Association Taskforce On Radioiodine Safety. Sisson JC, Freitas J, McDougall IR, Dauer LT, Hurley JR, et al. Radiation safety in the treatment of patients with thyroid diseases by radioiodine 131I : Practice recommendations of the American thyroid association. Thyroid. 2011;21(4): Rosario PW, Mineiro Filho AF, Lacerda RX, dos Santos DA, Calsolari MR. The value of diagnostic whole-body scanning and serum thyroglobulin in the presence of elevated serum thyrotropin during follow-up of anti-thyroglobulin antibody-positive patients with differentiated thyroid carcinoma who appeared to be free of disease after total thyroidectomy and radioactive iodine ablation. Thyroid. 2012;22(2): Doi SA, Woodhouse NJ. Ablation of the thyroid remnant and 131I dose in differentiated thyroid cancer. Clin Endocrinol (Oxf). 2000;52: Hackshaw A, Harmer C, Mallick U, Haq M, Franklyn JA. 131I activity for remnant ablation in patients with differentiated thyroid cancer: A systematic review. J Clin Endocrinol Metab. 2007;92: International histological classification of tumours, 2nd ed. Geneva, World Health Organization, Sacks W, Fung CH, Chang JT, Waxman A, Braunstein GD. The effectiveness of radioactive iodine for treatment of low-risk thyroid cancer: a systematic analysis of the peer-reviewed literature from 1966 to April Thyroid. 2010;20(11): Nixon IJ, Ganly I, Patel SG, Palmer FL, Di Lorenzo MM, Grewal RK, et al. The results of selective use of radioactive iodine on survival and on recurrence in the management of papillary thyroid cancer, based on Memorial Sloan-Kettering Cancer Center risk group stratification. Thyroid. 2013;23(6): Ringel MD, Nabhan F. Approach to follow-up of the patient with differentiated thyroid cancer and positive anti-thyroglobulin antibodies. J Clin Endocrinol Metab. 2013; 98(8): Caglar M, Bozkurt FM, Akca CK, Vargol SE, Bayraktar M, Ugur O, Karaağaoğlu E. Comparison of 800 and 3700 MBq iodine-131 for the postoperative ablation of thyroid remnant in patients with low-risk differentiated thyroid cancer. Nucl Med Commun. 2012;33(3): Sawka AM, Brierley JD, Tsang RW, Thabane L, Rotstein L, Gafni A, et al. An updated

37 276 R. Alimanović-Alagić et al. systematic review and commentary examining the effectiveness of radioactive iodine remnant ablation in well-differentiated thyroid cancer. Endocrinol Metab Clin North Am. 2008;37(2): Sirisalipoch S, Buachum V, Pasawang P, Tepmongkol S. Prospective randomised trial for the evaluation of the efficacy of low vs high dose I-131 for post-operative remnant ablation in differentiated thyroid cancer. World J Nuclear Med. 2004;3: Bal CS, Kumar A, Pant GS. Radioiodine dose for remnant ablation in differentiated thyroid carcinoma: a randomized clinical trial in 509 patients. J Clin Endocrinol Metab. 2004;89: Reprint requests and correspondence: Rubina Alimanović-Alagić, MD, PhD Clinic of Nuclear Medicine University Clinical Centre Sarajevo Bolnička 25, Sarajevo Bosnia and Herzegovina Phone: rubinaalimanovic@yahoo.com Hipertiroidizam (povećano lučenje hormona) Anksioznost, razdražljivost Ubrzan rad srca Povećano znojenje Gubitak na težini Drhtanje ruku Strahovi, strepnja Opadanje kose Tanka i glatka koža Netolerancija toplote Smanjena pažnja Promene raspoloženja Dijareja Nesanica Ubrzan rast noktiju Poremećaj menstrualnog ciklusa Hipotiroidizam (smanjeno lučenje hormona) Umor Usporen rad srca Vrtoglavica, malaksalost Smanjena koncentracija i pamćenje Nizak krvni pritisak Depresija Dobitak na težini Suva koža Netolerancija na hladnoću Zatvor Neplodnost Bol u mišićima Krti nokti Poremećaj menstrualnog ciklusa

38 Medical Journal (2015) Vol. 21, No. 4, Professional article Length of hospital stay in patients treated for bronchiolitis at the Pediatric Clinic in Sarajevo Dužina trajanja hospitalizacije pacijenata liječenih od bronhiolitisa na Pedijatrijskoj klinici u Sarajevu Ganimeta Bakalović *, Jovana Panić, Amra Džinović, Selma Dizdar, Amina Selimović Pediatric Clinic, University Clinical Center Sarajevo, Patriotske lige 81, Sarajevo, Bosnia and Herzegovina *Corresponding author ABSTRACT Aim: to show the length of hospitalization in relation to the clinical and therapeutic approach in infants hospitalized for bronchiolitis at the Department of Pulmology of the Pediatric Clinic of the University Clinical Centre Sarajevo. Introduction: bronchiolitis is the most common respiratory disease in infancy, and its etiology is viral and in most cases it is Respiratory syncytial virus (RSV). It usually begins with the clinical signs of the common cold, such as runny nose, mild cough, fever and after a day or two, the cough intensifies and the baby gets tachydispnoic. Symptoms are more expressed in young infants due to small diameter of the airways. There is no specific therapy for RSV or any other virus causing bronchiolitis. Antibiotics are not recommended given that it is a virus caused infection. Materials and methods: this is a retrospective study in which we analyzed the histories of the disease in 155 patients hospitalized for bronchiolitis at the Department of Pulmology of the Pediatric Clinic in Sarajevo in a period of one year. Results: in the clinical picture of our patients the predominant symptoms were represented in the following order: dyspnea in 139 patients (89.7%), cough in 136 (87.7%), nasal secretion in 112 (72.3%), fever in 53 (34.2%), dehydration in 44 (28.4%), wheezing in 42 (27.1%) and vomiting in 17 (11%) patients. Bronchopneumonia as an early complication was seen in 7 patients (4.5%). The most commonly used drugs were: corticosteroids in 115 (74.2%), oxygen supplementation in 81 (52.3%), salbutamol in 109 (70.3%), ipratropium bromide in 3 (1.9%), adrenaline in 31 (20%), antibiotics in 95 (61.3%), aminophylline in 9 (5.8%) and antileukotriene in 38 (24.5%) patients. The largest number of hospitalized infants was in the group hospitalized up to seven days, 119 (76.8%) patients, followed by 34 (21.9%) infants hospitalized in the period from seven to fifteen days, and 2 (1.3%) infants were in the group hospitalized over fifteen days. We had no patients on mechanical ventilation or with lethal outcome. Conclusion: the largest number of infants was hospitalized for the period up to seven days. Length of hospitalization of patients with oxygen therapy was statistically significantly shorter in comparison to patients without oxygen therapy, whereas hospitalization of patients who were treated with adrenaline, ipratropium bromide, salbutamol, corticosteroids, antibiotics, antileukotriene and aminophylline was statistically significantly longer. Key words: hospitalization, bronchiolitis, treatment SAŽETAK Cilj rada: prikazati dužinu hospitalizacije u odnosu na kliničku sliku i terapijski pristup kod dojenčadi hospitalizirane zbog bronhiolitisa na pulmološkom odjeljenju Pedijatrijske klinike Univerzitetskog kliničkog centra u Sarajevu. Uvod: bronhiolitis je najčešća bolest respiratornog sistema u dojenačkoj dobi, virusne etiologije. Najčešći uzročnik je respiratorni sincicijelni virus. Obično počinje sa kliničkim znacima prehlade kao što su curenje nosa, blag kašalj, povišena temperatura a nakon dan, dva kašalj se intenzivira i dojenče biva tahidispnoično. Simptomi su izraženiji kod mlađe dojenčadi zbog malog promjera disajnih puteva. Ne postoji specifična terapija za RSV ili nekim drugim virusom uzrokovan bronhiolitis. Antibiotici se ne preporučuju s obzirom da je riječ o virusom uzrokovanoj infekciji. Materijali i metode: retrospektivno su analizirane historije bolesti 155 pacijenata dojenačke dobi koji su u jednogodišnjem periodu bolnički liječeni od bronhiolitisa na Pulmološkom odjeljenu Pedijatrijske klinike u Sarajevu. Rezultati: u kliničkoj slici kod naših pacijenata dominantni simptomi su bili zastupljeni sljedećim redosljedom: dispnea kod 139 pacijenata (89.7%), kašalj 136(87.7%), nazalna sekrecija 112 (72.3%), povišena tjelesna temperatura 53 (34.2%), dehidracija 44 (28.4%), wheesing 42 (27.1%), povraćanje 17 (11%). Bronhopneumonija kao rana komplikacija bila je zastupljena kod 7 pacijenata (4.5%). Najčešće korišteni lijekovi bili su: kortikosteroidi 115 (74.2%), kiseonik 81 (52.3%), salbutamol 109 ( 70.3%), ipratropium bromid (1.9%), adrenalin 31 ( 20%), antibiotici 95 (61.3%), aminofilin 9 ( 5.8%), antileukotrijeni 38 ( 24.5%). U odnosu na dužinu hospitalnog boravka dojenčad smo podijelili u tri grupe. Najveći broj hospitaliziranih bio je grupi do sedam dana 119 (76.8%), od sedam do 15 dana bilo je 34 (21.9%) dojenčadi, dok je u grupi iznad petnaest dana bilo njih 2 (1.3%). Nismo imali pacijenata na mehaničkoj ventilaciji niti letalnih ishoda. Zaključak: najveći broj hospitalizirane dojenčadi imao je dužinu hospitalnog boravka do sedam dana. Dužina hospitalizacije kod pacijenata na oksigenoterapiji je bila statistički značajno kraća u odnosu na one pacijente koji nisu bili na oksigenoterapiji. Dužina hospitalizacije pacijenata koji su primali terapiju poput adrenalina, ipratropium bromida, salbutamola, kortikosteroida, antibiotika, antileukotrijena i aminofilina je bila statistički značajno duža. Ključne riječi: hospitalizacija, bronhiolitis, tretman

39 278 G. Bakalović et al. INTRODUCTION Bronchiolitis is an infection of the lower respiratory tract that is seen in children under two years of age. It is usually caused by a virus. The most common cause is RSV. By the end of the second year of life 90% of children are infected by RSV and 40% of them will develop an infection of the lower respiratory tract during the primary infection (1). In a study of Miller et al. which involved hospitalized as well as outpatient treated for bronchiolitis (2) it was found that RSV was present in 76% of patients, Rhinovirus in 39%, Influenza in 10%, Coronavirus in 2%, Human metapneumovirus in 3% and Parainfluenza in 1% of patients. Some patients had co-infection hence the summation was over 100%. This produces inflammation of small airways (bronchioles). Inflammation partially or completely obstructs the small airways resulting in wheezing. These and usually small (diameter up to 300 microns) airways are fully obliter by cellular debris and thick mucus as well as epithelial cells fused in syncytium by activity of the virus. Bronchiolitis is the main cause of morbidity and the leading cause of hospitalization in infants and small children. Bronchiolitis may be more severe in some children such as premature babies, children with chronic lung or heart disease, immunodeficiency. So it is very important to recognize the signs and symptoms that require treatment (3). In the early infant age (younger than two months) or in preterm children, apnoic crisis are frequent, which at the same time can be the first symptom of the disease (4). In a small number of children, progressive deterioration is observed. The child starts to develop cyanosis and respiratory fatigue. Such children require hospitalization (1-2% of all patients). Disorder of respiratory ventilation that occurs in bronchiolitis leads to hypoxemia and hypercapnia, which is manifested by cyanosis, especially expressed on the lips and nails. This often happens in high-risk groups (malnourished children, premature or children with congenital heart defects with right-left shunt) where we observe fatigue, nostrils flutter, reduced number of respirations, decreased level of wheezing. (5) Although bronchiolitis as an entity is known for almost seventy years we do not have unified and clear pharmacotherapeutic guidelines (6). In everyday clinical practice and the available medical literature there are number of concerns and controversial data, and at the same time a small number of evidence-based recommendations for effective therapy of the disease, that occurs frequently and can be life threatening. Most controversies are related to the use of bronchodilators and glucocorticosteroids. There is no specific therapy for RSV or another virus causing bronchiolitis. Treatment for acute bronchiolitis is symptomatic. Antibiotics are not recommended given the viral etiology. Treatment includes measures to ensure adequate amounts of fluids and ability of sufficient and independent breathing without significant difficulties. RESULTS For the purpose of statistical analysis, the SPSS statistical package 21.0 was used. The distribution of frequency was tested by Kolmogorov-Smirnovljev test, the data was shown by median and interquartile range. The Mann Whitney U test was used for testing the differences among continuous variables. Our sample comprised 155 patients of which 91 boys (58.7%) and 64 girls (41.3%). Majority of patients were from 1 to 3 months of age, 74 (47.7%) patients, followed by patients aged 3-6 months, 54 (34.8%), and patients aged 6-12 months, 27 (17.4%). Among the symptoms within the clinical picture of patients with bronchiolitis, as shown in Figure 1, the most common were: dyspnea in 139 (89.7%) patients, cough in 136 (87.7%), and nasal secretion in 112 (72.3%) patients, and somewhat less common were fever in 53 (34.2%), dehydration in 44 (28.4%), wheezing in 42 (27.1%) and vomiting in 17 (11%) patients. Pneumonia as an early complication occurred only in 7 (4.5%) patients. In the treatment of our patients, as shown in Figure 2, the most commonly used was systemic corticosteroid in 115 (74.2%) patients, followed by inhalation of salbutamol in 109 (70.3%), antibiotics in 95 (61.3%), and oxygen support in 81 (52.3%) patients. Among other medicaments antileukotrienes were used in 38 (24.5%), adrenalin in inhalation in 31 (20%), aminophylline in 9 (5.8%), and ipratropium bromide in 3 (1.9%) patients. Patients treated in our hospital spent approximately 4 days (Iq 3-6), as shown in Figure 3. Majority of patients were hospitalized for less than 7 days, 119 (76.8%) patients, 34 (21.9%) patients were hospitalized from 7 to 15 days, while only 2 (1.3%) patients were hospitalized for 15 or more days. Regarding the impact of drugs on the duration of hospitalization, we could conclude that only patients with oxygen support in the treatment were less hospitalized (Me 4, Iq 2.5-6) as compared to those without oxygen support (Me 5, Iq 3-7). The difference was statistically significant (p = 0.021), as shown in Figure 4. Among the other therapeutic options statistically significant negative impact was observed in the use of antibiotics, antileukotriene and adrenaline in inhalation. Patients who received antibiotics were significantly longer hospitalized (Me 5, Iq 3-7) in comparison to patients who did not have the same in therapy (Me 4, Iq 2.5-6) p = The use of antileukotriene showed a similar result: patients treated with antileukotriene were hospitalized significantly longer (Me 5.5, Iq ), than those who were not treated with antileukotriene (Me 4, Iq ), p = (Figure 5). Similarly, patients treated with adrenaline inhalation were hospi- MATERIALS AND METHODS We analyzed the histories of disease in 155 infants hospitalized at the Department of Pulmonary Medicine of the Pediatric Clinic, in the period from February 2013 to February The study included infants with primary infection of the lower respiratory tract, not those with relapses. Figure 1 Percentage of symptoms occurred in patients with bronchiolitis.

40 Length of hospital stay in patients treated for bronchiolitis at the Pediatric Clinic in Sarajevo 279 talized significantly longer (Me 5, Iq 3-8) as compared to patients who were not treated with adrenaline inhalation (Me 4, Iq 3-6), p= The use of aminophylline and ipratropium bromide showed a statistically significant difference in the length of hospitalization of our patients, but due to extremely small number of patients treated with aminophylline and ipratropium bromide we could not give any statistical conclusions. Finally, the use of salbutamol inhalation and systemic corticosteroids showed no effect on shortening the hospitalization. Figure 2 Percentage of treatment applied in patients with bronchiolitis. Figure 3 Length of hospitalization in patients with bronchiolitis in days Me 4 Iq 3-6. Figure 5 Length of hospitalization in relation to treatment with antileukotrene (p=0.011). *1 treated (Me 5.5, Iq ), 2 not treated (Me 4 Iq 3-5.5) Figure 4 Length of hospitalization in relation to use of oxygen supplementation in treatment (p=0.021). *1 treated (Me 4 Iq 2.5-6), 2 not treated (Me 5 Iq 3-7) DISCUSSION Bronchiolitis usually begins with symptoms of cold in the period from one to three days including: nasal congestion, moderate cough, decreased appetite, generally without a fever. The general aspect of child is not drastically changed. As the general infection progresses and the small airways are affected, obstruction is gradually leveling up. Further symptoms that occur are: tachypnea (60-80 respirations per minute), dyspnea and wheezing, which usually takes about seven days or longer (postbronchiolitic wheezing). There is a persistent cough that can last for 14 days or more. The child manifests expiratory dyspnea which is presented by tachypnea and inspiratory retractions. There is a good correlation between the number of respirations and severity (7). In almost 1/3 of patients dehydration symptom was present. Feeding problem was also one of the symptoms associated with nasal congestion and tachypnea, which actually could result in dehydration. It is mainly seen in severe forms of bronchiolitis where the child is unable to drink and additionally loses through vomiting and perspiratio insensibilis. Rehydration, as a very important measure, is necessary to take into account in acute bronchiolitis, especially in more severe clinical forms of the disease. One-third of hospitalized infants require supplementation of fluid, either intravenously or through a nasogastric tube (8). Corticosteroids are routinely used in the treatment of infants with bronchiolitis. Routinely, systemic administration of glucocorticoids is not supported by the results of clinical trials, but in case of severe clinical course the same will be applied. Most of the controversies in the treatment of bronchiolitis are specifically related to the use of corticosteroids and bronchodilators. The answer we can find in clinical presentation of children with bronchiolitis is similar to that of asthma and for that reason children with bronchiolitis almost always receive treatment with both medicines (9). Infants with bronchiolitis often receive antibiotics due to fever, younger age and the physician s concerns for secondary bacterial infection. Circa 25% of hospitalized infants with bronchiolitis has radiographic finding of atelectasis, and it is sometimes difficult to distinguish between atelectasis and bacterial infiltrates and consolidation. Antibiotic therapy may be justified in children with bronchiolitis that require intubation and mechanical ventilation due to respiratory failure (10). Oxygen supplementation for the children with bronchiolitis is applied if the oxygen saturation is below 90%. The small increase in arterial partial pressure of oxygen is associated with a significant increase in oxygen saturation when it is less than 90%. When the oxygen saturation in blood is above 90% it requires very high elevation in the arterial partial pressure of oxygen in order to have an impact on growth of oxygen saturation (10). The majority of children treated for bronchiolitis feel better after two to five days from the start of symptoms. The mean duration of illness is 15 days, and the majority of these infections resolve uneventfully within 3 to 4 weeks. Of note, up to 25% of infants with bronchiolitis remained symptomatic after 21 days of illness highlighting the prolonged disease course of this acute disease (11). Oxygen therapy reduces the need for hospitalization and length of hospitalization. Hypoxemia is associated with an increased number of hospitalizations, longer stay in hospital and higher costs. Use of high flow nasal cannula to deliver a mixture of air and oxygen provides multiple assistance to infants with bronchiolitis. Clinical data suggest that it leads to a reduction of the respiratory muscle work and reduces the need for intubation (12). The study of Bisgaard and Montelukast did not show therapeutic effect regarding bronchiolitis (13). Cochrane s recent meta-analysis Hartling et al. (14) systematically evaluates the evidence on the use of adrenaline in these children and concludes that there is no evidence of efficiency in hospitalized children. Two large multicenter randomized trials compared the use of nebulized adrenaline with placebo or salbutamol in hospital conditions and found no improvement in terms of length of hospital stay or other hospital outcomes. Several meta-analyzes and systematic research such as Zorc JJ et al. and Wainwright C (15,16) have shown that they can improve

41 280 G. Bakalović et al. clinical score but do not affect the resolution of the disease, the need for hospitalization and the length of hospital stay. Although transient improvements in the clinical picture are observed, most of the infants treated with bronchodilators will not benefit of their use. The recently updated Cochrane systematic study Gadomski AM et al. assessing the impact on the value of bronchodilators on oxygen saturation and primarily obtained results through the 30 randomized controlled trials including 1,992 infants in 12 countries (17) indicates that there is no benefit in clinical course in infants with bronchiolitis who received bronchodilators. Potential side effects (tachycardia and tremor) and the cost of these drugs, exceed any potential benefit from them. Considering the pathophysiological events where we know that bronchoconstriction in bronchiolitis results from mucosal edema, hypersecretion of mucus and desquamation of respiratory epithelium, not the result of bronchospasm, the question which arises is related to the role of bronchodilators in this disease. CONCLUSION The largest number of infants were hospitalized for the period up to seven days. Length of hospitalization in patients treated with oxygen therapy, standard 0,9% NaCl inhalation and parenteral rehydration was statistically significantly shorter in comparison to those without oxygen therapy. Length of hospitalized patients treated with inhalation adrenaline therapy and/or ipratropium bromide and/ or salbutamol was statistically significantly longer. Use of parenteral corticosteroid and/or antibiotic and/or aminophylline in the treatment of bronchiolitis resulted in statistically significantly longer hospitalization. Use of antileukotriene in the treatment of infant bronchiolitis showed no effects in terms of shorter hospitalization. The outcome was satisfying because we did not have any patients on mechanical ventilation or lethal outcomes. 3. Scottish Intercollegiate Guidelines Network. Bronchiolitis in children. A national clinical guideline (Accessed on February 24, 2015). 4. Bronchiolitis Guideline Team, Cincinnati Children s Hospital Medical Center. Bronchiolitis pediatric evidence based care guidelines (Accessed on February 24, 2015). 5. Gern JE. Viral respiratory infection and the link to asthma. Pediatr Infect Dis J. 2004;23: Kimpen JLL. Management of respiratory syncytial virus infection. Curr Opin Pediatr. 2001;14(3): Nestorović B. Pedijatrijska pulmologija: III izdanje. Beograd. 2011; Kennedy N, Flanagan N. Is nasogastric fluid therapy a safe alternative to the intravenous route in infants with bronchiolitis? Arch Dis Child. 2005;90(3): Banac S, Ahel V, Rožmanić V, Zubović I. Farmakoterapijski aspekti krupa i bronhiolitisa. Pediatr Croat. 2007;51(Supl I): Raiston SL, Liberthal AS, Meissner HC, et al. Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis. Pediatrics. 2014;134:e Petruzella FD, Gorelick MM. Duration of illness in infants with bronchiolitis evaluated in the emergency department. Pediatrics. 2010;126: Ganu SS, Gautam A, Wilkins B, Egan J. Increase in use of non-invasive ventilation for infants with severe bronchiolitis is associated with decline in intubation rates over a decade. Intensive Care Med. 2012; 38(7): Bisgaard H. Montelukast in RSV-bronchiolitis. Am J Respir Crit Care Med. 2004;169: Hartling L, Fernandes RM, Bialy L, Milne A, Johnson D, Plint A, et al. Steroids and bronchodilatators for acute bronchiolitis in the first two years of life: systematic review and meta-analysis. BMJ. 2011;342: d Zorc JJ, Hall CB. Bronchiolitis: recent evidence on diagnosis and management. Prdiatrics. 2010;125(2): Wainwright C. Acute viral bronchiolitis in children-a very common condition with few therapeutic options. Pediatr Respir Rev. 2010;11(1): Gadomski AM, Scribani MB. Bronchodilatators for bronchiolitis. Cochrane Database Syst Rev. 2014;(6):CDOO1266 Conflict of interest: none declared. REFERENCES 1. Meissner HC. Selected populations at increased risk from respiratory syncytial virus infection. Pediatr Infect Dis J. 2003;22(suppl 2): Miller EK, Gebretsadik T, Carroll KN, Dupont WD, Mohamed YA, Morin LL, et al. Viral etiologies of infant bronchiolitis, croup and upper respiratory illness during 4 consecutive years. Pediatr Infect Dis J. 2013; 32(9): Reprint requests and correspondence: Ganimeta Bakalović, MD Pediatric Clinic University Clinical Center Sarajevo Patriotske lige Sarajevo Bosnia and Herzegovina ganimeta.bakalovic@gmail.com

42 Medical Journal (2015) Vol. 21, No. 4, Professional article Glomerular filtration rate and proteinuria in children with cyanotic congenital heart disease Glomerularna filtracija i proteinurija kod djece sa cijanotičnom urođenom srčanom bolešću Admir Hadžimuratović *, Senka Mesihović-Dinarević, Emina Hadžimuratović Pediatric Clinic, University Clinical Center Sarajevo, Patriotske lige 81, Sarajevo, Bosnia and Herzegovina *Corresponding author ABSTRACT Objective: pediatric patients with cyanotic congenital heart disease (CCHD) consequently develope nephropathy due to chronic hypoxia. We conducted this trail to estimate effects of chronic hypoxia in these patients on glomerular filtration rate (GFR) and proteinuria. Materials and methods: a prospective clinical trial conducted from January 2003 to December 2015 studied 70 patients with cyanotic and 70 patients with acyanotic CHD. We measured hemoglobin/hematocrit, serum creatinine, proteinuria and GFR. In cyanotic group, six months after corrective surgery the same tests were repeated. Results: the mean hemoglobin and hematocrit were significantly higher and GFR significantly lower in cyanotic compared to acyanotic group (164.3 mg/dl (56.54±3.2%) vs mg/dl (42.12±3.15%); 71.99ml/min/1.73m² vs ml/min/1.73m²) (P<0.01). In cyanotic group alone, there was a significant difference in mean values of hemoglobin and GFR before and six months after corrective surgery ( mg/dl (56.54±3.2%) vs mg/dl (43.48±3.2%); 71.99ml/min/1.73m² vs ml/min/1.73m²) (P<0.01). Significant proteinuria was more frequent in cyanotic group, before and six months after corrective surgery, compared to acyanotic group (P<0.01). Conclusions: the effects of chronic hypoxia on GFR and quantity of urinary protein secretion demonstrate the importance of close monitoring of renal function parameters in children with CCHD. Six-months after surgery, GFR improved, but significant proteinuria persisted. Key words: glomerular filtration rate, proteinuria, cyanotic congenital heart disease SAŽETAK Uvod: pedijatrijski pacijenti sa kongenitalnom cijanotičnom srčanom bolešću (eng. cyanotic congenital heart disease (CCHD) posljedično razvijaju nefropatiju zbog hronične hipoksije. Mi smo proveli ovo istraživanje da bi ocijenili posljedice hronične hipoksije kod ovih pacijenata na glomerularnu filtraciju (eng. glomerular filtration rate, GFR) i proteinuriju. Materijali i metode: proveli smo prospektivno kliničko istraživanje od januara godine do decembra godine koje je obuhvatilo 70 pacijenata sa cijanotičnom i 70 pacijenta sa acijanotičnom urođenom srčanom bolešću (eng. congenital heart disease, CHD). Mjerili smo hemoglobin/hematokrit, serumski kreatinin, proteinuriju i GFR. U cijanotičnoj skupini pacijenata, šest mjeseci nakon korektivne operacije, isti testovi su ponovljeni. Rezultati: srednje vrijednosti hemoglobina i hematokrita su bile značajno više, a GFR značajno niža u cijanotičnoj skupini u odnosu na acijanotičnu (164.3 mg/dl (56.54±3.2%) vs mg/dl (42.12±3.15%); 71.99ml/min/1.73m² vs ml/min/1.73m²) (P<0.01). U cijanotičnoj skupini, postojala je statistički značajna razlika u srednjim vrijednostima hemoglobina i GFR prije i šest mjeseci nakon korektivne operacije ( mg/dl (56.54±3.2%) vs mg/dl (43.48±3.2%); 71.99ml/min/1.73m² vs ml/min/1.73m²) (P<0.01). Signifikantna proteinurija je bila češća u cijanotičnoj skupini, prije i šest mjeseci nakon korektivne opearacije, u poređenju sa acijanotičnom skupinom (P<0.01). Zaključak: efekti hronične hipoksije na GFR i proteinuriju pokazuju značaj praćanja parametara bubrežne funkcije kod djece sa CCHD. Šest mjeseci nakon hirurške korekcije, GFR se popravila, ali je signifikantna proteinurija perzistirala. Ključne riječi: glomerularna filtracija, proteinurija, cijanotična urođena srčana bolest INTRODUCTION It is well known that older pediatric patients with cyanotic congenital heart disease (CCHD) develop nephropathy. This nephropathy is mainly secondary to glomerular dysfunction, but tubules are also affected. One of the mechanisms in which chronic hypoxia affects renal function is through alterations of serum erythropoietin stimulation (1) with a rise in red-cell mass and total blood volumes (2,3). This raise in hematocrit increases blood viscosity with repercussions on renal blood flow and glomerular filtration rate (GFR). Besides, structural glomerular changes cause hyperfiltration with consequent proteinuria as the major urinary abnormality in patients with CCHD (4-7). MATERIALS AND METHODS We conducted a clinical trial including 70 children with CCHD and 70 children with acyanotic congenital heart disease (ACHD) admitted to Pediatric Clinic, University Clinical Center Sarajevo (Bosnia and Herzegovina) between January 2003 and December In both

43 282 A. HadŽimuratović et al. groups we measured hemoglobin, hematocrit, serum creatinine, proteinuria and GFR. In cyanotic group the same tests were repeated six months after cardiac surgery. To avoid 24-hours urine collecting, GFR was measured by Schwartz formula: GFR (ml/min/1.73m²)=k Χ length (cm)/serum creatinine (mg/dl), where K was defined 0.45 for infant up to two years and 0.55 for girls and boys under the age 12 (8,9). Statistical analysis was performed by software Statistical Package for the Social Sciences (SPSS), version Informed consent was obtained from the parents of all participants. RESULTS Of 140 children involved 74 (52.86%) were males and 66 (47.14%) females. Mean age was evenly matched between the groups (4.8 +/- 0.2; 5.1 +/-0.3 years). In cyanotic group, 60 (85.71%) patients had transposition of great vessels (TGA) and 10 (14.29%) tetralogia of Fallot (ToF). In acyanotic group, atrial septal defect (ASD) had 24 (34.29%), coarctation of aorta (CoA) 18 (25.71%), ventricular septal defect (VSD) 14 (20%), atrioventricular septal defect (AVSD) 10 (14,29%) and patient ductus arteriosus (PDA) 4 (5.71%). Mean hemoglobin and hematocrit were significantly higher in cyanotic compared to acyanotic group, and also, in cyanotic group preoperatively compared to six months postoperatively ( ± 4.57 mg/dl (56.54 ± 3.12%) vs ±7.10mg/dl (42.12 ± 3.15%); ± 4.57mg/dl (56.54+/- 3.12%) vs ±6.33 mg/dl (43.48+/-3.2%)) (P<0,01) (Figure 1). The difference between cyanotic group postoperatively and acyanotic group was not significant (P=0.97). Mean serum creatinine values were significantly higher in cyanotic group preoperatively compared to cyanotic group postoperatively and acyanotic group (0.51±0.06 mg/dl vs. 0,39±0,06 mg/dl; 0.51±0.06 mg/dl vs. 0.38±0.05 mg/dl) (P<0.01) (Figure 1). Mean GFR was significantly lower in cyanotic group compared to acyanotic and in cyanotic group preoperatively compared to six months postoperatively (71.99ml/min/1.73m² vs ml/ min/1.73m²; 71.99ml/min/1.73m² vs ml/min/1.73m²) (P<0.01). The difference between acyanotic group and cyanotic group postoperatively was not significant (P=0.98) (Figure 1). In cyanotic group 42 (60%) children had significant proteinuria related to their age compared to 22 (31.43%) children in acyanotic group (P<0.01). This proteinuria persisted six months after corrective surgery in all patients where it was preoperatively present. Figure 1 Mean hemoglobin (Hb), hematocrit (Hct), glomerular filtration rate (GFR) and serum creatinine (Cr) in cyanotic (pre-and postoperatively) and acyanotic group. DISCUSSION Non-immune nephropathy is a well known complication of CHD and the risk of developing renal impairment is particularly high in patients with CCHD. Rheological changes have been suspected to be involved in the pathogenesis since chronic hypoxia increases hematocrit and blood viscosity. Hypoxia itself affects glomerular and tubular cells, causing structural changes, such as glomerular enlargement, thickening of glomerular basal membrane, focal sclerosis and others (4-7). These changes affect normal renal function in children with CCHD. Proteinuria is the major urinary abnormality in patients with CCHD, but nephrotic syndrome is an uncommon complication and renal biopsy has been seldom performed. This complication occurs with long duration of disease. It has been reported that significant proteinuria may occur in as high as 70% of patients with CCHD over 10 years of age (11). Serum creatinine was significantly higher and GFR significantly lower in children with CCHD compared to those with ACHD and postoperative findings in children with CCHD. Passwel at al. reported about similar results (12). In our study which was performed on children aged below 10 years it has been shown that in cyanotic group 65% of patients and in acyanotic group 24% had significant proteinuria. In children with CCHD, six months postoperatively, proteinuria was present to the same extent probably because of the structural glomerular changes. CONCLUSION The effects of chronic hypoxia on GFR and quantity of urinary protein secretion demonstrate the importance of close monitoring of renal function parameters in children with CCHD. Six months after corrective surgery, as hemoglobin, hematocrit and blood viscosity were decreasing, GFR raised. On the other hand, proteinuria which results from structural glomerular changes, and depends less on rheological factors, persisted. To investigate further outcome of this proteinuria long-term follow-up should be considered. Conflict of interest: none declared. REFERENCES 1. Koeffler HP, Goldwasser E. Erythropoetin radioimmunoassay in evaluating patients with polycythaemia. Ann Intern Med. 1981;94: Erslev AJ, Caro J. Pure erythrocytosis classified according to erythropoietin titres. Am J Med. 1984;76: Rosenthal A, Button LN, Nathan DG, Miettinen OS, Nadas AS. Blood volume changes in cyanotic congenital heart disease. Am J Cardiol. 1971;27: Bauer WC, Rosenberg BF. A quantitive study of glomerular enlargement in children with tetralogy of Fallot. A condition of glomerular enlargement without an increase in renal mass. Am J Pathol. 1960;37: Hagley MT, Murphy DP, Mullins D, Zarconi J. Decline in creatinine clearance in a patient with glomerulomegaly associated with a congenital heart disease. Am J Kidney Dis. 1992;20: Agras PI, Derbent M, Ozcay F, Baskin E, Turkoglu S, Aldemir D, et al. Effect of congenital heart disease on renal function in childhood. Nephron Physiol. 2005;99:10-15.

44 Glomerular filtration rate and proteinuria in children with cyanotic congenital heart disease Dittrich S, Haas NA, Bührer C, Müller C, Dähnert I, Lange PE. Renal impairment in patients with long-standing cyanotic congenital heart disease. Acta Paediatr. 1998;87: Schwartz GJ, Haycock GB, Edelmann CM, Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics. 1976;58: Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20(3): Guignard JP, Santos F. Laboratory investigations. In: Avner ED, Harmon WE, Niaudet P (Eds.). Pediatric Nephrology, 5th ed. Lippincott Williams Wilkins; Philadelphia, 2004, p Krull F, Ehrich JH, Wurster U, Toel U, Rothgänger S, Luhmer I. Renal involvement in patients with congenital cyanotic heart disease. Acta Paediatr Scand. 1991;80: Passwell J, Orda S, Modan M. Abnormal renal functions in cyanotic congenital heart disease. Arch Dis Child. 2002;51(10): Reprint requests and correspondence: Admir Hadžimuratović, MD, MSc Pediatric Clinic University Clinical Center Sarajevo Patriotske lige 81, Sarajevo Bosnia and Herzegovina Phone: Fax: admirhadzimuratovic@yahoo.com Our contribution to the reduction of cardiovascular diseases in Bosnia and Herzegovina! Naš prilog redukciji kardiovaskularnih bolesti u Bosni i Hercegovini!

45 Medical Journal (2015) Vol. 21, No. 4, Review article Evaluation of dermoscopic findings and follow up for patients with dysplastic nevi Evaluacija dermoskopskih nalaza i praćenje pacijenata sa displastičnim nevusima Hana Helppikangas *, Samra Šoškić, Emina Kasumagić-Halilović Dermatology Clinic, University Clinical Center Sarajevo, Bolnička 25, Sarajevo, Bosnia and Herzegovina *Corresponding author ABSTRACT Patients with multiple dysplastic nevi have an increased risk of malignant melanoma, and dysplastic nevi themselves have at least some potential for malignant transformation. Dysplastic nevi have become an increasing clinical focus, based on the evidence that they are associated with a higher risk of melanoma development. However, there are still dilemmas regarding the significance of dysplastic nevi monitoring. Given the alarming rates of melanoma increase worldwide, dysplastic nevi, especially those that clinically change in size, color, or borders, seem to play the key role in a tumor stage progression. Dysplastic nevi may occur in multiples in family members of heritable malignant melanoma. Key words: dysplastic nevi, melanoma SAŽETAK Pacijenti s višestrukim displastičnim nevusima imaju povećan rizik za nastanak malignog melanoma, a displastični nevusi sami po sebi, imaju predispoziciju za malignu transformaciju. Displastični nevusi su sve više u kliničkom fokusu zbog dokaza da su povezani s većim rizikom za razvoj melanoma. Međutim, još uvijek postoje dileme o značaju praćenja displastičnih nevusa. Zbog alarmantno povećane stope rasta melanoma u svijetu, displastični nevusi, posebno oni koji klinički mijenjaju veličinu, boju, ili granice, smatra se da igraju ključnu ulogu u progresiji stupnja tumora. Poznato je da se multipli displastični nevusi mogu pojaviti kod članova porodice heriditarnog malignog melanoma. Ključne riječi: displastični nevusi, melanom INTRODUCTION Various names are used in the literature for dysplastic nevi, including BK moles (after the initials of the first two patients in whom these lesions were described)(1), Clark s nevi, and atypical moles or nevi. All these terms refer to lesions with specific clinicopathological characteristics associated with an increased risk of melanoma. In 1974, Munro (2) described an association of lesions and a family history of melanoma. These nevi had the clinical and microscopic appearance of what are now called atypical moles (AMs). In 1978 and 1981, Clark et al. (1,3) described these lesions as dysplastic nevi when they were observed as a familial phenomenon. In 1978, Clark (1) reported an increased incidence of cutaneous melanoma in families with multiple melanocytic lesions, introducing the melanoma tumor progression model from melanocytic nevi (1,4). Currently, the terms AMS, Dysplastic Nevus Syndrome and Familial Atypical Multiple-Mole Melanoma Syndrome (FAMMM) have been employed (4). In 1985, Elder (5) extended the theory of nevus-melanoma for sporadic dysplastic nevi as a possible precursor to sporadic melanoma. The term dysplastic nevus syndrome is used arbitrarily. Some clinicians use it to describe patients with only one atypical nevus (6), although the classic dysplastic nevus syndrome refers to patients who have the triad of 100 or more nevi, at least 1 nevus 8 mm or larger in diameter, and at least 1 nevus with clinically atypical features (7). The syndrome can occur sporadically or in a familial setting. To diagnose sporadic dysplastic nevus syndrome with certainty, clinical examination of the first-degree relatives is necessary (8). Several studies have shown that the presence of dysplastic nevi considerably increases the risk of developing melanoma, which demonstrates that these lesions, aside from being precursors to disease are also important risk markers (3,9-12). There are still controversies in the literature regarding the nomenclature, clinical definition, dermoscopic characteristics and histopathological, genetic and molecular patterns of dysplastic nevi (3,13-15) (Figure 2). Epidemiology caracteristics Dysplastic nevi are relatively common in the general population (11,16). The estimated prevalence of clinically atypical nevi ranges from 7 percent to 18 percent in population - based samples (17,18), and the prevalence of histologic melanocytic dysplasia is approximately 10 percent (19, 20). The reported frequency of clinically atypical nevi among patients with a history of melanoma is higher, ranging from 34

46 Evaluation of dermoscopic findings and follow up for patients with dysplastic nevi 285 percent to 59 percent (18,21-24). Dysplastic nevi also appear to be more prevalent in younger populations (those less than 30 to 40 years of age) than in older groups (5,11). Evidence suggests that sun exposure, in addition to genetic susceptibility, may increase the appearance of such nevi (11,15,25). Clinically atypical nevi may evolve from normal appearing nevi or may be dysplastic from their first appearance (3). As dynamic lesions, dysplastic nevi can become progressively more or progressively less clinically atypical, but majority either remain stable or regress over time (26,27). New dysplastic nevi may develop after the age of 30 years (26). The predilection of atypical nevi for intermittently sun-exposed areas (especially the trunk), their positive association with a history of painful sunburn (in which the pain lasts more than two days) or blistering sunburn, and the finding that persons with clinically atypical nevi often have sun-sensitive skin types suggest that the development of dysplastic nevi could relate to acute, intense sun exposure (18,28). Genetic factors also appear to be important; an autosomal dominant mode of inheritance has been reported in families with the dysplastic nevus melanoma syndrome (8). Clinical diagnosis Clinically, a dysplastic nevus is most often a spotted lesion of 5 mm or more in diameter, with irregular and poorly defined borders and variable shades of brown, and it may present a reddish hue, with bleaching accomplished using vitropressure (15). It often presents a central papule, surrounded by a pigmented macular ring, giving the appearance of a fried egg (15). Thus, there is considerable overlap with the ABCDE rule used for clinical diagnosis of melanoma, namely, A: asymmetry, B: irregular borders C: varied colors, D: diameter > 6 mm and E: elevation (simultaneous presentation of macular and papular components) (Figure 1) (15,29,30). Clinically they represent a transitional lesion in the spectrum between common melanocytic nevi and melanoma. Their biologic potential and histological criteria are still not perfectly understood. The term atypical naevus is sometimes used to mean any funny-looking mole. However, strictly speaking, an atypical naevus is defined as a mole with at least 3 of the following features. Size >5 mm diameter Ill-defined or blurred borders Irregular margin resulting in an unusual shape Varying shades of colour (mostly pink, tan, brown, black) Flat and bumpy components Atypical mole may be inherited (FAMM syndrome) or appear sporadically (6). Sporadic atypical nevi Sporadic atypical nevi mainly affect fair-skinned individuals with light coloured hair and freckles (phototype 1-2), especially if they have been frequently exposed to the sun. Atypical nevi may develop at any time throughout life but most of them develop during childhood, usually within the first 15 years of life. Typically, people with sporadic atypical nevi have one to ten lesions (Figure 1). Familial atypical nevi Atypical nevi that run in families may be part of the FAMM syndrome. FAMM is an abbreviation for Familial Atypical Mole and Melanoma. People with FAMM syndrome must have the following: One or more first-degree or second-degree relative with malignant melanoma; A large number of nevi (often more than 50), some of which are atypical nevi; Nevi that are dysplastic on histopathology. FAMM syndrome was previously known as dysplastic naevus syndrome. People with FAMM syndrome may have several hundred atypical nevi (Figure 2). Figure 2 Several hundred atypical nevi. Histopathology Although the histopathologic exam is considered to be the gold standard for the diagnosis of melanocytic tumors, there are limitations in the histologic distinction between early melanomas and dysplastic nevi (30). Dysplastic nevi may be confused with melanoma, both clinically and histologically. In one study, lesions histologically diagnosed as dysplastic nevi by an expert panel were diagnosed by other pathologists as melanoma in 21 percent of the readings (in situ in 86 percent of the cases), and thin or in situ melanomas were misdiagnosed as dysplastic nevi in 12 percent of the readings (31). Dermoscopic caracteristics Figure 1 Sporadic atypical nevi. In recent decades, several diagnostic algorithms have been described in dermoscopy for the recognition of melanoma including

47 286 H. Helppikangas et al. the Pattern Analysis Method, the ABCD rule, the 7-Point Checklist, the CASH algorithm, the Menzies method and others (32). In a comparison of three algorithms (Pattern Analysis, ABCD Rule and the 7-Point Checklist), Annensi et al. (33) demonstrated that the Pattern Analysis method provided the highest sensitivity, specificity and accuracy for the diagnosis of thin melanomas. Although they do not solve all the diagnostic difficulties surrounding the atypical nevus, dermoscopic evaluation and especially monitoring greatly improve the management of these lesions of uncertain behavior (30). Both benign and indeterminate patterns can be identified in dysplastic nevi, using dermoscopy (34) (Figure 2). The features most commonly found in dysplastic nevi, described by the Pattern Analysis are the following: atypical pigment network, areas of irregular and peripheral depigmentation, pigmentation with central heterogeneity and abrupt termination and brown globules of different shapes and sizes with irregular distribution (35,36). In dysplastic nevi, black dots in the periphery, pseudopods, branched streaks and bluewhitish veil are rarely found. These structures are more frequently found in cutaneous melanoma (35,36). The pigmented skin lesions with very atypical or nonspecific dermoscopic patterns should be excised for definitive diagnosis by pathology (37,38). Follow up and recommendation for follow up In patients with multiple nevi, including those with dysplastic nevi and AMS, who tend to have a large number of evolving lesions, dermoscopy alone is not always sufficient to distinguish between benign lesions or new individually suspicious ones (11, 39). Thus, the monitoring of nevi in at-risk patients by total body mapping and digital dermoscopy is crucial for both early identification of malignant lesions and the minimization of unnecessary biopsies of benign lesions (40,41). Total body mapping and digital dermoscopy allow for storage of macroscopic and dermoscopic images for comparison over time. Follow-up procedures using this technique can be accomplished in short and long term. The long-term follow-up is performed at intervals of 9 to 12 months and is more suitable for risk patients with multiple nevi, including those with AMS (42). In this type of follow-up, changes that indicate lesion excision include the following: growth, change in shape, regression, changes in color and appearance of dermoscopic structures known to be associated with melanomas (43). In short term follow-up, the revaluation of the lesions must occur within 3 months from the first visit and is indicated for suspicious melanocytic lesions that have no dermoscopic features of melanoma. These include clinically moderate atypical lesions and less atypical ones that present a change history (42). The lesion should be excised when it presents any kind of morphological change except alterations in the number of milia cysts or global aspect of pigmentation (44). As the majority of melanomas arise de novo and only about 20-30% of them arise in a pre-existing nevus, atypical melanocytic nevi are considered important risk markers (45). Thus, prophylactic excision of all clinically dysplastic nevi in a subject with multiple nevi is unfounded and often not feasible (15). This approach could give the patient a false sense of security since their increased risk of melanoma persists even with the removal of all melanocytic lesions. A periodic dermatological examination is generally recommended for patients with dysplastic nevi or AMS, ranging from an examination every 3-12 months, depending on a patient s position within the risk spectrum described above (29). Physical examination of the entire integument is essential because most melanomas occur on covered areas and previous studies have demonstrated that the detection of melanoma was 6 times more frequent in patients who undressed completely (29,46). CONCLUSION Currently, it is known that only 20% to 30% of melanomas arise in association with a melanocytic nevus, which indicates that the Clark s theory of progression can explain only one of the paths from carcinogenesis to melanoma. When encountering a patient with clinically dysplastic nevi, the physician should take a detailed personal history, including information on any history of skin or other cancer, prior excisions of nevi, episodes of sunburn, and UVradiation exposure (e.g. during childhood while residing in a sunny region) and should ask whether any family members have or have had melanoma or dysplastic nevi. During the complete examination of the skin at base line (which should include examination of the doubly protected areas and the scalp), the total number of nevi should be evaluated and the presence or absence of atypical nevi assessed. Patients should be educated about the risk of melanoma and should be advised to watch for alarming signs (changes in a mole or findings according to the ABCD rule for melanoma detection [asymmetry, border irregularity, color variation, or a diameter greater than 6 mm]). Avoidance of sun exposure during the hours of peak UV intensity (noon to 4 p.m.) and routine use of sun-protective clothing, sunglasses, and broad-spectrum sunscreens (SPF 15 or higher) should be routinely advised. Conflict of interest: none declared. REFERENCES 1. Clark WH, Reimer RR, Greene MH, Ainsworth AM, Mastrangelo MJ. Origin of familial malignant melanomas from heritable melanocytic lesons: the B-K mole syndrome. Arch Dermatol. 1978;114: Munro DD. Multiple active junctional naevi with family history of malignant melanoma. Proc R Soc Med. 1974;67(7): Clark WH Jr, Elder DE, Guerry D 4th, Epstein MN, Greene MH, Van Horn M. A study of tumor progression: the precursor lesions of superficial spreading and nodular melanoma. Hum Pathol. 1984;15(12): Burgdorf W, Stolz W, Landthaler M, Vogt T. Dermatoscopy of dysplastic nevi : A beacon in diagnostic darkness. Eur J Dermatol. 2006;16: Elder DE. The dysplastic nevus. 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48 Evaluation of dermoscopic findings and follow up for patients with dysplastic nevi Miller AJ, Mihm MC Jr. Melanoma. N Engl J Med. 2006;355: Tsao H, Atkins MB, Sober AJ. Management of Cutaneous Melanoma. N Engl J Med. 2004;351: Friedman RJ, Farber MJ, Warycha MA. The dysplastic nevus. Clin Dermatol. 2009;27: Rigel DS, Rivers JK, Friedman RJ, Kopf AW. Risk gradient for malignant melanoma in individuals with dysplastic naevi. Lancet. 1988;1: Kraemer KH, Greene MH, Tarone R, Elder DE, Clark WH Jr, Guerry D 4th. Dysplastic naevi and cutaneous melanoma risk. Lancet. 1983; 2: , 14. Carey WP, Thompson CJ, Synnestvedt M, Guerry D 4th, Halpern A, Schultz D, et al. Dysplastic Nevi as a Melanoma Risk Factor in Patients with Familial Melanona. Cancer. 1994;74: Naeyaert JM, Brochez L. Dysplastic Nevi. N Engl J Med. 2003;349: Berwick M, Erdel E, Hay Jennifer. Melanoma Epidemiology and Public Health. 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49 Medical Journal (2015) Vol. 21, No. 4, Review article Viral load as a predictor during and after peg interferon alfa-2a therapy in chronic hepatitis B Viremija kao prediktor za vrijeme i nakon peg interferona alfa-2a terapije kod hroničnog hepatitis B Arben Vishaj I*, Tritna Kalo 2, Salih Ahmeti 1, Bahrije Halili 1 1 Infectious Disease Clinic of Prishtina, University Clinical Centre of Kosova, Rr. M. Kosova Hy 4 Nr 65, Prishtinë, Kosovo; 2 Infectious Disease Clinic, University Hospital of Tirana, Tirana, Republic of Albania *Corresponding author ABSTRACT HBV viral load in chronic hepatitis B patients is a predictor of cirrhosis and hepatocellular carcinoma development. Aim: to present viral load as a predictor of efficacy peg interferon alfa-2a therapy in chronic hepatitis B patients treated at the Infectious Disease Clinic in Prishtina and to present their association with HBeAg status. This study does not include other hepatotropic viruses and chronic liver diseases. Materials and methods: the study included patients treated with chronic hepatitis B at the Infectious Disease Clinic of the University Clinical Center of Kosova in the period from 2009 to The study analyzed the serological and laboratory aspects and followed serum hepatitis B virus (HBV) DNA level at the beginning of therapy, after 24 weeks at the end of treatment, and one year after the therapy. Results: the study included 41 patients of which 30 (73.17 %) males and 11 (26.33 %) females. All patients were HBsAg positive, over 18 years of age. Mean age of the patients was 42.8 years. Majority of individuals 34 (82.9%) were HBeAg negative. Median serum ALT level was 41.8 U/L. Median HBV- DNA level in patients with negative HBeAg was 5.02 log UI/ml before the therapy and 1.25 logui/ml after the therapy. In patients with positive HBeAg, median HBV-DNA level at baseline was 5.02 log IU/ml and 3.04 UI/ml after the therapy. After one year follow up for all 41 patients the HBV-DNA was undetectable in 27(65.85%) patients. Conclusion: the HBV-DNA level in patients with chronic hepatitis B is a significant predictor of efficacy peg interferon alfa-2a therapy and the risk for the disease progression. Key words: dysplastic nevi, melanoma INTRODUCTION Worldwide hepatitis B virus (HBV) infection has a high prevalence ( million people are chronic HBV surface antigen carriers) and also an increased morbidity and mortality because of end stage liver disease (0.5-1 million deaths annually) and limited possibilities of therapy (1,2). Chronic hepatitis B (CHB) remains a difficult to treat disease because, at this time, no treatment provides both an optimal virological and immunological control and there is a high rate of relapse following any antiviral therapy. Chronic hepatitis B patients are at increased risk of developing liver cirrhosis. Cirrhosis develops as a result of hepatic inflammation and subsequent fibrosis. Ongoing viral replication is associated with hepatic inflammatory activity, and suppression of viral replication in clinical trials is associated with improvements in liver histology. HBV DNA levels (viral load) are associated with disease progression, that reducing viral load (virus replication) can reduce the risk for disease progression to cirrhosis, liver cancer and death. The goal of the therapy for CHB is to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensation, end-stage liver disease, HCC and death. This goal can be achieved if HBV replication could be suppressed in a sustained manner. Then, the accompanying reduction in histological activity of CHB lessens the risk of cirrhosis and decreases the risk of HCC, particularly in non-cirrhotic patients (3). The longterm goals of treatment are virological clearance, delayed progression to cirrhosis or liver cancer and increased survival (1,4,5). The response to antiviral therapy could be classified in three categories: biochemical, virological and histological. Initially HBeAg positive-patients effective treatment of chronic HBV is defined in terms of sustained clearance of circulating HBeAg with development of HBe antibodies and HBV-DNA decline to levels below UI/mL. or 4.3 log UI/ml. The improvement of liver disease could be assessed by documenting the normalization of serum alanine transaminase levels (biochemical response), at least a two point reduction of necro inflammatory index and stable fibrosis score (no worsening) on liver biopsies (histological response). Furthermore, loss of HBsAg is associated with improved survival and reduced risk of HCC. Although loss of HBsAg is clearly the ultimate goal aimed at achieving by therapy in a HBV-related disease and is therefore a useful surrogate endpoint, its relatively rare occurrence limits its utility for evaluation of new therapies (1,6). Currently, there are two different treatment strategies for both HBeAg-positive and HBeAg negative CHB patients: Treatment finite duration with (PEG-) IFN or NA and long-term treatment with NA(s) (1).

50 Viral load as a predictor during and after peg interferon alfa-2a therapy in chronic hepatitis B 289 MATERIALS AND METHODS This was nonrandomized prospective study including patients from all centers of Kosovo. The study included patients treated with chronic hepatitis B. A total of 41 patiens were included in the study. The study analyzed clinical picture serological and laboratory aspects and followed serum hepatitis B virus (HBV) DNA level at the beginning of therapy, after 24 weeks, and at the end of treatment. This was a 72 week study comprising 48 weeks of treatment and 24 weeks of follow-up. There were two main efficacy HBV DNA suppressions below UI/ml and normalization of aminotransferase ALT. A dose of Peg interferon alfa-2a 180 mcg was administered s.c. every week, for 48 weeks. The study was conducted in compliance with the Helsinki Declaration and with the Good Clinical Practice principles. All patients had to sign an informed consent form, before any procedure of the study was performed. The study included 41 patients. Subjects were over 18 years of age, HBsAg positive for at least 6 months; HBsAb negative. Majority of individuals, 34 (82.9%),were HBeAg negative. HBV DNA > UI / ml( log4.3 UI/ml) by PCR, a serum alanine aminotransferase (ALT) level within the range of >1x U/ml and 37 x U/ml. Exclusion criteria included co-infection with HAV, HCV, HDV, HIV infection, liver disease decompensation, retinopathy, hematological disease, malignity, alcohol and drug abuse. Patients have not received any antiviral treatment for the chronic hepatitis B. The objective of the study was to measure Viral load as a predictor during and after peg interferon alfa-2a therapy in chronic hepatitis B. RESULTS Out of 41 patient included in the study there were 30 (73.17%) males and 11 (26.33%) females. Out of 41 patients at the beginning of therapy all of them were HBsAg positive, 34 (82.9%) were HBeAg negative and 7 (13.1%) were HBeAg positive. Dynamic of HBV DNA viral loud is a real predictor for the effect of therapy with peg interferon in chronic hepatitis B. Viral loud DNA level was monitored in all patients at the beginning of therapy, after 24 weeks and at the end of the treatment. This was a 72-week study comprising 48 weeks of treatment and 24 weeks of follow-up. Table 3 HBV-DNA negative after therapy and follow up. Table 4 Value of viral loud during the treatment. We observed that after 3 months of the therapy the viral loud was log 1.1 UI/ml, significantly lower than the baseline log of 5.6 log IU/ml. After follow up the value was The difference of viral lour value between the end of the therapy and end of the follow up was log 0.11UI/ml. Table 5 Response in therapy with negative HBV -DNA. Table 1 Baseline characteristics of patients with chronic hepatitis. Female 11 (26.33 %) Male 30 (73.17 %) Age > 18 year Medium Age 44.5 Medium serum ALT Level 40.2 UI/L Previous use of antiviral treatment IFN no Duration of IFN month 6 month Previous use of antiviral treatment lamivudine no Cirrhosis - no Table 2 Serological aspects at the beginning of therapy. At the end of the therapy HBV-DNA negative in patients with HBeAg negative was 88.5%. In patients with HbeAg positive response in therapy was registered in 11.5% of cases. Out of total of 41 patient response in therapy with negative PCR- HBV-DNA after 3 month was registered in 24 cases (58.5%) and after 6 month in 31 case (74.4%). After one year fellow up HBV DNA was positive in 14 cases (34.1%).We observe that from the beginning of the therapy untill one year follow up the negative HBV DNA was registered in 27 cases (65.8%). DISCUSSION The primary objective of antiviral treatment is stopping or de-

51 290 A. Vishaj et al. laying disease progression to Cirrhosis or hepatocellular carcinoma. There are a number of predictive factors for response to treatment. These factors should be evaluated at baseline, during the treatment and in the end of the therapy. The viral loud is one of the relevant predictor in efficiency of therapy (5,7). Suppression of viral replication at lowest possible levels is crucial for future clinical disease evolution ensuring achievement of therapeutic objectives but also lowering the risk for hepatocellular carcinoma as proved by disease natural history studies (REVEAL study). The viral response is if the level of HBV DNA is less then 20000UI/ml or undetectable HBV- DNA, HBV DNA. In this study out of 41 patient the viral loud at the baseline of the treatment was 5.6 log UI/ml and after 3 month the decrease of the level for 1,1 log UI/ml was registered. In the end of the therapy the PCR-HBV DNA was 1.42 log UI/ml. We registered relevant decrease of HBV DNA viral loud from the baseline to the end of therapy for 4.5 log UI/ml. Out of 41 patients 34 was HBeAg negative and 7 was HBeAg positive. We observed the difference in the response of therapy in two groups, HBeAg positive and HBeAg negative. In the group of patients with HBeAg negative viral loud at the baseline was 5.2 log UI/ml and after the end of the therapy it was 0.6 log UI/ml. We observed the significant decrease of the viral loud for 4.6 log UI/mL. Response in therapy with HBV-DNA negative was recorded in 30 patients (88.5%). In the group of patients with HBeAg positive, viral loud at the baseline was much higher, 7.55 log UI/ml. negative HBV- DNA was registered in 27 cases (64.8%). The HBV DNA viral loud was a good predictor for efficiency of peg interferon peg interferon alfa-2a in the treatment and follow up of patients with chronic hepatitis B. Conflict of interest: none declared. REFERENCES 1. The Natural History of Chronic Hepatitis B Virus Infection Brian J. McMahon McMahon BJ. The natural history of chronic hepatitis B virusinfecti on. Hepatology. 2009;49 (5 Suppl):S45-S Ganem D, Prince AM. Hepatitis B virus infection - natural history and clinical consequences. N Engl J Med. 2004;350: Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351: Lok AS, McMahon BJ; Practice Guidelines Committee, American Association for the Study of Liver Diseases. Chronic hepatitis B: update of recommendations. Hepatology. 2004;39: European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of chronic hepatitis B. J Hepatol. 2009;50: HBsAg kinetics in patients with chronic hepatitis B (CHB) treated with tenofovir disoproxil fumarate (TDF) for up to 4 years. J Hepatol. 2011;54:S Yuen MF, Yuan HJ, Wong DK, et al. Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications. Gut. 2005;54: CONCLUSION Level of HBV-DNA in patients with chronic hepatitis B is a significant predictor of efficacy peg interferon alfa-2a therapy and the risk of the disease progression. Out of total number of patients (41) the response in therapy with negative PCR-HBV-DNA after 3 month was in peg interferon alfa-2a therapy and the risk of the disease progression. Out of total number of patients (41) the response in therapy with negative PCR-HBV-DNA after 3 month was recorded in 24 cases (58.5%) and after 6 month in 31 cases (74.4%). After one year follow up HBV DNA was positive in 14 cases (33,6%).We observed that from the beginning of the therapy untill one year fellow up the Reprint requests and correspondence: Arben Vishaj, MD, MSc Infectious Disease Clinic of Prishtina University Clinical Centre of Kosova Rr. M. Kosova Hy 4 Nr 65, Prishtinë, Kosovo dr_arbenvishaj@hotmail.com

52 Medical Journal (2015) Vol. 21, No. 4, Case report Hemorrhagic pancreatitis as a rare complication after surgery of choledochal cysts type 1 in a six year old girl Hemoragični pankreatitis kao rijetka komplikacija nakon operacije ciste duktus holedohusa tip 1 kod šestogodišnje djevojčice Verica Mišanović 1*, Fedžat Jonuzi 1, Duško Anić 1, Asmir Jonuzi 2, Selma Dizdar 1, Semra Rahmanović 1 1 Pediatric Clinic, University Clinical Center Sarajevo, Patriotske lige 81, Sarajevo, Bosnia and Herzegovina; 2 Pediatric Surgery, University Clinical Center Sarajevo, Bolnička 25, Sarajevo, Bosnia and Herzegovina *Corresponding author ABSTRACT Choledochal cyst is rare congenital anomaly which presents cystic dilation of the extrahepatitic and/or intrahepatitic billary radicle. We presented a case of a six year old girl admitted to the Clinic of Pediatrics due to epigastric pain accompanied by vomiting and acholic stool in the last six days. On admission the patient was afebrile (with an axillar temperature 36.5ºC) and subicteric. On physical examination the patient had epigastric pain, blood pressure was 99/56 Hg mm, puls rate 94 beats/min, respiratory rate - 32/min, sat 02 98%, slight abdominal rigidity and tense muscles. Laboratory tests showed anemia, mild hiperbilirubinemia, regular CRP levels, mildly elevated liver transaminase levels and amylase in serum. Abdominal ultrasound (US) showed a cystic formation between the liver and duodenum, 4.5x6cm in the diameter, in progression in respect to the previous findings (2.6x1.86cm in the diameter). MR cholangiography showed the oval extrahepatic cystic formation on choledochal place in which a short canal of gallbladder influxed (type I choledochal cyst). The treatment of choice is surgery. Through the right subcostal laparotomy cystectomy, cholecistectomy and Rouxen-Y hepatojejunostomy were done. The postoperative course got complicated due to development of hemorrhagic pancreatitis with significant increase of amylase concentration in abdominal drainage fluid, and anemia. The pancreas ultrasound and CT showed: unclear shape of the pancreas, elevated in the head area, AP diametar 43mm, and 22.6mm in the tail area. The pancreatic pseudocyst, 34.8x26.6mm in the diameter, was detected in this area. The main pancreatic duct, fully dilated, 3.5mm in the diameter, flew into the described pseudocyst. The pancreatitis was treated conservatively with success. Conclusion: the choldedochal cyst is suspected when the clinical picture of the patient shows icterus, acholic stool and cyst formation on the ultrasound. Postoperative pancreatitis is a rare complication. Key words: choledochal cyst, acholic stool, pancreatitis SAŽETAK Cista holedokusa je rijetka kongenitalna anomalija koja predstavlja cističnu dilataciju ekstrahepatičnih i/ili intrahepatičnih žučnih puteva. Prikazat ćemo slučaj šestogodišnje djevojčice koja se na Pedijatrijsku kliniku javila zbog bola u epigastriju koji je praćen povraćanjem, aholičnim stolicama,trajao šest dana. Na prijemu pacijentica afebrilna (Tax 36.5C), subikterična. Fizikalnim pregledom prisutan bol u epigastriju, TA 99/56 mmhg, P 94/min, R 32/min, sat 02 98%,abdomen palpatorno tvrđi, napete muskulature.u lab.nalazima: anemija uz umjerenu hiperbilirubinemiju,uredan CRP, lako povišene transaminaze i amilazu u serumu. UZ abdomena pristna cistična formacija između jetre i duodenuma veličine 4.5x6cm, što je u progresiji u odnosu na prethodni nalaz (2.6x1.86cm). MR holangiografija prikazala je ovalnu ekstrahepatičnu cističnu formaciju na mjestu holedohusa u koju se ulijeva kratkim kanalom žučna kesa (tip 1 ciste holedohusa). Terapija je isključivo kirurška. Subkostalnom desnom laparotomijom urađena je cistektomija sa holecistektomijom i Roux-en-Y hepatojejunostomija. Postoperativni tok se komplicirao razvojem hemoragičnog pankreatitisa sa jako povišenim vrijednostima amilaze u sadržaju abdominalnog drena, anemijom. Nalaz UZ i CT pankreasa pokazao je sljedeće: pankreas nejasno konturiran, uvećan u području glave AP dijametar 43mm, u području repa 22.6mm, u ovom području detektira se pankreatična pseudocista 34.8x26.6mm, Glavni pankreatični vod, dilatiran u cjelosti promjera 3.5mm, koji se ulijeva u opisanu pseudocistu. Pankreatitis je tretiran konzervativno, uspješno. Zaključak: na cistu duktus holedohusa treba posumnjati kad se kod pacijenta u kliničkoj slici pojave žutilo kože i saluznica, aholična stolica, a na UZ detektuje se cistična formacija. Pankreatitis kao postoperativna komplikacija je jako rijedak. Ključne riječi: cista duktus holedohusa, aholična stolica, pankreatitis.

53 292 V. Mišanović et al. INTRODUCTION Choledochal cyst is a rare surgical entity with a small number of cases described in world literature (1). It occurs as a consequence of abnormal junction of the common bile and pancreatic duct (anomaly of pancreaticobiliary junction), where pancreatic duct inflows into choledoch 1-2 cm away from the ampulla of Vater, causing the reflux of pancreatic proenzyme and their activation due to alkaline environment, resulting in attenuation of the bile duct wall and dilatation. Some authors state that the reason is in defective epithelization and recanalization of the biliary tract during organogenesis (2) Todani classification of bile duct cysts divides choledochal cysts into 5 groups (Figure 1): - Type 1 a cystic or fusiform dilatation of the extrahepatic biliary system (90-95% cases), - Type 2 normal size choledochal cysts, with Diverticulum of the common bile duct - Type 3 - protrusion of a focally dilated, intramural segment of the distal common bile duct into the duodenum, - Type 4 cystic or fusiform dilation of the entire extrahepatic bile duct with extension of dilation of the intrahepatic bile ducts, - Type 5 - cystic or fusiform dilatation of intra hepatic biliary ducts with normal common bile duct (it can occur in both lobes of the liver, but most common in the left lobe) (3). Treatment is exclusively surgical (1). CASE REPORT After surgical treatment of choledochal cyst a six year old girl was admitted to the Intensive Care Unit, intubated, on mechanical ventilation, puls rate 111 beats/min, respiratory rate 18/min, sat 02 99%; blood pressure 125/76 (93) Hg mm. Auscultation symmetric breath sounds, normal heart rhythm, clear tones, no heart murmur, abdomen below the chest, postoperative incision under the right rib curve with placed abdominal drains (I pancreatic duct drain, II cavum Douglasi drain). Examination of external female genitalia regular, normal extremities, no edema, moveable. Laboratory tests showed the following: CRP 2.8, KS:Er 5.74, Hb 165, Hct 0.47, MCV 83, Le 22.5, TRb 456; Na 145, K 3.5, Ca 2.26, Cl 105, sugar in blood 9.5, check 5.1, AST 104, ALT 71, CK 1065, CK-MB 90, LDH 354, amylase (s) 550, total prot 69, alb.41, glob 28, APTT non mesurable, INR 2.03, D-dimer 2.9, fibrinogen 2.4. ABS:pH 7.35,pCO2 5.48, p02 9.5, sat 02 89%, HCO3 21-1, BE The girl was placed in the thermoneutral zone, connected to the mechanical ventilator with selection of adequate mode and ventilatory parameters. Triple antibiotic therepay was included (Kefzol, Amikacin, Metronidazol), Glucosaline and 5% HA infusion, correction of hypokalemia, analgosedation (Midazolan, Phentanyl, Tramadol). Duy to hypotension Dopamin was included in the therapy on the second day, and due to an elevated CRP level (89), Cefazolin was replaced with Meropenem. The girl was prepared and successfully disconnected from mechanical ventilator, spontaneous breathing with the oxygen tubing attached directly. The laboratoty tests performed on the third postoperative day showed: anemia Er 2.68, Hb 76, Hct 0.23, MCV 85, Le 11.1, Trb 314, AST 57, ALT 34, CK 1158, CK-MB 57, LDH 261, GGT 21, amylase (s) 458, total prot 51, alb 34, glob 17, APTT 50, INR 1.84, fibr.5.4, D-dimer 4.45, amylase (u) Abdominal ultrasound showed: appropriate location of the liver, homogenous parenchyma, longitudinal diameter of the right lobus 11.3 cm, gallbladder surgically removed, in cholecystic duct hypo to anechoic area 2.03x2.7 cm in the diameter responds to the preoperative sequelae. Intrahepatal bile ducts not dilated. Pancreas could not be visualized due to aerocoly. The spleen of homogeneous appearance, normal size, longitudinal diameter 7.95 cm. Kidneys at appropriate location, normal size, preserved parenchymal width, without ductal system dilation. Presence of free fluid in the perihepatic and perisplenic, especially in the lower right hemiabdomen and in the small pelvic, interintestinally, ticker content. The amount of fluid could most objectively be measured in the lower right hemiabdomen where it amounted to approximately 270 ml (8,8x7,24x8,19 cm). Volvulus of colabate appearance, giving impression of reduced peristaltic movements. Correlation with physical examination and laboratory tests was requested. Based on the clinical picture and laboratory tests Figure 1 Todani classification of Choledochal cyst. Figure 2 Abdominal ultrasound (US) showed a cystic formation.

54 Hemorrhagic pancreatitis as a rare complication after surgery of choledochal cysts type 1 in a six year old girl 293 the follow-up echo test was recommended. Figure 2 Abdominal ultrasound (US) showed a cystic formation. Figure 3 MR cholangiography showed the oval extrahepatic cystic formation on choledochal place in which a short canal of gallbladder influxed (type I choledochal cyst). After consultation with pediatric surgeons, the girl was prepared for surgery, which was performed at the Pediatric Clinic (Op. Relaparatomia, Lavage cavi abdominis, Drainage duplex). The girl was returned to the Pediatric Intensive Care Unit with tracheal intubation. Due to hypotension 5% HA, SSP with diuretics and inotrope was administered. Disconnection from mechanical ventilation was not permitted. The laboratory tests showed elevated amylase levels with the following values in the abdominal drain: 47040; amylase (s) 1064, amylaze (u) CRP 101, Er 4.37, Hb 129, Hct 0.38, MCV 87, Le 12.6, Trb 301, AST 92, ALT 43, CK 5868, CK-MB 106, LDH 288, bil uk. 14.1, dir 3.2, ind 10.9, APTT 47.4, INR 1.17, fibrinogen 4.3, D-dimer Emergency abdominal ultrasound and CT scan were performed and manual blood count was requested. The examination was done in postcontrast series, for the arae of upper abdomen. Oro/nasogastric tube in appropriate position. Drain was noted, with its top placed in the portal triad, on the back of the splenic vein flowing into portal vein and ventral to inferior vena cava. Volvulus of 25 mm in diameter occupied the cholecystic duct (post OP pp choledochal cyst) with thicker wall up to 5.3 mm, surrounded by a halo fluid collection of approximately 3HU density fluid content. MR cholangiography (Figure 3) showed the oval extrahepatic cystic formation on choledochal place in which a short canal of gallbladder influxed (type I choledochal cyst) Pancreas of unclear shape, enlarged in the ventral head area, and towards the body. This area was filled with fluid collection, 34.8x26.6 mm in diameter, which was unclearly followed in cranial part of the head and ventrally, which in cranial part was in direct contact with drainage volvulus occupying cholecystic duct. The main pancreatic bile duct was dilated along the entire flow lenght, 3.5 mm wide, and followed to inflow in the described pancreatic pseudocyst. The pancreas was volumized, the major volumization in the head area, with AP diameter 43 mm, whereas its diameter in the body and tail area was 22.6 mm. Smaller pleural inflow was registered mutually basally in the back of fc. sulcus, with zones of atelectasis and discreat consolidation mutually basally. Smaller amount of free fluid intertestinal, perisplenic. The finding corresponds to acute pancreatitis, with pancreatic pseudocyst, and fluid correlation around volvulus draining the bile (st. post OP pp choledochal cyst). An increase in temperature up to 37.8 C was recorded which resulted in antipyretic therapy. Dopamine was administered in the evening due to fall of tension and pulse, and due to fall in erythrocytes and hematocrit the patient received deplasmatic erythrocytes, freshly frozen plasma, and flow of albumin was increased with noradrenalin to stabilize pressure. The drainage loss (total amount of 1600 ml) was recovered with infusion and fluids. Due to temperature increase three controlled hemocultures were done, and all were sterile. As a result of the INR increased value Octaplex was administered, contributing to a significant reduction of blood stained drainage content. From day 5 to 7 the patient was monitored on the mechanical ventilator with daily reduction of the mechanical ventilation parameters, and the amount of drainage content was monitored in consultation with the pediatric surgeon. The drainage loss was recovered with 5% human albumins and freshly frozen plasma. We monitored the amount of the drainage content as well as amylase and drain blood, and the blood test for lipase. On day seven the child was successfully extubated with previous cessation of sedation, and full parenteral diet was initiated (Oligoklimenal with Ringer and 5% humane albumin). Following the extubation the child was on inhalation and respiratory physical therapy. A drop in CRP level was noted, monitoring and correcting of hypokalemia and hyponatremia was continued along with continuous monitoring of amylases and lipases in serum, as well as amylases in surgical drains. From day 8 to 11 the patient was afebrile, eupnoic, conscious, communicative, heart and lung auscultation normal. Significant decrease of abdominal drain content was monitored and significant decrease of lipases and amylases in serum, as well as decrease of amylases in surgical drains. Due to triple antibiotic therapy protective prophylactic doses of Funzol was included along with continuation of Trodon sedation. The patient was constantly under control of the pediatric surgeon. From day 12 to 15 the patient was afebrile, eupnoic, conscious, communicative, cheerful, with minimum drain secretion, up to 30 ml. Peroral fat free diet was initiated, being slightly increased to the optimal amount for the condition of the child. One of the surgical drains (subhepatic drain) was extracted while the drain placed in the pouch of Douglas still remained. In agreement with pediatric surgeons the child was transferred to the Pediatric Surgery

55 294 V. Mišanović et al. Department for continuation of the treatment. On the day of the transfer the child was afebrile, eupnoic, conscious, communicative, physical system examination normal, abdomen soft, postoperative wound healing per primum, 15 ml of drainage fluid in 24 hours, serous content, diuresis sufficient for the age of the child. CRP 13.3, Na 140, K 4.5, Ca 2.29, Cl 98, sugar in blood 5.2, Nurea 6.3, creatinine 55, AST 23, ALT 35, CK 83, CK-MB 22, LDH 248. ABS normal, KS: Er 4.65, Hb 130, Hct 0.40, MCV 87, Le 11.3, Trb 538, amylase (s) 209,amylase (u) 196, amylase (drain) 140, HKT sterile. DISCUSSION Choledochal cyst is a rare congenital anomaly which presents cystic dilations of the extrahepatitic and/or intrahepatitic billary radical (1). The first description was given by Valter and Ezler in 1723, and in 1853 Douglas published the first complete clinical description of the anomaly in a patient and speculated about the congenital nature of this anomaly. (2). Lilly (1979) emphasized that abnormal distal anatomy of this part of bile duct could only be manifestation of disturbed embryology, which could involve the entire extrahepatic bile duct. Saito and Ishida assume that abnormality of embryonic development of extrahepatic part of bile duct results in weakness of its walls and obstruction of distal lumen. The incidence is 1/ , the most frequent in the eastern countries, especially in Japan, where incidence was 1/1200 (3). It predominately occurs in females in the ratio of 3-4:1, and the disease is mainly discovered in children under 10 years of age (in 67% of cases) (3). Alonso Lej (1959) categorized choledochal cysts in three and Todani (1977) in five types. Type 1 and 4 are four times more frequent in girls and type 2 and 5 in the same ration in both boys and girls (4,5). Our patient was a six year old girl diagnosed with choledochal cyst Type 1. The clinical picture has three dominant symptoms: abdominal pain (88% of cases), nausea (in 63% of patients), obstructive hepatitis of intermittent character which could be accompanied by signs of cholangitis and vomiting, especially in children, and palpable mass in the upper right quadrant (in 13-63% of cases) (6). Such symptoms occur in children over one year of age, whereas hepatomegaly, acholic stool and rarely vomiting occur in children under one year of age (7). In our case, the patient was subicteric, with epigastric pain, acholic stool, no presence of hepatomegaly. The laboratory tests showed elevated transaminases, GGT, direct bilirubin, along with the presence of leukocytosis, and high CRP levels. noninvasive method with % sensitivity for small choledochal cysts (6). The final diagnosis was set with the assistance of MR cholangiography which showed the oval extrahepatic cystic formation on choledochal place in which a short canal of gallbladder influxed and we concluded that it was type I choledochal cysts. Differential diagnosis may include: pancreatic pseudocysts, hepatic cyst, cholangiocarcinoma, cholangiolithiasis, cholangitis and gallbladder duplication (8). Therapy of the disease is exclusively surgical. In case of Type 1 choledocus the complete cysts excision is preformed and Roux-en-Y anastomosis which enables biliary duct reconstruction (8). Postoperative complications include: cholangitis (in 88% of cases after cystoenterotomy), choledocholithiasis, hepatolithiasis due to anastomosis structure and malignancy (9,10). Choledochal cyst is a rare clinical entity and should be suspected when the clinical picture of the patient shows icterus, acholic stool and cyst formation on the ultrasound (5). Conflict of interest: none declared. REFERENCES 1. Ono S, Sakai K, Kimura O, Iwai N. Development of bile duct cancer in a 26-year-old man after resectionof infantile choledochal cyst. J Pediatr Surg. 2008;43(6): Miroslava M.Stojanović. Prikaz slučaja ciste holedokusa tipa I kod dvogodišnje djevojčice Cista holedokusa-prikaz slučaja. M.Č ISSN UKD , 1 (28-30). 3. Singhavejsakul J, Ukarapol N. Choledochal Cysts in Children: epidemiology and outcomes.world J Surg. 2008;32: Todani T, Watanabe Y, Narusue M, et al. Congenital bile duct cysts: Classification, operative procedures, and review of thirty-seven cases including cancer arising from choledochal cyst. Am J Surg. 1977;134(2): Singhavejsakul J, Ukarapol N. Choledochal Cysts in Children: epidemiology and outcomes.world J Surg. 2008;32: Cvijanović R, Jokić R. Holedohalna cista komplikovana bilijarnim peritonitisom; Med. Pregl. 2007; LX (9-10): Conway WC, Telian SH, Wasif N, Gagandeep S. Type VI Biliary Cyst: Report of a Case. Surg Today. 2009;39: Lao OB, Stein S, Ely KA, Harold N, Lovvorn HN. Synchronous Todani types I and III choledochal cysts in a 10-month-old-infant: type Ivb. Pediatr Surg Int. 2008;24: Perišić M, Leković A, Fučkar Ž, Rubinić M. Akutni pankreatitis uzrokovan kongenitalnom cistom duktus koledohusa. Liječ Vjesn.1988:(9-10): Ono S, Sakai K, Kimura O, Iwai N. Development of bile duct cancer in a 26-year-old man after resection of infantile choledochal cyst. J Pediatr Surg. 2008;43(6):17-9. CONCLUSION In the diagnostics of choledochal cysts, ultrasound is the initial diagnostic procedure providing information on the cyst location and relation with other structures (portal vein, duodenum, liver). CT is more superior diagnostic tool used for visualization of the cyst as a dilated mass clearly separated from the gall bladder, but filled with bile. Endoscopic retrograde cholangiopancreatography shows clear anomalies of pancreatic-biliary junction. MR cholangiography is a Reprint requests and correspondence: Verica Mišanović, MD, PhD Pediatric Clinic University Clinical Center Sarajevo Patriotske lige 81, Sarajevo Bosnia and Herzegovina Phone: averica41@hotmail.com

56 Medical Journal (2015) Vol. 21, No. 4, Case report Surgical dilemmas during abdominal aortic aneurysm repair in the presence of horseshoe kidney Hirurške dvojbe tokom rekonstrukcije aneurizmatski promijenjene infrarenalne abdominalne aorte u prisustvu potkovičastog bubrega Amel Hadžimehmedagić 1*, Haris Vranić 1, Nermin Granov 1, Slavenka Štraus 1, Ljiljana Hećo 2 1 Clinic of Cardiosurgery, University Clinical Canter Sarajevo, Bolnička 25, Sarajevo, Bosnia and Herzegovina, 2 Public Institutes, Medical Institute Sarajevo, Organizational Unit Novi Grad, Bulever Meše Selimovića 2, Sarajevo, Bosnia and Herzegovina *Corresponding author ABSTRACT Horseshoe kidney is a relatively rare congenital anomaly with different types of fusion and specific blood supply. Incidence of the co-existence of horseshoe kidney and abdominal aortic aneurysm is even rarer. This unusual condition is also a kind of technical challenge for the vascular surgeon during the time of aneurysm repair. Our article presents a case report of abdominal aortic aneurysm repair in a patient with horseshoe kidney. Key words: horseshoe kidney, abdominal aortic aneurysm SAŽETAK Potkovičasti bubreg je relativno rijetka kongenitalna anomalija obilježena različitim tipovima fuzije i specifičnom vaskularizacijom. Učestalost prisustva potkovičastog bubrega u kombinaciji sa aneurizmom abdominalne aorte je posebno rijetka. Ukoliko kod pacijenta sa potkovičastim bubregom postoji indikacija za rekonstrukciju aneurizmatski promjenjenog infrarenalnog aortičnog segmenta, tehničko rješenje predstavlja i svojevrstan vaskularnohirurški izazov. Ovaj članak predstavlja prikaz takvog slučaja. Ključne riječi: potkovičasti bubreg, aneurizma abdominalne aorte INTRODUCTION Horseshoe kidney is a relatively rare congenital anomaly presented when two kidneys are linked by isthmus conecting them. This condition is a consequence of anomalous ascending and rotation of metanephros on his way from the pelvis to its characteristic position in the lumbar retroperitoneal space. This migration takes place from 4 to 6 weeks of embryonic development. In cases of horseshoe kidney left and right bud of metanephros are fusing which slowes down cephalic ascending of both organs. This is the main reason for the formation of isthmus, and the development of aberrant blood vessels and ureters. Renal fusion can occur at any level, but in more than 90% of cases isthmus connects them at the inferior poles (1). Most often junction is located in front of the aorta, usually at the level of L4-L5 vertebrae. The overarching isthmus can be made of functional parenchyma or he connective tissue. This anomaly occurs in a ratio of 1: 400 to 800 cases, and is twice as common in men then in women. It is asymptomatic by nature, but the incidence of hydronephrosis and renal calculosis in these patients is higher than in those with separate kidneys. Incidence of the co-existence of horseshoe kidney and aneurysm of the abdominal aorta (AAA) is 0.12% (2). This rare condition is also kind of technical challenge for the vascular surgeon during the time of aneurysm repair (3). Our article presents a case report of the abdominal aortic aneurysm repair in a patient with horseshoe kidney. CASE REPORT A 60 years old man, heavy smoker, with known hypertension was referred to a local surgery for a routine ultrasound diagnostic due to frequent polymorph complains in the central abdominal region. Ten years ago the patient underwent gastric resection due to peptic ulcer Figure 1 CT and 3D reconstruction of relationship between aneurysm and horseshoe kidney.

57 296 A. Hadžimehmedagić et al. perforation. After 5.5 cm diameter of abdominal aortic aneurysm was found, vascular surgeon recommended CT scan in order to make an operative strategy plan. Contrast enhanced series of scans pointing out horseshoe kidney with parenchymatous isthmus lying over the proximal and central portion of aneurysms sack. An accessory renal artery arising close to the aneurismal neck on both sides was also identified. There were no signs of the kidney tissue changes, ureteral duplication or kidney canal system aberrations. Existence of the accessory renal arteries arising from the aneurismal neck made us to choose classic open aortic repair with transperitoneal approach because EVAR procedure could cause covering and potential partial renal ischaemia. Figure 2 Isthmus isolation. was related to choice between endovascular aortic reconstruction (EVAR) and open aortic repair, and the second to choice between the isthmus division or preservation. To solve the first dilemma we relied on Eisendrath Classification which roughly classified horseshoe kidney in five subtypes according to the way of its vascularization (4). According to this classification, our patient was the closest to the type I. However, we were sure that endograft would cover the origins of accessory renal arteries and cause a certain degree of renal impairment. Unwilling to take the abovementioned risk, we decided to perform the open aortic reconstruction. In solving the second dilemma we took into account technical difficulties we would experience in creating the proximal anastomosis given that the isthmus was close to the aneurysm neck. Literature data suggest that the indications for division of the isthmus of horseshoe kidney are controversial. Since the renal isthmus is mostly located in front of the aneurysm, it frequently needs to be divided to expose the aorta (5). Some authors argue that isthmusectomy can be justified only as a simultaneous action in the treatment of other problems associated with horseshoe kidney (6). An example is the abdominal aortic aneurysm combined with horseshoe kidney. Recent reports refer to possibility of aortic reconstruction with preservation of horseshoe kidney isthmus. This option is even more easily achieved with EVAR technique which returned us to the first dilemma. However, it is well known that in the presency of horseshoe kidney the EVAR procedure could jeopardise renal tissue because of possible covering of the acessory renal arteries (7). Other potential risk relates to contrast media used during EVAR procedure which is responsible for the incidence of 18% of acute kidney injury (8). Taking into account all the above mentioned and the fact that we faced this combination of vascular and urological patology for the first time we decided for isthmus division and opened aortic reconstruction. Figure 3 Isthmus retraction and aorto-biiliacal reconstruction. Operation was formally realised in two parts. Isthmus division with encapsulation of lower poles of separated kidneys was done first followed by aneurismal aortic repair using bifurcational dacron graft (20x10:10mm). Proximal anastomosis was performed with preservation of accessory renal arteries, and both distal anastomoses attached graft limbs to common iliac arteries. Vascular graft was covered with remaining aneurismal sack, retroperitoneal space was closed, and draining tubes were positioned. Abdominal wall closing was done in usual manner. During the operation and postoperatively we noticed regular urine output and normal values of serum urea and creatinin. The patient was mobilised next day, and discharged seven days later. During the follow up period he had no complains, and returned to work fully recovered. DISCUSSION During the surgery preparation we had two dilemmas. The first CONCLUSION Although the indications for division of the horseshoe kidney isthmus for safe abdominal aortic aneurysm repair are controversial, in cases of need, open surgery may become method of choice. From our point of view, if we have any dilemma between EVAR or open surgery, or doubts about the success of the operation, the decision for open aortic surgery and isthmus division may be more reliable option. Conflict of interest: none declared. REFERENCES 1. Tan TW, Farber A. Percutaneous Endovascular Repair of Abdominal Aortic Aneurysm with Coexisting Horseshoe Kidney: Technical Aspects and Review of the Literature. Int J Angiol. 2011;30(4): Davidović L, Marković M, Ilić N, Končar I, Kostić D, Simić D, Tomić I. Repair of abdominal aortic aneurysms in the presence of the horseshoe kidney. Int Angiol. 2011;30(6): Stroosma OB, Koostra G, Schurink GW. Management of aortic aneurysm in the presence of a horseshoe kidney. Br J Surg. 2001;88(4):500-9.

58 Surgical dilemmas during abdominal aortic aneurysm repair in the presence of horseshoe kidney Tan TW, Farber A. Percutaneous Endovascular Repair of Abdominal Aortic Aneurysm with Coexisting Horseshoe Kidney: Technical Aspects and Review of the Literature. Int J Angiol. 2011;30(4): Ezzet F, Dorazio R, Herzberg R. Horseshoe and pelvic kidneys associated with abdominal aortic aneurysms. Am J Surg. 1977;134(2): Jarzemski P, Listopadzki S. Laparoscopic horseshoe kidney isthmusectomy: four case reports. Wideochir Inne Tech Maloinwazyjne Mar; 9(1): Saadi E. K, Dussin LH, Moura L, Zago AJ.Endovascular repair of an abdominal aortic aneurysm in patient with horseshoe kidney:a case report. Rev Bras Cir Cardiovasc. 2008;23(3): Saratzis A, Melas N, Mahmood A, Sarafidis P. Incidence of Acute Kidney Injury (AKI) after Endovascular Abdominal Aortic Aneurysm Repair (EVAR) and Impact on Outcome. Eur J Vasc Endovasc Surg. 2015;49(5): Reprint requests and correspondence: Amel Hadžimehmedagić MD, PhD Clinic of Cardiac Surgery University Clinical Center Sarajevo Bolnička 25, Sarajevo Bosnia and Herzegovina amelskih@yahoo.com Our contribution to the reduction of cardiovascular diseases in Bosnia and Herzegovina! Naš prilog redukciji kardiovaskularnih bolesti u Bosni i Hercegovini!

59 Medical Journal (2015) Vol. 21, No. 4, Case report Multiple capillary hemangioma with fast-flow arteriovenous malformation in the right hand Multipli kapilarni hemangiom sa brzoprotočnom arteriovenskom malformacijom desne šake Sanela Salihagić * Clinic of Plastic and Reconstructive Surgery, University Clinical Center Sarajevo, Bolnička 25, Sarajevo, Bosnia and Herzegovina *Corresponding author ABSTRACT Capillary hemangiomas are one of the most common benign congenital tumors in the children age, classified into the group of slow-flow vascular lesions. According to Mullinken classification, this type of congenital tumors have a tendency of gradual involution in the most cases, but with the existence of the small group of tumors with abnormal blood vessels and with no tendency of gradual involution. We presented the case of five- year-old boy with the vascular congenital malformation localized on the right side of the body, histopathologically verified as capillary hemangioma and with the clinical tendency to gradual involution combined with the fastflow arteriovenous malformation on the third digit of his hand. This type of vascular malformation, clinically manifested as the persistent hemangioma with a tendency of growth is verified by Doppler ultrasound and MRI arteriography. Ligature of the detected AV fistula did not give a satisfactory result. Propranolol, unselective beta blocker, is the potential treatment modality. Key words: vascular malformation, Mulliken classification, capillary hemangioma, AV fistula, propranolol INTRODUCTION Hemangiomas are frequent tumors in the children age, with the prevalence of 4-10%, classified as vascular malformations, incurred as a result of the abnormal embryonic development of the blood vessels. They consist of various congenital vascular lesions ranging from simple skin discolorations to large devastating malformations. Most of them affect the skin and are therefore obvious at birth. Vascular malformations are subdivided anatomically and rheologically into slow-flow lesions (capillary, venous and lymphatic malformations), fast-flow lesions (arterial and arteriovenous malformations) and complex combined lesions (capillaryvenous or capillary-lymphaticoarteriovenous malformations). Moreover, the malformations can involve only one type of vessel (simple malformation) or different type of vessels (complex or combined malformations) (1). Based on endothelial characteristics and clinical behavior, Mulliken and Glowacki introduced the classification, addopted by ISSVA (International Society of Vascular Malformation), which divided the field of vascular anomalies into vascular tumor (hemangioma, pyogenic granuloma SAŽETAK Haemangiomi su najčešći benigni tumori dječije dobi, koji se klasificiraju u skupinu niskoprotočnih vaskularnih malformacija. Prema Mullikenovoj klasifiikaciji, tumori imaju tendencu postepene involucije u najvećem broju slučajeva, sa postojanjem manje skupine tumora sa abnormalnim krvnim sudovima, bez tendence povlačenja. Prezentirali smo slučaj petogodišnjeg djeteta sa vaskularnom malformacijom koja zahvata desnu polovinu tijela, patohistološki verificirane kao kapilarni hemangiom, koja klinički pokazuje involutivan karakter. Na III prstu desne šake, u području zajedničke digitalne arterije, putem Doppler UZ dijagnostike i putem MRI, identificirana brzoprotočna AV malformacija, što se klinički manifestira kao perzistirajući hemangiom sa tendencom rasta. Operativni zahvat u smislu ligature AV fistule nije dao zadovoljavajući rezultat. Propranolol, simpatolitički neselektivni beta-bloker, je potencijalni modalitet tretmana. Ključne riječi: vaskularna malformacija, Mullikenova klasifikacija, kapilarni hemangiom, AV fistula, propranolol and hemangiopericytoma) and vascular malformations, simplex (capillary, venous, lymphatic, arterial and arteriovenous) and compex (lymphatic-venous, capillary-lymphatic-venous, capillary-arterialvenous) (2). Capillary hemangiomas are classified as the simplex vascular malformations. They are benign endothelial cell neoplasms with characteristically rapid growth in infancy and spontaneous involution later in life. This is in contrast to another known group of childhood vascular anomalies such as vascular malformations, lymphangiomas and arteriovenous malformations. These types of vascular anomalies are present at birth and are characterized by very slow growth with persistence in adult life (3,4). CASE REPORT A 5-year-old boy presented with large vascular malformations, histopathologically evaluated like as capillary hemangioma, localized on the right side of the chest wall up to midline, with involvement of

60 Multiple capillary hemangioma with fast-flow arteriovenous malformation in the right hand 299 the right upper arm and forearm and also of dorsal and palmar aspect of the right hand (Figure 1). We evaluated significant deformity on the dorsomedial aspect of the third digit on the area of the proximal phalanx projection (Figure 2,3). Vascular malformations on the right side of the chest wall and right upper extremity, with the exception of the right hand, show a tendency of gradual involution. Vascular malformations on the right hand persist with a tendency of gradual progression. Figure 1 Vascular malformation on the right side of the body with tendency of involution. dorsomedial aspect of the third finger, has arterial and venous flow with arteriovenous fistula. The main feeding artery has a origin on the third common digital artery with drainage system through basilic vein. The fast-flow vascular malformation on the third digit of the right hand has been evaluated also by Doppler ultrasound. Multiple hyperdense zones with irregular structure in subcutaneous adipose tissue have been evaluated by MRI of the right chest wall, right upper arm and forearm (Figure 4). On the angiograph sequences FLASH 3D we have evaluated no certain signs of the contrast opacification of the ulnar and radial artery lesions. Opacification of the displayed venous system was also not evaluated on the deferred angiographic sequences. MRI confirmed the existence of the slow-flow arteriovenous malformations of the displayed venous system. MRI angiography of the right hand has confirmed the completely changed appearance of the subcutaneous tissue, with the presence of multiple, round, clearly defined hyperintense areas of various sizes and with diameters from 7 to 20 mm, localized on the base of the second and third digit, on the central part od the medial edge of the third digit and on the area of the third metacarpal bone. Veins of the dorsal aspect of the right hand are wider, without Figure 2 Deformity on the posteromedial aspect of the third finger of the boy`s right hand with no functional impairment. Figure 4 MRI angiography of the right hand with multiple vascular malformations. Figure 3 Vascular malformation on the palmar aspect of the hand. Doppler ultrasound and MRI angiography of the right chest wall and mediastinum, with special emphasis on the right hand, applied as a part of the diagnostic evaluation, with special emphasis on the right hand. Multiple hypoechogenic areas of the right parasternal region and medial aspect of the right upper arm and forearm, varying in size from 6 to 25 mm, have been verified by Doppler ultrasound with Doppler`s characteristics of the slow-flow vascular malformations corresponding to capillary hemangiomas. A tumor formation, with diameter of 15 mm, localized on the Figure 5 MRI angiography of the right hand with draining venous system. Figure 6 Vascular malformations of the right hand evaluated by MRI angiography.

61 300 S. Salihagić complete information about venous drainage system (Figure 5 i 6). In this case sugical treatment indicated in the terms of ligature of arteriovenous fistula, which is the main feeding artery in the area of the third common digital artery. It was assumed that the communication breakdown would lead to gradual regresion of vascular malformation on the dorsomedial aspect of the third digit. Despite of the presence of this type of vascular malformation we have noticed no functional deficit of the hand. After volar surgical approach to the neurovascular and tendon elements of the hand, we have evaluated multiple hemangiomas formations with conglomerates and without clear borders with each other and to the surrounding tissue. We ligated arteriovenous fistula in the area of the third common digital artery in order to induce the regression of the vascular malformation (Figure 7). Figure 7 Exploration of the AV fistula in the area of the third common digital artery (marked blue). Infitration of the neurovascular, tendon and muscular elements by multiple vascular malformations (marked red). Parts of hemangioma formations and calcification within hemangioma have been sent for histopathological analysis. Compete extirpation was not surgically feasible. The diagnosis of the capillary hemangioma has been confirmed by histopathological analysis, with dilated vascular spaces filled with a greater amount of red blood cells and with smaller blood vessels proliferation. In some places, the presence of thrombosed blood vessels with intravascular proliferation of hemangioma has been recorded. Calcified formations within individual hemangioma histopathologically verified as dystrophic calcification. After ligation of the ateriovenous fistula on the area of the third common digital artery, no hemangioma regression has been evaluated postoperatively. We have evaluated the occurrence of the new vascular formations with zones of dystrophic calcification in the first six months after surgery with no indications for reoperation (Figure 8). Hemangioma of the right upper arm and forearm showed a pattern of spontaneous gradual regression, with paler colors. Although we evaluated significant regressive process of the vascular malformations on the right hand after ligation of arteriovenous fistula, no functional impairment was observed. DISCUSSION Hemangiomas are benign lesions caused by proliferation of endothelial cells. Hemangioma occurs with a tendency of rapid growth. In the first three months of life usually reaches 80 percent of the total size. Most of hemangiomas stop growing in the sixth month of life, in exceptional cases with the continued growth till eighteenth month of life. They have tendency of involutive growth up to five years of age (5). Gradual involution of the vascular malformation on the right chest wall and right upper extremity confirms expected clinical behavior of capllary hemangiomas, with exception of the fast-flow lesions on the right hand with tendency of no involution after ligation of arteriovenous fistula. Further operative treatment of this type of lesion is contraindicated. Application of propranolol, non-selective beta blocker, is the method of choice. Although corticosteroides are the gold standard of treatment, some studies prefers to use propranolol due to lower incidence of side effects. Propranolol has replaced cortocosteroids and preferred firstline therapy for the management of infantile hemangiomas. The topical beta-blocker timolol is an alternative to oral propranolol and watchful waiting for smaller hemangiomas (6). The mechanism of action of propranolol may include vasoconstriction with decreased expression of VEGF and VFGF genes, down regulation of the RAF-mitogen-activated protein kinase pathway, or triggering of apoptosis of endothelial cells (7). In the absence of indication for surgical treatment, propranolol can effects in terms of prevention of functional impairment or pain, prevention or improving scarring or disfigurement and avoiding of life threatening complications (8). CONCLUSION Due to the emergence of the new vascular malformations on the right hand and potential future functional impairment in our presented case, the treatment with propranolol is currently the most optimal therapeutic model, since the surgery did not give expected result. Conflict of interest: none declared. REFERENCES Figure 8 Progression of vascular malformation on the right hand (evident occurrence of new tumors in interdigital spaces of the hand). 1. Mulliken JB, Fishman SJ, Burrows PE, Vascular anomalies. Curr Probl Surg. 2000;37(8): Chiller KG, Frieden IJ, Arbiser JL. Molecular pathogenesis of vascular anomalies: classification into three categories based upon clinical and biochemical characteristics. Lymphat Res Biol. 2003;1(4): Haik BG, Karcioglu ZA, Gordon RA, Pechous BP. Capillary haemangioma (Infantile periocular hemangioma). Surv Ophtalmol. 1994;38(5): Rosca TI, Pop MI, Curca M, Vladescu TG, Tihoan CS, Serban AT, et al. Vascular tumors in the orbit-capillary and cavernous hemangiomas. Ann Diagn Pathol. 2006;10(1):13-19.