E. Fekaj. Surg Chron 2013; 18(1):1-5.

The management of patients with acute pancreatitis Enver Fekaj, Arben Gjata Department of Abdominal Surgery, University Clinical Centre of Kosova, Prishtina 10000, Republic of Kosovo Department of Surgery, University Clinical Centre “ Nene Tereza”, Rruga Dibres 370, Tirana, Albania

Abstract Based on Atlanta’s criteria, acute pancreatitis is classified as:-Edematous acute pancreatitis and necrotic acute pancreatitis. Acute necrotic pancreatitis is developed in 15 to 20% of cases. The pancreatic necrotic infection occurs in the second and third week of illness in 40 to 70% of the patients with acute necrotic pancreatitis. This infection is mainly one of major risk factor which influence in complication rate and mortality. Diagnosis of acute pancreatitis is based on clinical presentation, laboratory findings and radiological examinations. There are a number of prognostic systems for detection of illness severity and patient prognosis with acute pancreatitis, such as: Ranson’s criterias, APACHE II system, Glasgow system by Imrie, Baltazar stratification of CT-scan etc. The important thing in patients with acute pancreatitis is identification of pancreatic necrotic infection. Golden standard for necrotic infection identification is aspiration with fine needle “CHIBA” followed by US or CT-scan. The patients with acute pancreatitis can be treated conservatively or surgically. It is widely believed that all patients with infection of pancreatic necrosis need surgical treatment. Now, all scientists agree that surgical intervention has to be delayed as long as possible. The modern way of treatment, in the future has to be focused on a single multimodal therapy, which inhibits inflammatory excessive reaction, meanwhile preserves immunitary competence and antimicrobial defense. Key words: acute pancreatitis, pancreatic necrosis

Introduction Based on Atlanta’s criteria (1), acute pancreatitis (AP) is classified as: -Edematous acute pancreatitis and -Necrotic acute pancreatitis Based on these criteria, edematous acute pancreatitis, has been defined as a disease associated with minimal dysfunction of visceral organs, and characterized by fast recuperation. The necrotic form of pancreatitis is classified as the one with local and systemic complications. Local complications include the infection of necrosis and creation of abscesses or other cysts (1, 2). Acute necrotic pancreatitis is developed in 15 to 20% of cases. Now it is widely known that acute necrotic pancreatitis is a progressive disease and its course is developed on two stages. In the first stage (first two weeks), extensive pancreatic inflammation and necrosis are followed by systemic inflammatory response syndrome (SIRS) which can aggravate, in the first week, to multi-organ dysfunction syndrome (MODS). The release of proinflammatory mediators is thought to contribute on SIRS pathogenesis, and this syndrome is associated with pulmonary, cardiac and renal insufficiency. Proinflammatory mediators are pancreatic proteases, cytokines, free radicals of O2 etc. (3, 4). In most of the cases SIRS is developed even in absence of necrotic pancreatic infection. About 50% of deaths occurred in the first week are due to multi-organ insufficiency (5, 6, 7).

Second phase starts after the second week, and this phase is characterized by the developing of infection of pancreatic necrosis and fluid accumulation (4, 5, 8). The pancreatic necrotic infection occurs in the second and third week of illness on 40 to 70% of the patients with acute necrotic pancreatitis. This infection is mainly the major risk factor which influence in complication rate and mortality. Most of microorganisms, which are the cause of infection, are of enteric origin. In the past years, diversity of pathophysiologic ideas, technological development has changed about evaluation and management of these patients. After all, even despite the enrichment of the scientific knowledge about the disease, death-rate of patients with necrotic infection and visceral insufficiency as consistency is still high, about 20-50 % (8, 9, 10). Diagnosis of acute pancreatitis It’s based on clinical presentation, laboratory findings and radiological examinations. It isn’t easy to diagnose acute pancreatitis because there aren’t any specific clinical signs, which may diagnose acute pancreatitis. Most common signs are: pain of upper abdomen, meteorisms, muscular tenderness, temperature, nausea, vomiting, and jaundice (11). At 1-3% of cases, ecchymosis appear in lumbal region (Gray-Turner sign), and periumbilical region (Cullen sign). After all, none of these clinical signs can predict severity of illness (12). 1

E. Fekaj. Surg Chron 2013; 18(1):1-5.

Laboratory findings are based on evaluation of urine and serum level of amylase, determination of lipasemia, tripsin and phospholipase A2. If the levels of serum amylasemia are >500U/l, the probability of acute pancreatitis is 95%, while when the levels of lipasemia are 5 time higher than normal rate, than acute pancreatitis is present (13,14,15). Determination of tripsinogen2 in serum and urine, also measurement of the complex tripsin2-alfa1-antitripsin are potentially markers in diagnosis of AP (16). Urinary Strip-test of tripsinogen2 is very simple test, fast, and successful on identification of patients with acute pancreatitis in retro and prospective evaluation (16,17). Abdominal ultrasonography is important in evaluation of biliary tract, in detection of biliary calculosis and in the confirmation of biliary obstruction. Also it’s the method of dynamic evaluation of patients with local complication as: pseudocyst formation and abscesses. The CT-scan with contrast has 100% diagnostic specification. With this method is possible to diagnose pancreatic necrosis and other complications. After all, in 8-28% of cases with AP, mainly with edematous AP, gained image with CT is normal (18). This method is considered gold standard for detection of pancreatic necrosis. It is applicable also when we suspect on complications (18). Although, it was named as gold standard for diagnosis of pancreatic necrosis, in a study made by Werner(19) it has been concluded that the contrast used during examination by CT, reduce capillary circulation of pancreas and in this order it increase the degree of necrosis and in the same time mortality rate. In Magnetic Resonance where gadoliniumdiethylenetriamine pent acetic acid has been used for contrast, the conclusion has been taken that it doesn’t have negative repercussion in microcirculation and acinus’s impairment. Prognostic indicators There are various numbers of prognostic systems that can be applied in detection of illness severity and patient prognosis with AP. Those systems are applied to identify the patients who may have potentially high rate of local and systemic complications. The most known systems are: Ranson’s criterias, APACHE II score, Glasgow score by Imrie, Baltazar stratification by CT-scan etc. Prognostic system by Ranson is widely applied by many clinicians in many centers around the world. For complete evaluation are needed 48 hours, in which are included 11 variables, 5 of them can be calculated immediately after hospitalization, and the other 6 after 48 hours. This system has sensitivity about 37-94% and specificity 54-97 %( 20). APACHE II score is more complex, after all it can be completed within some hours after hospitalization and it can be evaluated every day (20, 21, 22). About the predominance of one or the other system there are still different opinions. Meantime Eachempati et al(22) ascertain that prognostic system by Ranson has greater value at stratification and prognosis of illness than APACHE II. Marja Leena et al (20) on

the other side proved that APACHE II score is superior. Further more, Eachempati et al show that the variables by Ranson don’t have the same prognostic value. According to that paper decrease of hct is associated with higher rate of mortality. According to Khan et al (21), calculation of APACHE II score, 48 hours after hospitalization, predict development of pancreatic necrosis, insufficiency of viscera and mortality, and when APACHE II is calculated immediately after hospitalization, can predict only the level of mortality. The tendency of scientist is to detect a simple test for stratification and prognosis of patients with acute pancreatitis. In this manner, concentration of tripsinogen2 has demonstrated correlation between the various forms the disease (16). The level of tripsin2-alfa1-antitripsin increase in both cases, edematous and necrotic cases, but these levels are significantly higher in necrotic cases (16). A simple marker for stratification is C reactive protein. Its levels are increasing after 48-72 hours, but it doesn’t have early prognostic role. It can be used for dynamic evaluation of illness (23). It was concluded that PCT (procalcitonin), calcitonin precursor, has role in detection of bacterial contamination of pancreatic necrosis (24). Also it is noticed that in acute necrotic pancreatitis the levels of phospholipase A2 in serum are high. Measurement of concentration of polymorphonuclear elastase in serum, as a marker of neutrophile activity, has been successfully used in stratification of patients with AP. After all, this test, still, is not used in routine manner (25). The levels of proinflammatory cytokines has been demonstrated that are in close correlation with the severity of illness (26). So the levels of interleukin-6 (IL-6), 24 hours after the beginning of illness has been proved that correlate with the mortality rate. In a study has been demonstrated that the levels of concentration of TNFα (alfa tumor necrosis factor), IL-6 and IL-8 were higher in patients with systemic complication than in those without complications. The level of IL-1 concentration was the same in both groups (27). Concentrations of anti-inflammatory cytokines (IL-10, IL-11, IL13), has been reported that shows the severity of illness and has been widely considered as potent marker for early prognosis for acute pancreatitis (28). As conclusion, the most important cytokines for prognosis of illness severity are IL-6 and IL-8. After all, their role toward prognostic systems (Ranson, APACHE II, Glasgow etc) has not been yet completely investigated (29). Since yet there is no simple test, which in low cost and fast period of time detects acute pancreatitis and its prognosis, the recommendation of scientists is that for stratification and prognosis of AP and identification of its early complications we have to use the combination of prognostic systems and tests (30). Identification of pancreatic necrosis infection There isn’t any specific biochemical marker who can help diagnose pancreatic necrosis. C reactive protein, when her val2

E. Fekaj. Surg Chron 2013; 18(1):1-5.

ues are above 150mg/l, is an indicator that infection is present. After all, there isn’t any correlation between its levels and necrotic infection. It has been demonstrated that procalcitonin is a potent marker which can reflect bacterial or fungal infection. Its levels ≥1.8 mg/ml detects the presence of necrotic infection with 94% of sensitivity and 90% specificity. After all, Procalcitonin is a non specific marker and interpretations of its values are useful only if we correlate them with other diagnostic procedures. Gold standard for necrotic infection identification is aspiration with fine-needle “CHIBA” followed by US or CTscan (51). Aspirated material then should be examined by Gram stain for bacterial detection (5, 8, 31).

Conservative management of acute pancreatitis Last years, conservative management of acute pancreatitis has been oriented to: -Inhibition of pancreatic secretion -Inhibition of inflammatory reaction -Prevention of infection (32), For many years it has been considered that inhibition of pancreatic secretion can be significant factor in acute pancreatitis treatment. For this purpose, glucagon, somatostatin,and octreotide have been widely used. Although, in the beginning, in some studies it was concluded that application of octreotide has a positive effects (33), one study in Germany demonstrated that there isn’t any effect from octreotide in acute pancreatitis treatment. The application of platelet activation factor antagonistlexipafant last years has been of a big behalf, focusing on its effects on treatment of acute pancreatitis. Platelet activation factor is an inflammatory mediator secreted from inflammatory cells and it has been widely considered that it has great role in amplification of inflammatory reaction. First studies by Kingsnorth et al. (34), a multicenter study in England (35), reported that lexipafant can reduce the levels of concentration of IL-6, IL-8. Although, in an international multicenter study, in which, have been involved 1500 patients for the treatment with lexipafant, the results were discouraging for complications and also for mortality rate (32). On the other side, gabexate-mesilate (protease-inhibitor) has been demonstrated that reduces systemic complications and reduces the number of cases which requires surgical interventions (36). Use of antibiotics in prevention of infection has been documented that has positive effect in reduction of infection rate and also in reduction of requirement for surgical operations. This effect has been shown to have only antibiotics that are able to penetrate into necrotic tissue. Imipenem has been shown to be the first choice as effective antibiotic, second choice has been considered ciprofloxacin, and ofloxacine in combination with methronidazole(37). According to Kumar Sharma-s et al (38), ampicillin, first generation of cephalosporins and aminoglucosides, doesn’t have any effect on pre-

vention of infection of pancreatic necrosis because these antibiotics don’t penetrate into necrotic pancreatic tissue. Many studies from different authors have been made to evaluate the role of antibiotics for prevention of infection in necrotic pancreatitis. Pederzoli et al. (39) after imipenem application, has demonstrated that antibiotics can reduces infection rate and septic episodes. Sainio et al. (40), after prophylactic application of cefuroxime, reported that this antibiotic doesn’t have positive effects in reduction of local infection and sepsis, but has reduced the rate of mortality. On his study, Schwartz et al. (41), after application of ofloxacine in combination with methronidasole, concluded that there isn’t any significant reduction of local infection, sepsis, and mortality. Bassi et al. (42), has compared the effectiveness of imipenem versus perfloxacine. He has concluded that perfloxacin is inferior compared with imipenem, in prevention of local pancreatic infection. Surgical treatment of acute pancreatitis If biliary stones are the cause of acute pancreatitis and, if biliary obstruction or cholangitis is developed, ERCP is indicated in order to perform sphincterotomy within 48-72 hours from the beginning of first symptoms (31). It is widely believed that all patients with infection of pancreatic necrosis need surgical treatment. Optimal time for surgery was controversial in the past years between scientists. Now, all of them agree that surgical intervention has to be delayed as more as it is possible (31, 37). Gotzinger et al(43), and Fernandez del –Castillo et al(44), recommended that surgical procedures in patients with infection of pancreatic necrosis can be done after the third week since the beginning of acute pancreatitis. On his study Gotzinger concluded that the mortality rate of patients, which have been surgically treated before third week was 46%, while in those, treated surgically after third week, the mortality rate was 25%. Today three modalities of surgical interventions are applied in patients with acute necrotic pancreatitis: -Necrosectomy with conventional drainage -Necrosectomy with open management and half opened. -Necrosectomy with closed continual retroperitoneal lavage In the third method, for lavage, has been applied the solution used for peritoneal dialysis. In the first seven days, the volume of 35-40 l/daily has to be applied, and the volume of solution is going to decrease depending of clinical signs evolution. Abdominal drains must be removed in the second or third week depending on the patient’s condition. Although authors have different preferences from one modality to the other, none of these modalities showed superiority over the other modality (31). Percutaneous Necrosectomy, the method reported from Carter et al. has been applied on 14 patients and is shown as a very successful method. Only two patients died. For investigation of the superiority of these methods more studies are needed (31). Baron et 3

E. Fekaj. Surg Chron 2013; 18(1):1-5.

al. published his successful treatment of infected pancreatic necrosis with endoscopic transgastric drainage. This kind of drainage with “pigtail” stents has been widely applied in treatment of simple pancreatic pseudocysts (32). The treatment of patients with sterile necrosis, in most of the cases, is conservative. Although, in sterile necrosis, treatment there is still controversial, Hartwig et al. (37), concluded that patients with sterile necrosis which are not benefiting from conservative treatment even after four weeks of intensive conservative treatment, they should be considered for surgical treatment. Modern ways of treatment in acute pancreatitis In absence of causal therapy, tendency has been oriented on identifying the late stage of acute pancreatitis patients with organ dysfunction, with hope that fast, adequate, and specialized intervention can help to improve prognosis (45). Identification of patients with necrotic AP, their hospitalization, and their treatment on intensive care units, administration of enteric food, and prophylaxis with antibiotics have been shown that decrease the complications and mortality rate. Although, now it is widely know the role of proinflammatory cytokines and leukocytes, the strategy is focused and oriented to prevent the activity of these mediators or in the blocking of their synthesis. Generally immunomodulators can be grouped in three categories: - Specific anticytokine antibodies - Anti-inflammatory cytokines - Nonspecific immunomodulators (46). In the early stage of AP when SIRS is predominating, the application of agents who inhibit the release of proinflammatory mediators’ activity has been shown useful (26). IL-1 receptor blockage with antagonists, decrease the damage of experimentally induced AP (26). Application of IL-10 in artificially caused AP has been ascertained that decrease severity of illness and increase survivals. On late stage of AP, when immunosuppression is dominating, application of immunitary stimulators (Gammainterferon), showed positive effects on improvement of patient’s prognosis (47). In the future, treatment strategy, based on scientists, has to be focused on a single multimodal therapy, which inhibit inflammatory excessive reaction, meanwhile preserves immunitary competence and antimicrobial defense capacity (48).

The patients with acute pancreatitis can be treated conservatively or surgically.It is widely opinion that all patients with infection of pancreatic necrosis need surgical treatment. Now, all scientists agree that surgical intervention has to be delayed as more as it is possible. The modern way of treatment strategy, in the future, based on scientists, has to be focused on a single multimodal therapy, which inhibits inflammatory excessive reaction, meanwhile preserves immunitary competence and antimicrobial defense.

Abbreviations AP- acute pancreatitis, US- ultrasonography, CT- computer tomography IL- interleukin

References 1. 2. 3. 4.

5. 6.

7.

8. 9. 10.

11. 12. 13. 14. 15. 16.

Conclusions Since yet there is no simple test, which detects acute pancreatitis and its prognosis, for stratification and prognosation of AP and identification of its early complications we have to use the combination of prognostic systems and tests.

17. 18. 19.

Braddly III EL. A clinical based classification system for acute pancreatitis. Arch Surg 1993;128:586-590. Beger HG. Surgery in acute pancreatitis. Hepato-Gastroenterol 1991;38:92-96. Uhl W, Schrag HL, Wheatley AM, Buchler MW. The role of infection in acute pancreatitis. Dig Surg 1994;11:214-219. Buchler MW, Gloor B, Muller CA, Friess H, Seiler CA, Uhl W. Acute necrotizing pancreatitis: treatment strategy according to the status of infection. Ann Surg 2000;232:619-626. Beger HG, Rau B, Mayer J, Pralle U. Natural course of acute pancreatitis. Word J Surg 1997;21:130-135. Gerzof SG, Banks PA, Robbins AH, Johnson WC, et al. Early diagnosis of pancreatic infection by computed tomography-guided aspiration. Gastroenterology 1987;93:1315-1320. Gloor B, Muller CA, Worni M, Martignoni ME, Uhl W, Buchler MW. Late mortality in patients with severe acute pancreatitis. Br J Surg 2001;88:975-979. Hartwig W, Werner J, Uhl W, Buchler MW. Managment of infection in acute pancreatitis. J Hepatobiliary Pancreat Surg 2002;9:423-428. Gullo A, Berlot G. Ingredients of organ dysfunction or failure. Word J Surg 1996;20:430-436. McKay C, Evans S, Sinclair M, Carter C, Imrie C. High early mortality rate from acute pancreatitis in Scotland, 1984-1995. Br J Surg 1999;86:13021306. Steinberg W, Tenner S. Acute pancreatitis. N Engl J Med 1994;330:11981210. Buchler M. Objectification of the severity of acute pancreatitis. HepatoGastroenterol 1991;38:101-108. Laderson JH, Scott MG, et al. The clinical chemistry laboratory and acute pancreatitis. Clin Chem 1993;39:234-243. Orebaugh SL. Normal amylase levels in the presentation of acute pancreatitis. Am J Emerg Med 1994;12:21-24. Panteghini M, Pagani F. Clinical evaluation of an algorithm for the interpretation of hyperamylasemia. Arch Pathol Lab Med 1991;115:355-358. Hedstrom J, Haglund C, Haapiainen R, Stenman UH. Serum trypsinogen-2 and trypsin-2-alfa1-antitrypsin complex in malignant and benign digestive-tract diseases. Preferential elevation in patients with cholangiocarcinomas. Int J Cancer 1996;66:326-333. Tietz NW, Shuey DF. Lipasee in serum-the elusive enzyme: An overwiev. Clin Chem 1993;39:746-756. Balthazar E, Freeny P, van Sonnenberg E. Imaging and intervention in acute pancreatitis. Radiology 1994;193:297-306. Werner J, Schmidt J, Warshaw A, et al. The relative safety of MRI contrast agent in acute necrotizing pancreatitis. Ann Surg 1998;227(1):105111.

4

E. Fekaj. Surg Chron 2013; 18(1):1-5. 20. M-L Kylanpaa-Back, Repo H. New laboratory tests in acute pancreatitis. Addiction Biology 2002;7:181-190. 21. Khan AA, Parekh D, Cho Y, et al. Improved prediction of outcome in patients with severe acute pancreatitis by the APACHE II score at 48 hours after hospital admission compared with the APACHE II score at admission. Arch Surg 2002;137:1136-1140. 22. Eachempati SR, Hydo LJ, Barie PS. Severity scoring for prognostication in patients with severe acute pancreatitis. Arch Surg 2002;137:730-736. 23. Neoptolemos J, Kemppainen E, Mayer J, et al. Early prediction of severity in acute pancreatitis by urinary trypsinogen activation peptide: a multicentre study. Lancet 2000;355:1955-1960. 24. Rau B, Steibach G, Gansauge F, Mayer J, Grunert A, Beger H. The potential tole of procalcitonin and interleukin-8 in the prediction of infected necrosis in acute pancreatitis. Gut 1997;41:832-840. 25. Ikei S, Ogawa M, Yamaguchi Y. Blood concentrations of polymorphonuclear leukocyte elastase and interleukin-6 are indicators for the occurrence of multiple organ failures at the early stage of acute pancreatitis. J Gastroenterol Hepatol 1998;13:1274-1283. 26. Norman J. The role of cytokines in the pathogenesis of acute pancreatitis. Am J Surg 1998;175:76-83. 27. McKay C, Gallagher G, Brooks B, Imrie C, Baxter J. Increased monocyte cytokine production in association with systemic complications in acute pancreatitis. Br J Surg 1996;83:919-923. 28. Chen CC, Wang SS, Lu RH, Chang FY, Lee SD. Serum interleukin-10 and interleukin-11 in patients with acute pancreatitis. Gut 1999;45:895-899. 29. Frossard JL, Hadengue A, Pastor C. New serum markers for the detection of severe acute pancreatitis in humans. Crit Care Med 2001;164:162170.0 30. Windsor J. Search for prognostic markers for acute pancreatitis. Lancet 2000;355:1924-1925. 31. Beger HG, Isenmann R. Acute pancreatitis:who needs an operation? J Hepatobiliary Pancreat Surg 2002;9:436-442. 32. McKay CJ. Recent developments in the management of acute pancreatitis. Dig Surg 2002;19:129-134. 33. Paran H, Neufeld D, Mayo A, et al. Preliminary report of a prospective randomized study of octreotide in the treatment of severe acute pancreatitis. J Am Coll Surg 1995;181:121-124. 34. Kingsnorth AN, Galloway SW, Formela LJ. Randomized,double-blind phase II trial of lexipafant, a platelet-activating factor antagonist, in human acute pancreatitis. Br J Surg 1995;82:1414-1420. 35. Imrie CW, McKay CJ. The scientific basis of medical therapy of acute pancreatitis: Could it work, and is there a role for lexipafant? Gastroenterol Clin North Am 1999;28:591-599.

36. Uomo G. Pancreatic head mass: How can we treat it? Acute pancreatitis: Conservative treatment. J Pancreas 2000;1(3 suppl):130-137. 37. Hartwig W, Werner J, Muller C, Uhl W, Buchler M. Surgical management of severe pancreatitis including sterile necrosis. J Hepatobiliary Pancreat Surg 2002;9:429-435. 38. Sharma VK, Howden CW. Profylactic antibiotic administration reduces sepsis and mortality in acute necrotizing pancreatitis:a meta-analysis. Pancreas 2001;22(1):28-31. 39. Pederzoli P, Bassi C, Vesentini S, et al. A randomized multicenter clinical trial of antibiotic prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem. Surg Gynecol Obstet 1993;176:480-483. 40. Sainio V, Kemppainen E, Puolakkainen P, et al. Early antibiotic treatment in acute necrotizing pancreatitis. Lancet 1995;346:663-667. 41. Schwartz M, Isenmann R, Meyer H, et al. Antibiotic use in necrotizing pancreatitis. Results of a controlled study. Dtsch Med Wochenschr 1997;122:356-361. 42. Bassi C, Falconi M, Talamini G, et al. Controlled clinical trial of perfloxacin versus imipenem in severe acute pancreatitis. Gastroenterology 1998;115:1513-1517. 43. Gotzinger P, Wamser P, Exner R, et al. Surgical treatment of severe acute pancreatitis: Timing of operation is crucial for survival. Surg Infect 2003;4(2):205-211. 44. Fernandez-del Castillo C, Rattner DW, Makary MA, et al. Debridement and closed packing for the treatment of necrotizing pancreatitis. Ann Surg 1998;228:676-684. 45. Neoptolemos JP, Raraty M, Finch M, Sutton R. Acute pancreatitis:the substantial human and financial cases. Gut 1998;42:886-891. 46. Osman M, Jensen S. Acute pancreatitis: The pathophysiological role of cytokines and integrins. Dig Surg 1999;16:347-362. 47. Davies M, Hagen P. Systemic inflammatory response syndrome. Br J Surg 1997;84:920-935. 48. Vuorte J, Lindsberg P, Kaste M, et al. Anti-ICAM-1 monoclonal antibody R6.5 (Enlimomab) promotes activation of neutrophils in whole blood. J Immunol 1999;162:2353-2357.

Address of correspondence: Ass. dr. Enver Fekaj, mr. sc. General surgeon Department of Abdominal Surgery, University Clinical Centre of Kosova, Rrethi i Spitalit, str: p.n.,Prishtina, 10000, Republic of Kosovo E-mail: [email protected]

5