Treatment of patients with advanced Hodgkin’s lymphoma with escalated BEACOPP

Cilj: Svrha rada je pokazati rezultate, kao i nuspojave, u bolesnika s Hodgkinovim limfomom stadija III ili IV, koji su liječeni s 4 ciklusa eBEACOPP-a i 4 ciklusa sBEACOPP-a. Metode: U razdoblju od listopada 2003. do ožujka 2011. godine liječeno je 15 bolesnika. Medijan dobi bio je 28 godina (19 – 47), s medijanom praćenja od 14 mjeseci (1 – 90). Svi su bolesnici liječeni s 4 ciklusa eBEACOPP-a, 11 bolesnika liječenje je nastavilo s 4 ciklusa sBEACOPP-a, kod 3 bolesnika, zbog značajnih nuspojava, primijenjen je program ABVD, dok je jedan bolesnik (plućna toksičnost) liječen programom COPP. Rezultati: U 10 bolesnika liječenjem je postignuta kompletna remisija bolesti, a u 5 bolesnika parcijalna remisija bolesti; ukupan odgovor na terapiju bio je 100 %. U 5 bolesnika koji su postigli parcijalnu remisiju bolesti provedena je radioterapija. Nakon praćenja od 14 mjeseci, preživljenje bez znakova bolesti, kao i ukupno preživljenje, iznosi 100 %. Kod većine bolesnika primijećena je ozbiljna hematotoksičnost, a 5 bolesnika (33 %) je zbog febrilne neutropenije liječeno bolnički. Rasprava i zaključak: Ova preliminarna studija potvrđuje da je program liječenja eBEACOPP-om izrazito učinkovit, a rezultati su u skladu s rezultatima dosad provedenih studija. Radi se o malom uzorku bolesnika s kratkim razdobljem praćenja. Treba naglasiti da za sada nisu zamijećeni rani relapsi bolesti. Toksičnost je značajna, naročito hematotoksičnost uz neutropenijske vrućice.Aim: We present the outcome and toxicity of intensive chemotherapy protocol escalated BEACOPP (eBEACOPP 4 cycles) followed by standard BEACOPP (sBEACOPP 4 cycles). Methods: From October 2003 untill March 2011, 15 patients were treated with eBEACOPP. The median age was 28 years with a range of 19 to 47 years; median follow-up was 14 months (range 1 to 90 months). All patients received 4 cycles of eBEACOPP; 11 patients continued their therapy with 4 cycles of sBEACOPP; in 3 patients ABVD was given because of severe toxicity, while in one patient with lung toxicity COPP was the therapy of choice after eBEACOPP. Results: Complete remission and partial remission has been achieved in 10 and 5 patients, respectively. The response to treatment was 100 %. In 5 patients with PR, radiotherapy was given after chemotherapy. After the median of 14 months follow-up the probability of progression-free survival and overall survival is 100 %. The majority of patients experienced serious hematological toxicity and 5 patients (33 %) had to be admitted to hospital because of febrile neutropenia. Discussion and conclusion: This study confirms the efficacy of eBEACOPP protocol, and the results are similar with the reported data. However, the number of patients and relatively short follow-up is the weakness of this study. It has to be stressed out that relapse of Hodgkin lymphoma was not reported. Toxicity is a serious problem, especially hematological toxicity with febrile neutropenia

High-dose ifosfamide and mitoxantrone (HDIM) in patients with relapsed or refractory Hodgkin's lymphoma

Relapsed/refractory Hodgkin's lymphoma (HL) is treated with salvage chemotherapy and autologous stem cell transplantation (ASCT). Optimal chemotherapy is unknown. We retrospectively analyzed outcomes of 58 patients treated with 2 cycles of high-dose ifosfamide and mitoxantrone (HDIM). HDIM consisted of ifosfamide 5 g/m(2)/day and MESNA 5 g/m(2)/day in continuous 24-h infusion (days 1 and 2), MESNA 2.5 g/m(2) over 12 h (day 3), and mitoxantrone 20 mg/m(2) (day 1) administered every 2 weeks. Stem cells were collected after the first cycle. Responding patients proceeded to ASCT. Toxicity was acceptable. Stem cell mobilization was successful in 96 % of patients. Overall response rate was 74 % (89 % in relapsing and 45 % in refractory patients) with 31 % complete remissions. After a median follow-up of 54 months, 5-year event-free survival was 56 % (69 % for relapsing and 35 % for refractory patients), and 5-year overall survival was 67 % (73 % for relapsing and 55 % for refractory patients). Significant adverse prognostic factors were refractoriness to previous therapy and HDIM failure. No differences in outcomes were noted between patients with early and late relapses or between complete and partial responders. HDIM is a well-tolerated and effective regimen for relapsed and refractory HL with excellent stem cell mobilizing properties. Patients failing HDIM may still benefit from other salvage options

Fludarabin, ciklofosfamid i rituksimab (FCR) u liječenju bolesnika s kroničnom limfocitnom leukemijom (KLL): iskustvo Kliničkoga bolničkog centra Zagreb [Fludarabine, cyclophosphamide and rituximab (FCR) in the treatment of chronic lymphocytic leukemia (CLL): University Hospital Centre Zagreb experience]

In clinical trials the combination of fludarabine, cyclophosphamide and rituximab (FCR) demonstrated superior results and became the gold standard for first-line treatment of fit patients with chronic lymphocytic leukemia (CLL). The aim of this study was to evaluate the efficacy, toxicity and feasibility of this protocol in everyday clinical practice. We ­retrospectively analyzed the outcomes of 43 CLL patients treated at the Division of Haematology, Department of Internal Medicine, University Hospital Centre Zagreb. The dosing of rituximab differed from that in clinical trials, we administered 375mg/m2 of rituximab per cycle, in previously untreated patients for eight and in relapsed/refractory patients for six cycles. The response rate was 95% with 83% of complete remissions. Twenty–nine patients received FCR as a front–line therapy; three-year overall and progression–free survival were 90% and 80%, respectively. In relapsed/refractory disease three–year overall and progression–free survival were 86% and 62%, respectively. Severe neutropenias occurred in 46% and serious infections in 9% of patients. According to these results, the toxicity profile and treatment outcomes in everyday routine clinical practice are similar to those reported in clinical trials

FLUDARABINE, CYCLOPHOSPHAMIDE AND RITUXIMAB (FCR) IN THE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): UNIVERSITY HOSPITAL CENTRE ZAGREB EXPERIENCE

U kliničkim je studijama kombinacija fludarabina, ciklofosfamida i rituksimaba (FCR) pokazala odlične rezultate u liječenju bolesnika s kroničnom limfocitnom leukemijom (KLL) i postala zlatni standard u prvoj liniji liječenja takvih bolesnika bez znatnijih komorbiditeta. Cilj rada bio je ispitati terapijsku djelotvornost, toksičnost i provedivost ovog protokola u svakodnevnoj kliničkoj praksi. Retrospektivno su analizirani tijek i ishodi liječenja 43-oje bolesnika s KLL-om sa Zavoda za hematologiju Klinike za unutarnje bolesti Kliničkoga bolničkog centra Zagreb. Shema primjene rituksimaba razlikovala se od one u kliničkim studijama; primjenjivan je infuzijski u dozi od 375 mg/m2 u svim ciklusima, u ukupno osam doza u prvoj, odnosno šest u kasnijim linijama liječenja. Na liječenje je odgovorilo 95% bolesnika, a 83% postignulo je kompletnu remisiju. Trogodišnje preživljenje i preživljenje bez progresije bolesti u prvoj liniji liječenja (29 bolesnika) bilo je 90 i 80%, a u kasnijim linijama 86 i 62%. Teške neutropenije zabilježene su u 46% bolesnika, a teške infekcije u 9% bolesnika. Ishodi liječenja i toksični profil u svakodnevnome kliničkom radu usporedivi su s onima iz kliničkih studijaIn clinical trials the combination of fludarabine, cyclophosphamide and rituximab (FCR) demonstrated superior results and became the gold standard for first-line treatment of fit patients with chronic lymphocytic leukemia (CLL). The aim of this study was to evaluate the efficacy, toxicity and feasibility of this protocol in everyday clinical practice. We ­retrospectively analyzed the outcomes of 43 CLL patients treated at the Division of Haematology, Department of Internal Medicine, University Hospital Centre Zagreb. The dosing of rituximab differed from that in clinical trials, we administered 375mg/m2 of rituximab per cycle, in previously untreated patients for eight and in relapsed/refractory patients for six cycles. The response rate was 95% with 83% of complete remissions. Twenty–nine patients received FCR as a front–line therapy; three-year overall and progression–free survival were 90% and 80%, respectively. In relapsed/refractory disease three–year overall and progression–free survival were 86% and 62%, respectively. Severe neutropenias occurred in 46% and serious infections in 9% of patients. According to these results, the toxicity profile and treatment outcomes in everyday routine clinical practice are similar to those reported in clinical trials

FLUDARABINE, CYCLOPHOSPHAMIDE AND RITUXIMAB (FCR) IN THE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): UNIVERSITY HOSPITAL CENTRE ZAGREB EXPERIENCE

U kliničkim je studijama kombinacija fludarabina, ciklofosfamida i rituksimaba (FCR) pokazala odlične rezultate u liječenju bolesnika s kroničnom limfocitnom leukemijom (KLL) i postala zlatni standard u prvoj liniji liječenja takvih bolesnika bez znatnijih komorbiditeta. Cilj rada bio je ispitati terapijsku djelotvornost, toksičnost i provedivost ovog protokola u svakodnevnoj kliničkoj praksi. Retrospektivno su analizirani tijek i ishodi liječenja 43-oje bolesnika s KLL-om sa Zavoda za hematologiju Klinike za unutarnje bolesti Kliničkoga bolničkog centra Zagreb. Shema primjene rituksimaba razlikovala se od one u kliničkim studijama; primjenjivan je infuzijski u dozi od 375 mg/m2 u svim ciklusima, u ukupno osam doza u prvoj, odnosno šest u kasnijim linijama liječenja. Na liječenje je odgovorilo 95% bolesnika, a 83% postignulo je kompletnu remisiju. Trogodišnje preživljenje i preživljenje bez progresije bolesti u prvoj liniji liječenja (29 bolesnika) bilo je 90 i 80%, a u kasnijim linijama 86 i 62%. Teške neutropenije zabilježene su u 46% bolesnika, a teške infekcije u 9% bolesnika. Ishodi liječenja i toksični profil u svakodnevnome kliničkom radu usporedivi su s onima iz kliničkih studijaIn clinical trials the combination of fludarabine, cyclophosphamide and rituximab (FCR) demonstrated superior results and became the gold standard for first-line treatment of fit patients with chronic lymphocytic leukemia (CLL). The aim of this study was to evaluate the efficacy, toxicity and feasibility of this protocol in everyday clinical practice. We ­retrospectively analyzed the outcomes of 43 CLL patients treated at the Division of Haematology, Department of Internal Medicine, University Hospital Centre Zagreb. The dosing of rituximab differed from that in clinical trials, we administered 375mg/m2 of rituximab per cycle, in previously untreated patients for eight and in relapsed/refractory patients for six cycles. The response rate was 95% with 83% of complete remissions. Twenty–nine patients received FCR as a front–line therapy; three-year overall and progression–free survival were 90% and 80%, respectively. In relapsed/refractory disease three–year overall and progression–free survival were 86% and 62%, respectively. Severe neutropenias occurred in 46% and serious infections in 9% of patients. According to these results, the toxicity profile and treatment outcomes in everyday routine clinical practice are similar to those reported in clinical trials

High-dose ifosfamide and mitoxantrone (HDIM) in patients with relapsed or refractory Hodgkin’s lymphoma

Relapsed/refractory Hodgkin's lymphoma (HL) is treated with salvage chemotherapy and autologous stem cell transplantation (ASCT). Optimal chemotherapy is unknown. We retrospectively analyzed outcomes of 58 patients treated with 2 cycles of high-dose ifosfamide and mitoxantrone (HDIM). HDIM consisted of ifosfamide 5 g/m(2)/day and MESNA 5 g/m(2)/day in continuous 24-h infusion (days 1 and 2), MESNA 2.5 g/m(2) over 12 h (day 3), and mitoxantrone 20 mg/m(2) (day 1) administered every 2 weeks. Stem cells were collected after the first cycle. Responding patients proceeded to ASCT. Toxicity was acceptable. Stem cell mobilization was successful in 96 % of patients. Overall response rate was 74 % (89 % in relapsing and 45 % in refractory patients) with 31 % complete remissions. After a median follow-up of 54 months, 5-year event-free survival was 56 % (69 % for relapsing and 35 % for refractory patients), and 5-year overall survival was 67 % (73 % for relapsing and 55 % for refractory patients). Significant adverse prognostic factors were refractoriness to previous therapy and HDIM failure. No differences in outcomes were noted between patients with early and late relapses or between complete and partial responders. HDIM is a well-tolerated and effective regimen for relapsed and refractory HL with excellent stem cell mobilizing properties. Patients failing HDIM may still benefit from other salvage options

Cell-free circulating DNA (cfDNA) as a marker in patients with lymphoma

Slobodna izvanstanična cirkulirajuća DNA (cfDNA) može se naći u malim količinama u plazmi zdravih pojedinaca, a povišene vrijednosti opisane su u različitim kliničkim stanjima kao što su maligne i autoimune bolesti, infarkt miokarda, trauma, upale te komplikacije trudnoće. cfDNA kod bolesnika s tumorom je tumorskog porijekla. Iako je dosta istraživana u solidnih tumora, postoji puno manje podataka o cfDNA u hematoloških malignih bolesti. Cilj ovog ispitivanje je bio odrediti razinu cfDNA u bolesnika s limfomima, njenu korelaciju s demografskim, biološkim i kliničkim značajkama bolesnika i tumora te istražiti može li se koristiti kao biljeg aktivnosti bolesti, prognostički biljeg ili kao biljeg odgovora na terapiju. Ispitivanje je provedeno na skupini od 129 bolesnika s limfomima liječenih na uobičajen način. Prosječna dob ispitanika bila je 56 godina, raspon 17-87, 66% su bili muškarci. Hodgkinov limfom (HL) je imalo 29, B-NHL 93, agresivni 66, a indolentni 27. Bolesnika s B-velikostaničnim limfomom (B-LCL) je bilo 47. Sedam bolesnika je imalo T-NHL. Koncentracija cfDNA određivana je kvantitativnom lančanom reakcijom polimeraze u stvarnom vremenu prije i po završetku liječenja. Koncentracija cfDNA je nešto viša nego u općoj populaciji (medijan 20.57 ng/ml naprema 12.1 ng/ml), no svega 1/3 bolesnika ima koncentraciju cfDNA iznad gornje granice normale. Nema jasne korelacije između agresivnosti tipova limfoma i koncentracije cfDNA. U bolesnika s NHL koncentracija cfDNA korelira s nepovoljnim prognostičkim čimbenicima: dobi, LDH, koncentracijom beta 2 mikroglobulina, stadijem bolesti i IPI. Najjača je korelacija s koncentracijom beta 2 mikroglobulina. Bolesnici s koncentracijama cfDNA iznad medijana imaju u univarijatnoj analizi lošije ishode liječenja od onih ispod medijana. U multivarijatnoj analizi se koncentracija cfDNA nije pokazala neovisnim prognostičkim čimbenikom. U bolesnika s HL, koncentracija cfDNA korelira s LDH, ali ne korelira s drugim čimbenicima niti s ishodom liječenja. Koncentracija cfDNA na kraju liječenja je niža od one na početku u skoro svih bolesnika, no ni apsolutni niti relativni pad koncentracije ne koreliraju s ishodom liječenja. Određivanje koncentracije cfDNA u bolesnika s limfomima nije ni od dijagnostičkog niti od prognostičkog značenja.Extracellular circulating DNA (cfDNA) can be found in small quantities in plasma of healthy persons; higher concentrations are found in various disorders including malignant and autoimmune diseases, myocardial infarction, trauma, inflammation and complications of pregnancy. In patients with tumors, cfDNA is of tumor origin. Although it has been studied extensively in solid cancers, there is a dearth of information on cfDNA in hematologic neoplasia. The goal of this study was to determine the concentration of cfDNA in patients with lymphoma, its relation to demographic, biologic and clinical patient and tumor characteristics and to investigate its potential role as a marker of disease activity, prognosis or response to treatment. The study was performed in 129 patients with lymphoma treated according to standard guidelines. Median age was 56 years, range 17-87; 66% were male. Twenty-nine had Hodgkin's lymphoma (HL), 93 B-NHL, 66 aggressive and 27 indolent. Forty-seven patients had B-large cell lymphoma (B-LCL). Seven had T-NHL. cfDNA concentration was determined using quantitative real-time PCR before any and at the end of treatment. cfDNA concentration is somewhat higher than in the general population (median 20.57 ng/ml vs. 12.1 ng/ml), but only 1/3 of patients had cfDNA concentrations above the highest normal values. We found no clear correlation between lymphoma type aggressivity and cfDNA concentration. In patients with NHL, cfDNA concentration correlated with unfavorable prognostic characteristics: age, LDH, beta 2 microglobulin concentration, disease stage and IPI. Correlation with beta 2 microglobulin was the strongest. In univariate analysis, patients with cfDNA concentrations above the median had worse treatment outcomes than those below the median. In multivariate analysis, cfDNA concentration was not an independent prognostic factor. In patients with HL, cfDNA concentration correlated with LDH, but neither with other tested parameters nor with treatment outcomes. At the end of treatment cfDNA concentrations were lower than at the beginning in the vast majority of patients but neither the absolute nor relative decline correlated with treatment outcomes. Measuring cfDNA oncentrations in lymphoma patients does not seem to be neither of diagnostic nor of prognostic value

The political crisis in SFRY after Josip Broz Tito's death

Stanje u SFRJ, krajem 1970-ih i poĉetkom 1980-ih, ukazivalo je na poĉetak vrlo duboke i ozbiljne politiĉke krize, koja je bila popraćena snažnom društvenom i ekonomskom krizom. Smrću kljuĉnih aktera jugoslavenske politiĉke scene, prije svega Josipa Broza Tita, nagomilani problemi i sukobi izašli su na vidjelo. Sukob unitaristiĉko-centralistiĉke i konfederalne koncepcije, koji se oĉitovao kroz sukob velikosrpske politike i hrvatskih i slovenskih zahtjeva za konfederalnim preustrojem jugoslavenske federacije, obilježio je posljednje desetljeće jugoslavenskoga politiĉkog života. Uspon Slobodana Miloševića i njegovi pokušaji da, kroz antibirokratsku revoluciju, prvo, nametne promjene u partijskim vodstvima, a onda i da ostvari, navodni san srpskog naroda, temeljen na Memorandumu SANU-a, o stvaranju tzv. velike Srbije, predstavlja presudni korak u raspadu jugoslavenske zajednice. Nemoć republiĉkih vodstava da uspješno odgovore na Miloševićeve planove dovela je razbuktavanja srpskih nacionalistiĉkih tendencija. Promjenom u republiĉkim rukovodstvima, usponom kadrova sklonih demokratskim promjena, zapoĉeo je proces liberalizacije i demokratizacije Hrvatske i Slovenije. Republiĉka vodstva nisu uspjela pronaći zajedniĉki jezik što je dovelo do raspada posljednjeg kohezivnog elementa federacije, Saveza komunista. Izlazak iz tzv. „hrvatske šutnje“, slovenska nacionalna agitacija i promjene u rukovodstvima Makedonije i BiH, doveli su do provođenja prvih višestranaĉkih izbora i odluka o razdruživanju Hrvatske i Slovenije od SFRJ. Kasnije su samostalnost proglasile Makedonija i BiH. No, kako ti potezi nisu bili u skladu s Miloševićevim velikosrpskim planom došlo je do izbijanja krvavog rata među narodima Jugoslavije, nanijevši potonjima neizbrisive traume. Unatoĉ pokušajima da se oĉuva jedinstvo naroda i narodnosti Jugoslavije, pregovorima na vrhu i snažnom potporom međunarodne zajednice, to nije bilo moguće. SFRJ se ugasila međunarodnim priznanjima novih, samostalnih i suverenih republika.The situation in the SFR Yugoslavia in the late 1970s and early 1980s indicated the beginning of a very deep and serious political crisis. The death of prominent individuals on Yugoslav political scene, above all Josip Broz Tito, brought the accumulated problems and conflicts to light. The last decade of the Yugoslav federation was marked by the conflict between Unitarian-centralist and Confederate concept. The conflict was manifested through the conflict between Great Serbia politics and Croatian and Slovenian demands for the reformation of the state along confederal lines. Crucial step in the breakup of Yugoslavia is the rise of Slobodan Milosevic and his attempts to impose changes in party leadership through the anti-bureaucratic revolution and then to realise the supposed dream of Serbian people of the so- called Great Serbia – a concept based on Memorandum of SANU. The leaders of the Republics were unable to successfully respond to Milosevic's plans which meant the overgrowth of serbian nationalist tendencies. The process of liberalization and democratization of Croatia and Slovenia started with the changes of the republican leadership and the rise of people inclined to democratic changes. The republican leaders couldn't find a common language which led to dissolution of the last cohesive element of the Federation, the Communist League. The end of the so-called 'croatian silence', slovenian national agitation and leadership changes in Macedonia and Bosnia and Herzegovina led to the first multy-party elections and decision to separate Croatia and Slovenia from the SFR Yugoslavia. Later, Macedonia and Bosnia proclaimed independence. Those events were not the part of Milosevic's Great Serbia plan so the bloody war broke out among the people of Yugoslavia causing indelible trauma. Despite the attempts to preserve the unity of people and nationalities of Yugoslavia with summits and strong support of the international community, this was not possible. The international recognition of new, independant and sovereign republics meant the end of the SFR Yugoslavia

The political crisis in SFRY after Josip Broz Tito's death

Stanje u SFRJ, krajem 1970-ih i poĉetkom 1980-ih, ukazivalo je na poĉetak vrlo duboke i ozbiljne politiĉke krize, koja je bila popraćena snažnom društvenom i ekonomskom krizom. Smrću kljuĉnih aktera jugoslavenske politiĉke scene, prije svega Josipa Broza Tita, nagomilani problemi i sukobi izašli su na vidjelo. Sukob unitaristiĉko-centralistiĉke i konfederalne koncepcije, koji se oĉitovao kroz sukob velikosrpske politike i hrvatskih i slovenskih zahtjeva za konfederalnim preustrojem jugoslavenske federacije, obilježio je posljednje desetljeće jugoslavenskoga politiĉkog života. Uspon Slobodana Miloševića i njegovi pokušaji da, kroz antibirokratsku revoluciju, prvo, nametne promjene u partijskim vodstvima, a onda i da ostvari, navodni san srpskog naroda, temeljen na Memorandumu SANU-a, o stvaranju tzv. velike Srbije, predstavlja presudni korak u raspadu jugoslavenske zajednice. Nemoć republiĉkih vodstava da uspješno odgovore na Miloševićeve planove dovela je razbuktavanja srpskih nacionalistiĉkih tendencija. Promjenom u republiĉkim rukovodstvima, usponom kadrova sklonih demokratskim promjena, zapoĉeo je proces liberalizacije i demokratizacije Hrvatske i Slovenije. Republiĉka vodstva nisu uspjela pronaći zajedniĉki jezik što je dovelo do raspada posljednjeg kohezivnog elementa federacije, Saveza komunista. Izlazak iz tzv. „hrvatske šutnje“, slovenska nacionalna agitacija i promjene u rukovodstvima Makedonije i BiH, doveli su do provođenja prvih višestranaĉkih izbora i odluka o razdruživanju Hrvatske i Slovenije od SFRJ. Kasnije su samostalnost proglasile Makedonija i BiH. No, kako ti potezi nisu bili u skladu s Miloševićevim velikosrpskim planom došlo je do izbijanja krvavog rata među narodima Jugoslavije, nanijevši potonjima neizbrisive traume. Unatoĉ pokušajima da se oĉuva jedinstvo naroda i narodnosti Jugoslavije, pregovorima na vrhu i snažnom potporom međunarodne zajednice, to nije bilo moguće. SFRJ se ugasila međunarodnim priznanjima novih, samostalnih i suverenih republika.The situation in the SFR Yugoslavia in the late 1970s and early 1980s indicated the beginning of a very deep and serious political crisis. The death of prominent individuals on Yugoslav political scene, above all Josip Broz Tito, brought the accumulated problems and conflicts to light. The last decade of the Yugoslav federation was marked by the conflict between Unitarian-centralist and Confederate concept. The conflict was manifested through the conflict between Great Serbia politics and Croatian and Slovenian demands for the reformation of the state along confederal lines. Crucial step in the breakup of Yugoslavia is the rise of Slobodan Milosevic and his attempts to impose changes in party leadership through the anti-bureaucratic revolution and then to realise the supposed dream of Serbian people of the so- called Great Serbia – a concept based on Memorandum of SANU. The leaders of the Republics were unable to successfully respond to Milosevic's plans which meant the overgrowth of serbian nationalist tendencies. The process of liberalization and democratization of Croatia and Slovenia started with the changes of the republican leadership and the rise of people inclined to democratic changes. The republican leaders couldn't find a common language which led to dissolution of the last cohesive element of the Federation, the Communist League. The end of the so-called 'croatian silence', slovenian national agitation and leadership changes in Macedonia and Bosnia and Herzegovina led to the first multy-party elections and decision to separate Croatia and Slovenia from the SFR Yugoslavia. Later, Macedonia and Bosnia proclaimed independence. Those events were not the part of Milosevic's Great Serbia plan so the bloody war broke out among the people of Yugoslavia causing indelible trauma. Despite the attempts to preserve the unity of people and nationalities of Yugoslavia with summits and strong support of the international community, this was not possible. The international recognition of new, independant and sovereign republics meant the end of the SFR Yugoslavia

STUDENTS´ATTITUDES TO WARDS COVID-19 VACCINATION: PEDAGOGICAL PERSPECTIVE

Pandemija COVID-a 19 na globalnoj razini je prouzrokovala nezamislive i nesagledive štetne posljedice na razini društva i pojedinca. Različite skupine u svijetu trpe zdravstvene, ekonomske, socijalne i psihološke posljedice ove pandemije. Sveobuhvatnost i intenzitet štetnih utjecaja i posljedica posebno je vidljiv na razini studentske populacije (mladih). Nametnute restrikcije u odgojno-obrazovnome i društvenome pogledu te briga za očuvanje vlastitoga zdravlja i zdravlja drugih postali su snažan izazov s kojim se mladi moraju nositi. U tom smislu, razvoj cjepiva protiv COVID-a 19 pružio je učinkovit alat za kontrolu i zaustavljanje širenja bolesti. Stoga, cilj ovoga rada je bio ispitati stavove studenata o cijepljenju protiv COVID-a 19 iz pedagogijske perspektive. Ispitivanje je provedeno pomoću upitnika, temeljenoga na mješovitoj metodologiji, na uzorku studenata (N=164) s različitih područja unutar Republike Hrvatske. Rezultati su pokazali da studenti, koji su se cijepili ili iskazuju namjeru cijepljenja, kao glavne razloge navode osobnu zaštitu i zaštitu bližnjih i rizičnih u široj zajednici, ali i želju za povratkom u način života prije izbijanja pandemije. Također, ispitivanje građanske odgovornosti studenata pokazalo je da studenti imaju relativno visoku razinu odgovornosti, a utvrđena je i pozitivna korelacija između doživljavanja cijepljenje kao izraza građanske odgovornosti i razumijevanja važnosti cijepljenja u zaustavljanju širenja bolesti i konačnom prestanku pandemije. Uz navedeno, analizom rezultata nije utvrđena statistički značajna razina korelacije između utjecaja medija i medijskoga izvještavanja i stavova studenata o različitim aspektima cijepljenja i razlozima za cijepljenje.The pandemic of COVID 19 globally has caused unimaginable and inconceivable detrimental consequences at the level of society and the individual. Different groups in the world are suffering the health, economic, social and psychological consequences of this pandemic. The comprehensiveness and intensity of adverse effects and consequences is particularly visible at the level of the student population (youth). The imposed restrictions in the educational and social sense, as well as the concern for preserving one's own health and the health of others, have become a powerful challenge that young people have to deal with. In this regard, the development of a vaccine against COVID 19 has provided an effective tool to control and stop the spread of the disease. Therefore, the aim of this paper was to examine students' attitudes about vaccination against COVID 19 from a pedagogical perspective. The survey was conducted using a questionnaire, based on a mixed methodology, on a sample of students from different areas within the Republic of Croatia (N = 164). The results showed that students who have been vaccinated or express the intention to get vaccinated, cite personal protection and protection of loved ones and high-risk idividuals in the wider community as the main reasons, but also the desire to return to the way of life that they had before the outbreak of the pandemic. Also, a study of student civic responsibility showed that students have a relatively high level of responsibility, and a positive correlation was found between experiencing vaccination as an expression of civic responsibility and understanding the importance of vaccination in stopping the spread of disease and finally ending the pandemic. In addition, the analysis of the results did not establish a statistically significant level of correlation between the influence of the media and media reporting and students' attitudes about different aspects of vaccination and the reasons for vaccination