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1.
Značilnosti poteka bolezni pri žleznem raku pljuč glede na aktivirajoče mutacije gena za epidermalni rastni faktor
Karmen Stanič, 2015, doktorsko delo/naloga

Opis: Uvod Zdravljenje žleznega raka pljuč je zaradi novih odkritij na področju molekularne biologije in novih tarčnih zdravil vse bolj prilagojeno posameznemu bolniku. Najbolj raziskan je receptor za epidermalni rastni dejavnik (EGFR), pri katerem aktivirajoče mutacije omogočajo zdravljenje z novimi tarčnimi zdravili. Pri kliničnem delu smo opažali precejšnje razlike med bolniki z žleznim rakom pljuč glede na EGFR-status, zato smo želeli ugotovili, ali se pri teh bolnikih mesta zasevkov ob diagnozi in njihovo pojavljanje med boleznijo, način zdravljenja, čas do napredovanja bolezni in preživetje, razlikujejo. Naša hipoteza je bila, da imajo bolniki z aktivirajočimi EGFR-mutacijami že ob diagnozi drugačen vzorec razsoja. Po kliničnih izkušnjah in do tedaj skromnih objavljenih podatkih smo domnevali, da imajo ti bolniki več zasevkov v centralni živčni sistem (CŽS) in kosti. Metode Raziskava je bila populacijsko observacijska, delno retrospektivna in delno prospektivna. Med bolniki z nedrobnoceličnim rakom pljuč, pri katerih je bilo opravljeno testiranje na aktivirajoče mutacije EGFR v letih 2010 in 2011, smo izbrali bolnike z žleznim rakom pljuč ter pregledali njihovo medicinsko dokumentacijo in njihovo zdravljenje spremljali do oktobra 2013. Rezultati Med 629 bolniki z žleznim rakom pljuč je imelo 137 (21,8 %) bolnikov prisotne aktivirajoče EGFR-mutacije. Značilno več bolnikov z EGFR-mutacijami je bilo med ženskami in nekadilci, mejno značilno več pa je bilo bolnikov z razsejanim stadijem bolezni. Bolniki z EGFR-mutiranimi tumorji, ki so kadarkoli med boleznijo razvili oddaljene zasevke, so imeli v primerjavi z bolniki brez mutacij značilno več zasevkov v CŽS (34 % proti 25 %), kosti (49 % proti 31 %), plevro (38 % proti 24 %) in pljuča (64 % proti 46 %). Razliko smo zaznali že ob diagnozi, saj so imeli EGFR-mutirani bolniki več zasevkov v kosti (35 % proti 22 %) in pljuča (37 % proti 22 %). Za CŽS je bila razlika ob diagnozi mejno značilna (19 % za mutirane in 13 % za nemutirane), vendar klinično pomembna. Pri tistih bolnikih, pri katerih je prišlo do razsoja bolezni, se je čas do razvoja zasevkov v posamezne organe razlikoval glede na EGFR-status. Zasevki so se značilno kasneje razvili pri EGFR-mutiranih bolnikih kot pri nemutiranih v CŽS (25,8 proti 11,8 meseca), pljuča (25,9 proti 9,9 meseca) in plevro (20,6 proti 9,9 meseca). Celokupno srednje preživetje vseh bolnikov je bilo 16,0 mesecev, značilno daljše za EGFR-pozitivne (32,7 meseca) kot za EGFR-negativne bolnike (13,7 meseca). Zaključki Bolniki z EGFR-mutacijami so imeli že ob diagnozi značilno več zasevkov v kosteh in pljučih, za CŽS pa je bila vrednost mejno značilna. Med potekom bolezni se je pojavilo pri bolnikih z EGFR-mutacijami več novih zasevkov v plevro, pri razsoju v druge organe pa ni bilo razlike med mutiranimi ter nemutiranimi tumorji. Bolniki z EGFR-mutiranimi tumorji so kasneje razvili zasevke v CŽS, pljuča in plevro kot nemutirani bolniki, pri napredovanju v ostale organe pa nismo beležili razlik glede na EGFR-status. Celokupno srednje preživetje bolnikov z EGFR-mutacijami je bilo značilno daljše kot za bolnike brez mutacij, ne glede na stadij bolezni in mesto ter število zasevkov. Pri polovici bolnikov z EGFR-mutacijami, lahko pričakujemo zasevke v kosti. Za bolnike, ki nimajo opravljene PET/CT preiskave v sklopu diagnostičnih preiskav za zamejitev bolezni, je zato kljub znanemu razsejanemu stadiju bolezni smiselno narediti scintigrafijo skeleta že ob diagnozi. Čas do razsoja bolezni v CŽS in preživetje sta za bolnike z odkritimi zasevki ob diagnozi za EGFR-mutirane bolnike ob ustreznem zdravljenju bistveno daljša kot za nemutirane bolnike, zato je tudi pri teh bolnikih pomembna skrbna diagnostika za prognozo ter zdravljenje bolezni.
Ključne besede: EGFR-mutacije, žlezni rak pljuč, zasevki, vzorec razsoja, preživetje
Objavljeno: 16.04.2015; Ogledov: 637; Prenosov: 178
.pdf Polno besedilo (5,75 MB)

2.
Imunohisotkemični in geentski označevalci pri glioblastomu multiforme
Uroš Smrdel, 2015, doktorsko delo/naloga

Opis: Glioblastom (GBM) je najpogostejši primarni možganski tumor. Njegova incidenca v Sloveniji znaša 2,9 bolnika na 100.000 prebivalcev. Na Onkološkem inštitutu Ljubljana smo v letih od 1997 do 2013 obravnavali 861 bolnikov z GBM, od teh jih je umrlo 730. Kljub slabi prognozi vedno več bolnikov preživi vsaj 2 leti in pol. Zanimalo nas je, v čem se ta skupina bolnikov razlikuje od večine bolnikov z GBM. Bolnike z GBM lahko razdelimo v prognostične skupine glede na klinične parametre, kot so starost, stanje zmogljivosti in obseg operacije glede na to jih lahko razdelimo naprej z rekurzivno particijsko analizo razrede. Naprej jih lahko opredelimo tudi glede na molekularne in genetske označevalce, kot so metilacija promotorja metil-gvanin-metil transferaze (MGMT), glede na nekatere podatke pa tudi mutacija izocitrat dehidrogenaze 1 (IDH1). Cilji naloge so bili opredeliti pojavljanje MGMT, IDH1in LoH1p/19q pri bolnikih z GBM z dolgim preživetjem in pri podobnih bolnikih, ki so imeli običajno preživetje. Hipoteza naše raziskave je bila, da lahko z uporabo imunohistokemičnih in genetskih označevalcev te skupine bolje opredelimo kakor z dosedaj uporabljanimi metodami. Pregledali smo populacijo bolnikov z GBM. Opredelili smo jih glede na klinične napovedne dejavnike, poiskali bolnike, ki so preživeli več kot 2 leti in pol in jim poiskali ustrezno kontrolno skupino. Pri obeh skupinah smo določili status metilacije promotorja MGMT, mutacije IDH1, IDH2, CDKN2A, CDKN2B in preureditev kromosomov 1p in 19q, opredelili smo tudi potrebo bolnikov po kortikosteroidih. Potrdili pomembnost RPA- razredov za preživetje. Opažamo značilno večjo incidenco metilacije promotorja MGMT, mutacije IDH1 R132H in nižjo potrebo po kortikosteroidih pri bolnikih z dolgim preživetjem. V multivariatni analizi sta se kot značilna za preživetje izkazala metilacija promotorja za MGMT, ki je prognostično ugodna in večja potreba po kortikosteroidih 3 mesece po zaključenem lokalnem zdravljenju, ki korelira s slabšim preživetjem. Izsledki raziskave potrjujejo prognostični pomen metilacije promotorja MGMT, še več, breztega praktično ni dolgega preživetja. Glede na to, da status metilacije promotorja MGMT ni stalno stanje, pač pa se lahko spreminja, se poraja vprašanje o dolgotrajni terapiji s kortikosteroidi. Z raziskavo smo potrdili pomen določanja imunohistokemičnih in genetskih označevalcev za napoved prognoze pri bolnikih z GBM. V prihodnje svetujemo rutinsko določanje metilacije promotorja MGMT ter določanje mutacij IDH1 in IDH2 na biopsijskih vzorcih GBM. Pri bolnikih, ki imajo metiliran promotor MGMT, so potrebne nadaljnje raziskave vpliva kortikosteroidov na metilacijski status promotorja MGMT.
Ključne besede: glioblastom, dolgotrajno preživetje, MGMT, IDH1, kortikosteroidi, RPA
Objavljeno: 14.11.2016; Ogledov: 453; Prenosov: 34
.pdf Polno besedilo (10,16 MB)

3.
Intercalated chemotherapy and erlotinib for advanced NSCLC
Izidor Kern, Viljem Kovač, Karmen Stanič, Matjaž Zwitter, Mirjana Rajer, Martina Vrankar, Natalija Edelbaher, 2014, izvirni znanstveni članek

Opis: Background: Pharmaco-dynamic separation of cytotoxic and targeted drugs might avoid their mutual antagonistic effect in the treatment of advanced non-small cell lung cancer (NSCLC). Patients and methods: Eligible patients were treatment-naive with stage IIIB or IV NSCLC. In addition, inclusion was limited to never-smokers or light smokers or, after 2010, to patients with activating epidermal growth-factor receptor (EGFR) mutations. Treatment started with 3-weekly cycles of gemcitabine and cisplatin on days 1, 2 and 4 and erlotinib on days 5 to 15. After 4 to 6 cycles, patients continued with erlotinib maintenance. Results: Fifty-three patients were recruited into the trial: 24 prior to 2010 (of whom 9 were later found to be positive for EGFR mutations), and 29 EGFR mutation-positive patients recruited later. Unfavourable prognostic factors included stage IV disease (51 patients - 96%), performance status 2%3 (11 patients - 21%) and brain metastases (15 patients - 28%). Grade 4 toxicity included 2 cases of neutropenia and 4 thrombo-embolic events. The 15 EGFR negative patients had 33% objective response rate, median progression-free survival (PFS) 6.0 months and median survival 7.6 months. Among 38 EGFR positive patients, complete response (CR) or partial response (PR) were seen in 16 (42.1%) and 17 (44.7%) cases, respectively. PET-CT scanning was performed in 30 patients and confirmed CR and PR in 16 (53.3%) and 9 (30.0%) cases, respectively. Median PFS for EGFR mutated patients was 21.2 months and median survival was 32.5 months. Conclusions: While patients with EGFR negative tumors do not benefit from addition of erlotinib, the intercalated schedule appears most promising for those with EGFR activating mutations.
Ključne besede: non-small cell lung cancer, EGFR activating mutations, gemicitabine, erlotinib
Objavljeno: 21.12.2015; Ogledov: 328; Prenosov: 2
.pdf Polno besedilo (648,72 KB)

4.
Intermittent chemotherapy and erlotinib for nonsmokers or light smokers with advanced adenocarcinoma of the lung
Matjaž Zwitter, Mirjana Rajer, Viljem Kovač, Izidor Kern, Martina Vrankar, Uroš Smrdel, 2011, izvirni znanstveni članek

Opis: Background. Intermittent application of chemotherapy and tyrosine kinase inhibitors may avoid antagonism between the two classes of drugs. This hypothesis was tested in a Phase II clinical trial. Patients and Methods. Eligible patients were nonsmokers or light smokers, chemo-naïve, with metastatic adenocarcinoma of the lung. Treatment: 4 to 6 cycles of gemcitabine 1250 mg/m2 on days 1 and 4, cisplatin 75 mg/m2 on day 2, and erlotnib 150 mg daily on days 5–15, followed by erlotinib as maintenance. Results. 24 patients entered the trial. Four pts had grade 3 toxicity. Complete remission (CR) and partial remission (PR) were seen in 5 pts and 9 pts, respectively (response rate 58%). Median time to progression (TTP) was 13.4 months and median overall survival (OS) was 23 months. When compared to patients with negative or unknown status of EGFR mutations, 8 patients with EGFR gene activating mutations had significantly superior experience: 4 CR and 4 PR, with median TTP 21.5 months and OS 24.2 months (P < .05). Conclusions. Intermittent schedule with gemcitabine, cisplatin and erlotinib has mild toxicity. For patients who are positive for EGFR gene activating mutations, this treatment offers excellent response rate, time to progression and survival.
Ključne besede: smokers, nonsmokers, cancer treatment, lung cancer, chemotherapy, erlotinib
Objavljeno: 14.06.2017; Ogledov: 47; Prenosov: 0
.pdf Polno besedilo (2,30 MB)

5.
Brain metastases in lung adenocarcinoma
Karmen Stanič, Matjaž Zwitter, Nina Turnšek Hitij, Izidor Kern, Aleksander Sadikov, Tanja Čufer, 2014, izvirni znanstveni članek

Opis: The brain represents a frequent progression site in lung adenocarcinoma. This study was designed to analyse the association between the epidermal growth factor receptor (EGFR) mutation status and the frequency of brain metastases (BM) and survival in routine clinical practice. Patients and methods. We retrospectively analysed the medical records of 629 patients with adenocarcinoma in Slovenia who were tested for EGFR mutations in order to analyse the cumulative incidence of BM, the time from the diagnosis to the development of BM (TDBM), the time from BM to death (TTD) and the median survival. Results. Out of 629 patients, 168 (27%) had BM, 90 patients already at the time of diagnosis. Additional 78 patients developed BM after a median interval of 14.3 months; 25.8 months in EGFR positive and 11.8 months in EGFR negative patients, respectively (p = 0.002). EGFR mutations were present in 47 (28%) patients with BM. The curves for cumulative incidence of BM in EGFR positive and negative patients demonstrate a trend for a higher incidence of BM in EGFR mutant patients at diagnosis (19% vs. 13%, p = 0.078), but no difference later during the course of the disease. The patients with BM at diagnosis had a statistically longer TTD (7.3 months) than patients who developed BM later (3.1 months). The TTD in EGFR positive patients with BM at diagnosis was longer than in EGFR negative patients (12.6 vs. 6.8, p = 0.005), while there was no impact of EGFR status on the TTD of patients who developed BM later. Conclusions. Except for a non-significant increase of frequency of BM at diagnosis in EGFR positive patients, EGFR status had no influence upon the cumulative incidence of BM. EGFR positive patients had a longer time to CNS progression. While EGFR positive patients with BM at diagnosis had a longer survival, EGFR status had no influence on TTD in patients who developed BM later during the course of disease.
Ključne besede: brain metastases, lung adenocarcinoma, EGFR mutations
Objavljeno: 05.04.2017; Ogledov: 55; Prenosov: 3
.pdf Polno besedilo (770,93 KB)

6.
Induction gemcitabine in standard dose or prolonged low-dose with cisplatin followed by concurrent radiochemotherapy in locally advanced non-small cell lung cancer
Martina Vrankar, Matjaž Zwitter, Tanja Bavčar-Vodovnik, Ana Milič, Viljem Kovač, 2014, izvirni znanstveni članek

Opis: Background: The optimal combination of chemotherapy with radiation therapy for treatment locally advanced non-small cell lung cancer (NSCLC) remains an open issue. This randomized phase II study compared gemcitabine in two different schedules and cisplatin - as induction chemotherapy, followed by radiation therapy concurrent with cisplatin and etoposid. Patients and methods: Eligible patients had microscopically confirmed inoperable non-metastatic non-small cell lung cancer; fulfilled the standard criteria for platin-based chemotherapy; and signed informed consent. Patients were treated with 3 cycles of induction chemotherapy with gemcitabine and cisplatin. Two different aplications of gemcitabine were compared: patients in arm A received gemcitabine at 1250 mg/m2 in a standard half hour i.v. infusion on days 1 and 8; patients in arm B received gemcitabine at 250 mg/m2 in prolonged 6-hours i.v. infusion on days 1 and 8. In both arms, cisplatin 75 mg/m2 on day 2 was administered. All patients continued treatment with radiation therapy with 60-66 Gy concurrent with cisplatin 50 mg/m2 on days 1, 8, 29 and 36 and etoposid 50 mg/m2 on days 1-5 and 29-33. The primary endpoint was response rate (RR) after induction chemotherapy; secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). Results: From September 2005 to November 2010, 106 patients were recruited to this study. No statistically signifficant differences were found in RR after induction chemotherapy between the two arms (48.1% and 57.4%, p = 0.34). Toxicity profile was comparable and mild with grade 3/4 neutropenia as primary toxicity in both arms. One patient in arm B suffered from acute peripheral ischemia grade 4 and an amputation of lower limb was needed. With a median follow-up of 69.3 months, progression-free survival and median survival in arm A were 15.7 and 24.8 months compared to 18.9 and 28.6 months in arm B. The figures for 1- and 3-year overall survival were 73.1% and 30.8% in arm A, and 81.5 % and 44.4% in arm B, respectively. Conclusions: Among the two cisplatin-based doublets of induction chemotherapy for inoperable NSCLC, both schedules of gemcitabine have a comparable toxicity profile. Figures for RR, PFS and OS are among the best reported in current literature. While there is a trend towards better efficacy of the treament with prolonged infusion of gemcitabine, the difference between the two arms did not reach statistical significance.
Ključne besede: induction chemotherapy, non-small cell lung cancer, radiation therapy, randomized clinical trial
Objavljeno: 05.04.2017; Ogledov: 63; Prenosov: 0
.pdf Polno besedilo (752,07 KB)

7.
Long-term survival in glioblastoma: methyl guanine methyl transferase (MGMT) promoter methylation as independent favourable prognostic factor
Uroš Smrdel, Mara Popović, Matjaž Zwitter, Emanuela Boštjančič, Andrej Zupan, Viljem Kovač, Damjan Glavač, Drago Bokal, Janja Jerebic, izvirni znanstveni članek

Opis: Background: In spite of significant improvement after multi-modality treatment, prognosis of most patients with glioblastoma remains poor. Standard clinical prognostic factors (age, gender, extent of surgery and performance status) do not clearly predict long-term survival. The aim of this case-control study was to evaluate immuno-histochemical and genetic characteristics of the tumour as additional prognostic factors in glioblastoma. Patients and methods: Long-term survivor group were 40 patients with glioblastoma with survival longer than 30 months. Control group were 40 patients with shorter survival and matched to the long-term survivor group according to the clinical prognostic factors. All patients underwent multimodality treatment with surgery, postoperative conformal radiotherapy and temozolomide during and after radiotherapy. Biopsy samples were tested for the methylation of MGMT promoter (with methylation specific polymerase chain reaction), IDH1 (with immunohistochemistry), IDH2, CDKN2A and CDKN2B (with multiplex ligation-dependent probe amplification), and 1p and 19q mutations (with fluorescent in situ hybridization). Results: Methylation of MGMT promoter was found in 95% and in 36% in the long-term survivor and control groups, respectively (p < 0.001). IDH1 R132H mutated patients had a non-significant lower risk of dying from glioblastoma (p = 0.437), in comparison to patients without this mutation. Other mutations were rare, with no significant difference between the two groups. Conclusions: Molecular and genetic testing offers additional prognostic and predictive information for patients with glioblastoma. The most important finding of our analysis is that in the absence of MGMT promoter methylation, longterm survival is very rare. For patients without this mutation, alternative treatments should be explored.
Ključne besede: glioblastoma, long-term survival, methyl guanine methyl transferase, prognostic factor
Objavljeno: 05.04.2017; Ogledov: 50; Prenosov: 0
.pdf Polno besedilo (556,97 KB)

8.
Independent clinical research may alleviate disparities in cancer treatment
Matjaž Zwitter, 2016, izvirni znanstveni članek

Opis: Disparities in cancer care are a reality of the modern world. Unfortunately, current clinical research is in the hands of for-profit pharmaceutical companies and of researchers from the developed world. Problems specific to cancer care in developing countries and among deprivileged populations are ignored. Independent clinical research can offer new valuable knowledge and identify affordable and cost-effective treatments. As such, research not depending on commercial sponsors should become one of the important avenues to alleviate the problem of cancer disparities.
Ključne besede: clinical research, disparities in cancer care, cost-effective treatment
Objavljeno: 04.08.2017; Ogledov: 70; Prenosov: 0
.pdf Polno besedilo (472,46 KB)

9.
Low-dose gemcitabine in long infusion
Matjaž Zwitter, 2012, kratki znanstveni prispevek

Ključne besede: lung cancer, gemcitabine
Objavljeno: 04.08.2017; Ogledov: 76; Prenosov: 1
.pdf Polno besedilo (293,79 KB)

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