Sistemsko zdravljenje bolnikov s pljučnim rakom

Zaviralci imunskih nadzornih točk (ZINT) predstavljajo pravo revolucijo v sistemskem zdravljenju raka pljuč in so v zadnjem desetletju korenito spremenili standardno zdravljenje teh bolnikov. Prepričljivo dobrobit s podaljšanjem preživetja so sprva izkazali kot samostojno zdravljenje pri bolnikih z razsejanim nedrobnoceličnim rakom pljuč (NDRP), ki je napredoval po predhodnem zdravljenju s kemoterapijo na osnovi platine. Kmalu zatem je sledil njihov premik v prvi red zdravljenja razsejane bolezni najprej kot samostojno zdravljenje, nato pa še v kombinaciji s kemoterapijo na osnovi platine in tudi kot kombinirana imunoterapija dveh ZINT. Korenito so spremenili tudi obravnavo bolnikov z NDRP v zgodnejših stadijih bolezni, predvsem lokalno napredovale oblike, še posebej veliko obetajo v perioperativnem obdobju. Imunoterapija z ZINT se pri raku pljuč uporablja kot monoterapija, kot kombinacija s kemoterapijo z ali brez zaviralca angiogeneze oziroma kombinacija dveh različnih ZINT

Screeening for Hepatitis B Infection and Prevention of its Reactivation in Cancer Patients under Sytemic Therapy - Current Clinical Recommendations

Septembra 2010 so bile v Zdravniškem vestniku objavljene slovenske nacionalne usmeritve za preprečevanje reaktivacije hepatitisa B pri bolnikih, ki potrebujejo imunosupresivno zdravljenje. Te smernice temeljijo na usmeritvi dveh mednarodnih združenj za preučevanje bolezni jeter, evropskega EASL in ameriškega AASLD in predlagajo presejanje na okužbo z virusom hepatitis B (HBV) pri vseh bolnikih, pri katerih je predvideno imunosupresivno zdravljenje, med katere spada tudi sistemsko zdravljenje raka. Če se pri teh bolnikih ugotovi latentna okužba, se priporoča uvedba protivirusne učinkovine. Protivirusno zdravljenje po podatkih posameznih raziskav in metaanalize 11 raziskav zmanjša tveganje za reaktivacijo hepatitisa B in umrljivost zaradi reaktivacije hepatitisa B, medtem ko značilnega vpliva na skupno umrljivost ni bilo zaznati. Skoraj istočasno je ameriško združenje za klinično onkologijo ASCO objavilo začasna klinična priporočila za presejanje in preprečevanje reaktivacije hepatitisa B pri rakavih bolnikih na citostatskem zdravljenju. V njih je priporočeno presejanje na okužbo s HBV samo pri rakavih bolnikih z velikim tveganjem za kronično okužbo s HBV ter pri vseh bolnikih, pri katerih je predvideno zdravljenje z močno imunosupresivnim sistemskim zdravljenjem, kot je visokodozna kemoterapija s presaditvijo matičnih krvotvornih celic ali zdravljenje limfomskih bolnikov z rituksimabom. Profilaktičnega zdravljenja z lamivudinom ta skupina ne priporoča pri vseh bolnikih z latentno okužbo, ampak svetuje individualni razmislek o zdravljenju, ki naj temelji na tehtanju koristi in slabosti zdravljenja z lamivudinom pri vsakem posameznem bolniku. Ti dve objavi in njuna ne povsem enoznačna priporočila postavljajo pred slovenske onkologe vprašanje o najprimernejši oskrbi bolnikov v trenutni vsakodnevni klinični praksi. Zato smo v okviru ozke skupine strokovnjakov internistične onkologije in infektologije novembra 2010 pripravili okroglo mizo, katere sklepe objavljamo v tem prispevku. Za jasne sklepe o tem, ali je smiselno presejanje na okužbo s HBV pri vseh rakavih bolnikih na sistemskem zdravljenju, ter o varnosti in učinkovitosti protivirusnega zdravljenja pri kroničnih nosilcih HBV potrebujemo dodatne podatke, pridobljene v okviru prospektivnih kliničnih raziskav. Tudi v Sloveniji bomo izvedli prospektivno klinično raziskavo, ki nam bo odgovorila na vprašanje o pojavnosti kroničnih nosilcev HBV med našimi bolniki z limfomi in solidnimi raki ter nam dala podatke o učinkovitosti in varnosti protivirusnega predčasnega zdravljenja oz. kemoprofilakse pri naših bolnikih. Samo na lastnih izsledkih, pridobljenih v okviru načrtovane prospektivne študije, in ob upoštevanju izsledkov dodatnih, že potekajočih mednarodnih kliničnih raziskav bo mogoče oblikovati jasna in dokončna priporočila o presejanju in preprečevanju reaktivacije hepatitisa B pri slovenskih bolnikih z rakom, ki se sistemsko zdravijo.As a supplement to the September 2010 issue, the Slovenian Medical Journal published Slovenian national guidelines for prevention of hepatitis B reactivation in the patients undergoing immunosuppressive treatment. These guidelines, based on the orientations provided by two international organizations for liver cancer prevention, the European EASL and the American AASLD, suggest screening for hepatitis B infection (HBV) in all patients to whom immunosuppressive treatment, including also systemic cancer treatment, is indicated. In cases where a latent infection is determined, application of antiviral therapy is suggested. In several individual studies as well as in a meta-analysis of 11 studies, antiviral therapy reduced the risk of hepatitis B reactivation and mortality due to it, while there is no proof of a significant impact on the overall survival. Within almost the same timeframe, several provisional clinical opinions on screening and prevention of reactivation of hepatitis B in cancer patients receiving cytostatic treatment were published by the American Society for Clinical Oncology (ASCO)they all promote the use of screening for HBV infection only in the group of cancer patients who show a high risk for chronic HBV infection and in all patients to whom highly immunosuppressive therapies, such as high-dose chemotherapy with bone marrow transplantation or treatment of lymphoma patients with rituximab, are indicated. ASCO does not suggest prophylactic treatment with lamivudin in all patients with latent infection, but promotes an individual approach to treatment based on cost-benefit analysis in each individual patient. These two publications and their not entirely unanimous guidelines are confronting the present Slovenian oncologists with the dilemma which of the current approaches to patient treatment is optimal in everyday clinical practice. To resolve these issues, a group of specialists in the field of medical oncology and infectology conducted a round table discussion in November 2010. The conclusions and proposals derived from this meeting are presented in this article. In order to obtain an even more clear statement on whether screening for HBV infection should be used in all cancer patients receiving systemic therapy as well as on the safety and efficiency of antivirus treatment in latent HBV carriers, additional data gathered in the frame of prospective clinical trials are needed. The decision was made to plan and conduct a prospective clinical trial in Slovenia, which will provide us with the data on the occurrence of chronic HBV carriers in the current population of patients with lymphoma and solid cancer patients as well as with the answers on the safety and efficiency of preemptive antivirus treatment or chemoprophylaxis in our patients. On the basis of the findings of this widely set out prospective trial and taking into account additional data obtained in the frame of international trials already under way, we will be able to define more precise and clear guidelines on screening and prevention of hepatitis B reactivation in Slovenian cancer patients receiving systemic therapy

Splay trees

V magistrskem delu je predstavljena podatkovna struktura imenovana lomljeno drevo. Gre za dvojiško iskalno drevo, kjer se oblika drevesa spremeni po vsakem posegu (operaciji) v drevo. Vozlišče, nad katerim izvajamo poljubno operacijo, je na koncu operacije vedno v korenu drevesa. Postopku, ki vozlišče premakne v koren drevesa, pravimo emph{lomljenje}. Namen lomljenih dreves je, da so podatki, ki jih pogosto uporabljamo, hitro dostopni. Tako podatki, ki jih večkrat uporabljamo, ostanejo bližje vrha drevesa in jih ob naslednji uporabi hitreje najdemo. Podatki, ki so redko v uporabi, se nahajajo nižje v drevesu. Na podlagi amortizirane časovne zahtevnosti je analizirana hitrost delovanja osnovnih operacij lomljenih dreves. Amortizirana časovna zahtevnost je povprečen čas posamezne operacije v najslabšem zaporedju operacij. V magistrskem delu je predstavljen tudi implementiran program za lomljena drevesa, v katerem so definirane osnovne operacije na lomljenih drevesih. Nazadnje je narejena še analiza hitrosti delovanja operacij implementiranega programa za lomljena drevesa in primerjava lomljenih dreves z drugimi uravnoteženimi drevesi.The master\u27s thesis presents the data structure called splay tree. It is a binary search tree, where the shape of the tree changes after each intervention (operation) in the tree. At the end of each operation, the node over which the operation is performed is always in the root of the tree. The process of moving a node to the root of a tree is called emph{splaying}. The purpose of splay trees is to make frequently used data quickly accessible. Thus, the data we use multiple times remains near the top of the tree and is then found faster. Data that is rarely used is located lower in the tree. Using the amortized time complexity, we analyse the speed of basic operations on splay trees. Amortized time complexity is the average time of an individual operation in the worst sequence of operations. In the master\u27s thesis an implementation for splay trees is also presented. Finally, the time complexity analysis is made for the operations of the implementation and a comparison of splay trees with other balanced trees is given

Usefulness of immunohistochemically determined epidermal growth factor receptor mutations in lung cancer

Namen Preučiti zanesljivost imunohistokemične (IHK) metode za določanje najpogostejših aktivirajočih mutacij v genu za receptor za epidermalni rastni dejavnik (EGFR) pri nedrobnoceličnem raku pljuč (NDRP) v primerjavi s standardno metodo verižne reakcije s polimerazo (PCR) ter napovedno vrednost IHK EGFR pozitivnih mutacij na izhode zdravljenja z zaviralci tirozin kinaz (TKI), usmerjenimi proti EGFR. Dodatno smo želeli preučiti še stroškovno učinkovitost IHK testiranja EGFR mutacij pred PCR testiranjem. Utemeljitev Aktivirajoče EGFR mutacije predstavljajo pozitiven napovedni dejavnik za zelo dober, okrog 70 % odgovor na zdravljenje z EGFR TKI pri bolnikih z razsejanim NDRP in jih standardno določamo s PCR metodo. Senzitivnost PCR metode omejuje delež tumorskih celic z EGFR mutacijo. Poleg tega je PCR testiranje relativno drago, kompleksno, zahteva usposobljen kader, analiza rezultatov pa razmeroma dolgotrajna. IHK metoda določanja specifičnih mutiranih EGFR proteinov z uporabo za pogosti mutaciji specifičnih protiteles, omogoča določitev EGFR mutacij v zelo majhnih tumorjev ali celo le tumorskih celic na enostavnejši, hitrejši, cenejši in dostopnejši način. V literaturi so dostopni podatki o zelo visoki, v povprečju okrog 90 % specifičnosti IHK metode za določanje pogostih EGFR mutacij, medtem ko je bila senzitivnost precej nižja in med posameznimi raziskavami močno spremenljiva, od 30 – 100 %. Podatki o napovedni vrednosti IHK določenih EGFR mutacij so v doslej objavljeni literaturi pičli. Bolniki in Metode V raziskavo smo vključili 79 EGFR mutacije pozitivnih in 29 EGFR mutacije negativnih bolnikov z NDRP, diagnosticiranih po principu refleksnega testiranja z metodo PCR. Za IHK testiranje smo uporabili za mutacije specifični protitelesi proti najpogostejši deleciji v eksonu 19, E746-A750del (klon SP111) in proti točkovni mutaciji L8585R (klon SP125). Reakcijo smo izvedli na avtomatskem barvalniku. 60 od 79 EGFR mutacije pozitivnih bolnikov je bilo zdravljenih z EGFR TKI za razsejano bolezen in so bili vključeni v analizo preživetja. Za oceno stroškovne učinkovitosti smo uporabili odločitveno drevo. &#8195Rezultati Celokupna senzitivnost in specifičnost IHK metode v primerjavi s PCR metodo sta bili 84,8 % (95 % interval zaupanja (CI) 74,6-91,6) in 100 % (95 % CI 85,4-100). Srednji čas brez napredovanja bolezni (PFS) in celokupno preživetje (OS) bolnikov, ki so bili IHK EGFR pozitivni sta bila visoko primerljiva s PFS in OS celotne kohorte PCR EGFR pozitivnih bolnikov (PFS: 14,3 vs. 14,0 mesOS: 34,4 vs. 34,4 mes). Razmerje stroškov PCR in IHK metode bi moralo znašati 8:1 za belo populacijo, oziroma 4:1 za Azijsko populacijo, da bi bilo IHK testiranje pred PCR testiranjem stroškovno učinkovito. Zaključek V naši raziskavi smo potrdili zelo visoko specifičnost in relativno nizko senzitivnost IHK metode za določanje dveh najpogostejših aktivirajočih EGFR mutacij z uporabo specifičnih protiteles. Potrdili smo tudi zanesljivost IHK metode za napoved odgovora na zdravljenje s TKI. Na stroškovno upravičenost IHK testiranja pred PCR testiranjem v največji meri vpliva delež EGFR mutacij v določeni populaciji.Purpose To evaluate the accuracy of immunohistochemistry (IHC) method compared to standard PCR-based method for detecting common activating epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) and to evaluate predictive value of IHC EGFR mutation-positive status for EGFR TKIs treatment outcome. Additionally, based on the results of our study we wanted to evaluate estimated cost-effectiveness for the upfront IHC testing. Background Activating EGFR mutations are predictive for excellent, approximately 70%, response rate for treatment with EGFR TKIs in patients with advanced NSCLC. Standard method for EGFR mutation detection is PCR method. The sensitivity of PCR method is limited by the amount of tumor cells in the tumor specimen. PCR-based EGFR mutation testing is relatively costly, technically comlex, labour demanding, and has relatively long turn-around-times. IHC method using mutant selective antibodies for detection of specific mutant EGFR proteins enables EGFR mutation analysis in small tumor tissue samples or even tumor cells. IHC is easy to conduct, cheaper, widely available and yields fast results. Previously, IHC EGFR mutation detection with mutation specific EGFR antibodies was studies, revealing very high specificity, around 90%, while sensitivity was limited and variable between studies, ranging 30 % - 100 %. Data on predictive value of IHC determined EGFR mutations on response to EGFR TKI are scarce in the available literature. Patients and Methods The trial included 79 consecutive EGFR mutation-positive and 29 EGFR mutation-negative NSCLC cases diagnosed with reflex PCR-based testing. Two mutation-specific antibodies against the most common exon 19 deletion, namely E746-A750del (clone SP111) and L858R mutation (clone SP125) were tested using automated immunostainer. 60/79 EGFR mutation-positive cases were treated with EGFR TKIs for advanced disease and included in treatment outcome analysis. Decision tree was used for the cost-effectiveness analysis. Results The overall sensitivity and specificity of IHC-based method compared to the PCR-based one were 84.8 % (95 % CI 75.6–91.6) and 100 % (95 % CI 85.4–100), respectively. The median PFS and OS of patients with IHC positive EGFR mutation status were highly comparable to the total cohort (PFS: 14.3 vs 14.0 monthsOS: 34.4 vs 34.4 months). The PCR and IHC cost ratio needs to be about eight-to-one and four-to-one in Caucasian and Asian population, respectively, to economically justify upfront use of IHC. Conclusion The trial confirmed an excellent specificity with fairly good sensitivity of IHC with mutation-specific antibodies for common EGFR mutations and the accuracy of IHC testing for predicting response to EGFR TKIs. The use of upfront IHC depends mainly on the population EGFR mutation positivity probability

Brain metastases in lung adenocarcinoma

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 months25.8 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

Presejanje na okužbo z virusom hepatitisa B in preprečevanje reaktivacije hepatitisa B: current clinical recommendations

As a supplement to the September 2010 issue, the Slovenian Medical Journal published Slovenian national guidelines for prevention of hepatitis B reactivation in the patients undergoing immunosuppressive treatment. These guidelines, based on the orientations provided by two international organizations for liver cancer prevention, the European EASL and the American AASLD, suggest screening for hepatitis B infection (HBV) in all patients to whom immunosuppressive treatment, including also systemic cancer treatment, is indicated. In cases where a latent infection is determined, application of antiviral therapy is suggested. In several individual studies as well as in a meta-analysis of 11 studies, antiviral therapy reduced the risk of hepatitis B reactivation and mortality due to it, while there is no proof of a significant impact on the overall survival. Within almost the same timeframe, several provisional clinical opinions on screening and prevention of reactivation of hepatitis B in cancer patients receiving cytostatic treatment were published by the American Society for Clinical Oncology (ASCO); they all promote the use of screening for HBV infection only in the group of cancer patients who show a high risk for chronic HBV infection and in all patients to whom highly immunosuppressive therapies, such as high-dose chemotherapy with bone marrow transplantation or treatment of lymphoma patients with rituximab, are indicated. ASCO does not suggest prophylactic treatment with lamivudin in all patients with latent infection, but promotes an individual approach to treatment based on cost-benefit analysis in each individual patient. These two publications and their not entirely unanimous guidelines are confronting the present Slovenian oncologists with the dilemma which of the current approaches to patient treatment is optimal in everyday clinical practice. To resolve these issues, a group of specialists in the field of medical oncology and infectology conducted a round table discussion in November 2010. The conclusions and proposals derived from this meeting are presented in this article. In order to obtain an even more clear statement on whether screening for HBV infection should be used in all cancer patients receiving systemic therapy as well as on the safety and efficiency of antivirus treatment in latent HBV carriers, additional data gathered in the frame of prospective clinical trials are needed. The decision was made to plan and conduct a prospective clinical trial in Slovenia, which will provide us with the data on the occurrence of chronic HBV carriers in the current population of patients with lymphoma and solid cancer patients as well as with the answers on the safety and efficiency of preemptive antivirus treatment or chemoprophylaxis in our patients. On the basis of the findings of this widely set out prospective trial and taking into account additional data obtained in the frame of international trials already under way, we will be able to define more precise and clear guidelines on screening and prevention of hepatitis B reactivation in Slovenian cancer patients receiving systemic therapySeptembra 2010 so bile v Zdravniškem vestniku objavljene slovenske nacionalne usmeritve za preprečevanje reaktivacije hepatitisa B pri bolnikih, ki potrebujejo imunosupresivno zdravljenje. Te smernice temeljijo na usmeritvi dveh mednarodnih združenj za preučevanje bolezni jeter, evropskega EASL in ameriškega AASLD in predlagajo presejanje na okužbo z virusom hepatitis B (HBV) pri vseh bolnikih, pri katerih je predvideno imunosupresivno zdravljenje, med katere spada tudi sistemsko zdravljenje raka. Če se pri teh bolnikih ugotovi latentna okužba, se priporoča uvedba protivirusne učinkovine. Protivirusno zdravljenje po podatkih posameznih raziskav in metaanalize 11 raziskav zmanjša tveganje za reaktivacijo hepatitisa B in umrljivost zaradi reaktivacije hepatitisa B, medtem ko značilnega vpliva na skupno umrljivost ni bilo zaznati. Skoraj istočasno je ameriško združenje za klinično onkologijo ASCO objavilo začasna klinična priporočila za presejanje in preprečevanje reaktivacije hepatitisa B pri rakavih bolnikih na citostatskem zdravljenju. V njih je priporočeno presejanje na okužbo s HBV samo pri rakavih bolnikih z velikim tveganjem za kronično okužbo s HBV ter pri vseh bolnikih, pri katerih je predvideno zdravljenje z močno imunosupresivnim sistemskim zdravljenjem, kot je visokodozna kemoterapija s presaditvijo matičnih krvotvornih celic ali zdravljenje limfomskih bolnikov z rituksimabom. Profilaktičnega zdravljenja z lamivudinom ta skupina ne priporoča pri vseh bolnikih z latentno okužbo, ampak svetuje individualni razmislek o zdravljenju, ki naj temelji na tehtanju koristi in slabosti zdravljenja z lamivudinom pri vsakem posameznem bolniku. Ti dve objavi in njuna ne povsem enoznačna priporočila postavljajo pred slovenske onkologe vprašanje o najprimernejši oskrbi bolnikov v trenutni vsakodnevni klinični praksi. Zato smo v okviru ozke skupine strokovnjakov internistične onkologije in infektologije novembra 2010 pripravili okroglo mizo, katere sklepe objavljamo v tem prispevku. Za jasne sklepe o tem, ali je smiselno presejanje na okužbo s HBV pri vseh rakavih bolnikih na sistemskem zdravljenju, ter o varnosti in učinkovitosti protivirusnega zdravljenja pri kroničnih nosilcih HBV potrebujemo dodatne podatke, pridobljene v okviru prospektivnih kliničnih raziskav. Tudi v Sloveniji bomo izvedli prospektivno klinično raziskavo, ki nam bo odgovorila na vprašanje o pojavnosti kroničnih nosilcev HBV med našimi bolniki z limfomi in solidnimi raki ter nam dala podatke o učinkovitosti in varnosti protivirusnega predčasnega zdravljenja oz. kemoprofilakse pri naših bolnikih. Samo na lastnih izsledkih, pridobljenih v okviru načrtovane prospektivne študije, in ob upoštevanju izsledkov dodatnih, že potekajočih mednarodnih kliničnih raziskav bo mogoče oblikovati jasna in dokončna priporočila o presejanju in preprečevanju reaktivacije hepatitisa B pri slovenskih bolnikih z rakom, ki se sistemsko zdravijo