Koštana pregradnja pomoću osteoklasta: što smo naučili iz ispitivanja knockout gena?

Osteopetroses are disorders of bone remodeling resulting in increased bone mass. Osteopetrosis abnormalities can include changes in osteoclast lineage, bone marrow microenvironment, or both. Little is known about the mechanisms that regulate the activity of different bone cell types. Various agents act on bone in a complicated web of interactions, with either synergistic or diverse effects. Advances in molecular biology have enabled studies in knockout or transgenic animals, providing an insight into the mechanism of bone remodeling.Osteopetroze su poremećaji pregradnje kostiju koji dovode do povećanja koštane mase. Osteopetrotične abnormalnosti mogu obuhvaćati promjene u staničnoj liniji osteoklasta, u mikrookolišu koštane srži ili oboje. Malo se zna o mehanizmima koji reguliraju aktivnost različitih vrsta koštanih stanica. Različiti čimbenici utječu na kost kroz čitav splet međusobnih aktivnosti sa sinergističnim ili raznovrsnim učincima. Napredak u molekularnoj biologiji omogućio je ispitivanja na knockout ili transgenskim životinjama, pružajući uvid u mehanizme koštane pregradnje

Klinička imunoterapija raka blokadom molekularnih interakcija negativne povratne sprege [Tumor immunotherapy in clinical setting based on the blockade of molecular interactions of the negative feedback mechanism]

The recent successful results of several relatively new immunotherapeutic anti-cancer strategies such as the blockade of immune inhibitory pathways by monoclonal antibodies against checkpoint molecules can be considered as a medical breakthrough in clinical cancer immunotherapy. This paper presents a basic overview of cancer immunoediting and the clinical application of monoclonal antibodies against checkpoint molecules in cancer patients. Interactions between the immune system and the malignancy are complex, but the results obtained by using the above mentioned therapeutic approaches indicate acceptable clinical utility, efficacy and safety against several types of cancer. Clinical application of monoclonal antibodies against checkpoint molecules CTLA-4, PD-1, and PD-L1, depending on which tumors these antibodies are tested and applied against, ranges from their already usage having been approved by regulatory agencies for patients with particular metastatic tumors to their testing in clinical studies with the aim of demonstrating their efficiency and consequently obtaining approval

TUMOR IMMUNOTHERAPY IN CLINICAL SETTING BASED ON THE BLOCKADE OF MOLECULAR INTERACTIONS OF THE NEGATIVE FEEDBACK MECHANISM

Nedavni uspješni rezultati više raznih novih imunoterapijskih pristupa u onkoloških bolesnika, kao, primjerice, blokada imunosnih inhibitornih molekularnih interakcija s monoklonskim protutijelima protiv molekula kontrolnih točaka, mogu se smatrati medicinskim iskorakom u kliničkoj onkologiji. Cilj je ovoga rada dati pojednostavnjeni prikaz imunosnog uređivanja raka i kliničke primjene monoklonskih protutijela protiv molekula kontrolnih točaka u onkoloških bolesnika. Interakcije između imunosnog sustava i autolognih tumora složene su, ali rezultati dobiveni primjenom monoklonskih protutijela protiv molekula kontrolnih točaka upućuju na prihvatljivu kliničku primjenjivost, učinkovitost i sigurnost u liječenju bolesnika s određenim tipovima raka. Klinička primjena monoklonskih protutijela protiv molekula kontrolnih točaka CTLA-4, PD-1 i PD-L1, ovisno o tome protiv kojih se tumora ta protutijela testiraju i primjenjuju, jest u rasponu od odobrenja regulatornih agencija i primjene u metastatskoj bolesti u bolesnika s određenim vrstama tumora pa do faza testiranja u kliničkim studijama, a radi istraživanja kliničke učinkovitosti i dobivanja odobrenja.The recent successful results of several relatively new immunotherapeutic anti-cancer strategies such as the blockade of immune inhibitory pathways by monoclonal antibodies against checkpoint molecules can be considered as a medical breakthrough in clinical cancer immunotherapy. This paper presents a basic overview of cancer immunoediting and the clinical application of monoclonal antibodies against checkpoint molecules in cancer patients. Interactions between the immune system and the malignancy are complex, but the results obtained by using the above mentioned therapeutic approaches indicate acceptable clinical utility, efficacy and safety against several types of cancer. Clinical application of monoclonal antibodies against checkpoint molecules CTLA-4, PD-1, and PD-L1, depending on which tumors these antibodies are tested and applied against, ranges from their already usage having been approved by regulatory agencies for patients with particular metastatic tumors to their testing in clinical studies with the aim of demonstrating their efficiency and consequently obtaining approval

TUMOR IMMUNOTHERAPY IN CLINICAL SETTING BASED ON THE BLOCKADE OF MOLECULAR INTERACTIONS OF THE NEGATIVE FEEDBACK MECHANISM

Nedavni uspješni rezultati više raznih novih imunoterapijskih pristupa u onkoloških bolesnika, kao, primjerice, blokada imunosnih inhibitornih molekularnih interakcija s monoklonskim protutijelima protiv molekula kontrolnih točaka, mogu se smatrati medicinskim iskorakom u kliničkoj onkologiji. Cilj je ovoga rada dati pojednostavnjeni prikaz imunosnog uređivanja raka i kliničke primjene monoklonskih protutijela protiv molekula kontrolnih točaka u onkoloških bolesnika. Interakcije između imunosnog sustava i autolognih tumora složene su, ali rezultati dobiveni primjenom monoklonskih protutijela protiv molekula kontrolnih točaka upućuju na prihvatljivu kliničku primjenjivost, učinkovitost i sigurnost u liječenju bolesnika s određenim tipovima raka. Klinička primjena monoklonskih protutijela protiv molekula kontrolnih točaka CTLA-4, PD-1 i PD-L1, ovisno o tome protiv kojih se tumora ta protutijela testiraju i primjenjuju, jest u rasponu od odobrenja regulatornih agencija i primjene u metastatskoj bolesti u bolesnika s određenim vrstama tumora pa do faza testiranja u kliničkim studijama, a radi istraživanja kliničke učinkovitosti i dobivanja odobrenja.The recent successful results of several relatively new immunotherapeutic anti-cancer strategies such as the blockade of immune inhibitory pathways by monoclonal antibodies against checkpoint molecules can be considered as a medical breakthrough in clinical cancer immunotherapy. This paper presents a basic overview of cancer immunoediting and the clinical application of monoclonal antibodies against checkpoint molecules in cancer patients. Interactions between the immune system and the malignancy are complex, but the results obtained by using the above mentioned therapeutic approaches indicate acceptable clinical utility, efficacy and safety against several types of cancer. Clinical application of monoclonal antibodies against checkpoint molecules CTLA-4, PD-1, and PD-L1, depending on which tumors these antibodies are tested and applied against, ranges from their already usage having been approved by regulatory agencies for patients with particular metastatic tumors to their testing in clinical studies with the aim of demonstrating their efficiency and consequently obtaining approval

Immunotherapy of kidney cancer

Rak je bubrega neoplazma koja je razmjerno otporna na postojeću kemoterapiju, hormonsko i iradijacijsko liječenje, stoga se u liječenju bolesnika s rakom bubrega primjenjuju i testiraju lijekovi ili terapije s imunomodulatornim djelovanjem. U kliničkoj praksi, a sa svrhom imunoterapije, najčešće se primjenjuju rekombinantni citokini interferon-alfa (INF-a) i interleukin-2 (IL-2). Ta dva citokina mogu izazvati terapijski odgovor u 10% do 30% bolesnika s metastatskim rakom bubrega. Dugoročno preživljenje ipak je rijetko, nešto češće u bolesnika koji su primali visokodozni IL-2. Kako liječenje raka bubrega usprkos brojnim studijama s različitim terapijama nije zadovoljavajuće, u tijeku su i kliničke studije s drugim imunoterapijskim postupcima.Renal cell carcinoma (RCC) is generally resistant to standard chemotherapy, hormonal or irradiation treatments. Therefore, various drugs or therapies with immunomodulatory action were or are tested in kidney cancer patients. In clinical praxis many approaches have been investigated of which interferon-alpha (INF-") and interleukin-2 (IL-2) are the most extensively studied ones. These two cytokines can achieve response rates in 10% to 30% of patients with metastatic RCC. Long-term survival, however, is achieved only in few patients. More frequently in the ones who have been receiving high-dose IL-2. Consequently, the treatment of RCC is far from being optimal. Therefore, other and novel immunotherapeutic strategies are ongoing or planned to be tested in clinical trials

HORMONAL THERAPY OF PROSTATE CANCER: ARE THERE ANY DILEMMAS LEFT?

Strategija liječenja bolesnika s adenokarcinomom prostate ovisi o procjeni proširenosti bolesti, procjeni rizika od povratka bolesti, dobi, očekivanom trajanju života, komorbiditetima, afinitetima i načinu života. Jedan od standardnih terapijskih modaliteta jest i hormonska terapija. Hormonska terapija raka prostate zapravo je terapija koja suprimira androgen (AST) ili koja terapija deprivira androgen (ADT). Njezinom primjenom dolazi do sniženja razine androgena u krvi, a kako su stanice adenokarcinoma najvećim dijelom (³80%) hormonski ovisne o androgenima, prestanak stimulacije stanica raka androgenima dovodi do njihove apoptoze, usporava se rast tumora i smanjuje se njegova veličina. Stoga se ta vrsta terapije rabi u liječenju karcinoma prostate. Hormonska terapija indicirana je kao prvi terapijski modalitet kod nalaza metastatske bolesti. U slučaju primjene radioterapije na prostatu zahvaćenu rakom s kurativnom namjerom (kod nemetastatske bolesti) preporučuje se primjena terapije koja deprivira androgen u bolesnika sa srednjim i visokim rizikom od povratka bolesti prije, za vrijeme i poslije radioterapije u trajanju od 6 mjeseci ili 2–3 godine ovisno o procijenjenom riziku od povratka bolesti. U vezi s primjenom terapije koja deprivira androgen, a koja se može primijeniti na više načina i u više kombinacija, za određene kliničke situacije ne postoje konačne preporuke. Razloga je više: premalen broj odgovarajućih kliničkih studija, heterogenost bolesnika u studijama što otežava interpretaciju podataka te nekonzistentni rezultati. Također, kako novije dijagnostičke metode i postupci omogućavaju ranije otkrivanje raka prostate, a ranije i sve uspješnije liječenje produžava život bolesnika s metastatskom bolešću, rezultati »ranijih« kliničkih studija mogu gubiti na aktualnosti. Isto tako, sa sve dužim preživljenjem bolesnika sve važnija postaje kvaliteta života, odnosno nuspojave liječenja, kao i procjena koristi u odnosu prema štetnosti same terapije. Cilj je prikaza da upozori na novije spoznaje, kao i na moguće dileme o mjestu i primjeni terapije koja deprivira androgen.The strategy for treating prostate cancer patients depends on the assessment of disease extent, assessment of the risk of disease relapse, assessment of life expectancy, comorbidities, affinities and life-style. Since the activity and survival of prostate cancer cells is at least initially dependent on androgen stimulation, hormonal therapy is one of the several standard treatment modalities. Hormonal therapy is aimed at decreasing this androgen stimulation either by lowering androgen production or by blocking receptor binding. Hormonal therapy is in fact androgen-suppressive therapy (AST) or androgen-deprivation therapy (ADT). If effective, it results in the lack of cancer cell stimulation, thus causing their apoptosis and consequently decline in tumor growth and size. Hormonal therapy is used as a first-line treatment modality for metastatic disease. In addition to this indication, hormonal therapy is also used as an adjunct to radiotherapy with curative intent for patients with non-metastic disease but having an intermediate and high risk of disease relapse. In combination with radiotherapy, hormonal therapy can be applied before, concomitantly and after radiotherapy for the duration of 6 months or 2 to 3 years depending on the risk estimation. Regarding hormonal therapy, it can be applied in combination with other treatments, in several ways, and sometimes there might be several options available. This possible lack of a specific recommendation is a consequence of the fact that there is a limited number of adequate clinical studies which, moreover, may have yielded inconsistent results sometimes simply due to the patients’ heterogeneity. Moreover, thanks to the newer and better diagnostic methods enabling the discovery of prostate cancer in earlier disease stages, as well as to the more effective treatments, there is also a prolongation of relapse-free survival and possibly of overall survival in patients having metastic disease. Consequently, the results of earlier clinical studies might no longer be applicable to the new »generations« of upcoming patients. As regards this improved survival, issues of patient’s quality of life and possible side-effects of hormonal therapy are also becoming increasingly relevant because hormonal adverse events are time-dependant and tend to increase in severity with prolongation of hormonal manipulation. Therefore, this paper aims to give an overview of the more recent findings, indications and observations regarding hormonal therapy

Lokalno liječenje moždanih metastaza raka dojke

Breast cancer, along with lung cancer and melanoma, is one of the most common origins of central nervous system metastases. Due to improvement of systemic therapy options for primary disease and consequential prolonged survival, treatment of brain metastasis (BM) is presenting an evolving challenge. While new systemic therapy approaches for breast cancer brain metastasis are focusing on overcoming the blood brain and blood tumor barrier, as well as targeted therapies, local therapy remains the primary line of treatment. The decision of which local therapies to use, depends upon the number and volume of BM, their localization, patient’s clinical status, previously used treatments, status of extracranial disease and patient’s prognosis. In cases when an active approach, including surgery and/or radiotherapy, does not bring benefit to the patient’s quality of life or overall survival, best supportive care is recommended.Rak dojke, uz tumore pluća te melanom, najčešći je tumor koji metastazira u središnji živčani sustav. Uslijed razvitka sistemske terapije primarne bolesti, i posljedičnog produljenog preživljenja bolesnika, liječenje moždanih metastaza predstavlja sve veći izazov. Dok se novi pristupi sistemskoj terapiji moždanih presadnica tumora dojke fokusiraju na savladavanje prepreke krvno-moždane i krvno-tumorske barijere te na ciljanu terapiju, lokalna terapija ostaje primarna linija liječenja. Odluka o izboru metode liječenja ovisi o broju i volumenu moždanih presadnica, njihovoj lokalizaciji, kliničkom statusu bolesnika, prethodno korištenim metodama liječenja, stadiju uznapredovalosti osnovne bolesti te prognozi bolesnika. U slučajevima kada aktivni pristup liječenju, koji uključuje operaciju i/ili radioterapiju, ne pridonosi kvaliteti života ili ukupnom preživljenju bolesnika, preporuča se najbolja potporna njega

MULTIPLE PRIMARY MALIGNANCIES

Multipli primarni tumori koji se javljaju kod istog bolesnika, metakrono ili sinkrono, relativno su rijedak događaj s porastom učestalosti posljednjih desetljeća. Cilj je ovog istraživanja utvrditi njihovu učestalost kod bolesnika liječenih hospitalno u Zavodu za radioterapijsku onkologiju Klinike za onkologiju Medicinskog fakulteta Sveučilišta u Zagrebu, KBC Zagreb u periodu od 2003. do 2009. godine. Učestalost je multiplih malignih tumora u navedenom periodu bila 2,4%. Od ukupno 103 bolesnika 97 je imalo dva, a 6 tri primarna tumora. Metakronih je tumora bilo 88, a sinkronih 20. Učestalost im je bila veća kod žena nego kod muškaraca, a i pojavljivali su se ranije kod žena nego kod muškaraca. Najčešće su kombinacije prvog i drugoga metakronog tumora kod muškaraca bile: rak prostate-maligni tumor probavnog sustava (osobito rak rektuma i debelog crijeva) i obrnutim redoslijedom te hematološke zloćudne bolesti-maligni tumor probavnog sustava; a kod žena: rak dojke-rak kontralateralne dojke i hematološke zloćudne bolesti (osobito ne-Hodgkinov limfom)-rak dojke. Valja očekivati da će učestalost bolesnika s višestrukim primarnim tumorima rasti, i zbog programa ranog otkrivanja tumora i zbog uspješnijeg liječenja i dužeg očekivanog trajanja života.Multiple primary malignancies, metachronous or synchronous, in a single patient are relatively rare event with the increase of incidence in recent decades. The aim of this research is to study their incidence in patients hospitalized at the Division of Radiotherapy, Department of Oncology, University of Zagreb, School of medicine, University Hospital Centre Zagreb from 2003 to 2009. The incidence of multiple primary malignancies was 2.4%. Among 103 patients, 97 had two, and 6 three primary tumors. Eighty-three cases were metachronous, while 20 cases were synchronous malignancies. The frequency was higher in females than males and their age at diagnosis of tumors was younger than in males. The most common tumor combinations in males were: prostate cancer-digestive system malignancy (especially colorectal cancer) and viceversa, and hematological malignant tumors-digestive system malignancy; while in women there were: breast cancer-cancer of contralateral breast and hematological malignant tumors (especially lymphoma non Hodgkin)-breast cancer. The incidence of multiple primary malignancies is expected to increase due to the better screening programs for early detection of malignancies as well as considerable improvement in their treatment and longer life expectancy

Immunotherapy of kidney cancer

Rak je bubrega neoplazma koja je razmjerno otporna na postojeću kemoterapiju, hormonsko i iradijacijsko liječenje, stoga se u liječenju bolesnika s rakom bubrega primjenjuju i testiraju lijekovi ili terapije s imunomodulatornim djelovanjem. U kliničkoj praksi, a sa svrhom imunoterapije, najčešće se primjenjuju rekombinantni citokini interferon-alfa (INF-a) i interleukin-2 (IL-2). Ta dva citokina mogu izazvati terapijski odgovor u 10% do 30% bolesnika s metastatskim rakom bubrega. Dugoročno preživljenje ipak je rijetko, nešto češće u bolesnika koji su primali visokodozni IL-2. Kako liječenje raka bubrega usprkos brojnim studijama s različitim terapijama nije zadovoljavajuće, u tijeku su i kliničke studije s drugim imunoterapijskim postupcima.Renal cell carcinoma (RCC) is generally resistant to standard chemotherapy, hormonal or irradiation treatments. Therefore, various drugs or therapies with immunomodulatory action were or are tested in kidney cancer patients. In clinical praxis many approaches have been investigated of which interferon-alpha (INF-") and interleukin-2 (IL-2) are the most extensively studied ones. These two cytokines can achieve response rates in 10% to 30% of patients with metastatic RCC. Long-term survival, however, is achieved only in few patients. More frequently in the ones who have been receiving high-dose IL-2. Consequently, the treatment of RCC is far from being optimal. Therefore, other and novel immunotherapeutic strategies are ongoing or planned to be tested in clinical trials