53 research outputs found
Genomika raka prostate: kliniÄka primjena i izazovi
The studying of prostate cancer genomics is important for understanding prostate
cancer biology, it can provide clinically relevant stratification into subtypes, the development of new
prognostic and predictive markers in the context of precision medicine, and the development of new
targeted therapies. Recent studies have provided detailed insight into genomics, epigenomics and proteomics
of prostate cancer, both primary and metastatic castration-resistant (mCRPC). Many mutations
have been discovered, both those that occur early in the carcinogenesis and progression as well as
those responsible for the resistance to therapy occurring later under the influence of treatment. A large
number of characteristic mutated signaling pathways has been identified, e.g. the mutations in DNA
repair pathway were found in 23% of mCRPC, which suggests potential response to PARP inhibitors.
Multifocality and intralesional genomic heterogeneity of prostate cancer make the clinical application
of genomics complicated. Although a great progress was made in understanding prostate cancer genomic,
and clinical studies related to its routine application are ongoing, prostate cancer genomics still
needs to find its standard wide routine application in patients with prostate cancer.Istraživanje genomike raka prostate je važno za razumijevanje biologije raka prostate, može omoguÄiti kliniÄki relevantnu
stratifikaciju u podtipove, razvoj novih prognostiÄkih i prediktivnih biljega u kontekstu precizne medicine i razvoj
novih ciljanih terapija. Novija istraživanja omoguÄila su detaljan uvid u genomiku, epigenomiku i proteomiku raka prostate, i
primarnog i metastatskog otpornog na kastraciju (mCRPC). Tako je otkriven velik broj karakteristiÄnih mutacija, kako onih
koje se dogaÄaju rano u nastanku i progresiji raka prostate, tako i onih koje nastaju kasnije pod utjecajem terapije i odgovorne
su za rezistenciju na lijeÄenje. Identificirani su signalni putovi karakteristiÄno pogoÄeni mutacijama, npr. u 23% mCRPC
naÄene su mutacije u genima za popravak oÅ”teÄenja DNA Å”to ukazuje na moguÄ odgovor na lijeÄenje PARP inhibitorima.
Ono Å”to komplicira kliniÄku primjenu genomike je multifokalnost te intralezijska i interlezijska genomska heterogenost raka
prostate. Iako je ostvaren veliki napredak u razumijevanju genomike raka prostate i provode se kliniÄka istraživanja vezana uz
njenu rutinsku primjenu, genomika joÅ” treba naÄi svoju standardnu Å”iroku rutinsku primjenu u bolesnika s rakom prostate
Izazovi manipuliranja imunoloÅ”kim sustavom u svrhu lijeÄenja raka prostate
First cancer vaccine that was approved for routine therapy was sipuleucel-T for treatment of patients with metastatic castration resistant prostate cancer. However, other immunotherapy drugs evaluated in prostate cancer, particularly immune checkpoint inhibitors, have failed to show therapeutic effect. There are several potential explanations for lack of response of prostate cancer to these drugs. These explanations, which are related to specific genetic (e.g. low mutational burden) and immunological (e.g. immunosuppressive tumor immune microenvironment) background of prostate cancer are discussed in this review. Also, new therapeutic strategies to overcome prostate cancer immunotherapy resistance and to select subgroups of patients that could benefit from immunotherapy are outlined.Prva vakcina za rak koja je odobrena za rutinsko lijeÄenje bio je sipuleucel-T za lijeÄenje bolesnika s metastatskim kastracijski rezistentnim rakom prostate. MeÄutim, drugi imunoterapijski lijekovi koji su bili istraživani u bolesnika s rakom prostate, posebno inhibitori imunoloÅ”ke kontrolne toÄke, nisu pokazali terapijski uÄinak. Nekoliko je moguÄih objaÅ”njenja za nedostatak terapijskog odgovora na ove lijekove kod raka prostate. Ta objaÅ”njenja koja su vezana uz specifiÄna genetiÄka (npr. nisko mutacijsko optereÄenje) i imunoloÅ”ka (npr. imunosupresivni tumorski imunoloÅ”ki mikrookoliÅ”) obilježja raka prostate opisana su u ovom preglednom radu. TakoÄer, prikazane su nove terapijske strategije s ciljem prevladavanja otpornosti raka
prostate na imunoterapiju i za odabir podskupina bolesnika u kojih se može oÄekivati korist od imunoterapije
The 4th Scientific Meeting on Tumors of the Gastrointestinal Tract: Immunotherapy and targeted therapy of colorectal cancer - Preface
Medularni karcinom Å”titnjaÄe - pregled znaÄajki i novosti u sustavnom lijeÄenju
Medullary thyroid carcinoma (MTC) is a rare malignancy that originates from
parafollicular (C cells) of the thyroid and accounts for 2-4% of all thyroid malignancies. MTC may be
sporadic or inherited, the latter as part of the MEN 2 syndromes. Germline mutations in the RET
proto-oncogene (REarranged during Transfection) are driver mutations in hereditary MTC, whereas
somatic RET mutations and, less frequently, RAS mutations, have been described in tumor tissues of
sporadic MTC. Genetic screening for germline mutations in RET proto-oncogene identifies gene
carriers of germline mutations. That enables primary prevention (the avoidance of disease onset by
total prophylactic thyroidectomy), or at least secondary prevention (early detection) of the disease.
Radical surgery with complete tumor resection is still pivotal in attaining cure for MTC. Despite recent
advances, the treatment of advanced, metastatic, and progressive MTC remains challenging.
Metastatic MTC can have an indolent clinical course; therefore, it is necessary to assess which patient
to cure and when to initiate the treatment. Multidisciplinary boards of various specialists involved in
the diagnostics and therapy of the patients with MTC in highly specialized centers with a high volume
of patients provide optimal patient management. Multikinase inhibitors (MKI) vandetanib and
cabozantinib were approved for the treatment of progressive or symptomatic metastatic/unresectable
MTC. Although these treatments have been shown to improve progression-free survival (PFS) with
higher overall response rates (ORR) compared with placebo, no MKI has been shown to increase the
overall survival (OS) yet, except in the subgroup of patients with RETM918T-mutations on cabozantinib
therapy. As these drugs are nonselective, significant off-target toxicities may occur. Recently,
next-generation small-molecule tyrosine kinase inhibitors (TKIs) have been developed. These highly
selective RET-inhibitors are specifically designed for highly potent and selective targeting of oncogenic
RET alterations, making them promising drugs for the treatment of advanced MTC. The selective
RET-inhibitor selpercatinib has been very recently registered for the treatment of RET-mutated
thyroid cancer.Medularni karcinomi Å”titnjaÄe (MKÅ ) rijetke su zloÄudne bolesti podrijetla parafolikularnih (C-stanica) Å”titnjaÄe i Äine
oko 2-4% svih zloÄudnih tumora Å”titnjaÄe. MKÅ može biti sporadiÄan ili nasljedan, potonji kao dio MEN 2 sindroma.
N
asljedne mutacije protoonkogena RET (od engl. REarranged during Transfection) pokretaÄke su mutacije kod nasljednih
MKÅ , dok su somatske RET mutacije, ili, rjeÄe, RAS mutacije, opisane u tumorskom tkivu kod sporadiÄnih MKÅ . Genetski
probir na nasljedne mutacije protoonkogena RET identificira nosioce nasljednih genetskih mutacija. To omoguÄuje primarnu
(sprjeÄavanje razvoja bolesti provoÄenjem profilaktiÄke totalne tireoidektomije) ili barem sekundarnu prevenciju bolesti
(rano otkrivanje MKÅ -a). Radikalna operacija s kompletnom resekcijom tumora joÅ” je uvijek kljuÄna u postizanju izljeÄenja
kod MKÅ . Naime, unatoÄ nedavnim dostignuÄima, lijeÄenje uznapredovalog, metastatskog i progresivnog MKÅ -a i dalje
predstavlja izazov. Metastatski MKÅ može biti indolentnog kliniÄkog tijeka, stoga je potrebno procijeniti kojeg bolesnika
lijeÄiti i kada lijeÄenje zapoÄeti. Multidisciplinarni timovi razliÄitih specijalista ukljuÄenih u dijagnostiku i lijeÄenje bolesnika
s MKÅ -om u visoko specijaliziranim centrima s velikim brojem bolesnika omoguÄuju njihovo optimalno zbrinjavanje. Multikinazni
inhibitori (MKI) vandetanib i kabozantinib, odobreni su za lijeÄenje progresivnog ili simptomatskog metastatskog/
neresektabilnog MKÅ . Premda je ovo lijeÄenje pokazalo dobit u preživljenju bez progresije bolesti (PFS, od engl. Progression
Free Survival) uz veÄu ukupnu stopu odgovora (ORR, od engl. Overall Response Rate) naspram placeba, MKI nisu poluÄili
dobit u ukupnom preživljenju (OS, od engl. Overall Survival), osim kod podskupine bolesnika s RETM918T-mutacijama na
terapiji kabozantinibom. Multikinazni inhibitori su neselektivni, stoga je moguÄa znaÄajna toksiÄnost terapije. Nedavno su
razvijene nove generacije tirozin-kinaznih inhibitora (TKI). Ovi visoko selektivni RET-inhibitori specifiÄno su dizajnirani
za visoko uÄinkovito i selektivno ciljanje onkogenih RET alteracija, Å”to ih Äini obeÄavajuÄim lijekovima u lijeÄenju uznapredovalog
MKÅ . Selektivni RET-inhibitor selperkatinib vrlo je nedavno registriran za lijeÄenje RET-mutiranih karcinoma
Å”titnjaÄe
Zadnja postignuÄa u radioterapiji raka prostate
Radiotherapy is the attractive treatment option for prostate cancer and has a clear
role in all stages of the disease. Over the last decade, advances in technology, imaging capabilities, and
improved radiobiological understanding have deeply transformed radiotherapy for prostate cancer,
allowing dose escalation and wide adoption of hypofractionation. Furthermore, the integration of
magnetic resonance imaging (MRI) and improved physical precision of dose delivery have given an
impetus to additionally target intraprostatic tumor lesions, previously agnostic to conventional radiotherapy
target definition concept. The emerging data from randomized clinical trials and observation
research show that ultra-hypofractionation is a safe approach while further follow-up is needed to
assess its efficacy compared to standard fractionation. There is an ongoing uncertainty surrounding
true alpha/beta ratio for prostate cancer since hypofractionation has so far failed to yield theoretically
envisioned superior biochemical control outcomes. Finally, recently published randomized trial settled
ongoing controversy regarding the role of elective pelvic lymph node radiotherapy in patients with
high-risk prostate cancer, showing clear benefit when pelvic nodes were treated to 50 Gy. The role of
partial gland dose escalation/tumor boosting is evolving, and more data is needed to adopt this approach
in routine clinical care. Going forward, molecular imaging will be crucial to assess biology of
the disease, predict a response potentially, and optimally personalize radiotherapy treatment decisions.
In this narrative review, we critically analyzed the published literature and provided practical summary
of recent prostate radiotherapy advances for busy clinicians.Radioterapija je neizostavan oblik lijeÄenja raka prostate i ima ulogu u svim fazama bolesti. Zadnjeg desetljeÄa
napreci u tehnologiji i radiobiologiji su preobrazili radioterapiju raka prostate te omoguÄili eskalaciju doze i hipofrakcioniranje.
Nadalje, integracija magnetske rezonance i poveÄana fizikalna preciznost isporuke radioterapije omoguÄila je
ciljanje intraprostatiÄkih tumora. Mnoge studije pokazuju da je ultra hipofrakcioniranje obeÄavajuÄi koncept lijeÄenja, iako
postoje mnoge nejasnoÄe o pravom alfa-beta omjeru raka prostate te posljediÄnom stvarnom terapijskom benefitu hipofrakcioniranja.
Recentno objavljena studija ukazala je na korist elektivne radioterapije zdjeliÄnih limfnih Ävorova u bolesnika sa
visokoriziÄnim rakom prostate. Nadalje, u tijeku su studije koje Äe ocijeniti valjanost daljnje intraprostatiÄke eskalacije doze.
Moderno molekularno oslikavanje donosi veliku promjenu u naÄinu kako shvaÄamo i lijeÄimo rak prostate. U ovom preglednom
Älanku kritiÄki smo analizirali literaturu i dali smjernice za svakodnevnu radioterapijsku kliniÄku praksu
Uloga moderne anti-androgene terapije u lijeÄenju lokaliziranog raka prostate
Anti-androgen therapy continues to be a basic pilar of treatment for both localized
and metastatic prostate cancer. The advent of new generation of androgen receptor targeted agents
(ARTA) transformed the care of patients with advanced disease. After such a success, the steps were
taken to incorporate a new generation of ARTAs into the treatment landscape of localized prostate
cancer. High-risk prostate cancer represents the most aggressive form of localized disease with
significant metastatic potential and poor outcome. Here, the impact of novel therapies will likely
be profound and transforming. This clinical space has already been a showcase for multidisciplinary
treatment where the combination of local therapies with systemic treatment gradually improved patient
outcomes and the chances of cure. The most recent step in redefining the treatment of localized
disease is the adoption of novel ARTAs moving forward the multidisciplinary platform. In this narrative
review, we discuss current clinical evidence supporting the use of novel ARTAs in patients with
localized high-risk prostate cancer and cover recent developments in biomarker-driven strategies for
treatment individualization in this clinical context.Anti-androgena terapija je temelj lijeÄenja lokaliziranog i uznapredovalog raka prostate. Dolazak nove
generacije lijekova koji inhibiraju androgenu osovinu preobrazila je lijeÄenje bolesnika sa uznapredovalim rakom prostate.
Temeljem uspjeha u uznapredovaloj bolesti, u tijeku su napori da se nova generacija anti-androgenih lijekova inkorporira u
lijeÄenje lokalizirane bolesti. VisokoriziÄan rak prostate predstavlja najagresivniji oblik lokalizirane bolesti sa znaÄajnim metastatskim
potencijalom. Za oÄekivati je da Äe u ovom stadiju utjecaj novih terapija biti preobražavajuÄi. Lokalizirani visokoriziÄni
rak prostate se lijeÄi multidisciplinarno. Tu su kombinacije lokalnog lijeÄenja i sustavne terapije postepeno popravljale
ishode lijeÄenja i omoguÄavale priliku za izlijeÄenje. Zadnji napor predstavlja usvajanje novih anti-androgenih terapija. U
ovom preglednom Älanku razmatramo kliniÄke dokaze za upotrebu nove generacije anti-adrogene terapije u bolesnika sa
lokaliziranim visokoriziÄnim rakom prostate i dajemo pregled zadnjih strategija za personalizaciju lijeÄenja
The 4th Scientific Meeting on Tumors of the Gastrointestinal Tract: Immunotherapy and targeted therapy of colorectal cancer - Preface
- ā¦