Renal cell carcinoma: molecular pathways and targeted therapy

Renal cell carcinoma (RCC) is not a single disease. A number of different types of cancer occur in the kidney and each is caused by different genes with different histology and clinical course. Studies of hereditary kidney cancer sydromes have led to identification of the main kidney cancer genes: VHL, MET, FH, SDH, FLCN, TSC1 and TSC2. Mutations in each of these genes lead to dysregulation of at least one metabolic pathway that is mediated by oxygen, iron, energy and nutrient sensing suggesting that renal cell cancer is a disease of dysregulated cellular metabolism. A more improved understanding of molecular pathways has led to development of targeted therapies. Targeted agents against VEGF, VEGFR and mTOR continue to play a crucial role in the management of metastatic RCC. However, complete response is extremely rare, resistance in tumor cells develops frequently and adverse effects of therapy are not unusual finding. For that reason further genetic and epigenetic changes, metabolic aberrations as well as immune response are beeing investigated in numerous studies to find new targets for more personalized therapy

U kojih bolesnika primijeniti hormonsku terapiju + docetaksel

Docetaxel improved the outcome of patients with mCSPC and became standard of care after CHAARTED , STAMPEDE arm C and GET UG-AFU 15 clinical trials and after subsequent meta-analysis. Patients with high-volume (CHAARTED definition) and high-risk (LATITUDE definition) disease, who have good performance status and are fit for chemotherapy, seem to benefit the most from addition of docetaxel to the androgen deprivation therapy. Results from TITAN trial with apalutamide showed the activity in the same setting. However, predictive biomarkers are still lacking. We have direct evidence of overall survival benefit from abiraterone, apalutamide and enzalutamide for patients with high-volume disease who are not fit for chemotherapy, as well as for patients with low-volume disease. Clinical trials will show is there place for triple therapy in clinical practice. Before obtaining the results of new clinical trial results, physicians should base their treatment decision on risks and benefits of each current approach and consider the patient´s other health issues such as access, costs, patient and patient´s preferences.Uvođenje kemoterapije docetakselom je dovelo do unaprijeđenja ishoda liječenja u bolesnika s metastatskim senzitivnim rakom prostate te je dodatak docetaksela postao standard liječenja što je temeljeno na rezultatima studija CHAARTED, STAMPEDE, grane C i GET UG-AFU 15 studiji te nakon toga učinjene meta analize. Bolesnici s visokim volumenom bolesti (definicija po CHAARTED studiji) i visokog rizika (definicija prema LATIT UTDE studiji), koji imaju dobar performance status i koji su pogodni za kemoterapiju, imaju najviše koristi od dodatka docetaksela androgenoj deprivacijskoj terapiji. Rezultati TITAN studije su pokazali aktivnosti apalutamida u istoj indikaciji. Ipak, prediktivni biomarkeri još uvijek nedostaju. Postoje jasni dokazi o koristi u ukupnom preživljenju od abiraterona, apalutamida i enzalutamida u bolesnika s bolesti visokog volumena koji nisu pogodni za kemoterapiju, kao i za bolesnike s bolesti niskog volumena. Kliničke studije će pokazati mjesto za trostruku terapiju u kliničkoj praksi. Prije objave rezultata novih kliničkih studija, liječnici trebaju temeljiti svoje odluke na temelju procjene rizika i koristi svakog trenutnog pristupa i razmotriti druge parametre poput troškova liječenja, dostupnosti skrbi te preferencije bolesnika

Rezultati liječenja bolesnika s metastatskim rakom bubrega nivolumabom – donacijskim programom na ime bolesnika (npp) u Kliničkom bolničkom centru Zagreb

Field of metastatic renal cell cancer (mRCC) treatments is now evolving at a rapid and unprecedented pace. Nivolumab prolongs survival in patients with metastatic kidney cancer with a favorable safety profile as demonstrated in the Check-Mate 025 clinical trial. Nivolumab compared to everolimus prolonged survival in patients with mRCC while exibiting favorbale safety profile. In this study we present the results of nivolumab treatment in patients with mRCC within named patient program (NPP) at UHC Zagreb. In 30% of included patients survival was longer than 30 months and 16.6% patients had a complete response.Područje liječenja metastatskog raka bubrega (mRCC) je područje ubrzanog razvoja terapijskih mogućnosti. Nivolumab produljuje preživljenje bolesnika s metastatskim rakom bubrega uz dobar sigurnosni profil što je pokazano u kliničkoj studiji CheckMate025. Nivolumab u usporedbi s everolimusom produljuje preživljenje kod bolesnika sa mRCC uz povoljni sigurnosni profil lijeka. U ovoj analizi smo prikazali rezultate liječenja bolesnika nivolumabom u NPP u Kliničkom bolničkom centru Zagreb tijekom 2016. do 2018. 30% bolesnika ima preživljenje dulje od 30 mjeseci, a 16.6% je imalo kompletni odgovor na terapiju

Liječenje germinativnog raka testisa

Germ-cell testicular cancer (GCTC) is a malignant neoplasm derived from the primordial germ cell. Although it accounts for approximately 1% of all malignancies in men, it is the most common cancer of younger male population, with the highest incidence between ages 15 and 35. Testicular cancer incidence rate has risen globally over the past several decades, with the average increase in the incidence of testicular cancer in Croatia of 7% per annum from the year 1983 to 2007. Two main groups are seminomas and non-seminomas, each accounting for 50% of cases, and they differ in treatment modalities and response to therapy. Despite increase in the incidence rate, a promising circumstance is that GCTC has become a model of curable cancer. Because of advances in diagnostic procedures, sophisticated radiation techniques and especially the introduction of cisplatin based chemotherapy protocols together with advanced postchemotherapy surgical techniques, curability is expected in about 95% of all patients diagnosed with testicular cancer and over 70% of patients with advanced disease. In this review, we will focus on treatment strategies of primary GCTC.Germinativni rak testisa je maligna novotvorina podrijetla primordijalne zametne stanice. Iako čini oko 1% svih malignih novotvorina muškaraca, najčešći je malignom mlađe muške populacije s najvećom incidencijom u dobi od 15 do 35 godina. Incidencija raka testisa povećala se globalno posljednjih nekoliko desetljeća, s prosječnim porastom u incidenciji od 7% godišnje u Hrvatskoj u razdoblju od 1983. do 2007. godine. S obzirom na histološku sliku, germinativni rak testisa dijeli se na seminome i neseminome koji se razlikuju u načinu liječenja i odgovoru na terapiju. Unatoč porastu u incidenciji, obećavajuća okolnost je da je rak testisa postao model izlječivog tumora. Zbog napretka u dijagnostičkim postupcima, sofisticiranih tehnika zračenja, a osobito uvođenja kemoterapijskih protokola baziranih na platini zajedno s naprednim postkemoterapijskim kirurškim tehnikama, izlječivost se očekuje u oko 95% svih dijagnosticiranih bolesnika s rakom testisa i oko 70% bolesnika s uznapredovalom bolešću. U ovom preglednom radu usredotočit ćemo se na strategije liječenja germinativnog raka testisa

Analiza bolesnika s metastatskim rakom bubrega srednje i loše prognostičke skupine liječnih u Kliničkom bolničkom centru Zagreb

Forty two to 57% of patients with metastatic renal cell carcinoma (mRCC) receive the second-line therapy according to available data. In our analysis we wanted to determine the percentage of patients within intermediate/poor prognostic group mRCC who continued the treatment with the second line following progression on the first line and the percentage of patients who were not able to receive the second line treatment. Patients received sunitinib (first started on 12 August 2018) or pazopanib (first started on May 2014) at University Hospital Center Zagreb. The latest treatment started in December 2018. Our results show that 39.4% of patients who received sunitinib and 37.9% of patients who received pazopanib, did not receive the second line treatment, which is consistent with available data. The question arises whether we could have helped those patients if we had access to newer therapeutic options.Prema literaturnim podacima oko 42% do 57% bolesnika smetastatskim karcinomom bubrega primi drugu liniju liječenja. Retrospektivnom analizom naših podataka htjeli smo prikazati postotak bolesnika s metastatskim karcinomom bubrega koji pripadaju srednjoj/lošoj prognostičkoj skupini a koji su nastavili liječenje drugom linijom nakon progresije na prvolinijsko liječenje. Također smo htjeli prikazati postotak bolesnika koji nisu bili u mogućnosti nastaviti drugolinijsko liječenje. Bolesnici su primali sunitinib (prvi bolesnik je započeo liječenje u svibnju 2014.) i pazopanib (prvi bolesnik je započeo liječenje 12. kolovoza 2018) u Kliničkom bolničkom centru Zagreb. Uključeni su bili bolesnici koji su liječenje započeli do kraja prosinca 2018. godine. 39.4% bolesnika koji su primali sunitinib i 37.9% bolesnika koji su primali pazopanib, nije primilo drugu liniju liječenja, što se podudara s literaturnim podacima. Nameće se pitanje, jesmo li navedenim bolesnicima mogli pomoći da smo imali dostupne novije terapijske opcije

Taksani u liječenju ranog raka dojke

Taxanes are irreplaceble drugs in treatment of many solid malignancies. In breast cancer they represent the backbone of adjuvant therapy and are important option in treatment of advanced and metastatic disease. Since their discovery in 1960’s they went through a long journey of clinical development and positioning in clinical practise of treatment of early breast cancer. Taxanes belong to the fourth group of cytotoxic drugs, which act as mytotic inhibitors, causing the death of the cell in metaphase. Clinical trials conducted in patients with breast cancer evaluated different combinations of other chemotherapeutics with taxanes, different modes of administration, effectiveness of different chemotherapy regimens including taxanes in different subtypes and stages of the disease and effectiveness of individual taxanes in comparison with one another. Based on the results of those trials, today the relevant global oncology associations reccomend the use of taxanes in treatment of early breast cancer, pointing out their significant benefit in total reduction of breast cancer mortality and risk of disease reccurence by 20-30% comparing to anthracycline only protocols. The purpose of this literature review was to provide comprehensive information about development of taxanes and their position in routine everyday clinical practise.Taksani su nezamjenjivi lijekovi u liječenju mnogih solidnih tumora. U karcinomu dojke predstavljaju okosnicu adjuvantne terapije i važna su opcija u liječenju uznapredovale i metastatske bolesti. Od njihovog otkrića 1960-ih prošli su dugi put kliničkog razvoja i pozicioniranja u kliničkoj praksi liječenja ranog raka dojke. Taksani pripadaju četvrtoj skupini citotoksičnih lijekova koji djeluju kao inhibitori mitoze, koji uzrokuju smrt stanice u metafazi. Klinička istraživanja provedena na bolesnicama s karcinomom dojke procjenjivala su različite kombinacije drugih kemoterapeutika s taksanima, različite načine primjene, djelotvornost različitih kemoterapijskih protokola koji uključuju taksane u različitim podtipovima i stadijima bolesti te učinkovitosti pojedinih taksana u usporedbi s drugim. Na temelju rezultata tih pokusa, danas relevantne globalne onkološke udruge preporučuju uporabu taksana u liječenju ranog raka dojke, pokazujući njihovu značajnu korist u ukupnom smanjenju rizika od smrti i povrata bolesti za 20-30% u odnosu na protokole bazirane samo na antraciklinu. Svrha ovog pregleda literature je pružanje sveobuhvatne informacije o razvoju taksana i njihove pozicije u rutinskoj svakodnevnoj kliničkoj praksi

Primjena inhibitora kinaza u liječenju bolesnika s uznapredovalim rakom štitnjače

Although most patients with thyroid cancer have a favorable clinical course, some patients develop a more aggressive type of cancer and exhibit more rapid disease progression with worse prognosis. Those patients usually exhibit mutations of proteins such as tyrosine kinase enzymes that play a significant role in regulation of tumor proliferation and spreading. Development of targeted therapies is based on the inhibition of mutated kinases which are involved in the MAPK signaling pathway. The aim of this study was to present the initial results of clinical experience with kinase inhibitors in patients with metastatic differentiated thyroid cancer (DT C), poorly differentiated thyroid cancer (PDT C), and medullary thyroid cancer (MTC) who exhibited rapid disease progression. A total of 17 adult patients (11 women, mean age 53.3 years) managed for progressive, metastatic disease were included in the study. Twelve patients with DT C and PDT C were previously tested for BRAF mutations, of whom nine that had tumor tissue negative for the BRAF V600E mutation received sorafenib, while three patients with tumors harboring the BRAF V600E mutation were treated with vemurafenib. Patients with MTC were treated with sunitinib, vandetanib, and sorafenib. Two patients with tumors harboring the BRAF mutation treated with vemurafenib showed restoration of radioiodine uptake. Most of patients showed significant improvement in disease status but of limited duration until disease progression. Although there was an improvement in progression-free survival, future research has to achieve a greater and longer-lasting response, probably by utilizing combined targeted therapy.Iako većina bolesnika s karcinomom štitnjače ima povoljan klinički tijek, ipak neki bolesnici pokazuju agresivniji tijek bolesti s razvojem uznapredovalih formi tumora i lošijom prognozom. Razlog su vjerojatno mutacije proteina, uglavnom enzima tirozin kinaza koji imaju značajnu ulogu u proliferaciji i rastu tumora. Razvoj ciljanih terapija zasnovan je na inhibiranju mutiranih kinaza BRAF, MEK, NRAS, c-KIT koje su uključene u signalni put MAPK. U radu su predstavljeni preliminarni rezultati liječenja inhibitorima kinaza u bolesnika s metastatskim diferenciranim karcinomom štitnjače (DT C), slabo diferenciranim karcinomom štitnjače (PDT C) i medularnim karcinomom štitnjače (MTC). U izvješće je uključeno ukupno 17 odraslih bolesnika (11 žena, prosječna dob 53,3 godine) liječenih zbog progresivne, metastatske bolesti. Dvanaest bolesnika s DT C i PDT C prethodno je testirano na BRAF mutacije. Devet bolesnika kod kojih je tumorsko tkivo bilo negativno na mutaciju BRAF V600E primali su sorafenib, dok su tri bolesnika s tumorima koji nose mutaciju BRAF V600E liječena vemurafenibom u cilju rediferencijacije tumora, a u dva bolesnika došlo je do ponovne akumulacije radiojoda na scintigramu tijela. Bolesnici s MTC-om liječeni su sunitinibom, vandetanibom i sorafenibom. U većine bolesnika došlo je do pozitivnog terapijskog odgovora uz poboljšanje stanja, ali ograničenog trajanja. Buduća istraživanja bi trebala osigurati bolji i trajniji terapijski odgovor, vjerojatno primjenom kombinirane ciljane terapije

RATIONAL USE OF SERUM TUMOUR MARKERS IN DIAGNOSTICS AND TREATMENT OF SOLID TUMOURS

Optimalno zbrinjavanje oboljelih od malignih bolesti, ovisno o vrsti tumora, uključuje i određivanje serumskih tumorskih biljega. Ti su biljezi heterogena skupina molekula čija je koncentracija povišena kod ljudi oboljelih od zloćudnih tumora, ali se u niskim koncentracijama mogu naći i u plazmi zdravih pojedinaca. Povišene koncentracije u plazmi nastaju zbog: promjena u samoj stanici, nekroze stanice te promjene izražaja ili izlučivanja različitih molekula. Kod nekih tumora same tumorske stanice mogu potaknuti druge stanice na lučenje određenih spojeva. U kliničkoj primjeni u ovom je trenutku između ostalih dostupno određivanje nekoliko serumskih tumorskih biljega: CEA, CA 19-9, CA 15-3, CA 125, CYFRA, NSE, PSA, HCG, AFP, LDH i tiroglobulin. Veći broj serumskih tumorskih biljega primjenjuje se eksperimentalno i čeka svoje mjesto u svakodnevnoj kliničkoj primjeni. Smjernice o primjeni tumorskih biljega Nacionalne akademije kliničke biokemije (National Academy of Clinical Biochemistry – NACB) osmišljene su da bi poticale prikladniju upotrebu testova tumorskih biljega od liječnika primarne zaštite, kirurga, onkologa, ginekologa te ostalih specijalista koji se bave bolesni­cima sa solidnim tumorima.Optimal management of patients with solid tumors, depending on the tumour type, includes measurement of serum tumour markers levels. Serum tumour markers are heterogeneous molecules with concentrations elevated in persons with solid tumours, but could also be found in small amounts in plasma of healthy individuals. Elevated plasma concentrations are caused by cell changes, necrosis, changed expression or secretion of different molecules. In some tumour types tumour cells by themselves could stimulate other cells to secrete particular molecules. There are several serum tumour markers in the routine clinical praxis: CEA, CA 19-9, CA15-3, CA 125, CYFRA, NSE, PSA, HCG, AFP, LDH, thyreoglobulin. There are also several serum tumour markers in experimental use, waiting to be included into the routine clinical use. National Academy of Clinical Biochemistry (NACB) practice guidelines for use of tumour markers in clinical practice are designated to encourage more appropriate use of serum tumour marker tests by general medicine practitioners, surgeons, oncologists, and other health care professionals giving care to patients with solid tumours

Racionalna primjena serumskih tumorskih biljega u dijagnostici i liječenju solidnih tumora [Rational use of serum tumour markers in diagnostics and treatment of solidtumours]

Optimal management of patients with solid tumors, depending on the tumour type, includes measurement of serum tumour markers levels. Serum tumour markers are heterogeneous molecules with concentrations elevated in persons with solid tumours, but could also be found in small amounts in plasma of healthy individuals. Elevated plasma concentrations are caused by cell changes, necrosis, changed expression or secretion of different molecules. In some tumour types tumour cells by themselves could stimulate other cells to secrete particular molecules. There are several serum tumour markers in the routine clinical praxis: CEA, CA 19-9, CA15-3, CA 125, CYFRA, NSE, PSA, HCG, AFP, LDH, thyreoglobulin. There are also several serum tumour markers in experimental use, waiting to be included into the routine clinical use. National Academy of Clinical Biochemistry (NACB) practice guidelines for use of tumour markers in clinical practice are designated to encourage more appropriate use of serum tumour marker tests by general medicine practitioners, surgeons, oncologists, and other health care professionals giving care to patients with solid tumours