Prva linija liječenja metastatskog urotelnog raka mokraćnog mjehura

This manuscript reviewes recent knowledge regarding first line therapy of metastatic urothelial bladder cancer. Bladder cancer is on the 10th place in the world by its incidence, and more prevalent in men. Patients with metastatic urothelial cancer should be classified into one of the two groups: cisplatin eligible and cisplatin-ineligible. Cisplatin-eligible can be treated with cisplatin based regimens and have better outcome. Cisplatin-ineligible patients (40-50%) are cisplatin-ineligible patients are primarily those with creatinine clirence les than 50 ml/min, the ones with certain comorbities and/or poor ECOG performance status, and, as an alternative, can be treated with carboplatin which is less effective. After the diagnosis of metastatic bladder cancer has been confirmed, it is necessary to choose one of the cisplatin based chemotherapy regimens. However, one should have in mind that cisplatin can cause certain side effects such as nephrotoxic, neurotoxic and ototoxic effects. A minority of patients are not eligible for any platinum-containing chemotherapy regimen. Besides chemotherapy regimens, checkpoint inhibitors (CPIs)-PD-1 and PD-L1 inhibitors play an important role in first-line therapy of metastatic urothelial cancer. NCCN guidelines have included avelumab, pembrolizumab and atezolizumab in a first-line systemic therapy. Recently, Javelin Bladder 100 study has confirmed a positive impact of avelumab as a maitenance therapy in cisplatin-eligible and cisplatin-ineligible patients, which is why the combination of chemotherapy and avelumab is nowadays deemed to be the best therapeutic option.Ovaj rukopis daje pregled nedavnih saznanja o prvoj liniji terapije metastatskog urotelnog raka mokraćnog mjehura. Rak mokraćnog mjehura je na 10. mjestu u svijetu po učestalosti, a češći je u muškaraca. Bolesnike s metastatskim urotelnim rakom svrstava se u dvije skupine: prihvatljivi za liječenjem cisplatinom i nepodobni za liječenje cisplatinom. Bolesnici prihvatljivi za liječenje cisplatinom mogu se liječiti režimima temeljenim na cisplatini i imati bolji ishod. Bolesnici koji ne ispunjavaju uvjete za liječenje cisplatinom, njih oko 40-50%, su oni s određenim komorbitetima i/ili lošim ECOG statusom te se mogu liječiti karboplatinom koja je, međutim, manje učinkovita. Nakon potvrde dijagnoze metastatskog urotelnog raka mokraćnog mjehura, potrebno je odabrati jedan od režima kemoterapije na bazi cisplatine. Međutim, treba imati na umu da cisplatina može uzrokovati nuspojave poput nefrotoksičnosti, neurotoksičnosti i ototoksičnosti. Danas u u prvoj liniji terapije važnu ulogu igraju inhibitori kontrolnih točaka (CPI), PD-1 i PD-L1. Smjernice NCCN-a uključuju avelumab, pembrolizumab i atezolizumab u sustavnu terapiju prve linije. Nedavno je studija ″Javelin bladder 100″ potvrdila pozitivan utjecaj avelumaba kao terapije održavanja u bolesnika koji ispunjavaju uvjete za liječenje cisplatinom i koji ne ispunjavaju uvjete za liječenje cisplatinom, zbog čega se kombinacija kemoterapije i avelumaba trenutno smatra najboljom terapijskom opcijom

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

Evaluation of DNA Damage in Radiotherapy-Treated Cancer Patients Using the Alkaline Comet Assay

The aim of this study was to evaluate primary DNA damage and the dynamics of the repair of radiotherapy-induced DNA lesions in non-target cells of cancer patients. This study included patients diagnosed with different solid tumors who received radiotherapy. The levels of DNA damage were evaluated using the alkaline comet assay on peripheral blood leukocytes. Altogether four blood samples per patient were collected: before and after receiving the first dose of radiotherapy, in the middle of radiotherapy cycle, and after the last dose of radiotherapy. The results indicate that after the first radiation dose significantly increased levels of DNA damage were recorded in almost all cancer patients compared to their baseline values. Specific patterns of DNA damage were recorded in samples analyzed in the middle of radiotherapy and after receiving the last dose, indicating the possibility of adaptive response in some patients. Our results indicate that persistence of post-irradiation damage in peripheral blood leukocytes (and possibly in other non-target cells) of cancer patients that are strong determinants for the secondary cancer risk. Moreover, the alkaline comet assay was confirmed as a rapid and sensitive assay for the assessment of genome damage after in vivo irradiation

Immunotherapy and Gamma knife \u27\u27stop and go\u27\u27 therapy in a mRCC patient

INTRODUCTION/OBJECTIVES: Incidence of kidney cancer is 3 % of the overall population, with most common type being clear cell kidney carcinoma (mccRCC). Our objective is to report a successful treatment of mccRCC with long survival

Rijetki intrakranijski multifokalni ne-germinomatozni tumor zametnih stanica kod 18-godišnjeg mladića: prikaz slučaja

Intracranial germ cell tumors are rare brain tumors that are distinguished based on their histology and selected tumor markers. Non-germinomatous germ cell tumors are a diverse group of such tumors having the poorest prognosis. Most commonly, they are located in the suprasellar and pineal regions. Since the exact treatment protocol has not yet been established, there is currently no standardized modality of management. We present a case of intracranial multifocal non-germinomatous germ cell tumor in an 18-year-old male, along with relevant literature review. We describe initial diagnostic and treatment procedures in a young adult presented with diplopia and ataxic gait. Neuroradiological findings and elevated alpha fetoprotein and beta chain of the human chorionic gonadotropin tumor markers indicated the possible mixed germ cell tumor. Chemotherapy regimen was adjusted accordingly, biopsy was not performed. The patient’s clinical condition improved significantly and his alpha fetoprotein values decreased remarkably after initiation of chemotherapy. In conclusion, initial evaluation with neuroimaging, tumor markers, and cytology from cerebrospinal fluid is important as guidance to further treatment and prognosis. In selected cases, biopsy may not be indicated to start adjuvant chemotherapy. We emphasize the importance of specific treatment modality selection based mainly on tumor markers, regardless of the precise histologic classification.Intrakranijski tumori zametnih stanica su rijetki tumori mozga koji se razlikuju na temelju histologije i tumorskih biljega. Ne-germinomatozni tumori zametnih stanica su raznolika podskupina tih tumora s najlošijom prognozom. Najčešće su locirani u supraselarnoj i pinealnoj regiji. S obzirom na to da točan protokol liječenja još nije utemeljen trenutno ne postoji standardizirani način liječenja. Predstavljamo slučaj intrakranijskog multifokalnog ne-germinomatoznog tumora zametnih stanica kod 18-godišnjeg mladića, popraćen relevantnim pregledom literature. Opisali smo početne dijagnostičke i terapijske postupke provedene kod mladića koji se prezentirao diplopijom i ataksičnim hodom. Neuroradiološki nalazi i povišeni tumorski biljezi, alfa fetoprotein te beta lanac humanog korionskog gonadotropina, upućivali su na mogući miješani tip tumora zametnih stanica. Propisana je odgovarajuća kemoterapija, a biopsija nije učinjena. Nakon početka kemoterapije bolesnikovo kliničko stanje se iznimno popravilo te su mu se vrijednosti alfa fetoproteina značajno snizile. Zaključno, početna neuroradiološka obrada, nalaz tumorskih biljega i citologija iz likvora važni su čimbenici u određivanju smjera liječenja i predviđanju prognoze. U određenim slučajevima biopsija ne mora biti indicirana kako bi se započelo s kemoterapijom. Naglašavamo važnost odabira specifičnog načina liječenja prvenstveno na temelju nalaza tumorskih biljega bez obzira na preciznu histološku klasifikaciju

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

Gastric Adenocarcinoma

Želučani karcinom spada među najčešće maligne bolesti u svijetu i drugi je na svjetskoj ljestvici uzroka smrti od malignih bolesti, premda mu incidencija u razvijenim zemljama s vremenom pada. U patogenezi želučanog raka važnu ulogu imaju i genetski čimbenici i čimbenici iz okoliša. Kronična infekcija Helicobacterom pylori glavni je pokretač pretkarcinoznog procesa. U karcinogenezi također važnu ulogu imaju i dijeta bogata nitratima, a siromašna antioksidansima. Još nije točno poznato kojim mehanizmom(-ima) infekcija potiče nastajanje želučanog karcinoma. Radi se o dugome latentnom vremenu, što je dobro potkrijepljeno dokazima. U tom periodu prepoznat je niz preteča, predmalignih, lezija želučane sluznice (kronični atrofi čni gastritis, intestinalna metaplazija, želučana displazija) koje stvaraju pretkarcinomsku kaskadu. Postoji više klasifi kacijskih sustava za rak želuca, a najčešća je TNM-klasifi kacija o kojoj ovisi izbor terapije te prognoza bolesti. U operabilnih, uznapredovalih karcinoma prva metoda izbora je kirurški zahvat. Temeljem rezultata kliničke studije III. faze Intergroup Study 0116 (INT-0116) koji se odnose na produljenje preživljenja i perioda bez bolesti, adjuvantna konkomitantna radiokemoterapija postala je standardni oblik liječenja u Americi i znatnom broju europskih zemalja, među kojima je i Hrvatska. Liječenje metastatske bolesti kemoterapijom daje dulje preživljenje u usporedbi sa simptomatskom terapijom.Gastric cancer is one of the most common malignant diseases worldwide, and the second leading cause of cancer-related death in the world, although its incidence has fallen over time in developed nations. Both genetic and environmental factors play important roles in the pathogenesis of gastric cancer. Chronic infection with Helicobacter pylori is a major force driving the precancerous process. Dietary factors including high nitrate intake and lack of the antioxidants also play an important role in carcinogenesis. The precise mechanism(s) by which the infection induces gastric cancer are still unknown. A very long latency period has been well documented. In this period, a number of sequential precursor (premalignant) lesions in the gastric mucosa (chronic atrophic gastritis, intestinal metaplasia, gastric dysplasia), i.e. the precancerous cascade, has been identifi ed. Several classifi cation systems for gastric cancer are available. TNM staging is most frequently used, and it determines the choice of the therapy and the prognosis of the disease. In operable advanced carcinomas, surgery is the method of fi rst choice. Based on the results of Phase III Intergroup Study 0116 (INT-0116), which demonstrated signifi cant benefi t in overall and disease-free survival, the adjuvant concomitant radiotherapy has ever since become the standard of health care in the United States and many European countries, including Croatia. The survival rate is higher in patients with metastatic disease treated with chemotherapy than in those receiving the best supportive care

Istraživanje genotoksičnih učinaka irinotekana na ljudskim limfocitima periferne krvi primjenom različitih biomarkera u uvjetima in vitro

In the present study a multi-biomarker approach was used to evaluate genotoxic effects of irinotecan administered in vitro in its therapeutic dose (350 mg/m2) on non-target cells, peripheral blood lymphocytes. The levels of primary DNA damage in lymphocyte genome and the dynamics of its removal were assessed using the alkaline and neutral comet assay. Lymphocyte viability and the induction of apoptosis following exposure to irinotecan were studied by simultaneous use of a fluorescent assay with ethidium bromide and acridine orange. The levels of residual DNA damage were assessed by SCE assay, while the possible influences of treatment on the progression through the mitotic cycles were studied by analyzing lymphocyte proliferative kinetics. We observed that the percentage of apoptotic cells was higher as compared to necrotic ones in all time-points when irinotecan-treated samples were analyzed. Positive results obtained using both modifications of the comet assay indicate that in lymphocyte DNA following treatment with irinotecan a lot of single and double strand breaks are induced. Dynamics of damage infliction as observed both in alkaline and neutral modification of the comet assay clearly reflects the ’poisoning’ of the topoisomerase I, reported as the main mechanism of the irinotecan cytotoxicity. After treatment with irinotecan we observed an almost 7-fold increase of SCE frequency in exposed as compared to untreated lymphocytes that was obviously caused by topoisomerase poisoning in S-phase. Considering the results obtained we can conclude that irinotecan caused a delay of in vitro cell proliferation in first mitotic cycle. Despite their limitations, the results of our study indicate that irinotecan in its therapeutic concentrations is able to cause significant amount of primary and residual DNA damage in human peripheral blood lymphocytes. We could assume that the actual levels of DNA damage produced in actively divided cells of patients treated with irinotecan are much higher as compared to those estimated in vitro, since DNA damaging potential of irinotecan in vivo is up to one thousand times higher due to effectively conversion to its more potent metabolite SN-38. Our results point to the significance of biomarker studies in non-target cells of cancer patients after successful chemotherapy since they could be a good predictive factor to detect sensitive subpopulations of patients with genome instability that have an increased risk for developing of secondary malignancies.Primjenom različitih biomarkera u uvjetima in vitro istraženi su genotoksični učinci terapijske koncentracije irinotekana (350 mg/m2) na limfocite periferne krvi. Razine primarnih oštećenja DNA u limfocitnoj DNA i dinamika njihovog popravka istraženi su primjenom komet testa u alkalnim i neutralnim uvjetima. Preživljenje limfocita i indukcija apoptoze nakon izlaganja stanica irinotekanu istraženi su istodobnom primjenom fluorescencijskog bojenja etidij-bromidom i akridin oranžom. Razine oštećenja DNA procijenjene su i s pomoću testa izmjena sestrinskih kromatida, a mogući učinci tretmana na progresiju mitotičkog ciklusa istraženi su analizom proliferacijske kinetike limfocita. Utvr|eno je da je postotak apoptoza u svim vremenima uzorkovanja i analize bio veći od postotka nekroza. Pozitivni rezultati dobiveni s obje modifikacije komet testa pokazuju da se u limfocitnoj DNA nakon tretmana irinotekanom inducira mnoštvo jednolančanih i dvolančanih lomova. Dinamika nastanka oštećenja uočena primjenom obje modifikacije komet testa, jasno upućuje na disfunkciju enzima topoizomeraze I, koje se navodi kao glavni mehanizam citotoksičnosti irinotekana. Nakon tretmana irinotekanom uočili smo gotovo sedmerostruki porast učestalosti SCE u izloženim limfocitima u odnosu na kontrolu, što upozorava na poremećenu funkciju topoizomeraze u S-fazi. Na osnovi rezultata zaključujemo da irinotekan uzrokuje zastoj proliferacije stanica u prvom mitotskom ciklusu in vitro. Dobiveni rezultati pokazuju da terapijske koncentracije irinotekana uzrokuju značajan porast oštećenja DNA i kromosoma u ljudskim limfocitima periferne krvi. Budući da su učinci irinotekana u uvjetima in vivo znatno pojačani metaboličkom pretvorbom u aktivni metabolit SN-38, možemo pretpostaviti da su razine oštećenja DNA u aktivno dijelećim stanicama u pacijenata liječenih primjenom irinotekana značajno više nego one utvr|ene u uvjetima in vitro. Rezultati upućuju i na važnost istraživanja biomarkera u ne-tumorskim stanicama pacijenata koji su liječeni primjenom kemoterapije jer takvi biomarkeri mogu biti dobri pretkazatelji u otkrivanju osjetljivih populacija pacijenata s nestabilnim genomom u kojih je prisutan veći rizik za razvoj sekundarnih karcinoma