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Ewing sarcoma is the second most prevalent paediatric malignant bone tumour. In most cases, it is driven by the fusion oncoprotein EWS::FLI1, which acts as an aberrant transcription factor and dysregulates gene expression. EWS::FLI1 and a large number of downstream dysregulated proteins are Hsp90 client proteins, making Hsp90 an attractive target for the treatment of Ewing sarcoma. In this article, we report a new structural class of allosteric Hsp90 C-terminal domain (CTD) inhibitors based on the virtual screening hit TVS24, which showed antiproliferative activity in the SK-N-MC Ewing sarcoma cell line with an IC$_{50}$ value of 15.9 ± 0.7 µM. The optimised compounds showed enhanced anticancer activity in the SK-N-MC cell line. Exposure of Ewing sarcoma cells to the most potent analogue 11c resulted in depletion of critical Hsp90 client proteins involved in cancer pathways such as EWS::FLI1, CDK4, RAF-1 and IGF1R, without inducing a heat shock response. The results of this study highlight Hsp90 CTD inhibitors as promising new agents for the treatment of Ewing sarcoma.

Ewingov sarkom treći je po učestalosti primarni zloćudni tumor kostiju, iza osteosarkoma i hondrosarkoma, te je drugi najčešći zloćudni tumor kostiju kod djece i adolescenata, a čini otprilike 10 do 15 % svih primarnih tumora kostiju. Najčešće je lokaliziran na donjim ekstremitetima (45 %). Slijede zdjelica (20 %), gornji ekstremiteti (13 %), aksijalni skelet i rebra (13 %) te kosti lica, gdje se najrjeđe javlja, u svega 2 % slučajeva. Tumor se razvija u medularnoj šupljini te se širi kroz kost i pokosnicu u meka tkiva. Može biti lokaliziran ili metastazirajući. Tipični su simptomi bol, oteklina, venski crtež, neuroispadi, ograničena pokretljivost, slabost, umor i vrućica. Dijagnostika uključuje rendgensko snimanje, CT, MR, scintigrafiju te biopsiju za postavljanje konačne dijagnoze. Liječenje se sastoji primarno od ciklusa polikemoterapija u trajanju od 12 do 24 tjedana. Nakon toga slijede operacija, radioterapija, kemoradioterapija ili amputacija. Prognoze su za petogodišnje preživljavanje pacijenata s lokaliziranim tumorom oko 70 %, a pacijenata s metastazirajućim tumorom oko 20 do 30 %. Prognoze su loše kod pacijenata s recidivom tumora, a njih ima oko 30 do 40 %. Trećina pacijenata s recidivom tumora ima manje od 20 % šanse da preživi. U današnje doba javlja se sve veća potreba za fizioterapijom i rehabilitacijom onkoloških bolesnika, kako bi pacijenti ostvarili što veću kvalitetu života. Fizioterapija u tretmanu onkoloških pacijenata započinje već u jedinici intenzivnog liječenja. Kod Ewingova sarkoma fizioterapija ima značajnu ulogu u prijeoperacijskom razdoblju, kao i nakon operacije ili amputacije., Ewing’s sarcoma is the third most common primary malignant bone tumor, following osteosarcoma and chondrosarcoma, it is also the second most common malignant bone tumor in children and adolescents, and makes up about 10 to 15% of all primary bone tumors. In most cases, it is localized in the lower extremities (45%), followed by the pelvic region (20%), the upper extremities (13%), the axial skeleton and the ribs (13%) and the face skeleton (2%). The tumor arises in the medullary cavity and spreads through the bone and periosteum to soft tissues. It can be localized or metastatic. Typical simptoms are pain, swelling, telangiectasias, neurological deficits, limited mobility, weakness, tiredness and fever. Diagnostics includes X-ray scanning, CT, MRI, scintigraphy and, for the final diagnosis, biopsy. The treatment consists primarily of polychemotherapy cycles lasting 12-24 weeks, followed by surgery, radiotherapy, chemoradiotherapy or amputation. The 5-year survival rate of patients with localized tumor is about 70% and with metastatic tumor it is about 20-30%. The prognosis is poor for patients with tumor relapse which occurs in 30-40% of the patients. About 30% of the patients with tumor relapse have less than 20% chance of survival. Nowadays, there is a growing need for physiotherapy and rehabilitation in the treatment of oncological patients, to help them to achieve the highest possible quality of life. Physiotherapy in the treatment of oncological patients starts in the intensive care unit. Physiotherapy in Ewing’s sarcoma treatment plays an important role in the preoperative, postoperative and postamputation period.

9 ABSTRACT Tatiana Labudová: Genetic changes in neuroectodermal tumours detected by molecular biological methods. Charles University in Prague, Faculty of Science, Department of Anthropology and Human Genetics Thesis, 75 pages,8 supplements, 2012 This thesis is concerned to neuroectodermal tumours that make a major group of infant tumour diseases. Genetic material gained from patients with neuroectodermal tumours was examined using comparative genomic hybridization (CGH) and interphasic fluorescence in situ hybridization (I-FISH). The aim of this Thesis is to prove chromosomal changes and to create the whole genetic profile. According to these profiles can be determined tumourgenetic cascade or specific genetic changes that lead to malignant tumours. In some cases (f.e. neuroblastoms) the genetic profile helps us to determine a subtype of disease and it's biological behaviour. Keywords: tumour diseases, neuroblastoma, CNS tumours, pheochromocytoma, Ewing's sarcoma, neuroectodermal tumour, comparative genomic hybridization, interphase fluorescence in situ hybridization

Koštani tumori su rijetki posebno u djece, no u dječjoj dobi ovi tumori su najčešće zloćudni. Tijekom posljednjih tridesestak godina došlo je do velikog napretka u poznavanju i liječenju sarkoma u djelce što je poboljšalo preživljenje i kakvoću života oboljelih. Uloga patologa u zbrinjavanju bolesnika s koštanim promjenama je kompleksnija nego u ostalim područjima. U ovom su pregledu dane najvažnije značajke pristupa morfološkoj dijagnostici koštanih tumora uz osvrt na specifičnosti u dječjoj populaciji.

Ewingov sarkom i primitivni neuroektodermalni tumor su maligni tumori kosti i mekih tkiva koji se najčešće pojavljuju u dječjoj dobi i u adolescenata. Recipročna translokacija EWS FLI 1 gena koja rezultira fuzijskim proteinom je visoko specifični marker za ovu grupu tumora. Zbog toga smo odlučili analizirati translokaciju EWS FLI 1 i najčešće tipove, tip 1 i tip2 u tumorskom tkivu, krvi i koštanoj srži. U razdoblju od 2003 - 2008 godine navedeni uzorci 24 ispitanika, su bili analizirani metodom reverzne transkriptaze polimeraza lančane reakcije (RT-PCR). Naime, tip 2 se nije pokazao kao prognostički marker lošijeg ishoda bolesti, kako se očekivalo, a rezultat pozitivne translokacije EWS-FLI 1 u koštanoj srži bio je pouzdaniji od rezultata u perifernoj krvi, u praćenju ispitanika, kao i u detekciji minimalne rezidulane bolesti i moguće ciljne terapije.

Desmoplastic small round cell tumor (DSRCT) is a rare malignant neoplasm of adolescent males with predilection for involvement of the peritoneum. It is an aggressive neoplasm with a poor prognosis. Herein we present a case of a 23 year old man with DSRCT which, at the beginning, has been a diagnostic and clinical problem., Dezmoplastični okrugli malostanični tumor ( DSRCT) je rijedak maligni tumor koji se pojavljuje u mla|ih muškaraca i najčešće zahvaća peritonej. To je agresivan tumor s lošom prognozom. Ovdje ćemo prikazati slučaj 23-godišnjeg muškarca s dijagnosticiranim DSRCT, koji je u početku predstavljao dijagnostički i klinički problem.

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