Therapeutic potential of epigenetic active substances in neoplastic disease treatment

Neoplastične bolesti drugi su najčešći uzrok smrti u svijetu, odmah nakon kardiovaskularnih bolesti. Visoka smrtnost uvjetovana je, pored ostalog, nedovoljno uspješnom konvencionalnom antitumorskom terapijom. Stoga se i dalje ulažu veliki napori kako bi se pronašli novi terapijski pristupi, posebice u okviru kemoterapije. Mnogi znanstvenici smatraju da su budućnost onkološke terapije lijekovi koji mogu modulirati ekspresiju gena poput epigenetički aktivnih tvari. Taj se novi pristup pokazao uspješnim u liječenju hematoloških zloćudnih bolesti, dočim rezultati niza istraživanja ukazuju na mogućnosti kliničke uporabe epigenetičke terapije u pacijenata sa solidnim tumorima, bilo samostalno bilo u kombinaciji s konvencionalnom terapijom. Međutim, još uvijek postoje prepreke za široku primjenu epigenetičkih lijekova. Uglavnom su to potencijalne nuspojave posebice zloćudna transformacija de novo. Pored toga, za pojedine epigenetički aktivne tvari s poznatim terapijskim učinkom još uvijek postoji problem farmakološke formulacije lijeka koja bi im omogućila maksimalni terapijski potencijal. Znanstvena istraživanja, pored otkrivanja novih lijekova, upozoravaju na sporedne epigenetičke učinke čitavog niza lijekova koji su odavno u primjeni. Iako ove spoznaje naglašavaju nepoznavanje ili čak ignoriranje sveobuhvatnog učinka pojedinih lijekova, također ukazuju na mogućnost alternativne primjene pojedinih lijekova u onkološkoj terapiji. Pored ispitivanja poznatih lijekova, izniman se napor ulaže u identifikaciju epigenetički aktivnih tvari prisutnih u svakodnevnoj prehrani kao vrijednim izvorom prirodnih supstanci s potencijalnim protutumorskim djelovanjem i potencijalom primjene u onkološkoj prevenciji i terapiji budućnosti.Neoplastic diseases are the second leading cause of death in the world, following cardiovascular diseases. A high mortality rate is the result of, among other things,insufficiently effective conventional cancer treatment. Therefore, great effort is still being put into finding new therapeutical approaches, especially in the domain of chemotherapy. Many scientists regard drugs which can modulate gene expression, such as epigenetic active substances, as future of oncologic therapy. The new approach was found to be successful in treating hematological malignancies, while the results of numerous research point to the possibility of clinical application of epigenetic therapy, both inidividually and in combination with conventional therapy. However,there are still obstacles to wide utilization of epigenetic drugs. Mostly, those are potential side effects of epigenetic drugs, especially de novo malignant tranformation. Furthermore, there are still difficulties with reaching pharmacological formulation of some epigenetic active substances with known therapeutic effect, which is vital in order for the drug to reach its full therapeutic potential. In addition to discovering new medicines, scientific research often warn about the secondary epigenetic effects of a number of medicines that have long been in use. Although these insights emphasize the fact that the overall effect of some medications is not known, or is sometimes even ignored, they also point to the possibility of an alternative application of some medicines in oncologic therapy. Along with testing new medicines, a significant effort is put into identifying epigenetic active substances present in daily diet as a significant source of natural substances with potential antitumor impact and a great potential for application in oncologic prevention and therapy of the future

Therapeutic potential of epigenetic active substances in neoplastic disease treatment

Neoplastične bolesti drugi su najčešći uzrok smrti u svijetu, odmah nakon kardiovaskularnih bolesti. Visoka smrtnost uvjetovana je, pored ostalog, nedovoljno uspješnom konvencionalnom antitumorskom terapijom. Stoga se i dalje ulažu veliki napori kako bi se pronašli novi terapijski pristupi, posebice u okviru kemoterapije. Mnogi znanstvenici smatraju da su budućnost onkološke terapije lijekovi koji mogu modulirati ekspresiju gena poput epigenetički aktivnih tvari. Taj se novi pristup pokazao uspješnim u liječenju hematoloških zloćudnih bolesti, dočim rezultati niza istraživanja ukazuju na mogućnosti kliničke uporabe epigenetičke terapije u pacijenata sa solidnim tumorima, bilo samostalno bilo u kombinaciji s konvencionalnom terapijom. Međutim, još uvijek postoje prepreke za široku primjenu epigenetičkih lijekova. Uglavnom su to potencijalne nuspojave posebice zloćudna transformacija de novo. Pored toga, za pojedine epigenetički aktivne tvari s poznatim terapijskim učinkom još uvijek postoji problem farmakološke formulacije lijeka koja bi im omogućila maksimalni terapijski potencijal. Znanstvena istraživanja, pored otkrivanja novih lijekova, upozoravaju na sporedne epigenetičke učinke čitavog niza lijekova koji su odavno u primjeni. Iako ove spoznaje naglašavaju nepoznavanje ili čak ignoriranje sveobuhvatnog učinka pojedinih lijekova, također ukazuju na mogućnost alternativne primjene pojedinih lijekova u onkološkoj terapiji. Pored ispitivanja poznatih lijekova, izniman se napor ulaže u identifikaciju epigenetički aktivnih tvari prisutnih u svakodnevnoj prehrani kao vrijednim izvorom prirodnih supstanci s potencijalnim protutumorskim djelovanjem i potencijalom primjene u onkološkoj prevenciji i terapiji budućnosti.Neoplastic diseases are the second leading cause of death in the world, following cardiovascular diseases. A high mortality rate is the result of, among other things,insufficiently effective conventional cancer treatment. Therefore, great effort is still being put into finding new therapeutical approaches, especially in the domain of chemotherapy. Many scientists regard drugs which can modulate gene expression, such as epigenetic active substances, as future of oncologic therapy. The new approach was found to be successful in treating hematological malignancies, while the results of numerous research point to the possibility of clinical application of epigenetic therapy, both inidividually and in combination with conventional therapy. However,there are still obstacles to wide utilization of epigenetic drugs. Mostly, those are potential side effects of epigenetic drugs, especially de novo malignant tranformation. Furthermore, there are still difficulties with reaching pharmacological formulation of some epigenetic active substances with known therapeutic effect, which is vital in order for the drug to reach its full therapeutic potential. In addition to discovering new medicines, scientific research often warn about the secondary epigenetic effects of a number of medicines that have long been in use. Although these insights emphasize the fact that the overall effect of some medications is not known, or is sometimes even ignored, they also point to the possibility of an alternative application of some medicines in oncologic therapy. Along with testing new medicines, a significant effort is put into identifying epigenetic active substances present in daily diet as a significant source of natural substances with potential antitumor impact and a great potential for application in oncologic prevention and therapy of the future

Myelodysplastic syndromes and autoimmune phenomena – case report and literature overview

SAŽETAK Mijelodisplastični sindromi heterogena su skupina poremećaja hematopoeze karakterizirana displazijom jedne ili više linija hematopoeze u koštanoj srži, te inefektivnom hematopoezom i citopenijama u perifernoj krvi. Većinom se javljaju u pacijenata starije životne dobi i nose rizik za transformaciju u akutnu mijeloičnu leukemiju. Temelj tradicionalnog shvaćanja patogeneze ovog poremećaja jesu stečene genetske abnormalnosti krvotvorne matične stanice, uslijed starenja ili određenih noksi. Međutim, sve više kliničkih opservacija i imunoloških studija mijelodisplastične sindrome povezuje i s kroničnom upalom. Prikazujemo bolesnicu u dobi od 57 godina, kod koje je inicijalno postavljena dijagnoza autoimunosne bolesti, nedeterminirane kolagenoze, koja je liječena od strane nadležnog imunologa/reumatologa. Postupno se u laboratorijskim nalazima uočava pancitopenija te se hematološkom obradom postavlja dijagnoza mijelodisplastičnog sindroma s viškom blasta tipa 1, visokog rizika po IPSS-u (engl. kratica za International prognostic scoring system). Tijek liječenja ove bolesnice kompliciran je mnogobrojnim infektivnim komplikacijama, što govori u prilog poremećene funkcije imunosnog sustava, čak i prije same pojave autoimunosnih fenomena i mijelodisplazije. Epidemiološke studije pokazuju veću incidenciju autoimunosnih fenomena i bolesti u populaciji bolesnika s mijelodisplastičnim sindromom, u čak 10 – 20% bolesnika. Također pojava autoimunosnih manifestacija može prethoditi dijagnozi mijelodisplastičnog sindroma, i obratno. Pretkliničke studije nam daju uvid u podležeće imunološke patofiziološke mehanizme, pokazujući prisutnost imunosne deregulacije u ovim dvjema, naizgled vrlo različitim, skupinama bolesti. S obzirom na sve više podataka na kliničkoj i pretkliničkoj razini o povezanosti mijelodisplastičnih sindroma i autoimunosnih poremećaja, svakako je potrebno uzeti u obzir mogućnost istovremene pojave obiju bolesti, radi praćenja i liječenja bolesnika.SUMMARY Myelodysplastic syndromes are a heterogeneous group of hematopoiesis disorders, characterized by dysplastic changes in one or more hematopoietic lineages, ineffective hematopoiesis, and peripheral blood cytopenias. They occur mostly in elderly patients and carry a significant risk of acute myeloid leukemia transformation. Acquired genetic abnormalities are the foundation of traditional pathogenesis understanding, however, a growing body of evidence links myelodysplastic syndromes to chronic inflammation. Here we present a case of a female patient with autoimmune phenomena and myelodysplasia, as well as a literature overview corroborating the inflammatory pathogenesis of myelodysplastic syndromes. We present a case of a 57-year-old female patient, initially diagnosed with an autoimmune disease, undifferentiated connective tissue disease, continuously assessed and treated by a clinical immunologist-rheumatologist. Peripheral blood cytopenias occurred and worsened gradually, leading to the diagnosis of myelodysplastic syndrome with excess blasts, type 1, high-risk disease. The disease course of this patient was complicated by numerous infectious complications, occurring even before autoimmune phenomena and myelodysplasia. Epidemiological studies show a greater incidence of autoimmune phenomena and diseases in the population of patients with diagnosed myelodysplastic syndromes, even up to 10–20%. Also, the occurrence of autoimmune manifestations can precede myelodysplastic syndromes diagnosis, and vice-versa. Preclinical studies give insight into underlying immunological pathophysiological mechanisms, implying the presence of immune dysregulation in these two, seemingly very different, disease groups. Given the growing body of clinical and preclinical data on the association of myelodysplastic syndromes and autoimmune phenomena, it is necessary to consider the possibility of a joint occurrence in everyday clinical practice, which can have significant implications for patient management and new therapeutic options development

Therapeutic potential of epigenetic active substances in neoplastic disease treatment

Neoplastične bolesti drugi su najčešći uzrok smrti u svijetu, odmah nakon kardiovaskularnih bolesti. Visoka smrtnost uvjetovana je, pored ostalog, nedovoljno uspješnom konvencionalnom antitumorskom terapijom. Stoga se i dalje ulažu veliki napori kako bi se pronašli novi terapijski pristupi, posebice u okviru kemoterapije. Mnogi znanstvenici smatraju da su budućnost onkološke terapije lijekovi koji mogu modulirati ekspresiju gena poput epigenetički aktivnih tvari. Taj se novi pristup pokazao uspješnim u liječenju hematoloških zloćudnih bolesti, dočim rezultati niza istraživanja ukazuju na mogućnosti kliničke uporabe epigenetičke terapije u pacijenata sa solidnim tumorima, bilo samostalno bilo u kombinaciji s konvencionalnom terapijom. Međutim, još uvijek postoje prepreke za široku primjenu epigenetičkih lijekova. Uglavnom su to potencijalne nuspojave posebice zloćudna transformacija de novo. Pored toga, za pojedine epigenetički aktivne tvari s poznatim terapijskim učinkom još uvijek postoji problem farmakološke formulacije lijeka koja bi im omogućila maksimalni terapijski potencijal. Znanstvena istraživanja, pored otkrivanja novih lijekova, upozoravaju na sporedne epigenetičke učinke čitavog niza lijekova koji su odavno u primjeni. Iako ove spoznaje naglašavaju nepoznavanje ili čak ignoriranje sveobuhvatnog učinka pojedinih lijekova, također ukazuju na mogućnost alternativne primjene pojedinih lijekova u onkološkoj terapiji. Pored ispitivanja poznatih lijekova, izniman se napor ulaže u identifikaciju epigenetički aktivnih tvari prisutnih u svakodnevnoj prehrani kao vrijednim izvorom prirodnih supstanci s potencijalnim protutumorskim djelovanjem i potencijalom primjene u onkološkoj prevenciji i terapiji budućnosti.Neoplastic diseases are the second leading cause of death in the world, following cardiovascular diseases. A high mortality rate is the result of, among other things,insufficiently effective conventional cancer treatment. Therefore, great effort is still being put into finding new therapeutical approaches, especially in the domain of chemotherapy. Many scientists regard drugs which can modulate gene expression, such as epigenetic active substances, as future of oncologic therapy. The new approach was found to be successful in treating hematological malignancies, while the results of numerous research point to the possibility of clinical application of epigenetic therapy, both inidividually and in combination with conventional therapy. However,there are still obstacles to wide utilization of epigenetic drugs. Mostly, those are potential side effects of epigenetic drugs, especially de novo malignant tranformation. Furthermore, there are still difficulties with reaching pharmacological formulation of some epigenetic active substances with known therapeutic effect, which is vital in order for the drug to reach its full therapeutic potential. In addition to discovering new medicines, scientific research often warn about the secondary epigenetic effects of a number of medicines that have long been in use. Although these insights emphasize the fact that the overall effect of some medications is not known, or is sometimes even ignored, they also point to the possibility of an alternative application of some medicines in oncologic therapy. Along with testing new medicines, a significant effort is put into identifying epigenetic active substances present in daily diet as a significant source of natural substances with potential antitumor impact and a great potential for application in oncologic prevention and therapy of the future

Treatment-Related Risk Factors for Adverse Outcomes of COVID-19 in Patients Treated for Lymphoid Malignancies in the Pre-Omicron Era—A Study of KroHem, the Croatian Group for Hematologic Diseases

Patients with lymphoid malignancies are at increased risk of death or prolonged infection due to COVID-19. Data on the influence of different antineoplastic treatment modalities on outcomes are conflicting. Anti-CD20 monoclonal antibodies increase the risk of prolonged infection. It is unclear whether this risk is affected by the choice of the antibody (rituximab vs. obinutuzumab). To elucidate the role of antineoplastic therapy on COVID-19 outcomes, KroHem collected data on patients with lymphoid malignancies diagnosed with COVID-19 between October 2020 and April 2021. A total of 314 patients were identified, 75 untreated, 61 off treatment and 178 on treatment. The mortality rate in untreated and off-treatment patients was 15% and 16%; 9% and 10% had prolonged infection. In the on-treatment group, 3% were still prolonged positive at time of data collection, 62% recovered and 35% died; 42% had prolonged infection. Disease type, use of anti-CD20 monoclonal antibodies, prior autologous stem-cell transplantation (ASCT) and line of treatment did not significantly affect mortality. Mortality was higher in older patients (p = 0.0078) and those treated with purine analogues (p = 0.012). Prolonged COVID-19 was significantly more frequent in patients treated with anti-CD20 monoclonal antibodies (p = 0.012), especially obinutuzumab, and purine analogues (p = 0.012). Age, prior ASCT and treatment line did not significantly affect risk of prolonged infection. These data suggest that increased age and use of purine analogues are main risk factors for increased mortality of COVID-19 in patients with lymphoid malignancies. Obinutuzumab further increases the risk of prolonged disease, but not of death, in comparison to rituximab. Epidemiological considerations should be taken into account when choosing the appropriate antineoplastic therapy for patients with lymphoid malignancies