IMUNOHISTOKEMIJSKA IZRAŽENOST PROTEINA BORIS U TUMORIMA ZAMETNIH STANICA TESTISA

Brother of the Regulator of Imprinted Sites (BORIS) has a role in intracellular signalization and is important in epigenetic mechanism control, such as methylation/demethylation of DNA and histones. BORIS may deregulate some tumor suppressor genes. Immunohistochemical expression of BORIS was found in different tumors, some of them showing correlation with poor prognosis. The aim of this study was to determine immunohistochemical expression of BORIS in pure seminomas and different components of testicular mixed germ cell tumors (MGCT). In this study, immunohistochemical expression of BORIS in testicular germ cell tumors (TGCT) was analyzed. Staining intensity and percentage of positive staining cells were used to evaluate the level of expression. Tumor samples from 44 patients were analyzed; 26 pure seminomas and 18 MGCT. In MGCTs, seminoma component was found in 4, yolk sac in 7, teratoma in 11 and embryonal carcinoma in 13 samples. Expression of BORIS was strong in 80.8% of seminoma cases and in 76.9% of embryonal carcinoma component, 71.4% of yolk sac, 63.6% of teratoma component and 25% of seminomatous component of MGCT. In MGCT, positive correlation was found between BORIS expression in teratomatous component and presence of yolk sac component (BORIS (engl. Brother of the Regulator of Imprinted Sites) sudjeluje u unutarstaničnoj signalizaciji i kontrolira epigenetske mehanizme kao što su metilacija/demetilacija DNK i histona. Aktivacija BORIS-a dovodi do poremećaja određenih tumorskih supresora. Imunohistokemijska izraženost BORIS-a utvrđena je u različitim tumorima. U nekim tumorima nađena je korelacija s lošijom prognozom. Cilj ovoga istraživanja bio je utvrditi imunohistokemijsku izraženost BORIS-a u čistim seminomima i različitim komponentama miješanih tumora zametnih stanica testisa (engl. mixed germ cell tumors, MGCT). Materijal i metode: Analizirana je imunohistokemijska izraženost BORIS-a u tumorima zametnih stanica testisa (engl. testicular germ cell tumors, TGCT), a intenzitet bojenja i postotak reaktivnih stanica korišten je za evaluaciju razine ekspresije. Analizirani su uzorci tumora 44 bolesnika; 26 čistih seminoma i 18 MGCT. Kod MGCT-a komponenta seminoma nađena je u 4, yolk sac-a u 7, teratoma u 11 te embrionalnog karcinoma u 13 uzoraka tumora. Rezultati: Imunohistokemijska izraženost bila je jaka kod 80,8% čistih seminoma te kod 76,9% komponente embrionalnog karcinoma, 71,4% yolk sac-a, 63,6% teratoma i 25% seminomske komponente MGCT-a. Dobivena je pozitivna korelacija izraženosti BORIS-a teratomske komponente i prisutnosti komponente yolc sac

DIAGNOSTIC APPROACH AND TREATMENT OF IMMUNE THROMBOCYTOPENIA IN ADULTS

Cilj ovog preglednog rada jest prikazati najnovija saznanja povezana s definicijom imune trombocitopenije u odraslih (ITP), pato¬fiziologijom bolesti, dijagnostičkim i terapijskim postupnikom. ITP je karakterizirana brojem trombocita manjim od 100x109/L te kroničnim tijekom u odsustvu neke druge bolesti koja bi mogla dovesti do smanjenja broja trombocita. Patogeneza ove bolesti temelji se na dva ključna mehanizma: destrukciji kompleksa trombocit-protutijelo i inhibiciji sazrijevanja prekursora trombocita. Dijagnoza ITP-a temelji se na isključenju drugih mogućih uzroka trombocitopenije. Odluka o početku liječenja donosi se individu¬alno, prema broju trombocita (manji od 30x109/L) te rizičnim faktorima krvarenja. Okosnica prve linije terapije su kortikosteroidi. U slučaju izostanka uspjeha liječenja kortikosteroidima preporuča se primjena intravenskih imunoglobulina s brzim, ali često i kratkotrajnim odgovorom. U drugoj liniji terapije su kirurški i farmakološki pristupi. Kirurški pristup, splenektomija, karakteriziran je vrlo visokom stopom dugotrajnog odgovora. Farmakološki pristup danas znači ili primjenu agonista trombopoetina (TPO) ili rituksimaba. Agonisti TPO pokazali su se kao lijekovi s visokom stopom odgovora, no potreba za kontinuiranim davanjem i cijena donekle ograničavaju njihovu upotrebu. Iako se rituksimab često koristi u drugoj liniji liječenja, za sada ne postoje randomizirana klinička istraživanja koja bi poduprla njegovu primjenu. U bolesnika s refraktornim ITP-om liječenje je potrebno samo u bolesni¬ka s brojem trombocita manjim od 30x109/L te krvarenjem. Terapija je primjena agonista TPO, polikemoterapija, alemtuzumab te transplantacija perifernih matičnih stanica.The aim of this review is to provide the Croatian medical public with novel insights into the definition, pathogenesis, diagnostic algorithms and treatment approaches to immune thrombocytopenia (ITP) in adults. Recently, primary ITP has been uniformly de¬fined as an autoimmune disorder characterized by an isolated platelet count lower than 100x109/L without preexisting disease or conditions, which could lead to thrombocytopenia. The recognition of primary and secondary ITP is important because they require different treatment strategies. In secondary ITP, therapeutic approach oriented towards the underlying disorder. Unlike childhood onset ITP, which is a self-limited condition with high rates of spontaneous remissions, adulthood onset ITP usually has chronic course. Previously, the pathogenesis of ITP was considered to be immune mediated destruction of platelets in liver and spleen, while recent findings have shown a novel pathophysiological pathway based on the inhibition of thrombopoiesis, leading to novel treatment approaches. The diagnosis of ITP is based on exclusion of the possible underlying causes of thrombocytope¬nia and consists of simple diagnostic procedures. The decision to treat ITP should be based individually: platelets count (lower than 30x109/L), various bleeding risk factors and patient’s preference. The use of corticosteroids is the mainstay of first line ther¬apy. Two most commonly used corticosteroids are prednisone and dexamethasone. Prednisone is administered continuously, while dexamethasone is applied in cycles. Due to the lack of randomized clinical trials, it is not possible to recommend certain class of corticosteroid therapy. Another two agents used as first line therapy in case of corticosteroid refractoriness or the need of rapid platelet elevation, are intravenous immunoglobulins and anti-D immunoglobulin (anti-D is not approved in Europe). They are characterized by rapid onset of platelet recovery and low long-term remission rates. Until recently, splenectomy, with adequate infectious and thromboprophylaxis, was the therapy of choice in patients who did not respond to corticosteroids due to high long-term remission rates and low relapse rates. This procedure can be offered to a younger patient without significant comorbidities after the first year of ITP duration. With advances in the understanding of ITP pathogenesis, a new class of drug has been established: thrombopoietin agonists (TPO). Eltrombopag and romiplostim, the TPO agonists currently approved for the management of ITP in patients who failed the first line therapy and are not suitable for splenectomy, are only two agents that have shown benefits in large clinical randomized trials. They are characterized by a high response rate and appropriate safety profile, but the need for continuous use, a high relapse rate after therapy withdrawal, and price limit their use in everyday practice. TPO agonists represent an appropriate treatment choice in patients who have relapse after splenectomy. Another agent, often used in everyday clinical practice, is rituximab with high response and relapse rates. Its use is based on small studies, and due to the lack of clinical randomized controlled trials, rituximab is not approved by the lead¬ing medical agencies for this indication. As shown in this review article, our understanding and therapy for ITP has improved, but further research is needed to implement evidence-based therapy in clinical practice

Quality of life in Croatian Homeland war (1991-1995) veterans who suffer from post-traumatic stress disorder and chronic pain

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to investigate the quality of life in Croatian homeland war veterans who suffer from post-traumatic stress disorder and chronic low back pain (LBP).</p> <p>Methods</p> <p>A total of 369 participants were included, classified in four study groups: those with post-traumatic stress disorder (PTSD; N = 59), those with both PTSD and lower back pain (PTSD+LBP; N = 80), those with isolated LBP (N = 95) and controls (N = 135). WHOQOL-BREF survey was used in the estimation of quality of life. The data were analysed using statistical methods and hierarchical clustering.</p> <p>Results</p> <p>The results indicated a general pattern of lowering quality of life in participants with both psychological (PTSD) and physical (LBP) burden. The average overall quality of life was 2.82 ± 1.14 for the PTSD+LBP group, 3.29 ± 1.28 for the PTSD group, 4.04 ± 1.25 for the LBP group and 4.48 ± 0.80 for the controls (notably, all the pair-wise comparisons were significantly different at the level of P < 0.001, except for the pair LBP-controls, which was insignificant). This result indicated that quality of life was reduced for 9.9% in patients with LBP, 26.6% in patients with PTSD and 37.1% in PTSD+LBP, suggesting strong synergistic effect of PTSD and LBP. The analysis also identified several clusters of participants with different pattern of quality of life related outcomes, reflecting the complex nature of this indicator.</p> <p>Conclusions</p> <p>The results of this study reiterate strong impact of PTSD on quality of life, which is additionally reduced if the patient also suffers from LBP. PTSD remains a substantial problem in Croatia, nearly two decades after the beginning of the 1991-1996 Homeland war.</p

Praćenje bolesnika s klasičnim Hodgkinovim limfomom nakon liječenja – suvremena saznanja i nedoumice. Pregled literature [Follow-up of patients with classical Hodgin lymphoma after treatment - novel evidence and dilemmas. Literature review]

In this review we present current evidence for the follow-up of patients treated for classical Hodgkin lymphoma (HL). Nowadays introduction of novel therapies enabled successful treatment in most patients with classical HL in first remission with 5-year overall survival rate estimation of 80%. We have performed extensive literature search on the methodological approach to detection of relapse. Evidence regarding imaging clinical methods in detecting relapse on serial computed tomography and/or positron emission tomography scans is scarce. These imaging modalities are associated with considerable economic cost, unnecessary exposure to radiation and patients' stress. Furthermore, the detection of asymptomatic relapse does not seem to be associated with improved outcome in this patient group. Available data on this subject indicate that standard imaging methods, such as ultrasound, and judicious clinical examination in detecting of relapse should be the basis of HL patient follow-up. Late toxicity due to various modalities of treatment represents serious morbidity in HL. They vary from secondary solid cancers and hematologic neoplasms, associated with poor outcome, to benign disorders (fertility issues, thyroid dysfunction, cardiovascular and lung disorders). Current data on the incidence, prevalence and etiological factors do not yet provide evidence on appropriate screening methods. Most recommendations in various guidelines are associated with low level of evidence (grade IV). We, therefore, propose individually-tailored screening methods for each patient based on the modality of treatment received

The Connection between Coping Mechanisms, Depression, Anxiety and Fatigue in Multiple Sclerosis

The aim of this study was to show how different coping mechanisms influence the prevalence of anxiety and depression in people suffering from multiple sclerosis. We also aimed at showing how different coping mechanisms contribute to subjective prosperity of the patients emphasizing general health, cognitive functions and fatigue. A questionnaire was given to attendants of the VI Symposium of Patients Suffering From Multiple Sclerosis. Scales were taken from Multiple Sclerosis Quality of Life Inventory (MSQLI), Hospital Anxiety and Depression Scale (HADS) and COPE inventory. A total of 68 anonymous questionnaires were handed in. A total of 57.9% of examinees had symptoms of depression, and 63.2% suffered from symptoms of anxiety. However, majority of the examinees suffered from the combination of these entities. Hypothesis about impact of various coping factors on depression, anxiety, fatigue was validated except an impact on physical state was not proven significant. Predictors improving these states were positive reinterpretation, social emotional support and humor, Predictors worsening these states were planning, acceptance, focus on emotional ventilation and denial. Psychiatric comorbidity has a high prevalence in people suffering from MS. Different coping mechanisms can help in improvement of everyday life

ARE WE ENTERING CHEMO-FREE ERA IN CHRONIC LYMPHOCYTIC LEUKEMIA? THE ROLE OF IBRUTINIB AND VENETOCLAX AND LESSONS LEARNT FROM IDELALISIB

Glavni cilj ovog preglednog rada je predstaviti novu klasu lijekova u kroničnoj limfocitnoj leukemiji (KLL), najčešćoj leukemiji odrasle dobi, inhibitore staničnog signaliziranja B receptora (BCR). KLL se klasično liječila imunokemoterapijom, no pojedini bolesnici (poodmakla životna dob, nepovoljni biološki faktori) imali su lošu prognozu. S boljim razumijevanjem patogeneze unutarstaničnih putova pojavila se mogućnost selektivne inhibicije i ciljane terapije u KLL. Prvi lijek u svojoj klasi ibrutinib, inhibitor bruton kinaze, pokazao se superiornim u fazama III kliničkih pokusa te je eliminirao negativne prognostičke faktore u liječenju KLL, pogotovo del (17p), s adekvatnim profi lom toksičnosti što su prepoznale regulatorne agencije. Drugi BCR inhibitori idelalisib i venetoklaks su iznimno aktivni u relapsnom okruženju, no idelalisib se pokazao neprihvatljivo toksičnim u prvoj liniji liječenja što nam može poslužiti kao lekcija u dizajnu kliničkih pokusa s ovim lijekovima. Usprkos učinkovitosti, potreban je dodatni napredak u ovom području koji se nalazi u kombinacijama s imunoterapijom ili imunokemoterapijom, te mogućoj međusobnoj kombinaciji kako bismo dodatno poboljšali ishode. No, najveća zapreka BCR inhibitorima da uđu u široku praksu je njihova cijena i utjecaj na zdravstveni sustav što nažalost ograničuje našu mogućnost da liječimo bolesnike s KLL u eri bez kemoterapije.The main aim of this review is to present a novel class of agents, the inhibitors of B cell receptor (BCR) signaling pathway, used in the treatment of chronic lymphocytic leukemia (CLL) as the most common leukemia in the Western world. Traditionally, CLL was treated with immunochemotherapy, but certain subpupulations (elderly, biological prognostic factors) had poor outcome. With advances in our understanding the pathogenesis of intracellular pathways, the possibility of selective inhibition and targeted therapy in CLL has arisen. The fi rst agent in the class of BCR inhibitors, ibrutinib, a Bruton kinase inhibitor, has been shown superior in phase III clinical trials eliminating negative prognostic factors such as del(17p), with adequate toxicity profi le, which was recognized by the respective regulatory agencies. Other BCR inhibitors idelalisib and venetoclax are extremely active in relapsed setting, but unfortunately, idelalisib combinations in fi rst line clinical trials resulted in unacceptable toxicity, which is a cautionary tale on designing trials. Despite their effi cacy, we are only at the beginning to improve them by combination with monoclonal antibodies, immunochemotherapy, or between each other to improve outcomes of CLL treatment even further. However, the main obstacle to chemo-free era in CLL is their price resulting in limited access to these agents and inequity in the modern treatment of CLL

FOLLOW-UP OF PATIENTS WITH CLASSICAL HODGIN LYMPHOMA AFTER TREATMENT – NOVEL EVIDENCE AND DILEMMAS. LITERATURE REVIEW

Cilj je ovoga preglednog rada prikazati suvremeno stajalište struke, ali i prijepore u svezi s medicinskom skrbi za bolesnike s klasičnim Hodgkinovim limfomom u prvoj remisiji. Većina bolesnika s klasičnim Hodgkinovim limfomom izliječena je prvom linijom terapije i u nastavku je važan medicinski pristup radi otkrivanja mogućeg relapsa. Pregledom literature nismo našli jednoznačne smjernice za rutinsko praćenje bolesnika slikovnim metodama, tj. kompjutoriziranom tomografijom ili pozitronskom emisijskom tomografijom. Prema dokazima u literaturi, otkriće asimptomatskog relapsa nije povezano s poboljšanim ishodom liječenja. Za sada se može smatrati da su standardne kliničke i radiološke metode ­dostatne za praćenje ovih bolesnika. Kasne toksičnosti uzrokovane mnogim lijekovima i zračenjem znatno pridonose morbiditetu bolesnika. To uključuje pojavu sekundarnih solidnih malignoma (ponajprije karcinoma pluća i dojke) i hematoloških ­neoplazma koštane srži te pojavu benignih toksičnosti kao što su poremećaji funkcije štitnjače, fertiliteta i kardiovaskularnih bolesti. Usprkos obilju literature i smjernica za praćenje ovih bolesnika nakon završetka liječenja, za sada ne postoje rezultati prospektivnih istraživanja koji bi pružili temelj zasnovan na dokazima za nove smjernice i preporuke. Smatramo da otkrivanje kasne toksičnosti treba biti prilagođeno pojedinačnom bolesniku, sukladno specifičnom liječenju i kasnijem utjecaju te toksičnosti na mogući morbiditet u ovih bolesnika.In this review we present current evidence for the follow-up of patients treated for classical Hodgkin lymphoma (HL). Nowadays introduction of novel therapies enabled successful treatment in most patients with classical HL in first remission with 5-year overall survival rate estimation of 80%. We have performed extensive literature search on the ­methodological approach to detection of relapse. Evidence regarding imaging clinical methods in detecting relapse on ­serial computed tomography and/or positron emission tomography scans is scarce. These imaging modalities are associated with considerable economic cost, unnecessary exposure to radiation and patients’ stress. Furthermore, the detection of ­asymptomatic relapse does not seem to be associated with improved outcome in this patient group. Available data on this subject indicate that standard imaging methods, such as ultrasound, and judicious clinical examination in detecting of ­relapse should be the basis of HL patient follow-up. Late toxicity due to various modalities of treatment represents serious morbidity in HL. They vary from secondary solid cancers and hematologic neoplasms, associated with poor outcome, to benign disorders (fertility issues, thyroid dysfunction, cardiovascular and lung disorders). Current data on the incidence, prevalence and etiological factors do not yet provide evidence on appropriate screening methods. Most recommendations in various guidelines are associated with low level of evidence (grade IV). We, therefore, propose individually-tailored screening methods for each patient based on the modality of treatment received

ARE WE ENTERING CHEMO-FREE ERA IN CHRONIC LYMPHOCYTIC LEUKEMIA? THE ROLE OF IBRUTINIB AND VENETOCLAX AND LESSONS LEARNT FROM IDELALISIB

Glavni cilj ovog preglednog rada je predstaviti novu klasu lijekova u kroničnoj limfocitnoj leukemiji (KLL), najčešćoj leukemiji odrasle dobi, inhibitore staničnog signaliziranja B receptora (BCR). KLL se klasično liječila imunokemoterapijom, no pojedini bolesnici (poodmakla životna dob, nepovoljni biološki faktori) imali su lošu prognozu. S boljim razumijevanjem patogeneze unutarstaničnih putova pojavila se mogućnost selektivne inhibicije i ciljane terapije u KLL. Prvi lijek u svojoj klasi ibrutinib, inhibitor bruton kinaze, pokazao se superiornim u fazama III kliničkih pokusa te je eliminirao negativne prognostičke faktore u liječenju KLL, pogotovo del (17p), s adekvatnim profi lom toksičnosti što su prepoznale regulatorne agencije. Drugi BCR inhibitori idelalisib i venetoklaks su iznimno aktivni u relapsnom okruženju, no idelalisib se pokazao neprihvatljivo toksičnim u prvoj liniji liječenja što nam može poslužiti kao lekcija u dizajnu kliničkih pokusa s ovim lijekovima. Usprkos učinkovitosti, potreban je dodatni napredak u ovom području koji se nalazi u kombinacijama s imunoterapijom ili imunokemoterapijom, te mogućoj međusobnoj kombinaciji kako bismo dodatno poboljšali ishode. No, najveća zapreka BCR inhibitorima da uđu u široku praksu je njihova cijena i utjecaj na zdravstveni sustav što nažalost ograničuje našu mogućnost da liječimo bolesnike s KLL u eri bez kemoterapije.The main aim of this review is to present a novel class of agents, the inhibitors of B cell receptor (BCR) signaling pathway, used in the treatment of chronic lymphocytic leukemia (CLL) as the most common leukemia in the Western world. Traditionally, CLL was treated with immunochemotherapy, but certain subpupulations (elderly, biological prognostic factors) had poor outcome. With advances in our understanding the pathogenesis of intracellular pathways, the possibility of selective inhibition and targeted therapy in CLL has arisen. The fi rst agent in the class of BCR inhibitors, ibrutinib, a Bruton kinase inhibitor, has been shown superior in phase III clinical trials eliminating negative prognostic factors such as del(17p), with adequate toxicity profi le, which was recognized by the respective regulatory agencies. Other BCR inhibitors idelalisib and venetoclax are extremely active in relapsed setting, but unfortunately, idelalisib combinations in fi rst line clinical trials resulted in unacceptable toxicity, which is a cautionary tale on designing trials. Despite their effi cacy, we are only at the beginning to improve them by combination with monoclonal antibodies, immunochemotherapy, or between each other to improve outcomes of CLL treatment even further. However, the main obstacle to chemo-free era in CLL is their price resulting in limited access to these agents and inequity in the modern treatment of CLL