Thrombophilia and other conditions associated with acute forms of cardiovascular disease

Svjedoci smo sve češćih slučajeva akutnih koronarnih sindroma u mlađih bolesnika, odnosno u bolesnika u kojih ne nalazimo prisutne tipične preinačive ili nepreinačive čimbenike rizika. Većina studija definira mlađe pacijente kao osobe dobi do 45 godina. U takvih se bolesnika obično dijagnosticira akutni infarkt miokarda (AIM) s normalnim koronarnim arterijama, odnosno koronarne arterije ne pokazuju intraluminalne nepravilnosti (stroga definicija) ili arterije s manjim stupnjem stenoze, ali hemodinamski bez značenja (u većini slučajeva < 30% stenoza). Nedavno objavljena studija (APPROACH) utvrdila je učestalost akutnog infarkta miokarda s normalnim koronarnim arterijama u iznosu od 2,8% u bolesnika podvrgnutih koronarnoj angiografiji kod AIM-a. Diferencijalna dijagnoza takvih akutnih koronarnih zbivanja uključuje miokarditis, stres miokardiopatije i sindrom baloniranja vrška lijeve klijetke. Ne postoji jedinstveno objašnjenje nastanka AIM-a s normalnim koronarnim arterijama, ali predloženo je nekoliko mogućih mehanizama: latentna ateroskleroza, vazospazam, tromboza i hiperkoagulabilno stanje, embolizacija i upala. Postoje stečeni i nasljedni sindrom trombofilije. U ovom ćemo prikazu opisati povezanost između nasljednih oblika tromboflije u koje ubrajamo mutaciju faktora V Leiden, mutacija gena za protrombin, manjak proteina C i proteina S, manjak antitrombina i mutacija gena za glikoprotein inhibitor plazminogen aktivatora-1 s akutnim oblicima srčanožilnih bolesti.We are witnessing increasingly frequent cases of acute coronary syndrome in younger patients, or in patients who did not present the typical risk factors. Most studies define younger patients as persons under 45 years of age. Such patients are typically diagnosed with acute myocardial infarction (AMI) with normal coronary arteries, i.e. the coronary artery does not show intraluminal anomalies (strict definition) or with a smaller artery stenosis but hemodynamically insignificant (in most cases <30% stenosis). A recently published study (APPROACH) determined the prevalence of AMI with normal coronary arteries was 2.8% in patients who underwent coronary angiography for AMI. Differential diagnosis of such acute coronary events includes myocarditis, stress cardiomyopathy, and Takotsubo syndrome. There is no single explanation for the origin of AMI with normal coronary arteries, but a few possible mechanisms have been suggested: latent atherosclerosis, vasospasm, thrombosis and hypercoagulability, embolization, and inflammation. We differentiate between acquired and inherited thrombophilia syndrome. In this report, we will describe a link between hereditary forms of trombophilia (a mutation of factor V Leiden, prothrombin gene mutation, deficiency of protein C and protein S, antithrombin deficiency, and mutations in the gene for glycoprotein plasminogen activator inhibitor-1) and acute forms of cardiovascular disease

Bendamustin: stari lijek u novoj eri za bolesnike s ne-Hodgkinovim limfomima i kroničnom limfocitnom leukemijom

The aim of this review is to present data on bendamustine, a non-cross resistant alkylating agent, alone or in combination for treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Bendamustine is currently approved for rituximab-resistant indolent NHL and CLL in patients not fit for conventional chemotherapy. Recent studies have shown superiority of bendamustine combination with rituximab (B-R) in first line treatment of indolent NHLs and mantle cell lymphoma, suggesting a shift of the standard of care in this setting. B-R regimen has also shown efficacy in relapsed setting suggesting the possible treatment option for patients failing conventional chemotherapy. In rituximab-resistant NHL, the recent GADOLIN study exploring the addition of obinutuzumab to bendamustine has yielded impressive result changing the standard of care in this hard-to-treat population. Concerning CLL, despite inferiority to the standard of care in young fit patients, as defined in CLL10 study, B-R has yielded a more beneficial toxicity profile and its use in first line treatment should be decided individually. In relapsed setting, the addition of ibrutinib to B-R has shown superior results compared to B-R alone, possibly changing the paradigm of treatment of relapsed CLL. In conclusion, bendamustine as a single agent or in combinations has shown activity with acceptable toxic profile in the treatment of patients with indolent NHLs or CLL without del(17p) mutation.Cilj ovoga preglednog rada je procijeniti aktivnost bendamustina te njegovih kombinacija u ne-Hodgkinovim limfomima (NHL) i kroničnoj limfocitnoj leukemiji (KLL). Bendamustin je sada indiciran u Republici Hrvatskoj za liječenje rituksimab-rezistentnog NHL-a i u bolesnika s KLL-om koji nisu kandidati za konvencionalnu terapiju. No, kombinacija bendamustina s rituksimabom (B-R) u prvoj liniji terapije indolentnog NHL-a i limfoma plaštene zone pokazala se boljom od konvencionalne kemoterapije pa bi B-R trebao postati zlatni standard u prvoj liniji liječenja ovih limfoma. Protokol B-R ­također ima aktivnost u relapsnom indolentnom NHL-u te predstavlja opciju za bolesnike koji su progredirali nakon konvencionalne kemoterapije. U rituksimab-rezistentnom NHL-u nedavna studija GADOLIN koja je proučavala dodatak ­obinutuzumaba bendamustinu pokazala je jasnu superiornost prema bendamustinu i promijenila zlatni standard u ovoj ­populaciji zahtjevnoj za liječenje. U KLL-u usprkos inferiornosti B-R prema FCR-u u studiji CLL10 B-R je bio obilježen boljim profilom toksičnosti te se može ponuditi pojedinim bolesnicima na temelju individualizirane odluke. U relapsnom okružju KLL-a dodatak ibrutiniba protokolu B-R pokazao je superiornost prema B-R s mogućom promjenom paradigme liječenja ovih bolesnika. Zaključno, bendamustin sam ili u kombinacijama pokazao je visoku aktivnost s povoljnim toksičnim profilom u liječenju indolentnih NHL-a i KLL bez mutacije del(17p)

Myelodysplastic syndrome in a patient with untreated chronic lymphoproliferative neoplasm

U bolesnika s kroničnom limfoproliferativnom bolesti (LPB) veća je učestalost nastanka sekundarnih neoplazma. Istodobna pojava limfoproliferativne neoplazme (LPN) i mijelodisplastičnog sindroma (MDS) vrlo je rijetka. Druga hematološka neoplazma dijagnosticira se slučajno tijekom kontrola ili pri dodatnim analizama zbog nesukladnih kliničkih ili laboratorijskih nalaza. Prikazujemo dijagnostički postupak, tijek bolesti i liječenje 65-godišnje bolesnice s kroničnom limfoproliferativnom neoplazmom i MDS-om sa suviškom blasta tipa 2 (MDS-EB2). Vodeći nalaz bila je neutropenija, a tek su citološkim analizama koštane srži i periferne krvi dijagnosticirane navedene neoplazme. Liječenje jedne i druge hematološke neoplazme nije dalo zadovoljavajuće rezultate i MDS je progredirao u akutnu mijeloičnu leukemiju. U bolesnika s limfoproliferativnom neoplazmom i citopenijom valja tragati za mogućim drugim uzrocima takvih aberantnih nalaza. Pri liječenju tih bolesnika razumno je liječiti dominantnu bolest.High frequency of second malignancies is observed in chronic lymphoproliferative disease (LPD) patients. The simultaneous occurrence of myelodysplastic syndrome (MDS) with untreated LPD is extremely rare. Second haematological neoplasms are usually diagnosed incidentally during a routine clinical check-up, or due to discordant clinical or laboratory findings. We are reporting diagnostic procedures, clinical course, and treatment of a 65-year-old woman with chronic lymphoproliferative neoplasm and MDS with excess of blasts type 2 (MDSEB2). Neutropenia was the most aberrant finding. A diagnosis of two malignant haematological neoplasms was done by cytological analysis and immunophenotyping of bone marrow and peripheral blood cells. In spite of treating both neoplasms no satisfactory results were achieved and MDS progressed to acute myeloid leukaemia. In patients with lymphoproliferative neoplasms and cytopenias it is important to find out other causes of these laboratory findings. In such patients the dominant disease should be treated. A concomitant MDS should be suspected and examined

Bendamustine: an Old Drug in the New Era for Patients with Non-Hodgkin Lymphomas and Chronic Lymphocytic Leukemia

The aim of this review is to present data on bendamustine, a non-cross resistant alkylating agent, alone or in combination for treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Bendamustine is currently approved for rituximab-resistant indolent NHL and CLL in patients not fit for conventional chemotherapy. Recent studies have shown superiority of bendamustine combination with rituximab (B-R) in first line treatment of indolent NHLs and mantle cell lymphoma, suggesting a shift of the standard of care in this setting. B-R regimen has also shown efficacy in relapsed setting suggesting the possible treatment option for patients failing conventional chemotherapy. In rituximab-resistant NHL, the recent GADOLIN study exploring the addition of obinutuzumab to bendamustine has yielded impressive result changing the standard of care in this hard-to-treat population. Concerning CLL, despite inferiority to the standard of care in young fit patients, as defined in CLL10 study, B-R has yielded a more beneficial toxicity profile and its use in first line treatment should be decided individually. In relapsed setting, the addition of ibrutinib to B-R has shown superior results compared to B-R alone, possibly changing the paradigm of treatment of relapsed CLL. In conclusion, bendamustine as a single agent or in combinations has shown activity with acceptable toxic profile in the treatment of patients with indolent NHLs or CLL without del(17p) mutation

Heart Failure with Mid-Range or Mildly Reduced Ejection Fraction in the Era of Sodium–Glucose Co-Transporter 2 Inhibitors: Do We Now Provide Better Care for the “Middle Child of HF”? Real-World Experience from a Single Clinical Centre

Heart failure (HF) with mid-range or mildly reduced ejection fraction (HFmrEF) is a separate clinical entity in the HF spectrum, with a left ventricular ejection fraction ranging from 40 to 49%. While sodium glucose co-transporter 2 inhibitors have become the cornerstone therapy for the entire HF spectrum, there are a few clinical trials of HFmrEF. This prospective observational study was conducted at Dubrava University Hospital, Zagreb, Croatia, from May 2021 to October 2023. We recruited 137 participants diagnosed with HFmrEF at admission. The majority were male, with a median age of 72 and overweight. A total of 110 participants were followed for 6 months and LVEF remained the same in the majority of patients (n = 62, 56.4%), improved in 32 patients (29.1%), and decreased in 3 patients (2.73%). A total of 64 participants were followed for 12 months: 39 remained the same (60.94%) and 25 improved. There were 13 deaths in (9.5%). While the empagliflozin group had a lower BMI at 6-month- and lower HbA1c at 12-month follow-up, there were no differences in death, HF hospitalizations, ER visits, or urinary tract infections in between groups. Despite recent and daily advances in the treatment of all HF phenotypes, HFmrEF still represents a challenge in everyday clinical practice

Systemic mastocytosis in Croatia

Cilj: Ciljevi ove studije bili su identificirati bolesnike sa sistemskom mastocitozom (SM) u Republici Hrvatskoj (RH) i analizirati njihove kliničke karakteristike. Ispitanici i metode: Retrospektivno su iz osam hematoloških centara u RH identificirani bolesnici sa SM. Analizirane su kliničke karakteristike, te načini i ishodi liječenja ovih bolesnika. Rezultati: Uključeno je 20 bolesnika, medijan dobi bio je 40,5 godina (raspon 24–77), a većinu su činile žene (n=12). Dominirali su bolesnici s indolentnom SM (ISM, n=11), dok je učestalost agresivne SM (ASM, n=4), „šuljajuće“ sistemske mastocitoze (SSM, n=3) i SM s pridruženom zloćudnom hematološkom bolešću (SM-AHND, n=2) bila manja. Gotovo su svi bolesnici imali kožni osip, a značajan broj njih i dispeptične smetnje, alergijsku dijatezu, bolove u kostima i osteoporozu. Antihistaminike je primala većina bolesnika, a citoredukciju 10 bolesnika (ISM=3, SSM=2, ASM=4, SM-AHND=1). Većina bolesnika koja je zahtijevala citoreduktivno liječenje primala je interferon alfa-2a (2 ISM, 1 SSM i 3 ASM), dva steroida (1 ISM i 1 SM-AHND), te po jedan imatinib (SSM) i kladribin (ASM). Svi su bolesnici liječeni u prvoj liniji interferonom alfa-2a i kladribinom postigli parcijalnu remisiju, a dva bolesnika liječena imatinibom i steroidom bila su refraktorna na liječenje. Nije bilo prekida liječenja interferonom zbog nuspojava. Nakon medijana praćenja od 33 mjeseca preminulo je troje bolesnika, jedan s ASM i oba s SM-AHND. Medijan preživljenja bolesnika s ISM/SSM nije dostignut naspram bolesnika s ASM/SM-AHND, gdje je iznosio 105 mjeseci (p=0,009). Zaključak: Kliničke karakteristike i ishodi liječenja bolesnika sa SM u RH slični su onima iz velikih svjetskih centara. Najčešće korišten citoreduktivni lijek u RH bio je interferon alfa-2a koji se pokazao sigurnim i učinkovitim.Aim: The aims of this study were to identify patients with systemic mastocytosis (SM) in Croatia and to analyze their clinical characteristics. Patients and methods: Patients with SM treated at eight hospitals in Croatia were retrospectively identified and their clinical characteristics, treatment patterns and outcomes were analyzed. Results:Twenty patients were included, median age was 40.5years (range 24-77), and most were females (n=12) . Patients with indolent SM (ISM, n=11) predominated, followed by aggressive SM (ASM, n=4), smoldering SM (SSM, n=3) and SM with an associated hematological neoplastic disorder (SM-AHND, n=2). Only one patient (with ASM) did not have cutaneous involvement, and a significant proportion of SM patients had dyspepsia, allergic diathesis, bone pains and osteoporosis. Antihistamines were administered in the majority of the patients, whereas ten patients needed cytoreductive treatment (ISM, n=3, SSM n=2, ASM, n=4, SM-AHND, n=1). Most SM patients in need for cytoreduction received interferon alpha-2a (two ISM, one SSM and three ASM), two received steroids (one ISM and one SM-AHND), one received imatinib (SSM) and the last patient was treated with cladribine (ASM). All patients treated first-line with interferons and cladribine achieved partial remission, whereas two patients treated with imatinib and steroid were refractory. None of the patients discontinued interferon due to drug-related side-effects. After a median follow-up of 33 months, three patients died, one with ASM and two with SM-AHND.The median survival of ISM/SSM patients was higher than in ASM/SM-AHND patients in whom it was 105 months (p=0.009). Conclusion: Clinical characteristics and treatment outcomes of SM patients in Croatia are comparable to those from large international centers. The most commonly administered cytoreductive drug in Croatia was interferon alpha-2a which was shown to be safe and effective