Hematopoietic and mesenchymal stem and progenitor cells are organized in the osteo-hematopoietic niche, a complex microenvironment ensuring self-renewal and differentiation. Perturbations of the ...niche architecture, the mutual cellular interactions and signaling pathways disrupt tissue homeostasis resulting in cytopenia and malignant diseases such as myelodysplastic syndromes (MDS), supporting the concept of niche-induced oncogenesis. Analyzing the available treatment options for patients harboring MDS, it becomes evident that many of them specifically modify components of the stem cell niche. Hereby especially compounds inhibiting the TGF-β superfamily seem to represent a promising novel approach for patients with anemia as a result of ineffective erythropoiesis. Moreover, apart from affecting tumorigenesis, these drugs appear to influence bone structure and function as well as hematopoiesis in elderly MDS patients with a disturbed microarchitecture of the bone marrow. In the present review we will dissect the contribution of components of the stem cell niche for the pathogenesis of MDS and discuss current therapeutic strategies targeting components of the niche, focusing on the modulation of TGF-β signaling.
We present the case of a 33-year-old chronic myeloid leukemia (CML) female patient, in whom the occurrence of nephrotic syndrome, during the treatment with tyrosine kinase activity inhibitors (TKIs), ...was potentially influenced by transient phenoconversion. Seven years after the CML diagnosis in 2004 and complete response, the patient experienced pain in the mandible and extremities. After this, imatinib was replaced by nilotinib, but generalized maculopapular rash was presented and successfully treated with antihistamines. The therapy was then discontinued due to planned pregnancy, and the patient experienced a relapse of CML with BCR-ABL/ABL1 transcripts of 18.9%. Dasatinib was introduced, and CML was in remission. Two years later, urine protein levels (6.19 g/L) and erythrocyte sedimentation rate were elevated (ESR=90 mm/3.6 ks). The patient was diagnosed with nephrotic syndrome. With dasatinib dose reduction, urine protein level returned to the reference range. In order to determine the best genotype-guided therapy, the patient underwent pharmacogenomic testing, showing a homozygous CYP3A4 genotype *1/*1, associated with extensive metabolizer (EM) enzyme phenotype, typical for normal rates of drug metabolism for TKIs. However, this was inconsistent with nephrotic syndrome occurrence. A possible explanation would be CYP3A4 EM genotype coding a poor metabolizer enzyme phenotype, leading to the drug accumulation in the patient's blood. This transient phenoconversion can be explained by inflammation with elevated ESR during nephrotic syndrome. This case shows that a broader approach that recognizes genetic, clinical, and epigenomic factors is required for a quality decision on the personalized therapy regimen.
ECHELON‐1 study is a randomized open‐labeled controlled trial investigating whether addition of brentuximab vedotin to chemotherapy offers benefit over the standard chemotherapy regimen in advanced ...Hodgkin lymphoma. After a median follow‐up of 24.6 months, it has met its primary endpoint the reduction of modified progression‐free survival being 23 percent. However, the beneficial effects have not been seen across all subgroups leading to further questions. The main aim of this review is to tackle these questions to provide the reader with in‐depth insight of pros and cons of this novel, promising but ultimately controversial regimen.
Immune thrombocytopenia (ITP) in adulthood is characterized by chronic relapsing course. Despite the efficacious first line treatment (corticosteroid, intravenous immunoglobulin), majority of ...patients will enter the chronic phase warranting another treatment approach. Until recently, splenectomy performed in ITP chronic phase represented the standard of care with longterm remissions in more than 70% of patients, but it has never been tested in clinical trials. However, with the advances of our understanding of ITP pathophysiology and the shifting focus on megakaryocyte impairment, novel drugs were introduced in the treatment paradigm, mainly trombopoietin receptor agonists (TPO-RAs); romiplostim and eltrombopag.
These TPO-RAs were tested in randomized controlled trials resulting in adequate platelet response with few side effects and less need for additional therapy leading to approval of corresponding regulatory agencies and wide acceptance by hematological community, but however TPO-RAs must be taken continuously to maintain the response. With their onset, the rate of splenectomy in chronic ITP has diminished in modern era.
The main aim behind conducting this review is to evaluate the pros and cons of splenectomy compared to TPO-RAs treatment in order to provide the critical overview which may help the practicing clinician in managing often challenging cases of chronic ITP.
Myelodysplastic syndromes (MDS) are heterogeneous group of hematologic disorders of mostly elderly and based on distinct clinical phenotypes. Current paradigm of their pathogenesis relies on somatic ...gene mutations combined with the predisposing defective osteohematopoietic niche, but due to the breakout in epigenetic research scientific focus has steered toward two most common epigenetic modifications: methylation mechanisms and histone modification. At the same time, relatively few studies have been undertaken regarding the third epigenetic pathway – microRNAs – in MDS. The main aim of this review is to provide the basics of microRNA biology and function in oncogenesis, showing the complexity of mechanisms behind this single‐stranded 22 nucleotides long RNA molecule, with further focus on its implication in MDS pathology and clinical context. By extensive literature search, we have shown enough evidence for their deregulation in MDS. However, few studies have addressed the issue on pathogenic events in MDS and its association with specific microRNAs. Preliminary research in clinical setting has shown the possible utility of microRNAs in terms of prognosis and therapy, although we are only beginning to understand various implications of microRNAs in MDS and further extensive research is warranted to answer multiple questions arising from interconnection of this epigenetic mechanism in MDS.
- 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.
Mijelodisplastični sindrom (MDS) klonska je bolest matične hematopoetske stanice, koja se očituje poremećenom proliferacijom, diferencijacijom i sazrijevanjem hematopoeze te displastičnim promjenama ...u koštanoj srži. U kliničkoj slici i laboratorijskim nalazima bolesnika s MDS-om dominira anemija, nešto rjeđe neutropenija
ili trombocitopenija različitih stupnjeva težine. Kardiokirurški zahvat u bolesnika s MDS-om velik je izazov jer su neutropenija i trombocitopenija vodeći uzroci infekcija i krvarenja tijekom operacije. Malen je broj izvješća u literaturi koja opisuju kardiokirurški zahvat u bolesnika s MDS-om. Prikazujemo 66-godišnju bolesnicu s MDS-om kod koje je uspješno izvedena rekonstrukcija mitralnog i trikuspidalnoga srčanog zalistka. Bolesnica se javila u hitnu službu zbog otežanog disanja, opće slabosti i znakova srčanog popuštanja. Radiološkom obradom verificirani su obostrani pleuralni izljev, izraženije lijevo, i povećana sjena srca s naglašenim vaskularnim hilusima. Daljnjom obradom dokazane su mitralna i trikuspidalna insuficijencija teškog stupnja pa je bolesnica operirana, a pet godina nakon zahvata ima dobru kvalitetu života. Multidisciplinarnom suradnjom kardiologa, hematologa, anesteziologa i kardiokirurga u bolesnice je uspješno izveden kirurški zahvat rekonstrukcije mitralne i trikuspidalne valvule. Ovaj prikaz bolesnice upućuje na važnost multidisciplinarnog pristupa specifičnoj i ranjivoj grupi bolesnika s MDS-om i kardiovaskularnim komorbiditetima.
Graft versus host disease (GVHD) is an uncommon complication after orthotopic liver transplantation (OLT) with an incidence of 0.1-2%, but an 80-100% mortality rate. Patients can present with skin ...rashes, diarrhea, and bone marrow aplasia between two to eight weeks after OLT. Diagnosis of GVHD is made based on clinical and histologic evidence, supported by chimerism studies showing donor HLA alleles in the recipient bone marrow or blood. Several therapeutic approaches have been used for the management of GVHD after OLT including increased immunosuppression, decreased immunosuppression, and cellular therapies. However, success rates have been low, and new approaches are needed.
Mijelodisplastični sindrom (MDS) grupa je klonskih mijeloidnih poremećaja s heterogenom kliničkom slikom, a najveći broj komplikacija posljedica je citopenija koje su karakteristično obilježje. ...Etiologija nije dovoljno poznata. Internacionalni bodovni sustav (engl. The International Prognostic Scoring System – IPSS) služi kao prognostički čimbenik za neliječene bolesnike s MDS-om. Nedjelotvorna hematopoeza, pa tako i eritropoeza, dovode do anemije, što je najčešći uzrok dolaska bolesnika s MDS-om u hitnu službu. Vrlo često bolesnici imaju brojna pridružena stanja poput kronične bubrežne bolesti i hipertenzije, a mogu imati i kliničku sliku akutnoga koronarnog sindroma. Prikazujemo 83-godišnju bolesnicu s MDS-om dijagnosticiranim 2014. godine i koja dosad nije liječena specifičnom hematološkom terapijom. Zbrinjavanje starijih hematoloških bolesnika u hitnoj službi nalaže sveobuhvatni pristup zbog često prisutnih pridruženih stanja koja se dodatno mogu pogoršati uz MDS.
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