Is There a Role for Growth and Differentiation Factor-15 in B-Cell Lymphoproliferative Neoplasms?

Growth and differentiation factor-15 (GDF-15) correlates with worse outcome of many tumours and any cause mortality. Data about its role in lymphoproliferative neoplasms (LPN) are scarce. Our research aimed to reveal the correlation between GDF-15 and standard laboratory parameters of LPN activity, and to get insight into the possible value of this cytokine assessment in lymphoma patients. Prospective research included 40 patients treated for aggressive or indolent LPN, and 31 with indolent LPN on "watch and wait" regimen. Analyses were performed before and after treatment in treated patients and on two separate occasions in the "watch and wait" group. ELISA technique with R&D assays according to the manufacturer manual, from stored sera at - 70 °C was used for GDF-15 level measurement. Statistical analyses were performed by IBM SPSS Statistics 22 using descriptive and inferential statistics. As appropriate, differences between groups were assessed by two tailed t-test, Mann-Whitney or x2 test. Spearman Rank Order Correlation was done to correlate GDF-15 with standard laboratory markers of disease activity. All tests are two-tailed with significance level p < 0. 05. GDF-15 (p = 0.028) and fibrinogen (p = 0.001) concentrations increased after treatment in indolent lymphoma patients while ß2 microglobulin decreased (p < 0.001). GDF-15 positively correlated with ß2microglobulin before (p < 0.001) and after (p = 0.031) therapy. There were no differences in any of the aforementioned parameters in the "watch and wait" group during observation. A positive correlation between GDF-15 and ß2 microglobulin in patients with indolent LPN who need treatment suggests potential value in risk assessment. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-023-01695-6.

Eculizumab for paroxysmal nocturnal hemoglobinuria: Two cases of successful pregnancy outcomes.

Paroxysmal nocturnal hemoglobinuria is a rare disease with the incidence ranging from 0.08 to 0.57 per 100,000 person-years. Up to 25% of cases in women are detected during pregnancy. We report two cases of successful pregnancy outcomes in patients treated with eculizumab, pointing out the importance of interdisciplinary approach in these high-risk pregnancies.

Outcomes in COVID-19 Patients with Pneumonia Treated with High-Flow Oxygen Therapy and Baricitinib-Retrospective Single-Center Study.

BACKGROUND: The aim of the study was to assess the effect of baricitinib on 28-day all-cause mortality and the progression of respiratory failure in patients needing transfer to the intensive care unit (ICU) with COVID-19 pneumonia treated with high-flow oxygen therapy. METHODS: This retrospective study included hospitalized patients with COVID-19 pneumonia treated with high-flow oxygen non-invasive ventilation receiving standard of care (SOC) or SOC in addition to baricitinib. Data on patients' characteristics, pro-inflammatory markers, D dimer, and National Early Warning Score 2 (NEWS2) values were collected and compared between groups. The primary endpoint was 28-day all-cause in-hospital mortality and the secondary outcome was transfer to the ICU. RESULTS: The study included 125 patients. The primary outcome was observed in 44.8% of them: 27% in the baricitinib group vs. 62% in the SOC group, p < 0.001. Transfer to the ICU ward was significantly lower in the baricitinib group: 29% vs. 81%, p < 0.001. A significant improvement was observed when the baricitinib group was compared to SOC in procalcitonin, CRP, D-dimer, neutrophil-to-lymphocyte ratio values, and NEWS2. CONCLUSION: Treatment with baricitinib in addition to SOC was associated with reduced mortality and a lower prevalence of transfer to the ICU in hospitalized patients with COVID-19 pneumonia treated with high-flow oxygen non-invasive therapy.

Implementation of Microelimination Strategy in Eradication of Chronic Hepatitis C Infection in Patients with Hemophilia in the Northern region of Serbia: Is Eradication Possible?

BACKGROUND: Treating HCV in people with hemophilia prevents the development of end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC) and greatly increases the quality of life for people living with hemophilia. There are many obstacles in reaching the WHO goal of globally eradicating HCV by 2030, mainly its scale, complexity, and implementation. That is why many countries have implemented a micro-elimination strategy: a pragmatic elimination approach in populations with the most efficacy. The aim of this publication is to present the morbidity and mortality rates, the clinical course and treatment outcomes of chronic HCV infection in people with hemophilia (PwH), as well as to show an example of a successfully conducted HCV micro-elimination strategy among people with hemophilia in the Province of Vojvodina. METHODS: A retrospective, single-center study, performed using medical documentation of all registered PwH in the Clinical Center of Vojvodina from 1994. until 2020. It included 74 hemophilia patients, out of which 32 were patients with hemophilia and chronic HCV infection. RESULTS: The mean age of HCV-positive positive people with hemophilia (PwH) was 42.3 years, with the duration of infection of 30-35 years. Co-infection with HIV was observed in 6.25% of cases. Furthermore, 18.75% of patients had spontaneous HCV elimination, and 75% were treated with antiviral protocols. Cirrhosis developed in 21.87% with an incidence rate of 0.6 per 100 patient-years. After treatment with Pegylated IFN and ribavirin (RBV), 58.3% achieved SVR. Side effects of IFN-based therapy regimens were recorded in 20.8% of treated (PwH). In 37.5% PWH, DAA protocols were administered, and these patients achieved SVR. HCV- PwH have a statistically higher mortality rate than non-infected people with hemophilia. Among the HCV-positive PwH, hemophilia-related deaths were 6.25%, and HCV-related deaths were 9.37%. Currently, in the Registry of PwH in Vojvodina, there are no patients with active HCV infection. CONCLUSION: The micro-elimination strategy in the subpopulation of PwH was successfully implemented in Vojvodina by hematologists and infectious diseases specialists in close collaboration.

Changing epidemiology of catheter-related bloodstream infections in neutropenic oncohematological patients.

BACKGROUND: We aimed to describe the epidemiology of catheter-related bloodstream infections (CRBSIs) in onco-hematological neutropenic patients during a 25-year study period, to evaluate the risk factors for Gram-negative bacilli (GNB) CRBSI, as well as rates of inappropriate empirical antibiotic treatments (IEAT) and mortality. MATERIALS/METHODS: All consecutive episodes of CRBSIs were prospectively collected (1994-2018). Changing epidemiology was evaluated comparing five-year time spans. A multivariate regression model was built to evaluate risk factors for GNB CRBSIs. RESULTS: 482 monomicrobial CRBSIs were documented. The proportion of CRBSIs among all BSIs decreased over time from 41.2% to 15.8% (p<0.001). CRBSIs epidemiology has been changing: the rate of GNB increased over time (from 11.9% to 29.4%; p<0.001), as well as the absolute number and rate of multidrug-resistant (MDR) GNB (from 9.5% to 40.0%; p = 0.039). P. aeruginosa increased and comprised up to 40% of all GNB. Independent factors related with GNB-CRBSIs were: longer duration of in-situ catheter (OR 1.007; 95%CI 1.004-1.011), older age (OR 1.016; 95%CI 1.001-1.033), prior antibiotic treatment with penicillins (OR 2.716; 95%CI 1.306-5.403), and current antibiotic treatment with glycopeptides (OR 1.931; 95%CI 1.001-3.306). IEATs were administered to 30.7% of patients, with the highest percentage among MDR P. aeruginosa (76.9%) and S. maltophillia (92.9%). Mortality rate was greater among GNB than GPC-CRBSI (14.4% vs 5.4%; p = 0.002), with mortality increasing over time (from 4.5% to 11.2%; p = 0.003). CONCLUSION: A significant shift towards GNB-CRBSIs was observed. Secondarily, and coinciding with an increasing number of GNB-MDR infections, mortality increased over time.

Immunomodulatory effects of galectin-1 in patients with chronic lymphocytic leukemia.

Galectin-1 (Gal-1) has been implicated in the progression of chronic lymphocytic leukemia (CLL) but also the development of immunodeficiency, which commonly accompany this malignancy. In this in vitro study, we investigated the effects of Gal-1 inhibition in the sera of immunocompromised CLL patients on immunomodulating properties of dendritic cells (DCs). DCs derived from peripheral blood mononuclear cells were treated with a healthy serum, CLL serum as well as the combination of CLL serum and Gal-1 inhibitor (OTX008). Following the treatment, the expression levels of DC maturation markers (CD80, CD83, CD86 and IDO-1) were determined as well as their cytokine profile and the ability to polarize the immune response in co-cultures with CD4+ T cells. After treatment with CLL serum, an increase in interleukin (IL)-10 production was observed in both DC cultures and co-cultures with CD4+ T cells. OTX008 caused a reduction in IL-10 production as well as IL-2, but no significant alteration in the expression of DC maturation markers or T regulatory cell (Treg) frequency was observed. The results of our study suggest that Gal-1 from CLL serum give rise to a specific IL-10+ CD4+ T cell phenotype, other than Treg, that could mediate immunodeficiency development in CLL patients.

Febrile neutropenia induces changes in insulin sensitivity similar to obesity.

Background/aim: To determine insulin sensitivity before chemotherapy and during febrile neutropenia in patients with acute leukemia and to assess its effect on the number of documented infections, the severity of infection and the outcome of the first hospitalization. To compare insulin sensitivity in the study group to a group of patient with obesity. Materials and methods: The study group consisted of 30 (37% of the total number) patients with newly diagnosed acute leukemia. Testing of insulin sensitivity was done before chemotherapy and during febrile neutropenia. Parameters were compared to a group of 30 age, and sex matched patients with obesity. Results: Insulin sensitivity was normal before chemotherapy. Obese patients were characterized by insulin resistance. Febrile neutropenia led to the development of insulin resistance (t = -2.43, p = 0.021). The level of insulin resistance was in positive correlation with fibrinogen (r = 0.59, p < 0.05). Patients with a documented site of infection had higher fasting insulin and an insulin resistance before chemotherapy (t = -2.38, p = 0.024). Insulin sensitivity did not influence outcome of the first hospitalization. Conclusion: Patients with acute leukemia in febrile neutropenia developed changes in insulin sensitivity similar to those seen in obesity. Insulin resistance was present in patients with a documented site of infection, and it worsened with the extent of inflammation. The outcome of the first hospitalization was not affected.

Dental extractions and risk of bleeding in patients taking single and dual antiplatelet treatment.

Our aim was to evaluate the effects of single and dual antiplatelet treatment on postoperative bleeding in patients having dental extractions. The prospective clinical study included 160 patients who were taking antiplatelet drugs. The first group (n=43) were taking 2 drugs, mostly aspirin and clopidogrel, and the second group (n=117) were taking a single antiplatelet drug in the form of aspirin (n=84), clopidogrel (n=20), and ticlopidine (n=13). All patients had simple dental extractions, and local haemostasis was with resorbable collagen sponges, without suturing of the wound. The control group comprised 105 healthy subjects with a similar number of dental extractions. Bleeding was an "event" if it continued for more than 12h, made the patient call or return to the dental practice or emergency department, induced a large haematoma or ecchymosis within the oral soft tissues, or required blood transfusion. A total of 110 teeth were extracted on 59 occasions in the dual drug group, and 232 teeth on 128 occasions in the single drug group. Bleeding was recorded after extraction in only one patient on dual aspirin-clopidogrel treatment, which was mild and easily controlled by local haemostasis. The incidence of postoperative bleeding did not differ significantly among the three groups (χ(2)=4.3, p=0.11). However, the wound was sutured to achieve effective initial local haemostasis in 4/59 (6.8%) and 2/128 (1.6%) occasions of tooth extractions in the dual and single drug groups, respectively, and none in the control group (χ(2)=10.02, p=0.007). Patients taking single or dual antiplatelet drugs may have teeth extracted safely without interruption of treatment using only local haemostatic measures.

Angiogenesis and survival in patients with myelodysplastic syndrome.

Angiogenesis has been implicated in the pathogenesis and prognosis of myelodysplastic syndrome (MDS). In this study, we investigated the relationship between microvessel density (MVD), vascular endothelial growth factor (VEGF) expression, common morphological and clinical factors, and survival in patients with MDS. We examined the MVD of paraffin-embedded bone marrow sections from 70 MDS patients and 31 controls. VEGF expression was determined in 50 patients and 20 controls. The median MVD in MDS patients was significantly higher than that in controls (p = 0.025), whereas there was no difference in VEGF expression between MDS patients and controls. In univariate analysis, increased MVD was associated with a shorter survival time (p = 0.023). However, in multivariate analysis, MVD was not an independent predictor of survival. The VEGF expression did not influence survival in univariate analysis. Survival was independently influenced by platelet count (p = 0.0073), cytogenetic risk category (p = 0.022), and transfusion dependence (p = 0.0073). Neither MVD nor VEGF expression were predictors for progression to acute myeloid leukemia in univariate analysis. Progression to acute myeloid leukemia was independently influenced only by the cytogenetic risk category (p = 0.022). This study confirmed increased MVD in MDS. It does not support an independent prognostic role of angiogenesis in MDS.

The hematopoietic cell transplantation comorbidity index is a predictor of early death and survival in adult acute myeloid leukemia patients.

The hematopoietic cell transplantation comorbidity index (HCT-CI) is predictive of early death and survival in elderly patients with acute myeloid leukemia (AML). The aim of this study was to determine the prognostic role of the HCT-CI for early death and survival in adult AML patients. In the single-center retrospective study, we analyzed the outcome of 233 adult AML patients. The results indicated that the HCT-CI score is an independent predictor of early death in entire cohort of adult patients with AML. In subgroup analysis, HCT-CI is an independent predictor for early death in elderly patients but not in patients younger than 60 years. A high HCT-CI score predicts shorter survival in adult patients with AML.

Results of bacteriological and cytological examinations of the endometrium of subfertile mares in stud farms in Serbia.

Uterine microbiology, antimicrobial susceptibility and endometrial cytology were investigated in a total of 51 mares with fertility problems from 16 different stud farms in Serbia. Uterine cultures were performed after collection with a double guarded uterine swab, and endometrial cytology was evaluated after collection of endometrial cells with a special device (cytology brush). In 21 of 51 mares, at least one bacterial species was isolated from the uterus; the most frequent were Streptococcus equi subsp. zooepidemicus (13 isolates) and E. coli (four isolates). All isolates of Streptococcus equi subsp. zooepidemicus were susceptible to penicillin. Results from endometrial cytology were inconsistent; in 17 animals with positive bacteriological culture, cytology was not altered. It can be concluded that in Serbia, as in many other contries, Streptococcus equi subsp. zooepidemicus is the main cause for equine endometritis. It can be easily diagnosed by uterine culture but endometrial cytology does not always prove the existence of an endometrial infection with this agent.

Syngeneic peripheral blood stem cell transplantation with immunosuppression for hepatitis-associated severe aplastic anemia.

Hepatitis-associated aplastic anemia occurs in up to 10% of all aplastic anemia cases. Syngeneic bone marrow transplantation is rare in patients with severe aplastic anemia and usually requires pre-transplant conditioning to provide engraftment. We report on a 29-year-old male patient with hepatitis-associated severe aplastic anemia who had a series of severe infectious conditions before transplantation, including tracheal inflammation. Life-threatening bleeding, which developed after bronchoscopy, was successfully treated with activated recombinant factor VII and platelet transfusions. Syngeneic peripheral blood stem cell transplantation using immunosuppressive treatment with antithymocyte globulin and cyclosporin A without high-dose pre-transplant conditioning was performed, followed by complete hematologic and hepatic recovery.

[Peripiheral blood hematopoietic stem cells--biology, apheresis collection and cryopreservation].

INTRODUCTION: ilematopoiesis is a continuous, dynamic and highly complex process resulting in production of various mature blood cells from a small population of pluripotent stem and progenitor cells through diverse proliferative and differentiative events. Numerous studies have demonstrated that a complex network of interactive cytokines regulates the survival, maturation, and proliferation of hematopoietic stem and progenitor cells. APPLICATION OF CELL-MEDIATED THERAPY: Massive application of different cell-mediated therapeutic methods has resulted in an increased need for both specific IISPCs and operating procedures providing minimal cell damage during collection, processing and storage in a liquid or fiozen state. Therefore, the basic aim of cell harvesting, selection, as well as cryopreservation is to minimize cell damage during these procedures. HSPCs are cells which exhibit extensive self-renewal and proliferative capacity, associated with the capacity to differentiate into all blood cells and other cell lineages (plasticity of HSPC). Thanks to these properties, stem cells can provide complete and permanent restoration of hematopoiesis, which is the basis for clinical employment of HSPC transplantation. In addition, totipotent stem cells can be used for the so called "cell-therapy" in different clinical settings (e.g. myocardial regeneration after acute infarction). CONCLUSION: Despite the fact that HSPC transplantation is already in routine use, some questions related to the optimal blood progenitor/cell collection, selection, storage and clinical use are still unresolved. Therefore, this review only briefly discusses the therapeutic use of HSPCs in different clinical areas and focuses on the recommendations, as well as the specific transfusion policies related to HSPC collection, processing, and cryopreservation with an emphasis on quality control.

[Current differential diagnosis of hypereosinophilic syndrome].

INTRODUCTION: Hypereosinophilic syndrome (HES) is a group of idiopathic disorders associated with single or multiple organ system dysfunction. HES must be distinguished from reactive eosinophilia in parasitic infections, allergic diseases, and especially from hematological diseases of clonal origin. REACTIVE EOSINOPHILIA DUE TO INFECTIOUS AND PARASITIC DISEASES: Tissue helminth infections, especially toxocariasis, cause severe and long-standing hypereosinophilia. Despite specific therapy, eosinophilia may persist for over a year after diagnosis, and decreases slowly. Other helminth infections, such as trichinellosis, strongyloidosis, and rarely taeniasis and cysticercosis may also be diagnosed in patients with eosinophilia. HEMATOLOGIC AND OTHER NEOPLASTIC DISEASES: Numerous neoplastic diseases, like Hodgkin's and other malignant lymphomas, myeloproliferative diseases, systemic mastocytosis etc., may be associated with marked eosinophilia. We had two patients with clinical and histological features resembling chronic eosinophilic leukemia, and many others with T-cell lymphoma, planocellular or adenocarcinoma etc. where eosinophilia persisted DRUG-INDUCED EOSINOPHILIA: Drugs associated with eosinophilia include penicillins, tetracyclines, especially minocycline, clarithromycin, tetrazepam, mefloquine, and many, others. Toxins associated with L-tryptophan cause eosinophilia-myalgia syndrome and toxic oil syndrome, also belonging in this group. Treatment includes drug discontinuation and administration of corticosteroids. HYPEREOSINOPHILIA WITH ORGAN DYSFUNCTION: Many severe diseases, such as sarcoidosis, Churg-Strauss syndrome, pemphigus vulgaris, eosinophilic gastrointestinal diseases, inflammatory bowel disease and many others are associated with hypereosinophilia and target organ damage, e.g. involvement of the heart, lungs, skin, or nervous tissue. CONCLUSION: Eosinophilia can be classified as either familial or acquired. Hypereosinophilic syndrome is a subcategory of idiopathic eosinophilia. If the differential diagnosis of hypereosinophilia fails to resolve the etiology succesfully, the diagnosis of idiopathic HES remains.

Autoantibodies to mitotic apparatus: association with other autoantibodies and their clinical significance.

The most important mitotic apparatus (MA) antigens are centrosome (CE), nuclear mitotic apparatus (NuMA-1, NuMA-2), midbody, and centromere F (CENP-F). We studied associations of anti-MA antibodies with other autoantibodies and their clinical significance. A total of 6270 patients were studied for the presence of anti-MA antibodies on HEp-2 cells. Sera positive for anti-MA were tested for anti-extractable nuclear antigens (ENA) antibodies. Anti-MA antibodies were detected in 56 (45 females and 11 males) of 6270 sera (0.9%). Of these 56, NuMA-1 was found in 23, NuMA-2 in 7, CE in 20, CENP-F in 5, and CENP-F/centrosome in 1 case. Anti-NuMA-1 were associated with anti-ENA antibodies (p < 0.001). Diagnoses were established in 43/56 patients: 22 connective tissue diseases, 7 infections, 6 autoimmune hepatitis, 3 vasculitis, 3 primary antiphospholipid syndrome, 1 malignancy, and 1 fever of unknown origin. The differential diagnosis of anti-NuMA-1-positive patients must include Sjögren's syndrome, while patients with anti-CE antibodies must be observed for HCV infection.

[Identification of anti-HLA-A1 antibodies in a multi-transfused patient--case report]. / Identofokacija anti-HLA-A1 antitela kod "politransfundovanog" bolesnika-prokaz slucaja.

INTRODUCTION: HLA antibodies develop as a result of alloimmunization to HLA class I and II antigens. Their appearance is associated with frequent blood transfusions, allogeneic tissue and organ transplantation, pregnancy and immunization. It is established that after usage of single dose HLA nonmatched leukocytes, circulating lymphocytotoxic antibodies appear in serum of recipients, 10 to 12 days after alloimmunization. CASE REPORT: This article describes a case report of a multi-transfused patient, with identified HLA-A1 antibodies established by using microlymphocytotoxicity test and two different panels of HLA typed lymphocytes. The case report shows occurrence of febrile posttransfusion nonhemolytic reaction (FNHTR) in our patient after application of 410 ml resuspended erythrocytes. After transfusiologists recommendations for detecting lymphocytotoxic antibodies in patient's serum, we determined a specificity of monospecific antibody which caused posttransfusion FNHTR. DISCUSSION AND CONCLUSION: FNHTR may be caused by antileukocyte antibodies or immunoinflammatory cytokines. It is more frequent in patients receiving platelet concentrates (15-30%) than those receiving red blood cell products (1%). This case report shows that FNHTR was caused by HLA-A1 antibody in a patient who received 111 various blood products.