The Association between Immune Checkpoint Proteins and Therapy Outcomes in Acute Myeloid Leukaemia Patients.

The development of novel drugs with different mechanisms of action has dramatically changed the treatment landscape of AML patients in recent years. Considering a significant dysregulation of the immune system, inhibitors of immune checkpoint (ICI) proteins provide a substantial therapeutic option for those subjects. However, use of ICI in haematological malignancies remains very limited, in contrast to their wide use in solid tumours. Here, we analysed expression patterns of the most promising selected checkpoint-based therapeutic targets in AML patients. Peripheral blood of 72 untreated AML patients was used for flow cytometric analysis. Expression of PD-1, PD-L1, CTLA-4, and B7-H3 was assessed within CD4+ (Th) lymphocytes and CD33+ blast cells. Patients were stratified based on therapy outcome and cytogenetic molecular risk. AML non-responders (NR) showed a higher frequency of PD-1 in Th cells compared to those with complete remission (CR). Reduced blast cell level of CTLA-4 was another factor differentiating CR from NR subjects. Elevated levels of PD-1 were associated with a trend for poorer patients' survival. Additionally, prognosis for AML patients was worse in case of a higher frequency of B7-H3 in Th lymphocytes. In summary, we showed the significance of selected ICI as outcome predictors in AML management. Further, multicentre studies are required for validation of those data.

Molnupiravir is effective in patients with haematological malignancies.

Patients with hematologic malignancies are particularly vulnerable to severe infectious complications. SARS-CoV-2 infection is associated with a high risk of severe course and death in this patient population. In addition, immune deficits associated with both the blood cancer and the treatment used make vaccination against SARS-CoV-2 less effective than in immunocompetent individuals. Molnupiravir is one of the first oral antiviral drugs to demonstrate a significant benefit in reducing hospitalisation and death in COVID-19 in the general population. In this context, 175 haematology patients with diagnosed COVID-19, and treated with MOL between January and April 2022, came under our scrutiny with a view to defining their clinical characteristics and outcomes. The most common underlying conditions were lymphomas (45%), multiple myelomas (21%) and acute leukaemias or myelodysplastic syndrome (35%). Of all, 77% of the patients were vaccinated, and half of them received a booster. At 28 days after the breakthrough COVID-19 diagnosis, 35 (20%) subjects required hospital admission. Out of those patients, seven (4%) died during the follow-up due to the progression of COVID. Our results corroborate what has been established to date with regard to the positive clinical and safety outcomes of MOL in haematology patients with mild or moderate COVID-19.

Response to anti-SARS-CoV-2 mRNA vaccines in multiple myeloma and chronic lymphocytic leukemia patients.

Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients have increased morbidity and mortality rates of COVID-19 due to immunosuppression associated with the disease and ongoing therapy. The same immune impairment accompanying CLL and MM also affects suboptimal vaccine response. The study assessed the effectiveness of the humoral and T cell-mediated immunity following mRNA COVID-19 vaccination (using either BNT162b2 or mRNA-1273) in short-term (2-5 weeks after second dose) and long-term follow-up (12 weeks after vaccination). Between March and August 2021, blood samples were obtained from 62 CLL and 60 MM patients from eight different hematology departments in Poland. Total anti-RBD antibodies were detected in 37% MM patients before vaccination, increased to 91% and 94% in short- and long-term follow-up, respectively. In CLL, serological responses were detectable in 21% of patients before vaccination and increased to 45% in the short-term and 71% in long-term observation. We detected a tendency to higher frequencies of specific CD8+ T cells against SARS-CoV-2 after vaccination compared to samples before vaccination in MM patients and no changes in frequencies of specific T cells in CLL patients. Our study provides novel insights into mRNA vaccination efficacy in immunocompromised MM and CLL patients, and our findings highlight that specific CD8+ T cells against SARS-CoV-2 might be induced by vaccination but do not correlate positively with serological responses.

A Proliferation-Inducing Ligand and B-Cell Activating Factor Are Upregulated in Patients with Essential Thrombocythemia.

A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) are cytokines belonging to the tumor necrosis factor family which play an essential role in B-cell maturation, differentiation, and survival. Recent evidence indicates their importance in hematological disorders; however, their function in essential thrombocytosis (ET) pathogenesis remains elusive. Therefore, we aimed to analyze the role of APRIL and BAFF in megakaryocytopoiesis in ET patients. We observed elevated levels of APRIL and BAFF in the plasma of ET patients compared with healthy controls, while no differences were found among patients with different JAK2(V617F) statuses. In addition, APRIL levels were positively associated with the number of platelets and WBC count. In the bone marrow, APRIL but not BAFF levels were higher in ET patients with the JAK2(V617F) mutation; however, JAK2(V617F)-negative patients showed slightly reduced levels of BAFF. In ET patients, we showed that the differentiation of CD34+ progenitor cells towards megakaryocytes induces the expression of both APRIL and BAFF. More importantly, APRIL neutralization significantly reduced platelet production. In conclusion, our data provide evidence that blocking APRIL signaling, which acts as an autocrine growth factor for terminal megakaryocytopoiesis, inhibits platelet production in ET patients, regardless of the status of JAK2(V617F) mutation.

Cladribine Combined with Low-Dose Cytarabine as Frontline Treatment for Unfit Elderly Acute Myeloid Leukemia Patients: Results from a Prospective Multicenter Study of Polish Adult Leukemia Group (PALG).

Acute myeloid leukemia (AML) in older unfit patients is a therapeutic challenge for clinical hematologists. We evaluated the efficacy and safety of a novel low-intensity regimen consisting of low-dose cytarabine and cladribine (LD-AC+cladribine) in first-line treatment of elderly (≥60 years) AML patients not eligible for intensive chemotherapy (IC) who had either the Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 or the hematopoietic cell transplantation comorbidity index (HCT-CI) score ≥3. The induction phase included two cycles of LD-AC+cladribine. Patients who achieved at least partial remission (PR) received maintenance treatment with LD-AC alone. Overall, 117 patients with a median age of 70 years were enrolled. Adverse cytogenetics, ECOG PS ≥2 and HCT-CI score ≥3 was observed in 43.5%, 60%, and 58% of patients, respectively. The response rate (≥PR) was 54% (complete remission [CR], 32%; CR with incomplete hematologic recovery [CRi], 5%). A median overall survival (OS) was 21 and 8.8 months in CR/CRi and PR group, respectively. Advanced age (≥75 years) and adverse cytogenetics had a negative impact on OS. The 56-day mortality rate was 20.5%. In conclusion, LD-AC+cladribine is a beneficial therapeutic option with a predictable safety profile in elderly AML patients not eligible for IC.

The causes of thrombocytopenia after transcatheter aortic valve implantation.

INTRODUCTION: Even though thrombocytopenia following transcatheter aortic valve implantation (TAVI) has been described, further investigation of this phenomenon is needed. AIMS: To determine which factors may explain the fall in platelet count that occurs after implantation of a TAVI device, including markers of platelet and blood coagulation activation. MATERIAL AND METHODS: 32 patients without previous indications for dual antiplatelet therapy (mean age 78.5±7.9 years, 62% females) with severe aortic valve stenosis (mean gradient 54.6±16.9mmHg) who qualified for TAVI procedure (Edwards Sapien XT) were prospectively analyzed. Platelet counts were analyzed before the surgery, on the day of the procedure and for the three following postoperative days (POD 1 to 3). To assess platelet activation P-selectin (PS, serum) and platelet factor 4 (PF-4, CTAD plasma) were measured, whereas for the evaluation of coagulation activation prothrombin fragments 1+2 (F1+2, plasma) were assessed before the procedure, on POD-1 and POD-3 (ELISA). RESULTS: During the postoperative period a significant platelet count drop, the most evident on POD-2, was observed followed by a platelet count raise. The platelet count drop correlated directly with the amount of iodinated contrast agent (r=0.42, p=0.016) and inversely with baseline mean platelet volume (r=-0.37, p=0.046). Neither clinical nor perioperative parameters, except contrast medium, influenced platelet count decrease. No significant differences regarding the concentration of the evaluated markers in patients with and without thrombocytopenia were found. PF-4 and F1+2 significantly changed during the study (p<0.05). Greater acute PF-4 decrease correlated with greater acute platelet count drop (r=0.48, p=0.043), and during the study slower PF-4 increase correlated with higher platelet count increase on POD-3 (r=-0.505, p=0.032). Lower baseline PS correlated with lower baseline platelet count and higher platelet count increase on POD-3 (r=0.45, p=0.04 and =-0.55, p=0.02, respectively). No significant correlations between F1+2 concentrations and platelet count changes have been found. CONCLUSIONS: Platelet reduction shortly after TAVI procedure is related to the amount of contrast agent applied during the procedure. Platelet activation and blood coagulation along with impaired baseline platelet renewal might be the mechanisms of thrombocytopenia following TAVI procedure.

Addition of cladribine to the standard induction treatment improves outcomes in a subset of elderly acute myeloid leukemia patients. Results of a randomized Polish Adult Leukemia Group (PALG) phase II trial.

Intensive induction chemotherapy using anthracycline and cytarabine backbone is considered the most effective upfront therapy in physically fit older patients with acute myeloid leukemia (AML). However, outcomes of the standard induction in elderly AML are inferior to those observed in younger patients, and they are still unsatisfactory. As addition of cladribine to the standard induction therapy is known to improve outcome in younger AML patients. The present randomized phase II study compares efficacy and toxicity of the DAC (daunorubicin plus cytarabine plus cladribine) regimen with the standard DA (daunorubicin plus cytarabine) regimen in the newly diagnosed AML patients over 60 years of age. A total of 171 patients were enrolled in the study (DA, 86; DAC, 85). A trend toward higher complete remission (CR) was observed in the DAC arm compared to the DA arm (44% vs. 34%; P = .19), which did not lead to improved median overall survival, which in the case of the DAC group was 8.6 months compared to in 9.1 months in the DA group (P = .64). However, DAC appeared to be superior in the group of patients aged 60-65 (CR rate: DAC 51% vs. DA 29%; P = .02). What is more, a subgroup of patients, with good and intermediate karyotypes, benefited from addition of cladribine also in terms of overall survival (P = .02). No differences in hematological and nonhematological toxicity between the DA and DAC regimens were observed.

To treat or not to treat: metabolomics reveals biomarkers for treatment indication in chronic lymphocytic leukaemia patients.

In chronic lymphocytic leukaemia (CLL), the clinical course of patients is heterogeneous. Some present an aggressive disease onset and require immediate therapy, while others remain without treatment for years. Current disease staging systems developed by Rai and Binet may be useful in forecasting patient survival time, but do not discriminate between stable and progressive forms of the disease in the early stages. Recently ample attention has been directed towards identifying new disease prognostic markers capable of predicting clinical aggressiveness at diagnosis. In the present study serum samples from stable (n = 51) and progressive (n = 42) CLL patients and controls (n = 45) were used with aim to discover metabolic indicators of disease status. First an LC-MS based metabolic fingerprinting method was used to analyse selected samples in order to find a potential markers discriminating aggressive from indolent patients. Ten of these discovered markers were validated on the whole set of samples with an independent analytical technique. Linoleamide (p = 0.002) in addition to various acylcarnitines (p = 0.001-0.000001) showed to be significant markers of CLL in its aggressive form. Acetylcarnitine (p = 0.05) and hexannoylcarnitine (p = 0.005) were also distinguishable markers of indolent subjects. Forming a panel of selected acylcarnitines and fatty acid amides, it was possible to reach a potentially highly specific and sensitive diagnostic approach (AUC = 0.766).

Expression of IL-1 and IL-6 and their natural regulators in leukocytes of B-cell chronic lymphocytic leukaemia patients.

PURPOSE: The purpose of the study was the assessment of the expression of IL-1ß and IL-6, and the proteins regulating their biological activity, namely IL-1RII, IL-1Ra, as well as sIL-6Rα, sgp-130 in leukemic lymphocytes and autologous neutrophils of B-CLL patients. MATERIAL/METHODS: The study involved a group of B-cell chronic lymphocytic leukemia patients and healthy volunteer blood donors. The presence of chosen proteins and their natural regulators was confirmed by Western blot. RESULTS: Western blot analysis showed a decreased expression of IL-1ß and IL-6 in the leukocytes of B-CLL patients. Decreased expression of sIL-6Rα has been observed in lymphocytes, with a simultaneous increase of expression in PMNs. Lower expression of sgp-130 was found in B cells while its expression was elevated in the neutrophils of patients in early stages of the disease. CONCLUSIONS: The changes observed in the expression of IL-1 and IL-6 seem to exclude their immediate involvement in the progress of B-CLL. However, the presented changes in the expression of proteins regulating IL-1ß and IL-6 in PMNs indicate a potential role of early immune response cells also in advanced stages of the disease.

Prognostic significance of PD-1 expression on peripheral blood CD4+ T cells in patients with newly diagnosed chronic lymphocytic leukemia.

INTRODUCTION: Recent studies in a mouse model of chronic lymphocytic leukemia (CLL) demonstrated that inhibition of the programmed death receptor 1 (PD­1)-PD­L1 axis resulted in correction of leukemia­induced CD8+ T cell­related immune dysfunction and protected mice against CLL development. However, it remains unclear whether CLL development and progression can be also associated with CD4+ T cells expressing PD­1. OBJECTIVES: We aimed to analyze whether a quantitative assessment of CD4+PD­1+ T cells performed at the time of diagnosis can have prognostic significance in patients with CLL. PATIENTS AND METHODS: We examined 56 patients with newly diagnosed CLL at different stages of the disease. The quantitative assessment of PD­1­expressing CD4+ T cells was performed in all patients, using multicolor flow cytometry. RESULTS: We demonstrated that CLL patients with an advanced (high and intermediate risk) stage had a significantly higher number of CD4+PD­1+ T cells compared with subjects with low­grade disease. Importantly, we showed that the number of PD­1­expressing CD4+ T cells in the peripheral blood of patients referred for immediate treatment due to the advanced stage of the disease was significantly higher compared with subjects on watchful waiting. Finally, we found that treatment­naive patients with higher numbers of CD4+PD­1+ T cells at baseline showed a significantly shortened time to the first treatment compared with patients with a low number of CD4+PD­1+ T cells. CONCLUSIONS: Our study showed that the quantative assessment of CD4+PD­1+ T cells in peripheral blood using flow cytometry can facilitate prognostication of patients with newly diagnosed CLL.

Circulating classical CD14++CD16- monocytes predict shorter time to initial treatment in chronic lymphocytic leukemia patients: Differential effects of immune chemotherapy on monocyte-related membrane and soluble forms of CD163.

Three main monocyte subsets: classical CD14++CD16-, intermediate CD14++CD16+ and non-classical CD14+CD16++, differentially regulate tumor growth and survival. Thereby, in the present study we aimed to determine the role of distinct monocyte subsets in the prognostication of chronic lymphocytic leukemia (CLL). Moreover, we set out to analyze the effects of standard immune chemotherapy on different monocyte subsets and levels of membrane-associated and soluble forms of CD163, a monocyte/macrophage-related immunomodulatory protein. We demonstrated that the number of peripheral blood classical CD14++CD16- monocytes assessed at the time of diagnosis was negatively correlated with lymphocytosis and was decreased in the CLL patients who required immediate treatment as opposed to patients who qualified to 'watch and wait' strategy. Notably, lower baseline levels of classical CD14++CD16- monocytes in CLL patients who were qualified for 'watch and wait' therapy were associated with shorter time to initial treatment. Notably, therapy with rituximab, cyclophosphamide and fludarabine resulted in a significant reduction in the number of non-classical CD14+CD16++ monocytes and soluble form of CD163 but upregulation of membrane-associated monocyte CD163. Our data indicate that distinct monocyte subsets and two forms of CD163 are differentially modulated by both CLL and immune chemotherapy. Moreover, we proposed that quantification of classical monocytes at the time of diagnosis contributes to better prognostication of CLL patients.

Treatment of elderly patients with acute myeloid leukemia adjusted for performance status and presence of comorbidities: a Polish Adult Leukemia Group study.

This prospective study estimated outcomes in 509 elderly patients with acute myeloid leukemia (AML) with different treatment approaches depending on Eastern Cooperative Oncology Group (ECOG) performance status and Charlson Comorbidity Index (CCI). Patients were stratified into fit (ECOG 0-2 and CCI 0-2) or frail (ECOG>2 and/or CCI>2) groups. Fit patients with CCI 0 received intensive chemotherapy whilst reduced-intensive chemotherapy (R-IC) was given to those with CCI 1-2. Frail patients received best supportive therapy. Fit patients presented a longer overall survival (OS) than frail subjects, but 8-week mortality rates were similar. The complete response (CR) rate between fit CCI 0 and CCI 1-2 subgroups was significantly different. Both of the fit subgroups showed similar 8-week mortality rates and OS probabilities. Allocating fit patients with CCI 1-2 to R-IC enabled an increase in the group of elderly patients who could be treated with the intention of inducing remission.

Relationship between tumour necrosis factor-related apoptosis inducing ligand (TRAIL) and vascular endothelial growth factor in human multiple myeloma patients.

Tumour necrosis factor-alfa (TNF-α) is an inflammatory cytokine with a wide spectrum of biological activity, including angiogenesis. Tumour necrosis factor-related apoptosis inducing ligand (TRAIL), which belongs to the TNF family of proteins, plays a role in the regulation of vascular responses, but its effect on the formation of new blood vessels (angiogenesis) is unclear. We analysed TRAIL concentrations in parallel with pro-angiogenic cytokines in serum and their expression in trephine biopsy (TB) in 56 patients with newly diagnosed IgG MM and 24 healthy volunteers. The study showed statistically higher concentrations of TRAIL and TNF-α, as well as of VEGF and its receptor, in MM patients compared to healthy volunteers and patients in advanced stages of the disease. Furthermore, we observed a significant decrease in all studied pro-angiogenic cytokines and significant increase of TRAIL concentration after anti-angiogenic therapy, with meaningful differences between responders (at least partial remission) and patients with progression during the induction treatment. It was also established that TRAIL correlated statistically and negatively with pro-angiogenic cytokines such as VEGF with its receptor and expression of VEGF and syndecan-1 in TB. In summary, our data indicate that in MM patients, both clinical course and treatment responsiveness are associated with dynamic yet corresponding changes of levels of TRAIL parallel pro-angiogenic mediators such as VEGF with its receptor and expression of VEGF and syndecan-1 in TB.

Platelet-related fibrinolysis resistance in patients suffering from PV. Impact of clot retraction and isovolemic erythrocytapheresis.

Using patients with polycythemia vera (PV) as an experimental model, we evaluated the impact of clot retraction (CR) and architecture of the clot on fibrinolysis. We studied the kinetics of clot retraction and the fibrinolysis rate in whole blood from 48 PV patients and 48 healthy controls. Measurements were performed before and after isovolemic eryhrocytapheresis (ECP). CR was measured by optical method. Clot lysis time (CLT) and maximum clot firmness (MCF) were measured by thromboelastometry in recalcified blood supplemented with t-PA and tissue factor. Compared with healthy controls, CR rate in PV patients was higher (0.0219 vs. 0.0138; p<0.001), the clot volume smaller and MCF elevated (64 vs. 58 mm). CR rate correlated with platelet count (r=0.546; p=0.001) but not with erythrocyte concentration (r=0.192; p>0.3). Compared with healthy controls, CLT in PV patients was significantly prolonged (158 min vs. 71 min). Fibrinolysis rate inversely correlated with CR rate (r=-0.566; p<0.001); MCF (r=-0.704; p<0.001) and platelet count (r=-0.461; p<0.001). As judged by confocal microscope, in comparison to healthy controls, clots formed in blood from PV patients demonstrated booth a distinctly higher degree of crosslinking and possessed thinner fibers. Altered CR, MCF and fibrinolysis speeds were not normalized following the ECP procedure. Tirofiban (a blocker of platelet GPIIb/IIIa receptors), unlike aspirin, normalized abnormal CR and fibrinolysis in blood from PV patients. Collectively, our data indicate that in PV patients, abnormal CR may result in formation of thrombi that are more resistant to fibrinolysis. ECP and aspirin failed to normalize platelet-related fibrinolysis resistance.

Prognostic relevance of HSP70 antigen and antibody measurement in patients with acute myeloid leukemia of intermediate and unfavorable cytogenetic risk.

INTRODUCTION: Heat shock proteins (HSPs) are overexpressed in many types of cancers and are implicated in tumor cell proliferation, differentiation, invasion, metastasis, death, and recognition by the immune system. It has been postulated that the HSP70 protein can be used as a prognostic indicator of overall patient survival in many types of cancer including leukemia. OBJECTIVES: The aim of the study was to evaluate the concentrations of anti­HSP70 antibody and its antigen in the peripheral blood of patients with acute myeloid leukemia (AML), as well as to assess the usefulness of this measurement. PATIENTS AND METHODS: The study included 80 patients with AML of intermediate and high cytogenetic risk, scheduled for allogenic stem cell transplantation after initial intensive chemotherapy. Plasma concentrations of anti­HSP70 antibodies and HSP70 antigen were measured by enzyme­linked immunosorbent assay. The antigen was additionally measured by Western blot analysis. The control group consisted of healthy subjects. RESULTS: Patients with AML had significantly higher anti­HSP70 antibody concentrations compared with the control group. The concentration of HSP70 antigen as well as anti­HSP70 antibody showed no associations with the type of response after induction chemotherapy. However, patients with higher antigen levels and lower anti­HSP70 antibody levels had significantly shorter overall survival. CONCLUSIONS: The study suggests that anti­HSP70 antibodies and HSP70 antigen may be valuable indicators of a poor prognosis in patients with AML.

Long-term results of the Polish Adult Leukemia Group PALG-CLL2 phase III randomized study comparing cladribine-based combinations in chronic lymphocytic leukemia.

Long-term outcomes following newer therapies for chronic lymphocytic leukemia (CLL) have rarely been reported. This article presents the results of the final analysis of the Polish Adult Leukemia Group PALG-CLL2 study performed 10 years from final patient enrollment. With the extended follow-up time, it was found that cladribine (2-CdA)-based combinations CMC (2-CdA, cyclophosphamide, mitoxantrone) and CC (2-CdA, cyclophosphamide) administered as first-line treatment of progressive CLL resulted in significantly longer progression-free survival, but similar overall survival compared to 2-CdA monotherapy. Furthermore, the risk of potentially fatal late adverse events including infections, autoimmune complications and, particularly, secondary neoplasms was comparable among patients treated with CMC, CC or 2-CdA. The results of our analysis support the importance of long-term outcome monitoring of randomized trials in CLL.

Expression of subtypes of interleukin-17 ligands and receptors in patients with B-cell chronic lymphocytic leukemia.

BACKGROUND: The diversity of biological effects of cytokines from the IL-17 family, as well as the wide range of cells sensitive to their influence, suggests that these molecules might play a significant role in the malignant pro- cess. METHODS: After the cells were initially isolated with Polymorphprep™, they were sorted with a MACS® magnetic separator, CD16 for neutrophils and CD19 for B lymphocytes. The presence of proteins: IL-17A, IL-17E, IL-17F, IL-17D, as well as receptors: IL-17R, IL-17BR, IL-17RC in cell lysates was confirmed by Western blot. The levels of IL-17A, IL-17E, and IL-17F in blood serum were determined with ELISA. RESULTS: The results indicate a lower expression of IL-17A, IL-17E, and IL-17F in PMNs and B lymphocytes of pa- tients with B-cell chronic lymphocytic leukemia compared to cells of healthy subjects. Elevated expression of IL- 17D was observed in the PMNs of patients, with a simultaneous decrease in the expression of this cytokine in leukemic B cells, in comparison to the control group. In patients with B-CLL, there also were observations of decreased expression of IL-17R, IL-17BR, and IL-17RC in leukemic B lymphocytes, compared to their expressions in the cells of healthy subjects. The blood serum of B-CLL patients demonstrated a significantly increased level of IL-17A at stage 0/I, II, and IV of disease; IL-17E at stage 0/I and II; IL-17F at stage 0/I, III, and IV of disease advancement, compared to the data obtained from the control group. CONCLUSIONS: The results clearly support the involvement of the studied proteins from the IL-17 family in the course of B-CLL and indicate that IL-17D may play a significant role in the course of this disease.

Differences and similarities between LC-MS derived serum fingerprints of patients with B-cell malignancies.

Multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) are closely related B-cell non-Hodgkin's lymphomas. MM, a plasma cell malignancy, is the second most common haematopoietic cancer in Western countries, with the median survival time of 3­4 years. CLL, a lymphocyte B malignancy, is the most common leukaemia in Western countries. About 25­30% of all CLL patients do not survive the period of 5 years following diagnosis. Both malignancies are complicated, not fully understood and incurable with the current standard treatment. Biologically, MM and CLL may be preceded by associated precursor conditions, that is, monoclonal gammopathy of undetermined significance for MM and its cellular counterpart and monoclonal B-cell lymphocytosis for CLL. Similarities and differences in the biology of these malignancies prompted us to evaluate their metabolomics in stages requiring chemotherapy. Fingerprinting of serum metabolites by the use of LC-MS has never been applied in studies on MM and CLL patients. Obtained results revealed metabolites common for both malignancies (e.g. fatty acids, acylcarnitines, sphingolipids, phospholipids, phenylalanylphenylalanine and isoprene) as well as those which render them different (e.g. lysophosphatidylcholines, monoacylglycerols, aminocaproic acid, phenylacetylglutamine).

Thrombocytopenia and perioperative complications after stentless Freedom Solo valve implantation.

BACKGROUND: Freedom Solo (FS) stentless bioprostheses have superior haemodynamic performance compared to stented valves; however, the data of thrombocytopenia after FS implantations is disturbing. AIM: To compare platelet count and perioperative complications between stentless and stented biological valves in patients undergoing aortic valve replacement. METHODS: In 29 patients, FS bovine valves (Sorin Group, Saluggia, Italy) were implanted. Platelet counts were analysed before surgery, on the day of operation, on four consecutive postoperative days (POD) as well as at discharge, and compared to 29 control patients with biological stented porcine valves (Labcor Laboratorios TLBP-A Supra). The analysis of the perioperative variables extracorporeal circulation (ECC), aortic cross clamping (XC) and mechanical ventilation times, as well as blood supply, was performed. RESULTS: Initial platelet counts were comparable in both groups. In the FS group, platelet levels on the four consecutive POD were significantly lower. The lowest platelet value (13 × 10³/µL), related to fatal thrombotic thrombocytopenic purpura, was found in one patient from the FS group. ECC as well as XC and mechanical ventilation times, were significantly longer in the FS group, and more blood transfusions in these patients were required. In multiple regression analysis, ECC and XC times did not correlate with platelet count. CONCLUSIONS: Implantations of FS stentless bioprostheses are related to significantly lower platelet counts. Severe perioperative complications and their relation to thrombocytopenia need further evaluation.

Protein Z concentrations in patients with acute leukemia.

Protein Z (PZ) deficiency may induce bleeding as well as thrombosis. The aim of our study was to estimate the concentration of PZ in patients with acute leukemia. Plasma levels of PZ were determined in 76 patients with newly diagnosed acute leukemia ([AML], n = 50; acute lymphoblastic leukemia [ALL], n = 26) and 62 healthy participants. In the patients, mean plasma concentrations of PZ were statistically lower than in healthy individuals: AML (1.24 ± 0.11 µg/mL vs 1.58 ± 0.05 µg/mL P = .01) and ALL (1.19 ± 0.16 µg/mL vs 1.58 ± 0.05 µg/mL P = .01). Levels of PZ below the fifth percentile (0.873 µg/mL) of normal value distribution in control participants were found in 30% of patients with AML and ALL and in 3% of controls (P < .0001). In this AML subgroup, we found statistically significant correlation between episodes of bleeding and PZ level (P = .01). There was no such correlation in ALL group. The results suggest that PZ can be a cofactor associated with an increased bleeding tendency in patients with AML.