Richter transformation - retrospective treatment outcomes analysis in Polish Adult Leukemia Study Group.

Richter transformation (RT) is defined as developing an aggressive lymphoma in 2-10% of patients suffering from chronic lymphocytic leukemia (CLL). So far, no complex analysis of RT demographics and treatment outcomes has been performed in Poland. Thus, the retrospective analysis of 124 patients with RT from Polish hematology centers was designed. Ninety-nine patients with diffuse large B-cell lymphoma (DLBCL-RT) were identified. The median overall survival (OS) for DLBCL-RT was 17.3 months, while for Hodgkin lymphoma (HL-RT)-21.3 months. In multivariate analysis, the independent factors of worse OS for DLBCL-RT were: prior CLL therapy, ECOG stage ≥2, and elevated serum LDH activity. Patients who proceeded to hematopoietic stem cell transplantation (HSCT) achieved better results. The median OS in allogeneic HSCT recipients was not reached, while in autologous HSCT median OS was 51.3 months. In conclusion, our study represents the largest dataset of patients diagnosed with RT in Poland and confirms its dismal prognosis.

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.

Maxillary transverse deficiency, with closed intermaxillary suture, does bone-anchored appliance during SARPE cause predictable, and stable maxillary expansion compared to the tooth-borne appliance during SARPE - Systematic review.

INTRODUCTION: Managing maxillary transverse deficiency (MTD) with closed intermaxillary suture is a challenge in orthodontic treatment plans; over the years, clinicians have developed many approaches to treat this significant dentofacial deformity. Therefore, it is crucial to understand the underlying causes of MTD and to establish an effective treatment method for restoring the ideal aesthetics and functions for patients. A current and effective SARPE technique for expanding the maxillary arch involves performing 2-piece Le Fort I osteotomy to surgically apply horizontal force to the maxilla along the midpalatal suture in conjunction with either a tooth-borne or bone-borne appliance. MATERIAL AND METHODS: A systemic review was conducted in order to investigate the differences between the two treatment methods for MTD with matured and closed intermaxillary suture: bone-anchored and tooth-borne appliance during SARPE (surgically-assisted rapid palatal expansion). The review was conducted in the English language through PubMed and Google Scholar electronic databases. The protocol is being reported in accordance with the PRISMA Statement. RESULTS: This research, however, is subject to several limitations, including minimal randomization, limited sample size, indefinite measurement methods, and a short follow-up period. Each method of maxillary transverse deficiency therapy has been proven to be effective in expanding the maxillary arch. CONCLUSION: From the analysis of the articles, it was concluded that bone-anchored appliances have a more predictable and stable expansion compared to the tooth-borne appliance during SARPE. Nevertheless, further studies are needed to confirm its long-term effectiveness.

What factors determine the pregnancy outcome in patients with essential thrombocythemia?

Objectives: Treatment of essential thrombocythemia (ET) is particularly challenging in pregnancy due to the increased risk of thromboembolic complications. Therefore, the use of antithrombotic regimens are recommended in pregnant women with ET.Methods: The study included 52 pregnancies in 27 patients diagnosed with ET, who were treated in Department of Haematology. The influence of anticoagulant, antiplatelet and cytoreductive therapy on the course and outcome of pregnancy was analysed. This study also examined if there was any correlation between molecular and clinical features such as mutational profile, blood count, presence of acquired von Willebrand syndrome (AvWS), the International Prognostic Score for Essential Thrombocythemia (IPSET) risk group and the IPSET-thrombosis risk group and pregnancy outcome.Results: Study participants who received antithrombotic therapy were significantly more likely to give birth to a healthy child. The best outcomes were observed in patients who received low dose acetylsalicylic acid (ASA) together with low-molecular-weight heparin (LMWH). There was a statistically significant correlation between classification to the high-risk group according to the IPSET-thrombosis score and incidence of miscarriage. Cytoreductive treatment with interferon-α2, as well as the presence of AvWS did not increase the likelihood of pregnancy loss. Blood counts and presence of specific gene mutations profile were also not found to be significant determinants of pregnancy outcome.Conclusion: To our best knowledge, this is the first clinical study investigating the correlation between risk group (according to IPSET and IPSET-thrombosis) and pregnancy outcome in women with ET.

Early Administration of Convalescent Plasma Improves Survival in Patients with Hematological Malignancies and COVID-19.

The use of convalescent plasma in the treatment of COVID-19 may lead to a milder course of infection and has been associated with improved outcomes. Determining optimal treatments in high risk populations is crucial, as is the case in those with hematological malignancies. We analyzed a cohort of 23 patients with hematological malignancies and COVID-19 who had received plasma 48-72 h after the diagnosis of infection and compared it with a historical group of 22 patients who received other therapy. Overall survival in those who received convalescent plasma was significantly higher than in the historical group (p = 0.03460). The plasma-treated group also showed a significantly milder course of infection (p = 0.03807), characterized by less severe symptoms and faster recovery (p = 0.00001). In conclusion, we have demonstrated that convalescent plasma is an effective treatment and its early administration leads to clinical improvement, increased viral clearance and longer overall survival in patients with hematological malignancies and COVID-19. To our knowledge, this is the first report to analyze the efficacy of convalescent plasma in a cohort of patients with hematological malignancies.

Treatment of Essential Thrombocythemia with Anagrelide Is Associated with an Increased Risk of Worsened Kidney Function.

BACKGROUND AND PURPOSE: When choosing a cytoreduction method for patients suffering from essential thrombocythemia (ET), it is important to know the safety profile of the medicine used. Few articles have been published about the effects of hydroxycarbamide (hydroxyurea, HU) and anagrelide (ANA) on renal function in ET patients. This study is the largest analysis of nephrotoxicity of cytoreductive drugs used in ET therapy so far, which additionally includes risk factors for the progression of kidney disease and coexisting genetic mutation. EXPERIMENTAL APPROACH: The retrospective study included 310 patients diagnosed with ET. Demographic data, comorbidities, Cr, and estimated glomerular filtration rate (eGFR) were all taken into account prior to diagnosis and after 6 months of HU and ANA treatment. KEY RESULTS: A statistically significant difference was found between Cr and eGFR levels at baseline and after 6 months of treatment (p < 0.001). The applied treatment (HU and ANA) had the greatest impact on kidney function. ANA significantly increased the risk of worsening renal function in contrary to hydroxycarbamide after 6 months of treatment (eGFR change: median +1 mL/min/1.73 m2 [interquartile range (IQR) (-4)-(+7)] in the HU group vss. median -13 mL/min/1.73 m2 [IQR (-18)-(-6)] in the ANA group, odds ratio [OR] 7.92 95% confidence interval [95% CI] [4.17-15.08], p < 0.001). Lowering of eGFR <60 mL/min/1.73 m2 occurred in 31 patients (31.0%) from the ANA group and 10 people (4.8%) treated with HU (p = 0.000). In 1 patient from the ANA group, >50% decrease in eGFR was observed. The chance for an increase in Cr levels was higher in people with pre-existing arterial hypertension (OR 1.92 CI = 95% [1.21-3.05], p = 0.006). Sex, type of mutation found (JAK2 V617F or CALR), and previous renal impairment did not affect renal function after 6 months of treatment. In addition, there was no difference in the efficacy of ET treatment between HU and ANA (p = 0.998). CONCLUSIONS AND IMPLICATIONS: The observations indicate that ANA should be used in patients with ET with great caution and taking into account the risk of worsened kidney function.

Nosocomial outbreak of SARS-CoV-2 infection in a haematological unit - High mortality rate in infected patients with haematologic malignancies.

BACKGROUND: Here we report nosocomial outbreak of COVID-19 among patients in a haematological unit. To our knowledge this is the first report from Central Europe comparing morbidity and mortality in infected and non-infected patients after exposure to SARS-CoV-2. METHODS: The outbreak involved 39 individuals: 19 patients and 20 health care workers. The SARS-CoV-2 test by nasopharyngeal swabs was performed by real-time RT-PCR. Exposed patients were divided into two groups: quarantine patients with and without COVID-19. All patients were prospectively examined at the following time points: 0, 7 days, 14 days, 21 days and 28 days after confirmation or exclusion of SARS-CoV-2. RESULTS: Infection was confirmed in a total of 5/20 health care workers and 10/19 patients. Among the patients positive for SARS-CoV-2 infection, the mortality rate was 36.8 %. The probability of death in patients infected with SARS-CoV-2 increased 8-fold (p = 0.03). Bacterial, fungal, and viral co-infection significantly decreased survival in these patients (p < 0.05). Additionally, the probability of death was much higher in patients older than 40 years of age (p = 0.032). CONCLUSION: This study showed significantly higher mortality rate in COVID-19 patients with haematologic diseases compared to the non-infected patient group. Haematologic patients with COVID-19 have 50 % less chance of survival.

Stepwise Evolution of Fragment Hits against MAPK Interacting Kinases 1 and 2.

Dysregulation of translation initiation factor 4E (eIF4E) activity occurs in various cancers. Mitogen-activated protein kinase (MAPK) interacting kinases 1 and 2 (MNK1 and MNK2) play a fundamental role in activation of eIF4E. Structure-activity relationship-driven expansion of a fragment hit led to discovery of dual MNK1 and MNK2 inhibitors based on a novel pyridine-benzamide scaffold. The compounds possess promising in vitro and in vivo pharmacokinetic profiles and show potent on target inhibition of eIF4E phosphorylation in cells.

Hodgkin lymphoma transformation of chronic lymphocytic leukemia-A real life data from the Polish Lymphoma Research Group.

Richter transformation (RT) of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to Hodgkin lymphoma (HL) is a rare and unexpected event in the course of the disease and data on this phenomenon is still limited. To better understand the clinical and histological characteristics and the outcomes of HL variant of RT (HvRS) the Polish Lymphoma Research Group performed a nationwide survey which identified 22 patients with histologically proven HvRS diagnosed between 2002 and 2016. There were 16 (73%) males. The median age at CLL/SLL and HvRS diagnosis was 59 (39-77) and 64 (40-77) years, respectively. The median interval between CLL/SLL and HvRS diagnosis was 38 months (range: 0-187). All patients had an advanced stage HL, and majority, 17 (77%), presented with B symptoms. The predominant subtypes of HL were nodular sclerosis (12; 55%) and mixed cellularity (9; 41%). Eighteen patients received non-palliative treatment, including 13 who received driamycin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen first line. Objective response was: 50%, with 33% complete remissions (61% and 46% for ABVD, respectively). Median overall survival reached 13.3 months (95% CI, 3.7-NA). The only adverse prognostic factor for survival was a higher number (≤1 versus ≥2) of prior lines of treatment given for CLL/SLL with HR 3.57 (95% CI, 1.16-10.92). We conclude, HvRS harbors a poor prognosis, especially in patients heavily pretreated for CLL/SLL. Response to standard first-line anti-HL chemotherapy is unsatisfactory, and new agents should be tested to improve the outcome.

Fragment-based Discovery of a Small-Molecule Protein Kinase C-iota Inhibitor Binding Post-kinase Domain Residues.

The atypical protein kinase C-iota (PKC-ι) enzyme is implicated in various cancers and has been put forward as an attractive target for developing anticancer therapy. A high concentration biochemical screen identified pyridine fragment weakly inhibiting PKC-ι with IC50 = 424 µM. Driven by structure-activity relationships and guided by docking hypothesis, the weakly bound fragment was eventually optimized into a potent inhibitor of PKC-ι (IC50= 270 nM). Through the course of the optimization, an intermediate compound was crystallized with the protein, and careful analysis of the X-ray crystal structure revealed a unique binding mode involving the post-kinase domain (C-terminal tail) of PKC-ι.

Diet and Physical Activity as Determinants of Lifestyle Chosen by Women from Southern Poland.

The aim of the study was to assess the relationship between the lifestyle of Polish women (characterized by the quality of diets and levels of reported physical activity) and their characteristics such as age, place of residence, physical activity at work or school, reported health status, and BMI. The sample consisted of 882 women from Southern Poland. Diet quality and the level of physical activity were evaluated by the Nutrition Beliefs Questionnaire established by the Polish Academy of Sciences. The lifestyle category (healthy, moderate, or unhealthy) was based on "Prohealthy Diet Index-10" and participant's self-assessed physical activity during their leisure-time. The lifestyle category was significantly associated with age, BMI, physical activity at work/school, and health. Moderate lifestyle (high or moderate levels of physical activity combined with low prohealthy diet) was the most commonly found classification in examined women. Age (>35 years old) and overweight are the main factors determining unhealthy lifestyle behavior. Healthy lifestyle is more often chosen by the women from big cities. More intensive efforts should be undertaken to increase the knowledge and awareness of the health benefits of a healthy lifestyle. The main goal should be concentrated on increasing the level of physical activity, especially in leisure time, and promoting the tenets of a well-balanced diet.

Fragment-Based Drug Discovery of Potent Protein Kinase C Iota Inhibitors.

Protein kinase C iota (PKC-ι) is an atypical kinase implicated in the promotion of different cancer types. A biochemical screen of a fragment library has identified several hits from which an azaindole-based scaffold was chosen for optimization. Driven by a structure-activity relationship and supported by molecular modeling, a weakly bound fragment was systematically grown into a potent and selective inhibitor against PKC-ι.

Application of the apparent diffusion coefficient in magnetic resonance imaging in an assessment of the early response to treatment in Hodgkin's and non-Hodgkin's lymphoma - pilot study.

PURPOSE: Lymphoproliferative neoplasms are the largest and most frequently diagnosed entities in the group of haematological malignancies. The aim of the study was to assess whether apparent diffusion coefficient (ADC) measured on the first day of the second cycle of chemotherapy could be a predictor of prognosis and of the final treatment's outcome. MATERIAL AND METHODS: The study included 27 patients with diagnosed Hodgkin's and non-Hodgkin's lymphoma, who had magnetic resonance (MR) performed with diffusion weighted imaging/apparent diffusion coefficient (DWI/ADC) before and on the first day of the second cycle of chemotherapy. Imaging was performed using a 1.5 T MR scanner. ADC was measured in lymphoma infiltration in the area of the lowest signal in the ADC map and the highest signal on ß 800 images in post-treatment study. After that, the corresponding area was determined in a pre-treatment study and an ADC value was measured. RESULTS: The difference between ADC values in pre-treatment (ADC = 720 mm2/s) and post-treatment (ADC = 1059 mm2/s) studies was statistically significant (p < 0.001). Cutoff values for estimating response to treatment were established at the level of ADC 1080 mm2/s, and ADC to muscle ratio at 0.82 in post-treatment study. Patients with ADC > 752 mm2/s before treatment manifested lower probability of progression than patients with ADC < 752 mm2/s. CONCLUSIONS: ADC measurement's before treatment and on the first day of the second cycle of chemotherapy can be used as a prognostic marker in lymphoma therapy. ADC values lower than 1080 mm2/s and an increase of the ratio after the treatment can be considered as a marker of disease progression.

Burden of Aquagenic Pruritus in Polycythaemia Vera.

Aquagenic pruritus (AP) has a significant influence on quality of life (QoL) in patients with polycythaemia vera. This study analysed the impact of AP on patient well-being in 102 patients with polycythaemia vera. Intensity of pruritus was evaluated using a visual analogue scale (VAS), verbal rating scale (VRS) and a 4-item Itch Questionnaire. Psychosocial aspects of AP were assessed with the Hospital Anxiety and Depression Scale (HADS), EQ-5D and itch-specific QoL questionnaire (ItchyQoL). AP of mean duration 6.6 ± 8.6 years and intensity 4.8 ± 1.9 points (VAS) was present in 42/102 individuals. The prevalence of depression and anxiety among patients with AP was 23.8% and 9.5%, respectively. Depression was more frequent in the AP group (vs. non-AP). Moreover, patients with AP had higher HADS-anxiety scoring than those without pruritus (p = 0.005). A negative correlation was found between duration of AP and EQ-5D-VAS. The ItchyQol score of 37.3 ± 12.3 points was influenced by the extent (p =0.01) and duration of episodes of AP (p = 0.02). In conclusion, AP places an additional burden on patients with polycy-thaemia vera, negatively influencing their QoL.

Peripheral circulatory disorders in essential thrombocythemia.

A significant number of patients with essential thrombocythemia (ET) complain of symptoms including distal parts of the extremities (e.g., paresthesias or Raynaud's phenomenon). The aim of the present study was to examine peripheral circulation in the upper extremities of individuals with ET. The study included 45 ET patients and 30 control subjects. All participants were subjected to thermography, photoplethysmography, impedance plethysmography, and applanation tonometry pulse wave analysis. The patients with ET differed significantly from the control subjects in terms of 3rd finger skin temperature (mean 31.04 vs. 32.45°C), skin temperature gradient (mean 1.82 vs. 0.11°C), photoplethysmographic amplitude (median 0.25 vs. 0.74%), and pulse waveform in the radial artery (more frequent occurrence of type B waveform). Pulse wave parameters correlated with the skin temperature gradient. The study findings imply the altered regulation of peripheral circulation in ET, including a decreased flow and an increased resistance.

Altered plasma fibrin clot properties in essential thrombocythemia.

Patients with increased thromboembolic risk tend to form denser fibrin clots which are relatively resistant to lysis. We sought to investigate whether essential thrombocythemia (ET) is associated with altered fibrin clot properties in plasma. Ex vivo plasma fibrin clot permeability coefficient (Ks), turbidimetry and clot lysis time (CLT) were measured in 43 consecutive patients with ET (platelet count from 245 to 991 × 10(3)/µL) and 50 control subjects matched for age, sex and comorbidities. Fibrinolysis proteins and inhibitors together with platelet activation markers were determined. Reduced Ks (-38%, p < 0.0001) and prolonged CLT (+34%, p < 0.0001) were observed in ET. The differences remained significant after adjustment for fibrinogen and platelet count. ET was associated with a slightly shorter lag phase (-5%, p = 0.01) and higher maximum absorbency of the turbidimetric curve (+6%, p < 0.001). The ET patients had higher plasma P-selectin by 193% (p < 0.00001) and platelet factor 4 (PF4) by 173% (p < 0.00001), with higher P-selectin observed in 19 (44%) patients with JAK-2 gene V617F mutation. Higher t-PA (+20%, p < 0.001), 23% higher plasminogen activator inhibitor-1, PAI-1 (+23%, p < 0.01) and unaltered thrombin-activatable fibrinolysis inhibitor, plasminogen and α2-antiplasmin activity were found in the ET group. Ks inversely correlated with fibrinogen, PF4 and C-reactive protein. CLT positively correlated only with PAI-1. Patients with ET display prothrombotic plasma fibrin clot phenotype including impaired fibrinolysis, which represents a new prothrombotic mechanism in this disease.

Evaluation of flavonoid contents and antioxidant capacity of the aerial parts of common and tartary buckwheat plants.

The analysis of major and minor flavonoids, and antioxidant capacity of stems, leaves, flowers, unripe seeds and ripe seeds of common and tartary buckwheat plants collected during different growth periods was addressed in this study. The highest rutin contents were observed in flowers and leaves collected from common and tartary buckwheat at early flowering as well as flowering and seed formation states. A low quercetin contents were found in all studied aerial part of buckwheat plants. Quercitrin (quercetin-3-rhamnoside) was only found in flowers collected at different growth periods while flavone C-glucosides were accumulated preferentially only in unripe seeds collected from common buckwheat at an early flowering state. The rank of antioxidant capacity provided for aerial parts of common and tartary buckwheat at early flowering state was as follows: flowers > leaves > stems. The highest contribution of rutin to the antioxidant capacity of the aerial parts of common and tartary buckwheat was found for stems followed by leaves, flowers and unripe seeds. The results demonstrate that flowers from common and tartary buckwheat collected at early flowering as well as flowering and seed formation states have the future potential to be a useful food ingredient.

Indole-3-acetic acid and auxin herbicides up-regulate 9-cis-epoxycarotenoid dioxygenase gene expression and abscisic acid accumulation in cleavers (Galium aparine): interaction with ethylene.

Interaction between auxin and auxin-induced ethylene was suggested in previous work to up-regulate abscisic acid (ABA) biosynthesis in cleavers (Galium aparine) through stimulated cleavage of xanthophylls to xanthoxin, catalysed by 9-cis-epoxycarotenoid dioxygenase (NCED). Here, the effects of auxin on NCED gene expression were studied in relation to changes in ethylene synthesis and ABA levels. A gene from G. aparine shoot tissue was cloned based on sequence similarity to cloned NCED genes from tomato (LeNCED1), potato, Phaseolus, and Arabidopsis. When the roots of G. aparine plants were treated with 0.5 mM indole-3-acetic acid (IAA), IAA concentrations increased from 0.2 microM to 65 microM IAA in the shoot tissue after 3 h. Transient increases in GaNCED1 mRNA levels were detectable as early as 1 h after treatment and reached maximum values of 40-fold, relative to the control, after 3 h. Increases in GaNCED1 mRNA preceded increases in 1-aminocyclopropane-1-carboxylic acid and ethylene. Levels of ABA began to increase more slowly and, significantly, with a lag phase of 2 h, and reached levels 24-fold higher than those in controls after 24 h. GaNCED1 gene expression was also stimulated by auxin herbicides. The ethylene-releasing compound ethephon induced GaNCED1 transcript levels only moderately. In accordance with this, aminoethoxyvinylglycine and cobalt ions, which inhibit ethylene synthesis, only slightly affected the increase in GaNCED1 transcript levels by IAA. However, both ethylene inhibitors decreased IAA-induced ABA accumulation by up to 70%. This suggests that auxin and auxin-induced ethylene are involved in ABA accumulation. While auxin is the primary trigger for NCED gene expression, ethylene appears to enhance ABA biosynthesis, possibly by up-regulation of NCED activity post-transcriptionally.