Effect of Thermal Shock Conditions on the Low-Cycle Fatigue Performance of 3D-Printed Materials: Acrylonitrile Butadiene Styrene, Acrylonitrile-Styrene-Acrylate, High-Impact Polystyrene, and Poly(lactic acid).

3D printing technology is becoming a widely adopted alternative to traditional polymer manufacturing methods. The most important advantage of 3D printing over traditional manufacturing methods, such as injection molding or extrusion, is the short time from the creation of a new design to the finished product. Nevertheless, 3D-printed parts generally have lower strength and lower durability compared to the same parts manufactured using traditional methods. Resistance to the environmental conditions in which a 3D-printed part operates is important to its durability. One of the most important factors that reduces durability and degrades the mechanical properties of 3D-printed parts is temperature, especially rapid temperature changes. In the case of inhomogeneous internal geometry and heterogeneous material properties, rapid temperature changes can have a significant impact on the degradation of 3D-printed parts. This degradation is more severe in high-humidity environments. Under these complex service conditions, information on the strength and fatigue behavior of 3D-printed polymers is limited. In this study, we evaluated the effects of high humidity and temperature changes on the durability and strength properties of 3D-printed parts. Samples made of commonly available materials such as ABS (Acrylonitrile Butadiene Styrene), ASA (Acrylonitrile-Styrene-Acrylate), HIPS (High-Impact Polystyrene), and PLA (Poly(lactic acid)) were subjected to temperature cycling, from an ambient temperature to -20 °C, and then were heated to 70 °C. After thermal treatment, the samples were subjected to cyclic loading to determine changes in their fatigue life relative to non-thermally treated reference samples. The results of cyclic testing showed a decrease in durability for samples made of ASA and HIPS. The ABS material proved to be resistant to the environmental effects of shocks, while the PLA material exhibited an increase in durability. Changes in the internal structure and porosity of the specimens under temperature changes were also evaluated using microcomputed tomography (microCT). Temperature changes also affected the porosity of the samples, which varied depending on the material used.

Substrate Affinity Is Not Crucial for Therapeutic L-Asparaginases: Antileukemic Activity of Novel Bacterial Enzymes.

L-asparaginases are used in the treatment of acute lymphoblastic leukemia. The aim of this work was to compare the antiproliferative potential and proapoptotic properties of novel L-asparaginases from different structural classes, viz. EcAIII and KpAIII (class 2), as well as ReAIV and ReAV (class 3). The EcAII (class 1) enzyme served as a reference. The proapoptotic and antiproliferative effects were tested using four human leukemia cell models: MOLT-4, RAJI, THP-1, and HL-60. The antiproliferative assay with the MOLT-4 cell line indicated the inhibitory properties of all tested L-asparaginases. The results from the THP-1 cell models showed a similar antiproliferative effect in the presence of EcAII, EcAIII, and KpAIII. In the case of HL-60 cells, the inhibition of proliferation was observed in the presence of EcAII and KpAIII, whereas the proliferation of RAJI cells was inhibited only by EcAII. The results of the proapoptotic assays showed individual effects of the enzymes toward specific cell lines, suggesting a selective (time-dependent and dose-dependent) action of the tested L-asparaginases. We have, thus, demonstrated that novel L-asparaginases, with a lower substrate affinity than EcAII, also exhibit significant antileukemic properties in vitro, which makes them interesting new drug candidates for the treatment of hematological malignancies. For all enzymes, the kinetic parameters (Km and kcat) and thermal stability (Tm) were determined. Structural and catalytic properties of L-asparaginases from different classes are also summarized.

Immune escape of B-cell lymphoblastic leukemic cells through a lineage switch to acute myeloid leukemia.

Acute leukemia (AL) with a lineage switch (LS) is associated with poor prognosis. The predisposing factors of LS are unknown, apart from KMT2A rearrangements that have been reported to be associated with LS. Herein, we present two cases and review all 104 published cases to identify risk factors for LS. Most of the patients (75.5%) experienced a switch from the lymphoid phenotype to the myeloid phenotype. Eighteen patients (17.0%) experienced a transformation from acute myelogenous leukemia (AML) to acute lymphoblastic leukemia (ALL). Forty-nine (46.2%) patients carried a KMT2A rearrangement. Most of the cases involved LS from B-cell ALL (B-ALL) to AML (59.4%), and 49 patients (46.2%) carried KMT2A-rearrangements. Forty patients (37.7%) received lineage-specific immunotherapy. Our findings suggest that the prevalence of KMT2A rearrangements together with the lineage-specific immunotherapy may trigger LS, which supports the thesis of the existence of leukemia stem cells that are capable of lymphoid or myeloid differentiation.

The Depth of the Molecular Response in Patients with Chronic Myeloid Leukemia Correlates with Changes in Humoral Immunity.

Background and Objectives: The effective treatment of chronic myeloid leukemia leads to the restoration of proper immune system function. We aimed to investigate fluctuations in circulating cytokines, angiogenic factors and complement components in patients with CML during the first year of treatment with TKI and correlate them with the degree of achieved molecular response. Material and Methods: We recruited 31 patients with newly diagnosed CML. Peripheral blood and bone marrow samples were obtained, and concentrations of serum proteins were measured using an immunology multiplex assay. Results: The study cohort was divided into two groups of optimal or non-optimal in accordance with the European Leukemia Net (ELN) guidelines. We found significantly higher concentrations of C1q, C4 and C5a in serum after 3 months of TKI treatment in patients who achieved optimal responses in the 6 months after diagnosis. The most alterations were observed during 12 months of therapy. Patients in the optimal response group were characterized by higher serum concentrations of TGF-ß, EGF, VEGF, Angiopoietin 1, IFN-γ and IL-8. Conclusions: The later plasma concentrations of complement components were significantly increased in patients with optimal responses. The changes after 12 months of treatment were particularly significant. Similar changes in bone marrow samples were observed.

Multiscale Carbon Fibre-Carbon Nanotube Composites of Poly(Vinyl Chloride)-An Evaluation of Their Properties and Structure.

To date, there has been limited information in the literature on the application of carbon fibre-carbon nanotube systems for the modification of poly(vinyl chloride) (PVC) matrixes by micro- and nanometric fillers and an evaluation of the properties of the unique materials produced. This paper presents the results of newly designed unique multiscale composites. The advantages of the simultaneous use of carbon fibres (CFs) and carbon nanotubes (CNTs) in PVC modification are discussed. To increase the dispersibility of the nanofiller, CFs together with nanotubes were subjected to a sonication process. The resulting material was introduced into PVC blends, which were processed by extrusion. The ratio of components in the hybrid filler with CF_CNT was 20:1, and its proportion in the PVC matrix was 1, 5, and 10 wt.%, respectively. Comparatively, PVC composites modified only with carbon fibres were obtained. The structure, thermal, electrical, and mechanical properties and swelling resistance of the composites were studied. The study showed a favourable homogeneous dispersion of nanotubes in the PVC matrix. This enabled effective modification of the structure at the nanometric level and the formation of an interpenetrating network of well-dispersed hybrid filler, as evidenced by a decrease in volume resistivity and improvement in swelling resistance, as well as an increase in glass transition temperature in the case of PVC/CF_CNT composites.

Management and outcome of patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era - analysis of the European LeukemiaNet Blast Phase Registry.

Blast phase (BP) of chronic myeloid leukemia (CML) still represents an unmet clinical need with a dismal prognosis. Due to the rarity of the condition and the heterogeneity of the biology and clinical presentation, prospective trials and concise treatment recommendations are lacking. Here we present the analysis of the European LeukemiaNet Blast Phase Registry, an international collection of the clinical presentation, treatment and outcome of blast phases which had been diagnosed in CML patients after 2015. Data reveal the expected heterogeneity of the entity, lacking a clear treatment standard. Outcomes remain dismal, with a median overall survival of 23.8 months (median follow up 27.8 months). Allogeneic stem cell transplantation (alloSCT) increases the rate of deep molecular responses. De novo BP and BP evolving from a previous CML do show slightly different features, suggesting a different biology between the two entities. Data show that outside clinical trials and in a real-world setting treatment of blast phase is individualized according to disease- and patient-related characteristics, with the aim of blast clearance prior to allogeneic stem cell transplantation. AlloSCT should be offered to all patients eligible for this procedure.

The Utility of Intravenous Methylprednisolone as an Adjunct Treatment for Drug-Resistant Amiodarone-Induced Thyrotoxicosis.

BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) may pose treatment challenges. We present a series of patients in which we achieved the normalisation of free T3 (FT3) using intravenous methylprednisolone (ivMP) in AIT refractory to thiamazole and oral prednisone. Namely, in three males (aged 56, 50 and 64, all with a history of AF and/or a low ejection fraction), an addition of ivMP resulted in the normalisation of FT3, which allowed successful thyroidectomy. In another case of a 65-year-old man, we initially succeeded in the normalisation of FT3 using ivMP from FT4 > 7.77 ng/dL (0.93-1.7) to 2.41 ng/dL and in that of FT3 from 14.95 pg/mL (2-4.4) to 2.05 pg/mL), but four weeks after stopping ivMP, despite the continuation of thiamazole and prednisone, there was rebound thyrotoxicosis: FT4 > 7.77 ng/dL and FT3-5.46 pg/mL. Intravenous MP was restated leading to a decline in FT4 to 2.51 ng/dL and in FT3 to 1.92 pg/mL, thus allowing a successful thyroidectomy. Finally, in a 78-year-old man with AF, goitre, and AIT resistant to thiamazole, prednisone and lithium carbonate, we obtained a reduction in FT4 to 1.51 ng/dL and in FT3 to 3.17 pg/mL after seven pulses of ivMP. Oral prednisone was gradually reduced and successfully stopped about six months later. He remained on low-dose thiamazole (5 mg od). CONCLUSIONS: Pulse ivMP in addition to oral steroids may be a useful adjunct therapy either for the preparation of a thyroidectomy or as a treatment modality in drug-resistant AIT. Though a total cure is possible, there is a danger of a rebound worsening of thyrotoxicosis after premature discontinuation of ivMP.

Prognostic Impact of Copy Number Alterations' Profile and AID/RAG Signatures in Acute Lymphoblastic Leukemia (ALL) with BCR::ABL and without Recurrent Genetic Aberrations (NEG ALL) Treated with Intensive Chemotherapy.

Adult acute lymphoblastic leukemia (ALL) is associated with poor outcomes. ALL is initiated by primary aberrations, but secondary genetic lesions are necessary for overt ALL. In this study, we reassessed the value of primary and secondary aberrations in intensively treated ALL patients in relation to mutator enzyme expression. RT-PCR, genomic PCR, and sequencing were applied to evaluate primary aberrations, while qPCR was used to measure the expression of RAG and AID mutator enzymes in 166 adult ALL patients. Secondary copy number alterations (CNA) were studied in 94 cases by MLPA assay. Primary aberrations alone stratified 30% of the patients (27% high-risk, 3% low-risk cases). The remaining 70% intermediate-risk patients included BCR::ABL1pos subgroup and ALL lacking identified genetic markers (NEG ALL). We identified three CNA profiles: high-risk bad-CNA (CNAhigh/IKZF1pos), low-risk good-CNA (all other CNAs), and intermediate-risk CNAneg. Furthermore, based on RAG/AID expression, we report possible mechanisms underlying the CNA profiles associated with poor outcome: AID stratified outcome in CNAneg, which accompanied most likely a particular profile of single nucleotide variations, while RAG in CNApos increased the odds for CNAhigh/IKZF1pos development. Finally, we integrated primary genetic aberrations with CNA to propose a revised risk stratification code, which allowed us to stratify 75% of BCR::ABL1pos and NEG patients.

Superior sagittal sinus thrombosis in the course of mixed phenotype acute leukaemia treated with acute lymphoblastic leukaemia-like therapy-a case report.

Mixed phenotype acute leukaemia (MPAL) is associated with worse overall survival, compared with other acute leukaemias in adults. Lack of clear treatment guidelines makes the therapy challenging. ALL-like induction and consolidation treatment followed by allo-HSCT is the preferred first-line treatment. We present a case of a 36-year-old woman diagnosed with MPAL (EGIL Myelo/B) with KMT2A rearrangement, treated with the PALG-ALL-7 (including PEG-asparaginase) protocol. On day 25 after the induction therapy initiation, numbness of limbs and dizziness were observed. Therefore, the imaging studies (CT and MRI) were performed and a diagnosis of thrombosis of superior sagittal sinus of the brain was established. Routinely performed blood coagulation tests showed prolonged APTT and PT, decreased antithrombin III activity and decreased free protein S concentration. LMWH treatment and substitutional therapy with antithrombin III were started, which resulted in a significant reduction in the thrombosis associated symptoms and improvement of the neurological status after 3 days. After induction and consolidation therapy, the patient obtained complete haematological remission and negative measurable residual disease. Six months after the diagnosis, allo-HSCT was successfully performed. During the 4 months follow-up, the patient remained MRD negative and thrombotic symptoms free. To the best of our knowledge, our communication has been the first report of such complication in an MPAL patient treated with PEG-asparaginase containing protocol in adults. We recommend increased vigilance in patients manifesting any mild neurological symptoms and early decision about the MRI study performance.

The role of daratumumab in relapsed/refractory CD38 positive acute leukemias-case report on three cases with a literature review.

Primary refractory or relapsed T-cell acute lymphoblastic leukemia (T-ALL) and mixed phenotype myeloid/T-cell acute leukemia have dismal prognoses. New treatment approaches, preferably targeting specific leukemic aberrations to overcome resistance, are urgently needed. The bright expression of the CD38 antigen found in several cases of T-ALL led to an investigation into the role of anti-CD38 antibodies in the treatment of T-ALL. Here, we present three cases of resistant and relapsed T-ALL and myeloid/T-cell treated with daratumumab-based therapy, including venetoclax and bortezomib (Dara-Ven-Bor). All patients achieved complete remission, with minimal residual disease negativity within four weeks of treatment, allowing them to proceed to allogeneic hematopoietic cell transplantation. The toxicity of the triple schema was acceptable. Our patients and other cases reviewed here suggest that daratumumab combined with venetoclax and bortezomib may be a very effective and relatively safe salvage treatment, even in primary resistant T-ALL.

Prediction of major bleeding events in 1381 patients with essential thrombocythemia.

The goal of therapy in essential thrombocythemia (ET) is reducing thrombotic risk. No algorithm to predict hemorrhage risk exists. The impact ofanti-platelet, cytoreductive and anticoagulation therapies on risk of major bleeding (MB) was evaluated. MB events were retrospectively analyzed in 1381 ET from 10 European centers. There were 0.286 MB events/person-year. Neither the International Thrombosis Prognostic Score for thrombosis in essential thrombocythemia (IPSET-t) nor the revised IPSET-t (r-IPSET-t) was predictive for hemorrhage-free survival at 10 years (p = 0.092 vs p = 0.1). Ageand leukocyte count were MB risk factors, while low hemoglobin was protective. For ET with extreme thrombocytosis (ExtT) and leukocytosis cytoreduction was not protective. MB were more frequent in ET with ExtT who received anticoagulation. Antiplatelet therapy was not, while anticoagulation was a risk factor for MB (HR 3.05, p = 0.016, CI 1.23-7.56), in particular vitamin K antagonists (22.6% of those treated had a MB event, HR 2.96, p = 0.004, CI 1.41-6.22). Survival at 10 years was associated with hemorrhage (OR 2.54, p < 0.001) but not thrombosis (HR 0.95, p = 0.829). Hemorrhage has a higher risk of mortality than thrombosis. Improved risk stratification for MB is necessary. The choice of anticoagulation, cytoreduction and antiplatelet therapies is an important area of research in ET.

The presence of additional cytogenetic aberrations in chronic myeloid leukemia cells at the time of diagnosis or their appearance on tyrosine kinase inhibitor therapy predicts the imatinib treatment failure.

Currently used treatment of CML dramatically improved the prognosis of disease. However, additional chromosome aberrations (ACA/Ph+) are still one of the adverse prognostic factors. OBJECTIVES: evaluation of the impact of ACA/Ph+ appearance during disease outcome on the response to treatment. THE STUDY GROUP: consisted of 203 patients. The median time of follow-up was 72 months. ACA/Ph+ was found in 53 patients. RESULTS: patients were divided into four groups: standard risk, intermediate, high and very high risk. When ACA/Ph+ presence was documented at diagnosis time the optimal response was observed in 41.2%, 25%, and 0% of pts with intermediate, high and very high risk, respectively. If ACA/Ph+ were detected during imatinib treatment the optimal response was in 4.8% of patients. The risk of blastic transformation for patients with standard risk, intermediate, high and very high risk was 2.7%, 18.4%, 20% and 50%, respectively. CONCLUSIONS: the presence of ACA/Ph+ at diagnosis time or their appearance on therapy seems to be clinically relevant not only in terms of the risk of blastic transformation but also in terms of the treatment failure. Gathering patients with various karyotypes and their responses to treatment would allow to set better guidelines and predictions.

BCR::ABL1-like acute lymphoblastic leukaemia: a single institution experience on identification of potentially therapeutic targetable cases.

BACKGROUND: BCR::ABL1-like acute lymphoblastic leukaemia (BCR::ABL1-like ALL) is characterized by inferior outcomes. Current efforts concentrate on the identification of molecular targets to improve the therapy results. The accessibility to next generation sequencing, a recommended diagnostic method, is limited. We present our experience in the BCR::ABL1-like ALL diagnostics, using a simplified algorithm. RESULTS: Out of 102 B-ALL adult patients admitted to our Department in the years 2008-2022, 71 patients with available genetic material were included. The diagnostic algorithm comprised flow cytometry, fluorescent in-situ hybridization, karyotype analysis and molecular testing with high resolution melt analysis and Sanger Sequencing. We recognized recurring cytogenetic abnormalities in 32 patients. The remaining 39 patients were screened for BCR::ABL1-like features. Among them, we identified 6 patients with BCR::ABL1-like features (15.4%). Notably, we documented CRLF2-rearranged (CRLF2-r) BCR::ABL1-like ALL occurrence in a patient with long-term remission of previously CRLF2-r negative ALL. CONCLUSIONS: An algorithm implementing widely available techniques enables the identification of BCR::ABL1-like ALL cases in settings with limited resources.

High molecular risk variants, severe thrombocytopenia and large unstained cells count affect the outcome in primary myelofibrosis.

Apart from the driver mutations, high molecular risk (HMR) variants and other factors have been reported to influence the prognosis of primary myelofibrosis (PMF). The aim of our study was to investigate the impact of laboratory and molecular characteristics at the time of diagnosis (TOD) on the PMF outcome. The study group consisted of 82 patients recruited from three Polish university centers. Among the driver mutations, only CALR type 1 positively influenced the overall survival (OS). The risk of progression to accelerated or blastic disease phase (AP/BP) did not depend on the driver mutation type, but was closely associated with the presence of HMR variants (p = 0.0062). The risk of death (ROD) was higher in patients with HMR variants (OR[95%CI] = 4.33[1.52;12.34], p = 0.0044) and in patients with a platelet count at the TOD between 50-100 G/L (HR[95%CI] = 2.66[1.11;6.35]) and < 50 G/L (HR[95%CI] = 8.44[2.50;28.44]). Median survival time was 7.8, 2.2 and 1.4 years in patients with large unstained cells (LUC) count of [0.0-0.2], (0.2-0.4] and > 0.4 G/L at the TOD, respectively. We found an unexpected, hitherto undescribed, association between LUC count at the TOD and PMF prognosis. Our analysis led to the following conclusions: in PMF patients at the TOD 1) the presence of HMR variants, especially combined, is associated with an increased risk of progression to the AP and BP, and shorter OS, 2) severe thrombocytopenia confers worse prognosis than the moderate one, 3) LUC count is closely related with the disease phase, and associated with the ROD and OS.

Modification of Poly(vinyl chloride) with Bio-Based Cassia Oil to Improve Thermo-Mechanical and Antimicrobial Properties.

The purpose of this study was to modify plasticised PVC to obtain a material with antimicrobial properties and selected mechanical properties. Natural cassia oil (CO) was used to modify plasticised PVC materials. The modified material was produced by extrusion. The introduced modifier had a maximum concentration of 20 phr. Rheological and mechanical properties were evaluated, and the glass transition temperature was determined. The antioxidant and antimicrobial activity of the agar diffusion method was investigated by analysing the growth inhibition zones against Enterococcus faecalis and Listeria monocytogenes. A favourable effect of the cassia oil content on the increase in antioxidant activity of the developed polymeric materials was found with an increase in the modifier content and the duration of action (30 days). The largest growth restriction zones were observed for L. monocytogenes, i.e., they showed the highest sensitivity to the modified material. The simultaneous decrease in modulus of elasticity, increase in elongation at break, and decrease in Tg indicate that the modifier has a plasticising effect on PVC. The developed material may find application as an active and/or functional material, especially as an emitter of antimicrobial agents, in the packaging used to store minimally processed food.

Frequency of COVID-19 Infection as a Function of Vitamin D Levels.

BACKGROUND: It has been speculated that higher concentrations of 25-hydroxy-vitamin D (25OHD) provide some protection against COVID-19. We assessed whether there is any relationship between 25OHD concentrations and the subsequent development of COVID-19 infection. MATERIALS AND METHODS: Concentrations of 25OHD were measured in March-April 2020 in 134 healthy subjects (57 males), age range 6-50, from a single urban general practice in central Poland. Data on COVID-19 infection during the subsequent 12 months (prior to the vaccination program) were obtained from the national database of COVID-19 cases. None of the subjects received any 25OHD supplements. RESULTS: The average 25OHD concentrations were 18.1 ± 7.39 ng/mL (37.3% had 25OHD above 20 ng/mL). Thirty-one (23.1%) patients developed COVID-19 infection, but an increased risk was only observed in individuals with 25OHD concentrations below 12 ng/mL (COVID-19 infection in 11 out of 25 patients (44%) with 25OHD < 12 ng/mL versus 20 out of 109 (18.3%) for those with 25OHD above 12 ng/mL, p = 0.0063). Such a relationship was no longer observed for subjects with 25OHD concentrations above 20 ng/mL (p = 0.2787). CONCLUSIONS: Although only a minority of healthy subjects had 25OHD concentrations above 20 ng/mL in spring, an increased risk of subsequent COVID-19 infection was only observed in those with severe 25OHD deficiency (<12 ng/mL).

Renin, Aldosterone, and Cortisol in Pregnancy-Induced Hypertension.

INTRODUCTION: We aimed to assess renin, aldosterone, and cortisol in the early stages of pregnancy-induced hypertension (PIH), i. e., at the time of diagnosis. METHODS: During the postural test, we measured aldosterone, renin [Liason DiaSorin Inc. (Italy)], as well as cortisol, sodium, potassium, and 24-h urinary sodium and potassium excretion in 62 women with newly diagnosed PIH, 70 healthy women during the 3rd trimester of pregnancy, and in 22 healthy non-pregnant women. RESULTS: In all groups, there was a significant increase in aldosterone and renin in upright versus supine posture (p<0.01). Both supine and upright aldosterone concentrations were higher in healthy pregnant women than in women with PIH and the lowest in healthy not-pregnant [supine (median±intequartile range): 25.04±18.4 ng/dL, 18.03±12.58 ng/dL, and 7.48±4.78 ng/dL, p<0.001, upright: 31.60±21.32 ng/dL, 25.11±13.15 ng/dL, and 12.4±12.4 ng/dL, p<0.001, for healthy pregnant, pregnant with PIH, and non-pregnant, respectively]. Supine renin concentrations were higher only in healthy pregnant (p<0.001), while in the upright position, there was a difference only between healthy pregnant and women with PIH (p=0.002). Both in supine and upright positions, there was no difference in the aldosterone-to-renin ratio between healthy pregnant women and women with PIH, though, in both groups, the ratio was higher than in non-pregnant women (p<0.001). Morning cortisol concentrations and 24-h urinary sodium excretion were lower in women with PIH than in healthy pregnant (p<0.001, p=0.002, respectively). CONCLUSION: Hyperaldosteronism is not involved in the etiology of PIH. In PIH, there is also a tendency towards lower sodium excretion and lower morning cortisol concentrations.

HRAS mutation positive multiple myeloma in the type 2 CALR mutation positive essential thrombocythemia: A case report.

Out of BCR-ABL negative myeloproliferative neoplasm (MPNPh- ) patients, 3%-14% display a concomitant monoclonal gammopathy of unknown significance (MGUS). In most cases, the diagnosis of plasma cell dyscrasia is either synchronous with that of MPNPh- or occurs later on. We present a 50-year-old patient with type 2 CALR Lys385Asnfs*47 mutation positive essential thrombocythemia (ET) who developed symptomatic multiple myeloma (MM) 13 years after the diagnosis of ET during PEG-INF2α treatment. The NGS study performed at the time of the MM diagnosis revealed the HRAS Val14Gly/c.41T〉G mutation and the wild type CALR, JAK2 and MPL gene sequence. In the presented case, the complete molecular remission of ET was achieved after 16 months of PEG-INF2α treatment. The origin of MM cells in MPNPh- patients remains unknown. Published data suggests that type 2 CALRins5 up-regulate the ATF6 chaperone targets in hematopoietic cells and activate the inositol-requiring enzyme 1α-X-box-binding protein 1 pathway of the unfolded protein response (UPR) system to drive malignancy. It cannot be excluded that endoplasmic reticulum stress induced by the increased ATF6 resulted in an abnormal redox homeostasis and proteostasis, which are factors linked to MM. The presented case history and the proposed mechanism of mutant CALR interaction with UPR and/or ATF6 should initiate the discussion about the possible impact of the mutant CALR protein on the function and genomic stability of different types of myeloid cells, including progenitor cells.

Analysis of Predictive Factors for Early Response to Ruxolitinib in 320 Patients with Myelofibrosis From the Polish Adult Leukemia Group (PALG) Registry.

INTRODUCTION: Ruxolitinib is widely used in myelofibrosis (MF). However, some patients do not optimally respond and require more efficacious treatment. Our analysis aimed to establish predictors of ruxolitinib response. PATIENTS AND METHODS: We designed a multicenter, retrospective analysis of the efficacy of ruxolitinib treatment in patients with MF in 15 Polish hematology centers. As responses to ruxolitinib occur within the first 6 months, we used this point to evaluate the efficacy of treatment. Symptoms response was defined as ≥50% reduction of the MF constitutional symptoms assessed by Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS). Spleen response was defined as ≥50% reduction of the difference between the spleen's baseline length and the upper limit norm measured by ultrasonography. RESULTS: 320 MF patients were enrolled. At 6 months of therapy, the spleen response was detected in 140 (50%) patients, and symptoms response in 241 patients (76%). Multivariable analysis identified leukocytosis <25 G/L (OR 2.06, 95%CI: 1.12-3.88, P = .0200), and reticulin fibrosis MF 1 (OR 2.22, 95%CI: 1.11-4.46, P = .0249) contributed to better spleen response. The time interval between MF diagnosis and ruxolitinib administration shorter than 3 months, and platelets ≥150 G/L (OR 1.69, 95% CI 1.01-2.83, P = .0466) influenced symptoms response. CONCLUSION: Establishing predictive factors for ruxolitinib response is particularly important given the potential for new therapies in MF. In patients with a low likelihood of responding to ruxolitinib, using other JAK inhibitors or adding a drug with a different mechanism of action to ruxolitinib may be of clinical benefit.