The Clinical Tumor Lysis Syndrome in a Patient with Mixed Phenotype Acute Leukemia Undergoing Induction with Venetoclax and Azacitidine: A Case Report.

A combination of azacitidine and venetoclax (AZA-VEN) has been approved for the treatment of adult treatment-naïve acute myeloid leukemia (AML) patients, ineligible for intensive chemotherapy. The protocol may also constitute an alternative for the treatment of patients with mixed phenotype acute leukemia (MPAL), for which no established treatment guidelines exist. It may be anticipated, that alike in AML or chronic lymphocytic leukemia, the treatment of MPAL may be complicated by the tumor lysis syndrome (TLS). No case of TLS in MPAL after VEN has been however reported so far. Here, we present a case of a patient with MPAL, who received AZA-VEN. The patient had a substantial bulk of disease with generalized lymphadenopathy and increased white blood cell count. Despite preventive measures, the patient developed the clinical TLS, which was successfully treated. Based on the current case and other published cases, the incidence of TLS after AZA-VEN was established at 17%.

Negative Impact of Borderline Creatinine Concentration and Glomerular Filtration Rate at Baseline on the Outcome of Patients With Multiple Myeloma Treated With Autologous Stem Cell Transplant.

BACKGROUND: Renal impairment (RI) is one of the multiple myeloma (MM)-defining events for initiating therapy. After induction therapy, high-dose chemotherapy followed by autologous peripheral blood stem cell transplant (ASCT) remains the standard of care for transplant-eligible patients with MM. According to the International Myeloma Working Group (IMWG), the organ criterion for kidney damage is defined by a serum creatinine concentration (CrC) > 2 mg/dL or estimated glomerular filtration rate (eGFR) < 40 mL/min. In this long-term study, we evaluated the impact of CrC and eGFR calculated by the Modification of Diet in Renal Disease equation on progression-free and overall survival using a lower threshold than the IMWG criteria. PATIENTS AND METHODS: We studied the longitudinal outcomes as measured by progression-free survival and overall survival in 59 transplant-eligible patients with MM: 38 patients with normal renal function and 21 patients with RI defined as a CrC higher than upper limit of normal (≥ 1.1 mg/dL), eGFR < 60 mL/min, treated with ASCT from 1998 to 2004. RESULTS: The risk of disease progression and death following ASCT increased by 16.5% (P = .005) and 19% (P < .0009) per 1 mg/dL of CrC, respectively. The thresholds for the association of renal insufficiency and negative outcomes were CrC > 1.4 mg/dL and eGFR < 55mL/min. CONCLUSIONS: We observed a negative correlation between minimal renal insufficiency and long-term outcomes. Management of patients with even marginally increased CrC and/or decreased eGFR not fulfilling IMWG RI criteria requires more concentrated effort to reverse even minimal renal insufficiency.

Cardiac rehabilitation in patients with ST-segment elevation myocardial infarction: can its failure be predicted?

BACKGROUND: The prognosis in patients after acute coronary syndromes (ACS) is significantly burdened by coexisting anaemia, leukocytosis and low glomerular filtration rate (GFR). Hyperglycaemia in the early stages of ACS is a strong predictor of death and heart failure in non-diabetic subjects. This study aimed to evaluate the effect of hyperglycaemia, anaemia, leukocytosis, thrombocytopaenia and decreased GFR on the risk of the failure of cardiac rehabilitation (phase II at the hospital) in post-ST-segment elevation myocardial infarction (STEMI) patients. METHODS: The study included 136 post-STEMI patients, 96 men and 40 women, aged 60.1 ± 11.8 years, admitted for cardiac rehabilitation (phase II) to the Department of Internal Medicine and Cardiac Rehabilitation, WAM University Hospital in Lodz, Poland. On admission fasting blood cell count was performed and serum glucose and creatinine level was determined (GFR assessment). The following results were considered abnormal: glucose ⩾ 100 mg/dl, GFR < 60 ml/min/1, 73 m², red blood cells (RBCs) < 4 × 106/µl, white blood cells (WBCs) > 10 × 103/µl; platelets (PLTs) < 150 × 10³/ml. In all patients an exercise test was performed twice, before and after the completion of the second stage of rehabilitation, to assess its effects. RESULTS: Based on logistic regression analysis and the results of an individual odds ratio (OR) of the tested parameters, their prognostic impact was determined on the risk of failure of cardiac rehabilitation. This risk has been defined on the basis of the patient's inability to tolerate workload increment >5 Watt in spite of the applied program of cardiac rehabilitation. As a result of building a logistic regression model, the most statistically significant risk factors were selected, on the basis of which cardiac rehabilitation failure index was determined. leukocytosis and reduced GFR determined most significantly the risk of failure of cardiac rehabilitation (respectively OR = 6.42 and OR = 3.29, p = 0.007). These parameters were subsequently utilized to construct a rehabilitation failure index. CONCLUSIONS: Peripheral blood cell count and GFR are important in assessing the prognosis of cardiac rehabilitation effects. leukocytosis and decreased GFR determine to the highest degree the risk of cardiac rehabilitation failure. Cardiac rehabilitation failure index may be useful in classifying patients into an appropriate model of rehabilitation. These findings support our earlier reports.

[The usefulness of complete blood count in predicting cardiac rehabilitation failure in post-NSTEMI patients]. / Przydatnosc badania morfologicznego krwi w przewidywaniu niepowodzenia rehabilitacji kardiologicznej u chorych po NSTEMI.

ACS (acute coronary syndrome) NSTEMI is more prevalent than ACS STEMI. Within four years the mortality rate was twice higher in NSTEMI group than in the STEMI group. Studies have demonstrated that cardiac rehabilitation decreases the risk of all-cause mortality as well as the mortality related to cardiovascular events. AIM: The aim of the study was to evaluate with the use of an index of own design the prognostic value of the complete blood count (CBC) in predicting cardiac rehabilitation failure in post-NSTEMI patients. MATERIALS AND METHODS: The study comprised 116 post-NSTEMI patients, 81 men and 35 women, aged 64,12±11,29 years, admitted for cardiac rehabilitation to the Department of Internal Medicine and Cardiac Rehabilitation, MU in Lodz. On admission fasting blood cell count was performed, serum glucose and creatinine level was determined (GFR assessment). The following results were considered abnormal: glucose level ≥100 mg/dl, GFR<60 ml/min/1.73m2, RBC < 4x106 µl, WBC > 10x103/µl, PLT < 150x103/µl. Exercise test (cycloergometer) was performed twice in all patients - before and after the completion (4 weeks) of the II phase of the rehabilitation to assess its effects. RESULTS: Basing on logistic regression analysis and the results of individual odds ratio (OR) of the tested blood parameters, their prognostic impact on the risk of cardiac rehabilitation failure was determined. This risk was defined on the basis of patient's inability to tolerate any workload increment (0 Watt) between the initial and final result of the exercise test despite the applied cardiac rehabilitation program. The most statistically significant risk factors were selected as the result of logistic regression model building on the basis of which cardiac rehabilitation failure index was determined. Anemia and leucocytosis determined most significantly the failure of cardiac rehabilitation (respectively OR=2,77 and OR=2,36; p=0,01). They were used to construct a rehabilitation failure index with the values ranging from 0 to 2, where 0 - corresponds to absence of anemia and leucocytosis, 1 - corresponds to the occurrence of anemia or leucocytosis in post-NSTEMI patients and was associated with 2,65-fold increase of the risk of cardiac rehabilitation failure, 2 - corresponds to simultaneous occurrence of anemia and leucocytosis and was associated with 7,02-fold increase of the risk of cardiac rehabilitation failure. CONCLUSIONS: Complete blood count is useful in predicting cardiac rehabilitation failure. Anemia and leucocytosis are the most significant determinants of cardiac rehabilitation failure in post-NSTEMI patients. Cardiac rehabilitation failure index can be used for its individual programming. Then optimal rehabilitation effects can be obtained maintaining its safety in post-NSTEMI patients.

[Leukocytosis and decreased glomerular filtration rate increase the risk of cardiac rehabilitation failure in post-STEMI patients]. / Leukocytoza i obnizona wartosc filtracji klebuszkowej zwiekszaja ryzyko niepowodzenia rehabilitacji kardiologicznej u chorych po STEMI.

Recently, in the prognostic assessment of ACS patients attention has been paid to hyperglycemia, leukocytosis, decreased GFR, anemia and thrombocytopenia as they are believed to worsen the prognosis. AIM: The aim of this study was to evaluate the results of basic laboratory blood tests in predicting the failure of in-hospital cardiac rehabilitation in post-STEMI patients - using an index of own design. MATERIALS AND METHODS: The study comprised 100 post-STEMI patients, 70 men and 30 women, aged 60,1±10,3 years, admitted for cardiac rehabilitation (phase II) to the Department of Internal Medicine and Cardiac Rehabilitation, WAM University Hospital in Lodz. On admission fasting blood cell count and glucose and creatinine level was determined (for GFR assessment). The following results were considered abnormal: glucose level ≥100 mg/dl, GFR<60 ml/min/ 1,73m2, WBC> 10x103/µl, RBC<4x106/µl, PLT<150x103/µl. Exercise test was performed twice in all patients - before and after the completion of the II phase of cardiac rehabilitation to assess its effects. RESULTS: Basing on logistic regression analysis and on the results of individual odds ratio (OR) of the tested blood parameters, their prognostic impact on the risk of cardiac rehabilitation failure was determined. This risk was defined on the basis of post-STEMI patients' inability to tolerate any workload increment (0 Watt) between the initial and final result of the exercise test despite the applied cardiac rehabilitation program. This concerned 54 out of 100 post- STEMI patients. Leukocytosis (WBC>10x103/µl) and GFR<60 ml/ min/1,73 m2 determined most significantly the failure of cardiac rehabilitation (respectively: OR=6,65 and OR=3,43; p=0,05). Thus, they were used to construct a cardiac rehabilitation index. The occurrence of leukocytosis or decreased GFR in post-STEMI patients was associated with a 4,5-fold increase of the risk of cardiac rehabilitation failure, whereas simultaneous occurrence of leukocytosis and decreased GFR was associated with over 20-fold increase of this risk. CONCLUSIONS: The results of peripheral blood laboratory tests are useful in predicting cardiac rehabilitation effects. Leukocytosis and decreased GFR (<60 ml/min/1,73 m2) determine to the highest degree the risk of cardiac rehabilitation failure (phase II) in post-STEMI patients. Cardiac rehabilitation failure index can be useful in developing individualized rehabilitation program for post-STEMI patients.

Similarities and differences in the nucleic acid chaperone activity of HIV-2 and HIV-1 nucleocapsid proteins in vitro.

BACKGROUND: The nucleocapsid domain of Gag and mature nucleocapsid protein (NC) act as nucleic acid chaperones and facilitate folding of nucleic acids at critical steps of retroviral replication cycle. The basic N-terminus of HIV-1 NC protein was shown most important for the chaperone activity. The HIV-2 NC (NCp8) and HIV-1 NC (NCp7) proteins possess two highly conserved zinc fingers, flanked by basic residues. However, the NCp8 N-terminal domain is significantly shorter and contains less positively charged residues. This study characterizes previously unknown, nucleic acid chaperone activity of the HIV-2 NC protein. RESULTS: We have comparatively investigated the in vitro nucleic acid chaperone properties of the HIV-2 and HIV-1 NC proteins. Using substrates derived from the HIV-1 and HIV-2 genomes, we determined the ability of both proteins to chaperone nucleic acid aggregation, annealing and strand exchange in duplex structures. Both NC proteins displayed comparable, high annealing activity of HIV-1 TAR DNA and its complementary nucleic acid. Interesting differences between the two NC proteins were discovered when longer HIV substrates, particularly those derived from the HIV-2 genome, were used in chaperone assays. In contrast to NCp7, NCp8 weakly facilitates annealing of HIV-2 TAR RNA to its complementary TAR (-) DNA. NCp8 is also unable to efficiently stimulate tRNALys3 annealing to its respective HIV-2 PBS motif. Using truncated NCp8 peptide, we demonstrated that despite the fact that the N-terminus of NCp8 differs from that of NCp7, this domain is essential for NCp8 activity. CONCLUSION: Our data demonstrate that the HIV-2 NC protein displays reduced nucleic acid chaperone activity compared to that of HIV-1 NC. We found that NCp8 activity is limited by substrate length and stability to a greater degree than that of NCp7. This is especially interesting in light of the fact that the HIV-2 5'UTR is more structured than that of HIV-1. The reduced chaperone activity observed with NCp8 may influence the efficiency of reverse transcription and other key steps of the HIV-2 replication cycle.

Developmentally regulated expression and complex processing of barley pri-microRNAs.

BACKGROUND: MicroRNAs (miRNAs) regulate gene expression via mRNA cleavage or translation inhibition. In spite of barley being a cereal of great economic importance, very little data is available concerning its miRNA biogenesis. There are 69 barley miRNA and 67 pre-miRNA sequences available in the miRBase (release 19). However, no barley pri-miRNA and MIR gene structures have been shown experimentally. In the present paper, we examine the biogenesis of selected barley miRNAs and the developmental regulation of their pri-miRNA processing to learn more about miRNA maturation in barely. RESULTS: To investigate the organization of barley microRNA genes, nine microRNAs - 156g, 159b, 166n, 168a-5p/168a-3p, 171e, 397b-3p, 1120, and 1126 - were selected. Two of the studied miRNAs originate from one MIR168a-5p/168a-3p gene. The presence of all miRNAs was confirmed using a Northern blot approach. The miRNAs are encoded by genes with diverse organizations, representing mostly independent transcription units with or without introns. The intron-containing miRNA transcripts undergo complex splicing events to generate various spliced isoforms. We identified miRNAs that were encoded within introns of the noncoding genes MIR156g and MIR1126. Interestingly, the intron that encodes miR156g is spliced less efficiently than the intron encoding miR1126 from their specific precursors. miR397b-3p was detected in barley as a most probable functional miRNA, in contrast to rice where it has been identified as a complementary partner miRNA*. In the case of miR168a-5p/168a-3p, we found the generation of stable, mature molecules from both pre-miRNA arms, confirming evolutionary conservation of the stability of both species, as shown in rice and maize. We suggest that miR1120, located within the 3' UTR of a protein-coding gene and described as a functional miRNA in wheat, may represent a siRNA generated from a mariner-like transposable element. CONCLUSIONS: Seven of the eight barley miRNA genes characterized in this study contain introns with their respective transcripts undergoing developmentally specific processing events prior to the dicing out of pre-miRNA species from their pri-miRNA precursors. The observed tendency to maintain the intron encoding miR156g within the transcript, and preferences in splicing the miR1126-harboring intron, may suggest the existence of specific regulation of the levels of intron-derived miRNAs in barley.