Thrombin generation is increased in patients with Clostridium difficile colitis - a pilot study.

Background: There are only limited data in the literature on the thrombotic risk of patients with Clostridium difficile (CD) colitis, although this disease is widespread throughout the world. Objective: The aim of this study was to explore thrombin generation in these patients - the best way to evaluate their coagulation. Methods: A prospective observational study was conducted during 15 months on hospitalized patients with CD colitis. Thrombin generation was performed in platelet-poor plasma using a Ceveron® alpha analyzer and was compared with a group of volunteer control subjects. Results: Thirty-three patients and 51 control subjects were enrolled in the study. Two biomarkers - mean velocity index and peak thrombin - were significantly higher in patient group, compared to the control subjects (p = 0.010, respectively, p = 0.0395). This pattern of thrombin generation suggests that patients with CD colitis without septic shock have a potential thrombotic risk. The mean velocity index significantly correlated with the estimated related risk of death according to the Charlson age-comorbidity index. Conclusions: The higher values of thrombin generation suggest that CD colitis increases the thromboembolic risk. The pattern of thrombin generation could identify patients with particularly higher thromboembolic risk. They are potential candidates for thromboprophylaxis strategies and monitorization.

MECOM, HBS1L-MYB, THRB-RARB, JAK2, and TERT polymorphisms defining the genetic predisposition to myeloproliferative neoplasms: A study on 939 patients.

Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are classical myeloproliferative neoplasms (MPN), characterized by specific somatic mutations in JAK2, CALR or MPL genes. JAK2 46/1 and TERT rs2736100 polymorphisms are known to significantly predispose to MPN. This study aimed to establish the additional contribution of the recently described MECOM rs2201862, HBS1L-MYB rs9376092 and THRB-RARB rs4858647 polymorphisms to the occurrence of MPN. These three polymorphisms, along with JAK2 46/1 and TERT rs2736100 were genotyped in 939 MPN patients (454 with ET, 337 with PV and 148 with PMF) and 483 controls. MECOM rs2201862 associated significantly with each MPN entity, except for ET, and with all major molecular sub-types, especially those CALR-mutated (OR = 1.4; 95% CI = 1.1-1.8; P-value = .005). HBS1L-MYB rs9376092 associated only with JAK2 V617F-mutated ET (OR = 1.4; 95% CI = 1.1-1.7; P-value = .003). THRB-RARB rs4858647 had a weak association with PMF only (OR = 1.5; 95% CI = 1-2.1; P-value = .04). Surprisingly, JAK2 46/1 haplotype was associated significantly not only with JAK2 V617F-mutated MPN, but also with CALR-mutated MPN (OR = 1.4; 95% CI = 1.1-1.8; P-value = .01). TERT rs2736100 was associated equally strong with all MPN, regardless of phenotype or molecular sub-type. In conclusion, JAK2 46/1, TERT rs2736100 and MECOM rs2201862 are the chief predisposing polymorphisms to MPN.

TERT rs2736100 A>C SNP and JAK2 46/1 haplotype significantly contribute to the occurrence of JAK2 V617F and CALR mutated myeloproliferative neoplasms - a multicentric study on 529 patients.

Polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) represent typical myeloproliferative neoplasms (MPN), usually characterized by specific somatic driver mutations (JAK2 V617F, CALR and MPL). JAK2 46/1 haplotype and telomerase reverse transcriptase gene (TERT) rs2736100 A>C single nucleotide polymorphism (SNP) could represent a large fraction of the genetic predisposition seen in MPN. The rs10974944 C>G SNP, tagging the JAK2 46/1 haplotype, and the TERT rs2736100 A>C SNP were genotyped in 529 MPN patients with known JAK2 V617F, CALR and MPL status, and 433 controls. JAK2 46/1 haplotype strongly correlated to JAK2 V617F-positive MPN and, to a lesser extent, CALR-positive MPN. The TERT rs2736100 A>C SNP strongly correlated to all MPN, regardless of the phenotype (PV, ET or PMF) and major molecular subtype (JAK2 V617F- or CALR-positive). While both variants have a significant contribution, they have nuanced consequences, with JAK2 46/1 predisposing essentially to JAK2 V617F-positive MPN, and TERT rs2736100 A>C having a more general, non-specific effect on all MPN, regardless of phenotype or major molecular subtype.

Challenges and Complications in Treating Total Knee Arthroplasty in Morbidly Obese Patients.

The number of total hip and total knee replacements has increased steadily each year. Today, they are routinely performed all over the world. The increasing prevalence of obesity has led to an increase in the number of total knee arthroplasties (TKAs) performed in patients with a higher body mass index (BMI) and also has a higher rate of complications. Possible complications are infection, instability, misalignment, osteolysis, or fracture. Revision arthroplasty can be challenging due to bone defects, ligament instability, and difficulty in fixation. We present the case of a 66-year-old morbidly obese patient who underwent TKA. After the operation, infection and a mechanical complication of periprosthetic fracture of the tibial component occurred. The infection made the treatment more difficult. The patient had to undergo several surgeries in several stages to address the post-surgical complications. TKA in obese patients leads to a higher risk of postoperative complications.

Venetoclax in Acute Myeloid Leukemia.

BACKGROUND: Substantial progress in the therapeutic arsenal used to treat acute myeloid leukemia became possible in the last decade, as a result of advances in gene editing and descriptive and functional genomics. OBJECTIVE: The aim of this study is to analyze the efficacy and safety of venetoclax in the treatment of acute myeloid leukemia. METHODS: A mini-review was achieved using the articles published in PubMed and Web of Science in the last year, prior to 05.05.2021, which were searched using the terms "acute myeloid leukemia" and "venetoclax" and the new patents published in this field. RESULTS: BCL-2 inhibitors administered in monotherapy are active against acute myeloid leukemia cells, but their efficacy is partially limited because they do not target other antiapoptotic proteins and venetoclax induced overexpression of the other antiapoptotic molecules. Venetoclax-based combinations (including those with hypomethylating agents) were able to improve outcomes for older patients with acute myeloid leukemia, including both remission rates and overall survival. Other drugs used in combination with venetoclax include: FLT3 inhibitors, IDH2 inhibitors, chidamide, ibrutinib, lapatinib, mivebresib, triptolide, metabolic inhibitors, nucleoside analogs, and classical chemotherapeutics. Both the mechanisms of venetoclax resistance and the ways to overcome it, as well as the adverse effects of venetoclax are analyzed. CONCLUSION: The management of unfit and older patients with acute myeloid leukemia should be personalized and be the result of evaluating patient- and disease-specific factors that are essential to their care. Combinations that include venetoclax are an increasingly well-documented option for many of them.

Monoclonal Antibodies, Bispecific Antibodies and Antibody-Drug Conjugates in Oncohematology.

BACKGROUND: The therapeutic outcomes and the prognosis of patients with various hematologic malignancies are not always ideal with the current standard of care. OBJECTIVE: The aim of this study is to analyze the results of the use of monoclonal antibodies, bispecific antibodies and antibody-drug conjugates for the therapy of malignant hemopathies. METHODS: A mini-review was achieved using the articles published in Web of Science and PubMed between January 2017 and January 2020 and the new patents were made in this field. RESULTS: Naked monoclonal antibodies have improved the therapeutic results obtained with standard of care, but they also have side effects and the use of some of them can lead to the loss of the target antigen through trogocytosis, which explains the resistance that occurs during therapy. The results obtained with naked monoclonal antibodies have been improved by a better monoclonal antibody preparation, the use of bispecific antibodies (against two antigens on the target cell surface or by binding both surface antigen on target cells and T-cell receptor complex, followed by cytotoxic T-lymphocytes activation and subsequent cytolysis of the target cell), the use of monoclonal or bispecific constructs in frontline regimens, combining immunotherapy with chemotherapy, including through the use of antibody-drug conjugates (which provides a targeted release of a chemotherapeutic agent). CONCLUSION: Immunotherapy and immuno-chemotherapy have improved the outcome of the patients with malignant hemopathies through a targeted, personalized therapy, with reduced systemic toxicity, which in some cases can even induce deep complete remissions, including minimal residual disease negativity.

Chimeric Antigen Receptor-Engineered T-Cells - A New Way and Era for Lymphoma Treatment.

BACKGROUND: Patients with refractory or relapsed diffuse large B-cell lymphoma have a poor prognosis with the current standard of care. OBJECTIVE: Chimeric Antigen Receptor T-cells (CAR T-cells) are functionally reprogrammed lymphocytes, which are able to recognize and kill tumor cells. The aim of this study is to make progress in this area. METHODS: A mini-review was achieved using the articles published in Web of Science and PubMed in the last year and the new patents were made in this field. RESULTS: The responses to CAR T-cell products axicabtagene ciloleucel and tisagenlecleucel are promising; the objective response rate can reach up to 83%, and the complete response rate ranges between 40 and 58%. About half of the patients may have serious side effects, such as cytokine release syndrome and neurotoxicity. Current and future developments include the improvement of CAR T-cell expansion and polyfunctionality, the combined use of CAR T-cells with a fusion protein between interferon and an anti-CD20 monoclonal antibody, with checkpoint inhibitors or small molecule sensitizers that have apoptotic-regulatory effects. Furthermore, the use of IL-12-expressing CAR T-cells, an improved technology for the production of CAR T-cells based on targeted nucleases, the widespread use of allogeneic CAR T-cells or universal CAR T-cells obtained from genetically engineered healthy donor T-cells are future developments actively considered. CONCLUSION: CAR T-cell therapy significantly improved the outcome of patients with relapsed or refractory diffuse large B-cell lymphoma. The advances in CAR T-cells production technology will improve the results and enable the expansion of this new immunotherapy.

From a Better Understanding of the Mechanisms of Action of Histone Deacetylases Inhibitors to the Progress of the Treatment of Malignant Lymphomas and Plasma Cell Myeloma.

BACKGROUND: Notable progress has been made in chemo- and immunotherapy of B-cell lymphomas, but less in the treatment of T-cell lymphomas. OBJECTIVE: Histone deacetylases inhibitors are a potentially useful therapeutic mean, as an epigenetic dysregulation is present in lymphomas, and especially in T-cell types. We aimed to study the progress made in this area. METHOD: A mini-review was achieved using the articles published in PubMed in the last two years and the new patents made in this field. RESULTS: Histone deacetylases inhibitors are involved in the derepression of tumor suppressor genes through a histone deacetylase-mediated transcriptional process. Their inhibition is followed by cell cycle arrest, cell differentiation, apoptosis, sometimes autophagy, and a reversal of the transformed phenotype. They can also remove the resistance to chemo- or immunotherapy through different pathways. Some of them, as romidepsin, may decrease the protein level of multi-drug resistance associated protein 1, followed by a decrease in cellular drug export activity for DNA alkylating agents. Some compounds are approved for relapsed/refractory T-cell lymphomas or multiple myeloma treatment. The recent patents and the clinical trials with a histone deacetylases inhibitor administred in a synergistic drug combination with a demethylating, immunomodulatory, or anticancer agent as well as the discovery of more selective histone deacetylases inhibitors, with fewer side effects, could be a way to increase the treatment efficacy. CONCLUSION: New and more effective histone deacetylases inhibitors given alone or in drug combination are a solution for an improved response to the treatment of patients with relapsed/refractory lymphoproliferative disorders.

Could resveratrol be a useful drug for the treatment of malignant hemopathies?

Resveratrol is a poly-phenol with many beneficial effects: not only as an antioxidant, anti-inflammatory, and antiatherogenic agent, as well as a platelet aggregation inhibitor, but also as an antiproliferative and proapoptotic factor in various types of cancers. There are reviews about the mechanisms responsible for its effects in leukemia and lymphomas, emphasizing the chemosensitizing role of resveratrol, which allows overcoming the multidrug resistance of cancers. The action of resveratrol occurs preferentially on leukemic cells, and not on the normal ones. In addition, it is one of the few drugs that act on leukemic stem cells. If experimental results are promising, its application in humans encounters some difficulties. The paper presents the causes of its low bioavailability, as well as recent patents that allow improvement of its bioavailability, development of new extraction procedures, obtaining new formulae, and associating resveratrol with other drugs in order to increase its effects. These patents allow optimizing its effects in order to obtain an adjuvant agent for treatment of oncohematological disorders.