Search

Here we show that surface-enhanced Raman scattering (SERS) analysis captures the relative hypomethylation of DNA from patients with acute leukemia associated with Down syndrome (AL-DS) compared with patients diagnosed with transient leukemia associated with Down syndrome (TL-DS), an information inferred from the area under the SERS band at 1005 cm–1 attributed to 5-methycytosine. The receiver operating characteristic (ROC) analysis of the area under the SERS band at 1005 cm–1 yielded an area under the curve (AUC) of 0.77 in differentiating between the AL-DS and TL-DS groups. In addition, we showed that DNA from patients with non-DS myeloproliferative neoplasm (non-DS-MPN) is hypomethylated compared to non-DS-AL, the area under the SERS band at 1005 cm–1 yielding an AUC of 0.78 in separating between non-DS-MPN and non-DS-AL. Overall, in this study, the area of the 1005 cm–1 DNA SERS marker band shows a stepwise decrease in DNA global methylation as cells progress from a pre-leukemia to a full-blown acute leukemia, highlighting thus the potential of SERS as an emerging method of analyzing the methylation landscape of DNA in the context of leukemia genesis and progression.

Myelodysplastic syndromes (MDS) are a heterogeneous group of malignant disorders of hematopoietic stem and progenitor cells (HSPC), mainly characterized by ineffective hematopoiesis leading to peripheral cytopenias and progressive bone marrow failure. While clonal dominance is nearly universal at diagnosis, most genetic mutations identified in patients with MDS do not provide a conspicuous advantage to the malignant cells. In this context, malignant cells alter their adjacent bone marrow microenvironment (BME) and rely on cell extrinsic factors to maintain clonal dominance. The profoundly disturbed BME favors the myelodysplastic cells and, most importantly is detrimental to normal hematopoietic cells. Thus, the MDS microenvironment not only contributes to the observed cytopenias seen in these patients but could also negatively impact the engraftment of normal, allogeneic HSPCs in patients with MDS undergoing bone marrow transplant. Therefore, successful therapies in MDS should not only target the malignant cells but also reprogram their bone marrow microenvironment. Here, we will provide a synopsis of how drugs currently used or on the verge of being approved for the treatment of MDS may achieve this goal.

Acute promyelocytic leukemia (APL) is characterized by a unique chromosome translocation t(15;17)(q24;q21), which leads to the PML/RARA gene fusion formation. However, it is acknowledged that this rearrangement alone is not able to induce the whole leukemic phenotype. In addition, epigenetic processes, such as DNA methylation, may play a crucial role in leukemia pathogenesis. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), involves the covalent transfer of a methyl group (-CH3) to the fifth carbon of the cytosine ring in the CpG dinucleotide and results in the formation of 5-methylcytosine (5-mC). The aberrant gene promoter methylation can be an alternative mechanism of tumor suppressor gene inactivation. Understanding cancer epigenetics and its pivotal role in oncogenesis, can offer us not only attractive targets for epigenetic treatment but can also provide powerful tools in monitoring the disease and estimating the prognosis. Several genes of interest, such as RARA, RARB, p15, p16, have been studied in APL and their methylation status was correlated with potential diagnostic and prognostic significance. In the present manuscript we comprehensively examine the current knowledge regarding DNA methylation in APL pathogenesis. We also discuss the perspectives of using the DNA methylation patterns as reliable biomarkers for measurable residual disease (MRD) monitoring and as a predictor of relapse. This work also highlights the possibility of detecting aberrant methylation profiles of circulating tumor DNA (ctDNA) through liquid biopsies, using the conventional methods, such as methylation-specific polymerase chain reaction (MS-PCR), sequencing methods, but also revolutionary methods, such as surface-enhanced Raman spectroscopy (SERS).

Introduction: Childhood acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by the acquisition of several genetic lesions in the lymphoid progenitors with subsequent proliferation advantage and lack of maturation. Along the years, it has been repeatedly shown that minimal residual disease (MRD) plays an important role in prognosis and therapy choice. The aim of the current study was to determine the prognostic role of MRD in childhood ALL patients in conjunction with other relevant patient and disease characteristics, thus showing the real-life scenario of childhood ALL.Patients and Methods: The retrospective study includes childhood ALL patients that were treated according to the BFM ALL IC 2009 between January 2016 and December 2018 at the Fundeni Clinical Institute, Bucharest, Romania.Results: None of the variables significantly influenced the induction-related death in our study. None of the variables independently predicted relapse-free survival (RFS) with the highest tendency for statistical significance being represented by poor prednisone response. Non-relapse mortality (NRM) was independently predicted by age, prednisone response, and day 33 flow cytometry-MRD (FCM-MRD). Overall survival (OS) was independently predicted by prednisone response and day 33 FCM-MRD. Event-free survival (EFS) was independently predicted by age, prednisone response, and day 33 FCM-MRD.Conclusion : Prednisone response, day 15 FCM-MRD, day 33 FCM-MRD, and the risk group represent the most important factors that in the current study independently predict childhood ALL prognosis.

Recently, an increasing number of novel drugs were approved in oncology and hematology. Nevertheless, pharmacology progress comes with a variety of side effects, of which cytokine release syndrome (CRS) is a potential complication of some immunotherapies that can lead to multiorgan failure if not diagnosed and treated accordingly. CRS generally occurs with therapies that lead to highly activated T cells, like chimeric antigen receptor T cells or in the case of bispecific T-cell engaging antibodies. This, in turn, leads to a proinflammatory state with subsequent organ damage. To better manage CRS there is a need for specific therapies or to repurpose strategies that are already known to be useful in similar situations. Current management strategies for CRS are represented by anticytokine directed therapies and corticosteroids. Based on its pathophysiology and the resemblance of CRS to sepsis and septic shock, as well as based on the principles of initiation of continuous renal replacement therapy (CRRT) in sepsis, we propose the rationale of using CRRT therapy as an adjunct treatment in CRS where all the other approaches have failed in controlling the clinically significant manifestations.

Background: Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm diagnosed in young children, characterized by somatic or germline mutations that lead to hyperactive RAS signaling. The only curative option is hematopoietic stem cell transplantation (HSCT). Recent data showing that aberrant DNA methylation plays a significant role in pathogenesis and correlates with clinical risk suggest a possible benefit of hypomethylating agents (HMA) in JMML treatment.Aim: The aim is to report the results of HMA-based therapy with 5-azacytidine (AZA) in three JMML patients treated in a single center, non-participating in EWOG-MDS study.Methods: The diagnosis and treatment response were evaluated according to international consensus criteria. AZA 75 mg/m2 intravenous (i.v.) was administered once daily on days 1–7 of each 28-day cycle. All patients were monitored for hematologic response, spleen size, and evolution of extramedullary disease. Targeted next generation sequencing (NGS) were performed after the 3rd AZA cycle and before SCT to evaluate the molecular alterations and genetic response.Results: Three patients diagnosed with JMML were treated with AZA (off-label indication) in Pediatric Department of Fundeni Clinical Institute, Bucharest, Romania between 2017 and 2019. There were two females and one male with median age 11 months, range 2–16 months. The cytogenetic analysis showed normal karyotype in all patients. Molecular analysis confirmed KRAS G13D mutation in two patients and NRAS G12D mutation in one patient. The clinical evaluation showed important splenomegaly and hepatomegaly in all 3 pts. One patient received AZA for early relapse after haploidentical HSCT and the other two patients received upfront AZA, as bridging therapy before HSCT. After HMA therapy, 2/3 patients achieved clinical partial response (cPR), 1/3 had clinical stable disease (cSD) and all had genetic stable disease (gSD) after 3 cycles and were able to receive the planned HSTC. One patient achieved clinical and genetic complete response before HSCT. During 22 cycles of AZA there were only four adverse events but only one determined dose reduction and treatment delay.Conclusion: Our data show that AZA monotherapy is safe and effective in controlling disease both in upfront and relapsed patients in order to proceed to HSCT.

Macrophages are known to have an impact in cytokine signaling in the myriad of organs in which they reside and are classically known to be either pro-inflammatory (M1), anti-inflammatory (M2). Different classes of signaling molecules influence these states, of which, microRNAs represent key modulators. These are short RNA species approximately 21 to 23 nucleotides long that generally act by binding to the 3′ untranslated region of mRNAs, regulating their translation, and, thus, the quantity of protein they encode. From these species, microRNA-155 was observed to be of great importance for M1 polarization. Because of it’s major implication in M1 polarization microRNA-155 was shown to be implicated in different inflammatory diseases. To name a few, microRNA-155 was shown to be modified in patients with asthma and to correlate with asthma symptoms in mouse model; it has been shown to modulate the activity of foam cells and influence the dimensions of the atherosclerotic plaque and it has also been shown to be of crucial influence in transducing the signal of LPS in septic shock. Because of this, the current review aims to offer an overview of the role of microRNA-155 in M1 polarization, the implication that this poses for the pathophysiology of inflammatory diseases and the potential therapeutic possibilities that this knowledge might bring. Currently, microRNA-155 has been used in clinical trials as a marker of inflammation, but the question remains if it’s inhibition will be useful in inflammatory diseases, as other products might have a better cost/benefit ratio.

Background: Therapy for acute lymphoblastic leukemia (ALL) are currently initially efficient, but even if a high percentage of patients have an initial complete remission (CR), most of them relapse. Recent data shows that immunotherapy with either bispecific T-cell engagers (BiTEs) of chimeric antigen receptor (CAR) T cells can eliminate residual chemotherapy-resistant B-ALL cells.Objective: The objective of the manuscript is to present improvements in the clinical outcome for chemotherapy-resistant ALL in the real-life setting, by describing Romania's experience with bispecific antibodies for B-cell ALL.Methods: We present the role of novel therapies for relapsed B-cell ALL, including the drugs under investigation in phase I-III clinical trials, as a potential bridge to transplant. Blinatumomab is presented in a critical review, presenting both the advantages of this drug, as well as its limitations.Results: Bispecific antibodies are discussed, describing the clinical trials that resulted in its approval by the FDA and EMA. The real-life setting for relapsed B-cell ALL is described and we present the patients treated with blinatumomab in Romania.Conclusion: In the current manuscript, we present blinatumomab as a therapeutic alternative in the bridge-to-transplant setting for refractory or relapsed ALL, to gain a better understanding of the available therapies and evidence-based data for these patients in 2019.

Background: The aim was to analyze, in vitro, four resin based composite systems (RBCs) immersed in saliva of leukemia patients before starting chemotherapy regiments. Material and methods: Saliva was collected from 20 patients (4 healthy patients, 16 leukemia patients). Resin disks were made for each RBC and were immersed in the acute leukemia (acute lymphocytic (ALL), acute myeloid (AML)), chronic leukemia (chronic lymphocytic (CLL), chronic myeloid (CML)), Artificial saliva and Control environment, and maintained for seven days. At the end of the experiment, the characteristics and the effective response of saliva from the studied salivas’ on RBCs was assessed using water sorption, water solubility, residual monomer and scanning electron microscopy (SEM). Data analysis was performed and a p-value under 0.05 was considered statistically significant. Results: The behaviour of RBCs in different immersion environments varies according to the characteristics of the RBCs. RBCs with a higher filler ratio have a lower water sorption. The solubility is also deteriorated by the types of organic matrix and filler; the results of solubility being inversely proportional on the scale of negative values compared to sorption values. Chromatograms of residual monomers showed the highest amount of unreacted monomers in ALL and AML, and the Control and artificial saliva environments had the smallest residual monomer peaks. Because of the low number of differences between the experimental conditions, we further considered that there were no important statistical differences between experimental conditions and analysed them as a single group. Conclusion: The influence of saliva on RBCs depends on the type of leukemia; acute leukemia influenced the most RBCs by changing their properties compared to chronic leukemia.

The aim of this systematic review and meta-analysis was to analyze the available evidence on the assessment of periodontal disease in patients with von Willebrand disease (VWD). An electronic search in three databases (PubMed, Web of Science, and Scopus) was conducted by three independent reviewers to identify cross-sectional, cohort, and clinical trial studies. Studies considered eligible for this review were evaluated according to the quality and risk assessment tool proposed by the CLARITY Group at McMaster University. In order to analyze the possible correlation of VWD patients and periodontitis and their susceptibility to bleeding during the periodontal screening phase, periodontal parameters evaluated were probing pocket depth (PPD), bleeding on probing (BOP), gingival bleeding index (GBI), and periodontal inflamed surface area (PISA). After a screening of 562 articles, three articles were selected for the qualitative analysis. Within the limitation of our review, VWD patients are not more susceptible to periodontitis as compared with non-VWD patients. Nevertheless, bleeding on probing and gingival index needs to be carefully taken into consideration during periodontal screening of VWD due to the possible presence of false positives.

In multiple myeloma the mutational profile is mainly represented by translocations involving chromosome 14 and by single nucleotide mutations, frequently involving genes implicated in the mitogen activated protein kinase (MAPK) pathway, as KRAS, NRAS, and, less frequently, BRAF. Because KRAS/NRAS/BRAF mutations are associated with a higher number of mutations per patient, we hypothesize that this group of patients could benefit from therapy with checkpoint inhibitors because of the higher frequency of neo-antigens that this group would present. This might also true for IMiD therapy, because of their activatory effect on T cells. Because, KRAS/NRAS/BRAF are members of the MAPK pathway, this subgroup of patients would also benefit from inhibitors of MAPK, either directly on the specific mutation or through downstream targeting of MEK1/2 or ERK1/2 to account for a possible compensatory collateral signaling that might activate as response to upstream inhibition.

High-dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplantation (ASCT) is widely used in patients with malignant lymphomas. In Europe over 8,000 ASCTs for lymphoma were performed out of a total of 40,000 transplants according to the European Bone Marrow Transplant (EBMT) activity survey in 2017. ASCT is considered the standard treatment for eligible patients failing to achieve remission after first line chemotherapy or patients with relapsed or refractory lymphomas, including classical Hodkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma, as well as consolidation therapy in first remission in mantle cell lymphoma. BEAM (BCNU/carmustine, etoposide, cytarabine, and melphalan) is the most commonly used conditioning regimen for ASCT in patients with relapsed/refractory (R/R) lymphomas in Europe, whereas the CBV (cyclophosphamide, BCNU, and etoposide) regimen is also widely used in North America. Recently, concerns regarding BCNU toxicity as well as restricted availability of BCNU and melphalan has determined an increasing number of transplant centers to use alternative conditioning regimens. Currently, only a few comparative studies, most of them retrospective, between different conditioning protocols regarding efficacy and toxicity have been published. Thus, in the current manuscript, we report the experience of 2 transplant centers in ASCT in R/R lymphomas with three types of conditioning: BEAM, CLV (cyclophosphamide, lomustine, etoposide) and LEAM (lomustine, etoposide, cytarabine, and melphalan), with the aim to evaluate the results of alternative conditioning regimens using lomustine (LEAM and CLV) and compare them with the standard BEAM regarding early toxicity, engraftment, and transplant related mortality (TRM). All patients developed grade IV neutropenia, anemia with/without transfusion necessity. Severe thrombocytopenia with transfusion requirements is reported in most cases. Median time to platelet engraftment and neutrophil engraftment was 13 days (range) and 10 days (range), respectively. Gastrointestinal toxicity was the most common non-hematologic toxicity after all three conditioning regimens. Oral mucositis in various grades from I to IV was diagnosed in most cases. Other side effects include vomiting, diarrhea, colitis, and skin rash but with low severity grades. For the LEAM arm, one patient died after transplant, before engrafting, one patient didn't achieve platelet engraftment in day 100, one patient developed grade 3 upper gastrointestinal bleeding, one patient died (grade 5 toxicity) with acute renal failure, one patient developed hypoxic events up to grade 4 acute respiratory failure and one patient developed grade 3 itchy skin rash. For the CLV arm, one patient died after transplant, before engrafting, one patient developed grade 3 colitis, one patient with grade 3 hepatic cytolysis, one patient with cardiac toxicity followed by death (grade 5) caused by an acute myocardial infarction with ST elevation and one patient with pulmonary toxicity clinically manifested with grade 3 pleurisy. For the BEAM arm, one patient developed grade 3 cardiac toxicity with sinus bradycardia and afterwards grade 4 with acute pulmonary edema, three patients presented a grade 3 pruritic skin rash and two patients developed grade 3 seizures. In the present study we presented the differences that were observed between BEAM, LEAM, and CLV conditioning regimens offering clinical arguments for an SCT practitioner choice in the ideal situation, but also of choice for alternative regimens in the case that one regimen cannot be used.

Chronic myelogenous leukemia (CML) is a malignancy of the myeloid cell lineage characterized by a recurrent chromosomal abnormality: the Philadelphia chromosome, which results from the reciprocal translocation of the chromosomes 9 and 22. The Philadelphia chromosome contains a fusion gene called BCR-ABL1. The BCR-ABL1 codes for an aberrantly functioning tyrosine kinase that drives the malignant proliferation of the founding clone. The advent of tyrosine kinase inhibitors (TKI) represents a landmark in the treatment of CML, that has led to tremendous improvement in the remission and survival rates. Since the introduction of imatinib, the first TKI, several other TKI have been approved that further broadened the arsenal against CML. Patients treated with TKIs require sensitive monitoring of BCR-ABL1 transcripts with quantitative real-time polymerase chain reaction (qRT-PCT), which has become an essential part of managing patients with CML. In this review, we discuss the importance of the BCR-ABL1 assay, and we highlight the growing importance of BCR-ABL1 dynamics. We also introduce a mathematical correction for the BCR-ABL1 assay that could help homogenizing the use of the ABL1 as a control gene. Finally, we discuss the growing body of evidence concerning treatment-free remission. Along with the continuous improvement in the therapeutic arsenal against CML, the molecular monitoring of CML represents the avant-garde in the struggle to make CML a curable disease.

Basophils are white blood cells that play an important role in the human immune system. These cells physiologically increase in number in immune response to certain allergies, chronic inflammation, and parasitic infections. Basophils are also a significant indicator for the presence of certain malignancies such as chronic myeloproliferative neoplasms and acute myeloid leukemia. In the current manuscript we present a statistically significant correlation between persistent basophilia in primary myelofibrosis (PMF) and the risk for the subsequent development of acute myeloid leukemia. We have retrospectively identified in the files of the Department of Hematology, Ion Chiricuta Clinical Cancer Center in Cluj Napoca, Romania 623 consecutive patients diagnosed with AML over a period spanning from 2008 to 2018. We afterwards identified 32 patients with AML diagnosis following a previous diagnosis of myelofibrosis (either post-PV, post-ET, or post-PMF). All the patients were diagnosed according to the WHO criteria. We subsequently established a control group consisting of 32 patients with underlying BCR–ABL-negative MPN who did not develop AML (AML-negative group). Following this, we assessed whether the AML-negative patients from our control group also had a persistent (>3 months) absolute basophilia. When comparing both groups of patients with myelofibrosis, the group with subsequent AML development and the one without AML, the follow-up did not present statistically significant differences between the two groups. In the univariate analysis, patients who progressed to AML had more frequently basophilia, longer basophilia duration, higher pre-therapy absolute, and relative basophil count and presented more frequently calreticulin (CALR) mutations. In the current study, we emphasize the need for a closer clinical monitoring for chronic MPNs with marked basophilia, with an important potential clinical impact.

Background and objectives: Mutational analysis has led to a better understanding of acute myeloid leukemia (AML) biology and to an improvement in clinical management. Some of the most important mutations that affect AML biology are represented by mutations in genes related to methylation, more specifically: TET2, IDH1, IDH2 and WT1. Because it has been shown in numerous studies that mutations in these genes lead to similar expression profiles and phenotypes in AML, we decided to assess if mutations in any of those genes interact with other genes important for AML. Materials and Methods: We downloaded the clinical data, mutational profile and expression profile from the TCGA LAML dataset via cBioPortal. Data were analyzed using classical statistical methods and functional enrichment analysis software represented by STRING and GOrilla. Results: The first step we took was to assess the 196 AML cases that had a mutational profile available and observe the mutations that overlapped with TET2/IDH1/2/WT1 mutations. We observed that RUNX1 mutations significantly overlap with TET2/IDH1/2/WT1 mutations. Because of this, we decided to further investigate the role of RUNX1 mutations in modulating the level of RUNX1 mRNA and observed that RUNX1 mutant cases presented higher levels of RUNX1 mRNA. Because there were only 16 cases of RUNX1 mutant samples and that mutations in this gene determined a change in mRNA expression, we further observed the correlation between RUNX1 and other mRNAs in subgroups regarding the presence of hypermethylating mutations and NPM1. Here, we observed that both TET2/IDH1/2/WT1 and NPM1 mutations increase the number of genes negatively correlated with RUNX1 and that these genes were significantly linked to myeloid activation. Conclusions: In the current study, we have shown that NPM1 and TET2/IDH1/2/WT1 mutations increase the number of negative correlations of RUNX1 with other transcripts involved in myeloid differentiation.

Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is the rarest subtype of primary cutaneous lymphoma, accounting for approximately 2% of cutaneous lymphomas. The rarity of primary cutaneous PTCL-NOS means that there is a paucity of data regarding clinical and histopathological features and its clinical course. This malignancy is an aggressive and life-threatening hematological malignancy that often presents mimicking other less severe plaque-like skin conditions. Due to the nonspecific nature of these lesions, CD4-positive cutaneous T-cell lymphoma (CTCL) is often misdiagnosed as either mycosis fungoides or Sezary syndrome. We describe a patient who presented with a large tumoral mass in the right frontal area, with involvement of the right upper eyelid and the ocular globe, causing loss of vision greatly impacting the quality of life. Biopsy revealed primary cutaneous PTCL-NOS, treated successfully with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus etoposide combination chemotherapy. As elderly patients are indicated to receive attenuated doses of chemotherapy, CHOP-based regimens represent viable options.

Background and Objectives: This research attempts to provide a clear view of the literature on randomized clinical trials (RCTs) concerning the efficacy of topical dexamethasone, clobetasol and budesonide in oral graft versus host disease (GVHD). Materials and Methods: An electronic search of the PubMed, Web of Science and Scopus databases was carried out for eligible RCTs. Studies were included if they had adult patients with oral GVHD treatment with topical corticosteroids, and if the RCT study was published in English. The Cochrane Risk of Bias tool was used to assess the quality of these studies. Overall, three RCTs were included (an Open, Randomized, Multicenter Trial; a Randomized Double-Blind Clinical Trial; and an Open-Label Phase II Randomized Trial). Results: The trials involved 76 patients, of which 44 patients received topical dexamethasone, 14 patients received topical clobetasol and 18 patients received topical budesonide. Topical agents were most frequently used when oral tissues were the sole site of involvement. It appears that the best overall response is present for budesonide with no difference between the four arms, followed by clobetasol, and then by dexamethasone. The limitation of the current study is mainly represented by the fact that overall response was derived in two of the studies from other parameters. Moreover, both budesonide and clobetasol were used in only one study each, while two assessed dexamethasone. Conclusions: Based on the clinical trials, all three agents seem to be effective in treating oral GVHD and had a satisfactory safety profile. There is still a need for assessing high quality RCTs to assess the efficacy of these therapies on a larger cohort.

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by abnormal proliferation and a lack of differentiation of myeloid blasts. Considering the dismal prognosis this disease presents, several efforts have been made to better classify it and offer a tailored treatment to each subtype. This has been formally done by the World Health Organization (WHO) with the AML classification schemes from 2008 and 2016. Nonetheless, there are still mutations that are not currently included in the WHO AML classification, as in the case of some mutations that influence methylation. In this regard, the present study aimed to determine if some of the mutations that influence DNA methylation can be clustered together regarding methylation, expression, and clinical profile. Data from the TCGA LAML cohort were downloaded via cBioPortal. The analysis was performed using R 3.5.2, and the necessary packages for classical statistics, dimensionality reduction, and machine learning. We included only patients that presented mutations in DNMT3A, TET2, IDH1/2, ASXL1, WT1, and KMT2A. Afterwards, mutations that were present in too few patients were removed from the analysis, thus including a total of 57 AML patients. We observed that regarding expression, methylation, and clinical profile, patients with mutated TET2, IDH1/2, and WT1 presented a high degree of similarity, indicating the equivalence that these mutations present between themselves. Nonetheless, we did not observe this similarity between DNMT3A- and KMT2A-mutated AML. Moreover, when comparing the hypermethylating group with the hypomethylating one, we also observed important differences regarding expression, methylation, and clinical profile. In the current manuscript we offer additional arguments for the similarity of the studied hypermethylating mutations and suggest that those should be clustered together in further classifications. The hypermethylating and hypomethylating groups formed above were shown to be different from each other considering overall survival, methylation profile, expression profile, and clinical characteristics. In this manuscript, we present additional arguments for the similarity of the effect generated by TET2, IDH1/2, and WT1 mutations in AML patients. Thus, we hypothesize that hypermethylating mutations skew the AML cells to a similar phenotype with a possible sensitivity to hypermethylating agents.

Chimeric antigen receptor (CAR) T-cell technology has seen a rapid development over the last decade mostly due to the potential that these cells may have in treating malignant diseases. It is a generally accepted principle that very few therapeutic compounds deliver a clinical response without treatment-related toxicity, and studies have shown that CAR T-cells are not an exception to this rule. While large multinational drug companies are currently investigating the potential role of CAR T-cells in hematological oncology, the potential of such cellular therapies are being recognized worldwide as they are expected to expand in the patient to support the establishment of the immune memory, provide a continuous surveillance to prevent and/or treat a relapse, and keep the targeted malignant cell subpopulation in check. In this article, we present the possible advantages of using CAR T-cells in treating acute lymphoblastic leukemia, presenting the technology and the current knowledge in their preclinical and early clinical trial use. Thus, this article first presents the main present-day knowledge on the standard of care for acute lymphoblastic leukemia. Afterward, current knowledge is presented about the use of CAR T-cells in cancer immunotherapy, describing their design, the molecular constructs, and the preclinical data on murine models to properly explain the background for their clinical use. Last, but certainly not least, this article presents the use of CAR T-cells for the immunotherapy of B-cell acute lymphoblastic leukemia, describing both their potential clinical advantages and the possible side effects.

Regarding cancer as a genetic multi-factorial disease, a number of aspects need to be investigated and analyzed in terms of cancer’s predisposition, development and prognosis. One of these multi-dimensional factors, which has gained increased attention in the oncological field due to its unelucidated role in risk assessment for cancer, is diet. Moreover, as studies advance, a clearer connection between diet and the molecular alteration of patients is becoming identifiable and quantifiable, thereby replacing the old general view associating specific phenotypical changes with the differential intake of nutrients. Respectively, there are two major fields concentrated on the interrelation between genome and diet: nutrigenetics and nutrigenomics. Nutrigenetics studies the effects of nutrition at the gene level, whereas nutrigenomics studies the effect of nutrients on genome and transcriptome patterns. By precisely evaluating the interaction between the genomic profile of patients and their nutrient intake, it is possible to envision a concept of personalized medicine encompassing nutrition and health care. The list of nutrients that could have an inhibitory effect on cancer development is quite extensive, with evidence in the scientific literature. The administration of these nutrients showed significant results in vitro and in vivo regarding cancer inhibition, although more studies regarding administration in effective doses in actual patients need to be done.

Triple negative breast cancer (TNBC) is currently associated with a lack of treatment options. Arsenic derivatives have shown antitumoral activity both in vitro and in vivo; however, their mode of action is not completely understood. In this work we evaluate the response to arsenate of the double positive MCF-7 breast cancer cell line as well as of two different TNBC cell lines, Hs578T and MDA-MB-231. Multimodal experiments were conducted to this end, using functional assays and microarrays. Arsenate was found to induce cytoskeletal alteration, autophagy and apoptosis in TNBC cells, and moderate effects in MCF-7 cells. Gene expression analysis showed that the TNBC cell lines’ response to arsenate was more prominent in the G2M checkpoint, autophagy and apoptosis compared to the Human Mammary Epithelial Cells (HMEC) and MCF-7 cell lines. We confirmed the downregulation of anti-apoptotic genes (MCL1, BCL2, TGFβ1 and CCND1) by qRT-PCR, and on the protein level, for TGFβ2, by ELISA. Insight into the mode of action of arsenate in TNBC cell lines it is provided, and we concluded that TNBC and non-TNBC cell lines reacted differently to arsenate treatment in this particular experimental setup. We suggest the future research of arsenate as a treatment strategy against TNBC.

Background and Objectives: Deep vein thrombosis (DVT) is a common cause of intra-hospital morbidity and mortality, and its most severe complication is pulmonary thromboembolism. The risk factors that influence the apparition of DVT are generally derived from Virchow’s triad. Since the most severe complications of DVT occur in proximal rather than distal deep vein thrombosis, the aim of this study was to identify the factors influencing the apparition of proximal DVT. Materials and Methods: This was a transversal, cohort study. The study included 167 consecutive patients with lower limb DVT over a two-year period. The following data were recorded or determined: general data, conditions that are known to influence DVT, medical history and coagulation or thrombophilia-related genetic variations. Results: In the univariate analysis, male gender, neoplasia, previous DVT and mutated factor V Leiden were all associated with proximal DVT, while bed rest was associated with distal DVT. In the multivariate analysis, male gender, previous DVT and factor V Leiden mutation were independently correlated with proximal DVT, while bed rest was independently associated with distal deep vein thrombosis. Conclusion: Our observations point out that the factors indicating a systemic involvement of coagulation were correlated with proximal DVT, while local factors were associated with distal DVT.