Recent advances and future directions in etiopathogenesis and mechanisms of reactive oxygen species in cancer treatment.

A class of exceptionally bioactive molecules known as reactive oxygen species (ROS) have been widely studied in the context of cancer. They play a significant role in the etiopathogenesis for cancer. Implication of ROS in cancer biology is an evolving area, considering the recent advances; insights into their generation, role of genomic and epigenetic regulators for ROS, earlier thought to be a chemical process, with interrelations with cell death pathways- Apoptosis, ferroptosis, necroptosis and autophagy has been explored for newer targets that shift the balance of ROS towards cancer cell death. ROS are signal transducers that induce angiogenesis, invasion, cell migration, and proliferation at low to moderate concentrations and are considered normal by-products of a range of biological activities. Although ROS is known to exist in the oncology domain since time immemorial, its excessive quantities are known to damage organelles, membranes, lipids, proteins, and nucleic acids, resulting in cell death. In the last two decades, numerous studies have demonstrated immunotherapies and other anticancer treatments that modulate ROS levels have promising in vitro and in vivo effects. This review also explores recent targets for therapeutic interventions in cancer that are based on ROS generation or inhibition to disrupt the cell oxidative stress balance. Examples include-metabolic targets, targeted therapy with biomarkers, natural extracts and nutraceuticals and targets developed in the area of nano medicine. In this review, we present the molecular pathways which can be used to create therapy plans that target cancer by regulating ROS levels, particularly current developments and potential prospects for the effective implementation of ROS-mediated therapies in clinical settings. The recent advances in complex interaction with apoptosis especially ferroptosis and its role in epigenomics and modifications are a new paradigm, to just mechanical action of ROS, as highlighted in this review. Their inhibition by nutraceuticals and natural extracts has been a scientific challenging avenue that is explored. Also, the inhibition of generation of ROS by inhibitors, immune modulators and inhibitors of apoptosis and ferroptosis is explored in this review.

Infections Associated Hemophagocytosis-Secondary HLH Mimics in Children!"

Infection-associated hemophagocytosis is a diagnostic challenge. The varied presentation makes timely diagnosis difficult. We report two cases with unusual presentation of well-established secondary triggers for hemophagocytic lymphohistiocytosis.

Early prognosis prediction in acute myeloid and acute lymphoid leukemia patients using cell-free DNA concentration ratios.

Background: Cell-free DNA (cfDNA) is a promising biomarker for disease prediction in many cancers, including acute leukemia (acute myeloid leukemia [AML] and acute lymphoblastic leukemia [ALL]). This study investigated the role of cfDNA in predicting relapse or unfavorable outcomes in acute leukemia patients upon initial diagnosis. Methods: Paired peripheral blood samples of 25 patients with ALL and AML were compared at baseline and induction/follow-up and clinically correlated with clinicopathological and outcome variables according to the risk category. cfDNA was isolated using commercial cfDNA extraction kits. The probability of poor outcomes in high-risk groups and a cut-off value for risk stratification minimal residual disease (MRD) positivity and outcome prediction were derived. Results: Twenty-five patients diagnosed with AML and ALL were risk-stratified based on NCI risk stratification, and of these 25 patients, 4 patients were of standard risk (SR) and 1 patient was of intermediate risk (IR), while a majority of patients (80%) were of high risk (HR). Of these, four HR patients passed away. The ratio of cfDNA reduction at baseline and the end of induction was a strong predictor of poor outcomes in high-risk patients, regardless of the MRD status. A cfDNA ratio score of 2.6 or higher at diagnosis/remission predicted poor outcomes, with higher accuracy than conventional MRD detection by flow cytometry. Conclusion: A higher cfDNA ratio at diagnosis/remission or at baseline predicts poor outcomes in acute leukemia patients. This pilot study suggests that cfDNA ratio scoring may be a useful tool for predicting prognosis in acute leukemia patients, regardless of the MRD status.

Hypocellular AML versus MDS-diagnostic challenge case report with review of literature.

Hypocellular AML being a rare entity with considerable overlapping features and characteristics with various other entities brings a need to have a better and clear understanding of hypocellular AML to differentiate in the decision-making process for therapeutic patient management. With some degree of dysplasia inherently associated with AML it is challenging to differentiate hypocellular AML from Myelodysplastic syndromes. We present a case report where the diagnostic dilemma in an elderly male patient who presented with fever, pallor, weight loss and fatiguability. On clinical examination, the patient had hepatomegaly. The patient was non-affording and was hence given supportive treatment, and he died soon after. Here the diagnostic dilemma is discussed along with the review of literature on hypocellular AML. A better and clear understanding of hypocellular AML is required to differentiate it from other entities due to the considerable overlap in presentation hence improving the decision-making process for therapeutic patient management. The shortcomings are realised, especially when the bone marrow cellularity is less than 10%. Our case report is written to enrich more understanding of the limited published literature on the subject.

Systematic review of epigenetic targets in acute myeloid leukemia.

Acute myeloid leukemia (AML), although genetically and morphologically distinct from other B and T cell ALL subtypes, has one of the most rapidly progressing course and worse outcomes. The current diagnostic classification of AML offers best curative intent, the outcomes are not usually those that are expected at the start of therapy. This is partly attributed to the complex mechanism of leukemogenesis and resistance to chemotherapy. The underlying genetic mechanism of resistance is as complex as is the disease etiopathogenesis. Recent advances in therapy of drug resistant AML highlight the role of epigenetic targets. New FDA approved targeted therapy has also provided some evidence at improving outcomes in clinical trials. This review provides a detailed review of FDA approved targets and ongoing clinical trials for targeting CRISPER, CAR-T and other intestinal modalities for approach to epigenetictargets. However, this group of epigenetic targeted therapy needs more validation to prove its clinical efficacy. A systematic review of all published research on these targets, investigational agents and FDA approved targeted therapy summarizes this evidence. It also takes us through a brief review of mechanism of action and targets for therapy.

Analysing "tear-drop" prints of acute promyelocytic leukemia (APML): immunophenotypic prognostication of APML by FCM.

INTRODUCTION: Acute promyelocytic leukemia (APML), although genetically and morphologically distinct from other AML (acute myeloid leukemia) subtypes, is one of the most best responsive acute myeloid leukemia. -Conventional diagnostic methods and morphological hints often fail in the majority of the cases in the peripheral laboratories owing to resource constraints, unavailability of cytogenetic work-up, hypogranular variants, morphological mimicry by AML-monocytic and myelo-monocytic, etc. Flowcytometry (FCM), however, can be utilized as a feasible and reliable immunophenotypic diagnostic and prognostic tool for prompt identification of APML. In order to rapidly and sensitively diagnose APML we intended to suggest a cost effective, sensitive FCM panel and also to prognositicate patients. MATERIAL AND METHODS: In this retrospective study, flowcytometry characteristics of 123 cases of acute promyelocytic leukemia were studied including 40 hypogranular variants. The expression of markers was compared with the Mean flurescent Intensity (MFI) and percent expression of markers. A non-statistical comparison was made with cases of acute monocytic leukemia. The cases were grouped according to their immunophenotype characteristics and expression with comparison of MFI by multivariate logistic regression. The aberrant markers positive at diagnostic and remission flow test were compared with the survival outcomes, and their positive predictive values were calculated. RESULTS: The most common feature of side scatter property was the absence of blasts in the window and high side scatter, except hypogranular variants which had low side scatter. Immunophenotypically characterised by positivity for CD117, cMPO, and bright CD33 and CD13 positivity and lack of CD34 and HLA-DR was seen in the majority of APML including hypo-granular variant. We suggest a rapid diagnostic four-tube panel for fast and rapid diagnosis of APML, including hypogranular variants with 100% sensitivity. The study also identified six groups of immunophenotypes with significant prediction values of APML, including hypogranular variants. The study also highlights CD2, CD56, and CD9 as prognostic markers for acute promyelocytic leukemia.

Therapeutic lessons from transfusion in pregnancy-effect on hematological parameters and coagulation profile.

INTRODUCTION: Transfusion is commonly done in clinical indications and complications arising due to Anemia, shock, blood loss, thrombocytopenia due to any cause, ineffective erythropoiesis. Pregnancy is a physiological condition characterized by Anemia, fluid overload, hypercoagulable state, and antifibrinolytic condition, which can cause various reactions that could be anticipated during a blood transfusion. With an aim to understand the effects of transfusions on hematological parameters in pregnancy. The results of whole blood and component transfusion were studied to understand increments and their effects so that rationalized transfusion decisions during pregnancy can be undertaken, considering the physiological changes in pregnancy on hemodynamics are present. METHODOLOGY: A prospective study with 80 pregnant females undergoing blood transfusion was studied. Their coagulation and hematological profile were correlated to derive a conclusion for the effect of transfusion of blood and its products. RESULTS: A mean increment of 0.55+0.07 g/dL hemoglobin (Hb) was noted along with a slight increase in RBC count (0.25+0.07 millions/mm3), hematocrit (HCT) (1.9+0.42%), TLC (400+565 cells/mm3). This statistically significant mean increase in hemoglobin, RBC count, and hematocrit was significantly lower than that compared to studies in the west and non-anemic patients. A mean increment of 7.79+1.51 µg/dL (statistically significant) in serum iron was seen. A significant improvement in their coagulation profile was achieved by plasma transfusion (FFP). Clotting time (CT) decreased by a mean value of 196.43+56.69 secs and prothrombin time (PT) by 2.64+0.63 secs (P<0.05). All transfusion reactions in our study were associated with PRBC transfusion, non-hemolytic immunological type, urticarial transfusion reactions (UTR) more common in multiparous women-0.2% in primigravida to 21.7% and 37.5% in 3rd and 4th parity similar to that observed in other studies. CONCLUSION: Although different researchers have done numerous studies, the physiological profile of pregnant females in India is markedly different in nutritional profile, ethnicity, environmental factors, and background. The availability of tertiary care medical facilities during ANCs is also known to affect pregnancy outcomes and the presentation of patients at term or in labor. The variety of factors affect the baseline hematological status of pregnant females and, hence, post-transfusion hematological factors. These are therefore markedly different from prior published studies. It is concluded that PRBC transfusion in pregnant women causes a lower increase in mean Hb and HCT values than in the west, and ferritin and serum iron are not reliable indicators of Anemia in transfusion. Due to lower increments in all values except platelets could be the reason for this could be contributed by confounding factors like Anemia, hyperfibrinogenemia, volume overload, and ethnicity.