Administration Of Hydroxyurea Research Articles

A Case Report of Hyperhemolytic Syndrome in Sickle Cell Disease, with a Special Focus on Avoiding the Use of Transfusions

A Case Report of Hyperhemolytic Syndrome in Sickle Cell Disease, with a Special Focus on Avoiding the Use of Transfusions

Antioxidants as supplements during drug-induced thrombocytopenia: a comparative analysis of Vanillic acid, L-carnitine and Caripill™

Drug-induced thrombocytopenia (DIT) is a disorder where platelet count declines as an adverse effect of therapeutic drugs. Plant extract of C. papaya Caripill™ is known to elevate platelet count under thrombocytopenic conditions. To evaluate the contribution of supplements with antioxidant potential to treat DIT, the comparative study of Caripill™, vanillic acid L-carnitine effect on platelet count and indices of oxidative stress in a model of rat thrombocytopenia induced through oral administration of hydroxyurea was performed. Wistar rats were grouped into four categories with five animals in each group: control (without any treatment); control + antioxidants; thrombocytopenia; thrombocytopenia + antioxidants. The above-mentioned antioxidants were supplemented orally at 50 mg/kg for 7 days. The level of lipid peroxidation products­, superoxides, protein carbonyls and sulfhydryls, SOD and CAT activity in isolated platelets as oxidative stress markers, and indices of platelets aggregation and ATP secretion as functional markers were used. Vanillic acid was shown to be beneficial, similar to Caripill™, during hydroxyurea-induced thrombocytopenia by maintaining platelet functions, enhancing both the antioxidant capacity of platelets and its number. L-carnitine efficiently up-regulated the enzymatic antioxidants, maintained platelet functions and protected lipids and proteins from oxidation in thrombocytopenic rats, however, it could not improve the platelet count. These findings open new avenues for employing the studied antioxidants as supplements for therapeutic purposes.

Characterization of a cohort of Angolan children with sickle cell anemia treated with hydroxyurea

BackgroundSickle Cell Anemia (SCA) is a monogenic disease, although its severity and response to treatment are very heterogeneous. ObjectivesThis study aims to characterize a cohort of Angolan children with SCA and evaluate their response to hydroxyurea (HU) treatment and the potential side effects and toxicity. MethodsThe study enrolled 215 patients between 3 and 12 years old before and after the administration of HU, at a fix dose of 20 mg/kg/day for 12 months. ResultsA total of 157 patients started HU medication and 141 of them completed the 12-month treatment. After initiating HU treatment, the frequency of clinical events decreased (transfusions 53.4 %, hospitalizations 47.1 %). The response to HU medication varied among patients, with some experiencing an increase in fetal hemoglobin (HbF) of <5 %. The mean increase in HbF was 11.9 %, ranging from 1.8 % to 31 %. Responders to HU treatment were 57 %, inadequate responders 38.7 % and non-adherent 4.2 %. No clinical side effects related to HU were reported. Hematological toxicities were transient and reversible. Children naïve to HU and with lower HbF reported higher number of hospitalizations caused by malaria infection. During HU treatment, the frequency of malaria episodes did not appear to be affected by HbF levels. Conclusionsthe present study provided a valuable contribution to the understanding of the clinical and laboratory profiles of Angolan children with SCA. These findings support the evidence that the implementation of prophylactic measures and treatment with HU is associated with increased survival in children with SCA.

Prevalence and Proportion of Transcranial Doppler Screenings in a Population Children with Sickle Cell Disease and Association with Hydroxyurea Adherence

Sickle cell disease (SCD) is an inherited or genetic hemoglobinopathy in the United States and approximately 100,000 Americans are affected. The prevalence of stroke in unscreened children with sickle cell anemia (SCA) is 10% and can begin at infancy. National guidelines strongly recommend annual Transcranial Doppler (TCD) screenings as well as hydroxyurea (HU) administration in children with SS and Sβ o thalassemia (SCA) genotypes. The purpose of this project was to examine the prevalence and proportion of TCD screenings in North Carolina (NC) Medicaid enrollees and to identify associations with sociodemographic factors (age, sex, and rurality) and HU adherence. A longitudinal analysis of NC Medicaid claims data (2016-2019) was conducted for children with SCD ages 2-16 years. Prevalence of TCD screening claims was calculated to determine the number of children with TCD claims for each of the three, 12-month enrollment periods. The proportion of TCD screening claims was calculated based on NC Medicaid enrollees who had increasing TCD claims (0, 1, 2, or 3+) for 12, 24, and 36 months of Medicaid enrollment. HU adherence was measured using Proportion of Days Covered (PDC). HU PDC is a measure of HU prescription fills over 365 days within a 12-month period. HU PDC was used to categorize enrollees into good (≥80%), moderate (60-79%), or poor (&amp;lt;60%) adherence categories. Age (years) was declared as the age in years of each participant during each study observation period and was categorized into three groups: preschoolers (2-5 years), school aged (6-11 years), and adolescents (12-16 years). Rurality was identified by converting residential zip codes to rural/urban county codes (RUCC). An adjusted multivariable Poisson regression model was fit to assess the rate of TCD screenings by HU adherence while controlling for age, sex, and rurality. The prevalence of children with annual TCD screening claims ranged from 39.5% to 40.1%. The percentage of children with 2 or more TCD claims increased when they had extended months of NC Medicaid enrollment (10.5% at 12 months, 33.7% at 24 months, and 52.6% at 36 months). Overall, children with Good HU adherence were 2.48 (95% CI 2.00, 3.06) times more likely to have TCD claims than children with poor HU adherence. In conclusion, the prevalence of TCD screenings of children with SCD on NC Medicaid was extremely low. Children with better HU adherence and extended NC Medicaid enrollment time were associated with higher number of TCD screenings.

Assessment of Neurocognitive Functioning in Sickle Cell Disease and Thalassemia and the Association with Silent Cerebral Infarcts and Cerebral Hemodynamics and Oxygen Metabolism

Introduction Neurocognitive impairment is a significant problem in patients with sickle cell disease (SCD), affecting various life domains such as academic achievement, career progress, and general life quality. The cause of this impairment is not yet fully understood, however, it has been linked to silent cerebral infarcts (SCIs) and irregularities in blood perfusion and oxygenation, particularly in children with SCD. Previous research has identified cognitive deficits in adults with SCD, but the relationship with SCIs has not been thoroughly explored in this age group. This study aimed to examine the neurocognitive functioning among adult patients with three types of inherited chronic anemia (severe SCD, mild SCD, and thalassemia) and healthy controls. Additionally, we investigated potential associations of neurocognitive performance with cerebral perfusion and oxygenation, and SCIs. Methods This study included 70 severe SCD patients (60 HbSS, 10 HbSβ 0), 22 mild SCD patients (14 HbSC, 8 HbSβ +), 16 thalassemia patients (6 NTDT, 10 TDT), and 29 healthy controls. We assessed neurocognitive functioning through eight tasks divided into seven neurocognitive domains such as attention, processing speed, nonverbal IQ, working memory, verbal learning, visual memory, and fine motor dexterity. Each task score was standardized using published norm data, converted into Z-scores, and used to compute the mean Z-score per domain. SCIs were assessed and segmented using FLAIR MRI scans. Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were derived using time-encoded pseudo-continuous arterial spin labeling (te-pCASL) and T 2-relaxation-under-spin-tagging (TRUST) techniques, respectively. Cerebral metabolic rate of oxygen (CMRO 2) was calculated from the CBF, OEF and oxygen content (calculated from hemoglobin and arterial saturation). One-sample t-tests or one-sample Wilcoxon-signed rank tests were used to compare the seven neurocognitive domains of each group with normative test data and ANOVA was used to compare these domains between participant groups. Independent-sample t-tests or Mann-Whitney U tests were used to compare the neurocognitive domains between patients with and without SCIs. Lastly, correlation analyses explored the relationships between the neurocognitive domains and SCI volume, CBF, OEF, and CMRO 2. Results In the severe SCD group, only processing speed and fine motor dexterity were significantly impaired after adjusting for multiple comparisons (Table 1 &amp; Figure 1). Mild SCD patients exhibited lower scores in processing speed, working memory, and fine motor dexterity compared to the norms. In contrast, after adjustment for multiple comparisons, thalassemia patients and healthy controls only showed significantly lower scores in fine motor dexterity (Table 1). When comparing groups, SCD patients had significantly slower processing speed compared to thalassemia patients and healthy controls. Surprisingly, SCD patients without SCIs exhibited poorer fine motor dexterity than those with SCIs (p=0.03), while no such associations were identified in other groups. Finally, no associations were found between the neurocognitive domains and SCI volumes, CBF, OEF and CMRO 2. Conclusion Our results show slower processing speed in SCD patients compared to thalassemia patients and healthy controls, aligning with previous studies. However, unlike previous research, we did not find additional neurocognitive deficits in SCD patients. This could be due to variations in patient selection, environmental factors, socioeconomic status, or recent enhancements in SCD treatment approaches, such as the early administration of hydroxyurea and/or blood transfusion. Interestingly, all groups showed diminished fine motor dexterity, potentially due to the ongoing digital transition. A key observation from this study was the lack of association between neurocognitive performance and SCIs, hemodynamics, and oxygen metabolism, suggesting that SCIs and oxygenation might not be the only factors contributing to impaired processing speed. Our results suggest that recent developments in medical treatments could have improved the neurocognitive function of SCD patients residing in Western countries. However, concerning the domain of processing speed, further studies are required to investigate other SCD-related factors that might influence this particular area.

Determinants of splenic preservation among patients with sickle cell disease in North-Eastern Nigeria.

In patients with sickle cell disease (SCD), the spleen commonly enlarges during early childhood, but undergoes reduction in size and fibrosis from repeated episodes of vaso-occlusion and infarction. The rate of progression of this process varies markedly among these patients. The aim of current study was to explore clinical and laboratory factors associated with the preservation of the spleen among these patients. Two hundred four patients with SCD (103 females; age 1-45 years) underwent abdominal ultrasonography at the University of Maiduguri Teaching Hospital, Nigeria between October 2020 and November 2021 to assess for splenic visualisation and echotexture. Steady-state clinical parameters and blood samples for full blood count, serum chemistry, high-performance liquid chromatography and malaria parasitemia were obtained from all the patients. The spleen was visualised in 107 (52.4%; 95% confidence interval [CI], 46%-59%) patients with SCD on ultrasonography. While the spleen was visualised in all children less than 5 years of age, it was visualised in only 23.5% of those aged 15 years and older. Visualisation of the spleen was significantly associated with low mean corpuscular haemoglobin concentration and high haemoglobin F (HbF) in those younger than 10 years. The odds of visualisation of the spleen on ultrasonography increased by a factor of 1.17% for every 1% increase in HbF level. Only 32 (15%) patients were on regular hydroxyurea therapy. The HbF level was significantly higher among patients on hydroxyurea (median 12.7 vs. 7.4; p < 0.0001). In patients with SCD, failure to visualise the spleen was not found in children less than 5 years old. Patients with visualised spleens had a higher level of HbF than those with non-visualised spleens. HbF was significantly associated with visualisation of the spleen before 10 years of age. Since early administration of hydroxyurea will increase HbF level, we expect that it would help to preserve the spleen.

Alloimmunization in children with sickle cell disease: A tertiary care experience

IntroductionPatients with sickle cell disease (SCD) show a high prevalence of red blood cell (RBC) alloimmunization, however, few studies have focused on children. The present study was undertaken to determine the prevalence of alloimmunization and autoimmunity in children with SCD and to assess any correlation with age, number of transfusions received, and the number and frequency of crisis. Material & methodsSixty children affected with homozygous SCD, aged between five to eighteen years and having received more than one packed red blood cell (PRBC) transfusion were enrolled in the study.The preliminary tests included antiglobulin test (indirect and direct), alloantibody screening by three panel, antibody typing using 11 panel and auto-control test to detect autoantibodies. ResultsDirect antiglobulin test was negative in all the 60 patients, whereas indirect antiglobulin test was positive in 4/60 (6.6%) patients. Specific typing of alloantibodies revealed anti-D and anti-Kell antibodies in 2 (3.3%) each. Patients with alloantibody (4) had a higher mean age at onset of first symptom (7.05 ± 2.12 years) and age at first transfusion (7.5 ± 2.12 years) as compared to those without alloantibody, (4.48 ± 3.09 and 4.91 ± 3.12 years respectively). Patients with alloantibody received more PRBC transfusions, maintained low hemoglobin, required higher doses of hydroxyurea and also had a larger liver and spleen. ConclusionThe present study found a low prevalence of antibodies in patients with SCD. Patients presenting with symptoms of SCD at younger age received hydroxyurea at an earlier age. Starting hydroxyurea at an earlier age may decrease subsequent alloantibodies development. Larger studies to compare groups of patients related to administration of hydroxyurea are required to confirm this hypothesis.

Molecular and cellular effects of in vivo chronic intravascular hemolysis and anti-inflammatory therapeutic approaches

Intravascular hemolysis (IVH) occurs in numerous inherited and acquired disorders, including sickle cell disease (SCD), malaria and sepsis. These diseases display unique symptoms, but often share complications, such as vasomotor dysfunction and pulmonary hypertension. Consequently, in vivo models are needed to study the effects of continuous intravascular hemolytic processes, independently of the molecular alteration or extrinsic factor that leads to erythrocyte destruction. We gave twice-weekly low-dose phenylhydrazine (LDPHZ) to C57BL/6 J mice for 4 weeks, and measured parameters indicative of anemia, hemoglobin-clearance pathways, inflammation and iron turnover, comparing these to those of a murine model of SCD, which displays associated IVH. LDPHZ administration provoked discreet anemia in mice and significant reticulocytosis, in association with hemoglobin/heme-clearance pathway protein depletion. Mice subjected to chronic hemolysis displayed elevated leukocyte counts and plasma levels of interleukin (IL)-1β, TNF-α, IL-6, soluble ICAM-1, endothelin-1 and anti-inflammatory IL-10, closely emulating alterations indicative of systemic inflammatory and endothelial activation in SCD, and confirming chronic IVH in itself as a serious complication. Discreet accelerations in hepatic and splenic iron turnover also occurred in LDPHZ mice, without alterations in liver damage markers. Examining the effects of two therapies on hemolysis-induced inflammation, the administration of hydroxyurea (and to a lesser extent, l-glutamine) significantly abrogated hemolytic inflammation in mice, without apparent inhibition of hemolysis. In conclusion, the isolation of chronic IVH, a common disease mechanism, using this model, may allow the study of hemolysis-specific sequelae at the cellular and systemic level, and the investigation of candidate agents that could potentially counter hemolytic inflammation.

Adverse effects of hydroxyurea used for the treatment of myeloproliferative neoplasms

Background: Hydroxyurea is administered to control elevated blood counts in patients with myeloproliferative neoplasms (MPNs) to reduce the risk of thrombosis and mortality. We reviewed the side effects of hydroxyurea, development of secondary malignancies, and drug resistance observed in some patients.Current Concepts: The low incidences of malformed births, intrauterine deaths, and spontaneous abortions associated with hydroxyurea therapy suggest that adverse pregnancy and fetal effects are unlikely. However, animal studies have reported malformations; therefore, the use of hydroxyurea during pregnancy is not recommended. Low-grade adverse events associated with hydroxyurea therapy include gastrointestinal symptoms such as nausea, upper gastrointestinal discomfort, and diarrhea. These symptoms are usually resolved by dose adjustment or temporary discontinuation. Approximately 10% of patients with MPNs are resistant to hydroxyurea, and another 10% are unable to tolerate it owing to side effects. Drug intolerance and resistance are the most common causes of inadequate cytoreductive control in patients with MPNs. Second-line cytoreductive agents should be considered to overcome the high risk of thrombosis and poor survival. The evolution to secondary hematologic cancers is related to the duration of the disease, not hydroxyurea administration.Discussion and Conclusion: In pregnant patients accidentally exposed to hydroxyurea, the risk should be discussed with the patient to determine whether to continue the pregnancy. Hydroxyurea administration increases the risk of skin cancer but does not affect the incidence of other secondary hematologic or solid cancers. Ropeginterferon or Janus kinase (JAK) inhibitors, including ruxolitinib, are recommended as alternative treatments if the patient is intolerant or resistant to hydroxyurea, as this is associated with poorer survival.

Health Equity in Sickle Cell Research and Access to Therapy

Health Equity in Sickle Cell Research and Access to Therapy

Role of Hydroxyurea in Patients of Beta Thalassemia Majo

Objective: To study the role of Hydroxyurea in patients suffering from β-thalassemia major.&#x0D; Study Design: Prospective longitudinal study.&#x0D; Place and Duration of Study: Department Paediatrics, Combined Military Hospital, Malir Cantt, Karachi Pakistan, from Nov 2019 to Oct 2020.&#x0D; Methodology: Data from 73 beta-thalassemia major patients was collected using a structured questionnaire containing inquiries about basic socio-demographic details, disease history, laboratory reports and particulars of former treatment regimens. Hydroxyurea was administered, and its effects were noted among the subjects regarding the frequency of transfusion, haemoglobin levels and severity of clinical symptoms.&#x0D; Results: The mean age of study subjects was 9.15±3.99 years, and most study subjects (56.14%) were boys. The preintervention (before administration of Hydroxyurea) levels of Hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular haemoglobin concentration (MCHC), and serum ferritin levels were unremarkable when compared to postintervention levels. However, a significant difference was observed in HbF levels. In addition, an encouraging decrease was reported in the self-rated severity (using VAS) of symptoms such as fatigue (p&lt;0.05), weakness (p&gt;0.05), and shortness of breath (p&gt;0.05). In addition, the transfusion interval was significantly reduced (p&lt;0.05).&#x0D; Conclusion: After carefully considering the results, it can be concluded that Hydroxyurea plays a positive role and brings about significant improvement among patients suffering from β-thalassemia major.&#x0D; Keywords: Fetal hemoglobin, Genetic disease, Hydroxyurea, Thalassemia major.

Pilot study to estimate the safety and effectiveness of hydroxyurea and methotrexate recurrent langerhans cell histiocytosis (LCH-HU-pilot).

This study was a non-blinded, multicenter, single-arm study. Recurrent (relapsed) LCH is defined as the appearance of new lesions or the enlargement of preexisting lesions due to LCH. In this study, all patients received hydroxyurea, and if the treatment response was unsatisfactory, methotrexate was added. The duration of treatment was 48 weeks. The primary endpoint was the rate of non-active disease achievement, which was 24 weeks after initiating hydroxyurea administration. No active disease is defined as the resolution of all the signs and symptoms related to LCH.

Hydroxyurea Dosing in Very Young Children (HUGKISS): Challenges of Study Design

Introduction: The acute and chronic complications of sickle cell anemia (SCA) are well-known, with many of them arising in the first few years of life. The BABY HUG trial showed that 20 mg/kg/day of hydroxyurea therapy is safe, blunts the decline of fetal hemoglobin (HbF), and is clinically beneficial for very young infants and children with SCA. Nevertheless, children treated with hydroxyurea continued to develop acute complications and acquire end organ damage. Although the BABY HUG trial established the safety and efficacy of fixed dose hydroxyurea in very young children with SCA, further study was needed to define the optimal dosing regimen to maximize benefit in this group. We describe our approach to designing and implementing the Hydroxyurea Management in Kids: Intensive versus Stable Dosage Strategies (HUGKISS) study, which assessed the feasibility of enrolling and randomizing very young children with SCA to intensified versus fixed doses of hydroxyurea. The hematologic and clinical effects of both doses were also monitored. Methods: The HUGKISS trial was designed as a single-blind, multicenter, randomized controlled pilot study. It was felt that the objectives of HUGKISS could be safely and more efficiently obtained with a single-blind design (with investigators blinded), because a double-blind design would be logistically challenging and would place significant burden on families and pharmacies. For example, in one double-blind design, caregivers would have to administer two aliquots of study drug (hydroxyurea + hydroxyurea or hydroxyurea + placebo), thereby providing a potential source for medication error. However, because the HUGKISS study required dosage adjustment of hydroxyurea based on complete blood count results, a HUGKISS Enabled Local Provider for Evaluating Response (HELPER) was utilized. Each HELPER was an unblinded local medical provider, unaffiliated with the steering committee or data analysis, who was knowledgeable about SCA. This individual monitored hydroxyurea concordance and toxicities in real time. All patients received hydroxyurea at 20 mg/kg/day for 8 weeks. If they were stable and adherent, they were randomized to either continued fixed dosing or intensified dosing, which involved escalation of hydroxyurea dosing every 8 weeks to a maximum of 35 mg/kg/day. While the primary endpoint was assessing feasibility of enrollment and randomization, the main secondary endpoint assessed was changes in HbF levels. This choice reflected the age of the patient population, which would be undergoing a physiologic decline in HbF during the study period. We monitored adherence via the Medication Adherence Measure (MAM) and measurement of remaining hydroxyurea suspension in the prescribed bottle. Both were performed every four weeks. A medication possession ratio was calculated using the results from both methods, and used to quantitate adherence. Enrollment screening logs were also maintained at all sites. The most common reason for declining participation in HUGKISS was that families desired more time to "think about" hydroxyurea and participation in a trial, followed by disinterest in using hydroxyurea, and a fear of participating in clinical trials. Conclusion: Important considerations when designing trials involving young children with SCA include choice of endpoints, obtaining adequate enrollment, maintaining blinding of a liquid formulation with dose adjustments, and assessment of medication adherence. The HUGKISS study employed a novel single-blind design to facilitate safe and efficient administration of hydroxyurea for families, while also ensuring close monitoring of toxicities through a HELPER.

Challenging Management of Severe Differentiation Syndrome in Pediatric Acute Promyelocytic Leukemia Treated with ATRA/ATO.

The ATRA/ATO combination treatment of acute promyelocytic leukemia (APL) represents a paradigm of successful targeted and chemotherapy-free treatment in oncology. This therapeutic strategy is aimed at sparing patients from chemotherapy toxicity, while maintaining an excellent survival with a low risk of relapse. Main induction treatment-related complications are differentiation syndrome (DS) and hyperleukocytosis, which is related to DS and its severity. In the period December 2019 – December 2020, 8 children with newly diagnosed APL underwent induction therapy with ATRA/ATO in our center. In patients with WBC≥10x109/L two doses of Gemtuzumab Ozogamicin (GO) were added. In case of severe DS or hyperleukocytosis the differentiating agents were discontinued, high dose dexamethasone (DXM) and/or hydroxyurea (HU) were recommended. Five patients presented WBC&lt;10x109/L ; all developed hyperleukocytosis and three also had DS and were initially treated with HU and DXM; due to unsatisfactory control of the symptoms GO was added in two of them.. One of the three patients with presenting WBC≥10x109/L, developed pseudotumor cerebri and another one DS. The supportive treatment was effective in all cases. Our experience shows that patients, treated with ATRA/ATO only, may develop marked hyperleukocytosis and severe DS, which may be unresponsive to discontinuation of differentiating agents and administration of HU and DXM and may benefit from the use of GO. Adequate intensive support therapy is crucial to rescue patients with severe DS.

IVS I-5 (G > C) is associated with changes to the RBC membrane lipidome in response to hydroxyurea treatment in β-thalassemia patients.

The red blood cell membrane loses its integrity during hemoglobinopathies like β-thalassemia and sickle cell disease. Various mutations have been associated with β-thalassemia, the most prevalent of which is the IVS-1-5 (G > C) mutation. It is associated with poor prognosis of the disease with a dependency on transfusion. Here, we have investigated the effect of IVS mutation and the administration of hydroxyurea on the red blood cell membrane lipidome isolated from patients using a liquid chromatography coupled to tandem mass spectrometry based approach to identify changes in the red blood cell membrane lipidome of patients with/without the mutation and being/not being administered hydroxyurea. A total of 50 patients, with/without hydroxyurea treatment, were recruited and 62 lipid species were identified in all groups after statistical analyses using fold change analysis, ANOVA and lipids with higher VIP values extracted from the OPLS-DA loading plot. The presence of the IVS mutation showed altered expression levels of various lipid species as compared to non-IVS individuals, such as phosphatidylcholines, steroids, phenol lipids and fatty acids. Significant changes were though found with the administration of hydroxyurea where both the IVS and non-IVS groups showed a marked increase in complex lipids of the membrane, while a decrease was observed in those without hydroxyurea administration showing degradation of these membrane lipids. This study is the first to report changes incurred by IVS mutation and hydroxyurea administration in red blood cell membranes extracted from β-thalassemia patients. Hydroxyurea administration has been perceived to improve the lipid profile of the red blood cell membrane in both IVS and non-IVS patients.

High STAT5A Expression is Associated with Major Molecular Response Achievement Failure of Chronic Phase Chronic Myeloid Leukemia Patients Receiving Hydroxyurea before Imatinib: A Cross-sectional Study

BACKGROUND: STAT5 is a transcriptional factor which when highly expressed in chronic myeloid leukemia (CML) cells stimulate proliferation and mediate resistance from tyrosine kinase inhibitors, resulting in major molecular response (MMR) failure. STAT5 has two isoforms, STAT5A and STAT5B. However, prolonged use of imatinib appears to only upregulate STAT5A pathway. In addition, the resistance conferred by STAT5A does not extend to other drugs such as hydroxyurea. Hence, STAT5A and STAT5B might have different functions in CML cells. AIM: The objective of the study was to determine the association of STAT5A and STAT5B expression with MMR failure in CML patients. METHODS: This was a cross-sectional study of CML patients in chronic phase with age ≥ 18 years old, receiving IM therapy ≥ 12 months, and previously given hydroxyurea. MMR status was evaluated and patients were categorized as achieved or failed to achieve MMR. Expression levels of STAT5A and STAT5B were conducted using RT-PCR methods. Associations between STAT5A expression, STAT5B expression, hydroxyurea duration, and imatinib duration with MMR achievement were calculated using logistic regression. RESULTS: A total of 118 patients were analyzed; 71.1% failed to achieve MMR. Multivariate logistic regression analysis showed statistically significant association between high STAT5A expression (odds ratio [OR]: 3.852; 95% confidence interval [CI]: 1.420–10.452; p = 0.008), STAT5A/STAT5B interaction (OR: 0.150; 95% CI: 0.038–0.593; p = 0.007), longer hydroxyurea administration (OR: 3.882; 95% CI: 1.023–14.733; p = 0.046), and shorter imatinib administration (OR: 0.333; 95% CI: 0.132–0.840; p = 0.020) with MMR achievement failure. After adjusting STAT5A expression with STAT5A/STAT5B interaction, high STAT5A expression independently increased the likelihood of MMR achievement failure only in high expression STAT5B patients (OR: 3.852; 95% CI: 1.420–10.452; p = 0.008). CONCLUSION: High STAT5A expression which is induced by high STAT5B is associated with MMR achievement failure of chronic phase CML patients who received hydroxyurea before imatinib. Longer duration of hydroxyurea and shorter duration of IM confound of STAT5A expression to MMR achievement failure.

Nitric Oxide Synthase Dependency in Hydroxyurea Inhibition of Erythroid Progenitor Growth.

Hydroxyurea (HU) causes nitric oxide (NO) bioactivation, acting as both a NO donor and a stimulator of NO synthase (NOS). To examine whether HU effects are NO mediated by chemical degradation or enzymatic induction, we studied human and mouse erythroid cells during proliferation, apoptosis, and differentiation. The HU and NO donor demonstrated persisted versus temporary inhibition of erythroid cell growth during differentiation, as observed by γ- and β-globin gene expression. HU decreased the percentage of erythroleukemic K562 cells in the G2/M phase that was reversed by N-nitro l-arginine methyl ester hydrochloride (L-NAME). Besides activation of endothelial NOS, HU significantly increased apoptosis of K562 cells, again demonstrating NOS dependence. Administration of HU to mice significantly inhibited colony-forming unit-erythroid (CFU-E), mediated by NOS. Moreover, burst-forming-units-erythroid (BFU-E) and CFU-E ex vivo growth was inhibited by the administration of nitrate or nitrite to mice. Chronic in vivo NOS inhibition with L-NAME protected the bone marrow cellularity despite HU treatment of mice. NO metabolites and HU reduced the frequency of NOS-positive cells from CFU-E and BFU-E colonies that was reverted by NOS inhibition. HU regulation of the G2/M phase, apoptosis, differentiation, cellularity, and NOS immunoreactive cells was NOS dependent. Inhalation of NO therapy as well as strategies to increase endogenous NO production could replace or enhance HU activity.

Continuous Glucose Monitoring in the Intensive Care Unit Following Total Pancreatectomy with Islet Autotransplantation in Children: Establishing Accuracy of the Dexcom G6 Model.

Hyperglycemia is detrimental to postoperative islet cell survival in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT). This makes continuous glucose monitoring (CGM) a useful management tool. We evaluated the accuracy of the Dexcom G6 CGM in pediatric intensive care unit patients following TPIAT. Twenty-five patients who underwent TPIAT had Dexcom G6 glucose values compared to paired serum glucose values. All paired glucose samples were obtained within 5 minutes of each other during the first seven days post TPIAT. Data were evaluated using mean absolute difference (MAD), mean absolute relative difference (MARD), %20/20, %15/15 accuracy, and Clarke Error Grid analysis. Exclusions included analysis during the CGM “warm-up” period and hydroxyurea administration (known drug interference). A total of 183 time-matched samples were reviewed during postoperative days 2–7. MAD was 14.7 mg/dL and MARD was 13.4%, with values of 15.2%, 14.0%, 12.1%, 11.4%, 13.2% and 14.1% at days 2, 3, 4, 5, 6 and 7, respectively. Dexcom G6 had a %20/20 accuracy of 78%, and a %15/15 accuracy of 64%. Clarke Error Grid analysis showed that 77% of time-matched values were clinically accurate, and 100% were clinically acceptable. The Dexcom G6 CGM may be an accurate tool producing clinically acceptable values to make reliable clinical decisions in the immediate post-TPIAT period.

Hydroxyurea for the Treatment of Recurrence and Unresectable Meningiomas: A Systematic Review

BACKGROUND: Meningioma is mostly benign tumor (World Health Organization Grade 1) and surgery remains the best option in treating symptomatic or enlarging meningiomas where total removal of the tumor is the goal of surgery. Radiation therapy has shown to be effective to cease the growth of the tumor, but not in tumor regression. Adjuvant therapy may treat patients with recurrence or unresectable meningiomas yet the uses of hormone therapy, immunotherapy, or chemotherapy had many results and were not consistently effective. Hydroxyurea has promising results in patients with meningiomas.&#x0D; AIM: This study analyzed the efficacy and safety of hydroxyurea for the treatments of recurrence or unresectable meningiomas.&#x0D; MATERIALS AND METHODS: The study adapted PRISMA guidelines by searching electronic databases, PUBMED, Cochrane, and JNS in August 2020 and was full-text observational study or randomized control trial presented as PICO and assessed using the risk-of-bias assessment tool.&#x0D; RESULTS: A total of six articles (157 patients with meningioma) were reviewed from the total of 425. Hydroxyurea was administered orally for 28 days continuously and repeated every 28 days or after recovery with various dosages in six studies.&#x0D; DISCUSSION: Administration of hydroxyurea showed a varied stable disease rate ranging from 30 to 69% with a median progression-free survival med varying between 2 and 27.75 months. The studies performed oral hydroxyurea administration at a dose of 20–30 mg/kg body weight/day or 1000 mg/m2/day. However, the adverse events (AEs) that appear also, based on literature, are not much different from other chemotherapy administrations.&#x0D; CONCLUSION: Patients with unresected and recurrent meningiomas have limited treatment options due to difficulty for surgical management. However, this study offers another perspective addressing the efficacy and safety results with the use of hydroxyurea. Overall, hydroxyurea showed good outcomes, particularly in low-grade meningioma, with relatively low AEs. Further combination treatment may be used as a multimodal therapy.

Inaccurate Glucose Sensor Values After Hydroxyurea Administration

Objective: To assess the degree, duration, mean absolute relative difference (MARD), and error analysis of discrepant values per continuous glucose monitoring (CGM) systems after hydroxyurea (HU) administration. Research Design and Methods: Inpatient glucometer and CGM data from 16 total pancreatectomy/islet autotransplantation patients using Dexcom Professional G4 and 12 patients using Dexcom G6 were analyzed after daily dosing with HU. Timing of HU dosing and median of 9.5 days of sensor and glucometer values were assessed per patient. Results: A large positive elevation of sensor readings was identified after HU dosing. The greatest discrepancy between glucometer and sensor readings occurred 0.5-2 h after HU administration [G4 (mean 3.0 mmol/L, median 2.4 mmol/L, MARD 55%), G6 (mean 4.2 mmol/L, median 4.6 mmol/L, MARD 91%)]. The discrepancy was <1.1 mmol/L, mean (-0.5 mmol/L) and median (-0.5 mmol/L), MARD 14% (G4) and <1.1 mmol/L, mean (0.3 mmol/L) and median (0.3 mmol/L), MARD 17% (G6), by 6 h after administration. Error analysis with the G6 system found 94% of pairs in clinically acceptable range by 6-9 h after HU administration. Aspirin, also given once daily, did not result in glucose value discrepancy with the G6 system but variability was observed with the G4 system. Conclusions: There was marked elevation of sensor glucose readings compared with glucometer values [up to 13.9 mmol/L (G4), 13 mmol/L (G6)] from 0.5 to 6 h after HU administration. It is important to counsel a patient using a Dexcom CGM system and HU therapy on this finding and to advise reliance on glucometer testing for accurate glucose assessment up to 6-9 h after HU administration.