The where, who and how of adrenal vein sampling in Australia and New Zealand.

INTRODUCTION: Primary aldosteronism (PA) causes 10-15% of cases of hypertension, and it is increasingly recognised as being under-diagnosed. An interventional radiology procedure, adrenal vein sampling (AVS), is a necessary and important diagnostic procedure for complete workup of PA. There is an anticipated increase in demand for AVS as detection of PA improves. This study aims to describe the current landscape of AVS in Australia and New Zealand (NZ). METHODS: Two surveys exploring AVS methodology and performance were conducted of (i) Endocrinology Unit Heads and (ii) interventional radiologists who perform AVS, at public hospitals with Endocrinology Units across Australia and NZ. RESULTS: Responses were received from 48/53 Endocrinology Unit Heads (91%) and 35 radiologists from 26 sites (87% of AVS sites). AVS was provided at 28/48 Endocrinology sites (58%) across Australia and NZ. In Australia, sites were concentrated in Victoria, New South Wales and Queensland with none in the Northern Territory; in NZ, sites were more evenly distributed across the North and South Islands. AVS was performed by 1-2 dedicated radiologists at 24 sites, 2-3 radiologists at two sites and a rotating roster of radiologists at two sites. Responses to both surveys revealed significant variation in AVS methodology and interpretation of AVS results. CONCLUSION: There is significant heterogeneity in the availability of AVS, the procedural details and the interpretation of results across Australia and NZ, which potentially impacts the quality of patient care and ability to scale up AVS capacity to meet increasing demand.

Saline suppression to distinguish the primary aldosteronism subtype: a diagnostic study.

OBJECTIVES: The saline suppression test (SST) serves to confirm the diagnosis of primary aldosteronism (PA), while adrenal vein sampling (AVS) is used to subtype PA as unilateral or bilateral. Criteria that can accurately identify those with bilateral PA based on SST results could reduce the need for AVS. We previously demonstrated that a combination of plasma aldosterone concentration (PAC) < 300 pmol L-1 and a reduction in aldosterone-to-renin ratio (ARR) following recumbent SST had high specificity for predicting bilateral PA in an Australian cohort of 92 patients with PA who have undergone AVS. We sought to validate our predictive criteria in larger, independent cohorts of patients with PA. DESIGN: An international, multi-centre cohort study. METHODS: Data from 55 patients at Monash Health, Victoria, Australia, 106 patients from the First Affiliated Hospital of Chongqing Medical University, China, and 105 patients from Nihon University Itabashi Hospital, Japan were analysed. RESULTS: A combination of PAC <300 pmol L-1 and a reduction in ARR following recumbent SST predicted bilateral PA with specificities of 88.2%, 97.0%, and 100.0% in Australian, Chinese, and Japanese cohorts, respectively. This criterion could allow 22%-38% of patients with PA to bypass AVS and proceed directly to medical treatment. CONCLUSION: In patients undergoing the recumbent SST, a post-saline PAC <300 pmol L-1 together with a reduction in ARR can predict bilateral PA with high specificity and may allow targeted treatment to be commenced without AVS in up to a third of patients.

Aldosterone, Renin, and Aldosterone-to-Renin Ratio Variability in Screening for Primary Aldosteronism.

CONTEXT: The plasma aldosterone concentration (PAC), renin, and aldosterone-to-renin ratio (ARR) are used to screen for primary aldosteronism (PA). Substantial intra-individual variability of PAC and ARR using plasma renin activity in the context of usual antihypertensive therapy has been described, but there is no data on ARR variability calculated using direct renin concentration (DRC). OBJECTIVE: To describe the intra-individual variability of PAC, DRC, and ARR in the absence of interfering medications in patients with and without PA. DESIGN: Retrospective cohort study. PATIENTS: Hypertensive patients referred for investigation of PA, with at least 2 ARR measurements while off interfering medications. SETTING: Endocrine hypertension service of a tertiary center, from May 2017 to July 2021. MAIN OUTCOME MEASURES: PAC, DRC, and ARR variability was calculated as coefficient of variation (CV) and percent difference (PD). RESULTS: Analysis of 223 patients (55% female, median age 52 years), including 162 with confirmed PA, demonstrated high variability with a sample CV of 22-25% in the PAC and sample CV of 41% to 42% in the DRC and ARR in both the PA and non-PA groups. The degree of variability was substantially higher than the assays' analytical CV. Sixty-two patients (38%) with PA had at least one ARR below 70 pmol/L:mU/L (2.4 ng/dL:mU/L), a cut-off for first-line screening of PA. CONCLUSIONS: Significant intra-individual variability in PAC, DRC, and hence ARR occurs in a large proportion of patients being investigated for PA. These findings support the need for at least 2 ARR before PA is excluded or further investigated.

Impact of Intraprocedural Sedation on Adrenal Vein Sampling without Corticotropin Stimulation.

See also the editorial by Georgiades in this issue.

Assessment of analytical bias in ferritin assays and impact on functional reference limits.

Serum ferritin is currently the recommended laboratory test to investigate iron deficiency. There have been efforts to standardise serum ferritin assays with implementation of traceability to the World Health Organization reference standard. We evaluate the analytical bias among five widely used commercial ferritin assays in Australia. The relationship between serum ferritin and erythrocyte parameters was recently explored to derive functional reference limits. Residual patient serum specimens were analysed by five participating laboratories that utilised a different ferritin assay, Abbott, Beckman Coulter, Roche, Siemens, and Ortho. Using data mining approach, functional reference limits for Siemens, Abbott, and Ortho serum ferritin methods were derived and compared. At clinically relevant ferritin decision points, compared to the Beckman method, the Roche assay showed higher results ranging from 6 µg/L (31%) at the lowest decision point to 575 µg/L (57%) at the highest decision point. In contrast, the Ortho method underestimated ferritin results at lower decision points of 20 and 30 µg/L, with estimated ferritin results of 16 µg/L (-19%) and 27 µg/L (-12%), respectively. The Abbott and Siemens assays showed a positive bias which was introduced at differing decision points. The comparison of the Siemens and Ortho methods presents similar inflection points between the two assays in the establishment of functional reference limits for serum ferritin. There remain significant biases among some of the commonly used commercial ferritin assays in Australia. More studies are needed to assess if functional reference limits are a way to overcome method commutability issues.

The potential use of folate and its derivatives in treating psychiatric disorders: A systematic review.

OBJECTIVES: To examine the strengths and limitations of existing data to provide guidance for the use of folate supplements as treatment, with or without other psychotropic medications, in various psychiatric disorders. To identify area for further research in terms of the biosynthesis of mechanism of folate and genetic variants in metabolic pathway in human. METHODS: A systematic review of published literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to assess whether folate supplements are beneficial in certain psychiatric disorders (depression, bipolar disorder, schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder). Methodology of this review is registered with Prospero (Registration number CRD 42021266605). DATA SOURCES: Eligible studies were identified using a systematic search of four electronic databases: Embase, Pubmed, PsycINFO, and Cochrane. The search strategy covered the time period from 1974 to August 16th, 2021. Therefore, this review examines randomized control trials or open-label trials completed during this period. RESULTS: We identified 23 studies of folate supplements in various psychiatric disorders for critical review. Of these, 9 studies investigated the efficacy of folate supplements in major depressive disorders, 5 studies in schizophrenia, 6 studies in autism spectrum disorder, 2 studies in bipolar affective disorder and 1 study in attention deficit hyperactive disorder. The most consistent finding association of oral levomefolic acid or 5-methylfolate with improvement in clinical outcomes in mental health conditions as mentioned above, especially in major depressive disorder (including postpartum and post-menopausal depression), schizophrenia, autism spectrum disorder, attention deficit hyperactivity disorder and bipolar affective disorder. Folate supplements were well tolerated. LIMITATION: Our results are not representative of all types of studies such as case reports or case series studies, nor are they representative of the studies conducted in languages that are not in English or not translated in English. CONCLUSION: Increasing evidence from clinical trials consistently demonstrate folate supplements, especially levomefolic acid or 5-methylfolate, may improve clinical outcomes for certain psychiatric diseases, especially as an adjunct pharmacotherapy with minimal side effects.

Comparison of the efficacy of tea tree (Melaleuca alternifolia) oil with other current pharmacological management in human demodicosis: A Systematic Review.

Various treatments are found to be moderately effective in managing Demodex-related diseases except tea tree oil (TTO) and terpinen-4-ol (T4O), which showed superior miticidal and anti-inflammatory effects in numerous clinical studies. Their possible effects include lowering mite counts, relieving Demodex-related symptoms, and modulating the immune system. This review summarizes the current clinical topical and oral treatments in human demodicosis, their possible mechanisms of action, side-effects and resistance in treating this condition. TTO (especially T4O) is found to be the most effective followed by metronidazole, ivermectin and permethrin in managing the disease. This is because TTO has anti-parasitic, anti-bacterial, anti-fungal, anti-inflammatory and wound-healing effects. Furthermore, nanoTTO can even release its contents into fungus and Pseudomonas biofilms. Combinations of different treatments are occasionally needed for refractory cases, especially for individuals with underlying genetic predisposal or are immuno-compromised. Although the current treatments show efficacy in controlling the Demodex mite population and the related symptoms, further research needs to be focused on the efficacy and drug delivery technology in order to develop alternative treatments with better side-effects profiles, less toxicity, lower risk of resistance and are more cost-effective.

Utility of adrenocorticotropic hormone in adrenal vein sampling despite the occurrence of discordant lateralization.

BACKGROUND: Adrenal vein sampling (AVS) is crucial for accurate lateralization of aldosterone excess but it is technically challenging due to the difficulty of adrenal vein cannulation. The use of adrenocorticotropic hormone (ACTH) to improve cannulation success is controversial and can lead to discordant lateralization outcomes. OBJECTIVE: To evaluate the utility of ACTH in two centres with different levels of AVS expertise and formulate a strategy for interpreting discordant results. DESIGN: A retrospective cross-sectional analysis of AVS results and postoperative patient outcomes. SETTING: Two large tertiary hospitals with harmonized AVS protocols where adrenal venous samples are collected both before and after ACTH stimulation. MEASUREMENTS: Cannulation success (measured by selectivity index, SI), lateralization (measured by lateralization index, LI) and postoperative biochemical cure. RESULTS: Number of AVS procedures judged to have successful bilateral adrenal vein cannulation increased from 53% pre- to 73% post-ACTH. The increase in cannulation success was significantly higher in centre where AVS was performed by multiple radiologists with a lower basal success rate. In both centres, the proportion of cases deemed to display lateralization significantly decreased with the use of ACTH (70% pre- to 52% post-ACTH). Based on postoperative outcomes of patients with discordant results who underwent unilateral adrenalectomy, the combination of LI >3 pre-ACTH and LI >2 post-ACTH was predictive of a biochemical cure. CONCLUSION: Adrenocorticotropic hormone can increase the rate of cannulation success during AVS at the expense of reduced lateralization. The criteria for lateralization should be carefully determined based on local data when ACTH is used.

Age- and sex-specific reference ranges are needed for the aldosterone/renin ratio.

OBJECTIVE: Current Endocrine Society Clinical Practice Guidelines use a specific aldosterone/renin ratio (ARR) threshold to screen for primary aldosteronism (a treatable disease causing up to 15% of hypertension in primary care) in all patients. We sought to characterize demographic variations in the ARR, hypothesizing a need for age- and sex-specific reference ranges to improve the accuracy of the test. DESIGN: Retrospective cross-sectional analysis of ARR measurements at a single tertiary hospital from December 2016 to June 2018. PATIENTS: A total of 442 patients with clinically indicated ARR were included, after excluding those who were on spironolactone or the oral contraceptive pill, were pregnant or had an existing adrenal condition. MEASUREMENTS: Aldosterone, renin and the ARR. RESULTS: Among those aged 20-39 years (n = 74), females had significantly higher median aldosterone (369 vs 244 pmol/L, P = .028), lower median renin (17.0 vs 27.6 mIU/L, P = .034) and higher median ARR (20.7 vs 10.3 (pmol/L)/(mIU/L), P = .001) than males, despite having lower systolic (135 vs 145 mmHg, P = .021) and diastolic (89 vs 96.5 mmHg, P = .007) blood pressure. The ≥ 60-year age group (n = 157) also had significant sex differences in the ARR. With increasing age (20-39 vs ≥ 60 years), there was a significant fall in plasma aldosterone in females (369 pmol/L vs 264 pmol/L, P = .005), with no change observed in males. CONCLUSIONS: For those 20-39 years old, aldosterone and the ARR are significantly higher in females despite a lower systolic and diastolic BP, highlighting the potential for false-positive results. Our findings indicate the need for prospective studies with a control population to define age- and sex-specific ARR reference ranges.

Optimized Delta Check Rules for Detecting Misidentified Specimens in Children.

OBJECTIVES: Preanalytical processes in pediatric patients are generally manual and associated with a higher risk of error. The optimized delta check rules for detecting misidentified children samples are examined. METHODS: Relative difference and absolute different delta check limits were applied on original and reshuffled (to simulate sample mislabeling/mix-up) paired deidentified pediatric results of 57 laboratory tests. The sensitivity, specificity, and accuracy of a range of delta check limits were determined. The delta check limit associated with the highest accuracy was considered optimal. RESULTS: In general, the delta check limits had poor to moderate accuracy (0.50-0.81) in detecting misidentified patient samples. The sensitivity (rule out misidentified sample) quickly deteriorated at increasing delta check limits. At the same time, the specificity (rule in misidentified sample) of the delta check limit was also low. The performance of the relative difference and absolute difference delta check rules was similar. CONCLUSIONS: Our findings showed poor delta check performance in the pediatric population. The high false-positive flag rate may lead to wasteful resource-intensive investigations and delay in result reporting. In addition, we observed that the optimized pediatric delta check correlated strongly with within-subject biologic variation, whereas delta check accuracy correlated poorly with index of individuality.

Three-dimensional microfluidic tape-paper-based sensing device for blood total bilirubin measurement in jaundiced neonates.

More than 60% newborns experience hyperbilirubinemia and jaundice within the initial week after birth due to the accumulation of total bilirubin in blood. Left untreated high levels of bilirubin may result in brain impairment. Simple, fast, accurate, low-cost and timely point-of-care (POC) analysis of total bilirubin is an unmet need especially in resource-limited areas. This work introduces a novel sensing device, named a "tape-paper sensor", capable of separating plasma from whole blood and measuring total bilirubin by a colorimetric diazotization method. The tape-paper sensing method overcomes non-homogeneous color distribution caused by the "coffee stain" effect, which improves the accuracy of colorimetric evaluation on paper-based analytical devices. The level of hemolysis in the plasma extracted by the device is evaluated, confirming no interference in the detection of total bilirubin. The accuracy of the tape-paper sensing approach for neonatal blood sample measurement is verified by comparison with the hospital pathology laboratory method. The small volume of samples and reagents, minimal equipment (an office scanner), fast detection (<10 min) and low fabrication cost (∼A$ 0.6) reveal the suitability of the device for POC use and in resource-limited settings. The tape-paper sensor is a low-cost, fast, and user-friendly device for measurement of blood total bilirubin levels in neonatal jaundice diagnostics.

Routine free thyroxine reference intervals are suboptimal for monitoring children on thyroxine replacement therapy and target intervals need to be assay-specific.

Central hypothyroidism is a condition where there is (qualitatively or quantitatively) TSH deficiency, leading to reduced thyroid hormone production. In such patients, serum TSH does not accurately reflect the adequacy of thyroxine replacement, as the log-linear relationship between thyrotropin (TSH) and free thyroxine (FT4) is lost. We aimed to prospectively determine the optimal physiological FT4 treatment range for children treated for primary hypothyroidism, based on their serum TSH concentrations. This information could be used to guide optimal therapy for all children on thyroxine replacement, including those with central hypothyroidism. In total, sixty children (median age: 11 years, range: 11 months to 18 years) were recruited over 21 months. They were prescribed a stable dose of thyroxine for at least 6-8 weeks prior to a thyroid function test that consisted of serum TSH, FT4 and free triiodothyronine (FT3) measurements. The serum sample for the thyroid function tests was collected before ingestion of the daily dose, i.e. the trough concentration, and measured using Beckman Coulter UniCel DxI 800 instrument, Siemens Advia Centaur, Roche Cobas, Abbott Architect, Ortho Clinical Diagnostics Vitros 5600 (Ortho-Clinical Diagnostics, Raritan, NJ) platforms. The FT4 and FT3 reference intervals showed significant inter-method difference. The lower limit of the FT4 reference intervals were generally shifted mildly higher when the TSH concentration of the children were restricted from 0.5-5.0 mIU/L to 0.5-2.5 mIU/L. By contrast, the upper limit of the FT3 and FT4 reference intervals were relatively stable for the different TSH concentrations. Assay-specific target ranges for optimal thyroxine therapy are required until FT4 assay standardisation is realised.

The tertiary hospital laboratory; a novel avenue of opportunistic screening of familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a common monogenic hereditary lipid disorder characterised by increased serum low-density lipoprotein cholesterol (LDL-cholesterol) concentrations and high risk of premature atherosclerotic cardiovascular disease. The prevalence of FH identified in a tertiary hospital laboratory was investigated by performing an opportunistic screen for index cases. METHODS: The prevalence of likely FH based on LDL-cholesterol thresholds >4.9 mmol/L as employed by the Dutch Lipid Clinic Network Criteria (DLCNC) score was evaluated retrospectively in a single tertiary hospital laboratory over a six-month period (July to December 2016). RESULTS: 4943 lipid profiles screened, 106 patients (mean age 53.2 ±â€¯12.9 and 41% male) had LDL-cholesterol of >4.9 mmol/L after exclusion of 5 patients (0.1%) with secondary causes. Possible (n = 90) and probable/definite (n = 16) FH according to DLCNC score was seen in 1.8% and 0.4% of the overall screened population, respectively. CONCLUSIONS: Point prevalence of screening for FH in patients undergoing lipid profile testing in a tertiary hospital laboratory was comparable with prevalence of FH in general population (based on 1 in 200-250). This supports the benefit of establishing an efficient "alert system" in conjunction with a trigger "reflex testing" to facilitate further formal FH scoring and exclusion of possible secondary causes of hyperlipidemia in potential index FH.

MicroRNA from a 12-h versus 20-h acetylcysteine infusion for paracetamol overdose.

Paracetamol overdose is common and microRNA (miR)-122 expression is increased with liver injury. We aimed to measure miR-122 in the setting of an abbreviated paracetamol overdose treatment regimen. We compared miRNA expression in patients treated for paracetamol poisoning with an abbreviated 12-h intravenous acetylcysteine regimen (200 mg/kg over 4 h, 50 mg/kg over 8 h) or a 20-h regimen (200 mg/kg over 4 h, 100 mg/kg over 16 h) (NACSTOP trial). miR-122 expression is increased (decreased cycle threshold (Ct) values) with paracetamol liver injury. We assessed miR-122 expression in patients receiving the two acetylcysteine regimens and in a separate group with acute liver injury (ALI). We examined 121 blood samples in 38 patients. After 20 h of acetylcysteine, median alanine transaminase (ALT) was 12 U/L (18, 14) versus 16 U/L (11, 21) ( p = 0.17) and median miR-122 Ct was 30.1 (interquartile range (IQR): 28.9, 33.3) versus 31.4 (28.9, 33.9) ( p = 0.7) in the NACSTOP abbreviated and control groups, respectively. Median normalized miR-122 Ct after 20 h of acetylcysteine was 2.2 (IQR 1.9, 6.4), 1.1 (0.7, 2.9), 63.9 (2.5, 168), 123.2 (40.9, 207.8) in the NACSTOP-abbreviated, NACSTOP-control, ALI and hepatotoxicity groups, respectively. There was no significant difference in ALT or miRNA between NACSTOP treatment groups and no signal of increased liver injury from an abbreviated 12-h acetylcysteine regimen. These findings suggest that an abbreviated acetylcysteine regimen in low-risk patients who have overdosed on paracetamol is safe. Further study is required to validate this finding utilizing miRNA as a comparative biomarker.

Remnant cholesterol and coronary atherosclerotic plaque burden assessed by computed tomography coronary angiography.

BACKGROUND AND AIMS: There remains a substantial residual risk of ischaemic heart disease (IHD) despite optimal low-density lipoprotein cholesterol (LDLC) reduction. Part of this risk may be attributable to remnant cholesterol, which is carried in triglyceride-rich lipoproteins. We evaluated the relationship between remnant cholesterol and coronary atherosclerotic plaque burden assessed non-invasively by computed tomography coronary angiography (CTCA) in patients with suspected coronary artery disease (CAD). METHODS AND RESULTS: This was a multicentre study of 587 patients who had a CTCA and fasting lipid profile within 3 months. Calculated remnant cholesterol was total cholesterol minus LDLC minus high-density lipoprotein cholesterol (HDLC). Significant coronary atherosclerotic burden was defined as CT-Leaman score >5 (CT-LeSc), an established predictor of cardiac events. Mean age was 61 ±â€¯12 years and mean pretest probability of CAD was 23.2 ±â€¯19.8%. LDLC levels were <1.8 mmol/L in 134 patients (23%), of whom 82% were statin-treated. Patients with CT-LeSc >5 had higher mean remnant cholesterol than those with CT-LeSc ≤5 (0.76 ±â€¯0.36 mmol/L vs. 0.58 ±â€¯0.33 mmol/L, p = 0.01). On univariable analysis, remnant cholesterol (p = 0.01), LDLC (p = 0.002) and HDLC (p < 0.001) levels predicted CT-LeSc >5, whilst triglycerides (p = 0.79) had no association with CT-LeSc >5. On multivariable analysis in the subset of patients with optimal LDLC levels, remnant cholesterol levels remained predictive of CT-LeSc >5 (OR 3.87, 95% confidence interval 1.34-7.55, p = 0.004), adjusted for HDLC and traditional risk factors. CONCLUSIONS: Remnant cholesterol levels are associated with significant coronary atherosclerotic burden as assessed by CTCA, even in patients with optimal LDLC levels. Future studies examining whether lowering of remnant cholesterol can reduce residual IHD risk are warranted.

Paracetamol metabolite concentrations following low risk overdose treated with an abbreviated 12-h versus 20-h acetylcysteine infusion.

CONTEXT: To compare degree of liver injury and paracetamol metabolite concentrations after treatment with standard of care (20-h) vs. abbreviated (12-h) acetylcysteine regimens used in paracetamol overdose (NACSTOP trial). METHODS: Timed blood samples from a cohort of subjects enrolled in the cluster-controlled NACSTOP trial evaluating a 12-h acetylcysteine regimen (200 mg/kg over 4 h, 50 mg/kg over 8 h) were assayed for paracetamol metabolites as a pilot study, using liquid chromatography/mass spectrometry. Control group subjects received a 20-h course of acetylcysteine (200 mg/kg over 4 h, 100 mg/kg over 16 h). The intervention group received a 12-h acetylcysteine regimen (stopped after at least 12 h of treatment). Positive control groups not in the trial with acute liver injury (ALI) or hepatotoxicity were also studied. RESULTS: One hundred and forty-one blood samples were collected from 40 patients receiving acetylcysteine after paracetamol overdose. Median ALT after 20 h of acetylcysteine was 12 U/L (IQR 8.14) in the abbreviated regimen group, compared to the control group 16 U/L (IQR 11.21) (p = .46). There was no significant difference in median metabolite concentrations on presentation and after 20 h of acetylcysteine between these two groups (p > .05). Presentation median sum CYP-metabolite/total metabolite percentages were 2.5 and 3.0 in the abbreviated and control NACSTOP groups, respectively. CONCLUSIONS: An abbreviated 12-h acetylcysteine regimen for paracetamol overdose used in the NACSTOP trial had similar circulating metabolite concentrations compared to a 20-h regimen in selected subjects with low risk of hepatotoxicity. This suggests that further acetylcysteine may not be needed in the abbreviated group at time of cessation.

Artemisinin and its derivatives: a potential treatment for leukemia.

Artemisinin (ART) and its derivatives are one of the most important classes of antimalarial agents, originally derived from a Chinese medicinal plant called Artemisia annua L. Beyond their outstanding antimalarial and antischistosomal activities, ART and its derivatives also possess both in-vitro and in-vivo activities against various types of cancer. Their anticancer effects range from initiation of apoptotic cell death to inhibition of cancer proliferation, metastasis and angiogenesis, and even modulation of the cell signal transduction pathway. This review provides a comprehensive update on ART and its derivatives, their mechanisms of action, and their synergistic effects with other chemicals in targeting leukemia cells. Combined with limited evidence of drug resistance and low toxicity profile, we conclude that ART and its derivatives, including dimers, trimers, and hybrids, might be a potential therapeutic alternative to current chemotherapies in combating leukemia, although more studies are necessary before they can be applied clinically.