High-dose imatinib for newly diagnosed chronic phase chronic myeloid leukemia patients--systematic review and meta-analysis

Imatinib at a dose of 400 mg daily is considered frontline treatment in chronic phase chronic myeloid leukemia (CP-CML). We conducted a systematic review and meta-analysis of randomized controlled trials comparing frontline treatment with imatinib 400 mg daily versus higher doses (≥600 mg daily) in patients with CP-CML. The search yielded four trials, randomizing 1,673 patients. At 12 months, high dose compared with standard dose imatinib improved complete cytogenetic response (CCyR) (RR 1.17, 95% CI 1.08-1.26, four trials, I(2) = 33%) as well as major molecular response (MMolR) (RR 1.26, 95% CI 1.12-1.42, four trials, I(2) = 0%). There was no difference in all-cause mortality or disease progression at the end of follow up. Adverse events requiring discontinuation were more common in the high-dose arm (RR 1.98, 95% CI 1.20-3.26, three trials, I(2) = 0%), as were Grade III/IV neutropenia and thrombocytopenia: RR 1.56, 95% CI 1.15-2.12 and RR 1.86, 95% CI 1.28-2.70, respectively. There is currently insufficient evidence to support the routine use of higher doses of imatinib as frontline treatment for CP-CML. Extended follow up is needed to evaluate if the superior CCyR and MMolR with higher doses of imatinib will translate to long-term clinical benefit.     

Clinical outcomes with unfractionated heparin monitored by anti-factor Xa vs. activated partial Thromboplastin time

Anti-factor Xa (anti-Xa) monitoring of unfractionated heparin (UFH) is associated with less time to achieve therapeutic anticoagulation compared to the activated partial thromboplastin time (aPTT). However, it is unknown whether clinical outcomes differ between these methods of monitoring. The aim of this research was to compare the rate of venous thrombosis and bleeding events in patients that received UFH monitored by anti-Xa compared to the aPTT. A retrospective review of electronic health records identified adult patients that received UFH given intravenously (IV) for ≥2 days, with either anti-Xa or aPTT monitoring at an academic tertiary care hospital. This was a pre/post study design conducted between January 1 to December 30, 2014 (aPTT), and January 1 to December 30, 2016 (anti-Xa). All UFH adjustments were based on institutional nomograms. The primary outcome was venous thrombosis and the secondary outcome was bleeding, both of which occurred between UFH administration and discharge from the index hospitalization. A total of 2500 patients were in the anti-Xa group and 2847 patients aPTT group. Venous thrombosis occurred in 10.2% vs 10.8% of patients in the anti-Xa and aPTT groups, respectively (P = .49). Bleeding occurred in 33.7% vs 33.6% of patients in the anti-Xa and aPTT groups, respectively (P = .94). Anti-Xa monitoring was not an independent predictor of either outcome in multivariate logistic regression analyses. Our study found no difference in clinical outcomes between anti-Xa and aPTT-based monitoring of UFH IV.     

Identifying Tyrosine Kinase Inhibitor Nonadherence in Chronic Myeloid Leukemia: Subanalysis of TAKE-IT Pilot Study

Background

There are inconsistencies in reports on correlates for nonadherence (NA) to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). The diagnostic accuracy of subjective adherence measures using electronic monitoring (EM) as the reference standard is yet to be determined. This study aimed to evaluate correlates of TKI NA using EM and test the diagnostic accuracy of subjective adherence measures.

Multiple perifollicular fibromas

Perifollicular fibroma is a benign mesodermal tumour of the hair follicle. It can occur as a solitary papule or as multiple lesions that are clinically indistinguishable from other tumours of the pilar apparatus. Multiple perifollicular fibromas may be inherited although the pattern remains unclear. Adnexal tumours can be associated with internal malignancy and perifollicular fibromas have been linked with adenomatous colonic polyps. This report describes a patient with multiple perifollicular fibromas with no associated malignancy to date and a family pedigree suggestive of an autosomal dominant pattern of inheritance.     

Supplemental calcium for the prevention of hip fracture: potential health-economic benefits.

We assessed the cost-effectiveness of daily calcium supplementation for the prevention of primary osteoporotic hip fractures. The assessment was based on our meta-analysis of the published relative-risk estimates from 3 double-masked, placebo-controlled, clinical trials and our analysis of raw data from the National Health and Nutrition Examination Survey 1988-1994 on the daily intake of calcium supplements by adults in the United States. These data were then used to estimate the preventable proportion of hip fractures. The 1995 National Hospital Discharge Survey database provided the number and demographic characteristics of patients discharged with a primary diagnosis of hip fracture, as well as their discharge destination. The 1990 itemized costs of hip fractures, as estimated by the US Congress Office of Technology Assessment, were inflated to 1995 dollars using the medical care component of the Consumer Price Index. Using these inflated itemized costs, we then estimated the weighted average expenditures, reflecting both the types of services associated with specific hospital-discharge destinations and the demographic characteristics of discharged patients. The cost of supplements containing 1200 mg/d of elemental calcium for the mean duration (34 months) of the 3 clinical trials was calculated on the basis of 1998 unit-price and market-share data for 6 representative products. For 1995, the data indicate that 290,327 patients aged > or =50 years were discharged from US hospitals with a primary diagnosis of hip fracture, at our estimated direct cost of $5.6 billion. Based on the risk reductions seen in the 3 trials, we estimated that 134,764 hip fractures and $2.6 billion in direct medical costs could have been avoided if individuals aged > or =50 years consumed approximately 1200 mg/d of supplemental calcium. Additional savings could be expected, because this intervention is also associated with significant reductions in the risk for all nonvertebral fractures. Comparing the cost of calcium with the expected medical savings from hip fractures avoided, it is cost-effective to give 34 months of calcium supplementation to women aged > or =75 years in the United States. If, as the published studies suggest, shorter periods of supplementation result in an equivalent reduction in the risk of hip fractures, calcium supplementation becomes cost-effective for all adults aged > or =65 years in the United States. The data support encouraging older adults to increase their intake of dietary calcium and to consider taking a daily calcium supplement. Even small increases in the usage rate of supplementation are predicted to yield significant savings and to reduce the morbidity and mortality associated with hip fracture at an advanced age.     

Melioidosis in India and Bangladesh: A review of case reports

Objective: To conduct an epidemiological and clinical review of published case reports of melioidosis from India and Bangladesh. Methods: Data from published case reports were abstracted and summarized. We further compared the clinical epidemiology of the melioidosis cases in India with case series from highly endemic areas in Northern Australia and Southeast Asia to elucidate any differences in presentations and risk factors between the regions.Results: We identified a total of 99 cases published between 1953 and June 2016, originating from India(n=85) or Bangladesh(n=14). Cases were predominantly male and ranged in age from 1 month to 90 years. Diabetes mellitus was the most common risk factor reported(58%). About 28% of the cases had history of exposure via high-risk occupations or exposure to contaminated water. The overall case fatality rate(CFR) was 26%. Factors influencing mortality included the occurrence of septic shock(CFR, 80%), environmental exposure(CFR,39%), primary presentation of pneumonia(CFR, 38%), misdiagnosed and/or mistreated cases(CFR, 33%) or the presence of a risk factor(CFR, 29%). Because of the small number of cases in Bangladesh, pattern of clinical epidemiology is limited to India. Soft tissue abscess(37%)was the most common clinical presentation reported from India followed by pneumonia(24%)and osteomyelitis/septic arthritis(18%). Neurological melioidosis(n=10, 12%) presented as pyemic lesions of the brain or meninges. A few cases of prostatic abscess(n=4) in men and parotid abscess(n=4) were also noted. The above patterns were consistent with case series from Southeast Asia and Northern Australia for the most part, in terms of risk factors associated with infection and factors influencing mortality. Differences included clinical presentation of pneumonia which was notably lower than that reported in Southeast Asia and Northern Australia; a higher proportion of neurological and parotid abscess presentation; and a lower CFR compared to that reported in case series in Southeast Asia. About 39% of the cases were misdiagnosed and/or mistreated, suggesting underreporting and under estimation of the true disease burden. Conclusions: The concentration of melioidosis cases in southern and eastern states in India and in Bangladesh, which share climatic conditions and rice farming activities with known endemic areas in Southeast Asia, suggests an endemicity of melioidosis in this region. Thus, increased awareness among healthcare personnel, particularly among clinicians and nurses practicing in rural areas, and improved surveillance through case registries is essential to guide early diagnosis and prompt treatment.     

Cytochemical flow analysis of intracellular G6PD and aggregate analysis of mosaic G6PD expression

Background

Medicines that exert oxidative pressure on red blood cells (RBC) can cause severe hemolysis in patients with glucose‐6‐phosphate dehydrogenase (G6PD) deficiency. Due to X‐chromosome inactivation, females heterozygous for G6PD with 1 allele encoding a G6PD‐deficient protein and the other a normal protein produce 2 RBC populations each expressing exclusively 1 allele. The G6PD mosaic is not captured with routine G6PD tests.

Methods

An open‐source software tool for G6PD cytofluorometric data interpretation is described. The tool interprets data in terms of % bright RBC, or cells with normal G6PD activity in specimens collected from 2 geographically and ethnically distinct populations, an African American cohort (USA) and a Karen and Burman ethnic cohort (Thailand) comprising 242 specimens including 89 heterozygous females.

Results

The tool allowed comparison of data across 2 laboratories and both populations. Hemizygous normal or deficient males and homozygous normal or deficient females cluster at narrow % bright cells with mean values of 96%, or 6% (males) and 97%, or 2% (females), respectively. Heterozygous females show a distribution of 10‐85% bright cells and a mean of 50%. The distributions are associated with the severity of the G6PD mutation.

Conclusions

Consistent cytofluorometric G6PD analysis facilitates interlaboratory comparison of cellular G6PD profiles and contributes to understanding primaquine‐associated hemolytic risk.     

Biocompatible silver nanoparticles: An investigation into their protein binding efficacies,anti-bacterial effects and cell cytotoxicity studies

Green synthesis of silver nanoparticles (AgNPs) has garnered tremendous interest as conventional methods include the use and production of toxic chemicals, products, by-products and reagents. In this regard, the synthesis of AgNPs using green tea (GT) extract and two of its components, (−)-epigallocatechin gallate (EGCG) and (+)-catechin (Ct) as capping/stabilizing agents, is reported. The synthesized AgNPs showed antibacterial activity against the bacterial strains Staphylococcus aureus and Escherichia coli, along with anticancer activity against HeLa cells. After administering nanoparticles to the body, they come in contact with proteins and results in the formation of a protein corona; hence we studied the interactions of these biocompatible AgNPs with hen egg white lysozyme (HEWL) as a carrier protein. Static quenching mechanism was accountable for the quenching of HEWL fluorescence by the AgNPs. The binding constant (K_b) was found to be higher for EGCG-AgNPs ((2.309 ± 0.018) × 10⁴ M⁻¹) than for GT-AgNPs and Ct-AgNPs towards HEWL. EGCG-AgNPs increased the polarity near the binding site while Ct-AgNPs caused the opposite effect, but GT-AgNPs had no such observable effects. Circular dichroism studies indicated that the AgNPs had no such appreciable impact on the secondary structure of HEWL. The key findings of this research included the synthesis of AgNPs using GT extract and its constituent polyphenols, and showed significant antibacterial, anticancer and protein-binding properties. The –OH groups of the polyphenols drive the in situ capping/stabilization of the AgNPs during synthesis, which might offer new opportunities having implications for nanomedicine and nanodiagnostics.