Intermediate-dose cytarabine plus mitoxantrone versus standard-dose cytarabine plus daunorubicine for acute myeloid leukemia in elderly patients

Abstract

Background

The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) can induce high complete remission rates with acceptable toxicity in elderly patients with acute myeloid leukemia (AML). We present the final results of a randomized-controlled trial comparing IMA with the standard 7 + 3 induction regimen consisting of continuous infusion daunorubicin plus cytarabine (DA).

Patients and methods

Patients with newly diagnosed AML >60 years were randomized to receive either intermediate-dose cytarabine (1000 mg/m² BID days 1,3,5,7) plus mitoxantrone (10 mg/m² days 1-3) (IMA) or standard induction therapy with cytarabine (100 mg/m² continuously days 1-7) plus daunorubicin (45 mg/m² days 3-5) (DA). Patients in complete remission after DA received intermediate-dose cytarabine plus amsacrine as consolidation treatment, whereas patients after IMA were consolidated with standard-dose cytarabine plus mitoxantrone.

Results

Between February 2005 and October 2009, 485 patients were randomized; 241 for treatment arm DA and 244 for IMA; 76% of patients were >65 years. The CR rate after DA was 39% (95%-CI; 33-45) versus 55% (95%-CI; 49-61) after IMA (OR 1.89, p=0.001). The six-week early-death rate was 14% in both arms. Relapse-free survival (RFS) curves were superimposable in the first year, but separated afterwards, resulting in 3-year RFS rates of 29% versus 14% in the DA versus IMA arms, respectively (p=0.042). The median OS was 10 months in both arms (p=0.513).

Conclusion

The dose escalation of cytarabine in induction therapy lead to improved remission rates in the elderly AML patients. This did not translate into a survival advantage, most likely due to differences in consolidation treatment. Thus, effective consolidation strategies need to be further explored. In combination with an effective consolidation strategy, the use of intermediate dose cytarabine in induction may improve curative treatment for elderly AML patients.

Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC

Ann Oncol 2017; 28: 1339–1345 (doi: 10.1093/annonc/mdx075)

Simultaneous detection of barrier- and immune-related gene variations in patients with atopic dermatitis by reverse blot hybridization assay

Summary

Background

Hereditary factors are involved in the pathogenesis of atopic dermatitis (AD). However, AD-related gene variations are significantly different across ethnicities.

Aim

To identify mutations and single-nucleotide polymorphisms (SNPs) in barrier- or immune-related genes from Korean patients with AD and compare the variations with those observed in nonatopic healthy controls (HCs), and to use novel reverse blot hybridization assay (REBA) for AD-related gene variants.

Methods

We carried out REBA to simultaneously detect variations in genes related to barrier or immune function, namely, FLG, SPINK5, KLK7, DEFB1, TNFα, KDR, FCER1A, IL4, IL5,IL5RA, IL9, IL10, IL12, IL12R, IL13 and IL18, from Korean patients with AD, and compared the variation to that in nonatopic healthy controls.

Results

The homozygous mutants of KLK7 and SPINK5-2475, and the heterozygous mutants of FLG 3321delA, SPINK5-1156, DEFB1, KDR, IL5RA, IL9 and IL12RB1 were significantly more frequent in AD. It has been predicted that the larger the number of gene variants, the higher the odds ratio of AD prevalence; however, we did not find any significant correlation between the number of gene variants and AD severity.

Conclusion

Using REBA, we identified more genetic variants that can predict AD occurrence. We also verified that REBA can be used to easily and accurately detect multiple AD-related gene variants simultaneously. In addition, we identified a correlation between KLK7 mutation and AD in Koreans, which is the first such report, to our knowledge.

RE: “IMPACT OF BLAST INJURY ON HEARING IN A SCREENED MALE MILITARY POPULATION”

A topical treatment containing heat-treated Lactobacillus johnsonii NCC 533 reduces Staphylococcus aureus adhesion and induces antimicrobial peptide expression in an in vitro reconstructed human epidermis model

Abstract

Staphylococcus aureus colonization is thought to contribute to the pathophysiology of atopic dermatitis (AD). AD patients exhibit reduced levels of cutaneous antimicrobial peptides (AMPs), which may explain their increased susceptibility to infections. Using an in vitro reconstructed human epidermis (RHE) model, we sought to determine whether topical application of a non-replicating probiotic, heat-treated Lactobacillus johnsonii NCC 533 (HT La1), could inhibit S. aureus adhesion to skin and boost cutaneous innate immunity. We found that application of HT La1 suspension to RHE samples reduced the binding of radiolabeled S. aureus by up to 74%. To investigate a potential effect of HT La1 on innate immunity, we analyzed the expression of nine AMP genes, including those encoding beta defensins and S100 proteins, following topical application of HT La1 in suspension or in a daily moisturizer lotion. Analyzed genes were induced by up to four-fold in a dose-dependent manner by HT La1 in suspension, and by up to 2.4-fold by HT La1 in the moisturizer lotion. Finally, using ELISA and immunohistochemical detection, we evaluated the expression and secretion of the AMPs hBD-2 and psoriasin, and determined that both proteins were induced by topical HT La1, particularly in the stratum corneum of the RHE. These findings demonstrate that a topically applied, non-replicating probiotic can modulate endogenous AMP expression and inhibit binding of S. aureus to an RHE model in vitro. Moreover, they suggest that a topical formulation containing HT La1 could benefit atopic skin by enhancing cutaneous innate immunity and reducing S. aureus colonization.

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Post-transplant lymphoproliferative disease with features of cutaneous natural killer/T-cell lymphoma

Homeobox transcription factor DLX4 is not necessary for skin development and homeostasis

Abstract

Dlx4 is a member of a family of homeobox genes with homology to Drosophila distal-less (dll) gene. We show that Dlx4 expression pattern partially overlaps with its cis-linked gene Dlx3 during mouse development as well as in neonatal and adult skin. In mice, Dlx4 is expressed in the branchial arches, embryonic limbs, digits, nose, hair follicle and in the basal and suprabasal layers of mouse interfollicular epidermis in neonatal and adult skin. We show that inactivation of Dlx4 in mice did not result in any overtly gross pathology. Skin development, homeostasis and response to TPA treatment was similar in mice with loss of Dlx4 compared to wild type counterparts.

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The Location and Boundaries of Consciousness: a Structural Realist Approach

Abstract

Despite the remarkable progress made in consciousness research during recent decades, there is still no sign of a general agreement about the location of its object. According to internalists, consciousness resides inside the brain. According to externalists, consciousness is partly constituted by elements or aspects of the environment. Internalism comports better with the existence of dreams, hallucinations and sensory imaging. Externalism seems to provide a more promising basis for understanding how we can experience the world and refer to the content of our consciousness. I argue that the framework of structural realism supports internalism and helps to reveal the reasons behind the apparent explanatory success of the externalist approach. More specifically, structural realism supports the view that the structure of our consciousness is always present in our neural processes and only sometimes (additionally) in an extended system that includes elements of the environment.

Nickel hypersensitivity following closure of atrial septal defect: A case report and review of the literature

Abstract

We present an unusual case where symptoms of headache and chest pain persisted for 3 years following the implantation of a septal occluder device for an atrial septal defect despite endothelialisation of the device. The patient was found to have nickel hypersensitivity on patch testing. Following the removal of the device the patient had complete resolution of headaches and chest pain up to 10 months post-explantation.

Rapid exacerbation of malignant melanoma during short-term discontinuation of vemurafenib

Cd and Cu accumulation, translocation and tolerance in Populus alba clone (Villafranca) in autotrophic in vitro screening

Abstract

The present study investigated accumulation, translocation and tolerance of autotrophic Populus alba clone "Villafranca" in response to excess concentrations of cadmium (Cd) and copper (Cu) provided to the plants. For this purpose, increasing concentrations of Cd (0, 5, 50 and 250 μM) and Cu (0, 5, 50, 250 and 500 μM) were administered to the growth medium in which micropropagated poplar plantlets were exposed to metal treatments for 15 days. Filter bags, instead of the conventional in vitro screening, were applied to improve the experimental design. Results showed that Cd and Cu increased in shoots and roots at increasing metal concentration in the medium. The highest Cd content was found in leaves, while the highest Cu content was found in roots. In "Villafranca", Cu showed toxic effects on the development of the seedlings, especially at the highest concentrations, reducing plant dry mass. However, the tolerance index (Ti) indicated good tolerance in this clone under exposure to excess metal concentrations, whereas plants had higher translocation factor (Tf). We recommend in vitro selection of tolerant genotypes, aimed at providing early indication on accumulation potentiality and tolerance capability in research on plant sensitivity to excess heavy metal concentrations.

A study through batch tests on the analytical determination and the fate and removal of methamphetamine in the biological treatment of domestic wastewater

Abstract

Methamphetamine (MET) is one of the most used illicit drugs in Europe and is recognized as one of the Emerging Organic Micropollutants. It is discharged into the sewerage system from different sources and then enters the wastewater treatment plants. The present study aimed at providing a better knowledge of the fate of MET through the wastewater treatment plants. The study addressed two different issues: (1) optimization of the analytical methods for MET determination in both liquid and sludge phases, focusing on the effects of potentially interfering substances and (2) investigation on the behaviour of MET in the biological treatment process, with specific concern for the biomass activity at different drug concentrations. Results of the study on issue 1 highlighted that the applied analytical method for MET determination (UPLC–MS/MS) is affected by the main components of wastewater for about 9–23%, which is comparable with the uncertainties of the method (about ± 28%). The method showed also to be repeatable and reliable (recovery > 75%; repeatability < 10–15%; bias uncertainty < 30%), and relatively easy-to-use. Therefore, it can be considered suitable for measurements on routine base in the WWTPs. Batch tests conducted to address issue 2 showed total removal of 84, 90, and 96% at 50, 100, and 200 ng/L initial MET concentration, respectively, for a contact time of 6 h. The removal process was mainly ascribed to the biological activity of both heterotrophic and autotrophic bacteria. The pseudo first-order kinetic model provided the best fitting of the experimental data of the overall biological processes at all the tested concentrations. Furthermore, the respirometric tests showed that MET does not induce any inhibition. Adsorption of MET on activated sludge was always very low.

Effects of air pollution on hospital visits for pneumonia in children: a two-year analysis from China

Abstract

Although the effect of air pollution on respiratory health has been identified, few studies can be available to evaluate the association of air pollution with hospital visits for children's pneumonia in China. To explore whether high concentrations of air pollutants (including PM_2.5, PM₁₀, NO₂, and SO₂) are related to hospital visits for pneumonia in children, we conducted a population-based time-series study in Ningbo, China, from January 1st, 2014 to November 1st, 2015. We used a generalized additive Poisson regression model to calculate risk ratios and 95% confidence intervals for the associations of air pollutants and hospital visits for pneumonia in children and found that these four pollutants were associated with the increased hospital visits for pneumonia in children (1.3% for PM2.5, 1.0% for PM10, 2.9% for NO₂, 5.0% for SO₂ per 10-μg/m³ increase in PM2.5, PM10, NO₂, and SO₂, respectively). Stronger associations were observed in the cold seasons and among children under 5 years.

Characterization and cancer risk assessment of VOCs in home and school environments in gran La Plata, Argentina

Abstract

Three areas are highlighted in Gran La Plata, Argentina: industrial, urban, and residential. In this work, the levels of volatile organic compounds (VOCs) in indoor air of homes and schools in those areas were analyzed, through the use of passive monitors. The study period is between 2007 and 2010. Higher levels of VOCs were found in homes and schools in the industrial zone, higher than the levels corresponding to urban and residential. Taking into account the relationship between indoor and outdoor levels of VOCs, they have ratios (I/O) between 1.5 and 10 are evidenced contributions of emission sources of VOCs both indoor and outdoor. Complementarily, we estimated the life time cancer risk (LCR) for benzene, styrene, trichloroethylene, and tetrachloroethylene in children who spend their time mostly in such indoor environments. The results show high LCR values for benzene, which exceed acceptable values for the US EPA.

Acute sensitivity of the killifish Nothobranchius furzeri to a combination of temperature and reference toxicants (cadmium, chlorpyrifos and 3,4-dichloroaniline)

Abstract

Aquatic organisms of inland waters are often subjected to a combination of stressors. Yet, few experiments assess mixed stress effects beyond a select group of standard model organisms. We studied the joint toxicity of reference toxicants and increased temperature on the turquoise killifish, Nothobranchius furzeri, a promising model for ecotoxicological research due to the species' short life cycle and the production of drought-resistant eggs. The acute sensitivity of the larval stage (2dph) to three compounds (cadmium, 3,4-dichloroaniline and chlorpyrifos) was tested in combination with a temperature increase of 4 °C, mimicking global warming. Dose-response relationships were used to calculate 96h-LC₅₀ of 0.28 mg/L (24 °C) and 0.39 mg/L (28 °C) for cadmium, 96h-LC₅₀ of 9.75 mg/L (24 °C) and 6.61 mg/L (28 °C) for 3,4-dichloroaniline and 96h-LC₅₀ of 15.4 μg/L (24 °C) and 14.2 μg/L (28 °C) for chlorpyrifos. After 24 h of exposure, the toxicity of all tested compounds was exacerbated under increased temperature. Furthermore, the interaction effect of cadmium and temperature could be predicted by the stress addition model (SAM). This suggests the applicability of the model for fish and at the same time indicates that the model could be suitable to predict effects of temperature-toxicant interactions.

Identifying external nutrient reduction requirements and potential in the hypereutrophic Lake Taihu Basin, China

Abstract

Reducing external nutrient loads is the first step for controlling eutrophication. Here, we identified external nutrient reduction requirements and potential of strategies for achieving reductions to remediate a eutrophic water body, Lake Taihu, China. A mass balance approach based on the entire lake was used to identify nutrient reduction requirements; an empirical export coefficient approach was introduced to estimate the nutrient reduction potential of the overall program on integrated regulation of Taihu Lake Basin (hereafter referred to as the "Guideline"). Reduction requirements included external total nitrogen (TN) and total phosphorus (TP) loads, which should be reduced by 41–55 and 25–50%, respectively, to prevent nutrient accumulation in Lake Taihu and to meet the planned water quality targets. In 2010, which is the most seriously polluted calendar year during the 2008–2014 period, the nutrient reduction requirements were estimated to be 36,819 tons of N and 2442 tons of P, and the potential nutrient reduction strategies would reduce approximately 25,821 tons of N and 3024 tons of P. Since there is a net N remaining in the reduction requirements, it should be the focus and deserves more attention in identifying external nutrient reduction strategies. Moreover, abatement measures outlined in the Guideline with high P reduction potential required large monetary investments. Achieving TP reduction requirement using the cost-effective strategy costs about 80.24 million USD. The design of nutrient reduction strategies should be enacted according to regional and sectoral differences and the cost-effectiveness of abatement measures.

Dosage adjustments in patients with psoriasis on adalimumab: a retrospective chart review

Abstract

Adalimumab is a well-established treatment for chronic plaque psoriasis. While many clinical trials have shown its efficacy, few studies have looked at deviations from labeled dosing in the real-world setting.¹ The aim of this study was to determine the frequency of off-label dosing in patients with psoriasis on adalimumab and the reasons for these deviations.

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Patch testing in facial dermatitis using Chinese Baseline Series (60 allergens) and Cosmetic Series (58 allergens)

Abstract

Facial dermatitis (FD) is a common problem encountered in clinical practice. It effects patients' self-esteem and quality of life. Mild reactions such as itching, pricking, dryness can occur in more than 10% of patients[1]. Recurrence is common in FD. The cause of FD is often difficult to determine. Metals, cosmetics, air pollution and physical factors such as wind or changes in temperature and humidity in the environment may all contribute to the development of FD[2]. Patch test is useful in establishing the identification of FD[1,2]. The present study was carried out to determine the incidence and role of contact allergy in FD, using the Chinese Baseline Series and Cosmetic Series.

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The influence of exposome on acne

Abstract

Background

Acne vulgaris is one of the main reasons for dermatological consultations. Severity and response to treatment may be impacted by various external factors or exposome.

Aim

to assess the impact of environmental factors on acne and to provide a comprehensive overview of the acne exposome.

Methods

two consensus meetings of five European dermatologists and a comprehensive literature search on exposome factors triggering acne served as a basis for this review.

Results

acne exposome was defined as the sum of all environmental factors influencing the occurrence, duration and severity of acne. Exposome factors impact on the response and the frequency of relapse to treatments by interacting with the skin barrier, sebaceous gland, innate immunity and cutaneous microbiota. They may be classified in the following six main categories: nutrition, psychological and lifestyle factors, occupational factors including cosmetics, as well as pollutants, medication and climatic factors. Moreover, practical considerations for the dermatologist's clinical practice are proposed.

Conclusion

Exposome factors including nutrition, medication, occupational factors, pollutants, climatic factors, and psychosocial and lifestyle factors may impact on the course and severity of acne and on treatment efficacy. Identifying and reducing the impact of exposome is important for an adequate acne disease management.

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Retrospective study on the correlation between 18-fluorodeoxyglucose uptake in positron emission tomography-computer tomography and tumor volume, cytological activity as assessed with Ki-67 and GLUT-1 staining in 10 cases of Merkel cell carcinoma

Abstract

Merkel cell carcinoma (MCC) is a rare malignant neuro-endocrine tumor of the skin that shows aggressive behavior and has a high tendency for local recurrence and lymph node or distant metastasis.¹ Recently, some reports have stated that 18-fluorodeoxyglucose positron emission tomography-computer tomography (FDG PET-CT) is more useful than conventional CT.^{2, 3} However, the utility of FDG PET-CT for determining the proliferative or metabolic activity of MCC is unclear. In this study, we investigated the correlation between FDG uptake and proliferative of metabolic activity as revealed by PET-CT imaging with Ki-67 immunological staining or GLUT-1 immunological staining in 10 cases of MCC. In addition, we tested the correlation between FDG uptake and tumor volume.

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