Τετάρτη 4 Απριλίου 2018
Methodology of clinical trials evaluating the incorporation of new drugs in the first line treatment of patients with diffuse large B-cell lymphoma (DLBCL): a critical review
Abstract
Purpose
The first line treatment of diffuse large B-cell lymphoma (DLBCL) is the combination of rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, curing approximately 60% of patients. Many clinical trials have been performed over the last 10 years trying to improve the results of this treatment, but the appropriateness of their planning strategies could be rediscussed. Patients and Methods
Reports of phase 3 trials evaluating the addition of molecularly targeted agents (MTA) or new monoclonal antibodies to the classic R-CHOP backbone in first-line induction or maintenance treatment were reviewed. The trial design, primary end point, number of patients enrolled, patient selection criteria, treatment schedule and results were registered for each one. In addition, the phase1 and 2 trials which preceded these phase 3 trials were also reviewed. Results
Among six phase 3 trials with results, only one trial evaluating lenalidomide maintenance after response to R-CHOP induction was positive and reached its primary endpoint. The other 5 trials did not show an improved outcome with the addition of the new agent. The preceding phase 1 and 2 trials were very heterogeneous in their endpoints and design. Even though most of these trials were considered positive, thus encouraging further investigation, so far they failed to predict the results of the subsequent phase 3 trials. Conclusion
The standard of care for DLBCL is still R-CHOP. Phase 1/2 trials failed to predict the results of subsequent phase 3 trials evaluating non-chemotherapeutic agents added to R-CHOP. The methodology of phase 2 trials evaluating new agents in DLBCL needs to be better defined in the future.ADI-PEG 20 Plus Best Supportive Care versus Placebo Plus Best Supportive Care in Patients with Advanced Hepatocellular Carcinoma
Abstract
Background
Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme – arginine deiminase – conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and Patients
Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2:1 to ADI-PEG 20 18 mg/m2 vs. placebo intramuscular (IM) injection weekly. The primary endpoint was overall survival (OS), with 93% power to detect a 4 to 5.6 months increase in median OS (1-sided α = 0.025). Secondary endpoints included progression-free survival (PFS), safety, and arginine correlatives. Results
635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 vs 7.4 for placebo (p = 0.88, HR = 1.02) and median PFS 2.6 months vs. 2.6 (p = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in less than 5% of patients. Two patients on ADI-PEG 20 had ≥ grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 vs. 10.4% on placebo, none related to therapy. Post-hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion
ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway. Clinical Trial number
www.clinicaltrials (NCT 01287585)Sorption of 17β-estradiol to the dissolved organic matter from animal wastes: effects of composting and the role of fulvic acid-like aggregates
Abstract
Steroid estrogens, such as 17β-estradiol (E2), in animal manure pose a potential threat to the aquatic environment. The transport and estrogenicity of estrogens influence the sorption of estrogens to dissolved organic matter (DOM) in animal manure, and composting treatment alters the structure and composition of the manure. The objectives of the present study were to identify the contribution of the molecular composition of DOM of composted manure to the sorption of E2 and then elucidate the dominant mechanisms involved in the interaction of E2 with manure-derived DOM. The excitation–emission matrix (EEM) spectra and atomic force microscopy (AFM) showed that composting significantly altered the chemical composition and structure of DOM. A decrease in the atomic ratios of oxygen (O)/carbon (C) occurred in conjunction with the formation of DOM aggregates in the composted manure, indicating that the hydrophilicity and polarity of the DOM decreased after composting. Composting increased the sorption coefficients (KDOC-E2) for E2 to DOM, and KDOC-E2 was positively correlated with the proportion of the fulvic acid (FA)-like fraction and molecular weight (MW) fractions of the DOM (range of 1.0 × 103–7.0 × 103 Da and 7.0 × 103–1.4 × 104 Da). Specifically, E2 showed a tendency for sorption to medium-sized FA-like molecules of DOM aggregates in composted manure. Hydrophobic forces and π-π binding appeared to be the main mechanisms underlying the aforementioned interaction.
Intraoperative anaphylaxis secondary to systemic cooling in a pediatric patient with cold-induced urticaria
Publication date: Available online 4 April 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Michelle C. Maciag, Charles Nargozian, Ana Dioun Broyles
Occupational exposures and asthma prevalence among US farmworkers: National Agricultural Workers Survey, 2003-2014
Publication date: Available online 4 April 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Anna J. Chen Arroyo, Lacey B. Robinson, N. Lance Downing, Carlos A. Camargo
Risk assessment, spatial distribution, and source apportionment of heavy metals in Chinese surface soils from a typically tobacco cultivated area
Abstract
The heavy metals (As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn) in the surface soils of tobacco (Nicotiana tabacum L.) fields in Jiangxi Province were analyzed, and the mean heavy metal concentrations were 3.55, 0.19, 25.89, 14.96, 0.25, 10.89, 27.80, and 44.00 mg/kg, respectively. Spatial distribution analysis showed that the highest concentrations were recorded in the north-western, south-western, and mid-eastern parts of the study area. The index of geo-accumulation and pollution index indicated modest enrichment with Cd and Hg, which were the only two metals posing a potentially high ecological risk to the local agricultural environment. The health risk assessment showed no considerable non-carcinogenic or carcinogenic risks for children and adults from these elements. The principal component analysis (PCA) and cluster analysis (CA) found that the variations in the Cr and Ni concentrations were largely on account of the soil parent rocks, but the As, Cd, Cu, and Hg variations in the soil were largely owing to agricultural practices of years. However, the main factor influencing Pb and Zn was atmospheric deposition.
Efficient removal of arsenic(III) from aqueous media using magnetic polyaniline-doped strontium–titanium nanocomposite
Abstract
In this study, a novel nanocomposite adsorbent based on magnetic polyaniline and strontium–titanium (MP-SrTiO3) nanoparticles was synthesized via a simple and low-cost polymerization method for efficiently removing of arsenic(III) ions from aqueous samples. The chemical structure, surface properties, and morphology of the prepared adsorbent were studied using Fourier transform infrared spectroscopy (FTIR), energy-dispersive X-ray spectroscopy (EDX), and scanning electron microscopy (SEM). The main effective parameters on the removal efficiency, such as pH, adsorbent dosage, salt, and contact time, were studied and optimized. The validity of the proposed method was checked by adsorption isotherm and kinetics models. Consequently, the adsorption kinetics corresponded to the first order (R2 > 0.99), and the experimental equilibrium fitted the Langmuir model with a maximum monolayer adsorption capacity of 67.11 mg/g (R2 > 0.99) for arsenic(III) ions. Corresponding to thermodynamic Vant's Hof model (ΔG° (kJ/mol), ΔH° (kJ/mol), and ΔS° (kJ/mol K) − 8.19, − 60.61, and − 0.17, respectively), the mechanism and adsorption nature were investigated with that suggested exothermic and physisorption mechanism.
Corrigendum to “Disinfection and healing effects of 222-nm UVC light on methicillin-resistant Staphylococcus aureus infection in mouse wounds” [J. Photochem. Photobiol. B Biol. 178 (January 2018) 10–18]
Publication date: Available online 4 April 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Kouji Narita, Krisana Asano, Yukihiro Morimoto, Tatsushi Igarashi, Michael R. Hamblin, Tianhong Dai, Akio Nakane
Improved chemo-photothermal therapy of hepatocellular carcinoma using chitosan-coated gold nanoparticles
Publication date: Available online 4 April 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Dina S. Salem, Mahmoud A. Sliem, Mohamed El-Sesy, Samia A. Shouman, Yehia Badr
A green method was used for producing gold nanoparticles (Au NPs) using chitosan as a natural cationic, biodegradable and biocompatible polymer. In this method, chitosan acts as a reducing and stabilizing agent for the synthesis of Au NPs. Different concentrations of chitosan solutions (0.01%, 0.05%, 0.1%, 0.2%, 0.5% and 1%) were applied. In an attempt to mitigate the side effects of anti-cancer drug, 5-fluorouracil (5-FU), through reducing drug doses in photothermal therapy, the formed positively-charged chitosan-wrapped Au NPs were used as a drug delivery system for negatively charged 5-FU to hepatocellular carcinoma cells (HepG2). Au NPs as well as 5-FU@Au nanocomposites were characterized with UV-VIS spectroscopy, particle size, zeta potential, Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and High-Performance Liquid Chromatography (HPLC). The chitosan concentration was shown to be an important parameter for optimizing the dispersion of Au NPs and 5-FU@Au nanocomposites over long time. This stability offers the 5-FU@Au nanocomposites as good candidate for cancer treatment with reduced drug doses in photothermal therapy. A 72% loading-efficiency of 5-FU was obtained. Cytotoxic assay was carried out on HepG2 cell line and it reveals the effectiveness of 5-FU@Au nanocomposites in the presence and absence of laser irradiation compared with the free 5-FU. The cytotoxicity effect of free 5-FU and 5-FU@AuNPs nanocomposites was studied, and it was found that the concentration of 5-FU@Au nanocomposites required to attain 50% of inhibition growth rate was lower than that of free 5-FU in absence of laser radiation and was much lower in presence of laser radiation.
Graphical abstract
A novel approach to evaluate potential risk of organic enrichment in marine aquaculture farms: a case study in Sanggou Bay
Abstract
A novel approach was proposed to evaluate the potential risk of organic enrichment in marine aquaculture farms without obvious environmental degradation. The approach was based on historical environmental records preserved in sediment cores, and potential risk of organic enrichment can be effectively evaluated by comparing burial fluxes of marine organic carbon (OCM) during times before and after large-scale aquaculture. A case study was conducted in Sanggou Bay. The change trends on burial fluxes of organic carbon in sediment over the past 150 years were rebuilt. OCM burial fluxes have greatly increased since the beginning of large-scale aquaculture in 1980s, reaching 16.0~16.5 times higher than that before large-scale aquaculture. The results indicate that aquaculture activities have resulted in obvious accumulation of aquacultural organic matters, although sedimental environment has not degraded seriously. Besides, if the OCM burial fluxes further increase to 3.5~7.0 times higher than that in present, sedimental environment may degrade obviously. Therefore, potential risks of organic enrichment still exist with aquaculture development in Sanggou Bay.
Association of Hidradenitis Suppurativa With T Helper 1/T Helper 17 Phenotypes
This case series uses semantic map analysis to assess the association of hidradenitis suppurativa with T helper 1/T helper 17 phenotypes.
Task Shifting in Dermatology—A Call to Action
To the Editor In response to the Evidence Synopsis by Brown et al on the practice of task shifting, we would like to highlight how task shifting is currently being successfully implemented in health programs in India, with emphasis on National Leprosy Eradication Program.
Indoor Tanners as a Priority Population for Skin Cancer Screening
The study by Heckman et al published in this issue of JAMA Dermatology makes a significant contribution to our understanding of skin cancer screening for indoor tanners. The literature contains only a handful of studies that examined skin screening prevalence and factors that may be associated with this practice among indoor tanners. The National Health Interview Survey (NHIS), a national probability survey of the US adult population, collects data on skin screening and indoor tanning and provides a valuable opportunity to examine potential factors associated with these practices in a large sample. Results of previous studies of skin screening and indoor tanning using NHIS data have been mixed, possibly because of differences in methods and sampling. One study of 2010 NHIS data found a positive association between indoor tanning in the past year and ever having had a skin examination, whereas another study of a subsample of the 2015 NHIS data found no association.
Prevalence of Delusional Infestation—A Population-Based Study
This population-based study reports the prevalence of delusional infestation in Olmsted County, Minnesota.
Atorvastatin in Combination With Narrowband UV-B in Adult Patients With Active Vitiligo
This randomized clinical trial evaluates the use of atorvastatin combined with narrowband UV-B therapy vs narrowband UV-B therapy alone in adult patients with active vitiligo.
Task Shifting in Dermatology—A Call to Action—Reply
In Reply We greatly appreciate the response by Bishnoi et al to "Task Shifting in Dermatology: A Call to Action." Their group's use of task shifting for early diagnosis of leprosy throughout remote areas of India is highly commendable. They emphasize that the challenges of task shifting include both the need for well-resourced training centers and "meticulous strategies." As outlined in their letter, task shifting involves training of an available workforce to meet previously unmet needs in the health care system, which may include community and individual education, diagnosis, referral to tertiary care centers, or treatment. We propose task shifting as a potential means to meet dermatologic needs specifically in lower- and middle-income countries. Worldwide, there exists an inequitable dermatologic treatment gap, and dermatologic disease is the fourth leading cause of morbidity globally. What is lacking are large-scale trials assessing the efficacy of (1) training of these health care workers and (2) implementation of task-shifting interventions, specifically in areas of dermatology diagnosis, triage, and treatment. Assessment of efficacy in the dermatologic setting is necessary prior to scaling up task-shifting interventions. The field of psychiatry has demonstrated through large randomized clinical trials in lower- and middle-income countries that community health care providers can effectively implement psychological therapies for diseases such as depression and alcoholism, and we propose that task shifting in dermatology be similarly systematically assessed.
Skin Cancer Screening Among Indoor Tanners and Nontanners
This survey study of 30 352 participants investigates the association between indoor tanning and skin cancer screening.
Domain-General and Domain-Specific Patterns of Activity Supporting Metacognition in Human Prefrontal Cortex
Metacognition is the capacity to evaluate the success of one's own cognitive processes in various domains; for example, memory and perception. It remains controversial whether metacognition relies on a domain-general resource that is applied to different tasks or if self-evaluative processes are domain specific. Here, we investigated this issue directly by examining the neural substrates engaged when metacognitive judgments were made by human participants of both sexes during perceptual and memory tasks matched for stimulus and performance characteristics. By comparing patterns of fMRI activity while subjects evaluated their performance, we revealed both domain-specific and domain-general metacognitive representations. Multivoxel activity patterns in anterior prefrontal cortex predicted levels of confidence in a domain-specific fashion, whereas domain-general signals predicting confidence and accuracy were found in a widespread network in the frontal and posterior midline. The demonstration of domain-specific metacognitive representations suggests the presence of a content-rich mechanism available to introspection and cognitive control.
SIGNIFICANCE STATEMENT We used human neuroimaging to investigate processes supporting memory and perceptual metacognition. It remains controversial whether metacognition relies on a global resource that is applied to different tasks or if self-evaluative processes are specific to particular tasks. Using multivariate decoding methods, we provide evidence that perceptual- and memory-specific metacognitive representations coexist with generic confidence signals. Our findings reconcile previously conflicting results on the domain specificity/generality of metacognition and lay the groundwork for a mechanistic understanding of metacognitive judgments.
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