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Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. - Lancet (London, England)
Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis, evidenced by marked improvement after treatment with dupilumab, a fully-human monoclonal antibody that blocks both pathways. We aimed to assess the efficacy and safety of several dose regimens of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments.In this randomised, placebo-controlled, double-blind study, we enrolled patients aged 18 years or older who had an Eczema Area and Severity Index (EASI) score of 12 or higher at screening (â‰¥16 at baseline) and inadequate response to topical treatments from 91 study centres, including hospitals, clinics, and academic institutions, in Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Patients were randomly assigned (1:1:1:1:1:1), stratified by severity (moderate or severe, as assessed by Investigator's Global Assessment) and region (Japan vs rest of world) to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or placebo once a week for 16 weeks. We used a central randomisation scheme, provided by an interactive voice response system. Drug kits were coded, providing masking to treatment assignment, and allocation was concealed. Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) from baseline to week 16. Analyses included all randomly assigned patients who received one or more doses of study drug. This trial is registered with ClinicalTrials.gov, number NCT01859988.Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were randomly assigned. 379 patients received one or more doses of study drug (300 mg once a week [n=63], 300 mg every 2 weeks [n=64], 200 mg every 2 weeks [n=61], 300 mg every 4 weeks [n=65], 100 mg every 4 weeks [n=65]; placebo [n=61]). EASI score improvements favoured all dupilumab regimens versus placebo (p<0Â·0001): 300 mg once a week (-74% [SE 5Â·16]), 300 mg every 2 weeks (-68% [5Â·12]), 200 mg every 2 weeks (-65% [5Â·19]), 300 mg every 4 weeks (-64% [4Â·94]), 100 mg every 4 weeks (-45% [4Â·99]); placebo (-18% [5Â·20]). 258 (81%) of 318 patients given dupilumab and 49 (80%) of 61 patients given placebo reported treatment-emergent adverse events; nasopharyngitis was the most frequent (28% and 26%, respectively).Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner, without significant safety concerns. Our findings show that IL-4 and IL-13 are key drivers of atopic dermatitis.Sanofi and Regeneron Pharmaceuticals.Copyright Â© 2015 Elsevier Ltd. All rights reserved.
BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties. - Oncoimmunology
In a recent adoptive cell therapy (ACT) clinical trial using autologous tumor-infiltrating lymphocytes (TILs) in patients with metastatic melanoma, we found an association between CD8(+) T cells expressing the inhibitory receptor B- and T-lymphocyte attenuator (BTLA) and clinical response. Here, we further characterized this CD8(+)BTLA(+) TIL subset and their CD8(+)BTLA(-) counterparts. We found that the CD8(+) BTLA(+) TILs had an increased response to IL-2, were less-differentiated effector-memory (TEM) cells, and persisted longer in vivo after infusion. In contrast, CD8(+)BTLA(-) TILs failed to proliferate and expressed genes associated with T-cell deletion/tolerance. Paradoxically, activation of BTLA signaling by its ligand, herpes virus entry mediator (HVEM), inhibited T-cell division and cytokine production, but also activated the Akt/PKB pathway thus protecting CD8(+)BTLA(+) TILs from apoptosis. Our results point to a new role of BTLA as a useful T-cell differentiation marker in ACT and a dual signaling molecule that curtails T-cell activation while also conferring a survival advantage for CD8(+) T cells. These attributes may explain our previous observation that BTLA expression on CD8(+) TILs correlates with clinical response to adoptive T-cell therapy in metastatic melanoma.
Effectiveness and safety of overnight orthokeratology with Boston XO2 high-permeability lens material: A 24 week follow-up study. - Contact lens & anterior eye : the journal of the British Contact Lens Association
To examine the effectiveness of overnight orthokeratology lenses made with Boston XO2, highly gas-permeable lens material for the temporary correction of myopia.Myopic individuals from 9 to 62 years of age were eligible. Participants â‰¤12 years of age were required to have myopia â‰¤-4.00D and astigmatism â‰¤1.50D, and for those 13-62 years of age myopia â‰¤-5.00D and astigmatism â‰¤3.00D. All participants were required to have normal healthy eyes and not be receiving any ocular medications or systemic medications likely to affect the results of visual acuity. Participants wore the lenses for a minimum of 7h during sleep, and were evaluated on day 1 and weeks 1, 2, 4, 12, and 24. Success was defined as LogMARâ‰¤0.1.A total of 126 participants (63.5% females) with a mean age of 20.4Â±11.5 years were recruited. Baseline LogMAR, and vertical and horizontal corneal curvature were 0.8, 7.7mm, and 7.9mm, respectively, in both eyes. A consistent decrease in LogMAR was noted from day 1 to week 12. The success rate increased with length of time (from 33.9% to 100% for the right eye and from 35.5% to 100% for the left eye from day 1 to week 24). No severe complications were noted.Overnight orthokeratology with lenses made of Boston XO2 material are effective and safe for the temporary reduction of myopia.Copyright Â© 2015 Elsevier Ltd. All rights reserved.
Chemoradiation therapy using cyclopamine-loaded liquid-lipid nanoparticles and lutetium-177-labeled core-crosslinked polymeric micelles. - Journal of controlled release : official journal of the Controlled Release Society
Cyclopamine (CPA), a potent inhibitor of the Hedgehog pathway, has produced promising anticancer results in a number of preclinical studies. CPA has also been found to enhance tumor response to radiation therapy. However, CPA is water insoluble. A drug delivery system suitable for systemic administration of CPA is needed before CPA can be considered for clinical translation. We hypothesized that CPA solubilized in a liquid-lipid nanoparticle system (CPA-LLP) for intravenous injection would have desirable pharmacokinetic properties and increased anticancer efficacy. We further hypothesized that CPA-LLP would enhance the response of tumor cells to targeted radiotherapy delivered selectively through intratumoral injection of lutetium-177 bound to core-crosslinked polymeric micelles (CCPM-(177)Lu). We tested the combination therapy in 4T1 murine breast cancer and Miapaca-2 human pancreatic adenocarcinoma models. The results showed that CPA-LLP had higher antitumor cytotoxicity than free CPA (IC50 values [meanÂ±SEM]: 2.7Â±0.2Î¼M vs. 11.3Â±1.2Î¼M against 4T1 cells; 1.8Â±0.2 vs. 17.1Â±1.26Î¼M against Miapaca-2 cells; p<0.0001). In both cell lines, CPA-LLP resulted in significantly lower clonogenicity than free CPA (p<0.05). Moreover, in both cell lines, CPA-LLP significantly enhanced the cell response to CCPM-(177)Lu radiotherapy as measured by clonogenic assay (p<0.05). In 4T1 and Miapaca-2 mouse xenograft models, the combination of CPA-LLP and CCPM-(177)Lu delayed tumor growth more than either monotherapy did alone. In the 4T1 tumor model, tumor size at 16days after treatment was significantly smaller with the combination therapy than with all the other treatments. In the Miapaca-2 model, the combination therapy resulted in the highest rate of mouse survival and prevented tumor relapse. In conclusion, the combination of CPA-LLP and CCPM-(177)Lu was an effective strategy for treating breast and pancreatic cancer and deserves further investigation.Copyright Â© 2015 Elsevier B.V. All rights reserved.
Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: A Phase II pooled analysis. - Postgraduate medicine
Alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, is in Phase III development for the treatment of hypercholesterolemia. In Phase II studies, 150 mg every 2 weeks (Q2W) was the highest Q2W dose studied, and it is currently the highest Q2W dose under development. To better assess the safety and efficacy of this dose, data across three Phase II studies were pooled.We analyzed data from three double-blind, randomized, placebo-controlled Phase II studies of 8 or 12 weeks' duration. In the current analysis, 77 patients were randomized to the control group and 108 were randomized to alirocumab 150 mg Q2W administered via a single 1 mL subcutaneous injection.Adverse events (AEs) occurred in 58.3% of alirocumab patients compared with 54.5% of placebo-controlled patients. The most common AE was mild, transient injection-site reactions. No signal for muscle symptoms such as myalgia and no cases of neurocognitive effects were reported or observed. One alirocumab patient, also receiving atorvastatin 80 mg/day, had an increase in aspartate transaminase 3 to 5 times the upper limit of normal. Alirocumab 150 mg Q2W reduced low-density lipoprotein cholesterol (LDL-C) from baseline by 68.4% compared with 10.5% for the control group. More than 90% of patients achieved an LDL-C target of < 70 mg/dL with alirocumab versus 8% with control. Marked reductions in other atherogenic lipids and modest increases in high-density lipoprotein cholesterol were also observed.At the highest Q2W dose under development (150 mg), alirocumab appears well tolerated and produces robust LDL-C reductions. These data suggest that alirocumab 150 mg Q2W is an appropriate dose for further evaluation in Phase III trials.
Dosimetric benefits of robust treatment planning for intensity modulated proton therapy for base-of-skull cancers. - Practical radiation oncology
The clinical advantage of intensity modulated proton therapy (IMPT) may be diminished by range and patient setup uncertainties. We evaluated the effectiveness of robust optimization that incorporates uncertainties into the treatment planning optimization algorithm for treatment of base of skull cancers.We compared 2 IMPT planning methods for 10 patients with base of skull chordomas and chondrosarcomas: (1) conventional optimization, in which uncertainties are dealt with by creating a planning target volume (PTV); and (2) robust optimization, in which uncertainties are dealt with by optimizing individual spot weights without a PTV. We calculated root-mean-square deviation doses (RMSDs) for every voxel to generate RMSD volume histograms (RVHs). The area under the RVH curve was used for relative comparison of the 2 methods' plan robustness. Potential benefits of robust planning, in terms of target dose coverage and homogeneity and sparing of organs at risk (OARs) were evaluated using established clinical metrics. Then the plan evaluation metrics were averaged and compared with 2-sided paired t tests. The impact of tumor volume on the effectiveness of robust optimization was also analyzed.Relative to conventionally optimized plans, robustly optimized plans were less sensitive for both targets and OARs. In the nominal scenario, robust and conventional optimization resulted in similar D95% doses (D95% clinical target volume [CTV]: 63.3 and 64.8 Gy relative biologic effectiveness [RBE]), P <.01]) and D5%-D95% (D5%-D95% CTV: 8.0 and 7.1 Gy[RBE], [P <.01); irradiation of OARs was less with robust optimization (brainstem V60: 0.076 vs 0.26 cm(3) [P <.01], left temporal lobe V70: 0.22 vs 0.41 cm(3), [P = .068], right temporal lobe V70: 0.016 vs 0.11 cm(3), [P = .096], left cochlea Dmean: 28.1 vs 30.1 Gy[RBE], [P = .023], right cochlea Dmean: 23.7 vs 25.2 Gy[RBE], [P = .059]). Results in the worst-case scenario were analogous.Robust optimization is effective for creating clinically feasible IMPT plans for tumors of the base of skull.
Gut microbiota and allergy: the importance of the pregnancy period. - Pediatric research
Limited microbial exposure is suggested to underlie the increase of allergic diseases in affluent countries, and bacterial diversity seems to be more important than specific bacteria taxa. Prospective studies indicate that the gut microbiota composition during the first months of life influences allergy development, and support the theory that factors influencing the early maturation of the immune system might be important for subsequent allergic disease. However, recent research indicates that microbial exposure during pregnancy may be even more important for the preventative effects against allergic disease. This review gives a background of the epidemiology, immunology, and microbiology literature in this field. It focuses on possible underlying mechanisms such as immune-regulated epigenetic imprinting and bacterial translocation during pregnancy, potentially providing the offspring with a pioneer microbiome. We suggest that a possible reason for the initial exposure of bacterial molecular patterns to the fetus in utero is to prime the immune system and/or the epithelium to respond appropriately to pathogens and commensals after birth.
Clinical implementation of intensity modulated proton therapy for thoracic malignancies. - International journal of radiation oncology, biology, physics
Intensity modulated proton therapy (IMPT) can improve dose conformality and better spare normal tissue over passive scattering techniques, but range uncertainties complicate its use, particularly for moving targets. We report our early experience with IMPT for thoracic malignancies in terms of motion analysis and management, plan optimization and robustness, and quality assurance.Thirty-four consecutive patients with lung/mediastinal cancers received IMPT to a median 66 Gy(relative biological equivalence [RBE]). All patients were able to undergo definitive radiation therapy. IMPT was used when the treating physician judged that IMPT conferred a dosimetric advantage; all patients had minimal tumor motion (<5 mm) and underwent individualized tumor-motion dose-uncertainty analysis and 4-dimensional (4D) computed tomographic (CT)-based treatment simulation and motion analysis. Plan robustness was optimized by using a worst-case scenario method. All patients had 4D CT repeated simulation during treatment.IMPT produced lower mean lung dose (MLD), lung V5 and V20, heart V40, and esophageal V60 than did IMRT (P<.05) and lower MLD, lung V20, and esophageal V60 than did passive scattering proton therapy (PSPT) (P<.05). D5 to the gross tumor volume and clinical target volume was higher with IMPT than with intensity modulated radiation therapy or PSPT (P<.05). All cases were analyzed for beam-angle-specific motion, water-equivalent thickness, and robustness. Beam angles were chosen to minimize the effect of respiratory motion and avoid previously treated regions, and the maximum deviation from the nominal dose-volume histogram values was kept at <5% for the target dose and met the normal tissue constraints under a worst-case scenario. Patient-specific quality assurance measurements showed that a median 99% (range, 95% to 100%) of the pixels met the 3% dose/3 mm distance criteria for the Î³ index. Adaptive replanning was used for 9 patients (26.5%).IMPT using 4D CT-based planning, motion management, and optimization was implemented successfully and met our quality assurance parameters for treating challenging thoracic cancers.Copyright Â© 2014 Elsevier Inc. All rights reserved.
A single-field integrated boost treatment planning technique for spot scanning proton therapy. - Radiation oncology (London, England)
Intensity modulated proton therapy (IMPT) plans are normally generated utilizing multiple field optimization (MFO) techniques. Similar to photon based IMRT, MFO allows for the utilization of a simultaneous integrated boost in which multiple target volumes are treated to discrete doses simultaneously, potentially improving plan quality and streamlining quality assurance and treatment delivery. However, MFO may render plans more sensitive to the physical uncertainties inherent to particle therapy. Here we present clinical examples of a single-field integrated boost (SFIB) technique for spot scanning proton therapy based on single field optimization (SFO) treatment-planning techniques.We designed plans of each type for illustrative patients with central nervous system (brain and spine), prostate and head and neck malignancies. SFIB and IMPT plans were constructed to deliver multiple prescription dose levels to multiple targets using SFO or MFO, respectively. Dose and fractionation schemes were based on the current clinical practice using X-ray IMRT in our clinic. For inverse planning, dose constraints were employed to achieve the desired target coverage and normal tissue sparing. Conformality and inhomogeneity indices were calculated to quantify plan quality. We also compared the worst-case robustness of the SFIB, sequential boost SFUD, and IMPT plans.The SFIB technique produced more conformal dose distributions than plans generated by sequential boost using a SFUD technique (conformality index for prescription isodose levels; 0.585 Â± 0.30 vs. 0.435 Â± 0.24, SFIB vs. SFUD respectively, Wilcoxon matched-pair signed rank test, p < 0.01). There was no difference in the conformality index between SFIB and IMPT plans (0.638 Â± 0.27 vs. 0.633 Â± 0.26, SFIB vs. IMPT, respectively). Heterogeneity between techniques was not significantly different. With respect to clinical metrics, SFIB plans proved more robust than the corresponding IMPT plans.SFIB technique for scanning beam proton therapy (SSPT) is now routinely employed in our clinic. The SFIB technique is a natural application of SFO and offers several advantages over SFUD, including more conformal plans, seamless treatment delivery and more efficient planning and QA. SFIB may be more robust than IMPT and has been the treatment planning technique of choice for some patients.
Aniseikonia following pneumatic retinopexy for rhegmatogenous retinal detachment. - American journal of ophthalmology
To evaluate the characteristics of aniseikonia in patients with rhegmatogenous retinal detachment (RD) after pneumatic retinopexy.Prospective, interventional case series study.Thirty patients who had undergone pneumatic retinopexy as the initial procedure for rhegmatogenous retinal detachment were selected for this study. The principal outcomes included visual acuity, postoperative aniseikonia measured by the New Aniseikonia Test, anatomical success, and measurement of central retinal thickness using optical coherence topography (OCT). These outcomes were measured postoperatively at 3, 6, and 12 months.The median patient age was 37 years (range, 13-57 years), with 17 cases of macula-off RD and 13 cases of macula-on RD. All of these patients achieved anatomical success, proven by OCT after surgical repair. Three months after pneumatic retinopexy, 18 patients (60.0%) developed micropsic aniseikonia and aniseikonia was diagnosed in 15 patients (88.2%) in the macula-off RD group, leaving 2 patients (11.8%) unaffected. In the macula-on RD group, 3 patients (23.1%) were found to have aniseikonia, while 10 patients (76.9%) were unaffected. The presence of aniseikonia was strongly linked to the difference in central retinal thickness, between the operated eye and the fellow eye, measured at 12 months postoperatively.Aniseikonia after pneumatic retinopexy for rhegmatogenous RD may be related to the preoperative macular status. Macula-off RD patients had a higher incidence of aniseikonia, compared to macula-on RD patients, following retina reattachment. There was a moderate to high correlation between the grading of aniseikonia and the difference in central retinal thickness.Copyright Â© 2014 Elsevier Inc. All rights reserved.
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