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Lichenoid reactions are one of the most frequently observed toxicities with anticancer agents and, recently, a rapid emergence of immunotherapies in oncology has hastened the need to better characterize their unique toxicity profiles, particularly for less common skin toxicities, including anogenital lichen sclerosus et atrophicus (LSA). This case series describes four patients with advanced cancer (one melanoma, two lung cancers, and one kidney tumor) developing LSA lesions while receiving an immunotherapy. Medical records from 2017 to 2020 were retrospectively reviewed. Two patients received pembrolizumab, anti-programmed cell death-1 (PD-1), one nivolumab, anti-programmed cell death-1 (PD-1), and one ipilimumab, an immune checkpoint inhibitor. LSA emerged after a median of 3 months (range, 2–4 months) from starting immunotherapy. All LSA cases were grade 2. Three cases occurred on the penis and one case on the anus. All patients improved after a specific treatment for LSA, and no LSA-related antineoplastic treatment interruption/life-threatening condition were reported. To date, this is the first case series of LSA lesions associated with immunotherapy. Early LSA recognition and management is helpful in cancer patients on immunotherapy allowing a long survival and treatment response.

SummaryThis study deals with the role of texture analysis as a predictive factor of radiation-induced insufficiency fractures in patients undergoing pelvic radiation.IntroductionThis study aims to assess the texture analysis (TA) of computed tomography (CT) simulation scans as a predictive factor of insufficiency fractures (IFs) in patients with pelvic malignancies undergoing radiation therapy (RT).MethodsWe performed an analysis of patients undergoing pelvic RT from January 2010 to December 2014, 24 of whom had developed pelvic bone IFs. We analyzed CT-simulation images using ImageJ macro software and selected two regions of interest (ROIs), which are L5 body and the femoral head. TA parameters included mean (m), standard deviation (SD), skewness (sk), kurtosis (k), entropy (e), and uniformity (u). The IFs patients were compared (1:2 ratio) with controlled patients who had not developed IFs and matched for sex, age, menopausal status, type of tumor, use of chemotherapy, and RT dose. A reliability test of intra- and inter-reader ROI TA reproducibility with the intra-class correlation coefficient (ICC) was performed. Univariate and multivariate analyses (logistic regression) were applied for TA parameters observed both in the IFs and the controlled groups.ResultsInter- and intra-reader ROI TA was highly reproducible (ICC > 0.90). Significant TA parameters on paired t test included L5 m (p = 0.001), SD (p = 0.002), k (p = 0.006), e (p = 0.004), and u (p = 0.015) and femoral head m (p < 0.001) and SD (p = 0.001), whereas on logistic regression analysis, L5 e (p = 0.003) and u (p = 0.010) and femoral head m (p = 0.027), SD (p = 0.015), and sex (p = 0.044).ConclusionsIn our experience, bone CT TA could be correlated to the risk of radiation-induced IFs. Studies on a large patient series and methodological refinements are warranted.

Abstract Background Subaortic stenosis (SAS) is a common congenital heart disease in Boxers. Doppler-derived aortic peak velocity (AoPV) is a diagnostic criterion for the disease. Objectives To investigate the influence of emotional stress during echocardiographic examination on AoPV in normal and SAS-affected Boxers. To evaluate the effects of aortic root diameters on AoPV in normal Boxers. Dogs Two hundred and fifteen normal and 19 SAS-affected Boxers. Methods The AoPV was recorded at the beginning of echocardiographic examination (T0), and when the emotional stress of the dog was assumed to decrease based on behavioral parameters and heart rate (T1). AoPV0–AoPV1 was calculated. In normal dogs, stroke volume index was calculated at T0 and T1. Aortic root diameters were measured and their relationship with AoPV and AoPV0–AoPV1 was evaluated. Results In normal dogs, AoPV was higher at T0 (median, 1.95 m/s; range, 1.60–2.50 m/s) than at T1 (median, 1.76 m/s; range, 1.40–2.20 m/s; P < .0001; reduction 9.2%). The stroke volume index at T0 also was greater than at T1 (P < .0001). Weak negative correlations were detected between aortic root size and aortic velocities. In SAS-affected dogs, AoPV0 was higher than AoPV1 (P < .0001; reduction 7.3%). Conclusion and Clinical Importance Aortic peak velocity was affected by emotional stress during echocardiographic examination both in SAS-affected and normal Boxers. In normal Boxers, aortic root size weakly affected AoPVs, but did not affect AoPV0–AoPV1. Stroke volume seems to play a major role in stress-related AoPV increases in normal Boxers. Emotional stress should be taken into account when screening for SAS in the Boxer breed.

We have explored the role of allergen sensitization and challenge in defining the response of the airways of the Brown Norway (BN) rat to adenosine. In naïve animals or in rats sensitized to ovalbumin (OA) adenosine induced only weak bronchoconstrictor responses. Challenge of sensitized animals with OA induced a marked airway hyperresponsiveness to adenosine which was not seen with methacholine or bradykinin. The augmented bronchoconstrictor response to adenosine was not affected by acute bivagotomy or atropine nor mimicked by an i.v. injection of capsaicin. It was, however, blocked selectively by disodium cromoglycate methysergide or ketanserin and reduced in animals treated sub‐chronically with compound 48/80. The augmented response to adenosine was associated with increases in the plasma concentrations of both histamine and 5‐hydroxytryptamine (5‐HT), which were attenuated by pretreatment with disodium cromoglycate, and degranulation of mast cells in the lung. Parenchymal strips from lungs removed from sensitized rats challenged with OA gave augmented bronchoconstrictor responses to adenosine relative to strips from sensitized animals challenged with saline. Responses were inhibited by methysergide and disodium cromoglycate. These data demonstrate a marked augmentation of the bronchoconstrictor response to adenosine in actively sensitized BN rats challenged with OA. The augmented response is primarily a consequence of mast cell activation, leading to the release of 5‐HT, which in turn induces bronchoconstriction. Our data further suggest the involvement of a discrete lung‐based population of mast cells containing and releasing mainly 5‐HT and brought into play by prior exposure to allergen. British Journal of Pharmacology (2001) 132, 1509–1523; doi:10.1038/sj.bjp.0703961

In a recent prospective, multicenter, two-arm randomized controlled trial (RCT), we demonstrated that adjunctive reflectance confocal microscopy (RCM) in routine clinical practice provides clinical benefits, including safe melanoma detection and a 43.3% reduction in the number needed to excise (NNE). A cost-benefit analysis was conducted based on NNEs for standard care (5.3) and adjunctive RCM (3.0). Cost data were supplied by one center, applying a micro-costing approach from the hospital's perspective. Costs were calculated for dermatology exams, excisions, medications, histopathology, and follow-up. The outcomes were extrapolated to provincial and national settings to assess the economic benefits of RCM. The cost per patient for standard care was €143.63, compared to €114.74 for adjunctive RCM. The cost per melanoma excised with standard care (NNE 5.3) was €904.87, almost twice the cost for RCM (€458.96). Annual regional and national costs for standard care were €864,150.85 and €11,491,849.00, respectively, while RCM reduced these to €438,306.80 and €5,828,792.00. Estimated annual savings with adjunctive RCM were €425,844.05 regionally and €5,663,057.00 nationally. The cost-benefit ratio for RCM was 3.89, meaning that for every €1 spent on RCM, there is a benefit of €3.89. In real-world clinical practice, adjunctive RCM offers significant economic advantages at local, regional, and national levels while maintaining patient safety and reducing unnecessary surgical procedures.

Hoxb-5 is one of the few homeobox genes strongly expressed in the developing mouse lung. To explore the hypothesis that Hoxb-5 acts to regulate epithelial cell fate and branching morphogenesis in the developing lung, we studied the temporal, spatial, and cell-specific expression of Hoxb-5 from gestational day (d) 13.5 to postnatal day (P) 2. Immunocytochemistry demonstrated regional localization of Hoxb-5 protein to developing conducting airways and surrounding mesenchyme. The cellular expression pattern changed from diffusely positive nuclei of mesenchymal cells on d13.5 to become more localized to nuclei of subepithelial fibroblasts and some adjacent columnar and cuboidal epithelial cells on d14.5. After d14.5, Hoxb-5 protein expression continued to decrease in mesenchymal cells distal from developing airways, but persisted in fibroblasts underlying conducting airways. Hoxb-5 protein expression persisted in nuclei of columnar and cuboidal epithelial cells on d16.5 and d17.5, with expression in low cuboidal epithelial cells as well from d17.5 to P2. Western blot analysis showed temporal and quantitative changes in Hoxb-5 protein expression with peak expression on d14.5-15.5. We conclude that Hoxb-5 protein is developmentally regulated in a temporal, spatial, and cell-specific manner throughout the pseudoglandular, canalicular, and terminal saccular periods of lung development in the mouse. This localization and expression pattern suggests that Hoxb-5 may influence branching morphogenesis, cell-cell communication, cell fate, and differentiation of conducting airway epithelia.

The bronchoconstrictor response to adenosine is markedly and selectively increased following ovalbumin (OA) challenge in actively sensitized, Brown Norway rats. We present a pharmacological analysis of the receptor mediating this response. Like adenosine, the broad‐spectrum adenosine receptor agonist, NECA, induced dose‐related bronchoconstriction in actively sensitized, OA‐challenged animals. In contrast, CPA, CGS 21680 and 2‐Cl‐IB‐MECA, agonists selective for A1 A2A and A3 receptors, respectively, induced no, or minimal, bronchoconstriction. Neither the selective A1 receptor antagonist, DPCPX, nor the selective A2A receptor antagonist, ZM 241385, blocked the bronchoconstrictor response to adenosine. MRS 1754, which has similar affinity for rat A2B and A1 receptors, failed to block the bronchoconstrictor response to adenosine despite blockade of the A1 receptor‐mediated bradycardia induced by NECA. 8‐SPT and CGS 15943, antagonists at A1, A2A, and A2B but not A3 receptors, inhibited the bronchoconstrictor response to adenosine. However, the degree of blockade (approximately 3 fold) did not reflect the plasma concentrations, which were 139 and 21 times greater than the KB value at the rat A2B receptor, respectively. Adenosine and NECA, but not CPA, CGS 21680 or 2‐Cl‐IB‐MECA, induced contraction of parenchymal strip preparations from actively sensitized OA‐challenged animals. Responses to adenosine could not be antagonized by 8‐SPT or MRS 1754 at concentrations >50 times their affinities at the rat A2B receptor. The receptor mediating the bronchoconstrictor response to adenosine augmented following allergen challenge in actively sensitized BN rats cannot be categorized as one of the four recognized adenosine receptor subtypes. British Journal of Pharmacology (2002) 135, 685–696; doi:10.1038/sj.bjp.0704516

We have explored the effects of bacterial endotoxin (lipopolysaccharide; LPS) on the response of the airways of Brown Norway (BN) rats to adenosine. Comparisons have been drawn with the effects on responses to methacholine and 5‐hydroxytryptamine. In vehicle‐challenged animals, adenosine, given i.v. was only a weak bronchoconstrictor. In contrast, 1 h following intratracheal administration of LPS, 0.3 mg kg−1, bronchoconstrictor responses to adenosine were markedly and selectively enhanced. At this time point, there were no significant changes in leukocyte numbers, eosinophil peroxidase and myeloperoxidase activities or protein concentrations in bronchoalveolar lavage (BAL) fluid. Twenty‐four hours after challenge, the sensitivity of the airways to both adenosine and methacholine was reduced relative to the earlier time point and there were substantial increases in each marker of inflammation in BAL fluid. The bronchoconstrictor response to adenosine was blocked selectively by methysergide, disodium cromoglycate and the broad‐spectrum adenosine receptor antagonist, 8‐SPT, but not by DPCPX or ZM 243185, selective antagonists for the A1 and A2A receptors, respectively. Thus, the response to adenosine augmented following LPS is mast cell mediated and involves a receptor which can be blocked by 8‐SPT but not by selective A1 or A2A receptor antagonists. It thus bears similarity to the augmented response to adenosine induced by allergen challenge in actively sensitized BN rats. Exposure to LPS could be a factor along with allergen in determining the increased sensitivity of the airways of asthmatics to adenosine. British Journal of Pharmacology (2002) 136, 111–119; doi:10.1038/sj.bjp.0704688

Twenty existing case studies of state decision making on education issues from 1971 to 1991 are analyzed to portray the changing nature of Minnesota's education policy system and to consider whether Iannaccone's oft-used \"structural linkage\" typology retains explanatory power. Minnesota's system has become more pluralistic, politicized, and bureaucratized. It is buffeted by state revenue fluctuations and by national-and global-forces. But its reformist tradition continues as does its considerable capacity for policy innovation. Reformulations of the Iannaccone typology find some support in Minnesota data. Other perspectives, however, clearly hold more promise for policy process research in education.