Disease tolerance: concept and mechanisms

JL McCarville | JS Ayres

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IgE promotes type 2 innate lymphoid cells in murine food allergy

Abstract

Background

Mast cells serve an important sentinel function at mucosal barriers and have been implicated as key early inducers of Type 2 immune responses in food allergy. The generation of Th2 and IgE following food allergen ingestion is inhibited in the absence of mast cells. Group 2 innate lymphoid cells are also thought to play an important early role in nascent allergic responses.

Objective

To test whether IgE-mediated mast cell activation promotes intestinal ILC2 responses following ingestion of food allergens and whether ILC2 amplify food allergy.

Methods

Two different mouse models of food allergy, one using intraperitoneally ovalbumin (OVA) primed BALB/c animals and the other using enterally peanut-sensitized inherently atopic IL4raF709 mice, were applied to test the contributions of IgE antibodies and mast cells to ILC2 responses. The effect of ILC2 on mast cell activation and on anaphylaxis was tested.

Results

ILC2 responses were significantly impaired in both models of food allergy in Igh7^-/- mice harboring a targeted deletion of the gene encoding IgE. A similar reduction in food allergen-induced ILC2 was observed in mast cell deficient Il4raF709 Kit^W-sh mice and this was partially corrected by reconstituting these animals using cultured bone marrow mast cells. Mast cells activated ILC2 for IL-13 production in an IL-4Rα-dependent manner. Activated ILC2 amplified systemic anaphylaxis by increasing target tissue sensitivity to mast cell mediators.

Conclusions & clinical relevance

These findings support an important role for IgE-activated mast cells in driving intestinal ILC2 expansion in food allergy and reveal that ILC2, in turn, can enhance responsiveness to the mediators of anaphylaxis produced by mast cells. Strategies designed to inhibit IgE signaling or mast cell activation are likely to inhibit both Type 2 immunity and immediate hypersensitivity in food allergy.

This article is protected by copyright. All rights reserved.

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Typical sensory organization test findings and clinical implication in acute vestibular neuritis

Sensory organization test (SOT) is used to evaluate postural instability. We wanted to characterize the SOT findings in patients with acute vestibular neuritis (VN).

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The Burden of Inbox-Messaging Systems and Its Effect on Work-Life Balance in Dermatology

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Fibrous Cephalic Plaques in Tuberous Sclerosis Complex

Fibrous cephalic plaques (FCPs) stereotypically develop on the forehead of tuberous sclerosis complex (TSC) patients. They constitute a major feature for TSC diagnosis, and may present before other TSC-related cutaneous hamartomas.

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A systematic review of validated sinus surgery simulators

Abstract

Background

Simulation provides a safe and effective opportunity to develop surgical skills. A variety of endoscopic sinus surgery (ESS) simulators have been described in the literature. Validation of these simulators allows for effective utilisation in training.

Objective of review

To conduct a systematic review of the published literature to analyse the evidence for validated ESS simulation.

Search strategy

Pubmed, Embase, Cochrane and Cinahl were searched from inception of the databases to January 11^th, 2017.

Evaluation method

12,516 articles were retrieved of which 10,112 were screened following the removal of duplicates. 38 full text articles were reviewed after meeting the search criteria. Evidence of face, content, construct, discriminant and predictive validity was extracted.

Results

20 articles were included in the analysis describing 12 ESS simulators. 11 of these simulators had undergone validation; 3 virtual reality, 7 physical bench models and 1 cadaveric simulator. 7 of the simulators were shown to have face validity, 7 had construct validity and 1 had predictive validity. None of the simulators demonstrated discriminate validity.

Conclusion

This systematic review demonstrates that a number of ESS simulators have been comprehensively validated. Many of the validation processes, however, lack standardisation in outcome reporting, thus limiting a meta-analysis comparison between simulators.

This article is protected by copyright. All rights reserved.

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Prevalence of skin disease in a population based sample of adults out of five European countries

Abstract

Background

There is a lack of prevalence data on skin diseases in the general adult population, most studies were carried out in small, national or consecutive clinical samples.

Objectives

To determine the prevalence of common skin disease in the general European population and to additionally assess differences in the characteristics of treatment between countries.

Methods

A random sample consisting out of 12,377 subjects aged 18 to 74 years was drawn from the general population of five European countries (Germany, Italy, The Netherlands, Portugal and Sweden). This was a cross-sectional study and all participants were interviewed with a standardized questionnaire assessing the occurrence of 10 common skin diseases during lifetime, past year and past month. If a skin disease was reported we additionally assessed who performed diagnosis and treatment and if drugs were prescribed.

Results

The most common skin disease was warts (41.3%) followed by acne (19.2%) and contact dermatitis (15.0%). In general females were more often affected by skin diseases compared to males, only in skin cancer the prevalence in males was slightly higher. The prevalence of skin diseases in northern countries (Germany, Netherlands & Sweden) was in general higher than in the southern countries (Italy & Spain). In the Netherlands the treatment of skin diseases was less often performed by a dermatologist compared to the other countries.

Conclusion

The prevalence estimates reported in this study are derived from a representative sample of the general population. Data assessment was performed comprehensively across countries, thus country specific prevalence estimates are comparable.

This article is protected by copyright. All rights reserved.

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Scleroderma skin ulcers definition, classification and treatment strategies our experience and review of the literature

Publication date: Available online 2 December 2017
Source:Autoimmunity Reviews
Author(s): Dilia Giuggioli, Andreina Manfredi, Federica Lumetti, Michele Colaci, Clodoveo Ferri
BackgroundSkin ulcers (SU) are one of the most frequent manifestations of systemic sclerosis (SSc). SSc-SU are very painful, often persistent and recurrent; they may lead to marked impairment of patient's activities and quality of life. Despite their severe impact on the whole SSc patient's management, the proposed definition, classification criteria, and therapeutic strategies of SSc-SU are still controversial.ObjectiveThe present study aimed to elaborate a comprehensive proposal of definition, classification, and therapeutic strategy of SSc-SU on the basis of our long-term single center experience along with a careful revision of the world literature on the same topic.MethodsA series of 282 SSc patients (254 females and 28 males; 84% with limited and 16% diffuse cutaneous SSc; mean age of 51.5±13.9SD at SSc onset; mean follow-up 5.8±4.6SDyears) enrolled during the last decade at our Rheumatology Unit were retrospectively evaluated with specific attention to SSc-SU. The SSc-SU were classified in 5 subtypes according to prominent pathogenetic mechanism(s) and localization, namely 1. digital ulcers (DU) of the hands or feet, 2. SU on bony prominence, 3. SU on calcinosis, 4. SU of lower limbs, and 5. DU presenting with gangrene. This latter is a very harmful evolution of both DU of the hands and feet needing a differential diagnosis with critical limb ischemia.ResultsDuring the follow up period, one or more episodes of SSc-SU were recorded in over half patients (156/282, 55%); skin lesions were often recurrent and difficult-to-heal because of local complications, mainly infections (67.3%), in some cases associated to osteomyelitis (19.2%), gangrene (16%), and/or amputation (11.5%). SSc-SU were significantly associated with lower patients' mean age at the disease onset (p=0.024), male gender (p=0.03), diffuse cutaneous subset (p=0.015), calcinosis (p=0.002), telangiectasia (p=0.008), melanodermia (p<0.001), abnormal PAPs (p=0.036), and/or altered inflammation reactant (CRP, p=0.001).Therapeutic strategy of SSc-SU included both systemic and local pharmacological treatments with particular attention to complicating infections and chronic/procedural pain, as well as a number of non-pharmacological measures. Integrated local treatments were often decisive for the SSc-SU healing; they were mainly based on the wound bed preparation principles that are summarized in the acronym TIME (necrotic Tissue, Infection/Inflammation, Moisture balance, and Epithelization).The updated review of the literature focusing on this challenging issue was analyzed in comparison with our experience.ConclusionsThe recent advancement of knowledge and management strategies of SSc-SU achieved during the last years lead to the clear-cut improvement of patients' quality of life and reduced long-term disability.



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Clinical and immunological aspects of anti-peptidylarginine deiminase type 4 (anti-PAD4) autoantibodies in rheumatoid arthritis

Publication date: Available online 2 December 2017
Source:Autoimmunity Reviews
Author(s): Zyanya Reyes-Castillo, José Francisco Muñoz-Valle, Mara A. Llamas-Covarrubias
Rheumatoid arthritis (RA) is the most common rheumatic autoimmune disease worldwide, which causes progressive joint damage and can lead to functional disability. Despite prominent advances in RA diagnosis and treatment during the last 20years, there is still a need for novel biomarkers that aid in diagnosis and prognosis of this heterogeneous disease. Citrullination is a key post-translational modification implicated on anti-citrullinated protein/peptide antibodies (ACPA) production in RA, catalyzed by human peptidylarginine deiminases (PADs). Among these enzymes, PAD4 has been recognized as an important player in RA pathogenesis and the enzyme itself is a target of autoantibodies (anti-PAD4) in a subgroup of RA patients. Accumulating evidence suggests that anti-PAD4 autoantibodies may be useful as a severity biomarker in RA and recent studies have also shed light on the functional significance of these autoantibodies. This review summarizes the evidence on anti-PAD4 autoantibodies in RA, and addresses its usefulness for disease diagnosis and prognosis. Novel immunological aspects of anti-PAD4 antibodies and their relevance to RA pathogenesis are also discussed.



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Pitfalls in the detection of citrullination and carbamylation

Publication date: Available online 2 December 2017
Source:Autoimmunity Reviews
Author(s): M.K. Verheul, P.A. van Veelen, M.A.M. van Delft, A. de Ru, G.M.C. Janssen, T. Rispens, R.E.M. Toes, L.A. Trouw
Carbamylation and citrullination are both post-translational modifications against which (auto)antibodies can be detected in sera of rheumatoid arthritis (RA) patients. Carbamylation is the chemical modification of a lysine into a homocitrulline, whereas citrullination is an enzymatic conversion of an arginine into a citrulline. It is difficult to distinguish between the two resulting amino acids due to similarities in structure. However, differentiation between citrulline and homocitrulline is important to understand the antigens that induce antibody production and to determine which modified antigens are present in target tissues.We have observed in literature that conclusions are frequently drawn regarding the citrullination or carbamylation of proteins based on reagents that are not able to distinguish between these two modifications. Therefore, we have analyzed a wide spectrum of methods and describe here which method we consider most optimal to distinguish between citrulline and homocitrulline.We have produced several carbamylated and citrullinated proteins and investigated the specificity of (commercial) antibodies by both ELISA and western blot. Furthermore, detection methods based on chemical modifications, such as the anti-modified citrulline-"Senshu" method and also mass spectrometry were investigated for their capacity to distinguish between carbamylation and citrullination.We observed that some antibodies are able to distinguish between carbamylation and citrullination, but an overlap in reactivity is often present in the commercially available anti-citrulline antibodies. Finally, we conclude that the use of mass spectrometry is currently essential to differentiate between citrullinated and carbamylated proteins present in complex biological samples.



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Imaging modalities for the diagnosis and disease activity assessment of Takayasu's arteritis: A systematic review and meta-analysis

Publication date: Available online 5 December 2017
Source:Autoimmunity Reviews
Author(s): Lillian Barra, Tahir Kanji, Jacqueline Malette, Christian Pagnoux
BackgroundEarly diagnosis of Takayasu's Arteritis (TAK) and detection of disease activity may reduce the risk of vascular complications. The objective of this study was to determine the effectiveness of imaging modalities for the management of TAK.MethodsMEDLINE and EMBASE were searched for studies of patients undergoing various imaging modalities for TAK diagnosis or to assess disease activity. We excluded case reports, reviews and case series with <10 patients. The methodologic quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). Random effects meta-analyses with inverse-variance weighting were performed.ResultsFrom the 1126 citations screened, 57 studies met our inclusion criteria. Many of the studies were of small sample size (average N=27), cross-sectional design and low methodological quality. Ultrasound (US) had a lower pooled sensitivity (SN) of 81% (95% CI: 69–89%) than Magnetic Resonance Angiography (MRA) with SN=92% (95% CI: 88–95%) for TAK diagnosis (by clinical criteria and/or X-Ray angiography). Both had high specificities (SP) of >90% for TAK diagnosis. Fewer studies investigated computed tomography angiography (CTA), but SN and SP for TAK diagnosis was high (>90%). The utility of vessel wall thickening and enhancement by MRA and CTA to predict disease activity varied across studies. The pooled SN and SP of ¹⁸F-fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) for disease activity was 81% (95% CI: 69–89%) and 74% (95% CI: 55–86%), respectively.ConclusionUS, CTA and/or MRA are effective for the diagnosis of TAK. The utility of these imaging modalities for assessing disease activity remains unclear.



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Combined therapies to treat complex diseases: The role of the gut microbiota in multiple sclerosis

Publication date: Available online 28 November 2017
Source:Autoimmunity Reviews
Author(s): Laura Calvo-Barreiro, Herena Eixarch, Xavier Montalban, Carmen Espejo
The commensal microbiota has emerged as an environmental risk factor for multiple sclerosis (MS). Studies in experimental autoimmune encephalomyelitis (EAE) models have shown that the commensal microbiota is an essential player in triggering autoimmune demyelination. Likewise, the commensal microbiota modulates the host immune system, alters the integrity and function of biological barriers and has a direct effect on several types of central nervous system (CNS)-resident cells. Moreover, a characteristic gut dysbiosis has been recognized as a consistent feature during the clinical course of MS, and the MS-related microbiota is gradually being elucidated. This review highlights animal studies in which commensal microbiota modulation was tested in EAE, as well as the mechanisms of action and influence of the commensal microbiota not only in the local milieu but also in the innate and adaptive immune system and the CNS. Regarding human research, this review focuses on studies that show how the commensal microbiota might act as a pathogenic environmental risk factor by directing immune responses towards characteristic pathogenic profiles of MS. We speculate how specific microbiome signatures could be obtained and used as potential pathogenic events and biomarkers for the clinical course of MS. Finally, we review recently published and ongoing clinical trials in MS patients regarding the immunomodulatory properties exerted by some microorganisms. Because MS is a complex disease with a large variety of associated environmental risk factors, we suggest that current treatments combined with strategies that modulate the commensal microbiota would constitute a broader immunotherapeutic approach and improve the clinical outcome for MS patients.



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A concise review of significantly modified serological biomarkers in giant cell arteritis, as detected by different methods

Publication date: Available online 28 November 2017
Source:Autoimmunity Reviews
Author(s): B. Burja, T. Kuret, S. Sodin-Semrl, K. Lakota, Ž. Rotar, R. Ješe, K. Mrak-Poljšak, P. Žigon, G.G. Thallinger, J. Feichtinger, S. Čučnik, M. Tomšič, S. Praprotnik, A. Hočevar
Giant cell arteritis (GCA) is a primary systemic vasculitis present in subjects older than 50years with involvement of large- and medium-sized arteries. Early diagnosis for GCA is essential to prevent serious complications, such as permanent vision loss and/or cerebrovascular events. Elevated inflammatory cytokines, with acute phase and other proteins dominate large- and medium-sized arteries leading to stenosis or occlusion of arterial lumen. To date, there are no reliable serological markers for monitoring GCA. The review aims to provide concise overview of published GCA studies in order to: a) identify significantly changed serological biomarkers in GCA and compare the influences of techniques for marker evaluation and b) investigate most promising markers in GCA using analyte frequency and meta-analysis.



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Imaging aspects of interstitial lung disease in patients with rheumatoid arthritis: Literature review

Publication date: Available online 28 November 2017
Source:Autoimmunity Reviews
Author(s): Alexandra Balbir-Gurman, Ludmila Guralnik, Mordechai Yigla, Yolanda Braun-Moscovici, Emilia Hardak
ObjectiveInterstitial lung disease (ILD) is a frequent and severe complication of rheumatoid arthritis (RA), resulting in pulmonary fibrosis (PF) and respiratory failure.MethodsChest computed tomography (CT-c) or high resolution CT (HRCT) is the main modality for assessment of ILD. We performed a systematic literature review on CT-c/HRCT findings in patients with ILD-RA, using the MEDLINE database for the period from 1991 to 2015.ResultsFindings on CT-c/HRCT attributed to ILD-RA are variable (ground glass opacities, reticular and nodular pattern, as well as a combined pattern of emphysema and PF). Correlation of CT-c/HRCT findings with clinical data is inconsistent.ConclusionsILD-RA is part of a general autoimmune inflammation and should be integrated into the decision-making process for the treatment of RA. There is an unmet need to design an algorithm which will allow prediction of CT-c changes compatible with ILD-RA with a high probability. Hopefully, this will enable treating patients with ILD-RA early, with possible halting of the progression of ILD-RA toward PF.



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NK cells in autoimmune diseases: Linking innate and adaptive immune responses

Publication date: Available online 26 November 2017
Source:Autoimmunity Reviews
Author(s): Elena Gianchecchi, Domenico Vittorio Delfino, Alessandra Fierabracci
The pathogenesis of autoimmunity remains to be fully elucidated, although the contribution of genetic and environmental factors is generally recognized. Despite autoimmune conditions are principally due to T and B lymphocytes, NK cells also appear to play a role in the promotion and/or maintenance of altered adaptive immune responses or in peripheral tolerance mechanisms.Although NK cells are components of the innate immune system, they shows characteristics of the adaptive immune system, such as the expansion of pathogen-specific cells, the generation of long-lasting "memory" cells able to persist upon cognate antigen encounter, and the possibility to induce an increased secondary recall response to re-challenge.Human NK cells are generally identified as CD56⁺CD3⁻, conversely CD56⁺CD3⁺ cells represent a mixed population of NK-like T (NK T) cells and antigen-experienced T cells showing the up-regulation of several NK cell markers. CD56^dim constitute about 90% of NK cells in the peripheral blood, they are mature and involved in cytotoxicity responses; CD56^bright instead are more immature, mostly involved in cytokine production, having only a limited role in cytolytic responses, keen to leave the blood vessels as the principal population observed in lymph nodes. NK cells have been identified also in non-lymphoid tissues since, in pathologic conditions, they can quickly reach the target organs. A cross-talk between NK with dendritic cells and T cells is established throughout different receptor-ligand bindings.Several studies support the correlation between NK cell number and/or functional alterations, such as a defective cytotoxic activity and several autoimmune conditions. Among the different autoimmune pathologies and even within the same disease, NK cell function is significantly different either promoting or even protecting against the onset of the autoimmune condition.In this Review, we discuss recent literature supporting the role played by NK cells, as a bridge between innate and adaptive immunity, in the onset of autoimmune diseases.



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Curcumin: A natural modulator of immune cells in systemic lupus erythematosus

Publication date: Available online 24 November 2017
Source:Autoimmunity Reviews
Author(s): Amir Abbas Momtazi-Borojeni, Saeed Mohammadian Haftcheshmeh, Seyed-Alireza Esmaeili, Thomas P. Johnston, Elham Abdollahi, Amirhossein Sahebkar
Curcumin is a polyphenol natural product isolated from turmeric, interacting with different cellular and molecular targets and, consequently, showing a wide range of pharmacological effects. Recent preclinical and clinical trials have revealed immunomodulatory properties of curcumin that arise from its effects on immune cells and mediators involved in the immune response, such as various T-lymphocyte subsets and dendritic cells, as well as different inflammatory cytokines. Systemic lupus erythematosus (SLE) is an inflammatory, chronic autoimmune-mediated disease characterized by the presence of autoantibodies, deposition of immune complexes in various organs, recruitment of autoreactive and inflammatory T cells, and excessive levels of plasma proinflammatory cytokines. The function and numbers of dendritic cells and T cell subsets, such as T helper 1 (Th1), Th17, and regulatory T cells have been found to be significantly altered in SLE. In the present report, we reviewed the results of in vitro, experimental (pre-clinical), and clinical studies pertaining to the modulatory effects that curcumin produces on the function and numbers of dendritic cells and T cell subsets, as well as relevant cytokines that participate in SLE.



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Belimumab in the treatment of systemic lupus erythematous: An evidence based review of its place in therapy

Publication date: Available online 24 November 2017
Source:Autoimmunity Reviews
Author(s): Frederico Marcondes, Morton Scheinberg
IntroductionSystemic lupus erythematous is an autoimmune disease with diverse clinical features and has its development associated with a complexity of genetic, hormonal and environmental factors and the development of autoantibodies. Identification of new treatments is currently an area of intense investigation. Belimumab is the first biologic approved for the treatment of the disease inhibiting the excessive B cell activity observed in these patients and consequently reduction of autoantibodies.AimTo review the current transition of the evidence available of its use in real life patients with persistent active disease while on conventional therapies.EvidenceThe results observed on the large series of patients (over 50 patients) followed for at least six months confirm the observations from phase 3 trials. In clinical practice close to two third of the patients remained on belimumab and one third discontinued mostly due to evaluation by the doctor or the patient or both of no detectable positive response. The presence of adverse events was considerably low and the subgroups with skin and joint manifestations appear to benefit the most. Daily steroid use is usually reduced to a significantly low when compared with the intake before introduction of the biologic Although not seen on trials in real life the addition of belimumab to the conventional therapy in lupus nephritis is being reported in several patients. Cost of the medication is still an issue that hampers its use. Further evidence of its use in certain specific groups is under investigation and its results should shed light on additional indications.Place in therapyConsidering what is currently published on the evidence here reviewed in the use of belimumab in clinical practice it is our understanding that belimumab it will be gradually incorporated in the armamentarium of treatment not necessarily on refractory patients. We believe that with the upcoming of the subcutaneous route in the near future should also help in widen the use of the belimumab to be considered in first line combination set ups.



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Clinical and microbiological characteristics of the infections in patients treated with rituximab for autoimmune and/or malignant hematological disorders

Publication date: Available online 24 November 2017
Source:Autoimmunity Reviews
Author(s): Jean-Jacques Tudesq, Guillaume Cartron, Sophie Rivière, David Morquin, Laura Iordache, Alfred Mahr, Valérie Pourcher, Kada Klouche, Diane Cerutti, Alain Le Quellec, Philippe Guilpain
IntroductionRituximab is commonly used for the treatment of hematological malignancies and autoimmune diseases. Despite a reputation for good tolerance, case-series and registries reported rituximab-related infections of variable severity including opportunistic infections. We aimed at describing the natural history of infectious events (IE) after treatment by rituximab providing clinical and microbiological features and outcome.Patients and methodsWe retrospectively analyzed the medical records of patients treated with rituximab in an internal medicine department of a tertiary hospital between 2007 and 2015, and identified all IE after this therapy. Events' severity was assessed using the Common Terminological Criteria of Adverse Events (version 4.3) definitions.ResultsAmong 101 patients treated with rituximab, we identified 228 IE in 74 (73.3%) of these patients (median follow-up 30.4months). Indication for rituximab was either autoimmune disease (AID) (52.5% of patients), or monoclonal hematological disease (MHD) (47.5%). Patients received an overall median number of 5 rituximab infusions [interquartile range: 4–8], representing a cumulative dose of 4340mg [2620–6160]. After last rituximab infusion, IE occurred after 3.1months [0.7–9.4]. Respectively, IE were severe in 28.1% of cases in patients treated for AID vs 58.0% in patients treated for MHD (p<0.001), due to opportunistic pathogens in 7.8% vs 11.0% (p=0.49) and fatal in 4.7% vs 13.0% (p=0.044). Factor associated with mortality were polymicrobial infection (p<0.001), monoclonal hematological disease (p=0.035), use of steroids over 10mg/d within the last two weeks (p=0.003), and rituximab cumulative dose (p<0.001). We identified a group of 10 patients (9.9%) showing life-threatening, polymicrobial, and opportunistic infections constituting a 'catastrophic infectious syndrome', which was lethal in 7 cases.ConclusionIE after treatment by rituximab can be extremely severe, especially in patients immunocompromised by several other drugs. Further studies should focus on the group with life-threatening polymicrobial infections.



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Childhood- versus adult-onset ANCA-associated vasculitides: A nested, matched case–control study from the French Vasculitis Study Group Registry

Publication date: Available online 24 November 2017
Source:Autoimmunity Reviews
Author(s): Michele Iudici, Christian Pagnoux, Pierre Quartier, Matthias Büchler, Ramiro Cevallos, Pascal Cohen, Claire de Moreuil, Philippe Guilpain, Alain Le Quellec, Jacques Serratrice, Benjamin Terrier, Loïc Guillevin, Luc Mouthon, Xavier Puéchal
ObjectiveTo investigate differences between childhood-onset ANCA-associated vasculitides (cAAVs) and matched adult-onset controls (aAAVs).MethodscAAV clinical pictures at onset and outcomes were compared to a randomly selected sample of aAAV patients from the French Vasculitis Study Group Registry. Cases and controls were matched for AAV (granulomatosis with polyangiitis [GPA], microscopic polyangiitis [MPA] or eosinophilic granulomatosis with polyangiitis [EGPA]), sex and year of enrollment. Medications, disease activity and damage were prospectively recorded. Kaplan–Meier curves and the log-rank test were used to analyze case-vs.-control differences for predefined outcomes.ResultsComparing 35 cAAVs (25 GPA, 4 MPA, 6 EGPA) to 151 aAAVs (106 GPA, 17 MPA, 28 EGPA), their respective median follow-up durations were 71 and 64months (P=0.49), and, at baseline, children had less frequent myalgias (P=0.005) and peripheral neuropathy (P<0.001) but were more frequently febrile (P<0.05). Rates of renal involvement were comparable (13 [37%] cAAVs vs. 73 [48%] aAAVs; P=0.31). Initial GPA-associated ischemic abdominal pain and nasal cartilage damage were more common in cAAVs than aAAVs (P<0.05). During follow-up, the cAAV relapse rate was higher (24.5 vs. 18.7 flares per 100 patient-years; P<0.05) and, at last visit, cases had accumulated more damage, mostly ear, nose & throat sequelae (P=0.001), associated with longer maintenance therapy (P=0.03), than aAAV controls. Four (11.4%) cAAV and 13 (8.6%) aAAV patients died (P=0.53).ConclusioncAAVs are severe diseases, characterized by a higher relapse rate, more accrued damage and longer maintenance therapy than for aAAVs.



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Oropharynx-directed ipsilateral irradiation for p16-positive squamous cell carcinoma involving the cervical lymph nodes of unknown primary origin

Abstract

Background

The purpose of this study was to present our findings on the use of limited-field, oropharynx-directed ipsilateral irradiation for p16-positive squamous cell carcinoma of unknown primary origin.

Methods

Between April 2011 and January 2016, 25 patients with a histological diagnosis of p16-positive squamous cell carcinoma were selectively irradiated to the ipsilateral oropharynx and cervical neck for tumors of unknown primary origin. The dose to the oropharynx ranged from 54-60 Gy (median 60 Gy) in 30-33 fractions. Concurrent cisplatin-based chemotherapy was administered to 8 patients (32%).

Results

The actuarial 2-year estimates of locoregional control, progression-free survival, and overall survival were 91%, 87%, and 92%, respectively. One patient failed in the contralateral neck. There was no grade 3 + toxicity in either the acute or late setting.

Conclusion

Oropharynx-directed, ipsilateral radiation results in disease control that compares favorably with historical controls treated by comprehensive mucosal and bilateral neck radiation.

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American Thyroid Association ultrasound system for the initial assessment of thyroid nodules: Use in stratifying the risk of malignancy of indeterminate lesions

Abstract

Background

The ultrasound risk stratification system of the American Thyroid Association (ATA) is frequently adopted in clinical practice. Here, we evaluated its performance in a series of nodules with indeterminate fine-needle aspiration cytology (FNAC) report.

Methods

Indeterminate thyroid nodules diagnosed at 2 medical centers were retrospectively screened, ultrasound images were reevaluated, and lesions were classified according to the ATA. Single ultrasound parameters were also analyzed.

Results

One hundred seventy-three indeterminate lesions were included with 24.8% of malignancy. The high suspicion class showed a cancer rate (75%) significantly (P < .001) higher than that recorded in the other categories (16.8%). Between ultrasound parameters, halo and microcalcifications were the most sensitive and specific ones. The most accurate receiver operating characteristic (ROC)-derived cutoff of nodule's diameter was >4.1 cm. At multivariate analysis, only the ATA class of high suspicion and size >4.1 cm were significantly associated with cancer (odds ratios [ORs] 19.4 and 5.4, respectively).

Conclusion

The ATA ultrasound system is reliable in the risk stratification of indeterminate thyroid lesions.

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R-loops cause genomic instability in Wiskott-Aldrich syndrome Thelper lymphocytes

Publication date: Available online 15 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Koustav Sarkar, Seong-Su Han, Kuo-Kwang Wen, Hans D. Ochs, Loïc Dupré, Michael M. Seidman, Yatin M. Vyas
BackgroundWiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked neutropenia (XLN), caused by WAS mutations affecting WASp expression or activity, manifest in immunodeficiency, autoimmunity, genomic-instability, and lymphoid-cancer. WASp supports filamentous-actin formation in the cytoplasm and gene-transcription in the nucleus. Although the genetic basis for XLT/WAS has been clarified, the relationships between mutant forms of WASp and the diverse features of these disorders remain ill-defined.ObjectiveTo define how dysfunctional gene transcription is causally linked to the degree of Thelper (Th) cell deficiency and genomic instability in XLT/WAS clinical spectrum.MethodsIn human Th1- or Th2-skewing cell culture systems, co-transcriptional R-loops (RNA:DNA duplex and displaced single-stranded DNA) and DNA double-strand breaks (DSBs) were monitored in multiple XLT and WAS patient samples, and in normal T cells depleted of WASp.ResultsWASp-deficiency provokes increased R-loops and R-loop-mediated DSBs in Th1-cells relative to Th2-cells. Mechanistically, chromatin-occupancy of Serine2-unphosphorylated-RNA Polymerase II is increased and that of topoisomerase-1, a R-loop preventing factor, is decreased at R-loop-enriched regions of IFNG and TBX21 (Th1 genes) in Th1-cells. These aberrations accompany increased unspliced (intron-retained) and decreased spliced mRNA of IFNG and TBX21 but not of IL13 (Th2-gene). Significantly, increased cellular load of R-loops and DSBs, which are normalized upon RNaseH1-mediated suppression of ectopic R-loops, inversely correlates with disease severity scores.ConclusionTranscriptional R-loop imbalance is a novel molecular defect etiologic in Th1-immunodeficiency and genomic-instability in WAS. The study proposes that cellular R-loop load could be used as a potential biomarker for monitoring symptom severity in the XLT-WAS clinical spectrum, and could be targeted therapeutically.

Graphical abstract

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Neonatal hyperoxia promotes asthma-like features through IL-33-dependent ILC2 responses

Publication date: Available online 15 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): In Su Cheon, Young Min Son, Li Jiang, Nicholas P. Goplen, Mark H. Kaplan, Andrew H. Limper, Hirohito Kita, Sophie Paczesny, Y.S. Prakash, Robert Tepper, Shawn K. Ahlfeld, Jie Sun
BackgroundPremature infants often require oxygen supplementation and, therefore, are exposed to oxidative stress. Following oxygen exposure, preterm infants frequently develop chronic lung disease and have a significantly increased risk of asthma.ObjectiveWe sought to identify the underlying mechanisms by which neonatal hyperoxia promotes asthma development.MethodsMice were exposed to neonatal hyperoxia followed by a period room air recovery. A group of mice were also intranasally exposed to house dust mite antigen (HDM). Assessments were performed at various time points for evaluation of airway hyperresponsiveness (AHR), eosinophilia, mucus production, inflammatory gene expression, T helper (Th) and group 2 innate lymphoid cell (ILC2) responses. Sera from term- and preterm-born infants were also collected and the levels of IL-33 and type 2 cytokines were measured.ResultsNeonatal hyperoxia induced asthma-like features including AHR, mucus hyperplasia, airway eosinophilia, and type 2 pulmonary inflammation. In addition, neonatal hyperoxia promoted allergic Th responses to HDM exposure. Elevated IL-33 levels and ILC2 responses were observed in the lungs most likely due to oxidative stress caused by neonatal hyperoxia. IL-33 receptor signaling and ILC2s were vital for the induction of asthma-like features following neonatal hyperoxia. Serum IL-33 levels correlated significantly with serum levels of IL-5 and IL-13, but not IL-4 in preterm infants.ConclusionThese data demonstrate that an axis involving IL-33 and ILC2s is important for the development of asthma-like features following neonatal hyperoxia and suggest therapeutic potential for targeting IL-33, ILC2s, and oxidative stress to prevent and/or treat asthma development related to prematurity.



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Early prelingual auditory development in Italian infants and toddlers analysed through the Italian version of the Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS)

Abstract

Purpose

To evaluate the reliability and validity of the Italian version of the Infant-Toddler Meaningful Auditory Integration Scale (I-IT-MAIS), and to assess the normal trajectory of early prelingual auditory (EPLAD) development from birth to 24 months in a group of normal-hearing Italian children using the I-IT-MAIS.

Methods

The study consisted of four phases: item generation, reliability analysis, assessment of the normal trajectory for EPLAD, and validity analysis. A group of 120 normal-hearing children and a group of 31 deaf children wearing hearing aids and on a waiting list for cochlear implantation were enrolled. All the parents completed the I-IT-MAIS. Sixty of them completed the I-IT-MAIS twice, 2 weeks apart, for test–retest reliability analysis. The I-IT-MAIS scores were used to assess the normal trajectory of EPLAD development from birth to 24 months in normal-hearing children. For criterion validity analysis, the I-IT-MAIS scores were correlated with production of infant scale evaluation (PRISE) scores in 60 normal-hearing children. For discriminant validity analysis, the I-IT-MAIS scores obtained in normal and deaf children were compared.

Results

Internal consistency of I-IT-MAIS was satisfactory as well as individual item reliability, test–retest reliability, and discriminant validity. EPLAD development in normal-hearing Italian-speaking children was evaluated. As far as the criterion validity of the I-IT-MAIS is concerned, a strong correlation between I-IT-MAIS and PRISE scores was found.

Conclusion

I-IT-MAIS is reliable and valid. Its application is recommended for clinical practice and outcome research.

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Down-regulation of inflammatory signaling pathways despite up-regulation of Toll-like receptors; the effects of corticosteroid therapy in brain-dead kidney donors, a double-blind, randomized, controlled trial

Publication date: February 2018
Source:Molecular Immunology, Volume 94
Author(s): Reza Jafari, Reza Aflatoonian, Reza Falak, Gholamreza Pourmand, Sanaz Dehghani, Mojgan Mortazavi, Adeleh Adelipour, Abbas Rezaei, Nader Tajik
BackgroundThe brain death of a potential organ donor induces a systemic inflammatory response, resulting in inferior organ quality and function. Our study aimed to evaluate the effects of methylprednisolone (MPN) therapy on pattern recognition receptor (PRR) signaling in potential brain-dead (BD) kidney donors.Material and methodsTo evaluate the effects of MPN therapy on PRR signaling in BD kidney donors we performed a prospective randomized treatment-versus-control study. Fifty-one potential kidney donors were randomly divided into three groups: brain-dead donors (BDDs) who received 15 mg/kg/d of methylprednisolone (group T1, n = 17), BDDs who received 15 mg/kg/d of MPN at the time of filling consent for kidney donation and 100 mg/2 h until kidney harvest (group T2, n = 17), and normal donors as controls n = 17. Gene expression for Toll-like receptors (TLRs) 1–9 and their signaling pathway molecules including MYD88, TRIF, NF-KB1, IRAK, IRF3, and IRF7, as well as the inflammatory cytokines RANTES, IL-1β, TNF-α, IL-6, CXCL8, IL-18, IFN-α, and IFN-β was determined by PCR array. Due to the crucial role of TLRs 2 and 4 in pattern recognition, surface expression of these molecules was analyzed by flow cytometry. Plasma levels of inflammatory cytokines were measured by immunoassay. Finally, serum creatinine and cystatin C were measured in 100 kidney recipients one week and one, three, and six months after transplant.ResultPolymerase chain reaction (PCR) array gene expression revealed greater expression of TLRs and signaling molecules in group T1 than in the controls. Surface expression of TLRs 2 and 4 were significantly greater in group T2 than in group T1 (P < .05). Plasma concentrations of inflammatory cytokines were significantly greater in group T1 than in controls (P < .05). The recipients that received kidneys from group T1 had significantly higher levels of creatinine and cystatin C than the recipients of kidneys from both group T1 and controls (P<0.05).ConclusionAdministration of MPN to BDDs at specified periods until kidney harvest resulted in less systemic inflammation in the BDDs and improved renal function in kidney graft recipients compared with common MPN therapy.



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Loxosceles venom Sphingomyelinase D activates human blood leukocytes: Role of the complement system

Publication date: February 2018
Source:Molecular Immunology, Volume 94
Author(s): Daniel Manzoni-de-Almeida, Carla Cristina Squaiella-Baptistão, Priscila Hess Lopes, Carmen W. van den Berg, Denise V. Tambourgi
Envenomation by Loxosceles spiders can result in severe systemic and local reactions, which are mainly triggered by Sphingomyelinase D (SMase D), a toxic component of Loxosceles venom. SMase D induces a systemic inflammatory condition similar to the reaction observed during an endotoxic shock. Considering the potent pro-inflammatory potential of Loxosceles venom and the SMase D, in this study we have used the whole human blood model to study the endotoxic-like shock triggered by SMase D. Recombinant purified SMase D from L. intermedia venom, similarly to LPS, induced activation of blood leukocytes, as observed by the increase in the expression of CD11b and TLR4, production of reactive oxygen and nitrogen species (superoxide anion and peroxynitrite) and release of TNF-α. Complement consumption in the plasma was also detected, and complement inhibition by compstatin decreased the SMase D and LPS-induced leukocyte activation, as demonstrated by a reduction in the expression of CD11b and TLR4 and superoxide anion production. Similar results were found for the L. intermedia venom, except for the production of TNF-α. These findings indicate that SMase D present in Loxosceles venom is able to activate leukocytes in a partially complement-dependent manner, which can contribute to the systemic inflammation that follows envenomation by this spider. Thus, future therapeutic management of systemic Loxosceles envenomation could include the use of complement inhibitors as adjunct therapy.



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Outcomes Following Cordotomy by Coblation for Bilateral Vocal Fold Immobility.

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Outcomes Following Cordotomy by Coblation for Bilateral Vocal Fold Immobility.

JAMA Otolaryngol Head Neck Surg. 2017 Dec 14;:

Authors: Benninger MS, Xiao R, Osborne K, Bryson PC

Abstract
Importance: Bilateral vocal fold immobility (BVFI) can result in considerable voice and airway impairment. Although the carbon dioxide (CO2) laser is commonly used in transverse cordotomy, the coblator, a minimally invasive, low-thermal technology, has been increasingly used in otolaryngology.
Objective: To investigate outcomes associated with coblation to treat BVFI.
Design, Setting, and Participants: A retrospective case series was conducted between January 2012 and June 2017 including 19 patients with BVFI who underwent cordotomy by coblation in a single tertiary care institution.
Main Outcomes and Measures: Clinical, operative, and health status data for all patients were reviewed. Quality of life was measured by the EuroQol 5-Dimensions (EQ-5D), and the Voice Handicap Index (VHI) was used to measure vocal cord function.
Results: Nineteen patients were eligible for inclusion, 15 of which underwent cordotomy by coblation for BVFI without stenosis. Mean age was 57 years with 13 (68%) women. The etiology of BVFI included thyroidectomy in 8 (42%) patients and prolonged intubation in 7 (37%). Mean length of surgery for BVFI without stenosis was 17 minutes; mean operating room (OR) time was 63 minutes compared with 88 scheduled OR minutes (effect size, 25 minutes; 95% CI, 9 to 40 minutes). During follow-up, 4 (27%) of these patients developed granulation tissue postoperatively. Following surgery, patient-reported shortness of breath significantly improved, with 10 of 14 (71%; 95% CI, 45% to 88%) patients with some level of preoperative breathing difficulty experiencing improvement in their breathing. Stridor also significantly improved, with 10 of 12 (83%; 95% CI, 55% to 95%) patients with some level of preoperative stridor improved after surgery. The EQ-5D results trended toward improvement postoperatively (0.67 to 0.80; effect size, 0.13; 95% CI, -0.10 to 0.34). The functional (22 to 12; effect size, -10; 95% CI, -19 to -2), emotional (23 to 11; effect size, -12; 95% CI, -23 to -3), and total VHI all significantly improved (68 to 39; effect size, -29; 95% CI, -49 to -8).
Conclusions and Relevance: Initial outcomes of cordotomy by coblation revealed that this technique was a safe and efficient approach to treating BVFI. Coblation was associated with significant reduction in OR time compared with scheduled time, and patients experienced significant improvement in shortness of breath, stridor, and vocal cord function.

PMID: 29242922 [PubMed - as supplied by publisher]

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Cerebrospinal Fluid Rhinorrhea and a Lytic-Appearing Lesion of the Posterior Cranial Fossa.

Related Articles

Cerebrospinal Fluid Rhinorrhea and a Lytic-Appearing Lesion of the Posterior Cranial Fossa.

JAMA Otolaryngol Head Neck Surg. 2017 Dec 14;:

Authors: Mehta K, Naples J, Eisen M

PMID: 29242910 [PubMed - as supplied by publisher]

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Fever with lymphadenopathy – Kikuchi Fujimoto disease, a great masquerader: a case report

Kikuchi Fujimoto disease is an uncommon benign condition of necrotizing histiocytic lymphadenitis commonly seen in East Asian and Japanese populations. It commonly presents with fever, cervical lymphadenopathy...

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Biologic treatment sequences for plaque psoriasis: a cost-utility analysis based on 10 years of Dutch real-world evidence from BioCAPTURE

Abstract

Background

Treatment with biologics may be indicated for patients with moderate to severe plaque psoriasis, but comparative evidence on cost-effectiveness is limited. Switching of biologics is common, but it is unclear what the effect is of differences in sequences of biologics.

Objective

Evaluate the cost-effectiveness of different biologic treatment sequences for psoriasis based on real-world evidence.

Methods

A sequence model was developed to evaluate the costs and health effects of three consecutive lines of biologic treatments (for example adalimumab-etanercept-ustekinumab versus etanercept-ustekinumab-adalimumab) over a 10-year time horizon in the Netherlands. The model was populated with data from the Dutch BioCAPTURE registry and scientific literature. Analyses were conducted of cost per quality-adjusted life year (QALY) and uncertainty was addressed by probabilistic as well as scenario analyses.

Results

Treatment of psoriasis with biologics for a 10-year period was estimated to be associated with a cost of € 141,962 to € 148,442 per patient depending on the treatment sequence used. Cumulative health effects ranged from 7.79 to 8.03 QALYs. Starting with adalimumab or ustekinumab seems favourable concerning cost and utilities compared to strategies starting with etanercept, though credible intervals were partly overlapping.

Conclusions

The order in which biologics are used influences treatment cost-effectiveness, both in terms of costs and health effects. Initiation of a biologic treatment sequence for psoriasis may best be done with adalimumab or ustekinumab; etanercept seems less optimal from a health-economic perspective.

This article is protected by copyright. All rights reserved.

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The prevalence of antibody responses against Staphylococcus aureus antigens in patients with atopic dermatitis: a systematic review and meta-analysis

Abstract

Staphylococcus (S.) aureus plays a role in the pathogenesis of atopic dermatitis (AD), possibly via the expression of various virulence antigens. An altered antibody response towards these antigens might contribute to inflammation. We aimed to provide an overview of the varying prevalences and odds of antibody responses against S. aureus antigens in AD patients. Data were systematically obtained from Embase, Medline, Web of Science, Scopus, Cochrane, PubMed and Google Scholar (up to February 12^th 2016). We selected all original observational and experimental studies assessing anti-staphylococcal antibodies in serum of AD patients. Prevalences and odds ratios (ORs) of immunoglobulin (Ig) E, IgG, IgM, IgA against S. aureus in AD patients versus healthy controls were pooled using the random-effects model. We calculated I² statistics to assess heterogeneity and rated study quality using the Newcastle-Ottawa Scale. Twenty-six articles (2369 patients) were included of which 10 controlled studies. Study quality was fair to poor. AD patients had higher prevalences of IgE against staphylococcal enterotoxin (SE) A (OR 8.37, 95% CI 2.93-23.92) and SEB (OR 9.34, 95% CI 3.54-24.93) compared to controls. Prevalences of anti-staphylococcal IgE were 33% for SEA, 35% for SEB and 16% for toxic shock syndrome toxin (TSST)-1. However, study heterogeneity and imprecision should be taken into consideration when interpreting the results. Data on IgG, IgM and IgA as well as other antigens are limited. In conclusion, AD patients more often show an IgE antibody response directed against S. aureus superantigens compared to healthy controls supporting a role for S. aureus in the AD pathogenesis.

This article is protected by copyright. All rights reserved.

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La spongiose à éosinophiles

Publication date: Available online 15 December 2017
Source:Annales de Dermatologie et de Vénéréologie
Author(s): C. Lepelletier, M.-D. Vignon-Pennamen, M. Battistella




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What you should know about laser hair removal versus electrolysis

A look at laser hair removal versus electrolysis. Included is detail on how the procedures differ. ADD MORE ADD MORE ADD MORE ADD MORE ADD MORE

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Influence of tumor and microenvironment characteristics on diffusion-weighted imaging in oropharyngeal carcinoma: A pilot study

Publication date: February 2018
Source:Oral Oncology, Volume 77
Author(s): Justin E. Swartz, Juliette P. Driessen, Pauline M.W. van Kempen, Remco de Bree, Luuk M. Janssen, Frank A. Pameijer, Chris H.J. Terhaard, Marielle E.P. Philippens, Stefan Willems
ObjectivesDiffusion weighted imaging (DWI) is a frequently performed MRI sequence in cancer patients. While previous studies have shown the clinical value of the apparent diffusion coefficient (ADC) for response prediction and response monitoring, less is known about the biological background of ADC. In the tumor microenvironment, hypoxia and increased proliferation of tumor cells contribute to resistance to (radio-)therapy, while high T-cell influx is related to better prognosis. We investigated the correlation between these three tissue characteristics and ADC in 20 oropharyngeal squamous cell carcinoma patients.Materials and methods20 patients with oropharyngeal squamous cell carcinoma (OPSCC) who underwent 1.5 T MRI, including DWI were included in this pilot study. Corresponding formalin-fixed paraffin-embedded tumor tissues were immunohistochemically analyzed for protein expression of hypoxia-inducible factor 1a (HIF-1a), Ki-67 and CD3. Expression of these markers was correlated with ADC.ResultsADC negatively correlated with Ki-67 expression (p = .024) in tumor cells. There was a significant negative correlation between ADC and CD3-positive cell count (p = .009). No correlation was observed between HIF-1a expression and ADC.ConclusionThis study suggests that ADC reflects characteristics of tumor cells as well as the surrounding microenvironment. Interestingly, high tumor proliferation (a negative prognostic factor) and high T-cell influx (a beneficial prognostic factor) are both associated with a lower ADC. Further studies should be performed to correlate ADC to these histological characteristics in relation to previously known factors that affect ADC, to gain further knowledge on the role of DW-MRI in diagnostics and personalized medicine.



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Treatment outcomes of nasopharyngeal carcinoma in modern era after intensity modulated radiotherapy (IMRT) in Hong Kong: A report of 3328 patients (HKNPCSG 1301 study)

Publication date: February 2018
Source:Oral Oncology, Volume 77
Author(s): K.H. Au, Roger K.C. Ngan, Alice W.Y. Ng, Darren M.C. Poon, W.T. Ng, K.T. Yuen, Victor H.F. Lee, Stewart Y. Tung, Anthony T.C. Chan, Henry C.K. Sze, Ashley C.K. Cheng, Anne W.M. Lee, Dora L.W. Kwong, Anthony H.P. Tam
PurposeTo evaluate treatment outcomes, failure patterns and late toxicities in patients with nasopharyngeal carcinoma (NPC) treated by intensity modulated radiotherapy (IMRT) in 6 public hospitals in Hong Kong over a 10-year period from 2001 to 2010.Material and methodsEligible patients were identified through the Hong Kong Cancer Registry data base. Clinical information was retrieved and verified by oncologists working in the individual centers. Treatment details, survival outcomes and late toxicities were analyzed.ResultsA total of 3328 patients were recruited. The median follow-up time was 80.2 months. The 8-year actuarial overall survival (OS), local failure-free survival (LFFS), regional failure-free survival (RFFS), distant failure free survival (DFFS), progression-free survival (PFS) for the whole group was 68.5%, 85.8%, 91.5%, 81.5% and 62.6% respectively. Male gender, older age, advanced T and N stage were adverse prognostic factors for OS, DFFS and PFS, whereas use of chemotherapy in form of concurrent chemo-irradiation (CRT), neoadjuvant + CRT, or CRT + adjuvant chemotherapy were favorable prognostic factors for OS and PFS. The local control was adversely affected by advanced T stage. N stage remained as the single adverse prognostic factor for regional control. Distant metastasis was the commonest site of failure.ConclusionIMRT is an effective treatment for NPC with excellent overall loco-regional control. Distant metastasis is the major site of failure. Concurrent chemotherapy with cisplatin has an established role in NPC patients treated by IMRT.



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Venous thromboembolism incidence in head and neck surgery patients: Analysis of the Veterans Affairs Surgical Quality Improvement Program (VASQIP) database

Publication date: February 2018
Source:Oral Oncology, Volume 77
Author(s): Alia Mowery, Tyler Light, Daniel Clayburgh
ObjectiveVenous thromboembolism (VTE) may cause significant postoperative morbidity and mortality; research in other surgical fields suggests an elevated VTE risk persists up to 30 days after surgery, beyond hospital discharge. We performed a review of the Veteran's Affairs Surgical Quality Improvement Project (VASQIP) database to determine the 30-day incidence of VTE following head and neck surgery and assess the proportion of VTE that occur post-discharge.Materials and methodsA retrospective review was performed of all head and neck ablative procedures captured in the VASQIP database between 1991 and 2015. Post-operative VTE incidence was determined and the relationship of pre-operative data and post-operative mortality to VTE incidence was assessed.Results48,986 patients were included in the study; there were 152 VTE events (0.31%) and 39 (25.7%) occurred post-discharge. Lower VTE rates were found in parotidectomies (0.22%) and thyroid/parathyroid cases (0.23%), and higher rates in free flap (1.52%) and laryngectomy cases (0.69%). Age >70, recent weight loss, low serum albumin, and increased surgical time were all associated with increased VTE incidence on multivariate analysis. 90-day mortality in patients without VTE was 2.1% compared to 19.7% in patients who experienced a VTE.ConclusionWhile the documented rate of VTE in a national dataset is relatively low following head and neck surgeries, it is elevated with certain procedure categories and following long operations, and a significant proportion of VTE occur post-discharge. This study provides baseline data to better inform efforts to risk-stratify and customize thromboprophylaxis for patients undergoing head and neck procedures.



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Nanomedicine, an emerging therapeutic strategy for oral cancer therapy

Publication date: January 2018
Source:Oral Oncology, Volume 76
Author(s): Sabrina Marcazzan, Elena Maria Varoni, Elvin Blanco, Giovanni Lodi, Mauro Ferrari
Oral cavity and oropharyngeal carcinomas (oral cancer) represents a significant cause of morbidity and mortality. Despite efforts in improving early diagnosis and treatment, the 5-year survival rate of advanced stage of the disease is less than 63%. The field of nanomedicine has offered promising diagnostic and therapeutic advances in cancer. Indeed, several platforms have been clinically approved for cancer therapy, while other promising systems are undergoing exploration in clinical trials. With its ability to deliver drugs, nucleic acids, and MRI contrast agents with high efficiency, nanomedicine platforms offer the potential to improve drug efficacy and tolerability. The aim of the present mini-review is to summarize the current preclinical status of nanotechnology systems for oral cancer therapy. The nanoplatforms for delivery of chemopreventive agents presented herein resulted in significantly higher anti-tumor activity than free forms of the drug, even against a chemo-resistant cell line. Impressive results have also been obtained using nanoparticles to deliver chemotherapeutics, resulting in reduced toxicity both in vitro and in vivo. Nanoparticles have also led to improvements in efficacy of photodynamic therapies through the development of targeted magnetic nanoparticles. Finally, gene therapy using nanoparticles demonstrated promising results specifically with regards to inhibition of gene expression. Of the few in vivo studies that have been reported, many of these used animal models with several limitations, which will be discussed herein. Lastly, we will discuss several future perspectives in oral cancer nanoparticle-based therapy and the development of appropriate animal models, distinguishing between oral cavity and oropharyngeal carcinoma.



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Differences in incidence and survival of oral cavity and pharyngeal cancers between Germany and the United States depend on the HPV-association of the cancer site

Publication date: January 2018
Source:Oral Oncology, Volume 76
Author(s): L. Jansen, N. Buttmann-Schweiger, S. Listl, M. Ressing, B. Holleczek, A. Katalinic, S. Luttmann, K. Kraywinkel, H. Brenner
IntroductionThe epidemiology of squamous cell oral cavity and pharyngeal cancers (OCPC) has changed rapidly during the last years, possibly due to an increase of human papilloma virus (HPV) positive tumors and successes in tobacco prevention. Here, we compare incidence and survival of OCPC by HPV-relation of the site in Germany and the United States (US).Materials and methodsAge-standardized and age-specific incidence and 5-year relative survival was estimated using data from population-based cancer registries in Germany and the US Surveillance Epidemiology and End Results (SEER) 13 database. Incidence was estimated for each year between 1999 and 2013. Relative survival for 2002–2005, 2006–2009, and 2010–2013 was estimated using period analysis.ResultsThe datasets included 52,787 and 48,861 cases with OCPC diagnosis between 1997 and 2013 in Germany and the US. Incidence was much higher in Germany compared to the US for HPV-unrelated OCPC and more recently also for HPV-related OCPC in women. Five-year relative survival differences between Germany and the US were small for HPV-unrelated OCPC. For HPV-related OCPC, men had higher survival in the US (62.1%) than in Germany (45.4%) in 2010–2013. These differences increased over time and were largest in younger patients and stage IV disease without metastasis. In contrast, women had comparable survival for HPV-related OCPC in both countries.ConclusionsStrong survival differences between Germany and the US were observed for HPV-related OCPC in men, which might be explained by differences in HPV-attributable proportions. Close monitoring of the epidemiology of OCPC in each country is needed.



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Compositional and functional variations of oral microbiota associated with the mutational changes in oral cancer

Publication date: February 2018
Source:Oral Oncology, Volume 77
Author(s): Shun-Fa Yang, Hsien-Da Huang, Wen-Lang Fan, Yuh-Jyh Jong, Mu-Kuan Chen, Chien-Ning Huang, Chun-Yi Chuang, Yu-Lun Kuo, Wen-Hung Chung, Shih-Chi Su
ObjectivesBoth genetic and environmental factors are conceivably required to assess the prognosis of oral squamous cell carcinoma (OSCC), yet little is known regarding the relationship between oral microbiome and the mutational spectrum of OSCC.Materials and methodsHere, we used 16S rRNA amplicon sequencing to study the composition of oral microorganisms in OSCC patients, whose cancer mutational profiles were previously defined by whole-exome sequencing, to evaluate the relationship between oral microbiome and the mutational changes in OSCC.ResultsAnalyzing the contributions of the five mutational signatures extracted from the primary tumors revealed three groups of OSCC (mutational signature cluster, MSC1-3) that were significantly associated with demographic and clinical features. Taxonomic analysis of the predominant phyla in salivary samples showed variation in the relative abundance of Firmicutes and Bacteroidetes in the three MSC groups. In addition, significant differences in bacterial species richness (alpha diversity) and slight sample-to-sample dissimilarities in bacterial community structures (beta diversity) were noted among different MSC groups. Further, predicting the functional capabilities of microbial communities by reconstruction of unobserved states showed that many pathways related to cell motility were differentially enriched among the three MSC groups.ConclusionCollectively, these results indicate a potential association of oral microbiome with the mutational changes in OSCC.



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Pre-Radiation dental considerations and management for head and neck cancer patients

Publication date: January 2018
Source:Oral Oncology, Volume 76
Author(s): Kenneth Kufta, Michael Forman, Samuel Swisher-McClure, Thomas P. Sollecito, Neeraj Panchal
Treatment of head and neck cancer (HNC) is accompanied by a high rate of morbidity, and complications can have a lifelong, profound impact on both patients and caregivers. Radiation-related injury to the hard and soft tissue of the head and neck can significantly decrease patients' quality of life. The purpose of this study is to provide patent-specific guidelines for managing the oral health and related side effects of HNC patients treated with radiation therapy.Based on reviewed articles retrieved on the PubMed database, guidelines for management of the oral health of this patient population were organized into three separate categories: cancer, patient, and dentition. The location, type, and staging of the cancer, along with the radiation used to treat the cancer significantly impact dental treatment. Several unique patient characteristics such as motivation, presence of support system, socioeconomic status, nutrition, and race have all been found to affect outcomes. Dental disease and available supportive dental management was found to significantly impact treatment and quality of life in this patient population.By comprehensively assessing unique cancer, patient, and dental-related factors, this review provides individualized evidence-based guidelines on the proper management of this complex and vulnerable patient population.



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Optimising volumetric arc radiotherapy for dental rehabilitation in oropharynx cancer – A retrospective dosimetry review and feasibility planning study

Publication date: January 2018
Source:Oral Oncology, Volume 76
Author(s): Sean M. O'Cathail, Naveen Karir, Ketan Shah
PurposeTo assess the dosimetry to dentally relevant substructures within the mandible/maxilla, establish the predictors of increased mean anterior mandible dose and assess the feasibility of rationale optimisation of dose to the anterior mandible (AM) volume to aid reconstructive dental surgery planning, where the AM is a critical structure.Materials and methodsIn a cohort of radically treated oropharynx cancer patients we conducted a retrospective dosimetry analysis of mandible/maxilla volumes, created using a published atlas. Comparisons of mean AM dose and clinical parameters between groups were tested using Wilcoxon rank-sum and Kruskal-Wallis tests. A multivariate linear regression model was created to assess independent predictors of increased mean AM dose. Patients with a mean AM dose over 37.5 Gy were included in feasibility planning study to test the hypothesis that it is possible to safely limit the dose whilst maintaining dose tolerances for other organs at risk.Results57 patients were included. Median AM mean dose was 32.2 Gy (IQR 27.7–38.7). T stage, N stage and inclusion of Level 1B were significantly associated with increased mean AM dose. Only T stage (p = .0132) and Level Ib inclusion (p = .018) remained significant in the linear regression model. 88% of plans, all of which included Level Ib, were successfully re-optimised without breaching accepted constraints.ConclusionsOropharynx cancer patients with advanced T stage and who require Level Ib treatment receive increased mean AM dose, potentially limiting surgical dental rehabilitation options. The majority of patients can be optimised safely with appropriate AM contouring.



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Altered fractionation radiotherapy combined with concurrent low-dose or high-dose cisplatin in head and neck cancer: A systematic review of literature and meta-analysis

Publication date: January 2018
Source:Oral Oncology, Volume 76
Author(s): Petr Szturz, Kristien Wouters, Naomi Kiyota, Makoto Tahara, Kumar Prabhash, Vanita Noronha, David Adelstein, Jan B. Vermorken
ObjectivesAltered fractionation radiotherapy and concomitant chemoradiotherapy represent commonly used intensification strategies in the management of locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). This meta-analysis compares compliance, safety, and efficacy between two single-agent cisplatin schedules given concurrently with altered fractionation radiotherapy.MethodsWe systematically searched for prospective trials of patients with LA-SCCHN who received post-operative or definitive altered fractionation concurrent chemoradiotherapy. High-dose cisplatin once every three to four weeks (100 mg/m², 2 doses) was compared with a weekly low-dose protocol (≤50 mg/m², ≥4 doses). The primary outcome was overall survival. The secondary endpoints comprised treatment adherence, acute and late toxicities, and objective response rate.ResultsTwelve studies with 1373 patients treated with definitive chemoradiotherapy were included. Compared to the weekly low-dose cisplatin regimen, the three- to four-weekly high-dose cisplatin regimen improved overall survival (p=.0185), was more compliant with respect to receiving all planned cycles of cisplatin (71% versus 95%, p=.0353), and demonstrated less complications in terms of severe (grade 3—4) acute mucositis and/or stomatitis (75% versus 40%, p=.0202) and constipation (8% versus 1%, p=.0066), toxic deaths (4%, versus 1%, p=.0168), 30-day mortality (8% versus 3%, p=.0154), and severe late subcutaneous fibrosis (21% versus 2%, p<.0001). Overall and complete response rates were similar between both chemotherapy schedules.ConclusionIn chemoradiotherapy incorporating altered fractionation, two cycles of high-dose cisplatin with a three to four week interval are superior to weekly low-dose schedules. Further studies should identify those who might derive the greatest benefit from this intensified approach.



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RACK1 is an organ-specific prognostic predictor in OSCC

Publication date: January 2018
Source:Oral Oncology, Volume 76
Author(s): Sai Liu, JiaJia Liu, Jiongke Wang, Junxin Cheng, Xin Zeng, Ning Ji, Jing Li, Qianming Chen
ObjectivesThis study aims to verify that RACK1 is an organ-specific prognostic predictor in patients with oral squamous cell carcinoma (OSCC).Experimental designThe RACK1 expression level was assessed by immunohistochemistry (IHC) in a total of 342 OSCC patients from 3 independent cohorts. The multivariate hazard ratios for Overall Survival (OS) was determined by Cox proportional hazards regression model. OS was analyzed in 460 Head Neck Squamous Cell Carcinoma (HNSCC) patients from TCGA data set. The expression level of RACK1 was analyzed in 60 cases multiple organ tissue microarrays representing both normal and cancer tissues by IHC, and in TCGA database of mRNA abundance in cancers and paired normal tissues.ResultsThe median follow-up times of patients in the study was 74, 52, and 78 months. High expression of RACK1 was identified in tumors from 103 of 151 patients (68.2%), 51 of 83 patients (61.4%), and 59 of 108 patients (54.6%). Compared with low expression, high expression of RACK1 was strongly associated with worse OS, with HR of 0.5995 (95% CI, 0.3929 to 0.9147; P=0.0176), 0.4402 (95% CI, 0.2321 to 0.8348; P=0.0120), and 0.5010 (95% CI, 0.2886 to 0.8699; P=0.0141). This finding is consistent with TCGA HNSCC data (P=0.0276). Tissue microarrays analyses showed different protein expression level of RACK1 in multiple human carcinomas and this finding is consistent with the TCGA database analysis of RACK1 mRNA abundance.ConclusionOur findings demonstrated that RACK1 is a good independent organ-specific predictor of the risk of death in OSCC.



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Benzethonium chloride activates ER stress and reduces proliferation in HNSCC

Publication date: January 2018
Source:Oral Oncology, Volume 76
Author(s): Hani M. Rayess, Yue Xi, Danielle M. Garshott, Amy L. Brownell, George H. Yoo, Michael U. Callaghan, Andrew M. Fribley




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Erratum to “Reconstruction design before tumour resection: A new concept of through-and-through cheek defect reconstruction” [Oral Oncol. 74 (2017) 123–129]

Publication date: Available online 24 November 2017
Source:Oral Oncology
Author(s): Zhao-Jian Gong, Zhen-Hu Ren, Kai Wang, Hong-Yu Tan, Sheng Zhang, Han-Jiang Wu




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Suggestions for surveillance and radiation strategy in nasopharyngeal carcinoma treated with IMRT: Based on hazard-rate and patterns of recurrence

Publication date: January 2018
Source:Oral Oncology, Volume 76
Author(s): Tingting Xu, Xin Zhou, Chunying Shen, Chaosu Hu
ObjectiveThe study was designed to appraise the locoregional recurrence patterns using conventional two-dimensional radiotherapy (2D-RT) and intensity modulated radiation therapy (IMRT) in nasopharyngeal carcinoma (NPC) in order to better establish the scenario of the modern radiotherapy and the duration of surveillance.Materials and MethodsWe reviewed the institutional database to identify patients with pathologically confirmed, non-metastatic NPC who completed radical 2D-RT or IMRT at our center from 2000 to 2011. We collected data on clinicopathologic features, treatments and outcomes. Statistical analyses were performed using SPSS 20.0 or STATASE 14.0.ResultsThe median follow-up was 60.1 months. Of 2315 patients, 1289 (53%) were treated with 2D-RT and 1026 (47%) with IMRT. IMRT group achieved better locoregional control rate, with the 5-year locoregional relapse-free survival (LRRFS) were 84.9% and 87.7% among patients received 2D-RT and IMRT, respectively (P = 0.050). IMRT was superior to 2D technique in terms of local relapse-free survival (LRFS) (88.4% vs 91.1%, P = 0.047) and the advantage was only significant in T3-4 subgroup (81.6% vs 90.2%, P = 0.000). Similar neck control rates were observed using different RT techniques. And the recurrence time appeared to be postponed by IMRT, with peaks accounting for the year 1.5 and year 3–4 compared to which was predominant at the first two years using 2D-RT in nature.ConclusionsIMRT provided an improved LRRFS in overall stage and LRFS in advanced T stage for NPC compared with 2D-RT. Annual hazard of recurrence also changed with RT techniques.



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Editorial Board/Aims & Scope

Publication date: December 2017
Source:Oral Oncology, Volume 75





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Definitive (chemo)radiotherapy is a curative alternative for standard of care in advanced stage squamous cell carcinoma of the oral cavity

Publication date: December 2017
Source:Oral Oncology, Volume 75
Author(s): Joris B.W. Elbers, Abrahim Al-Mamgani, Danique Paping, Michiel W.M. van den Brekel, Katarzyna Jóźwiak, J.P. de Boer, Baris Karakullukcu, Marcel Verheij, Charlotte L. Zuur
ObjectiveTo compare outcome after definitive (chemo)radiotherapy (CRT group) with standard of care (surgery group) for advanced stage oral cavity carcinoma (OCC). Although definitive (chemo)radiotherapy is assumed to be inferior to surgery with regard to disease control, data on outcome of this approach are scarce.MethodsRetrospective analysis by chart review (2000–2013). Endpoints were locoregional control (LRC), disease-free survival (DFS), disease specific survival (DSS) and overall survival (OS).ResultsBetween the CRT-group (n = 100) and Surgery-group (n = 109), baseline characteristics were equally distributed except stage and local tumor diameter (all p ≤ .001). In the CRT group, at 5 years the LRC rate was 49%, DFS 22%, DSS 39% and OS 22%. In the surgery group, at 5 years the LRC rate was 77%, DFS 45%, DSS 64% and OS 45%. The survival curves of the two groups significantly differed for LRC (p < .001), DFS and DSS (p = .001) and OS (p = .002). After adjusting for confounders and prognostic factors, we found a significant difference between the treatment groups in LRC (adjusted HR = 2.88, 95%CI 1.35–6.16, p = .006). Within 100 days, 5 patients (5%) died from treatment-related toxicity in CRT group and 1 patient after surgery (p = .21).ConclusionsAlthough surgery with adjuvant radiotherapy for advanced stage OCC results in favorable locoregional control, definitive (chemo)radiotherapy is a curative alternative in patients often considered beyond cure and should be considered when surgery is not feasible.



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Reconstruction Special Edition, Issue 2

Publication date: December 2017
Source:Oral Oncology, Volume 75
Author(s): Matthew Old




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Pre-diagnostic dynamic HPV16 IgG seropositivity and risk of oropharyngeal cancer: Methodological issues

Publication date: Available online 22 November 2017
Source:Oral Oncology
Author(s): Erfan Ayubi, Saeid Safiri




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Psoriasis and risk of malignant lymphoma: A population-based cohort study

Abstract

In patients with psoriasis, the risk of lymphoma has been a subject of controversy and data from larger studies are limited^1-4. We therefore investigated the 5-year risk of new-onset Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) (excluding cutaneous T-cell lymphoma [CTCL]), and CTCL, respectively, in patients with psoriasis.

This article is protected by copyright. All rights reserved.

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Dermatologists across Europe underestimate depression and anxiety: results from 3635 dermatological consultations

Abstract

Background

It was recently demonstrated that a significant number of patients with common skin diseases across Europe are clinically depressed and anxious. Studies have shown that physicians not trained as psychiatrist underdiagnose depression. This has not been explored among dermatologists.

Objectives

To estimate the concordance between clinical assessment of depression and anxiety by a dermatologist and assessment with the Hospital Anxiety and Depression Scale.

Methods

The study was an observational cross-sectional multi-centre study of prevalent cases of skin diseases in 13 countries in Europe. Consecutive patients were recruited in out-patient clinics and filled in questionnaires prior to clinical examination by a dermatologist who reported any diagnosis of skin disease and signs of mood disorders.

Results

Analysis of the 3635 consultations showed that the agreement between dermatologist and HADS was poor to fair (lower than 0.4) for all diagnose categories. The true positive rate (represented by the percentage of dermatologists recognizing signs of depression or anxiety in depressed or anxious patients defined by HADS-value >=11) was 44.0% for depression and 35.6% for anxiety. The true negative rate (represented by the percentage of dermatologists not detecting signs of depression or anxiety in non-depressed or non-anxious patients defined byHADS-value < 11) was 56.0% for depression and 64.4% for anxiety.

Conclusions

Dermatologists in Europe tend to underestimate mood disorders. The results point out that further training for dermatologists to improve their skills in diagnosing depression and anxiety might be appropriate. The psychological suffering of dermatological patients needs to be addressed when present.

This article is protected by copyright. All rights reserved.

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Clinicopathological characteristics of cutaneous malignant melanoma in patients at a tertiary hospital in Macaronesia. Survival as a function of locoregional prognostic factors per the American Joint Committee on Cancer

Abstract

Background

Despite suffering high ultraviolet radiation levels, few data on malignant melanoma (MM) in Macaronesia are available.

Methods

Observational study of cutaneous MM cases diagnosed during a period of 12 years at a tertiary hospital in Canary Islands.

Results

A total of 532 patients (female/male = 1.4) with an average age of 56 years were included; 5% developed more than one MM, and 7% reported family history of MM. Phototype II (43%), dark eyes (41%), and dark hair (41%) predominated. There was a lower frequency of light-colored hair and eyes in those born in the Canary Islands. The most frequent locations of MM were on the back for men (37%) and on the lower extremities for women (35%). Among the infiltrating tumors (83%), the (median) thickness was 1.07 mm (women, 0.90 mm; men, 1.21 mm). Anatomopathological ulceration (AU) and a mitotic rate ≥1 mitosis/mm² (HMR) were recorded in 27% of patients. Patients with regional disease constituted 12% of the population. The most common stage was IA (34%). Melanoma-specific survival (MSSV) decreased significantly with thickness, presence of AU, HMR, and sentinel lymph node disease. These four variables were independent prognostic factors. The five-year MSSV varied between 100% (stage IA) and 39% (stage IIIC).

Conclusions

The characteristics of the patients were similar to those published in datasets from continental Europe, although the pigmentary features were darker in those originating from Macaronesia. The prognostic parameters described in the 7th edition of the American Joint Committee on Cancer (AJCC) independently predict MSSV in our patients.

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Primary Cutaneous Rhabdomyosarcoma: an illustrative case of an uncommon neoplasm

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