Clinical grade manufacturing of genetically modified, CAR-expressing NK-92 cells for the treatment of ErbB2-positive malignancies

Abstract

Background

The NK-92/5.28.z cell line (also referred to as HER2.taNK) represents a stable, lentiviral-transduced clone of ErbB2 (HER2)-specific, second-generation CAR-expressing derivative of clinically applicable NK-92 cells. This study addresses manufacturing-related issues and aimed to develop a GMP-compliant protocol for the generation of NK-92/5.28.z therapeutic doses starting from a well-characterized GMP-compliant master cell bank.

Materials and methods

Commercially available GMP-grade culture media and supplements (fresh frozen plasma, platelet lysate) were evaluated for their ability to support expansion of NK-92/5.28.z. Irradiation sensitivity and cytokine release were also investigated.

Results

NK-92/5.28.z cells can be grown to clinically applicable cell doses of 5 × 10⁸ cells/L in a 5-day batch culture without loss of viability and potency. X-Vivo 10 containing recombinant transferrin supplemented with 5% FFP and 500 IU/mL IL-2 in VueLife 750-C1 bags showed the best results. Platelet lysate was less suited to support NK-92/5.28.z proliferation. Irradiation with 10 Gy completely abrogated NK-92/5.28.z proliferation and preserved viability and potency for at least 24 h. NK-92/5.28.z showed higher baseline cytokine release compared to NK-92, which was significantly increased upon encountering ErbB2(+) targets [GZMB (twofold), IFN-γ (fourfold), IL-8 (24-fold) and IL-10 (fivefold)]. IL-6 was not released by NK cells, but was observed in some stimulated targets. Irradiation resulted in upregulation of IL-8 and downregulation of sFasL, while other cytokines were not impacted.

Conclusion

Our concept suggests NK-92/5.28.z maintenance culture from which therapeutic doses up to 5 × 10⁹ cells can be expanded in 10 L within 5 days. This established process is feasible to analyze NK-92/5.28.z in phase I/II trials.

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Mucus plugging in allergic bronchopulmonary aspergillosis: Implication of the eosinophil DNA traps

Publication date: Available online 5 September 2017
Source:Allergology International
Author(s): Ayumi Omokawa, Shigeharu Ueki, Yuta Kikuchi, Masahide Takeda, Mariko Asano, Kazuhiro Sato, Masaaki Sano, Hiroshi Ito, Makoto Hirokawa




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Multiple Myeloma Presenting as Massive Amyloid Deposition in a Parathyroid Gland Associated with Amyloid Goiter: A Medullary Thyroid Carcinoma Mimic on Intra-operative Frozen Section

Abstract

Clinical examples of amyloid deposition in parathyroid glands are exceedingly rare and usually present as an incidental finding in a patient with amyloid goiter. Here, we present the first histologically documented case of parathyroid amyloid deposition that presented as a mass. The patient did not have hyperparathyroidism. The parathyroid gland was submitted for intra-operative frozen section and concern for medullary thyroid carcinoma was raised. An important histologic clue arguing against medullary thyroid carcinoma was the evenly dispersed nature of the amyloid. Histologic perinuclear clearing and parathyroid hormone immunohistochemistry confirmed parathyroid origin on permanent sections. The patient was also found to have associated amyloid goiter. Mass spectrometry of the amyloid showed it to be composed of kappa light chains. On further work-up, the patient was diagnosed with multiple myeloma. Awareness of parathyroid amyloid deposition is important as it is a histologic mimic of medullary thyroid carcinoma, especially on frozen section. Amyloid typing with evaluation for multiple myeloma in any patient with kappa or lambda light chain restriction is also important.

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Multiple Myeloma Presenting as Massive Amyloid Deposition in a Parathyroid Gland Associated with Amyloid Goiter: A Medullary Thyroid Carcinoma Mimic on Intra-operative Frozen Section

Abstract

Clinical examples of amyloid deposition in parathyroid glands are exceedingly rare and usually present as an incidental finding in a patient with amyloid goiter. Here, we present the first histologically documented case of parathyroid amyloid deposition that presented as a mass. The patient did not have hyperparathyroidism. The parathyroid gland was submitted for intra-operative frozen section and concern for medullary thyroid carcinoma was raised. An important histologic clue arguing against medullary thyroid carcinoma was the evenly dispersed nature of the amyloid. Histologic perinuclear clearing and parathyroid hormone immunohistochemistry confirmed parathyroid origin on permanent sections. The patient was also found to have associated amyloid goiter. Mass spectrometry of the amyloid showed it to be composed of kappa light chains. On further work-up, the patient was diagnosed with multiple myeloma. Awareness of parathyroid amyloid deposition is important as it is a histologic mimic of medullary thyroid carcinoma, especially on frozen section. Amyloid typing with evaluation for multiple myeloma in any patient with kappa or lambda light chain restriction is also important.

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Clinical Features of a Family with Multiple Endocrine Neoplasia Type 2A Caused by the D631Y RET Mutation

Thyroid , Vol. 0, No. 0.


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The Absence of HCV RNA and NS5A Protein in Peripheral Blood Mononuclear Cells Is a Prognostic Tool for Sustained Virological Response

Viral Immunology , Vol. 0, No. 0.


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Bile-stained amniotic fluid: a case report

Green-stained amniotic fluid does not always indicate that meconium was passed in utero.

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Ureter metastatic castration-resistant prostate cancer: a case report

In most cases, prostate cancer metastasizes to the lymph nodes, bone, and liver. In very rare cases, it metastasizes to the ureter. Due to the difficulty in making a preoperative diagnosis, ureteral metastasis...

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Is a slow-progression baked-milk protocol of oral immunotherapy always a safe option for children with cow's milk allergy? A randomized controlled trial

Abstract

Immunoglobulin-E mediated-cow's milk allergy (IgE-CMA) is the one of the most frequent IgE mediated-food allergy in children in industrialized countries and may cause life- threatening anaphylaxis. The natural history of CM IgE mediated food allergy is favorable for most children. However, the clinical outcome of CMA seems worse than previously described, with less chance of recovery after the age of 3¹.

This article is protected by copyright. All rights reserved.

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UTHealth ORL & Hurricane Harvey

Learn more.

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UTHealth ORL & Hurricane Harvey

Hurricane Harvey brought catastrophic flooding to the 6 million inhabitants of the greater Houston region. We are happy to report... Read the full article...

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Probiotics for the prevention of atopic dermatitis and other allergic diseases: What are the real facts?

Publication date: Available online 5 September 2017
Source:Alergologia Polska - Polish Journal of Allergology
Author(s): Magdalena Czarnecka-Operacz, Anna Sadowska-Przytocka
Atopic dermatitis (AD) is one of the most common inflammatory skin diseases diagnosed all over the world. The course of this complicated disease is chronic and relapsing and there have been many variants both endogenic and phenotypic already described and despite of our better understanding of AD we have no well "structured" therapeutical approach to many of our patients. Mainly because we do not understand it in an adequate way and complexity of treatment must be highly individualized. Recent studies suggest prevention of AD can be achieved through early intervention to protect the disturbed skin barrier. While the skin lesions are developed AD requires appropriate control of local and systemic immune activation for optimal management which obviously may cause the whole variety of adverse events. Therefore it seems that early intervention might improve long-term outcomes of AD and reduce the risk of development of systemic sensitization that leads to associated allergic/atopic diseases within the gastrointestinal and respiratory tract. For some time probiotics have been suggested as an intervention to prevent allergic diseases such as AD. Therefore besides many publications, a systematic review of randomized trials assessing the effect of any probiotics administered to pregnant women breast-feeding mothers, and/or infants have been analyzed in this review paper in order to state what is the "real truth" about this type of preventive approach.



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The Lipid Kinase PIKfyve Coordinates the Neutrophil Immune Response through the Activation of the Rac GTPase [INNATE IMMUNITY AND INFLAMMATION]

Neutrophils rapidly arrive at an infection site because of their unparalleled chemotactic ability, after which they unleash numerous attacks on pathogens through degranulation and reactive oxygen species (ROS) production, as well as by phagocytosis, which sequesters pathogens within phagosomes. Phagosomes then fuse with lysosomes and granules to kill the enclosed pathogens. A complex signaling network composed of kinases, GTPases, and lipids, such as phosphoinositides, helps to coordinate all of these processes. There are seven species of phosphoinositides that are interconverted by lipid kinases and phosphatases. PIKfyve is a lipid kinase that generates phosphatidylinositol-3,5-bisphosphate and, directly or indirectly, phosphatidylinositol-5-phosphate [PtdIns(5)P]. PIKfyve inactivation causes massive lysosome swelling, disrupts membrane recycling, and, in macrophages, blocks phagosome maturation. In this study, we explored for the first time, to our knowledge, the role of PIKfyve in human and mouse neutrophils. We show that PIKfyve inhibition in neutrophils does not affect granule morphology or degranulation, but it causes LAMP1⁺ lysosomes to engorge. Additionally, PIKfyve inactivation blocks phagosome–lysosome fusion in a manner that can be rescued, in part, with Ca²⁺ ionophores or agonists of TRPML1, a lysosomal Ca²⁺ channel. Strikingly, PIKfyve is necessary for chemotaxis, ROS production, and stimulation of the Rac GTPases, which control chemotaxis and ROS. This is consistent with observations in nonleukocytes that showed that PIKfyve and PtdIns(5)P control Rac and cell migration. Overall, we demonstrate that PIKfyve has a robust role in neutrophils and propose a model in which PIKfyve modulates phagosome maturation through phosphatidylinositol-3,5-bisphosphate–dependent activation of TRPML1, whereas chemotaxis and ROS are regulated by PtdIns(5)P-dependent activation of Rac.

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Cytokine-Mediated Regulation of Human Lymphocyte Development and Function: Insights from Primary Immunodeficiencies [BRIEF REVIEWS]

Cytokine-mediated intracellular signaling pathways are fundamental for the development, activation, and differentiation of lymphocytes. These distinct processes underlie protection against infectious diseases after natural infection with pathogens or immunization, thereby providing the host with long-lived immunological memory. In contrast, aberrant cytokine signaling can also result in conditions of immune dysregulation, such as early-onset autoimmunity. Thus, balanced signals provided by distinct cytokines, and delivered to specific cell subsets, are critical for immune homeostasis. The essential roles of cytokines in human immunity have been elegantly and repeatedly revealed by the discovery of individuals with mutations in cytokine ligands, receptors, and downstream transcription factors that cause primary immunodeficiency or autoimmune conditions. In this article, we review how the discovery and characterization of such individuals has identified nonredundant, and often highly specialized, functions of specific cytokines and immune cell subsets in human lymphocyte biology, host defense against infections, and immune regulation.

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In This Issue [IN THIS ISSUE]

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Cutting Edge: 2B4-Mediated Coinhibition of CD4+ T Cells Underlies Mortality in Experimental Sepsis [CUTTING EDGE]

Sepsis is a leading cause of death in the United States, but the mechanisms underlying sepsis-induced immune dysregulation remain poorly understood. 2B4 (CD244, SLAM4) is a cosignaling molecule expressed predominantly on NK cells and memory CD8⁺ T cells that has been shown to regulate T cell function in models of viral infection and autoimmunity. In this article, we show that 2B4 signaling mediates sepsis lymphocyte dysfunction and mortality. 2B4 expression is increased on CD4⁺ T cells in septic animals and human patients at early time points. Importantly, genetic loss or pharmacologic inhibition of 2B4 significantly increased survival in a murine cecal ligation and puncture model. Further, CD4-specific conditional knockouts showed that 2B4 functions on CD4⁺ T cell populations in a cell-intrinsic manner and modulates adaptive and innate immune responses during sepsis. Our results illuminate a novel role for 2B4 coinhibitory signaling on CD4⁺ T cells in mediating immune dysregulation.

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IL-33 Signaling Regulates Innate IL-17A and IL-22 Production via Suppression of Prostaglandin E2 during Lung Fungal Infection [INNATE IMMUNITY AND INFLAMMATION]

Members of the IL-1 family play protective and regulatory roles in immune defense against the opportunistic mold Aspergillus fumigatus. In this study, we investigated the IL-1 family member IL-33 in lung defense against A. fumigatus. IL-33 was detected in the naive lung, which further increased after exposure to A. fumigatus in a dectin-1–independent manner. Mice deficient in the receptor for IL-33 (Il1rl1^–/–) unexpectedly demonstrated enhanced lung clearance of A. fumigatus. IL-33 functioned as a negative regulator of multiple inflammatory cytokines, as IL-1α, IL-1β, IL-6, IL-17A, and IL-22 were significantly elevated in fungal-exposed Il1rl1^–/– mice. Subsequently, IL-33 administration to normal mice attenuated fungal-induced IL-17A and IL-22, but not IL-1α, IL-1β, or IL-6, production. IL-33–mediated regulation of IL-17A and IL-22 did not involve the modulation of IL-23 but rather PGE₂; PGE₂ was significantly increased in fungal-exposed Il1rl1^–/– mice, and normal mice produced less PGE₂ after fungal exposure when administered IL-33, suggesting that IL-33–mediated regulation of IL-17A and IL-22 occurred at the level of PGE₂. This was confirmed by in vivo cyclooxygenase 2 inhibition, which attenuated fungal-induced IL-17A and IL-22, as well as IL-1α, IL-1β, and IL-6, production in Il1rl1^–/– mice, resulting in impaired fungal clearance. We also show that a PGE₂ receptor agonist increased, whereas a PGE₂ synthase inhibitor decreased, the levels of IL-17A and IL-22 but not IL-1α, IL-1β, or IL-6. This study establishes novel mechanisms of innate IL-17A/IL-22 production via PGE₂ and regulation of the PGE₂/IL-17A/IL-22 axis via IL-33 signaling during lung fungal exposure.

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Cutting Edge: IL-2-Induced Expression of the Amino Acid Transporters SLC1A5 and CD98 Is a Prerequisite for NKG2D-Mediated Activation of Human NK Cells [CUTTING EDGE]

Priming of human NK cells with IL-2 is necessary to render them functionally competent upon NKG2D engagement. We examined the underlying mechanisms that control NKG2D responsiveness in NK cells and found that IL-2 upregulates expression of the amino acid transporters SLC1A5 and CD98. Using specific inhibitors to block SLC1A5 and CD98 function, we found that production of IFN- and degranulation by CD56^bright and CD56^dim NK cells following NKG2D stimulation were dependent on both transporters. IL-2 priming increased the activity of mTORC1, and inhibition of mTORC1 abrogated the ability of the IL-2–primed NK cells to produce IFN- in response to NKG2D-mediated stimulation. This study identifies a series of IL-2–induced cellular changes that regulates the NKG2D responsiveness in human NK cells.

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HIV-1 Infection Is Associated with Depletion and Functional Impairment of Mycobacterium tuberculosis-Specific CD4 T Cells in Individuals with Latent Tuberculosis Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

Coinfection with HIV is the single greatest risk factor for reactivation of latent Mycobacterium tuberculosis infection (LTBI) and progression to active tuberculosis disease. HIV-associated dysregulation of adaptive immunity by depletion of CD4 Th cells most likely contributes to loss of immune control of LTBI in HIV-infected individuals, although the precise mechanisms whereby HIV infection impedes successful T cell–mediated control of M. tuberculosis have not been well defined. To further delineate mechanisms whereby HIV impairs protective immunity to M. tuberculosis, we evaluated the frequency, phenotype, and functional capacity of M. tuberculosis-specific CD4 T cells in HIV-infected and HIV-uninfected adults with LTBI. HIV infection was associated with a lower total frequency of cytokine-producing M. tuberculosis-specific CD4 T cells, and preferential depletion of a discrete subset of M. tuberculosis-specific IFN-⁺IL-2^–TNF-α⁺ CD4 T cells. M. tuberculosis-specific CD4 T cells in HIV-infected individuals expressed significantly higher levels of Ki67, compared with HIV-uninfected individuals, thus indicating recent activation and turnover of these cells in vivo. The ex vivo proliferative capacity of M. tuberculosis-specific CD4 T cells was markedly impaired in HIV-infected individuals, compared with HIV-uninfected individuals. Moreover, HIV infection was associated with increased M. tuberculosis Ag-induced CD4 T cell death ex vivo, indicating a possible mechanism contributing to impaired proliferative capacity of M. tuberculosis-specific CD4 T cells in HIV-infected individuals. These data provide new insights into the parameters of M. tuberculosis-specific CD4 T cell immunity that are impaired in HIV-infected individuals with LTBI, which may contribute to their increased risk of developing active tuberculosis disease.

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Cutting Edge: Murine NK Cells Degranulate and Retain Cytotoxic Function without Store-Operated Calcium Entry [CUTTING EDGE]

Sustained Ca²⁺ signaling, known as store-operated calcium entry (SOCE), occurs downstream of immunoreceptor engagement and is critical for cytotoxic lymphocyte signaling and effector function. CD8⁺ T cells require sustained Ca²⁺ signaling for inflammatory cytokine production and the killing of target cells; however, much less is known about its role in NK cells. In this study, we use mice deficient in stromal interacting molecules 1 and 2, which are required for SOCE, to examine the contribution of sustained Ca²⁺ signaling to murine NK cell function. Surprisingly, we found that, although SOCE is required for NK cell IFN- production in an NFAT-dependent manner, NK cell degranulation/cytotoxicity and tumor rejection in vivo remained intact in the absence of sustained Ca²⁺ signaling. Our data suggest that mouse NK cells use different signaling mechanisms for cytotoxicity compared with other cytotoxic lymphocytes.

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DOCK8 Drives Src-Dependent NK Cell Effector Function [INNATE IMMUNITY AND INFLAMMATION]

Mutations in the dedicator of cytokinesis 8 (DOCK8) gene cause an autosomal recessive form of hyper-IgE syndrome, characterized by chronic immunodeficiency with persistent microbial infection and increased incidence of malignancy. These manifestations suggest a defect in cytotoxic lymphocyte function and immune surveillance. However, how DOCK8 regulates NK cell–driven immune responses remains unclear. In this article, we demonstrate that DOCK8 regulates NK cell cytotoxicity and cytokine production in response to target cell engagement or receptor ligation. Genetic ablation of DOCK8 in human NK cells attenuated cytokine transcription and secretion through inhibition of Src family kinase activation, particularly Lck, downstream of target cell engagement or NKp30 ligation. PMA/Ionomycin treatment of DOCK8-deficient NK cells rescued cytokine production, indicating a defect proximal to receptor ligation. Importantly, NK cells from DOCK8-deficient patients had attenuated production of IFN- and TNF-α upon NKp30 stimulation. Taken together, we reveal a novel molecular mechanism by which DOCK8 regulates NK cell–driven immunity.

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IFN-{alpha} Negatively Regulates the Expression of Endothelial Nitric Oxide Synthase and Nitric Oxide Production: Implications for Systemic Lupus Erythematosus [AUTOIMMUNITY]

Systemic lupus erythematosus (SLE) is a known risk factor for endothelial dysfunction. Murine and human lupus studies revealed a role for IFN-α in vascular abnormalities associated with impaired blood vessel dilation. However, the impact of IFN-α on mediators that induce vasodilation and modulate inflammation, including endothelial NO synthase (eNOS) and NO bioavailability, are unknown. The objectives of this study were to determine how IFN-α promotes endothelial dysfunction in SLE, focusing on its regulation of eNOS and NO production in endothelial cells. We demonstrate that IFN-α promotes an endothelial dysfunction signature in HUVECs that is characterized by transcription suppression and mRNA instability of eNOS complemented by upregulation of MCP1 and VCAM1. These changes are associated with IFN-inducible gene expression. IFN-α impairs insulin-mediated NO production, and altered gene expression resulted from eNOS instability, possibly due to enhanced miR-155 expression. IFN-α significantly impaired NO production in insulin-stimulated HUVECs. IFN-α treatment also led to enhanced neutrophil adhesion. Our study introduces a novel pathway by which IFN-α serves as a proatherogenic mediator through repression of eNOS-dependent pathways. This could promote the development of endothelial dysfunction and cardiovascular disease in SLE.

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Analysis of Factor D Isoforms in Malpuech-Michels-Mingarelli-Carnevale Patients Highlights the Role of MASP-3 as a Maturase in the Alternative Pathway of Complement [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Factor D (FD), which is also known as adipsin, is regarded as the first-acting protease of the alternative pathway (AP) of complement. It has been suggested that FD is secreted as a mature enzyme that does not require subsequent activation. This view was challenged when it was shown that mice lacking mannose-binding lectin (MBL)–associated serine protease-1 (MASP-1) and MASP-3 contain zymogenic FD (pro-FD), and it is becoming evident that MASP-3 is implicated in pro-FD maturation. However, the necessity of MASP-3 for pro-FD cleavage has been questioned, because AP activity is still observed in sera from MASP-1/3–deficient Malpuech–Michels–Mingarelli–Carnevale (3MC) patients. The identification of a novel 3MC patient carrying a previously unidentified MASP-3 G665S mutation prompted us to develop an analytical isoelectric focusing technique that resolves endogenous FD variants in complex samples. This enabled us to show that although 3MC patients predominantly contain pro-FD, they also contain detectable levels of mature FD. Moreover, using isoelectric focusing analysis, we show that both pro-FD and FD are present in the circulation of healthy donors. We characterized the naturally occurring 3MC-associated MASP-3 mutants and found that they all yielded enzymatically inactive proteins. Using MASP-3–depleted human serum, serum from 3MC patients, and Masp1/3^–/– mice, we found that lack of enzymatically active MASP-3, or complete MASP-3 deficiency, compromises the conversion of pro-FD to FD. In summary, our observations emphasize that MASP-3 acts as an important maturase in the AP of complement, while also highlighting that there exists MASP-3–independent pro-FD maturation in 3MC patients.

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Notch Balances Th17 and Induced Regulatory T Cell Functions in Dendritic Cells by Regulating Aldh1a2 Expression [AUTOIMMUNITY]

Dendritic cells (DCs) are important for adaptive immune responses through the activation of T cells. The molecular interplay between DCs and T cells determines the magnitude of T cell responses or outcomes of functional differentiation of T cells. In this study, we demonstrated that DCs in mice that are Rbpj deficient in CD11c⁺ cells (Rbpj^–/– mice) promoted the differentiation of IL-17A–producing Th17 cells. Rbpj-deficient DCs expressed little Aldh1a2 protein that is required for generating retinoic acid. Those DCs exhibited a reduced ability for differentiating regulatory T cells induced by TGF-β. Rbpj protein directly regulated Aldh1a2 transcription by binding to its promoter region. The overexpression of Aldh1a2 in Rbpj-deficient DCs negated their Th17-promoting ability. Transfer of naive CD4⁺ T cells into Rag1-deficient Rbpj^–/– mice enhanced colitis with increased Th17 and reduced induced regulatory T cells (iTreg) compared with control Rag1-deficient mice. The cotransfer of iTreg and naive CD4⁺ T cells into Rag1-deficient Rbpj^–/– mice improved colitis compared with transfer of naive CD4⁺ T cell alone. Furthermore, cotransfer of DCs from Rbpj^–/– mice that overexpressed Aldh1a2 or Notch-stimulated DCs together with naive CD4⁺ T cells into Rbpj^–/–Rag1-deficient mice led to reduced colitis with increased iTreg numbers. Therefore, our studies identify Notch signaling in DCs as a crucial balancer of Th17/iTreg, which depends on the direct regulation of Aldh1a2 transcription in DCs.

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Dectin-1 Activation during Leishmania amazonensis Phagocytosis Prompts Syk-Dependent Reactive Oxygen Species Production To Trigger Inflammasome Assembly and Restriction of Parasite Replication [INFECTIOUS DISEASE AND HOST RESPONSE]

Protozoan parasites of the genus Leishmania are the causative agents of Leishmaniasis, a disease that can be lethal and affects 12 million people worldwide. Leishmania replicates intracellularly in macrophages, a process that is essential for disease progression. Although the production of reactive oxygen species (ROS) accounts for restriction of parasite replication, Leishmania is known to induce ROS upon macrophage infection. We have recently demonstrated NLRP3 inflammasome activation in infected macrophages, a process that is important for the outcome of infection. However, the molecular mechanisms responsible for inflammasome activation are unknown. In this article, we demonstrate that ROS induced via NADPH oxidase during the early stages of L. amazonensis infection is critical for inflammasome activation in macrophages. We identified that ROS production during L. amazonensis infection occurs upon engagement of Dectin-1, a C-type lectin receptor that signals via spleen tyrosine kinase (Syk) to induce ROS. Accordingly, inflammasome activation in response to L. amazonensis is impaired by inhibitors of NADPH oxidase, Syk, focal adhesion kinase, and proline-rich tyrosine kinase 2, and in the absence of Dectin-1. Experiments performed with Clec7a^–/– mice support the critical role of Dectin-1 for inflammasome activation, restriction of parasite replication in macrophages, and mouse resistance to L. amazonensis infection in vivo. Thus, we reported that activation of the Dectin-1/Syk/ROS/NLRP3 pathway during L. amazonensis phagocytosis is important for macrophage restriction of the parasite replication and effectively accounts for host resistance to Leishmania infection.

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Macrophages Induce Long-Term Trapping of {gamma}{delta} T Cells with Innate-like Properties within Secondary Lymphoid Organs in the Steady State [IMMUNE REGULATION]

So far, peripheral T cells have mostly been described to circulate between blood, secondary lymphoid organs (SLOs), and lymph in the steady state. This nomadic existence would allow them to accomplish their surveying task for both foreign Ags and survival signals. Although it is now well established that T cells can be rapidly recruited to inflammatory sites or in certain tumor microenvironments, the trafficking properties of peripheral T cells have been poorly studied in the steady state. In the present study, we highlight the existence of resident T cells in the SLOs of specific pathogen-free mice. Indeed, using several experimental approaches such as the injection of integrin-neutralizing Abs that inhibit the entry of circulating lymphocytes into lymph nodes and long-term parabiosis experiments, we have found that, contrary to Ly-6C^–/+CD44^lo and Ly-6C⁺CD44^hi T cells, a significant proportion of Ly-6C^–CD44^hi T cells are trapped for long periods of time within lymph nodes and the spleen in the steady state. Specific in vivo cell depletion strategies have allowed us to demonstrate that macrophages are the main actors involved in this long-term retention of Ly-6C^–CD44^hi T cells in SLOs.

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Erythroid Suppressor Cells Compromise Neonatal Immune Response against Bordetella pertussis [INFECTIOUS DISEASE AND HOST RESPONSE]

Newborns are highly susceptible to infection. The underlying mechanism of neonatal infection susceptibility has generally been associated with neonatal immune cell immaturity. In this study, we challenged this notion and built upon our recent discovery that neonates are physiologically enriched with erythroid TER119⁺CD71⁺ cells (Elahi et al. 2013. Nature 504: 158–162). We have used Bordetella pertussis, a common neonatal respiratory tract infection, as a proof of concept to investigate the role of these cells in newborns. We found that CD71⁺ cells have distinctive immune-suppressive properties and suppress innate immune responses against B. pertussis infection. CD71⁺ cell ablation unleashed innate immune response and restored resistance to B. pertussis infection. In contrast, adoptive transfer of neonatal CD71⁺ cells into adult recipients impaired their innate immune response to B. pertussis infection. Enhanced innate immune response to B. pertussis was characterized by increased production of protective cytokines IFN-, TNF-α, and IL-12, as well as recruitment of NK cells, CD11b⁺, and CD11c⁺ cells in the lung. Neonatal and human cord blood CD71⁺ cells express arginase II, and this enzymatic activity inhibits phagocytosis of B. pertussis in vitro. Thus, our study challenges the notion that neonatal infection susceptibility is due to immune cell–intrinsic defects and instead highlights active immune suppression mediated by abundant CD71⁺ cells in the newborn. Our findings provide additional support for the novel theme in neonatal immunology that immunosuppression is essential to dampen robust immune responses in the neonate. We anticipate that our results will spark renewed investigation in modulating the function of these cells and developing novel strategies for enhancing host defense to infections in newborns.

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Lamtor1 Is Critically Required for CD4+ T Cell Proliferation and Regulatory T Cell Suppressive Function [IMMUNE REGULATION]

Mechanistic target of rapamycin complex (mTORC)1 integrates intracellular sufficiency of nutrients and regulates various cellular functions. Previous studies using mice with conditional knockout of mTORC1 component proteins (i.e., mTOR, Raptor, and Rheb) gave conflicting results on the roles of mTORC1 in CD4⁺ T cells. Lamtor1 is the protein that is required for amino acid sensing and activation of mTORC1; however, the roles of Lamtor1 in T cells have not been investigated. In this article, we show that Lamtor1-deficient CD4⁺ T cells exhibited marked reductions in proliferation, IL-2 production, mTORC1 activity, and expression of purine- and lipid-synthesis genes. Polarization of Th17 cells, but not Th1 and Th2 cells, diminished following the loss of Lamtor1. Accordingly, CD4-Cre–driven Lamtor1-knockout mice exhibited reduced numbers of CD4⁺ and CD8⁺ T cells at rest, and they were completely resistant to experimental autoimmune encephalomyelitis. In contrast, genetic ablation of Lamtor1 in Foxp3⁺ T cells resulted in severe autoimmunity and premature death. Lamtor1-deficient regulatory T cells survived ex vivo as long as wild-type regulatory T cells; however, they exhibited a marked loss of suppressive function and expression of signature molecules, such as CTLA-4. These results indicate that Lamtor1 plays essential roles in CD4⁺ T cells. Our data suggest that Lamtor1 should be considered a novel therapeutic target in immune systems.

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Extracellular MicroRNAs Induce Potent Innate Immune Responses via TLR7/MyD88-Dependent Mechanisms [INNATE IMMUNITY AND INFLAMMATION]

Tissue ischemia, such as transient myocardial ischemia, leads to release of cellular RNA including microRNA(miRNA) into the circulation and extracellular (ex-) space, but the biological function of the ex-RNA is poorly understood. We recently reported that cardiac RNA of both human and rodent origins induced cytokine production and immune cell activation. However, the identity of the ex-RNA responsible for the proinflammatory effect remains unclear. In the current study, using an miRNA array, we profiled the plasma miRNAs 4 h after transient myocardial ischemia (45 min) or sham procedure. Among 38 plasma miRNAs that were elevated following ischemia, eight were tested for their ability to induce cytokine response in macrophages and cardiomyocytes. We found that six miRNA mimics (miR-34a, -122, -133a, -142, -146a, and -208a) induced cytokine production in a dose-dependent manner. The effects of miRNAs (miR-133a, -146a, and -208a) were diminished by uridine->adenosine mutation and by RNase pretreatment. The miRNA-induced cytokine (MIP-2, TNF-α, and IL-6) production was abolished in cells deficient of TLR7 or MyD88, or by a TLR7 antagonist, but remained the same in TLR3- or Trif-deficient cells. In vivo, mice i.p. injected with miR-133a or miR-146a had marked peritoneal neutrophil and monocyte migration, which was significantly attenuated in TLR7^–/– mice. Moreover, locked nucleic acid anti-miRNA inhibitors of these six miRNAs markedly reduced cardiac RNA-induced cytokine production. Taken together, these data demonstrate that ex-miRNA mimics (miR-34a, -122, -133a, -142, -146a, and -208a) are potent innate immune activators and that the miRNAs most likely induce cytokine production and leukocyte migration through TLR7 signaling.

http://ift.tt/2w4alis

PD-L2 Regulates B-1 Cell Antibody Production against Phosphorylcholine through an IL-5-Dependent Mechanism [IMMUNE REGULATION]

B-1 cells produce natural Abs which provide an integral first line of defense against pathogens while also performing important homeostatic housekeeping functions. In this study, we demonstrate that programmed cell death 1 ligand 2 (PD-L2) regulates the production of natural Abs against phosphorylcholine (PC). Naive PD-L2–deficient (PD-L2^–/–) mice produced significantly more PC-reactive IgM and IgA. This afforded PD-L2^–/– mice with selectively enhanced protection against PC-expressing nontypeable Haemophilus influenzae, but not PC-negative nontypeable Haemophilus influenzae, relative to wild-type mice. PD-L2^–/– mice had significantly increased PC-specific CD138⁺ splenic plasmablasts bearing a B-1a phenotype, and produced PC-reactive Abs largely of the T15 Id. Importantly, PC-reactive B-1 cells expressed PD-L2 and irradiated chimeras demonstrated that B cell–intrinsic PD-L2 expression regulated PC-specific Ab production. In addition to increased PC-specific IgM, naive PD-L2^–/– mice and irradiated chimeras reconstituted with PD-L2^–/– B cells had significantly higher levels of IL-5, a potent stimulator of B-1 cell Ab production. PD-L2 mAb blockade of wild-type B-1 cells in culture significantly increased CD138 and Blimp1 expression and PC-specific IgM, but did not affect proliferation. PD-L2 mAb blockade significantly increased IL-5⁺ T cells in culture. Both IL-5 neutralization and STAT5 inhibition blunted the effects of PD-L2 mAb blockade on B-1 cells. Thus, B-1 cell–intrinsic PD-L2 expression inhibits IL-5 production by T cells and thereby limits natural Ab production by B-1 cells. These findings have broad implications for the development of therapeutic strategies aimed at altering natural Ab levels critical for protection against infectious disease, autoimmunity, allergy, cancer, and atherosclerosis.

http://ift.tt/2wDlJ8A

Integrin-Linked Kinase Expression in Myeloid Cells Promotes Inflammatory Signaling during Experimental Colitis [INNATE IMMUNITY AND INFLAMMATION]

The pathology of inflammatory bowel diseases is driven by the inflammatory signaling pathways associated with mucosal epithelial damage. Myeloid cells are known to play an essential role in mediating epithelial inflammatory responses during injury. However, the precise role of these cells in stimulating intestinal inflammation and the subsequent tissue damage is unclear. In this article, we show that expression of integrin-linked kinase (ILK) in myeloid cells is critical for the epithelial inflammatory signaling during colitis induced by dextran sodium sulfate. Myeloid ILK (M-ILK) deficiency significantly ameliorates the pathology of experimental colitis. In response to dextran sodium sulfate, colonic infiltration of neutrophils and inflammatory cytokine production are impaired in M-ILK–deficient mice, and activation of epithelial NF-B and PI3K signaling pathways are restricted by the M-ILK deficiency. In contrast, reduced epithelial damage in M-ILK–deficient mice is correlated with elevated levels of epithelial Stat3 activation and proliferation. Moreover, M-ILK–dependent inflammatory signaling in the mucosal epithelium can be therapeutically targeted by the pharmacological inhibition of ILK during experimental colitis. Collectively, these findings identify M-ILK as a critical regulator of epithelial inflammatory signaling pathways during colitis and, as a consequence, targeting M-ILK could provide therapeutic benefit.

http://ift.tt/2w3AWwb

{alpha}3-Deletion Isoform of HLA-A11 Modulates Cytotoxicity of NK Cells: Correlations with HIV-1 Infection of Cells [IMMUNOGENETICS]

Alternative splicing occurs frequently in many genes, especially those involved in immunity. Unfortunately, the functions of many alternatively spliced molecules from immunologically relevant genes remain unknown. Classical HLA-I molecules are expressed on almost all nucleated cells and play a pivotal role in both innate and adaptive immunity. Although splice variants of HLA-I genes have been reported, the details of their functions have not been reported. In the current study, we determined the characteristics, expression, and function of a novel splice variant of HLA-A11 named HLA-A11svE4. HLA-A11svE4 is located on the cell surface without β2-microglobulin (β2m). Additionally, HLA-A11svE4 forms homodimers as well as heterodimers with HLA-A open conformers, instead of combining with β2m. Moreover, HLA-A11svE4 inhibits the activation of NK cells to protect target cells. Compared with β2m and HLA-A11, the heterodimer of HLA-A11svE4 and HLA-A11 protected target cells from lysis by NK cells more effectively. Furthermore, HLA-AsvE4 expression was upregulated by HIV-1 in vivo and by HSV, CMV, and hepatitis B virus in vitro. In addition, our findings indicated that HLA-A11svE4 molecules were functional in activating CD8⁺ T cells through Ag presentation. Taken together, these results suggested that HLA-A11svE4 can homodimerize and form a novel heterodimeric complex with HLA-A11 open conformers. Furthermore, the data are consistent with HLA-A11svE4 playing a role in the immune escape of HIV-1.

http://ift.tt/2w42elW

Assessing the Detection of Middle East Respiratory Syndrome Coronavirus IgG in Suspected and Proven Cases of Middle East Respiratory Syndrome Coronavirus Infection

Viral Immunology , Vol. 0, No. 0.


http://ift.tt/2wDjhz3

The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer

Abstract

The transcription factor signal activator and transducer or transcription (STAT3), which regulates genes controlling proliferation, survival, and invasion, is activated inappropriately in many human cancers, including breast cancer. Activation of STAT3 can lead to both malignant cellular behavior and suppression of immune cell function in the tumor microenvironment. Through a chemical-biology screen, pyrimethamine (PYR), an FDA approved anti-microbial drug, was identified as an inhibitor of STAT3 function at concentrations known to be achieved safely in humans. We report that PYR shows therapeutic activity in two independent mouse models of breast cancer, with both direct tumor inhibitory and immune stimulatory effects. PYR-inhibited STAT3 activity in TUBO and TM40D-MB metastatic breast cancer cells in vitro and inhibited tumor cell proliferation and invasion into Matrigel basement membrane matrix. In tumor-transplanted mice, PYR had both direct and indirect tumor inhibitory effects. Tumor-bearing mice treated with PYR showed reduced STAT3 activation in tumor cells, attenuated tumor growth, and reduced tumor-associated inflammation. In addition, expression of Lamp1 by tumor infiltrating CD8⁺ T cells was elevated, indicating enhanced release of cytotoxic granules. These findings suggest that PYR may have beneficial effects in the treatment of breast cancer.

http://ift.tt/2vI73WF

The impact of asthma on the cost effectiveness of surgery for chronic rhinosinusitis with nasal polyps

Background

The objective of this work was to evaluate the impact of asthma on the cost-effectiveness profile of endoscopic sinus surgery (ESS) compared to medical therapy for patients with chronic rhinosinusitis with nasal polyps (CRSwNP).

Methods

The study design consisted of a cohort-style Markov decision-tree cost utility analysis with a 35-year time horizon. Matched cohorts of CRSwNP patients with (n = 95) and without (n = 95) asthma who underwent ESS were compared with cohorts of patients from the national Medical Expenditures Survey Panel (MEPS) database who underwent medical management for chronic rhinosinusitis (CRS). Baseline, 1-year, and 2-year health utility values were calculated from responses to the EuroQol-5 Dimension (EQ-5D) instrument in both cohorts. The primary outcome measure was the incremental cost effectiveness ratio (ICER) for each cohort.

Results

The reference cases for CRSwNP patients with and without asthma yielded ICERs for ESS vs medical therapy alone of $12,066 per quality-adjusted life year (QALY) and $7,369 per QALY, respectively. At a willingness-to-pay threshold of $50,000/QALY, the ICER scatter plots demonstrated 86% and 99% certainty that the ESS strategy was the most cost-effective option for CRSwNP patients with and without asthma, respectively. ESS was not significantly more cost effective for CRSwNP patients without asthma (p = 0.494).

Conclusion

ESS remains cost effective compared to medical therapy for patients both with and without asthma. While the comorbidity of asthma results in an inferior ICER result, it does not result in a statistically significant negative impact on the overall cost effectiveness of ESS.

http://ift.tt/2gDDrj1

Cholinergic urticaria patients of different age groups have distinct features

Abstract

Background

Cholinergic Urticaria (CholU) is a common skin disease characterized by the development of pinpoint sized wheals and severe itch upon physical exercise. Little is known about the epidemiology of CholU. CholU can occur at any age and has the highest prevalence among young adults. As of now, it is unclear if patients of different age show differences in the clinical manifestation of CholU, duration of disease, comorbidities or response to treatment.

Methods

Here, we analysed the demographic data and clinical characteristics including disease duration and comorbidities of 200 CholU patients, 12 to 76 years of age.

Results

We identified two distinct types of CholU, one with early onset (EO, 71%) and one with late onset (LO, 29%). EO and LO CholU patients markedly differ in key characteristics: EO patients, who had a disease onset before the age of 36, showed no gender preponderance, and had a significantly higher rate of concomitant atopic dermatitis (16.9 vs. 5.2%; p= 0.028) and higher IgE-Levels (295.5 vs. 267.1 IU/ml; p= 0.020) as compared to LO patients, who were mainly female (69%), had a shorter duration of disease (33.3 vs. 63.7 months; p= 0.005), a higher rate of concomitant other forms of urticaria (48.3 vs. 33.1%; p=0.044), and a higher rate of psychiatric comorbidities (12.1 vs 1.4%; p= 0.001)..

Conclusion

There are two subtypes of CholU patients with different gender ratios, disease duration, and comorbidities. These findings suggest that two distinct underlying pathogenetic pathways are relevant in these two subgroups of CholU patients.

This article is protected by copyright. All rights reserved.

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Sequential hypoallergenic boiled peanut and roasted peanut oral immunotherapy

Abstract

Oral immunotherapy (OIT) using roasted peanut flour can effectively desensitize peanut-allergic children [1] but is considered not to be ready for clinical practice [2] due to high rates (≥45%) of adverse events (AEs) [3] [4]. This necessitates medically supervised up-dosing in hospital and limits the number of patients that can be treated. In 2001 Beyer et. al proposed that the prevalence of peanut allergy in China was lower than that of the Western world because peanuts consumed in China were boiled, not roasted [5]. They demonstrated that boiling peanuts for 20 minutes reduced IgE binding in vitro when compared to roasted peanut. We have subsequently shown that extended boiling progressively reduced peanut IgE binding to 12.5% at 2 hours and to 5.3% at 12 hours compared to raw peanut while still retaining T cell reactivity [6]. Further, Inhibition ELISAs demonstrated that boiled peanuts have restricted ability (2-h ~70%, 12-h ~50%) to block the binding of patient IgE to raw peanut [6] suggesting boiled peanuts possess an incomplete repertoire of epitopes. This indicates that boiled peanuts alone are unlikely to expose a patient to the full spectrum of peanut epitopes and will therefore require a roasted peanut phase following the initial boiled peanut therapy. We hypothesize that AEs can be reduced by commencing OIT with hypoallergenic boiled peanut. Here we describe a pilot study that aims to characterize the incidence of AEs and successful desensitization in mild/moderate peanut allergic children using hypoallergenic 2-hour boiled peanut prior to roasted peanut OIT. Due to the home-based up-dosing procedure, a cautious approach was adopted which excluded severely allergic children.

This article is protected by copyright. All rights reserved.

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Identification of Two Distinct Molecular Subtypes of Non-Invasive Follicular Neoplasm with Papillary-Like Nuclear Features by Digital RNA Counting

Thyroid , Vol. 0, No. 0.


http://ift.tt/2xMizxU

Vitamin D Levels in Premature Children Admitted to the Hospital with Viral Respiratory Infection

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


http://ift.tt/2eYWkNd

Reply to the letter to the editor concerning: Chronic rhinosinusitis with nasal polyps are associated with chronic otitis media in the elderly

http://ift.tt/2wBP8jw

Vitamin D Levels in Premature Children Admitted to the Hospital with Viral Respiratory Infection

Pediatric Allergy, Immunology, and Pulmonology , Vol. 0, No. 0.


http://ift.tt/2eZSTpu

Human pulpal blood flow in different root formation stages measured with transmitted-light plethysmography

Publication date: November 2017
Source:Archives of Oral Biology, Volume 83
Author(s): Khongorzul Ganbold, Satoko Kakino, Hideharu Ikeda, Michiyo Miyashin
ObjectivesTo determine the pulp vitality after traumatic injury, dentists often use pulp sensitivity tests, which can be ambiguous in young permanent teeth with incomplete root formation. Transmitted-light plethysmography (TLP) is a non-invasive objective method that uses a 525-nm LED to detect blood volume change in the pulp. The present study aimed (1) to investigate pulpal blood flow with TLP and optical characteristics in healthy permanent maxillary incisors in different root formation stages, and (2) to assess the influences of body growth of the children and tooth color on the TLP amplitude.DesignSeventy-eight fully erupted maxillary central incisors were divided into four groups, according to the root formation stages. Group 1: root with wide-open apex, Group 2: root completed in length with open apex, Group 3: root with half-closed apex, Group 4: root with complete formation. The TLP amplitude, optical density, electric pulp testing, and cervical tooth color measurements of each group were compared using a one-way analysis of variance followed by the Bonferroni method. The correlation between the weights/heights of children and TLP amplitudes was analyzed using Pearson coefficient.ResultsThe TLP amplitude was significantly higher in Group 3 than in the other groups. The amplitude was correlated with the weights/heights of children, but not with the tooth color. Optical density and electric sensitivity increased with tooth maturation.ConclusionThe amplitude of TLP and optical density may be affected by growth and development in children and indicate changes in the vascular dynamics of the pulp and hard tissue maturation during root formation stages.



http://ift.tt/2gHSFXM

Human papillomavirus infection in oral potentially malignant disorders and cancer

Publication date: November 2017
Source:Archives of Oral Biology, Volume 83
Author(s): Xun Chen, Yu Zhao
Human papillomavirus (HPV) infects keratinocytes in the mucosa or skin, and persistent infection with HPV may lead to premalignant lesions and invasive cancer, especially cervical cancer. It has also been hypothesized that HPV infection is an etiological factor of oral squamous cell carcinoma and oral precancerous disorders such as lichen planus, leukoplakia, and erythroplakia. A high percentage of HPV in oral lesions supports the possible viral contribution, but an association of HPV infection with these lesions remains to be established. The current paper will update the latest progress of HPV infection in several oral potentially malignant disorders and oral squamous cell carcinoma and discuss the impact of HPV infection on the progression of oral potentially malignant disorders.



http://ift.tt/2eZv41m

Deciding on Active Surveillance or Surgery for Primary Management of Low Risk Papillary Thyroid Cancer

Condition:   Thyroid Cancer Stage I
Intervention:  
Sponsors:   University Health Network, Toronto;   Ontario Ministry of Health and Long Term Care;   Canadian Cancer Society Research Institute (CCSRI)
Recruiting - verified August 2017

http://ift.tt/2iZgtap

Prediction of persistent post-surgery pain by preoperative cold pain sensitivity: biomarker development with machine-learning-derived analysis

Abstract

Background. To prevent persistent post-surgery pain, early identification of patients at high risk is a clinical need. Supervised machine-learning techniques were used to test how accurately the patients' performance in a preoperatively performed tonic cold pain test could predict persistent post-surgery pain.Methods. We analysed 763 patients from a cohort of 900 women who were treated for breast cancer, of whom 61 patients had developed signs of persistent pain during three yr of follow-up. Preoperatively, all patients underwent a cold pain test (immersion of the hand into a water bath at 2–4 °C). The patients rated the pain intensity using a numerical ratings scale (NRS) from 0 to 10. Supervised machine-learning techniques were used to construct a classifier that could predict patients at risk of persistent pain.Results. Whether or not a patient rated the pain intensity at NRS=10 within less than 45 s during the cold water immersion test provided a negative predictive value of 94.4% to assign a patient to the "persistent pain" group. If NRS=10 was never reached during the cold test, the predictive value for not developing persistent pain was almost 97%. However, a low negative predictive value of 10% implied a high false positive rate.Conclusions. Results provide a robust exclusion of persistent pain in women with an accuracy of 94.4%. Moreover, results provide further support for the hypothesis that the endogenous pain inhibitory system may play an important role in the process of pain becoming persistent.

http://ift.tt/2eGi6bW

Neuropathic pain in cancer: systematic review, performance of screening tools and analysis of symptom profiles

Abstract

Background: The objectives of this study were to evaluate the methodological quality of rigorous neuropathic pain assessment tools in applicable clinical studies, and determine the performance of screening tools for identifying neuropathic pain in patients with cancer.Methods: Systematic literature search identified studies reporting use of Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), Douleur Neuropathique en 4 (DN4) or painDETECT (PDQ) in cancer patients with a clinical diagnosis of neuropathic or not neuropathic pain. Individual patient data were requested to examine descriptor item profiles.Results: Six studies recruited a total of 2301 cancer patients of which 1564 (68%) reported pain. Overall accuracy of screening tools ranged from 73 to 94%. There was variation in description and rigour of clinical assessment, particularly related to the rigour of clinical judgement of pain as the reference standard. Individual data from 1351 patients showed large variation in the selection of neuropathic pain descriptor items by cancer patients with neuropathic pain. LANSS and DN4 items characterized a significantly different neuropathic pain symptom profile from non-neuropathic pain in both tumour- and treatment-related cancer pain aetiologies.Conclusions: We identified concordance between the clinician diagnosis and screening tool outcomes for LANSS, DN4 and PDQ in patients with cancer pain. Shortcomings in relation to standardized clinician assessment are likely to account for variation in screening tool sensitivity, which should include the use of the neuropathic pain grading system. Further research is needed to standardize and improve clinical assessment in patients with cancer pain. Until the standardization of clinical diagnosis for neuropathic cancer pain has been validated, screening tools offer a practical approach to identify potential cases of neuropathic cancer pain.

http://ift.tt/2gCAYp4

Non-steroidal anti-inflammatory drugs in the oncological surgical population: beneficial or harmful? A systematic review of the literature

Abstract

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are effective analgesic drugs. Recent studies have indicated a potential beneficial effect on long-term survival outcomes after cancer surgery but a negative impact on anastomotic leaks. The objective of this study was to objectively assess the implications of the perioperative NSAIDs use on anastomotic leaks and cancer recurrence.Methods: We searched PubMed, MEDLINE, Embase and Cochrane Library for publications up to mid-January 2017. Randomized controlled trials (RCTs) and observational studies in adults undergoing cancer surgery were included for quality assessment. We excluded animal studies, in vitro experiments and case reports. The selected sudies were graded using the Jadad score or Newcastle–Ottawa scale for RCTs and observational retrospective studies, respectively.Results: The systematic review identified 25 trials that explored the impact of NSAIDs on anastomotic leaks and 16 trials that assessed the association between perioperative NSAIDs and cancer recurrence. Meta-analyses were not performed because of high heterogeneity and low quality of the included studies.Conclusions: The literature is not conclusive on whether the use of NSAIDs is associated with anastomotic leaks after gastrointestinal cancer surgery. Also, the current evidence is equivocal regarding the effects of short-term NSAIDs on cancer recurrence after major cancer surgery. Three RCTs are being conducted to assess the impact of NSAIDs on cancer recurrence. There are no registered RCTs that are testing the hypothesis of whether the perioperative use of NSAIDs increases the rate of anastomotic leaks.

http://ift.tt/2eH0ht1

Downregulated expression of miR-223 promotes Toll-like receptor-activated inflammatory responses in macrophages by targeting RhoB

Publication date: November 2017
Source:Molecular Immunology, Volume 91
Author(s): Ningjie Zhang, Liyao Fu, Yanhong Bu, Yao Yao, Yongjun Wang
Toll-like receptors (TLRs) induced-inflammatory response must be tightly regulated to avoid impairment in host itself. Numerous factors have been identified in regulation of TLR-triggered inflammatory response. Among these, microRNAs (miRNAs) are small non-coding RNA molecules which have got much attention. MiR-223, which highly expresses in myeloid cells of the bone marrow, has reported to participate in kinds of inflammatory responses by targeting inflammasome sensor-NLRP3 to repress production of IL-6 and IL-1β, and thus attenuate inflammatory response. However, the function of miR-223 in TLRs-activated inflammatory response of macrophages is not clear. Here we found miR-223 expression is dramatically reduced in macrophages by TLR ligand stimulation (e.g. LPS, CpG and poly (I:C)). The down-regulated miR-223 leads to the increase in the RhoB expression, which induce the activation of NF-κB and MAPK signaling, promoting TNF-α, IL-6 and IL-1β production upon LPS stimulation. In addition, the histone deacetylase inhibitor trichostatin A increased miR-223 expression obviously in TLR-triggered macrophages, which in turn suppressed RhoB expression and downstream IL-6 production, suggesting that the inhibition of miR-223 by histone deacetylation may be involved in the regulation of TLR-activated inflammatory response. Herein, our findings suggest that miR-223-RhoB axis might be a novel target for the treatment of inflammatory diseases.



http://ift.tt/2wBUtr6

Diagnostik des malignen Melanoms der Haut

Zusammenfassung

Seit August 2016 liegt die aktualisierte S3-Leitlinie zum malignen Melanom vor. Grundlagen von Diagnostik und Klassifikation sind der histopathologische Befund des Primärtumors und ggf. des Wächterlymphknotens. Wichtigste Prognosefaktoren des Primärtumors sind Tumordicke nach Breslow und Nachweis einer Mikrometastasierung in der Wächterlymphknotenbiopsie. Die Tumordicke bestimmt den Sicherheitsabstand der Nachexzision. In die T‑Klassifikation gehen Ulzeration des Primärtumors und Vorhandensein von Mitosen im Melanom <1 mm mit ein. Der Wächterlymphknoten sollte mithilfe der HE-Färbung und immunhistologischer Methoden aufgearbeitet werden. Der größte Tumordurchmesser einer Mikrometastase wird ausgemessen und in Zehntelmillimetern (Rotterdam-Klassifikation) angegeben. Im Stadium der Metastasierung oder bei nichtresektablen Tumoren soll molekularpathologisch auf mutierte Onkogene BRAF und NRAS getestet werden, in akralen und mukosalen Melanomen zusätzlich auf cKIT. Bei nachgewiesener Mutation ist die Therapie mit Signaltransduktionsinhibitoren möglich.

http://ift.tt/2eGcSNa

Variable domain glycosylation of ACPA-IgG: A missing link in the maturation of the ACPA response?

Publication date: Available online 5 September 2017
Source:Clinical Immunology
Author(s): Ayla C. Kempers, Lise Hafkenscheid, Hans Ulrich Scherer, René E.M. Toes
Anti-citrullinated Protein Antibodies (ACPA) are excellent markers for Rheumatoid arthritis (RA) and are postulated to have a pathogenic role in the disease process. A multistep model for the evolution of the ACPA response in RA was proposed in which an initial break of tolerance causes, as "first hit", "silent" production of ACPA without any clinical symptoms. The model further proposes that the ACPA immune response matures upon a certain (unknown) trigger, a "second hit", which leads to epitope spreading, an increase in ACPA titres and extended isotype usage before clinical RA manifestations. These occurrences are indicative of an expansion of the citrulline-specific B cell response, though ACPA remain of low avidity even in established disease. This persistence of low avidity is puzzling, as the typical signs of maturation of the immune response seem to be uncoupled from the classical process of affinity maturation. In fact, it suggests that B cells expressing ACPA could bypass selection mechanisms that otherwise control the expansion of auto-reactive B cells. In the established, chronic phase, we recently found that ACPA-IgG are extensively glycosylated in the variable (Fab) domain. More than 90% of ACPA-IgG molecules carry Fab glycans that are highly sialylated. This molecular feature is striking and may provide a missing link in our understanding of the maturation of the ACPA immune response. This review, therefore, describes the current knowledge about ACPA Fab glycosylation in the pathogenesis of RA.



http://ift.tt/2iZpsIM

Antibodies targeting BTLA or TIM-3 enhance HIV-1 specific T cell responses in combination with PD-1 blockade

Publication date: Available online 4 September 2017
Source:Clinical Immunology
Author(s): Katharina Grabmeier-Pfistershammer, Carmen Stecher, Markus Zettl, Sandra Rosskopf, Armin Rieger, Gerhard J. Zlabinger, Peter Steinberger
Persistent stimulation with antigens derived from viruses that establish chronic infections or tumour antigens results in the exhaustion of T cells. Coinhibitory receptors like PD-1 and CTLA-4 function as immune checkpoints on exhausted T cells. Blocking these molecules with antibodies improve immunity to cancer cells. Immune checkpoint inhibitors targeting other coinhibitory receptors might have a similar role in improving T cell function and thus also utility in cancer therapy.Using HIV-specific T cells as a model for exhaustion we have evaluated the capacity of antibodies targeting TIM-3, BTLA, CD160, LAG-3 and CTLA-4 alone or in combination with a PD-1 antibody to enhance proliferation and cytokine production in response to Gag and Nef peptides.Antibodies targeting BTLA and TIM-3 enhanced CD8 T cell proliferation. Moreover, our results indicate that blocking BTLA and TIM-3 in combination with PD-1 might be especially effective in enhancing responses of exhausted human T cells.

Graphical abstract

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HLA class Ia and Ib molecules and FOXP3+ TILs in relation to the prognosis of malignant melanoma patients

Publication date: Available online 4 September 2017
Source:Clinical Immunology
Author(s): Wenna Nascimento, Lasse Lindholm Johansen, Jørgen Lock-Andersen, Nille Behrendt, Jens Ole Eriksen, Michael Bzorek, Thomas Scheike, Thomas Vauvert F. Hviid
HLA class Ia (HLA-ABC) and HLA class Ib (HLA-E, -F and -G) molecules and FOXP3+ tumor-infiltrating lymphocytes (TILs) are often reported as relevant factors of tumor immune regulation. We investigated their expression as prognostic factors in 200 patients with primary cutaneous melanoma (PCM). In our cohort, patients with tumors showing upregulation of HLA-ABC molecules had significantly thicker tumors (32% vs 7%, P<0.001), frequent ulceration (20% vs 6%, P=0.007) and frequent nodular melanomas (20% vs 4%, P=0.001). Additionally, high expression of HLA-G in the tumor was a sign of bad prognosis for the patients, being associated with thick tumors (30% vs 12%, P=0.017), ulceration (24% vs 5%, P<0.001) and positive sentinel node (13% vs 6%, P=0.015). HLA-E, HLA-F and FOXP3+ TILs were not indicative of the prognosis in PCM. High HLA-ABC and HLA-G were associated with tumor aggressiveness and could be relevant predictive markers for effective immunotherapy of melanoma tumors.



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DOCK8 and STAT3 dependent inhibition of IgE isotype switching by TLR9 ligation in human B cells

Publication date: Available online 4 September 2017
Source:Clinical Immunology
Author(s): Michel J. Massaad, Brittney Cangemi, Waleed Al-Herz, Gérard LeFranc, Alexandra Freeman, Sachin Baxi, Sevgi Keles, Ayse Metin, Majid Dasouki, Ali Sobh, Maria Kanariou, Nashat Al-Sukaiti, Ahmet Ozen, Hans Ochs, Talal A. Chatila, John P. Manis, Raif Geha




http://ift.tt/2eFC3j6

Aspergillus fumigatus alkaline protease 1 (Alp1/Asp f13) in the airways correlates with asthma severity

Publication date: Available online 4 September 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Trisha Basu, Seyedmojtaba Seyedmousavi, Janyce A. Sugui, Nariman Balenga, Ming Zhao, Kyung Joo Kwon Chung, Sabrina Biardel, Michel Laviolette, Kirk M. Druey
A fungal protease (Alp1/Asp f13) from Aspergillus fumigatus was detected in the airways of subjects with asthma but not controls, which correlated strongly with disease severity, respiratory dysfunction, and steroid use.



http://ift.tt/2w2b1VD

Test-retest reliability of speech-evoked auditory brainstem response in healthy children at a low sensation level

Publication date: November 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 102
Author(s): Mohd Normani Zakaria, Bahram Jalaei
ObjectiveAuditory brainstem responses evoked by complex stimuli such as speech syllables have been studied in normal subjects and subjects with compromised auditory functions. The stability of speech-evoked auditory brainstem response (speech-ABR) when tested over time has been reported but the literature is limited. The present study was carried out to determine the test-retest reliability of speech-ABR in healthy children at a low sensation level.MethodsSeventeen healthy children (6 boys, 11 girls) aged from 5 to 9 years (mean = 6.8 ± 3.3 years) were tested in two sessions separated by a 3-month period. The stimulus used was a 40-ms syllable /da/ presented at 30 dB sensation level.ResultsAs revealed by pair t-test and intra-class correlation (ICC) analyses, peak latencies, peak amplitudes and composite onset measures of speech-ABR were found to be highly replicable. Compared to other parameters, higher ICC values were noted for peak latencies of speech-ABR.ConclusionThe present study was the first to report the test-retest reliability of speech-ABR recorded at low stimulation levels in healthy children. Due to its good stability, it can be used as an objective indicator for assessing the effectiveness of auditory rehabilitation in hearing-impaired children in future studies.



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Pediatric tympanic membrane cholesteatoma: Systematic review and meta-analysis

Publication date: November 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 102
Author(s): Harry H. Ching, Alycia G. Spinner, Matthew Ng
IntroductionTympanic membrane cholesteatoma (TMC) is a rare anomaly found in pediatric patients with no significant otologic history. Its pathogenesis appears distinct from congenital mesotympanic cholesteatoma. This systematic review and meta-analysis evaluates the management of TMC.MethodsTwo authors independently conducted a systematic review using the PubMed-NCBI, Cochrane Library, and Web of Science databases. Studies describing cases of pediatric TMC were included. Patients with history of chronic otitis, otorrhea, trauma, or otologic surgery were excluded.ResultsSeventeen articles were included for a total of 45 patients. Mean age was 35.9 months with 56% female. Patients aged ≥36 months had significantly larger cholesteatomas than younger patients (4.2 vs 1.9 mm, p = 0.004). Nine patients (20%) had middle ear extension but none had middle ear or ossicular disease. CT scans influenced management in 1 of 26 patients. All patients were managed surgically by transcanal approach (93%) or retroauricular approach (7%). Surgery involved enucleation without TM perforation (80%) or complete excision with TM grafting (20%). In 23 patients, the fibrous TM remained intact, and there were no recurrences in this group at a mean follow-up of 11 months. Overall, there was 1 recurrence (2%), eventually requiring reoperation. No patients experienced persistent tympanic membrane perforation, chronic otitis, or hearing loss.ConclusionTMC occurs in pediatric patients without an otologic history. Associated middle ear involvement has not been reported. CT scanning may not be necessary for work up and management of this disorder. A transcanal approach with enucleation is often sufficient treatment. Risk of recurrence appears lower than with congenital mesotympanic cholesteatoma.



http://ift.tt/2iYksE8

Design and validation of key text messages (Tonsil-Text-To-Me) to improve parent and child perioperative tonsillectomy experience: A modified Delphi study

Publication date: November 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 102
Author(s): Jin Soo A. Song, Lori Wozney, Jill Chorney, Stacey L. Ishman, Paul Hong
ObjectiveParents can struggle while providing perioperative tonsillectomy care for their children at home. Short message service (SMS) technology is an accessible and direct modality to communicate timely, evidence-based recommendations to parents across the perioperative period. This study focused on validating a SMS protocol, Tonsil-Text-To-Me (TTTM), for parents of children undergoing tonsillectomy.MethodsThis study used a modified Delphi expert consensus method. Participants were an international sample of 27 clinicians/researchers. Participants rated level of agreement with recommendations across seven perioperative domains, derived systematically from scientific and lay literature. A priori consensus analysis was conducted using threshold criterion. A multidisciplinary team of local clinicians were also individually interviewed to consolidate text messages and implement recurrent suggestions.ResultsIn the modified Delphi panel, 30 statements reached threshold agreement (>3.0 of 4.0); recommendations surrounding diet (3.87) and hygiene (3.83) had the highest level of consensus, while recommendations regarding activity (3.42) and non-pharmacologic pain management (3.55) had the lowest consensus. The 30 statements reconfigured into 12 concise text messages. After further interviews with local clinicians, 14 final text messages were included in the SMS protocol to be sent two weeks preoperatively to one week postoperatively.ConclusionThis study illustrates the development of TTTM which is designed to deliver key sequential text messages at the optimal time during the perioperative setting to parents caring for their children who are undergoing tonsillectomy.



http://ift.tt/2eAvBGt

Introductory Head and Neck Imaging, first ed., Jaypee Brothers Medical Publishers, 4838/24, Ansari Road, Daryaganj, New Delhi 110 002, India.

Publication date: November 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 102
Author(s): Brian K. Reilly, Eugene Yuik, Lalitha Shankar




http://ift.tt/2iXy4zA

Genetic analysis of a Chinese family with members affected with Usher syndrome type II and Waardenburg syndrome type IV

Publication date: Available online 4 September 2017
Source:International Journal of Pediatric Otorhinolaryngology
Author(s): Xueling Wang, Xiao-Jiang Lin, Xiangrong Tang, Yong-Chuan Chai, De-Hong Yu, Dong-Ye Chen, Hao Wu
AimsThe purpose of this study was to identify the genetic causes of a family presenting with multiple symptoms overlapping Usher syndrome type II (USH2) and Waardenburg syndrome type IV (WS4).MethodsTargeted next-generation sequencing including the exon and flanking intron sequences of 79 deafness genes was performed on the proband. Co-segregation of the disease phenotype and the detected variants were confirmed in all family members by PCR amplification and Sanger sequencing.ResultsThe affected members of this family had two different recessive disorders, USH2 and WS4. By targeted next-generation sequencing, we identified that USH2 was caused by a novel missense mutation, p.V4907D in GPR98; whereas WS4 due to p.V185M in EDNRB. This is the first report of homozygous p.V185M mutation in EDNRB in patient with WS4.ConclusionThis study reported a Chinese family with multiple independent and overlapping phenotypes. In condition, molecular level analysis was efficient to identify the causative variant p.V4907D in GPR98 and p.V185M in EDNRB, also was helpful to confirm the clinical diagnosis of USH2 and WS4.



http://ift.tt/2eAW86s

Functional and quality of life outcomes after partial glossectomy: a multi-institutional longitudinal study of the head and neck research network

While aggressive treatment for oral cancer may optimize survival, decrements in speech and swallowing function and quality of life often result. This exploratory study investigated how patients recover their c...

http://ift.tt/2wD6Ukz

Erosion of the long process of the incus with incomplete ossicular discontinuity in simple chronic otitis media: should we reconstruct or leave it be?

Abstract

Objective

To determine whether patients with simple chronic otitis media and incomplete ossicular discontinuity should undergo ossicular reconstruction.

Design

Prospective, randomized surgical trial comparing no intervention with incus interposition over a 5-year period.

Setting

Tertiary referral hospital.

Participants

Seventy-six participants with simple chronic otitis media and erosion of the long process of the incus but apparent good transmission throughout the ossicular chain as tested intraoperatively. Forty-four patients had partial erosion of the incus but still bony contact with the stapes head (Group A –Type I), and 32 had mainly connective tissue binding the incus and stapes (Group B –Type II). Each of these groups was randomized to either leaving the ossicular chain as it was (A1 and B1) or performing an incus interposition (A2 and B2).

Main outcome measures

Average postoperative air bone gap and the degree of ABG closure. A postoperative air bone gap under 20 dB was considered a successful result.

Results

In group A, there was no significant difference between no intervention and incus interposition. In group B, patients in the no reconstruction subgroup had a significantly worse hearing result than the incus interposition subgroup (postoperative air bone gap of 27.5 dB and 31% closure within 20 dB versus 15 dB and 75% closure).

Conclusions

For Type I patients, the postoperative hearing results were similar for the reconstruction and no reconstruction groups. For Type II patients, the results clearly favor reconstruction.

This article is protected by copyright. All rights reserved.

http://ift.tt/2xL8EIJ

Deep Neck Space Infections-A Study in Diabetic Population in a Tertiary Care Centre

Abstract

This study is intended to analyze the clinical profile and outcomes of deep neck space infection in diabetic patients in our tertiary care centre. A prospective study of 1 year duration from 30th September 2015 to 30th September 2016 at department of Otorhinolaryngology, Gauhati Medical College and Hospital, Guwahati. A total of 45 diabetic patients who presented with DNSI are included in this study. Their demographic profile, etiology, bacteriology, treatment, duration of hospital stay, complications and outcomes have been analyzed. 45 patients were recorded; 32 (71.11%) were men, and 13 (45%) were women, with a mean age of 63.27 ± 7.55 years. There were 30 patients (66.67%) who had associated systemic diseases apart from diabetes mellitus. The parapharyngeal space in 13 patients (28.89%) was the most commonly involved space. Odontogenic infections in 18 patients (40%) and upper airway infections 9 patients (20%) were the two most common causes. Klebsiella pneumonia in 29 patients (64.44%), was the commonest organism isolated through pus cultures. All the patients except one (97.78%) came with abscess and underwent surgical drainage. One patient (2.22%) with carbuncle underwent regular dressing. Six patients (13.33%) had major complications. Those patients with other underlying systemic diseases or complications tended to have a longer hospital stay and were older. No cases of death has been reported. (mortality rate, 0%). DNSI patients with diabetes have a more severe clinical course. They are likely to have complications more frequently and a longer duration of hospital stay. In clinical practices while dealing with these patients more vigilance is required. On admission empirical antibiotics should cover K. pneumonia. Early surgical drainage remains the main method of treatment. Primary prevention can be achieved by orodental hygiene, regular dental check ups and in this part of the country by avoidance of substance abuse like tobacco chewing.

http://ift.tt/2w1NrIn

One hundred twenty five fat myringoplasties: does marginal perforation matter?

Abstract

Objective

to evaluate if calcified plaques adjacent to the perforation and marginal perforations are real contraindications to the fat graft myringoplasty.

Study Design

prospective study.

Methods

This study was conducted, from 1^st January 2008 to 31 December 2015 at our Otolaryngology Department of S.G. Moscati Hospital. The investigation included 125 patients, 60 males and 65 females, affected by COM who have undergone fat graft myringoplasty between 01/01/2008 to 31/12/2011. The average age of patients was 46 years (ranged 18 – 80).The patients were selected consecutively. For all the procedures the last otomicroscopic control was performed in 2015. Follow-up studies were done at 3 days, 7 days, 1 month, 3 months, 6 months and then once a year(mean follow-up 5.5 years, range 4-7 years). Informed consent was obtained after discussion of the alternative solutions. The consent of our institutional ethic committee was obtained. The inclusion criteria were the following: none previously ear surgery, dry ear at the time of surgery, persistent perforation for at least 6 months, absence of granulomatous tissue and cholesteatoma, perforation size of up to 35% of the eardrum surface, absence of ossicular chain damage. All patients who met inclusion criteria were enrolled. All patients included in the study accepted to be controlled for the entire follow-up. On the basis of tympanic membrane characteristics the study group was divided into 3 groups and 4 sub-groups: Group A (n=67) the fat myringoplasty was performed following the traditional indications, Group B(n=31) marginal perforations in which one side of the perforation is the fibrous annulus, was divided in 2 sub-groups B1(n=16) without calcified plaques adjacent to perforation and B2 (n=15) with plaques, Group C (n=27), marginal perforations in which one side is the bone annulus, was divided in 2 subgroups C1(n=15) without plaques and C2 (n=12) with plaques. The Fisher exact test (FET) was used to compare results in the described groups(sub-groups B1 with group A, sub-groups B2 with group A, subgroups C1 with group A and subgroups C2 with group A). A p<0.05 was considered significant. The surgical success is obtained with a complete closure of the tympanic membrane perforation. 0 dB. The mean pre-operative air bone gap (ABG) was 18,2 dB. Calculation of hearing results was in accordance with the American Academy of Otolaryngology Head and Neck Surgery 1995 guidelines for reporting conductive hearing loss ⁷ .

This article is protected by copyright. All rights reserved.

http://ift.tt/2x6SFYr

Metastases to the Parathyroid Glands: A Comprehensive Literature Review of 127 Reported Cases

Abstract

Metastases to the head and neck organs are uncommon, potentially representing the initial presentation of an occult malignancy. Single case reports and small series report metastases to the parathyroid gland, but there is no large review of the literature on secondary tumors involving the parathyroid glands. A review of the English literature between 1950 and 2017 was performed of all metastases or secondary involvement of the parathyroid glands. One hundred and twenty-seven cases of metastatic tumors were reported, although potentially significantly unrepresented in autopsy series (parathyroid glands are not routinely examined) and due to reporting bias. Women were affected more commonly than men (5.8:1; 99 vs. 17, respectively), with a mean age at presentation of 58.5 years, when reported. The most common primary sites of malignancies that metastasized to the parathyroid glands were breast carcinomas (66.9%, n = 85), melanoma (11.8%, n = 15), and lung carcinoma (5.5%, n = 7), with carcinomas representing 86.6% of metastases. Metastases were nearly always identified as part of widely metastatic disease, with only five (3.2%) cases reported as isolated metastases. Tumor-to-tumor metastases comprised 5.5% of all metastases to the parathyroid glands (metastases to parathyroid adenoma). A significant clinical finding of metastases to the parathyroid glands was the development of deranged calcium homeostasis, well beyond the 9 (7.2%) cases with primary parathyroid gland disease present. Although concurrent conditions (renal disease; bone metastases) may partially affect calcium metabolism, the onset of calcium derangement seemed to coincide with parathyroid gland metastases and not systemic disease. In summary, metastases to the parathyroid glands are uncommon, potentially under-recognized in patients who have otherwise widely metastatic tumors. Women are affected more often than men, with breast carcinomas (66.9%) and melanoma (11.8%) the most common primary tumors. Calcium homeostasis is affected, probably as a result of parathyroid gland parenchymal destruction.

http://ift.tt/2x6wjGu

Sinonasal Tract Alveolar Rhabdomyosarcoma in Adults: A Clinicopathologic and Immunophenotypic Study of Fifty-Two Cases with Emphasis on Epithelial Immunoreactivity

Abstract

Sinonasal tract (SNT) alveolar rhabdomyosarcoma (ARMS) are frequently misdiagnosed, especially in adults. Fifty-two adult (≥18 years) patients with SNT ARMS were reviewed and characterized by immunohistochemistry and molecular studies. Twenty-six females and 26 males (18–72 years; mean 43.2 years), presented after a short duration (mean 2.6 months) with a large (mean 5.5 cm) destructive nasal cavity mass, involving multiple contiguous paranasal sites (n = 46) and with cervical adenopathy (n = 41). The tumors showed an alveolar, nested to solid growth pattern below an intact, but often involved (n = 9) epithelium with frequent necrosis (n = 37), destructive bone invasion (n = 30), and lymphovascular invasion (n = 25). The neoplastic cells were dyshesive and dilapidated, with crush artifacts. Rhabdoid features (n = 36) and tumor cell multinucleation (n = 28) were common. Mitotic counts were high (mean 17/10 HPFs). The neoplastic cells showed the following immunohistochemical positive findings: desmin (100%), myogenin (100%), MYOD1 (100%), MSA (96%), SMA (52%), CAM5.2 (50%), AE1/AE3 (36%); other positive markers included S100 protein (27%), CD56 (100%), synaptophysin (35%), and chromogranin (13%). Overall, 54% show epithelial marker reactivity. Molecular studies showed FOXO1 translocations (81%) with PCR demonstrating PAX3 in 72.7% tested. Patients presented with high stage (IV 24; III 26) and metastatic disease (lymph nodes n = 41; distant metastases n = 25) (IRSG grouping). Surgery (n = 16), radiation (n = 41) and chemotherapy (n = 45) yielded an overall survival of 36.1 months (mean; range 2.4–286); 18 alive without disease (mean 69.6 months); 7 alive with disease (mean 11.0 months); 1 dead without disease (63.7 months); and 26 dead with disease (mean 18.5 months). SNT ARMS frequently present in adults as a large, destructive midline mass of short symptom duration, with high stage disease. The alveolar to solid pattern of growth of cells with rhabdoid-plasmacytoid features suggests the diagnosis, but epithelial immunohistochemistry markers are present in 54% of cases, leading to misdiagnosis as carcinomas if muscle markers are not also performed. Overall survival of 36.1 months is achieved with multimodality therapy, but 64% have incurable disease (16.9 months). Mixed anatomic site (p = 0.02) was a significant adverse prognostic indicator, while stage (0.06) and tumor size >5 cm (0.06) approached marginal significance.

http://ift.tt/2xLqPy6

Metastases to the Parathyroid Glands: A Comprehensive Literature Review of 127 Reported Cases

Abstract

Metastases to the head and neck organs are uncommon, potentially representing the initial presentation of an occult malignancy. Single case reports and small series report metastases to the parathyroid gland, but there is no large review of the literature on secondary tumors involving the parathyroid glands. A review of the English literature between 1950 and 2017 was performed of all metastases or secondary involvement of the parathyroid glands. One hundred and twenty-seven cases of metastatic tumors were reported, although potentially significantly unrepresented in autopsy series (parathyroid glands are not routinely examined) and due to reporting bias. Women were affected more commonly than men (5.8:1; 99 vs. 17, respectively), with a mean age at presentation of 58.5 years, when reported. The most common primary sites of malignancies that metastasized to the parathyroid glands were breast carcinomas (66.9%, n = 85), melanoma (11.8%, n = 15), and lung carcinoma (5.5%, n = 7), with carcinomas representing 86.6% of metastases. Metastases were nearly always identified as part of widely metastatic disease, with only five (3.2%) cases reported as isolated metastases. Tumor-to-tumor metastases comprised 5.5% of all metastases to the parathyroid glands (metastases to parathyroid adenoma). A significant clinical finding of metastases to the parathyroid glands was the development of deranged calcium homeostasis, well beyond the 9 (7.2%) cases with primary parathyroid gland disease present. Although concurrent conditions (renal disease; bone metastases) may partially affect calcium metabolism, the onset of calcium derangement seemed to coincide with parathyroid gland metastases and not systemic disease. In summary, metastases to the parathyroid glands are uncommon, potentially under-recognized in patients who have otherwise widely metastatic tumors. Women are affected more often than men, with breast carcinomas (66.9%) and melanoma (11.8%) the most common primary tumors. Calcium homeostasis is affected, probably as a result of parathyroid gland parenchymal destruction.

http://ift.tt/2x6wjGu

Sinonasal Tract Alveolar Rhabdomyosarcoma in Adults: A Clinicopathologic and Immunophenotypic Study of Fifty-Two Cases with Emphasis on Epithelial Immunoreactivity

Abstract

Sinonasal tract (SNT) alveolar rhabdomyosarcoma (ARMS) are frequently misdiagnosed, especially in adults. Fifty-two adult (≥18 years) patients with SNT ARMS were reviewed and characterized by immunohistochemistry and molecular studies. Twenty-six females and 26 males (18–72 years; mean 43.2 years), presented after a short duration (mean 2.6 months) with a large (mean 5.5 cm) destructive nasal cavity mass, involving multiple contiguous paranasal sites (n = 46) and with cervical adenopathy (n = 41). The tumors showed an alveolar, nested to solid growth pattern below an intact, but often involved (n = 9) epithelium with frequent necrosis (n = 37), destructive bone invasion (n = 30), and lymphovascular invasion (n = 25). The neoplastic cells were dyshesive and dilapidated, with crush artifacts. Rhabdoid features (n = 36) and tumor cell multinucleation (n = 28) were common. Mitotic counts were high (mean 17/10 HPFs). The neoplastic cells showed the following immunohistochemical positive findings: desmin (100%), myogenin (100%), MYOD1 (100%), MSA (96%), SMA (52%), CAM5.2 (50%), AE1/AE3 (36%); other positive markers included S100 protein (27%), CD56 (100%), synaptophysin (35%), and chromogranin (13%). Overall, 54% show epithelial marker reactivity. Molecular studies showed FOXO1 translocations (81%) with PCR demonstrating PAX3 in 72.7% tested. Patients presented with high stage (IV 24; III 26) and metastatic disease (lymph nodes n = 41; distant metastases n = 25) (IRSG grouping). Surgery (n = 16), radiation (n = 41) and chemotherapy (n = 45) yielded an overall survival of 36.1 months (mean; range 2.4–286); 18 alive without disease (mean 69.6 months); 7 alive with disease (mean 11.0 months); 1 dead without disease (63.7 months); and 26 dead with disease (mean 18.5 months). SNT ARMS frequently present in adults as a large, destructive midline mass of short symptom duration, with high stage disease. The alveolar to solid pattern of growth of cells with rhabdoid-plasmacytoid features suggests the diagnosis, but epithelial immunohistochemistry markers are present in 54% of cases, leading to misdiagnosis as carcinomas if muscle markers are not also performed. Overall survival of 36.1 months is achieved with multimodality therapy, but 64% have incurable disease (16.9 months). Mixed anatomic site (p = 0.02) was a significant adverse prognostic indicator, while stage (0.06) and tumor size >5 cm (0.06) approached marginal significance.

http://ift.tt/2xLqPy6

Quality of life in patients with vitiligo using the short form 36

Vitiligo is an acquired pigmentary disorder affecting 0.5-1% of the world's population. Affected individuals often have low self-esteem, and poor quality of life (QOL) due to the disfigurement caused by the disease [1]. Vitiligo's impact on QOL compared to other diseases using general health questionnaires like the Short Form 36 (SF-36) is not well understood. We performed a cross-sectional study of patients with vitiligo and controls using the SF-36 and compared our scores to studies of patients with depression, chronic lung disease, psoriasis, atopic dermatitis, arthritis, cancer, congestive heart failure, myocardial infarction, type 2 diabetes, hypertension, and healthy adults.

This article is protected by copyright. All rights reserved.

http://ift.tt/2wDy5vI

Relook on Mastoid Cavity Obliteration: A Prospective Study

Abstract

Canal wall down (CWD) mastoidectomy is the operation of choice for unsafe variety of chronic otitis media. But open mastoid cavity poses many problems. The solution of these problems is obliteration of mastoid cavity that is self-cleaning and easily maintained. In our study we aim to establish the effective technique for mastoid cavity obliteration in CWD mastoidectomy and review its efficacy in producing a dry, low maintenance cavity. This was a non-randomized longitudinal prospective study, performed over 2½ years in the department of ENT in a tertiary care hospital of Kolkata. Patients of chronic otitis media unsafe variety within the age group of 16–60 years were included in our study. Chronic otitis media unsafe variety with intratemporal or intracranial complications, and extensive cholesteatoma or granulation tissue that can't be cleared completely during operation were excluded. There was no statistical significance for hearing improvement between CWD mastoidectomy without obliteration and CWD mastoidectomy with obliteration. There was significant statistical significance for obliteration of cavity, epithelized cavity and dry cavity between CWD mastoidectomy without obliteration and CWD mastoidectomy with obliteration. Persistent discharge and granulation were significantly more in non-obliterated group. The time taken by the ear to become dry is much shorter after mastoid cavity obliteration. Moreover, lifelong aural toilet and dependence on an ENT surgeon is avoided. Inspite of all these, a few pre-conditions must be fulfilled before embarking on this type of surgery.

http://ift.tt/2eYoyrE

Deep Neck Space Infections-A Study in Diabetic Population in a Tertiary Care Centre

Abstract

This study is intended to analyze the clinical profile and outcomes of deep neck space infection in diabetic patients in our tertiary care centre. A prospective study of 1 year duration from 30th September 2015 to 30th September 2016 at department of Otorhinolaryngology, Gauhati Medical College and Hospital, Guwahati. A total of 45 diabetic patients who presented with DNSI are included in this study. Their demographic profile, etiology, bacteriology, treatment, duration of hospital stay, complications and outcomes have been analyzed. 45 patients were recorded; 32 (71.11%) were men, and 13 (45%) were women, with a mean age of 63.27 ± 7.55 years. There were 30 patients (66.67%) who had associated systemic diseases apart from diabetes mellitus. The parapharyngeal space in 13 patients (28.89%) was the most commonly involved space. Odontogenic infections in 18 patients (40%) and upper airway infections 9 patients (20%) were the two most common causes. Klebsiella pneumonia in 29 patients (64.44%), was the commonest organism isolated through pus cultures. All the patients except one (97.78%) came with abscess and underwent surgical drainage. One patient (2.22%) with carbuncle underwent regular dressing. Six patients (13.33%) had major complications. Those patients with other underlying systemic diseases or complications tended to have a longer hospital stay and were older. No cases of death has been reported. (mortality rate, 0%). DNSI patients with diabetes have a more severe clinical course. They are likely to have complications more frequently and a longer duration of hospital stay. In clinical practices while dealing with these patients more vigilance is required. On admission empirical antibiotics should cover K. pneumonia. Early surgical drainage remains the main method of treatment. Primary prevention can be achieved by orodental hygiene, regular dental check ups and in this part of the country by avoidance of substance abuse like tobacco chewing.

http://ift.tt/2w1NrIn

Metastases to the Parathyroid Glands: A Comprehensive Literature Review of 127 Reported Cases

Abstract

Metastases to the head and neck organs are uncommon, potentially representing the initial presentation of an occult malignancy. Single case reports and small series report metastases to the parathyroid gland, but there is no large review of the literature on secondary tumors involving the parathyroid glands. A review of the English literature between 1950 and 2017 was performed of all metastases or secondary involvement of the parathyroid glands. One hundred and twenty-seven cases of metastatic tumors were reported, although potentially significantly unrepresented in autopsy series (parathyroid glands are not routinely examined) and due to reporting bias. Women were affected more commonly than men (5.8:1; 99 vs. 17, respectively), with a mean age at presentation of 58.5 years, when reported. The most common primary sites of malignancies that metastasized to the parathyroid glands were breast carcinomas (66.9%, n = 85), melanoma (11.8%, n = 15), and lung carcinoma (5.5%, n = 7), with carcinomas representing 86.6% of metastases. Metastases were nearly always identified as part of widely metastatic disease, with only five (3.2%) cases reported as isolated metastases. Tumor-to-tumor metastases comprised 5.5% of all metastases to the parathyroid glands (metastases to parathyroid adenoma). A significant clinical finding of metastases to the parathyroid glands was the development of deranged calcium homeostasis, well beyond the 9 (7.2%) cases with primary parathyroid gland disease present. Although concurrent conditions (renal disease; bone metastases) may partially affect calcium metabolism, the onset of calcium derangement seemed to coincide with parathyroid gland metastases and not systemic disease. In summary, metastases to the parathyroid glands are uncommon, potentially under-recognized in patients who have otherwise widely metastatic tumors. Women are affected more often than men, with breast carcinomas (66.9%) and melanoma (11.8%) the most common primary tumors. Calcium homeostasis is affected, probably as a result of parathyroid gland parenchymal destruction.

http://ift.tt/2x6wjGu

Sinonasal Tract Alveolar Rhabdomyosarcoma in Adults: A Clinicopathologic and Immunophenotypic Study of Fifty-Two Cases with Emphasis on Epithelial Immunoreactivity

Abstract

Sinonasal tract (SNT) alveolar rhabdomyosarcoma (ARMS) are frequently misdiagnosed, especially in adults. Fifty-two adult (≥18 years) patients with SNT ARMS were reviewed and characterized by immunohistochemistry and molecular studies. Twenty-six females and 26 males (18–72 years; mean 43.2 years), presented after a short duration (mean 2.6 months) with a large (mean 5.5 cm) destructive nasal cavity mass, involving multiple contiguous paranasal sites (n = 46) and with cervical adenopathy (n = 41). The tumors showed an alveolar, nested to solid growth pattern below an intact, but often involved (n = 9) epithelium with frequent necrosis (n = 37), destructive bone invasion (n = 30), and lymphovascular invasion (n = 25). The neoplastic cells were dyshesive and dilapidated, with crush artifacts. Rhabdoid features (n = 36) and tumor cell multinucleation (n = 28) were common. Mitotic counts were high (mean 17/10 HPFs). The neoplastic cells showed the following immunohistochemical positive findings: desmin (100%), myogenin (100%), MYOD1 (100%), MSA (96%), SMA (52%), CAM5.2 (50%), AE1/AE3 (36%); other positive markers included S100 protein (27%), CD56 (100%), synaptophysin (35%), and chromogranin (13%). Overall, 54% show epithelial marker reactivity. Molecular studies showed FOXO1 translocations (81%) with PCR demonstrating PAX3 in 72.7% tested. Patients presented with high stage (IV 24; III 26) and metastatic disease (lymph nodes n = 41; distant metastases n = 25) (IRSG grouping). Surgery (n = 16), radiation (n = 41) and chemotherapy (n = 45) yielded an overall survival of 36.1 months (mean; range 2.4–286); 18 alive without disease (mean 69.6 months); 7 alive with disease (mean 11.0 months); 1 dead without disease (63.7 months); and 26 dead with disease (mean 18.5 months). SNT ARMS frequently present in adults as a large, destructive midline mass of short symptom duration, with high stage disease. The alveolar to solid pattern of growth of cells with rhabdoid-plasmacytoid features suggests the diagnosis, but epithelial immunohistochemistry markers are present in 54% of cases, leading to misdiagnosis as carcinomas if muscle markers are not also performed. Overall survival of 36.1 months is achieved with multimodality therapy, but 64% have incurable disease (16.9 months). Mixed anatomic site (p = 0.02) was a significant adverse prognostic indicator, while stage (0.06) and tumor size >5 cm (0.06) approached marginal significance.

http://ift.tt/2xLqPy6

Relook on Mastoid Cavity Obliteration: A Prospective Study

Abstract

Canal wall down (CWD) mastoidectomy is the operation of choice for unsafe variety of chronic otitis media. But open mastoid cavity poses many problems. The solution of these problems is obliteration of mastoid cavity that is self-cleaning and easily maintained. In our study we aim to establish the effective technique for mastoid cavity obliteration in CWD mastoidectomy and review its efficacy in producing a dry, low maintenance cavity. This was a non-randomized longitudinal prospective study, performed over 2½ years in the department of ENT in a tertiary care hospital of Kolkata. Patients of chronic otitis media unsafe variety within the age group of 16–60 years were included in our study. Chronic otitis media unsafe variety with intratemporal or intracranial complications, and extensive cholesteatoma or granulation tissue that can't be cleared completely during operation were excluded. There was no statistical significance for hearing improvement between CWD mastoidectomy without obliteration and CWD mastoidectomy with obliteration. There was significant statistical significance for obliteration of cavity, epithelized cavity and dry cavity between CWD mastoidectomy without obliteration and CWD mastoidectomy with obliteration. Persistent discharge and granulation were significantly more in non-obliterated group. The time taken by the ear to become dry is much shorter after mastoid cavity obliteration. Moreover, lifelong aural toilet and dependence on an ENT surgeon is avoided. Inspite of all these, a few pre-conditions must be fulfilled before embarking on this type of surgery.

http://ift.tt/2eYoyrE