Molecular pathology of thymomas: implications for diagnosis and therapy

AbstractThymomas exhibit a unique genomic landscape, comprising the lowest on average total mutational burden among adult human cancers; a unique point mutation in the GTF2I gene in WHO type A and AB thymomas (and rarely others); almost unique KMT2A-MAML2 translocations in rare WHO type B2 and B3 thymomas; a unique YAP1-MAML2 translocation in almost all metaplastic thymomas; and unique miRNA profiles in relation to GTF2I mutational status and WHO histotypes. While most thymomas can be diagnosed solely on the basis of morphological features, mutational analyses can solve challenging differential diagnostic problems. No molecular biomarkers have been identified that predict the response of unresectable thymomas to chemotherapy or agents with known molecular targets. Despite the common and strong expression of PDL1 in thymomas, immune checkpoint inhibitors are rarely applicable due to the poor predictability of common, life-threatening autoimmune side effects that are related to the unrivaled propensity of thymomas towards autoimmunity.

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Management of rheumatic complications of immune checkpoint inhibitor therapy – an oncological perspective

Rheumatology ◽

10.1093/rheumatology/kez536 ◽

2019 ◽

Vol 58 (Supplement_7) ◽

pp. vii29-vii39 ◽

Cited By ~ 4

Author(s):

Neil M Steven ◽

Benjamin A Fisher

Keyword(s):

Adverse Events ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Cancer Control ◽

Myasthenic Crisis ◽

Life Threatening ◽

Checkpoint Inhibitor Therapy ◽

The Common ◽

Risk And Benefit

Abstract Immune checkpoint inhibitors (CPIs) are an effective treatment for many cancers but cause diverse immune-related adverse events (IrAEs). Rheumatological IrAEs include arthralgia, arthritis, tenosynovitis, myositis, polymyalgia rheumatica and sicca syndrome. CPI use can unmask RA as well as causing flares of prior autoimmune or connective tissue disease. Oncologists categorize and grade IrAEs using the Common Terminology Criteria for Adverse Events and manage them according to international guidelines. However, rheumatological events are unfamiliar territory: oncologists need to work with rheumatologists to elicit and assess symptoms, signs, results of imaging and autoantibody testing and to determine the use of steroids and DMARDs. Myositis may overlap with myasthenic crisis and myocarditis and can be life-threatening. Treatment should be offered on balance of risk and benefit, including whether to continue CPI treatment and recognizing the uncertainty over whether glucocorticoids and DMARDs might compromise cancer control.

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The Genomic Landscape of Radioactive Iodine Refractory and Avid Papillary Thyroid Carcinomas

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1779 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A871-A871

Author(s):

Khawla Sami Al-Kuraya ◽

Sarah Siraj ◽

Tariq Masoodi ◽

Abdul Khalid Siraj ◽

Saud Azam ◽

...

Keyword(s):

Radioactive Iodine ◽

Excision Repair ◽

Checkpoint Inhibitors ◽

Disease Free Survival ◽

Driver Mutations ◽

Refractory Disease ◽

Papillary Thyroid ◽

Mutational Signatures ◽

Mutational Burden ◽

Genomic Landscape

Abstract Background: Although, standard treatment of Papillary Thyroid Carcinoma (PTC), involving surgery followed by radioactive iodine (RAI) therapy, is curative for most patients, 5-20% of patients develop RAI refractory disease. The repertoire of genomic events enabling RAI refractory disease in PTC needs elucidating. Methods: Whole-exome sequencing was performed on 100 primary PTC tumours, consisting of 47 RAI refractory and 53 RAI avid tumours, with matched germline. The resulting somatic variants were analysed to compare the genomic landscape, driver events and clinically actionable events between RAI refractory and avid PTC. Results: RAI refractory primary tumours were significantly associated with later stage, positive involvement of surgical margins, presence of extrathyroidal extension, lymph node metastases and poorer 5-year disease-free survival. Mutational burden was significantly higher, with additional subclonal mutations in RAI refractory compared to avid PTC patients. RAI refractory primary tumours showed significantly stronger PD-L1 expression. Mutations and PD-L1 expression in RAI Refractory PTC tumours significantly correlated with mutational signatures related to defective DNA base and nucleotide excision repair pathways. Driver mutations were acquired earlier in RAI refractory than in avid primary tumours. Conclusions: We conclude that RAI refractoriness is gained early in PTC, and is significantly associated with a higher mutational burden, PD-L1 expression, and mutational signatures, which may serve as important prognostic factors and indicate suitability for treatment with immune checkpoint inhibitors.

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Bringing Reformed Liturgy to Print at the New Monastery at Marienthal

Church History and Religious Culture ◽

10.1163/187124108x426565 ◽

2008 ◽

Vol 88 (3) ◽

pp. 415-436

Author(s):

Mary Kay Duggan

Keyword(s):

New Technology ◽

River Rhine ◽

Common Life ◽

German Translation ◽

Liturgical Texts ◽

The Common ◽

Almost All ◽

Spiritual Reading

AbstractThe reformed liturgical texts created at the Council of Basel (1431–1449) were not printed at Mainz, the birthplace of the new technology, but across the river Rhine at a new monastery of the Brothers of the Common Life at Marienthal. Documentation of the establishment of that monastery is sketchy but includes the involvement of Archbishop Adolph II of Nassau (1462–1475) and vicar general of the Mainz diocese, Gabriel Biel (1410–1495), who would become a Brother at Marienthal. The 21 editions (1474–1484) that were issued by the monastery were almost all newly written books by local clerics: the reformed liturgical texts for the new German Bursfeld Congregation of Benedictines and diocesan breviaries; spiritual reading in the vernacular so typical of the books of the Brothers, including the first German translation by Biel of Jean Gerson's Opus tripartitum, a confessional by Johannes Lupi, and a life of St. Martin of Tours by Sulpitius Severus. Who cast the six types, who did the printing, and who paid for the printing shop remain subjects of conjecture?

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Endocrine toxicity of cancer immunotherapy: clinical challenges

Endocrine Connections ◽

10.1530/ec-20-0489 ◽

2021 ◽

Author(s):

Bliss Anderson ◽

Daniel L Morganstein

Keyword(s):

Type 1 Diabetes ◽

Adverse Events ◽

Immune Checkpoint ◽

Thyroid Disease ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Endocrine Dysfunction ◽

Life Threatening ◽

The Common

Immune checkpoint inhibitors are now widely used in the treatment of multiple cancers. The major toxicities of these treatments are termed immune related adverse events and endocrine dysfunction is common. Thyroid disease, hypopituitarism and a form of diabetes resembling type 1 diabetes are now all well described, with different patterns emerging with different checkpoint inhibitors. We review the presentation and management of the common endocrine immune related adverse events, and discuss a number of recent advances in the understanding of these important, potentially life threatening toxicities. We also discuss some remaining dilemmas in management.

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Dermatology

10.1093/med/9780198786870.003.0016 ◽

2017 ◽

Author(s):

Ashis Banerjee ◽

Clara Oliver

Keyword(s):

Skin Diseases ◽

Management Plan ◽

Multisystem Disease ◽

Common Life ◽

Johnson Syndrome ◽

Short Answer Question ◽

Life Threatening ◽

The Common ◽

Skin Conditions ◽

Steven Johnson Syndrome

Dermatology encompasses a large number of conditions including both primary skin diseases as well as multisystem disease. This chapter covers the pertinent areas of dermatology required for the Intermediate FRCEM examination. It is highly possible that skin conditions could appear in the short-answer question (SAQ) paper and therefore this chapter provides candidates with the tools to describe a rash in terms of nomenclature as well as constructing a differential diagnosis and management plan. This chapter covers the common life-threatening rashes such as Steven-Johnson syndrome, as well as rashes associated with multisystem disease such as erythema nodosum and primary skin conditions.

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Pneumonitis als gravierende Nebenwirkung bei Asthmapatienten unter Immuntherapie

Karger Kompass Pneumologie ◽

10.1159/000509167 ◽

2020 ◽

Vol 8 (4) ◽

pp. 204-205

Author(s):

Susanne M. Lang

Keyword(s):

Medical Records ◽

Checkpoint Inhibitors ◽

Cancer Center ◽

Increased Risk ◽

Characteristic Imaging ◽

Life Threatening ◽

History Of ◽

Former Smokers ◽

The Common ◽

Grade 3

Introduction: Predicting the factors that increase the risk of immune-related pneumonitis, a potentially life-threatening complication of treatment with immune checkpoint inhibitors for cancer, is a clinical challenge. Baseline clinical factors such as asthma may portend the development of pneumonitis due to pre-existing airway inflammation prior to immunotherapy. Objective: The purpose of the study was to investigate whether a prior diagnosis of asthma is associated with an increased risk of immune-related pneumonitis in patients undergoing cancer immunotherapy. Methods: Patients at the Moores Cancer Center at UC San Diego Health undergoing immunotherapy were identified on an IRB-approved protocol. Clinical charts were reviewed for asthma documented in the medical records and CT scans were reviewed during and after treatment. Pneumonitis was defined as the onset of new pulmonary symptoms with characteristic imaging findings during or after a patient’s first course of immunotherapy that could not be readily explained as infection or a progression of malignancy. It was graded according to the Common Terminology Criteria for Adverse Events. Results: A total of 187 patients were included. A diagnosis of asthma was found in the records of 26 cases (13.9%). Pneumonitis was found in 10 cases (5.35%); 50% were grade 2 and 50% were grade 3–4. Two of the grade 3–4 cases (40%) occurred in patients with non-small-cell lung cancer. Three patients with asthma developed pneumonitis (11.5% of patients with asthma), all grade 3–4. Only 28.6% of the non-asthma-pneumonitis cases were grade 3–4. All (100%) of the asthma-pneumonitis patients were former smokers, while 71.4% of the non-asthma-pneumonitis patients were former smokers. Conclusion: A history of asthma may be associated with a higher grade of pneumonitis if it develops, and a history of smoking may augment this relationship.

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An Overview of Dementias

Perspectives on Swallowing and Swallowing Disorders (Dysphagia) ◽

10.1044/sasd21.3.75 ◽

2012 ◽

Vol 21 (3) ◽

pp. 75-84

Author(s):

Venkata Vijaya K. Dalai ◽

Jason E. Childress ◽

Paul E Schulz

Keyword(s):

Clinical Presentation ◽

Treatment Options ◽

Current Treatment ◽

Great Variability ◽

Health Concern ◽

Public Health Concern ◽

Life Threatening ◽

The Common ◽

Neurodegenerative Dementias ◽

Made In

Dementia is a major public health concern that afflicts an estimated 24.3 million people worldwide. Great strides are being made in order to better diagnose, prevent, and treat these disorders. Dementia is associated with multiple complications, some of which can be life-threatening, such as dysphagia. There is great variability between dementias in terms of when dysphagia and other swallowing disorders occur. In order to prepare the reader for the other articles in this publication discussing swallowing issues in depth, the authors of this article will provide a brief overview of the prevalence, risk factors, pathogenesis, clinical presentation, diagnosis, current treatment options, and implications for eating for the common forms of neurodegenerative dementias.

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Fibrinolytic Activity of the Arterial Wall

Thrombosis and Haemostasis ◽

10.1055/s-0038-1653503 ◽

1969 ◽

Vol 21 (01) ◽

pp. 001-011 ◽

Cited By ~ 9

Author(s):

K Onoyama ◽

K Tanaka

Keyword(s):

Carotid Artery ◽

Fibrinolytic Activity ◽

Arterial Wall ◽

Aortic Wall ◽

Internal Carotid ◽

Atheromatous Plaque ◽

Human Fibrinogen ◽

The Media ◽

The Common ◽

Almost All

SummaryThe tissue fibrinolysis was studied in 550 specimens of 7 kinds of arteries from 80 fresh cadavers, using Astrup’s biochemical method and Todd’s histochemical method with human fibrinogen.In the microscopically normal aortic wall, almost all specimens had the fibrinolytic activity which was the strongest in the adventitia and the weakest in the media.The fibrinolytic activity seemed to be localized in the endothelium.The stronger activity lay in the adventitia of the aorta and the pulmonary artery and all layers of the cerebral artery.The activity of the intima and media of the macroscopically normal areas seemed to be stronger in the internal carotid artery than in the common carotid artery.Mean fibrinolytic activity of the macroscopically normal areas seemed to decrease with age in the intima and the media of the thoracic aorta and seemed to be low in the cases with a high atherosclerotic index.The fibrinolytic activities of all three layers of the fibrous thickened aorta seemed to decrease, and those of the media and the adventitia of the atheromatous plaque to increase.The fibrinolytic activity of the arterial wall might play some role in the progress of atherosclerosis.

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Cutaneous Adverse Events of Immune Checkpoint Inhibitors: A Summarized Overview

Current Drug Safety ◽

10.2174/1574886313666180730114309 ◽

2019 ◽

Vol 14 (1) ◽

pp. 14-20 ◽

Cited By ~ 12

Author(s):

Kerasia-Maria Plachouri ◽

Eleftheria Vryzaki ◽

Sophia Georgiou

Keyword(s):

Side Effects ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Skin Toxicity ◽

Maculopapular Rash ◽

Symptomatic Treatment ◽

Stevens Johnson Syndrome ◽

Life Threatening ◽

Skin Side Effects

Background:The introduction of Immune Checkpoint Inhibitors in the recent years has resulted in high response rates and extended survival in patients with metastatic/advanced malignancies. Their mechanism of action is the indirect activation of cytotoxic T-cells through the blockade of inhibitory receptors of immunomodulatory pathways, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1) and its ligand (PD-L1). Despite their impressive therapeutic results, they can also induce immune-related toxicity, affecting various organs, including the skin.Objective:To provide an updated summarized overview of the most common immune-mediated cutaneous side effects and their management.Method:English articles derived from the databases PubMed and SCOPUS and published between 2009 and 2018, were analyzed for this narrative review.Results:The most common adverse cutaneous reactions include maculopapular rash, lichenoid reactions, vitiligo and pruritus, with severity Grade 1 or 2. Less frequent but eventually life-threatening skin side effects, including Stevens-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms and Toxic Epidermal necrolysis, have also been reported.Conclusion:Basic knowledge of the Immune-Checkpoint-Inhibitors-induced skin toxicity is necessary in order to recognize these treatment-related complications. The most frequent skin side effects, such as maculopapular rash, vitiligo and pruritus, tend to subside under symptomatic treatment so that permanent discontinuation of therapy is not commonly necessary. In the case of life-threatening side effects, apart from the necessary symptomatic treatment, the immunotherapy should be permanently stopped. Information concerning the management of ICIs-mediated skin toxicity can be obtained from the literature as well as from the Summary of Product Characteristics of each agent.

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The OSMR Gene Is Involved in Hirschsprung Associated Enterocolitis Susceptibility through an Altered Downstream Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms22083831 ◽

2021 ◽

Vol 22 (8) ◽

pp. 3831

Author(s):

Tiziana Bachetti ◽

Francesca Rosamilia ◽

Martina Bartolucci ◽

Giuseppe Santamaria ◽

Manuela Mosconi ◽

...

Keyword(s):

Immune Response ◽

Oncostatin M ◽

Common Life ◽

Downstream Signaling ◽

Whole Exome ◽

Gut Homeostasis ◽

Life Threatening ◽

Infection And Inflammation ◽

Susceptibility Variant ◽

Oncostatin M Receptor

Hirschsprung (HSCR) Associated Enterocolitis (HAEC) is a common life-threatening complication in HSCR. HAEC is suggested to be due to a loss of gut homeostasis caused by impairment of immune system, barrier defense, and microbiome, likely related to genetic causes. No gene has been claimed to contribute to HAEC occurrence, yet. Genetic investigation of HAEC by Whole-Exome Sequencing (WES) on 24 HSCR patients affected (HAEC) or not affected (HSCR-only) by enterocolitis and replication of results on a larger panel of patients allowed the identification of the HAEC susceptibility variant p.H187Q in the Oncostatin-M receptor (OSMR) gene (14.6% in HAEC and 5.1% in HSCR-only, p = 0.0024). Proteomic analysis on the lymphoblastoid cell lines from one HAEC patient homozygote for this variant and one HAEC patient not carrying the variant revealed two well distinct clusters of proteins significantly up or downregulated upon OSM stimulation. A marked enrichment in immune response pathways (q < 0.0001) was shown in the HAEC H187 cell line, while proteins upregulated in the HAEC Q187 lymphoblasts sustained pathways likely involved in pathogen infection and inflammation. In conclusion, OSMR p.H187Q is an HAEC susceptibility variant and perturbates the downstream signaling cascade necessary for the gut immune response and homeostasis maintenance.

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