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Ideggyogyaszati Szemle Sep 2015Meningiomas represent nearly one-third of all adult primary brain tumours. According to their clinical and histologic appearance, they can be divided into WHO grades... (Review)
Review
Meningiomas represent nearly one-third of all adult primary brain tumours. According to their clinical and histologic appearance, they can be divided into WHO grades I-III. Almost 90% of meningiomas are benign, showing favourable response to conventional therapies, however, patients diagnosed with grade 2 and 3 tumours may have a poor prognosis. In addition, high frequency of tumour recurrence renders treatments more challenging even in benign meningiomas. Molecular-pathological profiling of meningiomas could lead to development of more effective therapies. Although the cytogenetic background of these tumours are already well-characterised, the majority of related genes and mutations is still unknown. Recently, high-throughput techniques enabled better characterisation of mechanisms involved in meningioma development, progression and recurrence. Furthermore, epigenetic dysregulation could offer new opportunities for both diagnosis and treatment of meningiomas. We provide a comprehensive overview of cytogenetic and molecular genetic defects as well as epigenetic alterations in meningiomas. Many of these may serve as biomarker or therapeutic target in the near future.
Topics: Brain Neoplasms; CpG Islands; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genes, Neoplasm; Humans; Loss of Heterozygosity; Meningeal Neoplasms; Meningioma; MicroRNAs; Mutation; Neoplasm Grading; Neoplasm Recurrence, Local; Pathology, Molecular; Prognosis; Risk Factors
PubMed: 26665490
DOI: 10.18071/isz.68.0292 -
The Journal of Pathology Jan 2015Human coronaviruses (CoVs) mostly cause a common cold that is mild and self-limiting. Zoonotic transmission of CoVs such as the recently identified Middle East... (Review)
Review
Human coronaviruses (CoVs) mostly cause a common cold that is mild and self-limiting. Zoonotic transmission of CoVs such as the recently identified Middle East respiratory syndrome (MERS)-CoV and severe acute respiratory syndrome (SARS)-CoV, on the other hand, may be associated with severe lower respiratory tract infection. This article reviews the clinical and pathological data available on MERS and compares it to SARS. Most importantly, chest radiographs and imaging results of patients with MERS show features that resemble the findings of organizing pneumonia, different from the lesions in SARS patients, which show fibrocellular intra-alveolar organization with a bronchiolitis obliterans organizing pneumonia-like pattern. These findings are in line with differences in the induction of cytopathological changes, induction of host gene responses and sensitivity to the antiviral effect of interferons in vitro when comparing both MERS-CoV and SARS-CoV. The challenge will be to translate these findings into an integrated picture of MERS pathogenesis in humans and to develop intervention strategies that will eventually allow the effective control of this newly emerging infectious disease.
Topics: Animals; Antiviral Agents; Biopsy; Coronavirus Infections; Host-Pathogen Interactions; Humans; Middle East Respiratory Syndrome Coronavirus; Pathology, Molecular; Predictive Value of Tests; Prognosis; Respiratory System; Severe acute respiratory syndrome-related coronavirus; Severe Acute Respiratory Syndrome; Virology; Virulence
PubMed: 25294366
DOI: 10.1002/path.4458 -
Theranostics 2021As complex and heterogeneous diseases, cancers require a more tailored therapeutic management than most pathologies. Recent advances in anticancer drug development,... (Review)
Review
As complex and heterogeneous diseases, cancers require a more tailored therapeutic management than most pathologies. Recent advances in anticancer drug development, including the immuno-oncology revolution, have been too often plagued by unsatisfying patient response rates and survivals. In reaction to this, cancer care has fully transitioned to the "personalized medicine" concept. Numerous tools are now available tools to better adapt treatments to the profile of each patient. They encompass a large array of diagnostic assays, based on biomarkers relevant to targetable molecular pathways. As a subfamily of such so-called companion diagnostics, chemosensitivity and resistance assays represent an attractive, yet insufficiently understood, approach to individualize treatments. They rely on the assessment of a composite biomarker, the functional response of cancer cells to drugs, to predict a patient's outcome. Systemic treatments, such as chemotherapies, as well as targeted treatments, whose efficacy cannot be fully predicted yet by other diagnostic tests, may be assessed through these means. The results can provide helpful information to assist clinicians in their decision-making process. We explore here the most advanced functional assays across oncology indications, with an emphasis on tests already displaying a convincing clinical demonstration. We then recapitulate the main technical obstacles faced by researchers and clinicians to produce more accurate, and thus more predictive, models and the recent advances that have been developed to circumvent them. Finally, we summarize the regulatory and quality frameworks surrounding functional assays to ensure their safe and performant clinical implementation. Functional assays are valuable diagnostic tools that already stand beyond the "proof-of-concept" stage. Clinical studies show they have a major role to play by themselves but also in conjunction with molecular diagnostics. They now need a final lift to fully integrate the common armament used against cancers, and thus make their way into the clinical routine.
Topics: Biological Assay; Biomarkers, Pharmacological; Biomarkers, Tumor; Humans; Medical Oncology; Neoplasms; Pathology, Molecular; Precision Medicine
PubMed: 34646385
DOI: 10.7150/thno.55954 -
Ocular Immunology and Inflammation 2022To report the cytopathology of vitreous biopsy samples in patients with acute retinal necrosis (ARN) who underwent pars plana vitrectomy (PPV). We also describe two...
PURPOSE
To report the cytopathology of vitreous biopsy samples in patients with acute retinal necrosis (ARN) who underwent pars plana vitrectomy (PPV). We also describe two patients with unique clinical courses, cytopathologic findings, and immune response.
METHODS
A retrospective review of patients with ARN who developed retinal detachment (RD) and underwent PPV from 22011 to 2019 at the Emory Eye Center was performed to assess cytopathology findings of vitreous biopsy samples. Patient demographics and laboratory testing including aqueous humor PCR for viral pathogens were recorded. Additional clinical details abstracted included intravitreal injections, surgical procedures, and vitreous cytopathological reports including immunohistochemistry findings.
RESULTS
Fourteen eyes of 12 patients with RD were reviewed. Ten eyes showed HSV DNA (71%) and 4 demonstrated VZV DNA (29%). All eyes received intravitreal antivirals (i.e. ganciclovir or foscarnet) with a median of 8.5 intravitreal injections per eye. Diagnoses prompting PPV included tractional RD in 14 eyes (100%), rhegmatogenous RD in 8 eyes (57%), vitreous hemorrhage in 4 eyes (29%) and vitreous opacity in 4 (29%). Ophthalmic pathology reports showed lymphocyte populations in 10 eyes (71%) with a CD3 + T-cell predominance in two patients where immunohistochemistry of CD3+ and CD20+ for T- and B-cell populations was performed. Observed immune cell populations included macrophages or histiocytes (11 eyes, 79%) and polymorphonuclear cells in 4 eyes (29%). Initial median VA was 2.5 (IQR 2.0-3.0) and improved to 2.0 (IQR 1.48-3.00, = .48) at 6-months and 1.8 (IQR 1.2-3.0, = .45) at 12 months follow-up.
CONCLUSIONS
Our cohort of ARN patients undergoing PPV show a spectrum of immunologic findings with the majority demonstrating a lymphocytic response. Histiocytes, macrophages, and PMNs were also observed. Cytopathologic and immunologic studies suggest that both innate and adaptive immunity are responsible for the clinical disease findings observed in ARN. The variability of the response to treatment in patients with ARN may reflect patient-to-patient differences in their antigen-specific immune response. Understanding the immunologic response associated with ARN may provide valuable information regarding the dosing and timing of treatment.
Topics: Humans; Retinal Necrosis Syndrome, Acute; Cytology
PubMed: 34242097
DOI: 10.1080/09273948.2021.1922926 -
Virchows Archiv : An International... Jan 2021Thymomas exhibit a unique genomic landscape, comprising the lowest on average total mutational burden among adult human cancers; a unique point mutation in the GTF2I... (Review)
Review
Thymomas 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.
Topics: Biomarkers, Tumor; DNA Mutational Analysis; Humans; Mutation; Pathology, Molecular; Thymoma; Thymus Neoplasms
PubMed: 33674910
DOI: 10.1007/s00428-021-03068-8 -
Journal of Innate Immunity 2014Severe infection and the patient response constitute sepsis. Here, we review the meta-genome (patient genetics, pathogen communities and host response) and its impact... (Review)
Review
Severe infection and the patient response constitute sepsis. Here, we review the meta-genome (patient genetics, pathogen communities and host response) and its impact upon the outcome of severe sepsis. Patient genetics, both predisposition for infection and the subsequent response to infection are reviewed. The pathogen is discussed with particular emphasis upon the modern era of microbiome analysis and nucleic acid diagnostics. Finally, we discuss the host clinical and immune responses and present new data to suggest that the immune response is the key to understanding sepsis and improving a death rate of nearly 30%.
Topics: Acute Disease; Bacterial Infections; Biodiversity; Genetic Predisposition to Disease; High-Throughput Screening Assays; Humans; Immunity; Metagenome; Microbiota; Pathology, Molecular; Sepsis
PubMed: 24525633
DOI: 10.1159/000358835 -
Surgical Pathology Clinics Sep 2016Sarcomas are infrequent mesenchymal neoplasms characterized by notable morphological and molecular heterogeneity. Molecular studies in sarcoma provide refinements to... (Review)
Review
Sarcomas are infrequent mesenchymal neoplasms characterized by notable morphological and molecular heterogeneity. Molecular studies in sarcoma provide refinements to morphologic classification, and contribute diagnostic information (frequently), prognostic stratification (rarely) and predict therapeutic response (occasionally). Herein, we summarize the major molecular mechanisms underlying sarcoma pathogenesis and present clinically useful diagnostic, prognostic and predictive molecular markers for sarcoma. Five major molecular alterations are discussed, illustrated with representative sarcoma types, including 1. the presence of chimeric transcription factors, in vascular tumors; 2. abnormal kinase signaling, in gastrointestinal stromal tumor; 3. epigenetic deregulation, in chondrosarcoma, chondroblastoma, and other tumors; 4. deregulated cell survival and proliferation, due to focal copy number alterations, in dedifferentiated liposarcoma; 5. extreme genomic instability, in conventional osteosarcoma as a representative example of sarcomas with highly complex karyotype.
Topics: Biomarkers, Tumor; Gene Expression Profiling; Humans; Immunohistochemistry; Molecular Diagnostic Techniques; Pathology, Molecular; Predictive Value of Tests; Prognosis; Sarcoma; Soft Tissue Neoplasms
PubMed: 27523972
DOI: 10.1016/j.path.2016.04.009 -
International Journal of Molecular... Oct 2022This article describes commonly used experimental and clinical biomarkers of neuronal injury and neurodegeneration for the evaluation of neuropathology and monitoring of... (Review)
Review
This article describes commonly used experimental and clinical biomarkers of neuronal injury and neurodegeneration for the evaluation of neuropathology and monitoring of therapeutic interventions. Biomarkers are vital for diagnostics of brain disease and therapeutic monitoring. A biomarker can be objectively measured and evaluated as a proxy indicator for the pathophysiological process or response to therapeutic interventions. There are complex hurdles in understanding the molecular pathophysiology of neurological disorders and the ability to diagnose them at initial stages. Novel biomarkers for neurological diseases may surpass these issues, especially for early identification of disease risk. Validated biomarkers can measure the severity and progression of both acute neuronal injury and chronic neurological diseases such as epilepsy, migraine, Alzheimer's disease, Parkinson's disease, Huntington's disease, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and other brain diseases. Biomarkers are deployed to study progression and response to treatment, including noninvasive imaging tools for both acute and chronic brain conditions. Neuronal biomarkers are classified into four core subtypes: blood-based, immunohistochemical-based, neuroimaging-based, and electrophysiological biomarkers. Neuronal conditions have progressive stages, such as acute injury, inflammation, neurodegeneration, and neurogenesis, which can serve as indices of pathological status. Biomarkers are critical for the targeted identification of specific molecules, cells, tissues, or proteins that dramatically alter throughout the progression of brain conditions. There has been tremendous progress with biomarkers in acute conditions and chronic diseases affecting the central nervous system.
Topics: Alzheimer Disease; Biomarkers; Chronic Disease; Humans; Nervous System Diseases; Neuropathology
PubMed: 36233034
DOI: 10.3390/ijms231911734 -
Experimental and Molecular Pathology Dec 2012Pathologists and immunologists have collaborated over many years in their efforts to understand and properly diagnose cancer. The ability of pathologists to correctly... (Review)
Review
Pathologists and immunologists have collaborated over many years in their efforts to understand and properly diagnose cancer. The ability of pathologists to correctly diagnose this disease was facilitated by the development of immunohistology that utilized specificity of antibodies to distinguish between normal cells and cancer cells. Further boost was provided through the advent of monoclonal antibodies. The two disciplines are now together on the brink of a paradigm shift resulting from a better understanding of the importance for cancer diagnosis and prognosis to consider not only the characteristics of the cancer cells, but also the cancer microenvironment reflecting the host response to the disease. This new immunology and pathology alliance named "Immunoscore" will advance research in both disciplines as well as benefit patients.
Topics: Adenocarcinoma; Allergy and Immunology; Biomarkers, Tumor; Colonic Neoplasms; Female; Humans; Interprofessional Relations; Lymphocytes, Tumor-Infiltrating; Male; Mucin-1; Pathology; Patient Care Team; Prognosis; Referral and Consultation; Tissue Array Analysis
PubMed: 23099314
DOI: 10.1016/j.yexmp.2012.10.013 -
The Journal of Pathology Apr 2018Genomic instability and mutations are fundamental aspects of human malignancies, leading to progressive accumulation of the hallmarks of cancer. For some time, it has... (Review)
Review
Genomic instability and mutations are fundamental aspects of human malignancies, leading to progressive accumulation of the hallmarks of cancer. For some time, it has been clear that key mutations may be used as both prognostic and predictive biomarkers, the best-known examples being the presence of germline BRCA1 or BRCA2 mutations, which are not only associated with improved prognosis in ovarian cancer, but are also predictive of response to poly(ADP-ribose) polymerase (PARP) inhibitors. Although biomarkers as specific and powerful as these are rare in human malignancies, next-generation sequencing and improved bioinformatic analyses are revealing mutational signatures, i.e. broader patterns of alterations in the cancer genome that have the power to reveal information about underlying driver mutational processes. Thus, the cancer genome can act as a stratification factor in clinical trials and, ultimately, will be used to drive personalized treatment decisions. In this review, we use ovarian high-grade serous carcinoma (HGSC) as an example of a disease of extreme genomic complexity that is marked by widespread copy number alterations, but that lacks powerful driver oncogene mutations. Understanding of the genomics of HGSC has led to the routine introduction of germline and somatic BRCA1/2 testing, as well as testing of mutations in other homologous recombination genes, widening the range of patients who may benefit from PARP inhibitors. We will discuss how whole genome-wide analyses, including loss of heterozygosity quantification and whole genome sequencing, may extend this paradigm to allow all patients to benefit from effective targeted therapies. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Topics: Animals; BRCA1 Protein; BRCA2 Protein; Biomarkers, Tumor; Clinical Decision-Making; DNA Damage; DNA Repair; Female; Genetic Predisposition to Disease; Genomics; Humans; Mutation; Neoplasm Grading; Neoplasms, Cystic, Mucinous, and Serous; Ovarian Neoplasms; Pathology, Molecular; Phenotype; Precision Medicine; Predictive Value of Tests
PubMed: 29282716
DOI: 10.1002/path.5025