EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 1)

EBV is the most common persistent virus in humans. The interaction of EBV with B lymphocytes, which are considered the virus reservoir, is at the base of the life-long latent infection. Under circumstances of immunosuppression, the balance between virus and host immune system is altered and hence, EBV-associated lymphoid proliferations may originate. These disorders encompass several entities, ranging from self-limited diseases with indolent behavior to aggressive lymphomas. The virus may infect not only B-cells, but even T- and NK-cells. The occurrence of different types of lymphoid disorders depends on both the type of infected cells and the state of host immunity. EBV-driven lymphoproliferative lesions can rarely occur in the gastrointestinal tract and may be missed even by expert pathologists due to both the uncommon site of presentation and the frequent overlapping morphology and immunophenotypic features shared by different entities. The aim of this review is to provide a comprehensive overview of the current knowledge of EBV-associated lymphoproliferative disorders, arising within the gastrointestinal tract. The review is divided in three parts. In this part, the available data on EBV biology, EBV-positive mucocutaneous ulcer, EBV-positive diffuse large B-cell lymphoma, not otherwise specified and classic Hodgkin lymphoma are discussed.

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EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 3)

Cancers ◽

10.3390/cancers13236021 ◽

2021 ◽

Vol 13 (23) ◽

pp. 6021

Author(s):

Magda Zanelli ◽

Francesca Sanguedolce ◽

Andrea Palicelli ◽

Maurizio Zizzo ◽

Giovanni Martino ◽

...

Keyword(s):

Gastrointestinal Tract ◽

T Cell ◽

Nk Cell ◽

Daily Practice ◽

Lymphoproliferative Disorders ◽

Small Subset ◽

Common Denominator ◽

Complex Spectrum ◽

Host Immune System ◽

Ebv Infection

EBV is the first known oncogenic virus involved in the development of several tumors. The majority of the global population are infected with the virus early in life and the virus persists throughout life, in a latent stage, and usually within B lymphocytes. Despite the worldwide diffusion of EBV infection, EBV-associated diseases develop in only in a small subset of individuals often when conditions of immunosuppression disrupt the balance between the infection and host immune system. EBV-driven lymphoid proliferations are either of B-cell or T/NK-cell origin, and range from disorders with an indolent behavior to aggressive lymphomas. In this review, which is divided in three parts, we provide an update of EBV-associated lymphoid disorders developing in the gastrointestinal tract, often representing a challenging diagnostic and therapeutic issue. Our aim is to provide a practical diagnostic approach to clinicians and pathologists who face this complex spectrum of disorders in their daily practice. In this part of the review, the chronic active EBV infection of T-cell and NK-cell type, its systemic form; extranodal NK/T-cell lymphoma, nasal type and post-transplant lymphoproliferative disorders are discussed.

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EBV-Driven Lymphoproliferative Disorders and Lymphomas of the Gastrointestinal Tract: A Spectrum of Entities with a Common Denominator (Part 2)

Cancers ◽

10.3390/cancers13184527 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4527

Author(s):

Magda Zanelli ◽

Francesca Sanguedolce ◽

Andrea Palicelli ◽

Maurizio Zizzo ◽

Giovanni Martino ◽

...

Keyword(s):

Gastrointestinal Tract ◽

Epstein Barr Virus ◽

Primary Effusion Lymphoma ◽

Treatment Strategies ◽

Lymphoproliferative Disorders ◽

Common Denominator ◽

Adequate Treatment ◽

Barr Virus ◽

Molecular Features ◽

Epstein Barr

Epstein–Barr virus (EBV) is a common pathogen infecting people primarily early in life. The virus has the ability to persist throughout a person’s life, usually in B lymphocytes. Conditions of immunodeficiency as well as the introduction of immunosuppressive therapies and the advent of transplant technologies has brought immunodeficiency-associated lymphoproliferative disorders into view, which are often driven by EBV. The group of EBV-associated lymphoproliferative disorders includes different entities, with distinct biological features, ranging from indolent disorders, which may even spontaneously regress, to aggressive lymphomas requiring prompt and adequate treatment. These disorders are often diagnostically challenging due to their overlapping morphology and immunophenotype. Both nodal and extra-nodal sites, including the gastrointestinal tract, may be involved. This review, divided in three parts, summarizes the clinical, pathological, molecular features and treatment strategies of EBV-related lymphoproliferative disorders occurring in the gastrointestinal tract and critically analyzes the major issues in the differential diagnosis. In this part of the review, we discuss plasmablastic lymphoma, extra-cavitary primary effusion lymphoma and Burkitt lymphoma.

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Immunohistochemical Assessment of the Diagnostic Utility of PD-L1 (Clone SP142) for Methotrexate-Associated Lymphoproliferative Disorders With an Emphasis of Neoplastic PD-L1 (Clone SP142)–Positive Classic Hodgkin Lymphoma Type

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqz198 ◽

2020 ◽

Vol 153 (5) ◽

pp. 571-582 ◽

Cited By ~ 2

Author(s):

Kei Kohno ◽

Yuka Suzuki ◽

Ahmed A Elsayed ◽

Ayako Sakakibara ◽

Taishi Takahara ◽

...

Keyword(s):

B Cell ◽

Hodgkin Lymphoma ◽

Mononuclear Cells ◽

B Cell Lymphoma ◽

Lymphoproliferative Disorders ◽

Barr Virus ◽

Classic Hodgkin Lymphoma ◽

Fatal Course ◽

Immunohistochemical Assessment ◽

Lymphoma Type

Abstract Objectives We describe results of programmed death ligand 1 (PD-L1) immunohistochemical assessment in methotrexate (MTX)–associated lymphoproliferative disorders (LPDs) and highlight the characteristics of classic Hodgkin lymphoma (CHL) type MTX-LPD. Methods Fifty cases of MTX-LPD, including CHL type (n = 9), diffuse large B-cell lymphoma type (n = 15), and polymorphic B-cell LPD (n = 21), were investigated. Results Staining with anti–PD-L1 clone SP142 was exclusively found in CHL type (89%) but not in the others. Cases of CHL type MTX-LPD involved nodal disease and were associated with Epstein-Barr virus. They were histopathologically characterized by a vaguely nodular pattern, predominance of mononuclear cells, and strong expression of at least one pan–B-cell marker. Their clinical course was variable, with spontaneous regression in 5 patients, relapse in 2, and a fatal course in 1. Conclusions The PD-L1 (clone SP142) workup aids the diagnostic approach to patients with MTX-LPD. CHL type MTX-LPD appears to represent a unique morphologic variant of CHL.

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Immunomodulatory Effect of “Dr. M.S. Reddy’s Multiple Mixed Strain Probiotic Therapy” to Cure or Prevent Hospital Acquired (Nosocomial) Infections due to Clostridium difficile (C. diff), other Pathogenic Bacteria, and Autoimmune Diseases

International Journal of Pharmaceutical Sciences and Nanotechnology ◽

10.37285/ijpsn.2018.11.1.1 ◽

2018 ◽

Vol 11 (1) ◽

pp. 3937-3949

Author(s):

Malireddy S Reddy

Keyword(s):

Immune System ◽

Gastrointestinal Tract ◽

Pathogenic Bacteria ◽

Molecular Level ◽

Host Immune System ◽

Hospital Acquired Infections ◽

The World ◽

Probiotic Strains ◽

The Individual ◽

Hospital Acquired

The worldwide popularity of Dr. M.S. Reddy’s Multiple Mixed Strain Probiotic Therapy to treat or prevent the hospital acquired infections (nosocomial infections) arose a great interest in the medical community around the world (Reddy and Reddy, 2016; 2017). The following questions were raised on this subject: Does Multiple Mixed Strain Probiotics directly inhibit the pathogenic bacteria (C. diff) in the gastrointestinal tract or indirectly through modulation of the host immune system or both? To be more specific, what is the exact and/or hypothetical mechanism at molecular level behind the breakthrough discovery of Dr. M.S. Reddy’s Multiple Mixed Strain Probiotic Therapy? To answer these questions, the specific immunomodulation regulatory functions of the individual Probiotic strains (on host) have beenresearched, investigated andoutlined in this article. A detailed explanation(s) and hypotheses have been proposed outlining the possible cumulativedirect bacteriological and indirect immunomodulatory effects (at the molecular level) of the Multiple Mixed Strain Probiotics used in Dr. M.S. Reddy’s Multiple Mixed Strain Probiotic Therapy to successfully treat C. diff infection. A detailed scientific and research attempts were made to correlate the Probiotic induced immune activities in relation to the reduction of the symptoms associated with the hospital acquired Clostridium difficile infection during and after the Multiple Mixed Strain Probioitc Therapy. Results of the clinical trials, microbiological tests on feces, and the clinical blood tests significantly revealed that the reasons for the success of Dr. Reddy’s Multiple Mixed Strain Probiotic Therapy are multifold. Presumably, it is predominantly due to the immunomodulatory effect they have exerted on the host immune system along with the direct inhibition of C. diff bacteria by multiple Probiotics, due to the production of bacteriocins, lactic acid and nutritional competency.In addition, the size of the individual cells of the Probiotic strains in the Multiple Mixed Strain Probiotics and their significant effect on immunomodulation has been thoroughly discussed. Results clearly proved that if Probiotics are absent in the GI tract during C. diff infection, the chances of patient survival is zero. This is because of the excess immune stimulation and incurable damage to the epithelial cell barrier of the gastrointestinal tract caused by C. diff bacteria. The results also revealed, without any doubt, as of to-datethe latest discovery of Dr. M.S. Reddy’s Multiple Mixed Strain Probiotic Therapy is the best way to cure the deadly hospital acquired infections affecting millions of people around the world, with high degree of mortality. This has been attested by several practicng medical professionals and scientists around the world (Reddy and Reddy, 2017).

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Significance of indeterminate pulmonary nodules in resectable pancreatic adenocarcinoma—a review

Langenbeck s Archives of Surgery ◽

10.1007/s00423-020-02049-w ◽

2021 ◽

Author(s):

Li Lian Kuan ◽

Ashley R. Dennison ◽

Giuseppe Garcea

Keyword(s):

Overall Survival ◽

Pancreatic Adenocarcinoma ◽

Median Overall Survival ◽

Current Knowledge ◽

Pulmonary Nodules ◽

Preoperative Imaging ◽

Significant Finding ◽

Comprehensive Overview ◽

Significant Difference ◽

Clinical Dilemma

Abstract Background The clinical significance of indeterminate pulmonary nodules (IPN) in patients with resectable pancreatic adenocarcinoma (PDAC) is unknown. The rate of detection on IPN has risen due to enhanced staging investigations to determine resectability. IPNs detected on preoperative imaging represent a clinical dilemma and complicate decision-making. Currently, there are no recommendations on the management of IPN. This review provides a comprehensive overview of the current knowledge on the natural history of IPN detected among patients with resectable PDAC. Methods A systematic review based on a search in Medline and Embase databases was performed. All clinical studies evaluating the significance of IPN in patients with resectable PDAC were included. PRISMA guidelines were followed. Results Five studies met the inclusion criteria. The total patient population was 761. The prevalence of IPN reported ranged from 18 to 71%. The median follow-up duration was 17 months. The median overall survival was 19 months. Patients with pre-operative IPN which subsequently progressed to clinically recognizable pulmonary metastases, ranged from 1.5 to 16%. Four studies found that there was no significant difference in median overall survival in patients with or without IPNs. Conclusion This is a first review on the significance of IPN in patients with resectable PDAC. The preoperative presence of IPN does not demonstrate an association with overall survival after surgery. The identification of IPN is a significant finding however it should not preclude patients with resectable PDAC from undergoing curative resection.

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An Interesting Case Report of A Concurrent Classic Hodgkin Lymphoma and Gray Zone Lymphoma in the Mediastinum

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqaa161.240 ◽

2020 ◽

Vol 154 (Supplement_1) ◽

pp. S110-S110

Author(s):

B Mai ◽

J Huddin ◽

Z Hu

Keyword(s):

B Cell ◽

Hodgkin Lymphoma ◽

Mediastinal Mass ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Gray Zone ◽

Large B Cell Lymphoma ◽

Classic Hodgkin Lymphoma ◽

Atypical Cells ◽

Large B Cell

Abstract Casestudy A 52-year-old female presented with night sweats, chills, anorexia, and weight loss. Computed tomography and positron emission tomography showed a soft tissue infiltration in the anterior mediastinum and hypermetabolic bilateral supraclavicular, mediastinal, right hilar, and left internal mammary lymph nodes. An anterior mediastinal mass resection and thymectomy was subsequently performed. Results Sections of the mediastinal mass showed Hodgkin/Reed-Sternberg cells (HRS) admixed with small lymphocytes, histiocytes, plasma cells, and eosinophils. The HRS cells are positive for CD30, CD15, and MUM1, faintly positive for PAX5, and negative for CD20, CD45, CD79a, and BCL6. The morphology and immunophenotype is diagnostic of nodular sclerosis classic Hodgkin lymphoma (CHL). Sections of the thymectomy specimen showed similar morphology, however, in an area that represents 10-20% of the specimen, there are nodular and diffuse lymphoid infiltrates consisting of small lymphocytes, histiocytes, and large atypical cells. The large atypical cells are positive for CD20, CD23, CD30, CD45, CD79a, BCL2, BCL6, MUM-1, and PAX5, and negative for CD1a, CD3, CD57, and Cyclin D1. The background small CD3-positive lymphocytes form a rosette around most of the large atypical cells. CD21 and CD23 stains highlight residual follicular structures. In situ hybridization for EBV-encoded RNA (EBER) is negative. The presence of residual follicular meshwork with an immunophenotype of large B cell lymphoma supports a diagnosis of a gray zone lymphoma (GZL). Overall, CHL is involving 80-90% and GZL is involving 10-20% of the thymic tissue. The patient was subsequently placed on ABVD chemotherapy and achieved remission. Conclusion An accurate diagnosis of GZL is challenging. GZL is a rare type of lymphoma with morphological features between CHL and diffuse large B-cell lymphoma (DLBCL). It is even rarer to encounter a CHL concurrently present with a GZL. The optimal therapeutic approach for cases with concurrent lymphoma diagnosed with CHL and GZL needs further investigation.

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Host Cell Restriction Factors of Bunyaviruses and Viral Countermeasures

Viruses ◽

10.3390/v13050784 ◽

2021 ◽

Vol 13 (5) ◽

pp. 784

Author(s):

Solène Lerolle ◽

Natalia Freitas ◽

François-Loïc Cosset ◽

Vincent Legros

Keyword(s):

Host Cell ◽

Viral Entry ◽

Current Knowledge ◽

Restriction Factors ◽

Antiviral State ◽

Cellular Factors ◽

Pathogenic Viruses ◽

Genome Transcription ◽

Infected Cells ◽

Molecular Patterns

The Bunyavirales order comprises more than 500 viruses (generally defined as bunyaviruses) classified into 12 families. Some of these are highly pathogenic viruses infecting different hosts, including humans, mammals, reptiles, arthropods, birds, and/or plants. Host cell sensing of infection activates the innate immune system that aims at inhibiting viral replication and propagation. Upon recognition of pathogen-associated molecular patterns (PAMPs) by cellular pattern recognition receptors (PRRs), numerous signaling cascades are activated, leading to the production of interferons (IFNs). IFNs act in an autocrine and paracrine manner to establish an antiviral state by inducing the expression of hundreds of IFN-stimulated genes (ISGs). Some of these ISGs are known to restrict bunyavirus infection. Along with other constitutively expressed host cellular factors with antiviral activity, these proteins (hereafter referred to as “restriction factors”) target different steps of the viral cycle, including viral entry, genome transcription and replication, and virion egress. In reaction to this, bunyaviruses have developed strategies to circumvent this antiviral response, by avoiding cellular recognition of PAMPs, inhibiting IFN production or interfering with the IFN-mediated response. Herein, we review the current knowledge on host cellular factors that were shown to restrict infections by bunyaviruses. Moreover, we focus on the strategies developed by bunyaviruses in order to escape the antiviral state developed by the infected cells.

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Poxviral Strategies to Overcome Host Cell Apoptosis

Pathogens ◽

10.3390/pathogens10010006 ◽

2020 ◽

Vol 10 (1) ◽

pp. 6

Author(s):

Chathura D. Suraweera ◽

Mark G. Hinds ◽

Marc Kvansakul

Keyword(s):

Viral Infections ◽

B Cell Lymphoma ◽

Intrinsic Apoptosis ◽

Host Cell Apoptosis ◽

Successful Infection ◽

Infected Cells ◽

Host Virus Interactions ◽

Almost All ◽

Virus Interactions ◽

Multicellular Organisms

Apoptosis is a form of cellular suicide initiated either via extracellular (extrinsic apoptosis) or intracellular (intrinsic apoptosis) cues. This form of programmed cell death plays a crucial role in development and tissue homeostasis in multicellular organisms and its dysregulation is an underlying cause for many diseases. Intrinsic apoptosis is regulated by members of the evolutionarily conserved B-cell lymphoma-2 (Bcl-2) family, a family that consists of pro- and anti-apoptotic members. Bcl-2 genes have also been assimilated by numerous viruses including pox viruses, in particular the sub-family of chordopoxviridae, a group of viruses known to infect almost all vertebrates. The viral Bcl-2 proteins are virulence factors and aid the evasion of host immune defenses by mimicking the activity of their cellular counterparts. Viral Bcl-2 genes have proved essential for the survival of virus infected cells and structural studies have shown that though they often share very little sequence identity with their cellular counterparts, they have near-identical 3D structures. However, their mechanisms of action are varied. In this review, we examine the structural biology, molecular interactions, and detailed mechanism of action of poxvirus encoded apoptosis inhibitors and how they impact on host–virus interactions to ultimately enable successful infection and propagation of viral infections.

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A Crosstalk between Diet, Microbiome and microRNA in Epigenetic Regulation of Colorectal Cancer

Nutrients ◽

10.3390/nu13072428 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2428

Author(s):

Małgorzata Guz ◽

Witold Jeleniewicz ◽

Anna Malm ◽

Izabela Korona-Glowniak

Keyword(s):

Colorectal Cancer ◽

Gastrointestinal Tract ◽

Gut Microbiota ◽

Intestinal Microbiota ◽

Current Knowledge ◽

Vital Role ◽

Disease States ◽

Health And Disease ◽

Dietary Components ◽

Non Coding Rnas

A still growing interest between human nutrition in relation to health and disease states can be observed. Dietary components shape the composition of microbiota colonizing our gastrointestinal tract which play a vital role in maintaining human health. There is a strong evidence that diet, gut microbiota and their metabolites significantly influence our epigenome, particularly through the modulation of microRNAs. These group of small non-coding RNAs maintain cellular homeostasis, however any changes leading to impaired expression of miRNAs contribute to the development of different pathologies, including neoplastic diseases. Imbalance of intestinal microbiota due to diet is primary associated with the development of colorectal cancer as well as other types of cancers. In the present work we summarize current knowledge with particular emphasis on diet-microbiota-miRNAs axis and its relation to the development of colorectal cancer.

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