Publications by authors named "Antonino Carbone"

210 Publications

Immunodeficiency-associated Hodgkin lymphoma.

Expert Rev Hematol 2021 Jun 8;14(6):547-559. Epub 2021 Jul 8.

Medical Oncology, Centro di Riferimento Oncologico (CRO), IRCCS, National Cancer Institute, Aviano, Italy.

: Hodgkin lymphoma (HL) can occur in different host conditions, i.e. in the general population and immunocompromised individuals, either during HIV infection or solid organ/hematopoietic transplantation and immunosuppressive drug treatment.: Areas covered include multidimensional characteristics of tumor cells and cellular composition of tumor microenvironment of HL. Current conventional treatments and new treatment strategies for HL in immunosuppressed patients, especially in persons living with HIV (PLWH), are also discussed.PubMed and MEDLINE were used for database searches to identify articles in English published from 1989 to 2020.: For people with post-transplant HL or for those with HIV/AIDS-associated HL, standard treatments mirror those in the general population. In the last decade, the combination of cART with anti-neoplastic treatments, alongside with current anti-rejection therapies, has increased long-term survival of people with HL and acquired immune deficiencies. High-dose chemotherapy and autologous stem cell transplantation have been favorably proven as salvage therapy in PLWH with relapsed and refractory HL. Immune checkpoint inhibitors emerged as an area of clinical investigation for relapsed and refractory HL in the general population. Pembrolizumab, an anti-programmed cell death protein 1 (PD-1) drug, resulted safe in PLWH indicating that PD-1 ligand assessment should be advisable in HIV-associated HL.
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http://dx.doi.org/10.1080/17474086.2021.1935851DOI Listing
June 2021

Prevalence and determinants of quitting smoking after cancer diagnosis: a prospective cohort study.

Tumori 2021 Apr 20:3008916211009301. Epub 2021 Apr 20.

Cancer Epidemiology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy.

Objective: To describe smoking behaviours of patients with incident cancer attending an Italian cancer centre and to examine changes in their smoking habits within 12 months from cancer diagnosis, evaluating determinants of smoking cessation.

Methods: A hospital-based prospective cohort included patients hospitalized in an Italian cancer centre (2016-2018). Patients were mostly female (74%) and included a limited proportion of aerodigestive cancers (7%). Face-to-face interviews were performed during hospital stay to gather information on patient characteristics and smoking history. Changes in smoking habits were assessed through telephone interviews at 3, at 6, and at 12 months after cancer diagnosis.

Results: Among 1011 enrolled patients, 222 (22%) were current smokers at cancer diagnosis. Smoking prevalence was high in male patients (30%), in patients <50 years old (28%), in those with aerodigestive cancers (50%), and in those diagnosed at advanced stages (26%). Among current smokers at cancer diagnosis, 38% quit smoking after 12 months, 26% reduced intensity, and 36% did not modify smoking habits. Smoking cessation was associated with chemotherapy and, although not statistically significant, with female sex, older age, and advanced cancer stage. Patients with gastrointestinal, breast, or genitourinary cancer and those treated with surgery were less likely to quit smoking.

Conclusions: Our results highlighted that 62% of smoking patients with cancer did not quit the habit. Smoking cessation programs targeted to patients with cancer need intensification, particularly for those who may underestimate smoking effects after diagnosis.
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http://dx.doi.org/10.1177/03008916211009301DOI Listing
April 2021

Hodgkin lymphoma.

Nat Rev Dis Primers 2020 07 23;6(1):61. Epub 2020 Jul 23.

Division of Oncology, Washington University School of Medicine, St Louis, MO, USA.

Hodgkin lymphoma (HL) is a B cell lymphoma characterized by few malignant cells and numerous immune effector cells in the tumour microenvironment. The incidence of HL is highest in adolescents and young adults, although HL can affect elderly individuals. Diagnosis is based on histological and immunohistochemical analyses of tissue from a lymph node biopsy; the tissue morphology and antigen expression profile enable classification into one of the four types of classic HL (nodular sclerosis, mixed cellularity, lymphocyte-depleted or lymphocyte-rich HL), which account for the majority of cases, or nodular lymphocyte-predominant HL. Although uncommon, HL remains a crucial test case for progress in cancer treatment. HL was among the first systemic neoplasms shown to be curable with radiation therapy and multiagent chemotherapy. The goal of multimodality therapy is to minimize lifelong residual treatment-associated toxicity while maintaining high levels of effectiveness. Recurrent or refractory disease can be effectively treated or cured with high-dose chemotherapy followed by autologous haematopoietic stem cell transplantation, and prospective trials have demonstrated the potency of immunotherapeutic approaches with antibody-drug conjugates and immune checkpoint inhibitors. This Primer explores the wealth of information that has been assembled to understand HL; these updated observations verify that HL investigation and treatment remain at the leading edge of oncological research.
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http://dx.doi.org/10.1038/s41572-020-0189-6DOI Listing
July 2020

Cancer Classification at the Crossroads.

Authors:
Antonino Carbone

Cancers (Basel) 2020 Apr 15;12(4). Epub 2020 Apr 15.

Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via F. Gallini 2, I-33081 Aviano, Italy.

Internationally accepted classifications of malignant tumors, developed by the World Health Organization (WHO) and the Union for International Cancer Control (UICC), are based on the histotype, site of origin, morphologic grade, and spread of cancer throughout the body. The WHO classifications are the foundation of cancer diagnosis and the starting point for cancer management. Starting in 2000, the WHO classifications began to include biologic and molecular-genetic features. These developments are having a strong impact on cancer diagnosis and treatment, and this impact is amplifying, given the advances in cancer genomics. Molecular-genetic profiling can be used to refine existing classifications of tumors and, for a small but increasing number of cancers, even determine the treatment irrespective of histotype. Here I discuss how cancer classifications may change in the era of cancer genomics.
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http://dx.doi.org/10.3390/cancers12040980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226085PMC
April 2020

A new peg-filgrastim biosimilar, mecapegfilgrastim for primary prophylaxis of chemotherapy-related neutropenia is now available.

Ann Transl Med 2020 Mar;8(5):166

Department of Medical Oncology, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, IRCCS, Aviano (PN), Italy.

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http://dx.doi.org/10.21037/atm.2019.10.61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154413PMC
March 2020

Follicular lymphoma.

Nat Rev Dis Primers 2019 12 12;5(1):83. Epub 2019 Dec 12.

Barts Cancer Institute, Queen Mary University of London, London, UK.

Follicular lymphoma (FL) is a systemic neoplasm of the lymphoid tissue displaying germinal centre (GC) B cell differentiation. FL represents ~5% of all haematological neoplasms and ~20-25% of all new non-Hodgkin lymphoma diagnoses in western countries. Tumorigenesis starts in precursor B cells and becomes full-blown tumour when the cells reach the GC maturation step. FL is preceded by an asymptomatic preclinical phase in which premalignant B cells carrying a t(14;18) chromosomal translocation accumulate additional genetic alterations, although not all of these cells progress to the tumour phase. FL is an indolent lymphoma with largely favourable outcomes, although a fraction of patients is at risk of disease progression and adverse outcomes. Outcomes for FL in the rituximab era are encouraging, with ~80% of patients having an overall survival of >10 years. Patients with relapsed FL have a wide range of treatment options, including several chemoimmunotherapy regimens, phosphoinositide 3-kinase inhibitors, and lenalidomide plus rituximab. Promising new treatment approaches include epigenetic therapeutics and immune approaches such as chimeric antigen receptor T cell therapy. The identification of patients at high risk who require alternative therapies to the current standard of care is a growing need that will help direct clinical trial research. This Primer discusses the epidemiology of FL, its molecular and cellular pathogenesis and its diagnosis, classification and treatment.
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http://dx.doi.org/10.1038/s41572-019-0132-xDOI Listing
December 2019

Subclassifying peripheral T-cell lymphoma NOS.

Blood 2019 12;134(24):2120-2121

Fondazione IRCCS Istituto Nazionale dei Tumori di Milano.

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http://dx.doi.org/10.1182/blood.2019003385DOI Listing
December 2019

Optimizing checkpoint inhibitors therapy for relapsed or progressive classic Hodgkin lymphoma by multiplex immunohistochemistry of the tumor microenvironment.

Cancer Med 2019 06 8;8(6):3012-3016. Epub 2019 May 8.

University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, QLD, Australia.

Immune checkpoint-blocking antibodies have therapeutic activity against relapsed or progressive classic Hodgkin lymphoma (cHL), but Hodgkin Reed-Sternberg cells can develop resistance to this therapy via multiple mechanisms. To improve the efficacy of immune checkpoint blockade, we need a more precise understanding of the immune escape mechanisms active in individual cHL patients, and this requires a detailed characterization of immune cell populations in the tumor microenvironment. These cell-cell interactions can now be studied by multiplex immunohistochemistry coupled to digital image analysis. This method should allow the identification of actionable target molecules mediating resistance to immune checkpoint inhibitors in individual cHL patients, thereby favoring the implementation of personalized therapies.
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http://dx.doi.org/10.1002/cam4.2168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558469PMC
June 2019

Checkpoint blockade therapy resistance in Hodgkin's lymphoma.

Lancet 2018 10;392(10154):1194-1196

Department of Diagnostic Pathology and Laboratory Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori di Milano, Milano, Italy.

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http://dx.doi.org/10.1016/S0140-6736(18)31867-1DOI Listing
October 2018

Epstein Barr Virus-Associated Hodgkin Lymphoma.

Cancers (Basel) 2018 May 25;10(6). Epub 2018 May 25.

Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS, Istituto Nazionale Tumori, Via G. Venezian 1, I-20133 Milano, Italy.

: Classical Hodgkin lymphoma (cHL) is a distinct clinical and pathological entity with heterogeneous genetic and virological features, with regards to Epstein⁻Barr virus (EBV) infection. The variable association of cHL with EBV infection is probably related to the different levels of patient immunosuppression, both locally in the tumour tissue and at the systemic level. This review paper focuses on EBV-related cHL highlighting pathogenetic and pathological features that may impact pathobiology-driven treatment for the affected patients.
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http://dx.doi.org/10.3390/cancers10060163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025037PMC
May 2018

Are EBV-related and EBV-unrelated Hodgkin lymphomas different with regard to susceptibility to checkpoint blockade?

Blood 2018 07 1;132(1):17-22. Epub 2018 May 1.

Department of Biomedical Sciences, Humanitas University, Milan, Italy; and.

Epstein-Barr virus (EBV)-related and EBV-unrelated classical Hodgkin lymphomas (cHLs) are morphologically and phenotypically indistinguishable. However, the tumor microenvironment of EBV-related cHLs contains higher numbers of macrophages and higher expression levels of PD-L1 than that of EBV-unrelated cHLs. Moreover, viral oncoprotein LMP1 may sustain an immunosuppressive microenvironment by inducing/enhancing production of immunosuppressive cytokines and the expression of PD-1. The presence of enhanced immunosuppressive features in EBV-related cHL should make EBV-related cHL patients more susceptible to checkpoint blockade.
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http://dx.doi.org/10.1182/blood-2018-02-833806DOI Listing
July 2018

Bright-field in situ hybridization detects gene alterations and viral infections useful for personalized management of cancer patients.

Expert Rev Mol Diagn 2018 03 21;18(3):259-277. Epub 2018 Feb 21.

a Department of Pathology and Laboratory Medicine , Fondazione IRCCS, Istituto Nazionale dei Tumori , Milano , Italy.

Introduction: Bright-field in situ hybridization (ISH) methods detect gene alterations that may improve diagnostic precision and personalized management of cancer patients. Areas covered: This review focuses on some bright-field ISH techniques for detection of gene amplification or viral infection that have already been introduced in tumor pathology, research and diagnostic practice. Other emerging ISH methods, for the detection of translocation, mRNA and microRNA have recently been developed and need both an optimization and analytical validation. The review also deals with their clinical applications and implications on the management of cancer patients. Expert commentary: The technology of bright-field ISH applications has advanced significantly in the last decade. For example, an automated dual-color assay was developed as a clinical test for selecting cancer patients that are candidates for personalized therapy. Recently an emerging bright-field gene-protein assay has been developed. This method simultaneously detects the protein, gene and centromeric targets in the context of tissue morphology, and might be useful in assessing the HER2 status particularly in equivocal cases or samples with heterogeneous tumors. The application of bright-field ISH methods has become the gold standard for the detection of tumor-associated viral infection as diagnostic or prognostic factors.
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http://dx.doi.org/10.1080/14737159.2018.1440210DOI Listing
March 2018

Current and potential use of pathological targets in the treatment of Hodgkin lymphoma.

Am J Hematol 2018 May 14;93(5):E117-E120. Epub 2018 Feb 14.

Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

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http://dx.doi.org/10.1002/ajh.25054DOI Listing
May 2018

How immunologic and genetic biomarkers impact Hodgkin lymphoma classification, diagnosis, and management: a huge potential that yet needs to be exploited.

Int J Biol Markers 2018 May 28;33(2):137-140. Epub 2017 Oct 28.

2 Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano - Italy.

"Ne è passata di acqua sotto i ponti." It has been a long time since the diagnosis of Hodgkin lymphoma (HL) was exclusively based on the detection of typical Reed-Sternberg cells and the recognition of the characteristic morpho-histological background, as well as on the pathologist's skill. The discovery of immunologic, molecular genetic and virologic biomarkers has provided an objective contribution to the diagnosis and a scientific basis for a modern classification of HL. Recent updates have clarified the nature of the so-called nodular lymphocyte predominant HL and its link to the T-cell/histiocyte-rich large B-cell lymphomas as well as its relationship with the lymphocyte-rich subset of classical HL (CHL). Molecular virology studies assessed a role for the Epstein-Barr virus in the pathogenesis of a fraction of CHL of the general population, and virtually in all cases of CHL occurring in people infected by HIV. Finally, immunologic and genetic findings corroborated the existence of grey zone lymphomas at the edges of CHL. Overall, these advances provided additional and useful information to address the treatment of patients affected by HL.
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http://dx.doi.org/10.5301/ijbm.5000312DOI Listing
May 2018

In situ hybridization detection methods for HPV16 E6/E7 mRNA in identifying transcriptionally active HPV infection of oropharyngeal carcinoma: an updating.

Hum Pathol 2018 04 6;74:32-42. Epub 2017 Oct 6.

Department of Pathology and Laboratory Medicine, Fondazione IRCCS, Istituto Nazionale dei Tumori, 20133 Milan, Italy. Electronic address:

The aim of this study is to compare 2 in situ hybridization (ISH) detection methods for human papilloma virus (HPV) 16 E6/E7 mRNA, that is, the RNAscope 2.0 High Definition (HD) and the upgraded RNAscope 2.5 HD version. The RNAscope 2.5 HD has recently replaced the RNAscope 2.0 HD detection kit. Therefore, this investigation starts from the need to analytically validate the new mRNA ISH assay and, possibly, to refine the current algorithm for HPV detection in oropharyngeal squamous cell carcinoma with the final goal of applying it to daily laboratory practice. The study was based on HPV status and on generated data, interpreted by a scoring algorithm. The results highlighted that the compared RNAscope HPV tests had a good level of interchangeability and enabled to identify oropharyngeal squamous cell carcinoma that are truly driven by high-risk HPV infection. This was also supported by the comparison of the RNAscope HPV test with HPV E6/E7 mRNA real-time reverse-transcription polymerase chain reaction in a fraction of cases where material for HPV E6/E7 mRNA real-time reverse-transcription polymerase chain reaction was available. Furthermore, the algorithm that associates p16 immunohistochemistry with the identification of HPV mRNA by RNAscope was more effective than the one that associated p16 immunohistochemistry with the identification of HPV DNA by ISH.
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http://dx.doi.org/10.1016/j.humpath.2017.09.011DOI Listing
April 2018

Teaching Digital Pathology: The International School of Digital Pathology and Proposed Syllabus.

J Pathol Inform 2017 25;8:27. Epub 2017 Jul 25.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, USA.

Digital pathology is an interdisciplinary field where competency in pathology, laboratory techniques, informatics, computer science, information systems, engineering, and even biology converge. This implies that teaching students about digital pathology requires coverage, expertise, and hands-on experience in all these disciplines. With this in mind, a syllabus was developed for a digital pathology summer school aimed at professionals in the aforementioned fields, as well as trainees and doctoral students. The aim of this communication is to share the context, rationale, and syllabus for this school of digital pathology.
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http://dx.doi.org/10.4103/jpi.jpi_17_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545774PMC
July 2017

Hodgkin lymphoma classification: Are we at a crossroads?

Cancer 2017 10 16;123(19):3654-3655. Epub 2017 Jun 16.

Department of Diagnostic Pathology and Laboratory Medicine, National Cancer Institute, Scientific Institute for Research, Hospitalization, and Health Care Foundation, Milan, Italy.

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http://dx.doi.org/10.1002/cncr.30824DOI Listing
October 2017

Multiple viral infections in primary effusion lymphoma: a model of viral cooperation in lymphomagenesis.

Expert Rev Hematol 2017 06 16;10(6):505-514. Epub 2017 May 16.

e Department of Pathology , Centro di Riferimento Oncologico - IRCCS, National Cancer Institute , Aviano , Italy.

Introduction: Primary effusion lymphoma (PEL) is a rare B-cell lymphoid neoplasm mainly associated with HIV infection, presenting as pleural, peritoneal, and pericardial effusions. A defining property of PEL is its consistent association with Kaposi sarcoma associated herpesvirus (KSHV) infection, and, in most cases, Epstein Barr virus (EBV) co-infection. On these grounds, a review of the literature related to viral cooperation and lymphomagenesis can help to understand the complex interplay between KSHV and EBV in PEL pathogenesis. Areas covered: In this review, the authors highlight clinical, pathologic, genetic and proteomic features of PEL, in the context of viral cooperation in PEL lymphomagenesis. Expert commentary: Tumour cells are characterized by the overexpression of genes that are involved in inflammation and invasion. Coherently, PEL secretomes are enriched in proteins probably responsible for the particular tropism (cell adhesion and migration) of PEL cells. The development of PEL in HIV+ patients is multifactorial and involves a complex interplay among co-infection with oncogenic viruses (EBV and KSHV), inflammatory factors, and environmental conditions.
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http://dx.doi.org/10.1080/17474086.2017.1326815DOI Listing
June 2017

The impact of EBV and HIV infection on the microenvironmental niche underlying Hodgkin lymphoma pathogenesis.

Int J Cancer 2017 03 27;140(6):1233-1245. Epub 2016 Oct 27.

Cancer Bio-Immunotherapy Unit, Centro di Riferimento Oncologico - IRCCS, National Cancer Institute, Aviano, PN, Italy.

The pathogenesis of classical Hodgkin lymphoma (cHL) is still enigmatic, largely because its tumor cells, the so-called Hodgkin and Reed-Stenberg (HRS) cells, invariably reside in a prominent reactive microenvironment, are rare and therefore difficult to analyze. On the other hand, the broadly investigated cHL-derived cell lines are not unequivocally considered as suitable and representative models for this puzzling disease. Based on current knowledge, it appears that the cross talk between the tumor cells and the reactive infiltrate of the microenvironment is complex and that multiple mechanisms occur, making cHL a very heterogeneous disease. In 20-40% of cHL cases, HRS cells carry a monoclonal infection by Epstein Barr virus (EBV), which is considered a tumor-initiating factor. In these cases, EBV shows a latency type II infection pattern with the expression of latent membrane protein-1 (LMP-1), a viral oncoprotein that mimics CD40 activation. This scenario is particularly intriguing for the pathogenesis of cHL arising in HIV-infected patients, which, for still obscure reasons, is invariably EBV-associated with LMP-1 expression in HRS cells. Recent evidences are consistent with the occurrence of different pathogenic pathways variably triggered by virus infections (EBV and HIV), genetic alterations, and interactions with critical microenvironmental components. This review focuses on the different microenvironmental niches that characterize cHL of the general population as well as cases of HIV-infected patients. A more comprehensive understanding of the complex interplay existing between HRS and tumor microenvironment is pivotal for the development of more effective treatments, particularly for relapsed or refractory diseases.
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http://dx.doi.org/10.1002/ijc.30473DOI Listing
March 2017

Epstein-Barr virus associated lymphomas in people with HIV.

Curr Opin HIV AIDS 2017 01;12(1):39-46

aDepartment of Pathology, Centro di Riferimento Oncologico Aviano (CRO), Istituto Nazionale Tumori, IRCCS, Aviano bDepartment of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Purpose Of Review: The present review summarizes the association of the different histotypes of Epstein-Barr virus (EBV)-associated lymphomas with known genetic lesions and/or oncogenic viruses. A more comprehensive understanding of the complex interplay existing between genetic abnormalities of tumor cells and the viral contribution to the development of EBV-associated lymphomas is pivotal for the development of more effective treatments.

Recent Findings: Recent evidence indicates that HIV may contribute to lymphomagenesis by acting directly on B lymphocytes as a critical microenvironmental factor. The pathogenesis of EBV-associated lymphomas in patients with HIV infection is considered the result of the concerted action of different factors, mainly including impaired immune surveillance, genetic alterations, and concomitant viral infection (EBV and HIV).

Summary: Immunodeficiency states usually increase susceptibility to cancer as a result of reduced immune surveillance and enhanced chances for virus-driven oncogenesis. Lymphoma remains the most frequent neoplastic cause of death among patients infected with HIV. Several of the HIV-associated lymphomas are related to EBV infection. EBV-associated lymphomas in patients infected with HIV are heterogeneous, not only pathologically but also in terms of pathogenetic pathways and cellular derivation.
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http://dx.doi.org/10.1097/COH.0000000000000333DOI Listing
January 2017

A lymphomagenic role for HIV beyond immune suppression?

Blood 2016 Mar 14;127(11):1403-9. Epub 2016 Jan 14.

Department of Pathology, Centro di Riferimento Oncologico-Istituto di ricovero e cura a carattere scientifico, National Cancer Institute, Aviano, Italy.

Despite the immune reconstitution promoted by combined antiretroviral therapy (cART), lymphomas still represent the most common type of cancer in HIV-infected individuals. Cofactors related to immunodeficiency such as oncogenic viruses, chronic antigenic stimulation, and cytokine overproduction are thought to be the main drivers of HIV lymphomagenesis, although the current scenario does not convincingly explain the still-high incidence of lymphomas and the occurrence of peculiar lymphoma histotypes in HIV-infected patients under cART. Recent findings are challenging the current view of a mainly indirect role of HIV in lymphoma development and support the possibility that HIV may directly contribute to lymphomagenesis. In fact, mechanisms other than immune suppression involve biologic effects mediated by HIV products that are secreted and accumulate in lymphoid tissues, mainly within lymph node germinal centers. Notably, HIV-infected patients with lymphomas, but not those not affected by these tumors, were recently shown to carry HIV p17 protein variants with enhanced B-cell clonogenic activity. HIV p17 protein variants were characterized by the presence of distinct insertions at the C-terminal region of the protein responsible for a structural destabilization and the acquisition of novel biologic properties. These data are changing the current paradigm assuming that HIV is only indirectly related to lymphomagenesis. Furthermore, these recent findings are consistent with a role of HIV as a critical microenvironmental factor promoting lymphoma development and pave the way for further studies that may lead to the design of more effective strategies for an early identification and improved control of lymphomas in the HIV setting.
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http://dx.doi.org/10.1182/blood-2015-11-681411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826146PMC
March 2016

TAFRO syndrome: An atypical variant of KSHV-negative multicentric Castleman disease.

Am J Hematol 2016 Feb;91(2):171-2

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

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http://dx.doi.org/10.1002/ajh.24274DOI Listing
February 2016

Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis.

Proc Natl Acad Sci U S A 2015 Nov 2;112(46):14331-6. Epub 2015 Nov 2.

Department of Molecular and Translational Medicine, University of Brescia Medical School, 25123 Brescia, Italy;

Although in decline after successful anti-HIV therapy, B-cell lymphomas are still elevated in HIV-1-seropositive (HIV+) persons, and the mechanisms are obscure. The HIV-1 matrix protein p17 persists in germinal centers long after HIV-1 drug suppression, and some p17 variants (vp17s) activate Akt signaling and promote growth of transformed B cells. Here we show that vp17s derived from four of five non-Hodgkin lymphoma (NHL) tissues from HIV+ subjects display potent B-cell growth-promoting activity. They are characterized by amino acid insertions at position 117-118 (Ala-Ala) or 125-126 (Gly-Asn or Gly-Gln-Ala-Asn-Gln-Asn) among some other mutations throughout the sequence. Identical dominant vp17s are found in both tumor and plasma. Three of seven plasma samples from an independent set of NHL cases manifested multiple Ala insertions at position 117-118, and one with the Ala-Ala profile also promoted B-cell growth and activated Akt signaling. Ultradeep pyrosequencing showed that vp17s with C-terminal insertions are more frequently detected in plasma of HIV+ subjects with than without NHL. Insertion of Ala-Ala at position 117-118 into reference p17 (refp17) was sufficient to confer B-cell growth-promoting activity. In contrast, refp17 bearing the Gly-Asn insertion at position 125-126 did not, suggesting that mutations not restricted to the C terminus can also account for this activity. Biophysical analysis revealed that the Ala-Ala insertion mutant is destabilized compared with refp17, whereas the Gly-Asn form is stabilized. This finding provides an avenue for further exploration of structure function relationships and new treatment strategies in combating HIV-1-related NHL.
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http://dx.doi.org/10.1073/pnas.1514748112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655530PMC
November 2015

Microenvironment and HIV-related lymphomagenesis.

Semin Cancer Biol 2015 Oct 26;34:52-7. Epub 2015 Jun 26.

Cancer Bio-Immunotherapy Unit, Centro di Riferimento Oncologico, IRCCS, National Cancer Institute, Aviano, PN, Italy.

Patients with HIV infection are at increased risk of developing non-Hodgkin lymphoma and Hodgkin lymphoma. While the pathogenesis of these lymphomas is incompletely understood, evidence indicates that immune deregulation, genetic alterations and cytokine production play an important role in HIV lymphomagenesis. The lymphoma microenvironment in this heterogeneous group of lymphomas plays an equally critical role in their development, growth and progression. Important components of the microenvironment in HIV-related lymphomas include EBV and/or HHV-8 coinfection, reactive inflammatory cells, tumor microvasculature, and soluble factors. This paper provides a brief overview of HIV-related lymphomas and focuses on their lymphomagenesis and microenvironment.
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http://dx.doi.org/10.1016/j.semcancer.2015.06.002DOI Listing
October 2015

Lymphomas and microenvironment: Impact on lymphomagenesis. Foreword.

Semin Cancer Biol 2015 Oct 28;34:1-2. Epub 2015 May 28.

Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

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http://dx.doi.org/10.1016/j.semcancer.2015.05.001DOI Listing
October 2015

Primary refractory and early-relapsed Hodgkin's lymphoma: strategies for therapeutic targeting based on the tumour microenvironment.

J Pathol 2015 Sep 3;237(1):4-13. Epub 2015 Jun 3.

Department of Oncology and Haematology, Humanitas Cancer Centre, Humanitas Clinical and Research Centre, Milan, Italy.

Classical Hodgkin's lymphoma (cHL), a distinct disease entity with characteristic clinical and pathological features, accounts for approximately 10% of all malignant lymphomas. cHL can be considered a prototype model for how the tumour microenvironment influences cancer pathogenesis. Cellular components of the cHL microenvironment express molecules involved in cancer cell growth and survival, such as CD30L or CD40L. Moreover, several signal transduction pathways that are critical for the proliferation and survival of neoplastic Hodgkin Reed-Sternberg (HRS) cells, including NF-κB, JAK-STAT, PI3K-AkT and ERK, are deregulated in cHL. Although most patients can be cured with modern treatment strategies, approximately a quarter experience either primary or secondary chemorefractoriness or disease relapse, thus requiring novel treatments. Preclinical and clinical evidence has elucidated a complex crosstalk between malignant HRS cells and the reactive cells of the microenvironment, which suggests that novel therapeutic approaches capable of targeting HRS cells along with reactive cells might overcome chemorefractoriness. In the near future, these novel therapies will also be tested in chemosensitive patients, to reduce the long-term toxicity of chemo-radiotherapy.
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http://dx.doi.org/10.1002/path.4558DOI Listing
September 2015

A novel semi-automated in situ hybridisation protocol for microRNA detection in paraffin embedded tissue sections.

J Clin Pathol 2015 Aug 30;68(8):661-4. Epub 2015 Apr 30.

Department of Diagnostic Pathology and Laboratory Medicine, Fondazione IRCCS, Istituto Nazionale Tumori, Milano, Italy.

MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression by binding to complementary sequences on target messenger RNA transcripts. In situ hybridisation (ISH) methods have been applied to the study of miRNA in tissue samples in order to understand which is the source of the miRNA of interest. In this paper, the authors describe a novel semi-automated bright field ISH method to visualise miRNAs in formalin fixed paraffin embedded tissue sections. The relevance of this work resides in the use of 3,3'-diaminobenzidine and peroxidase as the detection method, which provides a good defined deposition within tissues This method, which reveals the cells of origin of specific miRNAs, will enable investigators to further explore the biological role of miRNAs.
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http://dx.doi.org/10.1136/jclinpath-2015-203005DOI Listing
August 2015

Microenvironmental abnormalities induced by viral cooperation: Impact on lymphomagenesis.

Semin Cancer Biol 2015 Oct 30;34:70-80. Epub 2015 Mar 30.

Department of Pathology, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.

When stringent criteria have been used, the Epstein Barr virus (EBV), the Kaposi's sarcoma herpesvirus (KSHV), human immunodeficiency virus type 1 (HIV-1) and human hepatitis C virus (HCV) have been identified with sufficient evidence to be causative agents of non-Hodgkin's Lymphomas. Initially, single viral infection was considered fully responsible for the oncogenic properties of each virus, while it is now established that in many cases, multiple viral agents collaborate as cofactors in inducing lymphomas, especially in the presence of HIV-dependent immunodeficiency. Viruses cooperate by using their specific pathogenetic mechanisms in different combinations. The aim of this review is to describe the cooperation between different viruses in the development of lymphomas including the evidences supporting their pathogenetic role. Viral cooperation, a mechanism by which different viruses coinfecting human tissues have synergistic or regulatory effects on carcinogenesis, targets neoplastic B cells as well as cells of the microenvironment, such as reactive T-cells, B cells and macrophages, as well as non-immune cells such as endothelial cells, that contribute to tumor microenvironment. The most important viral genes involved in cooperation include HIV-1 tat and vpu, EBV LMP-1 and EBNA-2 and KSHV KIE2, Rta and LANA. Lymphomagenesis related to viral cooperation represents an interesting topic where microenvironmental abnormalities may be particularly relevant, particularly because antiviral targeted therapies and therapies producing the reconstitution of the immune system may constitute areas of interest aiming at improving the outcome of virus associated lymphomas. While the immune component of the lymphoma microenvironment can be easily studied by immunological and molecular techniques, the definition of the non-immune component of the lymphoma microenvironment is largely incomplete and may be the issue of future investigations. Understanding the pathogenetic role of viral infection in specific malignancies and defining microenvironmental abnormalities and mechanisms of viral carcinogenesis are important steps toward precise diagnosis and accurate treatment strategies for HIV-associated cancers.
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http://dx.doi.org/10.1016/j.semcancer.2015.03.009DOI Listing
October 2015

A natural HIV p17 protein variant up-regulates the LMP-1 EBV oncoprotein and promotes the growth of EBV-infected B-lymphocytes: implications for EBV-driven lymphomagenesis in the HIV setting.

Int J Cancer 2015 Sep 9;137(6):1374-85. Epub 2015 Mar 9.

Cancer Bio-Immunotherapy Unit, CRO Aviano, IRCCS, National Cancer Institute, Aviano, Pordenone, Italy.

Human immunodeficiency virus p17 matrix protein is released by infected cells and may accumulate within lymphoid tissues where it may deregulate the biological activities of different cell populations by binding to CXCR1 and CXCR2 cellular receptors. S75X, a natural p17 variant, was recently shown to enhance the malignant properties of lymphoma cells. We investigated a reference p17 protein and the S75X variant for their ability to bind to Epstein-Barr virus (EBV)-infected primary and fully transformed B-lymphocytes and trigger downstream effects of potential pathogenic relevance. We demonstrate that EBV infection of primary B-lymphocytes or the ectopic expression of the latent membrane protein-1 viral oncoprotein in EBV-negative B-cells up-regulates CXCR2, but not CXCR1. Multispectral imaging flow cytometry showed that EBV-infected primary B-cells more efficiently bind and internalize p17 proteins as compared with activated B-lymphocytes. The S75X variant bound more efficiently to EBV-infected primary and fully transformed B-lymphocytes compared with reference p17, because of a higher affinity to CXCR2, and enhanced the proliferation of these cells, an effect associated with cyclin D2 and D3 up-regulation and increased interleukin-6 production. Notably, the S75X variant markedly up-regulated latent membrane protein-1 expression at both mRNA and protein levels and enhanced the activation of Akt, ERK1/2 and STAT3 signaling, thereby contributing to EBV(+) B-cell growth promotion. These results indicate that EBV infection sensitizes B-lymphocytes to CXCR2-mediated effects of p17 proteins and provide evidence supporting a possible contribution of natural p17 variants to EBV-driven lymphomagenesis in the human immunodeficiency virus setting.
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http://dx.doi.org/10.1002/ijc.29494DOI Listing
September 2015
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