65 results on '"Granai M"'
Search Results
2. BCR EXPRESSION IN BURKITT LYMPHOMA: NEW INSIGHT IN MUTATIONAL LANDSCAPE
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Siciliano, M., primary, Vannucchi, M., additional, Tornambè, S., additional, Granai, M., additional, Arcuri, F., additional, Sorrentino, E., additional, Mancini, V., additional, de Leone, N., additional, Lazzi, S., additional, Siebert, R., additional, Leoncini, L., additional, and Bellan, C., additional
- Published
- 2022
- Full Text
- View/download PDF
3. “BURKITT-LIKE LYMPHOMA WITH 11Q ABERRATION”: NEITHER BURKITT-LYMPHOMA NOR DIFFUSE LARGE B-CELL LYMPHOMA. WHAT THE MICROENVIRONMENT TELLS US
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Del Corvo, M., primary, Sapienza, M., additional, Siciliano, M., additional, Tornambè, S., additional, Mazzara, S., additional, Granai, M., additional, Mundo, L., additional, Arcuri, F., additional, Mancini, V., additional, Ferrara, D., additional, Ott, G., additional, Siebert, Reiner, additional, Fend, L. Quintanilla, additional, Fend, F., additional, Pileri, S., additional, Lazzi, S., additional, and Leoncini, L., additional
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- 2022
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4. EPSTEIN-BARR VIRUS ORCHESTRATE THE TUMOR MICROENVIRONMENT OF BURKITT LYMPHOMA
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Siciliano, M., primary, Tornambè, S., additional, Del Corvo, M., additional, Granai, M., additional, Mundo, L., additional, Sapienza, M., additional, Arcuri, F., additional, Mancini, V., additional, Santi, R., additional, Di Stefano, G., additional, Marafioti, T., additional, Ott, G., additional, Siebert, R., additional, Fend, L. Quintanilla, additional, Fend, F., additional, Pileri, S., additional, Leoncini, L., additional, and Lazzi, S., additional
- Published
- 2022
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- View/download PDF
5. Frequent traces of EBV infection in Hodgkin and non-Hodgkin lymphomas classified as EBV-negative by routine methods: expanding the landscape of EBV-related lymphomas [Tiacci and Lazzi are co-senior authors]
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Mundo, L., Del Porro, L., Granai, M., Siciliano, M. C., Mancini, V., Santi, R., Marcar, L., Vrzalikova, K., Vergoni, F., Di Stefano, G., Schiavoni, G., Segreto, G., Onyango, N., Nyagol, J. A., Amato, T., Bellan, C., Anagnostopoulos, I., Falini, B., Leoncini, L., Tiacci, E., and Lazzi, S.
- Published
- 2020
6. Correction to: IGHV mutational status of nodal marginal zone lymphoma by NGS reveals distinct pathogenic pathways with different prognostic implications (Virchows Archiv, (2020), 477, 1, (143-150), 10.1007/s00428-019-02712-8)
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Granai, M., Amato, T., Di Napoli, A., Santi, R., Vergoni, F., Di Stefano, G., Mancini, V., Kovalchuk, S., Cencini, E., Carta, A. G., Aversa, S., Ziepert, M., Cevenini, G., Lazzi, S., Leoncini, L., and Bellan, C.
- Published
- 2020
7. 068 - “BURKITT-LIKE LYMPHOMA WITH 11Q ABERRATION”: NEITHER BURKITT-LYMPHOMA NOR DIFFUSE LARGE B-CELL LYMPHOMA. WHAT THE MICROENVIRONMENT TELLS US
- Author
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Del Corvo, M., Sapienza, M., Siciliano, M., Tornambè, S., Mazzara, S., Granai, M., Mundo, L., Arcuri, F., Mancini, V., Ferrara, D., Ott, G., Siebert, Reiner, Fend, L. Quintanilla, Fend, F., Pileri, S., Lazzi, S., and Leoncini, L.
- Published
- 2022
- Full Text
- View/download PDF
8. 012 - EPSTEIN-BARR VIRUS ORCHESTRATE THE TUMOR MICROENVIRONMENT OF BURKITT LYMPHOMA
- Author
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Siciliano, M., Tornambè, S., Del Corvo, M., Granai, M., Mundo, L., Sapienza, M., Arcuri, F., Mancini, V., Santi, R., Di Stefano, G., Marafioti, T., Ott, G., Siebert, R., Fend, L. Quintanilla, Fend, F., Pileri, S., Leoncini, L., and Lazzi, S.
- Published
- 2022
- Full Text
- View/download PDF
9. 002 - BCR EXPRESSION IN BURKITT LYMPHOMA: NEW INSIGHT IN MUTATIONAL LANDSCAPE
- Author
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Siciliano, M., Vannucchi, M., Tornambè, S., Granai, M., Arcuri, F., Sorrentino, E., Mancini, V., de Leone, N., Lazzi, S., Siebert, R., Leoncini, L., and Bellan, C.
- Published
- 2022
- Full Text
- View/download PDF
10. EBV LEAVES ITS MARK: NEW EVIDENCE OF <> HYPOTHESIS IN B-CELL LYMPHOMAS FROM NON-CONVENTIONAL METHODS
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Mundo, L., primary, Ambrosio, M.R., additional, Del Porro, L., additional, Granai, M., additional, Mancini, V., additional, Schiavoni, G., additional, Anagnostopoulos, I., additional, Falini, B., additional, Lazzi, S., additional, Tiacci, E., additional, and Leoncini, L., additional
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- 2019
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11. Body image and health behaviors: is there a relationship between lifestyles and positive body image?
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Zanon, Alessandra, Tomassoni, Rosella, Gargano, Marialaura, and Granai, M. G.
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Male ,Adolescent ,Health Behavior ,physical activity ,Lifestyle ,Diet ,body image, physical activity, nutrition, Lifestyle ,Young Adult ,nutrition ,Sex Factors ,Italy ,Surveys and Questionnaires ,Body Image ,Humans ,Female ,Students ,Exercise ,Life Style - Abstract
The study illustrates a research on the relationship between body image and lifestyles in a sample of 262 young amateur athletes that have a regular attendance of a gym in Cassino (Central Italy). The following questionnaires were used: Body Shape Questionnaire (BSQ34), International Physical Activity Questionnaire (IPAQ), Short form 12 items (SF12). The participants were 257 (response rate 98.1%) mainly of young age (18-24 years, 63.8%), single (72%), with a senior high school diploma (57.2%), students (63%). For almost all the BSQ-34 questionnaire items differences for gender were found, with Females more worried than males. 187 (72.8%) reported some vigorous activity during a week, 207 (80.5%) some moderate activity, and 229 (89.1%) walking. The participants had a median PCS score of 54.2 (range: 24.5-64.8) and a median MCS score of 43.8 (range: 9.3 - 58.7). The mean score of the Mediterranean diet was 4.8 (median = 5; Range = 1-8), and only 72 individuals (11.7%) had optimal score (over or equal to 6).
- Published
- 2016
12. Deep endometriosis with pericolic lymph node involvement: A case report and literature review
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Cacciato Insilla, A, Granai, M, Gallippi, G, Giusti, P, Giusti, S, Guadagni, S, Morelli, Luca, Campani, Daniela, and CACCIATO INSILLA, Andrea
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Adult ,Pathology ,medicine.medical_specialty ,medicine.drug_class ,Endometriosis ,Case Report ,Enema ,Diagnosis, Differential ,Colon, Sigmoid ,medicine ,Humans ,Pelvis ,Gastrointestinal tract ,business.industry ,Gastroenterology ,Sigmoid colon ,Histology ,General Medicine ,medicine.disease ,Immunohistochemistry ,Magnetic Resonance Imaging ,medicine.anatomical_structure ,Treatment Outcome ,Receptors, Estrogen ,Estrogen ,Barium ,Female ,Neprilysin ,Lymph Nodes ,Differential diagnosis ,business ,Receptors, Progesterone - Abstract
Deep infiltrating endometriosis is an often-painful disorder affecting women during their reproductive years that usually involves the structures of the pelvis and frequently the gastrointestinal tract. We present the case of a 37-year-old female patient with an endometrial growth on the sigmoid colon wall causing pain, diarrhea and the presence of blood in the feces. The histology of the removed specimen also revealed the involvement of the utero-vesical fold, the recto-vaginal septum and a pericolic lymph node, which are all quite uncommon findings. To identify the endometrial cells, we performed immunohistochemical staining for CD10 and the estrogen and progesterone receptors.
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- 2014
13. Data-driven development of sparse multi-spectral sensors for urological tissue differentiation
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Fischer Felix, Frenner Karsten, Granai Massimo, Fend Falko, and Herkommer Alois
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biomarker detection ,feature selection ,infrared spectroscopy ,tissue differentiation ,Applied optics. Photonics ,TA1501-1820 ,Optics. Light ,QC350-467 - Abstract
Infrared spectroscopy is often used to spot differences between benign and malignant tissue. Due to the proliferation of tumorous cells, the composition of tissue changes drastically. In the consequence shifts occur in its optical properties that are indicated by spectral biomarkers in the so-called fingerprint region. In this work, we propose a new concept for a sparsified multi-spectral measurement of the most important and informative biomarker signals. The results of a data-driven feature selection approach show that a reliable discrimination of the tissue is still possible, even though utilizing only a small fraction of the measured data. A selected arrangement of only a few narrow-band quantum cascade lasers could provide proficient signal-to-noise ratios and can noticeably reduce the data acquisition time. Consequentially, real-time applications will be possible in short-term and in-vivo diagnostics in the long-term. First measurements of silicone phantoms validate the imaging capability of the sensor concept.
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- 2023
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14. EBV LEAVES ITS MARK: NEW EVIDENCE OF <<HIT AND RUN>> HYPOTHESIS IN B‐CELL LYMPHOMAS FROM NON‐CONVENTIONAL METHODS.
- Author
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Mundo, L., Ambrosio, M.R., Del Porro, L., Granai, M., Mancini, V., Schiavoni, G., Anagnostopoulos, I., Falini, B., Lazzi, S., Tiacci, E., and Leoncini, L.
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LYMPHOMAS ,LYMPHOPROLIFERATIVE disorders ,VIRAL genomes ,LEAVES ,HYPOTHESIS - Published
- 2019
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15. Burkitt lymphoma with a granulomatous reaction: an M1/Th1‐polarised microenvironment is associated with controlled growth and spontaneous regression
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Benedetta Puccini, Lorenzo Leoncini, Stefano Lazzi, Gioia Di Stefano, Virginia Mancini, Claudio Agostinelli, Nuray Bassullu, Elena Sabattini, Massimo Granai, Raffaella Santi, Leticia Quintanilla-Martinez, Ester Sorrentino, Tülay Tecimer, Stephan Dirnhofer, Ahu Senem Demiröz, Raffaella Guazzo, Maurilio Ponzoni, Teresa Marafioti, Federica Vergoni, Gabriele Cevenini, Falko Fend, Ayse U. Akarca, Lucia Mundo, Leah Mnango, Claudio Tripodo, Granai M., Lazzi S., Mancini V., Akarca A., Santi R., Vergoni F., Sorrentino E., Guazzo R., Mundo L., Cevenini G., Tripodo C., Di Stefano G., Puccini B., Ponzoni M., Sabattini E., Agostinelli C., Bassullu N., Tecimer T., Demiroz A.S., Mnango L., Dirnhofer S., Quintanilla-Martinez L., Marafioti T., Fend F., Leoncini L., and Acibadem University Dspace
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Male ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Histology ,Adolescent ,M1 polarised macrophages ,Th1 T cells ,Expression ,Biology ,T-Cell Responses ,Virus ,Pathology and Forensic Medicine ,Proinflammatory cytokine ,Molecular cytogenetics ,Origin ,Immunophenotyping ,EBV ,M1 polarised macrophage ,hemic and lymphatic diseases ,Tumor Microenvironment ,medicine ,Humans ,M1 polarized macrophages ,Aged ,Inhibition ,Macrophages ,Burkitt lymphoma ,In Situ lymphoid neoplasia ,Microenvironment ,granulomatous reaction ,B-Cells ,General Medicine ,Middle Aged ,Th1 Cells ,medicine.disease ,Burkitt Lymphoma ,microenvironment ,Regression ,Lymphoma ,in-situ lymphoid neoplasia ,Cancer research ,Female ,Therapy ,Cellular immunotherapy ,Infection ,Early phase ,Burkitt lymphoma, EBV, granulomatous reaction, in-situ lymphoid neoplasia, M1 polarised macrophages, microenvironment, Th1 T cells ,Epstein-Barr-Virus - Abstract
Aims Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that, in some instances, may show a granulomatous reaction associated with a favourable prognosis and occasional spontaneous regression. In the present study, we aimed to define the tumour microenvironment (TME) in four such cases, two of which regressed spontaneously. Methods and results All cases showed aggregates of tumour cells with the typical morphology, molecular cytogenetics and immunophenotype of BL surrounded by a florid epithelioid granulomatous reaction. All four cases were Epstein-Barr virus (EBV)-positive with type I latency. Investigation of the TME showed similar features in all four cases. The analysis revealed a proinflammatory response triggered by Th1 lymphocytes and M1 polarised macrophages encircling the neoplastic cells with a peculiar topographic distribution. Conclusions Our data provide an in-vivo picture of the role that specific immune cell subsets might play during the early phase of BL, which may be capable of maintaining the tumour in a self-limited state or inducing its regression. These novel results may provide insights into new potential therapeutic avenues in EBV-positive BL patients in the era of cellular immunotherapy.
- Published
- 2021
16. Metabolic Switch and Cytotoxic Effect of Metformin on Burkitt Lymphoma
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Irene Bagaloni, Axel Visani, Sara Biagiotti, Annamaria Ruzzo, Mohsen Navari, Maryam Etebari, Lucia Mundo, Massimo Granai, Stefano Lazzi, Alessandro Isidori, Federica Loscocco, Jiejin Li, Lorenzo Leoncini, Giuseppe Visani, Mauro Magnani, Pier Paolo Piccaluga, Bagaloni I., Visani A., Biagiotti S., Ruzzo A., Navari M., Etebari M., Mundo L., Granai M., Lazzi S., Isidori A., Loscocco F., Li J., Leoncini L., Visani G., Magnani M., and Piccaluga P.P.
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Cancer Research ,glucose metabolism ,Pentose phosphate pathway ,Biology ,anaerobic glycolysi ,glycolysi ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Glycolysis ,RC254-282 ,Original Research ,anaerobic glycolysis ,Burkitt lymphoma ,glycolysis ,metformin ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Germinal center ,medicine.disease ,Lymphoma ,Citric acid cycle ,Oncology ,Anaerobic glycolysis ,Cancer cell ,biology.protein ,Cancer research ,GLUT1 - Abstract
Altered cellular energetic metabolism has recently emerged as important feature of neoplastic cells. Indeed, interfering with cancer cell metabolism might represent a suitable therapeutic strategy. In this study, we aimed to assess glucose metabolism activation in human lymphomas and evaluate how metformin can exert its action on lymphoma cells. We studied a large series of human lymphomas (N = 252) and an in vitro model of Burkitt lymphoma (BL) cells. We combined molecular biology techniques, including global gene expression profiling (GEP) analysis, quantitative PCR (qPCR) and Western blotting, and biochemical assays, aimed to assess pentose phosphate pathway, tricarboxylic acid (TCA) cycle, and aerobic glycolysis rates. We found that glucose metabolism is overall enhanced in most lymphoma subtypes, based on gene expression profiling (GEP), with general shift to aerobic glycolysis. By contrast, normal B cells only showed an overall increase in glucose usage during germinal center transition. Interestingly, not only highly proliferating aggressive lymphomas but also indolent ones, like marginal zone lymphomas, showed the phenomenon. Consistently, genes involved in glycolysis were confirmed to be overexpressed in BL cells by qPCR. Biochemical assays showed that while aerobic glycolysis is increased, TCA cycle is reduced. Finally, we showed that metformin can induce cell death in BL cells by stressing cellular metabolism through the induction of GLUT1, PKM2, and LDHA. In conclusion, we unveiled glucose metabolism abnormalities in human lymphomas and characterized the mechanism of action of metformin in Burkitt lymphoma model.
- Published
- 2021
17. Molecular switch from MYC to MYCN expression in MYC protein negative Burkitt lymphoma cases
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Leonardo Del Porro, Reiner Siebert, Lucia Mundo, Joshua Nyagol, Stefano Lazzi, Noel Onyango, Isaac Ndede, Mohsen Navari, Robert B. Russell, Nicholas Othieno Abinya, Roshanak Bob, Cristina López, Virginia Mancini, Harald Stein, Bruno Jim Rocca, Kirkita Patel, Massimo Granai, Maria Margherita De Santi, Maria Raffaella Ambrosio, Susanne Bens, Francesco Raimondi, Lorenzo Leoncini, Raffaella Guazzo, Pier Paolo Piccaluga, Mundo, L., Ambrosio, M. R., Raimondi, F., Del Porro, L., Guazzo, R., Mancini, V., Granai, M., Jim Rocca, B., Lopez, C., Bens, S., Onyango, N., Nyagol, J., Abinya, N., Navari, M., Ndede, I., Patel, K., Paolo Piccaluga, P., Bob, R., de Santi, M. M., Russell, R. B., Lazzi, S., Siebert, R., Stein, H., and Leoncini, L.
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Adult ,Male ,Models, Molecular ,Adolescent ,Lymphoma ,Protein Conformation ,Genes, myc ,Biology ,medicine.disease_cause ,lcsh:RC254-282 ,Translocation, Genetic ,Article ,Immunophenotyping ,Proto-Oncogene Proteins c-myc ,Structure-Activity Relationship ,Young Adult ,Neoplasms ,Neuroblastoma ,medicine ,Humans ,Gene family ,RNA, Messenger ,Child ,neoplasms ,Gene ,MYC Gene Rearrangement ,Aged ,Neoplasms, Proto-Oncogene Proteins c-myc, Human cancers ,Regulation of gene expression ,Haematological cancer ,Mutation ,Human cancers ,Oncogene ,High-Throughput Nucleotide Sequencing ,Genomics ,Hematology ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Burkitt Lymphoma ,Immunohistochemistry ,Gene Expression Regulation, Neoplastic ,Oncology ,Cancer research ,Female ,N-Myc ,Genes, Switch - Abstract
MYC is the most altered oncogene in human cancer, and belongs to a large family of genes, including MYCN and MYCL. Recently, while assessing the degree of correlation between MYC gene rearrangement and MYC protein expression in aggressive B-cell lymphomas, we observed few Burkitt lymphoma (BL) cases lacking MYC protein expression despite the translocation involving the MYC gene. Therefore, in the present study we aimed to better characterize such cases. Our results identified two sub-groups of MYC protein negative BL: one lacking detectable MYC protein expression but presenting MYCN mRNA and protein expression; the second characterized by the lack of both MYC and MYCN proteins but showing MYC mRNA. Interestingly, the two sub-groups presented a different pattern of SNVs affecting MYC gene family members that may induce the switch from MYC to MYCN. Particulary, MYCN-expressing cases show MYCN SNVs at interaction interface that stabilize the protein associated with loss-of-function of MYC. This finding highlights MYCN as a reliable diagnostic marker in such cases. Nevertheless, due to the overlapping clinic, morphology and immunohistochemistry (apart for MYC versus MYCN protein expression) of both sub-groups, the described cases represent bona fide BL according to the current criteria of the World Health Organization.
- Published
- 2019
18. Aberrant p53 immunostaining patterns in breast carcinoma of no special type strongly correlate with presence and type of TP53 mutations.
- Author
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Armbruster H, Schotte T, Götting I, Overkamp M, Granai M, Volmer LL, Bahlinger V, Matovina S, Koch A, Dannehl D, Engler T, Hartkopf AD, Brucker SY, Bonzheim I, Fend F, Staebler A, and Montes-Mojarro I
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- Humans, Female, Middle Aged, Adult, Aged, DNA Mutational Analysis, Aged, 80 and over, Receptor, ErbB-2 genetics, Receptor, ErbB-2 analysis, Receptor, ErbB-2 metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 analysis, Breast Neoplasms genetics, Breast Neoplasms pathology, Mutation, Immunohistochemistry, Biomarkers, Tumor genetics, Biomarkers, Tumor analysis, Class I Phosphatidylinositol 3-Kinases genetics
- Abstract
Recent studies have revealed an association between TP53 mutations and endocrine resistance in hormone receptor-positive, HER2-negative breast cancer (HR + HER2 -BC). Aberrant p53 immunostaining (IHC) patterns may provide a surrogate marker for TP53 mutations. Building upon a ternary algorithm of aberrant staining patterns, this study evaluates the reliability of p53 IHC as screening tool for TP53 mutations in BC (NST). Furthermore, it describes the histopathological and molecular characteristics of TP53-mutated cases, along with the mutational status of PIK3CA. This study comprised 131 early-stage, node-negative BCs with available core biopsies and resection specimens. Cases were categorized as follows: HR + HER2 - (85 cases), HER2 + (21 cases) and triple negative (TN, 25 cases). Aberrant IHC staining patterns for p53 were defined as overexpression (OE), complete absence (CA) and cytoplasmic (CY). In addition, targeted sequencing of TP53 and PIK3CA genes was performed. TP53 mutations were identified in 53 of 126 cases (42.1%). Within HR + HER2 - cases, TP53 mutations were found in 17 of 80 cases (21.3%). IHC accurately predicted TP53 mutation in 96.2% of cases with a specificity of 100%. Additionally, there was a significant agreement between missense mutations and OE, as well as between truncating mutations and CA (κ 73% and 76%). CY was observed in two TN cases with truncating mutations within the nuclear localization signalling domain of p53. TP53-mutated cases exhibited higher grade, greater nuclear pleomorphism and higher Ki-67 proliferation index and were associated with the PIK3CA wild-type status (p < 0.001). p53 IHC may provide a useful screening tool for identifying TP53-mutated BC of NST., (© 2024. The Author(s).)
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- 2024
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19. Tumor microenvironment of Burkitt lymphoma: different immune signatures with different clinical behavior.
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Siciliano MC, Bertolazzi G, Morello G, Tornambè S, Del Corvo M, Granai M, Sapienza MR, Leahy CI, Fennell E, Belmonte B, Arcuri F, Vannucchi M, Mancini V, Guazzo R, Boccacci R, Onyango N, Nyagol J, Santi R, Di Stefano G, Ferrara D, Bellan C, Marafioti T, Ott G, Siebert R, Quintanilla-Fend L, Fend F, Murray P, Tripodo C, Pileri S, Lazzi S, and Leoncini L
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- Humans, Female, Male, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections immunology, Gene Expression Profiling, Herpesvirus 4, Human, Adult, Transcriptome, Middle Aged, Gene Expression Regulation, Neoplastic, Child, Adolescent, Prognosis, Tumor Microenvironment immunology, Burkitt Lymphoma immunology, Burkitt Lymphoma pathology, Burkitt Lymphoma genetics
- Abstract
Abstract: Burkitt lymphoma (BL) is characterized by a tumor microenvironment (TME) in which macrophages represent the main component, determining a distinct histological appearance known as "starry sky" pattern. However, in some instances, BL may exhibit a granulomatous reaction that has been previously linked to favorable prognosis and spontaneous regression. The aim of our study was to deeply characterize the immune landscape of 7 cases of Epstein-Barr virus-positive (EBV+) BL with granulomatous reaction compared with 8 cases of EBV+ BL and 8 EBV-negative (EBV-) BL, both with typical starry sky pattern, by Gene expression profiling performed on the NanoString nCounter platform. Subsequently, the data were validated using multiplex and combined immunostaining. Based on unsupervised clustering of differentially expressed genes, BL samples formed 3 distinct clusters differentially enriched in BL with a diffuse granulomatous reaction (cluster 1), EBV+ BL with typical starry sky pattern (cluster 2), EBV- BL with typical "starry sky" (cluster 3). We observed variations in the immune response signature among BL with granulomatous reaction and BL with typical "starry sky," both EBV+ and EBV-. The TME signature in BL with diffuse granulomatous reaction showed a proinflammatory response, whereas BLs with "starry sky" were characterized by upregulation of M2 polarization and protumor response. Moreover, the analysis of additional signatures revealed an upregulation of the dark zone signature and epigenetic signature in BL with a typical starry sky. Tumor-associated macrophages and epigenetic regulators may be promising targets for additional therapies for BL lymphoma, opening novel immunotherapeutic strategies., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2024
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20. [Clear cell sarcoma: Imaging findings of a newly described tumor entity].
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Heckl S, Lauer U, Granai M, Bösmüller H, Gohla G, and Horger M
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- Humans, Diagnosis, Differential, Tomography, X-Ray Computed, Male, Female, Middle Aged, Sarcoma, Clear Cell diagnostic imaging, Sarcoma, Clear Cell pathology, Magnetic Resonance Imaging methods
- Abstract
Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.
- Published
- 2024
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21. Differentiation of bladder cancer with water flow elastography (WaFE).
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Kalwa PL, Walz S, Granai M, Fend F, Stenzl A, and Schäffer TE
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- Humans, Elastic Modulus, Phantoms, Imaging, Water, Elasticity Imaging Techniques methods, Urinary Bladder Neoplasms diagnostic imaging
- Abstract
Cancer affects the mechanical properties of tissue. Therefore, elastography techniques can be used to differentiate cancerous from healthy tissue. Due to probe size and restricted handling, most elastography techniques are not applicable in minimally invasive surgery (MIS). Established techniques such as endoscopic ultrasound elastography measure under undefined boundary conditions, making the determination of quantitative mechanical properties challenging. Water flow elastography (WaFE) has recently been introduced for application in MIS. Here, we present an improved WaFE measurement method in which the probe attaches itself to the sample with a small suction pressure. This leads to defined boundary conditions, allowing for a quantitative determination of the Young's modulus of tissue. To facilitate fast measurements, we developed a correction model for the hydrodynamic resistance and the fluid inertia of the tubing. We used WaFE for ex vivo measurements on human bladders and found a significantly larger Young's modulus for cancerous vs. healthy tissue. We determined the optimal classification threshold for the Young's modulus to be 8 kPa and found that WaFE can differentiate between cancerous and healthy tissue with a sensitivity of 0.96 and a specificity of 1. Our results underline that WaFE can be a helpful differentiating tool in MIS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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22. Impact of P-selectin-PSGL-1 Axis on Platelet-Endothelium-Leukocyte Interactions in Fatal COVID-19.
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Granai M, Warm V, Vogelsberg A, Milla J, Greif K, Vogel U, Bakchoul T, Rosenberger P, Quintanilla-Martinez L, Schürch CM, Klingel K, Fend F, and Bösmüller H
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- Humans, Blood Platelets metabolism, Endothelial Cells metabolism, Interleukin-6 metabolism, SARS-CoV-2, Leukocytes metabolism, Endothelium metabolism, P-Selectin genetics, P-Selectin metabolism, COVID-19
- Abstract
In critically ill patients infected with SARS-CoV-2, early leukocyte recruitment to the respiratory system was found to be orchestrated by leukocyte trafficking molecules accompanied by massive secretion of proinflammatory cytokines and hypercoagulability. Our study aimed to explore the interplay between leukocyte activation and pulmonary endothelium in different disease stages of fatal COVID-19. Our study comprised 10 COVID-19 postmortem lung specimens and 20 control lung samples (5 acute respiratory distress syndrome, 2 viral pneumonia, 3 bacterial pneumonia, and 10 normal), which were stained for antigens representing the different steps of leukocyte migration: E-selectin, P-selectin, PSGL-1, ICAM1, VCAM1, and CD11b. Image analysis software QuPath was used for quantification of positive leukocytes (PSGL-1 and CD11b) and endothelium (E-selectin, P-selectin, ICAM1, VCAM1). Expression of IL-6 and IL-1β was quantified by RT-qPCR. Expression of P-selectin and PSGL-1 was strongly increased in the COVID-19 cohort compared with all control groups (COVID-19:Controls, 17:23, P < .0001; COVID-19:Controls, 2:75, P < .0001, respectively). Importantly, P-selectin was found in endothelial cells and associated with aggregates of activated platelets adherent to the endothelial surface in COVID-19 cases. In addition, PSGL-1 staining disclosed positive perivascular leukocyte cuffs, reflecting capillaritis. Moreover, CD11b showed a strongly increased positivity in COVID-19 compared with all controls (COVID-19:Controls, 2:89; P = .0002), indicating a proinflammatory immune microenvironment. Of note, CD11b exhibited distinct staining patterns at different stages of COVID-19 disease. Only in cases with very short disease course, high levels of IL-1β and IL-6 mRNA were observed in lung tissue. The striking upregulation of PSGL-1 and P-selectin reflects the activation of this receptor-ligand pair in COVID-19, increasing the efficiency of initial leukocyte recruitment, thus promoting tissue damage and immunothrombosis. Our results show that endothelial activation and unbalanced leukocyte migration play a central role in COVID-19 involving the P-selectin-PSGL-1 axis., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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23. Comprehensive analysis of SARS-CoV-2 receptor proteins in human respiratory tissues identifies alveolar macrophages as potential virus entry site.
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Bräutigam K, Reinhard S, Wartenberg M, Forster S, Greif K, Granai M, Bösmüller H, Klingel K, and Schürch CM
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- Humans, Macrophages, Alveolar metabolism, Virus Internalization, Angiotensin-Converting Enzyme 2 metabolism, Neuropilin-1 metabolism, Asialoglycoprotein Receptor metabolism, SARS-CoV-2, COVID-19
- Abstract
Aims: COVID-19 has had enormous consequences on global health-care and has resulted in millions of fatalities. The exact mechanism and site of SARS-CoV-2 entry into the body remains insufficiently understood. Recently, novel virus receptors were identified, and alveolar macrophages were suggested as a potential viral entry cell type and vector for intra-alveolar virus transmission. Here, we investigated the protein expression of 10 well-known and novel virus entry molecules along potential entry sites in humans using immunohistochemistry., Methods and Results: Samples of different anatomical sites from up to 93 patients were incorporated into tissue microarrays. Protein expression of ACE2, TMPRSS2, furin, CD147, C-type lectin receptors (CD169, CD209, CD299), neuropilin-1, ASGR1 and KREMEN1 were analysed. In lung tissues, at least one of the three receptors ACE2, ASGR1 or KREMEN1 was expressed in the majority of cases. Moreover, all the investigated molecules were found to be expressed in alveolar macrophages, and co-localisation with SARS-CoV-2 N-protein was demonstrated using dual immunohistochemistry in lung tissue from a COVID-19 autopsy. While CD169 and CD209 showed consistent protein expression in sinonasal, conjunctival and bronchiolar tissues, neuropilin-1 and ASGR1 were mostly absent, suggesting a minor relevance of these two molecules at these specific sites., Conclusion: Our results extend recent discoveries indicating a role for these molecules in virus entry at different anatomical sites. Moreover, they support the notion of alveolar macrophages being a potential entry cell for SARS-CoV-2., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)
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- 2023
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24. Endometriosis in Patients with Mayer-Rokitansky-Küster-Hauser-Syndrome-Histological Evaluation of Uterus Remnants and Peritoneal Lesions and Comparison to Samples from Endometriosis Patients without Mullerian Anomaly.
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Steinmacher S, Bösmüller H, Granai M, Koch A, Brucker SY, and Rall KK
- Abstract
Congenital Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a Mullerian-duct anomaly that is characterized by agenesis of the uterus and upper part of the vagina. Uterus remnants of varying sizes can often be found. Although a functional uterus is missing, the existence of endometriosis in this patient group has been described in the literature; however, a histopathological comparison of the characteristics of the endometrium within the uterus remnants versus endometriotic peritoneal lesions in the same patient is lacking. Moreover, the characteristics of endometriotic tissue in patients with MRKH syndrome have not been correlated with those of patients with endometriosis without Mullerian anomaly. Patients who underwent laparoscopic neovagina creation with the removal of uterus remnants and possible resection of endometriotic lesions between 2010 and 2022 at the Department of Women's health of the University of Tuebingen were included in our study. Uterine remnants and endometriotic tissue were evaluated via histopathology and immunohistochemistry and were compared to endometriotic samples from patients without Mullerian anomaly. Endometriosis was detected in nine MRKH patients; in four patients, endometrial remnants could be sufficiently compared to endometriotic lesions. All samples exhibited increased expression of hormonal receptors. In two patients, Ki67 proliferation index was significantly increased in peritoneal endometriotic lesions compared with the endometrium of the remnants. In contrast, endometrium and endometriotic lesions of endometriosis patients did not exhibit any differences in the Ki67 proliferation index. Our results demonstrate distinctive immunohistochemical variability between uterine remnants and endometriotic lesions in patients with MRKH syndrome compared with patients with endometriosis, indicating a possible explanation model of the yet-unknown etiology of endometriosis. For confirmation, investigation of a broader patient collective is necessary.
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- 2022
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25. Reporting of melanoma cell densities in the sentinel node refines outcome prediction.
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Ulmer A, Pfefferle V, Walter V, Granai M, Keim U, Fend F, Sulyok M, and Bösmüller H
- Subjects
- Cell Count, Eosine Yellowish-(YS), Humans, Lymph Nodes pathology, Lymphatic Metastasis pathology, Prognosis, Prospective Studies, Sentinel Lymph Node Biopsy methods, Lymphadenopathy, Melanoma pathology, Skin Neoplasms pathology
- Abstract
Introduction: Sentinel node biopsy is a key procedure to predict prognosis in melanoma. In a prospective study we compare reporting on melanoma cell densities in cytospin preparations with semiquantitative histopathology for predicting outcome., Patients and Methods: Sentinel nodes from 900 melanoma patients were bisected. One half of each node was disaggregated mechanically. The melanoma cell density (number of HMB45 positive cells per million lymphocytes with at least one cell showing morphological features of a melanoma cell) was recorded after examining two cytospins. For the second half the maximum diameter of metastasis was determined after haematoxylin and eosin (H&E) and immunohistological staining of three slides., Results: Cytospins were positive for melanoma in 218 of 900 patients (24%). Routine pathology was positive in 111 of 900 (12%) patients. A more extensive pathological workup in cytospin-only positive patients led to a revised diagnosis (from negative to positive) in 23 of 101 patients (22.7%). We found a moderate but significant correlation between melanoma cell densities (determined in cytospins) and the maximum diameter of metastasis (determined by pathology) (rho = 0.6284, p < 0.001). At a median follow-up of 37 months (IQR 25-53 months) melanoma cell density (cytospins) (p < 0.001), thickness of melanoma (p = 0.008) and ulceration status (p = 0.026) were significant predictors for melanoma specific survival by multivariable testing and were all confirmed as key predictive factors by the random forest model. Maximum diameter of metastases, age and sex were not significant by multivariable testing (all p > 0.05)., Conclusion: Recording melanoma cell densities by examining two cytospins accurately predicts melanoma outcome and outperforms semiquantitative histopathology., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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26. Unusual presentation of extra-nodal double-hit follicular lymphoma: a case report.
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Lazzi S, Granai M, Capanni M, and Fend F
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- Aged, Colonoscopy, Female, Humans, Lymphoma, Follicular complications, Lymphoma, Follicular diagnosis, Lymphoma, Follicular pathology
- Abstract
Background: To the best of our knowledge, this case represents the first report of an extranodal double-hit follicular lymphoma (DH-FL) as an intestinal polypoid lesion., Case Presentation: A 72-year-old woman presents with constipation. Colonoscopy reveals a sessile polypoid lesion of the colon bearing morphological, immunohistochemical and molecular hallmarks of DH-FL. Complete clinical staging and bone marrow biopsy showed no signs of disseminated disease. The patient, after two years of follow-up is still free of disease confirming the indolent behaviour of this limited lesion., Conclusions: A synoptic view at all the features of the patient and not merely at the molecular hallmarks of a disease are essential to establish the correct clinical approach., (© 2022. The Author(s).)
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- 2022
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27. Epigenetic Alteration of the Cancer-Related Gene TGFBI in B Cells Infected with Epstein-Barr Virus and Exposed to Aflatoxin B1: Potential Role in Burkitt Lymphoma Development.
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Manara F, Jay A, Odongo GA, Mure F, Maroui MA, Diederichs A, Sirand C, Cuenin C, Granai M, Mundo L, Hernandez-Vargas H, Lazzi S, Khoueiry R, Gruffat H, Herceg Z, and Accardi R
- Abstract
Burkitt lymphoma (BL) is a malignant B cell neoplasm that accounts for almost half of pediatric cancers in sub-Saharan African countries. Although the BL endemic prevalence is attributable to the combination of Epstein-Barr virus (EBV) infection with malaria and environmental carcinogens exposure, such as the food contaminant aflatoxin B1 (AFB1), the molecular determinants underlying the pathogenesis are not fully understood. Consistent with the role of epigenetic mechanisms at the interface between the genome and environment, AFB1 and EBV impact the methylome of respectively leukocytes and B cells specifically. Here, we conducted a thorough investigation of common epigenomic changes following EBV or AFB1 exposure in B cells. Genome-wide DNA methylation profiling identified an EBV-AFB1 common signature within the TGFBI locus, which encodes for a putative tumor suppressor often altered in cancer. Subsequent mechanistic analyses confirmed a DNA-methylation-dependent transcriptional silencing of TGFBI involving the recruitment of DNMT1 methyltransferase that is associated with an activation of the NF-κB pathway. Our results reveal a potential common mechanism of B cell transformation shared by the main risk factors of endemic BL (EBV and AFB1), suggesting a key determinant of disease that could allow the development of more efficient targeted therapeutic strategies.
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- 2022
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28. A refined approach to the diagnosis of Burkitt lymphoma in a resource-poor setting.
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Naresh KN, Lazzi S, Santi R, Granai M, Onyango N, and Leoncini L
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- Humans, Burkitt Lymphoma diagnosis, Burkitt Lymphoma pathology
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- 2022
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29. Pediatric autoimmune disorders with gastrointestinal expressions: from bench to bedside.
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Francalanci P, Cafferata B, Alaggio R, de Angelis P, Diamanti A, Parente P, Granai M, and Lazzi S
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- Child, Child, Preschool, Gastrointestinal Tract pathology, Humans, Intestinal Mucosa pathology, Intestine, Small pathology, Autoimmune Diseases diagnosis, Autoimmune Diseases pathology, Polyendocrinopathies, Autoimmune pathology
- Abstract
The gastrointestinal (GI) tract may be involved in systemic autoimmune diseases or may be the target of organ-specific autoimmunity. Autoimmune enteropathy (AIE) is a rare disorder characterized by severe and protracted diarrhea, weight loss from malabsorption and immune-mediated damage to the intestinal mucosa, generally occurring in infants and young children, only rarely in adult. The salient histopathologic features of AIE are most prominent in the small intestine: villous blunting, crypt hyperplasia, mononuclear cell inflammatory expansion of the lamina propria with intraepithelial lymphocytosis, crypt apoptosis and absence of Paneth cells, goblet cells or both. Esophagus, stomach and colon are frequently also involved. Anti-enterocyte antibodies are identified in the majority of cases, and their presence, even if variable, can help confirming the diagnosis., The purpose of this review is to provide an overview of the latest immunological advances in AIE, as well as to offer a practical approach for histological diagnosis for 'general' pathologist., (Copyright © 2022 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)
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- 2022
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30. The Grey Zones of Classic Hodgkin Lymphoma.
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Bosch-Schips J, Granai M, Quintanilla-Martinez L, and Fend F
- Abstract
Classic Hodgkin lymphoma (CHL) is a well-defined neoplasm characterized by the presence of a minority of pathognomonic Hodgkin and Reed-Sternberg (HRS) cells in a reactive inflammatory background. Although genotypically of B cell origin, HRS cells exhibit a downregulated B cell program and therefore are set apart from other B cell lymphomas in the current WHO classification. However, cases with morphological and phenotypic features overlapping with CHL have been recognized, and the category of B cell lymphoma-unclassifiable-with features intermediate between diffuse large B cell lymphoma (DLBCL) and CHL, also termed grey zone lymphoma, was first introduced into the WHO classification in 2008 as provisional entity. These cases, as well as others raising a differential diagnosis of CHL can present diagnostic problems, as well as therapeutic challenges. Whereas some of these lymphomas only represent biologically unrelated morphological mimics, others, especially mediastinal grey zone lymphoma, exhibit genetic and gene expression profiles which overlap with CHL, indicating a true biological relationship. In this review, we address areas of diagnostic difficulties between CHL and other lymphoma subtypes, discuss the biological basis of true grey zone lymphoma based on recent molecular studies and delineate current concepts for the classification of these rare tumors.
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- 2022
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31. Burkitt lymphoma with a granulomatous reaction: an M1/Th1-polarised microenvironment is associated with controlled growth and spontaneous regression.
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Granai M, Lazzi S, Mancini V, Akarca A, Santi R, Vergoni F, Sorrentino E, Guazzo R, Mundo L, Cevenini G, Tripodo C, Di Stefano G, Puccini B, Ponzoni M, Sabattini E, Agostinelli C, Bassüllü N, Tecimer T, Demiroz AS, Mnango L, Dirnhofer S, Quintanilla-Martinez L, Marafioti T, Fend F, and Leoncini L
- Subjects
- Adolescent, Aged, Female, Herpesvirus 4, Human, Humans, Male, Middle Aged, Burkitt Lymphoma pathology, Epstein-Barr Virus Infections pathology, Macrophages pathology, Th1 Cells pathology, Tumor Microenvironment
- Abstract
Aims: Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that, in some instances, may show a granulomatous reaction associated with a favourable prognosis and occasional spontaneous regression. In the present study, we aimed to define the tumour microenvironment (TME) in four such cases, two of which regressed spontaneously., Methods and Results: All cases showed aggregates of tumour cells with the typical morphology, molecular cytogenetics and immunophenotype of BL surrounded by a florid epithelioid granulomatous reaction. All four cases were Epstein-Barr virus (EBV)-positive with type I latency. Investigation of the TME showed similar features in all four cases. The analysis revealed a proinflammatory response triggered by Th1 lymphocytes and M1 polarised macrophages encircling the neoplastic cells with a peculiar topographic distribution., Conclusions: Our data provide an in-vivo picture of the role that specific immune cell subsets might play during the early phase of BL, which may be capable of maintaining the tumour in a self-limited state or inducing its regression. These novel results may provide insights into new potential therapeutic avenues in EBV-positive BL patients in the era of cellular immunotherapy., (© 2021 The Authors. Histopathology published by John Wiley & Sons Ltd.)
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- 2022
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32. Epstein-Barr virus reactivation influences clonal evolution in human herpesvirus-8-related lymphoproliferative disorders.
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Granai M, Facchetti M, Mancini V, Goedhals J, Sherriff A, Mundo L, Bellan C, Amato T, Sorrentino E, Ungari M, Raphael M, Leoncini L, Facchetti F, and Lazzi S
- Subjects
- Aged, Clonal Evolution, Epstein-Barr Virus Infections virology, Female, Herpesviridae Infections virology, Herpesvirus 4, Human physiology, Herpesvirus 8, Human, Humans, Lymphoproliferative Disorders pathology, Male, Middle Aged, Coinfection virology, Epstein-Barr Virus Infections complications, Herpesviridae Infections complications, Lymphoproliferative Disorders virology, Virus Activation
- Abstract
Background: Human herpesvirus-8 (HHV8) is a lymphotropic virus associated with different lymphoproliferative disorders, including primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD), diffuse large B-cell lymphomas, not otherwise specified, and the rare entity known as germinotropic lymphoproliferative disorder (GLPD). In PELs and GLPD the neoplastic cells also contain Epstein-Barr virus (EBV). In addition, occasional cases with atypical and overlapping features among these entities have been recognised, suggesting that the spectrum of the HHV8-related lesions may not be fully characterised., Aims: Here, we report two cases of lymphoproliferative disorder associated with HHV8 and EBV that further expand the spectrum of HHV8/EBV-positive lymphoproliferative disease., Methods and Results: Case 1 represented HHV8/EBV-positive extracavitary nodal PEL followed by pleural PEL. The striking characteristic of this case was the almost focal and intrasinusoidal localisation of the neoplastic cells and the association with Castleman's disease features. In the second case, we found the entire spectrum of HHV8-related disorders, i.e. MCD, GLPD, and PEL, coexisting in the same lymph node, underlining the variability, possible overlap and evolution among these entities. Both cases were well analysed with immunohistochemistry, determination of the EBV latency programme, and molecular analysis for clonality of immnoglobulin genes. In both patients, the disease followed an unexpected indolent course, both being still alive after 8 and 12 months, respectively., Conclusion: Our findings represent further evidence of the overlap among HHV8/EBV-positive lymphoproliferative disorders, and underline a grey zone that requires further study; they further confirm the experimental evidence that lytic EBV replication influences HHV8-related tumorigenesis., (© 2021 The Authors. Histopathology published by John Wiley & Sons Ltd.)
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- 2021
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33. Metabolic Switch and Cytotoxic Effect of Metformin on Burkitt Lymphoma.
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Bagaloni I, Visani A, Biagiotti S, Ruzzo A, Navari M, Etebari M, Mundo L, Granai M, Lazzi S, Isidori A, Loscocco F, Li J, Leoncini L, Visani G, Magnani M, and Piccaluga PP
- Abstract
Altered cellular energetic metabolism has recently emerged as important feature of neoplastic cells. Indeed, interfering with cancer cell metabolism might represent a suitable therapeutic strategy. In this study, we aimed to assess glucose metabolism activation in human lymphomas and evaluate how metformin can exert its action on lymphoma cells. We studied a large series of human lymphomas (N = 252) and an in vitro model of Burkitt lymphoma (BL) cells. We combined molecular biology techniques, including global gene expression profiling (GEP) analysis, quantitative PCR (qPCR) and Western blotting, and biochemical assays, aimed to assess pentose phosphate pathway, tricarboxylic acid (TCA) cycle, and aerobic glycolysis rates. We found that glucose metabolism is overall enhanced in most lymphoma subtypes, based on gene expression profiling (GEP), with general shift to aerobic glycolysis. By contrast, normal B cells only showed an overall increase in glucose usage during germinal center transition. Interestingly, not only highly proliferating aggressive lymphomas but also indolent ones, like marginal zone lymphomas, showed the phenomenon. Consistently, genes involved in glycolysis were confirmed to be overexpressed in BL cells by qPCR. Biochemical assays showed that while aerobic glycolysis is increased, TCA cycle is reduced. Finally, we showed that metformin can induce cell death in BL cells by stressing cellular metabolism through the induction of GLUT1, PKM2, and LDHA. In conclusion, we unveiled glucose metabolism abnormalities in human lymphomas and characterized the mechanism of action of metformin in Burkitt lymphoma model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bagaloni, Visani, Biagiotti, Ruzzo, Navari, Etebari, Mundo, Granai, Lazzi, Isidori, Loscocco, Li, Leoncini, Visani, Magnani and Piccaluga.)
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- 2021
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34. Xanthomatous Inflammatory Infiltrate Involving the Spleen: An Unusual Presentation of Erdheim-Chester Disease and Review of the Literature.
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Di Stefano G, Granai M, Giudici F, Roselli G, Lazzi S, and Santi R
- Subjects
- Fibrosis, Humans, Male, Middle Aged, Mutation, Spleen, Erdheim-Chester Disease diagnosis, Erdheim-Chester Disease genetics
- Abstract
BACKGROUND Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis characterized by foamy histiocytes, Touton-like giant cells, and fibrosis, typically affecting the diaphyseal and metaphyseal region of the long bones but that can involve any organ or tissue. ECD is usually associated with the BRAF V600E mutation or with other molecular mutations inserted in the MAPK cascade. CASE REPORT We present the case of a 63-year-old man with a previous history of myocardial infarction who underwent an emergency splenectomy for splenic rupture after an accidental fall. Histological examination of the spleen showed a diffuse xanthogranulomatous proliferation (CD68+, CD163+, S100-, CD1a-) with rare Touton-like giant cells in the red pulp. Based on the histologic findings, a diagnosis of ECD was made. However, skeletal involvement and BRAF V600E mutation were not detected. CONCLUSIONS Cases of non-Langerhans cell histiocytosis that are histologically consistent with ECD in unusual sites have been increasingly described. There is also anecdotal evidence for cases being associated with mutations besides BRAF V600E or with no genetic alteration and no skeletal involvement. Likewise, the spectrum of clinical and molecular features of ECD can be broader than previously considered. Furthermore, there is evidence that various phases of the disease can show different clinical presentations with distinct prognostic impact, according to the mutational spectrum. Recognizing ECD at an early stage allows more effective patient management, and pathologists and clinicians should be aware of the unusual clinical presentations of this rare condition.
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- 2021
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35. Comparative analysis of post-transplant lymphoproliferative disorders after solid organ and hematopoietic stem cell transplantation reveals differences in the tumor microenvironment.
- Author
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Overkamp M, Granai M, Bonzheim I, Steinhilber J, Schittenhelm J, Bethge W, Quintanilla-Martinez L, Fend F, and Federmann B
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Epstein-Barr Virus Infections virology, Female, Hematopoietic Stem Cell Transplantation adverse effects, Humans, Infant, Lymphoproliferative Disorders pathology, Lymphoproliferative Disorders virology, Male, Middle Aged, Young Adult, Epstein-Barr Virus Infections complications, Herpesvirus 4, Human pathogenicity, Organ Transplantation adverse effects, Transplantation, Homologous adverse effects, Tumor Microenvironment physiology
- Abstract
Post-transplant lymphoproliferative disorders (PTLD) occur after solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HCT) and are frequently associated with Epstein-Barr virus (EBV). Because of the complex immune setup in PTLD patients, the tumor microenvironment (TME) is of particular interest to understand PTLD pathogenesis and elucidate predictive factors and possible treatment options. We present a comparative study of clinicopathological features of 48 PTLD after HCT (n = 26) or SOT (n = 22), including non-destructive (n = 6), polymorphic (n = 23), and monomorphic (n = 18) PTLD and classic Hodgkin lymphoma (n = 1). EBV was positive in 35 cases (73%). A detailed examination of the TME with image analysis-based quantification in 22 cases revealed an inflammatory TME despite underlying immunosuppression and significant differences in its density and composition depending on type of transplant, PTLD subtypes, and EBV status. Tumor-associated macrophages (TAMs) expressing CD163 (p = 0.0022) and Mannose (p = 0.0016) were enriched in PTLD after HCT. Double stains also showed differences in macrophage polarization, with more frequent M1 polarization after HCT (p = 0.0321). Higher counts for TAMs (CD163 (p = 0.0008) and cMaf (p = 0.0035)) as well as in the T cell compartment (Granzyme B (p = 0.0028), CD8 (p = 0.01), and for PD-L1 (p = 0.0305)) were observed depending on EBV status. In conclusion, despite the presence of immunosuppression, PTLD predominantly contains an inflammatory TME characterized by mostly M1-polarized macrophages and cytotoxic T cells. Status post HCT, EBV positivity, and polymorphic subtype are associated with an actively inflamed TME, indicating a specific response of the immune system. Further studies need to elucidate prognostic significance and potential therapeutic implications of the TME in PTLD.
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- 2021
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36. Distinct pattern of lymphoid neoplasms characterizations according to the WHO classification (2016) and prevalence of associated Epstein-Barr virus infection in Nigeria population.
- Author
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Uzoma IC, Taiwo IA, Granai M, Di Stefano G, Sorrentino E, Mannucci S, Durosinmi MA, Lazzi S, Leoncini L, and Akinloye O
- Abstract
Background: The present study aimed to classify lymphoid neoplasms according to the latest World Health Organization (WHO) classification and outlining the distribution in Nigeria of different entities. Additionally, the study describes the prevalence of lymphoid neoplasms associated with Epstein-Barr virus (EBV) infection in the Nigerian population., Methods: We collected 152 formalin-fixed paraffin-embedded (FFPE) tissues diagnosed as lymphoma from 2008 to 2018, coming from three different institutions located within three geopolitical zone in Nigeria. These institutions included the University College Hospital (UCH), Ibadan, Oyo State, the Enugu State University of Science and Technology Teaching Hospital (ESUTH), Enugu, Enugu State, and the Meena Histopathology and Cytology Laboratory (MHCL), Jos, Plateau State., Results: From the total 152 cases retrieved, 50 were excluded due to insufficient tissue materials or inconclusive antigen reactivity. We confirmed 66 (64.7%) cases as lymphomas out of the remaining 102 FFPE with a male to female ratio of 2:1 and a mean age of 44.4 years. Ten entities were identified, and of these, chronic lymphocytic leukemia (CLL) was the most prevalent category (34.8%). For the diffuse large B-cell lymphomas not otherwise specified (DLBCL, NOS), the germinal centre B-cell type was the most common (71.4%). Ten lymphoma cases (15.2%) were positive for Epstein-Barr virus (EBV), most of which were Hodgkin lymphoma (HL). CLL was common in the Hausa ethnic group, HL in the Yoruba ethnic group, while the Igbo ethnic group had an equal distribution of CLL, HL, and DLBCL diagnosis., Conclusion: Although the distribution of lymphomas in Nigeria shares some similarities with those of other countries, we described distinct features of some subtypes of lymphomas. Also, the study underscores the need for a more precise diagnosis and classification of lymphoid neoplasms in Nigeria using the latest WHO classification.
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- 2021
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37. Correction: Frequent traces of EBV infection in Hodgkin and non-Hodgkin lymphomas classified as EBV-negative by routine methods: expanding the landscape of EBV-related lymphomas.
- Author
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Mundo L, Del Porro L, Granai M, Siciliano MC, Mancini V, Santi R, Marcar L, Vrzalikova K, Vergoni F, Di Stefano G, Schiavoni G, Segreto G, Onyango N, Nyagol JA, Amato T, Bellan C, Anagnostopoulos I, Falini B, Leoncini L, Tiacci E, and Lazzi S
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
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38. Frequent traces of EBV infection in Hodgkin and non-Hodgkin lymphomas classified as EBV-negative by routine methods: expanding the landscape of EBV-related lymphomas.
- Author
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Mundo L, Del Porro L, Granai M, Siciliano MC, Mancini V, Santi R, Marcar L, Vrzalikova K, Vergoni F, Di Stefano G, Schiavoni G, Segreto G, Onyango N, Nyagol JA, Amato T, Bellan C, Anagnostopoulos I, Falini B, Leoncini L, Tiacci E, and Lazzi S
- Subjects
- Epstein-Barr Virus Infections diagnosis, Hodgkin Disease diagnosis, Humans, Italy, Lymphoma, Non-Hodgkin diagnosis, Molecular Diagnostic Techniques, U937 Cells, Viral Load, Epstein-Barr Virus Infections virology, Epstein-Barr Virus Nuclear Antigens genetics, Herpesvirus 4, Human genetics, Hodgkin Disease virology, Lymphoma, Non-Hodgkin virology, RNA, Messenger genetics, RNA, Viral genetics
- Abstract
The Epstein-Barr virus (EBV) is linked to various B-cell lymphomas, including Burkitt lymphoma (BL), classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) at frequencies ranging, by routine techniques, from 5 to 10% of cases in DLBCL to >95% in endemic BL. Using higher-sensitivity methods, we recently detected EBV traces in a few EBV-negative BL cases, possibly suggesting a "hit-and-run" mechanism. Here, we used routine and higher-sensitivity methods (qPCR and ddPCR for conserved EBV genomic regions and miRNAs on microdissected tumor cells; EBNA1 mRNA In situ detection by RNAscope) to assess EBV infection in a larger lymphoma cohort [19 BL, 34 DLBCL, 44 cHL, 50 follicular lymphomas (FL), 10 T-lymphoblastic lymphomas (T-LL), 20 hairy cell leukemias (HCL), 10 mantle cell lymphomas (MCL)], as well as in several lymphoma cell lines (9 cHL and 6 BL). qPCR, ddPCR, and RNAscope consistently documented the presence of multiple EBV nucleic acids in rare tumor cells of several cases EBV-negative by conventional methods that all belonged to lymphoma entities clearly related to EBV (BL, 6/9 cases; cHL, 16/32 cases; DLBCL, 11/30 cases), in contrast to fewer cases (3/47 cases) of FL (where the role of EBV is more elusive) and no cases (0/40) of control lymphomas unrelated to EBV (HCL, T-LL, MCL). Similarly, we revealed traces of EBV infection in 4/5 BL and 6/7 HL cell lines otherwise conventionally classified as EBV negative. Interestingly, additional EBV-positive cases (1 DLBCL, 2 cHL) relapsed as EBV-negative by routine methods while showing EBNA1 expression in rare tumor cells by RNAscope. The relapse specimens were clonally identical to their onset biopsies, indicating that the lymphoma clone can largely loose the EBV genome over time but traces of EBV infection are still detectable by high-sensitivity methods. We suggest EBV may contribute to lymphoma pathogenesis more widely than currently acknowledged.
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- 2020
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39. A 70% cut-off for MYC protein expression in diffuse large B cell lymphoma identifies a high-risk group of patients.
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Ziepert M, Lazzi S, Santi R, Vergoni F, Granai M, Mancini V, Staiger A, Horn H, Löffler M, Pöschel V, Held G, Wulf G, Trümper LH, Schmitz N, Rosenwald A, Sabattini E, Naresh KN, Stein H, Ott G, and Leoncini L
- Subjects
- Humans, Prognosis, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-myc genetics, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Large B-Cell, Diffuse genetics
- Published
- 2020
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40. Prognostic impact of tumor-associated macrophages, lymphocyte-to-monocyte and neutrophil-to-lymphocyte ratio in diffuse large B-cell lymphoma.
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Cencini E, Fabbri A, Schiattone L, Sicuranza A, Mecacci B, Granai M, Mancini V, Lazzi S, Bocchia M, and Leoncini L
- Abstract
Introduction: Microenvironment has a prognostic influence in diffuse large B-cell lymphoma (DLBCL); among its components, tumor-associated macrophages (TAM) play a leading role. TAM can be classified into M1 (anti-tumor) and M2 (pro-tumor). Another prognostic factor could be represented by lymphocyte-to-monocyte and neutrophil-to-lymphocyte ratio (LMR and NLR)., Objective: The aim of the study is to evaluate the prognostic impact of M1 and M2 TAM subtypes, LMR and NLR in DLBCL., Methods: We analyzed 37 consecutive patients between 2009 and 2013. Out of 37 patients, 28/37 (75.6%) received R-CHOP/CHOP-like regimens, 9/37 (24.4%) less intensive therapies. Immunohistochemistry was performed with antibodies against CD68 and CD163. We divided our cohort into 2 categories according to the Steidl score. TAM who coexpressed CD68 and CD163 were considered as M2. For LMR and NLR we used previously published cut-offs of 2.71 and 2.81., Results: CR rate was 70.3%; we did not record a significant correlation between CD68+ TAM, CD163+ TAM, CD68+/CD163+ TAM, LMR, NLR and CR. We observed a reduced PFS in patients with IPI ≥ 2 and high M2 TAM expression and a trend between higher expression of CD68+ TAM and improved PFS., Conclusion: M2 TAM could have a prognostic role for IPI ≥ 2 DLBCL patients receiving R-CHOP, which thus warrants further investigation., Competing Interests: None., (AJBR Copyright © 2020.)
- Published
- 2020
41. Early pattern of large B-cell lymphoma with IRF4 rearrangement.
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Granai M and Lazzi S
- Subjects
- Appendectomy, Appendicitis complications, Child, Early Detection of Cancer, Germinal Center pathology, Humans, Immunophenotyping, In Situ Hybridization, Fluorescence, Incidental Findings, Lymphoma, Large B-Cell, Diffuse complications, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Large B-Cell, Diffuse genetics, Male, Interferon Regulatory Factors genetics, Lymph Nodes pathology, Lymphoma, Large B-Cell, Diffuse pathology, Neoplasm Proteins genetics
- Published
- 2020
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42. Correction to: IGHV mutational status of nodal marginal zone lymphoma by NGS reveals distinct pathogenic pathways with different prognostic implications.
- Author
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Granai M, Amato T, Di Napoli A, Santi R, Vergoni F, Di Stefano G, Mancini V, Kovalchuk S, Cencini E, Carta AG, Aversa S, Ziepert M, Cevenini G, Lazzi S, Leoncini L, and Bellan C
- Abstract
This error was caused due to the author's oversight and this does not change the views or the results presented in the manuscript.
- Published
- 2020
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43. IGHV mutational status of nodal marginal zone lymphoma by NGS reveals distinct pathogenic pathways with different prognostic implications.
- Author
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Granai M, Amato T, Di Napoli A, Santi R, Vergoni F, Di Stefano G, Mancini V, Kovalchuk S, Cencini E, Carta AG, Aversa S, Ziepert M, Cevenini G, Lazzi S, Leoncini L, and Bellan C
- Subjects
- Aged, Aged, 80 and over, B-Lymphocytes pathology, Female, High-Throughput Nucleotide Sequencing methods, Humans, Lymphoma, B-Cell, Marginal Zone genetics, Male, Prognosis, Splenic Neoplasms genetics, Splenic Neoplasms immunology, Immunoglobulin Heavy Chains genetics, Immunoglobulin Variable Region genetics, Lymphoma, B-Cell, Marginal Zone pathology, Mutation genetics, Splenic Neoplasms pathology
- Abstract
The precise B cell of origin and molecular pathogenesis of nodal marginal zone lymphoma (NMZL) remain poorly defined. To date, due to the rarity of NMZL, the vast majority of already-published studies have been conducted on a limited number of samples and the technical approach to analyze the immunoglobulin genes was of amplifying rearranged variable region genes with the classical direct sequencing of the PCR products followed by cloning. Here, we studied the B cell Ig heavy-chain repertoires by next-generation sequencing (NGS) in 30 NMZL cases. Most of the cases were mutated (20/28; 71.5%) with homologies to the respective germ line genes ranging from 85 to 97, 83%, whereas 8/28 (28.5%) were unmutated. In addition, our results show that NMZL cases have a biased usage of specific immunoglobulin heavy-chain variable (IGHV) region genes. Moreover, we documented intraclonal diversity in all (100%) of the mutated cases and ongoing somatic hypermutations (SHM) have been confirmed by hundreds of reads. We analyzed the mutational pattern to detect and quantify antigen selection pressure and we found a positive selection in 4 cases, whereas in the remaining cases there was an unspecific stimulation. Finally, the disease-specific survival and the progression-free survival were significantly different between cases with mutated and unmutated IGHV genes, pointing out mutational status as a possible new biomarker in NMZL.
- Published
- 2020
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44. Correction to: Immune landscape in Burkitt lymphoma reveals M2-macrophage polarization and correlation between PD-L1 expression and non-canonical EBV latency program.
- Author
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Granai M, Mundo L, Akarca AU, Siciliano MC, Rizvi H, Mancini V, Onyango N, Nyagol J, Abinya NO, Maha I, Margielewska S, Wei W, Bibas M, Piccaluga PP, Quintanilla-Martinez L, Fend F, Lazzi S, Leoncini L, and Marafioti T
- Abstract
[This corrects the article DOI: 10.1186/s13027-020-00292-w.]., (© The Author(s) 2020.)
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- 2020
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45. Immune landscape in Burkitt lymphoma reveals M2-macrophage polarization and correlation between PD-L1 expression and non-canonical EBV latency program.
- Author
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Granai M, Mundo L, Akarca AU, Siciliano MC, Rizvi H, Mancini V, Onyango N, Nyagol J, Abinya NO, Maha I, Margielewska S, Wi W, Bibas M, Piccaluga PP, Quintanilla-Martinez L, Fend F, Lazzi S, Leoncini L, and Marafioti T
- Abstract
Background: The Tumor Microenviroment (TME) is a complex milieu that is increasingly recognized as a key factor in multiple stages of disease progression and responses to therapy as well as escape from immune surveillance. However, the precise contribution of specific immune effector and immune suppressor components of the TME in Burkitt lymphoma (BL) remains poorly understood., Methods: In this paper, we applied the computational algorithm CIBERSORT to Gene Expression Profiling (GEP) datasets of 40 BL samples to draw a map of immune and stromal components of TME. Furthermore, by multiple immunohistochemistry (IHC) and multispectral immunofluorescence (IF), we investigated the TME of additional series of 40 BL cases to evaluate the role of the Programmed Death-1 and Programmed Death Ligand-1 (PD-1/PD-L1) immune checkpoint axis., Results: Our results indicate that M2 polarized macrophages are the most prominent TME component in BL. In addition, we investigated the correlation between PD-L1 and latent membrane protein-2A (LMP2A) expression on tumour cells, highlighting a subgroup of BL cases characterized by a non-canonical latency program of EBV with an activated PD-L1 pathway., Conclusion: In conclusion, our study analysed the TME in BL and identified a tolerogenic immune signature highlighting new potential therapeutic targets., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)
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- 2020
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46. Molecular switch from MYC to MYCN expression in MYC protein negative Burkitt lymphoma cases.
- Author
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Mundo L, Ambrosio MR, Raimondi F, Del Porro L, Guazzo R, Mancini V, Granai M, Jim Rocca B, Lopez C, Bens S, Onyango N, Nyagol J, Abinya N, Navari M, Ndede I, Patel K, Paolo Piccaluga P, Bob R, de Santi MM, Russell RB, Lazzi S, Siebert R, Stein H, and Leoncini L
- Subjects
- Adolescent, Adult, Aged, Burkitt Lymphoma epidemiology, Burkitt Lymphoma pathology, Child, Female, Genomics methods, High-Throughput Nucleotide Sequencing, Humans, Immunohistochemistry, Immunophenotyping, Male, Middle Aged, Models, Molecular, Mutation, Protein Conformation, RNA, Messenger genetics, Structure-Activity Relationship, Translocation, Genetic, Young Adult, Burkitt Lymphoma genetics, Burkitt Lymphoma metabolism, Gene Expression Regulation, Neoplastic, Genes, Switch, Genes, myc
- Abstract
MYC is the most altered oncogene in human cancer, and belongs to a large family of genes, including MYCN and MYCL. Recently, while assessing the degree of correlation between MYC gene rearrangement and MYC protein expression in aggressive B-cell lymphomas, we observed few Burkitt lymphoma (BL) cases lacking MYC protein expression despite the translocation involving the MYC gene. Therefore, in the present study we aimed to better characterize such cases. Our results identified two sub-groups of MYC protein negative BL: one lacking detectable MYC protein expression but presenting MYCN mRNA and protein expression; the second characterized by the lack of both MYC and MYCN proteins but showing MYC mRNA. Interestingly, the two sub-groups presented a different pattern of SNVs affecting MYC gene family members that may induce the switch from MYC to MYCN. Particulary, MYCN-expressing cases show MYCN SNVs at interaction interface that stabilize the protein associated with loss-of-function of MYC. This finding highlights MYCN as a reliable diagnostic marker in such cases. Nevertheless, due to the overlapping clinic, morphology and immunohistochemistry (apart for MYC versus MYCN protein expression) of both sub-groups, the described cases represent bona fide BL according to the current criteria of the World Health Organization.
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- 2019
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47. IGHV1 status in chronic lymphocytic leukemia identify ethnic groups with an aggressive clinical course (Comment to Giudice ID, Foà R. Haematologica. 2019;104(2):219-221) .
- Author
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Amato T, Granai M, Leoncini L, and Bellan C
- Subjects
- Ethnicity, Humans, Immunoglobulin Heavy Chains genetics, Immunoglobulin Variable Region genetics, Mutation, Leukemia, Lymphocytic, Chronic, B-Cell
- Published
- 2019
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48. p66Shc deficiency in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia enhances leukemogenesis by altering the chemokine receptor landscape.
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Patrussi L, Capitani N, Ulivieri C, Manganaro N, Granai M, Cattaneo F, Kabanova A, Mundo L, Gobessi S, Frezzato F, Visentin A, Finetti F, Pelicci PG, D'Elios MM, Trentin L, Semenzato G, Leoncini L, Efremov DG, and Baldari CT
- Subjects
- Animals, Carcinogenesis genetics, Carcinogenesis pathology, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Mice, Mice, Knockout, Neoplasm Proteins genetics, Neoplasms, Experimental genetics, Neoplasms, Experimental pathology, Receptors, Chemokine genetics, Src Homology 2 Domain-Containing, Transforming Protein 1 metabolism, Carcinogenesis metabolism, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Neoplasm Proteins metabolism, Neoplasms, Experimental metabolism, Receptors, Chemokine metabolism, Src Homology 2 Domain-Containing, Transforming Protein 1 deficiency
- Abstract
The Shc family adaptor p66Shc acts as a negative regulator of proliferative and survival signals triggered by the B-cell receptor and, by enhancing the production of reactive oxygen species, promotes oxidative stress-dependent apoptosis. Additionally, p66Shc controls the expression and function of chemokine receptors that regulate lymphocyte traffic. Chronic lymphocytic leukemia cells have a p66Shc expression defect which contributes to their extended survival and correlates with poor prognosis. We analyzed the impact of p66Shc ablation on disease severity and progression in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia. We showed that Eμ-TCL1/p66Shc
-/- mice developed an aggressive disease that had an earlier onset, occurred at a higher incidence and led to earlier death compared to that in Eμ-TCL1 mice. Eμ-TCL1/p66Shc-/- mice displayed substantial leukemic cell accumulation in both nodal and extranodal sites. The target organ selectivity correlated with upregulation of chemokine receptors whose ligands are expressed therein. This also applied to chronic lymphocytic leukemia cells, where chemokine receptor expression and extent of organ infiltration were found to correlate inversely with these cells' level of p66Shc expression. p66Shc expression declined with disease progression in Eμ-TCL1 mice and could be restored by treatment with the Bruton tyrosine kinase inhibitor ibrutinib. Our results highlight p66Shc deficiency as an important factor in the progression and severity of chronic lymphocytic leukemia and underscore p66Shc expression as a relevant therapeutic target., (Copyright© 2019 Ferrata Storti Foundation.)- Published
- 2019
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49. Role of Epstein-Barr virus in transformation of follicular lymphoma to diffuse large B-cell lymphoma: a case report and review of the literature.
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Granai M, Ambrosio MR, Akarca A, Mundo L, Vergoni F, Santi R, Mancini V, di Stefano G, Amato T, Bellan C, Puccini B, Sorrentino E, Naresh KN, Leoncini L, Marafioti T, and Lazzi S
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Disease Progression, Epstein-Barr Virus Infections diagnosis, Fatal Outcome, Female, Genetic Testing, Humans, Immunohistochemistry, Lymphoma, Follicular therapy, Lymphoma, Large B-Cell, Diffuse therapy, Male, Treatment Outcome, Cell Transformation, Viral, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections virology, Herpesvirus 4, Human, Lymphoma, Follicular diagnosis, Lymphoma, Follicular etiology, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Large B-Cell, Diffuse etiology
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- 2019
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50. MYC protein expression scoring and its impact on the prognosis of aggressive B-cell lymphoma patients.
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Ambrosio MR, Lazzi S, Bello GL, Santi R, Porro LD, de Santi MM, Guazzo R, Mundo L, Rigacci L, Kovalchuck S, Onyango N, Fabbri A, Cencini E, Zinzani PL, Zaja F, Angrilli F, Stelitano C, Cabras MG, Spataro G, Bob R, Menter T, Granai M, Cevenini G, Naresh KN, Stein H, Sabattini E, and Leoncini L
- Subjects
- Adult, Aged, Cyclophosphamide administration & dosage, Disease-Free Survival, Doxorubicin administration & dosage, Female, Humans, Male, Middle Aged, Prednisone administration & dosage, Rituximab administration & dosage, Survival Rate, Vincristine administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Gene Expression Regulation, Neoplastic drug effects, Lymphoma, B-Cell drug therapy, Lymphoma, B-Cell mortality, Lymphoma, B-Cell pathology, Proto-Oncogene Proteins c-myc biosynthesis
- Published
- 2019
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