301 results on '"Kikkeri N Naresh"'
Search Results
2. Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a post-mortem study
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Brian Hanley, MBBCh, Kikkeri N Naresh, ProfMD, Candice Roufosse, PhD, Andrew G Nicholson, ProfDM, Justin Weir, FRCPath, Graham S Cooke, ProfFRCP, Mark Thursz, ProfMD, Pinelopi Manousou, PhD, Richard Corbett, PhD, Robert Goldin, ProfMD, Safa Al-Sarraj, ProfFRCPath, Alireza Abdolrasouli, PhD, Olivia C Swann, MRes, Laury Baillon, BSc, Rebecca Penn, MSc, Wendy S Barclay, ProfPhD, Patrizia Viola, MD, and Michael Osborn, FRCPath
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Medicine (General) ,R5-920 ,Microbiology ,QR1-502 - Abstract
Summary: Background: Severe COVID-19 has a high mortality rate. Comprehensive pathological descriptions of COVID-19 are scarce and limited in scope. We aimed to describe the histopathological findings and viral tropism in patients who died of severe COVID-19. Methods: In this case series, patients were considered eligible if they were older than 18 years, with premortem diagnosis of severe acute respiratory syndrome coronavirus 2 infection and COVID-19 listed clinically as the direct cause of death. Between March 1 and April 30, 2020, full post-mortem examinations were done on nine patients with confirmed COVID-19, including sampling of all major organs. A limited autopsy was done on one additional patient. Histochemical and immunohistochemical analyses were done, and histopathological findings were reported by subspecialist pathologists. Viral quantitative RT-PCR analysis was done on tissue samples from a subset of patients. Findings: The median age at death of our cohort of ten patients was 73 years (IQR 52–79). Thrombotic features were observed in at least one major organ in all full autopsies, predominantly in the lung (eight [89%] of nine patients), heart (five [56%]), and kidney (four [44%]). Diffuse alveolar damage was the most consistent lung finding (all ten patients); however, organisation was noted in patients with a longer clinical course. We documented lymphocyte depletion (particularly CD8-positive T cells) in haematological organs and haemophagocytosis. Evidence of acute tubular injury was noted in all nine patients examined. Major unexpected findings were acute pancreatitis (two [22%] of nine patients), adrenal micro-infarction (three [33%]), pericarditis (two [22%]), disseminated mucormycosis (one [10%] of ten patients), aortic dissection (one [11%] of nine patients), and marantic endocarditis (one [11%]). Viral genomes were detected outside of the respiratory tract in four of five patients. The presence of subgenomic viral RNA transcripts provided evidence of active viral replication outside the respiratory tract in three of five patients. Interpretation: Our series supports clinical data showing that the four dominant interrelated pathological processes in severe COVID-19 are diffuse alveolar damage, thrombosis, haemophagocytosis, and immune cell depletion. Additionally, we report here several novel autopsy findings including pancreatitis, pericarditis, adrenal micro-infarction, secondary disseminated mucormycosis, and brain microglial activation, which require additional investigation to understand their role in COVID-19. Funding: Imperial Biomedical Research Centre, Wellcome Trust, Biotechnology and Biological Sciences Research Council.
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- 2020
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3. Does a subset of mature T‐cell leukemias with features akin to T‐cell prolymphocytic leukemia but lacking rearrangement of the TCL1 represent peripheral T‐cell lymphoma, NOS in a leukemic phase?
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David C. Gajzer, Xueyan Chen, Daniel E. Sabath, Christina Poh, and Kikkeri N. Naresh
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract In the current WHO classification, a T‐cell prolymphocytic leukemia (T‐PLL) diagnosis requires lymphocytosis of >5 × 109/L, evidence of monoclonality, and TCL1A or MTCP1 rearrangement. However, the 2019 consensus document suggested that in the absence of rearrangement of TCL1‐family, the presence of abnormalities involving chromosome 11 (11q22.3; ATM), chromosome 8 (idic(8)(p11), t(8;8), trisomy 8q), 5, 12, 13, 22, or a complex karyotype, as well as involvement specific sites (e.g., splenomegaly, effusions) would suffice for a diagnosis of T‐PLL. We present a patient diagnosed with T‐PLL with MTCP1 rearrangement who was successfully treated with alemtuzumab followed by consolidative allogeneic unrelated donor stem cell transplantation. Eight years later, the patient presented with inguinal lymphadenopathy with features more akin to peripheral T‐cell lymphoma, NOS (PTCL, NOS) of the GATA3 subtype, and there was no evidence of peripheral blood involvement. However, the lymphoma cells were clonally related to those at presentation. Currently, literature on T‐PLL‐like cases lacking the rearrangement of TCL1A is limited, and the possibility of whether a proportion of such cases could represent PTCL, NOS (with leukemic involvement) needs consideration.
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- 2024
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4. PD‐L1+ macrophage and tumor cell abundance and proximity to T cells in the pretreatment large B‐cell lymphoma microenvironment impact CD19 CAR‐T cell immunotherapy efficacy
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Alexandre V. Hirayama, Jocelyn H. Wright, Kimberly S. Smythe, Salvatore Fiorenza, Akira N. Shaw, Jordan Gauthier, David G. Maloney, Kikkeri N. Naresh, Cecilia C. S. Yeung, and Cameron J. Turtle
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract CD19‐targeted chimeric antigen receptor T‐cell (CAR‐T) immunotherapy has transformed the management of relapsed/refractory large B‐cell lymphoma (LBCL), yet durable remissions are observed in less than half of treated patients. The tumor microenvironment (TME) is a key and understudied factor impacting CD19 CAR‐T therapy outcomes. Using NanoString nCounter transcriptome profiling (n = 24) and multiplex immunohistochemistry (mIHC, n = 15), we studied the TME in pretreatment biopsies from patients with LBCL undergoing CD19 CAR‐T therapy. Patients who achieved complete response (CR) after CAR‐T therapy demonstrated higher expression of genes associated with T‐cell trafficking and function, whereas those who did not achieve CR had higher expression of genes associated with macrophages and T‐cell dysfunction. Distinct patterns of immune infiltration and fibrosis in the TME were associated with CAR‐T therapy outcomes, and these findings were corroborated using artificial intelligence‐assisted image analyses. Patients who achieved CR had a lower proportion of the biopsy occupied by an interspersed immune infiltrate and a higher proportion of hypocellular/fibrotic regions. Furthermore, mIHC revealed lower density of CD4+ T cells and higher densities of both macrophages and tumor cells expressing PD‐L1 in non‐CR patients. Spatial analysis revealed that PD‐1+ T cells were in close proximity to PD‐L1+ macrophages or PD‐L1+ tumor cells in patients who did not compared to those who did achieve CR after CAR‐T therapy. These findings suggest that morphologic patterns in the TME and engagement of the PD‐1/PD‐L1 axis in pretreatment biopsies may impact CD19 CAR‐T immunotherapy response in patients with LBCL.
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- 2024
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5. The alteration of lipid metabolism in Burkitt lymphoma identifies a novel marker: adipophilin.
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Maria R Ambrosio, Pier P Piccaluga, Maurilio Ponzoni, Bruno J Rocca, Valeria Malagnino, Monica Onorati, Giulia De Falco, Valeria Calbi, Martin Ogwang, Kikkeri N Naresh, Stefano A Pileri, Claudio Doglioni, Lorenzo Leoncini, and Stefano Lazzi
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Medicine ,Science - Abstract
Recent evidence suggests that lipid pathway is altered in many human tumours. In Burkitt lymphoma this is reflected by the presence of lipid droplets which are visible in the cytoplasm of neoplastic cells in cytological preparations. These vacuoles are not identifiable in biopsy section as lipids are "lost" during tissue processing.In this study we investigated the expression of genes involved in lipid metabolism, at both RNA and protein level in Burkitt lymphoma and in other B-cell aggressive lymphoma cases. Gene expression profile indicated a significant over-expression of the adipophilin gene and marked up-regulation of other genes involved in lipid metabolism in Burkitt lymphoma. These findings were confirmed by immunohistochemistry on a series od additional histological samples: 45 out of 47 BL cases showed strong adipophilin expression, while only 3 cases of the 33 of the not-Burkitt lymphoma category showed weak adipophilin expression (p
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- 2012
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6. Longitudinal expression profiling identifies a poor risk subset of patients with ABC-type diffuse large B-cell lymphoma
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Findlay Bewicke-Copley, Koorosh Korfi, Shamzah Araf, Brendan Hodkinson, Emil Kumar, Thomas Cummin, Margaret Ashton-Key, Sharon Barrans, Suzan van Hoppe, Cathy Burton, Mohamed Elshiekh, Simon Rule, Nicola Crosbie, Andrew Clear, Maria Calaminici, Hendrik Runge, Robert K. Hills, David W. Scott, Lisa M. Rimsza, Geetha Menon, Chulin Sha, John R. Davies, Ai Nagano, Andrew Davies, Daniel Painter, Alexandra Smith, John Gribben, Kikkeri N. Naresh, David R. Westhead, Jessica Okosun, Andrew Steele, Daniel J. Hodson, Sriram Balasubramanian, Peter Johnson, Jun Wang, and Jude Fitzgibbon
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Hematology - Abstract
Despite the effectiveness of immuno-chemotherapy, 40% of patients with diffuse large B-cell lymphoma (DLBCL) experience relapse or refractory disease. Longitudinal studies have previously focused on the mutational landscape of relapse but fell short of providing a consistent relapse-specific genetic signature. In our study, we have focused attention on the changes in GEP accompanying DLBCL relapse using archival paired diagnostic/relapse specimens from 38 de novo patients with DLBCL. COO remained stable from diagnosis to relapse in 80% of patients, with only a single patient showing COO switching from activated B-cell–like (ABC) to germinal center B-cell–like (GCB). Analysis of the transcriptomic changes that occur following relapse suggest ABC and GCB relapses are mediated via different mechanisms. We developed a 30-gene discriminator for ABC–DLBCLs derived from relapse-associated genes that defined clinically distinct high- and low-risk subgroups in ABC–DLBCLs at diagnosis in datasets comprising both population-based and clinical trial cohorts. This signature also identified a population of
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- 2023
7. Mutations of ATM Confer a Risk of Inferior Survival in Patients with TP53-wild Type Mantle Cell Lymphoma
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Jean L. Koff, Rachel Kositsky, David L Jaye, Michael C. Churnetski, Katelin Baird, Colin B. O'Leary, Christopher R. Flowers, Sirpa Leppa, Marja-Liisa Karjalainen-Lindsberg, Shaoying Li, Jie Xu, Mette Ø Pedersen, Anne Ortved Gang, Kikkeri N Naresh, Rebecca J Leeman-Neill, Kwok Him Rex Au Yeung, Hina Naushad Qureishi, Javeed Iqbal, Jennifer R Chapman-Fredricks, Chad M. McCall, Michael Crump, Amy Chadburn, Erin C. Mulvey, Izidore S. Lossos, Sandra L. Ondrejka, Eric D. Hsi, Abner Louissaint, Haley Martin, Eric Tse, Cassandra Love, Tushar Dave, Clay Parker, Choon Kiat Ong, Andrew G Evans, Amir Behdad, Lixin Yang, Nishitha Reddy, Mary Ann Arildsen, Ridas Juskevicius, Jiong Yan, Magdalena Czader, Andrew M. Evens, Dina Sameh Soliman, Yuri Fedoriw, Sandeep S. Dave, and Jonathon B. Cohen
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
8. 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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Marita Ziepert, Stefano Lazzi, Raffaella Santi, Federica Vergoni, Massimo Granai, Virginia Mancini, Annette Staiger, Heike Horn, Markus Löffler, Viola Pöschel, Gerhald Held, Gerald Wulf, Lorenz H. Trümper, Norbert Schmitz, Andreas Rosenwald, Elena Sabattini, Kikkeri N. Naresh, Harald Stein, German Ott, and Lorenzo Leoncini
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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9. Aleukemic mast cell leukemia, well-differentiated and chronic type
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Kenneth Chen, Paul C. Hendrie, and Kikkeri N. Naresh
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Hematology ,General Medicine - Published
- 2023
10. Predictors of risk of relapse in classic Hodgkin lymphoma
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Jonathan R Fromm, Claire Tang, and Kikkeri N Naresh
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General Medicine ,Pathology and Forensic Medicine - Abstract
Using multiparametric flow cytometric analysis, in a cohort of 62 patients with classic Hodgkin lymphoma having a median follow-up period of 69.5 months, we found—patients who experienced primary resistance or disease relapse (DR) had lower percentage of rosetted Hodgkin Reed-Sternberg cells (HRS-cells) as compared with patients who achieved sustained complete remission (SCR) (p=0.022); patients >35 years of age had higher percentage of HRS-cells (p=0.017) and lower percentage of B cells (p=0.017) and the nodular sclerosis subtype had higher percentage of B-cells (p=0.046) and activated B-cells (p=0.03). The proportion of SCR and DR subsets did not differ by histological subtypes, disease stage or age groups.
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- 2022
11. The impact of histological grade on outcomes in follicular lymphoma: An analysis of patients in the <scp>SEER</scp> database in the context of evolving disease classification and treatment
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Anisha Naik, Ted Gooley, Keith Loeb, Lorinda Soma, Stephen D. Smith, Ajay Gopal, and Kikkeri N. Naresh
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Databases, Factual ,Humans ,Hematology ,Prognosis ,Rituximab ,Lymphoma, Follicular - Abstract
Currently, there is no convincing evidence that the grade of follicular lymphoma (FL) impacts patient outcome. We correlated grades in 33 925 patients with nodal FL during 1992-2018 in the SEER database with disease-specific survival (DSS) and overall survival (OS). Patients with FL grade 3 had lower DSS and OS as compared to FL grades 1-2. During 1992-2005, the 10-year DSS for patients with FL grades 3 and grades 1-2 were 68.6%, and 71.4%, respectively, and in 2006-2018, they were 77.7% and 82.6%, respectively. The 10-year OS estimates in 1992-2005 were 49.9% and 54.2% for grade 3 and grades 1-2 respectively, and in 2006-2018, they were 59.1% and 63.5% for grade 3 and grades 1-2, respectively. After adjustment for stage and age, the hazard ratios for death due to FL and death from any cause for patients with FL grade 3 during 1992-2005 were 1.09 (1.02-1.16) and 1.07 (1.02-1.12), respectively, compared to FL grades 1-2; and during 2006-2018, the hazard ratios for death due to FL and death from any cause for patients with FL grade 3 were 1.34 (1.22-1.45) and 1.16 (1.10-1.23), respectively compared to FL grades 1-2. The grade of FL is an important determinant of disease biology.
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- 2022
12. High-grade B-cell lymphoma, not otherwise specified: a multi-institutional retrospective study
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Adam Stephen Zayac, Daniel J. Landsburg, Mitchell E. Hughes, Allison M. Bock, Grzegorz S. Nowakowski, Emily C. Ayers, Mark Ryan Girton, Marie Hu, Amy K. Beckman, Shaoying Li, L. Jeffrey Medeiros, Julie E Chang, Adam Stepanovic, Habibe Kurt, Jose Sandoval-Sus, Mohammad Ali Ansari-Lari, Shalin K. Kothari, Anna Kress, Mina L Xu, Pallawi Torka, Suchitra Sundaram, Stephen D Smith, Kikkeri N Naresh, Yasmin H. Karimi, Narendranath Epperla, David A Bond, Umar Farooq, Mahak Saad, Andrew M Evens, Karan Pandya, Seema G. Naik, Manali Kamdar, Bradley M Haverkos, Reem Karmali, Timothy S Oh, Julie M Vose, Heather R Nutsch, Paul G. Rubinstein, Amina Chaudhry, and Adam J Olszewski
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Hematology - Abstract
In this multi-institutional retrospective study, we examined characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS). This rare lymphoma category is defined by high-grade morphologic features, most commonly Burkitt-like, and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements (so-called double-hit). Our results show that HGBL-NOS tumors are heterogeneous: 83% had a germinal center B-cell immunophenotype, 37% a dual expressor immunophenotype (MYC and BCL2 expression), 28% (single-hit) MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage 4 disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included DA-EPOCH-R (43%), R-CHOP (33%), or other intensive chemotherapy programs (11%). We found no significant differences in the rates of complete response (CR, P=0.32), progression-free (PFS, P=0.82), or overall survival (OS, P=0.60) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% (95%CI, 46.9-62.7), and OS was 68.1% (95%CI, 59.7-75.0). In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3x upper limit of normal, and a dual expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS (13% at 2 years). Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R versus R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.
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- 2023
13. Response to the Comments from the Groupe Francophone de Cytogénétique Hématologique (GFCH) on the 5th edition of the World Health Organization classification of haematolymphoid tumors
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Reiner Siebert, Anna Schuh, German Ott, Ian A. Cree, Ming-Qing Du, Judith Ferry, Andreas Hochhaus, Kikkeri N. Naresh, Eric Solary, Joseph D. Khoury, Siebert, Reiner [0000-0001-7433-3703], Schuh, Anna [0000-0002-3938-8490], Cree, Ian A [0000-0001-5007-9456], Du, Ming-Qing [0000-0002-1017-5045], Hochhaus, Andreas [0000-0003-0626-0834], Naresh, Kikkeri N [0000-0003-3807-3638], Solary, Eric [0000-0002-8629-1341], Khoury, Joseph D [0000-0003-2621-3584], and Apollo - University of Cambridge Repository
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Chromosome Aberrations ,Cancer Research ,Oncology ,Neoplasms ,Cytogenetic Analysis ,Humans ,Hematology - Published
- 2023
14. Nodular Lymphocyte Predominant Hodgkin Lymphoma with Splenic Involvement Is Characterized By Inflamed Tumor Microenvironment, High Expression of Checkpoint Molecule Gene-Signature and Adverse Outcome
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Ilja Kalashnikov, Marja-Liisa Karjalainen-Lindsberg, Panu Kovanen, Johannes Dunkel, Annika Pasanen, Rachel Kositsky, Sarah L. Ondrejka, Eric D. Hsi, Andrew G Evans, Mette Ø Pedersen, Peter H. Norgaard, Anne Ortved Gang, Magdalena Czader, Jiehao Zhou, Mina L Xu, Nathan Paulson, Ridas Juskevicius, Yasodha Natkunam, Abner Louissaint, Haley Martin, Elizabeth Thacker, Cassandra Love, Shari Tian, Choon Kiat Ong, Chee Leong Cheng, Chad M. McCall, Jean L. Koff, Sheren F. Younes, Mary Ann Arildsen, Jennifer R Chapman-Fredricks, Catalina Amador, Yuri Fedoriw, Carla Casulo, Amy Chadburn, Payal Sojitra, Amir Behdad, Eric Tse, Kikkeri N Naresh, C. Cameron Yin, Rashmi S. Goswami, Sandeep Dave, and Sirpa Leppa
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
15. Extranodal Marginal Zone Lymphomas Show Recurrent Mutations in DNA Repair Genes, Cancer-Associated Proliferative Signaling and NOTCH1 Signaling Pathways, Regardless of Anatomic Site
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Jennifer R Chapman-Fredricks, Devang Thakkar, Juan Pablo Alderuccio, Kikkeri N Naresh, Sarah L. Ondrejka, Eric D. Hsi, Mina L Xu, Nathan Paulson, Jean L. Koff, David L Jaye, Jonathon B. Cohen, Anne Ortved Gang, Rebecca J Leeman-Neill, Tushar Dave, Lanie Happ, Cassandra Love, Sasan Zandi, Hina Naushad, Emily F Mason, Abner Louissaint, Haley Martin, Choon Kiat Ong, Raju Pillai, Mette Ø Pedersen, C. Cameron Yin, William Choi, Rex Kwok Him Au-Yeung, Marja-Liisa Karjalainen-Lindsberg, Amy Chadburn, Vincent Sarno, Matthew McKinney, Payal Sojitra, Andrew G Evans, Amir Behdad, Carlos Galvez, Chee Leong Cheng, Magdalena Czader, Jiong Yan, Sandeep S. Dave, and Izidore S. Lossos
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
16. High-Grade B-Cell Lymphoma, Not Otherwise Specified (HGBL, NOS): Central Nervous System (CNS) Involvement, Prophylaxis, and Recurrence Risk in a Multi-Institutional Series
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Narendranath Epperla, Adam Zayac, Daniel J. Landsburg, Mitchell Hughes, Allison M. Bock, Grzegorz S. Nowakowski, Emily C. Ayers, Mark Girton, Marie Hu, Amy Beckman, Shaoying Li, L. Jeffrey Medeiros, Julie E. Chang, Adam Stepanovic, Habibe Kurt, Jose Sandoval-Sus, M. Ali Ansari-Lari, Shalin K. Kothari, Anna Kress, Mina L Xu, Pallawi Torka, Suchitra Sundaram, Stephen D Smith, Kikkeri N Naresh, Yasmin Karimi, David A. Bond, Umar Farooq, Mahak Saad, Andrew Matthew Evens, Karan Pandya, Seema G Naik, Manali Kamdar, Bradley M. Haverkos, Reem Karmali, Timothy S Oh, Julie M. Vose, Heather Nutsch, Paul Rubinstein, Amina Chaudhry, and Adam J. Olszewski
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
17. 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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Massimo Granai, Maria Raffaella Ambrosio, Ayse Akarca, Lucia Mundo, Federica Vergoni, Raffaella Santi, Virginia Mancini, Gioia di Stefano, Teresa Amato, Cristiana Bellan, Benedetta Puccini, Ester Sorrentino, Kikkeri N. Naresh, Lorenzo Leoncini, Teresa Marafioti, and Stefano Lazzi
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2019
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18. MYC protein expression scoring and its impact on the prognosis of aggressive B-cell lymphoma patients
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Maria R. Ambrosio, Stefano Lazzi, Giuseppe Lo Bello, Raffaella Santi, Leonardo Del Porro, Maria M. de Santi, Raffaella Guazzo, Lucia Mundo, Luigi Rigacci, Sofia Kovalchuck, Noel Onyango, Alberto Fabbri, Emanuele Cencini, Pier Luigi Zinzani, Francesco Zaja, Francesco Angrilli, Caterina Stelitano, Maria G. Cabras, Giuseppe Spataro, Roshanak Bob, Thomas Menter, Massimo Granai, Gabriele Cevenini, Kikkeri N. Naresh, Harald Stein, Elena Sabattini, and Lorenzo Leoncini
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2019
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19. A retrospective study of MYC rearranged diffuse large B-cell lymphoma in the context of the new WHO and ICC classifications
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Dima El-Sharkawi, Amit Sud, Catherine Prodger, Jahanzaib Khwaja, Rohan Shotton, Brian Hanley, Victoria Peacock, Ying Ying Peng, Anita Arasaretnam, Sarkhara Sharma, Frances Aldridge, Bhupinder Sharma, Andrew Wotherspoon, Betty Cheung, Corinne De Lord, Rosalynd Johnston, Shireen Kassam, Ruth Pettengel, Kim Linton, Paul Greaves, Lucy Cook, Kikkeri N. Naresh, Kate Cwynarski, Toby A. Eyre, Ian Chau, David Cunningham, and Sunil Iyengar
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Oncology ,Hematology - Published
- 2023
20. Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma
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Nikolaos Trasanidis, Alexia Katsarou, Kanagaraju Ponnusamy, Yao-An Shen, Ioannis V. Kostopoulos, Bien Bergonia, Keren Keren, Paudel Reema, Xiaolin Xiao, Richard M. Szydlo, Pierangela M. R. Sabbattini, Irene A. G. Roberts, Holger W. Auner, Kikkeri N. Naresh, Aristeidis Chaidos, Tian-Li Wang, Luca Magnani, Valentina S. Caputo, and Anastasios Karadimitris
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Systems Analysis ,Chromosomes, Human, Pair 1 ,Forkhead Box Protein M1 ,Pre-B-Cell Leukemia Transcription Factor 1 ,Immunology ,Humans ,Cell Biology ,Hematology ,Multiple Myeloma ,Prognosis ,Biochemistry ,Transcription Factors - Abstract
Understanding the biological and clinical impact of copy number aberrations (CNAs) on the development of precision therapies in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring an adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although several genes across chromosome 1 (chr1q) portend high-risk MM disease, the underpinning molecular etiology remains elusive. Here, with reference to the 3-dimensional (3D) chromatin structure, we integrate multi-omics data sets from patients with MM with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent among these genes, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed superenhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional program. Together, PBX1 and FOXM1 activate a proliferative gene signature that predicts adverse prognosis across multiple types of cancer. Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small molecule inhibitor (T417) is selectively toxic against chr1q-amp myeloma and solid tumor cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes, and proposes novel CNA-targeted therapy strategies in MM and other types of cancer.
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- 2022
21. 'Blasts' in myeloid neoplasms – how do we define blasts and how do we incorporate them into diagnostic schema moving forward?
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Xueyan Chen, Jonathan R. Fromm, and Kikkeri N. Naresh
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Cancer Research ,Oncology ,Hematology - Published
- 2022
22. 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report
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Gill Wilson, Anna de Burca, Marta Bleda, Lucy R. Wedderburn, Matthew Welland, Kathleen Stirrups, Valentina Cipriani, Kerrie Woods, Vijeya Ganesan, Susan Hill, Rosaline Quinlivan, Georgia Chan, Mehul T. Dattani, Robert McFarland, Graeme C.M. Black, Rutendo Mapeta, Augusto Rendon, Francesco Muntoni, James O.J. Davies, Mina Ryten, Rebecca E. Foulger, Arianna Tucci, Dina Halai, Tom Fowler, Noemi B.A. Roy, Sarah Leigh, Dragana Josifova, Philip Twiss, Ana L.T. Tavares, Zerin Hyder, Detlef Bockenhauer, Patrick Yu-Wai-Man, Lara Abulhoul, Nikolas Pontikos, Anthony T. Moore, Huw R. Morris, Patrick F. Chinnery, Nicholas W. Wood, Ellen A. Thomas, Shehla Mohammed, Sofia Douzgou, Tanya Lam, Kate Gibson, Robert Sarkany, Teofila Bueser, Wei Wei, Siddharth Banka, Alexander Broomfield, Hiva Fassihi, Nils Koelling, Carolyn Campbell, James Buchanan, Melita Irving, Sandrine Compeyrot-Lacassagne, Karola Rehmström, Austen Worth, Nikhil Thapar, Andrew R. Webster, Paul Brennan, Rita Horvath, Gavin Arno, Richard H Scott, Sam Malka, Andrew O.M. Wilkie, Sofie Ashford, Maria Bitner-Glindzicz, Jana Vandrovcova, William G. Newman, Caroline F. Wright, Andrew M. Schaefer, Roger F.L. James, Robert W. Taylor, Melanie Babcock, Arjune Sen, Emma Baple, Ellen M. McDonagh, Stephanie Grunewald, Loukas Moutsianas, Melissa A. Haendel, Olivera Spasic-Boskovic, Eleanor G. Seaby, Anna Need, Clarissa Pilkington, Sarah Wordsworth, Shamima Rahman, Christine Patch, Colin Wallis, Kristina Ibanez, Bishoy Habib, Eik Haraldsdottir, Huw B. Thomas, Razvan Sultana, Andrea H. Németh, Agata Wolejko, Claire Palles, Phil Beales, Adam C. Shaw, Letizia Vestito, Emily Li, Sarah Rose, Sarah Hunter, Angela Matchan, Genevieve Say, Dalia Kasperaviciute, Henry Houlden, Raymond T. O’Keefe, R. Andres Floto, Jill Clayton-Smith, John B. Taylor, Hywel J. Williams, Volker Straub, Val Davison, Helen Savage, John Chisholm, Eleanor Dewhurst, Charles Crichton, Andrea Haworth, Clare Turnbull, Carolyn Tregidgo, Carme Camps, Christopher Penkett, Emer O’Connor, Georgina Hall, Lyn S. Chitty, Sally Halsall, Andrew D. Mumford, Annette G. Wagner, Eleanor Williams, Mark Bale, Julius O. Jacobsen, Willem H. Ouwehand, Charu Deshpande, Gavin Burns, Smita Y. Patel, James Polke, Thiloka Ratnaike, Gavin Fuller, John Burn, Kenneth E. S. Poole, Emma Footitt, John R. Bradley, Suzanne Wood, Russell J. Grocock, Jenny C. Taylor, Louise Izatt, Kikkeri N. Naresh, Katherine R. Smith, Nigel Burrows, Katrina Newland, Peter N. Robinson, Sarju G. Mehta, Michael A. Simpson, Michael R. Barnes, Pilar Cacheiro, Olivia Niblock, Tracy Lester, Dimitris Polychronopoulos, Helen Brittain, John A. Sayer, Antonio Martin, Eshika Haque, Sean Humphray, Douglass M. Turnbull, Damian Smedley, Andrew Devereau, Stefan Gräf, Sian Ellard, Ivone U.S. Leong, Martin G. Reese, Matthias Wielscher, Louise C. Daugherty, Perry M. Elliott, F. Lucy Raymond, Cecilia Compton, David Bentley, Catherine Snow, James Welch, Frances Flinter, Dom McMullan, Mark J. Caulfield, Paul Aurora, Mark Gurnell, Mary Kasanicki, I. Karen Temple, Michel Michaelides, Deborah Ruddy, Leema Robert, Janice Yip, Grainne S. Gorman, Andrew C. Browning, Richard Quinton, Maureen Cleary, Jamie M. Ellingford, Angela Douglas, Christopher Boustred, and Investigators, The 100,000 Genomes Project Pilot
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Adult ,Male ,Proband ,medicine.medical_specialty ,Adolescent ,Pilot Projects ,Genomics ,Polymerase Chain Reaction ,Genome ,State Medicine ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Health care ,Human Phenotype Ontology ,Humans ,Medicine ,Child ,Exome sequencing ,030304 developmental biology ,Family Characteristics ,0303 health sciences ,Whole Genome Sequencing ,Genome, Human ,business.industry ,Genetic Variation ,Rare Diseases/diagnosis ,General Medicine ,Middle Aged ,United Kingdom ,3. Good health ,Child, Preschool ,Family medicine ,Medical genetics ,Female ,business ,Bristol ,030217 neurology & neurosurgery ,Rare disease - Abstract
BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection.METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis.RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).
- Published
- 2021
23. Proposal of 'reactive-lymphocyte/histiocyte rich large B-cell lymphoma' as an alternate term for 'nodular lymphocyte predominant Hodgkin lymphoma' that would also address its overlap with T-cell/histiocyte rich large B-cell lymphoma
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Kikkeri N. Naresh
- Published
- 2022
24. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms
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Joseph D. Khoury, Eric Solary, Oussama Abla, Yassmine Akkari, Rita Alaggio, Jane F. Apperley, Rafael Bejar, Emilio Berti, Lambert Busque, John K. C. Chan, Weina Chen, Xueyan Chen, Wee-Joo Chng, John K. Choi, Isabel Colmenero, Sarah E. Coupland, Nicholas C. P. Cross, Daphne De Jong, M. Tarek Elghetany, Emiko Takahashi, Jean-Francois Emile, Judith Ferry, Linda Fogelstrand, Michaela Fontenay, Ulrich Germing, Sumeet Gujral, Torsten Haferlach, Claire Harrison, Jennelle C. Hodge, Shimin Hu, Joop H. Jansen, Rashmi Kanagal-Shamanna, Hagop M. Kantarjian, Christian P. Kratz, Xiao-Qiu Li, Megan S. Lim, Keith Loeb, Sanam Loghavi, Andrea Marcogliese, Soheil Meshinchi, Phillip Michaels, Kikkeri N. Naresh, Yasodha Natkunam, Reza Nejati, German Ott, Eric Padron, Keyur P. Patel, Nikhil Patkar, Jennifer Picarsic, Uwe Platzbecker, Irene Roberts, Anna Schuh, William Sewell, Reiner Siebert, Prashant Tembhare, Jeffrey Tyner, Srdan Verstovsek, Wei Wang, Brent Wood, Wenbin Xiao, Cecilia Yeung, Andreas Hochhaus, HAL UVSQ, Équipe, Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Open Access funding enabled and organized by Projekt DEAL.
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[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology ,Cancer Research ,Haematological cancer ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,Hematology ,World Health Organization ,Oncology ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Hematologic Neoplasms ,Diagnosis ,Humans ,Histiocytosis - Abstract
The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.
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- 2022
25. CD5 + Gamma Delta T-Cell Lymphoproliferative Disorder/Lymphoma Without Cytotoxic Granules in the Skin
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Jennifer Y. Ju, Eric P. Sorensen, John S. Walsh, Michi M. Shinohara, and Kikkeri N. Naresh
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Lymphoma ,T-Lymphocytes ,Humans ,Receptors, Antigen, T-Cell, gamma-delta ,Dermatology ,General Medicine ,Antigens, CD20 ,Pathology and Forensic Medicine ,Immunophenotyping - Abstract
We report a case of an unusual and aggressive gamma delta T-cell lymphoproliferative disorder/lymphoma presenting in the skin that lacked the expected cytotoxic markers and had increased expression of CD5, CD20, CD79a, CD30, and PD-1 without CD56. Monoclonal TCR-γ gene rearrangement was identified. A computed tomography scan of the chest, abdomen, and pelvis revealed a 7.7-cm soft-tissue inguinal mass and prominent retroperitoneal and pelvic lymphadenopathy, without hepatosplenomegaly. Flow cytometry finding on peripheral blood was normal. The clinical, morphologic, and immunophenotypic features of this case defy the current World Health Organization and European Organization for Research and Treatment of Cancer classifications, and a similar case has not been reported previously.
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- 2022
26. Variant histology in nodular lymphocyte predominant Hodgkin lymphoma in an adult population: disease investigations and characteristics from a retrospective cohort
- Author
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Arthur Stacey, Alexandra Jane Marks, and Kikkeri N Naresh
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General Medicine ,Pathology and Forensic Medicine - Abstract
A subset of variant histological patterns of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) has been associated with advanced disease stage and increased recurrence risk. Histopathology reports on core needle (CNB) and/or surgical excision biopsies (SEB) for 33 adult patients with NLPHL were examined for variant histology prevalence and association with disease stage and clinical outcome. Variant histological pattern was present in 13/33 patients (39%). Obtained tissue was inadequate for diagnosis in 1/23 (4.3%) cases of CNB. Variant histology was associated with stage IV disease at presentation (p
- Published
- 2022
27. Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a post-mortem study
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Wendy S. Barclay, Mark Thursz, Rebecca Penn, Justin Weir, Patrizia Viola, Graham S Cooke, Andrew G. Nicholson, Candice Roufosse, Richard Corbett, Pinelopi Manousou, Robert D. Goldin, Laury Baillon, Safa Al-Sarraj, Olivia C. Swann, Alireza Abdolrasouli, Kikkeri N. Naresh, Michael Osborn, Brian Hanley, and National Institute for Health Research
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Microbiology (medical) ,medicine.medical_specialty ,lcsh:QR1-502 ,Autopsy ,Nonbacterial thrombotic endocarditis ,Microbiology ,lcsh:Microbiology ,Article ,Pericarditis ,Virology ,Internal medicine ,medicine ,Humans ,Mucormycosis ,Diffuse alveolar damage ,Lung ,Cause of death ,lcsh:R5-920 ,SARS-CoV-2 ,business.industry ,COVID-19 ,Thrombosis ,medicine.disease ,United Kingdom ,Viral Tropism ,Infectious Diseases ,medicine.anatomical_structure ,Pancreatitis ,Infarction ,Acute Disease ,Acute pancreatitis ,lcsh:Medicine (General) ,business - Abstract
Summary: Background: Severe COVID-19 has a high mortality rate. Comprehensive pathological descriptions of COVID-19 are scarce and limited in scope. We aimed to describe the histopathological findings and viral tropism in patients who died of severe COVID-19. Methods: In this case series, patients were considered eligible if they were older than 18 years, with premortem diagnosis of severe acute respiratory syndrome coronavirus 2 infection and COVID-19 listed clinically as the direct cause of death. Between March 1 and April 30, 2020, full post-mortem examinations were done on nine patients with confirmed COVID-19, including sampling of all major organs. A limited autopsy was done on one additional patient. Histochemical and immunohistochemical analyses were done, and histopathological findings were reported by subspecialist pathologists. Viral quantitative RT-PCR analysis was done on tissue samples from a subset of patients. Findings: The median age at death of our cohort of ten patients was 73 years (IQR 52–79). Thrombotic features were observed in at least one major organ in all full autopsies, predominantly in the lung (eight [89%] of nine patients), heart (five [56%]), and kidney (four [44%]). Diffuse alveolar damage was the most consistent lung finding (all ten patients); however, organisation was noted in patients with a longer clinical course. We documented lymphocyte depletion (particularly CD8-positive T cells) in haematological organs and haemophagocytosis. Evidence of acute tubular injury was noted in all nine patients examined. Major unexpected findings were acute pancreatitis (two [22%] of nine patients), adrenal micro-infarction (three [33%]), pericarditis (two [22%]), disseminated mucormycosis (one [10%] of ten patients), aortic dissection (one [11%] of nine patients), and marantic endocarditis (one [11%]). Viral genomes were detected outside of the respiratory tract in four of five patients. The presence of subgenomic viral RNA transcripts provided evidence of active viral replication outside the respiratory tract in three of five patients. Interpretation: Our series supports clinical data showing that the four dominant interrelated pathological processes in severe COVID-19 are diffuse alveolar damage, thrombosis, haemophagocytosis, and immune cell depletion. Additionally, we report here several novel autopsy findings including pancreatitis, pericarditis, adrenal micro-infarction, secondary disseminated mucormycosis, and brain microglial activation, which require additional investigation to understand their role in COVID-19. Funding: Imperial Biomedical Research Centre, Wellcome Trust, Biotechnology and Biological Sciences Research Council.
- Published
- 2020
28. Parallel evolution of two distinct lymphoid proliferations in clonal haematopoiesis
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Ayoma D Attygalle, Rachel Dobson, Pui Kwan Chak, Katherine M Vroobel, Dorte Wren, Hood Mugalaasi, Yvonne Morgan, Manmit Kaur, Raida Ahmad, Zi Chen, Kikkeri N Naresh, Ming‐Qing Du, Attygalle, Ayoma D [0000-0001-5034-8150], Naresh, Kikkeri N [0000-0003-3807-3638], Du, Ming-Qing [0000-0002-1017-5045], and Apollo - University of Cambridge Repository
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Male ,Proto-Oncogene Proteins B-raf ,Histology ,T Follicular Helper Cells ,CD8 Antigens ,General Medicine ,clonal haematopoiesis ,Lymphoma, T-Cell ,Pathology and Forensic Medicine ,angioimmunoblastic T-cell lymphoma ,DNA Methyltransferase 3A ,Dioxygenases ,DNA-Binding Proteins ,Diagnosis, Differential ,secondary lymphoid neoplasm ,Immunoblastic Lymphadenopathy ,Mutation ,Humans ,TET2 and DNMT3A mutation ,Female ,Clonal Hematopoiesis ,rhoA GTP-Binding Protein ,Aged ,Cell Proliferation ,T-Lymphocytes, Cytotoxic - Abstract
AIMS: Angioimmunoblastic T-cell lymphoma (AITL) is genetically characterized by TET2 and DNMT3A mutations occurring in haematopoietic progenitor cells, and late events (e.g. the RHOA-G17V mutation) associated with malignant transformation. As TET2/DNMT3A-mutated progenitor cells can differentiate into multilineage progenies and give rise to both AITL and myeloid neoplasms, they may also have the potential to lead to other metachronous/synchronous neoplasms. We report two cases showing parallel evolution of two distinct potentially neoplastic lymphoid proliferations from a common mutated haematopoietic progenitor cell population. METHODS AND RESULTS: Both cases presented with generalized lymphadenopathy. In case 1 (a 67-year-old female), an initial lymph node (LN) biopsy was dismissed as reactive, but a repeat biopsy showed a nodal marginal zone lymphoma (NMZL)-like proliferation with an increase in the number of T-follicular helper (TFH) cells. Immunohistochemistry, and clonality and mutational analyses by targeted sequencing of both whole tissue sections and microdissected NMZL-like lesions, demonstrated a clonal B-cell proliferation that harboured the BRAF-G469R mutation and shared TET2 and DNMT3A mutations with an underlying RHOA-G17V-mutant TFH proliferation. Review of the original LN biopsy showed histological and immunophenotypic features of AITL. In case 2 (a 66-year-old male), cytotoxic T-cell lymphoma with an increase in the number of Epstein-Barr virus-positive large B cells was diagnosed on initial biopsy. On review together with the relapsed biopsy, we identified an additional occult neoplastic TFH proliferation/smouldering AITL. Both T-cell proliferations shared TET2 and DNMT3A mutations while RHOA-G17V was confined to the smouldering AITL. CONCLUSIONS: In addition to demonstrating diagnostic challenges, these cases expand the potential of clonal haematopoiesis in the development of different lineage neoplastic proliferations.
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- 2022
29. A refined approach to the diagnosis of Burkitt lymphoma in a resource-poor setting
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Stefano Lazzi, Raffaella Santi, Noel Onyango, Massimo Granai, Lorenzo Leoncini, and Kikkeri N Naresh
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Resource poor ,Acute leukemia ,Histology ,business.industry ,Locus (genetics) ,Chromosomal translocation ,General Medicine ,medicine.disease ,medicine.disease_cause ,Burkitt Lymphoma ,Epstein–Barr virus ,Pathology and Forensic Medicine ,Lymphoma ,Basophilic ,Immunophenotyping ,hemic and lymphatic diseases ,medicine ,Cancer research ,Humans ,business - Abstract
Burkitt lymphoma (BL) is among the most studied human malignancies. The distinction of BL from other aggressive B-cell lymphomas is important for providing optimal oncological care. In the revised 4th edition of the World Health Organization (WHO) classification, BL is defined as "a highly aggressive but curable lymphoma that often presents in extranodal sites or as an acute leukemia. It is composed of monomorphic medium-sized B-cells with basophilic cytoplasm and numerous mitotic figures, usually with a demonstrable MYC gene translocation to an IG locus. The frequency of EBV (Epstein Barr virus) infection varies according to the epidemiological subtype of BL. No single parameter, such as morphologic, genetic analysis or immunophenotyping can be used as the gold standard for diagnosis of BL; a combination of several diagnostic techniques is necessary."
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- 2022
30. Systems medicine dissection of chromosome 1q amplification reveals oncogenic regulatory circuits and informs targeted therapy in cancer
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Irene Roberts, Tian Li Wang, Pierangela Sabbattini, Luca Magnani, Xiaolin Xiao, Keren Keren, Kikkeri N. Naresh, Richard Szydlo, Anastasios Karadimitris, Valentina S. Caputo, Bien Bergonia, Kanagaraju Ponnusamy, Nikolaos Trasanidis, Ioannis Kostopoulos, Aristeidis Chaidos, Paudel Reema, Holger W. Auner, Yao-An Shen, and Alexia Katsarou
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business.industry ,medicine.medical_treatment ,Cancer ,Disease ,Gene signature ,medicine.disease ,Targeted therapy ,Systems medicine ,Cancer cell ,Cancer research ,medicine ,FOXM1 ,Epigenetics ,business - Abstract
Understanding the biological and clinical impact of copy number aberrations (CNA) in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring adverse prognosis in several cancers, including the blood cancer, multiple myeloma (MM). Although several chr1q genes portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here we integrate patient multi-omics datasets with genetic variables to identify 103 adverse prognosis genes in chr1q-amp MM. Amongst these, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways, whilst in co-operation with FOXM1, activates a proliferative gene signature which predicts adverse prognosis across multiple cancers. Notably, pharmacological disruption of the PBX1-FOXM1 axis, including with a novel PBX1 inhibitor is selectively toxic against chr1q-amp cancer cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapy strategies in cancer.SignificanceWe provide a comprehensive systems medicine strategy to unveil oncogenic circuitries and inform novel precision therapy decisions against CNA in cancer. This first clinical multi-omic analysis of chr1q-amp in MM identifies a central PBX1-FOXM1 regulatory axis driving high-risk prognosis, as a novel therapeutic target against chr1q-amp in cancer.
- Published
- 2021
31. Report of a Case With Clinical and Pathologic Features of Castleman Disease That Predates Castleman's Report by More Than 50 Years
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Sanjay A. Pai, Kikkeri N. Naresh, and Anita M. Borges
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Medical Laboratory Technology ,Hyperplasia ,Castleman Disease ,Mediastinum ,Humans ,Lymphadenopathy ,General Medicine ,Lymph Nodes ,Pathology and Forensic Medicine - Abstract
Context.— In 1954, Benjamin Castleman, MD, described what was then believed to be a new entity in lymph node pathology. Initially labeled “Hyperplasia of the mediastinal node” and then “Localized mediastinal lymph node hyperplasia resembling thymoma,” we now recognize the condition with the eponym “Castleman disease.” We document a paper that describes the same condition, a half century before Castleman did. Objective.— To report the striking resemblance between Castleman disease and the lymph node reported in the paper published by Edwin R. LeCount, MD, titled “Lymphoma, a benign tumor representing a lymph gland in structure,” published in Journal of Experimental Medicine in 1899. We also provide an overview of the remarkable achievements of LeCount. Design.— We compared the elucidation in the original paper by LeCount with the morphologic details in the papers published by Castleman et al. Material on the life of LeCount was compiled from the scientific literature, the Internet, and the files of the University of Chicago. Results.— LeCount's description and illustrations of the lymph node are uncannily similar to the onion-skinning and vascularity that Castleman documented. Conclusions.— LeCount deserves credit for his depiction of a hitherto-unreported entity.
- Published
- 2021
32. Single-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemia
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C Christodoulidou, H Ren, M H Zaidi, Adam J. Mead, Anindita Roy, Alexia Katsarou, Bethan Psaila, Leena Karnik, Q Al-Oqaily, Deena Iskander, Valentina S. Caputo, Yvonne Harrington, Kanagaraju Ponnusamy, David M. Bodine, Pritesh Trivedi, Aristeidis Chaidos, Nikolaos Trasanidis, Supat Thongjuea, Mark Robinson, J de la Fuente, Marjorie Brand, Zeinab Mokhtari, Kikkeri N. Naresh, Guanlin Wang, C G Palii, Elisabeth F. Heuston, Irene Roberts, Richard Szydlo, and Anastasios Karadimitris
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Ribosomal Proteins ,Ribosomopathy ,GATA1 ,General Medicine ,Biology ,medicine.disease ,Phenotype ,Cell biology ,medicine.anatomical_structure ,Ribosomal protein ,Bone Marrow ,hemic and lymphatic diseases ,medicine ,Erythropoiesis ,Humans ,Bone marrow ,Diamond–Blackfan anemia ,Progenitor cell ,Anemia, Diamond-Blackfan - Abstract
Ribosome dysfunction underlies the pathogenesis of many cancers and heritable ribosomopathies. Here, we investigate how mutations in either ribosomal protein large (RPL) or ribosomal protein small (RPS) subunit genes selectively affect erythroid progenitor development and clinical phenotypes in Diamond-Blackfan anemia (DBA), a rare ribosomopathy with limited therapeutic options. Using single-cell assays of patient-derived bone marrow, we delineated two distinct cellular trajectories segregating with ribosomal protein genotypes. Almost complete loss of erythroid specification was observed in RPS-DBA. In contrast, we observed relative preservation of qualitatively abnormal erythroid progenitors and precursors in RPL-DBA. Although both DBA genotypes exhibited a proinflammatory bone marrow milieu, RPS-DBA was characterized by erythroid differentiation arrest, whereas RPL-DBA was characterized by preserved GATA1 expression and activity. Compensatory stress erythropoiesis in RPL-DBA exhibited disordered differentiation underpinned by an altered glucocorticoid molecular signature, including reduced ZFP36L2 expression, leading to milder anemia and improved corticosteroid response. This integrative analysis approach identified distinct pathways of erythroid failure and defined genotype-phenotype correlations in DBA. These findings may help facilitate therapeutic target discovery.
- Published
- 2021
33. Leukemic presentation of a highly aggressive ALK-negative anaplastic large cell lymphoma
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Danmei Xu and Kikkeri N. Naresh
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CD4-Positive T-Lymphocytes ,Male ,Leukemia ,business.industry ,Immunology ,Ki-1+ Anaplastic Large Cell Lymphoma ,Cell Biology ,Hematology ,Biochemistry ,Antigens, CD ,Cancer research ,Medicine ,Humans ,Lymphoma, Large-Cell, Anaplastic ,ALK-Negative Anaplastic Large Cell Lymphoma ,Anaplastic Lymphoma Kinase ,Lymph Nodes ,Presentation (obstetrics) ,business ,Aged - Published
- 2021
34. 'Blasts' in myeloid neoplasms - how do we define blasts and how do we incorporate them into diagnostic schema moving forward?
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Xueyan, Chen, Jonathan R, Fromm, and Kikkeri N, Naresh
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Leukemia, Myeloid, Acute ,Myeloproliferative Disorders ,Humans ,Blast Crisis - Published
- 2021
35. Carfilzomib Enhances the Suppressive Effect of Ruxolitinib in Myelofibrosis
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Carme Ripoll Fiol, Michael Albert, Antinisca Di Marco, Simone Claudiani, Jane F. Apperley, Mark Robinson, Jamshid S. Khorashad, Clinton C. Mason, Cristina Pellegrini, Alistair Reid, Avirup Chowdhury, Kikkeri N. Naresh, Michael W. Deininger, Dragana Milojkovic, Andrea Bianchi, Katya Mokretar, and Kanagaraju Ponnusamy
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shRNA library screen ,Cancer Research ,Ruxolitinib ,medicine.drug_class ,ruxolitinib ,myelofibrosis ,Tyrosine-kinase inhibitor ,Article ,chemistry.chemical_compound ,medicine ,Myelofibrosis ,RC254-282 ,STAT5 ,carfilzomib ,biology ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Carfilzomib ,medicine.anatomical_structure ,Oncology ,chemistry ,Proteasome ,Cell culture ,biology.protein ,Cancer research ,Bone marrow ,business ,medicine.drug - Abstract
Simple Summary Myelofibrosis (MF) is a progressive myeloproliferative neoplasm with tendency towards leukemic transformation and has the poorest prognosis amongst the Philadelphia-negative classical myeloproliferative neoplasms (MPN). Ruxolitinib, the first FDA-approved JAK1/2 tyrosine kinase inhibitor, is efficient in reducing spleen size and improving patient symptoms, but it has not been shown to eradicate the MF clone. In this study, using functional genomics techniques, we identified the proteasome family as an additional therapeutic target and demonstrated that inhibition of the proteasome family by carfilzomib in combination with ruxolitinib enhanced suppression of primary MF cells in vitro. Abstract As the first FDA-approved tyrosine kinase inhibitor for treatment of patients with myelofibrosis (MF), ruxolitinib improves clinical symptoms but does not lead to eradication of the disease or significant reduction of the mutated allele burden. The resistance of MF clones against the suppressive action of ruxolitinib may be due to intrinsic or extrinsic mechanisms leading to activity of additional pro-survival genes or signalling pathways that function independently of JAK2/STAT5. To identify alternative therapeutic targets, we applied a pooled-shRNA library targeting ~5000 genes to a JAK2V617F-positive cell line under a variety of conditions, including absence or presence of ruxolitinib and in the presence of a bone marrow microenvironment-like culture medium. We identified several proteasomal gene family members as essential to HEL cell survival. The importance of these genes was validated in MF cells using the proteasomal inhibitor carfilzomib, which also enhanced lethality in combination with ruxolitinib. We also showed that proteasome gene expression is reduced by ruxolitinib in MF CD34+ cells and that additional targeting of proteasomal activity by carfilzomib enhances the inhibitory action of ruxolitinib in vitro. Hence, this study suggests a potential role for proteasome inhibitors in combination with ruxolitinib for management of MF patients.
- Published
- 2021
36. Indolent T-Cell Lymphoproliferative Disorder of the Uterine Corpus: A Case Report
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Hany Lashen, Malee Fernando, Kikkeri N. Naresh, Nicholas Morley, and Sally J Thomas
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Adult ,0301 basic medicine ,Systemic disease ,Pathology ,medicine.medical_specialty ,T-Lymphocytes ,T cell ,Uterus ,Lymphoproliferative disorders ,Disease ,Immunophenotyping ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Medicine ,business.industry ,Obstetrics and Gynecology ,medicine.disease ,Lymphoproliferative Disorders ,Lymphoma ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,business ,CD8 - Abstract
Primary lymphoproliferative disorders of the uterus are rare, with the majority being B-cell diseases or aggressive T-cell disease. We present the case of a 31-yr old in whom an Indolent T-cell lymphoproliferative disorder (iTCLPD) was identified in resection chippings for a suspected fibroid, following presentation with menorrhagia. Laboratory investigations revealed an oligoclonal T-cell infiltrate with the immunophenotype of nonactivated cytotoxic T cells, and a proliferative fraction of 10% to 15%. There was no clinical or radiologic evidence of systemic disease, and the patient remained well with no indication of relapse 1 yr from resection and diagnosis. iTCLPD of the uterine corpus has features in common with the recently described iTCLPD of the gastrointestinal tract and primary cutaneous acral CD8 T-cell lymphoma. Recognition of these parallels is important as few other cases of iTCLPD have been described, and it suggests local resection rather than systemic treatment as the best therapeutic strategy.
- Published
- 2019
37. Whole genome sequencing for diagnosis of neurological repeat expansion disorders
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Greenhalgh L, Fowler T, Karen Temple, Kane Smith, Deshpande, Subramanian S. Ajay, Bourn D, Menzies L, James M. Polke, Pasko D, Polychronopoulos D, Augusto Rendon, Pietro Fratta, Madeleine Reilly, Daugherty L, Chitty Ls, Eggleton K, Raymond Fl, Thomas T. Warner, Paul Brennan, Sian Ellard, Denise L. Perry, Jill Davison, A. C. Need, Arianna Tucci, Prasad Korlipara Lv, Mark J. Caulfield, Meriel McEntagart, Huw R. Morris, Kikkeri N. Naresh, Jenny C. Taylor, Patrick F. Chinnery, Anette Schrag, Aditi Chawla, Deans Zc, Henry Houlden, Twiss P, Douglas A, Sheikh I, Jonathan M. Schott, Hill S, Moutsianas L, Nicholas W. Wood, Tanner Hagelstrom, Robinson R, D. Kasperaviciute, Faravelli F, Rajan, Kristina Ibáñez, Antonio Rueda Martin, Emma L. Baple, Robin Howard, Ellen M. McDonagh, Elisabeth Rosser, Oprych K, Richard Festenstein, John A. Sayer, Kailash P. Bhatia, Michael A. Eberle, Andrew D Mumford, Angus-Leppan H, Thomas E, Matilde Laura, McMullan D, Brittain H, Paola Giunti, Richard H. Scott, Wilson G, Taylor Tavares Al, Ryan J. Taft, Patch C, Hyder Z, Robyn Labrum, Almheiri G, Frances Flinter, Egor Dolzhenko, Santos L, Abbs S, William G. Newman, and Jana Vandrovcova
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Whole genome sequencing ,Pediatrics ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Genome ,Medicine ,Social care ,False positive rate ,Allele ,Family history ,business ,Trinucleotide repeat expansion ,Genetic testing - Abstract
BackgroundRepeat expansion (RE) disorders affect ~1 in 3000 individuals and are clinically heterogeneous diseases caused by expansions of short tandem DNA repeats. Genetic testing is often locus-specific, resulting in under diagnosis of atypical clinical presentations, especially in paediatric patients without a prior positive family history. Whole genome sequencing (WGS) is emerging as a first-line test for rare genetic disorders, but until recently REs were thought to be undetectable by this approach.MethodsWGS pipelines for RE disorder detection were deployed by the 100,000 Genomes Project and Illumina Clinical Services Laboratory. Performance was retrospectively assessed across the 13 most common neurological RE loci using 793 samples with prior orthogonal testing (182 with expanded alleles and 611 with alleles within normal size) and prospectively interrogated in 13,331 patients with suspected genetic neurological disorders.FindingsWGS RE detection showed minimum 97·3% sensitivity and 99·6% specificity across all 13 disease-associated loci. Applying the pipeline to patients from the 100,000 Genomes Project identified pathogenic repeat expansions which were confirmed in 69 patients, including seven paediatric patients with no reported family history of RE disorders, with a 0.09% false positive rate.InterpretationWe show here for the first time that WGS enables the detection of causative repeat expansions with high sensitivity and specificity, and that it can be used to resolve previously undiagnosed neurological disorders. This includes children with no prior suspicion of a RE disorder. These findings are leading to diagnostic implementation of this analytical pipeline in the NHS Genomic Medicine Centres in England.FundingMedical Research Council, Department of Health and Social Care, National Health Service England, National Institute for Health Research, Illumina Inc
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- 2020
38. The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma
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Valentina S. Caputo, Kanagaraju Ponnusamy, Aristeidis Chaidos, Anastasios Karadimitris, Pritesh Trivedi, I Roberts, Ioannis Kostopoulos, Xiaolin Xiao, Maria Myrsini Tzioni, Kikkeri N. Naresh, Nikolaos Trasanidis, Holger W. Auner, Alexia Katsarou, Deena Iskander, Murshida Begum, and Mark Robinson
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Necroptosis ,Biology ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Animals ,Humans ,Phosphorylation ,Transcription factor ,B cell ,Multiple myeloma ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Cell growth ,RNA-Binding Proteins ,Hematology ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Cell Cycle Gene ,Immunity, Innate ,Cell biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Interferon Regulatory Factor-3 ,IRF3 ,Multiple Myeloma ,IRF4 - Abstract
Multiple myeloma is a malignancy of plasma cells initiated and driven by primary and secondary genetic events. However, myeloma plasma cell survival and proliferation might be sustained by non-genetic drivers. Z-DNA-binding protein 1 (ZBP1; also known as DAI) is an interferon-inducible, Z-nucleic acid sensor that triggers RIPK3-MLKL-mediated necroptosis in mice. ZBP1 also interacts with TBK1 and the transcription factor IRF3 but the function of this interaction is unclear, and the role of the ZBP1-IRF3 axis in cancer is not known. Here we show that ZBP1 is selectively expressed in late B-cell development in both human and murine cells and it is required for optimal T-cell-dependent humoral immune responses. In myeloma plasma cells, the interaction of constitutively expressed ZBP1 with TBK1 and IRF3 results in IRF3 phosphorylation. IRF3 directly binds and activates cell cycle genes, in part through co-operation with the plasma cell lineage-defining transcription factor IRF4, thereby promoting myeloma cell proliferation. This generates a novel, potentially therapeutically targetable and relatively selective myeloma cell addiction to the ZBP1-IRF3 axis. Our data also show a noncanonical function of constitutive ZBP1 in human cells and expand our knowledge of the role of cellular immune sensors in cancer biology.
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- 2020
39. Improving precise counting of mitotic cells in mantle cell lymphoma using phosphohistone H3 (PHH3) antibody
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Mohamed Elshiekh, Kikkeri N. Naresh, and Hanine Medani
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0301 basic medicine ,Male ,Mitosis ,Cell Count ,Lymphoma, Mantle-Cell ,Biology ,Pathology and Forensic Medicine ,Histones ,03 medical and health sciences ,Histone H3 ,0302 clinical medicine ,Predictive Value of Tests ,medicine ,Biomarkers, Tumor ,Mitotic Index ,Humans ,Phosphorylation ,Aged ,Aged, 80 and over ,Cell growth ,Reproducibility of Results ,General Medicine ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Lymphoma ,030104 developmental biology ,Ki-67 Antigen ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Mantle cell lymphoma ,Female ,Antibody ,Progressive disease - Abstract
AimsMantle cell lymphoma (MCL) has a highly heterogeneous clinical course ranging from indolent, to aggressive and rapidly progressive disease. Proliferation is a strong predictor for disease outcome. In routine clinical practice, Ki-67 expression is used as a measure of proliferation. However, several studies have documented a high degree of inter-laboratory and inter-observer variation with Ki-67 immunohistochemistry. Phosphorylation of histone H3 occurs specifically during mitosis and hence serves as a specific marker for cells in mitosis.Methods and resultsWe investigated phosphohistone H3 (PHH3) immunohistochemistry as a proliferation maker in 28 tissue biopsies of MCL and compared the PHH3 results (as evaluated by direct microscopic visualisation and image analysis-aided scoring) with morphological subtyping, mitotic counts and Ki-67 index. We found PHH3-mitotic count was about sixfold higher than H&E-mitotic count (mitoses in 10 high power fields). Furthermore, PHH3-mitotic count in aggressive morphological variants of MCL was significantly higher than in usual MCL. The PHH3-mitotic count showed a strong linear correlation with PHH3-mitotic index (percentage positive cells).ConclusionsWe found PHH3 immunohistochemistry, a reliable mitosis-specific marker, in MCL. Performing precise counts and evaluating precise proliferation indices is easier with PHH3 immunohistochemistry. This contrasts with the conventional estimation of Ki-67 percentages by ‘eye-balling’.
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- 2020
40. The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma
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Kanagaraju Ponnusamy, Aristeidis Chaidos, Mark Robinson, Ioannis Kostopoulos, Xiaolin Xiao, I Roberts, Anastasios Karadimitris, Maria Myrsini Tzioni, Nikolaos Trasanidis, Pritesh Trivedi, Murshida Begum, Valentina S. Caputo, Alexia Katsarou, Deena Iskander, Holger W. Auner, and Kikkeri N. Naresh
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Chemistry ,Cell growth ,viruses ,virus diseases ,biochemical phenomena, metabolism, and nutrition ,Plasma cell ,Cell Cycle Gene ,Cell biology ,Immune system ,medicine.anatomical_structure ,medicine ,IRF3 ,Transcription factor ,B cell ,IRF4 - Abstract
ZBP1 is an inducible, non-constitutively expressed cellular nucleic acid sensor that triggers type I interferon (IFN) responses via phosphorylation and activation of the transcription factor (TF) IRF3 by TBK1. However, the role of the ZBP1-IRF3 axis in cancer is not known. Here we show that ZBP1 is selectively and constitutively expressed in late B cell development and it is required for optimal T cell-dependent humoral immune responses. In the plasma cell (PC) cancer multiple myeloma, interaction of constitutively expressed ZBP1 with TBK1 and IRF3 results in IRF3 phosphorylation. Notably, rather than IFN type I response genes, IRF3 directly activates, in part through co-operation with the PC lineage-defining TF IRF4, cell cycle genes thus promoting myeloma cell proliferation. This generates a novel, potentially therapeutically targetable and relatively selective myeloma cell addiction to the ZBP1-IRF3 axis. These data expand our knowledge of the role of cellular immune sensors in cancer biology.
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- 2020
41. Convalescent donor SARS‐COV‐2‐specific cytotoxic T lymphocyte infusion as a possible treatment option for COVID‐19 patients with severe disease has not received enough attention till date
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Brian Hanley, Kikkeri N. Naresh, Candice Roufosse, and Michael Osborn
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medicine.medical_specialty ,Lymphocyte Transfusion ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,media_common.quotation_subject ,Pneumonia, Viral ,Immunology ,Severe disease ,Blood Donors ,SARS-COV-2 ,NK cells ,CD8+ T cells ,Severity of Illness Index ,Betacoronavirus ,Internal medicine ,Severity of illness ,medicine ,Cytotoxic T cell ,Humans ,EPSTEIN-BARR-VIRUS ,cytotoxic cells ,Pandemics ,1102 Cardiorespiratory Medicine and Haematology ,media_common ,Hematology ,Science & Technology ,business.industry ,Convalescence ,COVID-19 ,CD8+T cells ,business ,Coronavirus Infections ,Life Sciences & Biomedicine - Published
- 2020
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42. Gastrointestinal lymphomas
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Kikkeri N. Naresh
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immune system diseases ,hemic and lymphatic diseases - Abstract
Primary gastrointestinal lymphoma is the most common extranodal lymphoma and is almost exclusively of non-Hodgkin type. It is defined as lymphoma that has presented with the main bulk of disease in the gastrointestinal tract, with or without involvement of contiguous lymph nodes. MALT lymphoma is an indolent B-cell lymphoma whose histology recapitulates the features of mucosa-associated lymphoid tissue (MALT). It most commonly affects the stomach, presenting with nonspecific dyspepsia. Most cases appear to be driven by Helicobacter pylori, with 75% regressing following eradication of the organism with appropriate antibiotics. Deeply invasive lymphomas and those with adverse histological or cytogenetic features are unlikely to respond. Mantle cell lymphoma and follicular lymphoma are adult B-cell lymphomas that can present as gastrointestinal lymphomas. Diffuse large B-cell lymphoma is an aggressive lymphoma that is relatively frequently encountered in gastrointestinal locations. Burkitt’s lymphoma is also an aggressive B-cell lymphoma, and is the most frequent childhood gastrointestinal lymphoma. Enteropathy-associated T-cell lymphoma is an intestinal lymphoma of intraepithelial T lymphocytes that occurs most commonly in the jejunum or ileum and is associated with coeliac disease. It presents with abdominal pain, often due to intestinal perforation. The prognosis is usually poor, with death frequently resulting from abdominal complications in patients already weakened by uncontrolled malabsorption.
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- 2020
43. 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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Lorenz Trümper, Viola Pöschel, Gerald Wulf, Raffaella Santi, Annette M. Staiger, Federica Vergoni, Kikkeri N. Naresh, Gerhald Held, Harald Stein, Andreas Rosenwald, Virginia Mancini, Marita Ziepert, Stefano Lazzi, Markus Löffler, Elena Sabattini, Heike Horn, Norbert Schmitz, Massimo Granai, Lorenzo Leoncini, and German Ott
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Oncology ,medicine.medical_specialty ,BCL-2 ,Myc ,Protein expression ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,0302 clinical medicine ,Risk groups ,Internal medicine ,medicine ,Humans ,Letters to the Editor ,business.industry ,Hematology ,Prognosis ,medicine.disease ,Proto-Oncogene Proteins c-bcl-2 ,030220 oncology & carcinogenesis ,DLBCL ,outcome ,Lymphoma, Large B-Cell, Diffuse ,business ,Diffuse large B-cell lymphoma ,030215 immunology - Published
- 2020
44. In situ mantle cell lymphoma: clinical implications of an incidental finding with indolent clinical behavior
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Alejandra Carvajal-Cuenca, Luz F. Sua, Nhora M. Silva, Stefania Pittaluga, Cristina Royo, Joo Y. Song, Rachel L. Sargent, Blanca Espinet, Fina Climent, Samuel A. Jacobs, Jan Delabie, Kikkeri N. Naresh, Adam Bagg, Pierre Brousset, Roger A. Warnke, Sergi Serrano, Nancy Lee Harris, Steven H. Swerdlow, Elaine S. Jaffe, and Elías Campo
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background Cyclin D1-positive B cells are occasionally found in the mantle zones of reactive lymphoid follicles, a condition that has been called “in situ mantle cell lymphoma”. The clinical significance of this lesion remains uncertain.Design and Methods The clinical and pathological characteristics, including SOX11 expression, of 23 cases initially diagnosed as in situ mantle cell lymphoma were studied.Results Seventeen of the 23 cases fulfilled the criteria for in situ mantle cell lymphoma. In most cases, the lesions were incidental findings in reactive lymph nodes. The t(11;14) was detected in all eight cases examined. SOX11 was positive in seven of 16 cases (44%). Five cases were associated with other small B-cell lymphomas. In two cases, both SOX11-positive, the in situ mantle cell lymphoma lesions were discovered after the diagnosis of overt lymphoma; one 4 years earlier, and one 3 years later. Twelve of the remaining 15 patients had a follow-up of at least 1 year (median 2 years; range, 1–19.5), of whom 11 showed no evidence of progression, including seven who were not treated. Only one of 12 patients with an in situ mantle cell lymphoma lesion and no diagnosis of mantle cell lymphoma at the time developed an overt lymphoma, 4 years later; this case was also SOX11-positive. The six remaining cases were diagnosed as mantle cell lymphoma with a mantle zone pattern. Five were SOX11-positive and four of them were associated with lymphoma without a mantle zone pattern.Conclusions In situ mantle cell lymphoma lesions are usually an incidental finding with a very indolent behavior. These cases must be distinguished from mantle cell lymphoma with a mantle zone pattern and overt mantle cell lymphoma because they may not require therapeutic intervention.
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- 2012
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45. Lymphoproliferative disorders and lymphoreticular malignancies in the setting of immunodeficiency
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Mohamed Elshiekh and Kikkeri N. Naresh
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,education.field_of_study ,Histology ,Disease entity ,business.industry ,medicine.medical_treatment ,Population ,Lymphoproliferative disorders ,Immunosuppression ,Context (language use) ,medicine.disease ,Pathology and Forensic Medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,030220 oncology & carcinogenesis ,medicine ,Identification (biology) ,business ,education ,Immunodeficiency - Abstract
Lymphoid proliferations occurring in the background of immunodeficiency range from benign lymphoid proliferations to full-blown lymphomas. They occur at a higher frequency in immunosuppressed patients compared to the general population. Immunosuppression is the main underlying pathogenic cause in these disorders and their histological appearances and immunophenotypic features are varied. Some resemble lymphoproliferative disorders seen in immune competent patients whilst others have unique characteristics; some of these also pose unique diagnostic problems. Furthermore, within some clinical contexts like the post-transplant setting, the distinction between benign and malignant proliferations is blurred. Identification of specific entities requires a clear understanding of morphology, clinical context, a wide immunohistochemistry panel, investigations for viral association, clonality investigations, and in some situations analysis of chromosomal translocations by fluorescent in-situ hybridisation studies. Precise identification of the disease entity impacts patient management and follow-up.
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- 2018
46. Subclonal mutation selection in mouse lymphomagenesis identifies known cancer loci and suggests novel candidates
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Juan J. Caceres, James I. Elliott, Anthony G. Uren, Jakub Kaczor, Bruce J. Bolt, Katerina Rekopoulou, Philip Webster, Mohammad M. Karimi, Kikkeri N. Naresh, Hamlata Dewchand, Marian Dore, Katalin Takacs, Ge Tan, Thomas Adejumo, Laurence Game, Barbara Iadarola, Gopuraja Dharmalingam, Joanna C. Dawes, Alberto Paccanaro, and Medical Research Council (MRC)
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0301 basic medicine ,SUSCEPTIBILITY LOCI ,Science ,General Physics and Astronomy ,Mutagenesis (molecular biology technique) ,Genome-wide association study ,Computational biology ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Negative selection ,MD Multidisciplinary ,Genotype ,medicine ,RECURRENT ,GENOME-WIDE ASSOCIATION ,lcsh:Science ,ACUTE LYMPHOBLASTIC-LEUKEMIA ,Mutation ,Science & Technology ,Multidisciplinary ,CHRONIC LYMPHOCYTIC-LEUKEMIA ,B-CELL LYMPHOMA ,Cancer ,General Chemistry ,medicine.disease ,Phenotype ,3. Good health ,Multidisciplinary Sciences ,Immunosurveillance ,030104 developmental biology ,Science & Technology - Other Topics ,INTEGRATION SITE ,GENE DISCOVERY ,lcsh:Q ,FOLLICULAR LYMPHOMA ,INSERTIONAL MUTAGENESIS - Abstract
Determining whether recurrent but rare cancer mutations are bona fide driver mutations remains a bottleneck in cancer research. Here we present the most comprehensive analysis of murine leukemia virus-driven lymphomagenesis produced to date, sequencing 700,000 mutations from >500 malignancies collected at time points throughout tumor development. This scale of data allows novel statistical approaches for identifying selected mutations and yields a high-resolution, genome-wide map of the selective forces surrounding cancer gene loci. We also demonstrate negative selection of mutations that may be deleterious to tumor development indicating novel avenues for therapy. Screening of two BCL2 transgenic models confirmed known drivers of human non-Hodgkin lymphoma, and implicates novel candidates including modifiers of immunosurveillance and MHC loci. Correlating mutations with genotypic and phenotypic features independently of local variance in mutation density also provides support for weakly evidenced cancer genes. An online resource http://mulvdb.org allows customized queries of the entire dataset. Evidence implicating cancer drivers can be sparse when limited to clonal events. Here, the authors present a retrovirus driven in vivo lymphomagenesis time course including hundreds of thousands of subclonal mutations and demonstrate the utility of these in mapping the selective forces affecting cancer gene loci, including negatively selected mutations.
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- 2018
47. MYC protein expression scoring and its impact on the prognosis of aggressive B-cell lymphoma patients
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Massimo Granai, Maria Raffaella Ambrosio, Alberto Fabbri, Elena Sabattini, Raffaella Santi, Roshanak Bob, Kikkeri N. Naresh, Emanuele Cencini, Stefano Lazzi, Harald Stein, Maria Giuseppina Cabras, Raffaella Guazzo, Sofia Kovalchuck, Giuseppe Lo Bello, Luigi Rigacci, Francesco Zaja, Gabriele Cevenini, Noel Onyango, Maria Margherita De Santi, Caterina Stelitano, Giuseppe Spataro, Leonardo Del Porro, Lucia Mundo, Lorenzo Leoncini, Pier Luigi Zinzani, Thomas Menter, Francesco Angrilli, Ambrosio, Maria R., Lazzi, Stefano, Bello, Giuseppe Lo, Santi, Raffaella, Porro, Leonardo Del, de Santi, Maria M., Guazzo, Raffaella, Mundo, Lucia, Rigacci, Luigi, Kovalchuck, Sofia, Onyango, Noel, Fabbri, Alberto, Cencini, Emanuele, Zinzani, Pier Luigi, Zaja, Francesco, Angrilli, Francesco, Stelitano, Caterina, Cabras, Maria G., Spataro, Giuseppe, Bob, Roshanak, Menter, Thoma, Granai, Massimo, Cevenini, Gabriele, Naresh, Kikkeri N., Stein, Harald, Sabattini, Elena, Leoncini, Lorenzo, Ambrosio, Maria R, de Santi, Maria M, Cabras, Maria G, and Naresh, Kikkeri N
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Adult ,Male ,medicine.medical_specialty ,Lymphoma, B-Cell ,MYC, aggressive B-cell lymphoma ,Aggressive Non-Hodgkin's Lymphoma ,Disease-Free Survival ,Immunophenotyping ,Proto-Oncogene Proteins c-myc ,Text mining ,Quality of life ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,MYC protein expression, prognosis, aggressive B-cell lymphoma ,Online Only Articles ,B-cell lymphoma ,Cyclophosphamide ,Survival rate ,Aged ,Regulation of gene expression ,Hematology ,business.industry ,Middle Aged ,medicine.disease ,Lymphoma ,Quality of Life ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Doxorubicin ,Vincristine ,Cancer research ,Prednisone ,Female ,Rituximab ,business - Abstract
This study examined the reproducibility of MYC and BCL-2 immunohistochemical scoring as well as the impact of higher expression of both proteins (double expressor status, DE) on survival and progression in a large retrospective cohort of aggressive B-cell lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or R-CHOP-like regimens with a median follow up of 67 months (range 0–138). We also investigated possible MYC protein expression cut offs with the highest reproducibility among pathologists and predictability of gene translocation. We showed that immunohistochemistry (IHC) for MYC and BCL-2 is highly reproducible when cut-off values of >70% for MYC and >50% for BCL-2 are used. This threshold not only predicts the presence of rearrangements (with respect to MYC), but is also clinically valuable. In fact, it identifies a subset of patients who are poor responders and who may benefit from alternate therapeutic strategies
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- 2018
48. An unusual case of post-kala-azar dermal leishmaniasis in a patient with HIV and visceral leishmaniasis co-infection
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Tamara Elliott, Angela C Bailey, Diana Lockwood, Kikkeri N. Naresh, and Jacqueline Simpson
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Adult ,Male ,medicine.medical_specialty ,Biopsy ,030231 tropical medicine ,Human immunodeficiency virus (HIV) ,HIV Infections ,Dermatology ,Disease ,medicine.disease_cause ,Polymerase Chain Reaction ,03 medical and health sciences ,0302 clinical medicine ,Acquired immunodeficiency syndrome (AIDS) ,Antiretroviral Therapy, Highly Active ,parasitic diseases ,medicine ,Humans ,Pharmacology (medical) ,Leishmania infantum ,Post-kala-azar dermal leishmaniasis ,0303 health sciences ,Coinfection ,030306 microbiology ,business.industry ,Public Health, Environmental and Occupational Health ,Leishmaniasis ,medicine.disease ,Rash ,Infectious Diseases ,Visceral leishmaniasis ,Splenomegaly ,HIV-1 ,Leishmaniasis, Visceral ,RNA ,medicine.symptom ,Tomography, X-Ray Computed ,business ,Leishmania donovani ,Co infection - Abstract
Visceral leishmaniasis (VL) is a vector-borne disease caused by Leishmania donovani complex. Post-kala-azar dermal leishmaniasis (PKDL) is a rash that can occur following treatment for VL due to L. donovani species. We describe an unusual case of PKDL occurring during treatment for Leishmania infantum VL in a patient with human immunodeficiency virus-co infection.
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- 2019
49. High-Grade B-Cell Lymphoma, Not Otherwise Specified (HGBL, NOS): Characteristics, Treatment, and Outcomes from 17 Academic US Centers
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M. Ali Ansari-Lari, Brad M. Haverkos, Anna Kress, Andrew M. Evens, Yasmin Karimi, Adam J. Olszewski, Julie M. Vose, Adam Zayac, L. Jeffrey Medeiros, David A. Bond, Paul Rubinstein, Emily C. Ayers, Manali Kamdar, Amina Chaudhry, Mitchell E. Hughes, Karan Pandya, Shalin Kothari, Amy Beckman, Suchitra Sundaram, Mina L. Xu, Stephen D. Smith, Marie Hu, Daniel J. Landsburg, Mark Girton, Habibe Kurt, Reem Karmali, Timothy S. Oh, Heather Nutsch, Jose Sandoval-Sus, Seema Naik, Pallawi Torka, Shaoying Li, Narendranath Epperla, and Kikkeri N Naresh
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,High grade B-cell lymphoma ,Not Otherwise Specified ,Medicine ,Cell Biology ,Hematology ,business ,Biochemistry - Abstract
Background: The term HGBL, NOS was introduced by the World Health Organization (WHO) in 2016 for aggressive B-cell lymphomas with Burkitt lymphoma-like (BLL) or blastoid cytomorphology that lack double-hit genetics and do not meet criteria for other entities. Diagnostic patterns and prognosis of these rare tumors are not well understood. We examined the characteristics and outcomes of patients (pts) with HGBL, NOS diagnosed in 17 academic centers across the United States. Methods: We collected retrospective data on HGBL, NOS cases diagnosed by academic hematopathologists in 2017-2021; 8 centers performed a local review by lymphoma pathology experts to confirm fulfillment of the WHO criteria; pathology reports were reviewed centrally. We excluded pts not tested for MYC rearrangement (MYC-R), any double/triple-hit, diffuse large B-cell, or lymphoblastic lymphomas. Immunohistochemistry (IHC) and cytogenetic tests were done locally. Outcomes included rates of complete response (CR), progression-free (PFS) and overall survival (OS) estimated with 95% confidence intervals (CI). Results: Among 126 pts with HGBL, NOS, median age was 64 years (range 18-91), 67% were male, and 3 were HIV+. Advanced stage was present in 68%, poor performance status (PS, ECOG ≥2) in 21%, high serum lactate dehydrogenase (LDH) in 68%, extranodal (EN) sites in 79%, central nervous system (CNS) involvement in 6%, and International Prognostic Index (IPI) ≥ 3 in 55%. Cytomorphology was reported as BLL in 59 (47%) cases, blastoid in 28 (22%), and unspecified in 39 (31%). By IHC, 83% had germinal center B-cell (GCB) phenotype. Using cases with available data, CD10 was expressed in 79%, BCL6 in 81%, MUM1/IRF4 in 48%, MYC in 73%, BCL2 in 55% (dual MYC/BCL2 expressor [DEL]: 37%), CD5 in 13%, and median Ki-67 was 95%. MYC-R (single-hit) was detected in 27% (Fig A), MYC extra copies (EC) in 9%, BCL2-R in 13%, and BCL6-R in 10%. MYC-EC were present in 16% of cases with BCL2-R or BCL6-R, and BCL2/BCL6-EC in 12% of those with MYC-R. Blastoid tumors were more likely than BLL to involve >1 EN site or to have BCL2-R (Fig B). 9 cases were assessed by next generation sequencing and 5 (56%) had a TP53 mutation. Cases which underwent confirmatory pathology review (N=74) did not differ from others clinically but more often had a well-defined HGBL morphology (77% vs 58%, P=.031) and less often MYC-R (20% vs. 37%, P=.004). The most common first-line regimens (among treated pts, N=121) were DA-EPOCH-R (50%) and RCHOP (35%), with few pts receiving HyperCVAD/MA (5%) or CODOX-M±IVAC (2%); 97% received rituximab, and 44% CNS prophylaxis. Pts selected for DA-EPOCH-R vs. RCHOP were younger (median 61 vs. 68 years, P=.006), more often had stage 3/4 (P=.04), BLL morphology (56% vs. 29%, P=.009) or MYC-R (31% vs. 14%, P=.06). CR was attained in 62% of pts, whereas 20% had progressive disease. The most frequent salvage regimens (± rituximab) included ICE (N=12), DHAP (N=6), and GemOx (N=5). 3 pts underwent autologous, and 3 allogeneic transplant (2/3 subsequently relapsed). 13 received chimeric antigen receptor (CAR) T-cells, with response noted in 7 (54%) and CR in 4 (31%); HGBL relapsed in 3/7 (43%) responders. With median follow-up of 2.7 years, 39% of pts relapsed, and 33% died. Of 49 observed relapses, 13 (27%) involved the CNS. PFS estimate at 2 years was 51% (95% CI, 42-60%) and OS was 68% (95% CI, 58-76%; Fig C). PFS and OS were not significantly associated with age or PS, but stage and LDH were prognostic (Fig D-G). Furthermore, PFS did not differ by BLL/blastoid morphology, MYC-R status or DEL status, but non-GCB tumors had somewhat worse PFS (Fig H-J). We observed no significant PFS (or OS) difference between pts selected for RCHOP vs. DA-EPOCH-R (P=.83 for PFS, Fig K; P=.55 for OS) in aggregate or in any subset, except for de novo tumors with BLL morphology (N=41), where DA-EPOCH-R showed a superior 2-year PFS (73% vs 38% for RCHOP, P=.027; stratified by IPI: P=.040, Fig L). Conclusions: HGBL, NOS, as diagnosed in current academic practice, is highly heterogeneous, highlighting the need to classify high-grade lymphomas using molecular rather than morphologic features. Considering poor survival in all age groups (except for few pts with early stage and normal LDH), lack of prognostic significance of MYC-R, DEL status, or cytomorphology, HGBL, NOS needs prospective trials to delineate prognostic biomarkers, the role of intensified chemotherapy, and novel therapeutic approaches. Figure 1 Figure 1. Disclosures Landsburg: Triphase: Research Funding; Takeda: Research Funding; Curis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; ADCT: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees. Hughes: Acerta Pharma: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genzyme: Consultancy; Janssen: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Sandoval-Sus: SeaGen, Janssen, MassiveBio, TG: Other: Advisory Board; BMS: Other: Advisory Board, Speakers Bureau. Kothari: Incyte pharmaceuticals: Consultancy, Honoraria; Karyopharm pharmaceuticals: Consultancy, Honoraria. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Smith: Acerta Pharma BV: Research Funding; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy, Research Funding; De Novo Biopharma: Research Funding; Ignyta (spouse): Research Funding; Beigene: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Incyte: Consultancy; Incyte Corporation: Research Funding; Karyopharm: Consultancy; KITE pharm: Consultancy; Merck Sharp & Dohme Corp: Research Funding; Ayala (spouse): Research Funding; Bayer: Research Funding; Genentech: Research Funding; Bristol Myers Squibb (spouse): Research Funding; Millenium/Takeda: Consultancy. Epperla: Genzyme: Honoraria; Karyopharm: Other: Ad Board; Beigene: Speakers Bureau; Verastem: Speakers Bureau. Bond: Kite/Gilead: Honoraria. Naik: Sanofi: Other: Virtual Advisory Board Member ; Takeda: Other: Virtual Advisory Board Member ; Kite: Other: Virtual Advisory Board Member. Kamdar: ADC Therapeutics: Consultancy; AbbVie: Consultancy; KaryoPharm: Consultancy; Kite: Consultancy; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy; Celgene (BMS): Consultancy; TG Therapeutics: Research Funding; Genentech: Research Funding; Genetech: Other; Celgene: Other; SeaGen: Speakers Bureau. Haverkos: Viracta Therapeutics: Consultancy. Karmali: BMS/Celgene/Juno: Consultancy, Research Funding; Takeda: Research Funding; Roche: Consultancy; Epizyme: Consultancy; Janssen/Pharmacyclics: Consultancy; EUSA: Consultancy; Genentech: Consultancy; Karyopharm: Consultancy; AstraZeneca: Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Olszewski: PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; TG Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding.
- Published
- 2021
50. ALK-Negative Anaplastic Large Cell Lymphomas Encompass Distinct Subgroups Including an ALK-Positive-like Subgroup with Favorable Prognosis
- Author
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Kwok Him Rex Au Yeung, Veronica Russell, William Choi, Alice Wong, Lawrence Tsui, Yu Yan Carmen Lee, Jamilla Li, Harinder Gill, Ho-Wan Ip, Yok Lam Kwong, Tushar Dave, Sarah L. Ondrejka, Govind Bhagat, Amy Chadburn, Sarah C. Rutherford, Jean L. Koff, David L Jaye, Magdalena Czader, Abner Louissaint, Shaoying Li, Jie Xu, C. Cameron Yin, Choon Kiat Ong, Chee Leong Cheng, Amir Behdad, Andrew M. Evens, Peter H. Norgaard, Anne Ortved Gang, Sirpa Leppa, Marja-Liisa Karjalainen-Lindsberg, Jennifer R Chapman, Catalina Amador, Javeed Iqbal, Yuri Fedoriw, Agata M. Bogusz, Andrew G Evans, Ridas Juskevicius, Eric D. Hsi, Kikkeri N Naresh, Sandeep S. Dave, and Eric Tse
- Subjects
hemic and lymphatic diseases ,Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Introduction ALK-negative anaplastic large cell lymphoma (ALK- ALCL) is an uncommon type of T-cell non-Hodgkin lymphoma (T-NHL) with worse prognosis compared to ALK-positive (ALK+) ALCLs. Most published studies on the genomics of T-NHL have focused on peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and previous studies of ALCL described rearrangements in DUSP22 and TP63 and mutations in genes comprising the JAK/STAT pathway as common genetic drivers in ALK- ALCL. The degree to which these drivers affect survival or other molecular features of ALK- ALCL remains unknown. Here, we describe novel subgroups of ALK- ALCL that exhibit distinct survival. One subgroup appears molecularly similar to ALK+ALCLs and is associated with favorable survival while the second subgroup is quite distinct from ALK- ALCLs and associated with poor outcomes. Methods and Results Eighty-two ALK- ALCL patients were recruited to the Atlas of Blood Cancer (ABC) genomes project, a worldwide consortium established to define the molecular origins of blood cancers. Tumor biopsies from these patients, as well as 10 ALK+ ALCL samples for comparison were obtained from participating institutions. Each case was subjected to centralized pathology review by an experienced panel of hematopathologists to ensure the accuracy of the diagnosis. All cases, along with paired normal tissues, were subjected to DNA and RNA (whole exome-level) sequencing on the Illumina platform to identify mutations and expression changes for each of these cases using methods well established in our group and described previously. We first examined the genetic alterations in ALK- ALCLs. In addition to frequently described genetic alterations such as TP63 and DUSP22 rearrangements, as well as mutations in JAK1, STAT3 and TP53, we also detected mutations in ERBB4, SETD2 and KMT2D, which may serve as potential novel drivers and have not been described previously to our knowledge. We next performed comparative gene expression analysis of the ALK- and ALK+ ALCLs. Surprisingly, a proportion of ALK- ALCL cases (38%) clustered together with ALK+ ALCLs and had a signature resembling ALK+ cases, which we designated as "ALK-like ALCL" here. Both the ALK-like ALCLs and the other ALK- ALCL cases showed decreased ALK expression compared to the ALK+ ALCLs by gene expression analysis. These results point to downstream pathways that are common among ALK+ALCLs and ALK-like ALCLs, but different from the other ALK- ALCLs. Gene set enrichment analysis revealed that the ALK-like ALCLs overexpressed genes in pathways related to monocyte and fibroblast activation, whereas the remaining ALK- ALCLs overexpressed genes in the T follicular helper cells, memory T cells and adaptive immune response-related pathways (P Conclusion Our data indicate that ALK- ALCLs represent a heterogeneous group of diseases and comprise at least two distinct subgroups that can be identified based on their similarity to the ALK+ ALCLs. The ALK-like ALCLs demonstrated distinct molecular features and favorable outcomes. Our results provide a potentially new approach to patient risk-stratification and pathological classification of this disease. Disclosures Kwong: Celgene: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Jaye: Stemline Therapeutics: Honoraria. Behdad: Roche/Foundation Medicine: Speakers Bureau; Thermo Fisher: Speakers Bureau; Lilly: Speakers Bureau. Hsi: AbbVie Inc, Eli Lilly: Research Funding. Dave: Data Driven Bioscience: Current equity holder in publicly-traded company.
- Published
- 2021
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