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1
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Gao D. The role of non-malignant B cells in malignant hematologic diseases. Hematology 2025; 30:2466261. [PMID: 39964954 DOI: 10.1080/16078454.2025.2466261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 02/08/2025] [Indexed: 02/20/2025] Open
Abstract
The tumor microenvironment (TME) represents a heterogeneous, complicated ecosystem characterized by intricate interactions between tumor cells and immune cells. During the past decade, immune cells especially T cells were found to play an important role in the progression of tumor and many related immune checkpoints drugs were created. In recent years, more and more scientists revealed the critical role of B-cells within the TME, particularly various populations of non-malignant B cells. Some studies indicated that non-malignant B cells may exert a 'double-edged sword' role in solid tumors. However, there has been comparatively less focus on the role of non-malignant B cells in hematologic malignancies. In this review, we characterized the development of B cells and summarized its functions of antitumor immunity within TME, with an emphasis on elucidating the roles and potential mechanisms of non-malignant B cells in the progression of hematologic diseases including classical Hodgkin's lymphoma, non-Hodgkin's B-cell lymphoma, non-Hodgkin's T-cell lymphoma, leukemia and multiple myeloma.
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Affiliation(s)
- Daquan Gao
- Department of Hematology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, People's Republic of China
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2
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Santisteban-Espejo A, Benavides-De la Fuente C, Mangas-Rojas A, Montero-Pavon P, Bernal-Florindo I, Aldaco-Puntas E, Prieto-Conde I, Perez-Requena J, Atienza-Cuevas L, Fernández-Valle MDC, Garzón-López S, Garcia-Rojo M. Computational pathology identifies a low B-cell content in the tumour microenvironment as a predictor of adverse outcome in patients with classic Hodgkin lymphoma treated with ABVD. J Clin Pathol 2025; 78:381-389. [PMID: 39837608 DOI: 10.1136/jcp-2024-209848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Accepted: 12/30/2024] [Indexed: 01/23/2025]
Abstract
AIMS The prognostic impact of B lymphocytes surrounding Hodgkin and Reed Sternberg (HRS) cells in classic Hodgkin lymphoma (cHL) and pathogenic variants in genes associated with apoptosis regulation remains undefined. METHODS We have quantified the proportion of B lymphocytes in tumour microenvironment (TME) in 220 diagnostic slides from 110 cHL patients applying computational pathology (CP) and sequenced cases using a targeted panel including 47 genes recurrently mutated in mature B-cell neoplasms. Kaplan-Meier estimators and multivariate Cox regression on overall survival (OS) and progression-free survival (PFS) were assessed following the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis guidelines. RESULTS The mean percentage of B lymphocytes was 45.1 (SD: 24.8). Genes recurrently affected by nonsynonymous somatic mutations in 25% or more of patients included EP300, NOTCH and ABL1. A lower number of mutations were discovered in Epstein-Barr virus-positive cHL (21.1% vs 78.8%) reinforcing the notion that viral infection could functionally replace the need for genomic aberrations. Classic Hodgkin lymphoma (cHL) patients that jointly presented a reduction in the number of B lymphocytes in TME (<8%) and the absence of mutations in apoptosis-associated genes (ABL1, BIRC3, CASP8 and FAS) presented a lower OS (mean OS: 31.5 months, 95% CI: 0 to 69.7 months) in comparison with patients without this event (mean OS: 84.7 months, 95% CI: 61.9 to 107.5 months) (p=0.01). This high-risk cHL subgroup also presented a significantly lower PFS (mean PFS: 8.5 months, 95% CI: 7.5 to 9.5 months) in comparison with B-cell-enriched or apoptosis-mutated cHL (mean PFS: 55.2 months; 95% CI: 42.4 to 68 months) (p<0.001). CONCLUSIONS This study expands previous data on the value of CP in cHL, and specifically, the distribution of B cells, identifying patients with an increased risk of treatment failure and progression. Furthermore, immune escape by apoptosis dysregulation during clonal selection occurring in germinal centres constitutes a landmark of cHL. These results could be the basis for further development of targeted therapies directed against apoptosis modulators in cHL.
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Affiliation(s)
- Antonio Santisteban-Espejo
- Department of Medicine and Surgery, Faculty of Medicine, University of Cadiz, Cadiz, Andalucía, Spain
- Institute of Research and Biomedical Innovation of Cadiz, Cadiz, Andalucia, Spain
| | - Cristian Benavides-De la Fuente
- Department of Pathology, Puerta del Mar University Hospital, Cadiz, Andalucía, Spain
- Health Sciences Program, Doctoral School, University of Cadiz, Cadiz, Spain
| | - Alipio Mangas-Rojas
- Department of Medicine and Surgery, Faculty of Medicine, University of Cadiz, Cadiz, Andalucía, Spain
- Institute of Research and Biomedical Innovation of Cadiz, Cadiz, Andalucia, Spain
| | - Pedro Montero-Pavon
- Department of Pathology, Hospital San Agustin, Linares Jaen, Andalucía, Spain
| | - Irene Bernal-Florindo
- Institute of Research and Biomedical Innovation of Cadiz, Cadiz, Andalucia, Spain
- Department of Pathology, Jerez de la Frontera University Hospital, Jerez de la Frontera, Andalucía, Spain
| | - Eduardo Aldaco-Puntas
- Department of Medicine and Surgery, Faculty of Medicine, University of Cadiz, Cadiz, Andalucía, Spain
| | - Isabel Prieto-Conde
- Department of Medicine and Surgery, Faculty of Medicine, University of Cadiz, Cadiz, Andalucía, Spain
| | - Jose Perez-Requena
- Department of Pathology, Puerta del Mar University Hospital, Cadiz, Andalucía, Spain
| | - Lidia Atienza-Cuevas
- Department of Pathology, Puerta del Mar University Hospital, Cadiz, Andalucía, Spain
| | | | - Sebastian Garzón-López
- Department of Hematology, Jerez de la Frontera University Hospital, Jerez de la Frontera, Spain
| | - Marcial Garcia-Rojo
- Institute of Research and Biomedical Innovation of Cadiz, Cadiz, Andalucia, Spain
- Department of Pathology, Jerez de la Frontera University Hospital, Jerez de la Frontera, Andalucía, Spain
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Ikemoto M, Kotani T, Okada K, Matsuda S, Takeuchi T. A hybrid protein is a functional molecule to reduce the cytokine storm caused by excessively activated macrophages. Immunol Cell Biol 2025; 103:350-364. [PMID: 39953927 PMCID: PMC11964790 DOI: 10.1111/imcb.70000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 06/16/2024] [Accepted: 01/23/2025] [Indexed: 02/17/2025]
Abstract
We recently developed a hybrid protein, tentatively named human MIKO-1 (hMIKO-1), based on the amino acid sequences of human S100A8 (hS100A8) and hS100A9. Human THP-1 macrophages (THP-1m), differentiated from THP-1 cells by phorbol 12-myristate 13-acetate, were used to investigate the immune function of hMIKO-1 as a drug for inflammatory diseases. Western blotting was conducted to confirm whether hMIKO-1 binds with β-actin and nuclear factor-kappa B to form complexes in THP-1m. A polymerase chain reaction (PCR) and quantitative PCR were performed to examine changes in the messenger RNA levels of proinflammatory cytokines in THP-1m. Fluorescent immunochemical staining was used to observe the intracellular localization of hMIKO-1 and hS100A8 or hS100A9 in THP-1m. As observed microscopically, the intracellular localization of hMIKO-1 in THP-1m was consistent with that of hS100A8, suggesting the close involvement of hS100A8 in the intracellular behavior of hMIKO-1 in THP-1m. Western blotting revealed that hMIKO-1 formed complexes with intracellular proteins, such as β-actin and nuclear factor-kappa B, to negatively regulate inflammatory signal transduction in THP-1m. Flow cytometry showed that the binding of hMIKO-1 to THP-1m significantly decreased when THP-1m were preliminarily treated with a sialidase (neuraminidases) cocktail. Therefore, the present results strongly suggest that the binding of hMIKO-1 to THP-1m closely involves the sugar chains of the surface proteins of cells. The messenger RNA expression of each proinflammatory cytokine was significantly suppressed in THP-1m preliminarily treated with hMIKO-1 despite a subsequent stimulation with lipopolysaccharide. In conclusion, hMIKO-1 is a functional molecule that significantly inhibits inflammatory signal transduction in THP-1m.
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Grants
- 21K08450 Ministry of Education, Science, Sports, and Culture of Japan
- 23K07914 Ministry of Education, Science, Sports, and Culture of Japan
- 24K11353 Ministry of Education, Science, Sports, and Culture of Japan
- C Ministry of Education, Science, Sports, and Culture of Japan
- 2646066 Ministry of Education, Science, Sports, and Culture of Japan
- 21K15422 Ministry of Education, Science, Sports, and Culture of Japan
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Affiliation(s)
- Masaki Ikemoto
- Division of Rheumatology, Department of Internal Medicine IVOsaka Medical and Pharmaceutical UniversityOsakaJapan
| | - Takuya Kotani
- Division of Rheumatology, Department of Internal Medicine IVOsaka Medical and Pharmaceutical UniversityOsakaJapan
| | - Kohki Okada
- Department of Medical Technology and Sciences, Faculty of Health SciencesKyoto Tachibana UniversityKyotoJapan
| | - Shogo Matsuda
- Division of Rheumatology, Department of Internal Medicine IVOsaka Medical and Pharmaceutical UniversityOsakaJapan
| | - Tohru Takeuchi
- Division of Rheumatology, Department of Internal Medicine IVOsaka Medical and Pharmaceutical UniversityOsakaJapan
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Gajzer DC, Fromm JR. Flow Cytometry for B-Cell Non-Hodgkin and Hodgkin Lymphomas. Cancers (Basel) 2025; 17:814. [PMID: 40075660 PMCID: PMC11898643 DOI: 10.3390/cancers17050814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/14/2025] [Accepted: 01/24/2025] [Indexed: 03/14/2025] Open
Abstract
Multi-parametric flow cytometry is a powerful diagnostic tool that permits rapid assessment of cellular antigen expression to quickly provide immunophenotypic information suitable for disease classification. This chapter describes the classification of B-cell non-Hodgkin lymphoma (B-NHL) by flow cytometry suitable for the clinical and research environment. In addition to describing the immunophenotypic patterns of the most common B-NHL (including examples of common B-NHL), the effect of anti-CD19, -CD20, and -CD38 therapies on the evaluation of flow cytometric data is also discussed. Over the last 15 years, our laboratory has developed flow cytometry combinations that can immunophenotype classic Hodgkin lymphoma (CHL), nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), and T-cell/histocyte-rich large B-cell lymphoma (THRLBCL) and the use of these assays will be presented. The CHL assay combination is also particularly well suited to immunophenotype primary mediastinal large B-cell lymphoma (PMLBCL) and our experience immunophenotyping PMLBCL by flow cytometry will be discussed. Finally, an approach to the evaluation of the reactive infiltrate of CHL, NLPHL, and THRLBCL that can provide diagnostic information will also be provided.
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Affiliation(s)
| | - Jonathan R. Fromm
- Department of Laboratory Medicine and Pathology, University of Washington, 825 Eastlake Ave E, Seattle, WA 98109, USA;
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Wahyudianingsih R, Sanjaya A, Jonathan T, Pranggono EH, Achmad D, Hernowo BS. Chemotherapy's effects on autophagy in the treatment of Hodgkin's lymphoma: a scoping review. Discov Oncol 2024; 15:269. [PMID: 38976168 PMCID: PMC11231119 DOI: 10.1007/s12672-024-01142-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 07/02/2024] [Indexed: 07/09/2024] Open
Abstract
BACKGROUND Classical Hodgkin Lymphomas (HL) are a unique malignant growth with an excellent initial prognosis. However, 10-30% of patients will still relapse after remission. One primary cellular function that has been the focus of tumor progression is autophagy. This process can preserve cellular homeostasis under stressful conditions. Several studies have shown that autophagy may play a role in developing HL. Therefore, this review aimed to explore chemotherapy's effect on autophagy in HL, and the effects of autophagy on HL. METHODS A scoping review in line with the published PRISMA extension for scoping reviews (PRISMA-ScR) was conducted. A literature search was conducted on the MEDLINE database and the Cochrane Central Register of Controlled Trials (CENTRAL). All results were retrieved and screened, and the resulting articles were synthesized narratively. RESULTS The results showed that some cancer chemotherapy also induces autophagic flux. Although the data on HL is limited, since the mechanisms of action of these drugs are similar, we can infer a similar relationship. However, this increased autophagy activity may reflect a mechanism for increasing tumor growth or a cellular compensation to inhibit its growth. Although evidence supports both views, we argued that autophagy allowed cancer cells to resist cell death, mainly due to DNA damage caused by cytotoxic drugs. CONCLUSION Autophagy reflects the cell's adaptation to survive and explains why chemotherapy generally induces autophagy functions. However, further research on autophagy inhibition is needed as it presents a viable treatment strategy, especially against drug-resistant populations that may arise from HL chemotherapy regimens.
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Affiliation(s)
- Roro Wahyudianingsih
- Postgraduate Program of Biomedical Science, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia
- Department of Anatomical Pathology, Faculty of Medicine, Maranatha Christian University, Bandung, West Java, Indonesia
| | - Ardo Sanjaya
- Department of Anatomy, Faculty of Medicine, Maranatha Christian University, Bandung, Indonesia.
| | - Timothy Jonathan
- Undergraduate Program in Medicine, Faculty of Medicine, Maranatha Christian University, Bandung, Indonesia
| | - Emmy Hermiyanti Pranggono
- Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran/Rumah Sakit Hasan Sadikin, Bandung, West Java, Indonesia
| | - Dimyati Achmad
- Department of Oncological Surgery, Faculty of Medicine, Universitas Padjadjaran/Rumah Sakit Hasan Sadikin, Bandung, West Java, Indonesia
| | - Bethy Suryawathy Hernowo
- Department of Anatomical Pathology, Faculty of Medicine, Universitas Padjadjaran/Rumah Sakit Hasan Sadikin, Bandung, West Java, Indonesia
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Kishida M, Fujisawa M, Steidl C. Molecular biomarkers in classic Hodgkin lymphoma. Semin Hematol 2024:S0037-1963(24)00069-6. [PMID: 38969539 DOI: 10.1053/j.seminhematol.2024.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 05/27/2024] [Indexed: 07/07/2024]
Abstract
Classic Hodgkin lymphoma is a unique B-cell derived malignancy featuring rare malignant Hodgkin and Reed Sternberg (HRS) cells that are embedded in a quantitively dominant tumor microenvironment (TME). Treatment of classic Hodgkin lymphoma has significantly evolved in the past decade with improving treatment outcomes for newly diagnosed patients and the minority of patients suffering from disease progression. However, the burden of toxicity and treatment-related long-term sequelae remains high in a typically young patient population. This highlights the need for better molecular biomarkers aiding in risk-adapted treatment strategies and predicting response to an increasing number of available treatments that now prominently involve multiple immunotherapy options. Here, we review modern molecular biomarker approaches that reflect both the biology of the malignant HRS cells and cellular components in the TME, while holding the promise to improve diagnostic frameworks for clinical decision-making and be feasible in clinical trials and routine practice. In particular, technical advances in sequencing and analytic pipelines using liquid biopsies, as well as deep phenotypic characterization of tissue architecture at single-cell resolution, have emerged as the new frontier of biomarker development awaiting further validation and implementation in routine diagnostic procedures.
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Affiliation(s)
- Makoto Kishida
- Centre for Lymphoid Cancer department, BC Cancer, Vancouver, British Columbia, Canada
| | - Manabu Fujisawa
- Centre for Lymphoid Cancer department, BC Cancer, Vancouver, British Columbia, Canada; Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Christian Steidl
- Centre for Lymphoid Cancer department, BC Cancer, Vancouver, British Columbia, Canada; Institute of Medicine, University of Tsukuba, Ibaraki, Japan; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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Duminuco A, Santuccio G, Chiarenza A, Figuera A, Motta G, Caruso AL, Petronaci A, Ippolito M, Cerchione C, Di Raimondo F, Romano A. Baseline IgM Amounts Can Identify Patients with Poor Outcomes: Results from a Real-Life Single-Center Study on Classical Hodgkin Lymphoma. Cancers (Basel) 2024; 16:826. [PMID: 38398216 PMCID: PMC10886525 DOI: 10.3390/cancers16040826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 02/10/2024] [Accepted: 02/16/2024] [Indexed: 02/25/2024] Open
Abstract
Hodgkin Lymphoma (HL) is characterized by an inflammatory background in which the reactive myeloid cells may exert an immune-suppressive effect related to the progression of the disease. Immunoglobulin M is the first antibody isotype produced during an immune response, which also plays an immunoregulatory role. Therefore, we investigated if, as a surrogate of defective B cell function, it could have any clinical impact on prognosis. In this retrospective, observational, single-center study, we evaluated 212 newly diagnosed HL patients, including 132 advanced-stage. A 50 mg/dL level of IgM at baseline resulted in 84.1% sensitivity and 45.5% specificity for predicting a complete response in the whole cohort (area under curve (AUC) = 0.62, p = 0.013). In multivariate analysis, baseline IgM ≤ 50 mg/dL and the presence of a large nodal mass (<7 cm) were independent variables able to predict the clinical outcome, while, after two cycles of treatment, IgM ≤ 50 mg/dL at baseline and PET-2 status were independent predictors of PFS. The amount of IgM at diagnosis is a valuable prognostic factor much earlier than PET-2, and it can also provide information for PET-2-negative patients. This can help to identify different HL classes at risk of treatment failure at baseline.
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Affiliation(s)
- Andrea Duminuco
- Hematology Unit with BMT, A.O.U. Policlinico “G.Rodolico-San Marco”, 95123 Catania, Italy; (G.S.); (A.C.); (A.F.); (G.M.); (A.L.C.); (A.P.); (F.D.R.)
| | - Gabriella Santuccio
- Hematology Unit with BMT, A.O.U. Policlinico “G.Rodolico-San Marco”, 95123 Catania, Italy; (G.S.); (A.C.); (A.F.); (G.M.); (A.L.C.); (A.P.); (F.D.R.)
| | - Annalisa Chiarenza
- Hematology Unit with BMT, A.O.U. Policlinico “G.Rodolico-San Marco”, 95123 Catania, Italy; (G.S.); (A.C.); (A.F.); (G.M.); (A.L.C.); (A.P.); (F.D.R.)
| | - Amalia Figuera
- Hematology Unit with BMT, A.O.U. Policlinico “G.Rodolico-San Marco”, 95123 Catania, Italy; (G.S.); (A.C.); (A.F.); (G.M.); (A.L.C.); (A.P.); (F.D.R.)
| | - Giovanna Motta
- Hematology Unit with BMT, A.O.U. Policlinico “G.Rodolico-San Marco”, 95123 Catania, Italy; (G.S.); (A.C.); (A.F.); (G.M.); (A.L.C.); (A.P.); (F.D.R.)
| | - Anastasia Laura Caruso
- Hematology Unit with BMT, A.O.U. Policlinico “G.Rodolico-San Marco”, 95123 Catania, Italy; (G.S.); (A.C.); (A.F.); (G.M.); (A.L.C.); (A.P.); (F.D.R.)
| | - Alessandro Petronaci
- Hematology Unit with BMT, A.O.U. Policlinico “G.Rodolico-San Marco”, 95123 Catania, Italy; (G.S.); (A.C.); (A.F.); (G.M.); (A.L.C.); (A.P.); (F.D.R.)
| | - Massimo Ippolito
- Nuclear Medicine Center, Azienda Ospedaliera Cannizzaro, 95021 Catania, Italy;
| | - Claudio Cerchione
- Hematology Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy;
| | - Francesco Di Raimondo
- Hematology Unit with BMT, A.O.U. Policlinico “G.Rodolico-San Marco”, 95123 Catania, Italy; (G.S.); (A.C.); (A.F.); (G.M.); (A.L.C.); (A.P.); (F.D.R.)
- Department of General Surgery and Medical-Surgical Specialties, Hematology Section, University of Catania, 95123 Catania, Italy
| | - Alessandra Romano
- Department of General Surgery and Medical-Surgical Specialties, Hematology Section, University of Catania, 95123 Catania, Italy
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Ribatti D, Tamma R, Annese T, Ingravallo G, Specchia G. Macrophages and angiogenesis in human lymphomas. Clin Exp Med 2024; 24:26. [PMID: 38285283 PMCID: PMC10824884 DOI: 10.1007/s10238-023-01291-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 12/27/2023] [Indexed: 01/30/2024]
Abstract
A link exists between chronic inflammation and cancer and immune cells, angiogenesis, and tumor progression. In hematologic malignancies, tumor-associated macrophages (TAMs) are a significant part of the tumor microenvironment. Macrophages are classified into M1/classically activated and M2/alternatively activated. In tumors, TAMs are mainly constituted by M2 subtype, which promotes angiogenesis, lymphangiogenesis, repair, and remodeling, suppressing adaptive immunity, increasing tumor cell proliferation, drug resistance, histological malignancy, and poor clinical prognosis. The aim of our review article is to define the role of TAMs and their relationship with the angiogenesis in patients with lymphoma reporting both an analysis of main published data and those emerging from our studies. Finally, we have discussed the anti-angiogenic approach in the treatment of lymphomas.
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Affiliation(s)
- Domenico Ribatti
- Department of Translational Biomedicine and Neuroscience, University of Bari Medical School, Bari, Italy.
| | - Roberto Tamma
- Department of Translational Biomedicine and Neuroscience, University of Bari Medical School, Bari, Italy
| | - Tiziana Annese
- Department of Translational Biomedicine and Neuroscience, University of Bari Medical School, Bari, Italy
- Department of Medicine and Surgery, Libera Università del Mediterraneo (LUM) Giuseppe Degennaro University, Bari, Italy
| | - Giuseppe Ingravallo
- Section of Pathology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Medical School, Bari, Italy
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9
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Georgoulis V, Papoudou-Bai A, Makis A, Kanavaros P, Hatzimichael E. Unraveling the Immune Microenvironment in Classic Hodgkin Lymphoma: Prognostic and Therapeutic Implications. BIOLOGY 2023; 12:862. [PMID: 37372147 PMCID: PMC10294989 DOI: 10.3390/biology12060862] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/06/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023]
Abstract
Classic Hodgkin lymphoma (cHL) is a lymphoid neoplasm composed of rare neoplastic Hodgkin and Reed-Sternberg (HRS) cells surrounded by a reactive tumor microenvironment (TME) with suppressive properties against anti-tumor immunity. TME is mainly composed of T cells (CD4 helper, CD8 cytotoxic and regulatory) and tumor-associated macrophages (TAMs), but the impact of these cells on the natural course of the disease is not absolutely understood. TME contributes to the immune evasion of neoplastic HRS cells through the production of various cytokines and/or the aberrant expression of immune checkpoint molecules in ways that have not been fully understood yet. Herein, we present a comprehensive review of findings regarding the cellular components and the molecular features of the immune TME in cHL, its correlation with treatment response and prognosis, as well as the potential targeting of the TME with novel therapies. Among all cells, macrophages appear to be a most appealing target for immunomodulatory therapies, based on their functional plasticity and antitumor potency.
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Affiliation(s)
- Vasileios Georgoulis
- Department of Hematology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45 500 Ioannina, Greece;
| | - Alexandra Papoudou-Bai
- Department of Pathology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45 500 Ioannina, Greece;
| | - Alexandros Makis
- Department of Child Health, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45 500 Ioannina, Greece;
| | - Panagiotis Kanavaros
- Department of Anatomy-Histology-Embryology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45 000 Ioannina, Greece;
| | - Eleftheria Hatzimichael
- Department of Hematology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45 500 Ioannina, Greece;
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10
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Grund J, Iben K, Reinke S, Bühnen I, Plütschow A, Müller-Meinhard B, Garcia Marquez MA, Schlößer HA, von Tresckow B, Kellermeier F, Borchmann P, Engert A, Bröckelmann PJ, Klapper W. Low B-cell content is associated with a CD73-low tumour microenvironment and unfavourable prognosis in classic Hodgkin lymphoma. Br J Haematol 2023. [PMID: 36921595 DOI: 10.1111/bjh.18762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/17/2023] [Accepted: 03/07/2023] [Indexed: 03/17/2023]
Abstract
B-cell content in the tumour microenvironment (TME) of classic Hodgkin lymphoma (HL) is known to be associated with prognosis. Here we demonstrate that whole slide image analysis using routinely available slides predicts outcomes in patients treated with ABVD in a prospective trial with a high B-cell content being associated with a favourable prognosis. B cells in the TME did not correlate with B cells in peripheral blood. In the TME maturation, stages of B cells (naive and memory) were consistent. However, we detected down-regulation of CD73 in HL with low B cells suggestive of an antibody-independent function of B cells in the TME of HL.
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Affiliation(s)
- Johanna Grund
- Hematopathology Section and Lymph Node Registry, Department of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Katharina Iben
- Hematopathology Section and Lymph Node Registry, Department of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Sarah Reinke
- Hematopathology Section and Lymph Node Registry, Department of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Ina Bühnen
- Department I of Internal Medicine, Centre for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.,German Hodgkin Study Group (GHSG), Cologne, Germany
| | - Annette Plütschow
- Department I of Internal Medicine, Centre for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.,German Hodgkin Study Group (GHSG), Cologne, Germany
| | - Berit Müller-Meinhard
- Hematopathology Section and Lymph Node Registry, Department of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Maria A Garcia Marquez
- Center of Molecular Medicine, Cologne Translational Immunology, University of Cologne, Cologne, Germany.,Department of General, Visceral, Cancer and Transplantation Surgery; Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Hans A Schlößer
- Center of Molecular Medicine, Cologne Translational Immunology, University of Cologne, Cologne, Germany.,Department of General, Visceral, Cancer and Transplantation Surgery; Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany
| | - Bastian von Tresckow
- Department I of Internal Medicine, Centre for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.,German Hodgkin Study Group (GHSG), Cologne, Germany.,Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Fabian Kellermeier
- Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
| | - Peter Borchmann
- Department I of Internal Medicine, Centre for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.,German Hodgkin Study Group (GHSG), Cologne, Germany
| | - Andreas Engert
- Department I of Internal Medicine, Centre for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.,German Hodgkin Study Group (GHSG), Cologne, Germany
| | - Paul J Bröckelmann
- Department I of Internal Medicine, Centre for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne, Germany.,German Hodgkin Study Group (GHSG), Cologne, Germany.,Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Cologne, Germany.,Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Wolfram Klapper
- Hematopathology Section and Lymph Node Registry, Department of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany
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11
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Qu Y, Liu H. Construction of a predictive model for clinical survival in male patients with non-metastatic rectal adenocarcinoma. Asian J Surg 2023; 46:132-142. [PMID: 35227564 DOI: 10.1016/j.asjsur.2022.02.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/15/2021] [Accepted: 02/11/2022] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND No clinical prediction model is available for non-metastatic rectal adenocarcinoma in males. Based on demographic and clinicopathological characteristics, we constructed a survival prediction model for the study population. METHODS At a ratio of 7:3, 3450 eligible patients were divided into training and validation sets. Optimal cutoff values were calculated using X-tile software. Cox proportional hazards regression was used to find prognostic factors for cancer-specific survival (CSS) and overall survival (OS). Corresponding nomogram prognostic models were also constructed based on predictors.The validity, discriminative ability, predictability, and clinical usefulness of the model were analyzed and assessed. RESULTS We identified predictors of survival in the target population and successfully constructed nomograms. In the nomogram prediction model for OS and CSS, the C-index was 0.724 and 0.735, respectively, for the training group and 0.754 and 0.760, respectively, for the validation group. In the validation group, the area under the curve (AUC) of the receiver operating characteristic curve for OS and CSS nomograms was 0.768 and 0.769, respectively, for the 3-year survival rate and 0.755 and 0.747, respectively, for the 5-year survival rate. Kaplan-Meier Survival Curves showed excellent risk discrimination performance of the nomogram (P < 0.05) Calibration curves, time-dependent AUC and decision curve analysis showed that the prediction model constructed in this study had excellent clinical prediction and decision ability and performed better than the TNM staging system. CONCLUSION Our nomogram is helpful to evaluate the prognosis of non-metastatic male patients with rectal adenocarcinoma and has guiding significance for clinical treatment.
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Affiliation(s)
- Yidan Qu
- Department of Clinical Medicine, Qingdao University, 266000, Shandong, China
| | - Hao Liu
- Department of Clinical Medicine, Fudan University, 200032, Shanghai, China.
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12
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Ullah F, Dima D, Omar N, Ogbue O, Ahmed S. Advances in the treatment of Hodgkin lymphoma: Current and future approaches. Front Oncol 2023; 13:1067289. [PMID: 36937412 PMCID: PMC10020509 DOI: 10.3389/fonc.2023.1067289] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 02/07/2023] [Indexed: 03/06/2023] Open
Abstract
Hodgkin lymphoma (HL) is a rare type of lymphoma with unique histologic, immunophenotypic, and clinical features. It represents approximately one-tenth of lymphomas diagnosed in the United States and consists of two subtypes: classical Hodgkin's lymphoma (cHL), which accounts for majority of HL cases, and nodular lymphocyte predominant Hodgkin lymphoma represent approximately 5% of Hodgkin lymphoma cases. From this point, we will be focusing on cHL in this review. In general, it is considered a highly curable disease with first-line chemotherapy with or without the addition of radiotherapy. However, there are patients with disease that relapses or fails to respond to frontline regimens and the standard treatment modality for chemo sensitive cHL is high dose chemotherapy followed by autologous hematopoietic stem cell transplant (AHSCT). In recent years, targeted immunotherapy has revolutionized the treatment of cHL while many novel agents are being explored in addition to chimeric antigen receptor (CAR) T-cell therapy which is also being investigated in clinical trials as a potential treatment option.
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Affiliation(s)
- Fauzia Ullah
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Danai Dima
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH, United States
- Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Najiullah Omar
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Olisaemeka Ogbue
- Department of Translational Hematology and Oncology Research, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Sairah Ahmed
- Department of Lymphoma/Myeloma and Stem Cell Transplant & Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
- *Correspondence: Sairah Ahmed,
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13
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Santisteban-Espejo A, Bernal-Florindo I, Perez-Requena J, Atienza-Cuevas L, Catalina-Fernandez I, Fernandez-Valle MDC, Romero-Garcia R, Garcia-Rojo M. Identification of prognostic factors in classic Hodgkin lymphoma by integrating whole slide imaging and next generation sequencing. Mol Omics 2022; 18:1015-1028. [PMID: 36382626 DOI: 10.1039/d2mo00195k] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Digital pathology and genomics are increasingly used to improve our understanding of lymphoid neoplasms. Algorithms for quantifying cell populations in the lymph node and genetics can be integrated to identify new biomarkers with prognostic impact in classic Hodgkin lymphoma (cHL). In 16 cHL patients, we have performed whole slide imaging (WSI) analysis and quantification of CD30+, CD20+, CD3+ and MUM1+ cells in whole tissue slides, and Next Generation Sequencing (NGS) in formalin fixed paraffin-embedded (FFPE) tissue, using a widely used NSG panel (Oncomine® Focus Assay) to define genetic variants underlying tumor development. The different cell populations could be successfully identified in scanned slides of cHL, supporting the inclusion of WSI in the histopathological evaluation of cHL as an adequate method for the quantification of different cell populations. We also performed genetic profiling in FFPE samples of cHL leading to the identification of copy number variations in the Neurofibromin 1 gene (17q11.2) and the Androgen Receptor gene (Xq12) accompanied by chromosomal gains and losses in CDK4, KRAS and FGFR2 genes. Progression-free survival (PFS) was statistically significantly higher in cHL patients with amplification in the NF1 gene combined with CD3+ cells above 28.6% (p = 0.006) and MUM1+ cells above 21.8% (p < 0.001). Moreover, patients with MUM1+ cells above 21.8% showed a statistically significantly higher PFS when combined with amplification of the AR gene (p < 0.001) and wild-type KRAS (p < 0.001). The integration of WSI analysis and DNA sequencing could be useful to improve our understanding of the biology of cHL and define risk subgroups.
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Affiliation(s)
- Antonio Santisteban-Espejo
- Pathology Department, Puerta del Mar University Hospital, Av. Ana de Viya, 21. 11009, Cadiz, Spain. .,Institute of Research and Innovation in Biomedical Sciences of the Province of Cadiz (INiBICA), Cadiz, Spain.,Department of Medicine, University of Cadiz, Cadiz, Spain
| | - Irene Bernal-Florindo
- Institute of Research and Innovation in Biomedical Sciences of the Province of Cadiz (INiBICA), Cadiz, Spain.,Pathology Department, Jerez de la Frontera University Hospital, Cadiz, Spain
| | - Jose Perez-Requena
- Pathology Department, Puerta del Mar University Hospital, Av. Ana de Viya, 21. 11009, Cadiz, Spain.
| | - Lidia Atienza-Cuevas
- Pathology Department, Puerta del Mar University Hospital, Av. Ana de Viya, 21. 11009, Cadiz, Spain.
| | | | | | - Raquel Romero-Garcia
- Institute of Research and Innovation in Biomedical Sciences of the Province of Cadiz (INiBICA), Cadiz, Spain
| | - Marcial Garcia-Rojo
- Institute of Research and Innovation in Biomedical Sciences of the Province of Cadiz (INiBICA), Cadiz, Spain.,Pathology Department, Jerez de la Frontera University Hospital, Cadiz, Spain
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14
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Wang F. Risk and outcome of second primary malignancy in patients with classical Hodgkin lymphoma. Medicine (Baltimore) 2022; 101:e31967. [PMID: 36482535 PMCID: PMC9726421 DOI: 10.1097/md.0000000000031967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Hodgkin lymphoma survivors demonstrated increased risk of secondary primary malignancies (SPMs), but comprehensive analysis of the risk and outcome of SPMs in classical Hodgkin lymphoma (cHL) patients has not yet been reported. METHODS Patients with cHL from 1975 to 2017 were identified from the Surveillance, Epidemiology and End Results (SEER) database. Standardized incidence ratios were calculated for the risk of solid and hematologic SPMs in cHL patients compared to the general population. The outcome of cHL patients developing SPMs were assessed by performing survival, competing risks regression, and cox proportional regression analyses. RESULTS In a follow-up of 26,493 cHL survivors for 365,156 person years, 3866 (14.59%) secondary cancers were identified, with an standardized incidence ratio of 2.09 (95% CI: 2.02-2.15). The increased risk was still notable after follow-up of 10 years or more, and the risk is more pronounced for patients with female gender, younger age, advanced stage, chemotherapy, and radiation therapy. The overall survival is worse for cHL patients with SPMs after 11 years of follow-up (P < .0001). The main cause of death for cHL patients with SPMs is not cHL but other causes including SPMs. Multivariate Cox regression analysis confirmed SPMs as an independently adverse prognostic factor for cHL survivors (hazard ratio, 1.13; 95% CI, 1.05-1.21, P = .001). CONCLUSIONS There is a significantly increased risk of developing SPMs for cHL survivors. The overall survival is worse for cHL patients and SPMs is an independent prognostic factor for cHL.
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Affiliation(s)
- Fan Wang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, The People’s Republic of China
- * Correspondence: Fan Wang, Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei 430030, China (e-mail: )
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15
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Santisteban-Espejo A, Bernal-Florindo I, Perez-Requena J, Atienza-Cuevas L, Maira-Gonzalez N, Garcia-Rojo M. Whole-slide image analysis identifies a high content of Hodgkin Reed-Sternberg cells and a low content of T lymphocytes in tumor microenvironment as predictors of adverse outcome in patients with classic Hodgkin lymphoma treated with ABVD. Front Oncol 2022; 12:1000762. [PMID: 36338756 PMCID: PMC9631766 DOI: 10.3389/fonc.2022.1000762] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Accepted: 09/26/2022] [Indexed: 11/13/2022] Open
Abstract
Classic Hodgkin lymphoma (cHL) constitutes the most frequent lymphoma in young adults. Its histopathology is unique as a scattered tumor population, termed Hodgkin Reed-Sternberg (HRS) cells is diluted in a prominent tumor microenvironment (TME) composed of T lymphocytes, B lymphocytes, macrophages, neutrophils, eosinophils and histiocytes. Traditionally, the identification of prognostic biomarkers in the cHL TME has required visual inspection and manual counting by pathologists. The advent of whole-slide imaging (WSI) and digital image analysis methods could significantly contribute to improve this essential objective in cHL research, as a 10-20% of patients are still refractory or relapsed after conventional chemotherapy. In this work, we have digitized a total of 255 diagnostic cHL slides and quantified the proportion of HRS cells (CD30), B cells (CD20) and T cells (CD3) by digital image analysis. Data obtained where then correlated with the overall survival (OS) and progression free survival (PFS) of cHL patients. Quantification of HRS cells, B cells and T cells reflects the biological heterogeneity of the different cHL histological subtypes analyzed. A percentage of 2.00% of HRS cells statistically significantly discriminated between patients achieving a complete metabolic response (CMR) and refractory or relapsed (R/R) patients both for the OS (P=0.001) and PFS (P=0.005). Furthermore, patients with a percentage of T cells below the 26.70% in the TME showed a statistically significantly shorter OS (P=0.019) and PFS (P=0.041) in comparison with patients above this threshold. A subgroup of patients with a low content of T cells and high content of HRS cells exhibited a special aggressive clinical course. Currently, there is the need to implement quantitative and easy scalable methods to enhance clinical translation, as the cHL TME plays a central role in the clinical course of the disease. The results of this study could contribute to the identification of prognostic biomarkers specifically looking at the cHL TME and their inclusion in future clinical trials.
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Affiliation(s)
- Antonio Santisteban-Espejo
- Department of Pathology, Puerta del Mar University Hospital, Cadiz, Spain
- Institute of Research and Innovation in Biomedical Sciences of the Province of Cadiz (INiBICA), Cadiz, Spain
- Department of Medicine, Faculty of Medicine, University of Cadiz, Cadiz, Spain
| | - Irene Bernal-Florindo
- Institute of Research and Innovation in Biomedical Sciences of the Province of Cadiz (INiBICA), Cadiz, Spain
- Department of Pathology, Jerez de la Frontera University Hospital, Cadiz, Spain
- *Correspondence: Irene Bernal-Florindo,
| | - Jose Perez-Requena
- Department of Pathology, Puerta del Mar University Hospital, Cadiz, Spain
| | | | | | - Marcial Garcia-Rojo
- Institute of Research and Innovation in Biomedical Sciences of the Province of Cadiz (INiBICA), Cadiz, Spain
- Department of Pathology, Jerez de la Frontera University Hospital, Cadiz, Spain
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16
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Lacet DFR, Oliveira CC. The role of immunohistochemistry in the assessment of classical Hodgkin lymphoma microenvironment. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2022; 15:412-424. [PMID: 36381421 PMCID: PMC9638837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 08/21/2022] [Indexed: 06/16/2023]
Abstract
INTRODUCTION Classical Hodgkin lymphoma (CHL) has a unique cellular composition, containing a minority of neoplastic cells - Hodgkin and Reed-Sternberg (HRS) cells - in an inflammatory background. Investigations into this microenvironment have been given special importance in scientific hematopathology, playing an important role in elucidating its composition and its relationship to the prognosis of patients. OBJECTIVE To investigate microenvironment tumor markers in CHL, in order to analyze their interactions with clinical-morphological aspects of interest in onco-hematopathology. METHODS This retrospective study analyzed 184 patients with a pathologic diagnosis of CHL. Clinical data were reviewed from medical records. A morphological and immunophenotypic study with CD20, CD30, CD15, PAX-5, CD3, CD4, CD8, CD68, CD34, CD138 and PD-1 were performed. The data were tabulated and p value less than 0.05 was considered significant. RESULTS The time-to-cure was shorter in CD20+ patients, especially in those with more than 25% positivity (P=0.0183). The time-to-cure (P=0.0309) and the death (P=0.016) rates were shorter in PD-1 negative patients. Among patients with the presence of plasma cells in the microenvironment, those with lower numbers tend to be cured earlier (P=0.0374). Higher vascular density is associated with lower frequency of B symptoms (P=0.036) and presence of disease recurrence (P=0.004). CONCLUSIONS The microenvironment is certainly the setting of increasingly robust studies and the findings of this work highlight non-neoplastic B lymphocytes, plasma cells, PD-1 lymphocytes, and vascular density, related to prognosis of CHL patients.
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Affiliation(s)
- Dominique Fonseca Rodrigues Lacet
- Department of Pathology, Botucatu School of Medicine, São Paulo State University (FMB UNESP) and Department of Pathology, Luxemburgo HospitalBelo Horizonte, Brazil
| | - Cristiano Claudino Oliveira
- Department of Pathology, Botucatu School of Medicine, São Paulo State University (FMB UNESP) and Department of Pathology - AC Carmargo Cancer CenterSão Paulo, Brazil
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17
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Fromm JR, Tang C, Naresh KN. Predictors of risk of relapse in classic Hodgkin lymphoma. J Clin Pathol 2022; 76:414-417. [PMID: 36241372 DOI: 10.1136/jcp-2022-208552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 09/28/2022] [Indexed: 11/04/2022]
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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Affiliation(s)
- Jonathan R Fromm
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Claire Tang
- University of Washington, Seattle, Washington, USA
| | - Kikkeri N Naresh
- Pathology / Cancer Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
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18
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Miyawaki K, Sugio T. Lymphoma Microenvironment in DLBCL and PTCL-NOS: the key to uncovering heterogeneity and the potential for stratification. J Clin Exp Hematop 2022; 62:127-135. [PMID: 36171096 DOI: 10.3960/jslrt.22027] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) are the most common subtypes of mature B cell neoplasm and T/NK cell lymphoma, respectively. They share a commonality in that they are, by definition, highly heterogeneous populations. Recent studies are revealing more about the heterogeneity of these diseases, and at the same time, there is an active debate on how to stratify these heterogeneous diseases and make them useful in clinical practice. The various immune cells and non-cellular components surrounding lymphoma cells, i.e., the lymphoma microenvironment, have been the subject of intense research since the late 2000s, and much knowledge has been accumulated over the past decade. As a result, it has become clear that the lymphoma microenvironment, despite its paucity in tissues, significantly impacts the lymphoma pathogenesis and clinical behavior, such as its prognosis and response to therapy. In this article, we review the role of the lymphoma microenvironment in DLBCL and PTCL-NOS, with particular attention given to its impact on the prognosis and stratification.
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Affiliation(s)
- Kohta Miyawaki
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Takeshi Sugio
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
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19
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Durmo R, Donati B, Rebaud L, Cottereau AS, Ruffini A, Nizzoli ME, Ciavarella S, Vegliante MC, Nioche C, Meignan M, Merli F, Versari A, Ciarrocchi A, Buvat I, Luminari S. Prognostic value of lesion dissemination in doxorubicin, bleomycin, vinblastine, and dacarbazine-treated, interimPET-negative classical Hodgkin Lymphoma patients: A radio-genomic study. Hematol Oncol 2022; 40:645-657. [PMID: 35606338 PMCID: PMC9796042 DOI: 10.1002/hon.3025] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 05/16/2022] [Indexed: 12/30/2022]
Abstract
We evaluated the prognostic role of the largest distance between two lesions (Dmax), defined by positron emission tomography (PET) in a retrospective cohort of newly diagnosed classical Hodgkin Lymphoma (cHL) patients. We also explored the molecular bases underlying Dmax through a gene expression analysis of diagnostic biopsies. We included patients diagnosed with cHL from 2007 to 2020, initially treated with ABVD, with available baseline PET for review, and with at least two FDG avid lesions. Patients with available RNA from diagnostic biopsy were eligible for gene expression analysis. Dmax was deduced from the three-dimensional coordinates of the baseline metabolic tumor volume (MTV) and its effect on progression free survival (PFS) was evaluated. Gene expression profiles were correlated with Dmax and analyzed using CIBERSORTx algorithm to perform deconvolution. The study was conducted on 155 eligible cHL patients. Using its median value of 20 cm, Dmax was the only variable independently associated with PFS (HR = 2.70, 95% CI 1.1-6.63, pValue = 0.03) in multivariate analysis of PFS for all patients and for those with early complete metabolic response (iPET-). Among patients with iPET-low Dmax was associated with a 4-year PFS of 90% (95% CI 82.0-98.9) significantly better compared to high Dmax (4-year PFS 72.4%, 95% CI 61.9-84.6). From the analysis of gene expression profiles differences in Dmax were mostly associated with variations in the expression of microenvironmental components. In conclusion our results support tumor dissemination measured through Dmax as novel prognostic factor for cHL patients treated with ABVD.
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Affiliation(s)
- Rexhep Durmo
- Nuclear Medicine UnitAzienda USL‐IRCCSReggio EmiliaItaly,PhD Program in Clinical and Experimental Medicine (CEM)University of Modena and Reggio EmiliaModenaItaly
| | - Benedetta Donati
- Translational Research LaboratoryAzienda USL‐IRCCSReggio EmiliaItaly
| | - Louis Rebaud
- Laboratoire d’Imagerie Translationnelle en OncologieInstitut Curie, U1288 Inserm, PSLOrsayFrance,Siemens HealthineersSaint‐DenisFrance
| | | | | | | | - Sabino Ciavarella
- Hematology and Cell Therapy UnitIRCCS‐Istituto Tumori 'Giovanni Paolo II'BariItaly
| | | | - Christophe Nioche
- Laboratoire d’Imagerie Translationnelle en OncologieInstitut Curie, U1288 Inserm, PSLOrsayFrance
| | - Michel Meignan
- Lysa ImagingHenri Mondor University Hospital, AP‐HP, University Paris EastCreteilFrance
| | | | | | | | - Irene Buvat
- Laboratoire d’Imagerie Translationnelle en OncologieInstitut Curie, U1288 Inserm, PSLOrsayFrance
| | - Stefano Luminari
- Hematology UnitAzienda USL‐IRCCSReggio EmiliaItaly,Surgical, Medical and Dental Department of Morphological Sciences Related to Transplant, Oncology and Regenerative MedicineUniversity of Modena and Reggio EmiliaReggio EmiliaItaly
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20
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Zhao X, Ma Y, Bian H, Liu Z. CD20 expression is closely associated with Epstein–Barr virus infection and an inferior survival in nodular sclerosis classical Hodgkin lymphoma. Front Oncol 2022; 12:993768. [PMID: 36147921 PMCID: PMC9486205 DOI: 10.3389/fonc.2022.993768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 08/17/2022] [Indexed: 11/17/2022] Open
Abstract
Background Nodular sclerosis classical Hodgkin lymphoma (NSCHL) is a rare disease in which Epstein–Barr virus (EBV) and CD20 can be detected. The clinical significance of EBV infection, CD20 expression and their relationship are still unclear in NSCHL presently. The aim of this research was to systematically explore the clinical significance of EBV infection, expression of CD20 and their relationship in NSCHL. Methods 109 NSCHL patients diagnosed in Qingdao University’s Affiliated Hospital were chosen from January 2010 to July 2019, and the clinical and survival data of all patients were collected retrospectively. Results Among 109 patients, 33 patients were assigned to the group of EBV-positives, following the results of the EBV-encoded RNA (EBER1). Compared with EBV-negative group patients, those in the group of EBV-positive were older (P=0.004) and their β2-microglobulin (β2-MG) levels were higher (P=0.006). The CD20 positivity rate in the group of EBV-positive was substantially higher than that in the EBV-negative group (54.5% vs 27.6%, P=0.007). Among 109 patients, EBV+ and CD20+ double positive patients acquired the least overall survival (OS), and patients with EBV- and CD20- double negative had the best OS (P < 0.001). Although old age, gender, EBV infection and CD20 positive were the risk factors for OS in NSCHL, multivariate analysis showed that CD20 positivity was the only characteristic that showed to be an independent risk factor for OS in NSCHL patients. Conclusion CD20 was found to be strongly expressed in NSCHL patients who had been infected with EBV, and it was found to be an independent risk factor for NSCHL patients’ survival.
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Affiliation(s)
- Xia Zhao
- Department of Lymphoma, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yushuo Ma
- Department of Medicine, Medical College of Qingdao University, Qingdao, China
| | - Haiyan Bian
- Department of Medicine, Medical College of Qingdao University, Qingdao, China
| | - Zhihe Liu
- Department of Lymphoma, The Affiliated Hospital of Qingdao University, Qingdao, China
- *Correspondence: Zhihe Liu,
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21
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Zawati I, Adouni O, Manai M, Nagara M, Tacam M, Reduzzi C, Gamoudi A, Manai M. FOXP3+/CD68+ ratio within the tumor microenvironment may serve as a potential prognostic factor in classical Hodgkin lymphoma. Hum Immunol 2022; 83:843-856. [PMID: 36068099 DOI: 10.1016/j.humimm.2022.08.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 08/21/2022] [Accepted: 08/23/2022] [Indexed: 11/19/2022]
Abstract
Classical Hodgkin lymphoma (CHL) is characterized by extensive inflammatory immune cells, which predict the disease prognosis. Therefore, this study aimed to explore the significance of different tumor-infiltrated immune cells and subpopulation ratios observed in the tumor microenvironment of CHL, particularly relating to the disease's prognosis-focusing on overall survival (OS) and event-free survival (EFS). Utilizing immunohistochemistry, the quantification and exploration of selected immune cells' subsets, including CD3+, CD4+, CD8+, FOXP3+, CD20+, and CD68+ were conducted on 102 histological samples with primary CHL. Eosinophils were pathologically assessed. Besides, we determined the ratios between different tumor-infiltrated immune cells for each patient. Kaplan-Meier method and Cox regression modeling were used for survival analysis. We demonstrated that among all ratios and immune cells individually, only a higher FOXP3+/CD68+ ratio (≥1.36 cutoff) displayed a tendency towards a favorable OS (p = 0.057, HR = 0.43 [0.18-1.02]) and EFS (p = 0.067, HR = 0.44 [0.18-1.06]) using Cox regression modeling. Moreover, the Kaplan-Meier method showed an association of a higher FOXP3+/CD68+ ratio with a longer 5-years OS (p = 0.037) and a tendency to a better EFS (p = 0.051); however, neither the combined FOXP3+ and CD68+ nor FOXP3+ or CD68+ separately was correlated to the CHL survival. Together, these results demonstrated that the FOXP3+/CD68+ ratio could predict the outcomes of CHL, providing more informative significance than FOXP3+ and CD68+ combined or FOXP3+ and CD68+ individually and might be a potential indicator of risk stratification, which has an important value for guiding the clinical treatment.
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Affiliation(s)
- Imen Zawati
- Department of Immuno-Histo-Cytology, Salah Azaiez Institute, 1006 Tunis, Tunisia; Department of Biology, Mycology, Pathologies, and Biomarkers Laboratory (LR16ES05), Faculty of Sciences of Tunis, University of Tunis El Manar, 2092 Ariana, Tunisia.
| | - Olfa Adouni
- Department of Immuno-Histo-Cytology, Salah Azaiez Institute, 1006 Tunis, Tunisia; Department of Biology, Mycology, Pathologies, and Biomarkers Laboratory (LR16ES05), Faculty of Sciences of Tunis, University of Tunis El Manar, 2092 Ariana, Tunisia
| | - Maroua Manai
- Department of Immuno-Histo-Cytology, Salah Azaiez Institute, 1006 Tunis, Tunisia; Laboratory of Human Genetics (LR99ES10), Faculty of Medicine of Tunis, University of Tunis El Manar, 2092 Tunis, Tunisia; Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, 1300 York Ave, 10021 NY, NY, USA
| | - Majdi Nagara
- Inserm, UMR-S 1251, MMG, Faculty of Medicine Timone, Aix Marseille University, Marseille, France
| | - Moisis Tacam
- Department of OB/Gyn, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
| | - Carolina Reduzzi
- Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, 1300 York Ave, 10021 NY, NY, USA
| | - Amor Gamoudi
- Department of Immuno-Histo-Cytology, Salah Azaiez Institute, 1006 Tunis, Tunisia
| | - Mohamed Manai
- Department of Biology, Mycology, Pathologies, and Biomarkers Laboratory (LR16ES05), Faculty of Sciences of Tunis, University of Tunis El Manar, 2092 Ariana, Tunisia
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Cook MR, Dunleavy K. Targeting The Tumor Microenvironment in Lymphomas: Emerging Biological Insights and Therapeutic Strategies. Curr Oncol Rep 2022; 24:1121-1131. [DOI: 10.1007/s11912-022-01250-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/13/2022] [Indexed: 11/03/2022]
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23
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Friend BD, Muhsen IN, Patel S, Hill LC, Lulla P, Ramos CA, Pingali SR, Kamble RT, John TD, Salem B, Bhar S, Doherty EE, Craddock J, Sasa G, Wu M, Wang T, Martinez C, Krance RA, Heslop HE, Carrum G. Rituximab as adjunctive therapy to BEAM conditioning for autologous stem cell transplantation in Hodgkin lymphoma. Bone Marrow Transplant 2022; 57:579-585. [PMID: 35105965 DOI: 10.1038/s41409-022-01599-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 01/20/2022] [Accepted: 01/24/2022] [Indexed: 11/09/2022]
Abstract
While high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) leads to improved disease-free survival (DFS) for children and adults with relapsed/refractory Hodgkin lymphoma (HL), relapse remains the most frequent cause of mortality post-transplant. Rituximab has been successfully incorporated into regimens for other B-cell lymphomas, yet there have been limited studies of rituximab in HL patients. We hypothesized that adding rituximab to BEAM (carmustine, etoposide, cytarabine, melphalan) conditioning would reduce relapse risk in HL patients post-transplant. Here, we retrospectively review the outcomes of patients with relapsed/refractory HL who received rituximab in addition to BEAM. The primary outcome was DFS. Our cohort included 96 patients with a median age of 28 years (range, 6-76). Majority of patients (57%) were diagnosed with advanced (Stage III-IV) disease, and 62% were PET negative pre-transplant. DFS was 91.5% at 1 year [95% CI 86-98%], and 78% at 3 years [95% CI 68-88%]. NRM was 0% and 3.5% at 1-year [95% CI 0-3%] and 3-years [95% CI 0-8.5%], respectively. 25% of patients developed delayed neutropenia, with 7% requiring infection-related hospitalizations, and one death. We have demonstrated excellent outcomes for patients receiving rituximab with BEAM conditioning for relapsed/refractory HL. Future comparative studies are needed to better determine whether rituximab augments outcomes post-transplant.
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Affiliation(s)
- Brian D Friend
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.
| | - Ibrahim N Muhsen
- Department of Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Shreeya Patel
- Department of Pediatrics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - LaQuisa C Hill
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Premal Lulla
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Carlos A Ramos
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital, Houston, TX, USA
| | | | - Rammurti T Kamble
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Tami D John
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
| | - Baheyeldin Salem
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
| | - Saleh Bhar
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
| | - Erin E Doherty
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
| | - John Craddock
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
| | - Ghadir Sasa
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
| | - Mengfen Wu
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Tao Wang
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - Caridad Martinez
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
| | - Robert A Krance
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
| | - Helen E Heslop
- Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital, Houston, TX, USA
| | - George Carrum
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital, Houston, TX, USA
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24
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The Hodgkin Lymphoma Immune Microenvironment: Turning Bad News into Good. Cancers (Basel) 2022; 14:cancers14051360. [PMID: 35267668 PMCID: PMC8909875 DOI: 10.3390/cancers14051360] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 02/09/2022] [Accepted: 03/02/2022] [Indexed: 02/05/2023] Open
Abstract
The classic Hodgkin lymphoma (cHL) tumor microenvironment (TME) is by far the most abundant component of tumors and is responsible for most of their biological and clinical characteristics. Recent advances in our knowledge of these networks in cellular interactions allow us to understand that the neoplastic Hodgkin and Reed Sternberg (HRS) cells, although they are in the minority, are the main architects of this dysregulated immune milieu. Here, we review the major changes that have happened in recent years: from TME as a helpless bystander, reflecting an ineffective immune response, to a dynamic tumor-promoting and immunosuppressive element. The HRS cells promote survival through interconnected intrinsic and extrinsic alterations, boosting pro-tumoral signaling pathways through genetic aberrations and autocrine growth signals, in parallel with abnormal cytokine secretion for the recruitment and selection of the best cell partners for this immunosuppressive TME. In turn, cHL is already proving to be the perfect model with which to address an immune checkpoint blockade. Preliminary data demonstrate the utility of druggable key signaling pathways in this ensemble, such as JAK-STAT, NF-κB, and others. In addition, myriad biomarkers predicting a response await validation by new in situ multiplex analytical methods, single-cell gene expression, and other techniques. Together, these components will define the functional phenotypes with which we will elucidate the molecular pathogenesis of the disease and improve the survival of patients who are refractory to conventional therapies.
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Tao Y, Chen H, Zhou Y, He X, Qin Y, Liu P, Zhou S, Yang J, Zhou L, Zhang C, Yang S, Gui L, Shi Y. A new prognostic model including platelet/lymphocyte ratio and International Prognostic Score 3 for freedom from progression in patients with previously untreated advanced classical Hodgkin lymphoma. Asia Pac J Clin Oncol 2022; 18:e486-e494. [PMID: 35238169 DOI: 10.1111/ajco.13770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 02/06/2022] [Indexed: 11/25/2022]
Abstract
PURPOSE We aimed to develop a new risk stratification tool to predict freedom from progression (FFP) for newly diagnosed advanced classical Hodgkin lymphoma (cHL). METHODS We collected data from 386 patients with advanced cHL diagnosed between December 8, 2000 and October 29, 2018, and treated with curative intent with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or an ABVD-equivalent regimen. Cases were randomly divided into training and validation cohorts at a ratio of 7:3. The new model was constructed based on the results of Cox proportional hazards model in the training cohort. Comparisons of discrimination between the new model and other models in the training and validation cohorts for FFP prediction were measured by time-dependent area under curve (tAUC) and Harrell's C-index. Calibration plots were constructed to compare the consistency between the predicted and observed estimates of survival probability for the new model in the training and validation cohorts. RESULTS The new model (IPSPLR) composed of International Prognostic Score (IPS)-3 and platelet/lymphocyte ratio (PLR) provided four distinct risk groups. The IPSPLR showed better discriminative ability when compared with IPS-3 and IPS-7. The AUC of IPSPLR was consistently higher than that of IPS-3 and IPS-7 between 12 and 120 months. The C-index of the IPSPLR was higher than that of IPS-7 and IPS-3. The calibration plots showed an excellent agreement between the IPSPLR-predicted and observed estimates of 5-year FFP. CONCLUSION The IPSPLR is an easily used tool for FFP prediction for newly diagnosed advanced cHL. Validation of this tool in other large datasets is needed.
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Affiliation(s)
- Yunxia Tao
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Haizhu Chen
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Yu Zhou
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Xiaohu He
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Yan Qin
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Peng Liu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Shengyu Zhou
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Jianliang Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Liqiang Zhou
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Changgong Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Sheng Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Lin Gui
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Yuankai Shi
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
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Ingravallo G, Tamma R, Opinto G, Annese T, Gaudio F, Specchia G, Perrone T, Musto P, Cazzato G, Bellitti E, Capodiferro S, Maiorano E, Ribatti D. The Effect of the Tumor Microenvironment on Lymphoid Neoplasms Derived from B Cells. Diagnostics (Basel) 2022; 12:573. [PMID: 35328127 PMCID: PMC8947733 DOI: 10.3390/diagnostics12030573] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 02/17/2022] [Accepted: 02/22/2022] [Indexed: 02/07/2023] Open
Abstract
Lymphomas are characteristic tumors surrounded by an inflammatory microenvironment. The cells of the microenvironment are essential for the growth and survival of neoplastic cells and are recruited through the effect of cytokines/chemokines. Lymphomas include heterogeneous groups of neoplasms infiltrating various lymphoid structures which may arise from B lymphocytes, T lymphocytes, and natural killer (NK) cells at various stages of their differentiation state. In this review article, we analyze the literature data concerning the involvement of the tumor microenvironment (TME) in the progression of lymphomas and the recent advances in the analysis of microenvironment components in the most common forms: some mature B cell lymphoma neoplasms and classic Hodgkin lymphomas. The complex crosstalk between the TME and tumor cells led to the discovery of many mechanisms usable as molecular-targeted therapy through the control of diverse elements of the TME, varying from inhibitors of angiogenic cytokines and their receptors to the regulation of cells' activities and the novel immune checkpoint inhibitors.
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Affiliation(s)
- Giuseppe Ingravallo
- Section of Pathology, Department of Emergency and Organ Transplantation (DETO), University of Bari Aldo Moro, Policlinico-Piazza G. Cesare, 11, 70124 Bari, Italy; (E.B.); (E.M.)
| | - Roberto Tamma
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Policlinico-Piazza G. Cesare, 11, 70124 Bari, Italy; (T.A.); (D.R.)
| | - Giuseppina Opinto
- Haematology and Cell Therapy Unit, IRCCS-Istituto Tumori ‘Giovanni Paolo II’, Viale Orazio Flacco 65, 70124 Bari, Italy;
| | - Tiziana Annese
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Policlinico-Piazza G. Cesare, 11, 70124 Bari, Italy; (T.A.); (D.R.)
| | - Francesco Gaudio
- Hematology Section, Department of Emergency and Transplantation, University of Bari Medical School, 70124 Bari, Italy; (F.G.); (T.P.); (P.M.)
| | - Giorgina Specchia
- School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Tommasina Perrone
- Hematology Section, Department of Emergency and Transplantation, University of Bari Medical School, 70124 Bari, Italy; (F.G.); (T.P.); (P.M.)
| | - Pellegrino Musto
- Hematology Section, Department of Emergency and Transplantation, University of Bari Medical School, 70124 Bari, Italy; (F.G.); (T.P.); (P.M.)
| | - Gerardo Cazzato
- Section of Pathology, Department of Emergency and Organ Transplantation (DETO), University of Bari Aldo Moro, Policlinico-Piazza G. Cesare, 11, 70124 Bari, Italy; (E.B.); (E.M.)
| | - Emilio Bellitti
- Section of Pathology, Department of Emergency and Organ Transplantation (DETO), University of Bari Aldo Moro, Policlinico-Piazza G. Cesare, 11, 70124 Bari, Italy; (E.B.); (E.M.)
| | - Saverio Capodiferro
- Department of Interdisciplinary Medicine, University of Bari Aldo Moro, Policlinico-Piazza G. Cesare, 11, 70124 Bari, Italy;
| | - Eugenio Maiorano
- Section of Pathology, Department of Emergency and Organ Transplantation (DETO), University of Bari Aldo Moro, Policlinico-Piazza G. Cesare, 11, 70124 Bari, Italy; (E.B.); (E.M.)
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Policlinico-Piazza G. Cesare, 11, 70124 Bari, Italy; (T.A.); (D.R.)
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27
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Klimaszewska-Wiśniewska A, Buchholz K, Durślewicz J, Villodre ES, Gagat M, Grzanka D. SPDL1 Is an Independent Predictor of Patient Outcome in Colorectal Cancer. Int J Mol Sci 2022; 23:ijms23031819. [PMID: 35163739 PMCID: PMC8836361 DOI: 10.3390/ijms23031819] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/27/2022] [Accepted: 01/30/2022] [Indexed: 02/05/2023] Open
Abstract
Spindle Apparatus Coiled-Coil Protein 1 (SPDL1) is a relatively recently identified coiled-coil domain containing protein and an important determinant of DNA fidelity by ensuring faithful mitosis. Hence, SPDL1 is suspected to underlie genomic (in-)stability in human cancers, yet its exact roles in these diseases remain largely underexplored. Given that genomic instability (GIN) is a crucial feature in colorectal cancer (CRC), we primarily asked whether the expression of this protein may account for differences in clinicopathological features and survival rates of CRC patients. Protein expression was evaluated by immunohistochemistry in the institutional tissue microarray (TMA), and gene expression by the analysis of publicly available datasets. To place the prognostic relevance in a predicted biological context, gene co-expression set around SPDL1 identified by public data mining was annotated and assessed for enrichment in gene ontology (GO) categories, BRITE hierarchies, and Reactome pathways. The comparison with adjacent normal tissue revealed a high expression of SPDL1 protein in a subset of tumor cases (48.84%), and these had better prognosis than the SPDL1-low expression counterpart even after adjustment for multiple confounders. SPDL1-high expression within tumors was associated with a median 56-month survival advantage, but not with any clinicopathological characteristics of our cohort. In the TCGA cohort, SPDL1 was overexpressed in tumor tissue and positively associated with improved survival, chromosome instability phenotype, and various GIN markers. In addition to the genes critically involved in the cell cycle and mitosis, a gene set co-expressed with SPDL1 contained checkpoint members of both chromosome segregation and DNA replication, as well as those associated with defective DNA repair, and retrograde vesicle-mediated transport. In conclusion, SPDL1 is an independent predictor of CRC patient survival in a possible connection with chromosomal instability.
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Affiliation(s)
- Anna Klimaszewska-Wiśniewska
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland; (K.B.); (J.D.); (D.G.)
- Correspondence: ; Tel.: +48-52-585-42-00; Fax: +48-52-585-40-49
| | - Karolina Buchholz
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland; (K.B.); (J.D.); (D.G.)
- Department of Histology and Embryology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-092 Bydgoszcz, Poland;
| | - Justyna Durślewicz
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland; (K.B.); (J.D.); (D.G.)
| | - Emilly Schlee Villodre
- Department of Breast Medical Oncology and MD Anderson Morgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Maciej Gagat
- Department of Histology and Embryology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-092 Bydgoszcz, Poland;
| | - Dariusz Grzanka
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, 85-094 Bydgoszcz, Poland; (K.B.); (J.D.); (D.G.)
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Chen X, Kong H, Luo L, Han S, Lei T, Yu H, Guo N, Li C, Peng S, Dong X, Yang H, Wu M. High efficacy of PD-1 inhibitor after initial failure of PD-L1 inhibitor in Relapsed/Refractory classical Hodgkin Lymphoma. BMC Cancer 2022; 22:9. [PMID: 34980000 PMCID: PMC8722342 DOI: 10.1186/s12885-021-09028-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 11/17/2021] [Indexed: 01/15/2023] Open
Abstract
PURPOSE We sought to understand the clinical course and molecular phenotype of patients who showed disease progression after programmed cell death ligand 1 (PD-L1) inhibitor treatment but subsequently responded to PD-1 inhibitor treatment. We also explored the response to PD-1-axis targeted therapy of classical Hodgkin lymphoma (cHL) according to genetically driven PD-L1 and programmed cell death ligand 2 (PD-L2) expression. METHODS Five patients in a phase II clinical trial of CS1001 (PD-L1 inhibitor) for relapsed or refractory (R/R) cHL were retrospectively reviewed. Formalin-fixed, paraffin-embedded whole tissues from the five patients were evaluated for 9p24.1 genetic alterations based on FISH and the expression of PD-L1, PD-L2, PD-1, major histocompatibility complex (MHC) class I-II, and the tumor microenvironment factorsCD163 and FOXP3 in the microenvironmental niche, as revealed by multiplex immunofluorescence. RESULTS All five patients showed primary refractory disease during first-line treatment. Four patients received PD-1 inhibitor after dropping out of the clinical trial, and all demonstrated at least a partial response. The progression-free survival ranged from 7 to 28 months (median = 18 months), and 9p24.1 amplification was observed in all five patients at the PD-L1/PD-L2 locus. PD-L1 and PD-L2 were colocalized on Hodgkin Reed-Sternberg (HRS) cells in four of the five (80%) patients. There was differential expression of PD-L1 and PD-L2 in cells in the tumor microenvironment in cHL, especially in HRS cells, background cells and tumor-associated macrophages. CONCLUSIONS PD-L1 monotherapy may not be sufficient to block the PD-1 pathway; PD-L2 was expressed in HRS and background cells in cHL. The immunologic function of the PD-L2 pathway in anti-tumor activity may be underestimated in R/R cHL. Further study is needed to elucidate the anti-tumor mechanism of PD-1 inhibitor and PD-L1 inhibitor treatment.
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Affiliation(s)
- Xi Chen
- Department of Lymphoma, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Haiying Kong
- Department of Pharmacy, Zhejiang Medical and Health Group Hangzhou Hospital (Hangzhou Hanggang Hospital), Hangzhou, China
| | - Linxiang Luo
- Department of Hematology, Zhejiang Quhua Hospital, Quhua, China
| | - Shuiyun Han
- Department of Lymphoma, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Tao Lei
- Department of Lymphoma, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Haifeng Yu
- Department of Lymphoma, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Na Guo
- Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China.,Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), No. 1 Banshan East Road, Hangzhou, China
| | - Cong Li
- Department of Lymphoma, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Shuailing Peng
- Department of Lymphoma, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.,Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Xiaowu Dong
- Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Haiyan Yang
- Department of Lymphoma, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China. .,Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China.
| | - Meijuan Wu
- Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China. .,Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), No. 1 Banshan East Road, Hangzhou, China.
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Checkpoint protein expression in the tumor microenvironment defines the outcome of classical Hodgkin lymphoma patients. Blood Adv 2021; 6:1919-1931. [PMID: 34941990 PMCID: PMC8941476 DOI: 10.1182/bloodadvances.2021006189] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 11/28/2021] [Indexed: 11/20/2022] Open
Abstract
Emerging evidence indicates a major impact for the tumor microenvironment (TME) and immune escape in the pathogenesis and clinical course of classical Hodgkin lymphoma (cHL). We used gene expression profiling (n=88), CIBERSORT, and multiplex immunohistochemistry (n=131) to characterize the immunoprofile of cHL TME, and correlated the findings with survival. Gene expression analysis divided tumors into subgroups with T cell-inflamed and non-inflamed TME. Several macrophage-related genes were upregulated in samples with the non-T cell-inflamed TME, and based on the immune cell proportions, the samples clustered according to the content of T cells and macrophages. A cluster with high proportions of checkpoint protein (PD-1, PD-L1, IDO-1, LAG-3, and TIM-3) positive immune cells translated to unfavorable overall survival (OS) (5-year OS 76% vs. 96%, P=0.010), and remained as an independent prognostic factor for OS in multivariable analysis (HR 4.34, 95% CI 1.05-17.91, P=0.043). cHLs with high proportions of checkpoint proteins overexpressed genes coding for cytolytic factors, proposing paradoxically that they were immunologically active. This checkpoint molecule gene signature translated to inferior survival in a validation cohort of 290 diagnostic cHL samples (P<0.001) and in an expansion cohort of 84 cHL relapse samples (P=0.048). Our findings demonstrate the impact of T cell- and macrophage-mediated checkpoint system on the survival of patients with cHL.
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Brice P, de Kerviler E, Friedberg JW. Classical Hodgkin lymphoma. Lancet 2021; 398:1518-1527. [PMID: 33493434 DOI: 10.1016/s0140-6736(20)32207-8] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 06/11/2020] [Accepted: 10/15/2020] [Indexed: 11/29/2022]
Abstract
Classical Hodgkin lymphoma is one of the more frequent lymphomas and is generally considered a highly curable disease with standard first-line chemotherapy and radiotherapy in some cases. Despite these outstanding results, major problems remain unresolved. First, there are still patients who will not be cured with front-line regimens and, second, many patients who are cured of classical Hodgkin lymphoma continue to die prematurely due to the late toxic effects of their therapy. Because the median age of patients with classical Hodgkin lymphoma is in the mid-30s, the disease's impact on the number of years lost from productive life is remarkable. In recent years, the gold standard of chemotherapy (often combined with radiotherapy) has changed, with the approval of immunotherapy mostly in relapse settings.
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Affiliation(s)
- Pauline Brice
- Department of Oncohaematology, Hôpital saint Louis APHP, Université Paris 7, Paris, France.
| | - Eric de Kerviler
- Department of Radiology, Hôpital saint Louis APHP, Université Paris 7, Paris, France
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Single-cell profiling reveals the importance of CXCL13/CXCR5 axis biology in lymphocyte-rich classic Hodgkin lymphoma. Proc Natl Acad Sci U S A 2021; 118:2105822118. [PMID: 34615710 PMCID: PMC8521678 DOI: 10.1073/pnas.2105822118] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/17/2021] [Indexed: 11/18/2022] Open
Abstract
Lymphocyte-rich classic Hodgkin lymphoma (LR-CHL) is a rare subtype of Hodgkin lymphoma. Recent technical advances have allowed for the characterization of specific cross-talk mechanisms between malignant Hodgkin Reed-Sternberg (HRS) cells and different normal immune cells in the tumor microenvironment (TME) of CHL. However, the TME of LR-CHL has not yet been characterized at single-cell resolution. Here, using single-cell RNA sequencing (scRNA-seq), we examined the immune cell profile of 8 cell suspension samples of LR-CHL in comparison to 20 samples of the mixed cellularity (MC, 9 cases) and nodular sclerosis (NS, 11 cases) subtypes of CHL, as well as 5 reactive lymph node controls. We also performed multicolor immunofluorescence (MC-IF) on tissue microarrays from the same patients and an independent validation cohort of 31 pretreatment LR-CHL samples. ScRNA-seq analysis identified a unique CD4+ helper T cell subset in LR-CHL characterized by high expression of Chemokine C-X-C motif ligand 13 (CXCL13) and PD-1. PD-1+CXCL13+ T cells were significantly enriched in LR-CHL compared to other CHL subtypes, and spatial analyses revealed that in 46% of the LR-CHL cases these cells formed rosettes surrounding HRS cells. MC-IF analysis revealed CXCR5+ normal B cells in close proximity to CXCL13+ T cells at significantly higher levels in LR-CHL. Moreover, the abundance of PD-1+CXCL13+ T cells in the TME was significantly associated with shorter progression-free survival in LR-CHL (P = 0.032). Taken together, our findings strongly suggest the pathogenic importance of the CXCL13/CXCR5 axis and PD-1+CXCL13+ T cells as a treatment target in LR-CHL.
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Opinto G, Agostinelli C, Ciavarella S, Guarini A, Maiorano E, Ingravallo G. Hodgkin Lymphoma: A Special Microenvironment. J Clin Med 2021; 10:4665. [PMID: 34682791 PMCID: PMC8541076 DOI: 10.3390/jcm10204665] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 09/18/2021] [Accepted: 09/28/2021] [Indexed: 12/11/2022] Open
Abstract
Classical Hodgkin's lymphoma (cHL) is one of the most particular lymphomas for the few tumor cells surrounded by an inflammatory microenvironment. Reed-Sternberg (RS) and Hodgkin (H) cells reprogram and evade antitumor mechanisms of the normal cells present in the microenvironment. The cells of microenvironment are essential for growth and survival of the RS/H cells and are recruited through the effect of cytokines/chemokines. We summarize recent advances in gene expression profiling (GEP) analysis applied to study microenvironment component in cHL. We also describe the main therapies that target not only the neoplastic cells but also the cellular components of the background.
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Affiliation(s)
- Giuseppina Opinto
- Haematology and Cell Therapy Unit, IRCCS-Istituto Tumori ‘Giovanni Paolo II’, 70124 Bari, Italy; (G.O.); (S.C.); (A.G.)
| | - Claudio Agostinelli
- Haematopathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, Italy
| | - Sabino Ciavarella
- Haematology and Cell Therapy Unit, IRCCS-Istituto Tumori ‘Giovanni Paolo II’, 70124 Bari, Italy; (G.O.); (S.C.); (A.G.)
| | - Attilio Guarini
- Haematology and Cell Therapy Unit, IRCCS-Istituto Tumori ‘Giovanni Paolo II’, 70124 Bari, Italy; (G.O.); (S.C.); (A.G.)
| | - Eugenio Maiorano
- Section of Pathology, Department of Emergency and Organ Transplantation (DETO), University of Bari Aldo Moro, 70124 Bari, Italy;
| | - Giuseppe Ingravallo
- Section of Pathology, Department of Emergency and Organ Transplantation (DETO), University of Bari Aldo Moro, 70124 Bari, Italy;
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Immune Microenvironment Features and Dynamics in Hodgkin Lymphoma. Cancers (Basel) 2021; 13:cancers13143634. [PMID: 34298847 PMCID: PMC8304929 DOI: 10.3390/cancers13143634] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 07/12/2021] [Accepted: 07/14/2021] [Indexed: 01/01/2023] Open
Abstract
Simple Summary As happens in all neoplasms, the many reciprocal interactions taking place between neoplastic cells and the other reactive cells impact the course of the disease. Hodgkin Lymphoma is an haematologic malignancy where most of the pathological tissue is indeed composed by reactive cells and few neoplastic cells. Consequently, it represents an interesting subject for the description of the neoplastic and non-neoplastic cells interaction. In this review we report and discuss the more recent findings of microenvironmental studies about this disease. Abstract Classical Hodgkin’s lymphoma (cHL) accounts for 10% of all lymphoma diagnosis. The peculiar feature of the disease is the presence of large multinucleated Reed–Sternberg and mononuclear Hodgkin cells interspersed with a reactive microenvironment (ME). Due to the production of a large number of cytokines, Hodgkin cells (HCs) and Hodgkin Reed–Sternberg cells (HRSCs) attract and favour the expansion of different immune cell populations, modifying their functional status in order to receive prosurvival stimuli and to turn off the antitumour immune response. To this purpose HRSCs shape a biological niche by organizing the spatial distribution of cells in the ME. This review will highlight the contribution of the ME in the pathogenesis and prognosis of cHL and its role as a possible therapeutic target.
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Cencini E, Fabbri A, Sicuranza A, Gozzetti A, Bocchia M. The Role of Tumor-Associated Macrophages in Hematologic Malignancies. Cancers (Basel) 2021; 13:cancers13143597. [PMID: 34298810 PMCID: PMC8304632 DOI: 10.3390/cancers13143597] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/11/2021] [Accepted: 07/15/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Tumor-associated macrophages (TAM) represent a leading component of the tumor microenvironment in hematologic malignancies. TAM could display antitumor activity or, conversely, could contribute to tumor growth and survival, depending on their polarization. TAM are polarized towards form M1, with a pro-inflammatory phenotype and an antineoplastic activity, or M2, with an alternately activated phenotype, associated with a poor outcome in patients presenting with leukemia, lymphoma or multiple myeloma. The molecular mechanisms of TAM in different types of hematologic malignancies are different due to the peculiar microenvironment of each disease. TAM could contribute to tumor progression, reduced apoptosis and angiogenesis; a different TAM polarization could explain a reduced treatment response in patients with a similar disease subtype. The aim of our review is to better define the role of TAM in patients with leukemia, lymphoma or multiple myeloma. Finally, we would like to focus on TAM as a possible target for antineoplastic therapy. Abstract The tumor microenvironment includes dendritic cells, T-cytotoxic, T-helper, reactive B-lymphoid cells and macrophages; these reactive cells could interplay with malignant cells and promote tumor growth and survival. Among its cellular components, tumor-associated macrophages (TAM) represent a component of the innate immune system and play an important role, especially in hematologic malignancies. Depending on the stimuli that trigger their activation, TAM are polarized towards form M1, contributing to antitumor responses, or M2, associated with tumor progression. Many studies demonstrated a correlation between TAM, disease progression and the patient’s outcome in lymphoproliferative neoplasms, such as Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL), even if with conflicting results. A critical hurdle to overcome is surely represented by the heterogeneity in the choice of the optimal markers and methods used for TAM analysis (gene-expression profile vs. immunohistochemistry, CD163vs. CD68vs. CD163/CD68 double-positive cells). TAM have been recently linked to the development and progression of multiple myeloma and leukemia, with a critical role in the homing of malignant cells, drug resistance, immune suppression and angiogenesis. As such, this review will summarize the role of TAM in different hematologic malignancies, focusing on the complex interplay between TAM and tumor cells, the prognostic value of TAM and the possible TAM-targeted therapeutic strategies.
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Jachimowicz RD, Pieper L, Reinke S, Gontarewicz A, Plütschow A, Haverkamp H, Frauenfeld L, Fend F, Overkamp M, Jochims F, Thorns C, Leo Hansmann M, Möller P, Rosenwald A, Stein H, Reinhardt HC, Borchmann P, von Tresckow B, Engert A, Klapper W. Whole-slide image analysis of the tumor microenvironment identifies low B-cell content as a predictor of adverse outcome in patients with advanced-stage classical Hodgkin lymphoma treated with BEACOPP. Haematologica 2021; 106:1684-1692. [PMID: 32381573 PMCID: PMC8168506 DOI: 10.3324/haematol.2019.243287] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Indexed: 01/18/2023] Open
Abstract
Asubset of patients with advanced-stage classical Hodgkin lymphoma (cHL) relapse or progress following standard treatment. Given their dismal prognosis, identifying this group of patients upfront represents an important medical need. While prior research has identified characteristics of the tumor microenvironment, which are associated with cHL outcomes, biomarkers that are developed and validated in this high-risk group are still lacking. Here, we applied wholeslide image analysis (WSI), a quantitative, large-scale assessment of tumor composition that utilizes conventional histopathology slides. We conducted WSI on pre-treatment biopsies from 340 patients with advanced-stage cHL enrolled in the HD12 and HD15 trials of the German Hodgkin Study Group (GHSG), and tested our results in a validation cohort of 147 advanced-stage cHL patients within the GHSG HD18 trial. All patients were treated with BEACOPP-based regimens. By quantifying T cells, B cells, Hodgkin and Reed-Sternberg cells and macrophages with WSI, 80% of all cells in the tumor tissue were identified. Crucially, low B-cell count was associated with significantly reduced progression-free survival and overall survival, while the content of T cells, macrophages and Hodgkin and Reed-Sternberg cells was not associated with the risk of progression or relapse in the study cohort. We further validated low Bcell content as a prognostic factor for progression-free survival and overall survival in the validation cohort and demonstrated the good interobserver agreement of WSI. WSI may represent a key tool for risk stratification of advanced-stage cHL and can easily be added to the standard diagnostic histopathology work-up.
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Affiliation(s)
| | - Luise Pieper
- University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany
| | - Sarah Reinke
- University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany
| | - Artur Gontarewicz
- University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany
| | - Annette Plütschow
- University of Cologneand University Hospital Cologne, German Hodgkin Study Group, Germany
| | - Heinz Haverkamp
- University of Cologneand University Hospital Cologne, German Hodgkin Study Group, Germany
| | | | - Falko Fend
- Department of Pathology, University of Tübingen, Germany
| | | | - Franziska Jochims
- University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany
| | - Christoph Thorns
- Department of Pathology, University Hospital Schleswig-Holstein, University of Lübeck, Germany
| | | | - Peter Möller
- Department of Pathology, University Hospital Ulm, Germany
| | - Andreas Rosenwald
- Institute of Pathology, University of Würzburg, Comprehensive Cancer Center Mainfranken, Germany
| | | | | | - Peter Borchmann
- University of Cologne, German Hodgkin Study Group, Cologne, Germany
| | | | - Andreas Engert
- University of Cologne, German Hodgkin Study Group, Cologne, Germany
| | - Wolfram Klapper
- University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany
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Tobin JWD, Bednarska K, Campbell A, Keane C. PD-1 and LAG-3 Checkpoint Blockade: Potential Avenues for Therapy in B-Cell Lymphoma. Cells 2021; 10:cells10051152. [PMID: 34068762 PMCID: PMC8151045 DOI: 10.3390/cells10051152] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 05/04/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023] Open
Abstract
The dependence of cancer on an immunotolerant tumor microenvironment (TME) is well established. Immunotherapies that overcome tumor-induced immune suppression have been central to recent advancements in oncology. This is highlighted by the success of agents that interrupt PD-1 mediated immune suppression in a range of cancers. However, while PD-1 blockade has been paradigm-shifting in many malignancies, the majority of cancers show high rates of primary resistance to this approach. This has led to a rapid expansion in therapeutic targeting of other immune checkpoint molecules to provide combination immune checkpoint blockade (ICB), with one such promising approach is blockade of Lymphocyte Activation Gene 3 (LAG-3). Clinically, lymphoproliferative disorders show a wide spectrum of responses to ICB. Specific subtypes including classical Hodgkin lymphoma have demonstrated striking efficacy with anti-PD-1 therapy. Conversely, early trials of ICB have been relatively disappointing in common subtypes of Non-Hodgkin lymphoma. In this review, we describe the TME of common lymphoma subtypes with an emphasis on the role of prominent immune checkpoint molecules PD-1 and LAG3. We will also discuss current clinical evidence for ICB in lymphoma and highlight key areas for further investigation where synergistic dual checkpoint blockade of LAG-3 and PD-1 could be used to overcome ICB resistance.
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Affiliation(s)
- Joshua W. D. Tobin
- Mater Research Institute, University of Queensland, Brisbane, QLD 4102, Australia; (J.W.D.T.); (K.B.)
- Department of Haematology, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia;
| | - Karolina Bednarska
- Mater Research Institute, University of Queensland, Brisbane, QLD 4102, Australia; (J.W.D.T.); (K.B.)
| | - Ashlea Campbell
- Department of Haematology, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia;
| | - Colm Keane
- Mater Research Institute, University of Queensland, Brisbane, QLD 4102, Australia; (J.W.D.T.); (K.B.)
- Department of Haematology, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia;
- Correspondence: ; Tel.: +617-3443-7912
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Li WX, Dai SX, An SQ, Sun T, Liu J, Wang J, Liu LG, Xun Y, Yang H, Fan LX, Zhang XL, Liao WQ, You H, Tamagnone L, Liu F, Huang JF, Liu D. Transcriptome integration analysis and specific diagnosis model construction for Hodgkin's lymphoma, diffuse large B-cell lymphoma, and mantle cell lymphoma. Aging (Albany NY) 2021; 13:11833-11859. [PMID: 33885377 PMCID: PMC8109084 DOI: 10.18632/aging.202882] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 03/02/2021] [Indexed: 01/20/2023]
Abstract
Transcriptome differences between Hodgkin's lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), and mantle cell lymphoma (MCL), which are all derived from B cell, remained unclear. This study aimed to construct lymphoma-specific diagnostic models by screening lymphoma marker genes. Transcriptome data of HL, DLBCL, and MCL were obtained from public databases. Lymphoma marker genes were screened by comparing cases and controls as well as the intergroup differences among lymphomas. A total of 9 HL marker genes, 7 DLBCL marker genes, and 4 MCL marker genes were screened in this study. Most HL marker genes were upregulated, whereas DLBCL and MCL marker genes were downregulated compared to controls. The optimal HL-specific diagnostic model contains one marker gene (MYH2) with an AUC of 0.901. The optimal DLBCL-specific diagnostic model contains 7 marker genes (LIPF, CCDC144B, PRO2964, PHF1, SFTPA2, NTS, and HP) with an AUC of 0.951. The optimal MCL-specific diagnostic model contains 3 marker genes (IGLV3-19, IGKV4-1, and PRB3) with an AUC of 0.843. The present study reveals the transcriptome data-based differences between HL, DLBCL, and MCL, when combined with other clinical markers, may help the clinical diagnosis and prognosis.
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Affiliation(s)
- Wen-Xing Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong, China
| | - Shao-Xing Dai
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - San-Qi An
- Biosafety Level-3 Laboratory, Life Sciences Institute & Guangxi Key Laboratory of AIDS Prevention and Treatment & Guangxi Collaborative Innovation Center for Biomedicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Tingting Sun
- National School of Development, Peking University, Beijing 100871, China
| | - Justin Liu
- Department of Statistics, University of California, Riverside, CA 92521, USA
| | - Jun Wang
- Foshan Stomatology Hospital, School of Medicine, Foshan University, Foshan, Guangdong, China
| | | | - Yang Xun
- Foshan Stomatology Hospital, School of Medicine, Foshan University, Foshan, Guangdong, China
| | - Hua Yang
- Foshan Stomatology Hospital, School of Medicine, Foshan University, Foshan, Guangdong, China
| | - Li-Xia Fan
- Foshan Stomatology Hospital, School of Medicine, Foshan University, Foshan, Guangdong, China
| | - Xiao-Li Zhang
- Foshan Stomatology Hospital, School of Medicine, Foshan University, Foshan, Guangdong, China
| | - Wan-Qin Liao
- Foshan Stomatology Hospital, School of Medicine, Foshan University, Foshan, Guangdong, China
| | - Hua You
- Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Luca Tamagnone
- Istituto di Istologia ed Embriologia, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Fang Liu
- Foshan Stomatology Hospital, School of Medicine, Foshan University, Foshan, Guangdong, China
| | - Jing-Fei Huang
- Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
| | - Dahai Liu
- Foshan Stomatology Hospital, School of Medicine, Foshan University, Foshan, Guangdong, China
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Liu H, Li Y, Qu YD, Zhao JJ, Zheng ZW, Jiao XL, Zhang J. Construction of a clinical survival prognostic model for middle-aged and elderly patients with stage III rectal adenocarcinoma. World J Clin Cases 2021; 9:1563-1579. [PMID: 33728300 PMCID: PMC7942048 DOI: 10.12998/wjcc.v9.i7.1563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 11/10/2020] [Accepted: 12/16/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Nomograms for prognosis prediction in colorectal cancer patients are few, and prognostic indicators differ with age.
AIM To construct a new nomogram survival prediction tool for middle-aged and elderly patients with stage III rectal adenocarcinoma.
METHODS A total of 2773 eligible patients were divided into the training cohort (70%) and the validation cohort (30%). Optimal cutoff values were calculated using the X-tile software for continuous variables. Univariate and multivariate Cox proportional hazards regression analyses were used to determine overall survival (OS) and cancer-specific survival (CSS)-related prognostic factors. Two nomograms were successfully constructed. The discriminant and predictive ability and clinical usefulness of the model were also assessed by multiple methods of analysis.
RESULTS The 95%CI in the training group was 0.719 (0.690-0.749) and 0.733 (0.702-0.74), while that in the validation group was 0.739 (0.696-0.782) and 0.750 (0.701-0.800) for the OS and CSS nomogram prediction models, respectively. In the validation group, the AUC of the three-year survival rate was 0.762 and 0.770, while the AUC of the five-year survival rate was 0.722 and 0.744 for the OS and CSS nomograms, respectively. The nomogram distinguishes all-cause mortality from cancer-specific mortality in patients with different risk grades. The time-dependent AUC and decision curve analysis showed that the nomogram had good clinical predictive ability and decision efficacy and was significantly better than the tumor-node-metastases staging system.
CONCLUSION The survival prediction model constructed in this study is helpful in evaluating the prognosis of patients and can aid physicians in clinical diagnosis and treatment.
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Affiliation(s)
- Hao Liu
- Department of Colonrectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Yu Li
- Department of Colonrectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Yi-Dan Qu
- Rheumatology and Immunology Department, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Jun-Jiang Zhao
- Department of Colonrectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Zi-Wen Zheng
- Department of Colonrectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Xue-Long Jiao
- Department of Colonrectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Jian Zhang
- Department of Colonrectal Surgery, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
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Grover NS, Tschernia N, Dotti G, Savoldo B. Extending the Promise of Chimeric Antigen Receptor T-Cell Therapy Beyond Targeting CD19 + Tumors. J Clin Oncol 2021; 39:499-513. [PMID: 33434072 PMCID: PMC8462586 DOI: 10.1200/jco.20.01738] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/09/2020] [Indexed: 01/24/2023] Open
Affiliation(s)
- Natalie S. Grover
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC
- Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Nicholas Tschernia
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC
- Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Gianpietro Dotti
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC
- Departments of Immunology and Microbiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Barbara Savoldo
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC
- Department of Pediatrics, The University of North Carolina at Chapel Hill, Chapel Hill, NC
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40
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Antel K, Chetty D, Oosthuizen J, Mohamed Z, Van der Vyver L, Verburgh E. CD68-positive tumour associated macrophages, PD-L1 expression, and EBV latent infection in a high HIV-prevalent South African cohort of Hodgkin lymphoma patients. Pathology 2021; 53:628-634. [PMID: 33558066 DOI: 10.1016/j.pathol.2020.11.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 09/30/2020] [Accepted: 11/02/2020] [Indexed: 10/22/2022]
Abstract
A higher proportion of CD68-positive tumour associated macrophages (TAMs) has been associated with poorer outcomes in HIV-negative patients with Hodgkin lymphoma (HL), but whether this is true in HIV-positive patients with HL is not known. In this study, we investigated the number of CD68-positive TAMs and expression of programmed cell death-ligand 1 (PD-L1) in lymph node specimens from HL patients and correlated expression with clinical features (HIV status, disease severity and survival) and histopathological features (EBV latent positivity and subtype of HL). We stained archived lymph node specimens from 77 patients diagnosed with HL for CD68 and PD-L1. Stains were graded as: CD68 low (≤25%), CD68 high (>25%), PD-L1 low (≤50%), and PD-L1 high (>50%). Expression levels were correlated with the clinical and histopathological features using bivariate and multivariate analyses. Survival was analysed by overall and progression-free survival. Thirty-four of the 77 included patients (44%) were HIV-positive. EBV latency was detected in 97% of HIV-positive HL patients and in 14% of HIV-negative HL patients. A high CD68 score was associated with lower median haemoglobin levels (9.4 vs 11.4 g/dL; p=0.02), platelet numbers (262 vs 424 cells ×109/L; p=0.01), and lymphocyte numbers (0.99 vs 1.70 cells ×109/L, p=0.01) and a trend towards advanced disease (international prognostic score ≥4; hazard ratio 2.4; confidence interval 0.89-6.47; p=0.08). HIV status did not affect CD68 or PD-L1 expression. A higher proportion of CD68-positive TAMs was found in samples that were EBV-positive. HIV positivity and EBV negativity correlated with poorer survival. CD68 and PD-L1 expression were not predictive of survival. High CD68 expression was associated with EBV positivity but not HIV positivity and did not predict adverse outcomes. PD-L1 expression was unaffected by HIV status or EBV positivity and did predict adverse outcomes.
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Affiliation(s)
- Katherine Antel
- Division of Clinical Haematology, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa.
| | - D Chetty
- Division of Anatomical Pathology, Department of Pathology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, Groote Schuur Hospital, Cape Town, South Africa
| | - J Oosthuizen
- Division of Clinical Haematology, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
| | - Z Mohamed
- Department of Radiation Oncology, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
| | - L Van der Vyver
- Division of Clinical Haematology, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
| | - E Verburgh
- Division of Clinical Haematology, Department of Medicine, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
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41
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Aoki T, Savage KJ, Steidl C. Biology in Practice: Harnessing the Curative Potential of the Immune System in Lymphoid Cancers. J Clin Oncol 2021; 39:346-360. [PMID: 33434057 DOI: 10.1200/jco.20.01761] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Affiliation(s)
- Tomohiro Aoki
- Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Kerry J Savage
- Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.,Department of Medical Oncology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Christian Steidl
- Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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42
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Defining the Inflammatory Plasma Proteome in Pediatric Hodgkin Lymphoma. Cancers (Basel) 2020; 12:cancers12123603. [PMID: 33276546 PMCID: PMC7761312 DOI: 10.3390/cancers12123603] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/24/2020] [Accepted: 11/27/2020] [Indexed: 01/08/2023] Open
Abstract
Simple Summary Hodgkin lymphoma (HL) is a common type of cancer that is characterized by rare, malignant cells among an inflammatory microenvironment. Specific systemic, inflammatory plasma proteins have demonstrated prognostic significance in adult HL; however, systemic inflammation has not been well-characterized in childhood HL. The aim of our study was to better define the inflammatory pre-therapy plasma proteome and identify plasma proteins associated with clinical features of childhood HL. We measured plasma concentrations of 135 proteins in 56 pediatric subjects with newly diagnosed HL and 47 healthy pediatric controls. We found that the plasma protein profile was distinct from controls, and unique proteins were associated with high-risk disease (IL-10, TNF-α, IFN-γ, IL-8), slow early therapy response (CCL13, IFN-λ1, IL-8), and relapse (TNFSF10). These proteins could be used to improve risk stratification, and thus optimize outcomes and minimize unnecessary toxic exposures for those with childhood HL. Abstract Hodgkin lymphoma (HL) histopathology is characterized by rare malignant Reed–Sternberg cells among an inflammatory infiltrate. We hypothesized that characteristics of inflammation in pediatric HL lesions would be reflected by the levels of inflammatory cytokines or chemokines in pre-therapy plasma of children with HL. The study objectives were to better define the inflammatory pre-therapy plasma proteome and identify plasma biomarkers associated with extent of disease and clinical outcomes in pediatric HL. Pre-therapy plasma samples were obtained from pediatric subjects with newly diagnosed HL and healthy pediatric controls. Plasma concentrations of 135 cytokines/chemokines were measured with the Luminex platform. Associations between protein concentration and disease characteristics were determined using multivariate permutation tests with false discovery control. Fifty-six subjects with HL (mean age: 13 years, range 3–18) and 47 controls were analyzed. The cytokine/chemokine profiles of subjects with HL were distinct from controls, and unique cytokines/chemokines were associated with high-risk disease (IL-10, TNF-α, IFN-γ, IL-8) and slow early response (CCL13, IFN-λ1, IL-8). TNFSF10 was significantly elevated among those who ultimately relapsed and was significantly associated with worse event-free survival. These biomarkers could be incorporated into biologically based risk stratification to optimize outcomes and minimize toxicities in pediatric HL.
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43
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Li W. Letter to the Editor: Protein Disulfide Isomerase Family A Member 3 Pseudogene 1 Level Could Predict Recurrence-Free Survival in Hepatocellular Carcinoma: Reliable? Hepatology 2020; 72:1887. [PMID: 32378221 DOI: 10.1002/hep.31299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Affiliation(s)
- Weizheng Li
- Department of Gastroenterology, Maoming People's Hospital, Maoming, China
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44
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Peng F, Qin Y, Mu S, Li J, Ai L, Hu Y. Prognostic role of regulatory T cells in lymphoma: a systematic review and meta-analysis. J Cancer Res Clin Oncol 2020; 146:3123-3135. [PMID: 32995955 DOI: 10.1007/s00432-020-03398-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 09/16/2020] [Indexed: 12/14/2022]
Abstract
PURPOSE The regulatory T cells (Tregs) are a subpopulation of lymphocytes that suppress the immune responses. The prognostic value of Tregs in lymphoma patients remains controversial. Thus, we conducted this meta-analysis to clarify the role of Tregs in the prognosis of lymphoma patients. METHODS We searched PubMed, Embase, and Web of Science to obtain eligible studies that evaluated the prognostic factor of Tregs for lymphoma patients. Hazards ratios (HRs) with the matching 95% confidence intervals (95%CIs) were merged to estimate the prognostic value of Tregs. RESULTS We finally retrieved 23 eligible studies, including a total of 2269 patients. The overall pooled analysis on all types of lymphomas showed that Tregs had a significantly positive association with prolonged overall survival (OS) (HR = 0.633, 95% CI 0.528-0.758) and progression-free survival (PFS) (HR = 0.451, 95% CI 0.261-0.779). Subgroup analysis indicated that high Tregs were significantly correlated with longer OS in Hodgkin lymphoma, diffuse large B cell lymphoma, and natural killer/T cell lymphoma. However, there was no significant association of Tregs with T cell lymphoma and follicular lymphoma. CONCLUSIONS Increased Tregs indicates a better prognosis for patients with lymphoma. Tregs could be used as a valuable prognostic biomarker of lymphoma patients.
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Affiliation(s)
- Fei Peng
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei, China
| | - You Qin
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shidai Mu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei, China
| | - Jingwen Li
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei, China
| | - Lisha Ai
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei, China.
| | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan, 430022, Hubei, China. .,Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Abstract
Hodgkin lymphoma (HL) is a B cell lymphoma characterized by few malignant cells and numerous immune effector cells in the tumour microenvironment. The incidence of HL is highest in adolescents and young adults, although HL can affect elderly individuals. Diagnosis is based on histological and immunohistochemical analyses of tissue from a lymph node biopsy; the tissue morphology and antigen expression profile enable classification into one of the four types of classic HL (nodular sclerosis, mixed cellularity, lymphocyte-depleted or lymphocyte-rich HL), which account for the majority of cases, or nodular lymphocyte-predominant HL. Although uncommon, HL remains a crucial test case for progress in cancer treatment. HL was among the first systemic neoplasms shown to be curable with radiation therapy and multiagent chemotherapy. The goal of multimodality therapy is to minimize lifelong residual treatment-associated toxicity while maintaining high levels of effectiveness. Recurrent or refractory disease can be effectively treated or cured with high-dose chemotherapy followed by autologous haematopoietic stem cell transplantation, and prospective trials have demonstrated the potency of immunotherapeutic approaches with antibody-drug conjugates and immune checkpoint inhibitors. This Primer explores the wealth of information that has been assembled to understand HL; these updated observations verify that HL investigation and treatment remain at the leading edge of oncological research.
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46
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Gupta GK, Agrawal T, Pilichowska M. Immunohistochemical expression of vitamin D receptor and forkhead box P3 in classic Hodgkin lymphoma: correlation with clinical and pathologic findings. BMC Cancer 2020; 20:535. [PMID: 32513132 PMCID: PMC7282135 DOI: 10.1186/s12885-020-07026-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 06/01/2020] [Indexed: 11/10/2022] Open
Abstract
Background Expression of forkhead box P3 (FOXP3), a key regulator of T-cell function, in the tumor immune microenvironment is related to survival in classic Hodgkin lymphoma (CHL). Vitamin D receptor (VDR), a transcription factor agonists have been shown to induce FOXP3 expression in T-cells and enhance recruitment of these cells to the inflammatory sites. VDR expression is CHL has been described. However, there is no data on expression of VDR in context of quantity of FOXP3 positive cells in CHL. Methods We examined and correlated immunohistochemical expression of VDR and FOXP3 along with clinical and pathology findings in 29 cases of CHL. Results VDR was expressed in Hodgkin Reed-Sternberg (HRS) cells and background lymphocytes and FOXP3 was expressed in background lymphocytes. 82% of CHL cases, regardless of the subtype, expressed VDR and in majority of the cases, VDR expression was directly proportional to the quantity of FOXP3 expressing lymphocytes in the tumor microenvironment. In cases with higher clinical stage (III/IV), only 28.5% of cases diffusely expressed VDR and FOXP3 compared to 71.4% showing focal positivity. Whereas in cases with lower clinical stages (I/II), the expression pattern of VDR and FOXP3 was almost similar (41.6% diffuse versus 33.3% focal). Interestingly, focal VDR and FOXP3 expression pattern was significantly higher among males. Mixed cellularity cases showed predilection for focal VDR and FOXP3 expression (80% cases); whereas nodular sclerosis subtype had focal and diffuse VDR and FOXP3 expression patterns in similar proportion. Cases with diffuse VDR and FOXP3 expression were less likely to have bone marrow involvement. Epstein Barr virus- encoded small RNA (EBER) positive cases were predominantly focally positive (80%) for VDR and FOXP3. Conclusions In summary, quantity of FOXP3 positive T-cells in CHL microenvironment seems to correlate with VDR expression. Clinical stage show a trend of inverse correlation with expression of VDR and quantity of FOXP3 positive T-cells. These findings suggest that VDR could be a possible prognostic and therapeutic target in CHL.
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Affiliation(s)
- Gaurav K Gupta
- Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, MA, USA. .,Department of Laboratory Medicine, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA.
| | - Tanupriya Agrawal
- Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, MA, USA.,Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, NY, USA
| | - Monika Pilichowska
- Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, MA, USA
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47
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Abstract
Introduction: Hodgkin Lymphoma (HL) carries an overall excellent prognosis for young patients treated with multimodal therapy. Predicting an individual patient's prognosis is currently heavily dependent on imaging modalities such as Positron Emission Tomography (PET).Areas covered: Potential biomarkers from serum, tissue, circulating nucleic acids and non-tumor derived cells have all been reported to be of prognostic relevance in HL. We review a range of these biomarkers and discuss the integration of new biomarkers into individualized patient care.Expert opinion: Better prognostic markers are needed to predict an individuals response to HL therapy. Interim PET-scan improves the ability to predict long-term treatment responders. However, it is our opinion that supplementation of PET results with additional biomarkers (including circulating tumor DNA, protein biomarkers, tissue genotyping and metabolic tumor volume) are likely to improve risk stratification for future patients with HL.
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Affiliation(s)
- Melita Cirillo
- Faculty of Medicine and University Hospital of Cologne, Department I Of Internal Medicine, GHSG, University of Cologne, Cologne, Germany.,Faculty of Medicine and University Hospital of Cologne, Centre for Molecular Medicine, University of Cologne, Cologne, Germany.,Department of Hematology, Royal Perth Hospital, Perth, Australia.,University of Western Australia, Perth, Australia
| | - Sven Borchmann
- Faculty of Medicine and University Hospital of Cologne, Department I Of Internal Medicine, GHSG, University of Cologne, Cologne, Germany.,Faculty of Medicine and University Hospital of Cologne, Centre for Molecular Medicine, University of Cologne, Cologne, Germany.,Faculty of Medicine and University Hospital of Cologne, Else Kröner Forschungskolleg Clonal Evolution in Cancer, University of Cologne, Cologne, Germany
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48
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Mohamed O, El Bastawisy A, Allahlobi N, Abdellateif MS, Zekri ARN, Shaarawy S, Korany Z, Mohanad M, Bahnassy AA. The role of CD68+ macrophage in classical Hodgkin lymphoma patients from Egypt. Diagn Pathol 2020; 15:10. [PMID: 32019558 PMCID: PMC7001371 DOI: 10.1186/s13000-019-0912-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 12/06/2019] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND CD68+ tumor-associated macrophages (TAM) play an important role in the progression of classical Hodgkin lymphoma (cHL). We assessed the role of CD20 and CD68 + TAM in a cohort of cHL patients from Egypt and correlated the number of CD68 + cells with patients' characteristics, response to treatment, overall and progression free survival rates (OS & PFS). METHODS CD20 expression and CD68 + TAM numbers were assessed in representative tumor tissues obtained from 81 cHL patients using flowcytometry (FCM), immunohistochemistry (IHC), and Rt-PCR techniques. RESULTS The expression levels of CD68 protein by IHC was high in 27 (33.3%), moderate in 15 (18.5%), low in 15 (18.5%), and negative in 24 (29.6%) patients (p = 0.13). CD68-mRNA expression was high in 43/81(53.1%), and low in 38(46.9%) patients (p = 0.6). The number of CD68 + TAM (by FCM) was low (< 20 cells) in 42/81 (51.9%), and high (≥20 cells) in 39/81 (48.1%) patients (p = 0.74). CD68 expression (by FCM, IHC& Rt-PCR) associated significantly with poor response to treatment, decreased CD20 expression, reduced OS and PFS rates (p < 0.001 for all). CD68 expression (by Rt-PCR only) associated significantly with advanced disease stage (p = 0.04). The age of the patients, high CD20 expression & high CD68+ macrophage number were independent prognostic factors for OS (p= 0.02, p = 0.008 & p = 0.009; respectively). However, the age of the patient, high CD20, and high CD68+ macrophage expression (by FCM&IHC) were independent prognostic factors for DFS (p. = 0.004, p. = 0.01, p. = 0.007 and p. = 0.01; respectively). CONCLUSION CD68 + TAM expression (by Rt-PCR, FCM and/or IHC) can identify patients with poor response to treatment and reduced survival rates (OS& PFS). Assessment of CD68 + positive macrophages by FCM is superior to other methods (Rt-PCR and IHC) as a prognostic factor for DFS and OS rates.
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Affiliation(s)
- Osama Mohamed
- Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo, 11976, Egypt
| | - Ahmed El Bastawisy
- Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo, 11976, Egypt
| | - Nasr Allahlobi
- Department of Medical Oncology, National Cancer Institute, Cairo University, Cairo, 11976, Egypt
| | - Mona S Abdellateif
- Medical Biochemistry and molecular biology, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, 11976, Egypt
| | - Abdel Rahman N Zekri
- Molecular Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, 11976, Egypt
| | - Sabry Shaarawy
- Medical Biochemistry and molecular biology, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, 11976, Egypt
| | - Zeinab Korany
- Medical Biochemistry and molecular biology, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, 11976, Egypt
| | - Marwa Mohanad
- Biochemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th October, Cairo, 12945, Egypt
| | - Abeer A Bahnassy
- Pathology Department, National Cancer Institute, Cairo University, Cairo, 11976, Egypt.
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Novel HDAC inhibitor Chidamide synergizes with Rituximab to inhibit diffuse large B-cell lymphoma tumour growth by upregulating CD20. Cell Death Dis 2020; 11:20. [PMID: 31907371 PMCID: PMC6944697 DOI: 10.1038/s41419-019-2210-0] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 12/14/2019] [Accepted: 12/17/2019] [Indexed: 12/24/2022]
Abstract
Loss of CD20 is a major obstacle for the retreatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL) with Rituximab-associated regimens. Histone deacetylation causes gene silencing and inhibits CD20 expression. Chidamide is a novel inhibitor for histone deacetylases (HDACs). We hypothesize that Chidamide could overcome Rituximab-mediated down-regulation of CD20 and facilitate Rituximab-induced killing. In this study, we determine the mechanism of synergy of Chidamide with Rituximab in DLBCL using in vitro and in vivo models. We found that the levels of CD20 protein surface expression on five DLBCL cell lines were significantly and positively correlated with the sensitivities of cells to Rituximab. Treatment with Rituximab significantly reduced CD20 surface expression at the protein levels. RNA sequencing showed that Chidamide significantly increased expression of more than 2000 transcriptomes in DLBCL cells, around 1000 transcriptomes belong to the cell membrane and cell periphery pathways, including MS4A1. Chidamide significantly increased CD20 surface expression in DLBCL cell lines. Combination with Chidamide significantly synergized Rituximab-induced cell death in vitro and significantly inhibited tumour growth in DLBCL-bearing xenograft mice. A patient with relapsed/refractory DLBCL achieved a complete response after three cycles combined treatment with Chidamide and Rituximab. In conclusion, our data demonstrate for the first time that inhibition of HDACs by Chidamide significantly enhanced Rituximab-induced tumour growth inhibition in vitro and in vivo. We propose that CD20 surface expression should be used clinically to evaluate treatment response in patients with DLBCL. Chidamide is a promising sensitizer for the retreatment of DLBCL with Rituximab.
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50
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Hayden AR, Lee DG, Villa D, Gerrie AS, Scott DW, Slack GW, Sehn LH, Connors JM, Savage KJ. Validation of a simplified international prognostic score (IPS-3) in patients with advanced-stage classic Hodgkin lymphoma. Br J Haematol 2019; 189:122-127. [PMID: 31822034 DOI: 10.1111/bjh.16293] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 08/24/2019] [Indexed: 01/06/2023]
Abstract
A novel prognostic score (IPS-3), comprised of only three of the seven IPS-7 indicators (age ≥45, stage IV, haemoglobin <105 g/l), was recently proposed as a simplified model for advanced-stage classic Hodgkin lymphoma (cHL). We aimed to validate this model in advanced-stage cHL patients treated with doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) in British Columbia. The estimated five-year freedom from progression (FFP) for scores of 0, 1, 2 and 3 were very similar to the original report at 84%, 76%, 72% and 68% respectively. The IPS-3 score is highly reproducible in this independent dataset and its simplicity makes it appealing for everyday clinical practice.
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Affiliation(s)
- Anna R Hayden
- Department of Medical Oncology, British Columbia Cancer, Centre for Lymphoid Cancer, Vancouver, Canada
| | - Derrick G Lee
- Department of Math, Statistics, and Computer Science, St. Francis Xavier University, Antigonish, NS, Canada.,Cancer Control Research, BC Cancer, Vancouver, Canada
| | - Diego Villa
- Department of Medical Oncology, British Columbia Cancer, Centre for Lymphoid Cancer, Vancouver, Canada
| | - Alina S Gerrie
- Department of Medical Oncology, British Columbia Cancer, Centre for Lymphoid Cancer, Vancouver, Canada
| | - David W Scott
- Department of Medical Oncology, British Columbia Cancer, Centre for Lymphoid Cancer, Vancouver, Canada
| | - Graham W Slack
- Department of Pathology, British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, Canada
| | - Laurie H Sehn
- Department of Medical Oncology, British Columbia Cancer, Centre for Lymphoid Cancer, Vancouver, Canada
| | - Joseph M Connors
- Department of Medical Oncology, British Columbia Cancer, Centre for Lymphoid Cancer, Vancouver, Canada
| | - Kerry J Savage
- Department of Medical Oncology, British Columbia Cancer, Centre for Lymphoid Cancer, Vancouver, Canada
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