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Mah JK, Tam PCK, Chang YC, Saullo JH, Baker AW, Maziarz EK, Messina JA, Sim B, Abusalem L, Hanna S, Pipeling MR, Snyder LD, Reynolds JM, Wolfe CR, Lee MJ, Alexander BD, Heldman MR. Limited utility of Epstein-Barr virus (EBV) surveillance for predicting post-transplant lymphoproliferative disorders in adult EBV seropositive lung transplant recipients. J Clin Virol 2025; 176:105758. [PMID: 39700902 PMCID: PMC11975427 DOI: 10.1016/j.jcv.2024.105758] [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: 09/05/2024] [Revised: 11/15/2024] [Accepted: 12/12/2024] [Indexed: 12/21/2024]
Abstract
BACKGROUND EBV DNAemia surveillance, with reduction of immunosuppression at certain viral load (VL) thresholds, is a common practice for mitigating progression from EBV DNAemia to post-transplant lymphoproliferative disorder (PTLD) in lung transplant recipients (LTRs). The utility of EBV surveillance in adult EBV seropositive LTRs is unknown. METHODS We performed a retrospective cohort study of EBV seropositive adult LTRs who underwent lung transplant between 1/1/19 and 12/31/20 and received whole blood (WB) EBV PCR surveillance. We compared peak WB EBV VLs among 3 groups: 1) asymptomatic LTRs who developed PTLD, before PTLD was clinically suspected, 2) LTRs who developed PTLD, after PTLD was clinically suspected, and 3) LTRs who did not develop PTLD. We calculated the positive predictive value (PPV) of moderate-grade DNAemia (2840 to 11,360 IU/mL) and high-grade DNAemia (≥ 11,360 IU/mL) for identifying active or future PTLD. RESULTS Six (2.6 %) of 229 LTRs developed PTLD. Among LTRs who developed PTLD, median peak EBV VL was significantly higher after PTLD was suspected than before clinical signs of PTLD were present (16,004 IU/mL vs. ≤568 IU/mL, p = 0.016). Median peak EBV VLs were similar between asymptomatic LTRs who later developed PTLD and LTRs who did not develop PTLD (median peak EBV VL ≤568 IU/mL vs. ≤568 IU/mL, p = 0.62). The PPVs for moderate- and high-grade DNAemia were 14.7 % and 33.3 %, respectively. CONCLUSIONS EBV surveillance did not accurately identify EBV seropositive LTRs at risk for progressing to PTLD. EBV PCR testing in asymptomatic EBV seropositive transplant recipients may represent an opportunity for diagnostic stewardship.
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Affiliation(s)
- Jordan K Mah
- Division of Infectious Diseases, Department of Medicine, Duke University, Durham, NC, USA.
| | - Patrick C K Tam
- Division of Infectious Diseases, Department of Medicine, Duke University, Durham, NC, USA
| | - Yeh-Chung Chang
- Division of Infectious Diseases, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX USA
| | - Jennifer H Saullo
- Division of Infectious Diseases, Department of Medicine, Duke University, Durham, NC, USA
| | - Arthur W Baker
- Division of Infectious Diseases, Department of Medicine, Duke University, Durham, NC, USA
| | - Eileen K Maziarz
- Division of Infectious Diseases, Department of Medicine, Duke University, Durham, NC, USA
| | - Julia A Messina
- Division of Infectious Diseases, Department of Medicine, Duke University, Durham, NC, USA
| | - Beatrice Sim
- Division of Infectious Diseases, Department of Medicine, Duke University, Durham, NC, USA
| | - Lana Abusalem
- Division of Infectious Diseases, Department of Medicine, Duke University, Durham, NC, USA
| | - Sandrine Hanna
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University, Durham, NC, USA
| | - Matthew R Pipeling
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University, Durham, NC, USA
| | - Laurie D Snyder
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University, Durham, NC, USA
| | - John M Reynolds
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University, Durham, NC, USA
| | - Cameron R Wolfe
- Division of Infectious Diseases, Department of Medicine, Duke University, Durham, NC, USA
| | - Mark J Lee
- Division of Microbiology, Department of Pathology, Duke University, Durham, NC, USA
| | - Barbara D Alexander
- Division of Infectious Diseases, Department of Medicine, Duke University, Durham, NC, USA
| | - Madeleine R Heldman
- Division of Infectious Diseases, Department of Medicine, Duke University, Durham, NC, USA.
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Barrera FJ, Mostofsky E, Salia S, Lehman L, Liou L, Mucci L, Mittleman MA. Incidence of de novo malignancy and all-cause mortality among heart transplant recipients. Int J Cardiol 2024; 415:132455. [PMID: 39153512 PMCID: PMC11426084 DOI: 10.1016/j.ijcard.2024.132455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 07/23/2024] [Accepted: 08/13/2024] [Indexed: 08/19/2024]
Abstract
BACKGROUND Heart transplant recipients develop cancer at two-times the rate compared to the general population. However, the incidence and mortality rates and the adjusted association between cancer and mortality remains unclear. METHODS We estimated the incidence and mortality rates and the adjusted association between developing cancer (any, skin, hematologic, and solid tumor subtypes) and the all-cause mortality rates among adult heart transplant recipients from the Scientific Registry of Transplant Recipients from October 1, 1987, until June 28, 2020. RESULTS Among 51,597 adult heart transplant recipients, 13,191 (25.6%) were diagnosed with de novo malignancy throughout the follow-up period. The cumulative incidence cancer at years 1, 5, 10, and 20 was 3%, 16.4%, 32.8%, and 56.6%, respectively. Among those with cancer, the cumulative mortality was 17.5%, 42.3%, 65%, and 91% at years 1, 5, 10, and 20, respectively. The incidence rate of any de novo malignancy was 38.7 cases per 1000 person-years and the mortality rate (for those with cancer) was 115.2 cases per 1000 person-years. Compared to those without cancer, those with cancer had a higher adjusted mortality association [HR: 2.14 (2.07, 2.21)]. The strongest associations were estimated for pancreatic [10.63 (8.34, 13.54)], leukemia [8.06 (4.33, 15.00)], and esophagus [6.94 (5.43, 8.87)] malignancies. The association between de novo malignancies and mortality was higher in the earlier years of follow-up. CONCLUSION Compared to not developing cancer, those with de novo malignancy have a 2-fold higher mortality rate, on average. The strength of the association varies by cancer subtype and by follow-up time.
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Affiliation(s)
- Francisco J Barrera
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Elizabeth Mostofsky
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Soziema Salia
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Medicine, MedStar Union Memorial Hospital, Baltimore, MD, United States of America.
| | - Laura Lehman
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
| | - Lathan Liou
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Icahn School of Medicine at Mount Sinai, NY, USA
| | - Lorelei Mucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Murray A Mittleman
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Division of Cardiovascular Medicine, Department of Medicine, Beth, Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
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3
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Furlano PL, Böhmig GA, Puchhammer-Stöckl E, Vietzen H. Mechanistic Understanding of EBV+Lymphoproliferative Disease Development After Transplantation. Transplantation 2024; 108:1867-1881. [PMID: 39166902 DOI: 10.1097/tp.0000000000004919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
Posttransplant lymphoproliferative disorders (PTLDs) are among the most common malignant complications after transplantation, leading to a drastic reduction in patient survival rates. The majority of PTLDs are tightly linked to Epstein-Barr virus (EBV+PTLDs) and are the result of an uncontrolled proliferation of EBV-infected cells. However, although EBV infections are a common finding in transplant recipients, most patients with high EBV loads will never develop EBV+PTLD. Natural killer cells and EBV-specific CD8+ T lymphocytes are critical for controlling EBV-infected cells, and the impairment of these cytotoxic immune responses facilitates the unfettered proliferation of EBV-infected cells. Recent years have seen a considerable increase in available literature aiming to describe novel risk factors associated with the development of EBV+PTLD, which may critically relate to the strength of EBV-specific natural killer cell and EBV-CD8+ T lymphocyte responses. The accumulation of risk factors and the increased risk of developing EBV+PTLD go hand in hand. On the one hand, most of these risk factors, such as the level of immunosuppression or the EBV donor and recipient serologic mismatch, and distinct genetic risk factors are host related and affect cytotoxic EBV-specific immune responses. On the other hand, there is growing evidence that distinct EBV variants may have an increased malignant potential and are thus more likely to induce EBV+PTLD. Here, we aim to review, from a mechanistic point of view, the risk factors for EBV+PTLD in the host and the infecting EBV variants that may explain why only a minority of transplant recipients develop EBV+PTLD.
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Affiliation(s)
| | - Georg A Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | | | - Hannes Vietzen
- Center for Virology, Medical University of Vienna, Vienna, Austria
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4
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Hoshida Y, Tsujii A, Ohshima S, Saeki Y, Yagita M, Miyamura T, Katayama M, Kawasaki T, Hiramatsu Y, Oshima H, Murayama T, Higa S, Kuraoka K, Hirano F, Ichikawa K, Kurosawa M, Suzuki H, Chiba N, Sugiyama T, Minami Y, Niino H, Ihata A, Saito I, Mitsuo A, Maejima T, Kawashima A, Tsutani H, Takahi K, Kasai T, Shinno Y, Tachiyama Y, Teramoto N, Taguchi K, Naito S, Yoshizawa S, Ito M, Suenaga Y, Mori S, Nagakura S, Yoshikawa N, Nomoto M, Ueda A, Nagaoka S, Tsuura Y, Setoguchi K, Sugii S, Abe A, Sugaya T, Sugahara H, Fujita S, Kunugiza Y, Iizuka N, Yoshihara R, Yabe H, Fujisaki T, Morii E, Takeshita M, Sato M, Saito K, Matsui K, Tomita Y, Furukawa H, Tohma S. Effect of Recent Antirheumatic Drug on Features of Rheumatoid Arthritis-Associated Lymphoproliferative Disorders. Arthritis Rheumatol 2024; 76:869-881. [PMID: 38272827 DOI: 10.1002/art.42809] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 01/06/2024] [Accepted: 01/22/2024] [Indexed: 01/27/2024]
Abstract
OBJECTIVE In this study, we examine how advancements in novel antirheumatic drugs affect the clinicopathologic features of lymphoproliferative disorder (LPD) in patients with rheumatoid arthritis (RA). METHODS In this multicenter study across 53 hospitals in Japan, we characterized patients with RA who developed LPDs and visited the hospitals between January 1999 and March 2021. The statistical tools used included Fisher's exact test, the Mann-Whitney U-test, the log-rank test, logistic regression analysis, and Cox proportional hazards models. RESULTS Overall, 752 patients with RA-associated LPD (RA-LPD) and 770 with sporadic LPD were included in the study. We observed significant differences in the clinicopathologic features between patients with RA-LPD and those with sporadic LPD. Histopathological analysis revealed a high frequency of LPD-associated immunosuppressive conditions. Furthermore, patients with RA-LPD were evaluated based on the antirheumatic drugs administered. The methotrexate (MTX) plus tacrolimus and MTX plus tumor necrosis factor inhibitor (TNFi) groups had different affected site frequencies and histologic subtypes than the MTX-only group. Moreover, MTX and TNFi may synergistically affect susceptibility to Epstein-Barr virus infection. In case of antirheumatic drugs administered after LPD onset, tocilizumab (TCZ)-only therapy was associated with lower frequency of regrowth after spontaneous regression than other regimens. CONCLUSION Antirheumatic drugs administered before LPD onset may influence the clinicopathologic features of RA-LPD, with patterns changing over time. Furthermore, TCZ-only regimens are recommended after LPD onset.
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Affiliation(s)
- Yoshihiko Hoshida
- National Health Organization (NHO) Osaka Minami Medical Center, Osaka, Japan
| | - Atsuko Tsujii
- National Health Organization (NHO) Osaka Minami Medical Center, Osaka, Japan
| | - Shiro Ohshima
- National Health Organization (NHO) Osaka Minami Medical Center, Osaka, Japan
| | - Yukihiko Saeki
- National Health Organization (NHO) Osaka Minami Medical Center, Osaka, Japan
| | - Masato Yagita
- Tazuke-Kofukai Medical Research Institute Kitano Hospital, Osaka, Japan
| | | | | | | | | | | | | | | | - Kazuya Kuraoka
- NHO Kure Medical Center and Chugoku Cancer Center, Hiroshima, Japan
| | | | | | | | | | | | | | - Yuko Minami
- NHO Ibarakihigashi National Hospital, Tokai, Japan
| | | | | | - Ikuo Saito
- NHO Sagamihara National Hospital, Sagamihara, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Keigo Setoguchi
- Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Shoji Sugii
- Tokyo Metropolitan Hiroo Hospital, Tokyo, Japan
| | - Asami Abe
- Niigata Rheumatic Center, Shibata, Japan
| | | | | | | | - Yasuo Kunugiza
- Japan Community Health Care Organization Hoshigaoka Medical Center, Hirakata, Japan
| | | | | | | | | | | | | | - Masakazu Sato
- Kurashiki University of Science and the Arts, Kurashiki, Japan
| | - Kazuyoshi Saito
- University of Occupational and Environmental Health, Kitakyushu, Japan
| | | | - Yasuhiko Tomita
- International University of Health and Welfare, Narita, Japan
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Dharnidharka VR, Ruzinova MB, Marks LJ. Post-Transplant Lymphoproliferative Disorders. Semin Nephrol 2024; 44:151503. [PMID: 38519279 PMCID: PMC11213680 DOI: 10.1016/j.semnephrol.2024.151503] [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] [Indexed: 03/24/2024]
Abstract
Post-transplant lymphoproliferative disorders (PTLDs) are a heterogenous set of unregulated lymphoid cell proliferations after organ or tissue transplant. A majority of cases are associated with the Epstein-Barr virus and higher intensity of pharmacologic immunosuppression. The clinical presentations are numerous. The diagnosis is ideally by histology, except in cases where the tumor is inaccessible to biopsy. While some pre-emptive therapies and treatment strategies are available have reasonable success are available, they do not eliminate the high morbidity and significant mortality after PTLD.
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Affiliation(s)
- Vikas R Dharnidharka
- Division of Pediatric Nephrology, Hypertension and Apheresis, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO.
| | - Marianna B Ruzinova
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - Lianna J Marks
- Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Stanford University School of Medicine, Palo Alto, CA
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6
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Lee J, Yang AWJ, Chung LIY, Yu J, Lee Y, Kim HS, Shin HJ, Choi YG, Bharat A, Chae YK. A Comprehensive Landscape of De Novo Malignancy After Double Lung Transplantation. Transpl Int 2023; 36:11552. [PMID: 37663524 PMCID: PMC10468575 DOI: 10.3389/ti.2023.11552] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 07/31/2023] [Indexed: 09/05/2023]
Abstract
Although the association between post-transplant malignancy (PTM) and immunosuppressive therapy after organ transplantation has been studied, an integrated review of PTM after lung transplantation is lacking. We investigated the incidence and types of de novo PTM and its impact on survival following double lung transplantation (DLT). The incidence and type of PTM as well as the annual and cumulative risks of each malignancy after DLT were analyzed. The overall survival (OS) of recipients with or without PTM was compared by the Kaplan-Meier survival method and landmark analysis. There were 5,629 cases (23.52%) with 27 types of PTMs and incidences and OS varied according to the types of PTMs. The recipients with PTM showed a significantly longer OS than those without PTM (p < 0.001). However, while the recipients with PTM showed significantly better OS at 3, and 5 years (p < 0.001, p = 0.007), it was worse at the 10-year landmark time (p = 0.013). And the single PTM group showed a worse OS rate than the multiple PTM group (p < 0.001). This comprehensive report on PTM following DLT can help understand the risks and timing of PTM to improve the implementation of screening and treatment.
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Affiliation(s)
- Jeeyeon Lee
- Department of Surgery, School of Medicine, Kyungpook National University Chilgok Hospital, Kyungpook National University, Daegu, Republic of Korea
- Department of Internal Medicine, Northwestern Memorial Hospital, Chicago, IL, United States
| | - Andrew Won Jun Yang
- Department of Internal Medicine, Northwestern Memorial Hospital, Chicago, IL, United States
| | - Liam Il-Young Chung
- Department of Internal Medicine, Northwestern Memorial Hospital, Chicago, IL, United States
| | - Jisang Yu
- Department of Internal Medicine, Northwestern Memorial Hospital, Chicago, IL, United States
| | - Yunjoo Lee
- Department of Internal Medicine, Northwestern Memorial Hospital, Chicago, IL, United States
| | - Hye Sung Kim
- Department of Internal Medicine, Northwestern Memorial Hospital, Chicago, IL, United States
| | - Hyun Joon Shin
- Division of Cardiology, Department of Medicine, Lemuel Shattuck Hospital, Massachusetts Department of Public Health, Jamaica Plain, MA, United States
| | - Young-Geun Choi
- Department of Mathematics Education, Sungkyunkwan University, Seoul, Republic of Korea
| | - Ankit Bharat
- Department of Internal Medicine, Northwestern Memorial Hospital, Chicago, IL, United States
| | - Young Kwang Chae
- Department of Internal Medicine, Northwestern Memorial Hospital, Chicago, IL, United States
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Hicks B, Kaye JA, Azoulay L, Kristensen KB, Habel LA, Pottegård A. The Application of Lag Times in Cancer Pharmacoepidemiology: A Narrative Review. Ann Epidemiol 2023:S1047-2797(23)00090-X. [PMID: 37169040 DOI: 10.1016/j.annepidem.2023.05.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 04/27/2023] [Accepted: 05/05/2023] [Indexed: 05/13/2023]
Abstract
With the increasing utilization of medications worldwide, coupled with the increasing availability of long-term data, there is a growing opportunity and need for robust studies evaluating drug-cancer associations. One methodology of importance in such studies is the application of lag times. In this review, we discuss the main reasons for using lag times. Namely, we discuss the typically long latency period of cancer concerning both tumor promoter and initiator effects and outline why cancer latency is a key consideration when choosing a lag time. We also discuss how the use of lag times can help reduce protopathic and detection bias. Finally, we present practical advice for implementing lag periods. In general, we recommend that researchers consider the information that generated the hypothesis as well as clinical and biological knowledge to inform lag period selection. In addition, given that latency periods are usually unknown, we also advocate that researchers examine multiple lag periods in sensitivity analyses as well as duration analyses and flexible modeling approaches.
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Affiliation(s)
- Blánaid Hicks
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK; RTI Health Solutions, Waltham, Massachusetts; Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Québec, Canada; Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Québec, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, Québec, Canada; Clinical Pharmacology,Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Denmark; Division of Research, Kaiser Permanente Northern California, Oakland, California.
| | - James A Kaye
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK; RTI Health Solutions, Waltham, Massachusetts; Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Québec, Canada; Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Québec, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, Québec, Canada; Clinical Pharmacology,Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Denmark; Division of Research, Kaiser Permanente Northern California, Oakland, California
| | - Laurent Azoulay
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK; RTI Health Solutions, Waltham, Massachusetts; Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Québec, Canada; Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Québec, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, Québec, Canada; Clinical Pharmacology,Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Denmark; Division of Research, Kaiser Permanente Northern California, Oakland, California
| | - Kasper Bruun Kristensen
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK; RTI Health Solutions, Waltham, Massachusetts; Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Québec, Canada; Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Québec, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, Québec, Canada; Clinical Pharmacology,Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Denmark; Division of Research, Kaiser Permanente Northern California, Oakland, California
| | - Laurel A Habel
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK; RTI Health Solutions, Waltham, Massachusetts; Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Québec, Canada; Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Québec, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, Québec, Canada; Clinical Pharmacology,Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Denmark; Division of Research, Kaiser Permanente Northern California, Oakland, California
| | - Anton Pottegård
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK; RTI Health Solutions, Waltham, Massachusetts; Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Québec, Canada; Centre for Clinical Epidemiology, Lady Davis Institute, Montreal, Québec, Canada; Gerald Bronfman Department of Oncology, McGill University, Montreal, Québec, Canada; Clinical Pharmacology,Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Denmark; Division of Research, Kaiser Permanente Northern California, Oakland, California
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8
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Lateef N, Farooq MZ, Latif A, Ahmad S, Ahsan MJ, Tran A, Nickol J, Wasim MF, Yasmin F, Kumar P, Arif AW, Shaikh A, Mirza M. Prevalence of Post-Heart Transplant Malignancies: A Systematic Review and Meta-Analysis. Curr Probl Cardiol 2022; 47:101363. [PMID: 36007618 DOI: 10.1016/j.cpcardiol.2022.101363] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 08/16/2022] [Indexed: 11/03/2022]
Abstract
The prevalence of different cancers after heart transplant (HT) is unclear due to small and conflicting prior studies. Herein, we report a systematic review and meta-analysis to highlight the prevalence and pattern of malignancies post-HT. We conducted an extensive literature search on PubMed, Scopus, Cochrane databases for prospective or retrospective studies reporting malignancies after HT. The proportions from each study were subjected to random effects model that yielded the pooled estimate with 95% confidence intervals (CI). Fifty-five studies comprising 60,684 HT recipients reported 7,759 total cancers during a mean follow-up of 9.8 ± 5.9 years, with an overall incidence of 15.3% (95% CI = 12.7%-18.1%). Mean time from HT to cancer diagnosis was 5.1 ± 4 years. The most frequent cancers were gastrointestinal (7.6%), skin (5.7%), and hematologic/blood (2.5%). Meta-regression showed no association between incidence of cancer and mean age at HT (coeff: -0.008; p=0.25), percentage of male recipients (coeff: -0.001; p=0.81), donor age (coeff: -0.011; p=0.44), 5-year (coeff: 0.003; p=0.12) and 10-year (coeff: 0.02; p=0.68) post-transplant survival. There is a substantial risk of malignancies in HT recipients, most marked for gastrointestinal, skin, and hematologic. Despite their occurrence, survival is not significantly impacted.
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Affiliation(s)
- Noman Lateef
- Department of Cardiovascular Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.
| | | | - Azka Latif
- Department of Cardiovascular Medicine, Baylor University, Houston, USA
| | - Soban Ahmad
- Department of Internal Medicine, East Carolina University, North Carolina, USA
| | | | - Amy Tran
- Department of Internal Medicine, Creighton University, Nebraska, USA
| | - Jennifer Nickol
- Department of Cardiovascular Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | | | - Farah Yasmin
- Department of Medicine, Dow University of Health Sciences, Karachi, PK
| | - Pankaj Kumar
- Department of Medicine, Dow University of Health Sciences, Karachi, PK
| | - Abdul Wahab Arif
- Department of Cardiovascular Medicine, Cook County Health Sciences, Chicago, Illinois, USA
| | - Asim Shaikh
- Department of Internal Medicine, Rochester General Hospital, Rochester, NY
| | - Mohsin Mirza
- Department of Internal Medicine, Creighton University, Nebraska, USA
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9
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Asleh R, Alnsasra H, Habermann TM, Briasoulis A, Kushwaha SS. Post-transplant Lymphoproliferative Disorder Following Cardiac Transplantation. Front Cardiovasc Med 2022; 9:787975. [PMID: 35282339 PMCID: PMC8904724 DOI: 10.3389/fcvm.2022.787975] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 02/01/2022] [Indexed: 11/24/2022] Open
Abstract
Post-transplant lymphoproliferative disorder (PTLD) is a spectrum of lymphoid conditions frequently associated with the Epstein Barr Virus (EBV) and the use of potent immunosuppressive drugs after solid organ transplantation. PTLD remains a major cause of long-term morbidity and mortality following heart transplantation (HT). Epstein-Barr virus (EBV) is a key pathogenic driver in many PTLD cases. In the majority of PTLD cases, the proliferating immune cell is the B-cell, and the impaired T-cell immune surveillance against infected B cells in immunosuppressed transplant patients plays a key role in the pathogenesis of EBV-positive PTLD. Preventive screening strategies have been attempted for PTLD including limiting patient exposure to aggressive immunosuppressive regimens by tailoring or minimizing immunosuppression while preserving graft function, anti-viral prophylaxis, routine EBV monitoring, and avoidance of EBV seromismatch. Our group has also demonstrated that conversion from calcineurin inhibitor to the mammalian target of rapamycin (mTOR) inhibitor, sirolimus, as a primary immunosuppression was associated with a decreased risk of PTLD following HT. The main therapeutic measures consist of immunosuppression reduction, treatment with rituximab and use of immunochemotherapy regimens. The purpose of this article is to review the potential mechanisms underlying PTLD pathogenesis, discuss recent advances, and review potential therapeutic targets to decrease the burden of PTLD after HT.
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Affiliation(s)
- Rabea Asleh
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States
- Heart Institute, Hadassah University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Hilmi Alnsasra
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States
- Soroka University Medical Center, Ben Gurion University of the Negev, Beer Sheva, Israel
| | - Thomas M. Habermann
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, United States
| | - Alexandros Briasoulis
- Division of Cardiovascular Disease, University of Iowa Hospitals and Clinics, Iowa City, IA, United States
| | - Sudhir S. Kushwaha
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States
- *Correspondence: Sudhir S. Kushwaha
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10
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Asleh R, Vucicevic D, Petterson TM, Kremers WK, Pereira NL, Daly RC, Edwards BS, Steidley DE, Scott RL, Kushwaha SS. Sirolimus-Based Immunosuppression Is Associated with Decreased Incidence of Post-Transplant Lymphoproliferative Disorder after Heart Transplantation: A Double-Center Study. J Clin Med 2022; 11:jcm11020322. [PMID: 35054016 PMCID: PMC8779206 DOI: 10.3390/jcm11020322] [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: 12/14/2021] [Revised: 01/03/2022] [Accepted: 01/07/2022] [Indexed: 02/01/2023] Open
Abstract
Mammalian target of rapamycin (mTOR) inhibitors have been shown to reduce proliferation of lymphoid cells; thus, their use for immunosuppression after heart transplantation (HT) may reduce post-transplant lymphoproliferative disorder (PTLD) risk. This study sought to investigate whether the sirolimus (SRL)-based immunosuppression regimen is associated with a decreased risk of PTLD compared with the calcineurin inhibitor (CNI)-based regimen in HT recipients. We retrospectively analyzed 590 patients who received HTs at two large institutions between 1 June 1988 and 31 December 2014. Cox proportional-hazard modeling was used to examine the association between type of primary immunosuppression and PTLD after adjustment for potential confounders, including Epstein-Barr virus (EBV) status, type of induction therapy, and rejection. Conversion from CNI to SRL as primary immunosuppression occurred in 249 patients (42.2%). During a median follow-up of 6.3 years, 30 patients developed PTLD (5.1%). In a univariate analysis, EBV mismatch was strongly associated with increased risk of PTLD (HR 10.0, 95% CI: 3.8-26.6; p < 0.001), and conversion to SRL was found to be protective against development of PTLD (HR 0.19, 95% CI: 0.04-0.80; p = 0.02). In a multivariable model and after adjusting for EBV mismatch, conversion to SRL remained protective against risk of PTLD compared with continued CNI use (HR 0.12, 95% CI: 0.03-0.55; p = 0.006). In conclusion, SRL-based immunosuppression is associated with lower incidence of PTLD after HT. These findings provide evidence of a benefit from conversion to SRL as maintenance therapy for mitigating the risk of PTLD, particularly among patients at high PTLD risk.
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Affiliation(s)
- Rabea Asleh
- Department of Cardiovascular Diseases and Health Sciences Research and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA; (W.K.K.); (N.L.P.); (R.C.D.); (B.S.E.); (S.S.K.)
- Heart Institute, Hadassah University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, Israel
- Correspondence: or
| | - Darko Vucicevic
- Department of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA;
| | - Tanya M. Petterson
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA;
| | - Walter K. Kremers
- Department of Cardiovascular Diseases and Health Sciences Research and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA; (W.K.K.); (N.L.P.); (R.C.D.); (B.S.E.); (S.S.K.)
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA;
| | - Naveen L. Pereira
- Department of Cardiovascular Diseases and Health Sciences Research and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA; (W.K.K.); (N.L.P.); (R.C.D.); (B.S.E.); (S.S.K.)
| | - Richard C. Daly
- Department of Cardiovascular Diseases and Health Sciences Research and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA; (W.K.K.); (N.L.P.); (R.C.D.); (B.S.E.); (S.S.K.)
| | - Brooks S. Edwards
- Department of Cardiovascular Diseases and Health Sciences Research and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA; (W.K.K.); (N.L.P.); (R.C.D.); (B.S.E.); (S.S.K.)
| | - D. Eric Steidley
- Department of Cardiovascular Diseases, Mayo Clinic Arizona, Phoenix, AZ 85054, USA; (D.E.S.); (R.L.S.)
| | - Robert L. Scott
- Department of Cardiovascular Diseases, Mayo Clinic Arizona, Phoenix, AZ 85054, USA; (D.E.S.); (R.L.S.)
| | - Sudhir S. Kushwaha
- Department of Cardiovascular Diseases and Health Sciences Research and the William J von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA; (W.K.K.); (N.L.P.); (R.C.D.); (B.S.E.); (S.S.K.)
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11
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Rodriguez ER, Santos-Martins C, Tan CD. Pathology of cardiac transplantation. Cardiovasc Pathol 2022. [DOI: 10.1016/b978-0-12-822224-9.00023-2] [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: 10/17/2022] Open
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12
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Bellumkonda L, Oikonomou EK, Hsueh C, Maulion C, Testani J, Patel J. The Impact of Induction Therapy on Mortality and Treated Rejection in Cardiac Transplantation: A Retrospective Study. J Heart Lung Transplant 2022; 41:482-491. [DOI: 10.1016/j.healun.2022.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 12/07/2021] [Accepted: 01/01/2022] [Indexed: 11/27/2022] Open
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13
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Bhavsar T, Crane GM. Immunodeficiency-Related Lymphoid Proliferations: New Insights With Relevance to Practice. Curr Hematol Malig Rep 2020; 15:360-371. [PMID: 32535851 DOI: 10.1007/s11899-020-00594-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
PURPOSE OF REVIEW Our understanding of risk factors and mechanisms underlying immunosuppression-related lymphoproliferative disorders continues to evolve. An increasing number of patients are living with altered immune status due to HIV, solid organ or hematopoietic stem cell transplant, treatment of autoimmune disease, or advanced age. This review covers advances in understanding, emerging trends, and revisions to diagnostic guidelines. RECENT FINDINGS The tumor microenvironment, including interactions between the host immune system and tumor cells, is of increasing interest in the setting of immunosuppression. While some forms of lymphoproliferative disease are associated with unique risk factors, common mechanisms are also emerging. Indolent forms, such as Epstein-Barr virus positive mucocutaneous ulcer, are important to recognize. As methods to modulate the immune system evolve, more data are needed to understand and minimize lymphoproliferative disease risk. A better understanding of individual risk factors and common mechanisms underlying immunosuppression-related lymphoproliferations will ultimately enable improved prevention and treatment of these disorders.
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Affiliation(s)
- Tapan Bhavsar
- Department of Pathology and Laboratory Medicine, George Washington School of Medicine, Washington, DC, USA
| | - Genevieve M Crane
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
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14
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Abstract
Lung transplantation is an established therapeutic option for selected patients with advanced lung diseases. As early outcomes after lung transplantation have improved, chronic medical illnesses have emerged as significant obstacles to long-term survival. Among them is post-transplant malignancy, currently representing the 2nd most common cause of death 5–10 years after transplantation. Chronic immunosuppressive therapy and resulting impairment of anti-tumor immune surveillance is thought to have a central role in cancer development after solid organ transplantation (SOT). Lung transplant recipients receive more immunosuppression than other SOT populations, likely contributing to even higher risk of cancer among this group. The most common cancers in lung transplant recipients are non-melanoma skin cancers, followed by lung cancer and post-transplant lymphoproliferative disorder (PTLD). The purpose of this review is to outline the common malignancies following lung transplant, their risk factors, prognosis and current means for both prevention and treatment.
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Affiliation(s)
- Osnat Shtraichman
- Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Pulmonary Institute, Rabin Medical Center, Affiliated with Sackler School of Medicine Tel Aviv University, Petach Tikva, Israel
| | - Vivek N Ahya
- Pulmonary, Allergy and Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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15
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Recent Advances in Electrochemical and Optical Biosensors Designed for Detection of Interleukin 6. SENSORS 2020; 20:s20030646. [PMID: 31979357 PMCID: PMC7038342 DOI: 10.3390/s20030646] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 12/06/2019] [Accepted: 12/18/2019] [Indexed: 12/11/2022]
Abstract
Interleukin 6 (IL-6), being a major component of homeostasis, immunomodulation, and hematopoiesis, manifests multiple pathological conditions when upregulated in response to viral, microbial, carcinogenic, or autoimmune stimuli. High fidelity immunosensors offer real-time monitoring of IL-6 and facilitate early prognosis of life-threatening diseases. Different approaches to augment robustness and enhance overall performance of biosensors have been demonstrated over the past few years. Electrochemical- and fluorescence-based detection methods with integrated electronics have been subjects of intensive research due to their ability to offer a better signal-to-noise ratio, high specificity, ultra-sensitivity, and wide dynamic range. In this review, the pleiotropic role of IL-6 and its clinical significance is discussed in detail, followed by detection schemes devised so far for their quantitative analysis. A critical review on underlying signal amplification strategies and performance of electrochemical and optical biosensors is presented. In conclusion, we discuss the reliability and feasibility of the proposed detection technologies for commercial applications.
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16
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Kaulen LD, Galluzzo D, Hui P, Barbiero F, Karschnia P, Huttner A, Fulbright R, Baehring JM. Prognostic markers for immunodeficiency-associated primary central nervous system lymphoma. J Neurooncol 2019; 144:107-115. [PMID: 31190317 DOI: 10.1007/s11060-019-03208-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Accepted: 06/04/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Immunodeficiency is a major risk factor for primary central nervous system lymphoma (PCNSL), but data on the disease in immunocompromised hosts are scarce. We aimed to define clinical and imaging features and determine prognostic factors for immunodeficiency-associated PCNSL. METHODS All PCNSL cases seen at Yale-New Haven Hospital between 2002 and 2017 were retrospectively screened for immunodeficiency. For patients with immunosuppression, biopsies were evaluated and clinical data were collected. Predictors of survival were identified using Kaplan-Meier survival analysis and log-rank test. p values < 0.05 were considered significant. RESULTS 23 patients with immunodeficiencies were identified: eleven on immunosuppressants after solid organ transplantation, seven with human immunodeficiency virus infection, and five on immunosuppressive treatment due to various autoimmune disorders. PCNSL cases were largely Epstein-Barr-Virus positive (78%), histologically classified as diffuse large B cell lymphomas (87%), and showed peripheral contrast enhancement (81%) and corresponding heterogeneous diffusion-weighted imaging patterns (DWI) on magnetic resonance imaging (MRI) (71%). Median overall survival was 31 months. Age > 60 years at diagnosis (p < 0.01), peripheral enhancement of the mass on MRI (p = 0.04), heterogeneous DWI patterns (p = 0.04), and clonal immunoglobulin heavy chain gene rearrangement (IgHR) (p = 0.03) were found to be negative prognostic markers. CONCLUSIONS Immunodeficiency-associated PCNSL presents with similar clinical, pathological and imaging features. Age > 60 years, clonal IgHR, heterogeneous DWI pattern and peripheral enhancement on MRI may serve as predictors of less favorable outcome.
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Affiliation(s)
- Leon D Kaulen
- Department of Neurology, Yale School of Medicine, New Haven, USA
| | - Daniela Galluzzo
- Department of Neurology, Yale School of Medicine, New Haven, USA
| | - Pei Hui
- Department of Pathology, Yale School of Medicine, New Haven, USA
| | - Frank Barbiero
- Department of Neurology, Yale School of Medicine, New Haven, USA
| | | | - Anita Huttner
- Department of Pathology, Yale School of Medicine, New Haven, USA
| | - Robert Fulbright
- Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, USA
| | - Joachim M Baehring
- Department of Neurology, Yale School of Medicine, New Haven, USA. .,Department of Neurosurgery, Yale School of Medicine, New Haven, USA. .,Departments of Neurology and Neurosurgery, Section of Neuro-Oncology, Yale School of Medicine, Yale Cancer Center, 333 Cedar Street, New Haven, CT, 06510, USA.
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17
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Shen T, Huh MH, Czer LS, Vaidya A, Esmailian F, Kobashigawa JA, Nurok M. Controversies in the Postoperative Management of the Critically Ill Heart Transplant Patient. Anesth Analg 2019; 129:1023-1033. [PMID: 31162160 DOI: 10.1213/ane.0000000000004220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Heart transplant recipients are susceptible to a number of complications in the immediate postoperative period. Despite advances in surgical techniques, mechanical circulatory support (MCS), and immunosuppression, evidence supporting optimal management strategies of the critically ill transplant patient is lacking on many fronts. This review identifies some of these controversies with the aim of stimulating further discussion and development into these gray areas.
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Affiliation(s)
- Tao Shen
- From the Departments of Anesthesiology.,Surgery, Cedars-Sinai Heart Institute, Los Angeles, California
| | | | - Lawrence S Czer
- Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, California
| | - Ajay Vaidya
- Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, California
| | | | - Jon A Kobashigawa
- Division of Cardiology, Cedars-Sinai Heart Institute, Los Angeles, California
| | - Michael Nurok
- From the Departments of Anesthesiology.,Surgery, Cedars-Sinai Heart Institute, Los Angeles, California
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18
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Hiesse C, Kriaa F, Alard P, Lantz O, Noury J, Bensadoun H, Benoit G, Charpentier B, Fries D, Bazin H. Prophylactic use of the IL-2 receptor-specific monoclonal antibody LO-Tact-1 with cyclosporin A and steroids in renal transplantation. Transpl Int 2018. [DOI: 10.1111/tri.1992.5.s1.444] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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19
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De Backer D, Abramowicz D, Goldman M, De Pauw L, Viseur P, Vanherweghem JL, Kinnaert P, Vereerstraeten P. High or low dose steroid therapy for acute renal transplant rejection after prophylactic OKT3 treatment: a prospective randomized study. Transpl Int 2018. [DOI: 10.1111/tri.1992.5.s1.437] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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20
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Brouwer RML, Balk AHMM, Weimar W. Occurrence of lymphoproliferative disorder after heart transplantation is related to the total immunosuppressive load. Transpl Int 2018. [DOI: 10.1111/tri.1992.5.s1.259] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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21
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Hotta M, Nakaya A, Fujita S, Satake A, Nakanishi T, Azuma Y, Tsubokura Y, Konishi A, Yoshimura H, Ito T, Ishii K, Nomura S. Blastic Epstein-Barr virus associated post-transplant lymphoproliferative disorder after allogeneic stem cell transplantation for severe aplastic anemia. Hematol Rep 2018; 10:7527. [PMID: 30046412 PMCID: PMC6036979 DOI: 10.4081/hr.2018.7527] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Accepted: 05/15/2018] [Indexed: 11/23/2022] Open
Abstract
Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized complication of organ transplantation. Progress has recently been made in the pathological classification of PTLD. However, the clinical course has not been clarified because of the rarity of this disease. We experienced a case of PTLD with a fulminant clinical course. The patient had been under longterm immunosuppressive treatment for aplastic anemia. He received related allogeneic hematopoietic stem cell transplantation. Soon after transplantation, he developed PTLD. According to the guidelines, we reduced immunosuppression. However, the disease course was so fulminant that there was no time for the patient to respond, and he died of multi-organ failure. There may be various clinical types of PTLD, which may include some fulminant cases. In such a case, it is not sufficient to reduce immunosuppression. The patient should be carefully observed and an appropriate individual treatment should be chosen.
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Affiliation(s)
- Masaaki Hotta
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Aya Nakaya
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Shinya Fujita
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Atsushi Satake
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Takahisa Nakanishi
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Yoshiko Azuma
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Yukie Tsubokura
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Akiko Konishi
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Hideaki Yoshimura
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Tomoki Ito
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Kazuyoshi Ishii
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Shosaku Nomura
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
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22
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23
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Dharnidharka VR. Comprehensive review of post-organ transplant hematologic cancers. Am J Transplant 2018; 18:537-549. [PMID: 29178667 DOI: 10.1111/ajt.14603] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2017] [Revised: 11/17/2017] [Accepted: 11/17/2017] [Indexed: 01/25/2023]
Abstract
A higher risk for a variety of cancers is among the major complications of posttransplantation immunosuppression. In this part of a continuing series on cancers posttransplantation, this review focuses on the hematologic cancers after solid organ transplantation. Posttransplantation lymphoproliferative disorders (PTLDs), which comprise the great majority of hematologic cancers, represent a spectrum of conditions that include, but are not limited to, the Hodgkin and non-Hodgkin lymphomas. The oncogenic Epstein-Barr virus is a key pathogenic driver in many PTLD cases, through known and unknown mechanisms. The other hematologic cancers include leukemias and plasma cell neoplasms (multiple myeloma and plasmacytoma). Clinical features vary across malignancies and location. Preventive screening strategies have been attempted mainly for PTLDs. Treatments include the chemotherapy regimens for the specific cancers, but also include reduction of immunosuppression, rituximab, and other therapies.
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Affiliation(s)
- Vikas R Dharnidharka
- Division of Pediatric Nephrology, Washington University School of Medicine, Saint Louis, MO, USA
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24
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Kanakry JA, Ambinder RF. Virus-Associated Lymphoma. Hematology 2018. [DOI: 10.1016/b978-0-323-35762-3.00083-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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25
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Kim IC, Youn JC, Kobashigawa JA. The Past, Present and Future of Heart Transplantation. Korean Circ J 2018; 48:565-590. [PMID: 29968430 PMCID: PMC6031715 DOI: 10.4070/kcj.2018.0189] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 06/18/2018] [Indexed: 01/04/2023] Open
Abstract
Heart transplantation (HTx) has become standard treatment for selected patients with end-stage heart failure. Improvements in immunosuppressant, donor procurement, surgical techniques, and post-HTx care have resulted in a substantial decrease in acute allograft rejection, which had previously significantly limited survival of HTx recipients. However, limitations to long-term allograft survival exist, including rejection, infection, coronary allograft vasculopathy, and malignancy. Careful balance of immunosuppressive therapy and vigilant surveillance for complications can further improve long-term outcomes of HTx recipients.
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Affiliation(s)
- In Cheol Kim
- Division of Cardiology, Keimyung University Dongsan Medical Center, Daegu, Korea
| | - Jong Chan Youn
- Division of Cardiology, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong, Korea.
| | - Jon A Kobashigawa
- Division of Cardiology, Cedars-Sinai Smidt Heart Institute, Los Angeles, CA, USA.
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Nagle SJ, Reshef R, Tsai DE. Posttransplant Lymphoproliferative Disorder in Solid Organ and Hematopoietic Stem Cell Transplantation. Clin Chest Med 2017; 38:771-783. [DOI: 10.1016/j.ccm.2017.08.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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27
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McPherson I, Kirk A. The incidence of non-melanoma skin cancer and post-transplant lympho-proliferative disorders in the Scottish cardiac transplant population and the provision of specialist dermatological follow-up. Scott Med J 2017; 63:3-10. [PMID: 29073846 DOI: 10.1177/0036933017736423] [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] [Indexed: 11/15/2022]
Abstract
Background Immunosuppression helps prevent acute rejection post-cardiac transplant but has been linked to malignancy development. This may be due to a reduction in T-lymphocyte function, a direct oncogenic effect or the increased impact of environmental carcinogens. There has been shown to be significant increases in non-melanoma skin cancers and post-transplant lympho-proliferative disorders, particularly in those treated with OKT3. Aim To investigate the survival and incidence of malignancy in the Scottish cardiac transplant population and whether rates of non-melanoma skin cancers justify the provision of specialist dermatological follow-up. Methods and results Retrospective case note analysis of patients transplanted (363) or followed up (2) in Scotland from 1992 to 2016. Kaplan-Meier survival analysis generated a survival curve. Patients had a 1-year survival of 82% and a median survival of 10.9 years. There were 60 (95% CI 47.5, 75.2) NMSCs and 8 (3.7, 12.4) post-transplant lympho-proliferative disorders diagnosed in the cohort (3110 person years follow-up). Fisher's exact test was employed to analyse the association between induction therapy (via OKT3 or rabbit antithymocyte globulin) and post-transplant lympho-proliferative disorder development. Patients treated with OKT3 had a 6.7 times greater risk ( P = 0.014) and a shorter experience of patients treated with rabbit antithymocyte globulin has so far shown no significantly altered risk ( P = 1.00) of developing a post-transplant lympho-proliferative disorder. Conclusion Incidences of non-melanoma skin cancers and post-transplant lympho-proliferative disorders were increased in the Scottish cardiac transplant population and there was a significant association between post-transplant lympho-proliferative disorder development and OKT3 therapy but not rabbit antithymocyte globulin therapy. These findings in Scottish patients reflect what is published in wider literature and support the provision of a dedicated post-transplant dermatology clinic.
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Affiliation(s)
| | - Alan Kirk
- 2 Consultant Thoracic Surgeon, Golden Jubilee National Hospital, UK
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28
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Lichtenberg S, Rahamimov R, Green H, Fox BD, Mor E, Gafter U, Chagnac A, Rozen-Zvi B. The incidence of post-transplant cancer among kidney transplant recipients is associated with the level of tacrolimus exposure during the first year after transplantation. Eur J Clin Pharmacol 2017; 73:819-826. [DOI: 10.1007/s00228-017-2234-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Accepted: 03/03/2017] [Indexed: 02/08/2023]
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29
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Eshraghian A, Imanieh MH, Dehghani SM, Nikeghbalian S, Shamsaeefar A, Barshans F, Kazemi K, Geramizadeh B, Malek-Hosseini SA. Post-transplant lymphoproliferative disorder after liver transplantation: Incidence, long-term survival and impact of serum tacrolimus level. World J Gastroenterol 2017; 23:1224-1232. [PMID: 28275302 PMCID: PMC5323447 DOI: 10.3748/wjg.v23.i7.1224] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 12/03/2016] [Accepted: 01/18/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate incidence and survival of post-transplant lymphoproliferative disorder (PTLD) patients after liver transplantation. METHODS A cross-sectional survey was conducted among patients who underwent liver transplantation at Shiraz Transplant Center (Shiraz, Iran) between August 2004 and March 2015. Clinical and laboratory data of patients were collected using a data gathering form. RESULTS There were 40 cases of PTLD in the pediatric age group and 13 cases in the adult group. The incidence of PTLD was 6.25% in pediatric patients and 1.18% in adult liver transplant recipients. The post-PTLD survival of patients at 6 mo was 75.1% ± 6%, at 1 year was 68.9% ± 6.5% and at 5 years was 39.2% ± 14.2%. Higher serum tacrolimus level was associated with lower post-PTLD survival in pediatric patients (OR = 1.07, 95%CI: 1.006-1.15, P = 0.032). A serum tacrolimus level over 11.1 ng/mL was predictive of post PTLD survival (sensitivity = 90%, specificity = 52%, area under the curve = 0.738, P = 0.035). CONCLUSION Incidence of PTLD in our liver transplant patients is comparable to other centers. Transplant physicians may consider adjustment of tacrolimus dose to maintain its serum level below this cutoff point.
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Le J, Durand CM, Agha I, Brennan DC. Epstein-Barr virus and renal transplantation. Transplant Rev (Orlando) 2016; 31:55-60. [PMID: 28089555 DOI: 10.1016/j.trre.2016.12.001] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 12/12/2016] [Accepted: 12/25/2016] [Indexed: 01/22/2023]
Abstract
Epstein-Barr virus (EBV) is a gamma herpesvirus associated with diseases ranging from asymptomatic viremia to post-transplant malignancies in kidney transplant recipients. EBV specifically is associated with post-transplantation lymphoproliferative disorder (PTLD), in kidney transplant recipients, with increased risk in EBV seronegative patients with EBV seropositive donors on intensified immunosuppression. The diagnosis of PTLD relies on clinical suspicion plus tissue biopsy with polymerase chain reaction (PCR) testing of blood currently used for risk determination in high-risk recipients. Therapeutic strategies for PTLD include reduction of immunosuppression, chemotherapy and rituximab, and consideration of sirolimus-based immunosuppression. Antivirals such as ganciclovir are used to prevent reactivation of cytomegalovirus and other herpes viruses but are not onco-therapeutic. Radiation therapy or surgery is indicated for bulky, disseminated or recalcitrant disease. Prognosis varies depending on the type of malignancy identified and stage of disease.
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Affiliation(s)
- Jade Le
- University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, United States
| | - Christine M Durand
- Johns Hopkins Medical Institute, 1830 East Monument Street, Room 450D, Baltimore, MD 21287, United States
| | - Irfan Agha
- Dallas Renal Group, 3571 W. Wheatland Road, Suite 101, Dallas, TX 75237, United States
| | - Daniel C Brennan
- Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110, United States.
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31
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Recent Advances in Mammalian Target of Rapamycin Inhibitor Use in Heart and Lung Transplantation. Transplantation 2016; 100:2558-2568. [DOI: 10.1097/tp.0000000000001432] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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32
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Abstract
The success of pediatric solid organ transplantation has been largely due to advancements in surgical techniques, technology, and preoperative and postoperative care. Potent immunosuppression continues to reduce the incidence and severity of rejection, and improve long-term survival. However, there is growing awareness of the role immunosuppression plays in contributing to the incidence of cytomegalovirus, Epstein-Barr virus, and Epstein-Barr virus–associated posttransplant lymphoproliferative disease. Herpes viruses such as these present as primary or recurrent disease and continue to be a significant source of morbidity and mortality in transplant recipients. This paper reviews the predictors of disease, clinical features, diagnosis, and methods of treatment of these major posttransplant viral syndromes. As part of the human herpes virus family, varicella-zoster virus will also be discussed. A case study shows the delicate balance of treating concomitant varicella infection at the time of transplantation.
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33
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Abstract
Infections and malignancies are the expected complications of immunosuppressive therapy, which non-specifically impairs cellular and humoral immune responses in renal transplant recipients. Infections were usually frequent and severe during the early post-transplant period (first year). Recent diagnostic methods (molecular biology) and availability of new antivirals, antifungal and antibiotic drugs made rapid diagnosis and systematic preventive strategies much easier and this resulted in a significant reduction of infections and infectious death in this population. However, new infectious agents like BK polyomavirus, hepatitis E virus, parvovirus (as well as Chigunkunya, West Nile and others in particular areas) were recently recognized as responsible of aggressive infections in the immunocompromised host. Malignancies are also common after transplantation, due to the intensity and duration of immunosuppression. Skin cancers and lymphoproliferative disorders are the most common and are undoubtedly caused by viral infections, but incidence of non-skin cancers is also increased. After reduction of immunosuppression, treatment is similar to non-transplant patients: Results are usually poor and cancer is now the third cause of death in transplant recipients. Due to their anti-proliferative and anti-tumoral properties, incidence of de novo cancer significantly decreased in patients receiving mTor inhibitors as maintenance immunosuppression; furthermore, in patients already diagnosed with Kaposi sarcoma or recurrent skin cancers, introduction of mTor was associated with stabilisation and/or regression of malignant lesions.
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34
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Dropulic LK, Lederman HM. Overview of Infections in the Immunocompromised Host. Microbiol Spectr 2016; 4:10.1128/microbiolspec.DMIH2-0026-2016. [PMID: 27726779 PMCID: PMC8428766 DOI: 10.1128/microbiolspec.dmih2-0026-2016] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Indexed: 12/12/2022] Open
Abstract
Understanding the components of the immune system that contribute to host defense against infection is key to recognizing infections that are more likely to occur in an immunocompromised patient. In this review, we discuss the integrated system of physical barriers and of innate and adaptive immunity that contributes to host defense. Specific defects in the components of this system that predispose to particular infections are presented. This is followed by a review of primary immunodeficiency diseases and secondary immunodeficiencies, the latter of which develop because of a specific illness or condition or are treatment-related. The effects of treatment for neoplasia, autoimmune diseases, solid organ and stem cell transplants on host defenses are reviewed and associated with susceptibility to particular infections. In conclusion, an approach to laboratory screening for a suspected immunodeficiency is presented. Knowledge of which host defects predispose to specific infections allows clinicians to prevent, diagnose, and manage infections in their immunocompromised patients most effectively.
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Affiliation(s)
- Lesia K Dropulic
- The National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of Intramural Research, Bethesda, MD 20892
| | - Howard M Lederman
- Departments of Pediatrics, Medicine, and Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287
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Abstract
Posttransplant lymphoproliferative disorders (PTLD) are an acknowledged complica tion of transplantation and immunosuppression that may be difficult to distinguish from severe rejection in small biopsy specimens. In this study we compared 19 exam ples of PTLD with 20 cases of severe rejection. Antibodies to CD20, CD43, CD45, CD45RO, MB2, Epstein-Barr virus-latent membrane protein, bcl-2 , proliferating cell nuclear antigen, cytomegalovirus early antigen, and hepatitis B surface and core anti gens were employed. The results expressed as percentage of positive cases of PTLD/ rejection, were: CD20, 89/0; CD43, 63/100; CD45, 100/100; CD45RO, 5/85; MB2, 32/0; Epstein-Barr virus-latent membrane protein, 79/0. Aberrant coexpression of CD20 and CD43 was seen in 11 cases of PTLD and no cases of severe rejection. The proliferating cell nuclear antigen index was 58% in PTLD cases, and 20% in rejection; stains for bcl-2 protein were nondiscriminatory. No examples of either process were reactive for cytomegalovirus or hepatitis B antigens. These results indicate that PTLD usually has a B-cell phenotype, often with associated necrosis, while acute rejection is a T-cell process. Expression of Epstein-Barr virus-latent membrane protein, and coexpression of CD43 and CD20 are additional attributes of PTLD. Int J Surg Pathol 2(2):105-116, 1994
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Affiliation(s)
- Jon H. Ritter
- Division of Surgical Pathology, Box 8118, Barnes Hospital, Washington University Medical Center, One Barnes Hospital Plaza, St. Louis, MO 63110
| | - Mark R. Wick
- Hospital-Washington University Medical Center, St. Louis, Mis souri
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36
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Post-transplant Lymphoproliferative Disorder (PTLD): Infection, Cancer? CURRENT TRANSPLANTATION REPORTS 2016. [DOI: 10.1007/s40472-016-0102-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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37
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Na R, Laaksonen MA, Grulich AE, Meagher NS, McCaughan GW, Keogh AM, Vajdic CM. Iatrogenic immunosuppression and risk of non-Hodgkin lymphoma in solid organ transplantation: A population-based cohort study in Australia. Br J Haematol 2016; 174:550-62. [DOI: 10.1111/bjh.14083] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Accepted: 01/19/2016] [Indexed: 12/11/2022]
Affiliation(s)
- Renhua Na
- Adult Cancer Program; Lowy Cancer Research Centre; Prince of Wales Clinical School; University of New South Wales; Sydney NSW Australia
| | - Maarit A. Laaksonen
- Adult Cancer Program; Lowy Cancer Research Centre; Prince of Wales Clinical School; University of New South Wales; Sydney NSW Australia
- Centre for Big Data Research in Health; University of New South Wales; Sydney NSW Australia
| | - Andrew E. Grulich
- Kirby Institute; University of New South Wales; Sydney NSW Australia
| | - Nicola S. Meagher
- Adult Cancer Program; Lowy Cancer Research Centre; Prince of Wales Clinical School; University of New South Wales; Sydney NSW Australia
| | - Geoffrey W. McCaughan
- The Centenary Research Institute; Australian National Liver Transplant Unit; Royal Prince Alfred Hospital and University of Sydney; Sydney NSW Australia
| | | | - Claire M. Vajdic
- Adult Cancer Program; Lowy Cancer Research Centre; Prince of Wales Clinical School; University of New South Wales; Sydney NSW Australia
- Centre for Big Data Research in Health; University of New South Wales; Sydney NSW Australia
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38
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Abstract
OBJECTIVES Epstein Barr virus (EBV) is a human herpes virus that infects 90% of the world's population and has been linked to the development of lymphoproliferative disorders (LPDs) and immunosuppression. Primary EBV infection in patients with IBD on thiopurines is a risk factor for LPD, including lymphoma. We aimed to describe EBV status in a pediatric population with IBD with an emphasis on those initiating thiopurines. METHODS Electronic medical records and EBV serologies were reviewed and categorized into asymptomatic screening versus suspicion for acute infection. EBV status before therapy was described by sex, age, and therapeutic regimen. Descriptive statistics and univariate analysis were employed. RESULTS Only 150 (22%) of our 688 pediatric patients with IBD had documented EBV status regardless of age or treatment regimen. Only 17% were assessed for suspicion of acute infection and 83% for screening. Sixty-four (52%) screened patients were checked before starting any treatment and only 40% were immunoglobulin (Ig)G positive. There was no difference in mean age between the seronegative and seropositive group. The majority (63%) of thiopurine-treated patients were IgG negative before starting therapy. Eighty percent of primary EBV infections occurred on thiopurines at a mean (SD) of 2 ± 1.5 years after initiating therapy. CONCLUSIONS The majority of our pediatric patients with IBD with documented EBV status were IgG negative at thiopurine initiation. Thiopurines were also associated with primary EBV infection. EBV status may be an important determinate of whether physicians prescribe thiopurines given the risk of primary EBV infections and lymphoproliferative diseases.
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39
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Lowered Immune Cell Function in Liver Recipients Recovered From Posttransplant Lymphoproliferative Disease Who Developed Graft Tolerance. Transplant Direct 2016; 2:e66. [PMID: 27500258 PMCID: PMC4946509 DOI: 10.1097/txd.0000000000000577] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Tolerance after treatment and recovery from posttransplant lymphoproliferative disease (PTLD) have been described but little is known about the immunology. The objective of this study is to evaluate the immunity of pediatric recipients who recovered from PTLD.
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40
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Rouphael B, Lankireddy S, Lazaryan A, Kukla A, Ibrahim HN, Matas AJ, Issa N. Outcomes of kidney retransplantation in recipients with prior post-transplant lymphoproliferative disorder. Clin Transplant 2016; 30:60-5. [DOI: 10.1111/ctr.12659] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/20/2015] [Indexed: 11/28/2022]
Affiliation(s)
- Bassem Rouphael
- Division of Renal Diseases and Hypertension; Department of Medicine; University of Minnesota; Minneapolis MN USA
| | - Srilakshmi Lankireddy
- Division of Renal Diseases and Hypertension; Department of Medicine; University of Minnesota; Minneapolis MN USA
| | - Aleksandr Lazaryan
- Division of Hematology, Oncology and Transplantation; Department of Medicine; University of Minnesota; Minneapolis MN USA
| | - Aleksandra Kukla
- Division of Renal Diseases and Hypertension; Department of Medicine; University of Minnesota; Minneapolis MN USA
| | - Hassan N. Ibrahim
- Division of Renal Diseases and Hypertension; Department of Medicine; University of Minnesota; Minneapolis MN USA
| | - Arthur J. Matas
- Division of Transplant Surgery; Department of Surgery; University of Minnesota; Minneapolis MN USA
| | - Naim Issa
- Division of Renal Diseases and Hypertension; Department of Medicine; University of Minnesota; Minneapolis MN USA
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41
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Tan C, Halushka M, Rodriguez E. Pathology of Cardiac Transplantation. Cardiovasc Pathol 2016. [DOI: 10.1016/b978-0-12-420219-1.00016-1] [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: 11/25/2022] Open
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42
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Lateef N, Abdul Basit K, Abbasi N, Kazmi SMH, Ansari AB, Shah M. Malignancies After Heart Transplant. EXP CLIN TRANSPLANT 2015; 14:12-6. [PMID: 26643469 DOI: 10.6002/ect.2015.0214] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Along with graft vasculopathy, malignancies comprise a major complication after heart transplant, with a rate of occurrence of 39.1% in 10 years. Skin cancers and posttransplant lymphoproliferative disorder are more common in adults, whereas lymphoma is more often shown in children. A major cause of malignancies after heart transplant is the use of increased doses of prophylactics needed during immunosuppressive therapy. Data, however, are scarce regarding the association between a particular immunosuppressive drug and a posttransplant malignancy. Compared with the general population, recipients have a higher incidence of malignancies after heart transplant, with an early onset and more aggressive disease. Solid tumors known to occur in heart transplant recipients include lung cancer, bladder and prostate carcinoma, adenocarcinoma of the oral cavity, stomach cancer, and bowel cancer, although the incidence is rare. The risk factors for development of a malignancy after heart transplant are the same as for the nontransplant population.
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Affiliation(s)
- Noman Lateef
- From the Dow Medical College, Dow University of Health Sciences, Karachi, Pakistan
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43
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Pardo F, Pons JA, Briceño J. V Consensus Meeting of the Spanish Society for Liver Transplant on high-risk recipients, immunosupression scenarios and management of hepatocarcinoma on the transplant waiting list. Cir Esp 2015; 93:619-637. [PMID: 26187597 DOI: 10.1016/j.ciresp.2015.04.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 04/17/2015] [Indexed: 12/11/2022]
Abstract
With the aim to promote the elaboration of consensus documents on state of the art topics in liver transplantation with multidisciplinary management, the Spanish Society for Liver Transplantation (SETH) organized the V Consensus Meeting with the participation of experts from all the Spanish liver transplant programs. In this edition, the following topics were revised, and we present the summary: 1. High-risk receptors; 2. Immunosuppression scenarios; and 3. Management of the patient with hepatocarcinoma in the waiting list.
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Affiliation(s)
- Fernando Pardo
- Servicio de Cirugía Hepatobiliar y Trasplantes, Clínica Universidad de Navarra, Pamplona, España
| | - José Antonio Pons
- Unidad de Hepatología y Trasplante Hepático, Servicio de Aparato Digestivo, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, España
| | - Javier Briceño
- Servicio de Cirugía General y del Aparato Digestivo, Unidad de Trasplante Hepático, Hospital Universitario Reina Sofía, Córdoba, España.
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44
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V Reunión de Consenso de la Sociedad Española de Trasplante Hepático sobre receptores de riesgo elevado, escenarios actuales de inmunosupresión y manejo del hepatocarcinoma en espera de trasplante. GASTROENTEROLOGIA Y HEPATOLOGIA 2015; 38:600-18. [DOI: 10.1016/j.gastrohep.2015.06.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 06/11/2015] [Accepted: 06/30/2015] [Indexed: 12/14/2022]
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45
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Lam GY, Halloran BP, Peters AC, Fedorak RN. Lymphoproliferative disorders in inflammatory bowel disease patients on immunosuppression: Lessons from other inflammatory disorders. World J Gastrointest Pathophysiol 2015; 6:181-192. [PMID: 26600976 PMCID: PMC4644882 DOI: 10.4291/wjgp.v6.i4.181] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Accepted: 09/28/2015] [Indexed: 02/06/2023] Open
Abstract
Immunosuppressive agents, such as thiopurines, methotrexate, and biologics, have revolutionized the treatment of inflammatory bowel disease (IBD). However, a number of case reports, case control studies and retrospective studies over the last decade have identified a concerning link between immunosuppression and lymphoproliferative disorders (LPDs), the oncological phenomenon whereby lymphocytes divide uncontrollably. These LPDs have been associated with Epstein-Barr virus (EBV) infection in which the virus provides the impetus for malignant transformation while immunosuppression hampers the immune system’s ability to detect and clear these malignant cells. As such, the use of immunosuppressive agents may come at the cost of increased risk of developing LPD. While little is known about the LPD risk in IBD, more is known about immunosuppression in the post-transplantation setting and the development of EBV associated post-transplantation lymphoproliferative disorders (PTLD). In review of the PTLD literature, evidence is available to demonstrate that certain immune suppressants such as cyclosporine and T-lymphocyte modulators in particular are associated with an increased risk of PTLD development. As well, high doses of immunosuppressive agents and multiple immunosuppressive agent use are also linked to increased PTLD development. Here, we discuss these findings in context of IBD and what future studies can be taken to understand and reduce the risk of EBV-associated LPD development from immunosuppression use in IBD.
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46
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Crane GM, Powell H, Kostadinov R, Rocafort PT, Rifkin DE, Burger PC, Ambinder RF, Swinnen LJ, Borowitz MJ, Duffield AS. Primary CNS lymphoproliferative disease, mycophenolate and calcineurin inhibitor usage. Oncotarget 2015; 6:33849-66. [PMID: 26460822 PMCID: PMC4741807 DOI: 10.18632/oncotarget.5292] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 09/04/2015] [Indexed: 12/24/2022] Open
Abstract
Immunosuppression for solid organ transplantation increases lymphoproliferative disease risk. While central nervous system (CNS) involvement is more rare, we noticed an increase in primary CNS (PCNS) disease. To investigate a potential association with the immunosuppressive regimen we identified all post-transplant lymphoproliferative disease (PTLD) cases diagnosed over a 28-year period at our institution (174 total, 29 PCNS) and all similar cases recorded in a United Network for Organ Sharing-Organ Procurement and Transplant Network (UNOS-OPTN) datafile. While no PCNS cases were diagnosed at our institution between 1986 and 1997, they comprised 37% of PTLD cases diagnosed from 2011-2014. PCNS disease was more often associated with renal vs. other organ transplant, Epstein-Barr virus, large B-cell morphology and mycophenolate mofetil (MMF) as compared to PTLD that did not involve the CNS. Calcineurin inhibitors were protective against PCNS disease when given alone or in combination with MMF. A multivariate analysis of a larger UNOS-OPTN dataset confirmed these findings, where both MMF and lack of calcineurin inhibitor usage were independently associated with risk for development of PCNS PTLD. These findings have significant implications for the transplant community, particularly given the introduction of new regimens lacking calcineurin inhibitors. Further investigation into these associations is warranted.
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Affiliation(s)
- Genevieve M. Crane
- 1 Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Helen Powell
- 2 Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Rumen Kostadinov
- 2 Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- 3 Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins, Baltimore, MD, USA
| | - Patrick Tim Rocafort
- 4 Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, Baltimore, MD, USA
| | - Dena E. Rifkin
- 5 Veterans’ Affairs Healthcare System and Division of Nephrology, Department of Medicine, University of California-San Diego, San Diego, CA, USA
| | - Peter C. Burger
- 1 Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Richard F. Ambinder
- 3 Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins, Baltimore, MD, USA
| | - Lode J. Swinnen
- 3 Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins, Baltimore, MD, USA
| | - Michael J. Borowitz
- 1 Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Amy S. Duffield
- 1 Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
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47
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Burra P, Rodriguez-Castro KI. Neoplastic disease after liver transplantation: Focus on de novo neoplasms. World J Gastroenterol 2015; 21:8753-8768. [PMID: 26269665 PMCID: PMC4528018 DOI: 10.3748/wjg.v21.i29.8753] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Revised: 05/31/2015] [Accepted: 07/08/2015] [Indexed: 02/06/2023] Open
Abstract
De novo neoplasms account for almost 30% of deaths 10 years after liver transplantation and are the most common cause of mortality in patients surviving at least 1 year after transplant. The risk of malignancy is two to four times higher in transplant recipients than in an age- and sex-matched population, and cancer is expected to surpass cardiovascular complications as the primary cause of death in transplanted patients within the next 2 decades. Since exposure to immunosuppression is associated with an increased frequency of developing neoplasm, long-term immunosuppression should be therefore minimized. Promising results in the prevention of hepatocellular carcinoma (HCC) recurrence have been reported with the use of mTOR inhibitors including everolimus and sirolimus and the ongoing open-label prospective randomized controlled SILVER. Study will provide more information on whether sirolimus-containing vs mTOR-inhibitor-free immunosuppression is more efficacious in reducing HCC recurrence.
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48
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Abstract
Post-transplant lymphoproliferative disorders (PTLD) are a serious complication after solid organ or allogeneic hematopoietic stem cell transplantation and include a range of diseases from benign proliferations to malignant lymphomas. Risk factors for developing PTLD include Epstein-Barr virus (EBV) infection, recipient age, transplanted organ, type of immunosuppression, and genetics. Uncontrolled proliferation of EBV-infected B cells is implicated in EBV-positive PTLD, whereas the pathogenesis of EBV-negative PTLD may be similar to non-Hodgkin's lymphoma in the general population. The World Health Organization (WHO) classifies PTLD into four categories: early lesions, polymorphic PTLD, monomorphic PTLD, and classical Hodgkin's lymphoma (cHL). Treatment is aimed at cure of PTLD, while maintaining transplanted organ function. However, there are no established guidelines for the treatment of PTLD. Immune suppression reduction (ISR) is the first line of treatment in most cases, with more recent data suggesting early use of rituximab. In more aggressive forms of PTLD, upfront chemotherapy may offer a better and more durable response. Sequential therapy using rituximab followed by chemotherapy has demonstrated promising results and may establish a standard of care. Novel therapies including anti-viral agents, adoptive immunotherapy, and monoclonal antibodies targeting cytokines require further study in the prevention and treatment of PTLD.
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Affiliation(s)
- Arun K Singavi
- Department of Internal Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
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49
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Wáng YXJ. Advance modern medicine with clinical case reports. Quant Imaging Med Surg 2014; 4:439-43. [PMID: 25525572 DOI: 10.3978/j.issn.2223-4292.2014.11.10] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 11/03/2014] [Indexed: 12/25/2022]
Abstract
Randomized clinical trial (RCT) can fail to demonstrate the richness of individual patient characteristics. Given the unpredictable nature of medicine, a patient may present in an unusual way, have a strange new pathology, or react to a medical intervention in a manner not seen before. The publication of these novelties as case reports is a fundamental way of conveying medical knowledge. Throughout history there have been famous case studies that shaped the way we view health and disease. Case reports can have the following functions: (I) descriptions of new diseases; (II) study of mechanisms; (III) discovery new therapies; (IV) recognition of side effects; and (V) education. Before submitting a case report, it is worthwhile to refer to the Case Report Check Sheet described by Green and Johnson [2006].
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Affiliation(s)
- Yì-Xiáng J Wáng
- Department of Imaging and Interventional Radiology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
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50
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Camacho JC, Moreno CC, Harri PA, Aguirre DA, Torres WE, Mittal PK. Posttransplantation lymphoproliferative disease: proposed imaging classification. Radiographics 2014; 34:2025-38. [PMID: 25384299 DOI: 10.1148/rg.347130130] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Posttransplantation lymphoproliferative disease (PTLD) is the second most common tumor in adult transplant recipients. Most cases of PTLD are attributed to Epstein-Barr virus. Decreased levels of immunosurveillance against this tumor virus as a result of immunosuppressive regimens are thought to account for most cases of PTLD. Histologically, PTLD ranges from relatively benign lymphoid hyperplasia to poorly differentiated lymphoma, and tissue sampling is required to establish the subtype. The frequency of PTLD varies depending on the type of allograft and immunosuppressive regimen. PTLD has a bimodal manifestation, with most cases occurring within the first year after transplantation and a second peak occurring 4-5 years after transplantation. Patients are often asymptomatic or present with nonspecific symptoms, and a mass visible at imaging may be the first clue to the diagnosis. Imaging plays an important role in identifying the presence of disease, guiding tissue sampling, and evaluating response to treatment. The appearance of PTLD at imaging can vary. It may be nodal or extranodal. Extranodal disease may involve the gastrointestinal tract, solid organs, or central nervous system. Solid organ lesions may be solitary or multiple, infiltrate beyond the organ margins, and obstruct organ outflow. Suggestive imaging findings should prompt tissue sampling, because knowledge of the PTLD subtype is imperative for appropriate treatment. Treatment options include reducing immunosuppression, chemotherapy, radiation therapy, and surgical resection of isolated lesions.
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Affiliation(s)
- Juan C Camacho
- From the Abdominal Imaging Division, Department of Radiology and Imaging Sciences, Emory University School of Medicine, 1365 Clifton Rd NE, Suite AT-627, Atlanta, GA 30322 (J.C.C., C.C.M., P.A.H., W.E.T., P.K.M.); and Abdominal Imaging Division, Department of Imaging, Fundación Santa Fe de Bogotá University Hospital, Bogotá, Colombia (D.A.A.)
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