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      De novo malignancies after liver transplantation: The effect of immunosuppression-personal data and review of literature

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          Abstract

          BACKGROUND

          Immunosuppression has undoubtedly raised the overall positive outcomes in the post-operative management of solid organ transplantation. However, long-term exposure to immunosuppression is associated with critical systemic morbidities. De novo malignancies following orthotopic liver transplants (OLTs) are a serious threat in pediatric and adult transplant individuals. Data from different experiences were reported and compared to assess the connection between immunosuppression and de novo malignancies in liver transplant patients.

          AIM

          To study the role of immunosuppression on the incidence of de novo malignancies in liver transplant recipients.

          METHODS

          A systematic literature examination about de novo malignancies and immunosuppression weaning in adult and pediatric OLT recipients was described in the present review. Worldwide data were collected from highly qualified institutions performing OLTs. Patient follow-up, immunosuppression discontinuation and incidence of de novo malignancies were reported. Likewise, the review assesses the differences in adult and pediatric recipients by describing the adopted immunosuppression regimens and the different type of diagnosed solid and blood malignancy.

          RESULTS

          Emerging evidence suggests that the liver is an immunologically privileged organ able to support immunosuppression discontinuation in carefully selected recipients. Malignancies are often detected in liver transplant patients undergoing daily immunosuppression regimens. Post-transplant lymphoproliferative diseases and skin tumors are the most detected de novo malignancies in the pediatric and adult OLT population, respectively. To date, immunosuppression withdrawal has been achieved in up to 40% and 60% of well-selected adult and pediatric recipients, respectively. In both populations, a clear benefit of immunosuppression weaning protocols on de novo malignancies is difficult to ascertain because data have not been specified in most of the clinical experiences.

          CONCLUSION

          The selected populations of tolerant pediatric and adult liver transplant recipients greatly benefit from immunosuppression weaning. There is still no strong clinical evidence on the usefulness of immunosuppression withdrawal in OLT recipients on malignancies. An interesting focus is represented by the complete reconstitution of the immunological pathways that could help in decreasing the incidence of de novo malignancies and may also help in treating liver transplant patients suffering from cancer.

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          Most cited references138

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          Skin cancers after organ transplantation.

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            Sirolimus for Kaposi's sarcoma in renal-transplant recipients.

            Recipients of organ transplants are susceptible to Kaposi's sarcoma as a result of treatment with immunosuppressive drugs. Sirolimus (rapamycin), an immunosuppressive drug, may also have antitumor effects. We stopped cyclosporine therapy in 15 kidney-transplant recipients who had biopsy-proven Kaposi's sarcoma and began sirolimus therapy. All patients underwent an excisional biopsy of the lesion and one biopsy of normal skin at the time of diagnosis. A second biopsy was performed at the site of a previous Kaposi's sarcoma lesion six months after sirolimus therapy was begun. We examined biopsy specimens for vascular endothelial growth factor (VEGF), Flk-1/KDR protein, and phosphorylated Akt and p70S6 kinase, two enzymes in the signaling pathway targeted by sirolimus. Three months after sirolimus therapy was begun, all cutaneous Kaposi's sarcoma lesions had disappeared in all patients. Remission was confirmed histologically in all patients six months after sirolimus therapy was begun. There were no acute episodes of rejection or changes in kidney-graft function. Levels of Flk-1/KDR and phosphorylated Akt and p70S6 kinase were increased in Kaposi's sarcoma cells. The expression of VEGF was increased in Kaposi's sarcoma cells and even more so in normal skin cells around the Kaposi's sarcoma lesions. Sirolimus inhibits the progression of dermal Kaposi's sarcoma in kidney-transplant recipients while providing effective immunosuppression. Copyright 2005 Massachusetts Medical Society.
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              ACG Clinical Guideline: Primary Sclerosing Cholangitis.

              Primary sclerosing cholangitis is a chronic cholestatic liver disease that can shorten life and may require liver transplantation. The cause is unknown, although it is commonly associated with colitis. There is no approved or proven therapy, although ursodeoxycholic acid is used by many on an empiric basis. Complications including portal hypertension, fat-soluble vitamin deficiency, metabolic bone diseases, and development of cancers of the bile duct or colon can occur.
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                Author and article information

                Contributors
                Journal
                World J Gastroenterol
                World J. Gastroenterol
                WJG
                World Journal of Gastroenterology
                Baishideng Publishing Group Inc
                1007-9327
                2219-2840
                21 September 2019
                21 September 2019
                : 25
                : 35
                : 5356-5375
                Affiliations
                HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy. tomanzia@ 123456libero.it
                Division of Abdominal Transplantation and HPB Surgery, Bambino Gesù Children's Hospital IRCCS, Rome 00165, Italy
                HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
                Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC 27101, United States
                Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
                Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
                Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC 27101, United States
                Division of Abdominal Transplantation and HPB Surgery, Bambino Gesù Children's Hospital IRCCS, Rome 00165, Italy
                HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
                Division of Abdominal Transplantation and HPB Surgery, Bambino Gesù Children's Hospital IRCCS, Rome 00165, Italy
                HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Rome 00133, Italy
                Hepatology and Liver Transplant Unit, University of Tor Vergata, Rome 00133, Italy
                Author notes

                Author contributions: Manzia TM and Angelico R contributed equally to the work, paper conception and design and critical revision; Gazia C, Lenci I, Milana M, Ademoyero OT, Pedini D and Toti L contributed to acquisition of data, analysis and interpretation, drafting of manuscript and critical revision; Spada M, Tisone G and Baiocchi L contributed to study conception and critical revision.

                Corresponding author: Tommaso Maria Manzia, MD, PhD, Assistant Professor, HPB and Transplant Unit, Department of Surgery, University of Rome Tor Vergata, Viale Oxford, 81, Rome 00133, Italy. tomanzia@ 123456libero.it

                Telephone: +39-6-20902498

                Article
                jWJG.v25.i35.pg5356
                10.3748/wjg.v25.i35.5356
                6761240
                31558879
                bd5ca3a0-108b-4380-b625-853ef32e9d9a
                ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.

                This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

                History
                : 2 May 2019
                : 8 August 2019
                : 24 August 2019
                Categories
                Systematic Reviews

                pediatric liver transplant,immunosuppression weaning,clinical operational tolerance,adult liver transplant,graft rejection,immune system,de novo malignancies,immunosuppression minimization,cancer

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