title: Analysis of malignancies in patients after heart transplantation with subsequent immunosuppressive therapy.
abstract: OBJECTIVE
  The aim of this study was to analyze the distribution of malignancies in patients after heart transplantation (HTX) and to evaluate the risk factors including immunosuppressive therapy with regard to the development of malignancies and survival. Special emphasis was placed on the effects of a mammalian target of rapamycin (mTOR) containing immunosuppressive regimen.
  
  
  METHODS
  A total of 381 patients (age ≥18 years) receiving HTX were included in the present analysis. All patients were followed-up at the University of Heidelberg Heart Center, Heidelberg, Germany. Data were retrieved from the Heidelberg Registry for Heart Transplantation being collected between 1989 and 2014. According to center standard, all patients received induction therapy with anti-thymocyte globulin guided by T-cell monitoring since 1994. The initial immunosuppressive regimen consisting of cyclosporine A (CsA) and azathioprine (AZA) was replaced by CsA and mycophenolate mofetil (MMF) in 2001 and by tacrolimus (TAC) and MMF in 2006. Additionally, mTOR inhibitors (everolimus/sirolimus) were applied since 2003.
  
  
  RESULTS
  Mean recipient age at HTX was 51.2±10.5 years and the mean follow-up period after HTX was 9.7±5.9 years. During follow-up, 130 patients developed a neoplasm (34.1% of total). Subgroup analysis revealed 58 patients with cutaneous malignancy only (15.2%), 56 patients with noncutaneous malignancy only (14.7%), and 16 patients with both cutaneous and noncutaneous malignancy (4.2%). Statistically significant risk factors associated with an increased risk of malignancy after HTX were older age (P<0.0001), male recipients (P=0.0008), dyslipidemia (P=0.0263), diabetes mellitus (P=0.0003), renal insufficiency (P=0.0247), and >1 treated rejection episode (TRE) in the first year after HTX (P=0.0091). Administration of CsA (P=0.0195), AZA (P=0.0008), or steroids (P=0.0018) for >1 year after HTX was associated with increased development of malignancy, whereas administration of MMF (P<0.0001) or mTOR inhibitors (P<0.0001) was associated with a lower risk for development of malignancy. Additionally, 5-year follow-up of cutaneous malignancy recurrence (P=0.0065) and noncutaneous malignancy mortality (P=0.0011) was significantly lower in patients receiving an mTOR inhibitor containing therapy after the development of a malignancy.
  
  
  CONCLUSIONS
  This study highlights the complexity of risk factors including immunosuppression with regard to the development of malignancies after HTX. mTOR-inhibitor-based immunosuppression is associated with a better outcome after HTX, particularly in cases with noncutaneous malignancy.
authors.affiliation: Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Rivinius
authors.affiliation: Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Helmschrott
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Arjang
authors.initials: A
authors.lastname: Ruhparwar
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Schmack
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Berthold
authors.initials: B
authors.lastname: Klein
authors.affiliation: Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Erbel
authors.affiliation: Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Gleissner
authors.affiliation: Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Mohammadreza
authors.initials: M
authors.lastname: Akhavanpoor
authors.affiliation: Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Frankenstein
authors.affiliation: Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Fabrice F
authors.initials: FF
authors.lastname: Darche
authors.affiliation: Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
authors.affiliation: Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Ehlermann
authors.affiliation: Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Tom
authors.initials: T
authors.lastname: Bruckner
authors.affiliation: Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Andreas O
authors.initials: AO
authors.lastname: Doesch
mesh_terms: D000328:Adult; D001379:Azathioprine / Q000009:adverse effects; D016572:Cyclosporine / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D008297:Male; D008545:Melanoma / Q000276:immunology; D008875:Middle Aged; D015999:Multivariate Analysis; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives; D009369:Neoplasms / Q000453:epidemiology* / Q000276:immunology; D012307:Risk Factors; D012878:Skin Neoplasms / Q000453:epidemiology* / Q000276:immunology; D016019:Survival Analysis; D016559:Tacrolimus / Q000009:adverse effects
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D001379:Azathioprine; D016559:Tacrolimus
keywords: azathioprine; cyclosporine A; immunosuppression; mTOR inhibitor; mycophenolate mofetil; risk factors; steroids; tacrolimus