Ghil Busnach

Everolimus with very low-exposure cyclosporine a in de novo kidney transplantation: a multicenter, randomized, controlled trial.

Background. In combination with everolimus (EVL), cyclosporine A (CsA) may be used at low exposure, so reducing the risk of renal dysfunction in renal transplant recipients (RTR). We evaluated whether higher exposure of EVL could allow a further reduction of CsA. Methods. De novo RTR were randomized to standard exposure EVL (C0 3–8 ng/mL) with low-concentration CsA (C2 maintenance levels 350–500 ng/mL, group A) or higher EVL exposure (C0 8–12 ng/mL) with very low-concentration CsA (C2 maintenance levels 150–300 ng/mL, group B). The primary endpoints were 6-month creatinine clearance (CrCl) and biopsy-proven acute rejection (BPAR) rate. After 6 months, patients were followed up (observational extension) to 12 months. Results. Two hundred eighty-five RTR (97% from deceased donors) were enrolled. Two patients per group died (1.4%). The 6-month death-censored graft survival was 90.2% in group A and 97.9% in group B and was unchanged at 12 months (P=0.007). There was no significant difference between groups at 6 months in CrCl (59.9 vs. 57.8 mL/min) and BPAR rates (14.7% vs. 11.9%) and also at 12 months (CrCl 62.5±20.7 vs. 61.3±22.0 mL/min, BPAR 14.7% vs. 14.1%). No significant differences were seen in treated acute rejections, steroid-resistant acute rejections, treatment failures, or delayed graft function, although there was a trend to better results in group B. Conclusions. EVL given at higher exposure for 6 months plus very low CsA concentration may obtain low acute rejection rate and good graft survival in De novo renal transplantation. However, there was no difference between groups in CrCl.

Kaposi's sarcoma in transplant and HIV-infected patients: an epidemiologic study in Italy and France.

Background. A follow-up study was conducted in Italy and in France to compare the epidemiology of Kaposi’s sarcoma (KS) between human immunodeficiency virus (HIV)-infected people and transplant recipients. Methods. In all, 8,074 HIV-positive individuals (6,072 from France and 2,002 HIV-seroconverters from Italy) and 2,705 Italian transplant recipients (1,844 kidney transplants, 702 heart transplants, and 159 liver transplants) were followed-up between 1970 and 2004. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were computed to estimate the risk of KS, as compared to sex- and age-matched Italian and French populations. Incidence rate ratios (IRRs) were used to identify risk factors for KS. Results. A 451-fold higher SIR for KS was recorded in HIV-infected subjects and a 128-fold higher SIR was seen in transplant recipients. Significantly increased KS risks were observed in HIV-infected homosexual men (IRR=9.7 in France and IRR=6.7 in Italy vs. intravenous drug users), and in transplant recipients born in southern Italy (IRR=5.2 vs. those born in northern Italy). HIV-infected patients with high CD4+ cell counts and those treated with antiretroviral therapies had reduced KS risks. In relation to duration of immunosuppression, KS occurred earlier in transplant patients than in HIV-seroconverters. Conclusions. This comparison highlighted that the risk of KS was higher among HIV-infected individuals than in transplant recipients, and that different co-factors are likely to influence the risk of KS. Moreover, the early KS occurrence in transplant recipients could be associated with different patterns of progressive impairment of the immune function.

De novo malignancies after organ transplantation: focus on viral infections.

Organ transplantation is an increasingly used medical procedure for treating otherwise fatal end stage organ diseases with 107,000 transplants performed worldwide in 2010. Newly developed anti-rejection drugs greatly helped to prolong long-term survival of both the individual and the transplanted organ, and they facilitate the diffusion of organ transplantation. Presently, 5-year patient survival rates are around 90% after kidney transplant and 70% after liver transplant. However, the prolonged chronic use of immunosuppressive drugs is well known to increase the risks of opportunistic diseases, particularly infections and virus-related malignancies. Although transplant recipients experience a nearly 2-fold elevated risk for all types of de-novo cancers, persistent infections with oncogenic viruses - such as Kaposi sarcoma herpes virus, high-risk human papillomaviruses, and Epstein-Barr virus - are associated with up to 100-fold increased cancer risks. This review, focusing on kidney and liver transplants, highlights updated evidences linking iatrogenic immunosuppression, persistent infections with oncogenic viruses and cancer risk. The implicit capacity of oncogenic viruses to immortalise infected cells by disrupting the cell-cycle control can lead, in a setting of induced lowered immune surveillance, to tumorigenesis and this ability is thought to closely correlate with cumulative exposure to immunosuppressive drugs. Mechanisms underlying the relationship between viral infections, immunosuppressive drugs and the risk of skin cancers, post-transplant lymphoproliferative disorders, Kaposi sarcoma, cervical and other ano-genital cancers are reviewed in details.

Epidemiology of de novo malignancies after solid-organ transplantation: Immunosuppression, infection and other risk factors

Organ transplantation is an increasingly used medical procedure for treating otherwise fatal end-stage organ diseases, and a large number of anti-rejection drugs have been developed to prolong long-term survival of both the individual and the transplanted organ. However, the prolonged use of immunosuppressive drugs is well known to increase the risk of opportunistic diseases, particularly infections and virus-related malignancies. Although transplant recipients experience a nearly twofold elevated risk for all types of de novo cancers, persistent infections with oncogenic viruses are associated with up to hundredfold increased risks. Women of the reproductive age are growing in number among the recipients of solid-organ transplants, but specific data on cancer outcomes are lacking. This article updates evidences linking iatrogenic immunosuppression, persistent infections with oncogenic viruses, other risk factors and post-transplant malignancies. Epidemiological aspects, tumourigenesis related to oncogenic viruses, clinical implications, as well as primary and secondary prevention issues are discussed to offer clinicians and researchers alike an update of an increasingly important topic.

Incidence of second primary cancer in transplanted patients.

Background. Solid organ transplanted patients have a three- to fourfold higher lifetime risk of developing a cancer than the general population. However, the incidence of a second primary cancer in transplanted patients has never been studied, despite the fact that the presence of regular follow-ups and the increased survival of these patients make them a very attractive model. Methods. We investigated the incidence of a second primary cancer (SPC) in 7,636 patients who underwent a kidney, liver, lung or heart transplant between 1970 and 2004, and were followed-up for 51,819 person-years. Results. During the follow-up, 499 subjects developed a first cancer (annual incidence: 98.6×10,000 PY), and 22 of them developed a SPC (annual incidence: 3.9×10,000 PY). The annual incidence of a SPC in the transplanted patients who developed a first cancer was 107.8×10,000 PY, giving a standardized incidence ratio of 1.1 (95% CI: 0.83–1.41). Conclusions. This result shows that the incidence of the SPC was the same as the incidence of a first cancer. Our study does not indicate an increased risk of SPC in transplanted subjects who already suffered a first malignancy.

Risk of renal cell cancer in people immunodepressed after solid organ transplant: Results from an Italian multicenter cohort study.

422 Background: The etiology of renal cell cancer (RCC) is poorly understood, and data from immunosuppressed population may help to highlights risk factors unknown in the immune competent population. To assess incidence and risk factors for renal cell cancer (RCC) after kidney and liver transplant (KT and LT, respectively), we carried out a cohort investigation in 24 Italian transplant centers. Methods: This study is part of an ongoing cohort investigation conducted in 24 transplant centers in all of Italy. Two cohorts have been implemented, including 7,217 KT recipients (64.2% men) and 2,770 LT recipients (74.7% men) transplanted between 1997 and 2009—and followed-up until 2010. Person years (PY) at risk of cancer were computed from 30 days after transplant to cancer diagnosis, death, return to dialysis (for KT) or to study closure. The number of observed cancers was compared to that expected in the general population through standardized incidence ratios (SIR) and 95% confidence intervals (CI). To ident...