Luigino Boschiero

Incidence of cancer after kidney transplant: Results from the north italy transplant program

Background. Patients undergoing kidney transplantation demonstrate a higher risk of developing cancer as the result of immunosuppressive treatment and concurrent infections. Methods. The incidence of cancer in a cohort of patients who underwent kidney transplantation between 1990 and 2000, and who survived the acute phase (10 days), was analyzed as part of the North Italy Transplant program. Results. A total of 3,521 patients underwent transplantation during a 10-year period in 10 of 13 participating centers; the length of follow-up after kidney transplant was 67.7±36.0 months. During the follow-up, 172 patients developed cancer (39 with Kaposi sarcoma, 38 with lymphoproliferative diseases, and 95 with carcinomas [17 kidney, 11 non-basal cell carcinoma of the skin, 10 colorectal, 8 breast, 7 gastric, 7 lung, 6 bladder, and 3 mesothelioma]). The average time to cancer development after transplant was 40.1±33.4 months (range 0–134 months). Twenty-four patients developed cancer within 6 months from the transplant (10 with carcinomas, 7 with Kaposi sarcoma, and 7 with lymphoproliferative diseases). Three patients demonstrated a second primary cancer. The average cancer incidence was 4.9%. The incidence of cancer was 0.01 per year. Independent determinants of cancer development were age, gender, and immunosuppressive protocol including induction. Ten-year mortality was significantly higher in patients with cancer (33.1%) than among patients without cancer (5.3%). The relative risk of death in subjects with cancer was 5.5 (confidence interval 4.1–7.4). Conclusions. These preliminary data underline the importance of long-term surveillance of transplant recipients, choice of immunosuppressive treatment, and careful donor selection.

Incidence and clinical predictors of a subsequent nonmelanoma skin cancer in solid organ transplant recipients with a first nonmelanoma skin cancer: a multicenter cohort study.

OBJECTIVE To compare the long-term risk of primary nonmelanoma skin cancer (NMSC) and the risk of subsequent NMSC in kidney and heart transplant recipients. DESIGN Partially retrospective cohort study. SETTING Two Italian transplantation centers. PATIENTS The study included 1934 patients: 1476 renal transplant recipients and 458 heart transplant recipients. MAIN OUTCOME MEASURES Cumulative incidences and risk factors of the first and subsequent NMSCs. RESULTS Two hundred patients developed a first NMSC after a median follow-up of 6.8 years after transplantation. The 3-year risk of the primary NMSC was 2.1%. Of the 200 patients with a primary NMSC, 91 (45.5%) had a second NMSC after a median follow-up after the first NMSC of 1.4 years (range, 3 months to 10 years). The 3-year risk of a second NMSC was 32.2%, and it was 49 times higher than that in patients with no previous NMSC. In a Cox proportional hazards regression model, age older than 50 years at the time of transplantation and male sex were significantly related to the first NMSC. Occurrence of the subsequent NMSC was not related to any risk factor considered, including sex, age at transplantation, type of transplanted organ, type of immunosuppressive therapy, histologic type of the first NMSC, and time since diagnosis of the first NMSC. Histologic type of the first NMSC strongly predicted the type of the subsequent NMSC. CONCLUSIONS Development of a first NMSC confers a high risk of a subsequent NMSC in transplant recipients. Intensive long-term dermatologic follow-up of these patients is advisable.

Incidence of Primary and Second Cancers in Renal Transplant Recipients: A Multicenter Cohort Study

Limited data exist about cancer prognosis and the development of second cancers in renal transplant recipients. In a retrospective cohort study on 3537 patients incidence rates of the first and, if any, of a second cancer, and standardized incidence ratios [SIR (95% CI)] were computed. Two hundred and sixty‐three (7.5%) patients developed a NMSC, and 253 (7.2%) another type of cancer after a median follow‐up of 6.5 and 9.0 years, respectively. A statistically significant excess risk, if compared to an age‐ and sex‐matched reference general population, was observed for Kaposi sarcoma and NMSC, followed by non‐Hodgkin lymphoma and carcinoma of cervix uteri; a small number of unusual cancers such as tumors of the salivary glands, small intestine and thyroid also were detected at a level worthy of additional scrutiny. Ten‐year survival rate of all noncutaneous cancers was 71.3%, with lower rates for lung carcinoma and non‐Hodgkin lymphoma (0% and 41.7%, respectively). Patients with NMSC had an increased risk of developing a second NMSC [SIR 8.3 (7.0–10.0)], and patients with a primary noncutaneous cancer had increased risk of developing a second noncutaneous cancer [SIR 1.8 (1.2–2.8)], if compared to the whole cohort. Our study underscore that the high risk of primary and second cancer in renal transplant recipients, including unusual cancers.

Association of functional gene variants in the regulatory regions of COX‐2 gene (PTGS2) with nonmelanoma skin cancer after organ transplantation

Summary Background  Overexpression of cyclooxygenase‐2 (COX‐2), resulting in excessive prostaglandin production, has been observed in human epidermal keratinocytes after ultraviolet B injury, in squamous cell skin carcinoma (SCC), in actinic keratoses, and in the early stages of carcinogenesis in a wide variety of tissues. The dysregulation of COX‐2 expression can in part be due to functional changes affecting regulatory elements in the promoter or 3′ untranslated region (UTR) of the gene. Two common polymorphisms (–765G→C, and –1195A→G) in the promoter region of the COX‐2 gene (now PTGS2), and one common polymorphism in the 3′ UTR (8473T→C) have been described, and reported as associated with various malignancies.

Systemic and Nonrenal Adverse Effects Occurring in Renal Transplant Patients Treated with mTOR Inhibitors

The mammalian target of rapamycin inhibitors (mTOR-I), sirolimus and everolimus, are immunosuppressive drugs largely used in renal transplantation. The main mechanism of action of these drugs is the inhibition of the mammalian target of rapamycin (mTOR), a regulatory protein kinase involved in lymphocyte proliferation. Additionally, the inhibition of the crosstalk among mTORC1, mTORC2, and PI3K confers the antineoplastic activities of these drugs. Because of their specific pharmacological characteristics and their relative lack of nephrotoxicity, these inhibitors are valid option to calcineurine inhibitors (CNIs) for maintenance immunosuppression in renal transplant recipients with chronic allograft nephropathy. However, as other immunosuppressive drugs, mTOR-I may induce the development of several adverse effects that need to be early recognized and treated to avoid severe illness in renal transplant patients. In particular, mTOR-I may induce systemic nonnephrological side effects including pulmonary toxicity, hematological disorders, dysmetabolism, lymphedema, stomatitis, cutaneous adverse effects, and fertility/gonadic toxicity. Although most of the adverse effects are dose related, it is extremely important for clinicians to early recognize them in order to reduce dosage or discontinue mTOR-I treatment avoiding the onset and development of severe clinical complications.

Glutathione S-transferase and CYP1A1 gene polymorphisms and non-melanoma skin cancer risk in Italian transplanted patients.

Abstract:  Solid organ transplant recipients are at higher risk of non‐melanoma skin cancer (NMSC), especially basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Genetic alterations in the production of detoxifying enzymes such as glutathione S‐transferase (GST) and CYP1A1 may enhance this risk. We investigated the frequency of GST genotypes (GSTM1, GSTM3, GSTT1 and GSTP1) and CYP1A1 in 239 transplant recipients: 107 cases with NMSC and 132 controls free from NMSC matched for type of transplanted organ, duration of transplantation, sex and age. Allele GSTP1*A was associated with a higher risk of NMSC [odds ratio (OR) 1.7 (1.1–2.5); P = 0.017]. Homozygosity for allele GSTP1 Val105 was lower in cases [OR 0.3 (0.1–0.8); P = 0.012], especially in patients with SCC [OR 0.1 (0.0–0.7); P = 0.012]. A higher risk of BCC was found in patients with GSTM1 null/null [null/null versus A + B, OR 3.1 (1.4–6.8); P = 0.003]. Analysis of allelism and interaction between allelic variants showed significant association between combined GSTM1 and CYP1A1 Val462 genotypes, where individuals homozygous for the risk allele GSTM1 null and carrying also the allele CYP1A1 Val462, show a higher risk of developing NMSC [OR 4.5 (1.1–21.4); P = 0.03], especially SCC [OR 6.5 (1.4–34.4); P = 0.01]. GSTP1 polymorphisms are associated with both BCC and SCC risk. GSTM1 polymorphisms seem to be involved in BCC risk, while GSTM1 null/null genotype combined with CYP1A1 allele Val462 are associated with a higher risk for SCC, indicating that allelism and/or interactions between allelic variants at other loci may also influence the risk of NMSC, particularly SCC.

Monoclonal antibody therapy and renal transplantation: focus on adverse effects.

A series of monoclonal antibodies (mAbs) are commonly utilized in renal transplantation as induction therapy (a period of intense immunosuppression immediately before and following the implant of the allograft), to treat steroid-resistant acute rejections, to decrease the incidence and mitigate effects of delayed graft function, and to allow immunosuppressive minimization. Additionally, in the last few years, their use has been proposed for the treatment of chronic antibody-mediated rejection, a major cause of late renal allograft loss. Although the exact mechanism of immunosuppression and allograft tolerance with any of the currently used induction agents is not completely defined, the majority of these medications are targeted against specific CD proteins on the T or B cells surface (e.g., CD3, CD25, CD52). Moreover, some of them have different mechanisms of action. In particular, eculizumab, interrupting the complement pathway, is a new promising treatment tool for acute graft complications and for post-transplant hemolytic uremic syndrome. While it is clear their utility in renal transplantation, it is also unquestionable that by using these highly potent immunosuppressive agents, the body loses much of its innate ability to mount an adequate immune response, thereby increasing the risk of severe adverse effects (e.g., infections, malignancies, haematological complications). Therefore, it is extremely important for clinicians involved in renal transplantation to know the potential side effects of monoclonal antibodies in order to plan a correct therapeutic strategy minimizing/avoiding the onset and development of severe clinical complications.

Incidence and clinical predictors of primary opportunistic deep cutaneous mycoses in solid organ transplant recipients: a multicenter cohort study

Tessari G, Naldi L, Piaserico S, Boschiero L, Nacchia F, Forni A, Rugiu C, Faggian G, Dall’Olio E, Fortina AB, Alaibac M, Sassi F, Gotti E, Fiocchi R, Fagioli S, Girolomoni G. Incidence and clinical predictors of primary opportunistic deep cutaneous mycoses in solid organ transplant recipients: a multicenter cohort study.
Clin Transplant 2010: 24: 328–333.

Long-term outcome of renal transplantation from octogenarian donors: A multicenter controlled study

To assess whether biopsy‐guided selection of kidneys from very old brain‐dead donors enables more successful transplantations, the authors of this multicenter, observational study compared graft survival between 37 recipients of 1 or 2 histologically evaluated kidneys from donors older than 80 years and 198 reference‐recipients of non–histologically evaluated single grafts from donors aged 60 years and younger (transplantation period: 2006‐2013 at 3 Italian centers). During a median (interquartile range) of 25 (13‐42) months, 2 recipients (5.4%) and 10 reference‐recipients (5.1%) required dialysis (crude and donor age‐ and sex‐adjusted hazard ratio [95% confidence interval] 1.55 [0.34‐7.12], P = .576 and 1.41 [0.10‐19.54], P = .798, respectively). Shared frailty analyses confirmed similar outcomes in a 1:2 propensity score study comparing recipients with 74 reference‐recipients matched by center, year, donor, and recipient sex and age. Serum creatinine was similar across groups during 84‐month follow‐up. Recipients had remarkably shorter waiting times than did reference‐recipients and matched reference‐recipients (7.5 [4.0‐19.5] vs 36 [19‐56] and 40 [24‐56] months, respectively, P < .0001 for both comparisons). Mean (± SD) kidney donor risk index was 2.57 ± 0.32 in recipients vs 1.09 ± 0.24 and 1.14 ± 0.24 in reference‐recipients and matched reference‐recipients (P < .0001 for both comparisons). Adverse events were similar across groups. Biopsy‐guided allocation of kidneys from octogenarian donors permits further expansion of the donor organ pool and faster access to a kidney transplant, without increasing the risk of premature graft failure.

PTCH1 gene haplotype association with basal cell carcinoma after transplantation

Background  Basal cell carcinoma (BCC) is 10 times more frequent in organ transplant recipients (OTRs) than in the general population. Factors in OTRs conferring increased susceptibility to BCC include ultraviolet radiation exposure, immunosuppression, viral infections such as human papillomavirus, phototype and genetic predisposition. The PTCH1 gene is a negative regulator of the hedgehog pathway, that provides mitogenic signals to basal cells in skin. PTCH1 gene mutations cause naevoid BCC syndrome, and contribute to the development of sporadic BCC and other types of cancers. Associations have been reported between PTCH1 polymorphisms and BCC susceptibility in nontransplanted individuals.