Alberto Forni

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.

Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

Familial dilated cardiomyopathy (DCM) is a heterogeneous disease; although 30 disease genes have been discovered, they explain only no more than half of all cases; in addition, the causes of intra-familial variability in DCM have remained largely unknown. In this study, we exploited the use of whole-exome sequencing (WES) to investigate the causes of clinical variability in an extended family with 14 affected subjects, four of whom showed particular severe manifestations of cardiomyopathy requiring heart transplantation in early adulthood. This analysis, followed by confirmative conventional sequencing, identified the mutation p.K219T in the lamin A/C gene in all 14 affected patients. An additional variant in the gene for titin, p.L4855F, was identified in the severely affected patients. The age for heart transplantation was substantially less for LMNA:p.K219T/TTN:p.L4855F double heterozygotes than that for LMNA:p.K219T single heterozygotes. Myocardial specimens of doubly heterozygote individuals showed increased nuclear length, sarcomeric disorganization, and myonuclear clustering compared with samples from single heterozygotes. In conclusion, our results show that WES can be used for the identification of causal and modifier variants in families with variable manifestations of DCM. In addition, they not only indicate that LMNA and TTN mutational status may be useful in this family for risk stratification in individuals at risk for DCM but also suggest titin as a modifier for DCM.

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.

First Successful Management of Aortic Valve Insufficiency Associated With HeartMate II Left Ventricular Assist Device Support by Transfemoral CoreValve Implantation : The Columbus's Egg?

Left ventricular assist device (LVAD) support has offered many individuals with end-stage heart failure an improved quality of life and enhanced survival. Prolonged mechanical assistance, however, has shown the potential to induce hemodynamic and structural changes in the native heart. One such

Results With Expanded Donor Acceptance Criteria in Heart Transplantation

OBJECTIVE Over the past years both donor and recipient profiles have changed in heart transplantation. Satisfactory clinical outcomes of marginal donors in candidates >60 years of age have led us to allocate suboptimal donors to younger recipients as well. Therefore, we retrospectively reviewed our experience. METHODS Among 199 patients undergoing heart transplantation from January 2000 to February 2010, there were 83 (41%) aged 61-72 years. The other 116 (59%) ranged in age between 18 and 60 years. According to their clinical conditions as heart transplantation candidates, They were classified into 4 groups: younger recipients (n=116) of either optimal donors (n=72; group 1 [G1]) or marginal donors (n=44; group 2 [G2]) and older recipients (n=83) of either marginal grafts (n=70, group 3 [G3]) or optimal grafts (n=13; group 4 [G4]). The gender distribution, cause of end-stage heart failure, preoperative pulmonary hypertension incidence, pretransplantation clinical status, and mean follow-up were not significantly different among the 4 groups. RESULTS Overall 30-day survival was 90 ± 1% and 10-year rate was 78 ± 9%. Among the groups, 30-day and 10-year actuarial survival rates were, respectively: 94 ± 4% and 87 ± 1% for G1; 86 ± 5% and 84 ± 7% for G2; 88 ± 4% and 71 ± 7% for G3 and were 100% and 82 ± 7% for G4 (P=.7). In comparison among the 4 groups, there was no significant difference regarding freedom from graft failure (P=.3), right ventricular failure (P=.3), acute rejection episodes (P = .2), chronic rejection (P=.2), neoplasia (P=.5), or chronic renal failure (P=.1). Older recipients of marginal donors [G3] had a 4% (n=3) prevalence of permanent pacemaker implant, versus G2: 3% (n=2) among (P=.1). CONCLUSION Our results suggest that extended donor and recipient criteria do not compromise clinical outcomes after transplantation.

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.

Blood versus crystalloid cardioplegia for myocardial protection of donor hearts during transplantation: a prospective, randomized clinical trial

OBJECTIVE To assess the safety and efficacy of myocardial protection of the donor heart during transplantation with the use of blood cardioplegia, a prospective randomized clinical trial was undertaken between January 1997 and March 1998. METHODS Forty-seven consecutive patients were assigned either to crystalloid (27 patients; group 1) or blood cardioplegia (20 patients; group 2). Comparison of recipient age (54 +/- 11 years vs 55 +/- 7 years; P =. 9), sex (89% vs 90% male patients; P =.9), diagnosis (63% vs 65% dilated cardiomyopathy; P =.8), elevated pulmonary vascular resistance (30% vs 30%; P =.9), prior cardiac operations (22% vs 30%; P =.5), need for urgent heart transplantation (7% vs 20%; P =. 2), donor age (32 +/- 11 years vs 31 +/- 13 years; P =.7), cause of death (33% vs 40% vascular; P =.5), and global myocardial ischemia (176 +/- 51 minutes vs 180 +/- 58 minutes; P =.5) showed no difference. Hemodynamically unstable donors (15% vs 45%; P =.02) were more prevalent in group 2. RESULTS Operative mortality rates (4% vs 5%; P =.8), high-dose inotropic support (41% vs 30%; P = 0.6), and postoperative mechanical assistance (11% vs 10%; P = 0.9) were comparable in the 2 groups. Prevalence of acute right heart failure (27% vs 0; P =.02) and of temporary complete atrioventricular block (52% vs 20%; P =.02) were greater in group 1. Spontaneous sinus rhythm recovery was more prevalent in group 2 (11% vs 40%; P =.02). Higher peak creatine kinase (1429 +/- 725 u/L vs 868 +/- 466 u/L; P =.01) and creatine kinase MB (144 +/- 90 u/L vs 102 +/- 59 u/L; P =. 06) levels suggested more severe ischemic injury in group I. CONCLUSION Use of blood cardioplegia was associated with a lower prevalence of right heart failure, cardiac rhythm dysfunction, and laboratory evidence of ischemia.

Impact of donor quality on outcome of heart transplantation

OBJECTIVE Over the last few years, there have been changes in both donor and recipient profiles in heart transplantation. Encouraging clinical outcome of marginal donors in candidates older than 60 years of age led us to allocate suboptimal donors for younger recipients as well. We reviewed our experience retrospectively so as to assess the impact of donor quality on heart transplantation. METHODS Among 181 patients who underwent heart transplantation between January 2000 and February 2009, there were 75 patients (41%) aged 61-70 years and 106 patients (59%) ranging in age between 18 and 60 years. According to the recipients age, they were classified into four groups. The younger recipients (106 patients) had either optimal donors (70 patients, group 1) or marginal donors (36 patients, group 2). The older recipients (75 patients) had either marginal grafts (64 patients, group 3) or optimal grafts (11 patients, group 4). Sex distribution, cause of end-stage heart failure, preoperative pulmonary hypertension, pre-heart-transplantation clinical status or mean follow-up duration did not show any statistically significant difference among the four groups. RESULTS Overall, the 9-year actuarial survival rate was 78%±1%. The 30 days and 9-year actuarial survival rates were 94%±2% and 80%±1% in group 1; 86%±5% and 55%±12% in group 2; 90%±4% and 73%±7% in group 3; 99%±1% and 82%±7% in group 4 (P=0.07). Comparison among the four groups did not show any statistical difference in terms of freedom from graft failure (P=0.3), right ventricular failure (P=0.3), acute rejection (P=0.2), chronic rejection (P=0.2), neoplasia (P=0.5) and chronic renal failure (P=0.2). Older recipients of marginal donors (group 3) had slightly higher prevalence of permanent pacemaker implants: eight permanent pacemakers versus two in group 2, and none in group 1 and group 4 (P=0.4). CONCLUSIONS Our results suggest that extended donor acceptance criteria may not compromise clinical outcome after heart transplantation. Further follow-up is warranted.

Myocardial protection in heart transplantation using blood cardioplegia: 12-year outcome of a prospective randomized trial.

BACKGROUND Blood cardioplegia yields a lower prevalence of right heart failure, arrhythmias, and myocardial ischemia early after heart transplantation (HTx). Because depolarizing (high [K(+)]) cardioplegic solutions may alledgedly cause endothelial damage, the 12-year outcome of a prospective randomized trial was reviewed. METHODS Between January 1997 and March 1998, 47 consecutive patients received crystalloid (Group 1, n = 27) or blood cardioplegia (Group 2, n = 20). The groups were similarly matched: recipient age (54 ± 11 vs 55 ± 7 years, p = 0.9), sex (89% vs 90% males, p = 0.9), diagnosis (63% vs 65% dilated cardiomyopathy, p = 0.8), elevated (>4 WU) pulmonary vascular resistance (30% vs 30%, p = 0.9), prior operations (22% vs 30%, p = 0.5), urgent HTx (7% vs 20%, p = 0.2), donor age (32 ± 11 vs 31 ± 13 years, p = 0.7), donor sex (78% vs 70% males, p = 0.5), donor cause of death (33% vs 40% vascular, p = 0.5), and global myocardial ischemia (176 ± 51 vs 180 ± 58 minutes p = 0.5). Hemodynamically unstable donors were more prevalent in Group 2 (15% vs 45%, p = 0.02). The 45 hospital survivors underwent yearly echocardiography, coronary angiography, and coronary intravascular ultrasound (IVUS) imaging during follow-up. RESULTS During follow-up (10.4 ± 5.2, range, 0.9-12.7 years), Groups 1 and 2 had comparable mortality (46% vs 42%, p = 0.7) and cause of death (chronic rejection: 50% vs 50%; neoplasia: 33% vs 25%, p = 0.8). Survival at 12 years was 50% ± 12% vs 52% ± 11% (p = 0.9). Follow-up echocardiogram showed similar mean left ventricular ejection fraction (LVEF; 47% ± 12% vs 49% ± 11%, p = 0.7) and prevalence of LVEF < 35% (21% vs 18%, p = 0.8). Prevalence of chronic rejection was comparable (42% vs 32%, p = 0.1), yet severe allograft vasculopathy (International Society for Heart and Lung Transplantation cardiac allograft vasculopathy 3) was more prevalent in Group 1 (64% vs 17%, p = 0.04). Freedom from chronic rejection was higher in Group 2 (44% ± 15% vs 63% ± 13%), albeit not significantly (p = 0.5). A trend toward greater prevalence of intimal disease at IVUS (thickness > 0.5 mm) in the proximal and distal left anterior descending artery (67% vs 40%; 58% vs 45%) and higher number of percutaneous coronary interventions (2.7 ± 0.5 vs 1.8 ± 0.3, p = 0.3) was noted in Group 1. CONCLUSIONS Use of blood cardioplegia is safe and results in comparable survival and prevalence of adverse events late after HTx. The trend towards greater freedom from chronic rejection and more limited extent of coronary artery disease in grafts protected with blood cardioplegia awaits confirmation.

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.