Henryk E. Wilczek

Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008—A Swedish population-based study

Organ transplant recipients are at increased risk of a wide range of malignancies, especially cutaneous squamous cell carcinomas (SCC). Few previous population‐based studies have quantified and compared cancer risks according to graft type and with long‐term follow‐up. Using nationwide Swedish registers, we identified 10,476 recipients transplanted from 1970 to 2008 and followed them for cancer occurrence. Relative risks of cancer in comparison with the general population were expressed as standardized incidence ratios (SIR) and within the transplanted cohort as incidence rate ratios (IRR). During a total follow‐up of 93,432 person‐years, patients were diagnosed with 1,175 cancers excluding SCC, and with 2,231 SCC, SIRcancer excl SCC 2.4 (95% CI, 2.2–2.5); SIRSCC 121 (95% CI, 116–127). Cancer risks were most increased among heart and/or lung recipients SIRcancer excl SCC 3.3 (95% CI, 2.8–4.0); SIRSCC 198 (95% CI, 174–224), followed by kidney SIRcancer excl SCC 2.3 (95% CI, 2.1–2.4); SIRSCC 121 (95% CI, 116–127) and liver recipients SIRcancer excl SCC 2.3 (95% CI, 1.9–2.8); SIRSCC 32 (95% CI, 24–42). During follow‐up, risk of cancer excluding SCC remained stable while risk of SCC tripled over 20 years irrespective of graft type, partly due to a subgroup of patients developing new SCCs at a rapidly increasing rate. In summary, post‐transplant cancer risk varied by transplanted organ and by cancer site, with the bulk of the excess risk driven by an exceptionally high and accelerating risk of SCC. These findings underscore the importance of regular skin screening in organ transplant recipients.

Long-term data from the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR)

Familial amyloidotic polyneuropathy (FAP) is a fatal systemic disease, caused by an amyloidogenic transthyretin (TTR) variant. Orthotopic liver transplantation (OLT) eliminates the main source of the TTR variant. Herein we present updated data from the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR). By June 30, 2009, 1516 patients from 70 Centres in 18 countries were reported. Approximately 110-120 OLTs/year is performed worldwide. The Val30Met mutation is reported in 85% of the FAP patients. About 50 other mutations are reported as well. Ninety-eight percent of the Val30Met patients underwent OLT only, while in the non-Val30Met group 11% of the patients also received a heart transplant. OLT remains so far the only established treatment demonstrating excellent patient survival that compares well with OLT performed for other chronic liver disorders. The FAPWTR has, since its foundation in 1995, played a pivotal role in elucidating the role of liver transplantation in this field. Introduction: Familial amyloid polyneuropathy (FAP) is a rather rare autosomal dominant disease associated with a large number of different point mutations in the gene for transthyretin (TTR). More than 95% of circulating TTR is produced in the liver [1,2]. Removing the liver abolishes the hepatic source of amyloidogenic TTR variants and thus orthotopic liver transplantation (OLT) is potentially curative of the disease. The procedure was first performed in FAP in 1990 [3,4] and is now a recognized treatment for patients with TTR systemic amyloidosis disorders. Attractive outcomes have been reported, including improvement in autonomic and to a lesser extent peripheral nerve function coupled with regression of visceral amyloid deposits. The OLT results are influenced by many factors, e.g. the particular TTR variant, nutritional status, age, severity of the neuropathy, and cardiac amyloid involvement. Disturbingly, in some patients there have been reports of paradoxical acceleration of amyloid in certain organs seemingly caused by ongoing TTR amyloid deposition on pre-existing amyloid ‘prototypes’, like the heart and vitreous body but perhaps also in nerves [5–8]. Remaining ongoing production of variant TTR in the choroid plexus and retina may also be the cause of disease progress posttransplantation or for new ocular and central nervous manifestations appearing after OLT [9]. Data on these patients are collected in the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR). Herein, we briefly present an update from the FAPWTR on the outcome following OLT for FAP. Results and discussion: By 30 June 2009, 1516 patients from 70 centers in 18 countries were reported. The Val30Met TTR mutation was reported in 85% of the FAP patients. About 50 other mutations are reported as well, including non-TTR mutations such as Glu526Val Fibrinogen alfa-chain and ApoA1 Gly26Arg. Ser77Tyr is the commonest non-Val30Met variant reported (n1⁄4 29). The main initial symptom in Val30Met patients was loss of sensory function (67%), cardiovascular dysfunction (1%), and extraneurological dysfunction (1%). NonVal30Met patients suffered more gastrointestinal dysfunction (20%) as well as having more cardiovascular and extraneurological manifestations (9% and 8%, respectively). Ninety-eight percent of the Val30Met patients were subjected to OLT only, while in the non-Val30Met group 11% of the patients also received a heart transplant (2% underwent heart transplantation before OLT and 9% were subjected to simultaneous liver–heart transplantation). Val30Met patients in different countries differ with regard to age at onset and initial symptoms. Brazil presents the youngest age at onset patients while the highest age at onset is found in Sweden. Sensory neuropathy is the most frequent initial symptom in Portuguese patients and least common in Japan. Gastrointestinal dysfunction is most often seen in Japan and Spain and less often met in Sweden while pain as initial symptom is most commonly encountered in Sweden and least in Spain. The 5-year patient survival in the Val30Met group was significantly better than for other TTR variants (82% and 59%, respectively, p5 0.0001). Val30Met patients with a modified body mass index (mBMI) 600 at time of transplantation have a shorter disease duration than those with mBMI 5600 (3.8+ 2.6 years and 5.7+ 3.6 years, respectively, p5 0.001). The mean age at the time of transplantation was the same in the two groups (39.0+ 10.4 years and 39.7+ 9.0 years, respectively). When analyzing Val30Met patients with regard to early ( 50 years) or late onset of the disease, female patients in the early onset group were significantly older than male patients at the time of transplantation (38.8+ 6.6 years and 34.5+ 7.1, respectively, p5 0.001). No difference in survival between female and male patients was found. In the late onset group, females were younger than male patients when transplanted (59.1+ 4.3 and 62.1+ 4.1 years, respectively, p5 0.001). Females 193

Domino liver transplantation: risks and benefits.

Domino liver transplantation, wherein a patient who himself undergoes liver transplantation in turn donates his liver to another recipient, has been performed since the mid-1990 s. Although livers from a handful of metabolic disorders cured by liver transplantation have been used for domino transplantation, familial amyloidotic polyneuropathy (FAP) livers are by far the most common source. FAP is an inherited disorder never presenting its clinical manifestation before the age of 15. In many carriers, the genetic disorder never manifests during lifetime. Thus, only a proportion of patients with FAP develop disease symptoms, which has been the rationale for using such livers for other patients on the waiting list for liver transplantation. According to the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR), only 2 out of more than 500 patients so far have developed symptoms after domino liver transplantation using an FAP liver. Domino recipients with nonmalignant indications for liver transplantation show excellent long-term survivals. With careful selection of recipients, the procedure helps to reduce the organ shortage and the time on the waiting list for patients with malignant disorders.

Long-term consequences of domino liver transplantation using familial amyloidotic polyneuropathy grafts

Domino liver transplantation (DLT) using grafts from patients with familial amyloidotic polyneuropathy (FAP) is an established procedure at many transplantation centers. However, data evaluating the long‐term outcome of DLT are limited. The aim of the present study was to analyze the risk of de novo polyneuropathy, possibly because of amyloidosis, and the patient survival after DLT. At our department, 28 DLT using FAP grafts were conducted between January 1997 and December 2005. One patient was twice subjected to DLT. Postoperative neurological monitoring of peripheral nerve function was performed with electroneurography (ENeG) in 20 cases. An ENeG index based on 12 parameters was calculated and correlated to age and/or height. Three patients developed ENeG signs of polyneuropathy 2–5 years after the DLT, but with no clinical symptoms. The 1‐, 3‐ and 5‐year actuarial patient survival in hepatocellular carcinoma (HCC) patients (n = 12) and non‐HCC patients (n = 15) was 67%, 15%, 15% and 93%, 93%, 80%, respectively (P = 0.001). Development of impaired nerve conduction in a proportion of patients may indicate that de novo amyloidosis occurs earlier than previously expected. Survival after DLT was excellent except in patients with advanced HCC.

Overall and cause-specific mortality in transplant recipients with a pretransplantation cancer history.

Background It is unclear to what extent cancer history affects posttransplantation mortality in solid organ transplant recipients. Methods We identified a Swedish population-based cohort of solid organ transplant recipients in the National Patient Register 1970 to 2008 and linked it to the Cancer and Cause-of-Death Register. Overall and cause-specific mortality was estimated using Cox regression. Results Of 10,448 eligible recipients, 416 (4%) had a prior malignancy unrelated to the indication for transplantation diagnosed 2 months or more before surgery (median, 5.7 years). Mortality among cancer history recipients was 30% increased after transplantation, compared with other recipients (adjusted hazard ratio [HR], 1.3; 95% confidence interval [CI], 1.1–1.5; P<0.001), driven by cancer-specific death with no increase in cardiovascular, infectious, or other noncancer mortality. An increased rate of death due to cancer history was primarily observed among nonkidney recipients (adjusted HRnonkidney, 1.8; 95% CI, 1.3–2.5; HRkidney, 1.2; 95% CI, 1.0–1.4). Rates were greatest for patients with waiting times of 5 years or less but persisted with waiting times more than 10 years among kidney and nonkidney recipients with prior aggressive cancer types (gastrointestinal, breast, kidney/urothelial, and hematologic malignancies). Conclusion We conclude that organ transplant recipients with cancer history are at a moderately increased rate of death after transplantation, driven primarily by death due to cancer recurrence.

Pediatric Organ Transplantation and Risk of Premalignant and Malignant Tumors in Sweden

Increased cancer risks are well documented in adult organ transplant recipients. However, the spectrum of malignancies and risk in the pediatric organ transplant population are less well described. We identified all solid organ transplanted patients aged <18 in Sweden between 1970–2007 (n = 536) in the National Patient Register and linked to the Cancer Register. Nationwide rates were used to calculate standardized incidence rate ratios and 95% CI estimating the association between transplant and cancer during maximum 36 years of follow‐up. Nearly 7% of pediatric solid organ transplant recipients developed a premalignant or malignant tumor during follow‐up. Transplantation was associated with an increased risk of any cancer (n = 24, SIR = 12.5, 95% CI: 8.0–18.6): non‐Hodgkin lymphoma (NHL) (n = 13, SIR = 127, 95% CI: 68–217), renal cell (n = 3, SIR = 105, 95% CI: 22–307), vulva/vagina (n = 3, SIR = 665, 95% CI: 137–1934) and nonmelanoma skin cancers (n = 2, SIR = 64.7, 95% CI: 7.8–233.8). NHL typically appeared during childhood, while other tumors were diagnosed during adulthood. Apart from short‐term attention toward the potential occurrence of NHL, our results suggest cancer surveillance into adulthood with special attention to skin, kidneys and the female genitalia.

Domino liver transplantation

Orthotopic liver transplantation is today an established treatment for end stage liver diseases. However, the ongoing shortage of suitable livers together with progressively longer waiting lists prevents many patients from being transplanted, and many patients die while being on the waiting list. Using livers from living donors is one way to increase the supply of liver grafts. Another group of potential living liver donors are some selected liver recipients, whose native explanted liver in turn can be considered for transplantation into another patient. This unorthodox procedure have been named domino liver transplantation (DLT). The domino approach can be considered in patients with some genetic or biochemical disorders that today are treated by liver transplantation. The underlying rationale is that such livers ultimately cause severe systemic disease but are otherwise normal. In this review we present the current world status of DLT as well as updated results from the Domino Liver World Transplant Register (DLTR) and our own experience at the Karolinska University Hospital Huddinge with the DLT procedure.

Decreasing incidence of cancer after liver transplantation-A Nordic population-based study over 3 decades

Cancer remains one of the most serious long‐term complications after liver transplantation (LT). Data for all adult LT patients between 1982 and 2013 were extracted from the Nordic Liver Transplant Registry. Through linkage with respective national cancer‐registry data, we calculated standardized incidence ratios (SIRs) based on country, sex, calendar time, and age‐specific incidence rates. Altogether 461 cancers were observed in 424 individuals of the 4246 LT patients during a mean 6.6‐year follow‐up. The overall SIR was 2.22 (95% confidence interval [CI], 2.02‐2.43). SIRs were especially increased for colorectal cancer in recipients with primary sclerosing cholangitis (4.04) and for lung cancer in recipients with alcoholic liver disease (4.96). A decrease in the SIR for cancers occurring within 10 years post‐LT was observed from the 1980s: 4.53 (95%CI, 2.47‐7.60), the 1990s: 3.17 (95%CI, 2.70‐3.71), to the 2000s: 1.76 (95%CI, 1.51‐2.05). This was observed across age‐ and indication‐groups. The sequential decrease for the SIR of non‐Hodgkin lymphoma was 25.0‐12.9‐7.53, and for nonmelanoma skin cancer 80.0‐29.7‐10.4. Cancer risk after LT was found to be decreasing over time, especially for those cancers that are strongly associated with immunosuppression. Whether immunosuppression minimization contributed to this decrease merits further study.

Similar lipid profile but improved long-term outcomes with sirolimus after cyclosporine withdrawal compared to sirolimus with continuous cyclosporine.

Renal transplant recipients show an increased risk of cardiovascular disease compared with a nontransplant population. Herein we have shown an analysis of a randomized controlled trial wherein 525 patients receiving a first or second (9.7%) renal allograft from a deceased (89.1%), a living-related (7.8%), or a living-unrelated donor (3.1%) received sirolimus (SRL), cyclosporine (CsA), and steroids (ST) at the time of transplantation with randomization at 3 months after transplantation of 430 eligible patients to continue on SRL-CsA-ST or to have CsA withdrawn with increased SRL trough targets (SRL-ST group). Graft survival, patient survival, and renal function at 5 years were analyzed by average fasting total cholesterol (<or=200 or >200 mg/dL) and triglyceride (<or=240 or >240 mg/dL) subgroups. At 5 years, total, high-density lipoprotein (HDL), and low-density lipoprotein [LDL] cholesterol and triglyceride values were similar between the groups. Statins ( approximately 80% of patients of both groups) were most effective to lower cholesterol ( approximately 50 mg/dL; P < .001; both groups), and fibrates ( approximately 25% of patients of both groups) were most effective to decrease triglycerides ( approximately 100 mg/dL; P < .001; both groups). Renal function and blood pressure were significantly better with SRL-ST. Hypercholesterolemia and hypertriglyceridemia were associated with reduced graft survival, patient survival, and calculated GFR, but the only significant difference was lower graft survival among SRL-CsA-ST patients with hypertriglyceridemia. Cardiovascular-related deaths were reported in 3.7% and 2.8% of patients in the SRL-CsA-ST and SRL-ST groups, respectively. In conclusion, when compared with continuous SRL-CsA-ST, CsA withdrawal at 3 months followed by SRL-ST significantly improved glomerular filtration rate (GFR) and blood pressure without a further increase in lipid parameters or an incidence of untoward effects from hyperlipidemia, despite a 2-fold higher SRL exposure.