Adding 3D automated breast ultrasound to mammography screening in women with heterogeneously and extremely dense breasts: Report from a hospital-based, high-volume, single-center breast cancer screening program.

PURPOSE: The aim of this study was to evaluate the impact of the 3D automated breast ultrasound (3D ABUS) when added to full field digital screening mammography (FFDSM), on breast cancer detection and recall rates in asymptomatic women with dense breasts examined in a high-volume breast cancer screening mammography center. METHODS AND MATERIAL: 1668 asymptomatic women, age 40-74 years, with heterogeneously dense parenchyma (ACR3) or extremely dense breast (ACR4) were included in the study. FFDSM was performed using standard craniocaudal (CC) and mediolateral oblique (MLO) views followed by anteroposterior (AP); lateral (LAT) and medial (MED) acquisitions of 3D ABUS in both breasts. All mammograms were double read by two dedicated breast radiologists. The 3D ABUS was read by the first radiologist immediately after reading the mammograms. The second reader looked at the 3D ABUS only if there was a need for consensus discussion because of unclear or abnormal mammograms or 3D ABUS. RESULTS: The combined FFDSM and 3D ABUS generated a total of 6.6 cancers per 1000 women screened (95% CI: 3.0, 10.2; p<0.001) compared with 4.2 cancers per 1000 women screened (95% CI) for FFDSM alone. The difference in yield was an additional 2.4 detected cancers per 1000 women screened (95% CI: 0.6, 4.8; p<0.001). The corresponding recall rate per 1000 women screened was 13.8 (95% CI: 9.0, 19.8) for FFDSM alone and 22.8 for combined FFDSM and ABUS (95% CI: 16.2, 30.0), yielding a difference of an additional 9.0 recalls per 1000 women screened (95% CI: 3.0, 15.0; p=0.004). CONCLUSION: The addition of 3D ABUS to FFDSM in women with ACR3 or ACR4 breast density significantly improved invasive breast cancer detection rate with an acceptable recall increase.

Survival After Transplantation in Patients With Mutations Other Than Val30Met: Extracts From the FAP World Transplant Registry.

BACKGROUND: Liver transplantation (LTx) has been performed for hereditary transthyretin amyloidosis (ATTR) since 1990. Outcomes for a relatively large series of LTx ATTR patients with the Val30Met (mutation are available, but for non-Val30Met patients, only a few reports with a small number of patients exist. Here, we present outcomes for non-Val30Met ATTR patients after LTx, as reported to the Familial Amyloid Polyneuropathy World Transplant Registry (FAPWTR). METHODS: Data regarding outcome were extracted for all non-Val30Met patients reported to the registry. Survival rates were analyzed by the Kaplan-Meier method and log-rank test. RESULTS: The total number of patients with a non-Val30Met mutation in the registry was 264 (174 men and 90 women), representing 57 mutations. The 10-year survival varied markedly for the 9 most common mutations, ranging from 21% for Ser50Arg to 85% for Val71Ala. Poor survival was noted for all mutations with leptomeningeal complications except for those with the Tyr114Cys mutation. CONCLUSIONS: Large differences in survival were observed relative to different mutations and between mutations with similar phenotypes. Excellent survival was noted for mutations, such as Leu111Met, Val71Ala, and Leu58His. Patients with mutations other than Val30Met are not a homogeneous group, and the term non-Val30Met should be used with caution or avoided. Moreover, for several mutations, data are too limited to allow evaluation of the efficacy of LTx, and continuous international collaboration is important for obtaining treatment guidance.

Liver Transplantation for Hereditary Transthyretin Amyloidosis: After 20 Years Still the Best Therapeutic Alternative?

BACKGROUND: Until recently, liver transplantation (Ltx) was the only available treatment for hereditary transthyretin (TTR) amyloidosis; today, however, several pharmacotherapies are tested. Herein, we present survival data from the largest available database on transplanted hereditary TTR patients to serve as a base for comparison. METHODS: Liver transplantation was evaluated in a 20-year retrospective analysis of the Familial Amyloidosis Polyneuropathy World Transplant Registry. RESULTS: From April 1990 until December 2010, data were accumulated from 77 liver transplant centers. The Registry contains 1940 patients, and 1379 are alive. Eighty-eight Ltx were performed in combination with a heart and/or kidney transplantation. Overall, 20-year survival after Ltx was 55.3%. Multivariate analysis revealed modified body mass index, early onset of disease (<50 years of age), disease duration before Ltx, and TTR Val30Met versus non-TTR Val30Met mutations as independent significant survival factors. Early-onset patients had an expected mortality rate of 38% that of the late-onset group (P < 0.001). Furthermore, Val30Met patients had an expected mortality rate of 61% that of non-TTR Val30Met patients (P < 0.001). With each year of duration of disease before Ltx, expected mortality increased by 11% (P < 0.001). With each 100-unit increase in modified body mass index at Ltx, the expected mortality decreased to 89% of the expected mortality (P < 0.001). Cardiovascular death was markedly more common than that observed in patients undergoing Ltx for end-stage liver disease. CONCLUSIONS: Long-term survival after Ltx, especially for early-onset TTR Val30Met patients, is excellent. The risk of delaying Ltx by testing alternative treatments, especially in early-onset TTR Val30Met patients, requires consideration.

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 HR(nonkidney), 1.8; 95% CI, 1.3-2.5; HR(kidney), 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.

Population pharmacokinetics of tacrolimus in pediatric liver transplantation: early posttransplantation clearance.

BACKGROUND: Tacrolimus is an immunosuppressant with a narrow therapeutic window, with considerable pharmacokinetic variability. Getting sufficient concentrations in pediatric liver transplantation is imperative, but it has proven difficult in the immediate posttransplantation period in particular. A predictive pharmacokinetic model could be the basis for development of a novel initial dose schedule, and therapeutic drug monitoring with Bayesian methodology. METHODS: The predictive capacity of 2 previously developed population pharmacokinetic models of tacrolimus in pediatric liver transplant recipients was tested in 20 new patients using Bayesian forecasting. Predictive performance was poor in the immediate posttransplant period with tacrolimus pharmacokinetics changing rapidly. A new population pharmacokinetic model, focusing on the immediate posttransplant period, was subsequently developed in 73 patients. RESULTS: An increase in the apparent clearance of tacrolimus in the first few weeks after transplant was evident. Typical apparent clearance of tacrolimus was 0.148 L·h(-1)·kg(-0.75) immediately after transplantation, increasing to a maximum of 1.37 L·h(-1)·kg(-0.75). Typical apparent distribution volume was 27.2 L/kg. Internal and external validation studies confirmed the predictive capabilities of the developed model. Simulation studies reveal that in 60% of subjects the current initial standard dose without subsequent dosage adjustments overshoot the desired trough concentration range of 10-20 ng/mL. An alternative dosing schedule was developed based on allometric scaling with an initial loading dose followed by a maintenance dose increasing with time. CONCLUSIONS: A population pharmacokinetic model for tacrolimus was developed, to better describe the early posttransplantation phase. This model has the potential to aid therapeutic drug monitoring and was also used to suggest a revised dosing scheme in the intended population.

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.

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.

Ten years of international experience with liver transplantation for familial amyloidotic polyneuropathy: results from the Familial Amyloidotic Polyneuropathy World Transplant Registry.

BACKGROUND: Transthyretin (TTR) amyloidosis is a group of systemic amyloidoses disorders caused by an amyloidogenic TTR variant. Untreated, it slowly leads to severely disabling symptoms that relentlessly progress until the death of the patient. Because the mutant form of TTR is produced mainly in the liver, successful orthotopic liver transplantation (OLT) results in the elimination of the source of the variant TTR molecule and is presently the only known curative treatment. OLT in patients with familial amyloidotic polyneuropathy (FAP) was first performed in 1990 at the Karolinska Institute in Sweden, and because the results were promising other centers took up the procedure. METHODS: To gain as great an experience as possible regarding this treatment, the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR) was initiated in 1995, and this article presents the 10-year registry results. RESULTS: A total of 54 centers in 16 countries have performed OLT for FAP, and today approximately 60 OLTs are performed annually worldwide. During the last decade, a total of 539 patients have undergone 579 OLTs. Patient survival is excellent (overall 5-year patient survival 77%) and comparable to the survival with OLT performed for other chronic liver disorders, but longer follow-up is needed to compare the outcome after OLT with the natural course of the disease. The main cause of death was cardiac related (39%). CONCLUSIONS: We believe that the FAPWTR has become a valuable tool that will help to accurately evaluate the potential risks and benefits of OLT in patients with FAP and promote a fruitful collaboration between centers engaged in this field.

Report from the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR) and the Domino Liver Transplant Registry (DLTR).

Familial amyloidotic polyneuropathy (FAP) is a fatal disease, belonging to a group of systemic disorders caused by an amyloidogenic transthyretin (TTR) variant. Orthotopic liver transplantation (OLT) eliminates the source of the variant TTR molecule, and is presently the only known curative treatment. A fascinating consequence of this treatment is the possibility of retransplanting the removed FAP liver into another non-FAP patient, which created the so-called domino liver transplantation (DLT) procedure. The Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR) was initiated in 1995, and in 1999 a Domino Liver Transplantation Registry (DLTR) was created. Herein data from these Registries are presented. A total number of 56 centers in 16 countries have performed OLT for FAP, and, today, approximately 65-70 OLTs are performed annually worldwide. During the last decade, a total of 623 patients have undergone 660 OLTs. Patient survival is excellent and comparable to the survival with OLT performed for other chronic liver disorders. Twenty-six centers in 12 countries have reported recipients of DLT grafts and presently 30-35 DLTs are performed annually. The FAPWTR and DLTR have become useful tools in evaluating the potential risks and benefits of these relatively new therapeutic options, in addition to encouraging a rewarding collaboration between centers involved in the management of these patients.