Andrea Frilling

Right living donor liver transplantation ; An option for adult patients ; Single institution experience with 74 patients

Objective: To present an institutional experience with the use of right liver grafts in adult patients and to assess the practicability and efficacy of this procedure by analyzing the results. Summary Background Data: Living donor liver transplantation (LDLT) for the pediatric population has gained worldwide acceptance. In the past few years, LDLT has also become feasible for adult patients due to technical evolution in hepatobiliary surgery and increased experience with reduced-size and split-liver transplants. Nevertheless, some graft losses remain unexplained and are possibly due to unrecognized venous outflow problems. Methods: From April 1998 to September 2002, we performed 74 right LDLTs (segments 5–8). The 74 donors were selected from 474 candidates according to standard protocol. The median age of the donors was 35 years (range 18–58 years) and 51 years (range 18–64 years) in recipients. Standard and extended indications for transplantation were considered. Over the period reported, technical modifications in the bile duct anastomosis (duct-to-duct, end-to-end, or end-to-side) and a new graft implantation technique that provides maximized venous outflow, leading to outcome improvement, were developed. Results: 64.9% of patients had liver cirrhosis and 35.1% had malignancy. While 44 donors (59.5%) presented an uneventful postoperative course, 27% minor (pleural effusion, pneumonia, venous thrombosis, wound infection, incisional hernia) and 13.5% major (biliary leakage, death of a donor due to unrecognized hereditary liver disease, and consecutive liver insufficiency) complications were documented. In recipients, 23% biliary complications and 6.8% hepatic artery thrombosis occurred. The overall patient and graft survival rate after 1 year was 79.4% and 75.3%, respectively. In cases with extended indication, the patient survival rate was 74% and the graft survival rate 68% at 12 months. Using technical modifications in the last 10 recipients, including 2 critically decompensated cirrhotics, the survival rate was 100% at a median follow-up of 3.5 months. Conclusions: In our transplant program, living donor liver transplantation has become a standard option in the adult patient population. The critical issue of this procedure is donor morbidity. Technical improvements in the harvesting and implantation of right grafts can also offer hope to patients with challenging forms of end-stage liver disease or malignant liver tumors.

Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma

BACKGROUND AND OBJECTIVES Medullary thyroid carcinoma (MTC) occurs both sporadically and In the autosomal domlnantly inherited multiple endocrine neoplasia (MEN) type 2 syndromes. The distinction between true sporadic MTC and a new mutation familial case is important for future clinical managment of both the patient and family. The susceptibility gene for MEN 2 is theRET proto‐oncogene. Systematic analysis for germ‐line mutations of theRET proto‐oncogene was performed in a series of 67 patients with apparently sporadic MTC to determine whether they were true sporadic cases or unsuspected de novo MEN 2 cases.

Experience after the evaluation of 700 potential donors for living donor liver transplantation in a single center

Adequate selection of donors is a major prerequisite for living donor liver transplantation (LDLT). Few centers report on the entire number of potential donors considered or rejected for living donation. From April 1998 to July 2003, a total of 111 living donor liver transplantations were performed at our institution, with 622 potential donors for 297 adult recipients and 78 potential donors for 52 pediatric recipients evaluated. In the adult group, only 89 (14%) potential donors were considered suitable, with a total of 533 (86%) potential donors rejected. Of these, 67% were excluded either at initial screening or during the first and second steps of the evaluation procedure. In 31% of all cases, the evaluation of donors was canceled because of recipient issues. In the pediatric group, 22 (28%) donors were selected, with the other 56 (72%) rejected. Costs of the complete evaluation process accounted for 4,589 Euro (€) per donor. The evaluation of a potential living donor is a complex and expensive process. We present the results on the evaluation of the largest group of potential donors for adults reported in the literature. Only 14% of potential donors in our series were considered suitable candidates. It has not yet been established who should cover the expenses of the evaluation of all rejected donors. In conclusion, all efforts should be made in order to develop an effective screening protocol for the evaluation of donors with the aim of saving time and resources for a liver transplantation program. (Liver Transpl 2004;10:1087–1096.)

Living donor liver transplantation in adults.

Abstract End-stage liver disease is being treated by liver transplantation. Despite legislative and social efforts, the number of cadaveric organs suitable for liver transplantation has not grown to match the increasing demand. The insufficient number of grafts results in high mortality for patients on the waiting list and prolonged waiting times with increasing morbidity. Following the success of living related-donor segmental liver transplantation in children, an amended concept has been applied to the adult patients. The early experience with this technique, the process concerning the selection of the donor for the recipient, the risks of the donor, and the future evolution of living related-donor liver transplantation are the topics of this article.

Volumetric and functional recovery of the liver after right hepatectomy for living donation

Our objective was to study the kinetics of recovery of the liver volume and liver function after right hepatectomy (RH) for living donation, comparing conventional and quantitative liver function tests, i.e., galactose elimination capacity (GEC). A total of 27 donors underwent RH averaging 61% of the whole liver volume. The conventional and quantitative liver function tests, as well as magnetic resonance imaging volumetric studies, were performed preoperatively at postoperative day (POD) 10, 90, 180, and 360. Mean residual volume increased by 88% within 10 days from RH and thereafter did not show any significant variation. After 1 year, only 83% of the original volume was reached. GEC per milliliter of liver volume expressed in percent of initial value (GEC/mL) showed a decrease of 25% at POD10, an increase up to 125% at POD 180, and returned to normal values at POD 360. Liver biochemistries, International Normalized Ratio (INR), and bilirubin returned to normal in 10 days. Cholinesterase showed a similar course like GEC. In conclusion, within 10 days of 61% loss of its initial volume, the liver is capable of regenerating a volume necessary to its function, although it corresponds to only 74% of the initial one. It takes only 10 days to normalize liver biochemistries, while cholinesterase and albumin recover over 90 days. However, a direct measure of the cytosolic liver function obtained by GEC shows that functional recovery occurs much more gradually than the recovery of volume and liver biochemistries. (Liver Transpl 2004;10:1024–1029.)

Detection of RET proto-oncogene codon 634 mutations using mass spectrometry

Abstract Mutations located in the RET proto-oncogene at codon 634 associated with multiple endocrine neoplasia type 2A and medullary thyroid carcinoma are detected by low-resolution and high-resolution mass spectrometry schemes not requiring labeling or electrophoretic separation of diagnostic products. The former requires measurement by matrix-assisted laser desorption ionization time-of-flight mass spectrometry of 21- to 27-mer oligonucleotides generated by a primer oligo base extension reaction. The latter is based upon direct measurement of artificial products which include the mutation site using matrix-assisted laser desorption ionization Fourier transform mass spectrometry. In this feasibility study a synthetic 25-mer representing the wildtype allele (7660.3 Da) was easily distinguished from G to A (7644.3 Da) and G to T (7635.3 Da) mutant alleles; the mutant alleles, which differed in mass by only 9.0 Da, were easily resolved when analyzed as a mixture. The results of both detection schemes were highly accurate and reliable, indicating mass spectrometry to be a high-quality alternative for future DNA diagnostics performed in clinical laboratories and genetic profiling studies.

Preoperative donor liver biopsy for adult living donor liver transplantation: Risks and benefits

The role of liver biopsy (LB) in donor selection for adult living donor liver transplantation remains controversial, since the procedure is associated with additional potential risks for the donor. From April 1998 to August 2004, 730 potential living donors for 337 adult recipients underwent our multistep evaluation program. In 144 candidates, LB was performed. LB was obtained in a percutaneous ultrasound‐guided fashion by means of Menghini needle (32 cases) or Tru‐cut needle (112 cases). The biopsy specimen was preserved in 5% formalin and processed with hematoxylin & eosin–stained sections. Thirty‐one (21%) of 144 candidates who underwent an LB had a positive finding at histological examination that induced their exclusion from donation, of whom 21 had liver steatosis of varying kind and grade (10%‐80%) and 10 had a nonsteatotic hepatopathy (non–A‐D hepatitis in 6 cases, diffuse granulomatosis in 2, schistosomiasis in 1, fibrosis in 1). The only observed major complications related to LB were 2 intraparenchymal haematomas, both of which resolved spontaneously within a few months. In conclusion, based on these findings, we believe that preoperative LB in the donor selection for adult LDLT is necessary, once the initial donor screening and noninvasive evaluation is complete. Because other screening modalities can be unreliable, without preoperative LB a fraction of potential donors will be operated on inappropriately, risking both donor and recipient. The main objective of LB should be to ensure the donors safety more than the preservation of the graft function. (Liver Transpl 2005;11:980–986.)

Liver transplantation for patients with metastatic endocrine tumors: Single‐center experience with 15 patients

In contrast to other secondary liver malignancy, orthotopic liver transplantation (OLT) is considered as a treatment modality for nonresectable endocrine liver metastases in selected patients. However, only few series have assessed patient selection criteria and long‐term results, and no reports have focused on the impact of new technologies in this regard. Between 1992 and 2004, 28 patients with malignant endocrine tumors underwent evaluation for OLT according to our protocol. Data were entered into a prospective database. During pretransplant evaluation, somatostatin receptor scintigraphy detected extrahepatic metastases not diagnosed in standard imaging in 10 patients. Of them, 3 showed aberrant Ki67 labeling results. One patient was excluded from further evaluation due to severe carcinoid heart. Thus far, 15 patients, 10 men and 5 women, aged 37 to 67 years, were subjected to the transplant procedure (11 deceased donor OLT, 3 living donor liver transplantations, and 1 cluster transplantation). Four patients died during the hospital treatment. The median follow‐up of the discharged patients was 60.8 months. The actuarial patient survival was 78.3% at 1 year and 67.2% at 5 years. The actuarial 1‐, 2‐, and 5‐year tumor‐free survival amounted to 69.4%, 48.3%, and 48.3%, respectively. Two patients underwent surgery for isolated tumor recurrence. In 2 patients, peptide receptor radiotherapy was carried out because of multilocular recurrent disease. In conclusion, liver transplantation is a realistic therapeutic option for highly selected patients with hepatic metastases of endocrine tumors. Our strategy, which implements strict pretransplant selection and aggressive surgical approach, in case of disease recurrence, in addition to systemic radiopeptide treatment, led to an excellent long‐term survival cure, however, is unlikely to be achieved. Liver Transpl 12:1089–1096, 2006.

Quality of Life and Psychiatric Complications After Adult Living Donor Liver Transplantation

We investigated the psychosocial effects of a right hepatectomy on donors for adult living donor liver transplantation (ALDLT). Questionnaires were sent to 66 actual donors, who had undergone ALDLT between August 1998 and September 2003, as well as to 139 potential donors, who had been examined as possible candidates for ALDLT; the latter had been excluded and had not undergone surgery. All actual donors reported full recovery within an average period of 14.41 (standard deviation = 8.86) weeks; all had returned to their preoperative employment. In preparation for ALDLT, they had received significantly more support from their families in the decision‐making process than the potential donors had (t = 2.02; degree of freedom = 79; P = 0.047); they also felt better informed about donation than the potential donors (t = 2.04; df = 64; P = 0.045). Psychiatric problems occurred in 6 (14%) female donors in the perioperative period, mostly in connection with unrealistic outcome expectations. Donors with severe postoperative complications (n = 3) demonstrated higher scores of psychiatric symptoms (chi‐square = 6.39; df = 2; P = 0.041). When we compared potential and actual donors, a significant difference in emotional quality of life was not demonstrated (t = 0.41; df = 76; P = 0.684), and it corresponded to that of the normative sample. For donors, perceived emotional quality of life did not depend on the course of recovery of the recipients. Six to 9 months after donation, potential donors reported a significantly higher physical quality of life than actual donors (t = 2.20; df = 56; P = 0.032). In conclusion, female donors, donors with their own major complications, or donors with unrealistic outcome expectations should be provided with adequate psychosocial care. With regard to the psychosocial outcome, ALDLT is a safe intervention for the donor. Liver Transpl 12:1782–1790, 2006.

Presymptomatic DNA screening in families with multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma

BACKGROUND Missense mutations of the ret proto-oncogene on chromosome 10q11.2 are the underlying cause of hereditary medullary thyroid carcinoma (MTC), either as familial MTC only (FMTC) or as a part of multiple endocrine neoplasia type 2 syndrome (MEN 2). This study presents our experience with direct presymptomatic DNA screening in MEN 2 and FMTC kindreds. METHODS Twenty one families with MEN 2 or FMTC were considered in the study. One hundred three individuals had been analyzed; 56 were at risk. The ret mutations were detected by DNA analysis of exons 10, 11, and 16 by using nonradioactive labeling method based on digoxigenin DNA sequencing technique. Serum calcitonin evaluation was carried out in all individuals at risk. Thyroidectomy was performed in those who had to undergo surgery. RESULTS The ret mutations were identified in all 21 families. In MEN 2A and FMTC families mutations occurred in exons 10 and 11. MEN 2B families had mutations in exon 16. The most frequent mutation in MEN 2A and FMTC affected codon 634. Twenty one gene carriers were identified in unaffected individuals at risk. Ten of 21 gene carriers had elevated calcitonin levels, and 11 had normal levels. MTC or C-cell hyperplasia was found in six gene carriers with pathologic calcitonin values who underwent operation. In a 5-year-old gene carrier with normal calcitonin values C-cell hyperplasia was evident. CONCLUSIONS Direct predictive DNA analysis allows us to identify MEN 2 or FMTC gene carriers and offer them prophylactic treatment.