Michael Olausson

In situ splitting of cadaveric livers. The ultimate expansion of a limited donor pool.

OBJECTIVE The authors evaluate the safety, applicability, and effectiveness of a new technique for split-liver transplantation. SUMMARY BACKGROUND DATA Split-liver transplantation offers an attractive way to increase the donor pool for cadaveric liver transplantation. The application of this concept has been hampered by inferior patient and graft survivals and higher complication rates. Without supportive data, the concern about increasing biliary leakage and poor initial graft function persisted. The authors focused on the causes of these complications by presenting a new technique to eliminate these problems. METHODS Liver splitting was performed in the heart-beating cadaveric organ donor, using the technique described for procurement of the left lateral lobe of a live donor. A detailed description of the technique is presented. A retrospective review of the first 14 transplantations resulting from 7 in situ splitting procedures was collected. The results were compared with 19 conventional split-liver transplants performed during the same period. RESULTS Six-month patient and graft survivals after in situ split-liver transplantation were 92.8% and 85.7%, respectively. Biliary complications were absent. Postoperative courses were mostly uneventful and characterized by lower peak transaminase levels compared with standard techniques. Early graft function of extrahepatic organs procured simultaneously was excellent. CONCLUSIONS In situ split-liver transplantation provides superior results, related mainly to reduction of cold ischemic damage of the grafts and avoidance of biliary complications. In situ split-liver transplantation renders graft reduction alone obsolete and opens a donor pool for adults to receive right lobes safely. It allows for long-distance sharing between pediatric and adult liver transplant units because the procedure abolishes ex situ benching and prolonged ischemia time and provides two anatomically perfect grafts with hemostasis accomplished.

Efficacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation

Patients undergoing orthotopic liver transplantation (OLT) have excessive blood loss during surgery that requires blood transfusions, leading to increased postoperative morbidity and mortality. We studied the efficacy and safety of activated recombinant factor VII (rFVIIa) in reducing transfusion requirements in OLT. This multicenter, randomized, double‐blind, placebo‐controlled trial enrolled patients undergoing OLT because of cirrhosis (Child‐Turcotte‐Pugh class B or C). Patients received a repeated intravenous bolus regimen of rFVIIa 60 or 120 μg/kg or placebo. The primary efficacy endpoint was the total number of red blood cell (RBC) units transfused during the perioperative period. A total of 182 patients were analyzed for efficacy and 183 for safety. No significant effect of rFVIIa was observed on the number of RBC units transfused or intraoperative blood loss compared with the placebo group. A significantly higher number of patients in the rFVIIa study groups avoided RBC transfusion. Administration of rFVIIa but not placebo restored the preoperative prolonged prothrombin time to normal value during surgery. Patients receiving rFVIIa and placebo did not experience a significant difference in rate of thromboembolic events. Additionally, there was no statistically significant effect of rFVIIa treatment on hospitalization rate, total surgery time, and the proportion of patients undergoing retransplantation. In conclusion, use of rFVIIa during OLT significantly reduced the number of patients requiring RBC transfusion. There was no increase in thromboembolic events with rFVIIa administration compared with placebo. (Liver Transpl 2005;11:973–979.)

Orthotopic liver or multivisceral transplantation as treatment of metastatic neuroendocrine tumors

Liver transplantation can be a therapeutic option for individual patients with neuroendocrine tumors metastatic only to the liver. In this consecutive series of 15 patients (5 multivisceral and 10 orthotopic liver transplantations) with well‐differentiated carcinoids, or endocrine pancreatic tumors, we allowed higher proliferation rate (Ki67 <10%), large tumor burden, and higher age than previous studies. Liver transplantation offered good relief of symptoms, long disease‐free intervals, and potential cure in individual patients. The survival of grafts and patients compared well with transplantation for benign disease. The overall 5‐year survival was 90%. The recurrence‐free survival of both multivisceral and liver transplantation related to the time after transplantation (about 20% at 5 years) despite inclusion of patients with higher risk. In conclusion, the critical prognosticators for long‐term outcome still remain to be defined. The experience with multivisceral transplantation for patients with endocrine tumors of the pancreatic head is still limited. Liver Transpl 13:327–333, 2007.

Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer

BackgroundHepatocellular cancer (HCC), as well as cholangiocellular cancer (CCC), has an extremely poor prognosis due to the extent of tumor at diagnosis and the underlying liver disease. Sirolimus is used in the transplantation setting as an immunosuppressive agent, but it also possesses antiproliferative and antiangiogenic properties. The objective of the study was to evaluate the effect of sirolimus on HCC and CCC.MethodsIn a prospective single-arm protocol, the tumor response to sirolimus as the primary endpoint was studied in 21 patients with advanced HCC and nine with CCC. Sirolimus was administered once daily by mouth, with the dose adjusted to a serum trough level between 4 and 15 μg/ml. Tumor response was evaluated by computed tomography (CT) or magnetic resonance imaging (MRI), according to the Response Evaluation Criteria in Solid Tumors (RECIST), every third month. Secondary measures were overall survival, time to tumor progression, tumor markers, and side effects.ResultsOf the patients with HCC, one had partial remission (PR) and fi ve patients had stable disease (SD) at 3 months. Of the patients with CCC, three had SD. The median survival for patients with HCC was 6.5 months (range, 0.2–36 months) and that for patients with CCC was 7 months (range, 2.6–35 months).ConclusionTreatment of HCC and CCC with sirolimus can induce temporary PD or SD. This pilot study indicates that sirolimus might be a promising drug for this treatment, but further clinical studies elucidating the biological effects are advocated.

Successful Combined Partial Auxiliary Liver and Kidney Transplantation in Highly Sensitized Cross-Match Positive Recipients

Combined liver and renal transplantations can be performed against a positive cross‐match, indicating that the liver protects the kidney from the harmful HLA antibodies. This led us to the hypothesis that a partial auxiliary liver graft may have a similar protective effect when performed together with the kidney in highly sensitized patients. Seven patients, with broadly reacting HLA antibodies and positive crossmatches, were transplanted with a partial liver and a kidney from the same donor. In one of the cases a living donor was used. We performed lymphocytotoxic and flow cross‐matches before and after the transplantation. Cross‐matches turned negative after grafting in five of seven cases. The kidney function was excellent, without rejections, during the follow‐up (24–60 months) in these patients. In two cases the cross‐match remained positive after transplantation, one with a never‐functioning renal graft and the other with an early graft failure, probably due to humoral rejection. A simultaneous transplantation of a partial auxiliary liver graft from the same donor, with the sole purpose of protecting the kidney from harmful lymphocytotoxic antibodies, can be performed successfully despite a positive cross‐match and may thus be a new option of treatment for highly sensitized patients waiting for a kidney transplant.

Transplantation of an allogeneic vein bioengineered with autologous stem cells: a proof-of-concept study

BACKGROUND Extrahepatic portal vein obstruction can have severe health consequences. Variceal bleeding associated with this disorder causes upper gastrointestinal bleeding, leading to substantial morbidity and mortality. We report the clinical transplantation of a deceased donor iliac vein graft repopulated with recipient autologous stem cells in a patient with extrahepatic portal vein obstruction. METHODS A 10 year old girl with extrahepatic portal vein obstruction was admitted to the Sahlgrenska University Hospital in Gothenburg, Sweden, for a bypass procedure between the superior mesenteric vein and the intrahepatic left portal vein (meso Rex bypass). A 9 cm segment of allogeneic donor iliac vein was decellularised and subsequently recellularised with endothelial and smooth muscle cells differentiated from stem cells obtained from the bone marrow of the recipient. This graft was used because the patients umbilical vein was not suitable and other strategies (eg, liver transplantation) require lifelong immunosuppression. FINDINGS The graft immediately provided the recipient with a functional blood supply (25-30 cm/s in the portal vein and 40 mL/s in the artery was measured intraoperatively and confirmed with ultrasound). The patient had normal laboratory values for 9 months. However, at 1 year the blood flow was low and, on exploration, the shunt was patent but too narrow due to mechanical obstruction of tissue in the mesocolon. Once the tissue causing the compression was removed the graft dilated. We therefore used a second stem-cell populated vein graft to lengthen the previous graft. After this second operation, the portal pressure was reduced from 20 mm Hg to 13 mm Hg and blood flow was 25-40 cm/s in the portal vein. With restored portal circulation the patient has substantially improved physical and mental function and growth. The patient has no anti-endothelial cell antibodies and is receiving no immunosuppressive drugs. INTERPRETATION An acellularised deceased donor vein graft recellularised with autologous stem cells can be considered for patients in need of vascular vein shunts without the need for immunosuppression. FUNDING Swedish Government.

Indications and Results of Liver Transplantation in Patients with Neuroendocrine Tumors

Metastases from neuroendocrine (NE) tumors of the gastrointestinal tract, carcinoids, and endocrine pancreatic tumors (EPTs) can be confined to the liver for long periods and may exhibit slow growth. When considering liver transplantation (LTx) for patients with NE tumors, the expected results with conventional treatment must be weighed against the risk of LTx and immunosuppression. The following indications for LTx may be considered for patients with metastatic NE tumors limited to the liver: (1) tumors not accessible to curative surgery or major tumor reduction; (2) tumors not responding to medical or interventional treatment; and (3) tumors causing life-threatening hormonal symptoms. We excluded patients with poorly differentiated NE carcinoma or well differentiated NE carcinoma with a high proliferation index (Ki 67 > 10%). Over 4 years (1997–2001) we have performed transplants in nine patients (five with EPTs, four with carcinoids) with a mean ± SEM follow-up of 22 ± 5 months (range 4–45 months). Seven patients underwent orthotopic LTx and two multivisceral LTx. Eight patients are alive, six without clinical evidence of disease. Four patients developed recurrent tumors 9 to 36 months after LTx; two were detected at an early stage and underwent resection with curative intent. One patient with multivisceral Tx died after 4 months of posttransplant lymphoproliferative disease without tumor recurrence. In selected series LTx can offer good control of hormonal symptoms, a relatively long disease-free interval, and in individual cases potential cure.

Long-term follow-up of patients with alcoholic liver disease after liver transplantation in Sweden: impact of structured management on recidivism.

Objective No systematic evaluation has been performed previously in the Scandinavian countries on patients transplanted for alcoholic liver disease (ALD). Data are limited on the impact of structured management of the alcohol problem on the risk of recidivism following transplantation in ALD. Material and methods A total of 103 ALD patients were compared with a control group of patients with non-alcoholic liver disease (NALD). The recidivism rates for ALD patients transplanted between 1988 and 1997 as well as after 1998 (institution of structured management) were compared. Results The median follow-up was 31 (6–60) months in the ALD group and 37 (12–63) months in the control group (NS). The overall survival rates at 1- and 5 years were, respectively, 81% and 69% for the ALD group and 87% and 83% for the non-alcoholic group. The proportion of patients with Child-Pugh C (75%) was higher in ALD patients than in NALD patients (44%) (p<0.01). Thirty-two (33%) ALD patients resumed taking some alcohol after transplantation; 17 patients (18%) were heavy drinkers. A multivariate analysis showed that: sex, age, marital and employment status, benzodiazepine use and a history of illicit drug abuse did not predict the risk of alcohol relapse post-Tx. Nineteen out of 40 (48%) patients transplanted before the start of structured management had resumed alcohol but 13 (22%) out of 58 after this intervention (p=0.002). Conclusions ALD is a good indication for liver transplantation, with similar results in the ALD patients. Structured management of the alcohol problem before and after transplantation is important in minimizing the risk of recidivism.

Liver Transplantation for Treatment of Metastatic Neuroendocrine Tumors

Abstract: Liver transplantation can be considered a therapeutic option for patients with neuroendocrine tumors only metastatic to the liver. Important selection criteria are well‐differentiated tumors and a low proliferation rate (Ki67 <10%). In this series, orthopic liver transplantation offered good relief of symptoms and long disease‐free intervals with initial survival of grafts and patients as in benign disease. The experience with multivisceral transplantation is still limited.

Uterus transplantation: animal research and human possibilities

Uterus transplantation research has been conducted toward its introduction in the human as a treatment of absolute uterine-factor infertility, which is considered to be the last frontier to conquer for infertility research. In this review we describe the patient populations that may benefit from uterus transplantation. The animal research on uterus transplantation conducted during the past two decades is summarized, and we describe our views regarding a future research-based human attempt.