Alan W. Hemming

Liver Transplantation for Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the commonest malignancies worldwide, and accounts for more than 1 million deaths annually. Identification of tumors early in the course of disease appears to be important for treatment, yet remains difficult to accomplish. Without treatment the prognosis is dismal with a median survival of 6-9 months. Partial hepatic resection is generally accepted as the treatment of choice for HCC with reported survival rates of up to 50% at 5 years. Unfortunately poor underlying liver function as well as tumor number or location preclude traditional hepatic resection in many cases. Total hepatectomy with transplantation (LT) has been advocated such cases, but the results have been variable. LT offers the advantage of radical tumor removal even in patients with multifocal disease or severe cirrhosis. Additionally, LT removes the possibility of metachronous lesions developing in the liver remnant and restores normal liver function. The critical limitation to advocating LT as primary oncotherapy in patients with HCC is the severe shortage of donor livers. Until organ availability improves, transplantation for HCC can only be offered to patients whose survival is predicted to be similar to that in patients transplanted for benign disease. This report reviews the current role and indications for liver transplantation as therapy for hepatocellular carcinoma.

The changing causes of graft loss and death after kidney transplantation.

Background. The results of kidney transplantation have improved markedly over the last three decades. Despite this, patients still lose grafts and die. We sought to determine whether the causes of graft loss and death have changed over the last 30 years. Methods. We reviewed patients who underwent transplantation or who died between January 1, 1970 and December 31, 1999. We compared the causes of graft loss or death for three decades: 1970 to 1979, 1980 to 1989, and 1990 to 1999. Results. From January 1, 1970 to December 31, 1999, we performed 2501 kidney transplantations in 2225 patients. For the three periods, 210, 588, and 383 patients lost their grafts, respectively. Graft survival increased substantially. Graft loss occurred later after transplantation, with 36.0% losing grafts in the first year during 1970 to 1970, 22.8% during 1980 to 1989, and 11.4% during 1990 to 1999. Death with a functioning graft increased from 23.8% for 1970 to 1979 to 37.5% for 1990 to 1999. Concomitantly, rejection as a cause of graft loss fell from 65.7% for 1970 to 1979 to 44.6% for 1990 to 1999. Approximately two thirds of the patients who died after transplantation died with a functioning graft and one third died after returning to dialysis. Cardiac disease as a cause of death increased from 9.6% for 1970 to 1979 to 30.3% for 1990 to 1999. Deaths from cancer and stroke also increased significantly over the three decades from 1.2% and 2.4%, respectively, for 1970 to 1979, to 13.2% and 8.0%, respectively, for 1990 to 1999. Conclusions. The causes of graft loss and death have changed over the last three decades. By better addressing the main causes of death, cardiac disease, and stroke with better prevention, graft loss due to death with a functioning graft will be reduced.

Obesity does not portend a bad outcome for kidney transplant recipients.

Background. Kidney transplant programs may avoid transplantation in obese patients because of reports indicating that obese patients have poorer outcomes than do nonobese patients. We recently reviewed our experience. Methods. Patients receiving a kidney transplant between January 1, 1990 and December 31, 1999 were divided according to body mass index (BMI): group 1, BMI<25 (n=457); group 2, BMI≥25 and <30 (n=278); and group 3, BMI≥35 (n=98). Results. Cadaveric graft survival rates at 2 years were 85% for group 1, 88% for group 2, and 85% for group 3 (P>0.10). Cadaveric patient survival rates at 2 years were 92% for group 1, 91% for group 2, and 94% for group 3 (P>0.10). There were no differences in technical losses or in posttransplantation wound complications. Group 3 patients, however, did have a higher incidence of steroid‐induced posttransplantation diabetes mellitus than the other two groups (P<0.01). Conclusion. Obese transplant recipients have similar outcomes to nonobese patients.

Hepatic vein reconstruction for resection of hepatic tumors

Summary Background DataInvolvement of the hepatic veins requiring reconstruction has traditionally been considered a contraindication to resection for advanced tumors of the liver because the surgical risks are high and the long-term prognosis poor. Recent advances in liver surgery gleaned from split and live donor liver transplantation that necessitate hepatic vein reconstruction can be applied to hepatic resection in some cases. MethodsSixteen patients who underwent hepatic resection requiring hepatic vein reconstruction from 1996-2001 were reviewed. The mean age was 43 years (range 2–61). Nine patients were resected for hepatocellular carcinoma (HCC), five patients for colorectal metastases, and one patient each for hepatoblastoma and cholangiocarcinoma. In six patients with HCC and cirrhosis, the right hepatic vein was reconstructed to provide venous outflow to liver segments not adequately drained by a remaining major hepatic vein. Four of these six patients required the use of Gore-Tex (W. L. Gore & Associates, Inc., Newark, DE) interposition grafts. In the 10 other cases the entire venous outflow from the remnant liver was reconstructed or reimplanted into the inferior vena cava primarily (n = 8) or using segments of the portal vein from the resected side of the liver as a graft (n = 2). Ex-vivo procedures with the use of veno-venous bypass were required in two cases and in-situ cold perfusion of the liver was used in one case. ResultsThere were two perioperative deaths (12%). One patient died of liver failure 3 weeks after right trisegmentectomy with reconstruction of the left hepatic vein and one patient died at 3 months after resection due to sepsis from a segment of small bowel that perforated into a diaphragmatic hernia. Four patients had evidence of postoperative liver failure that resolved with supportive management and one patient required temporary dialysis. All vascular reconstructions were patent at last followup. With median followup of 23 months, 3 patients have died of recurrent malignancy at 14, 18 and 30 months, while an additional patient went on to die of progressive liver failure at 22 months. Actuarial 1 and 3 year survival was 88% and 50% respectively. ConclusionHepatic vein involvement by hepatic malignancy does not necessarily preclude resection. Liver resection with reconstruction of the hepatic veins can be performed in selected cases. The increased risk associated with the procedure appears to be balanced by the possible benefits, particularly when the lack of alternative curative approaches is considered.

Liver transplantation from donation after cardiac death: a single center experience.

Background. Liver transplantation (LT) from controlled donation after cardiac death (DCD) donors has increased steadily during the past decade because of the donor shortage in the United States. Although early reports of LT from DCD donors provided evidence for acceptable outcomes, long-term graft and patient survival rates from these procedures have been reviewed only recently. Methods. From February 1990 to June 2006, 1209 LTs were performed from donation after brain death (DBD) donors, and 24 were performed from DCD donors at our institution. Detailed review of donor and recipient characteristics, and survival rates were evaluated in the two groups. Results. One- and 3-year patient survival was similar in both groups, (DCD 86.8%, 81.7% vs. DBD 84.0%, 76.0%, respectively; P=0.713). Graft survival appeared inferior in the DCD group compared with the DBD group at 1 year (69.1% vs. 78.7%) and 3 years (58.6% vs. 70.2%), but there was no statistical difference (P=0.082). There were no significant differences in hepatic artery thrombosis, portal vein thrombosis, primary nonfunction, and biliary stricture between the two groups. All cases with biliary stricture in DCD group finally led to graft loss, and all survived with retransplantation. Conclusion. The outcome of LT from DCD donors remains acceptable in our institution. Although biliary complication rate was similar in two groups, the consequence of this complication in DCD was more severe and often led to graft loss. Close observation of biliary complications after LT from DCD donors would be beneficial.

Portal Venous and Enteric Exocrine Drainage Versus Systemic Venous and Bladder Exocrine Drainage of Pancreas Grafts: Clinical Outcome of 40 Consecutive Transplant Recipients

ObjectiveTo test the hypothesis that pancreas transplantation using the more physiologic method of portal venous-enteric (PE) drainage could be performed without compromising patient and graft outcome, compared with the standard method of systemic venous-bladder (SB) drainage. MethodsBetween November 1995 and November 1998, the authors prospectively followed up 20 consecutive patients with SB drainage followed by 20 consecutive patients with PE drainage. All patients underwent simultaneous pancreas–kidney transplantation, and all were immunosuppressed with antilymphocyte serum, cyclosporin, azathioprine, and steroids. ResultsThe actuarial patient survival rate at 1 year was 95% in the SB group and 100% in the PE group. Death-censored kidney graft survival was 100% in both groups; pancreas graft survival was 95% in the SB group and 100% in the PE group. The mean initial hospital stay was 15 days for both groups. However, during the first 6 months after transplantation, the SB group required more medical day-unit visits, mostly for treatment of metabolic acidosis and dehydration. The incidence of urinary tract infections was similar in both groups. The incidence of cytomegalovirus infections was significantly less in the PE group. The incidence of acute rejection was 37% in the SB group and 15% in the PE group. Mean serum creatinine levels 6 months after transplantation were significantly lower in the PE group than in the SB group. Glycemic control was excellent in both groups, but fasting serum insulin levels were significantly lower in the PE group. ConclusionsThe PE method of pancreas transplantation can be performed with excellent patient and graft outcomes.

Outcome of kidney transplants in patients known to be flow cytometry crossmatch positive

Background. The clinical significance of the flow cytometry crossmatch has been addressed in several retrospective studies, but the results have been controversial. There are no prospective studies in which patients known to be antibody positive underwent transplantation. Methods. The flow cytometry crossmatch was performed prospectively in 1130 renal transplant recipients. A decision to perform transplantation was based on whether the positive results were on T or B cells, in the current or peak specimen, and taking into account the presence or absence of other immunological risk factors. One hundred antibody-positive patients received a transplant. Graft survival and rejection episodes were analyzed in this group and compared with 100 crossmatch-negative patients matched for age, sex, race, and time of transplantation. Results. The incidence of rejection at 1 month was higher in antibody-positive patients (26%) than in antibody-negative patients (12%, P <0.01). Early rejection seemed to be more frequent in antibody-positive patients regardless of whether the antibodies were current or historic, or against T or B cells. There were more steroid-resistant rejections in antibody-positive than in antibody-negative patients. However, biopsy specimens showed that vascular lesions that can be associated with humoral rejection were not more frequent in the antibody-positive patients than in the controls. There were no differences in graft survival between the two groups. Conclusions. Low-level preformed alloantibodies detected by flow cytometry represent a risk of rejection even for patients purposely selected for having no additional immunological risk factors. The risk seems to be due to donor-specific memory rather than to a direct effect of the antibodies. The results indicate that flow cytometry provides useful information to assess donor-recipient compatibility.

A microemulsion of cyclosporine without intravenous cyclosporine in liver transplantation.

A microemulsion formulation of cyclosporine (CsA) has improved absorption compared with the original form. The purpose of this case control study was to assess the safety and efficacy of the microemulsion without intravenous CsA for induction immunosuppression in adult liver transplantation. Twenty-one consecutive patients receiving induction immunosuppression with the microemulsion 15 mg/kg/day were compared with 20 patients receiving intravenous CsA and the original oral form. Both groups received the same dose of methylprednisilone. Twenty of 21 patients receiving the microemulsion required no intravenous CsA to achieve target CsA levels. All patients receiving the original form received initial intravenous CsA. There was no difference in trough CsA levels between the two groups at 24 and 48 hours. The microemulsion group had 24 hr and 48 hr trough CsA levels of 227+/-15 and 520+/-300 ng/ml by monoclonal RIA while the intravenous CsA group had 24 and 48 hr trough levels of 293+/-18 and 405+/-91 ng/ml. CsA levels analyzed by HPLC were 20% lower than by RIA. The frequency of adverse events resulting in reduction of drug dosage was similar for the microemulsion and the original form: neurotoxicity (23 vs. 40%, P=.30); nephrotoxicity (25 vs. 45%, P=.32), and no patients required dialysis. There was no difference in septic complications. One patient required discontinuation of the microemulsion in an attempt to reverse severe neurotoxicity. A total of 75% of microemulsion patients were rejection free at 3 months while only 35% of CsA patients remained rejection free (P=0.02). These data suggest that the use of the microemulsion without intravenous CsA in liver transplantation is safe and efficacious, and may result in decreased episodes of acute rejection.

Treatment outcomes and prognostic factors of intrahepatic cholangiocarcinoma.

The aim of the present study was to determine the treatment outcome and prognostic factors for survival in patients with peripheral intrahepatic cholangiocarcinoma (ICC). A retrospective chart review was performed for patients diagnosed with ICC between 2000 and 2009 at a single institution. We identified a total of 105 patients with ICC. Among them, 63.8% were older than 60 years of age, 50.5% were male and 88.6% were Caucasian. By preoperative imaging approximately half of the patients (50.5%) were surgical candidates and underwent resection. The other half of the patients (49.5%) were unresectable. The unresectable group received chemoradiotherapy (53%) and transarterial chemoembolization (7.7%) as palliative treatments while 23.0% of the patients (12/52) received best supportive care alone. The median survival rates were 16.1 months (13.1–19.2) for the entire cohort, 27.6 months (17.7–37.6) for curative resection, 12.9 months (6.5–19.2) for palliative chemoradiotherapy and 4.9 months (0.4–9.6) for best supportive care (P<0.001). Independent predictors on multivariate analysis were advanced stage at diagnosis and treatment received. In those patients who underwent resection, advanced AJCC stage and presence of microvascular invasion were also independent predictors of poor survival. We concluded that surgery offers the most beneficial curative option and outcome, emphasizing the importance of resectability as a major prognostic factor. The present study also revealed that use of chemoradiotherapy in the adjuvant setting failed to improve survival but its palliative use in those patients with unresectable ICC offered a modest survival advantage over best supportive care. The overriding factors influencing outcome were stage and the presence of microvascular invasion on pathology.

Liver Planning Software Accurately Predicts Postoperative Liver Volume and Measures Early Regeneration

BACKGROUND Postoperative or remnant liver volume (RLV) after hepatic resection is a critical predictor of perioperative outcomes. This study investigates whether the accuracy of liver surgical planning software for predicting postoperative RLV and assessing early regeneration. STUDY DESIGN Patients eligible for hepatic resection were approached for participation in the study from June 2008 to 2010. All patients underwent cross-sectional imaging (CT or MRI) before and early after resection. Planned remnant liver volume (pRLV) (based on the planned resection on the preoperative scan) and postoperative actual remnant liver volume (aRLV) (determined from early postoperative scan) were measured using Scout Liver software (Pathfinder Therapeutics Inc.). Differences between pRLV and aRLV were analyzed, controlling for timing of postoperative imaging. Measured total liver volume (TLV) was compared with standard equations for calculating volume. RESULTS Sixty-six patients were enrolled in the study from June 2008 to June 2010 at 3 treatment centers. Correlation was found between pRLV and aRLV (r = 0.941; p < 0.001), which improved when timing of postoperative imaging was considered (r = 0.953; p < 0.001). Relative volume deviation from pRLV to aRLV stratified cases according to timing of postoperative imaging showed evidence of measurable regeneration beginning 5 days after surgery, with stabilization at 8 days (p < 0.01). For patients at the upper and lower extremes of liver volumes, TLV was poorly estimated using standard equations (up to 50% in some cases). CONCLUSIONS Preoperative virtual planning of future liver remnant accurately predicts postoperative volume after hepatic resection. Early postoperative liver regeneration is measureable on imaging beginning at 5 days after surgery. Measuring TLV directly from CT scans rather than calculating based on equations accounts for extremes in TLV.