Antitumor efficacy of Mammalian target of rapamycin inhibitor therapy in liver transplant recipients with oncological disease: a case-control study

Introduction

The reported incidences of de novo malignancy following orthotopic liver transplantation (OLT) are significantly greater than those in the general population. We have analyzed the efficacy of mammalian target of rapamycin inhibitor (mTORi) as immunosuppressant therapy in patients with de novo malignancies or those engrafted because of a primary liver cancer.

Methods

We performed a case-control study of patients with hepatocellular carcinoma (HCC; n = 119), cholangiocarcinoma (n = 1) or de novo malignancies (n = 73). Thirty-seven patients with these tumors were treated with mTORi, and 167, with calcineurin inhibitors (CNI). Switching to mTORi was performed progressively, withdrawing the CNI over 15 days, until obtaining levels of 5-10 ng/dL.

Results

No incidence of rejection, serious adverse events, or death was observed with an overall actuarial survival of 68.5% in the mTORi group versus 45.7% among the CNI group. Overall rates of tumor recurrence were 15.2% and 36.8%, respectively (P < .05). Among patients with HCC, survival was 100% of mTORi with and 61.5% among CNI patients, with tumor recurrence rates of 6.2% and 19.1%, respectively (P < .05).

Discussion

Surprising differences in survival and tumor recurrence rates were observed among the mTORi-treated group compared with controls. Switching from CNI to mTORi immunosuppressant therapy appeared to be safe. It seems to be reasonable to employ this strategy in liver transplant patients with primary hepatic or “de novo” neoplasms.     

Everolimus in Lung Transplantation in Chile

Everolimus has shown good results in kidney and heart transplantation, achieving low rates of rejection, of infections, and of tumors compared with calcineurin inhibitors (CNI). Some publications have shown beneficial effects in bronchiolitis obliterans syndrome (BOS). We have presented herein the initial experience with everolimus among lung allograft recipients in Chile.

Methods

We retrospectively evaluated, charts of lung-transplanted patients who used everolimus (Certican) based on 2 years' follow-up, evaluating the indication for therapy; blood levels, rejection episodes, lung and kidney function, and side effects.

Results

Eight of 55 lung transplantation patients were switched to everolimus, targeting a (mean drug level of 4.2 ng/dL), in combination with low-dose tacrolimus (mean levels 5.5 ng/dL) and steroids. The Reasons for conversion were: CNI nephropathy (n = 3), BOS (n = 4), and lymphoma (n = 1). In patients with renal dysfunction, serum creatinine had risen from 1.1 to 1.8 mg/dl, but at 3 months after everolimus conversion, they had returned to baseline values, maintaining that level for at least 2 years' follow-up. Patients with BOS had decreased their ventricular ejection fraction (VEF₁) by 50%. Using everolimus, they maintained that VEF₁ with little improvement. The patient with lymphoma died 11 months after conversion. No patient experienced a rejection episode, and they suffered from fewer infections than the other lung allograft recipients. There were no adverse events related to everolimus, but one patient discontinued the drug after 1 year owing to intolerance.

Conclusion

Everolimus was effective to reverse CNI renal dysfunction in lung transplantation patients, possibly retarding the progression of BOS, without side effects over a 2-year follow-up.     

Calcineurin inhibitor-free immunosuppression using everolimus (Certican) after heart transplantation: 2 years' follow-up from the University Hospital Münster

Background

Everolimus is a proliferation-signal inhibitor which was introduced for heart transplant recipients in 2004. To date, there are only sparse data about long-term calcineurin inhibitor (CNI)-free immunosuppression using everolimus.

Methods

After heart transplantation, patients receiving everolimus were consecutively enrolled. Reasons for switching to everolimus were side effects of CNI immunosuppression, such as deterioration of kidney function and recurrent rejection episodes. All 60 patients underwent standardized switching protocols, 42 patients completed 24-month follow-up. Blood was sampled for lipid status, renal function, routine controls, and levels of immunosuppressive agents. On days 0, 14, and 28, and then every 3 months, echocardiography and physical examination were performed.

Results

After switching to everolimus, most patients recovered from the side effects. Renal function improved significantly after 24 months (creatinine, 2.1 ± 0.6 vs 1.8 ± 1 mg/dL; P < .001; creatinine clearance, 41.8 ± 22 vs 48.6 ± 21.8 mL/min; P < .001). Median blood pressure increased from 120.0/75.0 mm Hg at baseline to 123.8/80.0 mm Hg at month 24 (P values .008 and .003 for systolic and diastolic pressures, respectively). Tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved. Levels of interleukin-6 were stable between baseline and 24-month levels. Temporary adverse events occurred in 8 patients [13.3%: interstitial pneumonia (n = 2), skin disorders (n = 2); reactivated hepatitis B (n = 1), and fever of unknown origin (n = 3)].

Conclusion

CNI-free immunosuppression using everolimus is safe, with excellent efficacy in maintenance of heart transplant recipients. Arterial hypertension and renal function significantly improved. CNI-induced side effects, such as tremor, peripheral edema, hirsutism, and gingival hyperplasia, markedly improved in most patients.     

University of Modena experience in HIV-positive patients undergoing liver transplantation

Introduction

Highly effective antiretroviral therapy in the last decade has increased the survival rates of HIV-positive patients, yielding a greater number of HIV patients suffering from liver-related disease. Liver transplantation (LT) is the only curative treatment for end-stage liver disease (ESLD) associated or not with hepatocellular carcinoma (HCC).

Patients and methods

From June 2003 to September 2010, 23 patients underwent cadaveric donor LT for ESLD at our institution. Inclusion criteria followed the Italian Protocol for LT in HIV-positive patients. Immunosuppressive regimens were based on cyclosporine or tacrolimus, eventually switched to Rapamycin.

Results

The median CD4 T-cell count was 275/mmc (range = 119-924). All patients were affected by ESLD, which was associated with HCC in 14 cases. Ten patients were within the Milan criteria and four patients exceeded them but were within the San Francisco criteria. Conversion from calcineurin inhibitors (CNI) to rapamycin occurred in ten cases. Hepatitis C virus (HCV) recurrence occurred in 13/21 HCV-positive patients. Acute cellular rejection occurred in eight patients with one developing chronic cellular rejection. Overall patient and graft survivals at 80 months were 50% and 45% respectively.

Discussion

LT in HIV-positive patients is a feasible procedure, even if in our experience was burdened by a greater incidence of complications including HCV recurrence and infection compared with HIV-negative patients.     

Impact of Tumor Characteristic on the Outcome of Liver Transplantation in Patients With Hepatocellular Carcinoma

Introduction

Orthotopic liver transplantation (OLT) is a well-established treatment for cirrhotic patients with hepatocellular carcinoma (HCC) who meet the Milan criteria. The aim of this study was to identify predictors of survival among 65 patients with HCC in cirrhotic livers who underwent liver transplantation (OLT).

Methods

From January 2001 to December 2008, we performed 655 OLT in 615 patients. HCC was diagnosed in 58 patients before OLT and in 65 by histological examination of the explanted livers; 74% of the patients met Milan criteria by histological examination.

Results

The median follow-up was 27 months (range = 1-96). We analyzed patient age and gender, etiology of liver disease, Child score at transplantation, rejection episodes, tumor number/size, vascular invasion, and differentiation grade. There was no significant difference in survival among patients grouped according to the Model for End-stage Liver Disease staging system for HCC. The 5-year survival of patients with low differentiated (G3) HCC was significantly worse than that of those with moderately differentiated (G2) or well-differentiated (G1) HCC: 50%, 81%, and 86% respectively, (P < .01). Patients with microvascular invasion displayed a worse 5-year survival than those without vascular invasion (42% vs 80%; P < .01).

Conclusions

The analysis indicated that the histological grade of the tumors and evidences of microscopic vascular invasion were the most useful predictive factors for overall survival among patients with cirrhosis after liver transplantation for HCC.     

Immunosuppression With Low-Dose Daclizumab in Liver Transplant Recipients With Impaired Kidney Function: A Single-Center Experience

Background

Nephrotoxicity of calcineurin inhibitors (CNI) may exert detrimental effects, particularly in orthotopic liver transplantation (OLT) patients with impaired kidney function. Immunosuppression with daclizumab permits delayed introduction of CNI, and may be preferred for patients with kidney dysfunction. This retrospective analysis of our experience using daclizumab was performed among patients who underwent transplantation with impaired kidney function.

Methods

We analyzed 168 patients. A serum creatinine (Cr) level >1.5 mg/dL was the indication for a protocol with low-dose daclizumab (50 mg intravenous [IV], day 0 and day 4), mycophenolate mofetil (MMF; 500 mg twice daily IV/orally), and tapering doses of prednisolone from day 0 after OLT. CNI were introduced at day 4-15 after OLT. Patients with a Cr level <1.5 mg/dL received immunosuppression with CNI+MMF+steroids or CNI+steroids.

Results

Fourteen patients fulfilled the criterion for daclizumab immunosupression. Their Cr and creatinine clearance (CrCl) values at OLT were 2.85 ± 1.22 mg/dL and 19 ± 11 mL/min, respectively. In the remaining 154 patients, Cr and CrCl results were 0.88 ± 0.3 mg/dL and 107 ± 82 mL/min, respectively. At discharge, the daclizumab group showed Cr and CrCl estimates of 0.97 ± 0.45 mg/dL and 86 ± 34 mL/min (P < .0001 for both, when compared with prior to OLT). Both Cr and CrCl levels at discharge were not different from those values of patients who underwent transplantation with normal kidney function. The incidence of acuterejection was 14% in the daclizumab group and 18% in the other recipients (P = not significant [NS]).

Conclusions

Immunosuppression with low-dose daclizumab and delayed introduction of CNI was safe and did not increase the risk of an acute rejection episode, thus offerring an excellent therapeutic option for patients who undergo transplantation with impaired kidney function.     

Indications and effectiveness of the mammalian target of rapamycin in liver transplantation

Background

The mammalian target of rapamycin (mTOR) inhibitors are new immunosuppressive drugs for organ transplantation. They are interesting for liver transplantation because of their absence of nephrotoxicity and potential antitumor effects, because calcineurin inhibitors (CNI) are associated with renal dysfunction post-CNI and tumors. We sought to analyze the indications, safety, and efficacy of mTOR among liver transplant patients at our center.

Methods

We retrospectively identified patients who were treated with mTOR for their indications for liver transplantation, type of immunosuppressive therapy, acute rejection episodes, and evolution of kidney function.

Results

We identified 43 (19.02%) patients treated with mTOR including 35 (81.4%) males and 8 (18.6%) females of overall average age of 56.7 (range, 44-68). In 30% of patients, the drug was introduced for kidney failure, and in 23% for actual or a high risk of hepatocellular carcinoma (HCC) recurrence. The average time to introduction of the mTOR was 6.4 months (range, 1-46). The final immunosuppressive regimen was mTOR alone (73%), or mTOR plus CNI (23%), or mTOR plus mycophenolate mofetil (4%). The average values of creatinine and urea were lower after conversion to mTOR (P < .05) with a 6.9% incidence of acute rejection episodes.

Conclusion

The mTOR immunosuppressive drugs are safe for liver transplant patients, effectively controlling renal dysfunction. They can be used in other indications, such as neurotoxicity, de novo tumors, and high risk of HCC recurrence. More studies are needed to clarify their long-term effectiveness.     

Everolimus with reduced-dose cyclosporine versus full-dose cyclosporine and mycophenolate in de novo renal transplant patients: a 2-year single-center experience

Background

Although calcineurin inhibitors (CNIs) has improved short-term graft survival, long-term function remains a challenge. CNIs have been implicated in the development of chronic allograft failure. Low-dose cyclosporine with everolimus may mitigate CNI nephrotoxicity and prolong graft survival. We compared the efficacy and safety of de novo everolimus with low-dose cyclosporine and prednisone versus cyclosporine, mycophenolate, and prednisone among kidney transplant patients up to 24 months after transplantation.

Methods

Kidney transplant patients given low-dose cyclosporine, everolimus, and prednisone were compared with patients given cyclosporine, mycophenolate, and prednisone from December 2006 to December 2008. All had living donors, panel reactive antibody <15%, and follow-up for 2 years after transplantation. Continuous variables using mean and standard deviation, t test and test for proportions were used to determine significant differences between the baseline characteristics of the 2 treatment groups. Generalized linear regression and logistic regression were used to measure the effect of treatment on outcomes.

Results

Demographic characteristics were similar in both groups except for age, length of time awaiting kidney transplantation, type of renal replacement therapy, follow-up time, sex distribution, and number of HLA mismatches. These independent variables were used in the generalized linear regression model.There was no significant difference between the everolimus and mycophenolate groups up to 2 years in mean serum creatinine (1.2 mg/dL vs 1.4 mg/dL-, respectively P ≥ .05), acute rejection (12 months: 20% vs 31%; 24 months: 31% vs 40%; P ≥ .05), patient survival (98%), and graft survival (100%). Likewise, there were no significant differences in surgical, infectious, metabolic, and gastrointestinal side effects between the 2 groups.

Conclusions

Everolimus with low-dose cyclosporine and prednisone in de novo kidney transplant recipients was similar in efficacy and safety to cyclosporine, mycophenolate, and prednisone. Longer follow-up is needed to see whether everolimus with low-dose cyclosporine will result in improved kidney function.     

Increased incidence of acute graft rejection on calcineurin inhibitor-free immunosuppression after heart transplantation

Background

Calcineurin inhibitor (CNI)-free immunosuppression is used increasingly after heart transplantation to avoid CNI toxicity, but in the absence of a randomized trial, concerns remain over an increased rejection risk.

Methods

We studied the incidence of graft rejection episodes among all cardiac graft recipients, beginning with the first introduction of CNI-free protocols. We compared events during CNI-free and CNI-containing immunosuppression among 231 transplant recipients of overall mean age 55.2 ± 11.8 years, from a mean 5.2 ± 5.4 years after transplantation through a mean follow-up of 3.1 ± 1.4 years. We considered as acute rejection episodes requiring treatment those of International Society for Heart and Lung Transplantation.

Results

During the total follow-up of 685 patient years (CNI-containing, 563; CNI-free, 122), we performed 1,374 biopsies which diagnosed 78 rejection episodes. More biopsies were performed in CNI-free patients: biopsies/patient-month of CNI-containing, 0.13 versus CNI-free, 0.22 (P < .05). The incidence of rejection episodes per patient-month was significantly higher on CNI-free compared with CNI therapy, among patients switched both early and later after heart transplantation, namely, within 1 year, 0.119 versus 0.035 (P = .02); beyond 1 year, 0.011 versus 0.004 (P = .007); beyond 2 years, 0.007 versus 0.003 (P = .04); and beyond 5 years: 0.00578 versus 0.00173 (P = .04).

Conclusions

Rejection incidence during CNI-free immunosuppression protocols after heart transplantation was significantly increased in both early and later postoperative periods. Given the potentially long delay to rejection occurrence, patients should be monitored closely for several months after a switch to CNI-free immunosuppressive protocols.     

De novo malignancies after liver transplantation: incidence comparison with the Korean cancer registry

Purpose

De novo malignancy is not uncommon after liver transplantation (OLT). We have compared the incidence of novo malignancy following OLT with those among the general Korean population.

Methods

Between January 1998 and December 2008, 1952 adult OLT were performed, including 1714 living donor and 238 deceased donor grafts whose medical records were retrospectively reviewed.

Results

Among the 1952 patients, 44 (2.3%) showed de novo malignancies after a mean posttransplant period of 41 months. Among the 14 types of malignancy the most frequent was stomach cancer (n = 11; 25.0%), colorectal cancer (n = 9; 20.5%), breast cancer (n = 4; 9.1%), and thyroid cancer (n = 3; 6.8%). These patients underwent aggressive treatment, including surgery, chemotherapy, and radiotherapy, except for one patient with an aggressive primary liver cancer. Over a mean follow-up of 45 months after diagnosis of de novo malignancy, 13 patients (29.5%) died; the overall 3-year patient survival rate was 67.5%. The relative risk of malignancy following OLT was 7.7-fold higher in men and 7.3-fold higher in women than the Korean general population.

Conclusions

OLT recipients must be checked periodically for de novo malignancy throughout their lives, especially for cancers common in the general population.     

Milan Criteria Versus San Francisco Criteria in Hepatocellular Carcinoma: Our Center's Experience

Background and aim

Liver transplantation (OLT) represents the best treatment for hepatocellular carcinoma (HCC) in advanced cirrhosis showing a 70% 5-year survival rate. Our study sought to compare overall survivals among patients who underwent OLT under Milan Criteria (MC) or San Francisco Criteria (UCSFC).

Methods

We retrospectively analyzed patients who underwent liver transplantation for HCC in our institution from November 2001 to December 2007. We analyzed age, gender, OLT indication, maximal tumor size, histology, and survival. We compared survival among patients who met MC versus UCSFC.

Results

From November 2001 to December 2007, 48/177 (27%) liver transplantations performed in our hospital were indicated due to HCC. The two patients who did not show any tumor in the explanted liver (false-positive ratio 4.2%) were excluded from the analysis. Another two patients were included who showed incidental HCC lesions (false-negative ratio 1.7%), yielding 48 analyzed patients. The mean diameter of the HCC nodules were 3.1 cm before OLT and 3.8 cm in the pathologic examination, a statistically significant difference. Two patients exceeded MC before OLT, and six patients showed this feature in the explanted liver. There was a significant difference in the degree of vascular invasion between the two groups. Overall mortality was 25.9% at 4 years; the MC group show an 11.9% versus UCSFC group, a 66.6% rate.

Conclusions

HCC is a common indication for OLT. Hepatitis C virus is the most common etiology. Survival among the MC group was significantly better than that of subjects beyond the MC, a difference that supports the use of MC for HCC.     

Bortezomib is effective to treat acute humoral rejection after liver transplantation

Introduction

Acute humoral rejection (AHR), a rare complication in orthotopic liver transplantation (OLT), responds poorly to conventional therapies. Bortezomib, a proteasome inhibitor, has been shown to be effective in treating plasma cell-derived tumors and acute rejection episodes after renal transplantation. Herein, we have reported our clinical experience with bortezomib as a novel approach to treat AHR after OLT.

Methods

We retrospectively analyzed the 247 adult OLTs performed from January 2007 to April 2011. Patients with AHR who were treated with steroid pulses, rituximab (375 mg/m²), and plasmapheresis (PP) were assigned to group A. Group B subjects were prescribed steroid pulses, rituximab, PP, and bortezomib (1.3 mg/m²), after March 2009.

Results

Among the 9 patients (3.6%) diagnosed with AHR, all subjects in group A (n = 3) died within several days after AHR, whereas 4/6 (66.7%) group B patients were rescued and 3 (50%) survived at a mean follow-up 22.3 months (range, 18-26).

Conclusion

Proteasome inhibitor-based therapies provide a more effective strategy to treat AHR after OLT.     

BK Virus in Liver Transplant Recipients: A Prospective Study

Background

BK virus (BKV) is a polyomavirus that is associated with nephropathy and graft loss among kidney transplant recipients. The role of BK virus in nonrenal solid organ transplant recipients has not been clearly established; only anecdotal case reports have been published.

Methods

From August 2005 to September 2007, all orthotopic liver transplant (OLT) recipients who gave their consent were enrolled in this prospective longitudinal study. BK viral load was measured using real-time quantitative polymerase chain reaction assays of urine and plasma, using samples collected at week 1 and months 1, 3, 6, 9, 12, 15, 18, 21, and 24 posttransplantation. We also collected demographic and clinical data, including serum creatinine and immunosuppressive therapy.

Results

The mean age of the 62 patients was 51.4 years including 14 (22.5%) women. Hepatitis C infection was present in 24 patients (38.7%). BK viruria was detected in 14.5% of 290 samples, corresponding to 13 patients (21%). BK viremia was detected in 5.1% of 317 samples, corresponding to 11 patients (18%). Almost all cases of BK viremia (91%) occurred in the first 3 months after OLT. BK viremia was more common among patients experiencing a rejection episode (10.6 vs 40%, P = .01). We did not observe a relationship between single episodes of BKV replication and renal function: median plasma creatinine 1.1 mg/dL in patients without versus 1.2 mg/dL with BK viremia. The three patients with persistent viremia displayed renal insufficiency; one of them died due to multiorgan failure of unknown origin.

Conclusions

BKV is frequently detected in OLT recipients (viruria 21% and viremia 18%) early after transplantation. It is more common among patients with rejection episodes. Persistent BK viremia may be related to renal dysfunction in OLT patients.     

Management of Hepatocellular Carcinoma Recurrence After Liver Transplantation

Management of patients with hepatocellular carcinoma (HCC) recurrence after liver transplantation (OLT) is not well established. We conducted a retrospective analysis of our results in the treatment of HCC recurrence after OLT Patients. The 23 HCC recurrences developed after 182 OLT performed for HCC within Milan criteria, had an average follow-up of 60 months.

Results

The median time to recurrence was 23.4 months. Surgical resection of the recurrence was possible in 11 patients, but an R-0 resection was obtained in 8 patients. Four of these 8 patients developed another recurrence, with 3 succumbing due to tumor recurrence and 1 alive at 12 months with recurrence. The other 4 patients without recurrences, include 3 who are alive at 19, 31, and 86 months and 1 who died at 32.6 months due to hepatitis C recurrence. The 3 patients with palliative resections developed recurrences. Twelve patients were rejected for surgery: 8 were treated symptomatically, 2 with systemic chemotherapy, and 2 with everolimus and sorafenib. This last treatment was also prescribed for 2 patients after R-0 surgery who are alive at 19 and 31 months and for 1 patient after R-1 surgery who is alive at 19 months. Of 15 patients who died, 13 succumbed to HCC recurrence. The average survival from transplantation was 61.7 ± 37.5 and 48 ± 34.3 months for patients without and with recurrence, respectively (P < .001). The survival from the recurrence was significantly higher among patients with R-0 surgery: 32.3 ± 21.5 versus 11.9 ± 6.9 months (P = .006).

Conclusions

HCC recurrence after OLT of patients within Milan criteria was low but had a great impact on survival. Few cases are amenable to R-0 resection, but when possible it was associated with a significantly increased survival, although with an high incidence of a new recurrence. There is a rationale for the use of sorafenib and mammalian target of rapamycin based immunosuppression, which warrants randomized studies.     

Comparative analysis of adverse events requiring suspension of mTOR inhibitors: everolimus versus sirolimus

Background

Inhibitors of mammalian target of rapamycin (mTORi) have been suggested as an alternative to calcineurin inhibitors (CNIs) to treat stable renal transplant recipients. However, their use has been significantly limited owing to a high incidence of side effects.

Objective

To compare the rate of dropout (mTORi elimination and CNI reintroduction) caused by side effects among renal transplant patients converted to everolimus (EVL) or sirolimus (SRL).

Methods

Between October 1999 and February 2010, 409 subjects were converted to an mTORi at least 3 months after transplantation, including 220 (53.8%) to EVL and 189 (46.2%) to SRL. Most patients were under CNI therapy. Patients were followed for a median of 35 months (interquartile range [IQR], 18-50 months).

Results

mTORi treatment was prematurely eliminated due to adverse events in 112 patients. The median time between the initiation of mTORi and discontinuation was 5.7 months (IQR, 1.9-15.7 months; range, 0.2-48 months): 5.5 (IQR, 1.6-16.3) in the EVL group and 7.4 (IQR, 2.6-15.6) in the SRL group. In the EVL group, the drug was stopped in 69 patients (31.4%), and in the SRL group in 43 patients (22.8%; P = .051). The most important causes of discontinuation were severe infections (2.3% in EVL group and 4.8% in SRL group; P = .17), pneumonitis (6.8 % in EVL group and 4.8 in SRL group; P = .38), acute rejection episode (4.1% in EVL group and 1.6% in SRL group; P = .13), proteinuria (4.1% in EVL group and 1.6% in SRL group; P = .13), renal function deterioration (2.3% in EVL group and 2.1% in SRL group; P = .91), and severe dermal eruption (2.3% in EVL group and 0.5% in SRL group; P = .14).

Conclusions

Although the overall incidence discontinuations due to side effects was higher in the EVL group, there was no greater frequency of severe side effects, such as pneumonitis, proteinuria, acute rejection episodes, renal function deterioration, or dermal eruptions.     

Treatment of Hepatocellular Carcinoma With Liver Transplantation: A Single-Center Experience From Brazil

Introduction

Orthotopic liver transplantation (OLT) is the treatment of choice of hepatocellular carcinoma (HCC) for patients with cirrhosis, mainly those with early HCC. Herein we have present the clinical characteristics and outcomes of cirrhotic patients with HCC who underwent OLT from cadaveric donors in our institution.

Methods

From May 2001 to May 2009, we performed 121 OLT including 24 patients (19.8%) with cirrhosis and HCC within the Milan criteria. In 4 cases, HCC was an incidental finding in the explants.

Results

The patients' average age was 55 ± 10 years, including 82% men. Fifty percent of patients were Child class B or C. The average Model for End Stage Liver Disease for Child A, B, and C categories were 11, 15, and 18, respectively. The HCC diagnosis was made by 2 dynamic images in 16 cases; 1 dynamic image plus alphafetoprotein >400 ng/mL in 4; and 4 by histologic confirmation. Twenty patients received a locoregional treatment before OLT: 6 percutaneous ethanol injection, 9 transarterial chemoembolization, 1 transarterial embolization, and 4 a combination of these modalities. The median follow-up after OLT was 19.7 months (range, 1-51). A vascular invasion was observed in the explant of 1 patient, who developed an HCC recurrence and succumbed at 8 months after OLT. Two further patients, without vascular invasion or satellite tumor displayed tumor recurrences at 7 and 3 months after OLT, and death at 2 and 1 month after the diagnosis. The remaining 25 patients have not shown a tumor recurrence.

Conclusion

In the present evaluation, OLT patients with early HCC and no vascular invasion showed satisfactory results and good disease-free survival. Strictly following the Milan criteria for liver transplantation in patients with HCC greatly reduces but does not completely avoid, the chances of tumor recurrence.     

Once Daily Everolimus Is Safe and Effective in De Novo Renal Transplant Recipients: Six-Month Results of a Pilot Study

Introduction

The half-life of everolimus is approximately 28 hours, but everolimus is normally administered twice a day. The aim of this prospective, single-center, exploratory study was to compare the efficacy and safety of a once a day (OD) everolimus regimen versus the standard twice a day regimen (BID) for immunosuppressive therapy in renal transplantation.

Methods

Forty de novo renal transplant recipients prospectively assigned to OD (n = 21) or BID (n = 19) were followed for 6 months. In the OD group, everolimus was given orally once a day to target a trough blood level of 2-6 ng/mL. In the BID, group everolimus was given twice a day to target a trough blood level of 3-12 ng/mL. All patients also received induction treatment with basiliximab and low-dose calcineurin inhibitors.

Results

At 6 months follow-up, patient and graft survivals were 100%; renal function and acute rejection rates were similar between the 2 regimens. Patients in the OD group showed significantly lower cholesterol and triglyceride levels compared with those in the BID group, namely, total cholesterol level, OD 212 ± 54 versus BID 249 ± 59 mg/dL (P < .05), and serum triglycerides, OD 162 ± 72 versus BID 245 ± 133 mg/dL (P < .02).

Discussion

This study showed that OD administration of everolimus provided excellent patient and graft survivals and good renal function without an increased incidence of acute rejection episodes. The lipid profile was significantly better among patients receiving everolimus OD. These findings suggested that everolimus can be safely administered once a day.     

Pediatric Liver Transplantation in Iran: A 9-Year Experience

Background

Liver transplantation (OLT) is accepted as the standard therapy for end-stage liver disease. The current shortage of organ donors has led to the use of split grafts and living related donors to provide timely liver transplants for these children. Herein we have reported our experience with pediatric OLT over a 9-year period.

Materials and methods

We retrospectively studied 138 infants and children who underwent OLT from April 1999 to August 2008 including pretransplantation status, medical and surgical complications, and survival.

Results

There were 83 (60.1%) boys and 55 (39.9%) girls. The mean patient age was 9.1 ± 5.6 years (range = 0.5-18) with a mean weight of 28.1 ± 17.0 kg (range = 7-80). The main indications were Wilson's disease (20.3%); cryptogenic cirrhosis (16.7%); autoimmune cirrhosis (14.5%); biliary atresia (13.8%); tyrosinemia (9.4%); and progressive familial intrahepatic cholestasis (8.7%). We used living related donors in 54 (39.1%) and split livers in 20 (14.5%) cases with 64 (46.4%) patients receiving a whole liver from a deceased donor. The mean follow-up was 25.3 ± 20.3 months (range = 1-100). The mortality rate was 27.5% with a 26.1% in-hospital mortality. The main causes of mortality were vascular complications (32.6%); primary nonfunction (19.6%); sepsis (17.4%); chronic rejection (17.4%); and biliary complications (6.5%). The mortality rate among patients under 10 kg (58.8%) was higher than that of patients over 10 kg (23.1%). Among those patients who were discharged from the hospital (73.9%), the most common cause of mortality was chronic rejection from noncompliance (n = 4), chronic rejection (n = 3 cases), or posttransplant lymphoproliferative disease (n = 2).

Conclusion

Our results demonstrated that pediatric OLT is a feasible undertaking in Iran. The organ shortage in our area led to liberal use of living related and split-liver techniques. The overall results of pediatric OLT in Iran were acceptable.     

Efficacy, Tolerance, and Safety of Mammalian Target of Rapamycin Inhibitors as Rescue Immunosuppressants in Liver Transplantation

Background

Mammalian target of rapamycin (mTOR) inhibitors behave as potent immunosuppressants which have the advantages, with respect to calcineurin inhibitors (CNI: cyclosporine or tacrolimus), of no nephrotoxicity and inhibition of cell proliferation. They are particularly suitable for patients with renal insufficiency or neoplasias.

Materials and Methods

Twenty-two liver transplant patients were immunosuppressed with everolimus or sirolimus as rescue therapy after CNI treatment: 7 hepatocellular carcinomas; 5 de novo malignancies; 4 renal insufficiencies; 4 chronic rejections; and 2 acute rejection episodes.

Results

There were 16.7% tumor recurrences, and 25% improvements in renal function, 75% in chronic rejection, and 50% in acute rejection. There was no incidence of rejection, kidney failure, gastrointestinal intolerance, hydrocarbon intolerance, hypertension, or arterial or venous thrombosis. We observed incidences of 50% for hypercholesterolemia, 31.8% for hypertriglyceridemia, 22.7% for thrombocytopenia, 18.2% for leukopenia, and 9.1% for anemia. The intercurrent infection rate was 13.6%, including oral thrush in 13.6%. Lower limb edema occurred in 13.6%, with 1 case of facial edema and 1 of alopecia.

Conclusions

mTOR inhibitors were safe immunosuppressive drugs whose side effects were controlled and easily managed. They have advantages with respect to CNI due to their slight effects on kidney function and lack of promotion of diabetes mellitus. Although their long-term effectiveness for control of neoplastic diseases is yet to be seen, they can be used safely in these patients with no incidence of rejection. Their effectiveness to control chronic rejection seems significant, but it is doubtful for steroid-resistant acute rejection episodes.     

Bridge Therapy in Hepatocellular Carcinoma Before Liver Transplantation: The Experience of Two Chilean Centers

Background

Orthotopic liver transplantation (OLT) is currently an established therapy for small, early-stage hepatocellular carcinoma (HCC) within the Milan criteria. Long waiting times due to the shortage of donor organs can result in tumor progression and drop-out from OLT candidacy. Therefore a wide variety of procedures are necessary before OLT. The aim of this retrospective study was to review our experience in relation to bridge therapy prior to OLT for HCC.

Methods

This was a retrospective database review of all of the patient who underwent transplantation in our institutions between January 1993 and June 2009. We analyzed patients with a diagnosis of HCC in the explant.

Results

Among 29 patients, including 12 who were diagnosed by the explant and 17 prior to transplantation, 88% underwent bridge therapy during a mean waiting time to OLT of 12 months. Among the 23 procedures, namely 1.5 procedures per patient, included most frequently chemoembolization (48%), alcohol ablation (30%), radiofrequency ablation (13%), and surgery (9%). Thirty-three percent of the explants contained lesions within the Milan criteria. In our series the 5-year survival rate for patients transplanted for HCC was 86%; in the bridge therapy group, it was 73%.

Conclusions

The incidence of patients who underwent bridge therapy (52%) was similar to other reported experiences, but the fulfillment of Milan criteria in the explants was lower. Among the bridge therapy group, the survival was slightly lower, probably because this group displayed more advanced disease.