"Very early" intrahepatic cholangiocarcinoma in cirrhotic patients: should liver transplantation be reconsidered in these patients?

A retrospective cohort multicenter study was conducted to analyze the risk factors for tumor recurrence after liver transplantation (LT) in cirrhotic patients found to have an intrahepatic cholangiocarcinoma (iCCA) on pathology examination. We also aimed to ascertain whether there existed a subgroup of patients with single tumors ≤2 cm ("very early") in which results after LT can be acceptable. Twenty-nine patients comprised the study group, eight of whom had a "very early" iCCA (four of them incidentals). The risk of tumor recurrence was significantly associated with larger tumor size as well as larger tumor volume, microscopic vascular invasion and poor degree of differentiation. None of the patients in the "very early" iCCA subgroup presented tumor recurrence compared to 36.4% of those with single tumors >2 cm or multinodular tumors, p = 0.02. The 1-, 3- and 5-year actuarial survival of those in the "very early" iCCA subgroup was 100%, 73% and 73%, respectively. The present is the first multicenter attempt to ascertain the risk factors for tumor recurrence in cirrhotic patients found to have an iCCA on pathology examination. Cirrhotic patients with iCCA ≤2 cm achieved excellent 5-year survival, and validation of these findings by other groups may change the current exclusion of such patients from transplant programs.

Intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma in patients undergoing liver transplantation: a Spanish matched cohort multicenter study.

OBJECTIVE: To evaluate the outcome of patients with hepatocellular-cholangiocarcinoma (HCC-CC) or intrahepatic cholangiocarcinoma (I-CC) on pathological examination after liver transplantation for HCC. BACKGROUND: Information on the outcome of cirrhotic patients undergoing a transplant for HCC and with a diagnosis of HCC-CC or I-CC by pathological study is limited. METHODS: Multicenter, retrospective, matched cohort 1:2 study. STUDY GROUP: 42 patients undergoing a transplant for HCC and with a diagnosis of HCC-CC or I-CC by pathological study; and control group: 84 patients with a diagnosis of HCC. I-CC subgroup: 27 patients compared with 54 controls; HCC-CC subgroup: 15 patients compared with 30 controls. Patients were also divided according to the preoperative tumor size and number: uninodular tumors 2 cm or smaller and multinodular or uninodular tumors 2 cm or larger. Median follow-up: 51 (range, 3-142) months. RESULTS: The 1-, 3-, and 5-year actuarial survival rate differed between the study and control groups (83%, 70%, and 60% vs 99%, 94%, and 89%, respectively; P < 0.001). Differences were found in 1-, 3-, and 5-year actuarial survival rates between the I-CC subgroup and their controls (78%, 66%, and 51% vs 100%, 98%, and 93%; P < 0.001), but no differences were observed between the HCC-CC subgroup and their controls (93%, 78%, and 78% vs 97%, 86%, and 86%; P = 0.9). Patients with uninodular tumors 2 cm or smaller in the study and control groups had similar 1-, 3-, and 5-year survival rate (92%, 83%, 62% vs 100%, 80%, 80%; P = 0.4). In contrast, patients in the study group with multinodular or uninodular tumors larger than 2 cm had worse 1-, 3-, and 5-year survival rates than their controls (80%, 66%, and 61% vs 99%, 96%, and 90%; P < 0.001). CONCLUSIONS: Patients with HCC-CC have similar survival to patients undergoing a transplant for HCC. Preoperative diagnosis of HCC-CC should not prompt the exclusion of these patients from transplant option.

Liver transplantation for bile duct injury after open and laparoscopic cholecystectomy.

BACKGROUND: Bile duct injury (BDI) after cholecystectomy is a serious complication. In a small subset of patients with BDI, failure of surgical or non-surgical management might lead to acute or chronic liver failure. The aim of this study was to review the indications and outcome of liver transplantation (LT) for BDI after open and laparoscopic cholecystectomy. METHODS: Patients with BDI after cholecystectomy who were on the waiting list for LT between January 1987 and December 2010 were identified from LT centres in Spain. A standardized questionnaire was sent to each unit for extraction of data on diagnosis, previous treatments, indication and outcome of LT for BDI. RESULTS: Some 27 patients with BDI after cholecystectomy in whom surgical and non-surgical management for BDI failed were scheduled for LT over the 24-year interval. Emergency LT for acute liver failure was indicated in seven patients, all after laparoscopic cholecystectomy. Two patients died while on the waiting list and only one patient survived more than 30 days after LT. Elective LT for secondary biliary cirrhosis after a failed hepaticojejunostomy was performed in 13 patients after open and seven after laparoscopic cholecystectomy. One patient from the elective transplantation group died within 30 days of LT. The estimated 5-year overall survival rate was 68 per cent. CONCLUSION: Emergency LT for acute liver failure was more common in patients with BDI after laparoscopic cholecystectomy, and associated with a poor outcome.

Prevalence and characteristics of anemia in patients with diabetes mellitus aged 50 or older in health unit area of Cadiz (Spain).

BACKGROUND: Anemia is a common comorbidity in patients with diabetes mellitus (DM), particularly in older adults. However, there is a lack of data on the prevalence and the characteristics of anemia in this population in Spain. OBJECTIVE: To describe the prevalence and the characteristics of anemia in patients with DM aged 50 or older (PDM50) in a healthcare district in the province of Cádiz. METHODS: A retrospective cross-sectional study was conducted that included outpatient's laboratory tests (OLT) performed over 30 months at PDM50. RESULTS: The prevalence of anemia was 29.9% (95% CI: 28.7%-31.1%), predominating in women (33.3% vs 26.7%; P < 0.01), in older people stratified by decades (61.7% in 9th decade vs 12% in 5th decade; P < 0.01), and in those with kidney disease (44.7% vs 28%; P < 0.01). Most cases were mild (68.3%), normocytic (78.7%), and hypochromic (52%). Similarly, moderate-to-severe anemia was more frequent in women (39% vs 23%), their prevalence increased with age (45% in the 9th decade vs 24% in the 5th decade), and with the progression of kidney damage, either measured by a decreased glomerular filtration rate (GFR) (49% in G4 vs 25% in G1), or the presence of albuminuria (P < 0.01). No association was found between DM control, based on glycated hemoglobin (HbA1c), and anemia in either sex (P = 0.887). CONCLUSION: This study describes a high prevalence of anemia in PDM50, particularly in women, in the most advantageous people and in the presence of kidney disease, even in early stages, highlighting the clinical importance of this coexistence.

Cytoreductive surgery in patients with oligometastatic prostate cancer. Systematic review of the scientific literature.

INTRODUCTION: Interest in oligometastatic prostate cancer has spiked due to the emergence of new evidence regarding more specific and accurate imaging, and the wider use of minimally invasive techniques. Nevertheless, the optimal management of this pathology is yet to be determined. OBJECTIVE: Assess the efficacy and safety of cytoreductive surgery in patients suffering from oligometastatic prostate cancer. EVIDENCE GATHERING: Systematic review of the scientific literature (01/01/2010-31/12/2021) within the MedLine, Embase, Cochrane Library, Cinahl, Scopus, Spanish Healthcare Technology Assessment Agencies (AETS, Agencias de Evaluación de Tecnologías Sanitarias) and ClinicalTrials.gov databases. The keywords used were prostatectomy, prostatic neoplasm, radical prostatectomy; the free search terms were prostatectomy and oligometastatic prostate. The inclusion criteria comprised studies on patients with oligometastatic prostate cancer who had been operated on using radical cytoreductive prostatectomy. EVIDENCE SYNTHESIS: The systematic review included 4 observational studies, 2 clinical trials, and 2 case series, of moderate quality. The results observed suggest that oligometastatic prostate cancer patients who had undergone cytoreductive prostate surgery obtained a benefit in terms of efficacy. Conversely, the majority of these studies showed a reduction in the number of localized complications, when compared to the best systemic treatments. CONCLUSIONS: Cytoreductive surgery in this group of patients is a safe procedure that reduces the incidence of localized complications and that presents promising results with regard to survival rates. To date, the lack of prospective trials limits the use of this therapeutic option to experimental environments.

Is the use of the new Chronic Kidney Disease Epidemiology Consortium (CKD-EPI 2021) formula appropriate for the Spanish population?

INTRODUCTION: United States nephrology societies recommend changing from the CKD-EPI 2009 equation to the new CKD-EPI 2021 equation, which does not include the race coefficient, for calculating estimated glomerular filtration rate (eGFR). It is unknown how this change might affect the distribution of kidney disease in the predominantly Caucasian Spanish population. METHODS: Two databases of adults from the province of Cádiz, DB-SIDICA (N=264,217) and DB-PANDEMIA (N=64,217), that had plasma creatinine measurements recorded between 2017 and 2021 were studied. Changes in eGFR and the consequent reclassification into different categories of the KDIGO 2012 classification resulting from substituting the CKD-EPI 2009 equation for the 2021 equation were calculated. RESULTS: Compared to the 2009 equation, CKD-EPI 2021 yielded a higher eGFR, with a median of 3.8mL/min/1.73m2 (IQR 2.98-4.48) in DB-SIDICA and 3.89mL/min/1.73m2 (IQR 3.05-4.55) in DB-PANDEMIA. The first consequence was that 15.3% of the total population in DB-SIDICA and 15.1% of the total population in DB-PANDEMIA were reclassified into a higher category of eGFR, as were 28.1% and 27.3%, respectively, of the population with CKD (G3-G5); no subjects were classified into the more severe category. The second consequence was that the prevalence of kidney disease decreased from 9% to 7.5% in both cohorts. CONCLUSIONS: Implementing the CKD-EPI 2021 equation in the Spanish population, which is predominantly Caucasian, would increase eGFR by a modest amount (greater in men and those who are older or have a higher GFR). A significant proportion of the population would be classified into a higher eGFR category, with a consequent decrease in the prevalence of kidney disease.

Safety of anidulafungin in solid organ transplant recipients.

The aim of this study was the evaluation of the safety of anidulafungin in adult solid organ transplantation (SOT) recipients. During the study period (14 months), we included all consecutive SOT recipients from 14 centers who received anidulafungin for at least 48 hours for the treatment of invasive fungal infections (IFIs) or as prophylaxis. Relevant clinical and analytical information on clinical charts was reviewed. Clinical side effects, liver function tests, and serum creatinine levels were assessed at least weekly. The need for the modification of immunosuppressive drugs was also recorded by the investigators. All patients were followed for at least 1 week after the end of treatment (EOT) or until death. Eighty-six SOT recipients were evaluated (56 transplant recipients, 20 lung transplant recipients, 8 kidney transplant recipients, and 2 heart transplant recipients). Sixty-two patients (72%) received anidulafungin for prophylaxis, and 24 (28%) received anidulafungin for the treatment of IFIs [candidemia/invasive candidiasis (16) or invasive aspergillosis (8)]. At the baseline, only 5% of the patients were neutropenic (<500 neutrophils/mL). There was no need for the modification of immunosuppressive drug doses because of anidulafungin therapy. No patient discontinued anidulafungin because of severe adverse effects. While receiving anidulafungin, 1 patient developed mild liver toxicity, but the liver function normalized without the discontinuation of anidulafungin. At EOT, the median serum creatinine, aspartate aminotransferase, and alanine aminotransferase levels were significantly lower than the baseline levels, even in liver transplant recipients and patients who had higher baseline levels of serum creatinine. In conclusion, these results show that anidulafungin is a well-tolerated drug in SOT recipients.

Tuberculous hepatic abscess appearing after liver transplantation in a patient with human immunodeficiency virus and hepatitis B and C virus co-infection.

Tuberculosis infection occurs relatively frequently in solid organ transplant recipients, although the occurrence of tuberculous hepatic abscesses is uncommon. Anti-tuberculous therapy has several concerns in transplant recipients, including an increased risk of cellular rejection and potential hepatotoxicity. We present the case of a human immunodeficiency virus-infected liver transplant patient who developed multiple tuberculous liver abscesses. Treatment with isoniazid, ethambutol, pyrazinamide, and moxifloxacin was efficacious, well tolerated, and safe.

Safety of an immunosuppressant protocol based on sirolimus in liver transplant recipients with malignancies or high risk of tumor recurrence.

BACKGROUND: The mammalian target of rapamycin inhibitors are immunosuppressive agents with antiproliferative effects and consequent potential application as anticancer agents. The safety and tolerance of calcineurin inhibitor (CNI)-free sirolimus-based immunosuppressant protocols in liver transplant recipients with malignancies or high risk of tumor recurrence has been scarcely evaluated. PATIENTS AND METHODS: Fourteen liver transplant recipients, including 12 men, of overall mean age of 57.4 +/- 12.4 years were distributed into two groups: group I, corresponding to 11 patients with malignant neoplasia, eight de novo neoplasia, and three recurrent hepatocarcinoma and; group II, three patients with high risk of tumor recurrence due to cholangiocarcinoma. Sirolimus was initiated at 2 mg od, with target levels of 3 to 9 ng/mL. Withdrawal of CNI was performed after reaching target levels of sirolimus. Periodic examinations of weight, arterial pressure, liver function tests, serum creatinine, triglycerides, cholesterol, sirolimus blood levels, and creatinine clearance were performed at 30, 60, 90, 180, and 360 days. RESULTS: After a median follow-up of 221.5 days, eight group I patients (72.7%) were alive, including six with stable disease. All group II patients were alive without evidence of tumor recurrence after a median follow-up of 560 days. CNI was withdrawn in 11 patients (78.6%). Sirolimus was withdrawn in only one case due to severe symptomatic oral ulcers. No vascular complications or rejection episodes were observed. CONCLUSIONS: A sirolimus-based immunosuppressant protocol was well tolerated and safe in liver transplant recipients with malignancies or a high risk of recurrence of neoplastic disease.

Orthotopic liver transplantation for hepatocellular carcinoma: a thirteen-year single-center experience.

BACKGROUND: When restrictive selection criteria are applied orthotopic liver transplantation (OLT) is the most efficient option for the treatment of hepatocellular carcinoma (HCC) in terms of survival and recurrence rate. Nevertheless, tumor recurrence may occur in 3.5%-21% of recipients, with a consequent negative impact on prognosis. The aim of this study was to analyze the long-term survival and tumor recurrence rate among a cohort of liver transplant recipients with HCC. METHODS: During the period 1994-2007, 130 HCC patients, including 111 males with a mean overall age of 57.8 +/- 7.1 years (range, 38-70), underwent cadaveric donor-OLT. The etiology of liver disease was alcoholic cirrhosis in 66 patients (50.8%) and viral infection in 52 patients (40%). Baseline alpha fetoprotein values were 53.4 +/- 280.9 ng/mL (range, 1-2593). Median interval between inclusion date and transplantation was 179.5 days. RESULTS: After a median follow-up of 40.8 months, 93 recipients (71.5%) were alive. Tumor recurrence was detected in 11 patients (8.5%). Neoplasm recurrence sites were as follows: liver graft (45.4%), bone (36.4%), lymphoadenopathies (27.3%), adrenal glands (27.3%), and lung (27.3%). Overall survival rates at 1, 3, 5, and 10 years were 85.1%, 78.3%, 70.1%, and 57%, respectively. After examination of the explanted liver, Milan criteria were surpassed in 32 recipients (24.6%). Nevertheless, no differences in survival were observed according to fulfilment or not of Milan criteria (log-rank test, P > .05). Hepatitis C virus (HCV) infection, female gender, and tumor recurrence were associated with a worse survival rate (log-rank test, < .05). CONCLUSIONS: OLT is an effective option for the treatment of HCC with good long-term survival and low recurrence rates. In this series, survival was not affected by findings of poor prognostic factors in the explanted liver.

Initial immunosuppression in liver transplant recipients with impaired renal function.

Acute renal failure (ARF) after liver transplantation is a factor of poor prognosis associated with a high mortality. Selection of the donor, recipient, and intraoperative and postoperative treatment has crucial importance in the management of these critical patients. Thus, optimization of the use of calcineurin inhibitors (CNI), the main nephrotoxic substances in the immediate postoperative period, may decrease ARF incidence, allowing for early recovery of renal function in this period. Most protocols are based on the reduction or late introduction of CNI, based on the use of mycophenolate mofetil (MMF) with/without antiCD25 (basilximab/daclizumab). Recently, thymoglobulin (ATG) is also being tested to further delay the use of the CNI. A 20%-30% acute rejection incidence with the usual protocols allows recovery of renal function in more than 80% of patients without increasing the incidence of infections or adverse effects. However, it is still unknown whether there is a long-term negative effect of chimeric-humanized monoclonal antibodies and MMF combination on reinfection with hepatitis C virus in transplant recipients.

Prospective histopathological analysis of hepatocellular carcinoma treated with percutaneous ethanol injection in patients on the waiting list for liver transplantation.

INTRODUCTION: Liver transplantation (LT) improves survival in selected patients suffering from hepatocellular carcinoma (HCC). Unfortunately, the long time lapse between indication and LT may cause tumor progression. Thus, percutaneous ethanol injection (PEI) has been proposed as adjuvant therapy of HCC in patients awaiting LT. The efficacy of PEI assessed using histopathological analysis of hepatectomy specimens has not been adequately evaluated. PATIENTS AND METHODS: Twenty-nine nodules of HCC in 27 patients (21 men; mean age, 58.1 +/- 7.3 years) listed for LT were treated with PEI. Pretreatment mean serum alpha-fetoprotein (AFP) was 11 +/- 13.4 ng/mL. Mean tumor diameter was 30.8 +/- 12.9 mm. Data from the explanted livers after transplantation included percentage tumor necrosis, presence of satellite and distant nodules, vascular invasion, tumor capsule, and grade of differentiation. RESULTS: Nineteen patients with 20 treated lesions underwent transplantation. The median interval PEI-LT was 3 months. Complete necrosis was observed in 13 nodules (65%). Satellite nodules were present in 10% of lesions. Previously unrecognized distant lesions were seen in 15.8% of patients. Only 1 nodule presented microscopic vascular invasion. Most HCC were well differentiated (90%), and completely encapsulated (80%). No tumor-related deaths occurred. Seventeen patients are alive and recurrence-free after a median follow-up of 15 months. CONCLUSIONS: PEI may achieve significant necrosis in cases of HCC awaiting LT. Nevertheless, previously unrecognized satellite and distant lesions may be observed. Further studies are needed to evaluate the influence of tumor necrosis on overall survival of these patients.

Doppler ultrasonography for the assessment of tumor necrosis after percutaneous ethanol injection prior to liver transplantation as adjuvant therapy of hepatocellular carcinoma.

INTRODUCTION: Percutaneous ethanol injection (PEI) is considered to be a curative treatment for hepatocellular carcinoma (HCC). The imaging technique of choice for the assessment of local response after PEI has not been well defined, but helical computerized tomography (hCT) has been recommended. The aim of this study was to assess the accuracy of Doppler ultrasonography (US) for evaluation of tumor necrosis after PEI. PATIENTS AND METHODS: Twenty-one patients with single HCC listed for liver transplantation underwent multisession US-guided PEI. Liver Doppler US was done at the 4th week after PEI. Complete response was defined as the absence of any intratumoral Doppler signal. The liver was analyzed in transplant recipients during the follow-up. Complete pathological response was defined as necrosis > or = 90% of total tumor volume. Histological and sonographic findings were compared. RESULTS: Twelve patients underwent transplantation (9 men, mean age 60 +/- 5.2 years). Nine of these (75%) showed a complete ultrasonographic response. In the explanted liver, complete necrosis was present in 6 nodules, and incomplete necrosis was seen in the remaining 6 cases. In comparison with histology, Doppler US showed values of sensitivity, specificity, positive predictive values, and negative predictive values of 50%, 100%, 100%, and 60%, respectively. Overall accuracy was 75%. CONCLUSIONS: In our series, Doppler US showed low sensitivity but high specificity in the assessment of HCC necrosis after PEI. The ultrasonographic finding of complete response requires hCT for confirmation, but the presence in Doppler US of neoplastic viable tissue is enough to indicate a further cycle of PEI.

Circadian variability of blood pressure in liver transplant recipients without antihypertensive therapy.

Hypertension is a frequent cardiovascular risk factor in liver transplant recipients. The usefulness of ambulatory blood pressure monitoring (ABPM) in these patients is unknown. This study was aimed at evaluating the circadian rhythms of blood pressure in liver allograft recipients. In 53 liver transplant patients blood pressure was measured with the Spacelabs device program. No patient received antihypertensive therapy for at least 15 days beforehand. Clinical blood pressure measurement showed 26 patients to be hypertensive. Of these, ABPM verified the diagnosis in 23. Overall, 72% of the patients were hypertensive, and 39.5% showed a nondipper pattern. Diastolic hypertension was more frequent than systolic hypertension. No differences were found in renal function, immunosuppressive therapy, or corticosteroids.

Prospective interventional study to evaluate the efficacy and safety of liposomal amphotericin B as prophylaxis of fungal infections in high-risk liver transplant recipients.

INTRODUCTION: Invasive fungal infections are a life-threatening complication in transplant recipients. The prevalence of fungal infection after orthotopic liver transplantation (OLT) is 5% to 42%. The most common isolated pathogens are Candida and Aspergillus species. High-risk liver transplant recipients are more susceptible to the development of invasive fungal infections, with prevalence >40% and mortality rates of 78% to 100%. The strategy for fungal prophylaxis in this population has not been defined. PATIENTS AND METHODS: Among 100 consecutive OLT followed for 28 months, 21 recipients (15 men, overall mean age of 48.5 years, range 23-65 years) were considered to be high risk for the development of fungal infections when they presented at least one of the following criteria: acute liver failure, assisted ventilation >7 days, retransplantation, relaparotomy, antibiotic therapy >14 days, transfusion requirements >20 red blood cells units, and/or biliary leakage. This group received intravenous liposomal amphotericin B (1 mg/kg/d for 7-10 days). RESULTS: One-year survival in the high-risk group was 80%. Prevalence of invasive fungal infection was 9.5%. No Candida infection was observed. Two patients developed Aspergillus infection: an abdominal aspergillosis treated with percutaneous drainage and liposomal amphotericin B (5 mg/kg/d) showed a favorable clinical outcome. The other patient who developed brain aspergillosis died 25 days after OLT. Adverse events related to the drug were hypokalemia (n = 2), back pain (n = 3), and renal dysfunction (n = 2). None of these events required withdrawal of the prophylaxis regimen. CONCLUSION: In our series, prophylaxis with liposomal amphotericin B in high-risk liver graft recipients showed a low rate of severe fungal infections. More studies are needed in order to determine the highest risk population and the best drug dosage.

Safety of percutaneous ethanol injection as neoadjuvant therapy for hepatocellular carcinoma in waiting list liver transplant candidates.

UNLABELLED: Orthotopic liver transplantation (OLT) as therapy of hepatocellular carcinoma (HCC) improves the survival of a selected group of patients. Unfortunately, the progressive increase in waiting time for OLT may allow tumor progression. Percutaneous ethanol injection (PEI) has been proposed as neoadjuvant therapy for HCC in patients awaiting OLT, but its safety has not been defined. PATIENTS AND METHODS: During a 60-month period, 34 patients (27 men, overall mean age of 58.5 years, range 41-67) with HCC, were listed for OLT. Ultrasonography-guided PEI was delivered into 39 nodules at 117 sessions on an inpatient basis. Written informed consent was obtained from all patients before PEI. Doppler-ultrasonography was done before PEI, immediately after, and 4 weeks later. Noninvasive monitoring of arterial pressure, cardiac rate, and temperature was performed during the procedure and during a 24-hour period after each session. Pain was considered significant if analgesia was required or discontinuation of PEI necessary. Fever was defined as a temperature > or =37.5 degrees C after PEI. RESULTS: Minor complications included pain in 45 sessions (38.5%), fever in 17 (14.5%), arterial hypertension in 14 (12%), hypotension in 7 (7%), and vomiting in 2 (1.7%). The major complications were segmental liver infarction (n = 3), portal branch venous thrombosis (n = 2), ascites (n = 2), and one case each of subcapsular hematoma, duodenal ulcer, pneumonia, hepatic encephalopathy, and hepatic artery thrombosis. In all cases, clinical outcomes were favorable with conservative treatment. No evidence of tumor seeding in the needle track was reported and no PEI-related mortality observed. CONCLUSIONS: PEI is a safe neoadjuvant therapy for HCC on waiting list liver transplant candidates. In our series, pain and self-limited fever were the most frequent complications. Clinically significant severe complications were uncommon, and nonconservative treatments were not required.

Prolonged survival after liver transplantation for Hodgkin's disease-induced fulminant liver failure.

A 30-year-old male with a past history of nodular lymphocyte predominance Hodgkin's disease in apparent complete remission for two years received a liver transplantation because of fulminant liver failure. Histopathological examination of the explanted liver showed massive infiltration by Hodgkin's disease. In spite of a nodal recurrence of Hodgkin's disease, the patient is alive and in excellent general condition six years after liver transplantation.

Diminished anticoagulant and fibrinolytic activity following liver transplantation.

This study analyzed the coagulation changes in twenty patients after orthotopic liver transplantation. The procoagulant, anticoagulant, and fibrinolytic systems were studied during the first two postoperative weeks. Within the first postoperative day all extrinsic and intrinsic pathway factors became normal except factors IX, VII, and X, which recovered within the next 24 hr. Of interest are the changes in factor VIII, which reached a high concentration with an increase in its antigenic fraction during the study. However, coagulation inhibitors showed a different pattern. In fact, antithrombin III (AT-III) and protein C (PC) needed from 7 to 14 days to reach normal values. Total protein S (TPS) and free protein S (FPS) did not recover until day 7, whereas heparin cofactor II (HC-II) remained at subnormal levels throughout the study. Thrombin-antithrombin III complex (TAT) values were strikingly elevated in the immediate postoperative period. Fibrinolysis parameters showed plasminogen (PL) levels in the normal range until day 4. Antiplasmin (AP) followed a curve parallel to that of plasminogen but its levels were higher during this observation period. Similarly the initial elevation in plasminogen activator inhibitor 1 endothelial type (PAI-1) levels remained high until days 4 and 7. In summary, it can be concluded that during the postoperative phase after OLT a hypercoagulable state is developed as a result of diminished anticoagulant and fibrinolytic activity. This coagulation might be a nontechnical factor contributing to the thrombotic vascular complications of some liver recipients.

Improved clinical outcomes for liver transplant recipients using cyclosporine monitoring based on 2-hr post-dose levels (C2).

BACKGROUND: A prospective, open-label, study was conducted at 29 centers in 9 countries, involving 307 de novo liver transplant patients to compare the clinical usefulness of monitoring 2-hr post-dose cyclosporine (CsA) levels (C2) with conventional trough cyclosporine blood levels (pre-dose) (C0). METHODS: Neoral oral therapy was initiated at 15 mg/kg/day and dose adjusted according to predetermined C2 or C0 target level ranges. The primary efficacy variable was treatment failure at 3 months, where evaluation was based on a composite endpoint of biopsy-proven rejection, treatment for rejection, graft loss, death, or premature withdrawal/discontinuation from the study. RESULTS: Baseline characteristics were similar between groups. Graft loss at 12 weeks (retransplantation or death) occurred in 6.8% C2 and in 7.0% C0 patients. Overall incidence of treated acute rejection was lower for C2 (23.6%) than C0 patients (31.6%) (P=0.144, Cochran-Mantel-Haenszel [CMH] test). In hepatitis C virus (HCV)-negative patients, the incidence of rejection in the C2 group was significantly less than in the C0 group (21.2% vs. 33.0%; P<0.05), whereas in HCV-positive patients, the rejection rate was similar in both groups (26.7% for C2 group vs. 27.3% for C0 group: P=0.81). C2 patients (n=16) who reached minimum target CsA levels by day 3 had a notably low incidence of rejection (12.5%), whereas there was no difference in the incidence of rejection in C0 patients, irrespective of time to reach target level. For biopsy-proven acute rejections (21.6% for C2 vs. 30.4% for C0), the incidence of moderate and severe histological diagnosis was significantly lower in the C2 group than in the C0 group (47% vs. 73%; P=0.01). Safety profiles were similar between the two groups, with few patient withdrawals due to adverse events (9.5% for C2; 7.0% for C0). CONCLUSIONS: Using C2 monitoring, the overall incidence of acute cellular rejection was lower compared with the C0 group, and the histological severity of acute rejections was shown to be significantly milder for the C2 group, indicative of good long-term prognosis. These data demonstrate that the use of C2 monitoring is superior to C0 and results in a reduction in the incidence and severity of acute cellular rejection without detrimental effect on the drug safety profile.