Félix Alegre

Liver transplantation in patients with hepatocellular carcinoma across Milan criteria

Milan criteria are the most frequently used limits for liver transplantation (LT) in patients with hepatocellular carcinoma (HCC), but our previous experience with expanded criteria showed encouraging results. The aim of this study was to investigate whether our expanded Clinica Universitaria de Navarra (CUN) criteria (1 nodule up to 6 cm or 2–3 nodules up to 5 cm each) could be used to select patients with HCC for LT. Eighty‐five patients with HCC fulfilling CUN criteria were included as candidates for LT. Survival of transplanted HCC patients was compared with survival of patients without HCC (n = 180). After the exclusion of 2 patients with tumor seeding of the chest wall due to pre‐LT tumor biopsy, survival and recurrence rates were compared according to tumor staging. Twenty‐six out of 85 (30%) patients exceeded Milan criteria. Twelve patients had tumor progression on the waiting list. Patients exceeding Milan criteria had a higher dropout rate due to tumoral progression. One‐, 3‐, 5‐, 7‐, and 10‐year survival rates of the 73 transplanted HCC patients were 86%, 74%, 70%, 61%, and 50%, respectively. Survival of patients with HCC was significantly lower than that of patients without HCC, but by multivariate analysis, HCC was not associated with lower survival. Tumor recurrence and survival rates were similar for patients fulfilling Milan and CUN criteria. Pathological staging showed 55 patients within Milan criteria, 7 patients exceeding them but within CUN criteria, and 9 patients exceeding CUN criteria. Tumor recurrence rates were 2/55 (4%), 0/7 (0%), and 4/9 (44%) in each of these groups, respectively. In conclusion, following CUN criteria could increase the number of HCC patients who could benefit from LT, without worsening the results. Because of the short number of patients in this series, these data need external validation. Liver Transpl 14:272–278, 2008.

Risk factors of lung, head and neck, esophageal, and kidney and urinary tract carcinomas after liver transplantation: the effect of smoking withdrawal.

Liver transplant recipients have an increased risk of malignancy. Smoking is related to some of the most frequent causes of posttransplant malignancy. The incidence and risk factors for the development of neoplasia related to smoking (head and neck, lung, esophageal, and kidney and urinary tract carcinomas) were studied in 339 liver transplant recipients. Risk factors for the development of smoking‐related neoplasia were also studied in 135 patients who had a history of smoking so that it could be determined whether smoking withdrawal was associated with a lower risk of malignancy. After a mean follow‐up of 7.5 years, 26 patients were diagnosed with 29 smoking‐related malignancies. The 5‐ and 10‐year actuarial rates were 5% and 13%, respectively. In multivariate analysis, smoking and older age were independently associated with a higher risk of malignancy. In the smoker subgroup, the variables related to a higher risk of malignancy were active smoking and older age. In conclusion, smoking withdrawal after liver transplantation may have a protective effect against the development of neoplasia. Liver Transpl, 2011.

Spontaneous Regression of Hepatocellular Carcinoma: Three Case Reports and a Categorized Review of the Literature

Hepatocellular carcinoma (HCC) is the most frequent form of primary liver cancer and the fifth most prevalent cancer worldwide [1]. Spontaneous tumor regression was first defined by Cole and Everson [2] as complete or partial clearance of malignant cells in the absence of any specific treatment, particularly antineoplastic chemotherapy. However, it may also occur during or after therapy, a situation in which therapy could be endorsed with an undeserved antitumor effect. Spontaneous tumor regression was at first thought to be an extremely infrequent phenomenon, with an estimated incidence of 1 in 60,000–100,000 cases [3]. Its mechanism is largely unknown, however, it has important implications in clinical research and clinical practice. The number of cases of spontaneous regression reported in the literature is higher in HCC than in other neoplasms [4], possibly reflecting a higher incidence. However, due to its exceedingly low frequency it would probably not affect the results of any study on HCC therapy. Following our observation of two cases of spontaneous regression and one case of sustained, complete regression in the course of a chemotherapeutic regimen with marginal efficacy in the treatment of this tumor, we have searched the cases published in the English literature and reviewed the possible mechanisms involved in such remarkable events. We have retrospectively reviewed all the cases recorded in our liver unit in which an objective tumor remission was observed that could not be convincingly ascribed to a therapeutic effect of any rational intervention. These consist of tumor ablation, any sort of embolizing procedure performed in the hepatic artery or its branches (including intra-arterial injection of Lipiodol for diagnostic or staging purposes), or pharmacological therapy that might have a known antiproliferative effect. Medical records of these patients were thoroughly reviewed trying to find any possible event that may have triggered the observed remission.

Analysis of Prognostic Factors After Yttrium-90 Radioembolization of Advanced Hepatocellular Carcinoma

PURPOSE To analyze which patient-, tumor-, and treatment-related factors may influence outcome after (90)Y radioembolization ((90)Y-RE) for hepatocellular carcinoma (HCC). PATIENTS AND METHODS Seventy-two consecutive patients with advanced HCC treated with (90)Y-RE were studied to detect which factors may have influenced response to treatment and survival. RESULTS Median overall survival was 13 months (95% confidence interval, 9.6-16.3 months). In univariate analysis, survival was significantly better in patients with one to five lesions (19 vs. 8 months, p = 0.001) and in patients with alpha-fetoprotein <52 UI/mL (24 vs. 11 months, p = 0.002). The variation in target tumor size and the appearance of new lesions were analyzed among 50 patients with measurable tumors. A decrease in target tumor size was observed in most patients, and the intensity of such decrease was not associated with any of the factors under study. Patients who developed new lesions in the treated liver (and also in the nontargeted liver) at month 3 more frequently had more than five nodules, bilobar disease, and alpha-fetoprotein >52 UI/mL, and their survival in the multivariate analysis was significantly worse (hazard ratio, 4.7; 95% confidence interval, 13-1.73) (p = 0.002). CONCLUSIONS Yttrium-90 radioembolization results in control of target lesions in the majority of patients with HCC but does not prevent the development of new lesions. Survival of patients treated with (90)Y-RE seems to depend largely on factors related to the aggressiveness of the disease (number of nodules, levels of alpha-fetoprotein, and presence of microscopic disease).

Usefulness of a program of neoplasia surveillance in liver transplantation. A preliminary report

Abstract:  De novo malignancies are frequent complications after liver transplantation. Aim of the study is to evaluate whether a surveillance program for malignancy may improve patient survival. We have compared the survival after the diagnosis of malignancy (excluding cutaneous and hepatobiliary carcinomas and lymphoproliferative disease) of patients with symptomatic or incidental malignancies with patients with neoplasia diagnosed on screening. Two hundred and eighty patients with a follow‐up greater than three months were followed for a median of 77.5 months (total follow‐up: 1515 patient‐yr). Thirty‐three patients developed 41 malignancies. When compared with general population, the entire cohort of liver transplant recipients had a significantly higher risk of malignancy (relative risk: 2.34), gastrointestinal tract (relative risk: 2.52), urological tract (relative risk: 2.94) and head and neck cancer (relative risk: 4.14), and cancer‐related death (relative risk: 2.35). All nine patients diagnosed with cancer with active screening are currently alive and free of malignancy after a median follow‐up of 25 months. By contrast, 18/24 patients with diagnosis of cancer prompted by symptoms or incidentally diagnosed died as a consequence of the cancer (median survival: 13.5 months). The difference in survival between both groups was significant (p = 0.002). In conclusion, a close surveillance protocol for the diagnosis of malignancy could be life‐saving in liver transplant recipients.

Hepatic encephalopathy after liver transplantation in a patient with a normally functioning graft: Treatment with embolization of portosystemic collaterals

Received April 5, 2008; accepted May 11, 2008.Portosystemic encephalopathy is one of the most im-portant complications of liver cirrhosis. The restorationof normal hepatic function and the reduction of porto-systemic shunts by means of a liver graft are followedby the resolution of hepatic encephalopathy. We reportthe case of a patient with a normal functioning graftthat developed recurrent encephalopathy after trans-plantation. The patient was successfully treated by em-bolization of a large portosystemic shunt between thesuperior mesenteric vein and both gonadal veins, thiscausing an inversion of the superior mesenteric veinflow.

Performance of SAPS II and SAPS 3 in Intermediate Care

Objective The efficacy and reliability of prognostic scores has been described extensively for intensive care, but their role for predicting mortality in intermediate care patients is uncertain. To provide more information in this field, we have analyzed the performance of the Simplified Acute Physiology Score (SAPS) II and SAPS 3 in a single center intermediate care unit (ImCU). Materials and Methods Cohort study with prospectively collected data from all patients admitted to a single center ImCU in Pamplona, Spain, from April 2006 to April 2012. The SAPS II and SAPS 3 scores with respective predicted mortality rates were calculated according to standard coefficients. Discrimination was evaluated by calculating the area under receiver operating characteristic curve (AUROC) and calibration with the Hosmer-Lemeshow goodness of fit test. Standardized mortality ratios (SMR) with 95% confidence interval (95% CI) were calculated for each model. Results The study included 607 patients. The observed in-hospital mortality was 20.1% resulting in a SMR of 0.87 (95% CI 0.73-1.04) for SAPS II and 0.56 (95% CI 0.47-0.67) for SAPS 3. Both scores showed acceptable discrimination, with an AUROC of 0.76 (95% CI 0.71-0.80) for SAPS II and 0.75 (95% CI 0.71- 0.80) for SAPS 3. Calibration curves showed similar performance based on Hosmer-Lemeshow goodness of fit C-test: (X2=12.9, p=0.113) for SAPS II and (X2=4.07, p=0.851) for SAPS 3. Conclusions Although both scores overpredicted mortality, SAPS II showed better discrimination for patients admitted to ImCU in terms of SMR.

Results of a retrospective observational study of intermediate care staffed by hospitalists: Impact on mortality, co‐management, and teaching

BACKGROUND Hospitalized patients are complex and institutions have to face the high cost of critical care and the limited resources of the ward. Intermediate care appears as an attractive strategy to provide rational care according to patient needs. It is an interesting scenario to expand co-management and teaching. STUDY DESIGN Retrospective observational study. SETTING Intermediate care unit (ImCU) of a single academic hospital. PATIENTS AND METHODS 456 patients admitted from April 2006 to April 2010 were included in the study. Demographics, admission physiologic parameters and in-hospital mortality were recorded. We used the Simplified Acute Physiology Score II (SAPS II) as prognostic score system. Co-management with medical and surgical teams, and the number of training residents were evaluated. RESULTS In-hospital mortality was 20.6%, whereas the expected mortality was 23.2% based on SAPS II score. The correlation between SAPS II predicted and observed death rates was accurate and statistically significant (Rho = 1.0, p < 0.001). Co-management was performed with several medical and surgical teams, with an increase in perioperative comanagement of 22.7% (p = 0.014). The number of training residents in ImCU increased from 4.3% to 30.4% (p = 0.002) CONCLUSIONS An ImCU led by hospitalists showed encouraging results regarding patient survival and SAPS II is an useful tool for prognostic evaluation in this population. Intermediate care serves as an expansion of role for hospitalists; and clinicians, trainees and patients may benefit from co-management and teaching opportunities at this unique level of care.

Design and Performance of a New Severity Score for Intermediate Care

Background Application of illness-severity scores in Intermediate Care Units (ImCU) shows conflicting results. The aim of the study is to design a severity-of-illness score for patients admitted to an ImCU. Methods We performed a retrospective observational study in a single academic medical centre in Pamplona, Spain. Demographics, past medical history, reasons for admission, physiological parameters at admission and during the first 24 hours of ImCU stay, laboratory variables and survival to hospital discharge were recorded. Logistic regression analysis was performed to identify variables for mortality prediction. Results A total of 743 patients were included. The final multivariable model (derivation cohort = 554 patients) contained only 9 variables obtained at admission to the ImCU: previous length of stay 7 days (6 points), health-care related infection (11), metastatic cancer (9), immunosuppressive therapy (6), Glasgow comma scale 12 (10), need of non-invasive ventilation (14), platelets 50000/mcL (9), urea 0.6 g/L (10) and bilirubin 4 mg/dL (9). The ImCU severity score (ImCUSS) is generated by summing the individual point values, and the formula for determining the expected in-hospital mortality risk is: eImCUSS points*0.099 – 4,111 / (1 + eImCUSS points*0.099 – 4,111). The model showed adequate calibration and discrimination. Performance of ImCUSS (validation cohort = 189 patients) was comparable to that of SAPS II and 3. Hosmer-Lemeshow goodness-of-fit C test was χ2 8.078 (p=0.326) and the area under receiver operating curve 0.802. Conclusions ImCUSS, specially designed for intermediate care, is based on easy to obtain variables at admission to ImCU. Additionally, it shows a notable performance in terms of calibration and mortality discrimination.

Mortality Prediction in Patients Undergoing Non-Invasive Ventilation in Intermediate Care

Background Intermediate Care Units (ImCU) have become an alternative scenario to perform Non-Invasive Ventilation (NIV). The limited number of prognostic studies in this population support the need of mortality prediction evaluation in this context. Objective The objective of this study is to analyze the performance of Simplified Acute Physiology Score (SAPS) II and 3 in patients undergoing NIV in an ImCU. Additionally, we searched for new variables that could be useful to customize these scores, in order to improve mortality prediction. Design Cohort study with prospectively collected data from all patients admitted to a single center ImCU who received NIV. The SAPS II and 3 scores with their respective predicted mortality rates were calculated. Discrimination and calibration were evaluated by calculating the area under the receiver operating characteristic curve (AUC) and with the Hosmer-Lemeshow goodness of fit test for the models, respectively. Binary logistic regression was used to identify new variables to customize the scores for mortality prediction in this setting. Patients The study included 241 patients consecutively admitted to an ImCU staffed by hospitalists from April 2006 to December 2013. Key Results The observed in-hospital mortality was 32.4% resulting in a Standardized Mortality Ratio (SMR) of 1.35 for SAPS II and 0.68 for SAPS 3. Mortality discrimination based on the AUC was 0.73 for SAPS II and 0.69 for SAPS 3. Customized models including immunosuppression, chronic obstructive pulmonary disease (COPD), acute pulmonary edema (APE), lactic acid, pCO2 and haemoglobin levels showed better discrimination than old scores with similar calibration power. Conclusions These results suggest that SAPS II and 3 should be customized with additional patient-risk factors to improve mortality prediction in patients undergoing NIV in intermediate care.