Federico Piñero

Liver transplantation for hepatocellular carcinoma: evaluation of the alpha-fetoprotein model in a multicenter cohort from Latin America.

The French alpha‐fetoprotein (AFP) model has recently shown superior results compared to Milan criteria (MC) for prediction of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) in European populations. The aim of this study was to explore the predictive capacity of the AFP model for HCC recurrence in a Latin‐American cohort.

Fatty liver disease, an emerging etiology of hepatocellular carcinoma in Argentina

AIM To investigate any changing trends in the etiologies of hepatocellular carcinoma (HCC) in Argentina during the last years. METHODS A longitudinal cohort study was conducted by 14 regional hospitals starting in 2009 through 2016. All adult patients with newly diagnosed HCC either with pathology or imaging criteria were included. Patients were classified as presenting non-alcoholic fatty liver disease (NAFLD) either by histology or clinically, provided that all other etiologies of liver disease were ruled out, fatty liver was present on abdominal ultrasound and alcohol consumption was excluded. Complete follow-up was assessed in all included subjects since the date of HCC diagnosis until death or last medical visit. RESULTS A total of 708 consecutive adults with HCC were included. Six out of 14 hospitals were liver transplant centers (n = 484). The prevalence of diabetes mellitus was 27.7%. Overall, HCV was the main cause of liver disease related with HCC (37%) including cirrhotic and non-cirrhotic patients, followed by alcoholic liver disease 20.8%, NAFLD 11.4%, cryptogenic 9.6%, HBV 5.4% infection, cholestatic disease and autoimmune hepatitis 2.2%, and other causes 9.9%. A 6-fold increase in the percentage corresponding to NAFLD-HCC was detected when the starting year, i.e., 2009 was compared to the last one, i.e., 2015 (4.3% vs 25.6%; P < 0.0001). Accordingly, a higher prevalence of diabetes mellitus was present in NAFLD-HCC group 61.7% when compared to other than NAFLD-HCC 23.3% (P < 0.0001). Lower median AFP values at HCC diagnosis were observed between NAFLD-HCC and non-NAFLD groups (6.6 ng/mL vs 26 ng/mL; P = 0.02). Neither NAFLD nor other HCC etiologies were associated with higher mortality. CONCLUSION The growing incidence of NAFLD-HCC documented in the United States and Europe is also observed in Argentina, a confirmation with important Public Health implications.

A changing etiologic scenario in liver transplantation for hepatocellular carcinoma in a multicenter cohort study from Latin America

BACKGROUND AND AIM Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of hepatocellular carcinoma (HCC) and liver transplantation (LT). Our study focused on changing trends of liver related HCC etiologies during the last years in Latin America. METHODS From a cohort of 2761 consecutive adult LT patients between 2005 and 2012 in 17 different centers, 435 with HCC were included. Different periods including years 2005-2006, 2007-2008, 2009-2010 and 2011-2012 were considered. Etiology of liver disease was confirmed in the explant. RESULTS Participating LT centers per country included 2 from Brazil (n=191), 5 transplant programs from Argentina (n=98), 2 from Colombia (n=65), 4 from Chile (n=49), 2 from Mexico (n=12), and 1 from Peru (n=11) and Uruguay (n=9). Chronic hepatitis C infection was the leading cause of HCC in the overall cohort (37%), followed by HBV (25%) and alcoholic liver disease (17%). NAFLD and cryptogenic cirrhosis accounted for 6% and 7%, respectively. While HCV decreased from 48% in 2005-06 to 26% in 2011-12, NAFLD increased from 1.8% to 12.8% during the same period, accounting for the third cause of HCC. This represented a 6-fold increase in NAFLD-HCC, whereas HCV had a 2-fold decrease. Patients with NAFLD were older, had lower pre-LT serum AFP values and similar 5-year survival and recurrence rates than non-NAFLD. CONCLUSION There might be a global changing figure regarding etiologies of HCC in Latin America. This epidemiological change on the incidence of HCC in the world, although it has been reported, should still be confirmed in prospective studies.

Identifying patients at higher risk of hepatocellular carcinoma recurrence after liver transplantation in a multicenter cohort study from Argentina.

Background and aim The Up-to-7 criteria on the basis of the explanted liver features categorize patients at higher risk of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). The aim of this study was to propose a novel pretransplant scoring system to predict recurrence including pre-LT data. Patients and methods From 763 consecutive adult patients who underwent transplantation in four LT centers from Argentina, 124 patients with HCC were included. A scoring system was developed in 87 patients from pre-LT risk factors for recurrence as determined by hazard ratios (HRs) from a multivariate Cox regression analysis. Results Overall survival and recurrence rates at 5 years were 63.3 and 13.7%, respectively, during a follow-up period of 3.5±2.2 years. Variables associated with HCC recurrence on multivariate analysis were &agr;-fetoprotein more than 100 ng/ml (HR=5.6, P=0.001) and tumor beyond Up-to-7 imaging criteria (HR=6.3, P=0.001). Bootstrap validation showed that overfitting was negligible. Scoring points were assigned as follows (0–2 points): pre-LT &agr;-fetoprotein more than 100 ng/ml (presence=1 point, absence=0 point), and tumor beyond Up-to-7 imaging criteria (presence=1 point, absence=0 point). AUROC curve indicated a c-statistic of 0.74 (0.58–0.88, P=0.003). Two distinct subgroups of patients were identified with a cut-off more than or equal to 1 point (62% sensitivity and 82% specificity): low risk (0 point) and high risk (1–2 points). The 5-year recurrence rate was 9.4 and 44.5% (P=0.0001) and the 5-year overall survival was 78.1 and 34.8% (P=0.0001) in the low-risk and high-risk groups, respectively. Conclusion This scoring model may be a useful additional tool for HCC recurrence risk stratification before LT. Prospective studies are needed to evaluate our model.

A Case of Granulomatous Hepatitis and Pancytopenia Secondary toBacillus Chalmette Guerin Immunotherapy (BCG)

We describe the case of a 69-year-old female who developed pancytopenia and acute hepatitis as a complication of intravesical BCG instillations for the treatment of bladder urothelial carcinoma. Liver and bone marrow biopsies revealed multinucleated giant epithelioid cells and non-caseating granulomas. Treatment with antituberculosis drugs achieved complete resolution. This case illustrates an infrequent but severe complication of intravesical BCG instillations, whichcan be successfully treated without steroids.

Sicker Patients for Liver Transplantation: Meld, Meld Sodium, and Integrated Meld’s Prognostic Accuracy in the Assessment of Posttransplantation Events at a Single Center from Argentina

Background. MELD or MELD sodium promotes sicker patients for earlier liver transplantation (LT); the balance between pre- and post-LT outcomes is still controversial. Aim. To compare MELD and related scores’ risk assessment of short-term morbidity and mortality after LT. Methods. We included only transplanted cirrhotic patients from 6/2005 to 6/2010 (). Immediate pre-LT MELD, integrated MELD (iMELD), and two MELD sodium formulas “MELD Na1” and “MELDNa2” were calculated. Results. Pre-LT scores for nonsurvivors were higher than those for survivors: MELD (28 ± 8 versus 22 ± 7, ), MELD Na1 (33 ± 8 versus 27 ± 10, ), and iMELD (51 ± 6 versus 46 ± 8, ). Patient survival assessment was performed by AUROC analysis (95% CI): MELD 0.694 (0.56–0.82; ), MELD Na1 0.682 (0.56–0.79; ), MELD Na2 0.651 (0.54–0.76; ), and iMELD 0.698 (0.593–0.80; ). Patients with MELD ≥25 points had longer intensive care stay (mean 10 versus 7 days, ) and longer mechanical ventilatory support (5.4 versus 1.9 days, ). Conclusions. The addition of serum sodium to MELD does not improve assessment of mortality after LT. Patients with higher MELD may preclude higher morbidity after transplantation.

Hepatocellular carcinoma in Latin America: Diagnosis and treatment challenges

Latin America, a region with a population greater than 600000000 individuals, is well known due to its wide geographic, socio-cultural and economic heterogeneity. Access to health care remains as the main barrier that challenges routine screening, early diagnosis and proper treatment of hepatocellular carcinoma (HCC). Therefore, identification of population at risk, implementation of surveillance programs and access to curative treatments has been poorly obtained in the region. Different retrospective cohort studies from the region have shown flaws in the implementation process of routine surveillance and early HCC diagnosis. Furthermore, adherence to clinical practice guidelines recommendations assessed in two studies from Brazil and Argentina demonstrated that there is also room for improvement in this field, similarly than the one observed in Europe and the United States. In summary, Latin America shares difficulties in HCC decision-making processes similar to those from developed countries. However, a transversal limitation in the region is the poor access to health care with the consequent limitation to standard treatments for overall population. Specifically, universal health care access to the different World Health Organization levels is crucial, including improvement in research, education and continuous medical training in order to expand knowledge and generation of data promoting a continuous improvement in the care of HCC patients.

Case-control study highlights a different gut microbiome in cirrhotic patients with and without hepatocellular carcinoma

Background & Aims No specific microbiome in patients with hepatocellular carcinoma (HCC) has been reported to date. Our aim was to compare gut microbiome found in cirrhotic patients with and without HCC. Methods From 407 patients with Child Pugh A/B cirrhosis prospectively followed, 25 with HCC (cases) were matched with 25 without HCC (wo-HCC) in a 1:1 ratio according to age, gender, etiology, Child Pugh and severity of portal hypertension. In addition 25 healthy subjects were also compared. Faecal stool samples were collected noninvasively, aliquoted for DNA extraction and sequenced for the V3-V4 region of the microbial 16S rRNA (Illumina MiSeq Platform). Results Cases and control’s baseline characteristics were: age 64 ± 8 years, 88% males, body mass index (BMI) 28 ± 4 kg/m2, hepatitis C virus infection 26%, Child Pugh A/B 74% and 26%, respectively. Barcelona Clinic Liver Cancer stages in HCC patients were 0 (n=2), A (n=12), B (n=5) and C (n=6). A significant different microbiome was observed in HCC cases vs controls. Patients with HCC had lower quantities of genus Prevotella, Fusobacterium and family Leuconostocaccaceae among others and an elevated proportion of genus Bifidobacterium, Eggerthella, Haemophilus, family Erysipelotrichaceae and phylum Tenericutes when compared to controls without HCC. This pattern has been associated with an inflammatory milieu with a putative increased activation of NOD-like receptor signalling pathways. Conclusions A different pattern of microbiome in cirrhotic patients with HCC was observed. This pattern previously linked to inflammation, should be further explored as a novel risk factor for HCC development.Background: No specific microbiome in patients with hepatocellular carcinoma (HCC) has been reported to date. Aim: To compare the gut microbiome found in cirrhotic patients with and without HCC. Methods: From 407 patients with Child Pugh A/B cirrhosis prospectively followed, 25 with HCC (cases) were matched with 25 without HCC (wo-HCC) in a 1:1 ratio according to age, gender, etiology, Child Pugh and severity of portal hypertension. In addition results were also compared with 25 healthy subjects. Faecal stool samples were collected noninvasively, aliquoted for DNA extraction and sequenced for the V3-V4 region of the microbial 16S rRNA (Illumina MiSeq Platform). Results: There were no significant clinical differences among cases and controls. We found a differential abundance in family members of Firmicutes with a 3-fold increased of Erysipelotrichaceae and a 5-fold decrease in family Leuconostocaceae in HCC when compared to wo-HCC controls. Genus Fusobacterium was found 5-fold decreased in HCC versus wo-HCC. The ratio bacteriodes/prevotella was increased in HCC due to the significant decrease in the genus prevotella. Genus Odoribacter and Butyricimonas were more differentialy abundant in HCC. This pattern has been previously associated with an inflammatory milieu with a putative increased activation of NOD-like receptor signalling pathways. A Random Forest model trained with differential abundant taxa correctly classifyed HCC individuals with an error of 22%. Conclusions: A pattern of microbiome linked to inflammation was observed in cirrhotic patients with HCC. These findings open the discussion whether or not microbiota has a physiopathologic role in HCC development in cirrhosis.

Dropout rate from the liver transplant waiting list because of hepatocellular carcinoma progression in hepatitis C virus–infected patients treated with direct‐acting antivirals

We have read with interest the article recently published by Zanetto et al. in Liver Transplantation regarding the effect on radiologic progression of hepatocellular carcinoma (HCC) after the treatment with direct-acting antivirals (DAAs) for hepatitis C virus (HCV) in patients listed for liver transplantation. Although a previous call for attention to a higher, early, and aggressive HCC recurrence following the treatment with DAAs has been observed, Zanetto et al. reported similar outcomes while on the waiting list between patients treated with DAAs and controls in terms of dropout (8.7% versus 4.3%) and HCC radiological progression (35% versus 17%, respectively). Although both studies proposed a novel discussion whether DAAs promote an immunological disruption and tumor growth, its causal inference is still far away to reach robustness. The radiological HCC progression during the waiting list in previous studies ranges 4%-6% and close to 20% at 6 and 12 months of listing, respectively. The study by Zanetto et al. is limited by the fact that the nonrandom intervention already biases the results, even after adjusting for confounding variables such as serum alpha-fetoprotein values. Likewise, neither the intervention assignment nor the radiological evaluation were blinded from baseline variables. Finally, a sample size estimation is lacking. Observing “nonsignificant” differences in this study might be far away from the real effect as a consequence of this lack of power. In fact, the study published by Roayaie et al. might have gone through the reported confidence interval limits (95% CI of 17% to 40%). Ultimately, although the clinical question is novel, this research does not “illuminate” but rather “deepens the confusion” on this topic and further demands a randomized intervention study.

Domino liver graft with hepatocellular carcinoma used as bridge therapy for a patient with acute liver failure: A case report

We report a unique case of orthotopic domino livertransplantation for a patient with ALF: a noncirrhoticliver graft with HCC was used as bridge therapy untila permanent deceased donor graft became available.A 42-year-old Hispanic woman presenting with ALFwas admitted to the emergency department and waspromptly listed for emergency liver transplantation.However, her clinical deterioration progressed rapidly,the patient required mechanical ventilatory support,and an epidural intracranial pressure monitor wasplaced. The patient developed intracranial hyperten-sion (25-30 mm Hg), which was successfully con-trolled with medical therapy. Synchronously,scheduled living donor liver transplantation (LDLT)was being performed for a 60-year-old female patientwith a history of recurrent HCC in a noncirrhotic liver.This patient had previously undergone a series of sur-gical and ablative treatments. The actual tumor bur-den was 2 HCC lesions (each 20 mm in diameter), theserum alpha-fetoprotein level was 2.4 ng/mL, and novascular or extrahepatic metastasis was found at thetime of LDLT.Progressive worsening of an already critical clinicalcondition in the first patient, the absence of either adeceased donor or a living donor after 5 days on thewaiting list, and no access to liver support systems orbioartificial devices at that time led the transplantteam to consider a domino liver transplant using theexplanted noncirrhotic liver with HCC from the secondpatient undergoing synchronous LDLT as bridge ther-apy. Consent was obtained from both the recipientand donor families, the institutional ethics committee,and the Instituto Nacional Central Unico Coordinadorde Ablacion e Implante. A sequential triple-procedureschedule was followed: left lobe LDLT; back-tableresection of the two 2-cm HCC lesions in segments VIand IV; and, finally, domino implantation of the HCCliver graft with the piggyback technique. The coldischemia time lasted 4 hours, and the warm ischemiatime was 40 minutes. Shortly after transplantation,vasopressor infusion was discontinued, and the intra-cranial pressure parameters improved to 15 to 17 mmHg (Fig. 1). Twelve hours after the domino procedure,a deceased donor graft from a 49-year-old female,located 600 km from the hospital, was made availablefor this patient. The deceased donor liver transplanta-tion procedure began 11 hours after the completion ofthe bridge domino liver transplant with the resectedHCC graft, and it lasted a total of 165 minutes with acold ischemia time of 6 hours.A pathological examination of the explanted dominoHCC liver graft confirmed 2 small HCC nodules: one