Tumor Biology as Predictor of Mortality in Liver Transplantation for Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most frequent primary malignant liver tumor, with the Milan criteria considered to be the gold standard for patient selection for liver transplantation (LT). MATERIALS AND METHODS: We performed a descriptive observational study, reviewing 20 years of experience of LT in patients with HCC in the Fundacion Valle del Lilí in Cali, Colombia. Subgroup analysis was undertaken for periods 1999 to 2007 and 2008 to 2015. RESULTS: Fifty-seven cases with a pretransplant HCC diagnosis were reviewed. In the first period patients within the Milan criteria had a recurrence-free survival at 5 years of 66.6%, and in those who exceeded the Milan criteria, recurrence-free survival was 75%. In the second period, patients within the Milan criteria, recurrence-free survival at 5 years was 93.5%, and in those who exceeded the Milan criteria, recurrence-free survival was 75.7%. No statistically significant difference was found in either period. For patients with mild and moderate tumor differentiation, the relapse survival rate at 5 years was 69.4% (95% confidence interval [CI] 35.8-87.8) and 74.7% (95% CI 44.5-90), respectively. All patients with poor tumor differentiation relapsed and died within 3 years. CONCLUSION: Global and recurrence-free survival among patients who met and patients who exceeded the Milan criteria was not significantly different, suggesting an expansion of the Milan criteria to include potential recipients who were previously excluded. Obtaining histologic differentiation and identifying vascular invasion will provide a more worthwhile contribution to LT decision making.

Liver Transplantation in Hepatitis C-Infected Patients: Experience From a South American Transplant Center.

BACKGROUND: Around 2.4% of the world's population is infected with hepatitis C virus (HCV), and it is the most common cause of liver transplantation (LT) in the world. Latin America (LA), with nearly 9% of the world population, has had a continuous increase in the number of LTs per year. Yet, due to the lack of mandatory data collection and a well-developed health-care system, access to transplantation is limited in most LA countries. We report the first LA experience of HCV-infected LT patients. METHODS: We performed a retrospective cohort study by reviewing the medical histories of all HCV-infected LT patients between 1996 and 2016 who acquired HCV before their LT, at the Fundación Valle del Lilí, Cali, Colombia. RESULTS: Between January 1996 and December 2015, a total of 770 LTs were performed, of which 75 had a cirrhotic liver due to HCV infection. With a median follow-up time of 24.4 months (interquartile range [IQR] 4.7-61.2 months), patient survival was 44.9% and 66.9% for the time periods 1996-2006 and 2007-2015, respectively. Hepatocellular carcinoma (HCC) was present in 30.6% of the patients, and overall postoperative complications had an incidence of 80%. CONCLUSIONS: This is the first report of LT in HCV-infected patients in Colombia and in LA. Our results are comparable to those of other transplant centers worldwide with regard to postoperative complications and patient survival. Patients with LT in the 1996-2006 time frame had higher morbidity and mortality. Studies including larger numbers of patients are needed to determine the reason for this finding.

Kidney transplantation for end-stage renal disease in lupus nephritis, a very safe procedure: a single Latin American transplant center experience.

Background Lupus nephritis (LN) is one of the most frequent complications of SLE and occurs in up to 50% of cases depending on the studied population. Of these, approximately 20% progress to end-stage renal disease (ESRD), with the treatment of choice being a kidney transplant. Objective The objective of this study was to describe the clinical outcome of patients transplanted due to LN, compared with patients transplanted for other causes, in a Latin American population from the Fundación Valle del Lili in Cali, Colombia. Methods Observational, retrospective case study with controls matched by age, sex and type of donor in a single center between 1996 and 2014. Results Sixty-five kidney transplants were performed in patients with LN and ESRD. The survival of patients with LN was 98% at 1, 10 and 15 years ( p = .99). For controls by age and sex, survival was also 98% at 15 years post-transplant, and for controls by donor, the survival rate was 100% at 5 years and 98% at 15 years. Graft survival in patients with LN to 1, 5 and 15 years was 92%, 83% and 71%, respectively; for controls by age and sex, it was 90%, 84% and 64%, respectively, and for the controls by donor, it was 89%, 86% and 79%, respectively ( p = .7718). There were no statistically significant differences found in the cumulative incidence of acute graft rejection in the first year, but it was found that acute rejection is a factor that relates to the loss of function of the renal graft ( p = .032). Of the patients transplanted for LN, two (3.1%) experienced a recurrence of the disease. One patient died after a diagnosis of recurrence of LN due to an infection. Conclusions Kidney transplantation is a good option for patients with ESRD due to LN. In this Hispanic population, the survival of patients, graft survival, and cumulative incidence of graft rejection are not different from those of other transplanted patients. In addition, recurrence of LN was rare, showing the benefits of renal transplantation in LN patients with ESRD.

Marrow-derived mesenchymal stem cells restore biochemical markers of acute liver injury in experimental model.

Bone marrow-derived mesenchymal stem cells were investigated as prompters of liver regeneration in an experimental model of acute hepatic injury. A model was created in Wistar rats through intraperitoneal injection of carbon tetrachloride (CCl4). Bone marrow-derived mesenchymal stem cells collected from the long bones of 10 Wistar rats were intravenously infused 24 hours after induction of acute liver failure in 16 rats, group A. In group B, the control group, 16 rats received a peritoneal injection of CCl4, and an intravenous infusion of normal saline solution. All rats were sacrificed at 2, 3, 4, and 7 days post-CCl4 injection to examined biochemical markers and pathological appearances. The platelet counts were higher in group A versus group B on post-CCl4 infusion days 2 (P = .02) and 3 (P = .001), as were the transaminase trends in glutamic oxaloacetic (P = .002), and glutamic-pyruvic transaminases (P < .0001). Pathological examination showed a greater grade of hepatocellular necrosis with neutrophilic infiltration in group B (P = .02). In conclusion, infusion of bone marrow-derived mesenchymal stem cell resulted in a less aggressive picture of hepatic damage.

Development of a standardized model for liver failure in pigs: anatomopathophysiologic findings after extended liver resection.

Eighteen pigs weighing a mean 19 ± 4 kg, were divided into group 1 (n = 2), that underwent resection of the left lateral lobe, group 2 (n = 2), resection of the left median and right median lobes; and group 3 (n = 18), resection of the left lateral, left median, right median, and right lateral lobes. All animals were followed for 5 days. Liver failure (n = 8) leading to animal death within 3 days after surgery was observed in 65% of group 3, whereas no group 1 or 2 animal experienced liver insufficiency. Multivariate analysis revealed that the extent of liver resection expressed as a percentage of total body weight <2.3%, international normalized ratio > 1.6 as postoperative day 2, serum bilirubin > 4.2 on postoperative day 2, and serum lactates > 9 mmol/L after resection were independent predictors of liver failure (P < .05). The number of resected liver lobes was not a good predictor of liver failure in swine, whereas the extent of resection expressed as a percentage of total body weight was an independent predictor of early liver failure. A resected liver-to-body weight ratio >2.3% was associated with a 65% probability of developing liver insufficiency. This parameter may be useful when developing a model of liver failure after extended liver resection in swine.

Laparoscopic approach for an intra-abdominal kidney allograft nephrectomy after pediatric transplantation: a case report.

We report a case of minimally invasive nephrectomy of a kidney transplanted into the abdominal cavity in a child. A 15-year-old girl underwent transplantation with a cadaveric donor kidney due to congenital pyelonephritis, vesicoureteral reflux, and secondary bladder atrophy. The transplant was complicated by hyperacute rejection, cytomegalovirus infection, and anastomotic stenosis of the Bricker neobladder. After recurrent urinary tract infections, the patient was reintroduced to hemodialysis in 2010. After pneumo-peritoneum, we placed 2 10-mm trocars in the hypochondrium and left side and 2 5-mm in the left iliac fossa and right upper quadrant. The transplanted kidney was skeletonized, the artery and vein were cut to the end-to-side anastomoses to the juxta-renal aorta and cava using an automatic 35-mm, stapler, and the ureter was dissected and closed with clips. Via a Pfannestiel minilaparotomy we extracted the allograft. The patient was discharged on the third postoperative day. After 4 months of follow-up, she is alive an on dialysis. Laparoscopic nephrectomy of a kidney transplanted into the abdominal cavity is feasible and safe in centers with skilled minimally invasive techniques.

The Charlson comorbidity index as a predictor of outcomes in liver transplantation: single-center experience.

Several comorbidity indices, such as the Child-Turcotte-Pugh (CTP) score and the Model for End-Stage Liver Disease (MELD) score, have been used to optimize available organ resources and adjust priorities in diagnosis and allocation of grafts for patients who are candidates for liver transplantation. There have also been various attempts to create instruments to accurately predict outcomes after liver transplantation, but none has proved to be truly applicable, with the exception of the Charlson comorbidity index (CCI). We retrospectively reviewed data of 221 liver recipients, including living-related liver transplantation and multiple organ transplantation performed between January 2006 and September 2009. Survival analysis revealed a significant association of the CCI with decreased posttransplantation patient survival (P = .003). Furthermore, Kaplan-Meier plots and log-rank test showed a significant association between graft survival and the score (P = .039). Our data suggest that the CCI is a simple tool for the evaluation of comorbidity and that increased preoperative patient comorbidity increases the risk of graft loss and patient death after liver transplantation. The CCI should be considered an important tool for improving patient care because of its potential applications for patient management.

Unusual presentation of left hepatic vein in deceased donor: case report.

An anomaly of the left hepatic vein was discovered in a deceased donor for whole liver transplantation. This vein was attached by a thin bridge of tissue to the suprahepatic inferior vena cava cuff, which received the right and middle hepatic vein in a common trunk. The left hepatic vein and the common trunk drained together into the right atrium. The thin bridge of tissue connecting the 2 independent vessels was severed, and ex situ reduction of the left lateral segments was using a harmonic scalpel. Although a graft with reduced size is not ideal, ex situ reduction should be considered a valuable option when viability of the left lateral segments is uncertain in the donor or at the back table.

Recipient tissue factor expression is associated with consumptive coagulopathy in pig-to-primate kidney xenotransplantation.

Consumptive coagulopathy (CC) remains a challenge in pig-to-primate organ xenotransplantation (Tx). This study investigated the role of tissue factor (TF) expression on circulating platelets and peripheral blood mononuclear cells (PBMCs). Baboons (n = 9) received a kidney graft from pigs that were either wild-type (n = 2), alpha1,3-galactosyltransferase gene-knockout (GT-KO; n = 1) or GT-KO and transgenic for the complement-regulatory protein, CD46 (GT-KO/CD46, n = 6). In the baboon where the graft developed hyperacute rejection (n = 1), the platelets and PBMCs expressed TF within 4 h of Tx. In the remaining baboons, TF was detected on platelets on post-Tx day 1. Subsequently, platelet-leukocyte aggregation developed with formation of thrombin. In the six baboons with CC, TF was not detected on baboon PBMCs until CC was beginning to develop. Graft histopathology showed fibrin deposition and platelet aggregation (n = 6), but with only minor or no features indicating a humoral immune response (n = 3), and no macrophage, B or T cell infiltration (n = 6). Activation of platelets to express TF was associated with the initiation of CC, whereas TF expression on PBMCs was concomitant with the onset of CC, often in the relative absence of features of acute humoral xenograft rejection. Prevention of recipient platelet activation may be crucial for successful pig-to-primate kidney Tx.

Investigation of lymphocyte depletion and repopulation using alemtuzumab (Campath-1H) in cynomolgus monkeys.

As the target CD52 molecule is expressed on erythrocytes of most nonhuman primate strains, using alemtuzumab in these species would cause massive hemolysis. Six cynomolgus monkeys of Indonesian origin, screened by agglutination assay for absence of CD52 on erythrocytes, were administered alemtuzumab in a cumulative dose to a maximum of 60 mg/kg. In two monkeys, mycophenolate mofetil (MMF) was added as maintenance therapy. Complete depletion of T and B lymphocytes (>99.5%) was achieved with 20 mg/kg alemtuzumab and was more profound than in monkeys treated with antithymocyte globulin (n = 5), as quantified by flow cytometry. Repopulation was suppressed by weekly injections of 10 mg/kg. Without MMF, repopulation of CD20(+)B cells and CD8(+)T cells was complete within 2 and 3 months, respectively, and repopulation of CD4(+)T cells was 67% after 1 year. MMF significantly delayed CD4(+)T-cell repopulation. Among repopulating CD4(+) and CD8(+) T cells, a phenotypic shift was observed from CD45RA(hi)CD62L(hi) naïve cells toward CD45RA(lo)CD62L(lo) effector memory cells. In lymph nodes, the depletion of naïve cells was more profound than of memory cells, which may have initiated a proliferation of memory cells. This model offers opportunities to investigate lymphocyte depletion/repopulation phenomena, as well as the efficacy of alemtuzumab in preclinical transplantation models.

Ex vivo application of carbon monoxide in UW solution prevents transplant-induced renal ischemia/reperfusion injury in pigs.

I/R injury is a major deleterious factor of successful kidney transplantation (KTx). Carbon monoxide (CO) is an endogenous gaseous regulatory molecule, and exogenously delivered CO in low concentrations provides potent cytoprotection. This study evaluated efficacies of CO exposure to excised kidney grafts to inhibit I/R injury in the pig KTx model. Porcine kidneys were stored for 48 h in control UW or UW supplemented with CO (CO-UW) and autotransplanted in a 14-day follow-up study. In the control UW group, animal survival was 80% (4/5) with peak serum creatinine levels of 12.0 +/- 5.1 mg/dL. CO-UW showed potent protection, and peak creatinine levels were reduced to 6.9 +/- 1.4 mg/dL with 100% (5/5) survival without any noticeable adverse event or abnormal COHb value. Control grafts at 14 days showed significant tubular damages, focal fibrotic changes and numerous infiltrates. The CO-UW group showed significantly less severe histopathological changes with less TGF-beta and p-Smad3 expression. Grafts in CO-UW also showed significantly lower early mRNA levels for proinflammatory cytokines and less lipid peroxidation. CO in UW provides significant protection against renal I/R injury in the porcine KTx model. Ex vivo exposure of kidney grafts to CO during cold storage may therefore be a safe strategy to reduce I/R injury.

Impact of thrombocytopenia on survival of baboons with genetically modified pig liver transplants: clinical relevance.

A lack of deceased human donor livers leads to a significant mortality in patients with acute-on-chronic or acute (fulminant) liver failure or with primary nonfunction of an allograft. Genetically engineered pigs could provide livers that might bridge the patient to allotransplantation. Orthotopic liver transplantation in baboons using livers from alpha1,3-galactosyltransferase gene-knockout (GTKO) pigs (n = 2) or from GTKO pigs transgenic for CD46 (n = 8) were carried out with a clinically acceptable immunosuppressive regimen. Six of 10 baboons survived for 4-7 days. In all cases, liver function was adequate, as evidenced by tests of detoxification, protein synthesis, complement activity and coagulation parameters. The major problem that prevented more prolonged survival beyond 7 days was a profound thrombocytopenia that developed within 1 h after reperfusion, ultimately resulting in spontaneous hemorrhage at various sites. We postulate that this is associated with the expression of tissue factor on platelets after contact with pig endothelium, resulting in platelet and platelet-peripheral blood mononuclear cell(s) aggregation and deposition of aggregates in the liver graft, though we were unable to confirm this conclusively. If this problem can be resolved, we would anticipate that a pig liver could provide a period during which a patient in liver failure could be successfully bridged to allotransplantation.

Endoscopic gastric submucosal transplantation of islets (ENDO-STI): technique and initial results in diabetic pigs.

The results of transplantation of human donor islets into the portal vein (PV) in patients with diabetes are encouraging. However, there are complications, for example, hemorrhage, thrombosis and an immediate loss of islets through the 'instant blood-mediated inflammatory reaction' (IBMIR). The gastric submucosal space (GSMS) offers potential advantages. Islets were isolated from adult pigs. Recipient pigs were made diabetic by streptozotocin. Donor islets were injected into the GSMS through a laparotomy (Group 1A, n = 4) or endoscopically (Group 1B, n = 8) or into the PV through a laparotomy (Group 2, n = 3). The pigs were followed for a maximum of 28 days. Monitoring of C-peptide in Group 1 indicated that there was minimal immediate loss of islets whereas in Group 2 there was considerable loss from IBMIR. In Group 1, there were significant reductions in mean blood glucose and mean exogenous insulin requirement between pretransplantation and 20 days posttransplantation. In Group 2, there was no significant reduction in either parameter. Insulin-positive cells were seen in the GSMS in Group 1, but not in the liver in Group 2. Endoscopic gastric submucosal transplantation of islets (ENDO-STI) offers a minimally invasive and quick approach to islet transplantation, avoids IBMIR and warrants further exploration.

Estudio comparativo de patología psiquiátrica en pacientes con traumatismos generales y traumatismo craneoencefálico / Comparative study of psychiatric disorders in general traumatism and brain injuried patients

Introducción. El presente estudio evalúa diferentes patologías psiquiátricas asociadas a lesiones de origen traumático; su frecuencia de presentación, y la forma como se correlacionan según se trate de un traumatismo craneoencefálico o de zonas diferentes al cráneo. Métodos. Se trata de un estudio de cohorte prospectiva con una muestra de 249 pacientes: 122 con traumatismo craneoencefálico y 127 con lesiones de otras zonas corporales. Se entrevistaron al ingreso en el centro, con seguimiento a los 6 y los 12 meses de la lesión. Resultados. La incidencia de depresión y trastornos de ansiedad fue similar a la obtenida en estudios previos, sin diferencia significativa entre los pacientes con traumatismos craneoencefálicos comparados con los traumatismos generales. En ambos grupo hubo un descenso significativo de la calidad de vida, así como un incremento en los problemas con el alcohol al año del traumatismo. Entre los lesionados cerebrales se detectó con mayor frecuencia el cambio orgánico de la personalidad con síntomas de apatía. Conclusiones. La incidencia de trastornos psiquiátricos en el paciente con lesiones traumáticas es alta y contribuye de forma importante a un deterioro en el estado de salud y la calidad de vida del enfermo. Los pacientes con lesiones cerebrales tienen mayor probabilidad de desarrollar un cambio orgánico de la personalidad

Introduction. This study evaluates the presentation of different psychiatric pathologies secondary to traumatic injuries; assessing the presentation frequency and how it correlates with whether it is a brain injury (TBI) or one in a different corporal area. Methods. The study group consisted of 249 patients, 122 with TBI and 127 with injuries from different body areas. The patients conditions were evaluated at baseline and at 6 and 12 months after the traumatic episode. Psychiatric diagnosis was made using a structured clinical interview and DSM-IV criteria. Results. Depressive and anxiety disorders were observed in frequencies similar to prevoius reports; without significant differences between TBI and non-TBI groups. The organic change of personality was significantly more frequent among patients with TBI than among the non-TBI with apathy features. There was a significant decrease in quality of life one year after the traumatism in both groups. Conclusions. Psychiatric disease is a frequent complication of injured patients; and it is associated with deterioration of general health and quality of life. TBI patients have more probability of developing an organic change of personality

[Comparative study of psychiatric disorders in general traumatism and brain injured patients]. / Estudio comparativo de patología psiquiátrica en pacientes con traumatismos generales y traumatismo craneoencefálico.

INTRODUCTION: This study evaluates the presentation of different psychiatric pathologies secondary to traumatic injuries; assessing the presentation frequency and how it correlates with whether it is a brain injury (TBI) or one in a different corporal area. METHODS: The study group consisted of 249 patients, 122 with TBI and 127 with injuries from different body areas. The patients conditions were evaluated at baseline and at 6 and 12 months after the traumatic episode. Psychiatric diagnosis was made using a structured clinical interview and DSM-IV criteria. RESULTS: Depressive and anxiety disorders were observed in frequencies similar to previous reports; without significant differences between TBI and non-TBI groups. The organic change of personality was significantly more frequent among patients with TBI than among the non-TBI with apathy features. There was a significant decrease in quality of life one year after the traumatism in both groups. CONCLUSIONS: Psychiatric disease is a frequent complication of injured patients; and it is associated with deterioration of general health and quality of life. TBI patients have more probability of developing an organic change of personality.

Defects of the retinal pigment epithelium in scleroderma.

We completed ocular examination, including retinal fluoroangiography, in 19 unselected patients with diffuse systemic sclerosis (scleroderma) and compared the findings with those made in 50 consecutive patients with systemic lupus erythematosus, 18 with primary Sjögren's syndrome, 20 with mixed connective tissue disease, and 20 healthy women. Five of 19 scleroderma patients had atrophy of the retinal pigment epithelium (26.3%) while none of the controls and only four of the 88 (4.5%) patients with other connective tissue diseases (P less than 0.01) had this anomaly. Atrophy of the pigmented epithelium of the retina may occur in scleroderma as a result of damage of the choroidal plexus.