The role of living donor liver transplantation in treating intrahepatic cholangiocarcinoma.

Introduction: Intrahepatic cholangiocarcinoma (iCC) is the liver's second most common neoplasm. Until now, surgery is the only curative option, but only 35% of the cases are considered resectable at the diagnosis, with a post-resection survival of around 30%. Advancements in surgical techniques and perioperative care related to liver transplantation (LT) have facilitated the expansion of indications for hepatic neoplasms. Method: This study is a comprehensive review of the global experience in living donor LT (LDLT) for treating iCC and describes our first case of LDLT for an unresectable iCC. Results: While exploring LT for intrahepatic cholangiocarcinoma dates to the 1990s, the initial outcomes were discouraging, marked by poor survival and high recurrence rates. Nevertheless, contemporary perspectives underscore a reinvigorated emphasis on extending the frontiers of LT indications within the context of the "oncologic era." The insights gleaned from examining explants, wherein incidental iCC was categorized as hepatocellular carcinoma in the preoperative period, have demonstrated comparable survival rates to small hepatocellular carcinoma. These findings substantiate the potential viability of LT as a curative alternative for iCC. Another investigated scenario pertains to "unresectable tumors with favorable biological behavior," LT presents a theoretical advantage by providing free margins without the concern of a small future liver remnant. The constraint of organ shortage persists, particularly in nations with low donation rates. LDLT emerges as a viable and secure alternative for treating iCC. Conclusion: LDLT is an excellent option for augmenting the graft pool, particularly in carefully selected patients.

Liver transplantation as an alternative for the treatment of perihilar cholangiocarcinoma: A critical review.

BACKGROUND: Perihilar cholangiocarcinoma (phCCC) is a dismal malignancy. There is no consensus regarding the best treatment for patients with unresectable phCCC. The present review aimed to gather the current pieces of evidence for liver transplantation and liver resection as a treatment for phCCC and to build better guidance for clinical practice. DATA SOURCES: The search was conducted in PubMed, Embase, Cochrane, and LILACS. The related references were searched manually. Inclusion criteria were: reports in English or Portuguese literature that a) patients with confirmed diagnosis of phCCC; b) patients treated with a curative intent; c) patients with the outcomes of liver resection and liver transplantation. Case reports, reviews, letters, editorials, conference abstracts and papers with full-text unavailability were excluded from the analysis. RESULTS: Most of the current literature is based on observational retrospective studies with low grades of evidence. Liver resection has better long-term outcomes than systemic chemotherapy or palliation therapy and liver transplantation is a good alternative for selected patients with unresectable phCCC. All candidates for resection or transplantation should be medically fit and free of intrahepatic or extrahepatic diseases. As a general rule, patients presenting with a tumor having a longitudinal size > 3 cm or extending below the cystic duct, lymph node disease, confirmed extrahepatic dissemination; intraoperatively diagnosed metastatic disease; a history of other malignancies within the last five years, and did not complete chemoradiation regimen and were medically unfit should not be considered for transplantation. Some of these criteria should be individually assessed. Liver transplantation or resection should only be considered in highly experienced hepatobiliary centers, and any decision-making must be based on a multidisciplinary evaluation. CONCLUSIONS: phCCC is a complex condition with high morbidity. Surgical therapies, including hepatectomy and liver transplantation, are the best option for better long-term disease-free survival.

Immunomodulatory response in an experimental model of brain death.

Liver transplantation has come a long way and is now regarded as the gold standard treatment for end-stage liver failure. The great majority of livers utilized in transplantation come from brain-dead donors. A broad inflammatory response characterizes BD, resulting in multiorgan damage. This process is primarily mediated by cytokines, which increase the immunogenicity of the graft. In male Lewis rats, we evaluated the immune response in a BD liver donor and compared it to that of a control group. We studied two groups: Control and BD (rats subjected to BD by increasing intracranial pressure). After the induction of BD, there was an intense rise in blood pressure followed by a fall. There were no significant differences observed between the groups. Blood tissue and hepatic tissue analyzes showed an increase in plasma concentrations of liver enzymes (AST, ALT, LDH and ALP), in addition to pro-inflammatory cytokines and macrophages in liver tissue in animals submitted to BD. The current study found that BD is a multifaceted process that elicits both a systemic immune response and a local inflammatory response in liver tissue. Our findings strongly suggested that the immunogenicity of plasma and liver increased with time following BD.

Thalidomide modulates renal inflammation induced by brain death experimental model.

BACKGROUND: Brain death (BD) is characterized by a complex inflammatory response, resulting in dysfunction of potentially transplantable organs. This process is modulated by cytokines, which amplify graft immunogenicity. We have investigated the inflammatory response in an animal model of BD and analyzed the effects of thalidomide, a drug with powerful immunomodulatory properties. METHODS: BD was induced in male Lewis rats. We studied three groups: Control (sham-operated rats) (n = 6), BD (rats subjected to brain death) (n = 6) and BD + Thalid (BD rats treated with one dose of thalidomide (200 mg/Kg), administered by gavage) (n = 6). Six hours after BD, serum levels of urea and creatinine, as well as systemic and renal tissue protein levels of TNF-α and IL-6, were analyzed. We also determined the mRNA expression of ET-1, and macrophage infiltration by immunohistochemistry. RESULTS: BD induced a striking inflammatory status, demonstrated by a significant increase of plasma cytokines: TNF-α (2.8 ± 4.3 pg/mL [BD] vs. 9.4 ± 2.8 pg/mL [Control]), and IL-6 (6219.5 ± 1380.6 pg/mL [BD] vs. 1854.7 ± 822.6 pg/mL [Control]), and in the renal tissue: TNF-α (2.5 ± 0.3 relative expression [BD] vs. 1.0 ± 0.4 relative expression [Control]; p < 0.05), and IL-6 (4.0 ± 0.4 relative expression [BD] vs. 1.0 ± 0.3 relative expression [Control]; p < 0.05). Moreover, BD increased macrophages infiltration (2.47 ± 0.07 cells/field [BD] vs. 1.20 ± 0.05 cells/field [Control]; p < 0.05), and ET-1 gene expression (2.5 ± 0.3 relative expression [BD] vs. 1.0 ± 0.2 relative expression [Control]; p < 0.05). In addition, we have observed deterioration in renal function, characterized by an increase of urea (194.7 ± 25.0 mg/dL [BD] vs. 108.0 ± 14.2 mg/dL [Control]; p < 0.05) and creatinine (1.4 ± 0.04 mg/dL [BD] vs. 1.0 ± 0.07 mg/dL [Control]; p < 0.05) levels. Thalidomide administration significantly reduced plasma cytokines: TNF-α (5.1 ± 1.4 pg/mL [BD + Thalid] vs. BD; p < 0.05), and IL-6 (1056.5 ± 488.3 pg/mL [BD + Thalid] vs. BD; p < 0.05), as well as in the renal tissue: TNF-α (1.5 ± 0.2 relative expression [BD + Thalid] vs. BD; p < 0.05), and IL-6 (2.1 ± 0.3 relative expression [BD + Thalid] vs. BD; p < 0.05). Thalidomide treatment also induced a significant decrease in the expression of ET-1 (1.4 ± 0.3 relative expression [BD + Thalid] vs. BD; p < 0.05), and macrophages infiltration (1.17 ± 0.06 cells/field [BD + Thalid] vs. BD; p < 0.05). Also thalidomide prevented kidney function failure by reduced urea (148.3 ± 4.4 mg/dL [BD + Thalid] vs. BD; p < 0.05), and creatinine (1.1 ± 0.14 mg/dL [BD + Thalid] vs. BD; p < 0.05). CONCLUSIONS: The immunomodulatory properties of thalidomide were effective in decreasing systemic and local immunologic response, leading to diminished renal damage, as reflected in the decrease of urea and creatinine levels. These results suggest that use of thalidomide may represent a potential strategy for treating in BD kidney organ donors.

Immunomodulatory effects of thalidomide in an experimental brain death liver donor model.

Brain death is characterized by a generalized inflammatory response that results in multiorgan damage. This process is mainly mediated through cytokines, which amplify graft immunogenicity. We investigated the immunological response in a brain death liver donor model and analysed the effects of thalidomide, a drug with powerful immunomodulatory properties. Brain death was induced in male Lewis rats. We studied three groups: Control (sham-operated rats in which trepanation was performed without inserting the balloon catheter), BD (rats subjected to brain death by increasing intracranial pressure) and BD + Thalid (BD rats receiving thalidomide after brain death). After 6 h, serum levels of AST, ALT, LDH, and ALP as well as systemic and hepatic levels of TNF-α, IL1-ß, IL-6, and IL-10 were analysed. We also determined the mRNA expression of MHC Class I and Class II, NF-κB, and macrophage infiltration. NF-κB was also examined by electrophoretic mobility shift assay. Thalidomide treatment significantly reduced serum levels of hepatic enzymes and TNF-α, IL-1-ß, and IL-6. These cytokines were evaluated at either the mRNA expression or protein level in liver tissue. In addition, thalidomide administration resulted in a significant reduction in macrophages, MHC Class I and Class II, and NF-κB activation. This study reveals that thalidomide significantly inhibited the immunologic response and graft immunogenicity, possibly through suppression of NF-κB activation.

Indoleamine 2, 3-dioxygenase (IDO) increases during renal fibrogenesis and its inhibition potentiates TGF-ß 1-induced epithelial to mesenchymal transition.

BACKGROUND: Indoleamine 2, 3-dioxygenase (IDO) is an immunomodulatory molecule that has been implicated in several biological processes. Although IDO has been linked with some renal diseases, its role in renal fibrosis is still unclear. Because IDO may be modulated by TGF-ß1, a potent fibrogenic molecule, we hypothesized that IDO could be involved in renal fibrosis, especially acting in the TGF-ß1-induced tubular epithelial-mesenchymal transition (EMT). We analyzed the IDO expression and activity in a model of renal fibrogenesis, and the effect of the IDO inhibitor 1-methyl-tryptophan (MT) on TGF-ß1-induced EMT using tubular cell culture. METHODS: Male Wistar rats where submited to 7 days of UUO. Non-obstructed kidneys (CL) and kidneys from SHAM rats were used as controls. Masson's Tricrome and macrophages counting were used to chatacterize the tissue fibrosis. The EMT was analysed though immunohistochemistry and qRT-PCR. Immunohistochemestry in tissue has used to show IDO expression. MDCK cells were incubated with TGF- ß1 to analyse IDO expression. Additionally, effects of TGF- ß1 and the inhibition of IDO over the EMT process was acessed by immunoessays and scrath wound essay. RESULTS: IDO was markedly expressed in cortical and medular tubules of the UUO kidneys. Similarly to the immunolocalizaton of TGF- ß1, accompanied by loss of e-cadherin expression and an increase of mesenchymal markers. Results in vitro with MDCK cells, showed that IDO was increased after stimulus with TGF-ß1, and treatment with MT potentiated its expression. MDCK stimulated with TGF-ß1 had higher migratory activity (scratch-wound assay), which was exacerbated by MT treatment. CONCLUSIONS: IDO is constitutively expressed in tubular cells and increases during renal fibrogenesis. Although IDO is induced by TGF-ß1 in tubular cells, its chemical inhibitor acts as a profibrotic agent.