Immunosuppression protocols for emerging oncological indications in liver transplantation: A systematic review and pooled analysis.

The evolving field of liver transplant (LT) oncology calls for tailored immunosuppression protocols to minimize the risk of tumor recurrence. We systematically reviewed the available evidence from inception to May 2023 regarding immunosuppression protocols used in patients undergoing LT for cholangiocarcinoma, neuroendocrine tumors (NET), hepatic-endothelial hemangioendothelioma, and colorectal liver metastases (CRLM) to identify common practices and to evaluate their association with oncological outcomes. Studies not involving humans, case reports, and short case series (ie, n < 10) were excluded. Among 3374 screened references, we included 117 studies involving 6797 patients distributed as follows: cholangiocarcinoma (58.1%), NETs (18.8%), hepatic-endothelial hemangioendothelioma (7.7%), CRLM (6.8%), mixed neoplasms (6.8%), or others (1.7%). Only 41% of the studies disclosed details of the immunosuppression protocol, and 20.8% of studies provided drug trough concentrations during follow-up. The immunosuppression protocols described were heterogeneous and broadly mirrored routine practices for nontumoral indications. The only exception was CRLM, where tacrolimus minimization-or even withdrawal-in combination with inhibitors of the mammalian target of rapamycin (mTORi) were consistently reported. None of the studies evaluated the relationship between the immunosuppression protocol and oncological outcomes. In conclusion, based on low-quality and indirect scientific evidence, patients with tumoral indications for LT should receive the lowest tacrolimus level tolerated under close surveillance. The combination with mTORi titrated to achieve the top therapeutic range of trough concentrations could allow complete tacrolimus withdrawal. This approach may be particularly useful in patients with cholangiocarcinoma and CRLM, in whom tumor recurrence is the main cause of death. We propose a tool for reporting immunosuppression protocols, which could be implemented in future transplant oncology studies.

Donor Atheromatous Disease is a Risk Factor for Hepatic Artery Thrombosis After Liver Transplantation.

The increasing age of liver donors and transplant candidates, together with the growing prevalence of metabolic comorbidities, could impact the risk of vascular complications after liver transplantation. We enrolled a consecutive cohort of adult patients undergoing liver transplantation from 2012 to 2021 who had a blinded pathological assessment of atherosclerosis in the donor and recipient hepatic arteries (HA). Patients receiving partial or reduced grafts, retransplantation, or combined organ transplantation were excluded. The relationship between HA atherosclerosis and HA thrombosis after liver transplantation was evaluated using logistic regression in the whole study cohort and in a propensity score-matched subpopulation. Among 443 eligible patients, 272 had a full pathological evaluation of the donor and recipient HA and were included in the study. HA atheroma was present in 51.5% of donors and in 11.4% of recipients. HA thrombosis occurred in 16 patients (5.9%), being more likely in patients who received a donor with HA atherosclerosis than in those without (10.7% vs. 0.8%; p < 0.001). Donor HA atherosclerosis was an independent risk factor of HA thrombosis (OR = 17.79; p = 0.008), and this finding was consistent in the propensity score-matched analysis according to age, sex, complex arterial anastomosis, and alcoholic liver disease (OR = 19.29; p = 0.007). Atheromatous disease in the recipient had no influence on the risk of HA thrombosis (OR = 1.70; p = 0.55). In conclusion, patients receiving donors with HA atherosclerosis are at increased risk for HA thrombosis after liver transplantation. The evaluation of the donor graft vasculature could guide antiplatelet therapy in the postoperative period.

Liver transplantation immunology: Immunosuppression, rejection, and immunomodulation.

Outcomes after liver transplantation have continuously improved over the past decades, but long-term survival rates are still lower than in the general population. The liver has distinct immunological functions linked to its unique anatomical configuration and to its harbouring of a large number of cells with fundamental immunological roles. The transplanted liver can modulate the immunological system of the recipient to promote tolerance, thus offering the potential for less aggressive immunosuppression. The selection and adjustment of immunosuppressive drugs should be individualised to optimally control alloreactivity while mitigating toxicities. Routine laboratory tests are not accurate enough to make a confident diagnosis of allograft rejection. Although several promising biomarkers are being investigated, none of them is sufficiently validated for routine use; hence, liver biopsy remains necessary to guide clinical decisions. Recently, there has been an exponential increase in the use of immune checkpoint inhibitors due to the unquestionable oncological benefits they provide for many patients with advanced-stage tumours. It is expected that their use will also increase in liver transplant recipients and that this might affect the incidence of allograft rejection. Currently, the evidence regarding the efficacy and safety of immune checkpoint inhibitors in liver transplant recipients is limited and cases of severe allograft rejection have been reported. In this review, we discuss the clinical relevance of alloimmune disease, the role of minimisation/withdrawal of immunosuppression, and provide practical guidance for using checkpoint inhibitors in liver transplant recipients.

Enumeration and Characterization of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma Undergoing Transarterial Chemoembolization.

Circulating tumor cells (CTCs), and particularly circulating cancer stem cells (cCSC), are prognostic biomarkers for different malignancies and may be detected using liquid biopsies. The ex vivo culture of cCSCs would provide valuable information regarding biological aggressiveness and would allow monitoring the adaptive changes acquired by the tumor in real time. In this prospective pilot study, we analyzed the presence of EpCAM+ CTCs using the IsoFlux system in the peripheral blood of 37 patients with hepatocellular carcinoma undergoing transarterial chemoembolization (TACE). The average patient age was 63.5 ± 7.9 years and 91.9% of the patients were men. All patients had detectable CTCs at baseline and 20 patients (54.1%) showed CTC aggregates or clusters in their peripheral blood. The increased total tumor diameter (OR: 2.5 (95% CI: 1.3-4.8), p = 0.006) and the absence of clusters of CTCs at baseline (OR: 0.2 (95% CI: 0.0-1.0), p = 0.049) were independent predictors of a diminished response to TACE. Culture of cCSC was successful in five out of thirty-three patients, mostly using negative enrichment of CD45- cells, ultra-low adherence, high glucose, and a short period of hypoxia followed by normoxia. In conclusion, the identification of clusters of CTCs before TACE and the implementation of standardized approaches for cCSC culture could aid to predict outcomes and to define the optimal adjuvant therapeutic strategy for a true personalized medicine in hepatocellular carcinoma.

Development of a Prediction Model for Short-Term Remission of Patients with Crohn's Disease Treated with Anti-TNF Drugs.

Therapy with anti-tumor necrosis factor (TNF) has dramatically changed the natural history of Crohn's disease (CD). However, these drugs are not without adverse events, and up to 40% of patients could lose efficacy in the long term. We aimed to identify reliable markers of response to anti-TNF drugs in patients with CD. A consecutive cohort of 113 anti-TNF naive patients with CD was stratified according to clinical response as short-term remission (STR) or non-STR (NSTR) at 12 weeks of treatment. We compared the protein expression profiles of plasma samples in a subset of patients from both groups prior to anti-TNF therapy by SWATH proteomics. We identified 18 differentially expressed proteins (p ≤ 0.01, fold change ≥ 2.4) involved in the organization of the cytoskeleton and cell junction, hemostasis/platelet function, carbohydrate metabolism, and immune response as candidate biomarkers of STR. Among them, vinculin was one of the most deregulated proteins (p < 0.001), whose differential expression was confirmed by ELISA (p = 0.054). In the multivariate analysis, plasma vinculin levels along with basal CD Activity Index, corticosteroids induction, and bowel resection were factors predicting NSTR.

Identification of candidate biomarkers for hepatocellular carcinoma in plasma of HCV-infected cirrhotic patients by 2-D DIGE.

BACKGROUND: The current methods available for screening and detecting hepatocellular carcinoma (HCC) have insufficient sensitivity and specificity, and only a low percentage of diagnosis of small tumours is based on these assays. Because HCC is usually asymptomatic at potentially curative stages, identification of biomarkers for the early detection of HCC is essential to improve patient survival. AIM: The aim of this study was to identify candidate markers for HCC development in the plasma from hepatitis C virus (HCV)-infected cirrhotic patients. METHODS: We compared protein expression profiles of plasma samples from HCV-infected cirrhotic patients with and without HCC, using two-dimensional fluorescence difference gel electrophoresis (2-D DIGE) coupled with MALDI-TOF/TOF mass spectrometry. The 2-D DIGE results were analysed statistically using Decyder™ software, and verified by western blot and enzyme-linked immunosorbent assay (ELISA). RESULTS: In the plasma of HCV-infected HCC patients, we observed decreased expression of complement component 9, ficolin-3 (FCN3), serum amyloid P component (SAP), fibrinogen-gamma and immunoglobulin gamma-1 chain, and increased expression of vitronectin (VTN) and galectin-3 binding protein (G3BP) by DIGE analysis. ELISA confirmed DIGE results for VTN and G3BP but not for SAP or FCN3 in a larger patient population. CONCLUSIONS: The proteins VTN and SAP are candidate biomarkers for HCC development in HCV-infected cirrhotic patients.

Transarterial embolization as neo-adjuvant therapy pretransplantation in patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Neo-adjuvant transarterial therapies are commonly used for patients with HCC in the waiting list for liver transplantation (LT) to delay tumour progression, however, their effectiveness is not well-established. We studied the effect of pre-LT transarterial therapies on post-LT HCC recurrence, using the explanted liver histology to assess therapeutic efficacy and the predictors of response to these therapies. METHODS: We included 150 consecutive patients from our prospectively compiled database, listed for liver transplantation using the Milan criteria. Transarterial embolization without chemotherapeutic agents was the transarterial therapy used as standard of care. PVA particles were the embolizing agent of choice. RESULTS: Sixty-seven (45%) patients had TAE as bridging therapy to liver transplantation, of which 60 were transplanted after 2001. The majority of patients (36, 54%) had partial tumour necrosis after transarterial therapy, whereas 22 (33%) had complete tumour necrosis and 9 (13%) had no necrosis. HCC post-transplant recurrence was independently associated with no neo-adjuvant transarterial therapy (OR 5.395, 95% CI 1.289-22.577; P = 0.021) and the total radiological size of HCC nodules (OR 1.037, 95% CI 1.006-1.069; P = 0.020). CONCLUSIONS: Pre-transplant TAE with the more permanently occluding PVA particles significantly reduces post-transplant HCC recurrence in patients within the Milan criteria.

De Novo Malignancy After Liver Transplantation: Risk Assessment, Prevention, and Management-Guidelines From the ILTS-SETH Consensus Conference.

De novo malignancies (DNMs) following liver transplantation (LT) have been reported as 1 of the major causes of late mortality, being the most common cause of death in the second decade after LT. The overall incidence of DNMs is reported to be in the range of 3.1% to 14.4%, and the incidence is 2- to 3-fold higher in transplant recipients than in age- and sex-matched healthy controls. Long-term immunosuppressive therapy, which is the key in maintaining host tolerance and achieving good long-term outcomes, is known to contribute to a higher risk of DNMs. However, the incidence and type of DNM also depends on different risk factors, including patient demographics, cause of the underlying chronic liver disease, behavior (smoking and alcohol abuse), and pre-existing premalignant conditions. The estimated standardized incidence ratio for different DNMs is also variable. The International Liver Transplantation Society-Spanish Society of Liver Transplantation Consensus Conference working group on DNM has summarized and discussed the current available literature on epidemiology, risk factors, management, and survival after DNMs. Recommendations for screening and surveillance for specific tumors, as well as immunosuppression and cancer-specific management in patients with DNM, are summarized.

Post-colonoscopy colorectal cancer: Characteristics and predictive factors. / Cáncer colorrectal poscolonoscopia: características y factores predictivos.

INTRODUCTION AND AIMS: A high quality colonoscopy is key in preventing colorectal cancer, but the risk of colorectal cancer (CRC) exists. The aims of the study were to investigate the incidence, characteristics and predictive factors of post-colonoscopy colorectal cancer (PCCRC). MATERIAL AND METHOD: A retrospective and prospective observational study was designed. A population undergoing colonoscopy between 1-01-1997 and 31-12-2014 was included. We analysed demographic variables, characteristics of the diagnostic colonoscopy of CRC, of the previous ones and the lesions found in them. To compare the PCCRC group versus the CRC group without previous colonoscopy, the Student's t-test and multiple logistic regression were used to determine predictive factors of PCCRC (SPSS® 15). The statistical significance was P<.05. RESULTS: A total of 56,984 colonoscopies, 1,977 CRC and 132 patients (mean 70.8 years old, 56.8% male) with at least one colonoscopy in 10 years before were registered (PCCRC). Seventy and a half percent of the previous colonoscopies were completed and 63.7% had an adequate bowel preparation. Predictive factors of PCCRC were personal history of polyps (OR 35.01; 95% CI 11.1-110.8; P<.001), previous CRC (OR 176.64; 95% CI 51.5-606.1); P<.001), family history of CRC (OR 3.14; 95% CI 1.5-6.4); P=.002) and proximal CRC (OR 3.15; 95% CI 2.1-4.9; P<.001). CONCLUSIONS: PCCRC rate in 10 years was 6.7%. An adequate follow-up and a high-quality colonoscopy could prevent PCCRC, especially in patients with risk factors.

Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients: A Guidance Report and Clinical Checklist by the Consensus on Managing Modifiable Risk in Transplantation (COMMIT) Group.

Short-term patient and graft outcomes continue to improve after kidney and liver transplantation, with 1-year survival rates over 80%; however, improving longer-term outcomes remains a challenge. Improving the function of grafts and health of recipients would not only enhance quality and length of life, but would also reduce the need for retransplantation, and thus increase the number of organs available for transplant. The clinical transplant community needs to identify and manage those patient modifiable factors, to decrease the risk of graft failure, and improve longer-term outcomes.COMMIT was formed in 2015 and is composed of 20 leading kidney and liver transplant specialists from 9 countries across Europe. The group's remit is to provide expert guidance for the long-term management of kidney and liver transplant patients, with the aim of improving outcomes by minimizing modifiable risks associated with poor graft and patient survival posttransplant.The objective of this supplement is to provide specific, practical recommendations, through the discussion of current evidence and best practice, for the management of modifiable risks in those kidney and liver transplant patients who have survived the first postoperative year. In addition, the provision of a checklist increases the clinical utility and accessibility of these recommendations, by offering a systematic and efficient way to implement screening and monitoring of modifiable risks in the clinical setting.

Cáncer colorrectal poscolonoscopia: características y factores predictivos / Post-colonoscopy colorectal cancer: Characteristics and predictive factors

Introducción y objetivos: La calidad de la colonoscopia es clave para asegurar la prevención del adenocarcinoma colorrectal (ACCR), aunque el riesgo de ACCR existe. Los objetivos del estudio fueron investigar la incidencia, las características y los factores predictores de ACCR poscolonoscopia (ACCRPC). Material y método: Estudio observacional retrospectivo y prospectivo sobre una población sometida a colonoscopia entre 1-01-1997 y 31-12-2014. Se analizaron variables demográficas, características de la colonoscopia diagnóstica de ACCR, de las previas y de las lesiones encontradas en ellas. Se aplicaron test de contraste de hipótesis para comparar el grupo de ACCRPC con el de ACCR sin colonoscopia previa y regresión logística múltiple para identificar factores independientes de ACCRPC (SPSS® 15), considerando significación estadística una p<0,05. Resultados: Se registraron 56.984 colonoscopias, 1.977 ACCR y 132 pacientes (edad media de 70,8 años y 56,8% varones) con al menos una colonoscopia en los 10 años previos (ACCRPC). El 70,5% de las colonoscopias previas fueron completas y el 63,7% tenían una preparación adecuada. Los factores de riesgo independientes relacionados con la aparición de ACCRPC fueron los antecedentes personales de pólipos colónicos (OR 35,01; IC 95% 11,1-110,8; p<0,001), antecedentes personales de ACCR (OR 176,64; IC 95% 51,5-606,1); p<0,001), antecedentes familiares de ACCR (OR 3,14; IC 95% 1,5-6,4); p=0,002) y la localización del ACCR en el colon derecho (OR 3,15; IC 95% 2,1-4,9; p<0,001). Conclusiones: La tasa de ACCRPC a 10 años fue del 6,7%. Realizar un adecuado seguimiento y una colonoscopia de calidad puede evitar la aparición del ACCRPC, especialmente en los pacientes con factores de riesgo (AU)

Introduction and aims: A high quality colonoscopy is key in preventing colorectal cancer, but the risk of colorectal cancer (CRC) exists. The aims of the study were to investigate the incidence, characteristics and predictive factors of post-colonoscopy colorectal cancer (PCCRC). Material and method: A retrospective and prospective observational study was designed. A population undergoing colonoscopy between 1-01-1997 and 31-12-2014 was included. We analysed demographic variables, characteristics of the diagnostic colonoscopy of CRC, of the previous ones and the lesions found in them. To compare the PCCRC group versus the CRC group without previous colonoscopy, the Student's t-test and multiple logistic regression were used to determine predictive factors of PCCRC (SPSS® 15). The statistical significance was P<.05. Results: A total of 56,984 colonoscopies, 1,977 CRC and 132 patients (mean 70.8 years old, 56.8% male) with at least one colonoscopy in 10 years before were registered (PCCRC). Seventy and a half percent of the previous colonoscopies were completed and 63.7% had an adequate bowel preparation. Predictive factors of PCCRC were personal history of polyps (OR 35.01; 95% CI 11.1-110.8; P<.001), previous CRC (OR 176.64; 95% CI 51.5-606.1); P<.001), family history of CRC (OR 3.14; 95% CI 1.5-6.4); P=.002) and proximal CRC (OR 3.15; 95% CI 2.1-4.9; P<.001). Conclusions: PCCRC rate in 10 years was 6.7%. An adequate follow-up and a high-quality colonoscopy could prevent PCCRC, especially in patients with risk factors (AU)