Utilization of Immunotherapy as a Neoadjuvant Therapy for Liver Transplant Recipients with Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is widely recognized as the predominant type of primary liver malignancy. Orthotopic liver transplantation (OLT) has emerged as a highly effective treatment option for unresectable HCC. Immunotherapies as neoadjuvant options are now being actively investigated in the transplant oncology era to enhance outcomes in patients with HCC. Here, we report our experience with patients with HCC who had received Immune Checkpoint Inhibitors (ICPI) prior to curative OLT. Methods: This was a retrospective cohort that included patients with HCC who received ICPI prior to OLT at a single institution from January 2019 to August 2023. Graft rejection was assessed and reported along with the type of ICPI, malignancy treated, and the timing of ICPI in association with OLT. Results: During this cohort period, six patients with HCC underwent OLT after neoadjuvant ICPI. All patients were male with a median age of 61 (interquartile range: 59-64) years at OLT. Etiology associated with HCC was viral (N = 4) or Non-alcoholic steatohepatitis, NASH (N = 2). Tumor focality was multifocal (N = 4) and unifocal (N = 2). Lymphovascular invasion was identified in four patients. No perineural invasion was identified in any of the patients. All patients received ICPI including atezolizumab/bevacizumab (N = 4), nivolumab/ipilimumab (N = 1), and nivolumab as monotherapy (N = 1). All patients received either single or combined liver-directed/locoregional therapy, including transarterial chemoembolization (TACE), Yttrium-90 (Y90), stereotactic body radiotherapy (SBRT), and radiofrequency ablation (RFA). The median washout period was 5 months. All patients responded to ICPI and achieved a safe and successful OLT. All patients received tacrolimus plus mycophenolate as immunosuppressant (IS) therapy post-OLT and one patient received prednisone as additional IS. No patient had clinical evidence of rejection. Conclusions: This cohort emphasizes the success of tumor downstaging by ICPI for OLT when employed as the neoadjuvant therapy strategy. In addition, this study illustrated the importance of timing for the administration of ICPI before OLT. Given the lack of conclusive evidence in this therapeutic area, we believe that our study lays the groundwork for prospective trials to further examine the impact of ICPI prior to OLT.

Macrophage niche imprinting as a determinant of macrophage identity and function.

Macrophage niches are the anatomical locations within organs or tissues consisting of various cells, intercellular and extracellular matrix, transcription factors, and signaling molecules that interact to influence macrophage self-maintenance, phenotype, and behavior. The niche, besides physically supporting macrophages, imposes a tissue- and organ-specific identity on the residing and infiltrating monocytes and macrophages. In this review, we give examples of macrophage niches and the modes of communication between macrophages and surrounding cells. We also describe how macrophages, acting against their immune defensive nature, can create a hospitable niche for pathogens and cancer cells.

Gadolinium retention effect on macrophages - a potential cause of MRI contrast agent Dotarem toxicity.

Gadolinium is a component of the MRI contrast agent Dotarem. Although Dotarem is the least toxic among MRI contrasts used, gadolinium present in Dotarem accumulates for many years in various organs and tissues exerting toxic effects. We showed previously that gadolinium remains in macrophages for at least 7 days after exposure to Dotarem. However, very little is known about the effect of gadolinium retention on the immune cells such as macrophages. We studied the effect of 1-day and 7-day retention of gadolinium on various functions and molecular pathways of macrophages. Gadolinium retention for 7 days decreased macrophage adhesion and motility and dysregulated the expression of adhesion and fibrotic pathway-related proteins such as Notch1 and its ligand Jagged1, adhesion/migration-related proteins PAK1 and Shp1, immune response-related transcription factors Smad3 and TCF19, and chemokines CXCL10 and CXCL13, and dysregulated the mRNA expression of fibrosis-related genes involved in extracellular matrix (ECM) synthesis, such as Col6a1, Fibronectin, MMP9, and MMP12. It also completely (below a level of detection) shut down the transcription of anti-inflammatory M2 macrophage polarization marker the Arg-1. Such changes, if they occur in MRI patients, can be potentially detrimental to the patient's immune system and immune response-related processes.

Invertebrate Immunity, Natural Transplantation Immunity, Somatic and Germ Cell Parasitism, and Transposon Defense.

While the vertebrate immune system consists of innate and adaptive branches, invertebrates only have innate immunity. This feature makes them an ideal model system for studying the cellular and molecular mechanisms of innate immunity sensu stricto without reciprocal interferences from adaptive immunity. Although invertebrate immunity is evolutionarily older and a precursor of vertebrate immunity, it is far from simple. Despite lacking lymphocytes and functional immunoglobulin, the invertebrate immune system has many sophisticated mechanisms and features, such as long-term immune memory, which, for decades, have been exclusively attributed to adaptive immunity. In this review, we describe the cellular and molecular aspects of invertebrate immunity, including the epigenetic foundation of innate memory, the transgenerational inheritance of immunity, genetic immunity against invading transposons, the mechanisms of self-recognition, natural transplantation, and germ/somatic cell parasitism.

CD4+ T cell immunity is dependent on an intrinsic stem-like program.

CD4+ T cells are central to various immune responses, but the molecular programs that drive and maintain CD4+ T cell immunity are not entirely clear. Here we identify a stem-like program that governs the CD4+ T cell response in transplantation models. Single-cell-transcriptomic analysis revealed that naive alloantigen-specific CD4+ T cells develop into TCF1hi effector precursor (TEP) cells and TCF1-CXCR6+ effectors in transplant recipients. The TCF1-CXCR6+CD4+ effectors lose proliferation capacity and do not reject allografts upon adoptive transfer into secondary hosts. By contrast, the TCF1hiCD4+ TEP cells have dual features of self-renewal and effector differentiation potential, and allograft rejection depends on continuous replenishment of TCF1-CXCR6+ effectors from TCF1hiCD4+ TEP cells. Mechanistically, TCF1 sustains the CD4+ TEP cell population, whereas the transcription factor IRF4 and the glycolytic enzyme LDHA govern the effector differentiation potential of CD4+ TEP cells. Deletion of IRF4 or LDHA in T cells induces transplant acceptance. These findings unravel a stem-like program that controls the self-renewal capacity and effector differentiation potential of CD4+ TEP cells and have implications for T cell-related immunotherapies.

Transplant Oncology: An Emerging Discipline of Cancer Treatment.

Transplant oncology is an emerging concept of cancer treatment with a promising prospective outcome. The applications of oncology, transplant medicine, and surgery are the core of transplant oncology to improve patients' survival and quality of life. The main concept of transplant oncology is to radically cure cancer by removing the diseased organ and replacing it with a healthy one, aiming to improve the survival outcomes and quality of life of cancer patients. Subsequently, it seeks to expand the treatment options and research for hepatobiliary malignancies, which have seen significantly improved survival outcomes after the implementation of liver transplantation (LT). In the case of colorectal cancer (CRC) in the transplant setting, where the liver is the most common site of metastasis of patients who are considered to have unresectable disease, initial studies have shown improved survival for LT treatment compared to palliative therapy interventions. The indications of LT for hepatobiliary malignancies have been slowly expanded over the years beyond Milan criteria in a stepwise manner. However, the outcome improvements and overall patient survival are limited to the specifics of the setting and systematic intervention options. This review aims to illustrate the representative concepts and history of transplant oncology as an emerging discipline for the management of hepatobiliary malignancies, in addition to other emerging concepts, such as the uses of immunotherapy in a peri-transplant setting as well as the use of circulating tumor DNA (ctDNA) for surveillance post-transplantation.

Macrophages and stem/progenitor cells interplay in adipose tissue and skeletal muscle: a review.

Like all immune cells, macrophages do not act autonomously but in unison with other immune cells, surrounding tissues, and the niche they occupy. Constant exchange of information between cellular and noncellular participants within a tissue allows for preserving homeostasis and defining responses in a pathologic environment. Although molecular mechanisms and pathways involved in reciprocal signaling between macrophages and other immune cells have been known for decades, much less is known about interactions between macrophages and stem/progenitor cells. Based on the time when stem cells form, there are two stem cell types: embryonic stem cells existing only in an early embryo, which are pluripotent and can differentiate into any cell type present in an adult, and somatic (adult) stem cells formed in fetus and persisting for whole adult life. Tissues and organs have their own (tissue-specific and organ-specific) adult stem cells, which serve as a reserve for tissue homeostasis and regeneration after injury. It is still uncertain whether organ- and tissue-specific stem cells are actual stem cells or just progenitor cells. The important question is how stem/progenitor cells can sculpt macrophage phenotype and functions. Even less is known if or how macrophages can shape stem/progenitor cell functions, their divisions, and fate. We describe here examples from recent studies of how stem/progenitor cells can affect macrophages and how macrophages can influence stem/progenitor cell properties, functions, and destiny.

Progress in Combined Liver-lung Transplantation at a Single Center.

Combined liver-lung transplantation is an uncommon, although vital, procedure for patients with simultaneous end-stage lung and liver disease. The utility of lung-liver transplant has been questioned because of initial poor survival outcomes, particularly when compared with liver-alone transplant recipients. Methods: A single-center, retrospective review of the medical records of 19 adult lung-liver transplant recipients was conducted, comparing early recipients (2009-2014) with a recent cohort (2015-2021). Patients were also compared with the center's single lung or liver transplant recipients. Results: Recent lung-liver recipients were older (P = 0.004), had a higher body mass index (P = 0.03), and were less likely to have ascites (P = 0.02), reflecting changes in the etiologies of lung and liver disease. Liver cold ischemia time was longer in the modern cohort (P = 0.004), and patients had a longer posttransplant length of hospitalization (P = 0.048). Overall survival was not statistically different between the 2 eras studied (P = 0.61), although 1-y survival was higher in the more recent group (90.9% versus 62.5%). Overall survival after lung-liver transplant was equivalent to lung-alone recipients and was significantly lower than liver-alone recipients (5-y survival: 52%, 51%, and 75%, respectively). Lung-liver recipient mortality was primarily driven by deaths within 6 mo of transplant due to infection and sepsis. Graft failure was not significantly different (liver: P = 0.06; lung: P = 0.74). Conclusions: The severity of illness in lung-liver recipients combined with the infrequency of the procedure supports its continued use. However, particular attention should be paid to patient selection, immunosuppression, and prophylaxis against infection to ensure proper utilization of scarce donor organs.

Comparative transcriptome profile of mouse macrophages treated with the RhoA/Rock pathway inhibitors Y27632, Fingolimod (Gilenya), and Rezurock (Belumosudil, SLx-2119).

Macrophages play a crucial role in, the currently uncurable, chronic rejection of transplants. In rodent transplantation models, inhibition of the RhoA/Rock pathway disrupts actin-related functions of macrophages, preventing them from entering the graft, and reducing vessel occlusion, fibrosis, and chronic rejection. Among RhoA/Rock inhibitors that inhibit chronic rejection in mouse transplantation are Y27632, Fingolimod, and Rezurock. In a mouse model, Rezurok is more effective in preventing fibrosis and less effective in preventing vessel occlusion than Y27632 or Fingolimod. Fingolimod is FDA-approved for treating multiple sclerosis (MS) and Rezurock for chronic graft versus host disease (GVHD). Still, none had been tested for chronic rejection in humans. To explain the differences in the anti-chronic rejection properties of Y27632, Fingolimod, and Rezurock, we compared the transcriptome profile of mouse macrophages treated with these compounds separately. Treatment with Y27632 or Fingolimod downregulated GTPase and actin pathways involved in cell migration. Rezurock downregulated genes related to fibrosis, such as PTX3, CCR2, CCL2, cell cycle, DNA replication, adaptive immune response, and organelle assembly, while Fingolimod also specifically downregulated NOTCH1 at mRNA . The result of this study not only uncovers which pathways are shared or specific for these drugs but will help in the development of macrophage pathway-targeted therapies in human transplantation, MS, and GVHD. Because macrophages are the major players in immune response, tissue regeneration, renewal, and homeostasis, and development of many diseases, including cancer, the data compiled here will help in designing novel or improved therapies in many clinical applications.

Immune Checkpoint Inhibitors for Solid Tumors in the Adjuvant Setting: Current Progress, Future Directions, and Role in Transplant Oncology.

The rationale for administering immune checkpoint inhibitors (ICIs) in the adjuvant setting is to eradicate micro-metastases and, ultimately, prolong survival. Thus far, clinical trials have demonstrated that 1-year adjuvant courses of ICIs reduce the risk of recurrence in melanoma, urothelial cancer, renal cell carcinoma, non-small cell lung cancer, and esophageal and gastroesophageal junction cancers. Overall survival benefit has been shown in melanoma while survival data are still not mature in other malignancies. Emerging data also show the feasibility of utilizing ICIs in the peri-transplant setting for hepatobiliary malignancies. While ICIs are generally well-tolerated, the development of chronic immune-related adverse events, typically endocrinopathies or neurotoxicities, as well as delayed immune-related adverse events, warrants further scrutiny regarding the optimal duration of adjuvant therapy and requires a thorough risk-benefit determination. The advent of blood-based, dynamic biomarkers such as circulating tumor DNA (ctDNA) can help detect minimal residual disease and identify the subset of patients who would likely benefit from adjuvant treatment. In addition, the characterization of tumor-infiltrating lymphocytes, neutrophil-to-lymphocyte ratio, and ctDNA-adjusted blood tumor mutation burden (bTMB) has also shown promise in predicting response to immunotherapy. Until additional, prospective studies delineate the magnitude of overall survival benefit and validate the use of predictive biomarkers, a tailored, patient-centered approach to adjuvant ICIs that includes extensive patient counseling on potentially irreversible adverse effects should be routinely incorporated into clinical practice.

Outcomes in liver transplant recipients with nonalcoholic fatty liver disease-related HCC: results from the US multicenter HCC transplant consortium.

NAFLD will soon be the most common indication for liver transplantation (LT). In NAFLD, HCC may occur at earlier stages of fibrosis and present with more advanced tumor stage, raising concern for aggressive disease. Thus, adult LT recipients with HCC from 20 US centers transplanted between 2002 and 2013 were analyzed to determine whether NAFLD impacts recurrence-free post-LT survival. Five hundred and thirty-eight (10.8%) of 4981 total patients had NAFLD. Patients with NAFLD were significantly older (63 vs. 58, p<0.001), had higher body mass index (30.5 vs. 27.4, p<0.001), and were more likely to have diabetes (57.3% vs. 28.8%, p<0.001). Patients with NAFLD were less likely to receive pre-LT locoregional therapy (63.6% vs. 72.9%, p<0.001), had higher median lab MELD (15 vs. 13, p<0.001) and neutrophil-lymphocyte ratio (3.8 vs. 2.9, p<0.001), and were more likely to have their maximum pre-LT alpha fetoprotein at time of LT (44.1% vs. 36.1%, p<0.001). NAFLD patients were more likely to have an incidental HCC on explant (19.4% vs. 10.4%, p<0.001); however, explant characteristics including tumor differentiation and vascular invasion were not different between groups. Comparing NAFLD and non-NAFLD patients, the 1, 3, and 5-year cumulative incidence of recurrence (3.1%, 9.1%, 11.5% vs. 4.9%, 10.1%, 12.6%, p=0.36) and recurrence-free survival rates (87%, 76%, and 67% vs. 87%, 75%, and 67%, p=0.97) were not different. In competing risks analysis, NAFLD did not significantly impact recurrence in univariable (HR: 0.88, p=0.36) nor in adjusted analysis (HR: 0.91, p=0.49). With NAFLD among the most common causes of HCC and poised to become the leading indication for LT, a better understanding of disease-specific models to predict recurrence is needed. In this NAFLD cohort, incidental HCCs were common, raising concerns about early detection. However, despite less locoregional therapy and high neutrophil-lymphocyte ratio, explant tumor characteristics and post-transplant recurrence-free survival were not different compared to non-NAFLD patients.

Macrophage-, Dendritic-, Smooth Muscle-, Endothelium-, and Stem Cells-Derived Foam Cells in Atherosclerosis.

Atherosclerosis is an inflammatory disease depending on the buildup, called plaque, of lipoproteins, cholesterol, extracellular matrix elements, and various types of immune and non-immune cells on the artery walls. Plaque development and growth lead to the narrowing of the blood vessel lumen, blocking blood flow, and eventually may lead to plaque burst and a blood clot. The prominent cellular components of atherosclerotic plaque are the foam cells, which, by trying to remove lipoprotein and cholesterol surplus, also participate in plaque development and rupture. Although the common knowledge is that the foam cells derive from macrophages, studies of the last decade clearly showed that macrophages are not the only cells able to form foam cells in atherosclerotic plaque. These findings give a new perspective on atherosclerotic plaque formation and composition and define new targets for anti-foam cell therapies for atherosclerosis prevention. This review gives a concise description of foam cells of different pedigrees and describes the main mechanisms participating in their formation and function.

Ox40-Cre-mediated deletion of BRD4 reveals an unexpected phenotype of hair follicle stem cells in alopecia.

BRD4 is a bromodomain extraterminal domain family member and functions primarily as a chromatin reader regulating genes involved in cell-fate decisions. Here, we bred Brd4fl/fl Ox40-Cre mice in which Brd4 was conditionally deleted in OX40-expressing cells to examine the role of BRD4 in regulating immune responses. We found that the Brd4fl/fl Ox40-Cre mice developed profound alopecia and dermatitis, while other organs and tissues were not affected. Surprisingly, lineage-tracing experiments using the Rosa26fl/fl-Yfp mice identified a subset of hair follicle stem cells (HFSCs) that constitutively express OX40, and deletion of Brd4 specifically in such HFSCs resulted in cell death and a complete loss of skin hair growth. We also found that death of HFSCs triggered massive activation of the intradermal γδ T cells, which induced epidermal hyperplasia and dermatitis by producing the inflammatory cytokine IL-17. Interestingly, deletion of Brd4 in Foxp3+ Tregs, which also constitutively express OX40, compromised their suppressive functions, and this, in turn, contributed to the enhanced activation of γδ T cells, as well as the severity of dermatitis and hair follicle destruction. Thus, our data demonstrate an unexpected role of BRD4 in regulating skin follicle stem cells and skin inflammation.

Giant Multinucleated Cells in Aging and Senescence-An Abridgement.

This review introduces the subject of senescence, aging, and the formation of senescent multinucleated giant cells. We define senescence and aging and describe how molecular and cellular senescence leads to organismal senescence. We review the latest information on senescent cells' cellular and molecular phenotypes. We describe molecular and cellular features of aging and senescence and the role of multinucleated giant cells in aging-related conditions and cancer. We explain how multinucleated giant cells form and their role in aging arteries and gonads. We also describe how multinucleated giant cells and the reversibility of senescence initiate cancer and lead to cancer progression and metastasis. We also describe molecules and pathways regulating aging and senescence in model systems and their applicability to clinical therapies in age-related diseases.

Predicting a Positive Antibody Response After 2 SARS-CoV-2 mRNA Vaccines in Transplant Recipients: A Machine Learning Approach With External Validation.

BACKGROUND: Solid organ transplant recipients (SOTRs) are less likely to mount an antibody response to SARS-CoV-2 mRNA vaccines. Understanding risk factors for impaired vaccine response can guide strategies for antibody testing and additional vaccine dose recommendations. METHODS: Using a nationwide observational cohort of 1031 SOTRs, we created a machine learning model to explore, identify, rank, and quantify the association of 19 clinical factors with antibody responses to 2 doses of SARS-CoV-2 mRNA vaccines. External validation of the model was performed using a cohort of 512 SOTRs at Houston Methodist Hospital. RESULTS: Mycophenolate mofetil use, a shorter time since transplant, and older age were the strongest predictors of a negative antibody response, collectively contributing to 76% of the model's prediction performance. Other clinical factors, including transplanted organ, vaccine type (mRNA-1273 versus BNT162b2), sex, race, and other immunosuppressants, showed comparatively weaker associations with an antibody response. This model showed moderate prediction performance, with an area under the receiver operating characteristic curve of 0.79 in our cohort and 0.67 in the external validation cohort. An online calculator based on our prediction model is available at http://transplantmodels.com/covidvaccine/ . CONCLUSIONS: Our machine learning model helps understand which transplant patients need closer follow-up and additional doses of vaccine to achieve protective immunity. The online calculator based on this model can be incorporated into transplant providers' practice to facilitate patient-centric, precision risk stratification and inform vaccination strategies among SOTRs.

Immunotherapy as a Neoadjuvant Therapy for a Patient with Hepatocellular Carcinoma in the Pretransplant Setting: A Case Report.

Systemic combination therapy of immune checkpoint inhibitors and vascular endothelial growth factors have provided the basis for improved outcomes in select patients with unresectable or metastatic hepatocellular carcinoma. However, for patients with resectable disease, surgery alone or an orthotopic liver transplant remains the standard of care. Within the realms of transplant oncology, neoadjuvant systemic therapy is currently being evaluated as a potential strategy to improve outcomes in patients with HCC. Here, we report excellent response with significant downstaging in a safe manner after neoadjuvant treatment with atezolizumab and bevacizumab in a patient diagnosed with poorly differentiated HCC. As a result of the significant response observed with safe outcomes, the patient was listed for orthotopic liver transplant (OLT) evaluation and transplanted successfully.

Monocyte-Macrophage Lineage Cell Fusion.

Cell fusion (fusogenesis) occurs in natural and pathological conditions in prokaryotes and eukaryotes. Cells of monocyte-macrophage lineage are highly fusogenic. They create syncytial multinucleated giant cells (MGCs) such as osteoclasts (OCs), MGCs associated with the areas of infection/inflammation, and foreign body-induced giant cells (FBGCs). The fusion of monocytes/macrophages with tumor cells may promote cancer metastasis. We describe types and examples of monocyte-macrophage lineage cell fusion and the role of actin-based structures in cell fusion.

Gemcitabine Plus Cisplatin Versus Non-Gemcitabine and Cisplatin Regimens as Neoadjuvant Treatment for Cholangiocarcinoma Patients Prior to Liver Transplantation: An Institution Experience.

Background: Cholangiocarcinoma management is constantly being updated in view of existing evidence in order to establish practice guidelines and consensus statements. However, the available treatment guidelines to optimize outcomes for cholangiocarcinoma patients who require liver transplantation are still controversial. This study contributing to the cholangiocarcinoma care field by investigating a new promising neoadjuvant therapy that might be help to grant the liver transplant option to the patients with cholangiocarcinoma. Here, we evaluate and compare the potential efficacy of chemotherapy combination of Gemcitabine plus Cisplatin versus non- Gemcitabine and Cisplatin regimens as a neo-adjuvant treatment for cholangiocarcinoma patients prior to liver transplantation. Methods: In this retrospective study, patients with locally advanced, unresectable, hilar, or intrahepatic cholangiocarcinoma with no evidence of extrahepatic disease or vascular involvement were treated with either the combination of neo-adjuvant Gemcitabine plus Cisplatin with no radiation or other standard options of neo-adjuvant treatment. All patients included received chemotherapy prior to being listed for liver transplantation at a single cancer center in collaboration with the same institution's transplant center according to an open-labeled, and centers-approved clinical management protocol. Patients were listed for liver transplantation if they had a minimum of six months of scans showing response or confirmation of disease stability. The primary endpoints were the overall survival and recurrence-free survival after liver transplantation. This report, which was censored on March 18, 2022. Results: Out of a total of 707 liver transplant recipients were screened, 37 patients were confirmed with a diagnosis of cholangiocarcinoma and only 18 patients (11 males and 7 females) with a median age of 61.83 [interquartile range: 58.27-68.74] met inclusion criteria. Of the 18 patients enrolled, 10 received Gemcitabine/Cisplatin, while 8 patients received either Gemcitabine monotherapy or Capecitabine or FOLFIRI. Months for recurrence after transplantation was 20.1 (IRQ: 20.1-20.1) in the Gemcitabine/Cisplatin group and 9.5 (8.9-12.47) months in the non-Gemcitabine/Cisplatin group (p-value=0.18). Median months of follow-up in the Gemcitabine/Cisplatin group was 28.35 (27.1-32.23) months versus 40.12 (20.6-56.22) months in the non-Gemcitabine/Cisplatin group (p-value=0.33). In non-Gemcitabine/Cisplatin patients, overall survival was 75% (95% CI 31-93%) at both years 1 and 2; 63% (95% CI 23-86%) at years 3 to 5. In Gemcitabine/Cisplatin patients, overall survival was 100% (95% CI 100-100%) at both years 1 and 2; 75% (95% CI 13-96%) at years 3 to 5. Three non-Gemcitabine/Cisplatin patients died at 328 days, 340 days, and 896 days, respectively. One Gemcitabine/Cisplatin patient died at 885 days. Conclusion: Our findings suggest improved overall survival outcomes with Gemcitabine plus Cisplatin as neo-adjuvant treatment with no concomitant radiation compared to non-Gemcitabine/Cisplatin regimens in patients with cholangiocarcinoma prior to liver transplantation.

Gemcitabine and Cisplatin as Neo-Adjuvant for Cholangiocarcinoma Patients Prior to Liver Transplantation: Case-Series.

BACKGROUND: The management of cholangiocarcinoma is continually reviewed on a current evidence basis to develop practice guidelines and consensus statements. However, the standardized treatment guidelines are still unclear for cholangiocarcinoma patients who are listed for liver transplantation. We aimed to validate and evaluate the potential efficacy of chemotherapy combination of Gemcitabine and Cisplatin as a neo-adjuvant treatment for cholangiocarcinoma patients before liver transplantation. METHODS: In this prospective case series, patients with locally advanced, unresectable, hilar, or intrahepatic cholangiocarcinoma with no evidence of extrahepatic disease or vascular involvement were treated with a combination of neoadjuvant gemcitabine and cisplatin with no radiation. All patients included received chemotherapy prior to being listed for liver transplantation at a single cancer center according to an open-labeled, and center-approved clinical management protocol. The primary endpoints were the overall survival and recurrence-free survival after liver transplantation. RESULTS: Between 1 March 2016, and 15 March 2022, 10 patients (8 males and 2 females) with a median age of 62.71(interquartile range: 60.02-71.87) had a confirmed diagnosis of intrahepatic or hilar cholangiocarcinoma and underwent liver transplantation. Median days of neoadjuvant therapy for a given combination of gemcitabine and cisplatin were 181 (IRQ: 120-250). Nine patients (90%) were reported with no recurrence or metastasis, and only 1 patient had confirmed metastasis (10%); days for metastasis after transplantation were 612 for this patient. All patients received a combination of gemcitabine and cisplatin as neo-adjuvant while awaiting liver transplantation. The median days of follow-up were 851 (813-967). Overall survival was 100% (95% CI 100-100%) at both years one and two; 75% (95% CI 13-96%) at years three to five. One patient died at eight hundred and eighty-five days. No adverse events were reported after liver transplantation including the patient who was confirmed with recurrence. CONCLUSIONS: Our finding demonstrated that neo-adjuvant gemcitabine and cisplatin with no radiation prior to liver transplantation resulted in excellent outcomes for patients with cholangiocarcinoma.

Utilization of Immunotherapy for the Treatment of Hepatocellular Carcinoma in the Peri-Transplant Setting: Transplant Oncology View.

Hepatocellular carcinoma (HCC) represents the second most common cause of cancer-related deaths and accounts for over eighty percent of primary liver cancers worldwide. Surgical resection and radiofrequency ablation in small tumors are included in the treatment options for HCC patients with good liver function profiles. According to the Milan Criteria, only a small portion of HCC patients are eligible for liver transplantation due to advanced-stage disease and large tumor size preventing/delaying organ allocation. Recently, the use of anti-programmed cell death protein 1 and programmed cell death ligand 1 (PD-1 and PD-L1) checkpoint inhibitors in the treatment of cancers have evolved rapidly and these therapies have been approved for the treatment of HCC. Immune checkpoint inhibitors have resulted in good clinical outcomes in pre-and post-transplant HCC patients, although, some reports showed that certain recipients may face rejection and graft loss. In this review, we aim to illustrate and summarize the utilization of immune checkpoint inhibitor therapies in pre-and post-liver transplants for HCC patients and discuss the assessment of immune checkpoint inhibitor regulators that might determine liver transplant outcomes.