The Rochester Protocol for Living Donor Liver Transplantation of Unresectable Colorectal Liver Metastasis: A 5-Year Report on Selection, Approval, and Outcomes.

Living donor liver transplantation (LDLT) is a treatment option for select patients with unresectable colorectal liver metastasis (uCRLM). We describe our center's experience of patient selection, insurance approval, and outcomes after LDLT after first referral in March 2019. Of the 206 evaluated patients, twenty-three underwent LDLT. We found that patients who were referred earlier in their oncologic course were more likely to be eligible for transplantation. After completion of the Rochester Protocol for LDLT eligibility, recipients had a median delay of care of 10 days (IQR 0-36) related to insurance appeal, with six patients (30%) having a delay longer than 30 days. LDLT recipients had an overall survival proportion of 100% and 91% at 1, and 3 years; and a recurrence-free survival proportion of 100% and 40%, at 1 and 3 years, respectively. All donors underwent right hepatectomy, of which only one donor had a Clavien-Dindo IIIa complication and readmission. There was no donor mortality. We assert that multidisciplinary care and strict patient selection through the Rochester Protocol were paramount to our center's success. In the appropriately selected patient, LDLT for uCRLM may be justified, and patients should be referred to transplant oncology centers for evaluation.

Focal Update on Immunotherapy and Liver Transplantation in the Era of Transplant Oncology.

Transplant oncology is an expanding area of cancer therapy that specifically emphasizes the use of liver transplantation (LT) as the preferred treatment for patients with manageable, but unresectable, tumors. The management and optimization of overall survival strategies, accompanied by an arguably decent quality of life, have been at the forefront of liver oncology treatment, as a plurality of all primary liver cancers are identified as either hepatocellular carcinoma (HCC) or cholangiocarcinoma (CCA), which are classified as highly aggressive malignancies and frequently remain asymptomatic until they progress to advanced stages, rendering curative procedures, such as resection, impractical. This has led to an increase in utilization of neoadjuvant interventions conducted prior to surgery, which has yielded favorable outcomes. Though this treatment modality has prompted further investigations into the efficacy of immune checkpoint inhibitors (ICPIs) as standalone treatments and in combination with locoregional treatments (LRTs) to bridge more patients into curative eligibility. This multidisciplinary methodology and treatment planning has seen multiple successful trials of immunotherapy regimes and combinate treatments, setting the groundwork for increasing eligibility through downstaging and "bridging" previously ineligible patients within stringent LT criteria. Surveillance after LT is a crucial component of transplant oncology. The emergence of circulating tumor DNA (ctDNA) has provided a novel approach to identifying the recurrence of cancer in its early stages. Recent research has focused on liquid biopsy, a technique that effectively identifies the dynamics of cancer. This is another innovation to demonstrate the rate at which transplant oncology is rapidly advancing, making the focus of care feel disorienting. Modalities of care are constantly evolving, but when a field is changing as rapidly as this one, it is imperative to reorient to the data and the needs of the patients. In this commentary, we reflect on the update's utilization of ICPIs in neoadjuvant settings as well as the updates on the utilization of liquid biopsy in post-LT follow-up surveillance.

Reappraisal of liver resection as an alternative to transplantation in locally advanced hepatoblastoma: A systematic review and analysis of pooled individual patient data.

BACKGROUND: There is ongoing debate regarding liver transplantation (LT) versus liver resection (LR) for locally advanced hepatoblastoma. However, comparative studies are lacking. Consequently, a significant evidence gap persists, hindering the establishment of consensus guidelines. This study aimed to compare LT and LR for locally advanced hepatoblastoma, using predefined inclusion criteria to ensure comparable intervention groups. METHODS: According to current Children's Oncology Group (COG) and SIOPEL (European Childhood Liver Tumour Study Group) recommendations, hepatoblastoma that requires LT evaluation was defined as either PRETEXT (PRE-Treatment EXTent of tumor) IV F+, POST-TEXT (POST-Treatment EXTent of tumor) IV, POST-TEXT P+, and/or POST-TEXT V+. A systematic literature search (Medline/Web-of-Science/Embase) was performed. Only patients who met the aforementioned criteria were included. Patient data were extracted individually and pooled. RESULTS: A total of 189 patients with locally advanced hepatoblastoma from 55 studies met the specified criteria, with 111 undergoing LT and 78 LR. There were no significant differences between the two groups in age, alpha-fetoprotein (AFP), and PRETEXT stages. Local recurrence was more common after LR (14% vs. 3% in LT, p = .008), while distant recurrence was more often observed after LT (16% vs. 5% in LR, p = .035). Overall survival (OS) and event-free survival (EFS) did not differ significantly between LT and LR (5-year OS: LT = 75.3% [95% confidence interval: 66.5-85.2], LR = 87.6% [80.4-95.6], p = .140; 5-year EFS: LT = 68.5% [59.3-79.1], LR = 71.1% [60.7-83.3], p = .700). CONCLUSION: Real-life data revealed that a considerable number of patients with locally advanced hepatoblastoma underwent LR. This analysis suggests that outcomes are similar and favorable for both approaches. LR can therefore be considered an effective alternative to LT in selected cases even in locally advanced hepatoblastoma.

Innovations in Liver Preservation Techniques for Transplants from Donors after Circulatory Death: A Special Focus on Transplant Oncology.

Liver transplantation is the preferred treatment for end-stage liver disease. Emerging evidence suggests a potential role for liver transplantation in treating liver tumors such as colorectal liver metastases and cholangiocarcinoma. However, due to a limited donor pool, the use of marginal grafts from donation after circulatory death (DCD) donors is increasing to meet demand. Machine perfusion is crucial in this context for improving graft acceptance rates and reducing ischemia-reperfusion injury. Few studies have evaluated the role of machine perfusion in the context of transplant oncology. Perfusion machines can be utilized in situ (normothermic regional perfusion-NRP) or ex situ (hypothermic and normothermic machine perfusion), either in combination or as a complement to conventional in situ cold flush and static cold storage. The objective of this analysis is to provide an up-to-date overview of perfusion machines and their function in donation after circulatory death with particular attention to their current and likely potential effects on transplant oncology. A literature review comparing standard cold storage to machine perfusion methods showed that, so far, there is no evidence that these devices can reduce the tumor recurrence rate. However, some evidence suggests that these innovative perfusion techniques can improve graft function, reduce ischemia-reperfusion injury, and, based on this mechanism, may lead to future improvements in cancer recurrence.

Statin, aspirin and metformin use and risk of hepatocellular carcinoma related outcomes following liver transplantation: A retrospective study.

BACKGROUND: Liver transplantation (LT) is a potentially curative therapy for patients with hepatocellular carcinoma (HCC). HCC-recurrence following LT is associated with reduced survival. There is increasing interest in chemoprophylaxis to improve HCC-related outcomes post-LT. AIM: To investigate whether there is any benefit for the use of drugs with proposed chemoprophylactic properties against HCC, and patient outcomes following LT. METHODS: This was a retrospective study of adult patients who received Deceased Donor LT for HCC from 2005-2022, from a single Australian centre. Drug use was defined as statin, aspirin or metformin therapy for ≥ 29 days, within 24 months post-LT. A cox proportional-hazards model with time-dependent covariates was used for survival analysis. Outcome measures were the composite-endpoint of HCC-recurrence and all-cause mortality, HCC-recurrence and HCC-related mortality. Sensitivity analysis was performed to account for immortality time bias and statin dosing. RESULTS: Three hundred and five patients were included in this study, with 253 (82.95%) males with a median age of 58.90 years. Aetiologies of liver disease were 150 (49.18%) hepatitis C, 73 (23.93%) hepatitis B (HBV) and 33 (10.82%) non-alcoholic fatty liver disease (NAFLD). 56 (18.36%) took statins, 51 (16.72%) aspirin and 50 (16.39%) metformin. During a median follow-up time of 59.90 months, 34 (11.15%) developed HCC-recurrence, 48 (15.74%) died, 17 (5.57%) from HCC-related mortality. Statin, aspirin or metformin use was not associated with statistically significant differences in the composite endpoint of HCC-recurrence or all-cause mortality [hazard ratio (HR): 1.16, 95%CI: 0.58-2.30; HR: 1.21, 95%CI: 0.28-5.27; HR: 0.61, 95%CI: 0.27-1.36], HCC-recurrence (HR: 0.52, 95%CI: 0.20-1.35; HR: 0.51, 95%CI: 0.14-1.93; HR 1.00, 95%CI: 0.37-2.72), or HCC-related mortality (HR: 0.32, 95%CI: 0.033-3.09; HR: 0.71, 95%CI: 0.14-3.73; HR: 1.57, 95%CI: 0.61-4.04) respectively. Statin dosing was not associated with statistically significant differences in HCC-related outcomes. CONCLUSION: Statin, metformin or aspirin use was not associated with improved HCC-related outcomes post-LT, in a largely historical cohort of Australian patients with a low proportion of NAFLD. Further prospective, multicentre studies are required to clarify any potential benefit of these drugs to improve HCC-related outcomes.

Liver transplantation for hepatocellular carcinoma: Current status in Hong Kong, China.

With the advances in transplant oncology in recent years, the role of liver transplantation has expanded to make curative treatment a possibility for a wider patient population. We highlight strategies in Hong Kong, China that have enabled preoperative prognostication for judicious patient selection, downstaging therapy to definitive treatment, and postoperative therapies that have provided a growing role for liver transplantation in patients with more advanced hepatocellular carcinoma.

Outcomes of Liver Transplantation with Incidental Intrahepatic Cholangiocarcinoma-Own Experience and a Systematic Review.

Background: Cholangiocarcinoma, the second most common primary liver cancer, is still a contraindication for performing liver transplantation in most patients. Despite various trials being performed in large clinical centers, the results are still not satisfactory. The aim of this study was to present cases from our own cohort and perform a systematic review of the results of liver transplantation in patients with incidental intrahepatic cholangiocarcinoma. Materials and methods: We retrospectively reviewed the records of all patients who underwent liver transplantation and identified two patients with incidental intrahepatic cholangiocarcinoma via histopathological examination of the explanted liver. The results of radiological and biochemical screening performed during liver transplantation, standardized histopathological examination and follow-up data are presented. Additionally, a systematic review of PubMed and Cochrane Reviews based on the PRISMA protocol was performed, yielding 413 similar cases. Results: We present two cases of incidental intrahepatic cholangiocarcinoma found after liver transplantation. The patients were managed according to a standard protocol with no consecutive modification of immunosuppression or chemotherapy. There was no recurrence or mortality. In this systematic review, the mean reported number of lesions ranged between 1 and 2 per patient. A total of 42 recurrences were reported. The percentage of recurrences ranged between 28.6% and 80%. Conclusions: Despite not being a frequent finding, follow-up and further treatment of patients with incidental iCCA should be reported and analyzed. Extra carefulness in screening is advised in patients who are already diagnosed with oncological disease of the liver. In long-term follow-up, recurrence of the disease is rather probable.

Immunosuppression in liver transplant oncology: position paper of the Italian Board of Experts in Liver Transplantation (I-BELT).

Liver transplant oncology (TO) represents an area of increasing clinical and scientific interest including a heterogeneous group of clinical-pathological settings. Immunosuppressive management after LT is a key factor relevantly impacting result. However, disease-related guidance is still lacking, and many open questions remain in the field. Based on such a substantial lack of solid evidences, the Italian Board of Experts in Liver Transplantation (I-BELT) (a working group including representatives of all national transplant centers), unprecedently promoted a methodologically sound consensus conference on the topic, based on the GRADE approach. The group final recommendations are herein presented and commented. The 18 PICOs and Statements and their levels of evidence and grades of recommendation are reported and grouped into seven areas: (1) risk stratification by histopathological and bio-molecular parameters and role of mTORi post-LT; (2) steroids and HCC recurrence; (3) management of immunosuppression when HCC recurs after LT; (4) mTORi monotherapy; (5) machine perfusion and HCC recurrence after LT; (6) physiopathology of tumor-infiltrating lymphocytes and immunosuppression, the role of inflammation; (7) immunotherapy in liver transplanted patients. The interest in mammalian targets of rapamycin inhibitors (mTORi), for steroid avoidance and the need for a reduction to CNI exposure emerged from the consensus process. A selected list of unmet needs prompting further investigations have also been developed. The so far heterogeneous and granular approach to immunosuppression in oncologic patients deserves greater efforts for a more standardized therapeutic response to the different clinical scenarios. This consensus process makes a first unprecedented step in this direction, to be developed on a larger scale.

Current role and perspectives of living donor liver transplantation for hepatocellular carcinoma: systematic review of the past 20 years.

Hepatocellular carcinoma (HCC) poses a significant global health challenge, and liver transplantation (LT) remains the best curative option. Living donor liver transplantation (LDLT) emerged as a potential solution to organ scarcity, reducing waitlist times. This comprehensive review explores LDLT practices, focusing on patient selection criteria and oncologic outcomes. A systematic review following PRISMA guidelines included 50 studies (2004-2023) with 8062 patients. Data encompassed baseline characteristics, HCC features, and oncologic outcomes. Further analysis categorized results by geography and publication year. Heterogeneity in patient demographics, tumor burden, and transplant characteristics was observed. Recent LDLT series demonstrated a shift towards refined selection criteria, increased neoadjuvant treatment, and improved oncologic outcomes. Geographic disparities revealed unique challenges in Eastern and Western practices. LDLT proves effective for HCC, addressing donor shortages. Evolving practices highlight the importance of refining inclusion criteria and optimizing tumor management. While geographic differences exist, LDLT, when judiciously applied, offers promising outcomes.

Indications to LDLT: a changing pathway?

Liver transplantation (LT) revolutionized the outlook for cirrhotic patients, offering a potential cure with over 80% life expectancy after 5 years. Cirrhosis, with or without hepatocellular carcinoma (HCC), is the primary LT indication. Living donor LT (LDLT) initially explored as an alternative, declined due to poorer outcomes. Studies on LDLT improved outcomes through precise recipient selection, emphasizing the importance of careful donor/recipient matching. Emerging concepts like left lobe preference and minimally invasive donor approaches enhance LDLT outcomes. The RAPID technique shows promise in both cirrhotic and non-cirrhotic livers. LDLT gains significance in transplant oncology, particularly for liver tumors like colorectal liver metastases (CLM), offering better survival than alternatives. Optimal timing integrates chemotherapy with the transplant. As LT indications evolve, LDLT finds a growing role in oncology, surpassing deceased donor transplants in certain scenarios. The decreasing prevalence of virus-related uncompensated cirrhosis highlights the expanding space for LDLT in liver transplantation.

Transplant oncology - Current indications and strategies to advance the field.

Liver transplantation (LT) was originally described by Starzl as a promising strategy to treat primary malignancies of the liver. Confronted with high recurrence rates, indications drifted towards non-oncologic liver diseases with LT finally evolving from a high-risk surgery to an almost routine surgical procedure. Continuously improving outcomes following LT and evolving oncological treatment strategies have driven renewed interest in transplant oncology. This is not only reflected by constant refinements to the criteria for LT in patients with HCC, but especially by efforts to expand indications to other primary and secondary liver malignancies. With new patient-centred oncological treatments on the rise and new technologies to expand the donor pool, the field has the chance to come full circle. In this review, we focus on the concept of transplant oncology, current indications, as well as technical and ethical aspects in the context of donor organs as precious resources.

Liver transplantation as an alternative for the treatment of intrahepatic cholangiocarcinoma: Past, present, and future directions.

Intrahepatic cholangiocarcinoma (iCCA) is a rare biliary tract cancer with high mortality rate. Complete resection of the iCCA lesion is the first choice of treatment, with good prognosis after margin-negative resection. Unfortunately, only 12%-40% of patients are eligible for resection at presentation due to cirrhosis, portal hypertension, or large tumor size. Liver transplantation (LT) offers margin-negative iCCA extirpation for patients with unresectable tumors. Initially, iCCA was a contraindication for LT until size-based selection criteria were introduced to identify patients with satisfied post-LT outcomes. Recent studies have shown that tumor biology-based selection can yield high post-LT survival in patients with locally advanced iCCA. Another selection criterion is the tumor response to neoadjuvant therapy. Patients with response to neoadjuvant therapy have better outcomes after LT compared with those without tumor response to neoadjuvant therapy. Another index that helps predict the treatment outcome is the biomarker. Improved survival outcomes have also opened the door for living donor LT for iCCA. Patients undergoing LT for iCCA now have statistically similar survival rates as patients undergoing resection. The combination of surgery and locoregional and systemic therapies improves the prognosis of iCCA patients.

Hepatocellular Carcinoma: The Role of Immunotherapy and Transplantation in the Era of Transplant Oncology.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer deaths worldwide. As most patients present with advanced disease, curative therapy such as surgical resection and radiofrequency ablation are rarely utilized. With the advent of immunotherapy, historical treatment approaches such as liver transplantation are being challenged. In particular, the use of immune checkpoint inhibitors (ICIs) has emerged as a safe and useful option in the treatment of HCC. However, there is concern over adverse effects, such as graft rejection and graft loss. This updated review discusses the role of immunotherapy in the pre- and post-transplantation setting and provides insights into the potential of immunotherapy as an adjunct to liver transplantation. We deliberate on the use of ICI in the setting of the Milan criteria as well as the University of California San Francisco's expanded criteria for liver transplantation. Current data suggest that ICI has utility, especially in the pretransplantation setting. Nevertheless, larger, purposefully designed clinical trials are needed to clearly identify patients who will benefit most from ICI treatment in the transplant setting and determine parameters that will minimize the risk of graft rejection and maximize the benefits of this adjunct treatment.

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.

Primary versus Salvage Liver Transplantation after Curative-Intent Resection or Radiofrequency Ablation for Hepatocellular Carcinoma: Long-Term Oncological Outcomes.

Liver transplantation for hepatocellular carcinoma (HCC) may be performed ab initio, primary liver transplantation (PLT), or for HCC recurrence after previous treatments such as liver resection (LR) or radiofrequency ablation (RFA), salvage liver transplantation (SLT). The aim of this study was to evaluate the oncological outcomes of SLT vs. PLT. For this, a retrospective study was carried out on patients undergoing liver transplantation for HCC. The outcomes of PLT were compared with those of SLT. The primary outcome was disease-free survival (DFS). The secondary outcomes included overall survival (OS), cancer-specific survival (CSS), and major postoperative complications. A sub-analysis of SLT-LR and SLT-RFA was also performed. In total, 141 patients were included: 96 underwent PLT and 45 SLT. Among the SLT group, 25 patients had undergone previous LR while 20 had had RFA. There were no differences in the major postoperative complications. Unadjusted DFS was significantly longer in the PLT group (p = 0.02), as were OS (p = 0.025) and CSS (p = 0.001). There was no difference in DFS between PLT and SLT-LR groups, while a significant difference was found between the PLT and SLT-RFA groups (p = 0.035). Nonetheless, DFS was no different between the SLT-LR and SLT-RFA groups. PLT appears to offer superior long-term oncological outcomes to SLT. Both SLT-LR and SLT-RFA offer acceptable OS and CSS. Further prospective studies are needed to confirm these results, but the re-direction of grafts and transplant philosophy towards PLT rather than SLT may need to be considered.

The Role of Liver Transplantation in the Treatment of Liver Metastases from Neuroendocrine Tumors.

OPINION STATEMENT: Transplant oncology is a new field of medicine referred to the use of solid organ transplantation, particularly the liver, to improve prognosis and quality of life in cancer patients. In unresectable, liver-only metastases from neuroendocrine tumors (NETs) of the digestive tract, liver transplantation represents a competitive chance of cure. Due to the limited resource of donated organs, accurate patients' selection is crucial in order to maximize transplant benefit. Several tumor- and patient-related factors should be considered. Among them, primary tumors with a low grade of differentiation (G1-G2 or Ki67 < 10%), located in a region drained by the portal system and removed before transplantation with at least 3-6 months period of disease stability observed before transplant listing, can be considered for transplantation. In case of NET located in the pancreas, extended lymphadenectomy should complement curative pancreatic resection. A number of other features are described in this review of liver transplantation for NET metastases. Comprehensive approach including various forms of non-surgical treatment and detailed planning and timing of total hepatectomy are discussed. Open issues remain on possible expansion of current criteria while maintaining the same long-term benefit demonstrated with the Milan NET criteria with respect to other non-transplant options, with particular reference to liver resection, peptide receptor radionuclide therapy, and locoregional and systemic treatments.

New Developments and Challenges in Liver Transplantation.

Liver disease is increasing in incidence and is the third most common cause of premature death in the United Kingdom and fourth in the United States. Liver disease accounts for 2 million deaths globally each year. Three-quarters of patients with liver disease are diagnosed at a late stage, with liver transplantation as the only definitive treatment. Thomas E. Starzl performed the first human liver transplant 60 years ago. It has since become an established treatment for end-stage liver disease, both acute and chronic, including metabolic diseases and primary and, at present piloting, secondary liver cancer. Advances in surgical and anaesthetic techniques, refined indications and contra-indications to transplantation, improved donor selection, immunosuppression and prognostic scoring have allowed the outcomes of liver transplantation to improve year on year. However, there are many limitations to liver transplantation. This review describes the milestones that have occurred in the development of liver transplantation, the current limitations and the ongoing research aimed at overcoming these challenges.

Surgical approach to achieve R0 resections in primary and metastatic liver tumors: a literature review.

Background and Objective: Primary and metastatic liver tumors are a significant cause of mortality worldwide. Regardless of the etiology of the tumor, macro- and microscopically clear margins (R0) while preserving adequate function of the remaining organ are the main goals after liver resections. However, technically challenging procedures are required to achieve R0 resection. Currently, there is no consensus of which should be the ideal minimal safety margin for liver tumor resections, with contrasting reports in regards of safety, tumor recurrence and overall outcomes following R0. Therefore, we aim to review current worldwide surgical practices to achieve R0 resections for primary and metastatic liver tumors in challenging surgical techniques and their reported outcomes. Methods: PubMed database, Google Scholar, and OVID Medline were searched for peer-reviewed original articles related to surgical techniques performed to achieve R0 resections in the setting of primary and/or metastatic liver tumors. An up-to-date review of English-language articles published between 2015 to July 2022 was performed. Key Content and Findings: Primary and metastatic liver tumors can be effectively treated using hepatic resection. Current literature highlights that tumors involving major vascular structures are not uncommon. Surgical advances have allowed for vascular control techniques, as well as vascular resections to be performed in a feasible and safe manner to achieve R0 resections. Complex resections combining surgical techniques can be performed in certain population after a detailed evaluation. Liver transplantation (LT) have been used with varying degrees of success for treatment of patients with hepatocellular carcinoma, cholangiocarcinoma (CCA), colorectal liver metastases (CRLM), non-resectable CRLM and metastatic neuroendocrine tumors. Conclusions: Safety and feasibility of R0 resections have been reported for multiple techniques. Technical complexity should not be a limitation to achieve or pursue R0 tumor resection. However, there has to be a balance between patient risk/benefit in attempting R0 resections. Adequate training of surgeons on implementation of complex techniques, as well as transplant oncology techniques applied to hepato-pancreato-biliary (HPB) surgery represents as a promising path to improve short and long-term outcomes for liver-related oncology patients.