The potential use of extended criteria donors and eligible recipients in liver transplantation for unresectable colorectal liver metastases in Central Sweden

BackgroundUnresectable colorectal liver metastases (CRLM) is a condition with poor prognosis. A recent treatment alternative improving survival in patients with unresectable CRLM, has emerged with the introduction of liver transplantation (LT), yet not uncontroversial with the current organ shortage. This study aimed to retrospectively investigate the potential of declined donors with acceptable risk as liver graft donors and patients with unresectable CRLM as potential recipients.MethodsAll declined donors in central Sweden and all patients with CRLM discussed at multidisciplinary team conference at Karolinska University Hospital, January 2013–October 2018, were identified. Donors were classified according to the European Committee Guide to the quality and safety of organs for transplantation and potential recipients were evaluated by selection criteria, based on studies on the Norwegian Secondary Cancer study database.ResultsOut of 1,462 evaluated potential donors, 62 (2.7 pmp) donors were identified, corresponding to 6–18% of the utilized donor pool. Out of 1,008 included patients with CRLM, 25 (2.1 pmp) potential recipients were recognized. Eligibility for LT and left-sided colon cancer were favorable prognostic factors.ConclusionsToday’s donor pool could increase with the use of extended criteria donors, which is sufficient and display an acceptable risk-benefit ratio for patients with unresectable CRLM. With current selection criteria a small subset of patients with unresectable CRLM are eligible recipients. This subset of patients has a better survival compared to patients ineligible for LT.     

Liver transplantation versus liver resection for colorectal liver metastasis: a survival benefit analysis in patients stratified according to tumor burden score

Liver transplantation (LT) for colorectal liver metastasis (CRLM) may provide excellent survival rates in patients with unresectable disease. High tumor load is a risk factor for recurrence and low overall survival (OS) after liver resection (LR). We tested the hypothesis that LT could offer better survival than LR in patients with high tumor load. LR performed at Padua University Hospital for CRLM was compared with LT for unresectable CRLM performed both at Oslo and Padua. High tumor load was defined as tumor burden score (TBS) ≥ 9, and inclusion criteria were as in the SECA-I transplant study. 184 patients were eligible: 128 LRs and 56 LTs. 5-year OS after LR and LT was 40.5% and 54.7% (P = 0.102). In the high TBS cohort, 5-year OS after LR and LT was 22.7% and 52.2% (P = 0.055). In patients with Oslo score ≤ 2 and TBS ≥ 9 (13 LR; 24 LT) the 5-year OS after LR and LT was 14.6% and 69.1% (P = 0.002). The corresponding disease-free survival (DFS) was 0% and 22.9% (P = 0.005). Selected CRLM patients with low Oslo score and high TBS could benefit from LT with survival outcomes that are far better than what is achieved by LR.     

The role of liver transplantation for colorectal liver metastases: A systematic review and pooled analysis

BackgroundLiver transplantation (LT) has gained interest in the treatment of unresectable colorectal liver metastases (CRLM) over the last two decades. Despite the initial poor outcomes, recent reports from countries with graft abundance have provided further insights in the potential of LT as a treatment for unresectable CRLM.MethodsA systematic literature search was conducted in the MEDLINE (PubMed), Embase, Scopus, Cochrane Library, Google Scholar, Virtual Health Library, Clinicaltrials.gov, and Web of Science databases (end-of-search date: January 27th, 2020) to identify relevant studies. Pooled overall and recurrence-free survival analysis at 6 months, 1, 2, 3, and 5 years was conducted with the Kaplan-Meier (Product Limit) method.ResultsEighteen studies comprising 110 patients were included. The population consisted of 59.8% males with a mean age of 52.3 ± 9.3 years. CRLM diagnosis was synchronous in 83%, while 99% received chemotherapy, and 39% received liver resection prior to LT. The mean time from primary tumor resection to LT was 39.5 ± 32.5 months, the mean post-LT follow-up was 32.1 ± 22.2 months, and the mean time to recurrence was 15.0 ± 11.3 months. The pooled 6-month, 1-, 2-, 3-, and 5-year overall survival rates were 95.7% (95%CI: 89.1%–98.4%), 88.1% (95%CI: 79.6%–93.2%), 74.6% (95%CI: 64.2%–82.3%), 58.4% (95%CI: 47.2%–62.0%), and 50.5% (95%CI: 39.0%–61.0%), respectively. The pooled 6-months, 1-, 2-, 3-, and 5-year recurrence-free survival rates were 77.2% (95%CI: 67.2%–84.5%), 59.9% (95%CI: 49.0%–69.2%), 42.4% (95%CI: 31.8%–52.6%), 30.7% (95%CI: 20.9%–41.1%), and 25.6% (95%CI: 16.2%–36.0%), respectively.ConclusionLT should be considered in patients with unresectable liver-only CRLM under strict selection criteria and only under well-designed research protocols. Ongoing studies are expected to further elucidate the indications and prognosis of patients undergoing LT for unresectable CRLM.     

Complex vascular reconstructions in living donor liver transplantation

We describe here the indications for and our experience with complex vascular reconstructions in living donor liver transplantation. From December 1999 to June 2002, 59 patients underwent liver transplantation, 51 receiving the right lobe, and 8 the left lateral lobe, as a graft from a living donor. The indication for interpositional grafts on the arterial side (6/59, 10%) were stenoses of the celiac trunk and after resection of the hepatic artery for oncological reasons in adults. In children, arterial interpositional grafts were performed in situations of long distances between the donor and recipient artery, or in cases of inflow release from the aorta in patients with small hepatic arteries. On the portal-venous side, one interpositional graft was performed after an oncological resection. Once the portal vein was partially arterialized because of insufficient inflow. We used veins from the recipient, and native or cryopreserved arterial homografts for these grafts. All patients were treated during the first 6 months after transplantation with aspirine only. During the follow-up we did not observe vascular complications. If required, vascular interpositional grafts in the arterial and portal-venous position can be performed without adding postoperative complications.     

Regional hepatic therapies: an important component in the management of colorectal cancer liver metastases

The treatment of colorectal cancer liver metastases (CRLM) has evolved significantly in the last 15 years. Currently, complete surgical resection remains the only potentially curative option; unfortunately, approximately 80% of patients with CRLM are not candidates for complete tumor resection. For patients with unresectable CRLM the available treatment options were historically limited; however, the development of regional hepatic therapies (RHT) and improvement of systemic chemotherapeutic regimens have emerged as viable options to improve overall survival and quality of life for this group of patients. The selection, sequence and integration of interventions into a multi-modal approach is a complex and evolving discipline. In this article, the currently available RHT modalities for CRLM are presented as a guide to the options for clinical treatment decisions.Key Words: Colorectal, liver metastases, tumor ablation     

Fat and liver transplantation: clinical implications

Nonalcoholic steatohepatitis (NASH), with or without hepatocellular carcinoma, is a growing indication for liver transplantation (LT) worldwide, particularly in the Western world. Patients with NASH typically combine features of metabolic syndrome with cardiovascular comorbidities, which challenge pre‐LT evaluation, surgical approaches, post‐LT management, and outcomes. Post‐LT survival in NASH patients is excellent, similar to that achieved with other indications, particularly in the absence of cardiovascular comorbidities. Although disease recurrence on the liver allograft is common, progression to advanced disease is uncommon, at least in the short term. Whether this holds true with longer follow‐up remains to be determined. Owing to the increased prevalence of nonalcoholic fatty liver disease worldwide, along with a shortened organ pool donation in many countries, utilization of donor grafts with hepatic steatosis is now more common. Understanding the limitations of these grafts as well as potential mechanisms to improve graft quality and/or transplant outcome is clue for transplant centers. In this review, we will summarize current data on evaluation of NASH patients and whether it differs from that applied to other candidates, the natural history of NASH both pre‐ and post‐transplantation, emphasizing on waiting list management and recurrence of the original disease in the new graft as well as post‐transplant outcome. Finally, we will discuss the current use of steatotic liver donors and strategies to improve outcome when using this type of grafts.     

Colorectal liver metastases: Resect,ablate, or embolize

The management of colorectal liver metastases (CRLM) is complex and should be individualized to each patient. Resectable CRLM benefit from surgical resection, preferably minimally invasive and parenchymal sparing, when feasible. Ablation is a viable alternative. Chemotherapy in this setting is potentially indicated in select patients, however, it has a clear role in unresectable CRLM. Newer locoregional therapies may benefit some unresectable CRLM with resistance to chemotherapy. Liver transplantation, a new therapy on the horizon for unresectable disease, has encouraging preliminary long-term survival outcomes for carefully selected patients.     

Liver Transplantation for Progressive Unresectable Colorectal Liver Metastases: Case Report and Review of the Literature

BackgroundPrevious dismal clinical studies have stated that colorectal cancer with unresectable liver metastases is an absolute contraindication for liver transplantation (LT). During recent decades, it has been shown that patients with colorectal cancer with liver metastasis benefited from LT, but 100% recurrence was inevitable in progressive colorectal cancer with liver metastasis.Case presentationA 61-year-old man was found at the first visit to be suffering from unresectable liver metastases of colorectal cancer. This patient underwent colorectal radical surgery and palliative treatment after the operation. During a 2-year follow-up, we found that CEA and CA199 rebounded sharply to high levels, and liver metastasis lesions increased significantly, so we made the decision to perform LT 2 years after the first surgery. Chemotherapy and sirolimus were given post-LT. Slow-growing pulmonary metastases after transplantation were found 4 months post-LT. This patient survived the next 4 months tumor-free and by now has survived 34 months free of liver tumors. Here, we review the literature on LT for progressive liver metastasis of colorectal cancer and summarize our experience from this successful case.ConclusionThis case provides vital evidence that LT is an option and can provide curative therapy for patients with advanced unresectable liver metastasis. Careful selection of patients, postoperative comprehensive treatments, and rational application of immunosuppressive agents are vital factors for favorable prognosis.     

结直肠癌肝转移的微创治疗策略

结直肠癌是世界范围内常见的恶性肿瘤,也是肿瘤导致死亡的重要原因。肝脏是结直肠癌最常见的转移部位,约20%的患者伴有同时性肝转移,另20%患者在疾病的发展中也出现肝转移。结直肠癌肝转移（CRLM）是目前结直肠癌治疗的重点与难点,也是影响患者预后的重要因素。手术切除仍然是患者长期生存甚至治愈的最佳治疗选择,其中微创切除更是兼具微创的优势与根治的效果,长期的肿瘤学疗效也与开放手术相当。但受限于肿瘤大小、位置分布等解剖因素、患者的肝脏功能以及一般状态等因素,只有少数患者在初诊时适合手术切除。其他微创治疗策略包括消融治疗、立体定向放射治疗、介入治疗等,这些技术的发展为不可手术切除的患者提供了新的治疗机会,同时也提高了单纯系统治疗的生存率。消融治疗对于选择性的患者兼具有微创与类似手术的根治性效果,对于深部肿瘤也更具优势。立体定向放射治疗是不适合手术切除或消融困难或复发病灶的重要替代选择。Y⁹⁰选择性体内放射治疗更是兼具肿瘤控制与增大余肝的双重作用,在转化治疗时代其地位也不断上升。随着微创理念的深化与技术的进步,CRLM的微创治疗取得一定进展,但仍面临诸多挑战,如在精准、个体化与转化治疗时代微创治疗策略如何合理地联合或序贯使用等。在选择微创治疗策略时,应该根据多学科团队的指导进行个体化评估和综合治疗,尽可能实现R₀切除或无疾病证据状态,从而最大程度地提高患者的长期生存率。本文就近年来CRLM的微创治疗策略进行综述,以期为临床治疗的选择提供参考。     

Borderline resectable for colorectal liver metastases: Present status and future perspective

Surgical resection for colorectal liver metastases (CRLM) may offer the best opportunity to improve prognosis. However, only about 20% of CRLM cases are indicated for resection at the time of diagnosis (initially resectable), and the remaining cases are treated as unresectable (initially unresectable). Thanks to recent remarkable developments in chemotherapy, interventional radiology, and surgical techniques, the resectability of CRLM is expanding. However, some metastases are technically resectable but oncologically questionable for upfront surgery. In pancreatic cancer, such cases are categorized as “borderline resectable”, and their definition and treatment strategies are explicit. However, in CRLM, although various poor prognosis factors have been identified in previous reports, no clear definition or treatment strategy for borderline resectable has yet been established. Since the efficacy of hepatectomy for CRLM was reported in the 1970s, multidisciplinary treatment for unresectable cases has improved resectability and prognosis, and clarifying the definition and treatment strategy of borderline resectable CRLM should yield further improvement in prognosis. This review outlines the present status and the future perspective for borderline resectable CRLM, based on previous studies.     

Liberal policy of split liver for pediatric liver transplantation. A single centre experience

Abstract We adopted a liberal policy of extensive use of split liver in a pediatric liver transplantation (LT) program. Over a 19‐month period, we have performed 64 LT in 54 patients with pediatric indications. One patient received two liver grafts as a part of a liver‐small bowel transplantation and was not considered. Of the 60 LT considered, performed in 53 patients, 34 were with split grafts. The 1‐year actuarial survival for the patients transplanted with a split graft was 81 % and 89% when only elective cases were considered. The median time on the waiting list was 22 days with no mortality. The extensive use of split liver allowed transplantation in a large number of pediatric patients, with good results without the need for living donor liver transplantation. We envisage a trend towards systematic splitting of liver grafts.     

Rescue liver transplantation after post-hepatectomy acute liver failure: A systematic review and pooled analysis

BackgroundPost-hepatectomy liver failure is a severe complication after major liver resection and is associated with a high mortality rate. Nevertheless, there is no effective treatment for severe liver failure. In such a setting, rescue liver transplantation (LT) is used only in extraordinary cases with unclear results. This systematic review aims to define indication of LT in post-hepatectomy liver failure and post-LT outcomes, in terms of patient and disease-free survivals, to assess the procedure's feasibility and effectiveness.MethodsA systematic review of all English language full-text articles published until September 2022 was conducted. Inclusion criteria were articles describing patients undergoing LT for post-hepatectomy liver failure after liver resection, which specified at least one outcome of interest regarding patient/graft survival, postoperative complications, tumour recurrence and cause of death. A pseudo-individual participant data meta-analysis was performed to analyse data. Study quality was assessed with MINORS system. PROSPERO CRD42022349358.ResultsPostoperative complication rate was 53.6%. All patients transplanted for benign indications survived. For malignant tumours, 1-, 3- and 5-year overall survival was 94.7%, 82.1% and 74.6%, respectively. The causes of death were tumour recurrence in 83.3% of cases and infection-related in 16.7% of LT recipients. At Cox regression, being transplanted for unconventional malignant indications (colorectal liver metastasis, cholangiocarcinoma) was a risk factor for death HR = 8.93 (95%CI = 1.04–76.63; P-value = 0.046). Disease-free survival differs according to different malignant tumours (P-value = 0.045).ConclusionsPost-hepatectomy liver failure is an emergent indication for rescue LT, but it is not universally accepted. In selected patients, LT can be a life-saving procedure with low short-term risks. However, special attention must be given to long-term oncological prognosis before proceeding with rescue LT in an urgent setting, considering the severity of liver malignancy, organ scarcity, the country's organ allocation policies and the resource of living-related donation.     

结直肠癌肝转移的转化治疗

对结直肠癌肝转移来说,手术是惟一的治愈手段。但80%的病人初始是不可切除的,将不可切除肝转移转化为可切除是提高结直肠癌总体存活率的关键。目前常用的转化手段有全身化疗（包括单纯化疗、化疗联合靶向药物等）、肝动脉灌注（HAI）、射频消融（RFA）、联合门静脉结扎或栓塞的分期肝切除、联合肝脏分隔及门静脉结扎的二步肝切除等。了解各种转化治疗的有效率和适应证是选择合适治疗的前提。     

结直肠癌肝转移诊治中焦点问题

尽管已经有一些随机对照研究,但结直肠癌肝转移的诊治还存在很多争议。并非所有可切除病人都能从新辅助化疗中获益,应该选择高危病人进行新辅助化疗;对不可切除病人,除了全身化疗,肝动脉灌注（HAI）有望成为重要的转化手段;对于无法达到根治性切除（R0切除）的病人,如果能行R1切除也是有意义的;合并不可切除肺转移灶不再是肝转移灶切除的绝对禁忌;联合肝脏分隔和门静脉结扎的二步肝切除（ALPPS）由于其高并发症发生率和高病死率,应该客观看待。     

Outcome after laparoscopic radiofrequency ablation of technically resectable colorectal liver metastases

Background  

There continues to be controversy surrounding the appropriate use of radiofrequency ablation (RFA) for the treatment of colorectal liver metastases (CRLM). This study analyzes outcomes data of CRLM patients who underwent laparoscopic RFA. Outcomes of patients determined to be technically resectable were compared to patients with unresectable disease.     

结直肠癌肝转移危险及预后因素分析

肝脏是结直肠癌最常见的远处转移器官,结直肠癌病人出现肝转移一般预后较差。结直肠癌肝转移分为同时性肝转移和异时性肝转移,对众多的临床以及病理学特征进行的单因素和多因素回归分析提示,影响结直肠癌发生肝转移的危险因素有：浸润深度、淋巴结转移、癌结节、分化程度、癌胚抗原和糖类抗原等。影响结直肠癌肝转移病人预后的因素有：肝转移灶大小及数目、肝外器官转移、原发灶手术切除、肝转移灶手术切除、全身药物治疗等。因此,手术切除肝转移灶、药物治疗获得手术切除机会等治疗模式能够最大程度地提高结直肠癌肝转移病人的存活率。由众多因素组合起来的评分系统,能够较好地预测结直肠癌肝转移病人的预后。     

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结直肠癌肝转移发生率高,且临床就诊者大多数肝转移灶为不可切除。尽管关于不可切除结直肠癌肝转移病人原发灶的处理尚有一定争议,但随着结直肠癌原发灶处理经验的积累,多学科综合治疗团队(MDT)模式的开展,转化性治疗思维的应用,"个体化治疗"原则的实施,针对不可切除结直肠癌肝转移病人原发灶的处理逐步形成包括手术切除原发灶在内较合理的综合治疗体系。手术切除、新辅助治疗与姑息治疗的合理选择是改善不可切除结直肠癌肝转移病人生存质量及提高生存期,获得最佳治疗效果的关键。     

Oncologic aspects of the decision-making process for surgical approach for colorectal liver metastases progressing during chemotherapy

Colorectal cancer represents the third most diagnosed malignancy in the world. The liver is the main site of metastatic disease, affected in 30% of patients with newly diagnosed disease. Complete resection is considered the only potentially curative treatment for colorectal liver metastasis (CRLM), with a 5-year survival rate ranging from 35% to 58%. However, up to 80% of patients have initially unresectable disease, due to extrahepatic disease or bilobar multiple liver nodules. The availability of increasingly effective systemic chemotherapy has contributed to converting patients with initially unresectable liver metastases to resectable disease, improving long-term outcomes, and accessing tumor biology. In recent years, response to preoperative systemic chemotherapy before liver resection has been established as a major prognostic factor. Some studies have demonstrated that patients with regression of hepatic metastases while on chemotherapy have improved outcomes when compared to patients with stabilization or progression of the disease. Even if disease progression during chemotherapy represents an independent negative prognostic factor, some patients may still benefit from surgery, given the role of this modality as the main treatment with curative intent for patients with CRLM. In selected cases, based on size, the number of lesions, and tumor markers, surgery may be offered despite the less favorable prognosis and as an option for non-chemo responders.     

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尽管已经有一些随机对照研究,但结直肠癌肝转移的诊治还存在很多争议。并非所有可切除病人都能从新辅助化疗中获益,应该选择高危病人进行新辅助化疗;对不可切除病人,除了全身化疗,肝动脉灌注(HAI)有望成为重要的转化手段;对于无法达到根治性切除(R0切除)的病人,如果能行R1切除也是有意义的;合并不可切除肺转移灶不再是肝转移灶切除的绝对禁忌;联合肝脏分隔和门静脉结扎的二步肝切除(ALPPS)由于其高并发症发生率和高病死率,应该客观看待。     

Ischemia-reperfusion injury and its relationship with early allograft dysfunction in liver transplant patients

Ischemia-reperfusion injury (IRI) is believed to contribute to graft dysfunction after liver transplantation (LT). However, studies on IRI and the impact of early allograft dysfunction (EAD) in IRI grafts are limited. Histological IRI was graded in 506 grafts from patients who had undergone LT and classified based on IRI severity (no, minimal, mild, moderate, and severe). Of the 506 grafts, 87.4% had IRI (no: 12.6%, minimal: 38.1%, mild: 35.4%, moderate: 13.0%, and severe: 0.8%). IRI severity correlated with the incidence of EAD and graft survival at 6 months. Longer cold/warm ischemia time, recipient/donor hypertension, and having a male donor were identified as independent risk factors for moderate to severe IRI. Among 70 grafts with moderate to severe IRI, 42.9% of grafts developed EAD, and grafts with EAD had significantly inferior survival compared to grafts without EAD. Longer cold ischemia time and large droplet macrovesicular steatosis (≥20%) were identified as independent risk factors for EAD. Our study demonstrated that increased IRI severity was correlated with inferior short-term graft outcomes. Careful consideration of IRI risk factors during donor-recipient matching may assist in optimizing graft utilization and LT outcomes. Furthermore, identification of risk factors of IRI-associated EAD may guide patient management and possible timely graft replacement.