肝移植治疗原发性肝细胞癌的进展

肝移植已经成为治疗肝癌的重要手段.选择合适的病人是一个重要的问题,国际通行的是米兰标准,我国一般公认的适应证主要包括:合并有肝硬变失代偿、不能接受肝切除治疗的小肝癌患者和肿瘤多发且波及左右两叶、肝功能严重损害、行切除术后肿瘤容易复发或出现肝功能衰竭者.血管侵犯,细胞分化程度等因素可以影响治疗的预后.围手术期辅助治疗(经皮肝动脉化学栓塞、经皮无水酒精瘤内注射、射频消融,氩氦刀治疗)对于提高肝移植的疗效有一定的意义.     

Gut microbiota and immune system in liver cancer: Promising therapeutic implication from development to treatment

Liver cancer is a leading cause of death worldwide, and hepatocellular carcinoma (HCC) is the most frequent primary liver tumour, followed by cholangiocarcinoma. Notably, secondary tumours represent up to 90% of liver tumours. Chronic liver disease is a recognised risk factor for liver cancer development. Up to 90% of the patients with HCC and about 20% of those with cholangiocarcinoma have an underlying liver alteration. The gut microbiota-liver axis represents the bidirectional relationship between gut microbiota, its metabolites and the liver through the portal flow. The interplay between the immune system and gut microbiota is also well-known. Although primarily resulting from experiments in animal models and on HCC, growing evidence suggests a causal role for the gut microbiota in the development and progression of chronic liver pathologies and liver tumours. Despite the curative intent of “traditional” treatments, tumour recurrence remains high. Therefore, microbiota modulation is an appealing therapeutic target for liver cancer prevention and treatment. Furthermore, microbiota could represent a non-invasive biomarker for early liver cancer diagnosis. This review summarises the potential role of the microbiota and immune system in primary and secondary liver cancer development, focusing on the potential therapeutic implications.     

Prognostic factors for patients with hepatic metastases from breast cancer

Median survival from liver metastases secondary to breast cancer is only a few months, with very rare 5-year survival. This study reviewed 145 patients with liver metastases from breast cancer to determine factors that may influence survival. Data were analysed using Kaplan-Meier survival curves, univariate and multivariate analysis. Median survival was 4.23 months (range 0.16-51), with a 27.6% 1-year survival. Factors that significantly predicted a poor prognosis on univariate analysis included symptomatic liver disease, deranged liver function tests, the presence of ascites, histological grade 3 disease at primary presentation, advanced age, oestrogen receptor (ER) negative tumours, carcinoembryonic antigen of over 1000 ng ml(-1) and multiple vs single liver metastases. Response to treatment was also a significant predictor of survival with patients responding to chemo- or endocrine therapy surviving for a median of 13 and 13.9 months, respectively. Multivariate analysis of pretreatment variables identified a low albumin, advanced age and ER negativity as independent predictors of poor survival. The time interval between primary and metastatic disease, metastases at extrahepatic sites, histological subtype and nodal stage at primary presentation did not predict prognosis. Awareness of the prognostic implications of the above factors may assist in selecting the most appropriate treatment for these patients.British Journal of Cancer (2003) 89, 284-290. doi:10.1038/sj.bjc.6601038 www.bjcancer.com     

Combined pancreatoduodenectomy and orthotopic liver transplantation for hepatocellular carcinoma with portal vein tumor thrombus： A case report

Hepatocellular cancer (HCC) is the most common primary malignant hepatic tumor that accounts for over 80% of primary liver tumors. The outlook for HCC is dismal if it is left untreated and the treatment for patients with HCC evolved into a complex task. The treatments for HCC are mainly surgical therapies including hepatic resection (HR) and liver transplantation. Although HR is a well accepted therapy for HCC, it is not suitable for patients with advanced cirrhosis. Orthotopic liver transplantation (OLT) is considered more appropriate in cases with HCC related to cirrhosis, because it may eliminate both the tumor and the underlying liver disease. In this study, we reported a patient with HCC and portal vein tumor thrombus underwent combined pancreatoduodenectomy with OLT and survived 23 months in our center.     

Liver resection for metastatic gastric cancer: experience with 42 patients including eight long-term survivors

BACKGROUND: The indication for liver resection for gastric metastases remains controversial and few previous studies have reported the outcome of surgery in the treatment of liver metastases of gastric cancer. The aim of this study is to clarify the effectiveness of surgical resection for liver metastases arising from gastric cancer. METHODS: A retrospective analysis was performed on the outcome of 42 consecutive patients with synchronous (n = 20) or metachronous (n = 22) gastric liver metastases that were curatively resected. RESULTS: The overall 1, 3 and 5 year survival rates after hepatic resection were 76, 48 and 42%, respectively, and the median survival was 34 months. Univariate analysis revealed that survival significantly differed between cases of solitary and multiple metastases (P = 0.03). Multivariate analysis revealed that solitary liver metastasis and the absence of serosal invasion by primary gastric cancer were favorable independent prognostic factors (P = 0.005 and P = 0.02, respectively). All eight patients who survived for more than 5 years after initial hepatectomy had a solitary metastasis, and six of these had no serosal invasion by the primary gastric cancer. No patient with multiple metastatic diseases survived beyond 3 years. CONCLUSIONS: Patients with a solitary liver metastasis are good candidates for surgical resection, whereas those with multiple gastric liver metastases should be treated by multimodal approaches.     

Liver transplantation for malignancy

Liver transplantation for hepatic malignancies has emerged from an exotic and desperate approach to a well-documented and proven treatment modality for these unfortunate patients. However, early unsatisfactory results emphasized that only a highly selected patient population would benefit from transplantation. Currently, <10% of all liver transplants performed are for hepatocellular cancer (HCC). There is no controversy that hepatoblastoma is an excellent indication in pediatric patients with unresectable tumors. Similarly, liver transplantation for HCC in the adult population yields good results for patients whose tumor masses do not exceed the Milan criteria. It remains to be determined whether patients with more extensive tumors can be reliably selected to benefit from the procedure. Adjunctive procedures like radiofrequency ablation, chemoembolization, or cryotherapy might be indicated to limit tumor progression for patients on waiting lists. Epitheloid hemangioendothelioma is also an appropriate indication for liver transplantation, unlike angiosarcoma. Metastatic liver disease is not an indication for liver transplantation, with the exception of cases in which the primary is a neuroendocrine tumor, for which liver transplantation can result in long-term survival and even cure in a number of patients. And finally, while gallbladder cancers are never an indication for liver transplantation, rare cases of cholangiocellular cancer might qualify if aggressive combination therapies, including chemotherapy and radiotherapy followed by OLT, are carried through. Survival in these selected patients can approach that for patients with cholestatic liver disease.     

Liver transplantation for symptomatic liver metastases of neuroendocrine tumours

Numerous reports have demonstrated that liver transplantation for neuroendocrine tumour metastasis is feasible. However, perioperative risks and long-term recurrences remain significant concerns. When liver transplantation is combined with extensive intestinal or pancreatic resection, the risk is particularly high.We report our institutional experience of liver transplantations performed for liver metastases secondary to neuroendocrine tumours, and in combination with a review of the literature, we propose a set of selection criteria. The key points include unresectable hepatic metastases of neuroendocrine origin, absence of extrahepatic metastases, symptomatic disease that is refractory to medical therapy, a Ki-67 level less than 2%, previous resection of the primary disease, and previous therapy for metastatic neuroendocrine tumour.In our experience, the patient in the first case had, post-transplantation, rapid disease progression because of an unidentified primary, and patient in the second case had primary non-function of the liver graft, requiring urgent re-transplantation. More recently, two liver transplantations were successfully performed. The indications were, in the first case, refractory hormonal secretion and, in the other, secondary biliary cirrhosis attributable to hepatic artery therapy with tumour in situ. Subclinical and stable recurrent disease has been detected by scintigraphy in the mesentery and lumbar spine in the former patient. A mesenteric recurrence developed in the latter patient 2 years post transplantation and was subsequently completely resected. At 4 and 5 years post transplantation, both patients are symptom-free.Recurrence after transplantation remains a significant concern, even with careful patient selection, but recurrences may remain indolent. If recurrences are progressive, they may still be amenable to additional medical or surgical therapy. A national or international consensus between oncologists and transplant specialists regarding the indications for liver transplantation is vital, because future progress will depend on careful patient selection and prospective study.     

The use of radiofrequency in cancer

Radiofrequency ablation (RFA) provides an effective technique for minimally invasive tissue destruction. An alternating current delivered via a needle electrode causes localised ionic agitation and frictional heating of the tissue around the needle. Image-guided, percutaneous ablation techniques have been developed in most parts of the body, but the most widely accepted applications are for the treatment of hepatocellular carcinoma (HCC) in early cirrhosis, limited but inoperable colorectal liver metastases, inoperable renal cell carcinoma and inoperable primary or secondary lung tumours. The procedures are well tolerated and the complication rates low. Patients with coexistent morbidity who are not suitable for surgery are often able to undergo RFA. Most treatments in the lung, kidney and for HCC are performed under conscious sedation with an overnight hospital stay or as a day-case. Larger more complicated ablations, for example, in hepatic metastases may require general anaesthesia. Limitations of RFA include the volume of tissue that can be ablated in a timely fashion, that is, most centres will treat 3-5 tumours up to 4-5 cms in diameter. Early series reporting technical success and complications are available for lung and renal ablation. Liver ablation is better established and 5-year survival figures are available from several centres. In patients with limited but inoperable colorectal metastases, the 5-year survival ranges from 26 to 30% and for HCC it is just under 50%. In summary, RFA provides the opportunity for localised tissue destruction of limited volumes of tumour; it can be offered to nonsurgical candidates and used in conjunction with systemic therapy.     

Outcome after Simultaneous Resection of Gastric Primary Tumour and Synchronous Liver Metastases: Survival Analysis of a Single-center Experience in China

Background: The optimal surgical strategy for the treatment of synchronous resectable gastric cancer livermetastases remains controversial. The aims of this study were to analyze the outcome and overall survival ofpatients presenting with gastric cancer and liver metastases treated by simultaneous resection. Materials andMethods: Between January 1990 and June 2009, 35 patients diagnosed with synchronous hepatic metastasesfrom gastric carcinoma received simultaneous resection of both primary gastric cancer and synchronous hepaticmetastases. The clinicopathologic features and the surgical results of the 35 patients were retrospectively analyzed.Results: The 5-year overall survival rate after surgery was 14.3%. Five patients survived for more than 5 yearsafter surgery. No mortality has occurred within 30 days after resection, although two patients (5.7%) developedcomplications during the peri-operative course. Univariate analysis revealed that patients with the presenceof lymphovascular invasion of the primary tumor, bilateral liver metastasis and multiple liver metastasessuffered poor survival. Lymphovascular invasion by the primary lesion and multiple liver metastases weresignificant prognostic factors that influenced survival in the multivariate analysis (p=0.02, p=0.001, respectively).Conclusions: The presence of lymphovascular invasion of the primary tumor and multiple liver metastases aresignificant prognostic determinants of survival. Gastric cancer patients without lymphovascular invasion andwith a solitary synchronous liver metastasis may be good candidates for hepatic resection. Simultaneous resectionof both primary gastric cancer and synchronous hepatic metastases may effectively prolong survival in strictlyselected patients.     

肝癌肝移植16例体会

目的：总结肝癌肝移植的临床经验，探讨原位肝移植治疗原发性肝癌的疗效。方法：回顾分析2004年7月至2006年4月16例原发性肝癌肝移植的临床资料，均采用同种异体（尸体供肝）原位全肝移植，其中7例符合Milan标准，9例符合UCSF标准。结果：16例手术全部成功，围手术期死亡2例，随访2个月-24个月，死亡2例，1例术后3个月死于胆道铸型综合征、胆道感染，1例术后6个月死于胸腰椎转移、肺转移癌，现存活12例，1例带瘤生存。结论：肝移植是原发性肝癌的有效治疗手段，应严格掌握适应证。     

Morphologic analysis of microvessels in colorectal tumors with respect to the formation of liver metastases.

BACKGROUND AND OBJECTIVES: Overexpression of VEGF and proliferation of microvessels are strongly related to liver metastases, however, morphologic analyses of microvessels in liver metastases have not been reported. The purpose of the present study was to examine the correlation between liver metastases and the diameters of microvessel lumens in the tumor tissue. METHODS: Fifty-nine patients with liver metastases from colorectal cancers and 112 patients who underwent curative colorectal resection and survived without any recurrence were reviewed. Microvessel density (MVD) and the diameters of the lumens of individual microvessels were assessed. RESULTS: There was a significant difference in terms of the mean MVD of primary tumors between patients with liver metastases and those without liver metastases. The numbers of patients with liver metastases who had microvessels 100-200 microm in diameter and microvessels more than 200 microm in diameter were significantly greater than patients without liver metastases. Microvessels with lumens more than 100 microm in diameter were not detected in the liver metastatic lesion. CONCLUSION: Large microvessels in the primary tumor favor intravasation of cancer cells.     

大肠癌伴肝转移患者的预后因素

目的探讨影响大肠癌伴肝转移患者预后的因素.方法1995年5月-1999年12月间本院外科手术治疗的64例大肠癌伴肝转移患者,部分患者全身化疗或肝动脉插管化疗,并对其临床资料进行统计分析.结果本组大肠癌肝转移患者占大肠癌患者10.2%.肝转移灶大小、术前CEA水平、原发灶切除、辅助治疗方式为影响生存的独立的预后因素.年龄、性别、肿瘤部位、分化程度、肝转移灶数目与预后无关.肝转移灶＞5cm、术前CEA＞100μg/ml、原发灶未切除的患者的生存时间(3.52月)显著低于其他患者(21.60月).结论治疗方式对肠癌肝转移患者预后影响显著,应积极切除原发灶、治疗转移灶.肝动脉插管化疗优于全身化疗.肝转移灶大小、术前CEA水平是重要的预后指标.     

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.     

MR-guided laser-induced thermotherapy (LITT) of liver tumours: experimental and clinical data

MR-guided laser-induced interstitial thermotherapy (LITT) is a percutaneous, minimally invasive treatment modality for treating liver lesions/metastases, soft tissue tumours and musculoskeletal lesions. In this group, MR-guided LITT is currently performed under local anaesthesia on an out-patient basis with a specially designed saline-cooled laser application system. Nd:YAG laser (1064?nm wave length) was used for tumour ablation. Magnetic resonance imaging (MRI) using both open and closed MR units has proven clinically effective in validating the exact positioning of optical fibres. It also allows for real time-monitoring of thermal effects and the evaluation of treatment-induced coagulation necrosis. In liver tumours, percutaneous MR-guided LITT achieves a local tumour control rate of 98.7% at 3 months post-therapy and 97.3% at 6 months with metastases smaller than 5?cm in diameter. The mean survival rate for 1259 patients with 3440 metastases treated with 14 694 laser applications at the institute (calculated with the Kaplan-Meier method) was 4.4 years (95% confidence interval: 4.1–4.8?years) and median survival was 3.00 years. No statistically significant difference in survival rates was observed in patients with liver metastases from colorectal cancer vs metastases from other primary tumours. The rate of clinically relevant side effects and complications requiring secondary treatment was 2.2%. The clinical use of MR guided LITT (size<5?cm, number<5) is justified in patients with liver metastases of colorectal and/or breast cancers if the inclusion criteria are carefully observed. Further indications for MR guided LITT include recurrent cancer lesions in the head and neck, lung metastases and bone and soft tissue lesions.     

Liver Transplantation for Malignancies

Liver transplantation (LT) has become an acceptable and effective treatment for selected patients with hepatocellular carcinoma with excellent outcomes. More recently, LT has been tried in different primary and secondary malignancies of the liver. The outcomes of LT for very selected group of patients with hilar cholangiocarcinoma (CCA) have been promising. Excellent results have been reported in LT for patients with unresectable hepatic epithelioid hemangioendothelioma (HEHE). In contrast to excellent results after LT for HEHE, results of LT for angiosarcoma have been disappointing with no long-term survivors. Hepatoblastoma (HB) is the most common primary liver cancer in pediatric age group. Long-term outcomes after LT in patients with unresectable tumor and good response to chemotherapy have been promising. Indication for LT for hepatic metastasis from neuroendocrine tumors (NETs) is mainly for patients with unresectable tumors and for palliation of medically uncontrollable symptoms. Posttransplant survival in those patients with low tumor activity index is excellent, despite recurrence of the tumor. More recent limited outcomes data on LT for unresectable hepatic metastases from colorectal cancer have claimed some survival benefit compared to the previous reports. However, due to the high rate of tumor recurrence in a very short time after LT, especially in the era of organ shortage, this indication has not been favored by the transplant community.     

Liver transplantation for unresectable malignancies: Beyond hepatocellular carcinoma

Indications for liver transplantation have expanded over the past few decades owing to improved outcomes and better understanding of underlying pathologies. In particular, there has been a growing interest in the field of transplant oncology in recent years that has led to considerable developments which have pushed the boundaries of malignant indications for liver transplantation beyond hepatocellular carcinoma (HCC). In this article, we review and summarise the published evidence for liver transplantation in non-HCC primary and metastatic liver malignancies and highlight ongoing clinical trials that address unresolved questions therein. We also examine the current technical, immunological and oncological challenges that face liver transplantation in this growing field and explore potential approaches to overcome these barriers.     

Guidelines for the detection and treatment of liver metastases of colorectal cancer

The spread of the surgical treatment for hepatic metastases have been crucial in the improvement of treatment and survival of metastatic colorectal cancer. The early and accurate diagnosis of metastases and the assessment of their size are essential factors to reach the optimal results with this treatment strategy. The precise indication of the surgical technique with or without the previous administration of neoadjuvant chemotherapy is of significant importance for the choice of R0 surgery and the timing of intervention. Although there is an agreement regarding some parameters related to diagnosis techniques and surgical criteria such as the bilobar extension, the size of the remaining liver post-surgical removal and the indication of pre-operatory chemotherapy, it is necessary to consider all these factors to set up standard criteria and optimize the results. In this article we review all these parameters, from disease follow up to detect metastatic dissemination to the basic criteria for use of neoadjuvant chemotherapy, in order to suggest some general recommendations of evidence level II and recommendation grade A.     

Vascular density in colorectal liver metastases increases after removal of the primary tumor in human cancer patients

In animal models, explosive growth of metastases after removal of the primary tumor has been attributed to abolishment of angiogenesis inhibition. We investigated the influence of (removal of) the primary tumor on vascularization of liver metastases in human colorectal cancer patients. We analyzed vascular density in synchronous liver metastases from patients with the primary tumor in situ, in synchronous metastases from patients with the primary tumor resected and in metachronous metastases. In a limited number of cases, biopsies from metastases from the same patient before and within 3 months after resection were analyzed. In addition, vascular density in metastases was compared to the vascular density in the corresponding primary tumor. Peritumoral and intratumoral vascular density were determined by staining for endothelial antigens CD31 and CD34, respectively. Both peritumoral and intratumoral vascular density were elevated in synchronous metastases from patients with the primary tumor removed compared to synchronous metastases from patients with the primary tumor in situ. Comparable results were observed in patients with metachronous metastases. An increase in vascular density after resection of the colorectal malignancy was also observed in biopsies taken from the same patient before and after tumor resection. Remarkably, vascular density in the liver metastases was always lower than that in the corresponding primary tumor. Our data show for the first time in humans that the presence of a primary tumor is correlated with decreased vascularization of its distant metastases. Resection of the primary tumor results in an increased vascularization of metastatic lesions.     

Emerging role of transplantation for primary liver cancers

Liver transplantation (LT) has been utilized in the treatment of primary hepatic malignancy for decades. Hepatocellular cancer (HCC) remains the most common malignant condition treated with LT, with almost 400 such transplants performed annually in the US. Refinement in the selection criteria for LT in patients with HCC has led to survival rates similar to those for LT in nonmalignant conditions. Excellent results have also been reported following LT for select patients with epithelioid hemangioendothelioma and hepatoblastoma. Patients with cholangiocarcinoma treated with LT have generally faired poorly, with survival rates far below that of LT for nonmalignant conditions. Improved survival has recently been reported following LT for cholangiocarcinoma in highly select patients treated with aggressive neoadjuvant therapy. The future utility of LT in the treatment of malignancy will be influenced by several factors, including a profound organ donor shortage faced worldwide; increasing prevalence of hepatitis C, HCC and cirrhosis; and the evolution of live donor liver transplantation.     

Partial volume tolerance of the liver to radiation

The use of conformal radiotherapy (RT) and the follow-up of patients for radiation liver toxicities has led to a quantitative understanding of partial liver RT tolerance. The most common toxicity is radiation-induced liver disease (RILD), a syndrome of anicteric ascites and hepatomegaly. Elevation of transaminases and reactivation of viral hepatitis have also been reported after liver RT. The Lyman normal tissue complication probability (NTCP) model and a local damage-organ injury NTCP model have been used to describe the partial tolerance of the liver to RT. The liver exhibits a large volume effect and a low threshold volume for RILD. The RT tolerance of the liver is reduced in patients with primary liver cancer versus metastases. Elevated transaminases are more common in the presence of poor liver function and hepatitis B infection. If the effective liver volume irradiated is less than 25%, very high RT doses may be delivered with little risk of liver toxicity. The mean liver doses associated with a 5% risk of classic RILD for primary and metastatic liver cancer are 28 Gy and 32 Gy, respectively, in 2 Gy per fraction.