Liver transplantation as an alternative for the treatment of non-resectable liver colorectal cancer: Advancing the therapeutic algorithm

Colorectal cancer is a leading cause of cancerrelated mortality,with nearly half of the affected patients developing liver metastases.For three decades,liver resection(LR)has been the primary curative strategy,yet its applicability is limited to about 20%of cases.Liver transplantation(LT)for unresectable metastases was attempted unsuccessfully in the 1990s,with high rates of perioperative death and recurrence.There is now more interest in this strategy due to improvements in systemic therapies and surgical techniques.A significant study conducted by the Oslo group showed that patients receiving liver transplants had a 60%chance of survival after five years.Significantly better results have been achieved by using advanced imaging for risk stratification and further refining selection criteria,especially in the Norvegian SECA trials.This review carefully charts the development and history of LT as a treatment option for colorectal cancer liver metastases.The revolutionary path from the early days of exploratory surgery to the current situation of cautious optimism is traced,highlighting the critical clinical developments and improved patient selection standards that have made LT a potentially curative treatment for such challenging very well selected cases.

Current state of surgical treatment of liver metastases from colorectal cancer

Hepatic resection is the procedure of choice for curative treatment of colorectal liver metastases(CLM).Objectives of surgical strategy are low intraoperative blood loss,short liver ischemic times and minor postoperative morbidity and mortality.Blood loss is an independent predictor of mortality and compromises,in common with postoperative complications,long-term outcome after hepatectomy for CLM.The type of liver resection has no impact on the outcome of patients with CLM;wedge resections are not inferior to anatomical resections in terms of tumor clearance,pattern of recurrence or survival.Despite the lack of proof of survival benef it,routine lymphadenectomy has been advocated,allowing the detection of microscopic lymph node metastases and with prognostic value.In experienced hands,minimally invasive liver surgery is safe with acceptable morbidity and mortality and oncological results comparable to open hepatic surgery,but with reduced blood loss and earlier recovery.The European Colorectal Metastases Treatment Group recommended treating up front with chemotherapy for patients with both resectable and unresectable CLM.However,neoadjuvant chemotherapy can induce damage to the remnant liver,dependent on the number of chemotherapy cycles.Therefore,in our opinion,preoperative chemotherapy should be reserved for patients whose CLM are marginally resectable or unresectable.A meta analysis of randomized trials dealing with perioperative chemotherapy for the treatment of resectable CLM demonstrated a benefit of systemic chemotherapy but did not answer the question of whether a neoadjuvant or adjuvant approach should be preferred.Analysis of the literature demonstrates that the results of specialized centers cannot be attained in the reality of comprehensive patient care.Reasons behind the commonly poorer results seen in cancer networks as compared with literature-based data are,on the one hand,geographical disparities in access to specialized surgical and medical care.On the other hand,a selection bias in the reports of the literature may be assumed.Studies of surgical resection for CLM derive almost exclusively from case series generally drawn from large academic centers where patient selection or surgical expertise is superior to what is found in many communities.Therefore,we may conclude that the comprehensive propagation of the standards outlined in this paper constitutes a major task in the near future to reduce the variations in survival of patients with CLM.

Pathologic response after preoperative therapy predicts prognosis of Chinese colorectal cancer patients with liver metastases

Background: Pathologic response is evaluated according to the extent of tumor regression and is used to estimate the efficacy of preoperative treatment. Several studies have reported the association between the pathologic response and clinical outcomes of colorecal cancer patients with liver metastases who underwent hepatectomy.However, to date, no data from Chinese patients have been reported. In this study, we aimed to evaluate the association between the pathologic response to pre-hepatectomy chemotherapy and prognosis in a cohort of Chinese patients.Patients and methods: In this retrospective study, we analyzed the data of 380 liver metastases in 159 patients.The pathologic response was evaluated according to the tumor regression grade(TRG).The prognostic role of pathologic response in recurrence-free survival(RFS) and overall survival(OS) was assessed using Kaplan-Meier curves with the log-rank test and multivariate Cox models. Factors that had potential influence on pathologic response were also analyzed using multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests.Results: Patients whose tumors achieved pathologic response after preoperative chemotherapy had significant longer RFS and OS than patients whose tumor had no pathologic response to chemotherapy(median RFS: 9.9 vs.6.5 months, P = 0.009; median OS: 40.7 vs. 28.1 months, P = 0.040). Multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests showed that metastases with small diameter, metastases from the left-side primary tumors,and metastases from patients receiving long-duration chemotherapy had higher pathologic response rates than their control metastases(all P < 0.05). A decrease in the serum carcinoembryonic antigen(CEA) level after preoperative chemotherapy predicted an increased pathologic response rate(P < 0.05). Although the application of targeted therapy did not significantly influence TRG scores of all cases of metastases, the addition of cetuximab to chemotherapy resulted in a higher pathologic response rate when combined with irinotecan-based regimens rather than with oxaliplatin-based regimens.Conclusions: We found that the evaluation of pathologic response may predict the prognosis of Chinese colorectal cancer patients with liver metastases after preoperative chemotherapy. Small tumor diameter, long-duration chemotherapy, left primary tumor, and decreased serum CEA level after chemotherapy are associated with increased pathologic response rates.

Multidisciplinary approach of colorectal cancer liver metastases

Large bowel cancer is a worldwide public health challenge.More than one third of patients present an advanced stage of disease at diagnosis and the liver is the most common site of metastases.Selection criteria for early diagnosis,chemotherapy and surgery have been recently expanded.The definition of resectability remains unclear.The presence of metastases is the most significant prognostic factor.For this reason the surgical resection of hepatic metastases is the leading treatment.The most appropriate resection approach remains to be defined.The two step and simultaneous resection processes of both primary and metastases have comparable survival long-term outcomes.The advent of targeted biological chemotherapeutic agents and the development of loco-regional therapies(chemoembolization,thermal ablation,arterial infusion chemotherapy) contribute to extend favorable results.Standardized evidence-based protocols are missing,hence optimal management of hepatic metastases should be single patient tailored and decided by a multidisciplinary team.This article reviews the outcomes of resection,systemic and loco-regional therapies of liver metastases originating from large bowel cancer.

Artificial intelligence in the diagnosis and management of colorectal cancer liver metastases

Colorectal cancer(CRC)is the third most common malignancy worldwide,with approximately 50%of patients developing colorectal cancer liver metastasis(CRLM)during the follow-up period.Management of CRLM is best achieved via a multidisciplinary approach and the diagnostic and therapeutic decision-making process is complex.In order to optimize patients’survival and quality of life,there are several unsolved challenges which must be overcome.These primarily include a timely diagnosis and the identification of reliable prognostic factors.Furthermore,to allow optimal treatment options,a precision-medicine,personalized approach is required.The widespread digitalization of healthcare generates a vast amount of data and together with accessible high-performance computing,artificial intelligence(AI)technologies can be applied.By increasing diagnostic accuracy,reducing timings and costs,the application of AI could help mitigate the current shortcomings in CRLM management.In this review we explore the available evidence of the possible role of AI in all phases of the CRLM natural history.Radiomics analysis and convolutional neural networks(CNN)which combine computed tomography(CT)images with clinical data have been developed to predict CRLM development in CRC patients.AI models have also proven themselves to perform similarly or better than expert radiologists in detecting CRLM on CT and magnetic resonance scans or identifying them from the noninvasive analysis of patients’exhaled air.The application of AI and machine learning(ML)in diagnosing CRLM has also been extended to histopathological examination in order to rapidly and accurately identify CRLM tissue and its different histopathological growth patterns.ML and CNN have shown good accuracy in predicting response to chemotherapy,early local tumor progression after ablation treatment,and patient survival after surgical treatment or chemotherapy.Despite the initial enthusiasm and the accumulating evidence,AI technologies’role in healthcare and CRLM management is not yet fully established.Its limitations mainly concern safety and the lack of regulation and ethical considerations.AI is unlikely to fully replace any human role but could be actively integrated to facilitate physicians in their everyday practice.Moving towards a personalized and evidence-based patient approach and management,further larger,prospective and rigorous studies evaluating AI technologies in patients at risk or affected by CRLM are needed.

Incomplete radiofrequency ablation provokes colorectal cancer liver metastases through heat shock response by PKCα/Fra-1 pathway

Objective: Incomplete radiofrequency ablation(ICR) has been proposed as a major cause of recurrence in the treatment of hepatic metastatic tumors.We tried to determine the mechanisms of this progression in colorectal cancer(CRC) liver metastasis(CRLMs)Methods: We have established a mouse model of radiofrequency ablation(RFA) therapy to demonstrate increased risk of recurrence of CRLMs with ICR.Here we focused on heat shock-induced CRC malignancy.Sub-lethal heat shock(HS) in CRC cell lines provoked cell growth, invasion, and tumor initiation in vitro and in vivo.Results: We found that Fra-1, which lies downstream of PKCα-ERK1/2 signaling, was significantly increased by HS compared with the untreated CRC cells.Silencing Fra-1 reversed the tumor promoting effects of HS.Furthermore, proliferation and tumor initiation inducer c-Myc, together with tumor invasion inducer matrix-metalloprotase 1(MMP-1) expression were up-regulated by AP-1/Fra-1 induced genes transcription.Conclusions: Our study demonstrated that ICR generated HS induces CRC malignancy by targeting Fra-1, which could be a potential prognostic marker and a promising therapeutic strategy to prevent disease recurrence after radiofrequency ablation treatment.

Associating liver partition and portal vein ligation for staged hepatectomy in the treatment of colorectal cancer liver metastases

Colorectal cancer(CRC)is a common malignancy of the digestive system.Colorectal liver cancer metastasis(CRLM)occurs in approximately 50%of the patients and is the main cause of CRC mortality.Surgical resection is currently the most effective treatment for CRLM.However,given that the remnant liver volume after resection should be adequate,only a few patients are suitable for radical resection.Since Dr.Hans Schlitt first performed the associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)for CRLM in 2012,ALPPS has received considerable attention and has continually evolved in recent years.This review explains the technical origin of the ALPPS procedure for CRLM and evaluates its efficacy,pointing to its favorable postoperative outcomes.We also discuss the patient screening strategies and optimization of ALPPS to ensure long-term survival of patients with CRLM in whom surgery cannot be performed.Finally,further directions in both basic and clinical research regarding ALPPS have been proposed.Although ALPPS surgery is a difficult and high-risk technique,it is still worth exploration by experienced surgeons.

Association of p53 codon 72 polymorphism with liver metastases of colorectal cancers positive for p53 overexpression

在 72 多型性(R72P ) 和颜色的风险上评估在 p53 鳕鱼之间的协会的目的表面的肝转移。p53 R72P 遗传型被聚合酶链反应限制识别的方法碎裂在 78 连续颜色的长度多型性(PCR-RFLP ) 方法有肝转移和 214 年龄的表面的癌症病人 -- 并且有非变形的颜色的匹配性的盒子表面的癌症。p53 R72P 多型性的 R 等位基因更经常比在非变形的盒子(P=0.075 ) 中在变形情况中被发现的结果。72R 等位基因的搬运人有 2.25 褶层(95% CI (置信区间)= 1.05 &#8764;4.83 ) 肝转移的增加的风险。在层化分析上， 72R-carrying 遗传型授与 3.46 褶层(95% CI=1.02&#8764;11.72 ) ， 1.05 褶层(95% CI=0.36&#8764;3.08 ) 为 overexpression 积极、否定的 p53 增加了肝转移的风险分别地渲染表面的癌症。这些结果第一次表明的结论 p53 多型性的 72R 等位基因在颜色为肝转移有增加的风险为在表示上的 p53 积极的表面的癌症。

Differential analysis revealing APOC1 to be a diagnostic and prognostic marker for liver metastases of colorectal cancer

BACKGROUND Colorectal cancer(CRC)is one of the most malignant gastrointestinal cancers worldwide.The liver is the most important metastatic target organ,and liver metastasis is the leading cause of death in patients with CRC.Owing to the lack of sensitive biomarkers and unclear molecular mechanism,the occurrence of liver metastases cannot be predicted and the clinical outcomes are bad for liver metastases.Therefore,it is very important to identify the diagnostic or prognostic markers for liver metastases of CRC.AIM To investigate the highly differentially expressed genes(HDEGs)and prognostic marker for liver metastases of CRC.METHODS Data from three NCBI Gene Expression Omnibus(GEO)datasets were used to show HDEGs between liver metastases of CRC and tumour or normal samples.These significantly HDEGs of the three GEO datasets take the interactions.And these genes were screened through an online tool to explore the prognostic value.Then,TIMER and R package were utilized to investigate the immunity functions of the HDEGs and gene set enrichment analysis was used to explore their potential functions.RESULTS Based on the selection criteria,three CRC datasets for exploration(GSE14297,GSE41258,and GSE49355)were chosen.Venn diagrams were used to show HDEGs common to the six groups and 47 HDEGs were obtained.The HDEGs were shown by using STRING and Cytoscape software.Based on the TCGA database,APOC1 showed significantly different expression between N2 and N0,and N2 and N1.And there was also a significant difference in expression between T2 and T4,and between T2 and T3.In 20 paired CRC and normal tissues,quantitative real-time polymerase chain reaction illustrated that the APOC1 mRNA was strongly upregulated in CRC tissues(P=0.014).PrognoScan and GEPIA2 revealed the prognostic value of APOC1 for overall survival and diseasefree survival in CRC(P<0.05).TIMER showed that APOC1 has a close relationship with immune infiltration(P<0.05).CONCLUSION APOC1 is a biomarker that is associated with both the diagnosis and prognosis of liver metastases of CRC.

Clinical implications and mechanism of histopathological growth pattern in colorectal cancer liver metastases

Liver is the most common site of metastases of colorectal cancer,and liver metastases present with distinct histopathological growth patterns(HGPs),including desmoplastic,pushing and replacement HGPs and two rare HGPs.HGP is a miniature of tumor-host reaction and reflects tumor biology and pathological features as well as host immune dynamics.Many studies have revealed the association of HGPs with carcinogenesis,angiogenesis,and clinical outcomes and indicates HGP functions as bond between microscopic characteristics and clinical implications.These findings make HGP a candidate marker in risk stratification and guiding treatment decision-making,and a target of imaging observation for patient screening.Of note,it is crucial to determine the underlying mechanism shaping HGP,for instance,immune infiltration and extracellular matrix remodeling in desmoplastic HGP,and aggressive characteristics and special vascularization in replacement HGP(rHGP).We highlight the importance of aggressive features,vascularization,host immune and organ structure in formation of HGP,hence propose a novel"advance under camouflage"hypothesis to explain the formation of rHGP.

Improving definition of the term “synchronous liver metastases” from colorectal cancer

The liver is the most frequent site of metastasis in colorectal cancer with up to a quarter of patients having liver metastases at the time of initial diagnosis and a further third subsequently developing liver lesions.Patients who present with metastatic liver disease after treatment of the primary(termed metachronous disease)receive care focused on this new metastatic disease.In contrast,the management of patients who present with colorectal cancer and concurrent liver

Multisciplinary management of patients with liver metastasis from colorectal cancer

Colorectal cancer(CRC) is one of the leading causes of cancer-related death. Surgery, radiotherapy and chemotherapy have been till now the main therapeutic strategies for disease control and improvement of the overall survival. Twenty-five per cent(25%) of CRC patients have clinically detectable liver metastases at the initial diagnosis and approximately 50% develop liver metastases during their disease course. Twentythirty per cent(20%-30%) are CRC patients with metastases confined to the liver. Some years ago various studies showed a curative potential for liver metastases resection. For this reason some authors proposed the conversion of unresectable liver metastases to resectable to achieve cure. Since those results were published, a lot of regimens have been studied for resectability potential. Better results could be obtained by the combination of chemotherapy with targeted drugs, such as anti-VEGF and antiEGFR monoclonal antibodies. However an accurate selection for patients to treat with these regimens and to operate for liver metastases is mandatory to reduce the risk of complications. A multidisciplinary team approach represents the best way for a proper patient management. The team needs to include surgeons, oncologists, diagnostic and interventional radiologists with expertise in hepatobiliary disease, molecular pathologists, and clinical nurse specialists. This review summarizes the most important findings on surgery and systemic treatment of CRC-related liver metastases.

Multi-modality treatment of colorectal liver metastases

Liver metastases synchronously or metachronously occur in approximately 50% of colorectal cancer patients. Multimodality comprehensive treatment is the best therapeutic strategy for these patients. However, the optimal pattern of multimodality therapy is still controversial, and it raises several signif icant concerns. Liver resection is the most important treatment for colorectal liver metastases. The defi nition of resectability has shifted to focus on the completion of R0 resection and normal liver function maintenance. The role of neoadjuvant and adjuvant chemotherapy still needs to be clarified. The management of either progression or complete remission during neoadjuvant chemotherapy is challenging. The optimal sequencing of surgery and chemotherapy in synchronous colorectal liver metastases patients is still unclear. Conversional chemotherapy, portal vein embolization, two-stage resection, and tumor ablation are effective approaches to improve resectability for initially unresectable patients. Several technical issues and concerns related to these methods need to be further explored. For patients with def initely unresectable liver disease, the necessity of resecting the primary tumor is still debatable, and evaluatingand predicting the eff icacy of targeted therapy deserve further investigation. This review discusses different patterns and important concerns of multidisciplinary treatment of colorectal liver metastases.

Preoperative selection of patients with colorectal cancerliver metastasis for hepatic resection

Surgical resection of colorectal liver metastases(CRLM) has a well-documented improvement in survival. To benefit from this intervention, proper selection of patients who would be adequate surgical candidates becomes vital. A combination of imaging techniques may be utilized in the detection of the lesions. The criteria for resection are continuously evolving; currently, the requirements that need be met to undergo resection of CRLM are: the anticipation of attaining a negative margin(R0 resection), whilst maintaining an adequate functioning future liver remnant. The timing of hepatectomy in regards to resection of the primary remains controversial; before, after, or simultaneously. This depends mainly on the tumor burden and symptoms from the primary tumor. The role of chemotherapy differs according to the resectability of the liver lesion(s); no evidence of improved survival was shown in patients with resectable disease who received preoperative chemotherapy. Presence of extrahepatic disease in itself is no longer considered a reason to preclude patients from resection of their CRLM, providing limited extra-hepatic disease, although this currently is an area of active investigations. In conclusion, we review the indications, the adequate selection of patients and perioperative factors to be considered for resection of colorectal liver metastasis.

An update on chemotherapy of colorectal liver metastases

Surgical resection of liver metastases of colorectal cancer greatly improves the clinical outcome of patients with advanced disease. Developments in chemotherapeutic agents and strategies bring hope of a cure to patients with initially unresectable colorectal liver metastases (CLM). Perioperative chemotherapy signif icantly improves the survival time of patients who receive curative-intent hepatectomy. Even for unresectable CLM, recent studies demonstrated that active preoperative chemotherapy could achieve shrinkage of liver metastasis and thus render some for resection. Furthermore, an increase in tumor resection rate and prolonged survival time among patients with CLM has been observed following the application of monoclonal antibodies in recent years. However, the value of chemotherapy via hepatic arterial infusion is still unclear. More trials should be conducted in patients with CLM in order to improve survival.

Anti-EGFR and anti-VEGF agents:Important targeted therapies of colorectal liver metastases

Colorectal liver metastasis(CLM)is common worldwide.Targeted therapies with monoclonal antibodies have been proven effective in numerous clinical trials,and are now becoming standards for patients with CLM.Thedevelopment and application of anti-epidermal growth factor receptor(anti-EGFR)and anti-vascular endothelial growth factor(anti-VEGF)antibodies represents significant advances in the treatment of this disease.However,new findings continue to emerge casting doubt on the efficacy of this approach.The Kirsten ratsarcoma viral oncogene(KRAS)has been proven to be a crucial predictor of the success of anti-EGFR treatment in CLM.Whereas a recent study summarizedseveral randomized controlled trials,and showed thatpatients with the KRAS G13D mutation significantlybenefited from the addition of cetuximab in terms of progress-free survival(PFS,4.0 mo vs 1.9 mo,HR=0.51,P=0.004)and overall survival(OS,7.6 mo vs5.7 mo,HR=0.50,P=0.005).Some other studiesalso reported that the KRAS G13D mutation might notbe absolutely predictive of non-responsiveness to antiEGFR therapy.At the same time,"new"RAS mutations,including mutations in neuroblastoma RAS viral(vras)oncogene homolog(NRAS)and exons 3 and 4 of KRAS,have been suggested to be predictors of a poor treatment response.This finding was first reported by the update of the PRIME trial.The update showed that for patients with non-mutated KRAS exon 2 but other RAS mutations,panitumumab-fluorouracil,leucovorin,and oxaliplatin(FOLFOX)4 treatment led to inferior PFS(HR=1.28,95%CI:0.79-2.07)and OS(HR=1.29,95%CI:0.79-2.10),which was consistent with the findings in patients with KRAS mutations in exon 2.Then,the update of the PEAK trial and the FIRE-Ⅲtrial also supported this finding,which would reduce candidates for anti-EGFR therapy but enhance the efficacy.In firstline targeted combination therapy,the regimens of cetuximab plus FOLFOX was called into question because of the inferior prognosis in the COIN trial and the NORDIC-Ⅶtrial.Also,bevacizumab plus oxaliplatin-based chemotherapy was questioned because of the NO16966trial.By the update and further analysis of the COIN trial and the NORDIC-Ⅶtrial,cetuximab plus FOLFOX was reported to be reliable again.But bevacizumab plus oxaliplatin-based chemotherapy was still controversial.In addition,some trials have reported that bevacizumab is not suitable for conversion therapy.The results of the FIRE-Ⅲtrial showed that cetuximab led to a significant advantage over bevacizumab in response rate(72%vs 63%,P=0.017)for evaluable population.With the balanced allocation of second-line treatment,the FIRE-Ⅲtrial was expected to provide evidence for selecting following regimens after first-line progression.There is still no strong evidence for the efficacy of targeted therapy as a preoperative treatment for resectable CLM or postoperative treatment for resected CLM,although the combined regimen is often administered based on experience.Combination therapy with more than one targeted agent has been proven to provide no benefit,and even was reported to be harmful as first-line treatment by four large clinical trials.However,recent studies reported positive results of erlotinib plus bevacizumab for maintenance treatment.The mechanism of antagonism between different targeted agents deserves further study,and may also provide greater understanding of the development of resistance to targeted agents.

Non-invasive diagnostic imaging of colorectal liver metastases

Colorectal cancer is one of the few malignant tumors in which synchronous or metachronous liver metastases [colorectal liver metastases(CRLMs)] may be treated with surgery. It has been demonstrated that resection of CRLMs improves the long-term prognosis. On the other hand, patients with un-resectable CRLMs may benefit from chemotherapy alone or in addition to liverdirected therapies. The choice of the most appropriate therapeutic management of CRLMs depends mostly on the diagnostic imaging. Nowadays, multiple non-invasive imaging modalities are available and those have a pivotal role in the workup of patients with CRLMs. Although extensive research has been performed with regards to the diagnostic performance of ultrasonography, computed tomography, positron emission tomography and magnetic resonance for the detection of CRLMs, the optimal imaging strategies for staging and follow up are still to be established. This largely due to the progressive technological and pharmacological advances which are constantly improving the accuracy of each imaging modality. This review describes the non-invasive imaging approaches of CRLMs reporting the technical features, the clinical indications, the advantages and the potential limitations of each modality, as well as including some information on the development of new imaging modalities, the role of new contrast media and the feasibility of using parametric image analysis as diagnostic marker of presence of CRLMs.

Treatment strategy for colorectal cancer with resectable synchronous liver metastases:Is any evidence-based strategy possible?

Fifteen percent to twenty-five percent of patients affected by colorectal cancer presents with liver metastases at diagnosis. In resectable cases, surgery is the only potentially curative treatment and achieves survival rates up to 50% at 5 years. Management is complex, as colorectal resection, liver resection, chemotherapy, and, in locally advanced mid/low rectal tumors, radiotherapy have to be integrated. Modern medical practice usually relies on evidence-based protocols. Levels of evidence for synchronous metastases are poor:published studies include few recent prospective series and several retrospective analyses collecting a limited number of patients across long periods of time. Data are difficult to be generalized and are mainly representative of single centre's experience, biased by local recruitment, indications and surgical technique. In this context, surgeons have to renounce to "evidence-based medicine" and to adopt a sort of "experience-based medicine". Anyway, some suggestions are possible. Simultaneous colorectal and liver resection can be safely performed whenever minor hepatectomies are planned, while a case-by-case evaluation is mandatory in case of more complex procedures. Neoadjuvant chemotherapy is preferentially scheduled for patients with advanced metastatic tumors to assess disease biology and to control lesions. It can be safely performed with primarytumor in situ , even planning simultaneous resection at its end. Locally advanced mid/low rectal tumor represents a further indication to neoadjuvant therapies, even if treatment's schedule is not yet standardized. In summary, several issues have to be solved, but every single HPB centre should define its proper strategy to optimize patient's selection, disease control and safety and completeness of surgery.

Surgical treatment of hepatic metastases from colorectal cancer

Colorectal carcinoma is one of the most frequent cancers in Western societies with an incidence of around 700 per million people.About half of the patients develop metastases from the primary tumor and liver is the primary metastatic site.Improved survival rates after hepatectomy for metastatic colorectal cancer have been reported in the last few years and these may be the result of a variety of factors,such as advances in systemic chemotherapy,radiographic imaging techniques that permit more accurate determination of the extent and location of the metastatic burden,local ablation methods,and in surgical techniques of hepatic resection.These have led to a more aggressive approach towards liver metastatic disease,resulting in longer survival.The goal of this paper is to review the role of various forms of surgery in the treatment of hepatic metastases from colorectal cancer.

Preoperative administration of bevacizumab is safe for patients with colorectal liver metastases

AIM:To assess the impact of preoperative neoadjuvant bevacizumab(Bev)on the outcome of patients undergoing resection for colorectal liver metastases(CLM). METHODS:Eligible trials were identified from Medline, Embase,Ovid,and the Cochrane database.The data were analyzed with fixed-effects or random-effects models using Review Manager version 5.0. RESULTS:Thirteen nonrandomized studies with a total of 1431 participants were suitable for meta-analysis. There was no difference in overall morbidity and severe complications between the Bev+group and Bev-group (43.3%vs 36.8%,P=0.06;17.1%vs 11.4%,P=0.07,respectively).Bev-related complications including wound and thromboembolic/bleeding events were also similar in the Bev+and Bev-groups(14.4%vs 8.1%, P=0.21;4.1%vs 3.8%,P=0.98,respectively).The incidence and severity of sinusoidal dilation were lower in patients treated with Bev than in patients treated without Bev(43.3%vs 63.7%,P<0.001;16.8%vs 46.5%,P<0.00,respectively). CONCLUSION:Bev can be safely administered before hepatic resection in patients with CLM,and has a protective effect against hepatic injury in patients treated with oxaliplatin chemotherapy.