联合肝脏离断和门静脉结扎的二步肝切除治疗结直肠癌肝转移

目的探讨联合肝脏离断和门静脉结扎的2步肝切除新技术在提高结直肠癌肝转移患者可切除的意义.方法结直肠癌肝转移患者接受联合肝脏离断和门静脉结扎的2步肝切除,手术第1步,门静脉右支结扎后离断右三肝和左外侧叶肝实质,待健侧肝组织增生后再行右三肝切除.结果第1步手术后7 d,残肝体积从313.5 m L增加到559.1 m L,并在第1步手术后8 d,第2步手术行右三肝切除.第2步手术后8 d患者顺利出院,肝功能恢复基本正常,联合肝脏离断和门静脉结扎的二步肝切除诱导了残肝组织快速的增生.结论联合肝脏离断和门静脉结扎的二步肝切除提高了结直肠癌肝转移患者的可切除率.联合肝脏离断和门静脉结扎的二步肝切除有较高的并发症率和死亡率,因此需要仔细选择手术患者;该术式的可行性、安全性还需要进一步研究评估.

结肠直肠癌肝转移的射频消融治疗

目的:评价结直肠癌肝转移(colorectal cancer liver metastases,CRLM)射频消融(radiofrequency ablation,RFA)治疗的可行性。方法:2003年12月至2008年11月67例结直肠癌肝转移患者在西安交通大学医学院第一附属医院接受了RFA治疗。根据实施RFA治疗的方法将患者分成3组:经皮穿刺RFA(第1组)、开腹RFA(第2组)或经皮RFA与手术相结合的方法(第3组)。结果:RFA后90天,3组的死亡率均为零。一半的患者(34/67)出现手术后轻度发热。1/4的患者(17/67)有右肩部与右季肋部疼痛或不适。1例并发结肠瘘。随访显示1年、3年和5年生存率分别是100%、34.3%和4.5%。结论:对CRLM的患者,RFA或结合肝切除手术是相对微创、安全可行的方法,而且致死率低。

高龄结直肠癌肝转移患者手术切除的安全性和可行性

目的本研究比较不同年龄段结直肠癌肝转移患者手术切除后的总体生存率及无病生存率,对比分析高龄患者行手术切除的安全性及可行性。方法回顾分析137例结直肠癌肝转移患者。根据年龄分为高龄组(≥75岁,17例)、老年组(≥65岁~<75岁,75例)和年轻组(<65岁,45例)。比较3组患者间的手术切除时长、输血量、术后住院时间及术后相关并发症。结果肝转移癌患者30天、60天病死率均明显升高(高龄组:5.9%和5.9%;老年组:2.7%和4%;年轻组:0%和2.2%)与年龄无显著相关性。高龄组、老年组和年轻组的5年总体生存率(OS)均较高,分别为40%、32%和45%,其差异无统计学意义(P>0.05)。3组患者1、3、5年的无病生存率(DFS)没有明显差距。3组患者术后并发症及患者1、3、5年无病生存率(DFS)差异无统计学意义(P>0.05),且年龄无显著相关性。结论研究显示高龄患者手术后并发症发生率及病死率与青年患者相比差异无统计学意义(P>0.05)。因而,年龄并不能作为结直肠癌肝转移患者手术切除的禁忌证,手术切除治疗仍是高龄肝转移患者的首选治疗方案。伴随严格的术前患者情况评估后,高龄患者结直肠癌肝转移进行手术切除具有一定的安全性及可行性。

慢性肝病伴发趋化因子异变与结直肠癌肝转移的研究进展

近年来,中国结直肠癌(colorectal cancer,CRC)发病率快速上升,已成世界第一结直肠癌大国。肝脏局部微环境通过趋化因子-受体轴,募集特定亚群髓系细胞,促进结直肠癌肝转移(colorectal liver metastasis,CRLM)病灶进展。中国大部分CRC患者同时伴发慢性乙型肝炎(chronic hepatitis B,CHB)、非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)、酒精性肝病(alcoholic liver disease,ALD)等非肿瘤性慢性肝脏疾病,上述慢性肝病中也伴随有趋化因子表达的异常改变,其中有部分已被发现与肿瘤转移相关。本文对CRC、CHB、NAFLD及ALD近年来在中国的流行病学变化趋势进行简要回顾,对上述不同类型慢性肝病中所伴发的趋化因子的异常改变进行简要总结。对照已报道与CRLM相关的趋化因子种类及其机制,对不同慢性肝病可能通过类似的趋化因子-髓系细胞途径促进CRLM的发生及其机制进行综述。

无法治愈的晚期结直肠癌肝转移患者的临床病理特征与姑息性治疗预后的生存分析

目的:通过分析无法治愈的晚期结直肠癌肝转移患者临床病理特征与姑息性治疗预后的相互关系,探讨姑息性治疗对患者预后生存的影响。方法:回顾性分析第二军医大学东方肝胆外科医院自2009年1月至2009年12月收治的82例无法治愈的晚期结直肠癌肝转移患者临床资料。采用Kaplan-Meier法计算生存率及生存曲线,并进行单因素分析,采用Log-rank进行统计学检验。经单因素分析对预后有统计学意义的危险因素带入COX多因素回归模型,计算独立预后因素。结果:总体中位生存期为19.09个月,1、2、3年累计生存率分别为82%、28%、13%;对经过严格筛选,评估原发病灶与肝内转移灶可以完整切除而肝外不可切除的转移灶未予以手术处理但生长局限,术中发现肿瘤侵犯周围组织、器官仍可局部切除,且具备强烈手术意愿的晚期结直肠癌肝转移患者实施姑息性手术切除,术后中位生存期、1年、2年累计生存率均显著优于非手术治疗者:27.00个月vs 16.36个月,85%vs 79%,57%vs 0(P<0.001)。对于总体生存期而言,单因素分析显示:不同的治疗方式、肝转移瘤生长位置、肝内转移灶数目为影响患者预后的因素(P<0.05);COX多因素分析结果显示:非手术治疗方式、肝内转移灶多发是对无法治愈的晚期结直肠癌肝转移患者姑息性治疗预后产生影响的独立危险因素。结论:对于经过严格筛选,评估原发病灶与肝内转移灶可以完整切除而肝外不可切除的转移灶未予以手术处理但生长局限,术中发现肿瘤侵犯周围组织、器官仍可局部切除且具备强烈手术意愿的结直肠癌肝转移患者,接受姑息性手术治疗,其生存优于非手术治疗患者。

肝动脉灌注化疗治疗大肠癌肝转移的研究进展

肝脏是结直肠癌远处转移最为常见的器官之一,正确有效地处理肝转移将会为患者的预后提供良好保障。目前外科手术切除治疗仍是大肠癌肝转移的首选治疗手段,但肝内转移瘤的复发仍是目前治疗的难点。随着相关技术的不断发展以及人们对大肠癌肝转移研究的不断深人,肝动脉灌注化疗为大肠癌肝转移的临床治疗提供了新的研究方向。

KHK-A promotes fructose-dependent colorectal cancer liver metastasis by facilitating the phosphorylation and translocation of PKM2

Excessive fructose diet is closely associated with colorectal cancer(CRC)progression.Nevertheless,fructose’s specific function and precise mechanism in colorectal cancer liver metastasis(CRLM)is rarely known.Here,this study reported that the fructose absorbed by primary colorectal cancer could accelerate CRLM,and the expression of KHK-A,not KHK-C,in liver metastasis was higher than in paired primary tumors.Furthermore,KHK-A facilitated fructose-dependent CRLM in vitro and in vivo by phosphorylating PKM2 at Ser37.PKM2 phosphorylated by KHK-A inhibited its tetramer formation and pyruvic acid kinase activity but promoted the nuclear accumulation of PKM2.EMT and aerobic glycolysis activated by nuclear PKM2 enhance CRC cells’migration ability and anoikis resistance during CRLM progression.TEPP-46 treatment,targeting the phosphorylation of PKM2,inhibited the pro-metastatic effect of KHK-A.Besides,c-myc activated by nuclear PKM2 promotes alternative splicing of KHK-A,forming a positive feedback loop.

A machine learning model for colorectal liver metastasis post-hepatectomy prognostications: several strategies for the model evaluation

With great interest,we read the article by Lam et al.(1)entitled“A machine learning model for colorectal liver metastasis post-hepatectomy prognostications”.In this study,the authors included colorectal liver metastasis(CRLM)patients from four hospitals in Hong Kong who underwent hepatic resection,and developed a survival prediction model based on the patients’demographic,oncologic,clinicopathologic,and therapeutic characteristics using machine learning.Through Cox proportional hazards and least absolute shrinkage and selection operator(LASSO)regression analyses,the authors successfully developed a predictive model consisting of eight predictors that could accurately predict overall survival(OS)and recurrence-free survival(RFS)after hepatectomy in patients with CRLM.This is an intriguing study with significant clinical value,and the authors deserve to be commended for their efforts.However,there are still several issues that need to be addressed in this study.

Liver transplantation for colorectal liver metastasis:the exception,not the rule

Approximately half of individuals diagnosed with colorectal cancer(CRC)will develop colorectal liver metastasis(CRLM)during the course of their disease(1,2).Liver resection is the only potentially curative treatment for patients with CRLM,yet less than 20%of individuals are candidates for resection due to the extent or location of liver disease,underlying liver function and/or presence of extrahepatic metastases(1,2).In addition,the oncologic benefit of liver resection for CRLM is limited by recurrence rates than can be as high as 70%(3).Liver transplantation(LT)for CRLM was initially proposed as an alternative treatment strategy in the early 1990s but was abandoned due to the initial poor outcomes(3,4).The concept of transplantation for CRLM was later revisited in the 2000s by a group in Oslo,Norway that reported promising results in the SECA-I pilot study(5).Since the completion of the SECA-I study,the Norwegian group has also published other promising data from the SECA-II study(6).In addition,other notable outcomes have been reported in the RAPID study(7),as well as another study from specialized centers in North America(8),both of which have revitalized the concept of LT for CRLM.

The role of MRI in modifying surgical management of colorectal liver metastases:a lesson from the CAMINO trial

The CAMINO trial by Görgec et al.(1)assessed the added diagnostic value of contrast-enhanced(CE)magnetic resonance imaging(MRI)using gadoxetic acid and diffusion-weighted imaging for patients with colorectal liver metastases(CRLMs)scheduled for curative treatment(surgical resection,thermal ablation,or both).The study explored how often liver(MRI)changes therapeutic strategy compared to using only a CE computed tomography(CT)scan.Despite MRI’s widespread use in staging for CRLMs,guidelines remain vague,leaving decisions to the surgeon’s preference and expertise.

Clinical and molecular heterogeneity associated with tumor sidedness in colorectal liver metastasis: a multicenter propensity cohort study

Background:Colorectal liver metastasis(CRLM)exhibits highly heterogeneity,with clinically and molecularly defined subgroups that differ in their prognosis.The aim of this study is to explore whether left-sided tumors is clinically and gnomically distinct from right-sided tumors in CRLM.Methods:This retrospective study included 1,307 patients who underwent primary tumor and metastases resection at three academic centers in China from January 1,2012,to December 31,2020.Propensity score matching with 1:1 ratio matching was performed.The prognostic impact of tumor sidedness was determined after stratifying by the KRAS mutational status.Moreover,whole-exome sequencing(WES)of 200 liver tumor tissues were performed to describe the heterogeneity across the analysis of somatic and germline profiles.Results:The median follow-up was 68 months.Matching yielded 481 pairs of patients.Compared to right-sided CRLM,left-sided patients experienced with better 5-year overall survival(OS)in surgery responsiveness,with a 14.6 lower risk of death[hazard ratio(HR),1.36,95%confidence interval(CI),1.10-1.69,P=0.004].Interaction between tumor sidedness and KRAS status was statistically significant:left-sidedness was associated with better prognosis among KRAS wild-type patients(HR 1.71;95%CI:1.20-2.45;P=0.003),but not among KRAS mutated-type patients.Integrated molecular analyses showed that right-sided tumors more frequently harbored TP53,APC,KRAS,and BRAF alterations,and identified a critical role of KRAS mutation in correlation with their survival differences.Higher pathogenic germline variants were identified in the right-sided tumors compared with left-sided tumors(29.3%vs.15.5%,P=0.03).Conclusions:We demonstrated that the prognostic impacts of tumor sidedness in CRLM is restricted patients with KRAS wild-type tumors.Tumor sidedness displays considerable clinical and molecular heterogeneity that may associate with their therapy benefits and prognosis.

A machine learning model for colorectal liver metastasis post-hepatectomy prognostications

Background:Currently,surgical resection is the mainstay for colorectal liver metastases(CRLM)management and the only potentially curative treatment modality.Prognostication tools can support patient selection for surgical resection to maximize therapeutic benefit.This study aimed to develop a survival prediction model using machine learning based on a multicenter patient sample in Hong Kong.Methods:Patients who underwent hepatectomy for CRLM between 1 January 2009 and 31 December 2018 in four hospitals in Hong Kong were included in the study.Survival analysis was performed using Cox proportional hazards(CPH).A stepwise selection on Cox multivariable models with Least Absolute Shrinkage and Selection Operator(LASSO)regression was applied to a multiply-imputed dataset to build a prediction model.The model was validated in the validation set,and its performance was compared with that of Fong Clinical Risk Score(CRS)using concordance index.Results:A total of 572 patients were included with a median follow-up of 3.6 years.The full models for overall survival(OS)and recurrence-free survival(RFS)consist of the same 8 established and novel variables,namely colorectal cancer nodal stage,CRLM neoadjuvant treatment,Charlson Comorbidity Score,pre-hepatectomy bilirubin and carcinoembryonic antigen(CEA)levels,CRLM largest tumor diameter,extrahepatic metastasis detected on positron emission-tomography(PET)-scan as well as KRAS status.Our CRLM Machine-learning Algorithm Prognostication model(CMAP)demonstrated better ability to predict OS(C-index=0.651),compared with the Fong CRS for 1-year(C-index=0.571)and 5-year OS(C-index=0.574).It also achieved a C-index of 0.651 for RFS.Conclusions:We present a promising machine learning algorithm to individualize prognostications for patients following resection of CRLM with good discriminative ability.

Liver transplantation for non-resectable colorectal liver metastases

At present,there are no absolute practice guidelines for liver transplants in colorectal liver metastases(CRLM),and treatment protocols for unresectable CRLM are institution-specific(1).One of the first prospective studies evaluating the safety of liver transplants for CRLM was the SECA-I trial(1,2).A 5-year overall survival rate of 60% was observed in this trial,which far outperformed survival with chemotherapy alone(3).In the SECA-Ⅱ trial,enrollment was increased,and patients with better prognostic factors,including at least a 10% response to chemotherapy before the transplant,were selected.

Using the win ratio to compare laparoscopic versus open liver resection for colorectal cancer liver metastases

Background:We sought to assess the overall benefit of laparoscopic versus open hepatectomy for treatment of colorectal liver metastases(CRLMs)using the win ratio,a novel methodological approach.Methods:CRLM patients undergoing curative-intent resection in 2001-2018 were identified from an international multi-institutional database.Patients were paired and matched based on age,number and size of lesions,lymph node status and receipt of preoperative chemotherapy.The win ratio was calculated based on margin status,severity of postoperative complications,90-day mortality,time to recurrence,and time to death.Results:Among 962 patients,the majority underwent open hepatectomy(n=832,86.5%),while a minority underwent laparoscopic hepatectomy(n=130,13.5%).Among matched patient-to-patient pairs,the odds of the patient undergoing laparoscopic resection“winning”were 1.77[WR:1.77,95%confidence interval(CI):1.42-2.34].The win ratio favored laparoscopic hepatectomy independent of low(WR:2.94,95%CI:1.20-6.39),medium(WR:1.56,95%CI:1.16-2.10)or high(WR:7.25,95%CI:1.13-32.0)tumor burden,as well as unilobar(WR:1.71,95%CI:1.25-2.31)or bilobar(WR:4.57,95%CI:2.36-8.64)disease.The odds of“winning”were particularly pronounced relative to short-term outcomes(i.e.,90-day mortality and severity of postoperative complications)(WR:4.06,95%CI:2.33-7.78).Conclusions:Patients undergoing laparoscopic hepatectomy had 77%increased odds of“winning”.Laparoscopic liver resection should be strongly considered as a preferred approach to resection in CRLM patients.

Utility of circulating tumor DNA in patients undergoing hepatectomy for colorectal liver metastases

In this study recently published in Annals of Surgery,Newhook et al.studied the influence of circulating tumor DNA(ctDNA)in the management of patients undergoing hepatic resection for colorectal liver metastases(CRLM)(1).The primary objective was to study the association between the dynamic of ctDNA and somatic mutations with survival after resection of CRLM.The secondary objectives were to evaluate the impact of surgery on perioperative ctDNA dynamics and the impact of its detection on survival.

初始不可切除结直肠癌肝转移的转化化疗对残余肝脏体积增加的影晌

手术切除是治疗结直肠癌肝转移(CRLM)的有效手段。然而,初诊时可达到手术条件的CRLM患者比例不足20%。以化疗为主要手段的转化治疗为部分初始不可切除CRLM患者带来了手术治疗的希望,而足够的功能性残余肝脏体积(FLR)则是肝切除手术的关键因素。FLR不足可导致术后肝功能衰竭等严重并发症。运用门静脉栓塞/结扎、联合肝脏离断和门静脉结扎二步肝切除术等外科手段增加FLR,可增加CRLM患者根治性手术治疗的机会。接受二期肝切除手术的患者术前大多经历了全身化疔。随着对化疗相关性肝损伤认识的不断加深,不同化疗方案、化疗周期及手术间期等对FLR的影响日益受到关注。本文就提高FLR的外科治疗以及转化化疗对FLR的影响等问题进行综述。

Role of thermal ablation in the management of colorectal liver metastasis

With a recent randomized prospective trial revealing that thermal ablative therapy as local tumor control improved overall survival (OS) in patients with unresectable colorectal cancer liver metastases (CRLM), thermal ablation continues to remain as an important treatment option in this patient population. Our aim of this article is to review the current role of the ablative therapy in the management of CRLM patients. Main indications for thermal ablation include (Ⅰ) unresectable liver lesions;(Ⅱ) in combination with hepatectomy;(Ⅲ) in patients with significant medical comorbidities or poor performance status (PS);(Ⅳ) a small (<3 cm) solitary lesion, which would otherwise necessitate a major liver resection;and (Ⅴ) patient preference. There are several approaches and modalities for ablative therapy, including open, percutaneous, and laparoscopic approaches, as well as radiofrequency ablation (RFA) and microwave ablation (MWA). Each approach and ablation modality have its own pros and cons. Percutaneous and laparoscopic approaches are preferred due to minimally invasive nature, yet laparoscopic approach has more benefits from thorough intraoperative ultrasound (US) exam as well as complete peritoneal staging with laparoscopy. Similarly, whereas high local tumor failure rate has been a major concern with RFA, MWA or microwave thermosphere ablation (MTA) have demonstrated significantly improved local tumor control due to homogenous tissue heating, ability to reach higher tissue temperatures, and less susceptible to the "heat-sink" effect. Although liver resection is the standard of care for CRLM, there have been some retrospective studies demonstrating similar oncological outcome between ablative therapy and surgical resection in very selected populations with small (<3 cm) solitary CRLM. Lastly, ablative therapy and liver resection should not be mutually exclusive, especially in the management of bilobar liver metastases. Concomitant ablative therapy with hepatectomy may spare the patients from having two-stage hepatectomy with less morbidity. The role of the thermal ablation will continue to evolve in patients with resectable and ablatable lesions owing to newly emerging technology, in addition to new systemic treatment options, including immunotherapy for metastatic colorectal cancer (CRC). Keywords: Thermal ablation;radiofrequency ablation (RFA);microwave ablation (MWA);colorectal cancer liver metastasis (CRLM)

How should liver hypertrophy be stimulated?A comparison of upfront associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)and portal vein embolization(PVE)with rescue possibility

Background:The role of associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)in comparison to portal vein embolization(PVE)is debated.The aim of this study was to compare successful resection rates(RR)with upfront ALPPS vs.PVE with rescue ALPPS on demand and to compare the hypertrophy of the liver between ALPPS and PVE plus subsequent rescue ALPPS.Methods:A retrospective analysis of all patients treated with PVE for colorectal liver metastasis(CRLM)or ALPPS(any diagnosis,rescue ALPPS included)at five Scandinavian university hospitals during the years 2013-2016 was conducted.A Chi-square test and a Mann-Whitney U test were used to assess the difference between the groups.A successful RR was defined as liver resection without a 90-day mortality.Results:A total of 189 patients were included.Successful RR was in 84.5%of the patients with ALPPS upfront and in 73.3%of the patients with PVE and rescue ALPPS on demand(P=0.080).The hypertrophy of the future liver remnants(FLRs)with ALPPS upfront was 71%(48-97%)compared to 96%(82-113%)after PVE and rescue ALPPS(P=0.010).Conclusions:Upfront ALPPS offers a somewhat higher successful RR than PVE with rescue ALPPS on demand.The sequential combination of PVE and ALPPS leads to a higher overall degree of hypertrophy than upfront ALPPS.

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

Background:Unresectable 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.Methods:All 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.Results:Out 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.Conclusions:Today’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.

Molecular profiling and patient selection for the multimodal approaches for patients with resectable colorectal liver metastases

Colorectal cancer represents the third most common cancer and about 20%are diagnosed with synchronous metastatic disease.From a historical point of view,surgery remains the mainstream treatment for resectable colorectal liver metastases(CRLM).Furthermore,disease outcomes are improving due significant advances in systemic treatments and diagnostic methods.However,the optimal timing for neoadjuvant chemotherapy or upfront surgery for CRLM has not yet been established and remains an open question.Thus,patient selection combining image workouts,time of recurrence,positive lymph nodes,and molecular biomarkers can improve the decision-making process.Nevertheless,molecular profiling is rising as a promising field to be incorporated in the multimodal approach and guide patient selection and sequencing of treatment.Tumor biomakers,genetic profiling,and circulating tumor DNA have been used to offer as much personalized treatment as possible,based on the precision oncology concept of tailored care rather than a guideline-based therapy.This review article discusses the role of molecular pathology and biomarkers as prognostic and predictor factors in the diagnosis and treatment of resectable CRLM.