Studies on mechanism of Sialy Lewis-X antigen in liver metastases of human colorectal carcinoma

INTRODUCTIONSialyl Lewis-X antigen ,correlated with carcinoma, is a group of carbohydrate antigen containing oligosaccharide expressed of embryonic tisue and glycoproteins on cell surface of embryonic tissue[1].The SLeX antigen located on cell surface is synthesized principally by two enzymes ,al ,3fucosyltransfrease and a2, 3sialyctransferase.In adults ,SLeX antigen is expressed principally on the surfaces of granulocytic cells and some tumor cells .

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.

Conversion of Unresectable to Resectable Liver Metastases from Colorectal Carcinoma Using Hepatic Arterial Chronomodulated Chemotherapy: A Case Report and Short Literature Review

Background: The regional chronomodulated hepatic arterial infusion chemotherapy (HAIC) is an effective regimen for the treatment of patients with unresectable liver metastases from colorectal cancer, especially for the conversion into resectability. Aim: To demonstrate that chronomodulated HAI triplet chemotherapy according to OPTILIV protocol is well tolerated and displayed high antitumor activity in this heavily-pretreated patient. Case Presentation: A 54 years old patient from Russia was treated for a tumor in the ascending colon presented with 13 hepatic metastases ranging from 0.3 to 2.7 cm in diameter. He underwent a laparoscopic right hemicolectomy, 12 cycles of FOLFIRINOX combined to bevacizumab for the last 5 cycles, resulting in a partial response according to CT scan. It was decided to perform a two-stage hepatectomy at Paul Brousse hospital: left partial hepatectomy allowed the excision of 9 lesions. Radio frequency ablation was performed in 2 nodular lesions. Afterwards, the patient received 5 cycles of chronomodulated triplet chemotherapy into the hepatic artery, according to the OPTILIV protocol design, yet without cetuximab, because of the KRAS mutation in the liver metastases, with a partial re-sponse. The patient could then undergo the second stage of the planned right hepatectomy, which turned out to be an R0 resection followed by receiving three courses of chronomodulated HAIC. Disease progression was documented after 3 months. Chronomodulated FOLFIRI chemotherapy was re-started intravenously, in combination with Aflibercept and it was associated with further disease progression. The genetic analysis of our patient’s cancer revealed a high level of MSI. The patient was included in the Phase 2 CheckMate-142 trial and received nivolumab 3 mg/kg every 2 weeks within 3 months. Treatment was discontinued due to ineffectiveness. Then the patient underwent radiotherapy geared towards reduction of pain. Afterwards, the patient died from the disease progression 2 years after the beginning of treatment. Conclusion: In this article, the authors report a clinical case with chronomodulated HAIC as rescue therapy in a heavily pretreated patient with metastatic colorectal cancer, allowing to achieve an objective response despite prior progression on FOLFIRINOX (the same triplet chemo by IV route). This strategy permitted to overcome drug resistance and to perform further complete resection of the liver me-tastases with prolonged patient survival. Thus, chronomodulated HAI is useful in patients with liver metastases from colorectal cancer and de-serves to be further assessed prospectively in clinical trials chemotherapy.

Tumour response following preoperative chemotherapy is affected by body mass index in patients with colorectal liver metastases

BACKGROUND Colorectal cancer is the third most prevalent malignancy globally and ranks second in cancer-related mortality,with the liver being the primary organ of metastasis.Preoperative chemotherapy is widely recommended for initially or potentially resectable colorectal liver metastases(CRLMs).Tumour pathological response serves as the most important and intuitive indicator for assessing the efficacy of chemotherapy.However,the postoperative pathological results reveal that a considerable number of patients exhibit a poor response to preoperative chemotherapy.Body mass index(BMI)is one of the factors affecting the tumori-genesis and progression of colorectal cancer as well as prognosis after various antitumour therapies.Several studies have indicated that overweight and obese patients with metastatic colorectal cancer experience worse prognoses than those with normal weight,particularly when receiving first-line chemotherapy regimens in combination with bevacizumab.AIM To explore the predictive value of BMI regarding the pathologic response following preoperative chemotherapy for CRLMs.METHODS A retrospective analysis was performed in 126 consecutive patients with CRLM who underwent hepatectomy following preoperative chemotherapy at four different hospitals from October 2019 to July 2023.Univariate and multivariate logistic regression models were applied to analyse potential predictors of tumour pathological response.The Kaplan-Meier method with log rank test was used to compare progression-free survival(PFS)between patients with high and low BMI.BMI<24.0 kg/m^(2) was defined as low BMI,and tumour regression grade 1-2 was defined as complete tumour response.RESULTS Low BMI was observed in 74(58.7%)patients and complete tumour response was found in 27(21.4%)patients.The rate of complete tumour response was significantly higher in patients with low BMI(29.7%vs 9.6%,P=0.007).Multivariate analysis revealed that low BMI[odds ratio(OR)=4.56,95%confidence interval(CI):1.42-14.63,P=0.011],targeted therapy with bevacizumab(OR=3.02,95%CI:1.10-8.33,P=0.033),preoperative carcinoembryonic antigen level<10 ng/mL(OR=3.84,95%CI:1.19-12.44,P=0.025)and severe sinusoidal dilatation(OR=0.17,95%CI:0.03-0.90,P=0.037)were independent predictive factors for complete tumour response.The low BMI group exhibited a significantly longer median PFS than the high BMI group(10.7 mo vs 4.7 mo,P=0.011).CONCLUSION In CRLM patients receiving preoperative chemotherapy,a low BMI may be associated with better tumour response and longer PFS.

Effect of magnetic resonance imaging in liver metastases

This letter to the editor is a commentary on a study titled"Liver metastases:The role of magnetic resonance imaging."Exploring a noninvasive imaging evaluation system for the biological behavior of hepatocellular carcinoma(HCC)is the key to achieving precise diagnosis and treatment and improving prognosis.This review summarizes the role of magnetic resonance imaging in the detection and evaluation of liver metastases,describes its main imaging features,and focuses on the added value of the latest imaging tools(such as T1 weighted in phase imaging,T1 weighted out of phase imaging;diffusion-weighted imaging,T2 weighted imaging).In this study,I investigated the necessity and benefits of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid for HCC diagnostic testing and prognostic evaluation.

Colorectal liver metastases:An update on multidisciplinary approach

Liver metastasis is the commonest form of distant metastasis in colorectal cancer.Selection criteria for surgery and liver-directed therapies have recently been extended.However,resectability remains poorly defined.Tumour biology is increasingly recognized as an important prognostic factor;hence molecular profiling has a growing role in risk stratification and management planning.Surgical resection is the only treatment modality for curative intent.The most appropriate surgical approach is yet to be established.The primary cancer and the hepatic metastasis can be removed simultaneously or in a two-step approach;these two strategies have comparable long-term outcomes.For patients with a limited future liver remnant,portal vein embolization,combined ablation and resection,and associating liver partition and portal vein ligation for staged hepatectomy have been advocated,and each has their pros and cons.The role of neoadjuvant and adjuvant chemotherapy is still debated.Targeted biological agents and loco-regional therapies(thermal ablation,intra-arterial chemo-or radio-embolization,and stereotactic radiotherapy) further improve the already favourable results.The recent debate about offering liver transplantation to highly selected patients needs validation from large clinical trials.Evidencebased protocols are missing,and therefore optimal management of hepatic metastasis should be personalized and determined by a multi-disciplinary team.

Pembrolizumab in patients with gastric cancer and liver metastases: A paradigm shift in immunotherapy

In this editorial,we explore the impact of immunotherapy and its safety in pa-tients with advanced gastric cancer(GC)and liver involvement.GC,a formidable adversary in the oncology landscape,presents its most challenging battlefront when it reaches stage IV,often characterized by liver metastases.The prognosis for patients at this advanced stage is daunting,with systemic chemotherapy tra-ditionally offering a median overall survival slightly over a year.However,the landscape of treatment is evolving,with new strategies and therapies offering a glimmer of hope.

Simultaneous curative resection of double colorectal carcinoma with synchronous bilobar liver metastases

Synchronous colorectal carcinoma(SCRC) indicates more than one primary colorectal carcinoma(CRC) discovered at the time of initial presentation, accounts for 3.1%-3.9% of CRC, and may occur either in the same or in different colorectal segments. The accurate preoperative diagnosis of SCRC is difficult and diagnostic failures may lead to inappropriate treatment and poorer prognosis. SCRC requires colorectal resections tailored to individual patients, based on the number, location, and stage of the tumours, from conventional or extended hemicolectomies to total colectomy or proctocolectomy, when established predisposing conditions exist. The overall perioperative risks of surgery for SCRC seem to be higher than for solitary CRC. Simultaneous colorectal and liver resection represents an appealing surgical strategy in selected patients with CRC and synchronous liver metastases(CRLM), even though the cumulative risks of the two procedures need to be adequately evaluated. Simultaneous resections have the noticeable advantage of avoiding a second laparotomy, give the opportunity of an earlier initiation of adjuvant therapy, and may significantly reduce the hospital costs. Because an increasing number of recent studies have shown goodresults, with morbidity, perioperative hospitalization, and mortality rates comparable to staged resections, simultaneous procedures can be selectively proposed even in case of complex colorectal resections, including those for SCRC and rectal cancer. However, in patients with multiple bilobar CRLM, major hepatectomies performed simultaneously with colorectal resection have been associated with significant perioperative risks. Conservative or parenchymal-sparing hepatectomies reduce the extent of hepatectomy while preserving oncological radicality, and may represent the best option for selected patients with multiple CRLM involving both liver lobes. Parenchymal-sparing liver resection, instead of major or two-stage hepatectomy for bilobar disease, seemingly reduces the overall operative risk of candidates to simultaneous colorectal and liver resection, and may represent the most appropriate surgical strategy whenever possible, also for patients with advanced SCRC and multiple bilobar liver metastases.

Establishment and evaluation of a prognostic model for patients with unresectable gastric cancer liver metastases

BACKGROUND Liver metastases(LM)is the primary factor contributing to unfavorable outcomes in patients diagnosed with gastric cancer(GC).The objective of this study is to analyze significant prognostic risk factors for patients with GCLM and develop a reliable nomogram model that can accurately predict individualized prognosis,thereby enhancing the ability to evaluate patient outcomes.AIM To analyze prognostic risk factors for GCLM and develop a reliable nomogram model to accurately predict individualized prognosis,thereby enhancing patient outcome assessment.METHODS Retrospective analysis was conducted on clinical data pertaining to GCLM(type III),admitted to the Department of General Surgery across multiple centers of the Chinese PLA General Hospital from January 2010 to January 2018.The dataset was divided into a development cohort and validation cohort in a ratio of 2:1.In the development cohort,we utilized univariate and multivariate Cox regression analyses to identify independent risk factors associated with overall survival in GCLM patients.Subsequently,we established a prediction model based on these findings and evaluated its performance using receiver operator characteristic curve analysis,calibration curves,and clinical decision curves.A nomogram was created to visually represent the prediction model,which was then externally validated using the validation cohort.RESULTS A total of 372 patients were included in this study,comprising 248 individuals in the development cohort and 124 individuals in the validation cohort.Based on Cox analysis results,our final prediction model incorporated five independent risk factors including albumin levels,primary tumor size,presence of extrahepatic metastases,surgical treatment status,and chemotherapy administration.The 1-,3-,and 5-years Area Under the Curve values in the development cohort are 0.753,0.859,and 0.909,respectively;whereas in the validation cohort,they are observed to be 0.772,0.848,and 0.923.Furthermore,the calibration curves demonstrated excellent consistency between observed values and actual values.Finally,the decision curve analysis curve indicated substantial net clinical benefit.CONCLUSION Our study identified significant prognostic risk factors for GCLM and developed a reliable nomogram model,demonstrating promising predictive accuracy and potential clinical benefit in evaluating patient outcomes.

Value of multiple models of diffusion-weighted imaging to predict hepatic lymph node metastases in colorectal liver metastases patients

BACKGROUND About 10%-31% of colorectal liver metastases(CRLM)patients would concomitantly show hepatic lymph node metastases(LNM),which was considered as sign of poor biological behavior and a relative contraindication for liver resection.Up to now,there’s still lack of reliable preoperative methods to assess the status of hepatic lymph nodes in patients with CRLM,except for pathology examination of lymph node after resection.AIM To compare the ability of mono-exponential,bi-exponential,and stretchedexponential diffusion-weighted imaging(DWI)models in distinguishing between benign and malignant hepatic lymph nodes in patients with CRLM who received neoadjuvant chemotherapy prior to surgery.METHODS In this retrospective study,97 CRLM patients with pathologically confirmed hepatic lymph node status underwent magnetic resonance imaging,including DWI with ten b values before and after chemotherapy.Various parameters,such as the apparent diffusion coefficient from the mono-exponential model,and the true diffusion coefficient,the pseudo-diffusion coefficient,and the perfusion fraction derived from the intravoxel incoherent motion model,along with distributed diffusion coefficient(DDC)andαfrom the stretched-exponential model(SEM),were measured.The parameters before and after chemotherapy were compared between positive and negative hepatic lymph node groups.A nomogram was constructed to predict the hepatic lymph node status.The reliability and agreement of the measurements were assessed using the coefficient of variation and intraclass correlation coefficient.RESULTS Multivariate analysis revealed that the pre-treatment DDC value and the short diameter of the largest lymph node after treatment were independent predictors of metastatic hepatic lymph nodes.A nomogram combining these two factors demonstrated excellent performance in distinguishing between benign and malignant lymph nodes in CRLM patients,with an area under the curve of 0.873.Furthermore,parameters from SEM showed substantial repeatability.CONCLUSION The developed nomogram,incorporating the pre-treatment DDC and the short axis of the largest lymph node,can be used to predict the presence of hepatic LNM in CRLM patients undergoing chemotherapy before surgery.This nomogram was proven to be more valuable,exhibiting superior diagnostic performance compared to quantitative parameters derived from multiple b values of DWI.The nomogram can serve as a preoperative assessment tool for determining the status of hepatic lymph nodes and aiding in the decision-making process for surgical treatment in CRLM patients.

Consideration on immunotherapy of liver metastases of malignant tumors

In this editorial,we comment on the article“Analysis of the impact of immuno-therapy efficacy and safety in patients with gastric cancer and liver metastasis”by Liu et al that was published in the recent issue of the World Journal of Gastroin-testinal Surgery.It has prompted us to think and summarize some thoughts on immunotherapy for malignant tumor liver metastasis.Immunotherapy plays a crucial role in the treatment of malignant tumors;however,the presence of liver metastases in advanced tumors may impact its efficacy.Although patients with liver metastases can still benefit from immunotherapy,multiple clinical studies have indicated that,compared to other sites of metastasis,liver metastases may diminish the effectiveness of immunotherapy.The efficacy of immune checkpoint inhibitors in patients with liver metastases often fails to reach the ideal level,primarily due to the liver metastases exploiting the host's peripheral immune to-lerance mechanisms to promote systemic CD8(+)T cell exhaustion,resulting in a systemic immune-tolerant environment.This article aims to summarize the reasons for the decreased efficacy of immunotherapy following liver metastasis in various malignant tumors and propose potential clinical strategies for manage-ment.

A case of leptospirosis simulating colon cancer with liver metastases

We report a case of a 61-year-old man who presented with fatigue,abdominal pain and hepatomegaly.Computed tomography (CT) of the abdomen showed hepatomegaly and multiple hepatic lesions highly suggestive of metastatic diseases.Due to the endoscopic finding of colon ulcer,colon cancer with liver metastases was suspected.Biochemically a slight increase of transaminases,alkaline phosphatase and gammaglutamyl transpeptidase were present;α- fetoprotein,carcinoembryogenic antigen and carbohydrate 19-9 antigen serum levels were normal.Laboratory and instrumental investigations,including colon and liver biopsies revealed no signs of malignancy.In the light of spontaneous improvement of symptoms and CT findings,his personal history was revaluated revealing direct contact with pigs and their tissues.Diagnosis of leptospirosis was considered and confirmed by detection of an elevated titer of antibodies to leptospira.After two mo,biochemical data,CT and colonoscopy were totally normal.

Parenchymal-sparing liver surgery in patients with colorectal carcinoma liver metastases

Liver resection is the treatment of choice for patients with colorectal liver metastases(CLM).However,major resections are often required to achieve R0 resection,which are associated with substantial rates of morbidity and mortality.Maximizing the amount of residual liver gained increasing significance in modern liver surgery due to the high incidence of chemotherapyassociated parenchymal injury.This fact,along with the progressive expansion of resectability criteria,has led to the development of a surgical philosophy known as "parenchymal-sparing liver surgery"(PSLS).This philosophy includes a variety of resection strategies,either performed alone or in combination with ablative therapies.A profound knowledge of liver anatomy and expert intraoperative ultrasound skills are required to perform PSLS appropriately and safely.There is a clear trend toward PSLS in hepatobiliary centers worldwide as current evidence indicates that tumor biology is the most important predictor of intrahepatic recurrence and survival,rather than the extent of a negative resection margin.Tumor removal avoiding the unnecessary sacrifice of functional parenchyma has been associated with less surgical stress,fewer postoperative complications,uncompromised cancer-related outcomes and higher feasibility of future resections.The increasing evidence supporting PSLS prompts its consideration as the gold-standard surgical approach for CLM.

Predictive factors of histological response of colorectal liver metastases after neoadjuvant chemotherapy

BACKGROUND Colorectal cancer is the third most common cancer in men and the second most common in women worldwide. Almost a third of the patients has or will develop liver metastases. Neoadjuvant chemotherapy(NAC) has recently become nearly systematic prior to surgery of colorectal livers metastases(CRLMs). The response to NAC is evaluated by radiological imaging according to morphological criteria.More recently, the response to NAC has been evaluated based on histological criteria of the resected specimen. The most often used score is the tumor regression grade(TRG), which considers the necrosis, fibrosis, and number of viable tumor cells.AIM To analyze the predictive factors of the histological response, according to the TRG, on CRLM surgery performed after NAC.METHODSFrom January 2006 to December 2013, 150 patients who had underwent surgery for CRLMs after NAC were included. The patients were separated into two groups based on their histological response, according to Rubbia-Brandt TRG.Based on their TRG, each patient was either assigned to the responder(R) group(TRG 1, 2, and 3) or to the non-responder(NR) group(TRG 4 and 5). All of the histology slides were re-evaluated in a blind manner by the same specialized pathologist. Univariate and multivariate analyses were performed.RESULTS Seventy-four patients were classified as responders and 76 as non-responders.The postoperative mortality rate was 0.7%, with a complication rate of 38%.Multivariate analysis identified five predictive factors of histological response.Three were predictive of non-response: More than seven NAC sessions, the absence of a radiological response after NAC, and a repeat hepatectomy(P <0.005). Two were predictive of a good response: A rectal origin of the primary tumor and a liver-first strategy(P < 0.005). The overall survival was 57% at 3 yr and 36% at 5 yr. The disease-free survival rates were 14% at 3 yr and 11% at 5 yr.The factors contributing to a poor prognosis for disease-free survival were: No histological response after NAC, largest metastasis > 3 cm, more than three preoperative metastases, R1 resection, and the use of a targeted therapy with NAC(P < 0.005).CONCLUSION A non-radiological response and a number of NAC sessions > 7 are the two most pertinent predictive factors of non-histological response(TRG 4 or 5).

Mini-invasive vs open resection of colorectal cancer and liver metastases: A meta-analysis

BACKGROUND The safety and feasibility of the simultaneous resection of primary colorectal cancer (CRC) and synchronous colorectal liver metastases (SCRLM) have been demonstrated in some studies. Combined resection is expected to be the optimal strategy for patients with CRC and SCRLM. However, traditional laparotomy is traumatic, and the treatment outcome of minimally invasive surgery (MIS) is still obscure. AIM To compare the treatment outcomes of MIS and open surgery (OS) for the simultaneous resection of CRC and SCRLM. METHODS A systematic search through December 22, 2018 was conducted in electronic databases (PubMed, EMBASE, Web of Science, and Cochrane Library). All studies comparing the clinical outcomes of MIS and OS for patients with CRC and SCRLM were included by eligibility criteria. The meta-analysis was performed using Review Manager Software. The quality of the pooled study was assessed using the Newcastle-Ottawa scale. The publication bias was evaluated by a funnel plot and the Begg’s and Egger’s tests. Fixed- and random-effects models were applied according to heterogeneity. RESULTS Ten retrospective cohort studies involving 502 patients (216 patients in the MIS group and 286 patients in the OS group) were included in this study. MIS was associated with less intraoperative blood loss [weighted mean difference (WMD)=-130.09, 95% confidence interval (CI):-210.95 to -49.23, P = 0.002] and blood transfusion [odds ratio (OR)= 0.53, 95%CI: 0.29 to 0.95, P = 0.03], faster recovery of intestinal function (WMD =-0.88 d, 95%CI:-1.58 to -0.19, P = 0.01) and diet (WMD =-1.54 d, 95%CI:-2.30 to -0.78, P < 0.0001), shorter length of postoperative hospital stay (WMD =-4.06 d, 95%CI:-5.95 to -2.18, P < 0.0001), and lower rates of surgical complications (OR = 0.60, 95%CI: 0.37 to 0.99, P = 0.04). However, the operation time, rates and severity of overall complications, and rates of general complications showed no significant differences between the MIS and OS groups. Moreover, the overall survival and disease-free survival after MIS were equivalent to those after OS. CONCLUSION Considering the studies included in this meta-analysis, MIS is a safe and effective alternative technique for the simultaneous resection of CRC and SCRLM. Compared with OS, MIS has less intraoperative blood loss and blood transfusion and quicker postoperative recovery. Furthermore, the two groups show equivalent long-term outcomes.

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.

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.

Recurrence-free survival as a putative surrogate for overall survival in phase Ⅲ trials of curative-intent treatment of colorectal liver metastases:Systematic review

AIM To verify whether recurrence-free survival(RFS) surrogates overall survival(OS) in phase Ⅲ trials for resectable colorectal liver metastases(CRLM).METHODS MEDLINE,EMBASE,and Scopus databases were consulted.Eligible studies were phase Ⅲ trials testing any type of systemic therapy(neoadjuvant,adjuvant or perioperative) added to surgery in patients with resectable CRLM.A linear regression model based on hazard ratios(HR) of OS and RFS was performed.RESULTS Of 3059 studies,5 phase Ⅲ trials(1162 patients) were included for analyses.A linear regression weighted by each trial was used to estimate the association between each HR and RFS.The originated formula was:OS HR =(0.93 × RFS HR) + 0.14;with RFS 95%CI(0.48-1.38),with P = 0.007.CONCLUSION This association suggests that RFS could work as a putative surrogate endpoint of OS in this population,avoiding bigger,longer and more resource-consuming trials.The OS could be assumed based on RFS and our model could be useful to better estimate sample size calculations of phase Ⅲ trials of CRLM aiming for OS.

Surgical Treatment of Liver Metastases from Gastric Cancer

Background: Hepatectomy for gastric metastases remains controversial. We aimed at assessing the surgical results, clinicopathological features of gastric cancer liver metastases (GCLM) and prognostic factors. Methods: The outcome of 28 consecutive patients with synchronous (n = 24) or metachronous (n = 4) GCLM was retrospectively analyzed. Curatively, initial hepatectomies such as segmentectomy and hemihepatectomy or non-anatomical limited liver resection less extensive than segmentectomy followed complete primary gastric cancer (GC) resections. Results: Median survival time was 16 months (range, 5 - 66 months). The actuarial overall 12-, 36-, and 60-month survival rates after hepatectomy were 67.8% (n = 19), 39.2% (n = 11), and 28.5% (n = 8), respectively. In multivariate analysis, absent GC serosal invasion-hazard ratio (HR) 1;95% confidence interval (CI) 1.2 - 9.9;P = 0.020;solitary LM-HR 1;95% CI 1.6 - 16.0;P = 0.005, and?curative liver resection with negative resection margin (R0)-HR 1, 95% CI 2.2 - 18.0;P = 0.001 were independent prognostic factors. Conclusions: Surgery of GCLM is a good indication in well-selected patients with an absent serosal invasion of primary tumour, single GCLM and attainment of R0 liver resection. For most GCLM patients, however, there are no other therapeutic modalities. Thus systemic chemotherapy remains the best hope for a longer patient’s survival and an improved individual quality of life.

Malignant pheochromocytoma:Hepatectomy for liver metastases

Malignant pheochromocytoma accounts for approximately 10% of pheochromocytoma cases. The main site of distant metastasis is the liver. Hypertensive crisis due to catecholamine oversecretion is potentially fatal. We present a case of malignant pheochromocytoma with multiple liver metastases. A 60-year-old female with repeated hypertensive episodes was diagnosed with malignant pheochromocytoma. She underwent a left adrenalectomy and partial hepatectomy with resection of segment 6. Catecholamine levels remained high after surgery and she received repeated cycles of chemotherapy. Four months after surgery, multiple liver metastases were detected. In spite of ongoing chemotherapy, catecholamine levels eventually became uncontrollable. Serum and urine noradrenaline andvanillylmandelic acid levels increased, but adrenaline and dopamine levels stayed within the normal range. Preoperative liver imaging revealed multiple metastases in all segments except segment 4. Percutaneous transhepatic portal vein embolization(PTPE) of the right and lateral branches of the portal vein was performed. The functional liver volume of segment 4 increased after PTPE. Right hepatectomy, lateral segmentectomy and partial resection of segment 1 were performed 10 mo after the initial surgery. Intraoperative ultrasonography detected two small tumors in segment 4, which were treated with intraoperative microwave coagulation therapy. Noradrenaline levels normalized immediately after the second hepatectomy. As there was increased telomerase activity in the resected specimen, she received adjuvant chemotherapy. She remained in good health for 2 years. However, further metastases eventually occurred and she subsequently died due to a brain hemorrhage. Hepatectomy may be a therapeutic option for reduction of tumor mass in pheochromocytoma with liver metastases.