Gastric cancer liver metastasis will reduce the efficacy of immunotherapy

Immune checkpoint inhibitors augment the antitumor activity of T cells by inhibiting the negative regulatory pathway of T cells,leading to notable efficacy in patients with non-small cell lung cancer,melanoma,and other malignancies through immunotherapy utilization.However,secondary malignant liver tumors not only lower the liver's sensitivity to immunotherapy but also trigger systemic immune suppression,resulting in reduced overall effectiveness of immune therapy.Patients receiving immunotherapy for non-small cell lung cancer and melanoma experience reduced response rates,progression-free survival,and overall survival when secondary malignant tumors develop in the liver.Through Liu's retrospective analysis,valuable insights are provided for the future clinical management of these patients.Therefore,in patients with gastric cancer(GC),the occurrence of liver metastasis might be indicative of reduced efficacy of immuno-therapy.Overcoming liver immune tolerance mechanisms and their negative impacts allows for the potential benefits of immunotherapy in patients with GC and liver metastasis.INTRODUCTION Gastric cancer(GC)ranks among the prevalent malignancies affecting the digestive system globally.Based on the latest epidemiological data[1,2],it holds the fifth position for incidence and the fourth position for mortality among all malignant tumors.GC cases and fatalities in China make up roughly half of the worldwide figures.Earlier investigations[3]have demonstrated that the median overall survival(mOS)among advanced GC patients left untreated typically ranges from 3 to 4 months.Systemic chemotherapy recipients often experience a mOS of around one year,accompanied by a marked improvement in the quality of life among patients with advanced GC.The mainstay of treatment for advanced GC patients involves chemotherapeutic medications such as fluoropyrimidines,platinum compounds,and taxanes.However,their efficacy in tumor control is constrained by acquired resistance and primary resistance.The rise of personalized precision therapy has propelled immunotherapy into the spotlight as a crucial component of comprehensive treatment[4].By blocking the negative regulatory pathways of T cells,immune checkpoint inhibitors(ICIs)boost the anti-tumor effect of T cells.Immunotherapy has brought about significant therapeutic benefits for patients diagnosed with non-small cell lung cancer,melanoma,and related illnesses[5,6],instilling newfound hope in those with advanced GC[7].However,phase III clinical trial data[8-12]reveals that the incorporation of immunotherapy into chemotherapy regimens improves overall survival(OS)outcomes for patients with advanced GC.The liver's immune-exempt nature renders it less responsive to immunotherapy when secondary malignant tumors are present,fostering systemic immune suppression and yielding unfavorable outcomes in immune therapy[13-15].In retrospective research[16-20]pertaining to non-small cell lung cancer and melanoma,it has been observed that the presence of secondary liver malignancies may lower the response rate,progression-free survival(PFS),and OS rates in patients treated with immunotherapy,independent of factors such as tumor mutation burden and PD-L1 expression.Despite this,there is a paucity of studies examining whether the existence of secondary malignant liver tumors affects the effectiveness of immunotherapy in patients diagnosed with advanced HER-2 negative GC.

Current landscape of preoperative neoadjuvant therapies for initial resectable colorectal cancer liver metastasis

Colorectal cancer liver metastasis(CRLM)presents a clinical challenge,and optimizing treatment strategies is crucial for improving patient outcomes.Surgical resection,a key element in achieving prolonged survival,is often linked to a heightened risk of recurrence.Acknowledging the potential benefits of preoperative neoadjuvant chemotherapy in managing resectable liver metastases,this approach has gained attention for its role in tumor downsizing,assessing biological behavior,and reducing the risk of postoperative recurrence.However,the use of neoadjuvant chemotherapy in initially resectable CRLM sparks ongoing debates.The balance between tumor reduction and the risk of hepatic injury,coupled with concerns about delaying surgery,necessitates a nuanced approach.This article explores recent research insights and draws upon the practical experiences at our center to address critical issues regarding considerations for initially resectable cases.Examining the criteria for patient selection and the judicious choice of neoadjuvant regimens are pivotal areas of discussion.Striking the right balance between maximizing treatment efficacy and minimizing adverse effects is imperative.The dynamic landscape of precision medicine is also reflected in the evolving role of gene testing,such as RAS/BRAF and PIK3CA,in tailoring neoadjuvant regimens.Furthermore,the review emphasizes the need for a multidisciplinary approach to navigate the comp-lexities of CRLM.Integrating technical expertise and biological insights is crucial in refining neoadjuvant strategies.The management of progression following neoadjuvant chemotherapy requires a tailored approach,acknowledging the diverse biological behaviors that may emerge.In conclusion,this review aims to provide a comprehensive perspective on the considerations,challenges,and advancements in the use of neoadjuvant chemotherapy for initially resectable CRLM.By combining evidencebased insights with practical experiences,we aspire to contribute to the ongoing discourse on refining treatment paradigms for improved outcomes in patients with CRLM.

Microbiota in colorectal cancer related to liver metastasis

The prevalence of colorectal cancer(CRC) is increasing annually and metastasis is the principal cause of death in patients with CRC, with the liver being the most frequently affected site. Many studies have shown a strong interplay between the gut flora, particularly Fusobacterium nucleatum(F. nucleatum), Escherichia coli, and Bacteroides fragilis, and the development of gut tumors. Some strains can induce gut inflammation and produce toxins that directly harm gut epithelial cells, ultimately accelerating the onset and progression of CRC. However,little clinical evidence exists on the specific interplay between the gut microflora and colorectal cancer liver metastasis(CRLM). Some research showed the existence of viable F. nucleatum in distant metastasis of CRC.Subsequently, gut microbiota products, such as lipopolysaccharides, sodium butyrate, and protein cathepsin K, were also found to affect the development of CRC. This article summarizes the mechanism and research status of the interplay between gut microflora and CRLM, discusses the importance of gut microflora in the treatment of CRLM, and proposes a new approach to understanding the mechanism of CRLM and potential treatments for the microbiome. It is anticipated that the gut microbiota will be a formidable therapeutic and prophylactic tool for treating and preventing CRLM.

Immunotherapy for gastric cancer and liver metastasis: Is it time to bid farewell

Patients with metastatic gastric cancer have a grim prognosis.Palliative che-motherapy offers a limited survival improvement,but recent advancements in immunotherapy have sparked hope.However,the effectiveness of immunothe-rapy in patients with liver metastases remains debated.This article reviews a recent study by Liu et al and evaluates conflicting evidence on the impact of liver metastases on response to immunotherapy in metastatic gastric cancer.While some studies suggest no significant difference in treatment response based on liver involvement,others report varied response rates.The present study,a re-trospective analysis of 48 patients by Liu et al,examines this issue and concludes that immunotherapy is less effective in patients with liver metastases.Despite methodological limitations and a small sample size,the study contributes to the ongoing discourse.The nuanced response to immunotherapy in certain patients underscores the importance of understanding the tumor microenvironment,immune cell infiltration,and the expression of immune checkpoints.Rather than dismissing immunotherapy for patients with gastric cancer and liver metastases,a shift towards personalized treatment strategies and a more profound under-standing of tumor-specific biomarkers is essential.By unraveling the molecular intricacies of individual cases,clinicians may tailor more effective and customized treatments,offering a glimmer of hope for this challenging patient group.

Immunotherapy in gastric cancer with liver metastasis:Challenges and opportunities

In this editorial,we review the article by Liu et al published in the World Journal of Gastrointestinal Surgery investigating the efficacy and safety of immunotherapy in patients with gastric cancer(GC)and liver metastasis.GC,the fifth most com-monly diagnosed malignancy worldwide,presents a significant challenge due to its multifactorial etiology and a grim prognosis for unresectable or recurrent cases.The advent of immune checkpoint inhibitors(ICIs)has revolutionized oncology;yet liver metastasis has been associated with reduced response rates,progression-free survival,and overall survival in various malignancies.The Che-ckMate-649 and KEYNOTE-859 trials demonstrated promising results with ICIs in advanced GC,particularly in patients with liver metastasis.However,a meta-analysis of liver metastatic solid tumors revealed worse outcomes with ICIs,high-lighting the need for further investigation.While combined therapies,including ICIs with local treatments,show promise in improving outcomes,the nuanced landscape of ICIs in liver metastatic GC necessitates continued research for robust conclusions.The current contradictions in the literature underscore the impor-tance of cautious interpretation and the exploration of tailored approaches to enhance clinical efficacy in this challenging patient population.

Impact of immunotherapy on liver metastasis

This editorial discusses the article“Analysis of the impact of immunotherapy efficacy and safety in patients with gastric cancer and liver metastasis”published in the latest edition of the World Journal of Gastrointestinal Surgery.Immunotherapy has achieved outstanding success in tumor treatment.However,the presence of liver metastasis(LM)restrains the efficacy of immunotherapy in various tumors,including lung cancer,colorectal cancer,renal cell carcinoma,melanoma,and gastric cancer.A decrease in CD8+T cells and nature killer cells,along with an increase in macrophages and regulatory T cells,was observed in the microenvironment of LM,leading to immunotherapy resistance.More studies are necessary to determine the best strategy for enhancing the effectiveness of immunotherapy in patients with LM.

Impact of liver metastasis on immunotherapy in gastric carcinoma

The editorial discusses the impact of liver metastasis on immunotherapy efficacy in gastric cancer(GC)patients.Liver metastasis can hinder the effectiveness of immunotherapy by altering the immune microenvironment,leading to systemic loss of T-cells and reduced treatment response.Studies suggest that liver meta-stases serve as a negative baseline factor for immunotherapy efficacy,resulting in poorer progression-free survival and objective response rates.Strategies such as liver-mediated radiotherapy may help improve treatment outcomes by reshaping the liver’s immune microenvironment and reducing T-cell depletion.Understand-ing the complex interplay between liver metastasis and immunotherapy response is crucial for optimising patient care in GC.

Prognostic value of a nomogram model for postoperative liver metastasis of colon cancer

BACKGROUND Colon cancer is one of the most common malignant tumors of the digestive system.Liver metastasis after colon cancer surgery is the primary cause of death in patients with colon cancer.AIM To construct a novel nomogram model including various factors to predict liver metastasis after colon cancer surgery.METHODS We retrospectively analyzed 242 patients with colon cancer who were admitted and underwent radical resection for colon cancer in Zhejiang Provincial People’s Hospital from December 2019 to December 2022.Patients were divided into liver metastasis and non-liver metastasis groups.Sex,age,and other general and clinicopathological data(preoperative blood routine and biochemical test indexes)were compared.The risk factors for liver metastasis were analyzed using singlefactor and multifactorial logistic regression.A predictive model was then constructed and evaluated for efficacy.RESULTS Systemic inflammatory index(SII),C-reactive protein/albumin ratio(CAR),red blood cell distribution width(RDW),alanine aminotransferase,preoperative carcinoembryonic antigen level,and lymphatic metastasis were different between groups(P<0.05).SII,CAR,and RDW were risk factors for liver metastasis after colon cancer surgery(P<0.05).The area under the curve was 0.93 for the column-line diagram prediction model constructed based on these risk factors to distinguish whether liver metastasis occurred postoperatively.The actual curve of the column-line diagram predicting the risk of postoperative liver metastasis was close to the ideal curve,with good agreement.The prediction model curves in the decision curve analysis showed higher net benefits for a larger threshold range than those in extreme cases,indicating that the model is safer.CONCLUSION Liver metastases after colorectal cancer surgery could be well predicted by a nomogram based on the SII,CAR,and RDW.

Machine learning prediction model for gray-level co-occurrence matrix features of synchronous liver metastasis in colorectal cancer

BACKGROUND Synchronous liver metastasis(SLM)is a significant contributor to morbidity in colorectal cancer(CRC).There are no effective predictive device integration algorithms to predict adverse SLM events during the diagnosis of CRC.AIM To explore the risk factors for SLM in CRC and construct a visual prediction model based on gray-level co-occurrence matrix(GLCM)features collected from magnetic resonance imaging(MRI).METHODS Our study retrospectively enrolled 392 patients with CRC from Yichang Central People’s Hospital from January 2015 to May 2023.Patients were randomly divided into a training and validation group(3:7).The clinical parameters and GLCM features extracted from MRI were included as candidate variables.The prediction model was constructed using a generalized linear regression model,random forest model(RFM),and artificial neural network model.Receiver operating characteristic curves and decision curves were used to evaluate the prediction model.RESULTS Among the 392 patients,48 had SLM(12.24%).We obtained fourteen GLCM imaging data for variable screening of SLM prediction models.Inverse difference,mean sum,sum entropy,sum variance,sum of squares,energy,and difference variance were listed as candidate variables,and the prediction efficiency(area under the curve)of the subsequent RFM in the training set and internal validation set was 0.917[95%confidence interval(95%CI):0.866-0.968]and 0.09(95%CI:0.858-0.960),respectively.CONCLUSION A predictive model combining GLCM image features with machine learning can predict SLM in CRC.This model can assist clinicians in making timely and personalized clinical decisions.

Hepatic artery infusion with raltitrexed or 5-fluorouracil for colorectal cancer liver metastasis

AIM To evaluate the efficiency and safety of hepatic artery infusion chemotherapy(HAIC) using raltitrexed or 5-fluorouracil for colorectal cancer(CRC) liver metastasis(CRCLM).METHODS A retrospective analysis of patients with unresectable CRCLM who failed systemic chemotherapy and were subsequently treated with HAIC at our institute from May 2013 to April 2015 was performed. A total of 24 patients were treated with 5-fluorouracil, and 18 patients were treated with raltitrexed. RESULTS The median survival time(MST) from diagnosis of CRC was 40.8 mo in the oxaliplatin plus raltitrexed(TOMOX) arm and 33.5 mo in the oxaliplatin plus 5-fluorouracil(FOLFOX) arm(P = 0.802). MST from first HAIC was 20.6 mo in the TOMOX arm and 15.4 mo in the FOLFOX arm(P = 0.734). Median progression-free survival(PFS) from first HAIC was 4.9 mo and 6.6 mo, respectively, in the TOMOX arm and FOLFOX arm(P= 0.215). Leukopenia(P = 0.026) was more common in the FOLFOX arm, and hepatic disorder(P = 0.039) was more common in the TOMOX arm. There were no treatment-related deaths in the TOMOX arm and one treatment-related death in the FOLFOX arm. Analysis of prognostic factors indicated that response to HAIC was a significant factor related to survival.CONCLUSION No significant difference in survival was observed between the TOMOX and FOLFOX arms. HAIC treatment with either TOMOX or FOLFOX was demonstrated as an efficient and safe alternative choice.

Prognosis of HER2 over-expressing gastric cancer patients with liver metastasis

AIM:To study the risk factors for liver metastasis and the prognosis in patients with human epidermal growth factor receptor 2(HER2) over-expressing gastric cancer(GC).METHODS:A total of 84 GC patients recruited from the General Hospital of the People's Liberation Army(PLA) between 2003 and 2010 were randomly enrolled in this study.HER2 expression was detected by immunohistochemistry in 84 GC patients with liver metastases.The study group consisted of 66 men and 18 women,with an average age of 54 years(range:19-74 years).Liver metastasis was diagnosed by magnetic resonance imaging or computed tomography.Patients were followed-up and predictive factors of liver metastasis were evaluated.RESULTS:The median follow-up period was 47 mo(range:6-85 mo).The characteristics of 35(25.7%) patients with HER2 over-expression of liver metastatic GC are presented.HER2 over-expression was detected in 23 out of 49(46.9%) patients with intestinal GC,and 9 out of 35(25.7%) patients with diffuse GC.29 out of 59(49.2%) patients aged < 60 years were HER2positive,while 8 out of 25(32%) patients aged ≥ 60 were HER2-positive;a significant difference(P < 0.05).Univariate analysis(log-rank test) showed that HER2 over-expression,sex,Lauren classification,differentiation and disease-free interval were correlated with poor survival(P < 0.05).Survival analysis with a survival curve showed that HER2 over-expression was significantly relevant,with a reduced survival time in GC patients with liver metastases(P < 0.01).2-year survival was not associated with the patient's age.A diseasefree survival longer than 12 mo has a significant association with extended overall survival(OS) in GC patients with liver metastases.The median survival time after the diagnosis of liver metastases was 18 mo [95% confidence interval(CI):9.07-26.94] among HER2 positive GC patients with liver metastases.In comparison,for 49(69.4%) out of 84 HER2 negative patients with liver metastatic GC,the median survival time was 47 mo(95% CI:19.37-74.63).In patients with HER2 positive liver metastatic GC,the median OS was significantly shorter than in HER2 negative patients(median,20.32 mo;95% CI:16.51-24.13 vs median,50.14 mo;95% CI:37.83-62.45;P < 0.01).CONCLUSION:HER2 over-expressing GC patients with liver metastases have a poor prognosis.Overall survival was significantly lower in HER2 positive patients.HER2overexpression is correlated with a lower survival rate.

Serological diagnostic factors for liver metastasis in patients with colorectal cancer

AIM:To investigate the serological diagnostic factors for liver metastasis in patients with colorectal cancer.METHODS:One hundred and six adult in-patients with colorectal cancer were studied and divided into patients with liver metastasis(n = 56) and patients without liver metastasis(n = 50).Serum levels of tumor and biochemical markers for liver were measured at the time of diagnosis.RESULTS:The mean survival time was 55.9 mo,36.8 mo and 68.3 mo for the overall patients,patients with liver metastasis and patients without liver metastasis,respectively.Lactate dehydrogenase(LDH) level was significantly correlated with the survival time of colorectal cancer patients.The levels of alanine aminotransferase,aspartate aminotransferase,γ-glutamyltransferase(GGT),LDH and carcinoembryonic antigen(CEA) were significantly higher in patients with liver metastasis than in those without liver metastasis.Patients with lymph node metastasis had a higher risk of liver metastasis than those without lymph node metastasis.The cut points of LDH,GGT and CEA for screening liver metastasis were 180 U/L,30 U/L and 5.0 μg/L,respectively.The sensitivity was 64.3%,69.6% and 70.4%,and the specificity was 64.0%,60.0% and 52.4%,respectively.The sensitivity of parallel test was 85.2% for LDH and CEA,and 92.6% for GGT and CEA,respectively.The specificity of serial test was 85.7% for LDH(or GGT) and CEA.CONCLUSION:Early diagnosis of liver metastasis is of great significance.The sensitivity and specificity of combined tumor and biochemical markers are rather good in screening colorectal liver metastasis.

Differential expression of serum miR-126,miR-141 and miR-21 as novel biomarkers for early detection of liver metastasis in colorectal cancer

Objective：MicroRNAs （miRNAs） have potential as diagnostic biomarkers in cancer.Evaluation of the association between miRNA expression patterns and early detection of liver metastasis in colorectal cancer （CRC） has not been reported.Methods：We investigated the expression of metastasis-associated miRs-31,335,206,141,126,200b,200c,21,Let7a,Let7b and Let7c in localized,liver-metastatic and other organ-metastatic CRC （OM-CRC）.Expressions of target miRNAs in serum were evaluated in 116 consecutive localized CRC （L-CRC）,72 synchronous liver-metastatic CRC （SLM-CRC） and 36 other OM-CRC by quantitative real-time PCR.Results：Seven of 11 tested miRNAs could be detected from serum.Four miRNAs,miR-126,Let-7a,miR141 and miR-21 were identified as metastasis-associated miRNAs.Compared with L-CRC,significant upregulated expression was observed for miR-141 and miR-21 in SLM-CRC and OM-CRC,down-regulated expression was observed for miR-126 in SLM-CRC and OM-CRC,and up-regulated expression of Let-7a in OM-CRC.The receiver operating characteristic （ROC） curve showed serum miR-126 had a cut-off [log10 relative quantity （log10RQ）=--0.2005] with 77.78％ sensitivity and 68.97％ specificity with an area under curve （AUC） of 0.7564,miR-141 had a cut-off （1og10RQ=-0.2285） with 86.11％ sensitivity and 76.11％ specificity with an AUC of 0.8279,and miR-21 had a cut-off （log10RQ=-0.1310） with 73.61％ sensitivity and 66.38％ specificity with an AUC of 0.7479.Conclusions：We identified liver metastasis-associated miRNAs,suggesting serum miR-126,miR-141 and miR-21 may be novel biomarkers for clinical diagnosis of early stage liver-metastatic CRC.

HBV infection decreases risk of liver metastasis in patients with colorectal cancer:A cohort study

AIM:To evaluate the effect of hepatitis B virus (HBV) infection on liver metastasis of colorectal cancer.METHODS:A total of 1298 colorectal cancer patients were recruited from January 2001 to March 2005 in this study.Enzyme-linked immunosorbent assay was used to test serum HBV markers for colorectal cancer.Patients were divided into study (infection) group and control (non-infection) group.Clinical features of patients in two groups were compared.RESULTS:Liver metastasis was found in 319 out of the 1298 colorectal cancer patients.The incidence of liver metastasis was significantly lower in study group than in control group (14.2% vs 28.2%,P < 0.01).HBV infection significantly decreased the risk of liver metastasis [hazard ratio (HR):0.50,95% confidence interval (95% CI):0.38-0.66],but the incidence of extrahepatic metastasis was significantly higher in study group than in control group (31.9% vs 17.0%,P < 0.01).The HR was the lowest in chronic hepatitis B group (HR:0.29,95% CI:0.12-0.72).The number of liver metastatic lesions was significantly less in study group than in control group with a higher surgical resection rate.However,no significant difference was found in survival rate between the two groups (P=0.95).CONCLUSION:HBV infection decreases the risk of liver metastasis in patients with colorectal cancer and elevates the surgical resection rate of liver metastatic lesions.

CXCR7/CXCL12 axis is involved in lymph node and liver metastasis of gastric carcinoma

AIM To investigate the role of CXC chemokine receptor (CXCR)-7 and CXCL12 in lymph node and liver metastasis of gastric carcinoma. METHODS In 160 cases of gastric cancer, the expression of CXCR7 and CXCL12 in tumor and matched tumoradjacent non-cancer tissues, in the lymph nodes around the stomach and in the liver was detected using immunohistochemistry to analyze the relationship between CXCR7/CXCL12 expression and clinicopathological features and to determine whether CXCR7 and CXCL12 constitute a biological axis to promote lymph node and liver metastasis of gastric cancer. Furthermore, the CXCR7 gene was silenced and overexpressed in human gastric cancer SGC-7901 cells, and cell proliferation, migration and invasiveness were measured by the MTT, wound healing and Transwell assays, respectively. RESULTS CXCR7 expression was up-regulated in gastric cancer tissues (P = 0.011). CXCR7/CXCL12 expression was significantly related to high tumor stage and lymph node (r = 0.338, P = 0.000) and liver metastasis (r = 0.629, P = 0.000). The expression of CXCL12 in lymph node and liver metastasis was higher than that in primary gastric cancer tissues (chi(2) = 6.669, P = 0.010; chi(2) = 25379, P = 0.000), and the expression of CXCL12 in lymph node and liver metastasis of gastric cancer was consistent with the positive expression of CXCR7 in primary gastric cancer (r = 0.338, P = 0.000; r = 0.629, P = 0.000). Overexpression of the CXCR7 gene promoted cell proliferation, migration and invasion. Silencing of the CXCR7 gene suppressed SGC-7901 cell proliferation, migration and invasion. Human gastric cancer cell lines expressed CXCR7 and showed vigorous proliferation and migratory responses to CXCL12. CONCLUSION The CXCR7/CXCL12 axis is involved in lymph node and liver metastasis of gastric cancer. CXCR7 is considered a potential therapeutic target for the treatment of gastric cancer.

Preoperative evaluation of pancreatic ductal adenocarcinoma with synchronous liver metastasis: Diagnosis and assessment of unresectability

AIM To identify predictors for synchronous liver metastasis from resectable pancreatic ductal adenocarcinoma(PDAC) and assess unresectability of synchronous liver metastasis.METHODS Retrospective records of PDAC patients with synchronous liver metastasis who underwent simultaneous resections of primary PDAC and synchronous liver metastasis, or palliative surgical bypass, were collected from 2007 to 2015. A series of pre-operative clinical parameters, including tumor markers and inflammation-based indices, were analyzed by logistic regression to figure out predictive factors and assess unresectability of synchronous liver metastasis. Cox regression was used to identify prognostic factors in liver-metastasized PDAC patients after surgery, with intention to validate their conformance to the indications of simultaneous resections and palliative surgical bypass. Survival of patients from different groups were analyzed by the Kaplan-Meier method. Intra- and post-operative courses were compared, including complications. PDAC patients with no distant metastases who underwent curative resection served as the control group.RESULTS CA125 > 38 U/mL(OR = 12.397, 95%CI: 5.468-28.105, P < 0.001) and diabetes mellitus(OR = 3.343, 95%CI: 1.539-7.262, P = 0.002) independently predicted synchronous liver metastasis from resectable PDAC. CA125 > 62 U/mL(OR = 5.181, 95%CI: 1.612-16.665, P = 0.006) and age > 62 years(OR = 3.921, 95%CI: 1.217-12.632, P = 0.022) correlated with unresectability of synchronous liver metastasis, both of which also indicated a worse long-term outcome of liver-metastasized PDAC patients after surgery. After the simultaneous resections, patients with postoperatively elevated serum CA125 levels had shorter survival than those with post-operatively reduced serum CA125 levels(7.7 mo vs 16.3 mo, P = 0.013). The survival of liver-metastasized PDAC patients who underwent the simultaneous resections was similar to that of non-metastasized PDAC patients who underwent curative pancreatectomy alone(7.0 mo vs 16.9 mo, P < 0.001), with no higher rates of either pancreatic fistula(P = 0.072) or other complications(P = 0.230) and no greater impacts on length of hospital stay(P = 0.602) or post-operative diabetic control(P = 0.479).CONCLUSION The criterion set up by CA125 levels could facilitate careful diagnosis of synchronous liver metastases from PDAC, and prudent selection of appropriate patients for the simultaneous resections.

High levels of serum platelet-derived growth factor-AA and human epidermal growth factor receptor-2 are predictors of colorectal cancer liver metastasis

AIM To develop predictive markers in blood for colorectal cancer liver metastasis.METHODS Twenty colorectal cancer patients were selected and divided into two groups. Group A consisted of 10 patients whose pathological TNM stage was ⅢC(T3-4N2M0), while another 10 patients with synchronous liver metastasis(TNM stage Ⅳ) were recruited for group B. During the surgical procedure, a 10-ml drainage vein(DV) blood sample was obtained from the DV of the tumor-bearing segment prior to the ligation of the DV. At the same time, a 10-ml peripheral vein(PV) blood sample was collected via peripheral venipuncture. The serum levels of 24 molecules that are potentially involved in the mechanism of liver metastasis in both DV blood and PV blood were analyzed by using high-throughput enzyme-linked immunosorbent assay technology.RESULTS Univariate analysis revealed that platelet-derivedgrowth factor AA(PDGFAA) in DV blood(d PDGFAA)(P = 0.001), PDGFAA in PV blood(p PDGFAA)(P = 0.007), and human epidermal growth factor receptor-2 in PV blood(p HER2)(P = 0.001), p MMP7(P = 0.028), pR ANTES(P = 0.013), and pE GF(P = 0.007) were significantly correlated with synchronous liver metastasis. Multivariate analysis identified d PDGFAA(HR = 1.001, P = 0.033) and p HER2(HR = 1.003, P = 0.019) as independent predictive factors for synchronous liver metastasis. Besides, high peripheral HER2 level may also be a risk factor for metachronous liver metastasis, although the difference did not reach statistical significance(P = 0.06). Significant correlations were found between paired DV and PV blood levels for PDGFAA(r = 0.794, P < 0.001), but not for HER2(r = 0.189, P = 0.424).CONCLUSION PDGFAA in tumor drainage and HER2 in PV blood may be useful predictive factors for synchronous liver metastasis of colorectal cancer.

Magnetic resonance imaging-radiomics evaluation of response to chemotherapy for synchronous liver metastasis of colorectal cancer

BACKGROUND Synchronous liver metastasis(SLM)is an indicator of poor prognosis for colorectal cancer(CRC).Nearly 50%of CRC patients develop hepatic metastasis,with 15%-25%of them presenting with SLM.The evaluation of SLM in CRC is crucial for precise and personalized treatment.It is beneficial to detect its response to chemotherapy and choose an optimal treatment method.AIM To construct prediction models based on magnetic resonance imaging(MRI)-radiomics and clinical parameters to evaluate the chemotherapy response in SLM of CRC.METHODS A total of 102 CRC patients with 223 SLM lesions were identified and divided into disease response(DR)and disease non-response(non-DR)to chemotherapy.After standardizing the MRI images,the volume of interest was delineated and radiomics features were calculated.The MRI-radiomics logistic model was constructed after methods of variance/Mann-Whitney U test,correlation analysis,and least absolute shrinkage and selection operator in feature selecting.The radiomics score was calculated.The receiver operating characteristics curves by the DeLong test were analyzed with MedCalc software to compare the validity of all models.Additionally,the area under curves(AUCs)of DWI,T2WI,and portal phase of contrast-enhanced sequences radiomics model(Ra-DWI,Ra-T2WI,and Ra-portal phase of contrast-enhanced sequences)were calculated.The radiomicsclinical nomogram was generated by combining radiomics features and clinical characteristics of CA19-9 and clinical N staging.RESULTS The AUCs of the MRI-radiomics model were 0.733 and 0.753 for the training(156 lesions with 68 non-DR and 88 DR)and the validation(67 lesions with 29 non-DR and 38 DR)set,respectively.Additionally,the AUCs of the training and the validation set of Ra-DWI were higher than those of Ra-T2WI and Ra-portal phase of contrast-enhanced sequences(training set:0.652 vs 0.628 and 0.633,validation set:0.661 vs 0.575 and 0.543).After chemotherapy,the top four of twelve deltaradiomics features of Ra-DWI in the DR group belonged to gray-level run-length matrices radiomics parameters.The radiomics-clinical nomogram containing radiomics score,CA19-9,and clinical N staging was built.This radiomics-clinical nomogram can effectively discriminate the patients with DR from non-DR with a higher AUC of 0.809(95%confidence interval:0.751-0.858).CONCLUSION MRI-radiomics is conducive to predict chemotherapeutic response in SLM patients of CRC.The radiomics-clinical nomogram,involving radiomics score,CA19-9,and clinical N staging is more effective in predicting chemotherapeutic response.

Can molecular biomarkers replace a clinical risk score for resectable colorectal liver metastasis?

In resectable colorectal liver metastasis(CRLM) the role and use of molecular biomarkers is still controversial. Several biomarkers have been linked to clinical outcomes in CRLM, but none have so far become routine for clinical decision making. For several reasons, the clinical risk score appears to no longer hold the same predictive value. Some of the reasons include the ever expanding indications for liver resection, which now increasingly tend to involve extrahepatic disease, such as lung metastases(both resectable and non-resectable) and the shift in indication from "what is taken out"(e.g., how much liver has to be resected) to "what is left behind"(that is, how much functional liver tissue the patient has after resection). The latter is amenable to modifications by using adjunct techniques of portal vein embolization and the associating liver partition and portal vein ligation for staged hepatectomy techniques to expand indications for liver resection. Added to this complexity is the increasing number of molecular markers, which appear to hold important prognostic and predictive information, for which some will be discussed here. Beyond characteristics of tissue-based genomic profiles will be liquid biopsies derived from circulating tumor cells and cell-free circulating tumor DNA in the blood. These markers are present in the peripheral circulation in the majority of patients with metastatic cancer disease. Circulating biomarkers may represent more readily available methods to monitor, characterize and predict cancer biology with future implications for cancer care.

Proteomic analysis of differentially expressed proteins involving in liver metastasis of human colorectal carcinoma

BACKGROUND: Early diagnosis of liver metastasis of colorectal carcinoma is very important for the appropriate treatment of such patients. However, there has been no effective approach available for clinical application. The present study aimed to investigate the differential expression of proteins in patients with liver metastasis of colorectal carcinomas using proteomic analysis and evaluate its potentiality in clinical diagnosis. METHODS: Fluorescence two-dimensional differential in-gel electrophoresis (2-D DIGE) was used to analyze and compare the protein expression between normal mucosa, the primary focus, and liver metastases. Proteomic analysis was made to identify the differentially expressed proteins. Immunohistological staining was used to confirm the expression of differentially expressed proteins in colorectal carcinomas and areas of liver metastasis. RESULTS: A 1.5-fold difference was found with 46 differentially expressed proteins. In 20 differentially expressed proteins, 3 were down-regulated and 17 up-regulated in liver metastases. Proteomic analysis showed that the S-adenosylmethionine transgelin variant was down-regulated in liver metastasis tissues. Zinc finger protein 64 homolog (Zfp64), guanine nucleotide exchange factor 4 (GEF4), human arginase, glutathione S-transferases (GSTs) A3, and tumor necrosis factor a (TNF-alpha)-induced protein 9 were up-regulated in liver metastasis tissues. Immunohistochemical staining confirmed that human arginase expression was higher in liver metastases than in the primary focus. CONCLUSIONS: There was a significant difference in protein expression between the primary focus of colorectal carcinoma and liver metastases. The differentially regulated proteins were closely related to liver metastasis of colorectal carcinoma. Elevated human arginase may be an important molecular marker for liver metastasis from colorectal carcinoma. (Hepatobiliary Pancreat Dis Jut 2010; 9: 149-153)