Simultaneous hepatic resection benefits patients with synchronous colorectal cancer liver metastases

Objective： The safety of the simultaneous resection of synchronous colorectal cancer liver metastases （SCRLM） is still being debated. However, this simultaneous operative approach is more commonly adopted at present than in the past. Therefore, we compared simultaneous hepatic resection with delayed hepatic resection in this study.Methods： All patients with SCRLM diagnosed before initial treatment between January 2009 and September 2013 were retrospectively included in our study. Short-term and long-term outcomes were compared in patients who underwent simultaneous colorectal and hepatic resection and those treated by delayed hepatectomy.Results： Among the 73 patients diagnosed with SCRLM, simultaneous coloreetal and hepatic resection was performed in 60 patients （82.2%）, while delayed hepatic resection was performed in 13 patients （17.8%）. The mortality rate was zero. The postoperative complication rate after delayed resection was higher than, but not significantly different from, that after simultaneous resection （46% vs. 23%, P=0.166）. The duration of operating time （240 vs. 420 min, P〈0.05） and postoperative hospital stay time （11 vs. 18 days, P〈0.05） were shorter in the simultaneous resection group. After the initial treatments were given, the 1-, 2-, and 3-year survival rates in the simultaneous resection group were 77%, 59%, and 53%, respectively, whereas those in the delayed resection group were 67%, 42%, and 10%, respectively. The 5-year survival rate in the simultaneous resection group was 23%; overall survival differed significantly between the two groups （P=0.037）. Median disease-free survival （DFS） times were 19.1 months in the simultaneous resection group and 8.8 months in the delayed resection group. DFS differed significantly between the two groups. Coenclusions： Simultaneous colorectal and hepatic resection is safe and exhibits advantages in the longtime survival of patients.

Clinicopathological features and surgical outcomes of four rare subtypes of primary liver carcinoma

Objective：This study aimed to analyze clinicopathological and prognostic features of four rare pathological subtypes of primary liver malignancies to make better understanding of their clinical features.Methods：The clinicopathological data of 114 patients who were diagnosed with histologically proven four subtypes：clear cell carcinoma（CCC）,giant cell carcinoma（GCC）,sarcomatoid carcinoma（SC）,and combined hepatocellular-cholangiocarcinoma（CHC）between October 1998 and August 2015 were reviewed.Their survival data were compared with those of 908 patients with histologically proven common hepatocellular carcinoma（HCC）（early-and advanced-stage HCC）during the same period.Results：The outcome of the CCC group was better than that of the other three subgroups,and was similar to that of the early-stage HCC group.Also,the smallest tumor size and the highest incidence of pseudocapsule formation were observed in the CCC group.The SC group had the worst outcome among these four subgroups;the prognosis was much poorer than that of any other subgroups,even poorer than that of the advanced-stage common HCC group.No statistical difference was observed between the GCC,CHC and advanced-stage HCC groups on survival analysis.The incidences of tumor vascular emboli,TNM staging and non-radical resection were three risk factors of the prognosis.Conclusions：CCC is a low-degree malignancy and relatively favorably prognostic subtype of HCC.However,GCC,SC,and CHC are three rare high-degree malignancy subtypes of HCC with poor prognosis.

Validity of distress thermometer for screening of anxiety and depression in family caregivers of Chinese breast cancer patients receiving postoperative chemotherapy

Objective:Family caregivers(FCs)of breast cancer patients play a vital role throughout the treatment process.Psychological distress of FCs is common and often ignored.A simple and effective instrument for screening psychological distress would help in selecting those FCs requiring special attention and intervention.Here,the validity of distress thermometer(DT)in FCs of Chinese breast cancer patients receiving postoperative chemotherapy was assessed,and the prevalence of anxiety and depression was evaluated.Methods:We recruited 200 FCs of hospitalized breast cancer patients in this cross-sectional descriptive study.Before the first cycle of adjuvant chemotherapy,the levels of anxiety and depression among FCs were assessed using DT and Hospital Anxiety and Depression Scale(HADS).In total,191 valid cases were analyzed.HADS was used as the diagnostic standard to assess the effectiveness of DT as a screening tool for anxiety and depression as well as to analyze the diagnostic efficiency of DT at various cutoff points.Results:The definitive prevalence of both anxiety and depression was 8.90%.The mean level of anxiety and depression among FCs was 5.64±3.69 and 5.09±3.85,respectively,both of which were significantly higher than corresponding Chinese norms(P<0.01).The areas under receiver operating characteristic curves of DT for the diagnoses of FCs'anxiety and depression were 0.904 and 0.885,respectively.A cutoff value of 5 produced the best diagnostic effects of DT for anxiety and depression.Conclusions:The levels of both anxiety and depression were higher in the FCs of Chinese breast cancer patients receiving postoperative chemotherapy than the national norm.DT might be an effective tool to initially screen psychological distress among FCs.This process could be integrated into the palliative care of breast cancer patients and warrant further research.

A male-ABCD algorithm for hepatocellular carcinoma risk prediction in HBs Ag carriers

Objective: Hepatocellular carcinoma(HCC) development among hepatitis B surface antigen(HBs Ag) carriers shows gender disparity, influenced by underlying liver diseases that display variations in laboratory tests. We aimed to construct a risk-stratified HCC prediction model for HBs Ag-positive male adults.Methods: HBs Ag-positive males of 35-69 years old(N=6,153) were included from a multi-center populationbased liver cancer screening study. Randomly, three centers were set as training, the other three centers as validation. Within 2 years since initiation, we administrated at least two rounds of HCC screening using Bultrasonography and α-fetoprotein(AFP). We used logistic regression models to determine potential risk factors,built and examined the operating characteristics of a point-based algorithm for HCC risk prediction.Results: With 2 years of follow-up, 302 HCC cases were diagnosed. A male-ABCD algorithm was constructed including participant's age, blood levels of GGT(γ-glutamyl-transpeptidase), counts of platelets, white cells,concentration of DCP(des-γ-carboxy-prothrombin) and AFP, with scores ranging from 0 to 18.3. The area under receiver operating characteristic was 0.91(0.90-0.93), larger than existing models. At 1.5 points of risk score,26.10% of the participants in training cohort and 14.94% in validation cohort were recognized at low risk, with sensitivity of identifying HCC remained 100%. At 2.5 points, 46.51% of the participants in training cohort and 33.68% in validation cohort were recognized at low risk with 99.06% and 97.78% of sensitivity, respectively. At 4.5 points, only 20.86% of participants in training cohort and 23.73% in validation cohort were recognized at high risk,with positive prediction value of 22.85% and 12.35%, respectively.Conclusions: Male-ABCD algorithm identified individual's risk for HCC occurrence within short term for their HCC precision surveillance.

Prognostic relevance of number and ratio of metastatic lymph nodes in resected carcinoma of the ampulla of Vater

Objectives： To explore the prognostic relevance of the number and ratio of metastatic lymph nodes in resected Carcinoma of the ampulla of Vater （CAV）. Methods： The clinical data of 155 patients who underwent pancreaticoduodenectomy （PD） for cancer of the ampulla of Vater between January 1990 and December 2010 were retrospectively analyzed. Kaplan- Meier method was used in survival analysis and Log rank method in comparison. Multivariate analysis was performed using Cox proportional hazards model. Results： Among these 155 patients, the in-hospital mortality rate was 4.5%, lymph node positive disease was 21.3%, and the 5-year survival rate was 51.6%. Patients with a lymph node ratio （LNR） 〉20% were more likely to have tumor differentiation, depth of duodenal involvement, depth of pancreatic invasion, T-stage and TNM-Stage. The number of the metastatic lymph nodes is important prognostic factors of the CAV. Univariate analysis showed that the factors associated with the prognosis included tumor size （P=0.036）, tumor differentiation （P=0.019）, LNR （P=0.032）, mtmber of metastatic lymph nodes （P=0.024）, lymph node metastasis （P=0.03）, depth of pancreatic invasion （P=0.001）, T-stage （P=0.002）, TNM stage （P=0.001）, elevated CA 19-9 （P=0.000）, and jaundice （P=0.021）. Multivariate analysis showed that the factors associated with the prognosis were the number of metastatic lymph nodes （P=0.032; RR： 1.283; 95% CI： 1.022-1.611）, tumor size （P=0.043; RR： 1.736; 95% CI： 1.017-2.963）, and elevated CA 19-9 （P=0.003; RR： 3.247; 95% CI： 1.504-7.010）. Conclusions： LNR is a useful factor for predicting the prognosis of the radical treatment for CAV,, whereas the number of metastatic lymph nodes is the most important factor. Further research on the locations, number, and LNR will be clinically meaningful to improve survival in patients with CAV.

XCL1/Glypican-3 fusion protein induces potent CD8^+ T-cell generation and enhances the anti-PD1 effect to suspend hepatocellular carcinoma development

Objective:To induce potent CD8^+T-cells against glypican-3(GPC3),which is overexpressed in hepatocellular carcinoma(HCC),to suspend tumor development.Methods:Since the chemokine receptor XCR1 is selectively expressed on professional cross-presenting CD8α^+dendritic cells(DCs).

Adjuvant camrelizumab plus apatinib in resected hepatocellular carcinoma with microvascular invasion:a multi-center real world study

Background:It is well known that laparoscopic liver surgery can offer advantages over open liver surgery in selected patients.However,what type of procedures can benefit most from a laparoscopic approach has been investigated poorly thus far.The aim of this study is thus to define the extent of advantages of laparoscopic over open liver surgery for lesions in the anterolateral(AL)and posterosuperior(PS)segments.Methods:In this international multicentre retrospective cohort study,laparoscopic and open minor liver resections for lesions in the AL and PS segments were compared after propensity score matching.The differential benefit of laparoscopy over open liver surgery,calculated using bootstrap sampling,was compared between AL and PS resections and expressed as a Delta of the differences.Results:After matching,3,040 AL and 2,336 PS resections were compared,encompassing open and laparoscopic procedures in a 1:1 ratio.AL and PS laparoscopic liver resections were more advantageous in comparison to open in terms of blood loss,transfusion rate,complications,and length of stay.However,AL resections benefitted more from laparoscopy than PS in terms of overall and severe complications(D-difference were 4.8%,P=0.046 and 3%,P=0.046)and blood loss(D-difference was 195 mL,P<0.001).Similar results were observed in the subset for high-volume centres,while in recent years no significant differences were found in the differential benefit between AL and PS segments.Conclusions:The advantage of laparoscopic over open liver surgery is greater in the AL segments than in the PS segments.

Chinese expert consensus on multidisciplinary diagnosis and treatment of pancreatic neuroendocrine liver metastases

Many management strategies are available for pancreatic neuroendocrine neoplasms with liver metastases.However,a lack of biological,molecular,and genomic information and an absence of data from rigorous trials limit the validity of these strategies.This review presents the viewpoints from an international conference consisting of several expert working groups.The working groups reviewed a series of questions of particular interest to clinicians taking care of patients with pancreatic neuroendocrine neoplasms with liver metastases by reviewing the existing management strategies and literature,evaluating the evidence on which management decisions were based,developing internationally acceptable recommendations for clinical practice,and making recommendations for clinical and research endeavors.The review for each question will be followed by recommendations from the panel.

Chinese expert consensus on the overall management of liver function in conversion therapy for liver cancer(2022 edition)

Introduction Primary liver cancer is a significant health issue in China,where it ranks fourth in morbidity and second in mortality among all malignant tumors.[1-4]The 5-year overall survival rate of Chinese patients with liver cancer from 2012 to 2015 was only 12.2%for males and 13.1%for females.[5]Hepatocellular carcinoma(HCC)accounts for 75-85%of primary liver cancers.[6]Furthermore,most liver cancers are unresectable at diagnosis.To combat this,conversion therapy is used,which involves systematic treatments like anti-angiogenic drugs or molecular targeted therapy combined with immunotherapies,as well as locoregional treatments such as transcatheter arterial chemoembolization(TACE),hepatic artery infusion chemotherapy(HAIC),ablation therapy,and radiation therapy.The goal is to eliminate unresectable status and increase the chances of surgery.The reported 5-year survival rate after salvage surgery following tumor downstaging varied from 24.9-57%.

Chinese expert consensus on conversion therapy for hepatocellular carcinoma(2021 edition)

Recent advances in systemic and locoregional treatments for patients with unresectable or advanced hepatocellular carcinoma(HCC)have resulted in improved response rates.This has provided an opportunity for selected patients with initially unresectable HCC to achieve adequate tumor downstaging to undergo surgical resection,a‘conversion therapy’strategy.However,conversion therapy is a new approach to the treatment of HCC and its practice and treatment protocols are still being developed.Review the evidence for conversion therapy in HCC and develop consensus statements to guide clinical practice.Evidence review:Many research centers in China have accumulated significant experience implementing HCC conversion therapy.Preliminary findings and data have shown that conversion therapy represents an important strategy to maximize the survival of selected patients with intermediate stage to advanced HCC;however,there are still many urgent clinical and scientific challenges for this therapeutic strategy and its related fields.In order to summarize and learn from past experience and review current challenges,the Chinese Expert Consensus on Conversion Therapy for Hepatocellular Carcinoma(2021 Edition)was developed based on a review of preliminary experience and clinical data from Chinese and non-Chinese studies in this field and combined with recommendations for clinical practice.Sixteen consensus statements on the implementation of conversion therapy for HCC were developed.The statements generated in this review are based on a review of clinical evidence and real clinical experience and will help guide future progress in conversion therapy for patients with HCC.

Neoadjuvant radiotherapy for resectable hepatocellular carcinoma with portal vein tumor thrombus:a systematic review

Background:The prognosis of hepatocellular carcinoma(HCC)with portal vein tumor thrombus(PVTT)is extremely poor.The clinical outcome of preoperative radiotherapy(RT)is still controversial.This study aimed to compare the clinical outcomes of combined neoadjuvant RT and hepatectomy with hepatectomy alone for HCC with PVTT.Methods:Comprehensive database searches were performed in PubMed,the Cochrane Library,EMBASE,and the Web of Science to retrieve studies published from the database creation to July 1,2020.Only comparative studies that measured survival between neoadjuvant RT followed by hepatectomy and hepatectomy alone were included.The characteristics of the included studies and patients were extracted,and the included data are presented as relative ratio(RR)estimates with 95%confidence intervals(CIs)for all outcomes.The RRs of each study were pooled using a fixed or random effects model with Review Manager(the Cochrane Collaboration,Oxford,UK)version 5.3.The response rate to RT and the overall survival(OS)rate in neoadjuvant RT followed by hepatectomy and hepatectomy alone were measured.Results:One randomized and two non-randomized controlled trials with 302 patients were included.Most patients were classified as Child-Pugh A,and Type II and III PVTT were the most common types.After RT,29(22.8%)patients were evaluated as partial response(PR)and had a positive RT response,but nine(7.1%)had progressive disease(PD).Neoadjuvant RT followed by hepatectomy was received by 127(42.1%)patients after excluding 15(5.0%)patients with severe complications or PD after RT,and 160(53.0%)patients received hepatectomy alone.In the randomized controlled trial(RCT),the 1-year OS rate in the neoadjuvant RT group and the surgery alone group was 75.2%and 43.1%,respectively(P<0.001).In the two non-randomized studies,a meta-analysis with a fixed effects model showed a longer OS in patients undergoing neoadjuvant RT followed by hepatectomy compared with hepatectomy alone at 1-year follow-up(RR=2.02;95%CI:1.45-2.80;P<0.0001).Conclusions:This systematic review showed that neoadjuvant RT followed by hepatectomy in patients with resectable HCC and PVTT was associated with a longer OS than patients who received hepatectomy alone.

AHR mediates the aflatoxin B1 toxicity associated with hepatocellular carcinoma

Aflatoxin exposure is a crucial factor in promoting the development of primary hepatocellular carcinoma(HCC)in individuals infected with the hepatitis virus.However,the molecular pathways leading to its bioactivation and subsequent toxicity in hepatocytes have not been well-defined.Here,we carried out a genome-wide CRISPR-Cas9 genetic screen to identify aflatoxin B1(AFB1)targets.Among the most significant hits was the aryl hydrocarbon receptor(AHR),a ligand-binding transcription factor regulating cell metabolism,differentiation,and immunity.

AI based colorectal disease detection using real-time screening colonoscopy

Colonoscopy is an effective tool for early screening of colorectal diseases.However,the application of colonoscopy in distinguishing different intestinal diseases still faces great challenges of efficiency and accuracy.Here we constructed and evaluated a deep convolution neural network(CNN)model based on 117055 images from 16004 individuals,which achieved a high accuracy of 0.933 in the validation dataset in identifying patients with polyp,colitis,colorectal cancer(CRC)from normal.The proposed approach was further validated onmulti-center real-time colonoscopy videos and images,which achieved accurate diagnostic performance on detecting colorectal diseases with high accuracy and precision to generalize across external validation datasets.The diagnostic performance of the model was further compared to the skilled endoscopists and the novices.In addition,our model has potential in diagnosis of adenomatous polyp and hyperplastic polyp with an area under the receiver operating characteristic curve of 0.975.Our proposed CNN models have potential in assisting clinicians in making clinical decisions with efficiency during application.

Expert consensus on organizing the multidisciplinary team(MDT) diagnosis and treatment of hepato-pancreato-biliary diseases in China

Multidisciplinary team(MDT) discussion has been well established in some European countries and widely carried out in various clinical professional fields(Festen et al.,2021;Fleissig et al.,2006).Many studies have reported the benefits of MDT,including improving survival and quality of cancer care(Munro et al.,2015;Nixon et al.,2021;Tsai et al.,2020).

Novel gold nanoparticles targeting somatostatin receptor subtype two with near-infrared light for neuroendocrine tumour therapy

Neuroendocrine tumours(NETs)are rare cancers with positive somatostatin receptor 2(SSTR2)expression,and treatment strategies for NETs are not satisfactory.Nanomaterial-mediated therapy targeting SSTR2 in NETs is very promising.This study firstly combined mesoporous silica-coated gold nanorods(AuNRs@mSiO_(2))and targeting-SSTR2 dodecane tetraacetic acidtyrosine3-octreotate(DOTA-TATE)into AuNRs@mSiO_(2)@DOTA-TATE to investigate NETs inhibition under near-infrared light.AuNRs@mSiO_(2)@DOTA-TATE showed good photothermal conversion efficiency.In vitro,under light irradiation,the cell viability significantly decreased with increasing AuNR@mSiO_(2)@DOTA-TATE concentration;in two successfully established neuroendocrine tumour organoids with SSTR2 expression,AuNRs@mSiO_(2)@DOTA-TATE with light inhibited tumours significantly better than AuNRs@mSiO_(2) with light.In vivo,the SSTR2-targeting ability and biodistribution of AuNRs@mSiO_(2)@DOTA-TATE were confirmed with AuNRs@mSiO_(2)@64Cu-DOTA-TATE under micro-positron emission tomography/computed tomography(micro-PET/CT);in the AuNRs@mSiO_(2)@DOTA-TATE with laser group,the tumour surface temperature increased rapidly,with tumour volumes similar to those in the octreotide group and significantly lower than those in other groups.There was no significant difference in mice body weight between the AuNRs@mSiO_(2)@DOTA-TATE with laser group and other groups.No significant inflammatory lesions or cell necrosis was found in the main organs.In summary,we presented a feasible strategy to construct AuNRs@mSiO_(2)@DOTA-TATE with good photothermal conversion efficiency,targetingSSTR2 ability,significant antitumour effects,and good biocompatibility,warranting further explorations of AuNRs@mSiO_(2)@DOTA-TATE for NETs therapy applications.

Correction: AHR mediates the Aflatoxin B1 toxicity associated with hepatocellular carcinoma

Correction to:Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-021-00713-1 z published online 9 August 2021 After online publication of the article^(1),the authors noticed one inadvertent mistake occurred during the production process in Fig.7 that needs to be corrected.The correct data are provided as follows.The key findings of the article are not affected by these corrections.The original article has been corrected.

RING finger 138 deregulation distorts NF-κB signaling and facilities colitis switch to aggressive malignancy

Prolonged activation of nuclear factor(NF)-кB signaling significantly contributes to the development of colorectal cancer(CRC).New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction.Here,we discovered the critical role of RING finger 138(RNF138)in CRC tumorigenesis through regulating the NF-кB signaling,which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response.RNF138^(−/−) mice were hyper-susceptible to the switch from colitis to aggressive malignancy,which coincided with sustained aberrant NF-кB signaling in the colonic cells.Furthermore,RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein(NIBP)to the cytoplasm,which requires the ubiquitin interaction motif(UIM)domain.More importantly,we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings,raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling.Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients,we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth.Overall,our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression,and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation.