BACKGROUND Bile spillage occurs more frequently in patients with incidental gallbladder carcinoma(iGBC)and may be associated with poor survival due to presumed high risk of peritoneal seeding.AIM To investigate the im...BACKGROUND Bile spillage occurs more frequently in patients with incidental gallbladder carcinoma(iGBC)and may be associated with poor survival due to presumed high risk of peritoneal seeding.AIM To investigate the impact of bile spillage during primary surgery on the survival of patients with iGBC.METHODS Medical records of patients with iGBC diagnosed between 2000 and 2019 in 27 Dutch secondary centers and 5 tertiary centers were retrospectively reviewed.Patient medical records were assessed.Predictors for overall survival(OS)were determined using multivariable Cox regression.RESULTS Of the 346 included patients with iGBC,138(39.9%)had bile spillage,which was associated with higher American Society of Anesthesiologists classification(P=0.020),cholecystitis(P<0.001),higher tumor stage(P=0.005),and non-radical resection(P<0.001).Bile spillage was associated with poor OS[hazard ratio=1.97,95%confidence interval(CI):1.48-2.63,P<0.001]with a median OS of 12 months(95%CI:7-18 months)vs 34 months(95%CI:14-55 months,P<0.001).In multivariable analysis,spillage was not an independent prognostic factor for survival(hazard ratio=1.21,95%CI:0.84-1.74,P=0.313).CONCLUSION Although bile spillage correlates with prognostic factors,it lacks independent prognostic significance for survival.Patients with an indication for additional treatment should be promptly referred to a specialized hepatopancreatobiliary center,irrespective of whether bile spillage has occurred.展开更多
BACKGROUND Duodenal adenocarcinoma(DA)and intestinal-type papilla of Vater adenocarcinoma(it-PVA)are rare malignancies of the gastrointestinal tract.Current therapeutic options are translated nowadays from treatment s...BACKGROUND Duodenal adenocarcinoma(DA)and intestinal-type papilla of Vater adenocarcinoma(it-PVA)are rare malignancies of the gastrointestinal tract.Current therapeutic options are translated nowadays from treatment strategies for patients with colorectal cancer due to histopathological similarities.AIM To retrospectively investigate the clinical outcome of patients with DA and it-PVA.METHODS All patients with DA and it-PVA diagnosed between 2000 and 2017 were included at two academic centers in the Netherlands.All patients with histopathologically-confirmed DA or it-PVA were eligible for inclusion.Clinical outcome was compared between DA and it-PVA per disease stage.In the subgroup of stage IV disease,survival after local treatment of oligometastases was compared with systemic therapy or supportive care.RESULTS In total,155 patients with DA and it-PVA were included.Patients with it-PVA more often presented with stage I disease,while DA was more often diagnosed at stage IV(P<0.001).Of all patients,79%were treated with curative intent.The median survival was 39 mo,and no difference in survival was found for patients with DA and it-PVA after stratification for disease stage.Seven(23%)of 31 patients with synchronous stage IV disease underwent resection of the primary tumor,combined with local treatment of oligometastases.Local treatment of metastases was associated with an overall survival of 37 mo,compared to 14 and 6 mo for systemic therapy and supportive care,respectively.CONCLUSION Survival of patients with DA and it-PVA is comparable per disease stage.These results suggest a potential benefit for local treatment strategies in selected patients with oligometastases,although additional prospective studies are needed.展开更多
The development of artificial intelligence(AI)has increased dramatically in the last 20 years,with clinical applications progressively being explored for most of the medical specialties.The field of gastroenterology a...The development of artificial intelligence(AI)has increased dramatically in the last 20 years,with clinical applications progressively being explored for most of the medical specialties.The field of gastroenterology and hepatology,substantially reliant on vast amounts of imaging studies,is not an exception.The clinical applications of AI systems in this field include the identification of premalignant or malignant lesions(e.g.,identification of dysplasia or esophageal adenocarcinoma in Barrett’s esophagus,pancreatic malignancies),detection of lesions(e.g.,polyp identification and classification,small-bowel bleeding lesion on capsule endoscopy,pancreatic cystic lesions),development of objective scoring systems for risk stratification,predicting disease prognosis or treatment response[e.g.,determining survival in patients post-resection of hepatocellular carcinoma),determining which patients with inflammatory bowel disease(IBD)will benefit from biologic therapy],or evaluation of metrics such as bowel preparation score or quality of endoscopic examination.The objective of this comprehensive review is to analyze the available AI-related studies pertaining to the entirety of the gastrointestinal tract,including the upper,middle and lower tracts;IBD;the hepatobiliary system;and the pancreas,discussing the findings and clinical applications,as well as outlining the current limitations and future directions in this field.展开更多
BACKGROUND Preoperative biliary drainage in patients with presumed resectable perihilar cholangiocarcinoma(PHC)is hypothesized to promote the occurrence of seeding metastases.Seeding metastases can occur at the surgic...BACKGROUND Preoperative biliary drainage in patients with presumed resectable perihilar cholangiocarcinoma(PHC)is hypothesized to promote the occurrence of seeding metastases.Seeding metastases can occur at the surgical scars or at the site of postoperative drains,and in case of percutaneous biliary drainage,at the catheter port-site.To prevent seeding metastases after resection,we routinely treated PHC patients with preoperative radiotherapy(RT)for over 25 years until January 2018.AIM To investigate the incidence of seeding metastases following resection of PHC.METHODS All patients who underwent resection for pathology proven PHC between January 2000 and March 2019 were included in this retrospective study.Between 2000-January 2018,patients received preoperative RT(3×3.5 Gray).RT was omitted in patients treated after January 2018.RESULTS A total of 171 patients underwent resection for PHC between January 2000 and March 2019.Of 171 patients undergoing resection,111 patients(65%)were treated with preoperative RT.Intraoperative bile cytology showed no difference in the presence of viable tumor cells in bile of patients undergoing preoperative RT or not.Overall,two patients(1.2%)with seeding metastases were identified,both in the laparotomy scar and both after preoperative RT(one patient with endoscopic and the other with percutaneous and endoscopic biliary drainage).CONCLUSION The incidence of seeding metastases in patients with resected PHC in our series was low(1.2%).This low incidence and the inability of providing evidence that preoperative low-dose RT prevents seeding metastases,has led us to discontinue preoperative RT in patients with resectable PHC in our center.展开更多
Autologous T-cell therapies show limited efficacy in chronic lymphocytic leukemia(CLL),where acquired immune dysfunction prevails.In CLL,disturbed mitochondrial metabolism has been linked to defective T-cell activatio...Autologous T-cell therapies show limited efficacy in chronic lymphocytic leukemia(CLL),where acquired immune dysfunction prevails.In CLL,disturbed mitochondrial metabolism has been linked to defective T-cell activation and proliferation.Recent research suggests that lipid metabolism regulates mitochondrial function and differentiation in T cells,yet its role in CLL remains unexplored.This comprehensive study compares T-cell lipid metabolism in CLL patients and healthy donors,revealing critical dependence on exogenous cholesterol for human T-cell expansion following TCR-mediated activation.Using multi-omics and functional assays,we found that T cells present in viably frozen samples of patients with CLL(CLL T cells)showed impaired adaptation to cholesterol deprivation and inadequate upregulation of key lipid metabolism transcription factors.CLL T cells exhibited altered lipid storage,with increased triacylglycerols and decreased cholesterol,and inefficient fatty acid oxidation(FAO).Functional consequences of reduced FAO in T cells were studied using samples from patients with inherent FAO disorders.Reduced FAO was associated with lower T-cell activation but did not affect proliferation.This implicates low cholesterol levels as a primary factor limiting T-cell proliferation in CLL.CLL T cells displayed fewer and less clustered lipid rafts,potentially explaining the impaired immune synapse formation observed in these patients.Our findings highlight significant disruptions in lipid metabolism as drivers of functional deficiencies in CLL T cells,underscoring the pivotal role of cholesterol in T-cell proliferation.This study suggests that modulating cholesterol metabolism could enhance T-cell function in CLL,presenting novel immunotherapeutic approaches to improve outcome in this challenging disease.展开更多
Platelets are reprogrammed by cancer via a process called education,which favors cancer development.The transcriptional profile of tumor-educated platelets(TEPs)is skewed and therefore practicable for cancer detection...Platelets are reprogrammed by cancer via a process called education,which favors cancer development.The transcriptional profile of tumor-educated platelets(TEPs)is skewed and therefore practicable for cancer detection.This intercontinental,hospital-based,diagnostic study included 761 treatment-naive inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers(China,n=3;Netherlands,n=5;Poland,n=1)between September 2016 and May 2019.The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese(VC1 and VC2)and the European(VC3)validation cohorts collectively and independently.Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets.The AUCs for TEPs in the combined validation cohort,VC1,VC2,and VC3 were 0.918(95%CI 0.889-0.948),0.923(0.855-0.990),0.918(0.872-0.963),and 0.887(0.813-0.960),respectively.Combination of TEPs and CA125 demonstrated an AUC of 0.922(0.889-0.955)in the combined validation cohort;0.955(0.912-0.997)in VC1;0.939(0.901-0.977)in VC2;0.917(0.824-1.000)in VC3.For subgroup analysis,TEPs exhibited an AUC of o.858,0.859,and 0.920 to detect early-stage,borderline,non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis.TEPs had robustness,compatibility,and universality for preop.erative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities,heterogeneous histoiogical subtypes,and early-stage ovarian cancer.However,these observations warrant prospective validations in a larger population beforeclinicalutilities.展开更多
INTRODUCTION Cancer drug resistance has been and unfortunately still is a major problem in cancer therapy.Almost any therapy(except surgery)that is being used in the treatment of cancer can result in resistance.Unfort...INTRODUCTION Cancer drug resistance has been and unfortunately still is a major problem in cancer therapy.Almost any therapy(except surgery)that is being used in the treatment of cancer can result in resistance.Unfortunately there is a large group of patients that will either not respond to the applied therapy(intrinsic resistance)or will become resistant during therapy(acquired resistance).Sometimes patients can become resistant to one specific drug and remain sensitive to other drugs(one-drug resistance);another group of patients may become resistant to one drug and will be resistant to other unrelated drugs as well(multiple drug resistance,MDR).展开更多
Aim:Because mutations of splicing factor 3B subunit-1(SF3B1)have been identified in 4%of pancreatic ductal adenocarcinoma(PDAC)patients,we investigated the activity of new potential inhibitors of SF3B1 in combination ...Aim:Because mutations of splicing factor 3B subunit-1(SF3B1)have been identified in 4%of pancreatic ductal adenocarcinoma(PDAC)patients,we investigated the activity of new potential inhibitors of SF3B1 in combination with gemcitabine,one of the standard drugs,in PDAC cell lines.Methods:One imidazo[2,1-b][1,3,4]thiadiazole derivative(IS1)and three indole derivatives(IS2,IS3 and IS4),selected by virtual screening from an in-house library,were evaluated by the sulforhodamine-B and wound healing assay for their cytotoxic and antimigratory activity in the PDAC cells SUIT-2,Hs766t and Panc05.04,the latter harbouring the SF3B1 mutations.The effects on the splicing pattern of proto-oncogene recepteur d’origine nantais(RON)and the gemcitabine transporter human equilibrative nucleoside transporter-1(hENT1)were assessed by PCR,while the ability to reduce tumour volume was tested in spheroids of primary PDAC cells.Results:The potential SF3B1 modulators inhibited PDAC cell proliferation and prompted induction of cell death.All compounds showed an interesting anti-migratory ability,associated with splicing RON/ΔRON shift in SUIT-2 cells after 24 h exposure.Moreover,IS1 and IS4 potentiated the sensitivity to gemcitabine in both conventional 2D monolayer and 3D spheroid cultures,and these results might be explained by the statistically significant increase in hENT1 expression(P<0.05 vs.untreated control cells),potentially reversing PDAC chemoresistance.Conclusion:These results support further studies on new SF3B1 inhibitors and the role of RON/hENT1 modulation to develop effective drug combinations against PDAC.展开更多
In a recent study published in Signal Transduction and Targeted Therapy,Dr.Zhao and colleagues1 identify thrombin as a novel mediator of vasculogenic mimicry in non-small-cell lung cancer(NSCLC).This provides importan...In a recent study published in Signal Transduction and Targeted Therapy,Dr.Zhao and colleagues1 identify thrombin as a novel mediator of vasculogenic mimicry in non-small-cell lung cancer(NSCLC).This provides important mechanistic insight by which coagulation(factors)may drive tumor progression and several lessons to improve anticoagulant therapy of cancer patients can be learned from the paper.展开更多
SPECIAL ISSUE INTRODUCTION Targeted therapies in cancer aim to specifically block the activity of crucial proteins or signaling pathways necessary for the growth and/or survival of tumor cells.A major breakthrough in ...SPECIAL ISSUE INTRODUCTION Targeted therapies in cancer aim to specifically block the activity of crucial proteins or signaling pathways necessary for the growth and/or survival of tumor cells.A major breakthrough in targeted cancer therapy was the introduction nearly two decades ago of imatinib,an inhibitor of the BCR-ABL tyrosine kinase for the treatment of chronic myeloid leukemia.Over the last years,significant advances in our understanding of tumor biology have facilitated the development of many drugs targeting not only kinases,but also other protein families and cellular processes.Several of these agents are currently employed or being implemented for the treatment of different hematologic and solid malignancies,such as lung cancer.The special issue on“Targeted cancer therapy”will include reviews and commentaries updating the clinical use of targeted agents in the treatment of different tumor types,and the mechanisms that underlie the action of drugs directed to different types of targets.The special issue will also include research articles presenting novel outstanding data on all aspects of targeted cancer therapy.All submissions will undergo rigorous peer review and will be published free of charge upon acceptance.展开更多
The robotic platform enables surgeons to operate with a similar level of freedom and control as in open surgery,while still providing the patient with the benefits of a minimally invasive approach.More centres continu...The robotic platform enables surgeons to operate with a similar level of freedom and control as in open surgery,while still providing the patient with the benefits of a minimally invasive approach.More centres continue to adopt robotic liver surgery however standardized training materials and consensus on the surgical technique are currently lacking.The availability of a standardized surgical protocol could benefit the further dissemination of the robotic approach while promoting safe and effective operating techniques.We present a comprehensive surgical technique description for robotic hepatectomy agreed upon by seven expert robotic liver surgeons in Europe.They contributed insights from their extensive experience with the robot to develop this report,highlighting the key steps and important considerations for performing robotic hepatectomy.We describe the surgical technique for four most common hepatectomy types with varying complexity:partial anterolateral resections,partial posterosuperior resections,left hepatectomy and right hepatectomy.This report encompasses recommendations from the experts,covering the preparatory steps such as patient selection and pre-operative imaging,and extending through to care in the postoperative phase.The step-by-step surgical technique description serves as a compendium of best practice methods presently utilized in robotic liver surgery.Although some variations in technique cannot be eliminated from practice,general recommendations in a structured form will help to homogenize the technique,safeguarding surgical quality.This paper aims to inform and advise surgeons in the process of adopting robotic liver surgery and can act as a starting point for further optimization and refinement of the technique.展开更多
Background:With the rapid development of robotic surgery,especially for the abdominal surgery,robotic pancreatic surgery(RPS)has been applied increasingly around the world.However,evidence-based guidelines regarding i...Background:With the rapid development of robotic surgery,especially for the abdominal surgery,robotic pancreatic surgery(RPS)has been applied increasingly around the world.However,evidence-based guidelines regarding its application,safety,and efficacy are still lacking.To harvest robust evidence and comprehensive clinical practice,this study aims to develop international guidelines on the use of RPS.Methods:World Health Organization(WHO)Handbook for Guideline Development,GRADE Grid method,Delphi vote,and the AGREE-II instrument were used to establish the Guideline Steering Group,Guideline Development Group,and Guideline Secretary Group,formulate 19 clinical questions,develop the recommendations,and draft the guidelines.Three online meetings were held on 04/12/2020,30/11/2021,and 25/01/2022 to vote on the recommendations and get advice and suggestions from all involved experts.All the experts focusing on minimally invasive surgery from America,Europe and Oceania made great contributions to this consensus guideline.Results:After a systematic literature review 176 studies were included,19 questions were addressed and 14 recommendations were developed through the expert assessment and comprehensive judgment of the quality and credibility of the evidence.Conclusions:The international RPS guidelines can guide current practice for surgeons,patients,medical societies,hospital administrators,and related social communities.Further randomized trials are required to determine the added value of RPS as compared to open and laparoscopic surgery.展开更多
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 inve...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.展开更多
To address the increasing need for detecting and validating protein biomarkers in clinical specimens,mass spectrometry(MS)-based targeted proteomic techniques,including the selected reaction monitoring(SRM),parallel r...To address the increasing need for detecting and validating protein biomarkers in clinical specimens,mass spectrometry(MS)-based targeted proteomic techniques,including the selected reaction monitoring(SRM),parallel reaction monitoring(PRM),and massively parallel dataindependent acquisition(DIA),have been developed.For optimal performance,they require the fragment ion spectra of targeted peptides as prior knowledge.In this report,we describe a MS pipeline and spectral resource to support targeted proteomics studies for human tissue samples.To build the spectral resource,we integrated common open-source MS computational tools to assemble a freely accessible computational workflow based on Docker.We then applied the workflow to generate DPHL,a comprehensive DIA pan-human library,from 1096 data-dependent acquisition(DDA)MS raw files for 16 types of cancer samples.This extensive spectral resource was then applied to a proteomic study of 17 prostate cancer(PCa)patients.Thereafter,PRM validation was applied to a larger study of 57 PCa patients and the differential expression of three proteins in prostate tumor was validated.As a second application,the DPHL spectral resource was applied to a study consisting of plasma samples from 19 diffuse large B cell lymphoma(DLBCL)patients and 18 healthy control subjects.Differentially expressed proteins between DLBCL patients and healthy control subjects were detected by DIA-MS and confirmed by PRM.These data demonstrate that the DPHL supports DIA and PRM MS pipelines for robust protein biomarker discovery.DPHL is freely accessible at https://www.iprox.org/page/project.html?id=IPX0001400000.展开更多
Background: Liver regeneration is crucial to restore the functional liver mass after liver resection. The aim of this study was to evaluate the early postoperative changes in remnant liver function, volume and liver s...Background: Liver regeneration is crucial to restore the functional liver mass after liver resection. The aim of this study was to evaluate the early postoperative changes in remnant liver function, volume and liver stiffness after major liver resection and their correlation with postoperative outcomes. Methods: Patients undergoing major liver resection (≥3 segments) between February and November 2018 underwent both functional assessment using technetium-99m mebrofenin hepatobiliary scintigraphy (HBS) and CT-volumetry of the (future) remnant liver on preoperative day 1, the 5th postoperative day, and 4-6 weeks after resection. At the same time points, patients underwent transient elastography (TE) for the assessment of liver stiffness. Severe postoperative complications (Clavien-Dindo ≥ 3A) and mortality were correlated with the functional and volumetric increases of the remnant liver. Liver failure was graded according to the International Study Group of Liver Surgery (ISGLS) criteria. Results: A total of 18 patients were included of whom 10 (56%) had severe complications and one patient (5%) developed liver failure. Function and volume of the remnant liver had increased by the 5th postoperative day from 6.9 (5.4-10.9) to 9.6 (6.7-13.8) %/min/m2, P=0.004 and from 795.5 (538.3-1,037.5) to 1,080.0 (854.0-1,283.3) mL, P<0.001, respectively. After 4-6 weeks, remnant liver volume had further increased [from 1,080.0 (854.0-1,283.3) to 1,222.0 (1,016.0-1,380.5) mL, P=0.035], however, liver function did not show any significant, further increase [from 9.6 (6.7-13.8) to 10.9 (8.8-13.6) %/min/m2, P=0.177]. Liver elasticity of the future remnant liver (FRL) increased [from 10.8 (5.7-18.7) to 17.5 (12.4-22.6) kPa, P=0.018] and gradually recovered after 4-6 weeks to a median of 10.9 (5.7-18.8) kPa (T3 vs. T4, P=0.079). Patients who had severe postoperative complications did not show a significant increase in liver function on the 5th postoperative day (P=0.203), despite increase of volume (P<0.01). Conclusions: Functional regeneration of the remnant liver predominantly occurs during the first 5 days after resection. In case of severe complications, functional regeneration is delayed, in contrast to volume increase.展开更多
Background:The only potentially curative option for patients with perihilar cholangiocarcinoma(PHC)is resection,typically an extrahepatic bile duct resection in combination with(extended)liver resection.Complications ...Background:The only potentially curative option for patients with perihilar cholangiocarcinoma(PHC)is resection,typically an extrahepatic bile duct resection in combination with(extended)liver resection.Complications such as bile leakage and liver failure have been suggested to be more common after right-sided resections compared to left-sided resections,whilst superior oncological outcomes have been reported after right-sided resections.However,data on outcomes after right-sided or left-sided liver resections in PHC are scarce.Therefore,we aimed to investigate short-and long-term outcomes after left and right hemihepatectomy in patients with PHC.Methods:In this retrospective study,patients undergoing major liver resection for suspected PHC in a tertiary center between 2000-2018 were included.Patients who had undergone left-sided resections were compared to patients with right-sided resections in terms of complications(90-day mortality,overall and severe morbidity and specific complications).For long-term outcomes,only patients with pathologically proven PHC were included in the survival analysis.Results:A total of 178 patients undergoing hemihepatectomy for suspected PHC were analysed,including 76 left-sided and 102 right-sided resections.Overall 90-day mortality was 14%(24 out of 178),with no significant difference after left-sided resection(11%;8 out of 76)versus right-sided resection(16%;16 out of 102)(P=0.319).Severe morbidity(Clavein Dindo≥3)was also comparable in both groups:54%versus 61%(P=0.361).No differences in specific complications including bile leakage were observed,although liver failure appeared to occur more frequently after right hemihepatectomy(22%versus 11%,P=0.052).Five-year overall survival for pathologically proven PHC,excluding in-hospital mortality,did not differ;43.7%after left-sided resection vs.and 38.2%after right-sided resection(P=0.553).Conclusions:Both short-and long-term outcomes between patients undergoing left and right hemihepatectomy for PHC were comparable.Post-hepatectomy liver failure was more common after right-sided resection.展开更多
Background:Surgery for perihilar cholangiocarcinoma(PHCC)remains a challenging procedure with high morbidity and mortality.The Academic Medical Center(Amsterdam UMC)and Memorial Sloan Kettering Cancer Center proposed ...Background:Surgery for perihilar cholangiocarcinoma(PHCC)remains a challenging procedure with high morbidity and mortality.The Academic Medical Center(Amsterdam UMC)and Memorial Sloan Kettering Cancer Center proposed a postoperative mortality risk score(POMRS)and post-hepatectomy liver failure score(PHLFS)to predict patient outcomes.This study aimed to validate the POMRS and PHLFS for PHCC patients at Hokkaido University.Methods:Medical records of 260 consecutive PHCC patients who had undergone major hepatectomy with extrahepatic bile duct resection without pancreaticoduodenectomy at Hokkaido University between March 2001 and November 2018 were evaluated to validate the PHLFS and POMRS.Results:The observed risks for PHLF were 13.7%,24.5%,and 39.8%for the low-risk,intermediate-risk,and high-risk groups,respectively,in the study cohort.A receiver-operator characteristic(ROC)analysis revealed that the PHLFS had moderate predictive value,with an analysis under the curve(AUC)value of 0.62.Mortality rates based on the POMRS were 1.7%,5%,and 5.1%for the low-risk,intermediate-risk,and high-risk groups,respectively.The ROC analysis demonstrated an AUC value of 0.58.Conclusions:This external validation study showed that for PHLFS the threshold for discrimination in an Eastern cohort was reached(AUC>0.6),but it would require optimization of the model before use in clinical practice is acceptable.The POMRS were not applicable in the eastern cohort.Further external validation is recommended.展开更多
CD8+T cells differentiate into different types of memory T cells after priming in the lymphoid organs.Central memory T cells selectively express lymph node homing markers and recirculate between the blood and the seco...CD8+T cells differentiate into different types of memory T cells after priming in the lymphoid organs.Central memory T cells selectively express lymph node homing markers and recirculate between the blood and the secondary lymphoid organs.Effector memory T cells lack lymph node homing capacity,mainly circulate in the blood,and may enter peripheral tissues.The third subset consists of tissue-resident memory T(Trm)cells that express CD69 and adhesion molecules such as CD11a,CD103,and CD49a that prevent tissue egress.展开更多
Background:Lymph node ratio(LNR;positive/harvested lymph nodes)was identified as overall survival predictor in several cancers,including pancreatic adenocarcinoma.It remains unclear if LNR is predictive of overall sur...Background:Lymph node ratio(LNR;positive/harvested lymph nodes)was identified as overall survival predictor in several cancers,including pancreatic adenocarcinoma.It remains unclear if LNR is predictive of overall survival in pancreatic adenocarcinoma patients staged pN2.This study assessed the prognostic overall survival role of LNR in pancreatic adenocarcinoma patients in relation with lymph node involvement.Methods:A retrospective international study in six different centers(Europe and United States)was performed.Pancreatic adenocarcinoma patients who underwent pancreatoduodenectomy from 2000 to 2017 were included.Patients with neoadjuvant treatment,metastases,R2 resections,or missing data regarding nodal status were excluded.Survival curves were calculated using Kaplan-Meier method and compared using log-rank test.Multivariable Cox regressions were performed to find independent overall survival predictors adjusted for potential confounders.Results:A total of 1,327 patients were included.Lymph node involvement(pN+)was found in 1,026 patients(77%),561 pN1(55%)and 465 pN2(45%).Median LNR in pN+patients was 0.214[interquartile range(IQR):0.105-0.364].On multivariable analysis,LNR was the strongest overall survival predictor in the entire cohort[hazard ratio(HR)=5.5;95%confidence interval(CI):3.1-9.9;P<0.001]and pN+patients(HR=3.8;95%CI:2.2-6.6;P<0.001).Median overall survival was better in patients with LNR<0.225 compared to patients with LNR≥0.225 in the entire cohort and pN+patients.Similar results were found in pN2 patients(worse overall survival when LNR≥0.225).Conclusions:LNR appeared as an important prognostic factor in patients undergoing surgery for pancreatic adenocarcinoma and permitted to stratify overall survival in pN2 patients.LNR should be routinely used in complement to tumor-node-metastasis(TNM)stage to better predict patient prognosis.展开更多
P-glycoprotein(ABCB1),multidrug resistance protein-1(ABCC1)and breast cancer resistance protein(ABCG2)belong to the ATP-binding cassette(ABC)superfamily of proteins that play an important physiological role in protect...P-glycoprotein(ABCB1),multidrug resistance protein-1(ABCC1)and breast cancer resistance protein(ABCG2)belong to the ATP-binding cassette(ABC)superfamily of proteins that play an important physiological role in protection of the body from toxic xenobiotics and endogenous metabolites.Beyond this,these transporters determine the toxicity profile of many drugs,and confer multidrug resistance(MDR)in cancer cells associated with a poor treatment outcome of cancer patients.It has long been hypothesized that inhibition of ABC drug efflux transporters will increase drug accumulation and thereby overcome MDR,but until now no approved inhibitor of these transporters is available in the clinic.In this review we present molecular strategies to overcome this type of drug resistance and discuss for each of these strategies their promising value or indicate underlying reasons for their limited success.展开更多
文摘BACKGROUND Bile spillage occurs more frequently in patients with incidental gallbladder carcinoma(iGBC)and may be associated with poor survival due to presumed high risk of peritoneal seeding.AIM To investigate the impact of bile spillage during primary surgery on the survival of patients with iGBC.METHODS Medical records of patients with iGBC diagnosed between 2000 and 2019 in 27 Dutch secondary centers and 5 tertiary centers were retrospectively reviewed.Patient medical records were assessed.Predictors for overall survival(OS)were determined using multivariable Cox regression.RESULTS Of the 346 included patients with iGBC,138(39.9%)had bile spillage,which was associated with higher American Society of Anesthesiologists classification(P=0.020),cholecystitis(P<0.001),higher tumor stage(P=0.005),and non-radical resection(P<0.001).Bile spillage was associated with poor OS[hazard ratio=1.97,95%confidence interval(CI):1.48-2.63,P<0.001]with a median OS of 12 months(95%CI:7-18 months)vs 34 months(95%CI:14-55 months,P<0.001).In multivariable analysis,spillage was not an independent prognostic factor for survival(hazard ratio=1.21,95%CI:0.84-1.74,P=0.313).CONCLUSION Although bile spillage correlates with prognostic factors,it lacks independent prognostic significance for survival.Patients with an indication for additional treatment should be promptly referred to a specialized hepatopancreatobiliary center,irrespective of whether bile spillage has occurred.
基金Supported by the Bennink Foundation,No.2002262the Cancer Center Amsterdam Foundation
文摘BACKGROUND Duodenal adenocarcinoma(DA)and intestinal-type papilla of Vater adenocarcinoma(it-PVA)are rare malignancies of the gastrointestinal tract.Current therapeutic options are translated nowadays from treatment strategies for patients with colorectal cancer due to histopathological similarities.AIM To retrospectively investigate the clinical outcome of patients with DA and it-PVA.METHODS All patients with DA and it-PVA diagnosed between 2000 and 2017 were included at two academic centers in the Netherlands.All patients with histopathologically-confirmed DA or it-PVA were eligible for inclusion.Clinical outcome was compared between DA and it-PVA per disease stage.In the subgroup of stage IV disease,survival after local treatment of oligometastases was compared with systemic therapy or supportive care.RESULTS In total,155 patients with DA and it-PVA were included.Patients with it-PVA more often presented with stage I disease,while DA was more often diagnosed at stage IV(P<0.001).Of all patients,79%were treated with curative intent.The median survival was 39 mo,and no difference in survival was found for patients with DA and it-PVA after stratification for disease stage.Seven(23%)of 31 patients with synchronous stage IV disease underwent resection of the primary tumor,combined with local treatment of oligometastases.Local treatment of metastases was associated with an overall survival of 37 mo,compared to 14 and 6 mo for systemic therapy and supportive care,respectively.CONCLUSION Survival of patients with DA and it-PVA is comparable per disease stage.These results suggest a potential benefit for local treatment strategies in selected patients with oligometastases,although additional prospective studies are needed.
文摘The development of artificial intelligence(AI)has increased dramatically in the last 20 years,with clinical applications progressively being explored for most of the medical specialties.The field of gastroenterology and hepatology,substantially reliant on vast amounts of imaging studies,is not an exception.The clinical applications of AI systems in this field include the identification of premalignant or malignant lesions(e.g.,identification of dysplasia or esophageal adenocarcinoma in Barrett’s esophagus,pancreatic malignancies),detection of lesions(e.g.,polyp identification and classification,small-bowel bleeding lesion on capsule endoscopy,pancreatic cystic lesions),development of objective scoring systems for risk stratification,predicting disease prognosis or treatment response[e.g.,determining survival in patients post-resection of hepatocellular carcinoma),determining which patients with inflammatory bowel disease(IBD)will benefit from biologic therapy],or evaluation of metrics such as bowel preparation score or quality of endoscopic examination.The objective of this comprehensive review is to analyze the available AI-related studies pertaining to the entirety of the gastrointestinal tract,including the upper,middle and lower tracts;IBD;the hepatobiliary system;and the pancreas,discussing the findings and clinical applications,as well as outlining the current limitations and future directions in this field.
文摘BACKGROUND Preoperative biliary drainage in patients with presumed resectable perihilar cholangiocarcinoma(PHC)is hypothesized to promote the occurrence of seeding metastases.Seeding metastases can occur at the surgical scars or at the site of postoperative drains,and in case of percutaneous biliary drainage,at the catheter port-site.To prevent seeding metastases after resection,we routinely treated PHC patients with preoperative radiotherapy(RT)for over 25 years until January 2018.AIM To investigate the incidence of seeding metastases following resection of PHC.METHODS All patients who underwent resection for pathology proven PHC between January 2000 and March 2019 were included in this retrospective study.Between 2000-January 2018,patients received preoperative RT(3×3.5 Gray).RT was omitted in patients treated after January 2018.RESULTS A total of 171 patients underwent resection for PHC between January 2000 and March 2019.Of 171 patients undergoing resection,111 patients(65%)were treated with preoperative RT.Intraoperative bile cytology showed no difference in the presence of viable tumor cells in bile of patients undergoing preoperative RT or not.Overall,two patients(1.2%)with seeding metastases were identified,both in the laparotomy scar and both after preoperative RT(one patient with endoscopic and the other with percutaneous and endoscopic biliary drainage).CONCLUSION The incidence of seeding metastases in patients with resected PHC in our series was low(1.2%).This low incidence and the inability of providing evidence that preoperative low-dose RT prevents seeding metastases,has led us to discontinue preoperative RT in patients with resectable PHC in our center.
基金supported by:ERC Consolidator:BOOTCAMP(864815)and Lymph and Co:2018-LYCo-008.NZ is supported by a Vici grant from the Netherlands Organization for Scientific Research(NWO,016.176.643)and an NWO ENW grant(M.22.034,GENESIS).
文摘Autologous T-cell therapies show limited efficacy in chronic lymphocytic leukemia(CLL),where acquired immune dysfunction prevails.In CLL,disturbed mitochondrial metabolism has been linked to defective T-cell activation and proliferation.Recent research suggests that lipid metabolism regulates mitochondrial function and differentiation in T cells,yet its role in CLL remains unexplored.This comprehensive study compares T-cell lipid metabolism in CLL patients and healthy donors,revealing critical dependence on exogenous cholesterol for human T-cell expansion following TCR-mediated activation.Using multi-omics and functional assays,we found that T cells present in viably frozen samples of patients with CLL(CLL T cells)showed impaired adaptation to cholesterol deprivation and inadequate upregulation of key lipid metabolism transcription factors.CLL T cells exhibited altered lipid storage,with increased triacylglycerols and decreased cholesterol,and inefficient fatty acid oxidation(FAO).Functional consequences of reduced FAO in T cells were studied using samples from patients with inherent FAO disorders.Reduced FAO was associated with lower T-cell activation but did not affect proliferation.This implicates low cholesterol levels as a primary factor limiting T-cell proliferation in CLL.CLL T cells displayed fewer and less clustered lipid rafts,potentially explaining the impaired immune synapse formation observed in these patients.Our findings highlight significant disruptions in lipid metabolism as drivers of functional deficiencies in CLL T cells,underscoring the pivotal role of cholesterol in T-cell proliferation.This study suggests that modulating cholesterol metabolism could enhance T-cell function in CLL,presenting novel immunotherapeutic approaches to improve outcome in this challenging disease.
文摘Platelets are reprogrammed by cancer via a process called education,which favors cancer development.The transcriptional profile of tumor-educated platelets(TEPs)is skewed and therefore practicable for cancer detection.This intercontinental,hospital-based,diagnostic study included 761 treatment-naive inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers(China,n=3;Netherlands,n=5;Poland,n=1)between September 2016 and May 2019.The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese(VC1 and VC2)and the European(VC3)validation cohorts collectively and independently.Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets.The AUCs for TEPs in the combined validation cohort,VC1,VC2,and VC3 were 0.918(95%CI 0.889-0.948),0.923(0.855-0.990),0.918(0.872-0.963),and 0.887(0.813-0.960),respectively.Combination of TEPs and CA125 demonstrated an AUC of 0.922(0.889-0.955)in the combined validation cohort;0.955(0.912-0.997)in VC1;0.939(0.901-0.977)in VC2;0.917(0.824-1.000)in VC3.For subgroup analysis,TEPs exhibited an AUC of o.858,0.859,and 0.920 to detect early-stage,borderline,non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis.TEPs had robustness,compatibility,and universality for preop.erative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities,heterogeneous histoiogical subtypes,and early-stage ovarian cancer.However,these observations warrant prospective validations in a larger population beforeclinicalutilities.
文摘INTRODUCTION Cancer drug resistance has been and unfortunately still is a major problem in cancer therapy.Almost any therapy(except surgery)that is being used in the treatment of cancer can result in resistance.Unfortunately there is a large group of patients that will either not respond to the applied therapy(intrinsic resistance)or will become resistant during therapy(acquired resistance).Sometimes patients can become resistant to one specific drug and remain sensitive to other drugs(one-drug resistance);another group of patients may become resistant to one drug and will be resistant to other unrelated drugs as well(multiple drug resistance,MDR).
基金This work was supported by Cancer Center Amsterdam(CCA)Foundation grants 2015 and 2018Italian Association for Cancer Research(AIRC)IG grant to Giovannetti E,European Union 2014-2020 PON Ricerca e Innovazione grant from the Italian Ministry of Education,University and Research,entitled“PROGEMA-Processi Green per l’Estrazione di Principi Attivi e la Depurazione di Matrici di Scarto e Non”(ARS01_00432)to Diana P.
文摘Aim:Because mutations of splicing factor 3B subunit-1(SF3B1)have been identified in 4%of pancreatic ductal adenocarcinoma(PDAC)patients,we investigated the activity of new potential inhibitors of SF3B1 in combination with gemcitabine,one of the standard drugs,in PDAC cell lines.Methods:One imidazo[2,1-b][1,3,4]thiadiazole derivative(IS1)and three indole derivatives(IS2,IS3 and IS4),selected by virtual screening from an in-house library,were evaluated by the sulforhodamine-B and wound healing assay for their cytotoxic and antimigratory activity in the PDAC cells SUIT-2,Hs766t and Panc05.04,the latter harbouring the SF3B1 mutations.The effects on the splicing pattern of proto-oncogene recepteur d’origine nantais(RON)and the gemcitabine transporter human equilibrative nucleoside transporter-1(hENT1)were assessed by PCR,while the ability to reduce tumour volume was tested in spheroids of primary PDAC cells.Results:The potential SF3B1 modulators inhibited PDAC cell proliferation and prompted induction of cell death.All compounds showed an interesting anti-migratory ability,associated with splicing RON/ΔRON shift in SUIT-2 cells after 24 h exposure.Moreover,IS1 and IS4 potentiated the sensitivity to gemcitabine in both conventional 2D monolayer and 3D spheroid cultures,and these results might be explained by the statistically significant increase in hENT1 expression(P<0.05 vs.untreated control cells),potentially reversing PDAC chemoresistance.Conclusion:These results support further studies on new SF3B1 inhibitors and the role of RON/hENT1 modulation to develop effective drug combinations against PDAC.
文摘In a recent study published in Signal Transduction and Targeted Therapy,Dr.Zhao and colleagues1 identify thrombin as a novel mediator of vasculogenic mimicry in non-small-cell lung cancer(NSCLC).This provides important mechanistic insight by which coagulation(factors)may drive tumor progression and several lessons to improve anticoagulant therapy of cancer patients can be learned from the paper.
文摘SPECIAL ISSUE INTRODUCTION Targeted therapies in cancer aim to specifically block the activity of crucial proteins or signaling pathways necessary for the growth and/or survival of tumor cells.A major breakthrough in targeted cancer therapy was the introduction nearly two decades ago of imatinib,an inhibitor of the BCR-ABL tyrosine kinase for the treatment of chronic myeloid leukemia.Over the last years,significant advances in our understanding of tumor biology have facilitated the development of many drugs targeting not only kinases,but also other protein families and cellular processes.Several of these agents are currently employed or being implemented for the treatment of different hematologic and solid malignancies,such as lung cancer.The special issue on“Targeted cancer therapy”will include reviews and commentaries updating the clinical use of targeted agents in the treatment of different tumor types,and the mechanisms that underlie the action of drugs directed to different types of targets.The special issue will also include research articles presenting novel outstanding data on all aspects of targeted cancer therapy.All submissions will undergo rigorous peer review and will be published free of charge upon acceptance.
基金supported by a grant from Intuitive Foundation for the development of the LIVEROBOT European training program in robotic liver surgery.
文摘The robotic platform enables surgeons to operate with a similar level of freedom and control as in open surgery,while still providing the patient with the benefits of a minimally invasive approach.More centres continue to adopt robotic liver surgery however standardized training materials and consensus on the surgical technique are currently lacking.The availability of a standardized surgical protocol could benefit the further dissemination of the robotic approach while promoting safe and effective operating techniques.We present a comprehensive surgical technique description for robotic hepatectomy agreed upon by seven expert robotic liver surgeons in Europe.They contributed insights from their extensive experience with the robot to develop this report,highlighting the key steps and important considerations for performing robotic hepatectomy.We describe the surgical technique for four most common hepatectomy types with varying complexity:partial anterolateral resections,partial posterosuperior resections,left hepatectomy and right hepatectomy.This report encompasses recommendations from the experts,covering the preparatory steps such as patient selection and pre-operative imaging,and extending through to care in the postoperative phase.The step-by-step surgical technique description serves as a compendium of best practice methods presently utilized in robotic liver surgery.Although some variations in technique cannot be eliminated from practice,general recommendations in a structured form will help to homogenize the technique,safeguarding surgical quality.This paper aims to inform and advise surgeons in the process of adopting robotic liver surgery and can act as a starting point for further optimization and refinement of the technique.
文摘Background:With the rapid development of robotic surgery,especially for the abdominal surgery,robotic pancreatic surgery(RPS)has been applied increasingly around the world.However,evidence-based guidelines regarding its application,safety,and efficacy are still lacking.To harvest robust evidence and comprehensive clinical practice,this study aims to develop international guidelines on the use of RPS.Methods:World Health Organization(WHO)Handbook for Guideline Development,GRADE Grid method,Delphi vote,and the AGREE-II instrument were used to establish the Guideline Steering Group,Guideline Development Group,and Guideline Secretary Group,formulate 19 clinical questions,develop the recommendations,and draft the guidelines.Three online meetings were held on 04/12/2020,30/11/2021,and 25/01/2022 to vote on the recommendations and get advice and suggestions from all involved experts.All the experts focusing on minimally invasive surgery from America,Europe and Oceania made great contributions to this consensus guideline.Results:After a systematic literature review 176 studies were included,19 questions were addressed and 14 recommendations were developed through the expert assessment and comprehensive judgment of the quality and credibility of the evidence.Conclusions:The international RPS guidelines can guide current practice for surgeons,patients,medical societies,hospital administrators,and related social communities.Further randomized trials are required to determine the added value of RPS as compared to open and laparoscopic surgery.
文摘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.
基金supported by the National Natural Science Foundation of China(Grant No.81972492)National Science Fund for Young Scholars(Grant No.21904107)+7 种基金Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholars(Grant No.LR19C050001)Hangzhou Agriculture and Society Advancement Program(Grant No.20190101A04)Westlake Startup Grantresearch funds from the National Cancer Centre Singapore and Singapore General Hospital,Singaporethe National Key R&D Program of China(Grant No.2016YFC0901704)Zhejiang Innovation Discipline Project of Laboratory Animal Genetic Engineering(Grant No.201510)the Netherlands Cancer Society(Grant No.NKI 2014-6651)The Netherlands Organization for Scientific Research(NWO)-Middelgroot(Grant No.91116017)
文摘To address the increasing need for detecting and validating protein biomarkers in clinical specimens,mass spectrometry(MS)-based targeted proteomic techniques,including the selected reaction monitoring(SRM),parallel reaction monitoring(PRM),and massively parallel dataindependent acquisition(DIA),have been developed.For optimal performance,they require the fragment ion spectra of targeted peptides as prior knowledge.In this report,we describe a MS pipeline and spectral resource to support targeted proteomics studies for human tissue samples.To build the spectral resource,we integrated common open-source MS computational tools to assemble a freely accessible computational workflow based on Docker.We then applied the workflow to generate DPHL,a comprehensive DIA pan-human library,from 1096 data-dependent acquisition(DDA)MS raw files for 16 types of cancer samples.This extensive spectral resource was then applied to a proteomic study of 17 prostate cancer(PCa)patients.Thereafter,PRM validation was applied to a larger study of 57 PCa patients and the differential expression of three proteins in prostate tumor was validated.As a second application,the DPHL spectral resource was applied to a study consisting of plasma samples from 19 diffuse large B cell lymphoma(DLBCL)patients and 18 healthy control subjects.Differentially expressed proteins between DLBCL patients and healthy control subjects were detected by DIA-MS and confirmed by PRM.These data demonstrate that the DPHL supports DIA and PRM MS pipelines for robust protein biomarker discovery.DPHL is freely accessible at https://www.iprox.org/page/project.html?id=IPX0001400000.
基金The study was conducted in accordance with the Declaration of Helsinki(as revised in 2013)The study was approved by institutional ethics board of Amsterdam University Medical Centers(No.NL63868.018.17)informed consent was taken from all individual participants.
文摘Background: Liver regeneration is crucial to restore the functional liver mass after liver resection. The aim of this study was to evaluate the early postoperative changes in remnant liver function, volume and liver stiffness after major liver resection and their correlation with postoperative outcomes. Methods: Patients undergoing major liver resection (≥3 segments) between February and November 2018 underwent both functional assessment using technetium-99m mebrofenin hepatobiliary scintigraphy (HBS) and CT-volumetry of the (future) remnant liver on preoperative day 1, the 5th postoperative day, and 4-6 weeks after resection. At the same time points, patients underwent transient elastography (TE) for the assessment of liver stiffness. Severe postoperative complications (Clavien-Dindo ≥ 3A) and mortality were correlated with the functional and volumetric increases of the remnant liver. Liver failure was graded according to the International Study Group of Liver Surgery (ISGLS) criteria. Results: A total of 18 patients were included of whom 10 (56%) had severe complications and one patient (5%) developed liver failure. Function and volume of the remnant liver had increased by the 5th postoperative day from 6.9 (5.4-10.9) to 9.6 (6.7-13.8) %/min/m2, P=0.004 and from 795.5 (538.3-1,037.5) to 1,080.0 (854.0-1,283.3) mL, P<0.001, respectively. After 4-6 weeks, remnant liver volume had further increased [from 1,080.0 (854.0-1,283.3) to 1,222.0 (1,016.0-1,380.5) mL, P=0.035], however, liver function did not show any significant, further increase [from 9.6 (6.7-13.8) to 10.9 (8.8-13.6) %/min/m2, P=0.177]. Liver elasticity of the future remnant liver (FRL) increased [from 10.8 (5.7-18.7) to 17.5 (12.4-22.6) kPa, P=0.018] and gradually recovered after 4-6 weeks to a median of 10.9 (5.7-18.8) kPa (T3 vs. T4, P=0.079). Patients who had severe postoperative complications did not show a significant increase in liver function on the 5th postoperative day (P=0.203), despite increase of volume (P<0.01). Conclusions: Functional regeneration of the remnant liver predominantly occurs during the first 5 days after resection. In case of severe complications, functional regeneration is delayed, in contrast to volume increase.
文摘Background:The only potentially curative option for patients with perihilar cholangiocarcinoma(PHC)is resection,typically an extrahepatic bile duct resection in combination with(extended)liver resection.Complications such as bile leakage and liver failure have been suggested to be more common after right-sided resections compared to left-sided resections,whilst superior oncological outcomes have been reported after right-sided resections.However,data on outcomes after right-sided or left-sided liver resections in PHC are scarce.Therefore,we aimed to investigate short-and long-term outcomes after left and right hemihepatectomy in patients with PHC.Methods:In this retrospective study,patients undergoing major liver resection for suspected PHC in a tertiary center between 2000-2018 were included.Patients who had undergone left-sided resections were compared to patients with right-sided resections in terms of complications(90-day mortality,overall and severe morbidity and specific complications).For long-term outcomes,only patients with pathologically proven PHC were included in the survival analysis.Results:A total of 178 patients undergoing hemihepatectomy for suspected PHC were analysed,including 76 left-sided and 102 right-sided resections.Overall 90-day mortality was 14%(24 out of 178),with no significant difference after left-sided resection(11%;8 out of 76)versus right-sided resection(16%;16 out of 102)(P=0.319).Severe morbidity(Clavein Dindo≥3)was also comparable in both groups:54%versus 61%(P=0.361).No differences in specific complications including bile leakage were observed,although liver failure appeared to occur more frequently after right hemihepatectomy(22%versus 11%,P=0.052).Five-year overall survival for pathologically proven PHC,excluding in-hospital mortality,did not differ;43.7%after left-sided resection vs.and 38.2%after right-sided resection(P=0.553).Conclusions:Both short-and long-term outcomes between patients undergoing left and right hemihepatectomy for PHC were comparable.Post-hepatectomy liver failure was more common after right-sided resection.
基金the institutional review board of Hokkaido University(No.018-0429).
文摘Background:Surgery for perihilar cholangiocarcinoma(PHCC)remains a challenging procedure with high morbidity and mortality.The Academic Medical Center(Amsterdam UMC)and Memorial Sloan Kettering Cancer Center proposed a postoperative mortality risk score(POMRS)and post-hepatectomy liver failure score(PHLFS)to predict patient outcomes.This study aimed to validate the POMRS and PHLFS for PHCC patients at Hokkaido University.Methods:Medical records of 260 consecutive PHCC patients who had undergone major hepatectomy with extrahepatic bile duct resection without pancreaticoduodenectomy at Hokkaido University between March 2001 and November 2018 were evaluated to validate the PHLFS and POMRS.Results:The observed risks for PHLF were 13.7%,24.5%,and 39.8%for the low-risk,intermediate-risk,and high-risk groups,respectively,in the study cohort.A receiver-operator characteristic(ROC)analysis revealed that the PHLFS had moderate predictive value,with an analysis under the curve(AUC)value of 0.62.Mortality rates based on the POMRS were 1.7%,5%,and 5.1%for the low-risk,intermediate-risk,and high-risk groups,respectively.The ROC analysis demonstrated an AUC value of 0.58.Conclusions:This external validation study showed that for PHLFS the threshold for discrimination in an Eastern cohort was reached(AUC>0.6),but it would require optimization of the model before use in clinical practice is acceptable.The POMRS were not applicable in the eastern cohort.Further external validation is recommended.
文摘CD8+T cells differentiate into different types of memory T cells after priming in the lymphoid organs.Central memory T cells selectively express lymph node homing markers and recirculate between the blood and the secondary lymphoid organs.Effector memory T cells lack lymph node homing capacity,mainly circulate in the blood,and may enter peripheral tissues.The third subset consists of tissue-resident memory T(Trm)cells that express CD69 and adhesion molecules such as CD11a,CD103,and CD49a that prevent tissue egress.
基金This article was presented in parts at the Annual Meeting of the Swiss Congress of Surgery(September 2020)at the World Congress of the IHPBA(November 2020).
文摘Background:Lymph node ratio(LNR;positive/harvested lymph nodes)was identified as overall survival predictor in several cancers,including pancreatic adenocarcinoma.It remains unclear if LNR is predictive of overall survival in pancreatic adenocarcinoma patients staged pN2.This study assessed the prognostic overall survival role of LNR in pancreatic adenocarcinoma patients in relation with lymph node involvement.Methods:A retrospective international study in six different centers(Europe and United States)was performed.Pancreatic adenocarcinoma patients who underwent pancreatoduodenectomy from 2000 to 2017 were included.Patients with neoadjuvant treatment,metastases,R2 resections,or missing data regarding nodal status were excluded.Survival curves were calculated using Kaplan-Meier method and compared using log-rank test.Multivariable Cox regressions were performed to find independent overall survival predictors adjusted for potential confounders.Results:A total of 1,327 patients were included.Lymph node involvement(pN+)was found in 1,026 patients(77%),561 pN1(55%)and 465 pN2(45%).Median LNR in pN+patients was 0.214[interquartile range(IQR):0.105-0.364].On multivariable analysis,LNR was the strongest overall survival predictor in the entire cohort[hazard ratio(HR)=5.5;95%confidence interval(CI):3.1-9.9;P<0.001]and pN+patients(HR=3.8;95%CI:2.2-6.6;P<0.001).Median overall survival was better in patients with LNR<0.225 compared to patients with LNR≥0.225 in the entire cohort and pN+patients.Similar results were found in pN2 patients(worse overall survival when LNR≥0.225).Conclusions:LNR appeared as an important prognostic factor in patients undergoing surgery for pancreatic adenocarcinoma and permitted to stratify overall survival in pN2 patients.LNR should be routinely used in complement to tumor-node-metastasis(TNM)stage to better predict patient prognosis.
文摘P-glycoprotein(ABCB1),multidrug resistance protein-1(ABCC1)and breast cancer resistance protein(ABCG2)belong to the ATP-binding cassette(ABC)superfamily of proteins that play an important physiological role in protection of the body from toxic xenobiotics and endogenous metabolites.Beyond this,these transporters determine the toxicity profile of many drugs,and confer multidrug resistance(MDR)in cancer cells associated with a poor treatment outcome of cancer patients.It has long been hypothesized that inhibition of ABC drug efflux transporters will increase drug accumulation and thereby overcome MDR,but until now no approved inhibitor of these transporters is available in the clinic.In this review we present molecular strategies to overcome this type of drug resistance and discuss for each of these strategies their promising value or indicate underlying reasons for their limited success.
