Artificial intelligence in gastroenterology: A state-of-the-art review

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.

Clinical outcomes of patients with duodenal adenocarcinoma and intestinal-type papilla of Vater adenocarcinoma

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.

Occurrence of seeding metastases in resectable perihilar cholangiocarcinoma and the role of low-dose radiotherapy to prevent this

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.

Platelet RNA enables accurate detection of ovarian cancer:an intercontinental,biomarker identification study

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.

Cancer drug resistance: a new perspective

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).

Thrombin-mediated vasculogenic mimicry:important lessons to improve anticoagulant therapy of selected cancer patients

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.

SF3B1 modulators affect key genes in metastasis and drug influx: a new approach to fight pancreatic cancer chemoresistance

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.

Targeted therapies in cancer:where are we going?

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.

DPHL:A DIA Pan-human Protein Mass Spectrometry Library for Robust Biomarker Discovery

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.

Functional assessment of liver regeneration after major hepatectomy

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.

Validation study of postoperative liver failure and mortality risk scores after liver resection for perihilar cholangiocarcinoma

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.

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

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.

Short-and long-term outcomes after hemihepatectomy for perihilar cholangiocarcinoma:does left or right side matter?

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.

Staying home or leaving for a party:tissue-dependent choices of tissue-resident memory T cells

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.

Characteristics of leukemic stem cells in acute leukemia and potential targeted therapies for their specific eradication

In acute myeloid leukemia(AML),a small cell population that contains stem cell features such as lack of differentiation,self-renewal potential,and drug resistance,can be identified.These so-called leukemic stem cells(LSCs)are thought to be responsible for relapse initiation after initial treatment leading to successful eradication of the bulk AML cell population.Since many studies have aimed to characterize and eliminate LSCs to prevent relapse and increase survival rates of patients,LSCs are one of the best characterized cancer stem cells.The specific elimination of LSCs,while sparing the healthy normal hematopoietic stem cells(HSCs),is one of the major challenges in the treatment of leukemia.This review focuses on several surface markers and intracellular transcription factors that can distinguish AML LSCs from HSCs and,therefore,specifically eliminate these stem cell-like leukemic cells.Moreover,previous and ongoing clinical trials of acute leukemia patients treated with therapies targeting these markers are discussed.In contrast to knowledge on LSCs in AML,insight into LSCs in acute lymphoid leukemia(ALL)is limited.This review therefore also addresses the latest insight into LSCs in ALL.

International assessment and validation of the prognostic role of lymph node ratio in patients with resected pancreatic head ductal adenocarcinoma

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.