Comprehensive multi-omics profiling identifies novel molecular subtypes of pancreatic ductal adenocarcinoma

Pancreatic cancer,a highly fatal malignancy,is predicted to rank as the second leading cause of cancer-related death in the next decade.This highlights the urgent need for new insights into personalized diagnosis and treatment.Although molecular subtypes of pancreatic cancer were well established in genomics and transcriptomics,few known molec-ular classifications are translated to guide clinical strategies and require a paradigm shift.Notably,chronically developing and continuously improving high-throughput technologies and systems serve as an important driving force to further portray the molecular landscape of pancreatic cancer in terms of epigenomics,proteomics,metabonomics,and metagenomics.Therefore,a more comprehensive understanding of molecular classifications at multiple levels using an integrated multi-omics approach holds great promise to exploit more potential ther-apeutic options.In this review,we recapitulated the molecular spectrum from different omics levels,discussed various subtypes on multi-omics means to move one step forward towards bench-to-beside translation of pancreatic cancer with clinical impact,and proposed some methodological andscientific challengesinstore.

Long-term sustained clinical remission of peritoneal metastatic pancreatic ductal adenocarcinoma after sequential chemoradiation therapy: a case report

Patients with peritoneal metastatic pancreatic ductal adenocarcinoma(pmPDAC)with high-level serum carbohydrate antigens(CAs)always suffer extremely dismal prognosis,with a median survival of several months.Herein,we reported a case of pmPDAC with high serum CAs who had long-term clinical remission with normalization of CAs after chemoradiation.In November 2019,a 64-year-old male patient was admitted to our center with a solid mass measuring 2.8×2.5×2.0 cm in the body of the pancreas near the celiac trunk.Positron emission tomography-computed tomography(PET-CT)revealed an standardized uptake value max(SUVmax)of 4.2.The serum CA 242 level exceeded 150.0 U/mL(normal range:0–20 U/mL),and CA 19-9 was elevated at 975.2 U/mL(normal range:0–34 U/mL).During laparotomy,the tumor was found to encircle the celiac trunk over 180°,with several small peritoneal nodules in the lesser omental cavity.Pathological examination confirmed the diagnosis of pmPDAC.Nextgeneration sequencing revealed RAS G12V,EGFR mutation(-),low tumor mutation burden(TMB),and microsatellite stability(MSS).The patient underwent 6 cycles of the AG regimen(gemcitabine plus nab-paclitaxel),resulting in significant tumor shrinkage and a sharp decline in CAs.Partial remission was achieved.However,due to intolerant neurotoxicity,the AG regimen was discontinued.Subsequently,synchronous oral fluorouracil(S1)and radiation therapy were administered.Five months after radiation treatment,all CAs normalized.Oral S1 was continued for an additional 3 months.Eventually,all anti-cancer drugs were stopped.Computed tomography scans indicated that the tumor still surrounded the celiac trunk and common hepatic artery.After a thorough discussion,a wait-and-see strategy was adopted.Remarkably,32 months after stopping anti-cancer medication,the patient remains in good health,with sustained normalization of CAs.At the last follow-up,he had lived for 50 months,and the normalization of the CAs was sustained for 36 months.Although he still suffers the risk of disease progression,it is a successful case of state-of-the-art chemoradiation for a dismal pmPDAC patient.

Mechanisms of obesity-and diabetes mellitus-related pancreatic carcinogenesis:a comprehensive and systematic

Research on obesity-and diabetes mellitus(DM)-related carcinogenesis has expanded exponentially since these two diseases were recognized as important risk factors for cancers.The growing interest in this area is prominently actuated by the increasing obesity and DM prevalence,which is partially responsible for the slight but constant increase in pancreatic cancer(PC)occurrence.PC is a highly lethal malignancy characterized by its insidious symptoms,delayed diagnosis,and devastating prognosis.The intricate process of obesity and DM promoting pancreatic carcinogenesis involves their local impact on the pancreas and concurrent wholebody systemic changes that are suitable for cancer initiation.The main mechanisms involved in this process include the excessive accumulation of various nutrients and metabolites promoting carcinogenesis directly while also aggravating mutagenic and carcinogenic metabolic disorders by affecting multiple pathways.Detrimental alterations in gastrointestinal and sex hormone levels and microbiome dysfunction further compromise immunometabolic regulation and contribute to the establishment of an immunosuppressive tumor microenvironment(TME)for carcinogenesis,which can be exacerbated by several crucial pathophysiological processes and TME components,such as autophagy,endoplasmic reticulum stress,oxidative stress,epithelialmesenchymal transition,and exosome secretion.This review provides a comprehensive and critical analysis of the immunometabolic mechanisms of obesity-and DM-related pancreatic carcinogenesis and dissects how metabolic disorders impair anticancer immunity and influence pathophysiological processes to favor cancer initiation.

Cyst fluid glycoproteins accurately distinguishing malignancies of pancreatic cystic neoplasm

Pancreatic cystic neoplasms(PCNs)are recognized as precursor lesions of pancreatic cancer,with a marked increase in prevalence.Early detection of malignant PCNs is crucial for improving prognosis;however,current diagnostic methods are insufficient for accurately identifying malignant PCNs.Here,we utilized mass spectrometry(MS)-based glycosite-and glycoform-specific glycoproteomics,combined with proteomics,to explore potential cyst fluid diagnostic biomarkers for PCN.The glycoproteomic and proteomic landscape of pancreatic cyst fluid samples from PCN patients was comprehensively investigated,and its characteristics during the malignant transformation of PCN were analyzed.Under the criteria of screening specific cyst fluid biomarkers for the diagnosis of PCN,a group of cyst fluid glycoprotein biomarkers was identified.Through parallel reaction monitoring(PRM)-based targeted glycoproteomic analysis,we validated these chosen glycoprotein biomarkers in a second cohort,ultimately confirming N-glycosylated PHKB(Asn-935,H5N2F0S0;Asn-935,H4N4F0S0;Asn-935,H5N4F0S0),CEACAM5(Asn-197,H5N4F0S0)and ATP6V0A4(Asn-367,H6N4F0S0)as promising diagnostic biomarkers for distinguishing malignant PCNs.These glycoprotein biomarkers exhibited robust performance,with an area under the curve ranging from 0.771 to 0.948.In conclusion,we successfully established and conducted MS-based glycoproteomic analysis to identify novel cyst fluid glycoprotein biomarkers for PCN.These findings hold significant clinical implications,providing valuable insights for PCN decision-making,and potentially offering therapeutic targets for PCN treatment.

Heparin-induced thrombocytopenia thrombosis after pancreaticoduodenectomy without definitive prophylactic or therapeutic use of heparin:a case report

Heparin-induced thrombocytopenia thrombosis(HITT)is a rare and potentially life-threatening complication after abdominal surgery,and it always occurs after the prophylactic or therapeutic use of heparin.HITT after pancreaticoduodenectomy(PD)has not been reported before.Herein,we reported a case of HITT after PD without prophylactic or therapeutic use of heparin.A 74-year-old female patient who suffered resectable pancreatic head cancer was transferred to our center for surgery.An open PD procedure was performed,and the operation was smooth.No heparin was used after surgery.Nine days after surgery,the platelet sharply declined to 48×10^(9)/L(100-350),and the D-dimer soared up to 33.56 mg/L(0-0.55).Ultrasound examination showed vein thrombosis in both the lower limb and the right upper limb.HIT-antibody was 6.3 U/mL(0-0.6).The diagnosis of HITT was confirmed.Fondaparinux was used.On postoperative day(POD)23,the platelet recovered to the normal range.On POD 27,she was discharged without thromboembolism or active bleeding,and oral rivaroxaban was prescribed.One month after discharge,the platelet remained normal,and she did not complain of discomfort.

Immune-related signature identifies IL1R2 as an immunological and prognostic biomarker in pancreatic cancer

Objective:Pancreatic cancer is one of the most aggressive malignancies,a robust prognostic signature and novel biomarkers are urgently needed for accurate stratification of the patients and optimization of clinical decision-making.Methods:A list of bioinformatic analysis were applied in public dataset to construct an immune-related signature.Furthermore,the most pivotal gene in the signature was identified.The potential mechanism of the core gene function was revealed through GSEA,CIBERSORT,ESTIMATE,immunophenoscore(IPS)algorithm,single-cell analysis,and functional experiment.Results:An immune-related prognostic signature and associated nomogram were constructed and validated.Among the genes constituting the signature,interleukin 1 receptor type II(IL1R2)was identified as the gene occupying the most paramount position in the risk signature.Meanwhile,knockdown of IL1R2 significantly inhibited the proliferation,invasion,and migration ability of pancreatic cancer cells.Additionally,high IL1R2 expression was associated with reduced CD8+T cell infiltration in pancreatic cancer microenvironment,which may be due to high programmed cell death-ligand-1(PD-L1)expression in cancer cells.Finally,the IPS algorithm proved that patients with high IL1R2 expression possessed a higher tumor mutation burden and a higher probability of benefiting from immunotherapy.Conclusion:In conclusion,our study constructed an efficient immune-related prognostic signature and identified the key role of IL1R2 in the development of pancreatic cancer,as well as its potential to serve as a biomarker for immunotherapy efficacy prediction for pancreatic cancer.