Laparoscopic radical distal pancreatectomy with portal venous tumor thrombectomy for the treatment of pancreatic acinar cell carcinoma after neoadjuvant chemotherapy

We have read the article“Current status and future prospect of surgical treatment for pancreatic cancer”,published in HepatoBiliary Surgery and Nutrition in 2020(1).This article mentions that in the past two decades,there has been significant development and progress in the surgical treatment of pancreatic cancer,significantly improving the tumor resection rate and reducing perioperative mortality and the incidence of severe complications.

The Chinese guidelines for the diagnosis and treatment of pancreatic neuroendocrine neoplasms(2020)

Pancreatic neuroendocrine neoplasms(pNENs)are highly heterogeneous,and the management of pNENs patients can be intractable.To address this challenge,an expert committee was established on behalf of the Chinese Pancreatic Surgery Association,which consisted of surgical oncologists,gastroenterologists,medical oncologists,endocrinologists,radiologists,pathologists,and nuclear medicine specialists.By reviewing the important issues regarding the diagnosis and treatment of pNENs,the committee concluded evidence-based statements and recommendations in this article,in order to further improve the management of pNENs patients in China.

Genomic characterization reveals distinctmutation landscapes and therapeutic implications in neuroendocrine carcinomas of the gastrointestinal tract

Background:Neuroendocrine carcinomas of the gastrointestinal tract(GINECs)remain a disease of grim prognosis with limited therapeutic options.Their molecular characteristics are still undefined.This study aimed to explore the underlying genetic basis and heterogeneity of GI-NECs.Methods:Comprehensive genomic analysis using whole-exome sequencing was performed on 143 formalin-fixed,paraffin-embedded samples of surgically resected GI-NEC with a thorough histological evaluation.Mutational signatures,somatic mutations,and copy number aberrations were analyzed and compared across anatomic locations and histological subtypes.Survival analysis was conducted to identify the independent factors.Results:In total,143GI-NECswere examined:the stomach,87 cases(60.8%);the esophagus,29 cases(20.3%);the colorectum,20 cases(14.0%);and the small intestine,7 cases(4.9%).Eighty-three(58.0%)and 60(42.0%)cases were subclassified into small cell and large cell subtypes,respectively.GI-NECs showed distinct genetic alterations from their lung counterparts and non-neuroendocrine carcinomas in the same locations.Obvious heterogeneity of mutational signatures,somatic mutations,and copy number variations was revealed across anatomic locations rather than histological subtypes.Except for tumor protein p53(TP53)and retinoblastoma 1(RB1),the most frequently mutated genes in the stomach,esophagus,colorectum,and small intestine were low-density lipoprotein receptor-related protein 1B(LRP1B),notch receptor 1(NOTCH1),adenomatosis polyposis coli(APC),catenin beta 1(CTNNB1),respectively.Mutations in the WNT-β-catenin,NOTCH and erythroblastic leukemia viral oncogene B(ERBB)pathwayswere prevalently identified in gastric,esophageal,and colorectalNECs,respectively.Importantly,104(72.7%)GI-NECs harbored putative clinically relevant alterations,and non-gastric location and RB1 bi-allelic inactivation with copy number alterations were identified as two independent poor prognostic factors.Furthermore,we found that tumor cells in GI-NECs first gain clonal mutations in TP53,RB1,NOTCH1 and APC,followed by subsequent wholegenome doubling(WGD)and post-WGD clonal mutations in LRP1B,CUB and Sushi multiple domains 3(CSMD3),FAT tumor suppressor homolog 4(FAT4)and erb-b2 receptor tyrosine kinase 4(ERBB4),and finally develop subclonal mutations.Conclusions:GI-NECs harbor distinct genomic landscapes and demonstrate significant genetic heterogeneity across different anatomic locations.Moreover,potentially actionable alterations and prognostic factors were revealed for GI-NECs.

Notch signaling inhibitor and anti-PD-L1 antibody combination therapies decelerate tumor progression in pancreatic cancer

Objective:Pancreatic cancer(PC)is a highly lethal malignancy with an immunosuppressive environment.Yet,current immune checkpoint inhibitor monotherapies have shown limited efficacy in PC,prompting the need for combination therapies.Herein,we hypothesized that combinations of Notch signaling inhibitor and anti-ligand programmed death-ligand 1(PD-L1)antibody immunotherapy would show synergistic efficacy.Methods:The baseline expression of PD-L1 and HES1 was measured in PC cell lines,single-cell RNA-seq data of PC(GSA:CRA001160),and cBioPortal databases.In an in vitro study,MIA PaCa2 and SW1990 were used to explore the mechanism between Notch signaling and PD-L1.To study the effects in vivo,a subcutaneous tumor model was established using Pan02 cells treated with either anti-PD-L1 monoclonal antibody and/or Notch inhibitor DAPT.The study performed involving human samples was approved by the Ethics Committee of Peking Union Medical College Hospital(approval No.S-K460,approval date:April 23,2018).Animal studies were approved by the Animal Research Ethics Committee of Peking Union Medical College Hospital(approval No.XHDW-2019-049,approval date:November 28,2019).Results:The Notch signaling inhibitor upregulated PD-L1 expression in PC tumor cells both in vitro and in vivo.Notch effector HES1 knockdown produced PD-L1 upregulation in both MIA PaCa2 and SW1990 cells.Combined DAPT and anti-PD-L1 antibody treatment of Pan02 subcutaneous tumor model resulted in significantly reduced tumor weights compared to that with monotherapy,as well as significantly reduced Ki67 than that in the monotherapy group and control group.Flow cytometry analysis revealed significantly increased CD8+T cell infiltration in tumors of the combination group compared with those of the monotherapy group.Conclusion:Notch signaling blockade might enhance the antitumor effect of anti-PD-L1 therapy in PC.

Genomic evolution during locoregional recurrence in colorectal cancer determined by whole-exome sequencing: a retrospective observational study

Objective:The genomic landscapes of metastatic colorectal cancer(mCRC)have been extensively studied;however,the genetic mechanisms underlying the locoregional recurrence(LR)of CRC remain unclear.The objective of our study was to investigate genomic evolution during LR in CRC using high-throughput sequencing.Methods:Twenty-three CRC patients with matched primary and LR tissues were recruited from Nanfang Hospital and Zhejiang Cancer Hospital between January 2011 and December 2018.The last date of follow-up was March 2020.Tissue samples were analyzed by whole-exome sequencing and the genomic profiles were depicted by single nucleotide variation,mutational signature,copy number variation,clonal architecture,and other features.The evolutionary process was speculated with comparison of the genetic variations between primary and LR lesions.The disseminating clusters from primary to LR lesions were identified by variant allele frequency dynamics.Furthermore,the early-recurrent biomarker was explored by comparing the indel signature between early-and late-recurrent patients.The study was approved by the Institutional Review Board of Nanfang Hospital of Southern Medical University(approval No.2020010)on September 11,2020.Results:The results highlighted distinct origins of LR between patients with high microsatellite instability and microsatellite stability.LR lesions evolved independently in patients with high microsatellite instability,while LR lesions were highly clonally related to the primary lesions in patients with microsatellite stability.Late-acquired variations in LR lesions encompassed a wide range of driver genes involved in histone methylation,DNA replication,T cell activation,PDCD1 gain,and LMNA loss.Furthermore,clonal analysis of the disseminating cells identified a dominant polyclonal seeding pattern during LR.The indel signature ID4 was associated with significantly shorter disease-free survival in patients with relapsed CRC according to a public dataset.Conclusion:These findings pose a challenge for the development of new approaches targeting the interactions of multiple clones in the establishment of LR and in terms of optimizing the clinical management of susceptible patients.

Overexpression of catechol-O-methyltransferase occurs early in the progression of pancreatic cancer

Aims:Catechol-O-methyltransferase(COMT)plays a role in many kinds of cancer,and its high expression in pancreatic cancer has been found to be related to better prognosis.However,the expression and biological significance of COMT in multistep pancreatic cancerogenesis is not clear.Main methods:Six LSL-Kras^(G12D)-positive and Pdx1-Cre-positive mice(Kras^(G12D)mice),6 wild-type mice and 1 human tissue microarray were used in this study.COMT protein expression was measured by immunohistochemistry,and DNA chips were made for use in COMT mRNA assays.Keyfindings:The expression of COMT in pancreatic intraepithelial neoplasias(PanINs)from Kras^(G12D)mice was significantly higher than that in normal pancreatic tissue from wild-type mice,both in terms of protein level and mRNA expression.The median COMT immunohistochemistry expression scores in human PanIN-1 and PanIN-2 were 70 and 160,respectively,which were significantly lower than the score of 170 observed in pancreatic ductal adenocarcinoma(PDAC)(P=.024 and.037,respectively)and significantly higher than the score of 25 observed in pancreatitis(P=.01 and.008,respectively).Significance:In the development of pancreatic cancer from chronic pancreatitis and in the transition of PanIN to PDAC,we observed significantly increased expression of COMT.These data predict that the overexpression of COMT is an early event in the multistep process of pancreatic cancerogenesis.