Stereotactic body radiotherapy in pancreatic adenocarcinoma

Background:Stereotactic body radiotherapy(SBRT)in pancreatic cancer allows high delivery of radiation doses on tumors without affecting surrounding tissue.This review aimed at the SBRT application in the treatment of pancreatic cancer.Data sources:We retrieved articles published in MEDLINE/PubMed from January 2017 to December 2022.Keywords used in the search included:“pancreatic adenocarcinoma”OR“pancreatic cancer”AND“stereotactic ablative radiotherapy(SABR)”OR“stereotactic body radiotherapy(SBRT)”OR“chemoradiotherapy(CRT)”.English language articles with information on technical characteristics,doses and fractionation,indications,recurrence patterns,local control and toxicities of SBRT in pancreatic tumors were included.All articles were assessed for validity and relevant content.Results:Optimal doses and fractionation have not yet been defined.However,SBRT could be the standard treatment in patients with pancreatic adenocarcinoma in addition to CRT.Furthermore,the combination of SBRT with chemotherapy may have additive or synergic effect on pancreatic adenocarcinoma.Conclusions:SBRT is an effective modality for patients with pancreatic cancer,supported by clinical practice guidelines as it has demonstrated good tolerance and good disease control.SBRT opens a possibility of improving outcomes for these patients,both in neoadjuvant treatment and with radical intent.

Novel lactylation-related signature to predict prognosis for pancreatic adenocarcinoma

BACKGROUND Lactate,previously considered a metabolic byproduct,is pivotal in cancer progression and maintaining the immunosuppressive tumor microenvironment.Further investigations confirmed that lactate is a primary regulator,introducing recently described post-translational modifications of histone and non-histone proteins,termed lysine lactylation.Pancreatic adenocarcinomas are characterized by increased glycolysis and lactate accumulation.However,our understanding of lactylation-related genes in pancreatic adenocarcinomas remains limited.AIM To construct a novel lactylation-related gene signature to predict the survival of patients with pancreatic cancer.METHODS RNA-seq and clinical data of pancreatic adenocarcinoma(PDAC)were obtained from the GTEx(Genotype-Tissue Expression)and TCGA(The Cancer Genome Atlas)databases via Xena Explorer,and GSE62452 datasets from GEO.Data on lactylation-related genes were obtained from publicly available sources.Differential expressed genes(DEGs)were acquired by using R package“DESeq2”in R.Univariate COX regression analysis,LASSO Cox and multivariate Cox regressions were produced to construct the lactylation-related prognostic model.Further analyses,including functional enrichment,ESTIMATE,and CIBERSORT,were performed to analyze immune status and treatment responses in patients with pancreatic cancer.PDAC and normal human cell lines were subjected to western blot analysis under lactic acid intervention;two PDAC cell lines with the most pronounced lactylation were selected.Subsequently,RT-PCR was employed to assess the expression of LRGs genes;SLC16A1,which showed the highest expression,was selected for further investigation.SLC16A1-mediated lactylation was analyzed by immunofluorescence,lactate production analysis,colony formation,transwell,and wound healing assays to investigate its role in promoting the proliferation and migration of PDAC cells.In vivo validation was performed using an established tumor model.RESULTS In this study,we successfully identified 10 differentially expressed lactylation-related genes(LRGs)with prognostic value.Subsequently,a lactylation-related signature was developed based on five OS-related lactylationrelated genes(SLC16A1,HLA-DRB1,KCNN4,KIF23,and HPDL)using Lasso Cox hazard regression analysis.Subsequently,we evaluated the clinical significance of the lactylation-related genes in pancreatic adenocarcinoma.A comprehensive examination of infiltrating immune cells and tumor mutation burden was conducted across different subgroups.Furthermore,we demonstrated that SLC16A1 modulates lactylation in pancreatic cancer cells through lactate transport.Both in vivo and in vitro experiments showed that decreasing SLC16A1 Level and its lactylation significantly inhibited tumor progression,indicating the potential of targeting the SLC16A1/Lactylation-associated signaling pathway as a therapeutic strategy against pancreatic adenocarcinoma.CONCLUSION We constructed a novel lactylation-related prognostic signature to predict OS,immune status,and treatment response of patients with pancreatic adenocarcinoma,providing new strategic directions and antitumor immunotherapies.

Endoscopic ultrasound-guided fine-needle aspiration pancreatic adenocarcinoma samples yield adequate DNA for next-generation sequencing:A cohort analysis

BACKGROUND Genetic tests are increasingly performed for the management of unresectable pancreatic cancer.For genotyping aimed samples current guidelines recommend using core specimens,although based on moderate quality evidence.However,in clinical practice among the endoscopic ultrasound(EUS) guided tissue acquisition methods,fine needle aspiration(FNA) is the most widely performed.AIM To assess the adequacy for next generation sequencing(NGS) of the DNA yielded from EUS-FNA pancreatic adenocarcinoma(PDAC) samples.METHODS Between November 2018 and December 2021,105 patients with PDAC confirmed by EUS-FNA were included in the study at our tertiary gastroenterology center.Either 22 gauge(G) or 19G FNA needles were used.One pass was dedicated to DNA extraction.DNA concentration and purity(A260/280,A260/230) were assessed by spectrophotometry.We assessed the differences in DNA parameters according to needle size and tumor characteristics(size,location) and the adequacy of the extracted DNA for NGS(defined as A260/280 ≥ 1.7,and DNA yield:≥ 10 ng for amplicon based NGS,≥ 50 ng for whole exome sequencing [WES],≥ 100 ng for whole genome sequencing [WGS]) by analysis of variance and ttest respectively.Moreover,we compared DNA purity parameters across the different DNA yield categories.RESULTS Our cohort included 49% male patients,aged 67.02 ± 8.38 years.The 22G needle was used in 71%of the cases.The DNA parameters across our samples varied as follows:DNA yield:1289 ng(inter quartile range:534.75-3101),A260/280 = 1.85(1.79-1.86),A260/230 = 2.2(1.72-2.36).DNA yield was > 10 ng in all samples and > 100 ng in 93% of them(one sample < 50 ng).There were no significant differences in the concentration and A260/280 between samples by needle size.Needle size was the only independent predictor of A260/230 which was higher in the 22G samples(P =0.038).NGS adequacy rate was 90% for 19G samples regardless of NGS type,and for 22G samples it reached 89% for WGS adequacy and 91% for WES and amplicon based NGS.Samples with DNA yield > 100 ng had significantly higher A260/280(1.89 ± 0.32 vs 1.34 ± 0.42,P = 0.013).Tumor characteristics were not corelated with the DNA parameters.CONCLUSION EUS-FNA PDAC samples yield DNA adequate for subsequent NGS.DNA amount was similar between 22G and 19G FNA needles.DNA purity parameters may vary indirectly with needle size.

Nuclear PLD1 combined with NPM1 induces gemcitabine resistance through tumorigenic IL7R in pancreatic adenocarcinoma

Objective:Pancreatic ductal adenocarcinoma(PDAC)is a highly malignant gastrointestinal cancer with a 5-year survival rate of only 9%.Of PDAC patients,15%-20%are eligible for radical surgery.Gemcitabine is an important chemotherapeutic agent for patients with PDAC;however,the efficacy of gemcitabine is limited due to resistance.Therefore,reducing gemcitabine resistance is essential for improving survival of patients with PDAC.Identifying the key target that determines gemcitabine resistance in PDAC and reversing gemcitabine resistance using target inhibitors in combination with gemcitabine are crucial steps in the quest to improve survival prognosis in patients with PDAC.Methods:We constructed a human genome-wide CRISPRa/dCas 9 overexpression library in PDAC cell lines to screen key targets of drug resistance based on sgRNA abundance and enrichment.Then,co-IP,ChIP,ChIP-seq,transcriptome sequencing,and qPCR were used to determine the specific mechanism by which phospholipase D1(PLD1)confers resistance to gemcitabine.Results:PLD1 combines with nucleophosmin 1(NPM1)and triggers NPM1 nuclear translocation,where NPM1 acts as a transcription factor to upregulate interleukin 7 receptor(IL7R)expression.Upon interleukin 7(IL-7)binding,IL7R activates the JAK1/STAT5 signaling pathway to increase the expression of the anti-apoptotic protein,BCL-2,and induce gemcitabine resistance.The PLD1 inhibitor,Vu0155069,targets PLD1 to induce apoptosis in gemcitabine-resistant PDAC cells.Conclusions:PLD1 is an enzyme that has a critical role in PDAC-associated gemcitabine resistance through a non-enzymatic interaction with NPM1,further promoting the downstream JAK1/STAT5/Bcl-2 pathway.Inhibiting any of the participants of this pathway can increase gemcitabine sensitivity.

Radiofrequency ablation of locally advanced pancreatic adenocarcinoma:An overview

Radiofrequency ablation(RFA)of pancreatic neoplasms is restricted to locally advanced,non-resectable but nonmetastatic tumors.RFA of pancreatic tumors is nowadays an ultrasound-guided procedure performed during laparotomy in open surgery.Intraoperative ultrasound covers the mandatory role of staging,evaluation of feasibility,guidance and monitoring of the procedure.Different types of needle can be used.The first aim in the evaluation of RFA as a treatment for locally advanced pancreatic ductal adenocarcinoma,in order of evaluation but not of importance,is to determine the feasibility of the procedure.The second aim is to establish the effect of RFA on tumoral mass in terms of necrosis andcytoreduction.The most important aim,third in order of evaluation,is the potential improvement of quality of life and survival rate.Nowadays,only a few studies assess the feasibility of the procedure.The present paper is an overview of RFA for pancreatic adenocarcinoma.

Effect of the number of positive lymph nodes and lymph node ratio on prognosis of patients after resection of pancreatic adenocarcinoma

BACKGROUND： The prognostic factors related to lymph node involvement [lymph node status, the number of positive lymph nodes, lymph node ratio （LNR）] and the number of nodes evaluated in patients with pancreatic adenocarcinoma after pancreatectomy are poorly defined. METHODS： A total of 167 patients who had undergone resection of pancreatic adenocarcinoma from February 2010 to August 2011 were included in this study. Histological examination was performed to evaluate the tumor differentiation and lymph node involvement. Univariate and multivariate analyses were made to determine the relationship between the variables related to nodal involvement and the number of nodes and survival. RESULTS： The median number of total nodes examined was 10 （range 0-44） for the entire cohort. The median number of total nodes examined in node-negative （pN0） patients was similar to that in node-positive （pN1） patients. Patients with pN1 diseases had significantly worse survival than those with pN0 ones （P=0.000）. Patients with three or more positive nodes had a poorer prognosis compared with those with the negative nodes （P=0.000）. The prognosis of the patients with negative nodes was similar to that of those with one to two positive nodes （P=0.114）. The median survival of patients with an LNR ≥0.4 was shorter than that of patients with an LNR 〈0.4 in the pN1 cohort （P=0.014）. No significance was found between the number of total nodes examined and the prognosis, regardless of the cutoff of 10 or 12 and in the entire cohort or the pN0 and pN1 groups. Based on the multivariate analysis of the entire cohort and the pN1 group, the nodal status, the number of positive nodes and the LNR were all associated with survival. CONCLUSIONS： In addition to the nodal status, the number of positive nodes and the LNR can serve as comprehensive factors for the evaluation of nodal involvement. This approach may be more effective for predicting the survival of patients with pancreatic adenocarcinoma after pancreatectomy.

1-MT Enhances Potency of Tumor Cell Lysate-pulsed Dendritic Cells against Pancreatic Adenocarcinoma by Downregulating the Percentage of Tregs

This study examined whether 1-methyl-tryptophan [1-MT,an indoleamine 2,3-dioxygenase(IDO) inhibitor] could reduce CD4+CD25+ regulatory T cells(Tregs) proliferation and improve the anti-tumor efficacy of dendritic cells(DCs) pulsed with tumor cell lysate in the mice bearing pancreatic adenocarcinoma.The models of pancreatic adenocarcinoma were established in C57BL/6 mice by subcutaneous injection of Pan02 cells.Eight mice which were subcutaneously injected with PBS served as control.The expression of IDO was determined in tumor draining lymph nodes(TDLNs) and spleens of the murine pancreatic adenocarcinoma models.The prevalence of Tregs was measured in the TDLNs and spleens before and after 1-MT administration.The dendritic cells were pulsed with tumor cell lysate for preparing DC vaccine.The DC vaccine,as a single agent or in combination with 1-MT,was administered to pancreatic adenocarcinoma mice.The anti-tumor efficacy was determined after different treatments by regular observation of tumor size.The results showed that the levels of IDO mRNA and protein in tumor-bearing mice were significantly higher than those in the normal control mice.The percentage of Tregs in the spleen and TDLNs was also higer in tumor-bearing mice than in normal control mice(P<0.05).Foxp3 expression was significantly lower in the TDLNs and spleens of tumor-bearing mice administrated with 1-MT than that in normal control mice.Furthemore,in the mice that were administered 1-MT plus DC vaccine,the tumor was increased more slowly than in mice treated with DC vaccine or 1-MT alone,or PBS on day 36(P<0.01).Our results indicated that 1-MT may enhance anti-tumor efficacy of dendritic cells pulsed with tumor cell lysate by downregulating the percentage of Tregs.

Current controversies and advances in the management of pancreatic adenocarcinoma

Pancreatic adenocarcinoma is a lethal disease with a mortality rate that has not significantly improved over decades.This is likely due to several challenges unique to pancreatic cancer.Most patients with pancreatic cancer are diagnosed at a late stage of disease due to the lack of specific symptoms prompting an early investigation.A small subset of patients who are diagnosed at an early stage have a better chance at survival with curative surgical resection,but most patients still succumb to the disease in a few years.The dismal overall prognosis is due to suspected micro-metastasis at an early stage.Due to this reason,there is a recent interest in treating all patients with pancreatic cancers with systemic therapy upfront(including the ones that are surgically resectable).This approach is still not the standard of care due to the lack of robust prospective data available.Recent advancements in treatment regimens of chemotherapy,radiation and immunotherapy have improved the overall short-term survival but the long-term survival still remains poor.Novel approaches in diagnosis and treatment have shown promise in clinical studies but long-term clinical data is lacking.The following manuscript presents an overview of the epidemiology,diagnosis,staging,recent advances,novel approaches and controversies in the management of pancreatic adenocarcinoma.

Relationship between cachexia and perineural invasion in pancreatic adenocarcinoma

BACKGROUND Cachexia is responsible for the low quality of life in pancreatic adenocarcinoma(PDAC).The rapid disease progression and patient deterioration seems related to perineural invasion,but the relationship between cachexia and perineural invasion for the evolution of the disease has been rarely studied.As perineural invasion is difficult to be highlighted,a biomarker such as the neurotrophic factor Midkine(MK)which promotes the neuronal differentiation and the cell migration could be helpful.Also,Activin(ACV)has been described as cachexia related to PDAC.However,their role for assessing and predicting the disease course in daily practice is not known.AIM To assess the relationship between perineural invasion and cachexia and their biomarkers,MK and ACV,respectively,and their prognostic value.METHODS This study included prospectively enrolled patients with proven adenocarcinoma and a matched group of controls without any malignancies.Patients with other causes of malnutrition were excluded.The plasma levels of ACV and MK were analyzed using western blotting and were correlated with the clinicopathological features and survival data.These results were validated by immunohistochemical analyses of the pancreatic tumor tissue of the patients included in the study and a supplementary group of surgically resected specimens from patients with a benign disease.RESULTS The study comprised 114 patients with PDAC,125 controls and a supplementary group of 14 benign pancreatic tissue samples.ACV and MK were both overexpressed more frequently in the plasma of patients with PDAC than in the controls(63% vs 32% for ACV,P<0.001;47%vs 16%for MK,P<0.001),with similar levels in pancreatic tissue the MK protein expression was closely related to the advanced clinical stage(P=0.006),the presence of metastasis(P=0.04),perineural invasion(P=0.03)and diabetes(P=0.002),but with no influence on survival.No correlation between clinicopathological factors and ACV expression was noted.Cachexia,present in 19%of patients,was unrelated to ACV or MK level.Higher ACV expression was associated with a shorter survival(P=0.008).CONCLUSION The MK was a biomarker of perineural invasion,associated with tumor stage and diabetes,but without prognostic value as ACV.Cachexia was unrelated to perineural invasion,ACV level or survival.

Identification of hub genes and their novel diagnostic and prognostic significance in pancreatic adenocarcinoma

Objective:The main reasons for the poor prognoses of pancreatic adenocarcinoma(PA)patients are rapid early-stage progression,advanced stage metastasis,and chemotherapy resistance.Identification of novel diagnostic and prognostic biomarkers of PA is therefore urgently needed.Methods:Three mRNA microarray datasets were obtained from the Gene Expression Omnibus database to select differentially expressed genes(DEGs).Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses for hub genes were performed using DAVID.Correlations between expression levels of hub genes and cancer-infiltrating immune cells were investigated by TIMER.Cox proportional hazard regression analyses were also performed.Serum hub genes were screened using the HPA platform and verified for diagnostic value using ELISAs.Results:We identified 59 hub genes among 752 DEGs.GO analysis indicated that these 59 hub genes were mainly involved in the defense response to viruses and the type I interferon signaling pathway.We also discovered that RSAD2 and SMC4 were associated with immune cell infiltration in the PA microenvironment.Additionally,DLGAP5 mRNA might be used as an independent risk factor for the prognoses of PA patients.Furthermore,the protein encoded by ISG15,which exists in peripheral blood,was validated as a potential diagnostic biomarker that distinguished PA patients from healthy controls(area under the curve:0.902,95%confidence interval:0.819–0.961).Conclusions:Our study suggested that RSAD2 and SMC4 were associated with immune cell infiltration in the PA microenvironment,while DLGAP5 mRNA expression might be an independent risk factor for the survival prognoses of PA patients.Moreover,ELISAs indicated that serum ISG15 could be a potential novel diagnostic biomarker for PA.

Pancreatic adenocarcinoma: A review of recent paradigms and advances in epidemiology, clinical diagnosis and management

Pancreatic cancer is one of the dreaded malignancies for both the patient and the clinician.The five-year survival rate of pancreatic adenocarcinoma(PDA)is as low as 2%despite multimodality treatment even in the best hands.As per the Global Cancer Observatory of the International Agency for Research in Cancer estimates of pancreatic cancer,by 2040,a 61.7%increase is expected in the total number of cases globally.With the widespread availability of next-generation sequencing,the entire genome of the tumors is being sequenced regularly,providing insight into their pathogenesis.As invasive PDA arises from pancreatic intraepithelial neoplasia and mucinous neoplasm and intraductal papillary neoplasm,screening for them can be beneficial as the disease is curable with resection at an early stage.Routine preoperative biliary drainage has no role in patients suffering from PDA with obstructive jaundice.If performed,metallic stents are preferred over plastic ones.Minimally invasive procedures are preferred to open procedures as they have less morbidity.The duct-to-mucosa technique for pancreaticojejunostomy is presently widely practiced.The role of intraperitoneal drains after surgery for PDA is controversial.Neoadjuvant chemoradiotherapy has been proven to have a significant role both in locally advanced as well as in resectable PDA.Many new regimens and drugs have been added in the arsenal of chemoradiotherapy for metastatic disease.The roles of immunotherapy and gene therapy in PDA are being investigated.This review article is intended to improve the understanding of the readers with respect to the latest updates of PDA,which may help to trigger new research ideas and make better management decisions.

Pancreatic adenocarcinoma:Beyond first line,where are we?

Pancreatic cancer is considered one of the most aggressive cancers,with an increasing incidence in recent years.To date,chemotherapy is still the standard of care for advanced metastatic disease,unfortunately providing only a slight advantage in terms of survival.The molecular and cellular characteristics of pancreatic cancer cells,as well as the cells that characterize the pancreatic tumour microenvironment,are the basis of the mechanisms of resistance to treatment.After progression during first-line treatment,few patients are eligible for secondline treatment due to the loss of performance status.To date,a clear survival advantage has not yet been demonstrated for second-line chemotherapy.Precision medicine could be the key to increasing responses to cancer treatment and finally impacting survival in this difficult-to-treat disease.In this review,we analyze current recommendations in the second-line setting and potential future prospects.

Utility of different serum fibrosis markers in diagnosing patients with chronic pancreatitis and pancreatic adenocarcinoma

AIM: To estimate the levels of serum cytokines in chronic pancreatitis(CP) and pancreatic ductal adenocarcinoma(PDAC) patients in order to evaluate their usefulness as possible biomarkers.METHODS: The study included 167 Caucasian patients: 74 with PDAC(28 men and 42 women, aged 30-88 years), 78 with CP(50 men and 21 women, aged 20-79 years) and 15 age-matched healthy controls hospitalized in the Department of Digestive Tract Diseases, Medical University of Lodz, Poland between 2006 and 2013. Serum MCP-1, transforming growth factor(TGF)-β1, HA and s-Fr were measured in patients with CP(n = 78), PDAC(n = 74) and healthy controls(n = 15) using ELISA(Corgenix United Kingdom Ltd R and D Systems). The severity of CP was assessed according to the Cambridge classification.RESULTS: Both patients with CP and PDAC had a significantly higher mean TGF-β1 serum level(1066 ± 582and 888 ± 356 vs 264 ± 93, P < 0.0001), mean s-Fr(2.42 ± 1.385 and 2.41 ± 1.275 vs 0.6 ± 0.370, P < 0.0001) and mean HA(199 ± 254 and 270 ± 358 vs 40 ± 26, P < 0.0001) compared to controls. There was no difference in mean MCP-1 between all the groups. There were no significant differences in any cytokine levels between the PC and PDAC groups. No significant differences between serum cytokines depending on age, gender or smoking status were found in CP patients. Mean s-Fr concentration was significantly higher in CP, lasting longer than 5 years compared to those with a shorter disease clinical course(2.639 ± 1.125 vs 1.870 ± 0.970, P < 0.03). There was no correlation between tumor size, localization or TNM classification and serum TGF-β1, MCP-1, s-Fr and HA levels in patients with PDAC. No significant differences between cytokines depending on diabetes presence in CP were found. Nevertheless, mean serum TGF-β1 concentration in PDAC patients was higher in those with diabetes compared to the remaining group(986 vs 839, P = 0.043). CONCLUSION: Serum TGF-β1, s-Fr and HA may be considered additional diagnostic markers of CP and PDAC. TGF-β1 may be useful to predict endocrine insufficiency in PDAC.

Analysis of 300 consecutive cases of pancreatic adenocarcinoma in a single-center in China

BACKGROUND： Most of the reports on the prognostic indicators of patients with pancreatic adenocarcinoma are from developed countries. The present study focused on the prognostic indicators of Chinese patients with pancreatic adenocarcinoma. METHODS： A total of 300 patients with pancreatic adenocarcinoma who had undergone curative resection were included. The resection and R0/R1 resection rates for adenocarcinomas from different parts of the pancreas were calculated and clinical characteristics were analyzed.RESULTS： In 3427 patients diagnosed with pancreatic adenocarcinomas, only 300（8.8%） were eligible for radical resection. The total median survival of these patients was 19 months, and their 1-, 3-, and 5-year survival rates were 72.5%, 28.0% and 23.4%, respectively. The prognostic factors included socioeconomic status, smoking history, symptoms, high blood glucose, and various tumor characteristics, including perineural and vascular invasion, lymph node metastases, and CA19-9 levels before and after operation. Operation-associated prognostic indicators included operation time, blood loss and transfusions, pancreatic fistula, and complications. Independent predictors of mortality included poor socioeconomic status, smoking history, symptoms, CA19-9, perineural invasion and lymph node metastasis, grade of fistula and complications. Patient survival was not correlated with either resection margin or adjuvant chemotherapy in multivariate analysis.CONCLUSIONS： The survival rates of patients with curative resection for pancreatic adenocarcinoma in China are close to those in developed countries, but curative resection rate is far below. Socioeconomic status, symptoms, and CA19-9 are the three most prominent prognostic factors, which are helpful in patient selection and perioperative care.

Analysis on Survival and Prognostic Factors in Patients with Resectable Pancreatic Adenocarcinoma

Survival after pancreatic cancer surgery is extremely unfavorable even after curative resection. Prognostic factors have been explored but remain largely undefined. The present study was to identify the role of clinical and laboratory variables in the prognostic significance of resectable pancreatic adenocarcinoma. A total of 96 patients who underwent curative resection for pancreatic cancer were included. Survival was evaluated based on complete follow-up visits and was associated with potential prognostic factors using the Kaplan-Meier method and Cox proportional hazard model survival analyses. The results showed that prognostic variables significantly reduced survival, including old age, poorly differentiated tumors, elevated tumor markers and positive lymph node metastasis（LNM）. Age of older than 60 years（HR=1.83, P=0.04）, LNM（HR=2.22, P=0.01）, lymph node ratio（00.2, HR=1.92, P=0.017）, initial CA199（HR=4.80, P=0.004）, and CEA level（HR=2.59, P=0.019） were identified as independent prognostic factors by multivariate analysis. It was concluded that LNR may be potent predictor of survival and suggests that surgeons and the pathologists should thoroughly assess lymph nodes prior to surgery.

Artificial intelligence for early detection of pancreatic adenocarcinoma: The future is promising

Pancreatic ductal adenocarcinoma(PDAC) is a worldwide public health concern. Despite extensive research efforts toward improving diagnosis and treatment, the 5-year survival rate at best is approximately 15%. This dismal figure can be attributed to a variety of factors including lack of adequate screening methods, late symptom onset, and treatment resistance. Pancreatic ductal adenocarcinoma remains a grim diagnosis with a high mortality rate and a significant psychological burden for patients and their families. In recent years artificial intelligence(AI) has permeated the medical field at an accelerated pace, bringing potential new tools that carry the promise of improving diagnosis and treatment of a variety of diseases. In this review we will summarize the landscape of AI in diagnosis and treatment of PDAC.

Tunica vaginalis testis metastasis as the first clinical manifestation of pancreatic adenocarcinoma:A case report

BACKGROUND Metastases from pancreas or ampullary malignancies are common,but the spread to testicle and paratesticular tissue is exceedingly rare.To the best of our knowledge,fewer than 30 cases have been reported in the literature.More rarely,metastasis to tunica vaginalis testis occurs without involvement of the testes and epididymis.CASE SUMMARY A 65-year-old male who complained of painless swelling of the left scrotum for over 1 wk was referred to the Department of Urology.Scrotal ultrasound showed left testicular hydrocele with paratesticular masses.Chest computed tomography revealed lung metastasis and enlarged left supraclavicular lymph node.The blood tumor markersalpha-fetoprotein,human chorionic gonadotropin,and serum lactate dehydrogenase were withinnormal limits.The preoperative diagnosis was left testicular tumor with lung metastasis.Then radical orchidectomy of the left testicle and high ligation of the spermatic cord were performed,and postoperative histopathology suggested metastatic tumors that was confirmed by an abdominal computed tomographic scan.The positive computed tomography findings,in conjunction with the expression of cytokeratin 7(CK7),CK20,CK5/6,and absence of expression of Wilms’tumor suppressor gene 1,calretinin,melanocyte,prostate-specific antigen,thyroid transcription factor-1,GATA binding protein 3,caudal type homeobox 2,and napsinA supported the diagnosis of pancreatic adenocarcinoma.The outcome of this patient was unsatisfactory,and he died 3 mo later.CONCLUSION This case suggests that pancreatic metastatic carcinoma must be considered in the differential diagnosis of scrotal enlargement.The advanced age of the patient wassuggestive of a secondary testicular tumor.In addition,careful physical examination and ultrasonography as well as radiological examination have become a standard modality.

Computed tomography perfusion imaging evaluation of angiogenesis in patients with pancreatic adenocarcinoma

BACKGROUND Pancreatic adenocarcinoma is one of the most common malignant tumors of the digestive system.More than 80%of patients with pancreatic adenocarcinoma are not diagnosed until late stage and have distant or local metastases.AIM To investigate the value of computed tomography(CT)perfusion imaging in the evaluation of angiogenesis in pancreatic adenocarcinoma patients.METHODS This is a retrospective cohort study.Patients with pancreatic adenocarcinoma and volunteers without pancreatic diseases underwent CT perfusion imaging from December 2014 to August 2017 in Huashan Hospital,Fudan University Shanghai,China.RESULTS A total number of 35 pancreatic adenocarcinoma patients and 33 volunteers were enrolled.The relative blood flow(r BF),and relative blood volume(r BV)were significantly lower in patients with pancreatic adenocarcinoma than in the control group(P<0.05).Conversely,the relative permeability in patients with pancreatic adenocarcinoma was significantly higher than that in controls(P<0.05).In addition,r BF,r BV,and the vascular maturity index(VMI)were significantly lower in gradeⅢ-Ⅳpancreatic adenocarcinoma than in gradeⅠ-Ⅱpancreatic adenocarcinoma(P<0.05).Vascular endothelial growth factor(VEGF),CD105-MVD,CD34-MVD,and angiogenesis rate(AR)were significantly higher in gradeⅢ-Ⅳpancreatic adenocarcinoma than in gradeⅠ-Ⅱpancreatic adenocarcinoma(P<0.05).Significant correlations between r BF and VEGF,CD105-MVD,AR,and VMI(P<0.01)were observed.Moreover,the levels of r BV were statistically significantly correlated with those of VEGF,CD105-MVD,CD34-MVD,and VMI(P<0.01).CONCLUSION Perfusion CT imaging may be an appropriate approach for quantitative assessment of tumor angiogenesis in pancreatic adenocarcinoma.

Anti-tumor effect of statin on pancreatic adenocarcinoma:From concept to precision medicine

A statin is a cholesterol-lowering agent,which inhibits HMG-CoA(3-hydroxy-3-methylglutaryl-coenzyme A)reductase and subsequently reduces the cholesterol precursor,and was first used commercially in 1987.The concept of cholesterol restriction leading to cancer cell dysfunction was proposed in 1992.The interruption of different signaling pathways has been proved in preclinical experiments to elucidate the anti-tumor mechanism of statins in pancreatic adenocarcinoma.Observational studies have shown that the clinical use of statins is beneficial in patients with pancreatic adenocarcinoma,including a chemoprevention effect,post-surgical resection follow-up and therapeutic prognosis of advanced cancer stage.Arrest of the cancer cell cycle by the combined use of gemcitabine and statin was observed in a cell line study.The effect of microbiota on the tumor microenvironment of pancreatic adenocarcinoma is a new therapeutic approach as statins can modulate the gut microbiota.Hence,further randomized trials of statins in pancreatic adenocarcinoma treatment will be warranted with application of precision medicine from microbiota-derived,cell cycle-based and signaling pathway-targeted research.

KLF16 promotes pancreatic adenocarcinoma cell proliferation and migration by positively regulating SMAD6

BACKGROUND Pancreatic adenocarcinoma(PAAD)is a cancerous tumor with an extremely poor 5-year survival rate.The exploration of biomarkers for the diagnosis and treatment of PAAD is crucial in clinical practice.Krüppel-like factors(KLFs)are involved in a variety of biological functions in cells.According to multiple studies,KLF16 behave as an oncogene in prostate,breast and gastric cancers.However,no research has been done on the significance of KLF16 in PAAD.AIM To explore the molecular mechanisms of KLF16 in PAAD.METHODS KLF16 was identified in the tumor specimens and normal tissues by GEPIA database and verified by quantitative real-time PCR(qRT-PCR).Knockdown or exogenous expression of KLF16,combined with in vitro and in vivo assays,was performed to show the functional significance of KLF16.The molecular mechanism of KLF16 was demonstrated by qRT-PCR,western blotting,immunoprecipitation assay and flow cytometry.RESULTS We showed that KLF16 was highly expressed in PAAD patients based on the GEPIA database.KLF16 silencing suppressed while KLF16 overexpression promoted the malignant function of PAAD cells.Based on RNA sequencing,we discovered that KLF16 potentiated the expression of SMAD6 in PAAD cells.SMAD6 transcript abundance was increased and positively correlated with KLF16 expression in PAAD samples.In addition,inhibiting SMAD6 was able to mitigate the effects of KLF16 overexpression on PAAD cell processes,suggesting the importance of SMAD6 in the development of KLF16-triggered PAAD.CONCLUSION KLF16/SMAD6 axis might be explored as a therapeutic target for PAAD therapy.