PRaG 3.0 therapy for human epidermal growth factor receptor 2-positive metastatic pancreatic ductal adenocarcinoma:A case report

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly fatal disease with limited effective treatment especially after first-line chemotherapy.The human epidermal growth factor receptor 2(HER-2)immunohistochemistry(IHC)positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC.CASE SUMMARY We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn’t have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment.A novel combination therapy PRaG 3.0 of RC48(HER2-antibody-drug conjugate),radio-therapy,PD-1 inhibitor,granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month.She had not developed any grade 2 or above treatment-related adverse events at any point.Percentage of peripheral CD8^(+) Temra and CD4^(+) Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy.CONCLUSION PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.

Combining prognostic value of serum carbohydrate antigen 19-9 and tumor size reduction ratio in pancreatic ductal adenocarcinoma

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a common cancer with increasing morbidity and mortality due to changes of social environment.AIM To evaluate the significance of serum carbohydrate antigen 19-9(CA19-9)and tumor size changes pre-and post-neoadjuvant therapy(NAT).METHODS This retrospective study was conducted at the Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment,Chongqing University Cancer Hospital.This study specifically assessed CA19-9 levels and tumor size before and after NAT.RESULTS A total of 156 patients who completed NAT and subsequently underwent tumor resection were included in this study.The average age was 65.4±10.6 years and 72(46.2%)patients were female.Before survival analysis,we defined the post-NAT serum CA19-9 level/pre-NAT serum CA19-9 level as the CA19-9 ratio(CR).The patients were divided into three groups:CR<0.5,CR>0.5 and<1 and CR>1.With regard to tumor size measured by both computed tomography and magnetic resonance imaging,we defined the post-NAT tumor size/pre-NAT tumor size as the tumor size ratio(TR).The patients were then divided into three groups:TR<0.5,TR>0.5 and<1 and TR>1.Based on these groups divided according to CR and TR,we performed both overall survival(OS)and disease-free survival(DFS)analyses.Log-rank tests showed that both OS and DFS were significantly different among the groups according to CR and TR(P<0.05).CR and TR after NAT were associated with increased odds of achieving a complete or near-complete pathologic response.Moreover,CR(hazard ratio:1.721,95%CI:1.373-3.762;P=0.006),and TR(hazard ratio:1.435,95%CI:1.275-4.363;P=0.014)were identified as independent factors associated with OS.CONCLUSION This study demonstrated that post-NAT serum CA19-9 level/pre-NAT serum CA19-9 level and post-NAT tumor size/pre-NAT tumor size were independent factors associated with OS in patients with PDAC who received NAT and subsequent surgical resection.

FAM53B promotes pancreatic ductal adenocarcinoma metastasis by regulating macrophage M2 polarization

BACKGROUND Our study investigated the role of FAM53B in regulating macrophage M2 polarization and its potential mechanisms in promoting pancreatic ductal adenocarcinoma(PDAC)metastasis.AIM To further investigate the role of FAM53B in regulating macrophage M2 polarization and its potential mechanism in promoting PDAC metastasis.Our goal is to determine how FAM53B affects macrophage M2 polarization and to define its underlying mechanism in PDAC metastasis.METHODS Cell culture and various experiments,including protein analysis,immunohisto-chemistry,and animal model experiments,were conducted.We compared FAM53B expression between PDAC tissues and healthy tissues and assessed the correlation of FAM53B expression with clinical features.Our study analyzed the role of FAM53B in macrophage M2 polarization in vitro by examining the expression of relevant markers.Finally,we used a murine model to study the role of FAM53B in PDAC metastasis and analyzed the potential underlying mechanisms.RESULTS Our research showed that there was a significant increase in FAM53B levels in PDAC tissues,which was linked to adverse tumor features.Experimental findings indicated that FAM53B can enhance macrophage M2 polarization,leading to increased anti-inflammatory factor release.The results from the mouse model further supported the role of FAM53B in PDAC metastasis,as blocking FAM53B prevented tumor cell invasion and metastasis.CONCLUSION FAM53B promotes PDAC metastasis by regulating macrophage M2 polarization.This discovery could lead to the development of new strategies for treating PDAC.For example,interfering with the FAM53B signaling pathway may prevent cancer spread.Our research findings also provide important information for expanding our understanding of PDAC pathogenesis.

Computed tomography-based radiomics diagnostic approach for differential diagnosis between early-and late-stage pancreatic ductal adenocarcinoma

BACKGROUND One of the primary reasons for the dismal survival rates in pancreatic ductal adenocarcinoma(PDAC)is that most patients are usually diagnosed at late stages.There is an urgent unmet clinical need to identify and develop diagnostic methods that could precisely detect PDAC at its earliest stages.METHODS A total of 71 patients with pathologically proved PDAC based on surgical resection who underwent contrast-enhanced computed tomography(CT)within 30 d prior to surgery were included in the study.Tumor staging was performed in accordance with the 8th edition of the American Joint Committee on Cancer staging system.Radiomics features were extracted from the region of interest(ROI)for each patient using Analysis Kit software.The most important and predictive radiomics features were selected using Mann-Whitney U test,univar-iate logistic regression analysis,and minimum redundancy maximum relevance(MRMR)method.Random forest(RF)method was used to construct the radiomics model,and 10-times leave group out cross-validation(LGOCV)method was used to validate the robustness and reproducibility of the model.RESULTS A total of 792 radiomics features(396 from late arterial phase and 396 from portal venous phase)were extracted from the ROI for each patient using Analysis Kit software.Nine most important and predictive features were selected using Mann-Whitney U test,univariate logistic regression analysis,and MRMR method.RF method was used to construct the radiomics model with the nine most predictive radiomics features,which showed a high discriminative ability with 97.7%accuracy,97.6%sensitivity,97.8%specificity,98.4%positive predictive value,and 96.8%negative predictive value.The radiomics model was proved to be robust and reproducible using 10-times LGOCV method with an average area under the curve of 0.75 by the average performance of the 10 newly built models.CONCLUSION The radiomics model based on CT could serve as a promising non-invasive method in differential diagnosis between early and late stage PDAC.

Comparison of prognosis and postoperative morbidities between standard pancreaticoduodenectomy and the TRIANGLE technique for resectable pancreatic ductal adenocarcinoma

BACKGROUND Radical surgery combined with systemic chemotherapy offers the possibility of long-term survival or even cure for patients with pancreatic ductal adenocar-cinoma(PDAC),although tumor recurrence,especially locally,still inhibits the treatment efficacy.The TRIANGLE technique was introduced as an extended dissection procedure to improve the R0 resection rate of borderline resectable or locally advanced PDAC.However,there was a lack of studies concerning postoperative complications and long-term outcomes of this procedure on patients with resectable PDAC.PDAC.METHODS Patients with resectable PDAC eligible for PD from our hospital between June 2018 and December 2021 were enrolled in this retrospective cohort study.All the patients were divided into PDstandard and PDTRIANGLE groups according to the surgical procedure.Baseline characteristics,surgical data,and postoperative morbidities were recorded.All of the patients were followed up,and the date and location of tumor recurrence,and death were recorded.The Kaplan-Meier method and log-rank test were used for the survival analysis.RESULTS There were 93 patients included in the study and 37 underwent the TRIANGLE technique.Duration of operation was longer in the PDTRIANGLE group compared with the PDstandard group[440(410-480)min vs 320(265-427)min](P=0.001).Intraoperative blood loss[700(500-1200)mL vs 500(300-800)mL](P=0.009)and blood transfusion[975(0-1250)mL vs 400(0-800)mL](P=0.009)were higher in the PDTRIANGLE group.There was a higher incidence of surgical site infection(43.2%vs 12.5%)(P=0.001)and postoperative diarrhea(54.1%vs 12.5%)(P=0.001)in the PDTRIANGLE group.The rates of R0 resection and local recurrence,overall survival,and disease-free survival did not differ significantly between the two groups.CONCLUSION The TRIANGLE technique is safe,with acceptable postoperative morbidities compared with standardized PD,but it does not improve prognosis for patients with resectable PDAC.

Serum biomarkers for the differentiation of autoimmune pancreatitis from pancreatic ductal adenocarcinoma

Autoimmune pancreatitis(AIP),a chronic inflammation caused by the immune system attacking the pancreas,usually presents imaging and clinical features that overlap with those of pancreatic ductal adenocarcinoma(PDAC).Serum biomarkers,substances that quantitatively change in sera during disease development,are a promising non-invasive tool with high utility for differentiating between these diseases.In this way,the presence of AIP is currently suspected when serum concentrations of immunoglobulin G4(IgG4)antibody are elevated.However,this approach has some drawbacks.Notably,IgG4 antibody concentrations are also elevated in sera from some patients with PDAC.This review focuses on the most recent and relevant serum biomarkers proposed to differentiate between AIP and PDAC,evaluating the usefulness of immunoglobulins,autoantibodies,chemokines,and cytokines.The proposed serum biomarkers have proven useful,although most studies had a small sample size,did not examine their presence in patients with PDAC,or did not test them in humans.In addition,current evidence suggests that a single serum biomarker is unlikely to accurately differentiate these diseases and that a set of biomarkers will be needed to achieve adequate specificity and sensitivity,either alone or in combination with clinical data and/or radiological images.

Robotic versus laparoscopic distal pancreatectomy for pancreatic ductal adenocarcinoma: A propensity score-matched analysis

Background: Minimally invasive surgery is becoming increasingly popular in the field of pancreatic surgery. However, there are few studies of robotic distal pancreatectomy(RDP) for pancreatic ductal adenocarcinoma(PDAC). This study aimed to investigate the efficacy and feasibility of RDP for PDAC. Methods: Patients who underwent RDP or laparoscopic distal pancreatectomy(LDP) for PDAC between January 2015 and September 2020 were reviewed. Propensity score matching analyses were performed. Results: Of the 335 patients included in the study, 24 underwent RDP and 311 underwent LDP. A total of 21 RDP patients were matched 1:1 with LDP patients. RDP was associated with longer operative time(209.7 vs. 163.2 min;P = 0.003), lower open conversion rate(0% vs. 4.8%;P < 0.001), higher cost(15 722 vs. 12 699 dollars;P = 0.003), and a higher rate of achievement of an R0 resection margin(90.5% vs. 61.9%;P = 0.042). However, postoperative pancreatic fistula grade B or C showed no significant intergroup difference(9.5% vs. 9.5%). The median disease-free survival(34.5 vs. 17.3 months;P = 0.588) and overall survival(37.7 vs. 21.9 months;P = 0.171) were comparable between the groups. Conclusions: RDP is associated with longer operative time, a higher cost of surgery, and a higher likelihood of achieving R0 margins than LDP.

Robotic pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: Analysis of surgical outcomes and long-term prognosis in a high-volume center

Background: Robotic pancreaticoduodenectomy(RPD) has been reported to be safe and feasible for patients with pancreatic ductal adenocarcinoma(PDAC) of the pancreatic head. This study aimed to analyze the surgical outcomes and risk factors for poor long-term prognosis of these patients. Methods: Data from patients who underwent RPD for PDAC of pancreatic head were retrospectively analyzed. Multivariate Cox regression analysis was used to seek the independent prognostic factors for overall survival(OS), and an online nomogram calculator was developed based on the independent prognostic factors. Results: Of the 273 patients who met the inclusion criteria, the median operative time was 280.0 minutes, the estimated blood loss was 100.0 m L, the median OS was 23.6 months, and the median recurrence-free survival(RFS) was 14.4 months. Multivariate analysis showed that preoperative carbohydrate antigen 19-9(CA19-9) [hazard ratio(HR) = 2.607, 95% confidence interval(CI): 1.560-4.354, P < 0.001], lymph node metastasis(HR = 1.429, 95% CI: 1.005-2.034, P = 0.047), tumor moderately(HR = 3.190, 95% CI: 1.813-5.614, P < 0.001) or poorly differentiated(HR = 5.114, 95% CI: 2.839-9.212, P < 0.001), and Clavien-Dindo grade ≥ Ⅲ(HR = 1.657, 95% CI: 1.079-2.546, P = 0.021) were independent prognostic factors for OS. The concordance index(C-index) of the nomogram constructed based on the above four independent prognostic factors was 0.685(95% CI: 0.640-0.729), which was significantly higher than that of the AJCC staging(8th edition): 0.541(95% CI: 0.493-0.589)( P < 0.001). Conclusions: This large-scale study indicated that RPD was feasible for PDAC of pancreatic head. Preoperative CA19-9, lymph node metastasis, tumor poorly differentiated, and Clavien-Dindo grade ≥ Ⅲ were independent prognostic factors for OS. The online nomogram calculator could predict the OS of these patients in a simple and convenient manner.

Survival benefits and disparities in radiation therapy for elderly patients with pancreatic ductal adenocarcinoma

BACKGROUND Older patients represent a unique subgroup of the cancer patient population,for which the role of cancer therapy requires special consideration.However,the outcomes of radiation therapy(RT)in elderly patients with pancreatic ductal adenocarcinoma(PDAC)are not well-defined in the literature.AIM To explore the use and effectiveness of RT in the treatment of elderly patients with PDAC in clinical practice.METHODS Data from patients with PDAC aged≥65 years between 2004 and 2018 were collected from the Surveillance,Epidemiology,and End Results database.Multivariate logistic regression analysis was performed to determine factors associated with RT administration.Overall survival(OS)and cancer-specific survival(CSS)were evaluated using the Kaplan–Meier method with the log-rank test.Univariate and multivariate analyses with the Cox proportional hazards model were used to identify prognostic factors for OS.Propensity score matching(PSM)was applied to balance the baseline characteristics between the RT and non-RT groups.Subgroup analyses were performed based on clinical characteristics.RESULTS A total of 12245 patients met the inclusion criteria,of whom 2551(20.8%)were treated with RT and 9694(79.2%)were not.The odds of receiving RT increased with younger age,diagnosis in an earlier period,primary site in the head,localized disease,greater tumor size,and receiving chemotherapy(all P<0.05).Before PSM,the RT group had better outcomes than did the non-RT group[median OS,14.0 vs 6.0 mo;hazard ratio(HR)for OS:0.862,95%confidence interval(CI):0.819–0.908,P<0.001;and HR for CSS:0.867,95%CI:0.823–0.914,P<0.001].After PSM,the survival benefit associated with RT remained comparable(median OS:14.0 vs 11.0 mo;HR for OS:0.818,95%CI:0.768–0.872,P<0.001;and HR for CSS:0.816,95%CI:0.765–0.871,P<0.001).Subgroup analysis revealed that the survival benefits(OS and CSS)of RT were more significant in patients aged 65 to 80 years,in regional and distant stages,with no surgery,and receiving chemotherapy.CONCLUSION RT improved the outcome of elderly patients with PDAC,particularly those aged 65 to 80 years,in regional and distant stages,with no surgery,and who received chemotherapy.Further prospective studies are warranted to validate our results.

Derivation and validation of a preoperative prognostic model for resectable pancreatic ductal adenocarcinoma

Background: The prognosis of patients with pancreatic ductal adenocarcinoma(PDAC) remains poor even after radical pancreaticoduodenectomy(PD). The study aimed to develop and validate a novel preoperative prognostic model to accurately predict the long-term survival of patients with PDAC.Methods: Patients with PDAC of pancreatic head from Chinese PLA General Hospital were included. The preoperative PDAC model with contour plots was developed using a non-linear model in the training cohort and then tested in the validation cohort.Results: Of 421 patients who met the inclusion criteria, 280 were in the training cohort and 141 in the validation cohort. Contour plots for preoperative PDAC model were established to visually predict the survival probabilities of these patients, based on preoperative carbohydrate antigen 19-9, preoperative fibrinogen to albumin ratio and pain symptoms. This model stratified patients into low-and high-risk groups with distinctly different long-term survival in the training cohort [median overall survival(OS)32.1 vs. 17.5 months;median recurrence-free survival(RFS) 19.3 vs. 10.0 months, both P < 0.001] and the validation cohort(median OS 28.3 vs. 19.0 months;median RFS 17.5 vs. 11.2 months, both P < 0.001).Time-dependent receiver operating characteristic and decision curve analyses revealed that the model provided higher diagnostic accuracy and superior net benefit compared to other staging systems.Conclusions: This study constructed and validated a novel preoperative prognostic model that can accurately and conveniently predict the long-term survival of patients with resectable PDAC of pancreatic head. Besides, the model can screen high-risk patients with poor prognosis, which may provide references for personal treatment strategies in the future.

Roles of lncRNAs in pancreatic ductal adenocarcinoma: Diagnosis,treatment, and the development of drug resistance

Background: Pancreatic ductal adenocarcinoma(PDAC) is one of the most lethal cancers, primarily due to its late diagnosis, high propensity to metastasis, and the development of resistance to chemo-/radiotherapy. Accumulating evidence suggests that long non-coding RNAs(lnc RNAs) are intimately involved in the treatment resistance of pancreatic cancer cells via interacting with critical signaling pathways and may serve as potential diagnostic/prognostic markers or therapeutic targets in PDAC. Data sources: We carried out a systematic review on lnc RNAs-based research in the context of pancreatic cancer and presented an overview of the updated information regarding the molecular mechanisms underlying lnc RNAs-modulated pancreatic cancer progression and drug resistance, together with their potential value in diagnosis, prognosis, and treatment of PDAC. Literature mining was performed in Pub Med with the following keywords: long non-coding RNA, pancreatic ductal adenocarcinoma, pancreatic cancer up to January 2022. Publications relevant to the roles of lnc RNAs in diagnosis, prognosis, drug resistance, and therapy of PDAC were collected and systematically reviewed. Results: Lnc RNAs, such as HOTAIR, HOTTIP, and PVT1, play essential roles in regulating pancreatic cancer cell proliferation, invasion, migration, and drug resistance, thus may serve as potential diagnostic/prognostic markers or therapeutic targets in PDAC. They participate in tumorigenesis mainly by targeting mi RNAs, interacting with signaling molecules, and involving in the epithelial-mesenchymal transition process. Conclusions: The functional lnc RNAs play essential roles in pancreatic cancer cell proliferation, invasion, migration, and drug resistance and have potential values in diagnosis, prognostic prediction, and treatment of PDAC.

Regional differences in islet amyloid deposition in the residual pancreas with new-onset diabetes secondary to pancreatic ductal adenocarcinoma

BACKGROUND Islet amyloid deposition and reducedβ-cell mass are pathological hallmarks in type 2 diabetes mellitus subjects.To date,the pathological features of the islets in diabetes secondary to pancreatic ductal adenocarcinoma(PDAC)have not been specifically addressed.AIM To provide further insight into the relationship between islet amyloid deposition of the residual pancreas in PDAC patients and to explore whether regional differences(proximal vs distal residual pancreas)are associated with islet amyloid deposition.METHODS We retrospectively collected clinical information and pancreatic tissue removed from tumors of 45 PDAC patients,including 14 patients with normal glucose tolerance(NGT),16 patients with prediabetes and 15 new-onset diabetes(NOD)patients diagnosed before surgery by an oral glucose tolerance test at West China Hospital from July 2017 to June 2020.Pancreatic volume was calculated by multiplying the estimated area of pancreatic tissue on each image slice by the interval between slices based on abdominal computer tomography scans.Several sections of paraffin-embedded pancreas specimens from both the proximal and/or distal regions remote from the tumor were stained as follows:(1)Hematoxylin and eosin for general histological appearance;(2)hematoxylin and insulin for the determination of fractionalβ-cell area(immunohistochemistry);and(3)quadruple insulin,glucagon,thioflavin T and DAPI staining for the determination ofβ-cell area,α-cell area and amyloid deposits.RESULTS Screening for pancreatic histologic features revealed that duct obstruction with islet amyloid deposition,fibrosis and marked acinar atrophy were robust in the distal pancreatic regions but much less robust in the proximal regions,especially in the prediabetes and NOD groups.Consistent with this finding,the remnant pancreatic volume was markedly decreased in the NOD group by nearly one-half compared with that in the NGT group(37.35±12.16 cm^(3) vs 69.79±18.17 cm^(3),P<0.001).As expected,islets that stained positive for amyloid(islet amyloid density)were found in the majority of PDAC cases.The proportion of amyloid/islet area(severity of amyloid deposition)was significantly higher in both prediabetes and NOD patients than in NGT patients(P=0.002;P<0.0001,respectively).We further examined the regional differences in islet amyloid deposits.Islet amyloid deposit density was robustly increased by approximately 8-fold in the distal regions compared with that in the proximal regions in the prediabetes and NOD groups(3.98%±3.39%vs 0.50%±0.72%,P=0.01;12.03%vs 1.51%,P=0.001,respectively).CONCLUSION In conclusion,these findings suggest that robust alterations of the distal pancreas due to tumors can disturb islet function and structure with islet amyloid formation,which may be associated with the pathogenesis of NOD secondary to PDAC.

Colonic ductal adenocarcinoma case report: New entity or rare ectopic degeneration?

BACKGROUND Ectopic pancreatic tissue is a congenital anomaly where a part of pancreatic tissue is located outside of the pancreas and lacks vascular or anatomical communication with it but shows the same histological features.Currently,the literature reports only two anecdotal cases of malignant transformation of colonic ectopic pancreas.CASE SUMMARY We present a case of an 81-year-old patient presenting with anemia,with right colonic neoplasia and carbohydrate antigen 19-9 above the normal values.She underwent laparoscopic right hemicolectomy.The final histology was consistent with a primitive adenocarcinoma with ductal morphology and solid-predominant growth pattern.Benign ectopic pancreatic tissue was absent in the surgical specimen.CONCLUSION The case describes a very rare complete degeneration of a colonic ectopic pancreatic tissue.However,the absence of benign ectopic pancreatic tissue in the surgical specimen is suggestive of the first description of a primitive ductal adenocarcinoma of the colon.

Factors influencing spiritual wellbeing among pancreatic ductal adenocarcinoma patients receiving chemotherapy

BACKGROUND Spiritual wellbeing emphasizes optimistic and positive attitudes while selfregulating negative emotions when coping with stress.However,there have only been a few small studies of spiritual wellbeing of pancreatic ductal adenocarcinoma(PDAC)patients undergoing chemotherapy.The core factors influencing spiritual wellbeing in this clinical population are still unclear.AIM To identify factors influencing spiritual wellbeing among patients with PDAC receiving chemotherapy.METHODS A total of 143 PDAC patients receiving chemotherapy were enrolled from January to December 2022.Patients completed general information questionnaires including:Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being 12 Item Scale(FACIT-Sp-12),European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30(EORTC QLQ-C30)and Zung’s Self-rating Anxiety Scale(SAS).Independent sample t-test,one-way analysis of variance,Pearson’s correlation analysis,and multiple linear regression analysis were adopted for statistical analyses.P<0.05(two-tailed)was considered statistically significant for all tests.RESULTS Total spiritual wellbeing(FACIT-Sp-12)score was 32.16±10.06 points,while dimension sub-scores were 10.85±3.76 for faith,10.55±3.42 for meaning,and 10.76±4.00 for peace.Total spiritual wellbeing score was negatively correlated with SAS score for anxiety and with the symptom domain of EORTC QLC-C30.Conversely,spiritual wellbeing score was positively correlated with global health status and EORTC QLQ-C30 role functioning domain score.Multivariate regression analysis identified educational level,health insurance category,symptom domain,functional role domain,and global health status as significant independent factors influencing spiritual wellbeing among PDAC patients undergoing chemotherapy(R2=0.502,P<0.05).CONCLUSION Individualized spiritual support is needed for PDAC patients.Health,daily functioning,emotional,cognitive,and social function status should be taken into account to promote implementation of spirituality in nursing practice.

Research on Liposomal Irinotecan in Combination with 5-FU/LV for Metastatic Pancreatic Ductal Adenocarcinoma

Objective To systematically review the published clinical and economic research on liposomal irinotecan in combination with 5-FU/LV for metastatic pancreatic ductal adenocarcinoma(mPDAC)at home and abroad.Methods PubMed,Cochrane Library,Embase,CBM,CNKI,Wan Fang data,CRD database and health technology assessment official websites were searched to collect clinical and economic studies on liposomal irinotecan for mPDAC.Results and Conclusion Nine clinical studies and four economic studies were included.The result of clinical studies showed that liposomal irinotecan in combination with 5-FU/LV could extend survival with good drug compliance in patients with mPDAC who progressed on prior gemcitabine-based therapy.This agent represented a new treatment option for second-line chemotherapy in these patients.The results of the economic evaluations failed to reach a consistent conclusion due to different economic levels in various countries.

Expression and signifi cance of TLR4 and HIF-1α in pancreatic ductal adenocarcinoma

AIM:To investigate the expression of toll-like receptor(TLR) 4,nuclear factor-κB(NF-κB) p65 and hypoxiainducible transcription factor 1α(HIF-1α) in pancreatic ductal adenocarcinoma and their clinical significance.METHODS:The mRNA of TLR4 and HIF-1α were investigated by real-time polymerase chain reaction in 30 cases of pancreatic ductal adenocarcinoma and its adjacent tissues,and expression of TLR4,NF-κB p65 and HIF-1α protein were detected by immunohistochemistry in 65 cases of pancreatic ductal adenocarcinoma tissues and 38 cases of corresponding adjacent tissues.The relationship between TLR4 or HIF-1α and pathologic features,as well as the association between TLR4 and HIF-1α,were also analyzed.Kaplan-Meier method was used to assess the impact of expression of TLR4 and HIF-1α on survival of patients with pancreatic cancer.RESULTS:The relative quantif ication of TLR4 and HIF-1α mRNA in tumor tissues was 0.81±0.10 and 0.87±0.11,respectively,signif icantly higher than that in adjacent tissues(0.81±0.10 vs 0.70±0.16,P=0.002;0.87±0.11 vs 0.68±0.13,P=0.000).The protein expression of TLR4,NF-κB p65 and HIF-1α in tumor tissues was 69.20%,66.15% and 70.80%,respectively,being signif icantly higher than that in adjacent normal tissues(69.20% vs 39.50%,P=0.003;66.15% vs 31.58%,P=0.001;70.80% vs 36.80%,P=0.001).There was no signif icant correlation between TLR4 or HIF-1α expression and the age,gender,tumor location,the degree of tumor differentiation in the patients(P>0.05).However,there was signif icant correlation between the expression of TLR4 or HIF-1α and tumor size,lymph node metastasis,venous invasion and clinical staging(P<0.05).The expression of TLR4 and HIF-1α had a signif icant impact on survival of patients with pancreatic adenocarcinoma.CONCLUSION:TLR4,NF-κB p65 and HIF-1α are overexpressed in pancreatic adenocarcinoma,TLR4 may be partly involved in up-regulating HIF-1α,and both synergestically promote development of pancreatic adenocarcinoma.

Parasympathetic neurogenesis is strongly associated with tumor budding and correlates with an adverse prognosis in pancreatic ductal adenocarcinoma

Objective： To investigate the frequency of parasympathetic neurogenesis and determine its association with tumor budding and prognosis in pancreatic ductal adenocarcinoma （PDAC）. Methods： Parasympathetic neurogenesis was defined as the distribution of abnormal parasympathetic nerves in the stroma tissue. Staining of vesicular acetylcholine transporter （VAChT）, as a marker for parasympathetic neurogenesis, was performed on a representative specimen of the tumor for 59 PDAC patients with available clinical, pathologic, and follow-up information. Three specimens containing normal pancreatic tissues were stained in parallel. The number of parasympathetic nerve fibers was counted in five high-power microscopic fields （5×0.785 mm2）. Cut-offvalues were calculated by receiver operating characteristic curve analysis. Results： VAChT-positive parasympathetic nerve fibers were not seen in the stroma of 3 cases of normal pancreatic tissues. In 59 PDAC cases, the range of parasympathetic neurogenesis was 4-38 fibers/（5×0.785） mm2, with a median of 18 fibers/（5×0.785） mm2. Patients with parasympathetic neurogenesis 〉 15 fibers/（5×0.785） mm2 were defined as the high-density group （39 patients, 66.1%）, and those with parasympathetic neurogenesis 〈15 fibers/（5×0.785） mm2 as the low-density group （20 patients, 33.9%）. The high-density group had a higher occurrence of tumor budding （P=0.001） and a higher rate of early recurrence （P=0.035）. Parasympathetic neurogenesis appeared to be an independent adverse prognostic factor [hazard ratio （HR）=2.45, 95% confidence interval （95% CI）： 1.25-4.81, P=0.009], in addition to American Joint Committee on Cancer （AJCC） stage （P=0.010） and tumor budding （P=0.009）. Conclusions： Parasympathetic neurogenesis is strongly associated with tumor budding and correlates with an adverse prognosis in PDAC.

Inflammatory response related scoring systems in assessing the prognosis of patients with pancreatic ductal adenocarcinoma:a systematic review

BACKGROUND： Various scoring systems based on assessment of the systemic inflammatory response help assessing the prognosis of patients with pancreatic ductal adenocarcinoma.In the present systematic review we evaluated the validity of four pre-intervention scoring systems： Glasgow prognostic score（GPS） and its modified version（mGPS）, platelet lymphocyte ratio（PLR）, neutrophil lymphocyte ratio（NLR）, and prognostic nutrition index（PNI）.DATA SOURCES： MOOSE guidelines were followed and EMBASE and MEDLINE databases were searched for all published studies until September 2013 using comprehensive text word and MeSH terms. All identified studies were analyzed, and relevant studies were included in the systematic review.RESULTS： Six studies were identified for GPS/mGPS with3 reporting statistical significance for GPS/mGPS on both univariate analysis（UVA） and multivariate analysis（MVA）.Two studies suggested prognostic significance on UVA but not MVA, and in the final study UVA failed to show significance.Eleven studies evaluated the prognostic value of NLR. Six of them reported prognostic significance for NLR on UVA that persisted at MVA in 4 studies, and in the remaining 2 studies NLR was the only significant factor on UVA. In the remaining5 studies, all in patients undergoing resection, there was no significance on UVA. Seven studies evaluated PLR, with only one study demonstrated its prognostic significance on both UVAand MVA, the rest did not show the significance on UVA. Of the two studies identified for PNI, one demonstrated a statistically significant difference in survival on both UVA and MVA, and the other reported no significance for PNI on UVA.CONCLUSIONS： Both GPS/mGPS and NLR may be useful but further better-designed studies are required to confirm their value. PLR might be little useful, and there are at present inadequate data to assess the prognostic value of PNI. At present, no scoring system is reliable enough to be accepted into routine use for the prognosis of patients with pancreatic ductal adenocarcinoma.

Prognostic value of the preoperative fibrinogen-to-albumin ratio in pancreatic ductal adenocarcinoma patients undergoing R0 resection

BACKGROUND Inflammation plays an important role in tumor progression,and growing evidence has confirmed that the fibrinogen-to-albumin ratio(FAR)is an important prognostic factor for overall survival in malignant tumors.AIM To investigate the prognostic significance of FAR in patients undergoing radical R0 resection of pancreatic ductal adenocarcinoma(PDAC).METHODS We retrospectively analyzed the data of 282 patients with PDAC who underwent radical R0 resection at The Cancer Hospital of the Chinese Academy of Medical Sciences from January 2010 to December 2019.The surv_cutpoint function of the R package survminer via RStudio software(version 1.3.1073,http://www.rstudio.org)was used to determine the optimal cut-off values of biological markers,such as preoperative FAR.The Kaplan-Meier method and log-rank tests were used for univariate survival analysis,and a Cox regression model was used for multivariate survival analysis for PDAC patients who underwent radical R0 resection.RESULTS The optimal cut-off value of FAR was 0.08 by the surv_cutpoint function.Higher preoperative FAR was significantly correlated with clinical symptoms(P=0.001),tumor location(P<0.001),surgical approaches(P<0.001),preoperative plasma fibrinogen concentration(P<0.001),and preoperative plasma albumin level(P<0.001).Multivariate analysis showed that degree of tumor differentiation(P<0.001),number of metastatic lymph nodes[hazard ratio(HR):0.678,95%confidence interval(CI):0.509-0.904,P=0.008],adjuvant therapy(HR:1.604,95%CI:1.214-2.118,P=0.001),preoperative cancer antigen 19-9 level(HR:1.740,95%CI:1.288-2.352,P<0.001),and preoperative FAR(HR:2.258,95%CI:1.720-2.963,P<0.001)were independent risk factors for poor prognosis in patients with PDAC who underwent radical R0 resection.CONCLUSION The increase in preoperative FAR was significantly related to poor prognosis in patients undergoing radical R0 resection for PDAC.Preoperative FAR can be used clinically to predict the prognosis of PDAC patients undergoing radical R0 resection.

Validation and modification of the AJCC 8th TNM staging system for pancreatic ductal adenocarcinoma in a Chinese cohort:A nationwide pancreas data center analysis

Objective:To validate the 8 th edition of the American Joint Committee on Cancer(AJCC)staging system for pancreatic ductal adenocarcinoma(PDAC)in a Chinese cohort of radically resected patients and to develop a refined staging system for PDAC.Methods:Data were collected from the China Pancreas Data Center(CPDC)for patients with resected PDAC in 2016 and 2017,and cancer-specific survival(CSS)was evaluated using the Kaplan-Meier method and log-rank test.Univariate and multivariate analyses based on Cox regression were performed to identify prognostic factors.The recursive partitioning analysis(RPA),Kaplan-Meier method,and log-rank test were performed on the training dataset to generate a proposed modification for the 8 th TNM staging system utilizing the preoperative carbohydrate antigen(CA)19-9 level.Validation was performed for both staging systems in the validation cohort.Results:A total of 1,676 PDAC patients were retrieved,and the median CSS was significantly different between the 8 th TNM groupings,with no significant difference in survival between stage IB and IIA.The analysis of T and N stages demonstrated a better prognostic value in the N category.Multivariate analysis showed that the preoperative serum CA19-9 level was the strongest prognostic indicator among all the independent risk factors.All patients with CA19-9>500 U/mL had similar survival,and we proposed a new staging system by combining IB and IIA and stratifying all patients with high CA19-9 into stage III.The modified staging system had a better performance for predicting CSS than the 8 th AJCC staging scheme.Conclusions:The 8 th AJCC staging system for PDAC is suitable for a Chinese cohort of resected patients,and the N category has a better prognostic value than the T category.Our modified staging system has superior accuracy in predicting survival than the 8 th AJCC TNM staging system.