Survival In Pancreatic Ductal Adenocarcinoma Research Articles

Pancreatic ductal adenocarcinoma survival in South Australia: time trends and impact of tumour location.

It is unclear how global developments in management of pancreatic ductal adenocarcinoma (PDAC) have affected survival of Australian patients. This study aimed to determine trends in survival of PDAC over the last three decades in South Australia and to compare survival based on cancer location (head and uncinate process versus body and tail). A retrospective observational cohort study to include all cases of PDAC reported to the South Australian (state) Cancer Registry from 1990 to 2017. A total of 1051 patients diagnosed with PDAC between 1990 and 2017 were included. An overall increase in number of reported PDAC cases over time with more than a doubling in the crude rate from 1.73 to 3.50 per 100 000 persons between the decades 1990-1999 and 2010-2017 (P < 0.001) was noted. Overall median survival for PDAC was 7.4months (95% confidence interval 6.8-8.0months) and this has improved in recent decades. Overall median survival for PDAC affecting head and uncinate process of pancreas was significantly higher compared to body and tail (7.6months versus 4.1months; P < 0.001). This study from South Australia demonstrates an increased reporting of PDAC over the last three decades. Although overall survival for patients with PDAC remains low, there has been a modest improvement in recent decades. The overall survival is significantly lower for patients with PDAC involving the body and tail compared to the head and uncinate process of pancreas. Risk factors for poor survival include the male gender and advancing age (>70 years).

Long-term yield of pancreatic cancer surveillance in high-risk individuals

ObjectiveWe aimed to determine the long-term yield of pancreatic cancer surveillance in hereditary predisposed high-risk individuals.DesignFrom 2006 to 2019, we prospectively enrolled asymptomatic individuals with an estimated 10% or greater...

Deciphering the Prognostic Implications of the Components and Signatures in the Immune Microenvironment of Pancreatic Ductal Adenocarcinoma

Background: The treatment modalities for pancreatic ductal adenocarcinoma (PDAC) are limited and unsatisfactory. Although many novel drugs targeting the tumor microenvironment, such as immune checkpoint inhibitors, have shown promising efficacy for some tumors, few of them significantly prolong the survival of patients with PDAC due to insufficient knowledge on the tumor microenvironment.Methods: A single-cell RNA sequencing (scRNA-seq) dataset and seven PDAC cohorts with complete clinical and bulk sequencing data were collected for bioinformatics analysis. The relative proportions of each cell type were estimated using the gene set variation analysis (GSVA) algorithm based on the signatures identified by scRNA-seq or previous literature.Results: A meta-analysis of 883 PDAC patients showed that neutrophils are associated with worse overall survival (OS) for PDAC, while CD8+ T cells, CD4+ T cells, and B cells are related to prolonged OS for PDAC, with marginal statistical significance. Seventeen cell categories were identified by clustering analysis based on single-cell sequencing. Among them, CD8+ T cells and NKT cells were universally exhausted by expressing exhaustion-associated molecular markers. Interestingly, signatures of CD8+ T cells and NKT cells predicted prolonged OS for PDAC only in the presence of “targets” for pyroptosis and ferroptosis induction. Moreover, a specific state of T cells with overexpression of ribosome-related proteins was associated with a good prognosis. In addition, the hematopoietic stem cell (HSC)-like signature predicted prolonged OS in PDAC. Weighted gene co-expression network analysis identified 5 hub genes whose downregulation may mediate the observed survival benefits of the HSC-like signature. Moreover, trajectory analysis revealed that myeloid cells evolutionarily consisted of 7 states, and antigen-presenting molecules and complement-associated genes were lost along the pseudotime flow. Consensus clustering based on the differentially expressed genes between two states harboring the longest pseudotime span identified two PDAC groups with prognostic differences, and more infiltrated immune cells and activated immune signatures may account for the survival benefits.Conclusion: This study systematically investigated the prognostic implications of the components of the PDAC tumor microenvironment by integrating single-cell sequencing and bulk sequencing, and future studies are expected to develop novel targeted agents for PDAC treatment.

Clinical presentation and prognosis of adenosquamous carcinoma of the pancreas – Matched-pair analysis with pancreatic ductal adenocarcinoma

IntroductionAdenosquamous carcinoma of the pancreas (ASCP) is a rare subtype of pancreatic adenocarcinoma. The aim of this study was to investigate the characteristics and outcomes of ASCP in comparison to pancreatic ductal adenocarcinoma (PDAC). Materials and methodsAll patients with ASCP treated between December 2001 and December 2017 were identified from a prospective database. Clinicopathological and follow-up data were analyzed. A nested case-control-study with matched-pair analysis was performed to compare overall survival of ASCP and PDAC. ResultsOf 4009 patients undergoing surgery for pancreatic adenocarcinoma 91 patients had ASCP. Compared to PDAC ASCP were larger (4.0 vs. 3.2 cm; p < 0.0001), more frequently involved lymph nodes (88% vs. 78%; p = 0.0216), more frequently showed poor differentiation (G3: 79% vs. 36%; p < 0.0001) and more frequently were located in the pancreatic tail (19% vs. 10%; p = 0.0179). Overall median post-resection-survival was shorter in ASCP (10.8 vs. 20.5 months in PDAC; p = 0.0085), but 5-year survival rates were comparable (18.2% vs. 17.5%). After matching for the unevenly distributed prognostic factors survival after resection of ASCP and PDAC was comparable (p = 0.8301). Localization in the head or several parts of the pancreas, high CA 19-9 levels, and M1 disease were independent predictors of survival in patients with ASCP. ConclusionASCP is more aggressive with poorer differentiation and higher rates of lymph node metastases compared to PDAC. In spite of a shorter median survival, 5-year survival rates after surgical resection of about 18% can be expected in ASCP and support resection as part of a multimodal therapy as the treatment of choice in this rare cancer.

Combination Chemo-Immunotherapy for Pancreatic Cancer Using the Immunogenic Effects of an Irinotecan Silicasome Nanocarrier Plus Anti-PD-1.

There is an urgent need to develop new life‐prolonging therapy for pancreatic ductal adenocarcinoma (PDAC). It is demonstrated that improved irinotecan delivery by a lipid bilayer coated mesoporous silica nanoparticle, also known as a silicasome, can improve PDAC survival through a chemo‐immunotherapy response in an orthotopic Kras‐dependent pancreatic cancer model. This discovery is premised on the weak‐basic properties of irinotecan, which neutralizes the acidic lysosomal pH in PDAC cells. This effect triggers a linked downstream cascade of events that include autophagy inhibition, endoplasmic reticulum stress, immunogenic cell death (ICD), and programmed death‐ligand 1 (PD‐L1) expression. ICD is characterized by calreticulin expression and high‐mobility group box 1 (HMGB1) release in dying Kras‐induced pancreatic cancer (KPC) cells, which is demonstrated in a vaccination experiment to prevent KPC tumor growth on the contralateral site. The improved delivery of irinotecan by the silicasome is accompanied by robust antitumor immunity, which can be synergistically enhanced by anti‐PD‐1 in the orthotopic model. Immunophenotyping confirms the expression of calreticulin, HMGB1, PD‐L1, and an autophagy marker, in addition to perforin and granzyme B deposition. The chemo‐immunotherapy response elicited by the silicasome is more robust than free or a liposomal drug, Onivyde. The silicasome plus anti‐PD‐1 leads to significantly enhanced survival improvement, and is far superior to anti‐PD‐1 plus either free irinotecan or Onivyde.

Immune cell infiltrates as prognostic biomarkers in pancreatic ductal adenocarcinoma: a systematic review and meta-analysis.

Immune cell infiltration has been identified as a prognostic biomarker in several cancers. However, no immune based biomarker has yet been validated for use in pancreatic ductal adenocarcinoma (PDAC). We undertook a systematic review and meta‐analysis of immune cell infiltration, measured by immunohistochemistry (IHC), as a prognostic biomarker in PDAC. All other IHC prognostic biomarkers in PDAC were also summarised. MEDLINE, EMBASE and Web of Science were searched between 1998 and 2018. Studies investigating IHC biomarkers and prognosis in PDAC were included. REMARK score and Newcastle–Ottawa scale were used for qualitative analysis. Random‐effects meta‐analyses were used to pool results, where possible. Twenty‐six articles studied immune cell infiltration IHC biomarkers and PDAC prognosis. Meta‐analysis found high infiltration with CD4 (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.51–0.83.) and CD8 (HR = 0.68, 95% CI = 0.55–0.84.) T‐lymphocytes associated with better disease‐free survival. Reduced overall survival was associated with high CD163 (HR = 1.62, 95% CI = 1.03–2.56). Infiltration of CD3, CD20, FoxP3 and CD68 cells, and PD‐L1 expression was not prognostic. In total, 708 prognostic biomarkers were identified in 1101 studies. In summary, high CD4 and CD8 infiltration are associated with better disease‐free survival in PDAC. Increased CD163 is adversely prognostic. Despite the publication of 708 IHC prognostic biomarkers in PDAC, none has been validated for clinical use. Further research should focus on reproducibility of prognostic biomarkers in PDAC in order to achieve this.

Molecular profiling of advanced pancreatic ductal adenocarcinoma (PDAC): Role of ctDNA.

425 Background: Molecular profiling of tumour samples and circulating tumour DNA (ctDNA) may inform treatment of advanced cancer; the role of ctDNA to predict progression-free-survival (PFS) and overall survival (OS) in advanced PDAC is not fully understood. Methods: Eligible patients: those diagnosed with advanced PDAC undergoing molecular profiling [tumour (Foundation Medicine CDx/Caris) or ctDNA (FoundationMedicine Liquid (72 cancer-related genes))]. Baseline patient characteristics and molecular profiling outcomes, including mutant allele frequency (MAF) for pathological alterations were extracted. The primary aim was to assess the impact of presence of ctDNA at time of systemic chemotherapy initiation on PFS and OS. Results: Total of 26 samples (ctDNA 18 samples and 8 tumour samples) from 25 patients diagnosed with advanced PDAC underwent molecular profiling. When the whole population was analysed, the rate of sample analysis failure seemed to be higher when tumour tissue was tested (37.5%) compared to ctDNA (5.56%); p-value 0.072. The overall rate of identification of pathological findings was 72.73%, with 18.18% of patients having targetable findings [EGFRmut (1 patient), KRAS G12C mut (1 patient), FGFR2 fusion (1 patient), RNF43 mut (1 patient)]; these findings impacted treatment management in one patient only (RNF43 mutation; Wnt inhibitor). Variants of unknown significance were identified in 63.64% of samples. Patients with ctDNA analysis at time of palliative chemotherapy initiation (16 samples; 15 patients) were analysed [6 female (40.00%), median age 69.57 years (range 51.61-81.49), metastatic disease (66.67%), 80% first-line (80%), 20% second-line]. Pathological mutations were identified in 9/15 (60.00%) of these patients (KRAS mutation identified in 6/9). After median follow-up of 8.33 months from sample acquisition, 80% and 53.33% of patients had progressed and died, respectively. Median estimated PFS and OS were 5.65 months (95% CI 1.59-8.17) and 7.80 months (95% CI 4.13-not reached). Presence (vs absence) of pathological alterations in ctDNA showed a trend towards shorter PFS (2.91 vs 6.51 months; HR 1.38 (95% CI 0.40-4.77)) and OS (6.12 vs 9.72 months; HR 2.03 (95% CI 0.60-6.82)). Conclusions: This pilot study demonstrates the feasibility of ctDNA analysis in patients with advanced PDAC prior to initiation of palliative therapy. The presence of pathological alterations in ctDNA may prognosticate for worse PFS and OS. Larger studies are required to confirm these findings.

Laparoscopic versus open extended radical left pancreatectomy for pancreatic ductal adenocarcinoma: an international propensity-score matched study.

A radical left pancreatectomy in patients with pancreatic ductal adenocarcinoma (PDAC) may require extended, multivisceral resections. The role of a laparoscopic approach in extended radical left pancreatectomy (ERLP) is unclear since comparative studies are lacking. The aim of this study was to compare outcomes after laparoscopic vs open ERLP in patients with PDAC. An international multicenter propensity-score matched study including patients who underwent either laparoscopic or open ERLP (L-ERLP; O-ERLP) for PDAC was performed (2007-2015). The ISGPS definition for extended resection was used. Primary outcomes were overall survival, margin negative rate (R0), and lymph node retrieval. Between 2007 and 2015, 320 patients underwent ERLP in 34 centers from 12 countries (65 L-ERLP vs. 255 O-ERLP). After propensity-score matching, 44 L-ERLP could be matched to 44 O-ERLP. In the matched cohort, the conversion rate in L-ERLP group was 35%. The L-ERLP R0 resection rate (matched cohort) was comparable to O-ERLP (67% vs 48%; P = 0.063) but the lymph node yield was lower for L-ERLP than O-ERLP (median 11 vs 19, P = 0.023). L-ERLP was associated with less delayed gastric emptying (0% vs 16%, P = 0.006) and shorter hospital stay (median 9 vs 13days, P = 0.005), as compared to O-ERLP. Outcomes were comparable for additional organ resections, vascular resections (besides splenic vessels), Clavien-Dindo grade ≥ III complications, or 90-day mortality (2% vs 2%, P = 0.973). The median overall survival was comparable between both groups (19 vs 20months, P = 0.571). Conversion did not worsen outcomes in L-ERLP. The laparoscopic approach may be used safely in selected patients requiring ERLP for PDAC, since morbidity, mortality, and overall survival seem comparable, as compared to O-ERLP. L-ERLP is associated with a high conversion rate and reduced lymph node yield but also with less delayed gastric emptying and a shorter hospital stay, as compared to O-ERLP.

Intraoperative Radiation Mitigates the Effect of Microscopically Positive Tumor Margins on Survival Among Pancreatic Adenocarcinoma Patients Treated with Neoadjuvant FOLFIRINOX and Chemoradiation.

Microscopically positive margins (R1) negatively impact survival in pancreatic ductal adenocarcinoma (PDAC). For patients with close/positive margins, intraoperative radiotherapy (IORT) can improve local control. The prognostic impact of an R1 resection in patients who receive total neoadjuvant therapy (TNT; FOLFIRINOX with chemoradiation) and IORT is unknown. Clinicopathologic data were retrospectively collected for borderline/locally advanced (BR/LA) PDAC patients who received TNT and underwent resection between 2011 and 2019. Disease-free (DFS) and overall survival (OS) measured from time of diagnosis were compared between groups. Two hundred one patients received TNT and were resected, with a median DFS and OS of 24months and 47months, respectively. Eighty-eight patients (44%) received IORT; of these, 69 (78%) underwent an R0 and 19 (22%) an R1 resection. There was no significant difference in clinicopathologic factors between the IORT and no-IORT groups, except for resectability status (LA: IORT 69%, no-IORT 53%, p = 0.021) and surgeons' concern for a positive/close margin. R1 resection was associated with worse DFS and OS in the no-IORT population. However, among patients who received IORT, there was no difference in DFS (R0: 29months, IQR 14-47 vs R1: 20months, IQR 15-28; p = 0.114) or OS (R0: 48months, IQR 25-not reached vs R1: 37months, IQR 30-47; p = 0.307) between patients who underwent R0 vs R1 resection. In multivariate analysis, within the IORT group, R1 resection was not associated with DFS or OS. IORT may mitigate the adverse effect of an R1 resection on DFS and OS in BR/LA PDAC patients receiving TNT.

The Dual Role of Angiopoietin 2 in Pancreatic Cancer

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is well-known for its inflammatory nature. Inflammation affects the tumour in many ways, one of which is vascular remodeling. Angiopoietins are a family of proteins that interact in vascular remodeling. Angiopoietin-1 (Ang-1) is continuously secreted and works in vascular homeostasis. Inflammation causes endothelial secretion of angiopoietin-2 (Ang-2), which has more complex effects in vascular remodeling. Both endothelial and circulating Ang-2 is increased in various cancers and high circulating Ang-2 is a marker for shorter survival in PDAC. Different from other tumours, in addition to the endothelial expression, PDAC cells themselves express Ang-2. No correlation between tumour cell Ang-2 expression and survival has been published thus far. The aim of this study was to look into tumour cell Ang-2 expression and survival. Method: The study setting constituted of PDAC patients operated at Helsinki University Hospital between 2000 and 2013. Ang-2 immunohistochemistry (IHC) staining was done on 158 PDAC patient samples and staining intensity was scored (ranging from negative (0), weakly positive (1), moderately positive (2), to strongly positive (3)) by two examiners. We used ELISA assay to measure circulating Ang-2 levels in sera of 196 patients. IHC scores and circulating Ang-2 levels were assessed with respect to clinical data and patient outcomes. Results: Neither circulating nor tumour Ang-2 expression was affected by age or sex and had no relationship with tumour size, stage, grade, or lymph node metastasis number. There was a negative association between serum and tumour Ang-2 expession. Disease specific survival (DSS) was shorter in patients with a negative to weak tumour Ang-2 expression (0.95 years, IQR 1.99), when compared to those with an intermediate to high expression (1.84 years, IQR 2.73, p<0.017). In contrast, higher than median (≥2.72ng/ml) circulating Ang-2 associated with shorter DSS (1.49 years, IQR 2.02) when compared to patients with low circulating Ang-2 (2.17years, IQR 2.49, p = 0.002). Conclusion: We found that Ang-2 has a dual role in PDAC with respect to survival. Further studies need to be conducted to find out where the circulating Ang-2 originates and the mechanisms that cause tumour cell Ang-2 expression and its beneficial association with respect to survival.

Overall survival of pancreatic ductal adenocarcinoma is doubled by Aldh7a1 deletion in the KPC mouse.

Rationale: The activity of aldehyde dehydrogenase 7A1 (ALDH7A1), an enzyme that catalyzes the lipid peroxidation of fatty aldehydes was found to be upregulated in pancreatic ductal adenocarcinoma (PDAC). ALDH7A1 knockdown significantly reduced tumor formation in PDAC. We raised a question how ALDH7A1 contributes to cancer progression.Methods: To answer the question, the role of ALDH7A1 in energy metabolism was investigated by knocking down and knockdown gene in mouse model, because the role of ALDH7A1 has been reported as a catabolic enzyme catalyzing fatty aldehyde from lipid peroxidation to fatty acid. Oxygen consumption rate (OCR), ATP production, mitochondrial membrane potential, proliferation assay and immunoblotting were performed. In in vivo study, two human PDAC cell lines were used for pre-clinical xenograft model as well as spontaneous PDAC model of KPC mice was also employed for anti-cancer therapeutic effect.Results: ALDH7A1 knockdown significantly reduced tumor formation with reduction of OCR and ATP production, which was inversely correlated with increase of 4-hydroxynonenal. This implies that ALDH7A1 is critical to process fatty aldehydes from lipid peroxidation. Overall survival of PDAC is doubled by cross breeding of KPC (KrasG12D; Trp53R172H; Pdx1-Cre) and Aldh7a1-/- mice.Conclusion: Inhibitions of ALDH7A1 and oxidative phosphorylation using gossypol and phenformin resulted in a regression of tumor formation in xenograft mice model and KPC mice model.

Germinal center reactions in tertiary lymphoid structures associate with neoantigen burden, humoral immunity and long-term survivorship in pancreatic cancer

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) has traditionally been thought of as an immunologically quiescent tumor type presumably because of a relatively low tumor mutational burden (TMB) and poor responses to checkpoint blockade therapy. However, many PDAC tumors exhibit T cell inflamed phenotypes. The presence of tertiary lymphoid structures (TLS) has recently been shown to be predictive of checkpoint blockade response in melanomas and sarcomas, and are prognostic for survival in PDAC. In order to more comprehensively understand tumor immunity in PDAC patients with TLS, we performed RNA-seq, single and multiplex IHC, flow cytometry and predictive genomic analysis on treatment naïve, PDAC surgical specimens. Forty-six percent of tumors contained distinct T and B cell aggregates reflective of “early-stage TLS” (ES-TLS), which correlated with longer overall and progression-free survival. These tumors had greater CD8+ T cell infiltration but were not defined by previously published TLS gene-expression signatures. ES-TLS+ tumors were enriched for IgG1 class-switched memory B cells and memory CD4+ T cells, suggesting durable immunological memory persisted in these patients. We also observed the presence of active germinal centers (mature-TLS) in 31% of tumors with lymphocyte clusters, whose patients had long-term survival (median 56 months). M-TLS-positive tumors had equivalent overall T cell infiltration to ES-TLS, but were enriched for activated CD4+ memory cells, naive B cells and NK cells. Finally, using a TCGA-PDAC dataset, ES-TLS+ tumors harbored a decreased TMB, but M-TLS with germinal centers expressed significantly more MHCI-restricted neoantigens as determined by an in silico neoantigen prediction method. Interestingly, M-TLS+ tumors also had evidence of increased rates of B cell somatic hypermutation, suggesting that germinal centers form in the presence of high-quality tumor neoantigens leading to increased humoral immunity that confers improved survival for PDAC patients. AbbreviationsTLS: tertiary lymphoid structures; GC: germinal center(s); PDAC: pancreatic ductal adenocarcinoma; RNA-seq: RNA sequencing; BCRseq: B cell receptor sequencing; HEV: high endothelial venule; PNAd: peripheral node addressin; TMB: tumor mutational burden; TCGA: the cancer genome atlas; PAAD: pancreatic adenocarcinoma; FFPE: formalin fixed paraffin embedded; TIME: tumor immune microenvironment.

Survival of Pancreatic Ductal Adenocarcinoma According to Tumour Location

Purpose: The aim of this study is to analyse the survival of ductal adenocarcinoma of the pancreas (DACP) according to tumour location and stablish if there are any differences among different neoplasm locations. Methods: We retrospectively analysed the pancreatic resections performed Principe de Asturias Teaching Hospital between January 2008 and December 2020. Data concerning tumour location, histological analysis of the surgical specimen and patient survival were collected in Microsoft Excel 2019® and statistically analysed using SPSS 26®. Results: 133 patients underwent a pancreatic resection between January 2008 and December 2020 of which 49 patients were histologically diagnosed of DACP. In 8 patients the tumour was located at body or tail of the pancreas whereas 41 had head or uncinate process tumours. A Kaplan Meier curve was performed to represent the probability of survival over the time depending on different tumour locations. The median survival was 21,667±6.556 months for pancreatic body tumours and 32,333±18,050 months for tail tumours (Confidence interval: 95%). In the case of pancreatic head tumours, the median survival was 35.856±12.188 months and 44,217±20.886 months for uncinate process adenocarcinoma (Confidence interval: 95%). Conclusion: Statistical analysis of survival according to tumour location showed that patients with body tumours have a worse survival than those with head and uncinate process tumours. However, the number of pancreatic resections due to body and tail tumours were significantly lower than those due to head and uncinate process tumours.

Effect of Diabetes Mellitus on Survival in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-analysis

Effect of Diabetes Mellitus on Survival in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-analysis

Pancreatectomia distal com ressecção do eixo celíaco para carcinoma pancreático localmente avançado: relato de caso

Long-term survival of pancreatic ductal adenocarcinoma after surgery is still rare. One of the main reasons for unresectability is the tumor invasion of the main vessels, such as the celiac axis, common hepatic artery and superior mesenteric artery. The optimal management of these patients is controversial. Despite the challenges on the topic, we present a case of pancreatic ductal adenocarcinoma with invasion of the celiac axis treated with pancreatectomy and vascular resection plus perioperative chemoradiotherapy. After 30 months of follow-up, hepatic and peritoneal recurrence were identified. Palliative chemotherapy was administered until disease progression and death in March 2020. Surgical resection when used in selected patients, proved to be feasible with acceptable morbidity. Besides that, the aggressive surgical approach associated with multimodal schemes provided an improvement in disease-free and overall survival.

Development and Validation of Prognostic and Diagnostic Model for Pancreatic Ductal Adenocarcinoma Based on scRNA-Seq and Bulk-Seq Datasets

Background: The 5-year overall survival (OS) of pancreatic ductal adenocarcinoma (PDAC) is only 10%, partly due to the lack of reliable diagnostic and prognostic biomarkers. This study aimed to establish and validate prognostic and diagnostic model for PDAC based on scRNA-seq and bulk-seq datasets. Methods: The raw gene-cell matrix for scRNA-seq analysis was downloaded from GSA (Genome Sequence Archive) database. We drew cell atlas for PDAC and normal pancreatic tissues using t-SNE clustering, and identified cell subpopulations according to known cell markers. Then we isolated ductal cell subpopulations and conducted t-SNE analysis again. The inferCNV analysis was used to distinguish tumor cells from normal ductal cells. We identified differential expression genes (DEGs) by comparing tumor cells and normal ductal cells using FindMarkers algorithm. The common DEGs were used to conducted prognostic and diagnostic model using univariate and multivariate Cox or Logistic regression analysis. Finally, we drew an easy-to-use nomogram to predict 2-year and 3-year overall survival (OS) for PDAC. Results: We identified 9 cell types including stellate cells, macrophages, endothelial cells, ductal cells, T cells, fibroblast cells, B cells, acinar cells and endocrine cells in PDAC. The 222 common DEGs were identified to screen prognosis-related genes. Four genes, including MET, KLK10, PSMB9 and ITGB6, were utilized to create risk score formula to predict OS and establish diagnostic model for PDAC. Finally, we validated prognosis nomogram combining N stage, margin status and risk score. Conclusions: We developed and validated the prognostic and diagnostic model for PDAC based on scRNA-seq and bulk-seq datasets, which will help identify high-risk PDAC patients. Funding Information: This study was supported by The Natural Science Foundation of China (NO.81871954, 81672353) and Beijing Municipal Natural Science Foundation (NO.7212111). Declaration of Interests: We declare there are no any competing financial interests in relation to this work. Ethics Approval Statement: This study was approved by Ethics Committee of Peking University First Hospital (Approval No. 2019-147) and conducted in accordance with ethical guidelines (Declaration of Helsinki). Written informed consent was obtained from all participants.

Tumor infiltrating neutrophils and gland formation predict overall survival and molecular subgroups in pancreatic ductal adenocarcinoma.

ABSTRACTBackgroundRNA‐sequencing‐based classifiers can stratify pancreatic ductal adenocarcinoma (PDAC) into prognostically significant subgroups but are not practical for use in clinical workflows. Here, we assess whether histomorphological features may be used as surrogate markers for predicting molecular subgroup and overall survival in PDAC.MethodsNinety‐six tissue samples from 50 patients with non‐resectable PDAC were scored for gland formation, stromal maturity, mucin, necrosis, and neutrophil infiltration. Prognostic PDAC gene expression classifiers were run on all tumors using whole transcriptome sequencing data from the POG trial (NCT02155621). Findings were validated using digital TCGA slides (n = 50). Survival analysis used multivariate Cox proportional‐hazards tests and log‐rank tests.ResultsThe combination of low gland formation and low neutrophil infiltration was significantly associated with the poor prognosis PDAC molecular subgroup (basal‐like or squamous) and was an independent predictor of shorter overall survival, in both frozen section (n = 47) and formalin‐fixed paraffin‐embedded (n = 49) tissue samples from POG patients, and in the TCGA samples. This finding held true in the subgroup analysis of primary (n = 17) and metastatic samples (n = 79). The combination of high gland formation and high neutrophils had low sensitivity but high specificity for favorable prognosis subgroups.ConclusionsThe assessment of gland formation and neutrophil infiltration on routine histological sections can aid in prognostication and allow inferences to be made about molecular subtype, which may help guide patient management decisions and contribute to our understanding of heterogeneity in treatment response.

Pre-treatment serum vitamin D deficiency is associated with increased inflammatory biomarkers and short overall survival in patients with pancreatic cancer.

Vitamin D deficiency and inflammation are associated with increased mortality. We investigated the relationship between pre-treatment serum vitamin D levels, inflammatory biomarkers (IL-6, YKL-40 and CRP)and overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC) patients. Pre-treatment serum vitamin D, IL-6, YKL-40and CRP levels were determined in 1,267 patients with PDAC enrolled from July 2008 to September 2018 in the prospective BIOPAC study (NCT03311776). The patients were grouped according to vitamin D levels: sufficient >50nmol/L, insufficient 25-50nmol/Land deficient <25nmol/L. Across all tumour stages, vitamin D-deficient patients had the highest median levels of IL-6 (8.3pg/mL, range 0.7-91), YKL-40 (177ng/ml, range 25-5279)and CRP (15.5mg/L, range 0.8-384). The resected stage I and II patients with vitamin D deficiencies had a shorter median OS, 18.3 months (95% CI, 12.1-31.5 months)than those with sufficient levels, 29.7 months (95% CI, 22.3-36.1 months), and the hazard ratio for death was 1.55 (95% CI, 1.04-2.31; p=0.03). In advanced PDAC, there was no significant difference in OS between the vitamin D groups. Vitamin D deficiency was associated with increased inflammatory biomarkers in all PDAC stages. The resected stage I and II patients with sufficient vitamin D levels had a higher OS than those with a vitamin D deficiency. However, there was no correlation between vitamin D levels and survival in advanced PDAC. Future studies need to investigate vitamin D supplementation effects on survival in PDAC.

Role of FUT8 expression in clinicopathology and patient survival for various malignant tumor types: a systematic review and meta-analysis.

Dysregulation of α(1,6)-fucosyltransferase (FUT8) plays significant roles in development of a variety of malignant tumor types. We collected as many relevant articles and microarray datasets as possible to assess the prognostic value of FUT8 expression in malignant tumors. For this purpose, we systematically searched PubMed, Embase, Web of Science, Springer, Chinese National Knowledge Infrastructure (CNKI), and Wan Fang, and eventually identified 7 articles and 35 microarray datasets (involving 6124 patients and 10 tumor types) for inclusion in meta-analysis. In each tumor type, FUT8 expression showed significant (p< 0.05) correlation with one or more clinicopathological parameters; these included patient gender, molecular subgroup, histological grade, TNM stage, estrogen receptor, progesterone receptor, and recurrence status. In regard to survival prognosis, FUT8 expression level was associated with overall survival in non-small cell lung cancer (NSCLC), breast cancer, diffuse large B cell lymphoma, gastric cancer, and glioma. FUT8 expression was also correlated with disease-free survival in NSCLC, breast cancer, and colorectal cancer, and with relapse-free survival in pancreatic ductal adenocarcinoma. For most tumor types, survival prognosis of patients with high FUT8 expression was related primarily to clinical features such as gender, tumor stage, age, and pathological category. Our systematic review and meta-analysis confirmed the association of FUT8 with clinicopathological features and patient survival rates for numerous malignant tumor types. Verification of prognostic value of FUT8 in these tumor types will require a large-scale study using standardized methods of detection and analysis.

The value of a metabolic reprogramming-related gene signature for pancreatic adenocarcinoma prognosis prediction.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide. Extensive enhancement of glycolysis and reprogramming of lipid metabolism are both associated with the development and progression of PDAC. Previous studies have suggested that various gene signatures could convey prognostic information about PDAC. However, the use of these signatures has some limitations, perhaps because of a lack of knowledge regarding the genetic and energy supply backgrounds of PDAC. Therefore, we conducted multi-mRNA analysis based on metabolic reprogramming to identify novel signatures for accurate prognosis prediction in PDAC patients. In this study, a three-gene signature comprising MET, ENO3 and CD36 was established to predict the overall survival of PDAC patients. The three-gene signature could divide patients into high- and low-risk groups by disparities in overall survival verified by log-rank test in two independent validation cohorts and could differentiate tumors from normal tissues with excellent accuracy in four Gene Expression Omnibus (GEO) cohorts. We also found a positive correlation between the risk score of the gene signature and inherited germline mutations in PDAC predisposition genes. A glycolysis and lipid metabolism-based gene nomogram and corresponding calibration curves showed significant performance for survival prediction in the TCGA-PDAC dataset. The high-risk designation was closely connected with oncological signatures and multiple aggressiveness-related pathways, as determined by gene set enrichment analysis (GSEA). In summary, our study developed a three-gene signature and established a prognostic nomogram that objectively predicted overall survival in PDAC. The findings could provide a reference for the prediction of overall survival and could aid in individualized management for PDAC patients.