Overall Survival In Pancreatic Cancer Research Articles

Venous thromboembolism incidence and association with overall survival in pancreatic cancer: A Finnish nationwide cohort study.

Pancreatic cancer (PC) is associated with a high risk of venous thromboembolic events (VTEs). We investigated the incidence of VTE before and after the diagnosis of PC and its association with overall survival. We identified PC patients diagnosed in 2013-2016 from the Finnish Cancer Registry. Data on healthcare visits and death were collected, along with follow-up data through the end of 2020. We compared patients who underwent radical-intent surgery (RIS) to those who underwent palliative treatment (PT) alone. We identified 4086 PC patients, of whom 343 (8.4%) underwent RIS and 3743 (91.6%) received PT. VTE incidence within 1 year before a PC diagnosis was higher in the PT (4.2%, n = 156) than in the RIS group (0.6%, n = 2; p < 0.001). The cumulative incidence of VTE at 12 and 24 months after a PC diagnosis was 6% (n = 21) and 9% (n = 31), respectively, within the RIS group, and 8% (n = 286) and 8% (n = 304) within the PT group. In the PT group, a VTE within 1 year before a PC diagnosis was independently associated with a worse survival {hazard ratio, HR 1.9 [95% confidence interval (CI) 1.6-2.2]}. In both groups, VTE after a PC diagnosis was associated with a worse survival [RIS group: HR 2.6 (95%CI 1.8-3.7) vs. PT group: HR 2.2 (95%CI 1.9-2.4)]. A VTE within 1 year before a PC diagnosis more often occurred among PT PC patients than among patients who underwent RIS. VTE might serve as a diagnostic clue to detect PC at an earlier stage.

Identification of gemcitabine resistance-related AHNAK2 gene associated with prognosis and immune infiltration in pancreatic cancer

PurposeGemcitabine is a basic chemotherapy drug for pancreatic cancer (PC), but resistance is common and causes tumor recurrence and metastasis. Therefore, it is significant to explore gemcitabine resistance-related molecules for individualized treatment and prognosis assessment of PC. MethodsIn this study, transcriptome sequencing and TCGA database analysis were performed, and a differentiated gene AHNAK2 was screened. MEXPRESS database, tissue microarray analysis, and CIBERSORT and TIMER databases were used to correlate AHNAK2 expression with clinicopathological features and prognosis and immune infiltration of PC. Enrichment analysis was used to investigate the significant biological processes associated with AHNAK2. ResultsAHNAK2 was highly expressed in gemcitabine-resistant cells. High expression of AHNAK2 increased the risk of poor overall survival (OS) and progression-free survival (PFS) in PC. Clinicopathologic analysis revealed that AHNAK2 correlated with KRAS, TP53 mutations, histologic type, short OS, N stage, and elevated CA199 levels in PC. Knockdown of AHNAK2 inhibited the ability of cell proliferation and colony formation and enhanced the toxic effect of gemcitabine in PC. Meanwhile, the knockdown of AHNAK2 expression enhanced cell-ECM adhesion, inhibited cell-cell adhesion, and downregulated the KRAS/p53 signaling pathway in PC. Furthermore, AHNAK2 was correlated with immune infiltration, especially B cells and macrophages. ConclusionsOur study unveils for the first time the pivotal role of AHNAK2 in PC, particularly its association with gemcitabine resistance, clinical prognosis, and immune infiltration. AHNAK2 not only drives the proliferation and drug resistance of PC cells by potentially activating the KRAS/p53 pathway but also significantly impacts cell-cell and cell- ECM adhesion. Additionally, AHNAK2 plays a crucial role in modulating the tumor immune microenvironment. These insights underscore AHNAK2's unique potential as a novel therapeutic target for overcoming gemcitabine resistance, offering new perspectives for PC treatment strategies.

Abstract 6984: Investigating the function of the OSM-OSMR axis in pancreatic ductal adenocarcinoma (PDAC)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, characterized by a low survival rate and a significant global mortality impact. The interaction between PDAC and the immune system is complex and plays a crucial role in the progression of the disease. PDAC creates an immunosuppressive tumor microenvironment, which hampers the ability of immune cells to effectively infiltrate the tumor and mount an anti-cancer immune response. Additionally, there is an imbalance of cytokines, with an overabundance of immunosuppressive factors and a deficiency in pro-inflammatory cytokines. This hostile immunological landscape contributes to the aggressive nature of PDAC and hinders the success of immunotherapies and adjuvant treatments. One cytokine of particular interest is oncostatin M (OSM), a member of the interleukin-6 (IL-6) family. OSM has been implicated in the regulation of cancer and has been associated with poor overall survival in pancreatic cancer and other malignancies. Similar to other cytokines, OSM is secreted by immune cells and acts as a regulator of the inflammatory microenvironment surrounding the tumor. The levels of OSM in this milieu can potentially influence cancer development and regulation through multiple mechanisms. Despite the growing understanding of cytokines in cancer, research on the role of OSM in PDAC is still limited and requires further investigation to identify potential therapeutic targets. Therefore, there is a critical need to delve deeper into the functions of OSM and its receptor, oncostatin M receptor (OSMR), in the initiation and progression of pancreatic cancer. As such, our goal is to examine the functions of OSM and its receptor (OSMR) in initiating and advancing pancreatic cancer to better comprehend the role of the OSM-OSMR axis in PDAC, both in vivo and in vitro. Citation Format: Yuan Sui, Tony Hunter. Investigating the function of the OSM-OSMR axis in pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6984.

Impact of prior cancer diagnosis on pancreatic cancer outcomes: A Danish Nationwide, population-based Cohort study

BackgroundThe overall survival of pancreatic cancer (PC) remains low, underlining the need of further research to improve PC directed therapy. Some patients with PC may have experienced a prior cancer, refraining them from inclusion in clinical trials, despite not knowing the precise effect of a prior cancer on disease course of PC. ObjectiveTo examine the influence of prior cancer on the disease course in patients with PC. MethodsWe conducted a cohort study including Danish patients diagnosed with PC between 2004 and 2020 crosslinking data from the Danish Cancer Registry, the Danish National Patient Registry among several other databases. Using the Kaplan-Meier estimator, we calculated the overall and American Joint Committee on Cancer (AJCC) disease stage stratified survival, comparing patients with and without prior cancer. Furthermore, using inverse probability of treatment weighting (IPTW), we presented a covariate-adjusted model of the average treatment effect in the treated (ATT) of prior cancer on the overall PC survival and stratified for AJCC disease stage. ResultsWe included 11,147 patients diagnosed with PC, of which 906 (8.1%) had a prior cancer. Comparing patients with and without prior cancer, the IPTW-adjusted survival, indicated a slightly better survival (ATT: 1.5 months; 95% CI: 0.7; 2.2 months). After stratifying by PC tumor stage, the difference was restricted to patients with stage IV PC disease (ATT: 1.1 months; 95% CI: 0.5; 1.7 months). Patients with prior cancer were slightly less prone to present with stage IV PC disease and were more likely to not receive active treatment compared with patients without prior cancer. ConclusionPrior cancer was associated with a slightly better survival in patients with PC, but only in patients with stage IV PC disease. This is likely explained by lead time bias.

The Mutation Portraits of Oncogenes and Tumor Supressor Genes in Predicting the Overall Survival in Pancreatic Cancer: A Bayesian Network Meta-Analysis.

In pancreatic cancer, the carcinogenesis can not be separated from genetics mutations. The portraits of genes alterations majorily including oncogenes (KRAS, HER2, PD-L1) and tumor supressor genes (P53, CDKN2A, SMAD4). Besides being notorious a screening marker, the genetic mutations were related to the prognosis of pancreatic cancer. The aim of this study is to determine the genetic mutations portrait in predicting the overall survival in pancreatic cancer. The network meta analysis (NMA) was registered in PROSPERO (CRD42023397976) and conducted in accordance with the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) in addition of NMA extension guidance. Comprehensive searches were done including all studies which reported the overall survival of pancreatic cancer subjects with KRAS, HER2, PD-L1, P53, CDKN2A, SMAD4. Data were collected and analysis will be done based on Bayesian method, Markov Chain Monte Carlo algorithm, using BUGSnet package in R studio. Transivity was controlled by methods and consistency of the NMA will be fitted by deviance information criterion. Data analysis in NMA were presented in Sucra plot, league table, and forest plot. Twenty-four studies were included in this NMA with 4613 total subjects. The NMA was conducted in random-effects, consistent, and convergence model. Relative to control, the genetic mutation of SMAD4 (HR 1.84; 95%CI 1.39-2.46), HER2 (HR 1.76; 95%CI 1.14-2.71), and KRAS (HR 1.7; 95%CI 1.19-2.48) were significant to have worse survival. The mutations of PD-L1, P53, and CDKN2A also showed poor survival, but not statistically significant compared to control. In pancreatic cancer, the mutation of SMAD4 predicted the worst overall survival, compared to control, also mutation of HER2, KRAS, PD-L1, P53, and CDKN2A.

Prediction of risk and overall survival of pancreatic cancer from blood soluble immune checkpoint-related proteins.

Immune checkpoint inhibition holds promise as a novel treatment for pancreatic ductal adenocarcinoma (PDAC). The clinical significance of soluble immune checkpoint (ICK) related proteins have not yet fully explored in PDAC. We comprehensively profiled 14 soluble ICK-related proteins in plasma in 70 PDAC patients and 70 matched healthy controls. Epidemiological data of all subjects were obtained through structured interviews, and patients' clinical data were retrieved from electronical health records. We evaluated the associations between the biomarkers with the risk of PDAC using unconditional multivariate logistic regression. Consensus clustering (k-means algorithm) with significant biomarkers was performed to identify immune subtypes in PDAC patients. Prediction models for overall survival (OS) in PDAC patients were developed using multivariate Cox proportional hazards regression. Harrell's concordance index (C-index), time-dependent receiver operating characteristic (ROC) curve and calibration curve were utilized to evaluate performance of prediction models. Gene expressions of the identified ICK-related proteins in tumors from TCGA were analyzed to provide insight into underlying mechanisms. Soluble BTLA, CD28, CD137, GITR and LAG-3 were significantly upregulated in PDAC patients (all q < 0.05), and elevation of each of them was correlated with PDAC increased risk (all p < 0.05). PDAC patients were classified into soluble immune-high and soluble immune-low subtypes, using these 5 biomarkers. Patients in soluble immune-high subtype had significantly poorer OS than those in soluble immune-low subtype (log-rank p = 9.7E-03). The model with clinical variables and soluble immune subtypes had excellent predictive power (C-index = 0.809) for the OS of PDAC patients. Furthermore, the immune subtypes identified with corresponding genes' expression in PDAC tumor samples in TCGA showed an opposite correlation with OS to that of immune subtypes based on blood soluble ICK-related proteins (log-rank p =0.02). The immune-high subtype tumors displayed higher cytolytic activity (CYT) score than immune-low subtype tumors (p < 2E-16). Five soluble ICK-related proteins were identified to be significantly associated with the risk and prognosis of PDAC. Patients who were classified as soluble immune-low subtype based on these biomarkers had better overall survival than those of the soluble immune-high subtype.

Interim analysis results of gut microbiota in patients with unresectable cholangiopancreatic cancer: SCRUM-Japan MONSTAR-SCREEN.

733 Background: MONSTAR-SCREEN prospectively assessed the gut microbiota of 2000 patients (pts) with advanced solid cancer at 31 Japanese institutions. Here, we report the interim analysis results of the correlation between gut microbiota and the efficacy of first-line chemotherapy in pts with unresectable pancreatic cancer (PC) and bile tract cancer (BTC). Methods: We analyzed unresectable 205 PC and 83 BTC pts with clinical data as data cut-off on April 30, 2021, and 16S ribosome analysis results of stool samples. Among PC pts, 133 and 40 were treated with GnP (gemcitabine (GEM) plus nab-paclitaxel) and FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin), respectively. Among BTC pts, 32 and 33 were treated with GC (GEM plus cisplatin) and GCS (GEM, cisplatin, plus S-1), respectively. Pts with an above-median overall survival (OS) were defined as long-term survivors (LTS), and those with below-median OS and OS events were defined as short-term survivors (STS). We compared the alpha diversity index (ADI) of LTS and STS, and identified potential microbial biomarkers of LTS, STS, responders, and non-responders to first-line chemotherapy according to RECIST version 1.1, by linear discriminant analysis effect size (LEfSe). In each cohort, the top three microbiota with linear discriminant analysis scores of ≥ 3.0 were considered significant. Results: The median OS of PC and BTC pts was 13.5 and 15.9 months, respectively. In PC pts, no significant difference was noted in the ADI between LTS (n=20) and STS (n=40). In BTC pts, the ADI of LTS (n=10) was significantly higher than that of STS (n=20) in the Shannon index. LEfSe analysis in PC pts revealed that Burkholderiales and Sutterellaceae were predominant in LTS, while Lactobacillaceae was, in STS. In PC pts, Brachyspiraceae and Erysipelotrichales were predominant in responders (n=67), while Enterococcaceae and Lactobacillaceae were, in non-responders (n=137). In BTC pts, Peptostreptococcaceae, Fusobacteriaceae, and Clostridiaceae in LTS; Cardiobacteriaceae, Prevotellaceae, and Actinobacteriota in responders (n=24); and Bacilli in non-responders (n=59) were overrepresented. Conclusions: This interim analysis identified potential biomarkers of the gut microbiota that may contribute to the prognosis and efficacy of chemotherapy in pts with unresectable PC and BTC. The results of this analysis will be validated in the primary analysis.

Venous Thromboembolism Incidence and Association with Overall Survival in Pancreatic Cancer: A Finnish Nationwide Cohort Study

Venous Thromboembolism Incidence and Association with Overall Survival in Pancreatic Cancer: A Finnish Nationwide Cohort Study

Expression of Corticotropin-Releasing Hormone and Its Receptors May Be Associated With Survival Rate in Pancreatic Cancer.

Corticotropin-releasing hormone (CRH) is a major regulator of the stress response to internal and external factors. CRH and its receptors (CRHR1 and CRHR2) are expressed in the central nervous system and some cancer cells, suggesting the importance of CRH signaling in pancreatic cancers. However, the clinicopathological significance of CRH remains unknown because the immunolocalization of CRH, CRHR1, and CRHR2 has not been examined in pancreatic carcinoma tissues. We clarified the correlation of the expression of CRH and its receptors with overall survival in pancreatic cancer. This study evaluated 96 patients with pancreatic cancer who underwent microscopic complete resection (R0) but not neoadjuvant chemotherapy from 1988 to 2007 at Tohoku University Hospital, Japan. CRH, CRHR1, and CRHR2 immunoreactivity were detected in the pancreatic carcinoma cells. Overall survival curves were generated according to the Kaplan-Meier method. CRHR1 immunoreactivity was significantly associated with an increased risk of poorer prognosis in all patients (P= .038) and the adjuvant therapy group (P= .022). Overall survival was worse in the CRHR1-positive group than in the CRHR1-negative group among the 62 patients treated with gemcitabine hydrochloride (P= .046) and the 22 patients treated with other drugs (P= .047). CRHR1 expression was correlated with survival in univariate analysis but not in multivariate analysis. This study is the first to immunolocalize CRH, CRHR1, and CRHR2 in pancreatic carcinoma tissues and to examine the biological prognosis. This study revealed that survival in patients with pancreatic cancer was significantly associated with expression of CRHR1 by assessing biological progression according to CRH and the expression of its receptors. However, CRHR1 expression was correlated with survival in univariate analysis but not in multivariate analysis.

HPB P10 Evaluation of the prognostic role of aspirin and metformin in the ESPAC 4 randomised trial of adjuvant gemcitabine versus gemcitabine plus capecitabine in patients with resected pancreatic cancer

Abstract Background Pancreatic cancer is currently the world's seventh most common cancer with it's incidence being equivalent to it's mortality. It is the fourth most common cause of cancer-related mortality and is set to be the second most common by 2030. 5-year overall survival of pancreatic cancer is set at just below 10%, with only approximately 15% - 20% of diagnosed patients being eligible for resection. Patients eligible for resection have a 5-year overall survival improvement of up to 30% over recent years following the combination of resection and adjuvant therapy. The prognostic effects of chemo-preventive agents such as metformin and aspirin have been investigated previously in pancreatic cancer (PC) with variable results. ESPAC-4 was a phase-3 randomised controlled trial which recruited patients with resectable pancreatic cancer and examined the survival benefit between adjuvant monotherapy gemcitabine therapy and adjuvant gemcitabine-capecitabine (GEMCAP) combination therapy. This study aims to evaluate the prognostic impact of aspirin and metformin on survival among PC patients in the ESPAC 4 randomised trial. Methods Concomitant medication data was identified from ESPAC-4 trial database. Primary and secondaryoutcome measures were overall survival (OS) and disease-free survival (DFS) respectively for users and non-users of aspirin and metformin. Survival data was analysed using multivariate and univariate Cox-proportional hazard models and log-rank testing.The primary and secondary outcome was to investigate overall survival (OS) and Relapse-Free Survival (RFS) time respectively, between users and non- users of aspirin and metformin in either treatment arm. Results We identified 86 patients using aspirin and 55 patients using metformin out of 730 randomised trial patients at baseline . Aspirin usage led to a median OS of 30 months versus 26 months with non-users and a hazard ratio of 0.91 (95% CI:0.68–1.2; p=0.499). Median DFS with and without aspirin usage was 17.9 months versus 13.1 months respectively with a hazard ratio of 0.76 (95% CI: 0.58–0.99, p=0.044). Gemcitabine treatment amongst aspirin users demonstrated a median OS of 42.4 months compared to 24.7 months in non-aspirin users and a hazard ratio of 1.69 with non-users (95% CI:1.06–2.67; p=0.026). Aspirin users randomised to gemcitabine had a median DFS of 37.2 months, compared to non-aspirin users with 11.9 months and a hazard ratio of 2.01 (95% CI:1.31–3.08; p=0.001). Metformin usage resulted in a median OS of 23.8 months versus 27.7 months in non-users with a hazard ratio of 0.95 (95% CI:0.65–1.4; p=0.819). Median DFS with and without metformin usage was 14.7 months versus 12.5 months respectively, with a hazard ratio of 0.88 (95% CI:0.61–1.27; p=0.498). Metformin usage in either treatment arm did not demonstrate a significant survival difference Conclusions Though numbers are small, gemcitabine therapy and aspirin usage demonstrated a prognostic benefit in OS and DFS in this study. Further in vivo studies exploring the mechanism of this interaction would be beneficial. There was no survival benefit observed with metformin usage. Standardisation of dosages in chemopreventive agents such as metformin and aspirin in future trials could yield further standardised results.

Abstract A049: Is smoking prognostic for advanced metastatic pancreatic cancer (PC) patients undergoing treatment

Abstract Introduction: PC is the third leading cause of cancer-related death in the United States. Cigarette smoking is a known risk factor for PC. Furthermore, it has been evaluated as a possible prognostic marker and has been shown that increased number of pack years is associated with worsened overall survival in PC (Yuan et al). However, it has yet to be shown whether patients undergoing active treatment and are current smokers, are facing a worse prognosis. Our study aims to examine the effect of current smoking on survival outcomes of advanced/metastatic PC patients undergoing active treatment. Methods: This is a retrospective study. Patients diagnosed with advanced/metastatic pancreatic cancer at Henry Ford Health between January 2016 and January of 2021 were identified via chart review. Variables collected included age, gender, smoking status (subclassified as never smokers, former smokers, and active smokers), performance status (documented as Eastern Cooperative Oncology Group (ECOG), number of chemotherapy (CTX) lines, and survival status that is most recently documented by May 1st, 2002. Median survival time were calculated to present the survival time for which the proportion surviving reached 50 percent. Kaplan-Meier estimates were used to generate survival curves for each cohort. The log-rank test was performed to compare the survival distributions among smoking status. Cox model was fit to estimate the association between smoking behavior and overall survival, adjusted for demographics and cancer-related variables. CTX was treated as a time-dependent covariate. All statistical tests were 2-sided with an α (significance) level of 0.05. All data was analyzed using R version 4.1.2. Results: A total of 269 PC patients were included in the analysis. The mean age of the cohort was 66 years and 50.9% were males. The mortality rate (from time of diagnosis to May 1st, 2022 was about 89%. Around 8% of patients underwent surgery, 21% have taken radiation therapy, and only one patient did not undergo CTX. For smoking behavior, 46.1% were never smokers, 34.6% were former smokers, and 19.3% were current smokers. Looking at baseline characteristics, the mean age of active smokers were 4 to 5 years less than never/former smokers and the average ECOG score of non-smokers were 0.28 to 0.32 point less than former/active smokers. Median survival time for patients never smoking was 11.7 months, 8.9 months for former smokers, and 11.4 months for active smokers. The log-rank test did not show sufficient evidence of a difference in survival across patients’ smoking status. Conclusion: Active smoking status does not appear to influence overall survival in advanced/metastatic pancreatic cancer patients undergoing various chemotherapy treatments. This study was limited in its retrospective nature and a relatively small sample. Information regarding level of smoking (light smokers vs heavy smokers) was not readily available. The prognostic value of smoking in PC will need to be assessed prospectively. Citation Format: Aula Ramo, Zeinab Nasser, Mohamad Beidoun, Baha' Mustafa Abbad, Nayef Hikmat Abdel-Razeq, Gazala Khan. Is smoking prognostic for advanced metastatic pancreatic cancer (PC) patients undergoing treatment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A049.

Selected Articles from This Issue

Mutant NRASG12V drives acute myeloid leukemia (AML) cell proliferation and self-renewal in a mutually exclusive manner. Previous studies demonstrated that AML cell proliferation and self-renewal are associated with differential NRASG12V transcript levels, but whether different NRASG12V protein levels dictate proliferative versus self-renewal phenotypes is not known. To address that knowledge gap, Kurata and colleagues engineered AML cell lines in which tetracycline-inducible NRASG12V expression levels are tunable using various doxycycline doses. The authors found that moderate NRASG12V protein expression promotes AML cell proliferation, whereas higher NRASG12V protein expression facilitates AML cell senescence and self-renewal. Using mass cytometry, the authors showed that abundances of several downstream NRASG12V effectors, including known stemness mediators such as β-catenin, increase in a dose-dependent fashion, whereas others, such as phosphorylated STAT1, are not dose-dependent. Overall, this study demonstrates that differential NRASG12V protein levels disparately drive AML cell proliferation and self-renewal and illuminates the downstream signaling dynamics underlying each phenotype.Tumor cell heterogeneity is a major impedance in eliminating cancer, as it promotes therapy-resistant clone selection in response to treatment. Identifying biomarkers indicative of tumor heterogeneity may help quantify it and uncover therapeutic vulnerabilities, but such biomarkers remain elusive. In their study, So and colleagues discovered that DNA methyltransferase 3B (DNMT3B) protein expression displays marked heterogeneity in primary tumors from triple-negative breast cancer (TNBC) patients and TNBC mouse models. By selecting DNMT3B-high and -low clones from 4T1 cells, labeling them with different fluorescent dyes, and quantifying them in circulation and lung metastases after orthotopic injection, the authors found that DNMT3B-high cells are more metastatic than DNMT3B-low cells. Mechanistically, prostaglandin E2 (PGE2) induces DNMT3B expression, and DNMT3B regulates expression of epithelial–mesenchymal transition effectors including vimentin, Twist2, and Snai1. Perioperative treatment with celecoxib, which lowers PGE2 expression, alongside DNMT inhibitor 5-azacytidine and other chemotherapeutic drugs decreases tumor recurrence and metastasis after primary tumor removal. Taken together, this study presents DNMT3B as a therapeutically targetable marker and effector of tumor heterogeneity.Therapeutic challenges and poor outcomes in pancreatic cancer make further elucidating its underlying molecular mechanisms and therapeutic vulnerabilities critical. While long non-coding RNA (lncRNA) α-2-macroglobulin-antisense 1 (A2M-AS1) expression positively correlates with overall survival in pancreatic cancer as well as ferroptosis-related genes, how A2M-AS1 might regulate ferroptosis and whether it does so in pancreatic cancer has not been solved. In their study, Qiu and colleagues found that pharmacologically inducing ferroptosis in pancreatic cell lines augments A2M-AS1 expression, and that modulating A2M-AS1 abundance using shRNA and overexpression inhibits and enhances ferroptosis, respectively. Accordingly, A2M-AS1 overexpression limits pancreatic cancer cell growth both in vitro and in vivo. An RNA pull-down and mass spectrometry revealed that A2M-AS1 interacts with PCBP3. Additional experiments demonstrated that the interaction between A2M-AS1 and PCBP3 abrogates mTOR and AKT activation, while increasing p38 activation and ferroptosis. In sum, this study unveils a novel molecular mechanism by which ferroptosis evasion occurs in pancreatic cancer.Acute myeloid leukemia (AML) cells are dependent on oxidative metabolism. However, electron transport chain complex II (CII) targeting agents and their potential effects on AML cell metabolism and viability have not been assessed. To evaluate CII therapeutic targeting in AML, Roma and colleagues abrogated expression of CII chaperone protein succinate dehydrogenase assembly factor 1 (SDHAF1) using shRNA in AML cell lines. Using an in silico screen and HPLC analysis, the authors also identified shikonin as a CII small molecule inhibitor. Both SDHAF1 ablation and shikonin promote AML cell death in vitro and in vivo, and stable isotope tracing demonstrated concurrent tricarboxylic acid (TCA) cycle truncation. The authors also showed that SDHAF1 ablation and shikonin increase glutamine flux into the TCA cycle via deamination to α-ketoglutarate as well as reductive flux to aspartate. Accordingly, supplementing α-ketoglutarate undermines shikonin effectiveness, and pharmacologically inhibiting glutaminase augments it. Altogether, this study reveals a novel therapeutic target and accompanying therapeutic agent in AML and identifies anaplerotic glutamine metabolism as a compensatory mechanism and therapeutic vulnerability in CII inhibition.

Predicting the Overall Survival in Patients with Advanced Pancreatic Cancer by Calculating L3 Skeletal Muscle Index Derived from CT.

Pancreatic cancer is mostly diagnosed in advanced stages, and treatment results are not satisfactory. L3 skeletal muscle index (SMI) has emerged as a prognostic factor in pancreatic cancer patients. We aimed to assess the association between sarcopenia and overall survival in patients with pancreatic cancer in this study. Patients who were admitted to the Department of Oncology between March 2012 and December 2019 and diagnosed with pancreatic cancer were evaluated. The computerized tomography images and laboratory parameters of a total of 115 patients were included in this retrospective singlecenter study. We defined sarcopenia as an SMI <43,56 cm²/m² for females and <56,44 cm²/m² for males using the receiver operating characteristics (ROC) curve in the study population. Univariate and multivariate analyses were performed by using Cox-regression modelling, and survival curves were constructed by using Kaplan-Meier method. 70% of the patients were male, and the mean age was 64.9±9.9 years (mean ± SD). 70.6% of female patients and 67.9% of male patients were diagnosed with stage 4 cancer. The prevalence of sarcopenia in the whole patient group was 29.6%. By multivariate analysis, SMI (p=0.009) and advanced stage (p=0.003) were found as poor prognostic factors for overall survival (OS). The neutrophil to lymphocyte ratio (NLR) was statistically significantly higher in sarcopenic patients than in nonsarcopenic patients (p=0.031). Patients having sarcopenia at the time of diagnosis may demonstrate poorer overall survival of pancreatic cancer, and SMI may be considered as a potential prognostic factor.

Identification of a Novel Risk Model: A Five-Gene Prognostic Signature for Pancreatic Cancer.

Objective Biomarkers for pancreatic cancer (PCa) prognosis provide evidence for improving the survival outcome of this disease. This study aimed to identify a prognostic risk model based on gene expression profiling of microarray bioinformatics analysis. Methods Prognostic immune genes in the TCGA-PAAD cohort were identified using the univariate Cox regression and Kaplan–Meier survival analysis. Multivariate Cox regression (stepAIC) was used to identify prognostic genes from the top 20 hub genes in the protein-protein interaction (PPI) network. A prognostic risk model was established and its performance in predicting the overall survival in PCa was validated in GSE62452. Gene mutations and infiltration immune cells in PCa tumors were analyzed using online databases. Results Univariate Cox regression and Kaplan–Meier survival analyses identified 128 prognostic genes. Multivariate Cox regression (stepAIC) identified five prognostic genes (PLCG1, MET, TNFSF10, CXCL9, and TLR3) out of the 20 hub genes in the PPI network. A prognostic risk model was established using the signature of five genes. This model had moderate to high accuracies (AUC > 0.700) in predicting 3-year and 5-year overall survival in TCGA and GSE62452 cohorts. The Kaplan–Meier survival analysis showed that high-risk scores were correlated with poor survival outcomes in PCa (p < 0.05). Also, mutations in the five genes were related to poor survival. The five genes were related to multiple immune cells. Conclusions The prognostic risk model was significantly correlated with the survival in PCa patients. This model modulated PCa tumor progression and prognosis by regulating immune cell infiltration.

Remediating Desmoplasia with EGFR-Targeted Photoactivable Multi-Inhibitor Liposomes Doubles Overall Survival in Pancreatic Cancer.

Desmoplasia is characteristic of pancreatic ductal adenocarcinoma (PDAC), which exhibits 5‐year survival rates of 3%. Desmoplasia presents physical and biochemical barriers that contribute to treatment resistance, yet depleting the stroma alone is unsuccessful and even detrimental to patient outcomes. This study is the first demonstration of targeted photoactivable multi‐inhibitor liposomes (TPMILs) that induce both photodynamic and chemotherapeutic tumor insult, while simultaneously remediating desmoplasia in orthotopic PDAC. TPMILs targeted with cetuximab (anti‐EGFR mAb) contain lipidated benzoporphyrin derivative (BPD‐PC) photosensitizer and irinotecan. The desmoplastic tumors comprise human PDAC cells and patient‐derived cancer‐associated fibroblasts. Upon photoactivation, the TPMILs induce 90% tumor growth inhibition at only 8.1% of the patient equivalent dose of nanoliposomal irinotecan (nal‐IRI). Without EGFR targeting, PMIL photoactivation is ineffective. TPMIL photoactivation is also sixfold more effective at inhibiting tumor growth than a cocktail of Visudyne‐photodynamic therapy (PDT) and nal‐IRI, and also doubles survival and extends progression‐free survival by greater than fivefold. Second harmonic generation imaging reveals that TPMIL photoactivation reduces collagen density by >90% and increases collagen nonalignment by >103‐fold. Collagen nonalignment correlates with a reduction in tumor burden and survival. This single‐construct phototoxic, chemotherapeutic, and desmoplasia‐remediating regimen offers unprecedented opportunities to substantially extend survival in patients with otherwise dismal prognoses.

Combination cancer immunotherapy targeting TNFR2 and PD-1/PD-L1 signaling reduces immunosuppressive effects in the microenvironment of pancreatic tumors

BackgroundsIn advanced pancreatic ductal adenocarcinoma (PDAC), immune therapy, including immune checkpoint inhibitors, has limited efficacy, encouraging the study of combination therapy.MethodsTumor necrosis factor receptor 2 (TNFR2) was analyzed via immunohistochemistry,...

Intron-Retention Neoantigen Load Predicts Favorable Prognosis in Pancreatic Cancer.

PURPOSEHigh tumor mutation burden (TMB) in many cancer types is associated with the production of tumor-specific neoantigens, a favorable outcome and response to immune checkpoint blockade (ICB) therapy. Besides mutation-derived neoantigens, aberrant intron retention also produces tumor neopeptides that could trigger an immune response. The relationship between intron-retention–derived tumor neoantigens (IR-neoAg) and clinical outcomes in pancreatic cancer remains uncertain. Here, we quantify IR-neoAg in pancreatic cancer and evaluate whether IR-neoAg load might serve as a biomarker for selecting patients who may benefit from ICB therapy.METHODSWe developed a computational approach to estimate patient-specific IR-neoAg load from transcriptome data available in The Cancer Genome Atlas pancreatic cancer cohort. Associations between IR-neoAg load and patient overall survival were evaluated using Kaplan-Meier estimates and Cox regression. Differential expression of immune checkpoint and HLA-I genes was evaluated in tumors with high IR-neoAg load.RESULTSHigh IR-neoAg load predicted better overall survival in pancreatic cancer, although no association was found for TMB. IR-neoAg load remained a significant prognostic factor after adjusting for patient age, sex, tumor stage and grade, and TMB. Moreover, pancreatic tumors with both high IR-neoAg load and high HLA-I gene expression had similar gene expression profiles as other tumor types that showed response to anti–programmed cell death protein 1 therapy.CONCLUSIONIR-neoAg load is associated with favorable survival in pancreatic cancer. These findings provide strong evidence for considering IR-neoAgs when selecting patients who might benefit from ICB therapy.

CA9-Related Acidic Microenvironment Mediates CD8+ T Cell Related Immunosuppression in Pancreatic Cancer.

PurposeThis study aims to integrate pancreatic cancer TCGA, GEO, and single-cell RNA-sequencing (scRNA-seq) datasets, and explore the potential prognostic markers and underlying mechanisms of the immune microenvironment of pancreatic cancer through bioinformatics methods, in vitro and in vivo assays.MethodsExpression data and clinicopathological data of pancreatic cancer TCGA, GEO (GSE131050), single cell sequencing (PAAD_CRA001160) dataset were downloaded. We used R/Bioconductor edgeR for differential expression analysis. ClusterProfiler was utilized to perform GO enrichment analysis on differentially expressed genes. The online software CIBERSORT was used to reanalyze the mRNA expression data of pancreatic cancer. CellRanger, RunPCA, FindNeighbors, FindClusters, RunTSNE and RunUMAP were used to perform preprocessing, cell clustering and expression profile analysis on single-cell sequencing data sets. We analyzed intracellular pH with or without CA9 inhibitor SLC-0111. Indirect co-culture model of human pancreatic cancer cell lines and healthy individual-derived PBMCs were used to determine the effect of CA9-related Acidic Microenvironment on CD8+ T cells.ResultsThe CIBERSORT analysis of TCGA pancreatic cancer transcriptome sequencing data showed that among the 22 immune microenvironment components, CD8+ T cell infiltration was significantly correlated with the prognosis of pancreatic cancer patients. The differential expression analysis of the TCGA data grouped by the level of CD8+ T cell infiltration indicates that the expression of carbonic anhydrase 9 (CA9) is the most significant, and the survival analysis suggests that CA9 is associated with the overall survival of pancreatic cancer. TCGA data and GEO data set GSE131050 expression correlation analysis suggests that CA9 and CD8 expression are closely related. Pancreatic cancer single-cell sequencing data set PAAD_CRA001160 analysis results show that CA9 is mainly expressed in pancreatic cancer cell clusters, and the expression of the cancer cell subgroup CA9 in the single-cell data set is correlated with CD8+ T cell infiltration.ConclusionPancreatic cancer cells may inhibit the infiltration of CD8+ T cells through CA9. Further exploration of its related mechanisms can be used to explore the immune escape pathway of pancreatic cancer and provides new perspectives immune targeted therapy.

Pancreatic cancer

Pancreatic cancer Abstract. Pancreatic cancer is the second most common cancer in the GI tract in Europe and North America and it is associated with a poor prognosis due to its aggressive tumor biology. Each year the number of deaths from pancreatic cancer is almost the same as the number of new cases diagnosed. Most of the pancreatic cancers develop from exocrine cells, while endocrine pancreatic cancers (i. e., neuroendocrine tumors or islet cell tumors) are uncommon. The term "pancreatic cancer" is typically used to refer to pancreatic adenocarcinoma, which will be the focus of this paper. Despite the introduction of multimodal therapy concepts, advanced surgical techniques, and increasing surgical specialization, overall survival in pancreatic cancer has not significantly improved. Early and complete surgical tumor resection remains the only curative option; however, this is rarely achieved, mainly due to the advanced stage at diagnosis. Adjuvant chemotherapy has become the gold standard after upfront resection. Neoadjuvant chemotherapy regimens, such as FOLFIRINOX, represent a valid option in order to achieve complete surgical tumor resection in more advanced cases. However, the overall uptake of this promising concept is very low.

Identification of DNA methylation-driven genes and construction of a nomogram to predict overall survival in pancreatic cancer

BackgroundThe incidence and mortality of pancreatic cancer (PC) has gradually increased. The aim of this study was to identify survival-related DNA methylation (DNAm)-driven genes and establish a nomogram to predict outcomes in patients with PC.MethodsThe gene expression, DNA methylation database, and PC clinical samples were downloaded from TCGA. DNAm-driven genes were identified by integrating analyses of gene expression and DNA methylation data. Survival-related DNAm-driven genes were screened via univariate, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses to develop a risk score model for prognosis. Based on analyses of clinical parameters and risk score, a nomogram was built and validated. The independent cohort from GEO database were used for external validation.ResultsA total of 16 differentially expressed methylation-driven genes were identified. Based on LASSO Cox regression and multivariate Cox regression analysis, six genes (FERMT1, LIPH, LAMA3, PPP1R14D, NQO1, VSIG2) were chosen to develop the risk score model. In the Kaplan–Meier analysis, age, T stage, N stage, AJCC stage, radiation therapy history, tumor size, surgery type performed, pathological type, chemotherapy history, and risk score were potential prognostic factors in PC (P < 0.1). In the multivariate analysis, stage, chemotherapy, and risk score were significantly correlated to overall survival (P < 0.05). The nomogram was constructed with the three variables (stage, chemotherapy, and risk score) for predicting the 1-year, 2-year, and 3-year survival rates of PC patients. Nomogram performance was assessed by receiver operating characteristic (ROC) curves and calibration curves. 1-year, 2-year and 3-year AUC of nomogram model was 0.899, 0.765 and 0.776, respectively.ConclusionsIn our study, we successfully identified the six DNAm-driven genes (FERMT1, LIPH, LAMA3, PPP1R14D, NQO1, VSIG2) with a relationship to the outcomes of PC patients. The nomogram including stage, chemotherapy, and risk score could be used to predict survival in PC patients.