Survival In Pancreatic Cancer Research Articles

Pancreatic ductal adenocarcinoma, β-blockers and antihistamines: A clinical trial is needed.

Survival in pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) at just 5 months is the worst of all cancers. It is predicted to become the second highest cause of cancer deaths worldwide this decade and unlike most cancers, there has been little progress in improving survival in PDAC. Numerous studies including molecular and mechanistic studies, cancer biology studies and retrospective human epidemiological studies suggest that two well-known, approved drug classes - β-blockers and H1-antihistamines - may be beneficial and thus may potentially prolong life in patients with PDAC. In our opinion, the body of evidence has reached a point where the potential gains outweigh the very low risks involved in a clinical study in PDAC. We thus believe that it is now time for a clinical trial involving these two agents in PDAC patients. As a repurposing of generic drugs, this is not likely to be appealing to pharmaceutical companies and therefore is likely to require governmental, philanthropic and /or charitable organisational input. In this article, we opine and propose that an urgent clinical trial is needed to determine if repurposing these two orally administered, inexpensive, largely safe drug classes, either alone or in combination, could prolong survival in PDAC and thus improve the outcome for the 10,000 people worldwide who die from PDAC each week.

GATA6 amplification is associated with improved survival in TP53-mutated unresectable pancreatic cancer

Abstract Objectives: GATA6 expression has been recently recognized as a favorable prognostic marker of pancreatic cancer whereas TP53 is recognized as a poor prognostic marker. We evaluated treatment outcomes by genetic alterations in TP53 and GATA6 to determine the prognostic and predictive impact of co-alterations. Methods A single institution retrospective analysis was performed on patients diagnosed with PDAC between 2014 to 2023. TP53 genotype and GATA6 amplification status were included in an analysis of overall survival (OS) and progression free survival (PFS). Previously published patient-derived organoids were used to investigate correlation between genetic status and drug sensitivity. Results Patients with TP53 mutations had worse OS compared to the wild type TP53 population. In general, patients with GATA6 amplification had better OS and a trend towards better PFS than the non-amplified population. Among patients with a TP53 mutation, patients with GATA6 co-alteration had longer OS compared to those who were not GATA6 amplified. In contrast, among patients who were TP53 wild type, the presence or absence of a GATA6 amplification did not impact OS or PFS. GATA6 genotype was not associated chemotherapy drug response in an organoid pharmacotyping model. Conclusions We found that GATA6 amplification appeared to attenuate poor prognosis observed in TP53-mutant patients regardless of the type of standard chemotherapy received, suggesting the GATA6 amplification is a prognostic biomarker but not a predictive biomarker of standard-of-care chemotherapy.

Evaluation of prognostic significance of histopathological characteristics and tumor-infiltrating lymphocytes for pancreatic cancer survival

With a 5-year survival of ˂ 10%, pancreatic cancer is one of the leading causes of cancer-related deaths. Given the role of the distribution of tumor-infiltrating lymphocyte (TILs) subtypes in the tumor and its microenvironment in predicting prognosis, the development of new targeted therapies based on T-cell adaptive response has gained considerable attention. This study aimed to examine the peritumoral spread of TILs and its relationship with other prognostic parameters and survival. This study included 60 patients with pancreatic cancer who had undergone surgery with follow-up between 2011 and 2021. Demographic characteristics, tumor histopathological features, peritumoral TILs counts, and intratumoral programmed cell death protein-1 (PD-1) and programmed death ligand − 1 (PD-L1) positivity were evaluated. Furthermore, overall survival and their efficacy in predicting survival according to TNM stage were analyzed. The number of cluster differentiation-3 positive (CD3 P) TILs increased with advancing pathological T stage. CD3 P and CD8 P TIL counts were higher in patients with peripancreatic fatty tissue invasion. Patients with PD-L1 positivity and higher TIL counts had better survival rates. PD-L1-negative patients with a low CD8 positive/total lymph node count (P/T) ratio had a longer survival. Moreover, patients with poorly differentiated tumors with low CD3 P/T and CD8 P/T ratios had a longer survival. The CD3 P/T and CD8 P/T ratios were compatible with the automatic and manual measurements. Age, tumor differentiation, N stage, and peritumoral TIL count and subtype, when evaluated together with the presence of PD-L1 in the tumor tissue, may have prognostic significance for survival in patients with pancreatic cancer.

Defying the Odds: Outstanding Survival in Lung-only Pancreatic Cancer Treated by Trifluridine-Tipiracil

Defying the Odds: Outstanding Survival in Lung-only Pancreatic Cancer Treated by Trifluridine-Tipiracil

Real-world analysis of the correlation between overall survival and progression-free survival in advanced pancreatic cancer: Results of NAPOLEON-1 and 2 studies.

Fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improve overall survival (OS) and progression-free survival (PFS) in patients with pancreatic cancer, compared with gemcitabine (GEM). However, whether PFS is a surrogate marker of OS in pancreatic cancer chemotherapy focusing on FOLFIRINOX or GEM plus nab-paclitaxel remains unknown. We aimed to verify whether PFS can be a surrogate marker of OS in prognosis prediction. This was an integrated analysis of the NAPOLEON study and retrospective cohort of the NAPOLEON-2 study-a multicenter observational study conducted in Japan, using real-world data. The primary and secondary endpoints were OS and PFS, respectively. The correlation between OS and PFS in first- and second-line treatments was assessed using Method of Moments estimation. An analysis was performed in patients with confirmed OS at the end of follow-up. The NAPOLEON-2 cohort included only patients who received 5-fluorouracil, leucovorin, and nanoliposomal irinotecan (NFF) as second-line treatment. Among 479 patients, the correlation between PFS and OS from first- and second-line chemotherapies was calculated in 310 and 225 patients, respectively. The R-squared values for the correlation between PFS and OS from first- and second-line chemotherapies were 0.74 and 0.76, respectively. There was no statistically significant difference in first-line treatment between the FOLFIRINOX and gemcitabine plus nab-paclitaxel groups (P=0.92). Therefore, the FOLFIRINOX group may not have shown a stronger correlation than the NFF group. PFS can be a surrogate marker of OS in first- and second-line therapies. Appropriate prognostic estimation might contribute to proper treatment selection.

Abstract C047: Autophagy-mediated proline-supply is important for cell survival in pancreatic cancers

Abstract Oncogenic KRAS mutations present in 90–95% of pancreatic cancer patients. KRAS mutation in pancreatic cancer increased the dependency on glutamine and consumption of proline. Proline is a non-essential amino acid but it is important for the synthesis of proteins such as collagen, and also for precursors of antioxidant molecules. Several enzymes such as P5CS(ALDH18A1),PYCR1 and PYCR2 are involving proline synthesis. The effects of proline synthesis enzymes on pancreatic cancer cells are relatively less studied than that of enzymes catalyzing proline. Here, we examined the impact of proline synthesis enzymes on pancreatic cancer cell survival and proliferation. We first examined that exogenous proline promotes cell survival under low glutamine conditions in various pancreatic cancer cells. Exogenous proline supplementation increased some pancreatic cell survival even when glutamine was not sufficiently available, whereas proline supplement is dispensible for certain cell types of pancreatic cancer. Next, to investigate the importance of proline synthesis enzymes in cell survival, we measured the cell proliferation of pancreatic cancer with knock-down the proline synthesis enzymes. The knockdown of ALDH18A1 and PYCR1,2, which are proline biosynthesis enzyme genes, reduced cell survival in pancreatic cancer cells, suggesting that in PDAC cells, the enzymes that synthesize proline from glutamine are crucial for cancer cell survival and growth. To test the effect of proline-sysnthesis enzymes on autophagy, we measured autophagy flux in the cell harboring GFP-RFP-LC3 or GFP-LC3 as a reporter. Knockdown of proline synthesis enzymes, particularly ALDH18A1 or PYCR1 led to an increase in autophagy levels, indicating that proline-independent cells can bypass proline synthesis by autophagy induction in the absence of proline synthesis genes. Furthermore gemcitabine-resistant cells showed reduced levels of proline synthesis enzymes. In pancreatic cancer cell lines, proline promotes cancer cell survival, generated by both biosynthesis from glutamine and starvation-induced autophagy, which also critically important for supporting cellular drug resistance. Taken together, these results indicate that proline synthesis is mechanistically associated with autophagy induced by glutamine-starvation, which is pivotal for supplying proline in pancreatic cancer cells. Citation Format: Ji hyeon Kim, Heesun Cheong. Autophagy-mediated proline-supply is important for cell survival in pancreatic cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C047.

Abstract B011: Predictors of survival and cachexia in pancreatic cancer: results from the CAMPP study

Abstract Introduction: Pancreatic Ductal Adenocarcinoma (PDAC) is a major cause of cancer-related death in the US and has an overall 5-year survival rate of only 13%. Cachexia, or cancer associated muscle wasting, is common and negatively affects treatment outcomes and quality of life. Despite these poor outcomes, our understanding of PDAC disease processes and improvements in treatments are limited. Here, we present the first results of the Cancer Associations in MUSC PDAC Patients (CAMPP) study. Methods: This retrospective analysis of 133 surgically resectable PDAC patients at the Medical University of South Carolina (MUSC) between May 2016 to 2021 includes chart review data on survival, treatment, and clinical outcomes. Cancer cachexia was evaluated via total psoas area at the L3 vertebral level, which was standardized by height to produce a Total Psoas Index (TPI). Survival was plotted via unadjusted Kaplan-Meier analysis and TPI and cachexic status was examined for 124 patients with both linear and logistic regressions for unadjusted and adjusted data. Results: When analyzing population survival, we observed a mean overall survival (OS) of 23.6 months and mean progression free survival (PFS) of 17.3 months. Notable survival differences include perioperative vs adjuvant only chemotherapy groups in OS at 2 years (p=0.069) and 5 years (p=0.13). Within the perioperative population, there were differences in PFS (p=0.017) and OS (p=0.056) for patients who responded to therapy at 5 years. To explore potential relationships with cachexia, we performed simple bivariate linear regressions for TPI at diagnosis. We found preliminary associations with sex (p<0.001) and creatinine (p=0.062). When adjusting the model for the confounding effects of race, resection status, and perioperative status, sex (p<0.001) and age (p=0.02) were significantly associated. Importantly, creatinine was not significantly associated (p=0.16). Regardless, an adjusted logistic regression using sex-dependent cachexia cutoffs revealed a clinically relevant odds ratio of 0.9 (95% CI [0.72, 1.09]). This indicates a 10% reduction in the odds of cachexia with every 0.1 mg/dL increase in creatinine, all else held constant. Stratifying with sex-dependent cutoffs for both TPI and creatinine revealed significant differences in 5-year OS (p=0.1) between all four groups. Conclusions: Observing survival trends for patients receiving perioperative care is notable as there are currently no clear guidelines for perioperative chemotherapy despite growing evidence for its efficacy. Further, while sex and age are known predictors of cachexia, creatinine is much less studied. Our associations between creatinine and TPI agree with observations in lung cancer, supporting its use as a clinically relevant marker. Ongoing work is exploring longitudinal measures of cachexia and correlating the CAMPP dataset with tumor genomics to reveal individualized factors impacting patient outcomes. Citation Format: Julie A Disharoon, Arash Velayati, Chloe Matila, Andrew Disharoon, Joseph A Karam, John Redhead, Rachel Burge, Elizabeth G Hill, David T Long, Toros A Dincman. Predictors of survival and cachexia in pancreatic cancer: results from the CAMPP study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B011.

Abstract A022: Neoadjuvant ablative radiation downstages high-risk features and alters immune response in pancreatic cancer

Abstract Purpose: Increasing evidence shows neoadjuvant (NA) therapy benefits surgical selection and survival in localized pancreatic cancer. However, the optimal NA therapy for resectable, borderline resectable (BRPC), and locally advanced pancreatic cancer (LAPC) remains unclear. We hypothesize that NA stereotactic ablative radiotherapy (SAbR) benefits patients with BRPC and LAPC who do not progress on chemotherapy (CTH), especially with arterial involvement. To evaluate this, we retrospectively reviewed outcomes and molecular features of patients treated with NA CTH and NA CTH followed by SAbR to understand the contribution of radiation. Methods: We retrospectively reviewed clinical data for 133 patients treated with NA CTH and 48 with NA CTH + SAbR. Bulk RNA sequencing was performed on fresh surgical tissue from 29 CTH-treated and 14 CTH + SABR-treated patients. We conducted gene set enrichment analysis (GSEA), CIBERSORTx cellular deconvolution, and Single-Cell Identification of Subpopulations with Bulk Sample Phenotype Correlation (Scissor) analysis to correlate clinical outcomes with transcriptomic features. Results: Molecular subtyping of PDAC transcriptomic signatures from post-treatment tissues revealed similar subtype proportions after both treatments. However, at baseline and before surgery, patients receiving SABR had more advanced clinical T staging, NCCN resectability, and arterial involvement. Despite this, the NA CTH + SAbR cohort showed similar overall survival, local-regional progression-free survival (LRPFS), and distant metastasis progression-free survival (DPFS) compared to NA CTH only. NA CTH + SABR-treated patients had significantly improved post-treatment T and N staging, tumor size, and treatment effect. These improvements correlated with better survival, LRPFS, and DPFS. RNAseq analysis indicated that patients with nodal involvement had significantly increased GSEA of MYC targets and worse DPFS. Tumor-arterial involvement at diagnosis significantly reduced local-regional control for NA CTH only. In contrast, patients with arterial involvement receiving NA CTH + SAbR had significantly improved local control. CIBERSORTx cell fraction deconvolution revealed no significant differences in tumor and immune cell subsets between treatments, but GSEA indicated substantial changes in immune-related gene sets, particularly those related to myeloid and T cell activation, suggesting functional changes correlating with treatment response and local control. Scissor identified gene signatures from activated CD8 T cells correlating with improved local control, while signatures from Treg and naïve T cells negatively impacted LRPFS. Conclusions: Molecular analysis and clinical features showed that patients treated with NA CTH + SAbR experienced downstaging and had similar outcomes, with indications of a differential immune response. Given these findings, the role of SAbR in the NA setting should be further evaluated, especially in the context of improved chemotherapy and novel combination therapies that leverage biological responses. Citation Format: Peter Q. Leung, Eslam A. Elghonaimy, Ahmed M. Elamir, Megan Wachsmann, Song Zhang, Neha Barrows, Rachel von Ebers, Cassandra Hamilton, Grace Josephson, Salwan Al Mutar, Patricio M. Polanco, Nina N. Sanford, Syed M. Ali Kazmi, Matthew R. Porembka, David Hsieh, Adam C. Yopp, Muhammad S. Beg, Herbert J. Zeh, Todd A. Aguilera. Neoadjuvant ablative radiation downstages high-risk features and alters immune response in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A022.

SUMO3 inhibition by butyric acid suppresses cell viability and glycolysis and promotes gemcitabine antitumor activity in pancreatic cancer

BackgroundExcavation of key molecules can help identify therapeutic targets and improve the prognosis of pancreatic cancer. This study evaluated the roles of SUMO3 in cell viability, glycolysis, gemcitabine (GEM) sensitivity, and the antitumor activity of butyric acid (BA) in pancreatic cancer.MethodsThe mRNA and protein levels of SUMO3 were detected by qRT-PCR, Western blot, and immunohistochemical assay. SUMO3 was silenced or overexpressed in pancreatic cancer cells with or without Wnt/β-catenin pathway inhibitor, glycolysis inhibitor, GEM, or BA treatment. Cell viability was measured using the Cell Counting Kit-8 assay. Glycolysis was measured by determining the extracellular acidification rate, ATP level, and lactate content. Apoptosis was measured by flow cytometry, and TUNEL staining was used to examine in vitro and in vivo sensitivity to GEM chemotherapy. Luciferase reporter and chromatin immunoprecipitation assays were conducted to detect the binding of the SUMO3 promoter and NF-κB p65.ResultsSUMO3 was increased and associated with poor survival in pancreatic cancer. SUMO3 knockdown decreased cell viability and glycolysis in vitro and inhibited tumor growth in vivo. SUMO3 overexpression increased cell viability and glycolysis in vitro through the β-catenin pathway. SUMO3 knockdown increased GEM sensitivity, whereas SUMO3 overexpression decreased GEM sensitivity and inhibited the antitumor activity of BA. BA promoted histone acetylation and p-IκBα expression to inhibit NF-κB p65-mediated SUMO3 transcription.ConclusionSUMO3 acted as an active molecule in cell survival and growth by enhancing glycolysis in response to either GEM or BA. The mechanism was related to the constitutive IκBα/NF-κB/SUMO3/β-catenin signaling pathway.

Selective and effective suppression of pancreatic cancer through MNK inhibition

Objective The study aimed to explore the role of the Wnt/β-catenin signaling pathway in pancreatic cancer progression and chemoresistance, with a focus on identifying specific factors that distinguish between normal and tumor cells, thereby offering potential therapeutic targets. Materials and Methods We analyzed levels of total and phosphorylated eukaryotic translation initiation factor 4E (eIF4E) and β-catenin in pancreatic cancer and normal pancreatic tissues. Functional assays were used to assess the impact of eIF4E phosphorylation on β-catenin signaling, cell proliferation, and chemoresistance, with MNK kinase involvement determined through gene depletion studies. The MNK kinase inhibitor eFT508 was evaluated for its effects on eIF4E phosphorylation, β-catenin activation, and cell viability in both in vitro and in vivo models of pancreatic cancer. Results Both total and phosphorylated eIF4E, along with β-catenin, were significantly elevated in pancreatic cancer tissues compared to normal tissues. Phosphorylation of eIF4E at serine 209 was shown to activate β-catenin signaling, enhance cell proliferation, and contribute to chemoresistance in pancreatic cancer. Importantly, these effects were dependent on MNK kinase activity. Depletion of eIF4E reduced cell viability in both pancreatic cancer and normal cells, while depletion of MNK selectively decreased viability in pancreatic cancer cells. Treatment with eFT508 effectively inhibited eIF4E phosphorylation, suppressed β-catenin activation, and reduced pancreatic cancer cell growth and survival in vitro and in vivo, with minimal impact on normal cells. Conclusions: The MNK-eIF4E-β-catenin axis plays a critical role in pancreatic cancer progression and chemoresistance, distinguishing pancreatic cancer cells from normal cells. Targeting MNK kinases with inhibitors like eFT508 presents a promising therapeutic strategy for pancreatic cancer, with potential for selective efficacy and reduced toxicity.

Extranodal extension influences prognosis in pancreatic body/tail cancer: A retrospective cohort study.

Extranodal extension (ENE) is an established prognostic factor in various malignancies, affecting survival in pancreatic head cancer (PHC). However, its significance in pancreatic body/tail cancer (PBTC) remains unclear. Therefore, we aimed to investigate the impact of ENE on PTBC prognosis. We analyzed data collected from electronic medical records of patients with PBTC who underwent distal pancreatectomy at a single center between January 2011 and December 2015. The patients were categorized based on ENE presence and prognostic implications were evaluated using Kaplan-Meier survival curves and Cox proportional hazards model. PBTC cases involving lymph node (LN) metastasis and ENE exhibited significantly lower disease-free (DFS) and overall survival (OS) rates compared to cases without LN metastasis or ENE (median DFS; N0, 23 months; LN+/ENE-, 10 months; LN+/ENE+, 5 months; p < .001). No statistically significant difference was observed in DFS and OS rates between patients with N1/N2 in the group without ENE and those with ENE+. Multivariate analysis confirmed ENE as a significant adverse prognostic factor. ENE significantly predicts poor prognosis in PBTC, particularly in cases with nodal metastasis. The current cancer staging system for PBTC should incorporate ENE status. Moreover, different staging systems should be considered for PHC and PBTC.

Analysis of pancreatic cancer treatment and survival disparities in Florida throughout the Covid-19 pandemic

IntroductionPancreatic ductal adenocarcinoma (PDAC) is currently the third-leading cause of cancer-related death in the United States. African Americans (AAs) with PDAC have worse survival in comparison to other racial groups. The COVID-19 pandemic caused significant stress to the healthcare system. We aim to evaluate the pandemic's impact on already known disparities in newly diagnosed patients with PDAC in Florida. MethodsThis is a retrospective analysis of newly diagnosed patients with PDAC in the OneFlorida+ Data Trust based upon date of diagnosis: Pre-pandemic (01/01/2017- 09/30/2019), Transition (10/01/2019-02/28/2020), and Pandemic (03/1/2020-10/31/2020). Primary endpoints are time to treatment initiation and rate of surgery and secondary endpoint is survival time. Disparities due to age, sex, race, and income were also evaluated. Chi-squared or Fisher's exact test when necessary, Kruskal-Wallis test, and Kaplan-Meier analysis with log-rank test were performed to compare the differences between the comparative groups for categorical, quantitative, and survival outcomes, respectively. Multivariable regression analyses were conducted to estimate the effects of cofactors. Results934 patients with a median age of 67 years were included. There were 47.8% females and 52.2% males; 19.4% AA, 70.2% Caucasian, 10.4% Other race; median income was $53,551. While we observed a significant reduction in the diagnosis rate of new PDAC cases during the pandemic, there were no significant differences in demographic distributions among the three cohorts. Time to treatment did not significantly change from the pre-pandemic to the pandemic, and no difference was observed across all demographics. Rate of surgery increased significantly from the pre-pandemic (35.8%) to the pandemic (55.6%). AAs in the pre-pandemic cohort had a significantly lower rate of surgery of 25.0% compared to 41.7% in Caucasians. AAs, patients ≥ 67 years, and income < $53,000 had significantly higher hazards to death and shorter median survival time (mST). ConclusionsWhile no differences in time to initial treatment are observed among the newly diagnosed PDAC patients, there remain significant disparities in the rate of surgery and overall survival. Observing a significant reduction in diagnosis rate and analyzing disparities can provide insight into the effect of a resource-restricting pandemic for patients with newly diagnosed PDAC.

Probabilistic modelling of pancreatic cancer survival: can Markov chains predict survival in stage IV pancreatic cancer?

Probabilistic modelling of pancreatic cancer survival: can Markov chains predict survival in stage IV pancreatic cancer?

A Case of Five-Year Survival in Metastatic Pancreatic Cancer

Pancreatic cancer is often diagnosed at advanced stage, where chemotherapy is the mainstay of treatment. Despite new chemotherapy regimens improving overall survival over the past decade, the median survival for advanced pancreatic cancer remains around one year. However, we occasionally encounter long-term survivors among patients with advanced pancreatic cancer. Analyzing these cases may provide valuable insights for understanding pancreatic cancer and improving treatment strategies. We report a case of 61-year-old patient with metastatic pancreatic cancer who survived for approximately five years. Single-cell transcriptome analysis of tissues obtained at the time of pancreatic cancer diagnosis and at 57 months post-diagnosis revealed changes in the tumor immune microenvironment.

In Silico Identification of Dysregulated miRNAs Targeting KRAS Gene in Pancreatic Cancer.

Pancreatic cancer (PC) is highly lethal, with KRAS mutations in up to 95% of cases. miRNAs inversely correlate with KRAS expression, indicating potential as biomarkers. This study identified miRNAs targeting KRAS and their impact on PC characteristics using in silico methods. dbDEMC identified dysregulated miRNAs in PC; TargetScan, miRDB, and PolymiRTS 3.0 identified miRNAs specific for the KRAS gene; and OncomiR evaluated the association of miRNAs with clinical characteristics and survival in PC. The correlation between miRNAs and KRAS was analysed using ENCORI/starBase. A total of 210 deregulated miRNAs were identified in PC (116 overexpressed and 94 underexpressed). In total, 16 of them were involved in the regulation of KRAS expression and 9 of these (hsa-miR-222-3p, hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30e-5p, hsa-miR-377-3p, hsa-miR-495-3p, hsa-miR-654-3p, hsa-miR-877-5p and hsa-miR-885-5p) were associated with the clinical characteristics of the PC. Specifically, the overexpression of hsa-miR-30a-5p was associated with PC mortality, and hsa-miR-30b-5p, hsa-miR-377-3p, hsa-miR-495-3p, and hsa-miR-885-5p were associated with survival. Correlation analysis revealed that the expression of 10 miRNAs is correlated with KRAS expression. The dysregulated miRNAs identified in PC may regulate KRAS and some are associated with clinically relevant features, highlighting their potential as biomarkers and therapeutic targets in PC treatment. However, experimental validation is required for confirmation.

Pancreatic Cancer Surveillance and Survival of High-Risk Individuals

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with increasing incidence. The majority of PDACs are incurable at presentation, but population-based screening is not recommended. Surveillance of high-risk individuals for PDAC may lead to early detection, but the survival benefit is unproven. To compare the survival of patients with surveillance-detected PDAC with US national data. This comparative cohort study was conducted in multiple US academic medical centers participating in the Cancer of the Pancreas Screening program, which screens high-risk individuals with a familial or genetic predisposition for PDAC. The comparison cohort comprised patients with PDAC matched for age, sex, and year of diagnosis from the Surveillance, Epidemiology, and End Results (SEER) program. The Cancer of the Pancreas Screening program originated in 1998, and data collection was done through 2021. The data analysis was performed from April 29, 2022, through April 10, 2023. Endoscopic ultrasonography or magnetic resonance imaging performed annually and standard-of-care surgical and/or oncologic treatment. Stage of PDAC at diagnosis, overall survival (OS), and PDAC mortality were compared using descriptive statistics and conditional logistic regression, Cox proportional hazards regression, and competing risk regression models. Sensitivity analyses and adjustment for lead-time bias were also conducted. A total of 26 high-risk individuals (mean [SD] age at diagnosis, 65.8 [9.5] years; 15 female [57.7%]) with PDAC were compared with 1504 SEER control patients with PDAC (mean [SD] age at diagnosis, 66.8 [7.9] years; 771 female [51.3%]). The median primary tumor diameter of the 26 high-risk individuals was smaller than in the control patients (2.5 [range, 0.6-5.0] vs 3.6 [range, 0.2-8.0] cm, respectively; P < .001). The high-risk individuals were more likely to be diagnosed with a lower stage (stage I, 10 [38.5%]; stage II, 8 [30.8%]) than matched control patients (stage I, 155 [10.3%]; stage II, 377 [25.1%]; P < .001). The PDAC mortality rate at 5 years was lower for high-risk individuals than control patients (43% vs 86%; hazard ratio, 3.58; 95% CI, 2.01-6.39; P < .001), and high-risk individuals lived longer than matched control patients (median OS, 61.7 [range, 1.9-147.3] vs 8.0 [range, 1.0-131.0] months; 5-year OS rate, 50% [95% CI, 32%-80%] vs 9% [95% CI, 7%-11%]). These findings suggest that surveillance of high-risk individuals may lead to detection of smaller, lower-stage PDACs and improved survival.

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.

Adjuvant Chemotherapy With or Without Radiotherapy for Resected Pancreatic Cancer After Multiagent Neoadjuvant Chemotherapy.

Adjuvant therapy is associated with improved pancreatic cancer survival after neoadjuvant chemotherapy and surgery. However, whether adjuvant treatment should include radiotherapy is unclear in this setting. This study queried the National Cancer Database for pancreatic adenocarcinoma patients who underwent curative resection after multiagent neoadjuvant chemotherapy between 2010 and 2019 and received adjuvant treatment. Adjuvant chemotherapy plus radiotherapy (external beam, 45-50.4 gray) was compared with adjuvant chemotherapy alone. Uni- and multivariable Cox regression was used to assess survival associations. Analyses were repeated in a propensity score-matched subgroup. Of 1983 patients who received adjuvant treatment after multiagent neoadjuvant chemotherapy and resection, 1502 (75.7%) received adjuvant chemotherapy alone and 481 (24.3%) received concomitant adjuvant radiotherapy (chemoradiotherapy). The patients treated with adjuvant chemoradiotherapy were younger, were treated at non-academic facilities more often, and had higher rates of lymph node metastasis (ypN1-2), positive resection margins (R1), and lymphovascular invasion (LVI+). The median survival was shorter for the chemoradiotherapy-treated patients according to the unadjusted analysis (26.8 vs 33.2 months; p = 0.0017). After adjustment for confounders, chemoradiotherapy was associated with better outcomes in the multivariable model (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.61-0.93; p = 0.008). The association between chemoradiotherapy and improved outcomes was stronger for the patients with grade III tumors (HR, 0.53; 95% CI, 0.37-0.74) or LVI+ tumors (HR, 0.58; 95% CI, 0.44-0.75). In a subgroup of 396 propensity-matched patients, chemoradiotherapy was associated with a survival benefit only for the patients with LVI+ or grade III tumors. After multiagent neoadjuvant chemotherapy and resection for pancreatic cancer, additional adjuvant chemoradiotherapy versus adjuvant chemotherapy alone is associated with improved survival for patients with LVI+ or grade III tumors.

The Effect of Intratumor Heterogeneity in Pancreatic Ductal Adenocarcinoma Progression and Treatment.

Pancreatic cancer is one of the most lethal malignancies. Even though many substantial improvements in the survival rates for other major cancer forms were made, pancreatic cancer survival rates have remained relatively unchanged since the 1960s. Even more, no standard classification system for pancreatic cancer is based on cellular biomarkers. This review will discuss and provide updates about the role of stem cells in the progression of PC, the genetic changes associated with it, and the promising biomarkers for diagnosis. The search process used PubMed, Cochrane Library, and Scopus databases to identify the relevant and related articles. Articles had to be published in English to be considered. The increasing number of studies in recent years has revealed that the diversity of cancer-associated fibroblasts is far greater than previously acknowledged, which highlights the need for further research to better understand the various cancer-associated fibroblast subpopulations. Despite the huge diversity in pancreatic cancer, some common features can be noted to be shared among patients. Mutations involving CDKN2, P53, and K-RAS can be seen in a big number of patients, for example. Similarly, some patterns of genes and biomarkers expression and the level of their expression can help in predicting cancer behavior such as metastasis and drug resistance. The current trend in cancer research, especially with the advancement in technology, is to sequence everything in hopes of finding disease-related mutations. Optimizing pancreatic cancer treatment requires clear classification, understanding CAF roles, and exploring stroma reshaping approaches.