Survival In Pancreatic Ductal Adenocarcinoma Research Articles

Lymph node examination and survival in resected pancreatic ductal adenocarcinoma: retrospective study.

The minimum number of examined lymph nodes (ELN) required for adequate staging and best prediction of survival has not been established in pancreatic ductal adenocarcinoma (PDAC). The aim of the study was to investigate the influence of ELN on staging and survival in PDAC. Patients undergoing partial or total pancreatectomy for PDAC at two European university hospitals between 2007 and 2018 were retrospectively reviewed. Multivariate Cox regression model and survival analyses were performed to verify adequate staging. Overall 341 (73 per cent) patients showed lymph node metastasis (N1/N2), whereas 125 (27 per cent) patients had no lymph node involvement (N0). With increasing number of ELN, the proportion of positive lymph nodes increased. The minimum number of ELN needed to detect lymph node involvement was 21. In multivariate analysis, examination of <21 lymph nodes was a significant negative predictor for survival. Examination of ≥21 ELN reversed this effect and ruled out possible misclassification. The number of ELN affects survival in PDAC. Possible misclassification was identified when <21 lymph nodes were examined. Therefore, at least 21 lymph nodes must be examined to avoid false lymph node classification in all types of resection.

Association of textbook outcomes with improved survival in pancreatic ductal adenocarcinoma following pancreaticoduodenectomy: a retrospective study.

Assessing the perioperative outcomes of pancreaticoduodenectomy (PD) based solely on individual complications is not comprehensive, and the association between perioperative outcomes and the long-term prognosis of individuals diagnosed with pancreatic ductal adenocarcinoma (PDAC) remains uncertain. Our study is designed to evaluate the impact of a novel composite indicator, textbook outcomes (TO), on the long-term prognosis of patients undergoing PD for PDAC. This study conducted a retrospective analysis of 139 patients who underwent PD for pathologically confirmed PDAC at our hospital between January 2018 and December 2021. After applying exclusion criteria, a total of 111 patients were included in the subsequent analysis. These patients were categorized into two groups: the non-TO group (n=42) and the TO group (n=69). The Kaplan-Meier survival curve was employed to describe the relationship between TO and disease-free survival (DFS) and overall survival (OS). Cox regression was employed to assess the impact of achieving TO on long-term survival. Logistic regression was employed to investigate the risk factors affecting the achievement of TO. Out of the 111 PDAC patients, 69 (62.2%) achieved TO following PD. The achievement of TO significantly improved the OS of PDAC patients [P=0.03; hazard ratio (HR) =0.60; 95% confidence interval (CI): 0.37-0.83]. Cox regression analysis indicated that achieving TO was a protective factor for OS (P=0.04; HR =4.08; 95% CI: 1.07-15.61). Logistic regression analysis indicated that high amylase in drainage fluid on the third day after surgery (>1,300 U/L) was detrimental to achieve TO [odds ratio (OR) =0.10; 95% CI: 0.02-0.58; P=0.01], longer surgery durations (≥6.25 hours) was detrimental to achieve TO (OR =0.19; 95% CI: 0.06-0.54; P=0.002), and soft pancreatic texture was detrimental to achieve TO (OR =0.31; 95% CI: 0.10-0.93, P=0.04). Achievement of TO significantly improves the OS of PDAC patients and has the potential to serve as a robust prognostic indicator. Looking ahead, it is highly necessary for TO to become a standard surgical quality control measure in hospitals.

The concomitant use of the renin-angiotensin system inhibitors and survival outcomes of patients with pancreatic adenocarcinoma: an analysis from a tertiary center.

The limited efficacy of chemotherapy in improving survival in pancreatic ductal adenocarcinoma (PDAC) necessitates the exploration of novel strategies to overcome treatment resistance. This study aimed to investigate the impact of combining renin-angiotensin system (RAS) blockers with chemotherapy on survival outcomes in patients with PDAC. Patients with PDAC were enrolled in the retrospective study. We analyzed patients with PDAC (n = 384) at our institution between 2014 and 2021. Survival outcomes, including event-free survival (EFS) and overall survival (OS), were analyzed according to the concomitant use of RAS blockers. Among the 384 patients in the study, 70 (18.2%) concomitantly received angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Patients in the ACEI/ARB group, characterized by older age and more comorbidities, displayed a significantly superior 12-month EFS rate (22.86% versus 13.69%, p = 0.008) compared to the non-ACEI/ARB group, while OS remained similar between the groups. In the multivariate analysis, the use of ACEI/ARB was associated with better 12-month EFS (hazards ratio = 0.71, 95% confidence interval: 0.52-0.96; p = 0.024). Poor performance, advanced disease status, and higher CA19-9 levels were associated with poor survival outcomes. Concomitant use of ACEIs/ARBs in patients with pancreatic cancer resulted in significantly better 12-month EFS. Age, performance status, disease status, and higher CA19-9 levels were independent predictors of survival. The combination strategy might provide better treatment outcomes in patients with PDAC.

IQ Motif Containing GTPase-Activating Protein 3 Is Associated with Cancer Stemness and Survival in Pancreatic Ductal Adenocarcinoma

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of malignancy, with poor prognosis and rising incidence. IQ motif containing GTPase-activating protein 3 (IQGAP3) is a member of the IQGAPs family of scaffolding proteins that govern multiple cellular activities like cytoskeletal remodeling and cellular signal transduction. This study aimed to analyze the expression and biological function of IQGAP3 in PDAC. Methods: We analyzed IQGAP3 expression in 81 PDAC samples by immunohistochemistry. RNA interference was used to inhibit IQGAP3 expression in PDAC cell lines. Results: Immunohistochemical analysis of IQGAP3 showed that 54.3% of PDACs were positive for cytoplasmic expression of IQGAP3, with no expression found in non-neoplastic tissue. Furthermore, IQGAP3 expression was an independent poor prognostic factor in our immunostaining-based studies and analyses of public databases. Our cohort and the Cancer Genome Atlas database indicated that IQGAP3 is co-localized with kinesin family member C1 (KIFC1), which we previously reported as a cancer stem cell-associated protein. IQGAP3 small interfering RNA treatment decreased PDAC cell proliferation and spheroid colony formation via ERK and AKT pathways. Discussion/Conclusion: These results suggest that IQGAP3, a transmembrane protein, is involved in survival and stemness and may be a promising new therapeutic target for PDAC.

Recent Advances and Future Challenges in Pancreatic Cancer Care: Early Detection, Liquid Biopsies, Precision Medicine and Artificial Intelligence

The incidence of pancreatic ductal adenocarcinoma (PDAC) is rising. While surgical techniques and peri-operative care have improved, the overall survival for PDAC remains poor. Thus, novel and bold research initiatives are needed along the spectrum of clinical care, a few of which will be discussed in this article. Early detection is crucial, with specific high-risk groups possibly benefiting from targeted screening programs. Liquid biopsies (such as circulating exosomes, tumor DNA, or tumor cells) offer promise as multifunctional biomarkers for early detection, treatment guidance, and recurrence monitoring. Precision medicine is being explored via targeted therapies for actionable mutations, such as PARP inhibitors for BRCA mutations, and immunotherapy strategies. Artificial intelligence (AI) is emerging as a powerful tool in medical imaging, biomarker discovery, genetics research, and treatment planning, and it can aid in diagnosis, treatment selection, and patient monitoring. However, its associated challenges include ethics, data security, algorithm reliability, and validation. Collaborative efforts between medical professionals, researchers, and AI experts are vital for unlocking AI’s potential to enhance pancreatic cancer care. In conclusion, despite the challenges, advancements in liquid biopsies, precision medicine, and AI offer hope for enhancing the diagnosis, treatment, and management of pancreatic cancer.

The combination of the low immunohistochemical expression of peroxiredoxin 4 and perilipin 2 predicts longer survival in pancreatic ductal adenocarcinoma with peroxiredoxin 4 possibly playing a main role.

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor prognosis. Therefore, indicators that can be used for the early prediction of the prognosis of PDAC are needed. Peroxiredoxin (PRDX) 4 is a secretion-type antioxidant enzyme located in the cytoplasmic endoplasmic reticulum. Recent studies have reported that it is closely related to the development and prognosis of many types of cancer. Perilipin (PLIN) 2 is a lipid droplet coating protein. The high expression of PLIN2 is known to be an indicator of some types of cancer and oxidative stress management. It is highly suggestive of the interplay between PRDX4 and PLIN2 to some degree. In this study, we collected 101 patients' clinical data and paraffin-embedded specimens with PDAC and analyzed them with immunohistochemical staining of PRDX4 and PLIN2. We found that the low expression of PRDX4 predicts longer survival and a better clinical condition in PDAC patients. Moreover, when the low expression of PRDX4 is combined with the low expression of PLIN2, the 3-year survival is significantly improved. Univariate and multivariate Cox proportional hazard analyses showed that the PRDX4 expression in PDAC was an independent prognostic factor for survival. Taken together, between PRDX4 and PLIN2, PRDX4 plays a main role in prognosis and has the potential to become a clinical prognostic indicator of PDAC.

Overexpression of the adhesion signaling pathway is linked to short-term survival in pancreatic ductal adenocarcinoma

Background and objectivePancreatic ductal adenocarcinoma (PDAC) is known for its unfavorable prognosis. Gaining insights into the molecular mechanisms that contribute to its progression is crucial for developing effective therapies. In this study, our objective was to investigate the molecular pathways associated with short-term survival in patients with PDAC. MethodsImmune profiles were analyzed from both long-term survivors (n = 10) and short-term survivors (n = 10) after surgical resection. Pathway scores were calculated to compare the two groups. ResultsThe “Adhesion” pathway emerged as the most significant pathway, exhibiting a notably higher score in the samples of short-term survivors (P < 0.009). Within this pathway, significant findings were observed in genes related to integrins and CEACAM. ConclusionThe role of integrins in the tumor microenvironment of pancreatic cancer is of utmost importance, as they are found to be overexpressed in short-term survivors. These findings provide valuable insights into the underlying biology of PDAC and have potential implications for the development of therapeutic strategies.

Immunofluorescence profiling of collagen subtypes is a predictor of treatment outcomes in pancreatic cancer

Desmoplasia in pancreatic ductal adenocarcinoma (PDAC) is characterized by elevated levels of tumor collagen. Desmoplasia restricts drug delivery in PDAC, contributes to treatment resistance, and is associated with poor survival outcomes. We have previously shown that photodynamic therapy (PDT)-based treatment remediates desmoplasia in orthotopic PDAC tumors by reducing second harmonic generation signals from collagen by >90% and by reducing collagen alignment by >103-fold [19]. Remediating desmoplasia correlated with improved survival outcomes in mice. To understand this phenomenon at a fundamental level, it is important to dissect the impact of therapy on collagen subtypes. In this study, we demonstrate that immunofluorescence profiling of collagen subtypes I, II, III and IV in PDAC tumors 72 h following multiple treatment regimens is predictive of long-term outcomes. Treatment regimens include nanoliposomal irinotecan chemotherapy (nal-IRI; akin to ONIVYDE™), a combination of nal-IRI chemotherapy with PDT encapsulated in a single photoactivable multi-inhibitor liposome (PMIL) and an EGFR-targeted PMIL construct (TPMIL). Results show that the relative tumor content of collagen I, II and III was inversely correlated with overall survival (P ≤ 0.0013, P ≤ 0.0001, P ≤ 0.0011, respectively), while, surprisingly, the relative tumor content of collagen IV was directly correlated with overall survival (P ≤ 0.0001). Similar relationships were observed between the relative tumor content of collagen subtypes and the residual tumor volume at day 88 following treatment. Considering that the relationship between collagen subtypes and treatment outcomes is observed across multiple treatment regimens, immunofluorescence profiling at 72 h following treatment appears to be predictive of tumor growth inhibition and survival in PDAC. Early immunofluorescence collagen subtype profiling may therefore aid in treatment personalization and may inform the dosimetry and scheduling of combination regimens for PDAC, such as chemotherapy and emerging PDT-based combinations, to maximize patient survival benefit.

The possible dual role of Ang-2 in the prognosis of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) features a dense desmoplastic stroma, which raises the intratumoral interstitial pressure leading to vascular collapse and hypoxia, inducing angiogenesis. Vascular growth factors, such as vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2), increase in PDAC. A high VEGF and a high circulating Ang-2 associate with shorter survival in PDAC. In addition to the circulatory Ang-2, PDAC endothelial and epithelial cells express Ang-2. No correlation between tumor epithelial nor endothelial cell Ang-2 expression and survival has been published. We aimed to examine Ang-2 expression and survival. This study comprised PDAC surgical patients at Helsinki University Hospital in 2000–2013. Ang-2 immunohistochemistry staining was completed on 168 PDAC patient samples. Circulating Ang-2 levels were measured using ELISA in the sera of 196 patients. Ang-2 levels were assessed against clinical data and patient outcomes. A low tumor epithelial Ang-2 expression predicted shorter disease-specific survival (DSS) compared with a high expression (p = 0.003). A high serum Ang-2 associated with shorter DSS compared with a low circulating Ang-2 (p = 0.016). Ang-2 seemingly plays a dual role in PDAC survival. Further studies are needed to determine the mechanisms causing tumor cell Ang-2 expression and its positive association with survival.

Association of Long-Term, New-Onset, and Postsurgical Diabetes With Survival in Patients With Resectable Pancreatic Cancer: A Retrospective Cohort Study.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Identifying modifiable risk factors, such as diabetes, is crucial. In the context of PDAC diagnosis, diabetes manifests as long-term (LTD), new-onset (NOD), or postsurgical (PSD) phenotypes. The link between these diabetes phenotypes and PDAC survival is debated. We performed a retrospective study on patients with resectable PDAC who underwent pancreatectomy at Johns Hopkins Hospital from 2003 to 2017. We utilized the National Death Index and electronic medical records to determine vital status. We categorized diabetes as LTD, NOD, or PSD based on the timing of diagnosis relative to pancreatic resection. Using multivariable Cox models, we assessed hazard ratios (HRs) for survival times associated with each phenotype, considering known PDAC prognostic factors. Of 1556 patients, the 5-year survival was 19% (95% CI, 17-21). No significant survival differences were observed between diabetes phenotypes and non-diabetic patients. NOD and PSD presented nonsignificant increased risks of death (aHR: 1.14 [95% CI, 0.8-1.19] and 1.05 [95% CI, 0.89-1.25], respectively). LTD showed no survival difference (aHR, 0.98; 95% CI, 0.99-1.31). No link was found between diabetes phenotypes and survival in resectable PDAC patients. Comprehensive prospective studies are required to validate these results.

Circulating miRNAs as Noninvasive Biomarkers for PDAC Diagnosis and Prognosis in Mexico.

Among malignant neoplasms, pancreatic ductal adenocarcinoma (PDAC) has one of the highest fatality rates due to its late detection. Therefore, it is essential to discover a noninvasive, early, specific, and sensitive diagnostic method. MicroRNAs (miRNAs) are attractive biomarkers because they are accessible, highly specific, and sensitive. It is crucial to find miRNAs that could be used as possible biomarkers because PDAC is the eighth most common cause of cancer death in Mexico. With the help of microRNA microarrays, differentially expressed miRNAs (DEmiRNAs) were found in PDAC tissues. The presence of these DEmiRNAs in the plasma of Mexican patients with PDAC was determined using RT-qPCR. Receiver operating characteristic curve analysis was performed to determine the diagnostic capacity of these DEmiRNAs. Gene Expression Omnibus datasets (GEO) were employed to verify our results. The Prisma V8 statistical analysis program was used. Four DEmiRNAs in plasma from PDAC patients and microarray tissues were found. Serum samples from patients with PDAC were used to validate their overexpression in GEO databases. We discovered a new panel of the two miRNAs miR-222-3p and miR-221-3p that could be used to diagnose PDAC, and when miR-221-3p and miR-222-3p were overexpressed, survival rates decreased. Therefore, miR-222-3p and miR-221-3p might be employed as noninvasive indicators for the diagnosis and survival of PDAC in Mexican patients.

Clinical-radiomics nomogram using contrast-enhanced CT to predict histological grade and survival in pancreatic ductal adenocarcinoma.

Tumor grading is important for prognosis of pancreatic ductal adenocarcinoma (PDAC). In this study, we developed preoperative clinical-radiomics nomograms using features from contrast-enhanced CT (CECT), to discriminate high-grade and low-grade PDAC and predict overall survival (OS). In this single-center, retrospective study conducted from February 2014 to April 2021, consecutive PDAC patients who underwent CECT and had pathologically identified grading were randomized to training (n=200) and test (n=84) cohorts for development of model to predict histological grade based on radiomics scores from CECT (HGrad). Another 42 patients were used as external validation cohort of HGrad. A nomogram (HGnom) was constructed using radiomics score, CA12-5 and smoking to predict histological grade. A second nomogram (Pnom) was constructed using radiomics score, CA12-5, TNM, adjuvant treatment, resection margin and microvascular invasion to predict OS in radical resection patients (217 of 284). Among 326 patients, 122 were high-grade (120 poorly differentiated and 2 undifferentiated). The HGrad yielded AUCs of 0.75 (95% CI: 0.64, 0.85) and 0.76 (95% CI: 0.60, 0.91) in test and validation cohorts. The HGnom achieved AUCs of 0.77 (95% CI: 0.66, 0.87), and the predicted grades calibrated well with actual grades (P=.13). OS was different between the grades predicted by radiomics scores (P=.01). The integrated AUC of the Pnom for predicting OS was 0.80 (95% CI: 0.75, 0.88). Compared with the HGrad using features from CECT, the HGnom demonstrated higher performance for predicting histological grade. The Pnom helped identify patients with high survival outcome in pancreatic ductal adenocarcinoma.

1023 The Changing Indication and Outcomes of Patients Undergoing Pancreatectomy for Malignancy

Abstract Aim Pancreatic surgery has evolved significantly in terms of indications and peri-operative management to improve long term outcomes for patients. The aim of this study is to assess the change in indication and long-term outcome for patients undergoing pancreatectomy for malignancy. Method Patients who underwent pancreatectomy at the West of Scotland Pancreatic Unit, Glasgow Royal Infirmary between 2000 – 2020 for malignancy were included. Clinicopathological variables, survival and recurrence data were collected from patient notes and electronic patient records. Results 594 patients were identified. The majority were for pancreatic ductal adenocarcinoma (PDAC) n = 325 (54.7%). There was a significant increase in overall survival for all indications (28.6 months vs 41.8 months, P = 0.001), completion of adjuvant therapy and the use of neoadjuvant therapy (P&amp;lt;0.001) over the first and second decades in the study period. After adopting a neoadjuvant strategy for PDAC in the unit from 2013, the overall median survival increased from 24.6 months to 34.5 months (P&amp;lt;0.001). The overall survival for PDACs was higher for those receiving neoadjuvant chemotherapy compared to upfront resection (41.9 months vs 38.9 months, P = 0.151). For patients with PDAC who received upfront surgery, median survival increased from 24.2 to 40.3 months (P = 0.004) once a neoadjuvant strategy was adopted. Conclusions There has been significant changes to the indications and long-term outcomes for patients undergoing pancreatectomy. A neoadjuvant strategy improved survival even in those patients who received upfront surgery.

Identifying radiomics signatures in body composition imaging for the prediction of outcome following pancreatic cancer resection.

Computerized radiological image analysis (radiomics) enables the investigation of image-derived phenotypes by extracting large numbers of quantitative features. We hypothesized that radiomics features may contain prognostic information that enhances conventional body composition analysis. We aimed to investigate whether body composition-associated radiomics features hold additional value over conventional body composition analysis and clinical patient characteristics used to predict survival of pancreatic ductal adenocarcinoma (PDAC) patients. Computed tomography images of 304 patients undergoing elective pancreatic cancer resection were analysed. 2D radiomics features were extracted from skeletal muscle and subcutaneous and visceral adipose tissue (SAT and VAT) compartments from a single slice at the third lumbar vertebra. The study population was randomly split (80:20) into training and holdout subsets. Feature ranking with Least Absolute Shrinkage Selection Operator (LASSO) followed by multivariable stepwise Cox regression in 1000 bootstrapped re-samples of the training data was performed and tested on the holdout data. The fitted regression predictors were used as "scores" for a clinical (C-Score), body composition (B-Score), and radiomics (R-Score) model. To stratify patients into the highest 25% and lowest 25% risk of mortality compared to the middle 50%, the Harrell Concordance Index was used. Based on LASSO and stepwise cox regression for overall survival, ASA ≥3 and age were the most important clinical variables and constituted the C-score, and VAT-index (VATI) was the most important body composition variable and constituted the B-score. Three radiomics features (SATI_original_shape2D_Perimeter, VATI_original_glszm_SmallAreaEmphasis, and VATI_original_firstorder_Maximum) emerged as the most frequent set of features and yielded an R-Score. Of the mean concordance indices of C-, B-, and R-scores, R-score performed best (0.61, 95% CI 0.56-0.65, p<0.001), followed by the C-score (0.59, 95% CI 0.55-0.63, p<0.001) and B-score (0.55, 95% CI 0.50-0.60, p=0.03). Kaplan-Meier projection revealed that C-, B, and R-scores showed a clear split in the survival curves in the training set, although none remained significant in the holdout set. It is feasible to implement a data-driven radiomics approach to body composition imaging. Radiomics features provided improved predictive performance compared to conventional body composition variables for the prediction of overall survival of PDAC patients undergoing primary resection.

Aberrant accumulation of Kras-dependent pervasive transcripts during tumor progression renders cancer cells dependent on PAF1 expression

KRAS is the most commonly mutated oncogene in human cancer, and mutant KRAS is responsible for over 90% of pancreatic ductal adenocarcinoma (PDAC), the most lethal cancer. Here, we show that RNA polymerase II-associated factor 1 complex (PAF1C) is specifically required for survival of PDAC but not normal adult pancreatic cells. We show that PAF1C maintains cancer cell genomic stability by restraining overaccumulation of enhancer RNAs (eRNAs) and promoter upstream transcripts (PROMPTs) driven by mutant Kras. Loss of PAF1C leads to cancer-specific lengthening and accumulation of pervasive transcripts on chromatin and concomitant aberrant R-loop formation and DNA damage, which, in turn, trigger cell death. We go on to demonstrate that the global transcriptional hyperactivation driven by Kras signaling during tumorigenesis underlies the specific demand for PAF1C by cancer cells. Our work provides insights into how enhancer transcription hyperactivation causes general transcription factor addiction during tumorigenesis.

A comprehensive analysis of tumor-stromal collagen in relation to pathological, molecular, and immune characteristics and patient survival in pancreatic ductal adenocarcinoma

BackgroundAbundant collagen deposition is a hallmark of pancreatic ductal adenocarcinomas (PDACs). This study clarified the interactive relationship between tumor-stromal collagen, molecular and immune characteristics, and tumor pr ogression in human PDAC.MethodsWe performed a comprehensive examination using an integrative molecular pathological epidemiology database on 169 cases with resected PDAC . The amount of tumor-stromal collagen was quantified through digital imaging analysis for Elastica van Gieson-stained whole-section tumor slides. We analyzed the association of tumor-stromal collagen with gene alterations (KRAS, TP53, CDKN2A/p16, and SMAD4), immune parameters (CD4+ tumor-infiltrating lymphocytes [TILs], CD8+ TILs, FOXP3+ TILs, and tertiary lymphoid structures), and patient prognosis.ResultsLow amounts of tumor-stromal collagen were associated with poor differentiation (multivariable OR = 3.82, 95%CI = 1.41–12.2, P = 0.008) and CDKN2A/p16 alteration (OR [95%CI] = 2.06 [1.08–4.02], P = 0.03). Tumors with low collagen levels had shorter overall survival (HR [95%CI] = 2.38 [1.59–3.56], P < 0.0001). In the S-1 and gemcitabine (GEM) treatment groups, low tumor-stromal collagen was linked to poor prognosis of patients with PDAC (S-1 group: multivariable HR [95%CI] = 2.76 [1.36–5.79], P = 0.005; GEM group: multivariate HR [95%CI] = 2.91 [1.34–6.71], P = 0.007). Additionally, low amounts of tumor-stromal collagen were also linked to low levels of CD4+ TILs (P = 0.046), CD8+ TILs (P = 0.09), and tertiary lymphoid structures (P = 0.001).ConclusionsTumor-stromal collagen deposition may play a crucial role in modulating tumor-immune microenvironment and determining response to adjuvant chemotherapy and patient survival outcomes.

Tomatidine targets ATF4-dependent signaling and induces ferroptosis to limit pancreatic cancer progression

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high metastasis and therapeutic resistance. Activating transcription factor 4 (ATF4), a master regulator of cellular stress, is exploited by cancer cells to survive. Prior research and data reported provide evidence that high ATF4 expression correlates with worse overall survival in PDAC. Tomatidine, a natural steroidal alkaloid, is associated with inhibition of ATF4 signaling in multiple diseases. Here, we discovered that invitro and invivo tomatidine treatment of PDAC cells inhibits tumor growth. Tomatidine inhibited nuclear translocation of ATF4 and reduced the transcriptional binding of ATF4 with downstream promoters. Tomatidine enhanced gemcitabine chemosensitivity in 3D ECM-hydrogels and invivo. Tomatidine treatment was associated with induction of ferroptosis signaling validated by increased lipid peroxidation, mitochondrial biogenesis, and decreased GPX4 expression in PDAC cells. This study highlights a possible therapeutic approach utilizing a plant-derived metabolite, tomatidine, to target ATF4 activity in PDAC.

C-reactive protein is a prognostic biomarker in pancreatic ductal adenocarcinoma patients.

The 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) is approximately 11% and has only improved marginally over the last three decades. For operable PDAC, resection and adjuvant FOLFIRINOX chemotherapy is standard of care. There is growing interest in perioperative regimens to improve outcomes. The non-randomized Phase II study "Gemcitabine and Abraxane for resectable Pancreatic cancer" (GAP) demonstrated the feasibility of perioperative gemcitabine/abraxane. Long-term survival in PDAC requires an effective immune response; hence, we undertook this translational study of the GAP trial cohort to identify immune-oncology biomarkers for clinical use. We combined Nanostring nCounter technology with immunohistochemistry to investigate the correlation between gene expression and overall patient survival. Findings were investigated in samples from the International Cancer Genome Consortium (ICGC, n=88) and the Australian Pancreatic Genome Initiative (APGI, n=227). We confirmed that human equilibrative nucleoside transporter 1 (hENT1) expression was not a prognostic marker in PDAC but patients with high levels of hENT1 were more likely to live longer than 24 months post-surgery. Additionally, CD274 (PD-L1) and two novel biomarkers of survival, cathepsin W (CTSW) and C-reactive protein (CRP), were identified in the GAP cohort (n=19). CRP expression was confirmed in data from the ICGC. Although PD-L1 and CTSW proteins were not significant across all three cohorts, results show that low CRP mRNA and protein expression are associated with longer overall survival in all three patient groups. PDAC patients with long survival have higher hENT1 expression levels. Furthermore, CRP expression is a biomarker of poor prognosis following perioperative chemotherapy and resection in PDAC patients and thus may be useful for identifying patients who could benefit from more aggressive adjuvant strategies.

Recent onset diabetes is associated with better survival in pancreatic ductal adenocarcinoma—An analysis of preoperative symptoms within the DGAV StuDoQ|Pancreas Registry

BackgroundThis multicenter study analyzed the relationship between preoperative symptoms and postsurgical outcomes utilizing the German national DGAV StuDoQ|Pancreas database. MethodsThis retrospective study included 2,643 pancreatic ductal adenocarcinoma patients undergoing pancreatic head resection from 2013–2017 within the German pancreatic surgery registry (DGAV StuDoQ|Pancreas). The association of preoperative symptoms with overall survival was analyzed using Kaplan-Meier and Cox regression analysis. ResultsPreoperative symptoms were common, with 2,380 of 2,643 (90%) patients presenting with any one or more of the following symptoms: jaundice (40%), biliary obstruction treated with biliary stent (41%), pain (37%), weight loss (29%), nausea (18%), diabetes (31%), emesis (6%), and recent onset diabetes (5%). Patients were separated into 3 groups: no symptoms (n = 293), symptoms (n = 2,229), and recent onset diabetes (n = 121). The 3 groups differed in body mass index and nodal staging, where patients with recent onset diabetes had the highest values (body mass index: no symptoms: 24.5 kg/m2, symptoms: 25.1 kg/m2; recent-onset diabetes: 26.3 kg/m2, P = .007), (no symptoms: N1: 55%, N2: 10%; symptoms: N1: 53%, N2: 17%; recent-onset diabetes: N1: 56%, N2: 16%, P = .023). Other pathological characteristics, carbohydrate antigen 19-9 levels, and adjuvant chemotherapy receival did not differ between the groups. Interestingly, recent-onset diabetes was associated with better survival compared with the other groups (Median overall survival: 28 months [no symptoms at all], 22 months [symptoms] versus not reached [recent onset diabetes group], and 5-year overall survival rates of 28%, 11%, and 57%, respectively [log rank, P = .013]). Multivariable analysis revealed that recent-onset diabetes and preoperative symptoms were independently associated with overall survival (recent-onset diabetes, relative risk 0.052 P = .027, >5 symptoms relative risk 3.66, P < .001). ConclusionPancreatic ductal adenocarcinoma symptoms occured in up to 90% of patients with resectable pancreatic ductal adenocarcinoma. In addition, PDAC symptoms were associated with overall survival and might identify unique pancreatic ductal adenocarcinoma subtypes.

Antibiotics &amp; Improved Survival in Pancreatic Ductal Adenocarcinoma

Antibiotics &amp; Improved Survival in Pancreatic Ductal Adenocarcinoma