The impact of age on treatment for pancreatic ductal adenocarcinoma (PDAC) with curative intent: is age a barrier?

Abstract Background Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal malignancies, is increasing in incidence. However, the stromal reaction pathophysiology and its role in PDAC development remain unknown. We, therefore, investigated the potential role of histological chronic pancreatitis findings and chronic inflammation on surgical PDAC specimens and disease-specific survival (DSS). Methods Between 2000 and 2016, we retrospectively enrolled 236 PDAC patients treated with curative-intent pancreatic surgery at Helsinki University Hospital. All pancreatic transection margin slides were re-reviewed and histological findings were evaluated applying international guidelines. Results DSS among patients with no fibrosis, acinar atrophy or chronic inflammation identified on pathology slides was significantly better than DSS among patients with fibrosis, acinar atrophy and chronic inflammation [median survival: 41.8 months, 95% confidence interval (CI) 26.0–57.6 vs. 20.6 months, 95% CI 10.3–30.9; log-rank test p = 0.001]. Multivariate analysis revealed that Ca 19–9 > 37 kU/l [hazard ratio (HR) 1.48, 95% CI 1.02–2.16], lymph node metastases N1–2 (HR 1.71, 95% CI 1.16–2.52), tumor size > 30 mm (HR 1.47, 95% CI 1.04–2.08), the combined effect of fibrosis and acinar atrophy (HR 1.91, 95% CI 1.27–2.88) and the combined effect of fibrosis, acinar atrophy and chronic inflammation (HR 1.63, 95% CI 1.03–2.58) independently served as unfavorable prognostic factors for DSS. However, we observed no significant associations between tumor size (> 30 mm) and the degree of perilobular fibrosis (p = 0.655), intralobular fibrosis (p = 0.587), acinar atrophy (p = 0.584) or chronic inflammation (p = 0.453). Conclusions Our results indicate that the pancreatic stroma is associated with PDAC patients’ DSS. Additionally, the more severe the fibrosis, acinar atrophy and chronic inflammation, the worse the impact on DSS, thereby warranting further studies investigating stroma-targeted therapies.

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Management of Patients with Pancreatic Ductal Adenocarcinoma in the Real-Life Setting: Lessons from the French National Hospital Database

Cancers ◽

10.3390/cancers13143515 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3515

Author(s):

Christelle de la Fouchardière ◽

Mustapha Adham ◽

Anne-Marie Marion-Audibert ◽

Antoine Duclos ◽

Claude Darcha ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Real Life ◽

Ductal Adenocarcinoma ◽

University Hospitals ◽

National Hospital ◽

Curative Intent ◽

The Real ◽

Oncological Treatment ◽

Real Life Setting ◽

Number Of Patients

Pancreatic ductal adenocarcinoma (PDAC) remains a major public health challenge, and faces disparities and delays in the diagnosis and access to care. Our purposes were to describe the medical path of PDAC patients in the real-life setting and evaluate the overall survival at 1 year. We used the national hospital discharge summaries database system to analyze the management of patients with newly diagnosed PDAC over the year 2016 in Auvergne-Rhône-Alpes region (AuRA) (France). A total of 1872 patients met inclusion criteria corresponding to an incidence of 22.6 per 100,000 person-year. Within the follow-up period, 353 (18.9%) were operated with a curative intent, 743 (39.7%) underwent chemo- and/or radiotherapy, and 776 (41.4%) did not receive any of these treatments. Less than half of patients were operated in a high-volume center, defined by more than 20 PDAC resections performed annually, mainly university hospitals. The 1-year survival rate was 47% in the overall population. This study highlights that a significant number of patients with PDAC are still operated in low-volume centers or do not receive any specific oncological treatment. A detailed analysis of the medical pathways is necessary in order to identify the medical and territorial determinants and their impact on the patient’s outcome.

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MicroRNA-Regulated Signaling Pathways: Potential Biomarkers for Pancreatic Ductal Adenocarcinoma

Stresses ◽

10.3390/stresses1010004 ◽

2021 ◽

Vol 1 (1) ◽

pp. 30-47

Author(s):

Maria Mortoglou ◽

David Wallace ◽

Aleksandra Buha Buha Djordjevic ◽

Vladimir Djordjevic ◽

E. Damla Arisan ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Metabolic Stress ◽

Resistance Mechanisms ◽

Current Data ◽

Cellular Damage ◽

Ductal Adenocarcinoma ◽

Aberrant Expression ◽

Metabolic Alterations ◽

Limited Effectiveness ◽

The Impact

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and invasive type of pancreatic cancer (PCa) and is expected to be the second most common cause of cancer-associated deaths. The high mortality rate is due to the asymptomatic progression of the clinical features until the advanced stages of the disease and the limited effectiveness of the current therapeutics. Aberrant expression of several microRNAs (miRs/miRNAs) has been related to PDAC progression and thus they could be potential early diagnostic, prognostic, and/or therapeutic predictors for PDAC. miRs are small (18 to 24 nucleotides long) non-coding RNAs, which regulate the expression of key genes by targeting their 3′-untranslated mRNA region. Increased evidence has also suggested that the chemoresistance of PDAC cells is associated with metabolic alterations. Metabolic stress and the dysfunctionality of systems to compensate for the altered metabolic status of PDAC cells is the foundation for cellular damage. Current data have implicated multiple systems as hallmarks of PDAC development, such as glutamine redox imbalance, oxidative stress, and mitochondrial dysfunction. Hence, both the aberrant expression of miRs and dysregulation in metabolism can have unfavorable effects in several biological processes, such as apoptosis, cell proliferation, growth, survival, stress response, angiogenesis, chemoresistance, invasion, and migration. Therefore, due to these dismal statistics, it is crucial to develop beneficial therapeutic strategies based on an improved understanding of the biology of both miRs and metabolic mediators. This review focuses on miR-mediated pathways and therapeutic resistance mechanisms in PDAC and evaluates the impact of metabolic alterations in the progression of PDAC.

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Repression of MUC1 promotes expansion and suppressive function of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma and breast cancer murine models

10.1101/2020.12.07.415299 ◽

2020 ◽

Author(s):

S. Mahnaz ◽

L. Das Roy ◽

M. Bose ◽

C. De ◽

S. Nath ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Pancreatic Ductal Adenocarcinoma ◽

Signaling Pathways ◽

Suppressor Cells ◽

Ductal Adenocarcinoma ◽

Myeloid Derived Suppressor Cells ◽

Mucin 1 ◽

Transmembrane Glycoprotein ◽

The Impact

ABSTRACTMyeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC phenotype, we analyzed MDSCs derived from wild type (WT) and MUC1-knockout (MUC1KO) mice bearing pancreatic ductal adenocarcinoma KCKO and breast cancer C57MG xenografts. We observed enhanced tumor growth in MUC1KO mice compared to WT mice in both pancreatic KCKO and breast C57MG cancer models due to increased MDSC population and enrichment of Tregs in tumor microenvironment. Our current study shows that knockdown of MUC1 in MDSCs promotes proliferation and immature suppressive phenotype indicated by increased level of iNOS, ARG1 activity and TGF-β secretion under cancer conditions. Increased activity of MDSCs leads to repression of IL-2 and IFN-ɣ production by T-cells. We were able to find that MDSCs from MUC1KO mice have higher levels of c-Myc and activated pSTAT3 as compared to MUC1 WT mice, that are signaling pathways leading to increased survival, proliferation and prevention of maturation. In summary, MUC1 regulates signaling pathways that maintain immunosuppressive properties of MDSCs. Thus, immunotherapy must target only tumor associated MUC1 on epithelial cells and not MUC1 on hematopoietic cells to avoid expansion and suppressive functions of MDSC.

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Pancreatic ductal adenocarcinoma from a surgical perspective

International Journal of Cancer Research & Therapy ◽

10.33140/ijcrt.06.02.13 ◽

2021 ◽

Vol 6 (2) ◽

Keyword(s):

Risk Factors ◽

Pancreatic Ductal Adenocarcinoma ◽

Adjuvant Treatment ◽

Locally Advanced ◽

Historical Background ◽

Ductal Adenocarcinoma ◽

Curative Intent ◽

Pancreatic Cancers ◽

Operative Care ◽

Histological Staging

Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of pancreatic cancers. Whilst most patients present with locally advanced or metastatic disease, a minority are candidates for curative-intent resection. This review covers the aspects of PDAC which are relevant to the surgeon. Firstly, an up-to-date overview of epidemiology, risk factors and pathogenesis are provided. Secondly, presentation, diagnosis and staging are covered, including a summary of the most recent staging guidelines. The review will then focus on the historical background of the pancreatico-duodenectomy (PD), the modern procedure and post-operative care. Finally, short sections provide the reader with an update on histological staging and adjuvant treatment.

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P-P13 Long-term outcome after portal vein resection during pancreaticoduodenectomy for pancreatic ductal adenocarcinoma: a propensity score matched analysis

British Journal of Surgery ◽

10.1093/bjs/znab430.236 ◽

2021 ◽

Vol 108 (Supplement_9) ◽

Author(s):

James Russell ◽

Claire Stevens ◽

Rahul Bhome ◽

Dimitrios Karavias ◽

Ali Arshad ◽

...

Keyword(s):

Propensity Score ◽

Portal Vein ◽

Pancreatic Ductal Adenocarcinoma ◽

Perineural Invasion ◽

Nodal Metastasis ◽

Ductal Adenocarcinoma ◽

Safe Procedure ◽

Portal Vein Resection ◽

Vein Resection ◽

The Impact

Abstract Background Portal vein resection (PVR) with pancreaticoduodenectomy (PD) is often performed to achieve clear margins for patients with vascular involvement in pancreatic ductal adenocarcinoma (PDAC). However, there is evidence to suggest that patients undergoing PVR often have more advanced cancers, therefore the impact of PVR on survival and recurrence remains unclear. The aim of this study is to assess overall (OS) and recurrence free (RFS) survival in patients who underwent PVR during PD, with particular attention to margin positivity. Methods A retrospective analysis was performed on 638 patients who underwent PD during a 12-year period. Exclusion criteria included PD for non-PDAC tumours, neoadjuvant chemotherapy or intra-operative radiotherapy. 374 patients were included in the study (90 PVR and 284 non-PVR). Patient characteristics and histopathological factors associated with OS and RFS were then evaluated using univariate and multivariate Cox regression analyses. 270 patients (90 PVR and 180 non-PVR), were matched by propensity score based on perineural invasion, pT and pN staging. The Kaplan-Meier method was used to calculate survival and log-rank tests. Results Resection margin positivity was associated with shorter OS and RFS (p < 0.0001), and the superior mesenteric vein (SMV) margin was the most significant risk factor for survival on competing risks analysis. Absent adjuvant chemotherapy, nodal metastasis and margin positivity were independent risk factors for OS and RFS on multivariate analysis. PVR was associated with higher intra-operative blood loss (p = 0.009), but was not associated with increased length of stay, complications or readmissions. PVR patients had increased pT staging, nodal metastasis and perineural invasion, however, there was no difference in OS (p = 0.551) or RFS (p = 0.256) between PVR and non-PVR after propensity matching. Conclusions Positive resection margins are associated with shorter survival times, and the SMV margin is the most significant prognostic indicator for overall survival and recurrence compared to other margins. PVR is a relatively safe procedure, however, it does not achieve the intended survival benefits of complete margin clearance. The impact on survival for margin positivity, particularly the SMV margin, and nodal metastasis should be considered when making decisions with regards to vein resection and adjuvant treatments.

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Omics Approaches in Pancreatic Adenocarcinoma

Cancers ◽

10.3390/cancers11081052 ◽

2019 ◽

Vol 11 (8) ◽

pp. 1052

Author(s):

Iranzu González-Boja ◽

Antonio Viúdez ◽

Saioa Goñi ◽

Enrique Santamaria ◽

Estefania Carrasco-García ◽

...

Keyword(s):

Pancreatic Cancer ◽

Survival Rate ◽

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma ◽

Curative Intent ◽

Pancreatic Cancers ◽

Wide Range ◽

Prevention And Treatment ◽

Shed Light

Pancreatic ductal adenocarcinoma, which represents 80% of pancreatic cancers, is mainly diagnosed when treatment with curative intent is not possible. Consequently, the overall five-year survival rate is extremely dismal—around 5% to 7%. In addition, pancreatic cancer is expected to become the second leading cause of cancer-related death by 2030. Therefore, advances in screening, prevention and treatment are urgently needed. Fortunately, a wide range of approaches could help shed light in this area. Beyond the use of cytological or histological samples focusing in diagnosis, a plethora of new approaches are currently being used for a deeper characterization of pancreatic ductal adenocarcinoma, including genetic, epigenetic, and/or proteo-transcriptomic techniques. Accordingly, the development of new analytical technologies using body fluids (blood, bile, urine, etc.) to analyze tumor derived molecules has become a priority in pancreatic ductal adenocarcinoma due to the hard accessibility to tumor samples. These types of technologies will lead us to improve the outcome of pancreatic ductal adenocarcinoma patients.

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The Emerging Role of Microbiota and Microbiome in Pancreatic Ductal Adenocarcinoma

Biomedicines ◽

10.3390/biomedicines8120565 ◽

2020 ◽

Vol 8 (12) ◽

pp. 565

Author(s):

Sona Ciernikova ◽

Maria Novisedlakova ◽

Danka Cholujova ◽

Viola Stevurkova ◽

Michal Mego

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Malignant Tumors ◽

Current Knowledge ◽

Early Stage ◽

Poor Response ◽

Response To Therapy ◽

Oral Microbiome ◽

Ductal Adenocarcinoma ◽

The Impact

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant tumors due to the absence of biomarkers for early-stage detection and poor response to therapy. Since mounting evidence supports the role of microbiota composition in tumorigenesis and cancer treatment, the link between microbiome and PDAC has been described. In this review, we summarize the current knowledge regarding the impact of the gut and oral microbiome on the risk of PDAC development. Microenvironment-driven therapy and immune system interactions are also discussed. More importantly, we provide an overview of the clinical trials evaluating the microbiota role in the risk, prognosis, and treatment of patients suffering from PDAC and solid tumors. According to the research findings, immune tolerance might result from the microbiota-derived remodeling of pancreatic tumor microenvironment. Thus, microbiome profiling and targeting represent the potential trend to enhance antitumor immunity and improve the efficacy of PDAC treatment.

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Preoperative risk factors for early recurrence in patients with resectable pancreatic ductal adenocarcinoma after curative intent surgical resection

Hepatobiliary & Pancreatic Diseases International ◽

10.1016/j.hbpd.2018.09.003 ◽

2018 ◽

Vol 17 (5) ◽

pp. 450-455 ◽

Cited By ~ 4

Author(s):

Nam Hee Kim ◽

Hong Joo Kim

Keyword(s):

Risk Factors ◽

Pancreatic Ductal Adenocarcinoma ◽

Surgical Resection ◽

Early Recurrence ◽

Ductal Adenocarcinoma ◽

Preoperative Risk ◽

Curative Intent ◽

Preoperative Risk Factors

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KOC (K homology domain containing protein overexpressed in cancer) overexpression and progression-free survival after curative intent resection of pancreatic ductal adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.30_suppl.48 ◽

2012 ◽

Vol 30 (30_suppl) ◽

pp. 48-48

Author(s):

Benny Johnson ◽

Maged F. Khalil ◽

Fan Lin ◽

Shaobo Zhu ◽

Lester Kirchner

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Distant Metastasis ◽

Rna Binding ◽

Progression Free Survival ◽

The United States ◽

Ductal Adenocarcinoma ◽

Patient Specific ◽

Rank Test ◽

Curative Intent ◽

Free Survival

48 Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in the United States. Unfortunately, effective screening and early detection mechanisms are currently unavailable, thereby 80% of patients present with distant metastasis. Of the subset of patients eligible for curative intent surgery, the 5-year survival rate is only 20%. Negative surgical margins, tumor size, stage, and node negative disease are traditional prognostic indicators. However, these can be limited in their ability to predict patient specific prognosis. KOC is an oncofetal RNA-binding protein involved in RNA stabilization and cell growth during embryogenesis. Previous studies have revealed that KOC mRNA is inappropriately overexpressed in pancreatic cancer and that increased expression correlates with tumor stage. In this study, we attempt to identify whether KOC expression in patients who undergo curative intent surgery correlates with progression free survival. Methods: Tissue microarrays prepared from formalin-fixed, paraffin-embedded specimens of patients with PDAC who underwent curative intent surgery were assessed by immunohistochemistry. Results: A total of 35 patients were included. Comparisons between groups on progression free survival are estimated using the Kaplan-Meier method and the log-rank test. KOC was overexpressed in 23.6% of tumors. It was found that there were zero patients with a high KOC expression and no distant metastasis. Patients with a high KOC expression were more than 3 times more likely to progress compared to those with a low KOC expression (HR=3.54, 95% CI: 1.34, 9.36, p=0.011). Conclusions: KOC is a useful prognostic biomarker for predicting those patients with PDAC who have a high risk for early progression and distant metastasis. Identifying patients with high KOC expression upon initial diagnosis can serve as a way to risk stratify patients to aggressive treatment regimens upfront and early exposure to clinical trials.

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