Pancreatic fibrosis, acinar atrophy and chronic inflammation in surgical specimens associated with survival in patients with resectable pancreatic ductal adenocarcinoma

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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Liver Metastases in Newly Diagnosed Pancreatic Ductal Adenocarcinoma: A Population Based Analysis

10.21203/rs.2.20788/v1 ◽

2020 ◽

Author(s):

Guoyi Wu ◽

Xiaoben Pan ◽

Baohua Wang ◽

Xiaolei Zhu ◽

Jing Wu ◽

...

Keyword(s):

Risk Factors ◽

Liver Metastases ◽

Pancreatic Ductal Adenocarcinoma ◽

Tumor Size ◽

Cox Regression ◽

Population Based ◽

The Body ◽

Ductal Adenocarcinoma ◽

Rank Test ◽

Factors Associated

Abstract Background Estimates of the incidence and prognosis of developing liver metastases at the pancreatic ductal adenocarcinoma (PDAC) diagnosis are lacking.Methods In this study, we analyzed the association of liver metastases and the PDAC patients outcome. The risk factors associated with liver metastases in PDAC patients were analyzed using multivariable logistic regression analysis. The overall survival (OS) was estimated using Kaplan-Meier curves and log-rank test. Cox regression was performed to identify factors associated with OS.Results Patients with primary PDAC in the tail of the pancreas had a higher incidence of liver metastases (62.2%) than those with PDAC in the head (28.6%). Female gender, younger age, primary PDAC in the body or tail of the pancreas, and larger primary PDAC tumor size were positively associated with the occurrence of liver metastases. The median survival of patients with liver metastases was significantly shorter than that of patients without liver metastases. Older age, unmarried status, primary PDAC in the tail of the pancreas, and tumor size ≥4 cm were risk factors for OS in the liver metastases cohort.Conclusions Population-based estimates of the incidence and prognosis of PDAC with liver metastases may help decide whether diffusion-weighted magnetic resonance imaging should be performed in patients with primary PDAC in the tail or body of the pancreas. The location of primary PDAC should be considered during the diagnosis and treatment of primary PDAC.

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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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Pancreatic Cancer Stem Cells May Define Tumor Stroma Characteristics and Recurrence Patterns in Pancreatic Ductal Adenocarcinoma

10.21203/rs.3.rs-49165/v2 ◽

2020 ◽

Author(s):

Gokce Askan ◽

Ibrahim Halil Sahin ◽

Joanne F. Chou ◽

Aslihan Yavas ◽

Marinela Capanu ◽

...

Keyword(s):

Local Recurrence ◽

Pancreatic Ductal Adenocarcinoma ◽

Statistical Significance ◽

Specific Antigen ◽

Tumor Stroma ◽

Ductal Adenocarcinoma ◽

Rank Test ◽

Stem Cell Markers ◽

Significant Difference ◽

The Impact

Abstract Background: Herein, we investigate the relationship between pancreatic stem cell markers (PCSC markers), CD44, and epithelial-specific antigen (ESA), tumor stroma, and the impact on recurrence outcomes in pancreatic ductal adenocarcinoma (PDAC) patients.Methods: PDAC patients who underwent surgical resection between 01/2012 -06/2014 were identified. CD44 and ESA expression was assessed by immunohistochemistry. Stroma was classified as loose, moderate, and dense based on fibroblast content. Overall survival (OS) and relapse-free survival (RFS) were estimated using the Kaplan-Meier method and compared between subgroups by log-rank test. The association between PCSC markers and stroma type was assessed by Fisher`s exact test. Results: N= 93 PDAC patients were identified. The number of PDAC patients with dense, moderate density, and loose stroma was 11 (12%), 51 (54%), and 31 (33%) respectively. PDAC with CD44+/ESA- had highest rate of loose stroma (63%) followed by PDAC CD44+/ESA+ (50%), PDAC CD44-/ESA+ (35%), CD44-/ESA- (9%) (p=0.0033). No local recurrence was observed in patients with dense stroma and 9 had distant recurrence. The highest rate of cumulative local recurrence observed in patients with loose stroma. No statistically significant difference in RFS and OS were observed among subgroups (P=0.089). Conclusions: These data indicate PCSCs may have an important role in stroma differentiation in PDAC. Although not reaching statistical significance, we observed more local recurrences in patients with loose stroma, and no local recurrence was seen in patients with dense stroma suggesting tumor stroma may influence the recurrence pattern in PDAC patients.

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

HPB ◽

10.1016/j.hpb.2018.06.2154 ◽

2018 ◽

Vol 20 ◽

pp. S608-S609

Author(s):

A.K. Malik ◽

A. Lamarca ◽

A.K. Siriwardena ◽

D.A. O'Reilly ◽

R. Deshpande ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma ◽

Curative Intent ◽

The Impact

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Changes in CRP and CA19-9 during Preoperative Oncological Therapy Predict Postoperative Survival in Pancreatic Ductal Adenocarcinoma

Oncology ◽

10.1159/000517835 ◽

2021 ◽

pp. 1-13

Author(s):

Anna Maria Nurmi ◽

Harri Mustonen ◽

Caj Haglund ◽

Hanna Seppänen

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Median Survival ◽

Postoperative Outcome ◽

University Hospital ◽

Postoperative Survival ◽

Ductal Adenocarcinoma ◽

Preoperative Treatment ◽

Borderline Resectable ◽

Oncological Therapy ◽

The Impact

Introduction: Tumor and systemic inflammatory markers predict survival. This retrospective study aimed to explore the changes in CRP, CA19-9, and other routine laboratory tests during preoperative oncological therapy as prognostic factors in pancreatic ductal adenocarcinoma (PDAC). Methods: Between 2000 and 2016, 68 borderline resectable PDAC patients received preoperative oncological therapy and underwent subsequent surgery at Helsinki University Hospital, Finland. We investigated changes in CRP, CA19-9, CEA, albumin, leukocytes, bilirubin, and platelets and examined the impact on survival. Results: In the multivariate analysis, CRP remaining at ≥3 mg/L after preoperative oncological therapy predicted a poorer postoperative outcome when compared to CRP decreasing to or remaining at <3 mg/L (hazard ratio [HR] 2.766, 95% confidence interval [CI]: 1.300–5.885, p = 0.008). Furthermore, a CA19-9 decrease >90% during preoperative treatment predicted a favorable postoperative outcome (HR 0.297, 95% CI: 0.124–0.708, p = 0.006). In the Kaplan-Meier analysis, the median survival for patients with CRP remaining at <3 mg/L was longer than among patients with an increased CRP level at ≥3 mg/L (42 months vs. 24 months, p = 0.001). Patients with a CA19-9 decrease >90% or level normalization (to ≤37 kU/L) during preoperative treatment exhibited a median survival of 47 months; those with a 50–90% decrease, 15 months; and those with a <50% decrease, 17 months (p < 0.001). Conclusions: Changes in CRP and CA19-9 during preoperative oncological therapy predict postoperative survival.

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Pancreatic cancer stem cells may define tumor stroma characteristics and recurrence patterns in pancreatic ductal adenocarcinoma

BMC Cancer ◽

10.1186/s12885-021-08123-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Gokce Askan ◽

Ibrahim Halil. Sahin ◽

Joanne F. Chou ◽

Aslihan Yavas ◽

Marinela Capanu ◽

...

Keyword(s):

Local Recurrence ◽

Pancreatic Ductal Adenocarcinoma ◽

Specific Antigen ◽

Tumor Stroma ◽

Distant Recurrence ◽

Ductal Adenocarcinoma ◽

Rank Test ◽

Stem Cell Markers ◽

Significant Difference ◽

The Impact

Abstract Background Herein, we investigate the relationship between pancreatic stem cell markers (PCSC markers), CD44, and epithelial-specific antigen (ESA), tumor stroma, and the impact on recurrence outcomes in pancreatic ductal adenocarcinoma (PDAC) patients. Methods PDAC patients who underwent surgical resection between 01/2012–06/2014 were identified. CD44 and ESA expression was assessed by immunohistochemistry. Stroma was classified as loose, moderate, and dense based on fibroblast content. Overall survival (OS) and relapse-free survival (RFS) were estimated using the Kaplan-Meier method and compared between subgroups by log-rank test. The association between PCSC markers and stroma type was assessed by Fisher’s exact test. Results N = 93 PDAC patients were identified. The number of PDAC patients with dense, moderate density, and loose stroma was 11 (12%), 51 (54%), and 31 (33%) respectively. PDAC with CD44+/ESA− had highest rate of loose stroma (63%) followed by PDAC CD44+/ESA+ (50%), PDAC CD44−/ESA+ (35%), CD44−/ESA− (9%) (p = 0.0033). Conversely, lack of CD44 and ESA expression was associated with the highest rate of moderate and dense stroma (91% p = 0.0033). No local recurrence was observed in patients with dense stroma and 9 had distant recurrence. The highest rate of cumulative local recurrence was observed in patients with loose stroma. No statistically significant difference in RFS and OS was observed among subgroups (P = 0.089). Conclusions These data indicate PCSCs may have an important role in stroma differentiation in PDAC. Our results further suggest that tumor stroma may influence the recurrence pattern in PDAC patients.

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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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A High C-Reactive Protein Level on Postoperative Day 7 is Associated with Poor Survival of Patients with Pancreatic Ductal Adenocarcinoma after Resection

The American Surgeon ◽

10.1177/00031348211023406 ◽

2021 ◽

pp. 000313482110234

Author(s):

Masaji Tani ◽

Hiroya Iida ◽

Hiromitsu Maehira ◽

Haruki Mori ◽

Toru Miyake ◽

...

Keyword(s):

Adjuvant Chemotherapy ◽

Pancreatic Ductal Adenocarcinoma ◽

Median Overall Survival ◽

Cox Regression ◽

Ductal Adenocarcinoma ◽

C Reactive Protein ◽

Reactive Protein ◽

Retrospective View ◽

Node Metastases ◽

Common Malignancy

Introduction Pancreatic ductal adenocarcinoma (PDAC) is a common malignancy. While inflammation-related biomarkers influence patient survival after resection, it has not been known whether postoperative inflammations affect the survival of PDAC patients or not. Methods It was investigated whether the universal biomarkers on postoperative day (POD) 7 affect the survival of PDAC patients in the retrospective view, and univariate and multivariate analyses were performed via the Cox regression method. Results Overall, 108 consecutive patients underwent resection; 98 (90.7%) had T3 disease and 73 (67.6%) had lymph node metastases. Thirty-four patients (31.5%) experienced postoperative complications. Compared with preoperative values, the white blood cell count and C-reactive protein (CRP) level on POD 7 were significantly elevated ( P < .001 for both); conversely, the lymphocyte count was significantly reduced ( P < .001). Among 108 patients, 72 received adjuvant chemotherapy. The median overall survival was 21.0 months; the 5-year survival rate was 22.3%. On multivariate analysis, receiving adjuvant chemotherapy and low CRP levels on POD 7 (<7.6 mg/dL) were prognosticators of better survival. However, the CD classification was not a prognosticator of survival after resection. Conclusions Adjuvant chemotherapy and postoperative low CRP levels on POD 7 were prognosticators of better survival of PDAC patients after resection. Surgeons should be aware of managing postoperative infections because a high postoperative CRP level is related with unfavorable survival.

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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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