scholarly journals New Treatment Strategies for Metastatic Pancreatic Ductal Adenocarcinoma

Drugs ◽  
2020 ◽  
Vol 80 (7) ◽  
pp. 647-669 ◽  
Author(s):  
Ritu Raj Singh ◽  
Eileen M. O’Reilly
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Treatment Strategies ◽  
Ductal Adenocarcinoma ◽  
New Treatment

Morphological classification of pancreatic ductal adenocarcinoma that predicts molecular subtypes and correlates with clinical outcome

Gut ◽  
2019 ◽  
Vol 69 (2) ◽  
pp. 317-328 ◽  
Author(s):  
Sangeetha N Kalimuthu ◽  
Gavin W Wilson ◽  
Robert C Grant ◽  
Matthew Seto ◽  
Grainne O’Kane ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Subtypes ◽  
Differentially Expressed Gene ◽  
Biological Significance ◽  
Treatment Strategies ◽  
Ductal Adenocarcinoma ◽  
Rna Seq ◽  
Gene Signatures ◽  
Significant Difference ◽  
Morphological Patterns

IntroductionTranscriptional analyses have identified several distinct molecular subtypes in pancreatic ductal adenocarcinoma (PDAC) that have prognostic and potential therapeutic significance. However, to date, an indepth, clinicomorphological correlation of these molecular subtypes has not been performed. We sought to identify specific morphological patterns to compare with known molecular subtypes, interrogate their biological significance, and furthermore reappraise the current grading system in PDAC.DesignWe first assessed 86 primary, chemotherapy-naive PDAC resection specimens with matched RNA-Seq data for specific, reproducible morphological patterns. Differential expression was applied to the gene expression data using the morphological features. We next compared the differentially expressed gene signatures with previously published molecular subtypes. Overall survival (OS) was correlated with the morphological and molecular subtypes.ResultsWe identified four morphological patterns that segregated into two components (‘gland forming’ and ‘non-gland forming’) based on the presence/absence of well-formed glands. A morphological cut-off (≥40% ‘non-gland forming’) was established using RNA-Seq data, which identified two groups (A and B) with gene signatures that correlated with known molecular subtypes. There was a significant difference in OS between the groups. The morphological groups remained significantly prognostic within cancers that were moderately differentiated and classified as ‘classical’ using RNA-Seq.ConclusionOur study has demonstrated that PDACs can be morphologically classified into distinct and biologically relevant categories which predict known molecular subtypes. These results provide the basis for an improved taxonomy of PDAC, which may lend itself to future treatment strategies and the development of deep learning models.

scholarly journals Targeted Therapies for Pancreatic Cancer: Overview of Current Treatments and New Opportunities for Personalized Oncology

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 799 ◽  
Author(s):  
Cédric Leroux ◽  
Georgia Konstantinidou
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Patient Outcomes ◽  
Targeted Therapies ◽  
Median Overall Survival ◽  
Advanced Disease ◽  
Treatment Strategies ◽  
Ductal Adenocarcinoma ◽  
Cancer Associated Fibroblasts ◽  
Personalized Oncology

Cytotoxic chemotherapy remains the only treatment option for most pancreatic ductal adenocarcinoma patients. Currently, the median overall survival of patients with advanced disease rarely exceeds 1 year. The complex network of pancreatic cancer composed of immune cells, endothelial cells, and cancer-associated fibroblasts confers intratumoral and intertumoral heterogeneity with distinct proliferative and metastatic propensity. This heterogeneity can explain why tumors do not behave uniformly and are able to escape therapy. The advance in technology of whole-genome sequencing has now provided the possibility of identifying every somatic mutation, copy-number change, and structural variant in a given cancer, giving rise to personalized targeted therapies. In this review, we provide an overview of the current and emerging treatment strategies in pancreatic cancer. By highlighting new paradigms in pancreatic ductal adenocarcinoma treatment, we hope to stimulate new thoughts for clinical trials aimed at improving patient outcomes.

Low expression of DDX5 is associated with poor prognosis in patients with pancreatic ductal adenocarcinoma

2020 ◽  
pp. jclinpath-2020-207002
Author(s):  
Masashi Morimachi ◽  
Kenichi Hirabayashi ◽  
Yumi Takanashi ◽  
Aya Kawanishi ◽  
Tsubasa Saika ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Islet Cells ◽  
Tumour Size ◽  
Treatment Strategies ◽  
Immunohistochemical Analysis ◽  
Ductal Adenocarcinoma ◽  
Clinicopathological Parameters ◽  
Pancreatic Ducts ◽  
Venous Involvement ◽  
Dead Box

AimsPancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies. Hence, there is a need for new markers and treatment strategies. P68/DEAD box protein 5 (DDX5) is an ATP-dependent RNA helicase of the DEAD box protein family. It is a prognostic marker for several cancers. In this study, we aimed to evaluate the expression and clinical relevance of DDX5 in PDAC.MethodsDDX5 expression in tissue microarray blocks containing 230 PDAC samples was examined using immunohistochemical analysis. DDX5 expression was considered high when more than 50% of the cells were stained and low when less than 50% of the cells were stained. We investigated the association between DDX5 expression and clinicopathological parameters, including patient survival.ResultsThe nuclei of normal pancreatic ducts, normal acinar cells and PDAC cells were stained positive for DDX5 although the intensity and distribution of DDX5 expression varied. Islet cells showed strong and diffuse staining of DDX5. DDX5 expression was low and high in 148 (64.3%) and 82 cases (35.7%), respectively. Low DDX5 expression was significantly associated with an advanced pT factor (pT2–pT3: tumour size,>20 mm), lymphatic involvement, advanced tumour-node-metastasis (TNM) stage (stages IIB, III, and IV), and venous involvement. In addition, the multivariate analysis revealed that DDX5 expression is an independent prognostic factor for PDAC.ConclusionThese results suggest that DDX5 plays an important role in tumour invasiveness and PDAC prognosis.

scholarly journals Molecular Characteristics of Pancreatic Ductal Adenocarcinoma

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Niki A. Ottenhof ◽  
Roeland F. de Wilde ◽  
Anirban Maitra ◽  
Ralph H. Hruban ◽  
G. Johan A. Offerhaus
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Treatment Strategies ◽  
Genetic Alterations ◽  
Targeted Treatment ◽  
Ductal Adenocarcinoma ◽  
Molecular Characteristics ◽  
Genetic Characteristics ◽  
Complete Sequencing ◽  
Made In

Pancreatic cancer is an almost universally lethal disease and despite extensive research over the last decades, this has not changed significantly. Nevertheless, much progress has been made in understanding the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) suggesting that different therapeutic strategies based on these new insights are forthcoming. Increasing focus exists on designing the so-called targeted treatment strategies in which the genetic characteristics of a tumor guide therapy. In the past, the focus of research was on identifying the most frequently affected genes in PDAC, but with the complete sequencing of the pancreatic cancer genome the focus has shifted to defining the biological function that the altered genes play. In this paper we aimed to put the genetic alterations present in pancreatic cancer in the context of their role in signaling pathways. In addition, this paper provides an update of the recent advances made in the development of the targeted treatment approach in PDAC.

Tumor interface stability on CT imaging is an early marker of response to cytotoxic therapy in pancreatic ductal adenocarcinoma.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 284-284
Author(s):  
Christopher Wilke ◽  
Ahmed Amer ◽  
Dalia Elganainy ◽  
Priya Bhosale ◽  
Ott Le ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Treatment Strategies ◽  
Disease Free Survival ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Response To Therapy ◽  
Ductal Adenocarcinoma ◽  
Free Survival ◽  
Interface Stability ◽  
Visual Scoring

284 Background: There is currently no reliable biomarker for assessing the response to therapy of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated how changes in the tumor/parenchyma interface associate with response. Methods: We reviewed pre- and post-therapy scans of patients who received chemotherapy and/or chemoradiation for both localized and metastatic PDAC. We classified the interface between the PDAC tumor and surrounding pancreas parenchyma as stable (remains or becomes well-defined) or unstable (becomes poorly defined) using a novel visual scoring system and quantified changes in enhancement at this interface (Philips Intellispace Portal, quantitative European Association for the Study of Liver [qEASL]). Results: Three retrospective datasets were used to develop this method with consensus visual scoring performed by 3 radiologists. The first dataset included 99 patients with localized PDAC who received neoadjuvant chemoradiation. Patients who were classified as having a stable interface had significantly higher probability of achieving a complete or near-complete pathologic response (21% vs 0%, p = 0.01) and additionally demonstrated an improved median disease-free survival (DFS, 20.9 vs 7.9 mos., p < 0.01) and overall survival (OS, 47.7 vs 19.1 mos., p < 0.01). These results were validated in a separate dataset of 94 patients receiving protocol-based chemotherapy and chemoradiation (chemoRT cohort) and a cohort of 86 patients with stage IV disease. In both cohorts, a stable interface was associated with a significant improvement in progression free survival (PFS, Hazard Ratio [HR] 0.44, p = 0.01 for chemoRT and HR 0.70, p = 0.16 for stage IV) and OS (HR 0.42, p < 0.01 for chemoRT and HR 0.59, p = 0.05 for stage IV). Multivariate analyses for each cohort showed interface stability to be independently associated with both DFS/PFS and OS. Measurements obtained using qEASL were concordant with the visual scoring results. Conclusions: The interface stability of PDAC is an early readout of response to therapy. Integration of this imaging feature into clinical trials for localized and metastatic PDAC may aid in the future development of adaptive treatment strategies.

scholarly journals Micro- and Mycobiota Dysbiosis in Pancreatic Ductal Adenocarcinoma Development

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3431
Author(s):  
Ruben Bellotti ◽  
Cornelia Speth ◽  
Timon E. Adolph ◽  
Cornelia Lass-Flörl ◽  
Maria Effenberger ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Intestinal Flora ◽  
Treatment Strategies ◽  
Fusobacterium Nucleatum ◽  
Pancreatic Tissue ◽  
Individual Variability ◽  
Ductal Adenocarcinoma

Background: Dysbiosis of the intestinal flora has emerged as an oncogenic contributor in different malignancies. Recent findings suggest a crucial tumor-promoting role of micro- and mycobiome alterations also in the development of pancreatic ductal adenocarcinoma (PDAC). Methods: To summarize the current knowledge about this topic, a systematic literature search of articles published until October 2020 was performed in MEDLINE (PubMed). Results: An increasing number of publications describe associations between bacterial and fungal species and PDAC development. Despite the high inter-individual variability of the commensal flora, some studies identify specific microbial signatures in PDAC patients, including oral commensals like Porphyromonas gingivalis and Fusobacterium nucleatum or Gram-negative bacteria like Proteobacteria. The role of Helicobacter spp. remains unclear. Recent isolation of Malassezia globosa from PDAC tissue suggest also the mycobiota as a crucial player of tumorigenesis. Based on described molecular mechanisms and interactions between the pancreatic tissue and the immune system this review proposes a model of how the micro- and the mycobial dysbiosis could contribute to tumorigenesis in PDAC. Conclusions: The presence of micro- and mycobial dysbiosis in pancreatic tumor tissue opens a fascinating perspective on PDAC oncogenesis. Further studies will pave the way for novel tumor markers and treatment strategies.

scholarly journals SOURCE-PANC: A Prediction Model for Patients With Metastatic Pancreatic Ductal Adenocarcinoma Based on Nationwide Population-Based Data

2021 ◽  
Vol 19 (9) ◽  
pp. 1045-1053
Author(s):  
Héctor G. van den Boorn ◽  
Willemieke P.M. Dijksterhuis ◽  
Lydia G.M. van der Geest ◽  
Judith de Vos-Geelen ◽  
Marc G. Besselink ◽  
...  
Keyword(s):  
Prediction Model ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cross Validation ◽  
Cox Regression ◽  
Performance Status ◽  
Treatment Strategies ◽  
Population Based ◽  
Ductal Adenocarcinoma ◽  
Treatment Characteristics ◽  
Netherlands Cancer Registry

Background: A prediction model for overall survival (OS) in metastatic pancreatic ductal adenocarcinoma (PDAC) including patient and treatment characteristics is currently not available, but it could be valuable for supporting clinicians in patient communication about expectations and prognosis. We aimed to develop a prediction model for OS in metastatic PDAC, called SOURCE-PANC, based on nationwide population-based data. Materials and Methods: Data on patients diagnosed with synchronous metastatic PDAC in 2015 through 2018 were retrieved from the Netherlands Cancer Registry. A multivariate Cox regression model was created to predict OS for various treatment strategies. Available patient, tumor, and treatment characteristics were used to compose the model. Treatment strategies were categorized as systemic treatment (subdivided into FOLFIRINOX, gemcitabine/nab-paclitaxel, and gemcitabine monotherapy), biliary drainage, and best supportive care only. Validation was performed according to a temporal internal–external cross-validation scheme. The predictive quality was assessed with the C-index and calibration. Results: Data for 4,739 patients were included in the model. Sixteen predictors were included: age, sex, performance status, laboratory values (albumin, bilirubin, CA19-9, lactate dehydrogenase), clinical tumor and nodal stage, tumor sublocation, presence of distant lymph node metastases, liver or peritoneal metastases, number of metastatic sites, and treatment strategy. The model demonstrated a C-index of 0.72 in the internal–external cross-validation and showed good calibration, with the intercept and slope 95% confidence intervals including the ideal values of 0 and 1, respectively. Conclusions: A population-based prediction model for OS was developed for patients with metastatic PDAC and showed good performance. The predictors that were included in the model comprised both baseline patient and tumor characteristics and type of treatment. SOURCE-PANC will be incorporated in an electronic decision support tool to support shared decision-making in clinical practice.

scholarly journals The effect of the low stromal ratio induced by neoadjuvant chemotherapy on recurrence patterns in borderline resectable pancreatic ductal adenocarcinoma

2022 ◽  
Author(s):  
Kenji Kawahara ◽  
Shigetsugu Takano ◽  
Katsunori Furukawa ◽  
Tsukasa Takayashiki ◽  
Satoshi Kuboki ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Neoadjuvant Chemotherapy ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Treatment Strategies ◽  
Early Recurrence ◽  
Ductal Adenocarcinoma ◽  
Borderline Resectable ◽  
Ki 67 ◽  
Free Survival ◽  
Recurrence Patterns

AbstractThe optimal regimens of neoadjuvant chemotherapy (NAC) and its biological and physiological modification of the tumor microenvironment (TME) in patients with borderline resectable pancreatic ductal adenocarcinoma (BR PDAC) remain unknown. A deeper understanding of the complex stromal biology of the TME will identify new avenues to establish treatment strategies for PDAC patients. Herein, we sought to clarify whether stromal remodeling by NAC affects recurrence patterns and prognosis in BR PDAC patients. We retrospectively analyzed data from 104 BR PDAC patients who underwent pancreatectomy with or without NAC (upfront surgery [UpS], n = 44; gemcitabine + nab-paclitaxel [GnP], n = 28; and gemcitabine + S-1 [GS], n = 32) to assess the correlations of treatment with early recurrence, the stromal ratio, and Ki-67 levels. Eighty-six patients experienced recurrence, and those with liver metastasis had significantly shorter recurrence-free survival than those with other recurrence patterns. The frequency of liver metastasis was significantly higher in patients with a low stromal ratio than in those with a high stromal ratio in the NAC group but not in the UpS group. Patients in the GnP group had significantly higher Ki-67 than those in the GS and UpS groups. A low stromal ratio was positively correlated with high Ki-67 in the NAC group but not in the UpS group. The low stromal ratio induced by NAC promoted early liver metastasis in patients with BR PDAC. Our findings provide new insights into the complexity of stromal biology, leading to consideration of the optimal NAC regimen.

Sign in / Sign up

Export Citation Format

Share Document