Validation of Prognostic Radiomic Features From Resectable Pancreatic Ductal Adenocarcinoma in Patients With Advanced Disease Undergoing Chemotherapy

2020 ◽  
pp. 084653712096878
Author(s):  
Emmanuel Salinas-Miranda ◽  
Farzad Khalvati ◽  
Kashayar Namdar ◽  
Dominik Deniffel ◽  
Xin Dong ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Advanced Disease ◽  
Ductal Adenocarcinoma ◽  
P Value ◽  
Significant Prognostic Factor ◽  
Test Set ◽  
Cox Proportional Hazard ◽  
Stage Disease ◽  
Cox Proportional Hazard Models ◽  
Pre Treatment

Background: Radiomic features in pancreatic ductal adenocarcinoma (PDAC) often lack validation in independent test sets or are limited to early or late stage disease. Given the lethal nature of PDAC it is possible that there are similarities in radiomic features of both early and advanced disease reflective of aggressive biology. Purpose: To assess the performance of prognostic radiomic features previously published in patients with resectable PDAC in a test set of patients with unresectable PDAC undergoing chemotherapy. Methods: The pre-treatment CT of 108 patients enrolled in a prospective chemotherapy trial were used as a test cohort for 2 previously published prognostic radiomic features in resectable PDAC (Sum Entropy and Cluster Tendency with square-root filter[Sqrt]). We assessed the performance of these 2 radiomic features for the prediction of overall survival (OS) and time to progression (TTP) using Cox proportional-hazard models. Results: Sqrt Cluster Tendency was significantly associated with outcome with a hazard ratio (HR) of 1.27(for primary pancreatic tumor plus local nodes), (Confidence Interval(CI):1.01 -1.6, P-value = 0.039) for OS and a HR of 1.25(CI:1.00 -1.55, P-value = 0.047) for TTP. Sum entropy was not associated with outcomes. Sqrt Cluster Tendency remained significant in multivariate analysis. Conclusion: The CT radiomic feature Sqrt Cluster Tendency, previously demonstrated to be prognostic in resectable PDAC, remained a significant prognostic factor for OS and TTP in a test set of unresectable PDAC patients. This radiomic feature warrants further investigation to understand its biologic correlates and CT applicability in PDAC patients.

Change in Neutrophil-to-Lymphocyte Ratio During Neoadjuvant Treatment Does Not Predict Pathological Response and Survival in Resectable Pancreatic Ductal Adenocarcinoma

2021 ◽  
pp. 000313482198905
Author(s):  
James S. Strong ◽  
Elvira L. Vos ◽  
Caitlin A. Mcintyre ◽  
Joanne F. Chou ◽  
Mithat Gonen ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Neoadjuvant Treatment ◽  
Disease Free Survival ◽  
Pathological Response ◽  
Neutrophil To Lymphocyte Ratio ◽  
Ductal Adenocarcinoma ◽  
Proportional Hazard ◽  
Lymphocyte Ratio ◽  
Cox Proportional Hazard ◽  
Cox Proportional Hazard Models

Background Neutrophil-to-lymphocyte ratio (NLR) has been reported as prognostic in pancreatic ductal adenocarcinoma (PDAC). Data about NLR changes during neoadjuvant therapy (NAT) and its relationship with pathological tumor response and survival are lacking. Methods Pancreatic ductal adenocarcinoma patients with NAT followed by resection between 2009 and 2015 were identified from a prospective database. Neutrophil-to-lymphocyte ratio was collected prior to NAT (baseline), on chemotherapy (prior to cycle 3), and prior to surgery. Baseline NLR, and changes in NLR between baseline and on chemotherapy (delta 1) and between baseline and surgery (delta 2) were compared with pathologic response (<90% and ≥90% defined as poor and good), overall (OS), and disease-free survival (DFS) using Wilcoxon rank-sum and Cox proportional hazard models. Results Of 93 patients, 17% had good pathological response. Median (interquartile range) NLR at baseline, third cycle, and surgery were 2.7 (2.0-3.7), 2.5 (1.9-4.1), and 3.1 (2.1-5.3), respectively. Median change in NLR from baseline to third cycle was .06 ( P = .72), and .6 from baseline to surgery ( P < .01). Baseline NLR, delta 1, and delta 2 were not associated with pathological response, OS, or DFS. Discussion Neutrophil-to-lymphocyte ratio increased after NAT, but a significant association between NLR and pathological response, OS, and DFS in resected PDAC patients was not observed.

Abstract 16571: The Potential Impact of Expanding Cardiac Rehabilitation Coverage in Heart Failure: Insights From Get With the Guidelines Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jacob P Kelly ◽  
Brad G Hammill ◽  
Jacob A Doll ◽  
G. Michael Felker ◽  
Paul A Heidenreich ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Rehabilitation ◽  
Adverse Outcomes ◽  
P Value ◽  
Proportional Hazard ◽  
Cox Proportional Hazard ◽  
Kaplan Meier ◽  
Cox Proportional Hazard Models ◽  
Expanded Criteria ◽  
Get With The Guidelines

Background: In February 2014, coverage for cardiac rehabilitation (CR) was expanded by Centers for Medicare & Medicaid to include patients with chronic symptomatic heart failure (HF) on optimal medical therapy with ejection fraction <35%. Thus, we sought to characterize the patient population newly eligible for CR based on the expanded criteria and their associated outcomes. Methods: We analyzed the Get With The Guidelines-HF registry linked to Medicare claims data from 2008-2012 to assess three groups of patients age 65 or older: previously eligible (due to prior MI, CABG, stable angina, heart valve surgery, or PCI in the previous 12 months), newly eligible, and ineligible for CR. Ineligible patients met neither criteria. Incidence rate was calculated with Kaplan-Meier estimates and Cox proportional hazard models were used to determine the association of events. Results: Among 51,665 HF patients discharged alive, 27.2% (n=14,053) were newly eligible and 14.5% were previously eligible for CR (n=7477). Newly eligible patients were more likely to be black, have atrial fibrillation and EF < 35%, while having fewer previous hospitalizations than patients previously eligible for CR. Newly eligible and ineligible patients had similar risk for 1-year mortality compared with those previously eligible (adjusted Hazard Ratio [HR] 0.95, 95% Confidence Interval [CI] 0.88-1.02, p-value=0.13 and [HR] 1.05, 95% [CI] 0.98-1.13, p-value=0.17, respectively). However, newly eligible and ineligible patients had lower risk for 1-year readmission compared with those previously eligible (adjusted [HR] 0.89, 95% [CI] 0.85-0.93, p-value<0.001 and [HR] 0.94, 95% [CI] 0.90- 0.98, p-value<0.001). Conclusions: The extension of coverage for cardiac rehabilitation has tripled the potentially eligible HF population. As these newly eligible patients are at high risk for adverse outcomes, cardiac rehabilitation should be considered.

Multivariate assessment of SPARC expression in resected pancreatic ductal adenocarcinoma to identify subgroups that are sensitive to adjuvant gemcitabine.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 297-297
Author(s):  
Steve Kalloger ◽  
Joanna Karasinska ◽  
Hui-li Wong ◽  
Daniel John Renouf ◽  
David F. Schaeffer
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Advanced Disease ◽  
A Priori ◽  
Predictive Ability ◽  
Ductal Adenocarcinoma ◽  
Secreted Protein ◽  
Kaplan Meier ◽  
Observation Methods ◽  
Sparc Expression ◽  
Disease Specific

297 Background: Secreted Protein, Acid, Cysteine-Rich (SPARC) has recently been postulated as a therapeutic target in pancreatic ductal adenocarcinoma (PDAC). The clinical trial findings investigating SPARC expression and nab-paclitaxel sensitivity have been discordant. This study aims to develop an integrated component based approach to the quantification of SPARC in PDAC to identify discrete predictive subgroups in a cohort of resected patients treated with an gemcitabine (GEM) or subjected to post-surgical observation. Methods: Immunohistochemical quantification of SPARC was performed on the epithelial and stromal compartments of resected PDAC on 219 patient samples on a tissue-microarray. The staining was assessed by the generation of H-Scores. The resultant scores were subjected to unsupervised hierarchical clustering. The maximum number of clusters was determined through an a priori decision that no cluster could be composed of less than 15% of the cohort. Univariable disease specific survival (DSS) analysis was performed with the Kaplan-Meier method to examine the cluster specific survival profiles with regard to gemcitabine sensitivity. Results: Mean age was 67 [38-88] with 56% being male. Most of the cohort had advanced disease with pT3 = 95% and pN1 = 72%. Lymphovascular and perinueural invasion were found in 58% and 93% of the cohort respectively. Clusters ranging in size from 35 to 76 cases were derived and represented the four-biomarker combinations of Low/Low, Low/High, High/High, and High/Low for the epithelial and stromal components respectively. None of the clinico-pathologic variables were significantly enriched in the clusters. Assessment of the predictive ability of the 4 clusters demonstrated that only one cluster (High/High) representing 76 (35%) patients in this cohort was sensitive to adjuvant GEM (p = 0.0067). Conclusions: This study shows that there is enhanced value in a combinatorial approach to the examination of SPARC in the stromal and epithelial components of PDAC where we have discovered that co-expression in both the epithelial and stromal components is significantly associated with sensitivity to adjuvant GEM.

Evofosfamide (TH-302) in combination with gemcitabine in previously untreated patients with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma: Primary analysis of the randomized, double-blind phase III MAESTRO study.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 193-193 ◽  
Author(s):  
Eric Van Cutsem ◽  
Heinz-Josef Lenz ◽  
Junji Furuse ◽  
Josep Tabernero ◽  
Volker Heinemann ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Ductal Adenocarcinoma ◽  
Significant Prognostic Factor ◽  
Primary Analysis ◽  
Eligibility Criteria ◽  
Double Blind

193 Background: Pancreatic ductal adenocarcinoma (PDAC) is invariably diagnosed at an advanced stage and has poor clinical outcome. Hypoxia is a significant prognostic factor in PDAC progression and is associated with poor prognosis. Evofosfamide (Evo, previously known as TH-302) is a hypoxia-activated prodrug of bromo-isophosphoramide mustard (Br-IPM) that is preferentially activated under hypoxic conditions. The addition of Evo to gemcitabine (Gem) significantly improved progression-free survival (PFS) in a randomized phase II trial in advanced PDAC (NCT01144455). Methods: MAESTRO is an international, randomized, double-blind, placebo-controlled phase III trial of Evo/Gem vs Placebo/Gem in patients (pts) with measurable, locally advanced unresectable or metastatic PDAC (NCT01746979). Evo and Gem were administered intravenously at a dose of 340 mg/m2 and 1,000 mg/m2, respectively, on days 1, 8, and 15 of a 28-day cycle. Treatment continued until disease progression. Key eligibility criteria included ECOG PS 0/1 and no neoadjuvant or adjuvant chemotherapy <6 months prior to entry. The primary endpoint was overall survival (OS) with the study designed to detect a HR of 0.75 with 90% power. Secondary endpoints included PFS and objective response rate (ORR), employing a hierarchical testing procedure with a 2-sided α=0.05 at each level. Results: A total of 693 pts were randomized to treatment with Evo/Gem (n=xxx) or Placebo/Gem (n=yyy). Baseline pt characteristics were similar between treatment arms. The OS HR was X.XX (95% CI: Y.YY, Z.ZZ; p=A.AAA). Median OS was AA.A months (m) for Evo/Gem vs BB.B m for Placebo/Gem. Median PFS was C.C m and D.D m, respectively (HR E.EE [95% CI: F.FF, G.GG; p = H.HHH). ORR was JJ.J% with Evo/Gem vs KK.K% with Placebo/Gem (p = L.LLL). Grade ≥3 adverse events (AEs) occurring in >5% of pts in treated with Evo/Gem were: TBC. Conclusions: The data from the MAESTRO trial will make an important contribution to our understanding of PDAC treatment. Clinical trial information: NCT01746979.

Prognostic significance of nutritional and inflammatory markers in patients with unresectable pancreatic ductal adenocarcinoma treated with chemotherapy.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 219-219
Author(s):  
Ryosuke Kobiyama ◽  
Isaku Yoshioka ◽  
Takayuki Ando ◽  
Shinya Kajiura ◽  
Kazuto Shibuya ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Inflammatory Markers ◽  
Ductal Adenocarcinoma ◽  
Serum Cholinesterase ◽  
First Line ◽  
Lymphocyte Ratio ◽  
First Line Therapy ◽  
Line Therapy ◽  
Pre Treatment ◽  
Conut Score

219 Background: Recently, several nutritional and inflammatory markers have been reported to be involved in cancer progression. The aim of this study is to evaluate whether nutritional and inflammatory biomarkers such as the modified Glasgow prognostic score (mGPS), the neutrophil‐to-lymphocyte ratio (NLR), the platelet‐to-lymphocyte ratio, the systemic-immune-inflammation index (SIII), controlling nutritional status (CONUT) score, prognostic nutritional index, and the lymphocyte‐to-monocyte ratio (LMR) could predict the prognosis in patients with unresectable pancreatic ductal adenocarcinoma (UR-PDAC) who underwent chemotherapy as first-line therapy, using disease-specific survival as the primary outcome. Methods: All UR-PDAC patients were retrospectively evaluated between January 2011 and May 2017 at Toyama University Hospital. Baseline clinicopathological characteristics and pre-treatment laboratory values such as absolute neutrophil, lymphocyte and platelet counts, C-reactive protein, albumin and CA19-9 levels, were collected. Results: A total of 184 patients were diagnosed as UR-PDAC. Among them, 151 patients who underwent chemotherapy were enrolled in this study. There were significant relationships between survival and elevated mGPS, elevated NLR, elevated SIII, decreased LMR, decreased serum cholinesterase level, and low CONUT score (p < 0.001, p < 0.001, p = 0.001, p < 0.001, p = 0.026 and p < 0.001, respectively, by log-rank test). The median survival time of patients with metastatic lesions was significantly shorter than that of patients with unresectable locally advanced PDAC (9.0 vs 15.5 months, respectively; p = 0.033). There was no significant difference in survival in pre-treatment CA19-9 level and tumor location. Multivariate analysis using Cox regression model revealed that NLR and CONUT score were independent prognostic factors. Conclusions: Pre-treatment NLR and CONUT score may predict clinical outcome in patients with UR-PDAC undergoing chemotherapy as first-line therapy.

Predictive value of germline ATM mutations in the CCTG PA.7 trial: Gemcitabine (GEM) and nab-paclitaxel (Nab-P) versus GEM, nab-P, durvalumab (D) and tremelimumab (T) as first-line therapy in metastatic pancreatic ductal adenocarcinoma (mPDAC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4135-4135
Author(s):  
Daniel John Renouf ◽  
Jonathan M. Loree ◽  
Jennifer J. Knox ◽  
Petr Kavan ◽  
Derek J. Jonker ◽  
...  
Keyword(s):  
Predictive Value ◽  
Checkpoint Inhibitors ◽  
High Plasma ◽  
Ductal Adenocarcinoma ◽  
P Value ◽  
Mutation Status ◽  
First Line Therapy ◽  
Randomized Phase Ii ◽  
Significant Difference ◽  
Pre Treatment

4135 Background: PA.7 evaluated whether combining PD-L1 and CTLA-4 inhibition with GEM and Nab-P increases efficacy. A previous analysis of the PA.7 data demonstrated high plasma based TMB (≥9 mut/Mb) was associated with improved OS in the Gem, Nab-P, D+T arm. DNA repair pathway aberrations beyond mismatch repair have been associated with potential immune sensitivity. We assessed the predictive value of germline ATM mutations in the PA.7 trial. Methods: This randomized phase II study (ClinicalTrials.gov NCT02879318) assessed the efficacy and safety of GEM, Nab-P, D, and T (arm A) vs. GEM and Nab-P (arm B) in patients (pts) with mPDAC (n = 180). The primary endpoint was overall survival (OS). Pre-treatment plasma was sequenced with the Predicine ATLAS next generation assay (600 gene, 2.4 Mb panel). 2-sided alpha set at 0.1. Results: 180 pts were randomized (119 to arm A and 61 to arm B) There was no significant difference in OS (9.8 months in arm A vs. 8.8 months in arm B, p-value 0.72) or PFS (5.5 months and 5.4 months respectively, HR 0.98, p-value 0.91). Plasma analysis was performed on 174/180 pts with available samples. 16/174 (9.2%) pts had germline ATM mutations, 12 in arm A and 4 in arm B. GEM, Nab-P, D+T was associated with improved OS in patients with ATM mutations (HR 0.10, 90% CI 0.03-0.37; median OS 13.9 months vs. 4.9 months) while no activity was seen in pts with ATM Wild Type (HR 0.99, 90% CI 0.73-1.33; median OS 9.79 months vs. 10.2 months); interaction p = 0.014. Germline ATM mutation status was independent of plasma TMB levels (Wilcoxon p = 0.76). Conclusions: Germline ATM mutation appeared predictive of benefit from the addition of dual immune checkpoint inhibitors (D and T) to Gem and Nab-P, with a significant interaction p-value. In addition to previous data from this trial regarding the predictive value of high plasma TMB (≥9 mut/Mb), this data further supports that there may be independent subgroups of PDAC, beyond MSI-H, that may benefit from immunotherapy, and trials evaluating immunotherapy in subgroups of PDAC with these profiles are warranted. Clinical trial information: NCT02879318.

scholarly journals The clinicopathological significance of forkhead box P1 and forkhead box O3a in pancreatic ductal adenocarcinomas

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831769912 ◽  
Author(s):  
Xin Luo ◽  
Zhulin Yang ◽  
Xiao Liu ◽  
Ziru Liu ◽  
Xiongying Miao ◽  
...  
Keyword(s):  
Protein Expression ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Poor Prognosis ◽  
Ductal Adenocarcinoma ◽  
Tumor Node Metastasis ◽  
Tumor Mass ◽  
Node Metastasis ◽  
Forkhead Box ◽  
Stage Disease ◽  
Forkhead Box O3a

Pancreatic ductal adenocarcinoma is a highly malignant tumor with poor prognosis, and the biomarkers for the early diagnosis, targeting therapy, and prognosis are still not clinically available. This study investigated the expression of forkhead box P1 and forkhead box O3a proteins in human pancreatic ductal adenocarcinoma tumor tissues and pancreatic tissues with and without benign lesions using immunohistochemical staining. Results showed that the positive rates of forkhead box P1 and forkhead box O3a protein expression were significantly lower in pancreatic ductal adenocarcinoma tumors compared to peritumoral tissues, benign pancreatic tissues, and normal pancreatic tissues (p < 0.01). Pancreatic tissues with negative forkhead box P1 and forkhead box O3a protein expression exhibited dysplasia or intraepithelial neoplasia. The positive rates of forkhead box P1 and forkhead box O3a expression were significantly lower in cases with tumor mass >5 cm, lymph node metastasis, invasion to surrounding tissues and organs, and tumor–node–metastasis III + IV stage disease compared to cases with tumor mass ⩽5 cm (p < 0.05), no lymph node metastasis (p < 0.001 and p = 0.001, respectively), no invasion (p = 0.003 and p = 0.004, respectively), and tumor–node–metastasis I or II stage disease (p < 0.05). Kaplan–Meier survival analysis showed that pancreatic ductal adenocarcinoma patients with negative forkhead box P1 and forkhead box O3a expression survived significantly shorter than patients with positive forkhead box P1 and forkhead box O3a expression (p = 0.000). Cox multivariate analysis revealed that negative forkhead box P1 and forkhead box O3a expression was an independent poor prognosis factor in pancreatic ductal adenocarcinoma patients. The area under the curve of a receiver operating characteristic curve was 0.642 for forkhead box P1 (95% confidence interval: 0.553–0.730) and 0.655 for forkhead box O3a (95% confidence interval: 0.6568–0.742). Loss of forkhead box P1 and forkhead box O3a protein expression is associated with carcinogenesis, progression, and poor prognosis in patients with pancreatic ductal adenocarcinomas.

scholarly journals Procathepsin E is highly abundant but minimally active in pancreatic ductal adenocarcinoma tumors

2016 ◽  
Vol 397 (9) ◽  
pp. 871-881 ◽  
Author(s):  
Anthony J. O’Donoghue ◽  
Sam L. Ivry ◽  
Chaity Chaudhury ◽  
Daniel R. Hostetter ◽  
Douglas Hanahan ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immunoblot Analysis ◽  
Pancreatic Tissue ◽  
Tumor Burden ◽  
Ductal Adenocarcinoma ◽  
Aspartyl Protease ◽  
Altered Expression ◽  
Cathepsin E ◽  
Stage Disease ◽  
End Stage

Abstract The cathepsin family of lysosomal proteases is increasingly being recognized for their altered expression in cancer and role in facilitating tumor progression. The aspartyl protease cathepsin E is overexpressed in several cancers and has been investigated as a biomarker for pancreatic ductal adenocarcinoma (PDAC). Here we show that cathepsin E expression in mouse PDAC tumors is increased by more than 400-fold when compared to healthy pancreatic tissue. Cathepsin E accumulates over the course of disease progression and accounts for more than 3% of the tumor protein in mice with end-stage disease. Through immunoblot analysis we determined that only procathepsin E exists in mouse PDAC tumors and cell lines derived from these tumors. By decreasing the pH, this procathepsion E is converted to the mature form, resulting in an increase in proteolytic activity. Although active site inhibitors can bind procathepsin E, treatment of PDAC mice with the aspartyl protease inhibitor ritonavir did not decrease tumor burden. Lastly, we used multiplex substrate profiling by mass spectrometry to identify two synthetic peptides that are hydrolyzed by procathepsin E near neutral pH. This work represents a comprehensive analysis of procathepsin E in PDAC and could facilitate the development of improved biomarkers for disease detection.

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.

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