Morphologic changes associated with neoadjuvant-treated pancreatic ductal adenocarcinoma and comparison of two tumor regression grading systems

2021 ◽  
Vol 109 ◽  
pp. 1-11
Author(s):  
Jennifer Vazzano ◽  
Wendy L. Frankel ◽  
Adam R. Wolfe ◽  
Terence M. Williams ◽  
Wei Chen
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tumor Regression ◽  
Ductal Adenocarcinoma ◽  
Regression Grading ◽  
Grading Systems ◽  
Morphologic Changes

scholarly journals Objective assessment of tumor regression in post-neoadjuvant therapy resections for pancreatic ductal adenocarcinoma: comparison of multiple tumor regression grading systems

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yoko Matsuda ◽  
Satoshi Ohkubo ◽  
Yuko Nakano-Narusawa ◽  
Yuki Fukumura ◽  
Kenichi Hirabayashi ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Neoadjuvant Therapy ◽  
Patient Outcomes ◽  
Tumor Regression ◽  
Ductal Adenocarcinoma ◽  
Grading System ◽  
Tumor Spread ◽  
Prognostic Performance ◽  
Regression Grading ◽  
Grading Systems

Abstract Neoadjuvant therapy is increasingly used to control local tumor spread and micrometastasis of pancreatic ductal adenocarcinoma (PDAC). Pathology assessments of treatment effects might predict patient outcomes after surgery. However, there are conflicting reports regarding the reproducibility and prognostic performance of commonly used tumor regression grading systems, namely College of American Pathologists (CAP) and Evans’ grading system. Further, the M.D. Anderson Cancer Center group (MDA) and the Japan Pancreas Society (JPS) have introduced other grading systems, while we recently proposed a new, simple grading system based on the area of residual tumor (ART). Herein, we aimed to assess and compare the reproducibility and prognostic performance of the modified ART grading system with those of the four grading systems using a multicenter cohort. The study cohort consisted of 97 patients with PDAC who had undergone post-neoadjuvant pancreatectomy at four hospitals. All patients were treated with gemcitabine and S-1 (GS)-based chemotherapies with/without radiation. Two pathologists individually evaluated tumor regression in accordance with the CAP, Evans’, JPS, MDA and ART grading systems, and interobserver concordance was compared between the five systems. The ART grading system was a 5-tiered system based on a number of 40× microscopic fields equivalent to the surface area of the largest ART. Furthermore, the final grades, which were either the concordant grades of the two observers or the majority grades, including those given by the third observer, were correlated with patient outcomes in each system. The interobserver concordance (kappa value) for Evans’, CAP, MDA, JPS and ART grading systems were 0.34, 0.50, 0.65, 0.33, and 0.60, respectively. Univariate analysis showed that higher ART grades were significantly associated with shorter overall survival (p = 0.001) and recurrence-free survival (p = 0.005), while the other grading systems did not show significant association with patient outcomes. The present study revealed that the ART grading system that was designed to be simple and more objective has achieved high concordance and showed a prognostic value; thus it may be most practical for assessing tumor regression in post-neoadjuvant resections for PDAC.

scholarly journals Examination of Tumor Regression Grading Systems in Breast Cancer Patients Who Received Neoadjuvant Therapy

2020 ◽  
Vol 26 (4) ◽  
pp. 2747-2754
Author(s):  
Anita Sejben ◽  
Renáta Kószó ◽  
Zsuzsanna Kahán ◽  
Gábor Cserni ◽  
Tamás Zombori
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Therapy ◽  
Cancer Patients ◽  
Tumor Regression ◽  
Breast Cancer Patients ◽  
Regression Grading ◽  
Grading Systems

Combined SHP2 and ERK inhibition for the treatment of KRAS-driven Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Katrin J Ciecielski ◽  
Antonio Mulero-Sanchez ◽  
Alexandra Berninger ◽  
Laura Ruiz Canas ◽  
Astrid Bosma ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Tumor Regression ◽  
Mapk Pathway ◽  
Single Agent ◽  
Ductal Adenocarcinoma ◽  
Good Tolerability ◽  
Recent Emergence ◽  
Erk Inhibition

Mutant KRAS is present in over 90% of pancreatic as well as 30-40% of lung and colorectal cancers and is one of the most common oncogenic drivers. Despite decades of research and the recent emergence of isoform-specific KRASG12C-inhibitors, most mutant KRAS isoforms, including the ones frequently associated with pancreatic ductal adenocarcinoma (PDAC), cannot be targeted directly. Moreover, targeting single RAS downstream effectors induces adaptive mechanisms leading to tumor recurrence or resistance. We report here on the combined inhibition of SHP2, a non-receptor tyrosine phosphatase upstream of KRAS, and ERK, a serine/threonine kinase and a key molecule downstream of KRAS in PDAC. This combination shows synergistic anticancer activity in vitro, superior disruption of the MAPK pathway, and significantly increased apoptosis induction compared to single-agent treatments. In vivo, we demonstrate good tolerability and efficacy of the combination. Concurrent inhibition of SHP2 and ERK induces significant tumor regression in multiple PDAC mouse models. Finally, we show evidence that 18F-FDG PET scans can be used to detect and predict early drug responses in animal models. Based on these compelling results, we will investigate this drug combination in a clinical trial (SHERPA, SHP2 and ERK inhibition in pancreatic cancer, NCT04916236), enrolling patients with KRAS-mutant PDAC.

High CXCR4 expression in pancreatic ductal adenocarcinoma as characterized by an inflammatory tumor phenotype with potential implications for an immunotherapeutic approach.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4021-4021
Author(s):  
Andreas Seeber ◽  
Florian Kocher ◽  
Andreas Pircher ◽  
Alberto Puccini ◽  
Yasmine Baca ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immune Cell ◽  
Tumor Regression ◽  
Signal Transduction Pathway ◽  
Cxcr4 Expression ◽  
Ductal Adenocarcinoma ◽  
Rna Expression ◽  
Primary Tumors ◽  
Pathway Gene ◽  
Molecular Landscape

4021 Background: Immunotherapy is considered ineffective in the majority of patients with pancreatic ductal adenocarcinoma (PDAC), a consequence of a highly immunosuppressive tumor microenvironment (TME). However, treatment induced inhibition of CXC chemokine receptor 4 (CXCR4) and programmed cell death protein-1 (PD-1) in the COMBAT trial caused T cell infiltration and tumor regression in a subset of PDAC patients. Elucidating a phenotype that predicts response is clinically relevant. We performed a comprehensive molecular landscape study in PDAC evaluating CXCR4 RNA expression. Methods: 3,647 PDAC specimens were centrally analysed. NextGen DNA sequencing (NextSeq, 592 gene panel or NovaSeq, whole-exome sequencing), whole-transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ) were performed. Gene expression is reported as TPM (Transcripts per million). Pathway gene enrichment analyses were done using GSEA (Subramaniam 2015, PNAS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). The cohort was stratified in quartiles according to CXCR4 RNA expression status. Results: Overall, CXCR4 expression was higher in primary tumors compared to distant metastasis (38 vs. 28 TPM, p < 0.0001). CXCR4-high (top quartile: > 59 TPMs), when compared to CXCR4-low (bottom quartile: < 17 TPM) PDACs, were characterized by a high prevalence of mutations in signal transduction pathway genes (e.g. GNAS: 3.6 vs. 0.5%), an increased infiltration of immune cells (e.g. CD8+ T cells, M1 macrophages), and a higher expression of HLA-DRA and HLA-E (all p < 0.0001). We detected an upregulation of CXCL9, CXCL10, CXCL12, CCL5, IDO1 and LAG3 in CXCR4-high compared to CXCR4-low tumors. In contrast, lower PD-L1 expression (17.4 vs. 13.1%, p = 0.02), genomic loss of heterozygosity (17.4 vs. 10.8%), and a lower frequency of gene amplifications in ERBB2 (2.1 vs. 0.1%), TNFRSF14 (2.0 vs. 0.1%), and TP53 (82 vs. 73%, all p < 0.0001) were observed. Moreover, CXCR4-high expression was associated with a better survival (HR: 1.417, 95% CI [1.168-1.72], p < 0.001). Conclusions: This is the first study comprehensively investigating the molecular landscape of PDACs according to CXCR4 RNA expression. High CXCR4 expression is associated with an improved survival and a pro-inflammatory phenotype that may identify a subset of tumors with greater responsiveness to immunotherapeutic approaches.

scholarly journals Pathology of Treated Pancreatic Ductal Adenocarcinoma and Its Clinical Implications

2020 ◽  
Vol 144 (7) ◽  
pp. 838-845 ◽  
Author(s):  
Teddy Sutardji Nagaria ◽  
Hua Wang ◽  
Deyali Chatterjee ◽  
Huamin Wang
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Neoadjuvant Therapy ◽  
Tumor Response ◽  
Tumor Regression ◽  
Prognostic Significance ◽  
Systemic Review ◽  
Ductal Adenocarcinoma ◽  
Pathologic Evaluation ◽  
Pathologic Staging ◽  
Pathologic Parameters

Context.— Preoperative neoadjuvant therapy has been increasingly used to treat patients with potentially resectable pancreatic ductal adenocarcinoma (PDAC). Neoadjuvant therapy often induces extensive fibrosis in tumor, adjacent pancreatic parenchyma, and peripancreatic tissue. Histopathologic evaluations and histologic tumor response grading (HTRG) of posttherapy pancreatectomy specimens are very difficult and challenging. Studies on prognostic significance of posttherapy pathologic staging, optimal system for HTRG, and other pathologic parameters in treated PDAC patients are limited. Objective.— This review is to provide a timely update of the prognostic values of posttherapy pathologic staging, HTRG, and other pathologic parameters in PDAC patients who received neoadjuvant therapy and pancreas resection. Data Sources.— Systemic review of major studies on pathologic evaluation and its clinicopathologic implications in treated PDAC patients. Conclusions.— Systemic pathologic examination, histologic tumor regression grading, pathologic evaluation of the margins, tumor involvement of superior mesenteric vein/portal vein, accurate pathologic staging, and reporting of posttherapy pancreatectomy specimens provide highly valuable prognostic information for postoperative patient care. Our findings suggest for the first time that tumor size of 1.0 cm, instead of 2.0 cm, is a better cutoff for ypT2 in PDAC patients. The newly proposed 3-tier MD Anderson HTRG system not only has proved to be an independent prognostic marker for PDAC patients who received neoadjuvant therapy and pancreatectomy, but also improves interobserver agreement among pathologists in evaluation of tumor response. This grading system should be considered in future editions of the College of American Pathologists protocol for PDAC.

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