Publications by authors named "Anirban Maitra"

492 Publications

Improvement in lung health in PCD.

J Paediatr Child Health 2021 May 12. Epub 2021 May 12.

Department of Respiratory and Sleep Medicine, Royal Children's Hospital, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/jpc.15550DOI Listing
May 2021

Membrane-bound MMP-14 protease-activatable adeno-associated viral vectors for gene delivery to pancreatic tumors.

Gene Ther 2021 May 6. Epub 2021 May 6.

Department of Bioengineering, Rice University, Houston, TX, USA.

Adeno-associated virus' (AAV) relatively simple structure makes it accommodating for engineering into controllable delivery platforms. Cancer, such as pancreatic ductal adenocarcinoma (PDAC), are often characterized by upregulation of membrane-bound proteins, such as MMP-14, that propagate survival integrin signaling. In order to target tumors, we have engineered an MMP-14 protease-activatable AAV vector that responds to both membrane-bound and extracellularly active MMPs. This "provector" was generated by inserting a tetra-aspartic acid inactivating motif flanked by the MMP-14 cleavage sequence IPESLRAG into the capsid subunits. The MMP-14 provector shows lower background transduction than previously developed provectors, leading to a 9.5-fold increase in transduction ability. In a murine model of PDAC, the MMP-14 provector shows increased delivery to an allograft tumor. This proof-of-concept study illustrates the possibilities of membrane-bound protease-activatable gene therapies to target tumors.
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http://dx.doi.org/10.1038/s41434-021-00255-9DOI Listing
May 2021

Plasma MicroRNA Biomarkers in Limited Volume Samples for Detection of Early Stage Pancreatic Cancer.

Cancer Prev Res (Phila) 2021 Apr 23. Epub 2021 Apr 23.

Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center

Early detection of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcomes; however, PDAC is usually diagnosed late. Therefore, blood-based minimally invasive biomarker assays for limited volume clinical samples are urgently needed. A novel microRNA profiling platform (Abcam Fireplex-Oncology Panel) was used to investigate the feasibility of developing early detection miRNA biomarkers with 20ul plasma from a training set (58 stage II PDAC cases and 30 controls) and two validation sets (34 stage II PDAC cases and 25 controls; 44 stage II PDAC cases and 18 controls). miR-34a-5p (AUC = 0.77, 95% CI 0.66 to 0.87), miR-130a-3p (AUC = 0.74, 95% CI 0.63 to 0.84,), and miR-222-3p (AUC = 0.70, 95% CI 0.58 to 0.81,) were identified as significantly differentially abundant in plasma from stage II PDAC vs. controls. Although none of the miRNAs individually outperformed the currently used serological biomarker for PDAC, CA19-9, combining the miRNAs with CA 19-9 improved AUCs from 0.89 (95% CI 0.81 to 0.95) for CA 19-9 alone to 0.92 (95% CI 0.86 to 0.97), 0.94 (95% CI 0.89 to 0.98), and 0.92 (95% CI 0.87 to 0.97), respectively. Gene Set Enrichment Analyses of transcripts correlated with high and low expression of the three miRNAs in the TCGA PDAC sample set. These miRNA biomarkers, assayed in limited volume plasma together with CA19-9, discriminate stage II PDAC from controls with good sensitivity and specificity. Unbiased profiling of larger cohorts should help develop an informative early detection biomarker assay for diagnostic settings.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0303DOI Listing
April 2021

Oncogenic KRAS recruits an expansive transcriptional network through mutant p53 to drive pancreatic cancer metastasis.

Cancer Discov 2021 Apr 10. Epub 2021 Apr 10.

Genetics, The University of Texas MD Anderson Cancer Center.

Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal and characterized by early metastasis. Oncogenic KRAS mutations prevail in 95% of PDAC tumors and co-occur with genetic alterations in the TP53 tumor suppressor in nearly 70% of patients. Most TP53 alterations are missense mutations that exhibit gain-of-function phenotypes that include increased invasiveness and metastasis yet the extent of direct cooperation between KRAS effectors and mutant p53 remains largely undefined. We show that oncogenic KRAS effectors activate cyclic AMP responsive element binding protein 1 (CREB1) to allow physical interactions with mutant p53 that hyperactivate multiple pro-metastatic transcriptional networks. Specifically, mutant p53 and CREB1 upregulate the pro-metastatic, pioneer transcription factor, FOXA1, activating its transcriptional network while promoting Wnt/B-catenin signaling, together driving PDAC metastasis. Pharmacologic CREB1 inhibition dramatically reduced FOXA1 and B-catenin expression and dampened PDAC metastasis, identifying a new therapeutic strategy to disrupt cooperation between oncogenic KRAS and mutant p53 to mitigate metastasis.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1228DOI Listing
April 2021

Artificial Intelligence and Early Detection of Pancreatic Cancer: 2020 Summative Review.

Pancreas 2021 Mar;50(3):251-279

Sander Lab, Harvard Medical School, Boston, MA.

Abstract: Despite considerable research efforts, pancreatic cancer is associated with a dire prognosis and a 5-year survival rate of only 10%. Early symptoms of the disease are mostly nonspecific. The premise of improved survival through early detection is that more individuals will benefit from potentially curative treatment. Artificial intelligence (AI) methodology has emerged as a successful tool for risk stratification and identification in general health care. In response to the maturity of AI, Kenner Family Research Fund conducted the 2020 AI and Early Detection of Pancreatic Cancer Virtual Summit (www.pdac-virtualsummit.org) in conjunction with the American Pancreatic Association, with a focus on the potential of AI to advance early detection efforts in this disease. This comprehensive presummit article was prepared based on information provided by each of the interdisciplinary participants on one of the 5 following topics: Progress, Problems, and Prospects for Early Detection; AI and Machine Learning; AI and Pancreatic Cancer-Current Efforts; Collaborative Opportunities; and Moving Forward-Reflections from Government, Industry, and Advocacy. The outcome from the robust Summit conversations, to be presented in a future white paper, indicate that significant progress must be the result of strategic collaboration among investigators and institutions from multidisciplinary backgrounds, supported by committed funders.
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http://dx.doi.org/10.1097/MPA.0000000000001762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041569PMC
March 2021

Overexpression of CD73 in pancreatic ductal adenocarcinoma is associated with immunosuppressive tumor microenvironment and poor survival.

Pancreatology 2021 Apr 1. Epub 2021 Apr 1.

Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Background: CD73, a newly recognized immune checkpoint mediator, is expressed in several types of malignancies. However, CD73 expression and its impact on tumor microenvironment and clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) remain unclear.

Methods: This study included two cohorts: 138 patients from our institution (MDA) and 176 patients from TCGA dataset. CD73 expression, CD4, CD8, CD21 and CD45RO + tumor infiltrating lymphocytes (TILs) were evaluated by immunohistochemistry using tissue microarrays. The results of CD73 expression were correlated with clinicopathologic parameters, survival and TILs.

Results: CD73 overexpression correlated with poor differentiation (P = 0.002) and tumor size (P = 0.049). For CD73-low group, median overall survival (OS) and recurrence-free survival (RFS) were 26.9 ± 3.8 months and 12.6 ± 2.6 months, respectively, compared to 16.9 ± 4.4 months (P = 0.01) and 7.9 ± 1.2 months (P = 0.01), respectively, in CD73-high group. CD73 was an independent predictor for both RFS (P = 0.02) and OS (P = 0.01) by multivariate variate analysis. Similarly, CD73-high tumors had significantly shorter OS than CD73-low tumors in TCGA dataset (P < 0.0001). CD73-high correlated with decreased CD4 TILs in MDA cohort and decreased CD8A and CR2 (CD21) expression in TCGA cohort.

Conclusions: CD73 overexpression is associated with poor differentiation, tumor size, and shorter survival, and is an independent prognostic factor in PDAC patients. CD73 overexpression is associated with decreased CD4, CD8 and CD21 TILs. Our data support that CD73 plays an important role in immunosuppressive tumor microenvironment and promote tumor progression in PDAC.
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http://dx.doi.org/10.1016/j.pan.2021.03.018DOI Listing
April 2021

Characterisation of circulating tumour cell phenotypes identifies a partial-EMT sub-population for clinical stratification of pancreatic cancer.

Br J Cancer 2021 Mar 30. Epub 2021 Mar 30.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Limited accessibility of the tumour precludes longitudinal characterisation for therapy guidance in pancreatic ductal adenocarcinoma (PDAC).

Methods: We utilised dielectrophoresis-field flow fractionation (DEP-FFF) to isolate circulating tumour cells (CTCs) in 272 blood draws from 74 PDAC patients (41 localised, 33 metastatic) to non-invasively monitor disease progression.

Results: Analysis using multiplex imaging flow cytometry revealed four distinct sub-populations of CTCs: epithelial (E-CTC), mesenchymal (M-CTC), partial epithelial-mesenchymal transition (pEMT-CTC) and stem cell-like (SC-CTC). Overall, CTC detection rate was 76.8% (209/272 draws) and total CTC counts did not correlate with any clinicopathological variables. However, the proportion of pEMT-CTCs (prop-pEMT) was correlated with advanced disease, worse progression-free and overall survival in all patients, and earlier recurrence after resection.

Conclusion: Our results underscore the importance of immunophenotyping and quantifying specific CTC sub-populations in PDAC.
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http://dx.doi.org/10.1038/s41416-021-01350-9DOI Listing
March 2021

Impact of airway Exophiala spp. on children with cystic fibrosis.

J Cyst Fibros 2021 Mar 25. Epub 2021 Mar 25.

Division of Infection, Immunity & Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Manchester Adult Cystic Fibrosis Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, UK. Electronic address:

Introduction: Isolation of Exophiala species from sputum samples has become increasingly reported in Cystic Fibrosis (CF). However, the clinical significance of Exophiala spp. with regards to the paediatric CF population is unknown.

Methods: A case control study was undertaken to compare CF children with and without chronic Exophiala spp. in their sputum samples. Demographic and clinical data were collected retrospectively for each case from the date of Exophiala isolation and for 12 months preceding isolation. Each case was compared to three age and year-matched controls. To determine the effect of Exophiala on clinical course, patients were then followed for 12 months post isolation.

Results: In total, 27 of 244 eligible paediatric CF patients (11%) isolated Exophiala spp. on more than one occasion. There were no significant differences in the key clinical parameters: spirometry, mean number of intravenous (IV) antibiotic days and body mass index (BMI), between cases and controls (p = 0.91, p = 0.56 and p = 0.63 respectively). A higher proportion of cases isolated Candida spp. (67% vs 21%, p < 0.0001) and Aspergillus fumigatus (37% vs 26%, p = 0.37). There was no clinically significant difference in spirometry, mean number of IV antibiotic days and BMI in cases pre and post Exophiala spp. isolation. Posaconazole was the only drug used that successfully eradicated Exophiala.

Conclusion: Despite the frequent isolation of Exophiala spp. in this cohort, in most patients it is not associated with significant clinical deterioration. It does however seem to be associated with isolation of other fungi.
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http://dx.doi.org/10.1016/j.jcf.2021.03.012DOI Listing
March 2021

PTHrP drives pancreatic cancer growth and metastasis and reveals a new therapeutic vulnerability.

Cancer Discov 2021 Feb 15. Epub 2021 Feb 15.

Columbia University Medical Center

Pancreatic cancer metastasis is a leading cause of cancer-related deaths, yet very little is understood regarding the underlying biology. As a result, targeted therapies to inhibit metastasis are lacking. Here, we report that the parathyroid hormone-related protein (PTHrP encoded by PTHLH) is frequently amplified as part of the KRAS amplicon in pancreatic cancer patients. PTHrP upregulation drives the growth of both primary and metastatic tumors in mice and is highly enriched in PDAC metastases. Loss of PTHrP - either genetically or pharmacologically - dramatically reduces tumor burden, eliminates metastasis, and enhances overall survival. These effects are mediated in part through a reduction in epithelial-to-mesenchymal transition, which reduces the tumor cells' ability to initiate the metastatic cascade. Spp1, which encodes Osteopontin, is revealed to be a downstream effector of PTHrP. Our results establish a new paradigm in pancreatic cancer whereby PTHrP is a driver of disease progression and emerges as a novel therapeutic vulnerability.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1098DOI Listing
February 2021

Roles and Regulations of TET Enzymes in Solid Tumors.

Trends Cancer 2021 Jan 16. Epub 2021 Jan 16.

Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

The mechanisms governing the methylome profile of tumor suppressors and oncogenes have expanded with the discovery of oxidized states of 5-methylcytosine (5mC). Ten-eleven translocation (TET) enzymes are a family of dioxygenases that iteratively catalyze 5mC oxidation and promote cytosine demethylation, thereby creating a dynamic global and local methylation landscape. While the catalytic function of TET enzymes during stem cell differentiation and development have been well studied, less is known about the multifaceted roles of TET enzymes during carcinogenesis. This review outlines several tiers of TET regulation and overviews how TET deregulation promotes a cancer phenotype. Defining the tissue-specific and context-dependent roles of TET enzymes will deepen our understanding of the epigenetic perturbations that promote or inhibit carcinogenesis.
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http://dx.doi.org/10.1016/j.trecan.2020.12.011DOI Listing
January 2021

Imaging-Based Subtypes of Pancreatic Ductal Adenocarcinoma Exhibit Differential Growth and Metabolic Patterns in the Pre-Diagnostic Period: Implications for Early Detection.

Front Oncol 2020 2;10:596931. Epub 2020 Dec 2.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Background: Previously, we characterized subtypes of pancreatic ductal adenocarcinoma (PDAC) on computed-tomography (CT) scans, whereby conspicuous (high delta) PDAC tumors are more likely to have aggressive biology and poorer clinical outcomes compared to inconspicuous (low delta) tumors. Here, we hypothesized that these imaging-based subtypes would exhibit different growth-rates and distinctive metabolic effects in the period prior to PDAC diagnosis.

Materials And Methods: Retrospectively, we evaluated 55 patients who developed PDAC as a second primary cancer and underwent serial pre-diagnostic (T0) and diagnostic (T1) CT-scans. We scored the PDAC tumors into high and low delta on T1 and, serially, obtained the biaxial measurements of the pancreatic lesions (T0-T1). We used the Gompertz-function to model the growth-kinetics and estimate the tumor growth-rate constant (α) which was used for tumor binary classification, followed by cross-validation of the classifier accuracy. We used maximum-likelihood estimation to estimate initiation-time from a single cell (10 mm) to a 10 mm tumor mass. Finally, we serially quantified the subcutaneous-abdominal-fat (SAF), visceral-abdominal-fat (VAF), and muscles volumes (cm) on CT-scans, and recorded the change in blood glucose (BG) levels. T-test, likelihood-ratio, Cox proportional-hazards, and Kaplan-Meier were used for statistical analysis and p-value <0.05 was considered significant.

Results: Compared to high delta tumors, low delta tumors had significantly slower average growth-rate constants (0.024 month vs. 0.088 month, p<0.0001) and longer average initiation-times (14 years vs. 5 years, p<0.0001). α demonstrated high accuracy (area under the curve (AUC)=0.85) in classifying the tumors into high and low delta, with an optimal cut-off of 0.034 month. Leave-one-out-cross-validation showed 80% accuracy in predicting the delta-class (AUC=0.84). High delta tumors exhibited accelerated SAF, VAF, and muscle wasting (p <0.001), and BG disturbance (p<0.01) compared to low delta tumors. Patients with low delta tumors had better PDAC-specific progression-free survival (log-rank, p<0.0001), earlier stage tumors (p=0.005), and higher likelihood to receive resection after PDAC diagnosis (p=0.008), compared to those with high delta tumors.

Conclusion: Imaging-based subtypes of PDAC exhibit distinct growth, metabolic, and clinical profiles during the pre-diagnostic period. Our results suggest that heterogeneous disease biology may be an important consideration in early detection strategies for PDAC.
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http://dx.doi.org/10.3389/fonc.2020.596931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738633PMC
December 2020

Lead-Time Trajectory of CA19-9 as an Anchor Marker for Pancreatic Cancer Early Detection.

Gastroenterology 2021 Mar 14;160(4):1373-1383.e6. Epub 2020 Dec 14.

Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. Electronic address:

Background & Aims: There is substantial interest in liquid biopsy approaches for cancer early detection among subjects at risk, using multi-marker panels. CA19-9 is an established circulating biomarker for pancreatic cancer; however, its relevance for pancreatic cancer early detection or for monitoring subjects at risk has not been established.

Methods: CA19-9 levels were assessed in blinded sera from 175 subjects collected up to 5 years before diagnosis of pancreatic cancer and from 875 matched controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. For comparison of performance, CA19-9 was assayed in blinded independent sets of samples collected at diagnosis from 129 subjects with resectable pancreatic cancer and 275 controls (100 healthy subjects; 50 with chronic pancreatitis; and 125 with noncancerous pancreatic cysts). The complementary value of 2 additional protein markers, TIMP1 and LRG1, was determined.

Results: In the PLCO cohort, levels of CA19-9 increased exponentially starting at 2 years before diagnosis with sensitivities reaching 60% at 99% specificity within 0 to 6 months before diagnosis for all cases and 50% at 99% specificity for cases diagnosed with early-stage disease. Performance was comparable for distinguishing newly diagnosed cases with resectable pancreatic cancer from healthy controls (64% sensitivity at 99% specificity). Comparison of resectable pancreatic cancer cases to subjects with chronic pancreatitis yielded 46% sensitivity at 99% specificity and for subjects with noncancerous cysts, 30% sensitivity at 99% specificity. For prediagnostic cases below cutoff value for CA19-9, the combination with LRG1 and TIMP1 yielded an increment of 13.2% in sensitivity at 99% specificity (P = .031) in identifying cases diagnosed within 1 year of blood collection.

Conclusion: CA19-9 can serve as an anchor marker for pancreatic cancer early detection applications.
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http://dx.doi.org/10.1053/j.gastro.2020.11.052DOI Listing
March 2021

Predictive Modeling for Voxel-Based Quantification of Imaging-Based Subtypes of Pancreatic Ductal Adenocarcinoma (PDAC): A Multi-Institutional Study.

Cancers (Basel) 2020 Dec 5;12(12). Epub 2020 Dec 5.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Previously, we characterized qualitative imaging-based subtypes of pancreatic ductal adenocarcinoma (PDAC) on computed tomography (CT) scans. Conspicuous (high delta) PDAC tumors are more likely to have aggressive biology and poorer clinical outcomes compared to inconspicuous (low delta) tumors. Here, we developed a quantitative classification of this imaging-based subtype (quantitative delta; q-delta). Retrospectively, baseline pancreatic protocol CT scans of three cohorts (cohort#1 = 101, cohort#2 = 90 and cohort#3 = 16 [external validation]) of patients with PDAC were qualitatively classified into high and low delta. We used a voxel-based method to volumetrically quantify tumor enhancement while referencing normal-pancreatic-parenchyma and used machine learning-based analysis to build a predictive model. In addition, we quantified the stromal content using hematoxylin- and eosin-stained treatment-naïve PDAC sections. Analyses revealed that PDAC quantitative enhancement values are predictive of the qualitative delta scoring and were used to build a classification model (q-delta). Compared to high q-delta, low q-delta tumors were associated with improved outcomes, and the q-delta class was an independent prognostic factor for survival. In addition, low q-delta tumors had higher stromal content and lower cellularity compared to high q-delta tumors. Our results suggest that q-delta classification provides a clinically and biologically relevant tool that may be integrated into ongoing and future clinical trials.
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http://dx.doi.org/10.3390/cancers12123656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762105PMC
December 2020

Clinicopathological correlation of radiologic measurement of post-therapy tumor size and tumor volume for pancreatic ductal adenocarcinoma.

Pancreatology 2021 Jan 14;21(1):200-207. Epub 2020 Nov 14.

Department of Anatomical Pathology, University of Texas, MD Anderson Cancer Center, 515 Holcombe Blvd, Houston, TX, 77030, USA; Department of Translational Molecular Pathology, University of Texas MD, Anderson Cancer Center, 515 Holcombe Blvd, Houston, TX, 77030, USA. Electronic address:

Objectives: Tumor size measurement is critical for accurate tumor staging in patients with pancreatic ductal adenocarcinoma (PDAC). However, accurate tumor size measurement is challenging in patients who received neoadjuvant therapy before resection, due to treatment-induced fibrosis and tumor invasion beyond the grossly identified tumor area. In this study, we evaluated the correlation between the tumor size and tumor volume measured on post-therapy computed tomography (CT) scans and the pathological measurement. Also, we investigated the correlation between these measurements and clinicopathological parameters and survival.

Materials And Methods: Retrospectively, we evaluated 343 patients with PDAC who received neoadjuvant therapy, followed by pancreaticoduodenectomy and had pre-operative pancreatic protocol CT imaging. We measured the longest tumor diameter (RadL) and the radiological tumor volume (RadV) on the post-therapy CT scan, then we categorized RadL into four radiologic tumor stages (RTS) based on the current AJCC staging (8th edition) protocol and RadV based on the median. Pearson correlation or Spearman's coefficient (δ), T-test and ANOVA was used to test the correlation between the radiological and pathological measurement. Chi-square analysis was used to test the correlation with the tumor pathological response, lymph-node metastasis and margin status and Kaplan-Meier and Cox-proportional hazard for survival analysis. P-value < 0.05 was considered significant.

Results: As a continuous variable, RadL showed a positive linear correlation with the post-therapy pathologic tumor size in the overall patient population (Pearson correlation coefficient: 0.72, P < 0.001) and RadV (δ: 0.63, p < 0.0001). However, there was no correlation between RadL and pathologic tumor size in patients with ypT0 and those with pathologic tumor size of ≤1.0 cm. Post-therapy RTS and RadV group correlated with ypT stage, tumor response grades using either CAP or MDA grading system, distance of superior mesenteric artery margin and tumor recurrence/metastasis.

Conclusion: Although RadL tends to understage ypT in PDAC patients who had no radiologically detectable tumor or small tumors (RTS0 or RTS1), radiologic measurement of post-therapy tumor size may be used as a marker for the pathologic tumor staging and tumor response to neoadjuvant therapy.
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http://dx.doi.org/10.1016/j.pan.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855532PMC
January 2021

Defining the Comprehensive Genomic Landscapes of Pancreatic Ductal Adenocarcinoma Using Real-World Endoscopic Aspiration Samples.

Clin Cancer Res 2021 Feb 13;27(4):1082-1093. Epub 2020 Nov 13.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Purpose: Most patients with pancreatic ductal adenocarcinoma (PDAC) present with surgically unresectable cancer. As a result, endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is the most common biospecimen source available for diagnosis in treatment-naïve patients. Unfortunately, these limited samples are often not considered adequate for genomic analysis, precluding the opportunity for enrollment on precision medicine trials.

Experimental Design: Applying an epithelial cell adhesion molecule (EpCAM)-enrichment strategy, we show the feasibility of using real-world EUS-FNA for in-depth, molecular-barcoded, whole-exome sequencing (WES) and somatic copy-number alteration (SCNA) analysis in 23 patients with PDAC.

Results: Potentially actionable mutations were identified in >20% of patients. Further, an increased mutational burden and higher aneuploidy in WES data were associated with an adverse prognosis. To identify predictive biomarkers for first-line chemotherapy, we developed an SCNA-based complexity score that was associated with response to platinum-based regimens in this cohort.

Conclusions: Collectively, these results emphasize the feasibility of real-world cytology samples for in-depth genomic characterization of PDAC and show the prognostic potential of SCNA for PDAC diagnosis.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887035PMC
February 2021

Loss of ARID1A Promotes Epithelial-Mesenchymal Transition and Sensitizes Pancreatic Tumors to Proteotoxic Stress.

Cancer Res 2021 01 6;81(2):332-343. Epub 2020 Nov 6.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Cellular dedifferentiation is a key mechanism driving cancer progression. Acquisition of mesenchymal features has been associated with drug resistance, poor prognosis, and disease relapse in many tumor types. Therefore, successful targeting of tumors harboring these characteristics is a priority in oncology practice. The SWItch/Sucrose non-fermentable (SWI/SNF) chromatin remodeling complex has also emerged as a critical player in tumor progression, leading to the identification of several SWI/SNF complex genes as potential disease biomarkers and targets of anticancer therapies. AT-rich interaction domain-containing protein 1A (ARID1A) is a component of SWI/SNF, and mutations in represent one of the most frequent molecular alterations in human cancers. mutations occur in approximately 10% of pancreatic ductal adenocarcinomas (PDAC), but whether these mutations confer a therapeutic opportunity remains unclear. Here, we demonstrate that loss of ARID1A promotes an epithelial-mesenchymal transition (EMT) phenotype and sensitizes PDAC cells to a clinical inhibitor of HSP90, NVP-AUY922, both and . Although loss of ARID1A alone did not significantly affect proliferative potential or rate of apoptosis, ARID1A-deficient cells were sensitized to HSP90 inhibition, potentially by promoting the degradation of intermediate filaments driving EMT, resulting in cell death. Our results describe a mechanistic link between ARID1A defects and a quasi-mesenchymal phenotype, suggesting that deleterious mutations in associated with protein loss exhibit potential as a biomarker for patients with PDAC who may benefit by HSP90-targeting drugs treatment. SIGNIFICANCE: This study identifies ARID1A loss as a promising biomarker for the identification of PDAC tumors that are potentially responsive to treatment with proteotoxic agents.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3922DOI Listing
January 2021

Vestigial-like 1 is a shared targetable cancer-placenta antigen expressed by pancreatic and basal-like breast cancers.

Nat Commun 2020 10 21;11(1):5332. Epub 2020 Oct 21.

Department of Melanoma Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA.

Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regressions by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from 35 PDAC patient tumors. This identified a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1) as a putative TAA demonstrating overexpression in multiple tumor types and low or absent expression in essential normal tissues. Here we show that VGLL1-specific CTLs expanded from the blood of a PDAC patient could recognize and kill in an antigen-specific manner a majority of HLA-A*0101 allogeneic tumor cell lines derived not only from PDAC, but also bladder, ovarian, gastric, lung, and basal-like breast cancers. Gene expression profiling reveals VGLL1 as a member of a unique group of cancer-placenta antigens (CPA) that may constitute immunotherapeutic targets for patients with multiple cancer types.
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http://dx.doi.org/10.1038/s41467-020-19141-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577998PMC
October 2020

Diagnostic value of digital droplet polymerase chain reaction and digital multiplexed detection of single-nucleotide variants in pancreatic cytology specimens collected by EUS-guided FNA.

Gastrointest Endosc 2021 May 12;93(5):1142-1151.e2. Epub 2020 Oct 12.

Department of Gastroenterology, Hepatology and Nutrition, The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA.

Background And Aims: EUS-guided FNA is recommended as a first-line procedure for the histopathologic diagnosis of pancreatic cancer. Molecular analysis of EUS-FNA samples might be used as an auxiliary tool to strengthen the diagnosis. The current study aimed to evaluate the diagnostic performances of K-ras testing using droplet digital polymerase chain reaction (ddPCR) and a novel single-nucleotide variant (SNV) assay performed on pancreatic EUS-FNA samples.

Methods: EUS-FNA specimens from 31 patients with pancreatic masses (22 pancreatic ductal adenocarcinomas, 7 chronic pancreatitis, and 2 pancreatic neuroendocrine tumors) were included in the study. K-ras testing was initially performed by ddPCR. In addition, mutational status was evaluated using an SNV assay by NanoString technology, using digital enumeration of unique barcoded probes to detect 97 SNVs from 24 genes of clinical significance.

Results: The overall specificity and sensitivity of cytologic examination were 100% and 63%, respectively. K-ras mutation testing was performed using ddPCR, and the sensitivity increased to 87% with specificity 90%. The SNV assay detected at least 1 variant in 90% of pancreatic ductal adenocarcinoma samples; the test was able to detect 2 K-ras codon 61 mutations in 2 cases of pancreatic ductal adenocarcinoma, which were missed by ddPCR. The overall diagnostic accuracy of the cytologic examination alone was 74%, and it increased to 91% when the results of both molecular tests were considered for the cases with negative and inconclusive results.

Conclusions: The current study illustrated that integration of K-ras analysis with cytologic evaluation, especially in inconclusive cases, can enhance the diagnostic accuracy of EUS-FNA for pancreatic lesions.
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http://dx.doi.org/10.1016/j.gie.2020.09.051DOI Listing
May 2021

Kras mutation rate precisely orchestrates ductal derived pancreatic intraepithelial neoplasia and pancreatic cancer.

Lab Invest 2021 02 2;101(2):177-192. Epub 2020 Oct 2.

Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center, Houston, TX, 77030, USA.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. Despite the high prevalence of Kras mutations in pancreatic cancer patients, murine models expressing the oncogenic mutant Kras (Kras) in mature pancreatic cells develop PDAC at a low frequency. Independent of cell of origin, a second genetic hit (loss of tumor suppressor TP53 or PTEN) is important for development of PDAC in mice. We hypothesized ectopic expression and elevated levels of oncogenic mutant Kras would promote PanIN arising in pancreatic ducts. To test our hypothesis, the significance of elevating levels of K-Ras and Ras activity has been explored by expression of a CAG driven LGSL-Kras allele (cKras) in pancreatic ducts, which promotes ectopic Kras expression. We predicted expression of cKras in pancreatic ducts would generate neoplasia and PDAC. To test our hypothesis, we employed tamoxifen dependent CreER mediated recombination. Hnf1b:CreER;Kras (cKras) mice received 1 (Low), 5 (Mod) or 10 (High) mg per 20 g body weight to recombine cKras in low (cKras), moderate (cKras), and high (cKras) percentages of pancreatic ducts. Our histologic analysis revealed poorly differentiated aggressive tumors in cKras mice. cKras mice had grades of Pancreatic Intraepithelial Neoplasia (PanIN), recapitulating early and advanced PanIN observed in human PDAC. Proteomics analysis revealed significant differences in PTEN/AKT and MAPK pathways between wild type, cKras, cKras, and cKras mice. In conclusion, in this study, we provide evidence that ectopic expression of oncogenic mutant K-Ras in pancreatic ducts generates early and late PanIN as well as PDAC. This Ras rheostat model provides evidence that AKT signaling is an important early driver of invasive ductal derived PDAC.
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http://dx.doi.org/10.1038/s41374-020-00490-5DOI Listing
February 2021

Brain metabolites in cholinergic and glutamatergic pathways are altered by pancreatic cancer cachexia.

J Cachexia Sarcopenia Muscle 2020 12 2;11(6):1487-1500. Epub 2020 Oct 2.

Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Cachexia is a major cause of morbidity in pancreatic ductal adenocarcinoma (PDAC) patients. Our purpose was to understand the impact of PDAC-induced cachexia on brain metabolism in PDAC xenograft studies, to gain new insights into the causes of cachexia-induced morbidity. Changes in mouse and human plasma metabolites were characterized to identify underlying causes of brain metabolic changes.

Methods: We quantified metabolites, detected with high-resolution H magnetic resonance spectroscopy, in the brain and plasma of normal mice (n = 10) and mice bearing cachexia (n = 10) or non-cachexia (n = 9) inducing PDAC xenografts as well as in human plasma obtained from normal individuals (n = 24) and from individuals with benign pancreatic disease (n = 20) and PDAC (n = 20). Statistical significance was defined as a P value ≤0.05.

Results: The brain metabolic signature of cachexia-inducing PDAC was characterized by a significant depletion of choline of -27% and -21% as well as increases of glutamine of 13% and 9% and formate of 21% and 14%, relative to normal controls and non-cachectic tumour-bearing mice, respectively. Good to moderate correlations with percent weight change were found for choline (r = 0.70), glutamine (r = -0.58), and formate (r = -0.43). Significant choline depletion of -38% and -30%, relative to normal controls and non-cachectic tumour-bearing mice, respectively, detected in the plasma of cachectic mice likely contributed to decreased brain choline in cachectic mice. Similarly, relative to normal controls and patients with benign disease, choline levels in human plasma samples of PDAC patients were significantly lower by -12% and -20% respectively. A comparison of plasma metabolites from PDAC patients with and without weight loss identified significant changes in glutamine metabolism.

Conclusions: Disturbances in metabolites of the choline/cholinergic and glutamine/glutamate/glutamatergic neurotransmitter pathways may contribute to morbidity. Metabolic normalization may provide strategies to reduce morbidity. The human plasma metabolite changes observed may lead to the development of companion diagnostic markers to detect PDAC and PDAC-induced cachexia.
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http://dx.doi.org/10.1002/jcsm.12621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749557PMC
December 2020

Paradoxical Role of AT-rich Interactive Domain 1A in Restraining Pancreatic Carcinogenesis.

Cancers (Basel) 2020 Sep 21;12(9). Epub 2020 Sep 21.

Department of Translational Molecular Pathology and Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

: ARID1A is postulated to be a tumor suppressor gene owing to loss-of-function mutations in human pancreatic ductal adenocarcinomas (PDAC). However, its role in pancreatic pathogenesis is not clear despite recent studies using genetically engineered mouse (GEM) models. We aimed at further understanding of its direct functional role in PDAC, using a combination of GEM model and PDAC cell lines. : Pancreas-specific mutant -driven GEM model (-Cre; ; or "KAC") was generated by crossing -Cre; ("KC") mice with mice and characterized histologically with timed necropsies. was also deleted using CRISPR-Cas9 system in established human and murine PDAC cell lines to study the immediate effects of Arid1a loss in isogenic models. Cell lines with or without Arid1a expression were developed from respective autochthonous PDAC GEM models, compared functionally using various culture assays, and subjected to RNA-sequencing for comparative gene expression analysis. DNA damage repair was analyzed in cultured cells using immunofluorescence and COMET assay. : Retention of Arid1a is critical for early progression of mutant -driven pre-malignant lesions into PDAC, as evident by lower Ki-67 and higher apoptosis staining in "KAC" as compared to "KC" mice. Enforced deletion of in established PDAC cell lines caused suppression of cellular growth and migration, accompanied by compromised DNA damage repair. Despite early development of relatively indolent cystic precursor lesions called intraductal papillary mucinous neoplasms (IPMNs), a subset of "KAC" mice developed aggressive PDAC in later ages. PDAC cells obtained from older autochthonous "KAC" mice revealed various compensatory ("escaper") mechanisms to overcome the growth suppressive effects of Arid1a loss. : Arid1a is an essential survival gene whose loss impairs cellular growth, and thus, its expression is critical during early stages of pancreatic tumorigenesis in mouse models. In tumors that arise in the setting of ARID1A loss, a multitude of "escaper" mechanisms drive progression.
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http://dx.doi.org/10.3390/cancers12092695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564752PMC
September 2020

Computed Tomography-Based Biomarker Outcomes in a Prospective Trial of Preoperative FOLFIRINOX and Chemoradiation for Borderline Resectable Pancreatic Cancer.

JCO Precis Oncol 2019 23;3. Epub 2019 Aug 23.

University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Effective preoperative regimens and biomarkers for pancreatic ductal adenocarcinoma (PDAC) are lacking. We prospectively evaluated fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX)-based treatment and imaging-based biomarkers for borderline resectable PDAC.

Methods: Eligible patients had treatment-naïve, histology-confirmed PDAC and one or more high-risk features: mesenteric vessel involvement, CA 19-9 level of 500 mg/dL or greater, and indeterminate metastatic lesions. Patients received modified FOLFIRINOX and chemoradiation before anticipated pancreatectomy. Tumors were classified on baseline computed tomography as high delta (well-defined interface with parenchyma) or low delta (ill-defined interface). We designated computed tomography interface response after therapy as type I (remained or became well defined) or type II (became ill defined). The study had 80% power to differentiate a 60% from 40% resection rate (α = .10). Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and subgroups were compared using log-rank tests.

Results: Thirty-three patients initiated therapy; 45% underwent pancreatectomy. The median OS was 24 months (95% CI, 16.2 to 29.6 months). For patients who did and did not undergo pancreatectomy, the median OS was 42 months (95% CI, 17.7 months to not estimable) and 14 months (95% CI, 9.0 to 24.8 months), respectively. Patients with high-delta tumors had lower 3-year PFS (4% 40%) and 3-year OS rates (20% 60%) than those with low-delta tumors (both < .05). Patients with type II interface responses had lower 3-year PFS (0% 29%) and 3-year OS rates (16% 47%) than those with type I responses (both < .001).

Conclusion: Preoperative FOLFIRINOX followed by chemoradiation for high-risk borderline resectable PDAC was associated with a resection rate of 45% and median OS of approximately 2 years. Our imaging-based biomarker validation indicates that personalized treatment may be achieved using these biomarkers at baseline and post-treatment.
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http://dx.doi.org/10.1200/PO.19.00001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446521PMC
August 2019

Interleukin-17-induced neutrophil extracellular traps mediate resistance to checkpoint blockade in pancreatic cancer.

J Exp Med 2020 12;217(12)

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with an immunosuppressive microenvironment that is resistant to most therapies. IL17 is involved in pancreatic tumorigenesis, but its role in invasive PDAC is undetermined. We hypothesized that IL17 triggers and sustains PDAC immunosuppression. We inhibited IL17/IL17RA signaling using pharmacological and genetic strategies alongside mass cytometry and multiplex immunofluorescence techniques. We uncovered that IL17 recruits neutrophils, triggers neutrophil extracellular traps (NETs), and excludes cytotoxic CD8 T cells from tumors. Additionally, IL17 blockade increases immune checkpoint blockade (PD-1, CTLA4) sensitivity. Inhibition of neutrophils or Padi4-dependent NETosis phenocopies IL17 neutralization. NMR spectroscopy revealed changes in tumor lactate as a potential early biomarker for IL17/PD-1 combination efficacy. Higher expression of IL17 and PADI4 in human PDAC corresponds with poorer prognosis, and the serum of patients with PDAC has higher potential for NETosis. Clinical studies with IL17 and checkpoint blockade represent a novel combinatorial therapy with potential efficacy for this lethal disease.
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http://dx.doi.org/10.1084/jem.20190354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953739PMC
December 2020

Cost-effectiveness of consensus guideline based management of pancreatic cysts: The sensitivity and specificity required for guidelines to be cost-effective.

Surgery 2020 10 29;168(4):601-609. Epub 2020 Jul 29.

Department of Population Health Sciences, University of Utah School of Medicine, Salt Lake City, UT.

Background: Detection of cystic lesions of the pancreas has outpaced our ability to stratify low-grade cystic lesions from those at greater risk for pancreatic cancer, raising a concern for overtreatment.

Methods: We developed a Markov decision model to determine the cost-effectiveness of guideline-based management for asymptomatic pancreatic cysts. Incremental costs per quality-adjusted life year gained and survival were calculated for current management guidelines. A sensitivity analysis estimated the effect on cost-effectiveness and mortality if overtreatment of low-grade cysts is avoided, and the sensitivity and specificity thresholds required of methods of cyst stratification to improve costs expended.

Results: "Surveillance" using current management guidelines had an incremental cost-effectiveness ratio of $171,143/quality adjusted life year compared with no surveillance or operative treatment ("do nothing"). An incremental cost-effectiveness ratio for surveillance decreases to $80,707/quality adjusted life year if the operative overtreatment of low-grade cysts was avoided. Assuming a societal willingness-to-pay of $100,000/quality adjusted life year, the diagnostic specificity for high-risk cysts must be >67% for surveillance to be preferred over surgery and "do nothing." Changes in sensitivity alone cannot make surveillance cost-effective. Most importantly, survival in surveillance is worse than "do nothing" for 3 years after cyst diagnosis, although long-term survival is improved. The disadvantage is eliminated when overtreatment of low-grade cysts is avoided.

Conclusion: Current management of pancreatic cystic lesions is not cost-effective and may increase mortality owing to overtreatment of low-grade cysts. The specificity for risk stratification for high-risk cysts must be greater than 67% to make surveillance cost-effective.
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http://dx.doi.org/10.1016/j.surg.2020.04.052DOI Listing
October 2020

A Phase I Study of Dinaciclib in Combination With MK-2206 in Patients With Advanced Pancreatic Cancer.

Clin Transl Sci 2020 11 1;13(6):1178-1188. Epub 2020 Aug 1.

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

The combination of drugs targeting Ral and PI3K/AKT signaling has antitumor efficacy in preclinical models of pancreatic cancer. We combined dinaciclib (small molecule cyclin dependent kinase inhibitor with MK-2206 (Akt inhibitor) in patients with previously treated/metastatic pancreatic cancer. Patients were treated with dinaciclib (6-12 mg/m i.v.) and MK-2206 (60-135 mg p.o.) weekly. Tumor biopsies were performed to measure pAKT, pERK, and Ki67 at baseline and after one completed cycle (dose level 2 and beyond). Thirty-nine patients participated in the study. The maximum tolerated doses were dinaciclib 9 mg/m and MK-2206 135 mg. Treatment-related grade 3 and 4 toxicities included neutropenia, lymphopenia, anemia, hyperglycemia, hyponatremia, and leukopenia. No objectives responses were observed. Four patients (10%) had stable disease as their best response. At the recommended dose, median survival was 2.2 months. Survival rates at 6 and 12 months were 11% and 5%, respectively. There was a nonsignificant reduction in pAKT composite scores between pretreatment and post-treatment biopsies (mean 0.76 vs. 0.63; P = 0.635). The combination of dinaciclib and MK-2206 was a safe regimen in patients with metastatic pancreatic cancer, although without clinical benefit, possibly due to not attaining biologically effective doses. Given the strong preclinical evidence of Ral and AKT inhibition, further studies with better tolerated agents should be considered.
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http://dx.doi.org/10.1111/cts.12802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719383PMC
November 2020

Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours.

Nat Metab 2020 08 6;2(8):775-792. Epub 2020 Jul 6.

Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, MI, USA.

Branched-chain amino acids (BCAAs) supply both carbon and nitrogen in pancreatic cancers, and increased levels of BCAAs have been associated with increased risk of pancreatic ductal adenocarcinomas (PDACs). It remains unclear, however, how stromal cells regulate BCAA metabolism in PDAC cells and how mutualistic determinants control BCAA metabolism in the tumour milieu. Here, we show distinct catabolic, oxidative and protein turnover fluxes between cancer-associated fibroblasts (CAFs) and cancer cells, and a marked reliance on branched-chain α-ketoacid (BCKA) in PDAC cells in stroma-rich tumours. We report that cancer-induced stromal reprogramming fuels this BCKA demand. The TGF-β-SMAD5 axis directly targets BCAT1 in CAFs and dictates internalization of the extracellular matrix from the tumour microenvironment to supply amino-acid precursors for BCKA secretion by CAFs. The in vitro results were corroborated with circulating tumour cells (CTCs) and PDAC tissue slices derived from people with PDAC. Our findings reveal therapeutically actionable targets in pancreatic stromal and cancer cells.
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http://dx.doi.org/10.1038/s42255-020-0226-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438275PMC
August 2020

Multidisciplinary standards of care and recent progress in pancreatic ductal adenocarcinoma.

CA Cancer J Clin 2020 09 19;70(5):375-403. Epub 2020 Jul 19.

Department of Radiation Medicine, Oregon Health & Science University, Portland, Oregon.

Despite tremendous gains in the molecular understanding of exocrine pancreatic cancer, the prognosis for this disease remains very poor, largely because of delayed disease detection and limited effectiveness of systemic therapies. Both incidence rates and mortality rates for pancreatic cancer have increased during the past decade, in contrast to most other solid tumor types. Recent improvements in multimodality care have substantially improved overall survival, local control, and metastasis-free survival for patients who have localized tumors that are amenable to surgical resection. The widening gap in prognosis between patients with resectable and unresectable or metastatic disease reinforces the importance of detecting pancreatic cancer sooner to improve outcomes. Furthermore, the developing use of therapies that target tumor-specific molecular vulnerabilities may offer improved disease control for patients with advanced disease. Finally, the substantial morbidity associated with pancreatic cancer, including wasting, fatigue, and pain, remains an under-addressed component of this disease, which powerfully affects quality of life and limits tolerance to aggressive therapies. In this article, the authors review the current multidisciplinary standards of care in pancreatic cancer with a focus on emerging concepts in pancreatic cancer detection, precision therapy, and survivorship.
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http://dx.doi.org/10.3322/caac.21626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722002PMC
September 2020

Relative Abundance of SARS-CoV-2 Entry Genes in the Enterocytes of the Lower Gastrointestinal Tract.

Genes (Basel) 2020 06 11;11(6). Epub 2020 Jun 11.

Sheikh Ahmed Center for Pancreatic Cancer Research and the Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

There is increasing evidence of gastrointestinal (GI) infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We surveyed the co-expression of SARS-CoV-2 entry genes and throughout the GI tract to assess potential sites of infection. Publicly available and in-house single-cell RNA-sequencing datasets from the GI tract were queried. Enterocytes from the small intestine and colonocytes showed the highest proportions of cells co-expressing and . Therefore, the lower GI tract represents the most likely site of SARS-CoV-2 entry leading to GI infection.
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http://dx.doi.org/10.3390/genes11060645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349178PMC
June 2020

Biomarkers and Strategy to Detect Preinvasive and Early Pancreatic Cancer: State of the Field and the Impact of the EDRN.

Cancer Epidemiol Biomarkers Prev 2020 Dec 12;29(12):2513-2523. Epub 2020 Jun 12.

Van Andel Institute, Grand Rapids, Michigan.

Patients afflicted with pancreatic ductal adenocarcinoma (PDAC) face a dismal prognosis, but headway could be made if physicians could identify the disease earlier. A compelling strategy to broaden the use of surveillance for PDAC is to incorporate molecular biomarkers in combination with clinical analysis and imaging tools. This article summarizes the components involved in accomplishing biomarker validation and an analysis of the requirements of molecular biomarkers for disease surveillance. We highlight the significance of consortia for this research and highlight resources and infrastructure of the Early Detection Research Network (EDRN). The EDRN brings together the multifaceted expertise and resources needed for biomarker validation, such as study design, clinical care, biospecimen collection and handling, molecular technologies, and biostatistical analysis, and studies coming out of the EDRN have yielded biomarkers that are moving forward in validation. We close the article with an overview of the current investigational biomarkers, an analysis of their performance relative to the established benchmarks, and an outlook on the current needs in the field. The outlook for improving the early detection of PDAC looks promising, and the pace of further research should be quickened through the resources and expertise of the EDRN and other consortia.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710622PMC
December 2020

Early Detection of Pancreatic Intraepithelial Neoplasias (PanINs) in Transgenic Mouse Model by Hyperpolarized C Metabolic Magnetic Resonance Spectroscopy.

Int J Mol Sci 2020 May 25;21(10). Epub 2020 May 25.

Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.

While pancreatic cancer (PC) survival rates have recently shown modest improvement, the disease remains largely incurable. Early detection of pancreatic cancer may result in improved outcomes and therefore, methods for early detection of cancer, even premalignant lesions, may provide more favorable outcomes. Pancreatic intraepithelial neoplasias (PanINs) have been identified as premalignant precursor lesions to pancreatic cancer. However, conventional imaging methods used for screening high-risk populations do not have the sensitivity to detect PanINs. Here, we have employed hyperpolarized metabolic imaging in vivo and nuclear magnetic resonance (H-NMR) metabolomics ex vivo to identify and understand metabolic changes, towards enabling detection of early PanINs and progression to advanced PanINs lesions that precede pancreatic cancer formation. Progression of disease from tissue containing predominantly low-grade PanINs to tissue with high-grade PanINs showed a decreasing alanine/lactate ratio from high-resolution NMR metabolomics ex vivo. Hyperpolarized magnetic resonance spectroscopy (HP-MRS) allows over 10,000-fold sensitivity enhancement relative to conventional magnetic resonance. Real-time HP-MRS was employed to measure non-invasively changes of alanine and lactate metabolites with disease progression and in control mice in vivo, following injection of hyperpolarized [1-C] pyruvate. The alanine-to-lactate signal intensity ratio was found to decrease as the disease progressed from low-grade PanINs to high-grade PanINs. The biochemical changes of alanine transaminase (ALT) and lactate dehydrogenase (LDH) enzyme activity were assessed. These results demonstrate that there are significant alterations of ALT and LDH activities during the transformation from early to advanced PanINs lesions. Furthermore, we demonstrate that real-time conversion kinetic rate constants (k and k) can be used as metabolic imaging biomarkers of pancreatic premalignant lesions. Findings from this emerging HP-MRS technique can be translated to the clinic for detection of pancreatic premalignant lesion in high-risk populations.
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http://dx.doi.org/10.3390/ijms21103722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279395PMC
May 2020