The Use of Biomarkers in Early Diagnostics of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies with increasing incidence. The poor prognosis is due to the aggressive nature of the tumor, late detection, and the resistance to chemotherapy and radiotherapy. A radical surgery procedure is the only treatment that has been shown to improve the 5-year survival rate to 20-25%. However, the majority of patients (80-85%) are diagnosed with locally advanced or metastatic disease and just 15-20% patients are diagnosed in an early stage allowing them to undergo the potentially curative surgical resection. The early detection of PDAC without the use of invasive methods is challenging and discovery of a cost-effective biomarker with high specificity and sensitivity could significantly improve the treatment and survival in these patients. In this review, we summarize current and newly examined biomarkers in early PDAC detection.

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Ultra-low Input Circulating Tumor DNA Detection by MED-Amp in Early-Stage Pancreatic Cancer

10.1101/2021.03.28.437388 ◽

2021 ◽

Author(s):

Erica D Pratt ◽

David B Zhen ◽

Robert W Cowan ◽

Heather Cameron ◽

Kara Schradle ◽

...

Keyword(s):

Early Stage ◽

Locally Advanced ◽

Progression Free Survival ◽

Circulating Tumor Dna ◽

Fold Change ◽

Diagnostic Sensitivity ◽

Ductal Adenocarcinoma ◽

Kras Mutations ◽

The Relationship ◽

Tumor Dna

Purpose: The clinical utility of circulating tumor DNA (ctDNA) has been shown in advanced pancreatic ductal adenocarcinoma (PDA). However, diagnostic sensitivity of many ctDNA assays is low in resectable and locally advanced disease, where tumor burden is substantially lower. We have previously described Multiplex Enrichment using Droplet Pre-Amplification (MED-Amp), a multiplexed panel for the detection of the most common oncogenic KRAS mutations in PDA. In this study, we aimed to assess the diagnostic sensitivity of MED-Amp for detection of rare mutant alleles present in the plasma of patients with localized PDA. Experimental Design: We retrospectively analyzed ninety-eight plasma samples from 51 patients with various stages of localized disease. For comparison, we measured ctDNA levels in 20 additional patients with metastatic PDA. The MED-Amp assay was used to measure the abundance of the four most common KRAS codon 12 mutations (G12C/D/R/V). We correlated the presence and quantity of ctDNA with overall survival (OS) as well as progression-free survival (PFS). Using serial plasma draws, we also assessed the relationship between changes in ctDNA allelic frequency and progression. Results: KRAS-positive ctDNA was detected in 52.9% of localized PDA and 75% of metastatic samples tested using DNA inputs as low as 2 ng. As previously reported, the presence of KRAS mutant ctDNA was correlated with worse OS for all disease stages (p = 0.02). In patients with localized PDA high ctDNA levels also correlated with significantly worse median OS (533 days vs 1090 days) and PFS (192 days vs 787 days). We also studied a small cohort of serial plasma draws to observe the relationship between ctDNA fold change and PFS. We found 83% of patients with increased fold change in mutant KRAS experienced disease progression (n=6). In contrast, 75% (n=4) of patients with decreased fold change remained disease-free (p=0.03). Conclusions: MED-Amp is a flexible and cost-effective approach for measurement of ctDNA in patients with localized cancer. Though this study focused on KRAS mutation detection, this assay could be adapted for a number of common oncogenic alterations.

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Respiratory Tularemia: Francisella Tularensis and Microarray Probe Designing

The Open Microbiology Journal ◽

10.2174/1874285801610010176 ◽

2016 ◽

Vol 10 (1) ◽

pp. 176-182 ◽

Cited By ~ 8

Author(s):

Reza Ranjbar ◽

Payam Behzadi ◽

Caterina Mammina

Keyword(s):

Dna Microarray ◽

Francisella Tularensis ◽

High Specificity ◽

Cost Effective ◽

High Rate ◽

Molecular Diagnostic ◽

Microarray Technology ◽

Microarray Probe ◽

Specificity And Sensitivity ◽

Oligo Microarray

Background:Francisella tularensis(F. tularensis) is the etiological microorganism for tularemia. There are different forms of tularemia such as respiratory tularemia. Respiratory tularemia is the most severe form of tularemia with a high rate of mortality; if not treated. Therefore, traditional microbiological tools and Polymerase Chain Reaction (PCR) are not useful for a rapid, reliable, accurate, sensitive and specific diagnosis. But, DNA microarray technology does. DNA microarray technology needs to appropriate microarray probe designing.Objective:The main goal of this original article was to design suitable long oligo microarray probes for detection and identification ofF. tularensis.Method:For performing this research, the complete genomes ofF. tularensissubsp.tularensisFSC198,F. tularensissubsp.holarcticaLVS,F. tularensissubsp.mediasiatica,F. tularensissubsp.novicida(F. novicidaU112), andF. philomiragiasubsp.philomiragiaATCC 25017 were studiedviaNCBI BLAST tool, GView and PanSeq Servers and finally the microarray probes were produced and processedviaAlleleID 7.7 software and Oligoanalyzer tool, respectively.Results:In thisin silicoinvestigation, a number of long oligo microarray probes were designed for detecting and identifyingF. tularensis. Among these probes, 15 probes were recognized as the best candidates for microarray chip designing.Conclusion:Calibrated microarray probes reduce the biasis of DNA microarray technology as an advanced, rapid, accurate and cost-effective molecular diagnostic tool with high specificity and sensitivity. Professional microarray probe designing provides us with much more facility and flexibility regarding preparation of a microarray diagnostic chip.

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Correlation of fine needle aspiration cytology and histopathology of neck swellings

International Journal of Otorhinolaryngology and Head and Neck Surgery ◽

10.18203/issn.2454-5929.ijohns20180986 ◽

2018 ◽

Vol 4 (3) ◽

pp. 648

Author(s):

C. S. Asha ◽

B. R. Suchit Roy

Keyword(s):

Salivary Gland ◽

Lymph Node ◽

Predictive Value ◽

Age Groups ◽

Invasive Procedure ◽

High Specificity ◽

Cost Effective ◽

Needle Aspiration ◽

Predictive Values ◽

Specificity And Sensitivity

Background: Neck swellings are a common clinical finding affecting all age groups. FNAC is a minimally invasive procedure helpful in the diagnosis of various neck swellings. The purpose of this study is to determine the accuracy of FNAC in the diagnosis of neck swellings by comparing it with the histopathology which is taken as the gold standard.Methods: A prospective study which included 90 patients who attended ENT and surgery departments of Government Medical College, Trivandrum with neck swellings from July 2006-2007. FNAC of the swelling was done and the FNAC results were compared with the histopathology results. The specificity, sensitivity, positive and negative predictive values and accuracy of FNAC were calculated. Results: Of the 90 patients, thyroid swelling formed the major group followed by lymph node, salivary gland and miscellaneous swellings. Thyroid swellings had a female predominance while the other three groups namely lymph node, salivary gland and miscellaneous groups showed a male preponderance. When the neck swellings namely thyroid, salivary gland, lymph node and miscellaneous group were taken into consideration as a whole, the sensitivity of FNAC for detecting malignancy was 64.3%. The specificity, positive predictive value, negative predictive value and accuracy were 97.4%, 81.8%, 93.7% and 92% respectively.Conclusions: FNAC can be rated as a safe, simple, reliable, cost effective and rapid diagnostic tool with high specificity and sensitivity for the initial evaluation of neck swellings.

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Serum Proteomic Fingerprints of Adult Patients with Severe Acute Respiratory Syndrome

Clinical Chemistry ◽

10.1373/clinchem.2005.061689 ◽

2006 ◽

Vol 52 (3) ◽

pp. 421-429 ◽

Cited By ~ 62

Author(s):

Ronald TK Pang ◽

Terence CW Poon ◽

KC Allen Chan ◽

Nelson LS Lee ◽

Rossa WK Chiu ◽

...

Keyword(s):

Viral Load ◽

Severe Acute Respiratory Syndrome ◽

Roc Curve ◽

Serum Proteins ◽

Early Stage ◽

High Specificity ◽

Roc Curves ◽

Roc Curve Analysis ◽

Outbreak Period ◽

Specificity And Sensitivity

Abstract Background: Severe acute respiratory syndrome (SARS) is an emerging infectious disease caused by a new coronavirus strain, SARS-CoV. Specific proteomic patterns might be present in serum in response to the infection and could be useful for early detection of the disease. Methods: Using surface-enhanced laser desorption/ionization (SELDI) ProteinChip technology, we profiled and compared serum proteins of 39 patients with early-stage SARS infection and 39 non-SARS patients who were suspected cases during the SARS outbreak period. Proteomic patterns associated with SARS were identified by bioinformatic and biostatistical analyses. Features of interest were then purified and identified by tandem mass spectrometry. Results: Twenty proteomic features were significantly different between the 2 groups. Fifteen were increased in the SARS group, and 5 were decreased. Their concentrations were correlated with 2 or more clinical and/or biochemical variables. Two were correlated with the SARS-CoV viral load. Hierarchical clustering analysis showed that a majority of the SARS patients (95%) had similar serum proteomic profiles and identified 2 subgroups with poor prognosis. ROC curve analysis identified individual features as potential biomarkers for SARS diagnosis (areas under ROC curves, 0.733–0.995). ROC curve areas were largest for an N-terminal fragment of complement C3c α chain (m/z 28 119) and an internal fragment of fibrinogen α-E chain (m/z 5908). Immunoglobulin κ light chain (m/z 24 505) positively correlated with viral load. Conclusions: Specific proteomic fingerprints in the sera of adult SARS patients could be used to identify SARS cases early during onset with high specificity and sensitivity.

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Glycoprotein- and Lectin-Based Approaches for Detection of Pathogens

Pathogens ◽

10.3390/pathogens9090694 ◽

2020 ◽

Vol 9 (9) ◽

pp. 694

Author(s):

Sammer-ul Hassan ◽

Ahmed Donia ◽

Usman Sial ◽

Xunli Zhang ◽

Habib Bokhari

Keyword(s):

Infectious Diseases ◽

Point Of Care ◽

Healthcare Providers ◽

Basic Research ◽

High Specificity ◽

Cost Effective ◽

Emerging Diseases ◽

Public Healthcare ◽

Point Of Use ◽

Specificity And Sensitivity

Infectious diseases alone are estimated to result in approximately 40% of the 50 million total annual deaths globally. The importance of basic research in the control of emerging and re-emerging diseases cannot be overemphasized. However, new nanotechnology-based methodologies exploiting unique surface-located glycoproteins or their patterns can be exploited to detect pathogens at the point of use or on-site with high specificity and sensitivity. These technologies will, therefore, affect our ability in the future to more accurately assess risk. The critical challenge is making these new methodologies cost-effective, as well as simple to use, for the diagnostics industry and public healthcare providers. Miniaturization of biochemical assays in lab-on-a-chip devices has emerged as a promising tool. Miniaturization has the potential to shape modern biotechnology and how point-of-care testing of infectious diseases will be performed by developing smart microdevices that require minute amounts of sample and reagents and are cost-effective, robust, and sensitive and specific. The current review provides a short overview of some of the futuristic approaches using simple molecular interactions between glycoproteins and glycoprotein-binding molecules for the efficient and rapid detection of various pathogens at the point of use, advancing the emerging field of glyconanodiagnostics.

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Detection of early-stage pancreatic carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.4613 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 4613-4613

Author(s):

D. Gold ◽

D. E. Modrak ◽

G. Newsome ◽

Z. Karanjawala ◽

R. Hruban ◽

...

Keyword(s):

Pancreatic Carcinoma ◽

Early Stage ◽

High Specificity ◽

Antigen Expression ◽

Average Concentration ◽

Precursor Lesions ◽

Roc Curve Analysis ◽

Cystic Neoplasms ◽

Specificity And Sensitivity ◽

Labeling Pattern

4613 Background: Invasive pancreatic carcinoma is a virtually lethal disease, mostly because of the failure to detect it at a sufficiently early timepoint for successful treatment. Our laboratory has identified a unique biomarker detected by MAb PAM4 that shows high specificity for a mucin glycoprotein expressed by pancreatic carcinoma (PC). While identified in almost 90% of PC and its precursor lesions, the antigen is not detectable in normal pancreas. We are investigating this biomarker for the early detection of PC. Methods: Both immunohistochemical (IHC) and enzyme immunoassay (EIA) were employed for detection and/or quantitation of PAM4-mucin in tissue and sera, respectively. Results: We have extended our prior IHC results with precursor lesions (Clin Cancer Res 2007;13:7380–7); PAM4 gave an intense, diffuse labeling pattern in 81% of mucinous cystic neoplasms (MCN), with an additional 11% showing a focal pattern (n=27). Thus, a total of 92% of MCN showed evidence of PAM4-antigen expression. Of interest, a difference in the labeling pattern was observed in association with the grade of dysplasia, providing easy identification of MCN with high- grade dysplasia. We previously reported use of an EIA for quantitation of PAM4-antigen in sera. The assay demonstrated a sensitivity and specificity of 77% and 95%, respectively, for identification of PC (J Clin Oncol, 2006;24:252–8). We have now confirmed these results in a set of serum specimens (n= 49 PC, 13 normal) for which staging information was available. Overall specificity and sensitivity were 82% and 85%, respectively, calculated by ROC curve analysis (AUC=0.878±0.045; 95% CI=0.769–0.947). Although only a small number of specimens were from patients with stage I disease (n=12), 92% of these were above the cutoff value for positive response. A correlation was observed for average concentration of antigen in the circulation with stage of disease (R2=0.988). Conclusions: IHC and EIA results indicate that PAM4 identifies a biomarker for PC that is present at the earliest stages of neoplastic transformation, thus warranting controlled analyses of larger specimen numbers. (Supported in part by USPHS grant CA096924 from the NIH.) [Table: see text]

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A randomized phase III multi-institutional study of TNFerade biologic with 5-FU and radiotherapy for locally advanced pancreatic cancer: Final results

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.4055 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 4055-4055

Author(s):

Aaron Tyler Wild ◽

Dan Laheru ◽

Hao Wang ◽

Kenneth J. Chang ◽

Gretchen Elizabeth Taylor ◽

...

Keyword(s):

Early Stage ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Systemic Exposure ◽

Adenovirus Vector ◽

Phase Iii ◽

Ductal Adenocarcinoma ◽

Open Label ◽

Tnf Α ◽

Grade 3

4055 Background: TNFerade biologic (TNF) is a novel means of selective delivery of TNF-α to tumor cells by gene transfer through intratumoral (IT) injection. TNF is a replication deficient adenovirus vector containing TNF-α cDNA ligated downstream from a radiation-inducible Egr-1 promoter, allowing spatiotemporal constraint of TNF-α production to the radiation field. Herein we report the final results of a multi-center, randomized, open-label, controlled phase III trial of TNF with chemoradiotherapy for locally advanced pancreatic ductal adenocarcinoma (PDA). Methods: Pts with locally advanced PDA were randomized 1:2 to standard of care (SOC; 5-FU/RT followed by GEM) versus TNF + SOC. RT dose was 50.4 Gy in 28 fractions. Concurrent 5-FU (200 mg/m2/day IV) started on day 1 of RT each wk. TNF was injected IT ~4 hrs prior to RT weekly by percutaneous (PTA) or endoscopic (EUS) approach. 4 wks after RT, GEM (1000 mg/m2 IV) was given until progression or toxicity. Results: Of 277 pts, 187 were randomized to TNF and 90 to SOC. Demographic/baseline characteristics were similar between arms (all NS), as was GEM received (67 vs. 68%; 7.0 vs. 7.6 total wks). Median f/up was 9.1 mos (range, 0.1-50.5). Median OS for TNF by ITT analysis was 10.1 mos (95% CI, 9.1-11.7) vs. 10.0 mos (95% CI, 7.6-11.2) for SOC (p=0.6). TNF delivery method did not affect OS (9.4 mos for PTA vs. 11.5 for EUS; p=0.7). Baseline CA19-9 > 1000 was found to impart independent risk to TNF pts (HR=1.7; p=0.02). Subgroup analysis (SGA) of 86 pts with T1-T3 disease showed an OS benefit for TNF compared to SOC (10.9 vs. 9.0 mos, respectively; p=0.04). TNF resulted in more grade 1-2 fever/chills (p<0.001) as well as grade 3 (p<0.001) and 4 (p=0.05) toxicities (commonly lymphopenia, hypo/hyperkalemia, abd/chest pain) than SOC. Use of PTA vs. EUS did not affect grade 3/4 toxicity rates. Conclusions: TNF + SOC did not prolong OS for locally advanced PDA. SGA reveals a possible OS benefit for early stage (T1-T3) tumors and CA19-9 < 1000. PTA and EUS injection achieved similar rates of efficacy and toxicity. Grade 1-2 toxicity typical of systemic exposure to TNF-α (pyrexia/hypotension/chills) was common, but grade 3-4 was minimal.

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Differentiation of Pancreatic Ductal Adenocarcinoma From Chronic Pancreatitis by PAM4 Immunohistochemistry

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2013-0056-oa ◽

2014 ◽

Vol 138 (2) ◽

pp. 220-228 ◽

Cited By ~ 12

Author(s):

Chanjuan Shi ◽

Nipun Merchant ◽

Guy Newsome ◽

David M. Goldenberg ◽

David V. Gold

Keyword(s):

Monoclonal Antibody ◽

Chronic Pancreatitis ◽

Pancreatic Ductal Adenocarcinoma ◽

Early Stage ◽

High Specificity ◽

Intraepithelial Neoplasia ◽

Tissue Microarrays ◽

Ductal Adenocarcinoma ◽

Precursor Lesions ◽

Pancreatic Intraepithelial Neoplasia

Context.—PAM4 is a monoclonal antibody that shows high specificity for pancreatic ductal adenocarcinoma (PDAC) and its neoplastic precursor lesions. A PAM4-based serum immunoassay is able to detect 71% of early-stage patients and 91% with advanced disease. However, approximately 20% of patients diagnosed with chronic pancreatitis (CP) are also positive for circulating PAM4 antigen. The specificity of the PAM4 antibody is critical to the interpretation of the serum-based and immunohistochemical assays for detection of PDAC. Objective.—To determine whether PAM4 can differentiate PDAC from nonneoplastic lesions of the pancreas. Design.—Tissue microarrays of PDAC (N = 43) and surgical specimens from CP (N = 32) and benign cystic lesions (N = 19) were evaluated for expression of the PAM4 biomarker, MUC1, MUC4, CEACAM5/6, and CA19-9. Results.—PAM4 and monoclonal antibodies (MAbs) to MUC1, MUC4, CEACAM5/6, and CA19-9 were each reactive with the majority of PDAC cases; however, PAM4 was the only monoclonal antibody not to react with adjacent, nonneoplastic parenchyma. Although PAM4 labeled 19% (6 of 32) of CP specimens, reactivity was restricted to pancreatic intraepithelial neoplasia associated with CP; inflamed tissues were negative in all cases. In contrast, MUC1, MUC4, CEACAM5/6, and CA19-9 were detected in 90%, 78%, 97%, and 100% of CP, respectively, with reactivity also present in nonneoplastic inflamed tissue. Conclusions.—PAM4 was the only monoclonal antibody able to differentiate PDAC (and pancreatic intraepithelial neoplasia precursor lesions) from benign, nonneoplastic tissues of the pancreas. These results suggest the use of PAM4 for evaluation of tissue specimens, and support its role as an immunoassay for detection of PDAC.

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Concurrent and Convergent Validity of a Single, Brief Question for Physical Activity Assessment

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17061989 ◽

2020 ◽

Vol 17 (6) ◽

pp. 1989 ◽

Cited By ~ 1

Author(s):

Antonio Moreno-Llamas ◽

Jesús García-Mayor ◽

Ernesto De la Cruz-Sánchez

Keyword(s):

Physical Activity ◽

Convergent Validity ◽

High Specificity ◽

Cost Effective ◽

Classification Performance ◽

Short Version ◽

Operating Characteristics ◽

Time Saving ◽

Physically Active ◽

Specificity And Sensitivity

An extensive number of self-reported methods for physical activity (PA) measurement are available, including short and long recall questionnaires ranging from a few to tens of questions. Due to the fact that simple, time-saving methods could be more practical and desirable for use in a busy clinical context, as well as in public health surveys, we evaluated how a single-item question might be a useful and cost-effective method for assessing compliance with PA guidelines. Using multiple receiver operating characteristics (ROC), we assessed the classification performance of a single brief question, employing the short version of the International Physical Activity Questionnaire as criterion instrument, in a total of 55,950 people (30,601 women and 25,349 men). Both those who practice PA almost daily and a few times a week presented an upper threshold (1042.5 metabolic equivalent minutes (MET) minutes/week) to the established compliance PA guidelines (600 MET minutes/week) with high specificity and sensitivity, using a sedentary group as reference. Otherwise, the occasionally physically active group did not reach the minimum (349.5 MET minutes/week) and obtained a poorer classification performance. A single brief question is a pragmatic and alternative method for assessment of compliance with PA guidelines.

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Highly Sensitive and Cost-Effective Portable Sensor for Early Gastric Carcinoma Diagnosis

Sensors ◽

10.3390/s21082639 ◽

2021 ◽

Vol 21 (8) ◽

pp. 2639

Author(s):

Saw Lin Oo ◽

Shishir Venkatesh ◽

Vaithinathan Karthikeyan ◽

Clement Manohar Arava ◽

Spoorthy Pathikonda ◽

...

Keyword(s):

Gastric Carcinoma ◽

High Specificity ◽

Cost Effective ◽

Electrical Current ◽

Early Gastric Carcinoma ◽

Rna Modification ◽

Dependent Manner ◽

Cancer Antigen ◽

Concentration Dependent Manner ◽

Specificity And Sensitivity

Facile and efficient early detection of cancer is a major challenge in healthcare. Herein we developed a novel sensor made from a polycarbonate (PC) membrane with nanopores, followed by sequence-specific Oligo RNA modification for early gastric carcinoma diagnosis. In this design, the gastric cancer antigen CA72-4 is specifically conjugated to the Oligo RNA, thereby inhibiting the electrical current through the PC membrane in a concentration-dependent manner. The device can determine the concentration of cancer antigen CA72-4 in the range from 4 to 14 U/mL, possessing a sensitivity of 7.029 µAU−1mLcm−2 with a linear regression (R2) of 0.965 and a lower detection limit of 4 U/mL. This device has integrated advantages including high specificity and sensitivity and being simple, portable, and cost effective, which collectively enables a giant leap for cancer screening technologies towards clinical use. This is the first report to use RNA aptamers to detect CA72-4 for gastric carcinoma diagnosis.

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