Detection Of High-grade Dysplasia Research Articles

A Combined DNA/RNA-based Next-Generation Sequencing Platform to Improve the Classification of Pancreatic Cysts and Early Detection of Pancreatic Cancer Arising From Pancreatic Cysts.

We report the development and validation of a combined DNA/RNA next-generation sequencing (NGS) platform to improve the evaluation of pancreatic cysts. Despite a multidisciplinary approach, pancreatic cyst classification, such as a cystic precursor neoplasm, and the detection of high-grade dysplasia and early adenocarcinoma (advanced neoplasia) can be challenging. NGS of preoperative pancreatic cyst fluid improves the clinical evaluation of pancreatic cysts, but the recent identification of novel genomic alterations necessitates the creation of a comprehensive panel and the development of a genomic classifier to integrate the complex molecular results. An updated and unique 74-gene DNA/RNA-targeted NGS panel (PancreaSeq Genomic Classifier) was created to evaluate 5 classes of genomic alterations to include gene mutations (e.g., KRAS, GNAS, etc.), gene fusions and gene expression. Further, CEA mRNA ( CEACAM5 ) was integrated into the assay using RT-qPCR. Separate multi-institutional cohorts for training (n=108) and validation (n=77) were tested, and diagnostic performance was compared to clinical, imaging, cytopathologic, and guideline data. Upon creation of a genomic classifier system, PancreaSeq GC yielded a 95% sensitivity and 100% specificity for a cystic precursor neoplasm, and the sensitivity and specificity for advanced neoplasia were 82% and 100%, respectively. Associated symptoms, cyst size, duct dilatation, a mural nodule, increasing cyst size, and malignant cytopathology had lower sensitivities (41-59%) and lower specificities (56-96%) for advanced neoplasia. This test also increased the sensitivity of current pancreatic cyst guidelines (IAP/Fukuoka and AGA) by >10% and maintained their inherent specificity. PancreaSeq GC was not only accurate in predicting pancreatic cyst type and advanced neoplasia but also improved the sensitivity of current pancreatic cyst guidelines.

Post-endoscopy Esophageal Neoplasia in Barrett’s Esophagus: Consensus Statements From an International Expert Panel

Post-endoscopy Esophageal Neoplasia in Barrett’s Esophagus: Consensus Statements From an International Expert Panel

Diagnostic Performance of Artificial Intelligence-Based Models for the Detection of Early Esophageal Cancers in Barret's Esophagus: A Meta-Analysis of Patient-Based Studies.

IntroductionBarret’s esophagus (BE) is a precursor of adenocarcinoma of the esophagus. The detection of high-grade dysplasia and adenocarcinoma at an early stage can improve survival but is very challenging. Artificial intelligence (AI)-based models have been claimed to improve diagnostic accuracy. The aim of the current study was to carry out a meta-analysis of papers reporting the results of artificial intelligence-based models used in real-time white light endoscopy of patients with BE to detect early esophageal adenocarcinoma (EEAC).MethodsThis meta-analysis was registered with the International Prospective Register of Systematic Reviews (PROSPERO; Reg No. CRD42021246148) and its conduction and reporting followed the Preferred Reporting Items for Systematic Review and Meta-Analysis of Diagnostic Test Accuracy (PRISMA-DTA) statement guidelines. All peer-reviewed and preprint original articles that reported the sensitivity and specificity of AI-based models on white light endoscopic imaging as an index test against the standard criterion of histologically proven early oesophageal cancer on the background of Barret's esophagus reported as per-patient analysis were considered for inclusion. There was no restriction on type and year of publication, however, articles published in the English language were searched. The search engines used included Medline, PubMed, EMBASE, EMCARE, AMED, BNI, and HMIC. The search strategy included the following keywords for all search engines: ("Esophageal Cancer" OR "Esophageal Neoplasms" OR " Oesophageal Cancer" OR "Oesophageal Neoplasms” OR "Barrett's Esophagus" OR "Barrett's Oesophagus") And ("Artificial Intelligence" OR "Deep Learning" OR "Machine Learning" OR "Convolutional Network"). This search was conducted on November 30, 2020. Duplicate studies were excluded. Studies that reported more than one dataset per patient for the diagnostic accuracy of the AI-based model were included twice. Quantitative and qualitative data, including first author, year of publication, true positives (TP), false negatives (FN), false positives (FP), true negatives (TN), the threshold of the index test, and country where the study was conducted, were extracted using a data extraction sheet. The Quality Appraisal for Diverse Studies 2 (QUADS-2) tool was used to assess the quality of each study. Data were analyzed using MetaDTA, interactive online software for meta-analysis of diagnostic studies. The diagnostic performance of the meta-analysis was assessed by a summary receiver operating characteristics (sROC) plot. A meta-analysis tree was constructed using MetaDTA software to determine the effect of cumulative sensitivity and specificity on surveillance of patients with BE in terms of miss rate and overdiagnosis.ResultsThe literature search revealed 171 relevant records. After removing duplicates, 117 records were screened. Full-text articles of 28 studies were assessed for eligibility. Only three studies reporting four datasets met the inclusion criteria. The summary sensitivity and specificity of AI-based models were 0.90 (95% CI, 0.83- 0.944) and 0.86 (95% CI, 0.781-0.91), respectively. The area under the curve for all the available evidence was 0.88.ConclusionCollective evidence for the routine usage of AI-based models in the detection of EEAC is encouraging but is limited by the low number of studies. Further prospective studies reporting the patient-based diagnostic accuracy of such models are required.

Volumetric laser endomicroscopy features of dysplasia at the gastric cardia in Barrett’s oesophagus: results from an observational cohort study

ObjectiveVolumetric laser endomicroscopy (VLE) is an advanced imaging modality used in Barrett’s oesophagus (BE) to help identify dysplasia in the oesophagus. VLE criteria exist for oesophageal dysplasia but not for...

Excess Cost of Cervical Cancer Screening Beyond Recommended Screening Ages or After Hysterectomy in a Single Institution.

The aim of the study was to estimate the excess cost of guideline nonadherent cervical cancer screening in women beyond the recommended screening ages or posthysterectomy in a single healthcare system. All Pap tests performed between September 1, 2012, and August 31, 2014, in women younger than 21 years, older than 65 years, or after hysterectomy, were coded as guideline adherent or nonadherent per the 2012 America Society of Colposcopy and Clinical Pathology guidelines. We assumed management of abnormal results per the 2013 America Society of Colposcopy and Clinical Pathology management guidelines. Costs were obtained from a literature review and Center for Medicare and Medicaid Services data and applied to nonadherent screening and subsequent diagnostic tests. During this period, 1,398 guideline nonadherent Pap tests were performed (257 in women <21 years, 536 in women >65 years, and 605 after hysterectomy), with 88 abnormal results: 35 (13.5%) in women younger than 21 years, 14 (2.6%) in women older than 65 years, and 39 (6.5%) in women after hysterectomy. The excess cost for initial screening, diagnostic tests, and follow-up was US $35,337 for 2 years in women younger than 21 years, US $54,378 for 5 years in women older than 65 years, and US $77,340 for 5 years in women after hysterectomy, resulting in a total excess cost of US $166,100 for 5 years. Of the 1,398 women who underwent guideline nonadherent screening, there were only 2 (0.1%) diagnoses of high-grade dysplasia (VaIN3). Guideline nonadherent cervical cancer screening in women beyond the recommended screening ages and posthysterectomy resulted in costs exceeding US $160,000 for screening, diagnostic tests, and follow-up with minimal improvement in detection of high-grade dysplasia.

Application of Proteases as Molecular Imaging Tools for Early Gastric Cancer Detection: In Vitro and Ex Vivo Investigation

Background: Substantial miss-rate of gastric cancer by conventianl endoscope was reported, indicating the importance of novel biomarkers for early detection of precancerous and cancerous lesions. Objective: To identify potential biomarker molecules for early gastric cancer detection and evaluation of their application for molecular in vivo imaging. Method: Besides the CEA-TAG+/- mouse model, 3 human and 2 murine gastric cancer cell lines were applied in this study. Cells lines were cultured at standard conditions. To determine the expression pattern of the targets, total RNA was extracted from cultured cells; cDNA was synthesised and qPCR was performed using spcefic primers. The murine stomach was removed and washed with PBS. The stomach was macroscopically categorized into tumor region and normal tissues. Histopathology and imunohistochemitry was performed in one half of the tumor tissues using specific antibodies. In the other half of the tumour tissue, RNA was extracted, reverse transcribed into cDNA and qPCR was performed. Histopathology, immhunohistochemistry and qPCR was performed for tumor-adjescent normal tissues to compare the difference in expression pattern of the target. Finally, a cathepsin activatable probe was injected into mice intravenously. Ex vivo fluorescent imaging was performed after 24 h of intravenous injection of a cathepsin activatable probe. Gene expression was quantified by standard method with normalizing CT values to the housekeeping gene (Cyclophilin A). Results: Significantly elevated expression of cathepsins B, H and MMP2 in human and murine gastric cancer cell lines was detected. In addition, increased expression of cathepsins and MMPs was observed in murine primary gastric tumour specimens compared to the corresponding adjacent normal gastric mucosa (p<0.05, tumor versus normal mucosa). Accordingly, the NIRF probe was specifically activated in stomach tumor of CEA-TAG+/- mice and allowed ex vivo detection of the stomach tumor by Odyssey planar near-infrared scanner. Furthermore, immunohistochemical stainings with antibodies specific for cathepsins and MMPs indicated a stronger signal towards the tumor tissues compared to the adjacent normal mucosa. Conclusion: Cathepsins and MMPs are potential biomarkers for detection of high grade dysplasia and early gastric cancer in mouse models, revealing the potential applicability of the biomarkers in tumor imaging and therapeutic monitoring.

Enfermedad inflamatoria intestinal en la Digestive Disease Week 2016: novedades en epidemiología, seguimiento, monitorización y control terapéutico, y prevención del cáncer de colon

In Digestive Disease Week 2016, interesting data were presented on the eventual role of certain foods in inflammatory bowel disease, although the value of these data is relative. Also of interest were epidemiological studies, of which several analysed the natural history of the disease. Some presentations dealt with the search for individual predictive factors, a pressing need in clinical practice. Unfortunately, some of the findings presented were of dubious value. A study suggesting that a simple parameter as increased blood monocytes could be a clear predictive factor of poor outcome could perhaps be highlighted (the results were striking but had multiple limitations). In contrast, more interesting data were presented on monitoring and optimising biological therapy in the search for an individually-tailored approach. New studies were presented on the levels of distinct anti-TNF agents, vedolizumab and even ustekinumab. One study aimed to estimate the safety of anti-TNF agents on the basis of the patient's genetic (and clinical) features. There is no new evidence that will change our clinical practice. Equally, the data on colon cancer prevention will not modify our clinical practice, although one study reported a promising new strategy, consisting of the use of a new stool DNA test, with very promising results in the detection of high-grade dysplasia or colorectal cancer in these patients.

Classifying Barrett Esophagus with Narrow-Band Imaging

Narrow-band imaging (NBI) has shown variable results for improving endoscopists' detection of high-grade dysplasia (HGD) and early esophageal

Can we really continue to diagnose high grade dysplasia in Barrett’s esophagus in Europe without magnified virtual chromo-endoscopy?

Can we really continue to diagnose high grade dysplasia in Barrett’s esophagus in Europe without magnified virtual chromo-endoscopy?

Mo1647 Confocal Raman Spectroscopy for Real-Time In Vivo Detection of High-grade Dysplasia in Barrett's Esophagus During Endoscopic Examination

Mo1647 Confocal Raman Spectroscopy for Real-Time In Vivo Detection of High-grade Dysplasia in Barrett's Esophagus During Endoscopic Examination

Use of optical biomarkers from nondysplastic metaplastic cells on the detection of high-grade dysplasia and adenocarcinoma from Barrett’s esophagus.

14 Background: Patients with Barrett’s esophagus (BE), defined as presence of intestinal metaplasia (IM) in the esophagus, require surveillance due to an increased risk of developing esophageal adenocarcinoma (EAC). The biggest challenge in the current surveillance methodology (i.e., Seattle protocol) is random sampling with the inability to identify those patients with non-dysplastic BE on surveillance who have occult high grade dysplasia (HGD) or will eventually progress to HGD or EAC. We propose a novel approach based on the concept of field effect to detect HGD or EAC through the analysis of non-dysplastic IM, thus identifying a high risk BE population. Our group uses a unique microscope – spatial-domain low-coherence quantitative phase microscopy (SL-QPM) to detect changes in nuclear structure as small as 0.9 nm, a scale 1000 times smaller than what conventional microscopy detects. We hypothesize that the SL-QPM-derived optical biomarkers of non-dysplastic IM would distinguish BE patients with EAC/HGD from those without neoplasia. Methods: We performed a retrospective study of 60 BE patients who underwent Seattle protocol biopsies: 33 BE patients with IM only and 27 BE patients with HGD or EAC (21 HGD, 6 EAC). H&amp;E stained slides with non-dysplastic IM on review by an expert pathologist were used. The distance between the selected IM biopsy and HGD/EAC was 1 to 4 cm. Forty to 60 columnar cells from each case were analyzed. Results: We identified three optical biomarkers (nuclear optical path length, intra-nuclear uniformity, entropy) that can distinguish non-dysplastic BE from patients with HGD and EAC with statistical significance (P &lt; 0.01). A prediction model combining all three optical biomarkers can distinguish BE patients with HGD/EAC from those with IM only at 89% sensitivity and 76% specificity (accuracy = 0.87). Conclusions: The accurate assessment of nanoscale optical biomarkers by SL-QPM is a promising approach for detecting dysplastic/neoplastic Barrett’s epithelium from non-dysplastic IM. This approach could potentially simplify BE surveillance by identifying a subset of high-risk BE patients that warrant intensive surveillance.

A review of diagnostic utility of P16INK4A immunostaining as a marker of high-risk HPV and high-grade cervical intraepithelial neoplasia

The most frequent type of cervical cancer is squamous-cell carcinoma which develops from cervical intraepithelial neo-plasia (CIN) / squamous intraepithelial lesion (SIL). Its tumor-igenesis is related to human papillomavirus (HPV). High-risk HPV is integrated into the genome and leads to tumour progression. Cytological screening leads to detection of precursors and their mimics. P16 INK4a and Ki-67 immunohistochemistry assists in the histological differential diagnosis of precursors to reactive and metaplastic epithelium. P16 INK4a has emerged as a valuable surrogate marker for high-risk HPV infection and shows increased immunoexpression with worsening grades of CIN. Numerous studies have supported its role in the detection of high-grade dysplasia and have lead to the use of p16 INK4a immunohistochemistry in many laboratories. However, only a few studies have examined the possible predictive or prognostic value of p16 INK4a in CIN or cervical cancer. This review addresses some of the practical issues in the application of p16 INK4a in everyday practice, including the problems in the interpretation of the patterns of immunostaining and standardisation of the p16 INK4a scoring.

Equivocal and weakly positive hybrid capture 2 tests in women aged 50 and older

The performance of the Hybrid Capture 2 (HC2) test for human papilloma virus (HPV) detection depends on the prevalence of infection. However, the current HC2 manufacturer recommended interpretative algorithm is the same for all women. This test, which may be particularly useful in perimenopausal and postmenopausal women given the morphologic complexity of their Pap tests, could be affected by the overall lower prevalence of HPV infection in this age group. We investigated HC2 equivocal and weakly positive HPV tests in women 50 years and older and the detection of high-grade dysplasia (CIN2+) on their follow-up specimens. All HC2 test data from 1,067 consecutive specimens and 85 additional specimens from women ≥ 50-years-old with equivocal and weakly positive HC2 were analyzed. Follow-up specimens from women with HC2 tests within these ranges were reviewed. No CIN2+ was found on follow-up of 49 cases of women ≥ 50 with equivocal or weakly positive HC2 results. The current HC2 algorithm resulted in "positive" reports in 63% of specimens with initial equivocal HC2 due to retests mostly within the equivocal range. These results suggest that women 50 years and older may benefit from higher HC2 thresholds. The test could also be reported as HC2 values (RLU/CO) to be interpreted in view of risk factors.

Multicenter Study of a Fluorescence in Situ Hybridization Probe Set for the Detection of High Grade Dysplasia and Adenocarcinoma in Barrett's Esophagus

Multicenter Study of a Fluorescence in Situ Hybridization Probe Set for the Detection of High Grade Dysplasia and Adenocarcinoma in Barrett's Esophagus

W1159 Elastic Scattering Spectroscopy is Highly Accurate for the Detection of High Grade Dysplasia and DNA Ploidy Arising in Barrett's Esophagus Using a Red Enhanced Spectrometer

Introduction Elastic scattering spectroscopy (ESS) is an emerging optical diagnostic technique which detects cellular abnormalities in vivo. In patients undergoing endoscopic surveillance for Barrett9s oesophagus (BE), we have demonstrated ESS is able to detect high-grade dysplasia (HGD) and DNA ploidy, both associated with significant increase in 5-year cancer risk (59% and 28%, respectively). The spectrometer used had a wavelength range of 350–800 nm, where there is significant haemoglobin absorption. We hypothesise that a red enhanced spectrometer, more sensitive in the range 450 nm–1000 nm, would detect more scattering data and may improve detection rates. The aim of this in vivo study was to assess the influence of the spectral range of the spectrometer on accuracy of diagnosis. Methods Spectral data for each spectrometer were collected at matched sites in vivo. A biopsy of the site was then taken from each site and histopathology reviewed. DNA ploidy was then assessed by image cytometric DNA analysis (ICDA) on these biopsies as previously described. A diagnostic algorithm of best fit was generated by principle component and linear discriminant analysis on the histology and DNA ploidy data. Results 49 patients were enrolled in the study, with 217 sites analysed. ESS using a red enhanced spectra was able to distinguish squamous and columnar tissue with comparable accuracy to a standard spectrometer (91% sensitivity and 91% specificity). When comparing HGD vs non-dysplastic tissue, there was also little difference between the two spectrometers. Sensitivity with the red enhanced spectrometer was 84%, with specificity of 83%, respectively. The standard spectrometer sensitivity was 86% and specificity of 83%. When combining aneuploidy+HGD vs normal columnar tissue, however, the red spectrometer was more accurate with sensitivity 90% and specificity 80%. The standard spectrometer sensitivity was 90% but specificity was 74%. Conclusion These data demonstrate ESS is highly accurate for the detection of BE and associated HGD and molecular abnormalities in vivo, whichever spectrometer is used. The red enhanced spectrometer is somewhat more accurate for the detection of DNA ploidy abnormalities than a standard spectrometer. We intend to test this spectrometer in a prospective equivalence study, comparing ESS with targeted detection of HGD and aneuploidy vs surveillance with quadrantic biopsy.

511d: Is Biopsy Necessary in Narrow Band Imaging (NBI) Negative Patients?

NBI was developed primarily to emphasize the mucosal microvasculature and to identify vascular alterations indicative of dysplasia. In different studies, the sensitivity and positive predictive value for the detection of high grade dysplasia (HGD) using mucosal and vascular abnormalities in patients with Barrett's esophagus (BE) has been between 86-100%. There is limited data published on the significance of NBI negative examinations in patients with BE and subsequent progression of disease if any. The aim of this study was to determine the prevalence of HGD and intramucosal cancer (IMC) in patients who are NBI negative as well as to determine progression of disease in this subset of patients.

PWE-076 Elastic scattering spectroscopy is highly accurate for the detection of high-grade dysplasia and DNA ploidy arising in Barrett's oesophagus using a red enhanced spectrometer

PWE-076 Elastic scattering spectroscopy is highly accurate for the detection of high-grade dysplasia and DNA ploidy arising in Barrett's oesophagus using a red enhanced spectrometer

Biomarkers in Barrett's oesophagus

Biomarkers are needed to screen multiple stages in the clinical pathway of Barrett's oesophagus patients; from disease diagnosis to risk stratification and predicting response to therapy. Routes to the identification of biomarkers have been recognized by known molecular features of the disease and more recently through transcriptomic, methylation and proteomic screening approaches. The majority of Barrett's oesophagus patients remain undiagnosed in the general population. In order to develop a tool to screen for Barrett's oesophagus in the primary care setting, minimally invasive sampling methods coupled with immunocytology-based biomarkers are currently being assessed. Biomarkers may also have utility in surveillance programmes by allowing endoscopic interval to be adjusted according to individual neoplastic risk. Many individual biomarkers have been proposed in this regard, but have frequently been assessed in studies of limited power, or have lacked sufficient sensitivity or specificity when assessed in wider population-based studies. Biomarker panels may provide a route forward. In this regard, a panel of methylation markers has shown promise in a multicentre, double-blind, validation study. Biomarkers are also being developed to improve detection of high-grade dysplasia and oesophageal adenocarcinoma, utilizing brush cytology combined with FISH (fluorescence in situ hybridization), and to assess therapeutic success and risk of complication during photodynamic therapy. Finally, we outline progress in identifying alternative sources of biomarkers for this condition.

The role of HPV testing in patients with possible high‐grade cervical cytology

To assess the role of human papillomavirus (HPV) testing for high-risk types in an Australian population with the equivalent cytological result of atypical squamous cells of undetermined significance - possible high-grade (ASC-H). A retrospective review was conducted of all patients referred with a 'possible high-grade squamous abnormality' Pap-smear result who underwent HPV testing for 13 high-risk types, colposcopy and directed biopsy, and any subsequent treatment. The study included 100 patients. Overall, 79% of patients had a positive test for high-risk HPV DNA types. Histopathology was available for 98 patients and demonstrated that 47% of patients had confirmed high-grade dysplasia. HPV testing had a high sensitivity (98%), but low specificity (40%) for the detection of high grade dysplasia, and a negative predictive value of 95%. The results of this study suggest that among patients with the equivalent of ASC-H cytology, a negative HPV DNA test for high-risk types is a good predictor of the absence of high-grade dysplasia. HPV testing in this patient population therefore has the potential to reduce the number women referred for colposcopy.

Image-Guided Raman Endoscopic Probe for In Vivo Early Detection of High Grade Dysplasia

Objective: Raman spectroscopy is a molecular vibrational spectroscopic technique that is capable of optically detecting the biomolecular changes associated with diseased transformation. We have designed a rapid-acquisition dispersive-type near infrared (NIR) Raman system equipped with a specially designed Raman endoscopic probe which can be passed through the instrument channel of conventional endoscopes to acquire tissue Raman spectroscopic measurements at 785 nm laser excitation during endoscopy. The purpose of this study was to investigate the feasibility of applying this prototype for distinguishing high grade dysplasia from normal gastric mucosa tissues in vivo at endoscopy. Materials and Methods: A total of 24 in vivo tissue Raman spectra were acquired from different sites of the gastric antrum, in which 17 were from 4 patients who underwent endoscopic inspection for gastric cancer surveillance and 7 were from 1 patient who underwent endoscopic submucosal dissection (ESD). Histopathogical examinations of biopsy specimens obtained from the scanned sites of the 4 surveillance patients showed normal findings, while the dissected specimen from the ESD confirmed high grade dysplasia. Results: High-quality Raman spectra in the range of 800-1800 cm-1 were collected from in vivo gastric tissues in less than 1 second, together with the simultaneous utilization of white-light reflectance imaging modality for guiding the Raman endoscopic probe to the suspicious tissue sites. Raman spectral shapes were significantly different between normal and dysplasia, particularly in the spectral ranges of 850-900 cm-, 1000-1090 cm-, 1200-1305 cm- and 1600-1800 cm-, which contain signals related to hydroxyproline for collagen, phenylalanine, amide III, amide I and C=C stretching of lipids. The ratio of Raman intensities at 1450 to 1655 cm- provided a diagnostic sensitivity of 100%, specificity of 82.4% for identifying dysplasia from normal gastric tissues. The intensity ratio-based diagnostic algorithm achieved an integration area under the receiver operating characteristics curve of 0.9, confirming the diagnostic potential of near-infrared Raman spectroscopy for in vivo gastric dysplasia detection. Conclusion: This is the first in vivo Raman endoscopic spectroscopy in conjunction with white-light reflectance imaging to be used for distinguishing dysplasia from normal gastric mucosal tissues in real-time. This study suggests that near-infrared Raman technique may be a clinically useful endoscopic tool for in vivo detection and diagnosis of precancerous lesions in human stomach.