Vani J.A. Konda M.D.

Dougherty, U., Mustafi, R., Zhu, H., Zhu, X., Deb, D., Meredith, S.C., Ayaloglu-Butun, F., Fletcher, M., Sanchez, A., Pekow, J., Deng, Z., Amini, N., Konda, V.J., Rao, V.L., Sakuraba, A., Kwesi, A., Kupfer, S.S., Fichera, A., Joseph, L., Hart, J., He, F., He, T.C., West-Szymanski, D., Li, Y.C. and Bissonnette, M. (2020). “Upregulation of polycistronic microRNA-143 and microRNA-145 in colonocytes suppresses colitis and inflammation-associated colon cancer.” Epigenetics Dec 28;1-18. [Epub ahead of print].

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Because ADAM17 promotes colonic tumorigenesis, we investigated potential miRNAs regulating ADAM17; and examined effects of diet and tumorigenesis on these miRNAs. We also examined pre-miRNA processing and tumour suppressor roles of several of these miRNAs in experimental colon cancer. Using TargetScan, miR-145, miR-148a, and miR-152 were predicted to regulate ADAM17. miR-143 was also investigated as miR-143 and miR-145 are co-transcribed and associated with decreased tumour growth. HCT116 colon cancer cells (CCC) were co-transfected with predicted ADAM17-regulating miRNAs and luciferase reporters controlled by ADAM17-3’UTR. Separately, pre-miR-143 processing by colonic cells was measured. miRNAs were quantified by RT-PCR. Tumours were induced with AOM/DSS in WT and transgenic mice (Tg) expressing pre-miR-143/miR-145 under villin promoter. HCT116 transfection with miR-145, -148a or -152, but not scrambled miRNA inhibited ADAM17 expression and luciferase activity. The latter was suppressed by mutations in ADAM17-3’UTR. Lysates from colonocytes, but not CCC, processed pre-miR-143 and mixing experiments suggested CCC lacked a competency factor. Colonic miR-143, miR-145, miR-148a, and miR-152 were downregulated in tumours and more moderately by feeding mice a Western diet. Tg mice were resistant to DSS colitis and had significantly lower cancer incidence and tumour multiplicity. Tg expression blocked up-regulation of putative targets of miR-143 and miR-145, including ADAM17, K-Ras, XPO5, and SET. miR-145, miR-148a, and miR-152 directly suppress colonocyte ADAM17 and are down-regulated in colon cancer. This is the first direct demonstration of tumour suppressor roles for miR-143 and miR-145 in an in vivo model of colonic tumorigenesis.

Struyvenberg, M.R., de Groof, A.J., Bergman, J.J., van der Sommen, F., de With, P.H.N., Konda, V.J.A. and Curvers, W.L. (2021). “Advanced Imaging and Sampling in Barrett’s Esophagus: Artificial Intelligence to the Rescue?” Gastrointest Endosc Clin N Am 31(1): 91-103.

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Because the current Barrett’s esophagus (BE) surveillance protocol suffers from sampling error of random biopsies and a high miss-rate of early neoplastic lesions, many new endoscopic imaging and sampling techniques have been developed. None of these techniques, however, have significantly increased the diagnostic yield of BE neoplasia. In fact, these techniques have led to an increase in the amount of visible information, yet endoscopists and pathologists inevitably suffer from variations in intra- and interobserver agreement. Artificial intelligence systems have the potential to overcome these endoscopist-dependent limitations.

Podgaetz, E. and Konda, V. (2020). “Experience and Technique for Zenker’s Diverticulum Per Oral Endoscopic Myotomy: Z-POEM.” Thorac Cardiovasc Surg Oct 21. [Epub ahead of print].

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OBJECTIVE: With the advent of minimally invasive surgery, incisionless surgery, and third-space endoscopy, the treatment for Zenker’s diverticulum has also moved toward less invasive techniques METHODS:  New incisionless per oral techniques can be applied for cricopharyngeal myotomy in Zenker’s diverticulum. RESULTS:  Five patients underwent Zenker’s diverticulum per oral endoscopic myotomy (Z-POEM) without complications, minimal discomfort, and narcotic consumption, with complete resolution of their symptoms by history and Eckardt scores. CONCLUSIONS:  Z-POEM is performed entirely endoscopically with very little associated pain or complication rates, with short-term follow-up having excellent functional and symptomatic results.

Struyvenberg, M. R., A. J. de Groof, R. Fonollà, F. van der Sommen, P. H. N. de With, E. J. Schoon, B. Weusten, C. L. Leggett, A. Kahn, A. J. Trindade, E. K. Ganguly, V. J. A. Konda, C. J. Lightdale, D. K. Pleskow, A. Sethi, M. S. Smith, M. B. Wallace, H. C. Wolfsen, G. J. Tearney, S. L. Meijer, M. Vieth, R. Pouw, W. L. Curvers and J. J. Bergman (2020). “Prospective development and validation of a volumetric laser endomicroscopy computer algorithm for detection of Barrett’s neoplasia.” Gastrointest Endosc Jul 28;S0016-5107(20)34647-2. [Epub ahead of print.].

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BACKGROUND AND AIMS: Volumetric laser endomicroscopy (VLE) is an advanced imaging modality used to detect Barrett’s esophagus (BE) dysplasia. However, real-time interpretation of VLE scans is complex and time-consuming. Computer-aided detection (CAD) may aid in the process of VLE image interpretation. Our aim was to train and validate a CAD algorithm for VLE-based detection of BE neoplasia. METHODS: The multicenter, VLE PREDICT study, prospectively enrolled 47 BE patients. In total, 229 nondysplastic BE, and 89 neoplastic (HGD/EAC) targets were laser marked under VLE guidance and subsequently biopsied for histological diagnosis. Deep convolutional neural networks were used to construct a CAD algorithm for differentiation between nondysplastic and neoplastic BE tissue. The CAD algorithm was trained on a set consisting of the first 22 patients (134 NDBE and 38 neoplastic targets) and validated on a separate test set of patients 23 to 47 (95 NDBE and 51 neoplastic targets). Finally, algorithm performance was benchmarked against the performance of 10 VLE experts. RESULTS: Using the Training set to construct the algorithm resulted in an accuracy of 92%, sensitivity of 95% and specificity of 92%. When performance was assessed on the Test set, accuracy, sensitivity, and specificity were 85%, 91%, and 82%, respectively. The algorithm outperformed all 10 VLE experts, who demonstrated an overall accuracy of 77%, sensitivity of 70%, and specificity of 81%. CONCLUSIONS: We developed, validated, and benchmarked a VLE CAD algorithm for detection of BE neoplasia using prospectively collected and biopsy-correlated VLE targets. The algorithm detected neoplasia with high accuracy and outperformed 10 VLE experts.

Struyvenberg, M. R., A. J. de Groof, A. Kahn, B. Weusten, D. E. Fleischer, E. K. Ganguly, V. J. A. Konda, C. J. Lightdale, D. K. Pleskow, A. Sethi, M. S. Smith, A. J. Trindade, M. B. Wallace, H. C. Wolfsen, G. J. Tearney, S. L. Meijer, C. L. Leggett, J. Bergman and W. L. Curvers (2020). “Multicenter study on the diagnostic performance of multiframe volumetric laser endomicroscopy targets for Barrett’s esophagus neoplasia with histopathology correlation.” Dis Esophagus Jul 1;doaa062. [Epub ahead of print.].

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Volumetric laser endomicroscopy (VLE) has been shown to improve detection of early neoplasia in Barrett’s esophagus (BE). However, diagnostic performance using histopathology-correlated VLE regions of interest (ROIs) has not been adequately studied. We evaluated the diagnostic accuracy of VLE assessors for identification of early BE neoplasia in histopathology-correlated VLE ROIs. In total, 191 ROIs (120 nondysplastic and 71 neoplastic) from 50 BE patients were evaluated in a random order using a web-based module. All ROIs contained histopathology correlations enabled by VLE laser marking. Assessors were blinded to endoscopic BE images and histology. ROIs were first scored as nondysplastic or neoplastic. Level of confidence was assigned to the predicted diagnosis. Outcome measures were: (i) diagnostic performance of VLE assessors for identification of BE neoplasia in all VLE ROIs, defined as accuracy, sensitivity, and specificity; (ii) diagnostic performance of VLE assessors for only high level of confidence predictions; and (iii) interobserver agreement. Accuracy, sensitivity, and specificity for BE neoplasia identification were 79% (confidence interval [CI], 75-83), 75% (CI, 71-79), and 81% (CI, 76-86), respectively. When neoplasia was identified with a high level of confidence, accuracy, sensitivity, and specificity were 88%, 83%, and 90%, respectively. The overall strength of interobserver agreement was fair (k = 0.29). VLE assessors can identify BE neoplasia with reasonable diagnostic accuracy in histopathology-correlated VLE ROIs, and accuracy is enhanced when BE neoplasia is identified with high level of confidence. Future work should focus on renewed VLE image reviewing criteria and real-time automatic assessment of VLE scans.