Person: Srivastava, Amitabh
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Srivastava
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Amitabh
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Srivastava, Amitabh
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Publication Non-Invasive Monitoring of Chronic Liver Disease via Near-Infrared and Shortwave-Infrared Imaging of Endogenous Lipofuscin(Springer Science and Business Media LLC, 2020-08) Saif, Mari; Kwanten, Wilhelmus J.; Carr, Jessica A.; Chen, Ivy X.; Posada, Jessica; Srivastava, Amitabh; Zhang, Juanye; Zheng, Yi; Pinter, Matthias; Chatterjee, Sampurna; Softic, Samir; Kahn, C.; van Leyen, Klaus; Bruns, Oliver T.; Jain, Rakesh; Bawendi, Moungi G.Monitoring the progression of non-alcoholic fatty liver disease is hindered by a lack of suitable non-invasive imaging methods. Here, we show that the endogenous pigment lipofuscin displays strong near-infrared and shortwave-infrared fluorescence when excited at 808 nm, enabling label-free imaging of liver injury in mice and the discrimination of pathological processes from normal liver processes with high specificity and sensitivity. We also show that the near-infrared and shortwave-infrared fluorescence of lipofuscin can be used to monitor the progression and regression of liver necroinflammation and fibrosis in mouse models of non-alcoholic fatty liver disease and advanced fibrosis, as well as to detect non-alcoholic steatohepatitis and cirrhosis in biopsied samples of human liver tissue.Publication Lymphovascular Invasion in Colorectal Cancer: An Interobserver Variability Study(Ovid Technologies (Wolters Kluwer Health), 2008) Harris, Elizabeth I.; Lewin, David N.; Wang, Hanlin L.; Lauwers, Gregory Y.; Srivastava, Amitabh; Shyr, Yu; Shakhtour, Bashar; Revetta, Frank; Washington, Mary K.Background: Lymphovascular invasion (LVI) in colorectal cancer (CRC) is considered a strong stage-independent prognostic factor and influences decisions regarding adjuvant chemotherapy in patients with Stage II tumors. However, the degree of interobserver agreement among pathologists for LVI in CRC is largely unknown. This study was undertaken to examine such interobserver variability, and we hypothesized that the use of immunohistochemical markers for vascular and lymphatic channels could improve interobserver agreement. Design: Fifty cases of AJCC stage II moderately differentiated CRC from 1990 to 2005 from the pathology archives were selected; mucinous, medullary, and other recognized special subtypes were excluded. Fifty H&E slides (one from each case) were circulated to 6 GI pathologists, who independently assessed small and large vessel invasion. No diagnostic guidelines were given to the participating pathologists; each was instructed to apply the criteria for LVI that he or she used in daily practice. Immunohistochemistry (IHC) for D2-40 and CD31 was performed on corresponding paraffin blocks. The IHC slides were randomized, recirculated, and rescored for LVI. Results were analyzed by kappa (κ)statistics, which correct for agreement by chance, and for percent agreement. Results: The average κ values were determined for the H&E slides (large and small vessel), CD31 (small vessel), and D2-40 (small vessel) (Figure 1). Agreement was fair for H&E small vessel invasion (κ = 0.28; 95%CI 0.22–0.34). The least agreement was seen in interpretation of H&E large vessel invasion (κ = 0.18; 95%CI 0.11–0.26). Agreement was not improved by use of immunohistochemical stains: CD31 (large vessel, κ = 0.42, 95%CI 0.20–0.63, small vessel, κ = 0.26, 95%CI 0.10–0.42) and D2-40 (κ = 0.32, 95%CI 0.21–0.42). Conclusions: Interobserver variability in diagnosis of LVI was substantial on H&E slides and did not improve upon use of IHC. Agreement in evaluation of large vessel invasion was only slightly higher than would be seen by chance alone. This study highlights the need for criteria in evaluation of lymphovascular invasion, as this assessment may impact patient prognosis and thus change the course of clinical treatment.Publication Divergent Expression of MUC5AC, MUC6, MUC2, CD10, and CDX-2 in Dysplasia and Intramucosal Adenocarcinomas With Intestinal and Foveolar Morphology: Is This Evidence of Distinct Gastric and Intestinal Pathways to Carcinogenesis in Barrett Esophagus?(Ovid Technologies (Wolters Kluwer Health), 2012) Khor, Tze Sheng; Alfaro, Eduardo E.; Ooi, Esther M. M.; Li, Yuan; Srivastava, Amitabh; Fujita, Hiroshi; Park, Youn; Kumarasinghe, Marian Priyanthi; Lauwers, Gregory Y.Dysplasia in Barrett esophagus has been recognized to be morphologically heterogenous, featuring adenomatous, foveolar, and hybrid phenotypes. Recent studies have suggested a tumor suppressor role for CDX-2 in the metaplasia-dysplasia-carcinoma sequence. The phenotypic stability and role of CDX-2 in the neoplastic progression of different types of dysplasias have not been evaluated. Thirty-eight endoscopic mucosal resections with dysplasia and/or intramucosal carcinoma (IMC) arising in Barrett esophagus were evaluated for the expression of MUC5AC, MUC6, MUC2, CD10, and CDX-2. The background mucosa was also evaluated. The results were correlated with morphologic classification and clinicopathologic parameters. Of 38 endoscopic mucosal resections, 23 had IMC and dysplasia, 8 had IMC only, and 7 had dysplasia only. Among dysplastic lesions, 73% were foveolar, 17% were adenomatous, and 10% were hybrid. Twenty of 23 cases with dysplasia and adjacent IMC showed an identical immunophenotype of dysplasia and IMC comprising 16 gastric, 3 intestinal, and 1 mixed immunophenotype. Three cases showed discordance of dysplasia and IMC immunophenotype. These findings suggest that most Barrett-related IMC cases are either gastric or intestinal, with phenotypic stability during progression supporting separate gastric and intestinal pathways of carcinogenesis. CDX-2 showed gradual downregulation of expression during progression in adenomatous dysplasia but not in foveolar or hybrid dysplasia, supporting a tumor suppressor role, at least in the intestinal pathway. CDX-2 was also found to be expressed to a greater degree in intestinal metaplasia compared with nonintestinalized columnar metaplasia. Consistent with CDX-2 as a tumor suppressor, this suggests that nonintestinalized columnar metaplasia may be an unstable intermediate state at risk for neoplastic progression.Publication Gastric Hyperplastic Polyps: A Heterogeneous Clinicopathologic Group Including a Distinct Subset Best Categorized as Mucosal Prolapse Polyp(Ovid Technologies (Wolters Kluwer Health), 2011) Gonzalez-Obeso, Elvira; Fujita, Hiroshi; Deshpande, Vikram; Ogawa, Fumihiro; Lisovsky, Mikhail; Genevay, Muriel; Grzyb, Krzysztof; Brugge, William; Lennerz, Jochen K.; Shimizu, Michio; Srivastava, Amitabh; Lauwers, Gregory Y.BACKGROUND: Gastric hyperplastic polyps are the second most common subtype of gastric polyps. There has been an ongoing debate about their precise diagnostic criteria and etiological associations. MATERIALS AND METHODS: A total of 208 gastric polyps that were originally diagnosed as hyperplastic polyps in our department during an 8-year period were reviewed using recently emphasized diagnostic criteria, and their clinicopathologic associations were explored. RESULTS: Only 41 cases were confirmed as hyperplastic polyps, whereas 103 cases (49%) were reclassified as polypoid foveolar hyperplasia, and 64 cases (31%) were diagnosed as gastric mucosal prolapse polyps. Gastric mucosal prolapse polyps were distinguished by basal glandular elements, hypertrophic muscle fibers ascending perpendicularly from the muscularis mucosae, and by thick-walled blood vessels. This hitherto undescribed polyp is more commonly sessile than hyperplastic polyps (P=0.0452) and is found more often in the antropyloric region (P: 0.0053). Only 20.6% of hyperplastic polyps were associated with Helicobacter pylori infection. CONCLUSIONS: Our findings highlight that gastric polypoid lesions that have morphologic similarities may be related to various mechanisms, including inflammatory and prolapse processes. The predominantly antral location of gastric mucosal prolapse polyps, a zone of pronounced peristalsis, suggests that mucosal prolapse plays a role in the development of these common polyps. Evaluation of the prevalence and clinical associations of these distinctive polyps awaits further studies.Publication NSAIDs Modulate Clonal Evolution in Barrett's Esophagus(Public Library of Science, 2013) Kostadinov, Rumen L.; Kuhner, Mary K.; Li, Xiaohong; Sanchez, Carissa A.; Galipeau, Patricia C.; Paulson, Thomas G.; Sather, Cassandra L.; Srivastava, Amitabh; Odze, Robert; Blount, Patricia L.; Vaughan, Thomas L.; Reid, Brian J.; Maley, Carlo C.Cancer is considered an outcome of decades-long clonal evolution fueled by acquisition of somatic genomic abnormalities (SGAs). Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce cancer risk, including risk of progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA). However, the cancer chemopreventive mechanisms of NSAIDs are not fully understood. We hypothesized that NSAIDs modulate clonal evolution by reducing SGA acquisition rate. We evaluated thirteen individuals with BE. Eleven had not used NSAIDs for 6.2±3.5 (mean±standard deviation) years and then began using NSAIDs for 5.6±2.7 years, whereas two had used NSAIDs for 3.3±1.4 years and then discontinued use for 7.9±0.7 years. 161 BE biopsies, collected at 5–8 time points over 6.4–19 years, were analyzed using 1Million-SNP arrays to detect SGAs. Even in the earliest biopsies there were many SGAs (284±246 in 10/13 and 1442±560 in 3/13 individuals) and in most individuals the number of SGAs changed little over time, with both increases and decreases in SGAs detected. The estimated SGA rate was 7.8 per genome per year (95% support interval [SI], 7.1–8.6) off-NSAIDs and 0.6 (95% SI 0.3–1.5) on-NSAIDs. Twelve individuals did not progress to EA. In ten we detected 279±86 SGAs affecting 53±30 Mb of the genome per biopsy per time point and in two we detected 1,463±375 SGAs affecting 180±100 Mb. In one individual who progressed to EA we detected a clone having 2,291±78 SGAs affecting 588±18 Mb of the genome at three time points in the last three of 11.4 years of follow-up. NSAIDs were associated with reduced rate of acquisition of SGAs in eleven of thirteen individuals. Barrett's cells maintained relative equilibrium level of SGAs over time with occasional punctuations by expansion of clones having massive amount of SGAs.Publication Lymph node metastasis from intestinal-type early gastric cancer: experience in a single institution and reassessment of the extended criteria for endoscopic submucosal dissection(Elsevier BV, 2010) Kang, Hyun Jeong; Kim, Dae Hyun; Jeon, Tae-Yong; Lee, Soo-Han; Shin, Nari; Chae, Sue-Hye; Kim, Gwang Ha; Song, Geum Am; Kim, Dong-Heon; Srivastava, Amitabh; Park, Do Youn; Lauwers, Gregory Y.BACKGROUND: Given the increasing use of endoscopic resection as a therapeutic modality for cases of early gastric cancer (EGC), it is very important to define strict criteria for the use of endoscopic mucosal resection and endoscopic submucosal dissection. To date, the criteria are almost entirely based on Japanese literature evaluating the risk of lymph node (LN) metastasis in patients with EGC. OBJECTIVE: To analyze our own experience with the factors affecting LN metastasis and to reappraise the extended criteria for endoscopic submucosal dissection. DESIGN: Retrospective, single-center study. SETTING: University teaching hospital. PATIENTS: This study involved 478 patients who underwent gastrectomy with LN dissection (n = 270, mucosal [m] EGC; n = 208, submucosal [sm] EGC). INTERVENTION: Gastrectomy with LN dissection. MAIN OUTCOME MEASUREMENTS: LN metastasis. RESULTS: Overall, 12.6% (60/478) of patients with EGCs presented with LN metastasis (mEGC, 3.0% [8/270], smEGC, 25.0% [52/208]). Increased size, macroscopic type (elevated), depth of invasion, and lymphovascular invasion were associated with LN metastasis. In 270 cases of mEGC, there was no relationship between clinicopathologic features and LN metastasis. In the smEGC group, size, depth of invasion, and lymphovascular emboli were associated with an increased risk of LN metastasis. Significantly, LN metastasis was noted in EGCs falling within established extended endoscopic submucosal dissection criteria, that is, intestinal-type mucosal cancer of any size without ulcer and no lymphovascular emboli (2/146 [1.4%]) or < or =3 cm with no lymphovascular emboli and irrespective of the presence of ulceration (2/126 [1.6%]) or intestinal-type submucosal cancer (sm1, <500 microm) without lymphovascular invasion and measuring < or =3 cm in size (3/20 [15.0%]). LIMITATIONS: Retrospective review of a single-center study. CONCLUSION: We recommend that more centers survey their experiences of LN metastasis in cases of EGC to refine the criteria for endoscopic submucosal dissection as a therapeutic modality of intestinal-type EGC.Publication CDX2 Expression in the Intestinal-Type Gastric Epithelial Neoplasia: Frequency and Significance.(Nature Publishing Group, 2010) Park, Do Youn; Srivastava, Amitabh; Kim, Gwang Ha; Mino-Kenudson, Mari; Deshpande, Vikram; Zukerberg, Lawrence; Song, Geum Am; Lauwers, Gregory Y.CDX2 is an intestinal transcription factor responsible for regulating the proliferation and differentiation of intestinal epithelial cells. In gastric adenocarcinoma, CDX2 expression is known to be associated with limited invasiveness and intestinal phenotypes. The aims of this study were to analyze CDX2 expression in a series of well-characterized cases of gastric epithelial dysplasia, based on the morphologic and mucin phenotypes, and also to analyze CDX2 expression along the metaplasia–dysplasia–carcinoma sequence. CDX2 expression was evaluated in 69 cases of gastric epithelial dysplasia, 88 cases of intestinal-type early gastric cancers, and 56 cases of advanced gastric cancers. Increased CDX2 expression was more frequently associated with adenomatous-type gastric epithelial dysplasia (27/31, 87%) compared with foveolar (7/15, 47%) or hybrid (10/23, 44%) types of gastric epithelial dysplasia (P=0.001). CDX2 expression correlated with an increase in CD10 expression (P=0.005), and a decrease in MUC5AC expression (P=0.001) in gastric epithelial dysplasia. CDX2 expression was also gradually decreased from gastric epithelial dysplasia, to early and advanced gastric cancers (present in 64, 40 and 27% of the cases, respectively). A negative correlation was also observed between CDX2 expression and the depth of tumor invasion. Our results indicate that CDX2 expression is associated with specific morphological and mucin phenotypes of gastric epithelial dysplasias, and decreases progressively with the advancing stage of gastric cancers, suggesting a possible tumor suppressor role for CDX2.Publication Oberhuber versus Marsh: much ado about nothing?(Shaheed Beheshti University of Medical Sciences, 2015) Srivastava, AmitabhPublication Histology of gluten related disorders(Shaheed Beheshti University of Medical Sciences, 2015) N Marsh, Michael; Villanacci, Vincenzo; Srivastava, AmitabhPublication SOX15 Governs Transcription in Human Stratified Epithelia and a Subset of Esophageal Adenocarcinomas(Elsevier BV, 2015-11) Sulahian, Rita; Chen, Justina; Arany, Zoltan; Jadhav, Unmesh; Peng, Shouyong; Rustgi, Anil K.; Bass, Adam; Srivastava, Amitabh; Hornick, Jason; Shivdasani, RameshBackground & Aims Intestinal metaplasia (Barrett’s esophagus, BE) is the principal risk factor for esophageal adenocarcinoma (EAC). Study of the basis for BE has centered on intestinal factors, but loss of esophageal identity likely also reflects the absence of key squamous-cell factors. As few determinants of stratified epithelial cell-specific gene expression have been characterized, identifying the necessary transcription factors is important. Methods We tested regional expression of mRNAs for all putative DNA-binding proteins in the mouse digestive tract and verified the esophagus-specific factors in human tissues and cell lines. Integration of diverse data defined a human squamous esophagus-specific transcriptome. We used chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) to locate transcription factor binding sites, computational approaches to profile the transcripts in cancer data sets, and immunohistochemistry to reveal protein expression. Results The transcription factor Sex-determining region Y-box 15 (SOX15) is restricted to esophageal and other murine and human stratified epithelia. SOX15 mRNA levels are attenuated in BE, and its depletion in human esophageal cells reduces esophageal transcripts significantly and specifically. SOX15 binding is highly enriched near esophagus-expressed genes, indicating direct transcriptional control. SOX15 and hundreds of genes coexpressed in squamous cells are reactivated in up to 30% of EAC specimens. Genes normally confined to the esophagus or intestine appear in different cells within the same malignant glands. Conclusions These data identify a novel transcriptional regulator of stratified epithelial cells and a subtype of EAC with bi-lineage gene expression. Broad activation of squamous-cell genes may shed light on whether EACs arise in the native stratified epithelium or in ectopic columnar cells.