Intestinal Adenocarcinoma Research Articles

Analysis of the gastric microbiome in gastric cancer patients and in non-tumorous patients.

349 Background: Gastric cancer is the fifth most common cancer worldwide and it is the most commonly diagnosed cancer in Korea. The most clearly known microbiologic risk factor is Helicobacter pylori infection. Chronic inflammation of gastric mucosa accelerates a cascade of chronic active gastritis, multifocal atrophy intestinal metaplasia, gastric dysplasia and gastric adenocarcinoma. Studies proved H. pylori reduces microbial diversity, but it is reversible with H. pylori eradication. Thus, we could assume gastric carcinogenesis may not solely depend on H. pylori. In this study, we analyzed and compared gastric microbiome in gastric cancer patients and non-cancer patients to find changes between the two groups. Additionally, we analyzed microbial diversity of cancerous lesions and para-cancerous lesions in the cancer group in an effort to reveal the role of microbiome in carcinogenesis. Methods: Gastric mucosa collected by biopsy during esophagogastroduodenoscopy (EGD) from 10 patients with gastric cancer and 18 non-cancer patients. Gastric biopsies were obtained from the margin of cancer and para-cancerous lesions in cancer patients. In control group, samples were obtained from antrum with normal mucosal morphology. DNA was extracted from the gastric mucosal tissues and 16s rRNA genes were amplified. Then they were analyzed by microbiome analysis program. Results: Higher number of species was detected in the control group (average of 97.75 species) compared to the cancer group (average of 73.4 species). The gastric cancer microbiome was showed reduced microbial diversity compared to that of control group. Fusobacteria was more dominant in cancer group and Rhodobacterales was found more prominent in control group. We compared microbial diversity of the cancer lesion and the para-cancerous lesion within the cancer group and higher number of species was detected in non-tumorous lesion. Conclusions: Gastric microbiome of non-tumorous patients was more diverse and the composition of species was different between the two groups. These results suggest that microbial dysbiosis may be involved in gastric carcinogenesis. Further studies should include more detailed analysis of spatial and temporal composition and the comparison between different pathologic types and tumor location are necessary. Better understanding of microbial differences and changes in healthy and gastric cancer patients could verify the carcinogenesis of gastric cancer.

Association of an immunosuppressive macrophage transcriptional signature derived from peripheral blood macrophages with gastric cancer prognosis.

354 Background: Gastric cancer (GC) is the fourth most common cause of cancer death worldwide. Studies have shown an association of higher macrophage density in the tumor microenvironment with worse outcomes in GC. The presence of M2 specific gene signatures in the peripheral blood of cancer patients are associated with poor prognosis. However, it is unknown whether these immunosuppressive M2 markers are prognostic when found in the primary GC tumors. Methods: Based on previously published differential gene expression profiles that distinguish M1 versus M2 macrophages in the peripheral blood, we used the UCSC Xena webtool to analyze the TCGA Stomach Cancer cohort for tumor-associated immune signatures for their prognostic value. We excluded null entries, normal tissue, and entries with incomplete data. We investigated both M1- and M2-macrophage signatures (M1 signature: CCR7, IL2RA, CXCL11, CCL19, CXCL10, PLA1A, PTX3 and M2 signature: MRC1, MS4A4A, CD36, CCL13, CCL18, CCL23, SLC38A6, FGL2, FN1, MAF); as well as a T cell cytolytic signature defined by genes with cytolytic functions ( GZMA, GZMB, GZMH, GZMM, PRF1). We analyzed the impact of transcriptional gene expression with relation to stage, histological subtype, overall survival (OS), and disease free interval (DFI). The UCSC Xena webtool uses log-rank test to compare Kaplan-Meier curves. Results: A total of 341 entries were analyzed with age ranging from 30-90 and 39.4% female. Increased CD168 expression was associated with increased stage of GC (p = 0.017). Higher expression of the M2-macrophage signature was associated with diffuse type adenocarcinoma and mucinous type intestinal adenocarcinoma, compared to tubular and papillary type intestinal adenocarcinoma (p < 0.001). In addition, higher M2-macrophage signature expression was associated with late stage (Stage II or above) compared to early stage (stage I) (p = 0.022). A low M2-macrophage signature was associated with improved 5-year OS (p = 0.029), and a significantly improved 5-year DFI (p = 0.042). CD8A, cytolytic T cell signature, and M1 macrophage signature were not associated with stage of disease or survival. Conclusions: A transcriptional signature derived from peripheral blood immunosuppressive M2 macrophage phenotype is found in GC primary tumors and associated with higher pathologic staging and with worse outcomes. These M2 defining molecular biomarkers of GC has the potential to serve as targets of novel immune-therapeutic strategies.

Outcomes of patients with small intestine adenocarcinoma (SIA) in a Canadian province: A population-based cohort study.

641 Background: SIA is a rare cancer. Limited data is available about clinicopathological factors and interventions that correlate with its outcomes. The current study aims to determine outcomes of patients with SIA who were diagnosed in a Canadian province. Methods: In this retrospective population-based cohort study patients with biopsy proven SIA diagnosed during 2008-2017 in the province of Saskatchewan were assessed. A Cox Proportional multivariate regression analysis was performed to determine correlation between survival and exploratory factors. Results: 112 eligible patients with median age of 73 yrs and M:W 53: 59 were identified. 75% had a comorbid illness, 34% had a secondary cancer and 45% had WHO performance status (PS) < 2. Of 112 patients, 51 (46%) had early-stage disease and 61 (54%) had advanced-stage disease. Median neutrophil: lymphocyte (NLR) was 4.5. The median overall survival (mOS) in relation to stage of the disease were as follow: stage 1, 59 months, stage 2, 30 months, stage 3, 20 months and stage 4, 3 months (P < 0.001). The patients with early-stage disease had mOS of 36.0 months (95% CI: 8.0-64.0) vs. 3.0 months (1.74-4.26) with advanced disease (P < 0.0001). Of 21 patients with stage 3 disease their median disease-free survival was 26 months (23.1-28.9) with chemotherapy vs. 4 months (0.0-9.1) with no chemotherapy, p = 0.04. Patients with stage 4 disease who had surgery and or chemotherapy had mOS of 18 months (13.70-23.32) vs. 4 months (2.20-5.82) with chemotherapy alone p = 0.03. On univariate analysis age ≥70 yrs, WHO PS > 1, stage 4 disease, low albumin, elevated creatinine, high alkaline phosphatase, duodenal cancer, lack of surgery, and NLR of > 4.50 were significantly correlated with inferior survival. On multivariate analysis stage 4 disease, HR, 3.20 (95%CI:1.84-5.40), WHO PS > 1, HR, 2.22 (1.42-3.45), no surgery, HR, 2.10 (1.25-3.50), and NLR > 4.5, HR, 1.72 (1.10-2.71) were significantly correlated with inferior survival. Conclusions: Most patients with SIA were diagnosed with advanced-stage. In addition to advanced-stage disease and poor PS, lack of surgery and baseline LNR of > 4.5 were significantly correlated with inferior survival.

Metabolism and Health Effects of Rare Sugars in a CACO-2/HepG2 Coculture Model.

Non-alcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease worldwide and is impacted by an unhealthy diet with excessive calories, although the role of sugars in NAFLD etiology remains largely unexplored. Rare sugars are natural sugars with alternative monomers and glycosidic bonds, which have attracted attention as sugar replacers due to developments in enzyme engineering and hence an increased availability. We studied the impact of (rare) sugars on energy production, liver cell physiology and gene expression in human intestinal colorectal adenocarcinoma (Caco-2) cells, hepatoma G2 (HepG2) liver cells and a coculture model with these cells. Fat accumulation was investigated in the presence of an oleic/palmitic acid mixture. Glucose, fructose and galactose, but not mannose, l-arabinose, xylose and ribose enhanced hepatic fat accumulation in a HepG2 monoculture. In the coculture model, there was a non-significant trend (p = 0.08) towards higher (20–55% increased) median fat accumulation with maltose, kojibiose and nigerose. In this coculture model, cellular energy production was increased by glucose, maltose, kojibiose and nigerose, but not by trehalose. Furthermore, glucose, fructose and l-arabinose affected gene expression in a sugar-specific way in coculture HepG2 cells. These findings indicate that sugars provide structure-specific effects on cellular energy production, hepatic fat accumulation and gene expression, suggesting a health potential for trehalose and l-arabinose, as well as a differential impact of sugars beyond the distinction of conventional and rare sugars.

An extremely rare malignant tumour of nasopharynx: primary nasopharyngeal non salivary type adenocarcinoma

<p>Adenocarcinoma is commonly found in lung, prostate and gastrointestinal tract. Nasopharyngeal part contributes a very small percentage of adenocarcinoma as the most common histopathology found here is squamous cell carcinoma. We present a case of nasopharyngeal adenocarcinoma which is a very rare clinical presentation. This is 35 years old Iban gentleman, with underlying retroviral disease, hepatitis B on treatment, presented with right neck swelling for 3 months associated with right ear fullness. Examination showed unilateral right level II neck swelling and nasal endoscopy showed mass arising from right fossa of Rosen muller (FOR). The investigation done includes biopsy of right FOR and biopsy of right neck swelling with contrast enhanced computed tomography of neck, thorax and abdomen. The result of right FOR biopsy is non intestinal type adenocarcinoma, and biopsy of right neck swelling is reported as metastatic undifferentiated carcinoma. CECT NTAP showed asymmetry with fullness of right FOR associated with right level II cervical lymphadenopathy. Our centre managed this case with surgical intervention and patient underwent endoscopic nasopharyngectomy, and planned for right modified radical neck dissection (MRND). Patient defaulted our follow up after operation and was not keen for neck dissection surgery. He presented the second time with bilateral neck swelling and underwent chemotherapy and defaulted the follow up thereafter again. In conclusion the approach in treatment for nasopharyngeal carcinoma (NPC) and sino-nasal adenocarcinoma differs whereby the cornerstone management for the latter one is surgical intervention compared to the former which is radiotherapy. Hence early detection and treatment is essential.</p>

Clinical inflammatory biomarkers associated with the tumor stage of gastric cancer: retrospective analysis of a Hospital in Peru during the years 2018–2020

Introduction: Gastric cancer is a disease with a high rate of morbidity and mortality in the world. Objective: To determine which clinical inflammatory biomarkers are associated with the tumor stage of gastric cancer of the oncology service of the Hospital María Auxiliadora in Lima, Peru, during the years 2018-2020. Methodology: Observational, analytical, cross-sectional and retrospective study. There was a sample of 110 patients. The PR values ​​were obtained from the absolute frequencies of the variables: serum albumin, Platelet-Lymphocyte Ratio (PLR) and Neutrophil-Lymphocyte Ratio (NLR). Results: The average age was 63,727±13.85. 55.45% were female. The most frequent histopathological type was intestinal adenocarcinoma with 62.73%. In the bivariate analysis, an association was found between INL (PR:6.88 CI95% 2.36-20 p<0.001), IPL (PR:2.55 CI95% 1.68-3.86 p<0.001) and serum albumin (PR:3.16 CI95% 1.91-5.24 p<0.001) in the advanced clinical stage. The multivariate analysis found a relationship between INL and clinical stage (PR:4.11 CI95% 1.25-13.49 p=0.020) Conclusion: INL is an independent predictive factor in relation to the clinical stage of gastric cancer in this study.

Preneoplastic lesions in the liver: Molecular insights and relevance for clinical practice.

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the most frequent primary liver cancers, accounting for approximately 80% and 15%, respectively. HCC carcinogenesis occurs mostly in cirrhosis and is a complex multi-step process, from precancerous lesions (low-grade and high-grade dysplastic nodules) to progressed HCC. During the different stages of liver carcinogenesis, there is an accumulation of pathological, genetic and epigenetic changes leading to initiation, malignant transformation and finally tumour progression. In contrast, a small subset of HCC occurs in normal liver from the transformation of hepatocellular adenoma (HCA), a benign hepatocellular tumour. The recent molecular classification enables to stratify HCAs according to their risk of complication, in particular malignant transformation, associated with mutations in exon 3 of the catenin beta 1 (CTNNB1) gene. Cholangiocarcinoma (CCA) derives from the multistep malignant transformation of preneoplastic lesions, like biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB), for which a pre-operative diagnosis remains difficult. Different genetic alterations are involved in BilIN and IPNB progression, leading to the development of tubular or intestinal adenocarcinoma. The aims of this review are to describe the main clinical and molecular features of preneoplastic lesions leading to the development of HCC and CCA, their implications in clinical practice and the perspectives for future research.

Loss of MMR and TGFBR2 Increases the Susceptibility to Microbiota-Dependent Inflammation-Associated Colon Cancer.

Background and AimsMutations in DNA mismatch repair (MMR) genes are causative in Lynch syndrome and a significant proportion of sporadic colorectal cancers (CRCs). MMR-deficient (dMMR) CRCs display increased mutation rates, with mutations frequently accumulating at short repetitive DNA sequences throughout the genome (microsatellite instability). The TGFBR2 gene is one of the most frequently mutated genes in dMMR CRCs. Therefore, we generated an animal model to study how the loss of both TGFBR2 signaling impacts dMMR-driven intestinal tumorigenesis in vivo and explore the impact of the gut microbiota.MethodsWe generated VCMsh2/Tgfbr2 mice in which Msh2loxP and Tgfbr2loxP alleles are inactivated by Villin-Cre recombinase in the intestinal epithelium. VCMsh2/Tgfbr2 mice were analyzed for their rate of intestinal cancer development and for the mutational spectra and gene expression profiles of tumors. In addition, we assessed the impact of chemically induced chronic inflammation and gut microbiota composition on colorectal tumorigenesis.ResultsVCMsh2/Tgfbr2 mice developed small intestinal adenocarcinomas and CRCs with histopathological features highly similar to CRCs in Lynch syndrome patients. The CRCs in VCMsh2/Tgfbr2 mice were associated with the presence of colitis and displayed genetic and histological features that resembled inflammation-associated CRCs in human patients. The development of CRCs in VCMsh2/Tgfbr2 mice was strongly modulated by the gut microbiota composition, which in turn was impacted by the TGFBR2 status of the tumors.ConclusionsOur results demonstrate a synergistic interaction between MMR and TGFBR2 inactivation in inflammation-associated colon tumorigenesis and highlight the crucial impact of the gut microbiota on modulating the incidence of inflammation-associated CRCs.

A case of colorectal-type intestinal adenocarcinoma considered to be derived from a teratoma

A case of colorectal-type intestinal adenocarcinoma considered to be derived from a teratoma

Olfactomedin 4 Is Not a Precise Marker for Human Intestinal Stem Cells, But Is Involved in Intestinal Carcinogenesis

Olfactomedin 4 Is Not a Precise Marker for Human Intestinal Stem Cells, But Is Involved in Intestinal Carcinogenesis

Prognostic Value of LC3B and p62 Expression in Small Intestinal Adenocarcinoma.

Autophagy, a mechanism that maintains cellular homeostasis, is involved in tumor cell growth and survival in cancer, and autophagy inhibitors have been tested clinical trials for anticancer therapy. To elucidate the clinical and prognostic implications of autophagy in small intestinal adenocarcinoma (SIAC), we assessed the expression of autophagy markers, LC3B and p62, in 171 surgically resected primary SIACs using automated quantitative analysis. Positive LC3B, p62 nuclear (p62Nu), and p62 cytoplasmic (p62Cy) expression was observed in 23 (13.5%), 52 (30.4%), and 43 (25.1%) carcinomas, respectively. LC3B+ expression was correlated with undifferentiated carcinoma (p < 0.001) and high histologic grade (p = 0.029). The combined expression of LC3B and p62Nu (LC3+/p62Nu+) was related to the older age of patients (p = 0.017), undifferentiated carcinoma (p < 0.001), and high grade (p = 0.031). LC3B+ (p = 0.006), p62Cy+ (p = 0.041), or p62Nu+ (p = 0.006) expression were associated with worse survival. In addition, SIAC patients with either LC3B+/p62Nu+ (p = 0.001) or LC3B+/p62Cy+ (p = 0.002) expression had shorter survival times. In multivariate analysis, LC3B expression remained an independent prognostic factor (p = 0.025) for overall survival. In conclusion, autophagy may play a role in the tumorigenesis of SIACs, and LC3B and p62 could be used as prognostic biomarkers and potential therapeutic targets for SIACs.

Gastrointestinal Goblet Cell Adenocarcinomas Harbor Distinctive Clinicopathological, Immune, and Genomic Landscape

Goblet cell adenocarcinoma (GCA) is a rare amphicrine tumor and difficult to diagnose. GCA is traditionally found in the appendix, but extra-appendiceal GCA may be underestimated. Intestinal adenocarcinoma with signet ring cell component is also very rare, and some signet ring cell carcinomas are well cohesive, having some similar morphological features to GCAs. It is necessary to differentiate GCA from intestinal adenocarcinomas with cohesive signet ring cell component (IACSRCC). The goal of this study is to find occurrence of extra-appendiceal GCA and characterize the histological, immunohistochemical, transcriptional, and immune landscape of GCA. We collected 12 cases of GCAs and 10 IACSRCCs and reviewed the clinicopathologic characters of these cases. Immunohistochemical stains were performed with synaptophysin, chromogranin A, CD56, somatostatin receptor (SSTR) 2, and Ki-67. Whole transcriptome RNA-sequencing was performed, and data were used to analyze differential gene expression and predict immune cell infiltration levels in GCA and IACSRCC. RNA-sequencing data for colorectal adenocarcinoma were gathered from TCGA data portal. Of the 12 patients with GCA, there were 4 women and 8 men. There were three appendiceal cases and nine extra-appendiceal cases. GCAs were immunohistochemically different from IACSRCC. GCA also had different levels of B-cell and CD8+ T-cell infiltration compared to both colorectal adenocarcinoma and cohesive IACSRCCs. Differential gene expression analysis showed distinct gene expression patterns in GCA compared to colorectal adenocarcinoma, with a number of cancer-related differentially expressed genes, including upregulation of TMEM14A, GOLT1A, DSCC1, and HSD17B8, and downregulation of KCNQ1OT1 and MXRA5. GCA also had several differentially expressed genes compared to IACSRCCs, including upregulation of PRSS21, EPPIN, RPRM, TNFRSF12A, and BZRAP1, and downregulation of HIST1H2BE, TCN1, AC069363.1, RP11-538I12.2, and REG4. In summary, the number of extra-appendiceal GCA was underestimated in Chinese patients. GCA can be seen as a distinct morphological, immunohistochemical, transcriptomic, and immunological entity. The classic low-grade component of GCA and the immunoreactivity for neuroendocrine markers are the key points to diagnosing GCA.

SHANK2-FGFR1: A Novel FGFR1 Rearrangement in a Patient with Intestinal Adenocarcinoma.

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OLFM4-RET fusion is an oncogenic driver in small intestine adenocarcinoma.

Small intestine adenocarcinoma is a rare intestinal malignancy with distinct clinical, pathological, and molecular characteristics. Recently, a fusion of the intestinal stem-cell marker olfactomedin 4 (OLFM4) and the proto-oncogene RET has been identified in a small intestine adenocarcinoma patient. Here we investigated the biological effects of OLFM4-RET fusion and whether it can initiate tumorigenesis in small intestine. OLFM4 expression was found to be frequently lost or reduced in human small intestine adenocarcinoma, and its downregulation correlated with high tumor grade and advanced tumor stage. Expression of OLFM4-RET fusion-induced cellular transformation in HEK293 cells and blocked RET-induced inhibition of colony growth in HuTu 80 small intestine adenocarcinoma cells. Further, expression of OLFM4-RET activated the RAS-RAF-MAPK and STAT3 cell signaling pathways in both HEK293 cells and HuTu 80 cells. OLFM4-RET expression in HEK293 cells upregulated multiple families of genes related to carcinogenesis, cancer progression, and metastasis. Targeted expression of OLFM4-RET in the small intestine led to the development of hyperplasia, adenoma, or adenocarcinoma in transgenic mice. Our study suggests that OLFM4-RET is an oncogenic driver of small intestine tumorigenesis. Therefore, the small intestine adenocarcinoma patients with OLFM4-RET fusion may benefit from treatment with RET kinase inhibitor.

Preliminary study of CT features of intermediate- and high-grade alimentary lymphoma and adenocarcinoma in cats.

The ultrasonographic findings of many feline intestinal tumours are similar. This study evaluated the CT features of intermediate- and high-grade alimentary lymphoma and adenocarcinoma in cats. CT was performed on six cats with adenocarcinoma and 14 cats with lymphoma. Comparisons between tumour types were conducted, focusing on CT features, including obstruction (present or absent), growth patterns of lesions (symmetry or asymmetry), layering enhancement (present or absent), location of the lesion, number of lesions (solitary or multiple), lymphadenopathy (present or absent), location of lymphadenopathy, pulmonary metastasis (present or absent) and maximum thickness (mm) of the lesion. The cats with adenocarcinoma (n = 5/6 [83%]) experienced intestinal obstruction significantly more often than cats with lymphoma (n = 0/14 [0%]; P = 0.0004). Layering enhancement was observed significantly more often in cats with adenocarcinoma (n = 6/6 [100%]) than in cats with lymphoma (n = 1/14 [7%]; P = 0.0002). Lymphadenopathy was detected significantly more often in cats with lymphoma (n = 14/14 [100%]) than in cats with adenocarcinoma (n = 2/6 [33%]) (P = 0.003). In cats with lymphoma, the intestine (12.1 ± 3.9 mm) was significantly thicker than that in cats with adenocarcinoma (6.4 ± 2.3 mm; P = 0.005). To the best of our knowledge, no reports have described the characteristics of feline intestinal tumours using CT. Layering enhancement was observed in cats with intestinal adenocarcinomas. No layering enhancement was observed in alimentary lymphoma in cats, but enlarged regional nodes were noted. Lesions with lymphoma were thicker than those with adenocarcinoma. These findings may help differentiate between adenocarcinomas and lymphomas.

S3047 Small Intestinal Adenocarcinoma: Rarely Considered, Often Missed on Endoscopy

S3047 Small Intestinal Adenocarcinoma: Rarely Considered, Often Missed on Endoscopy

WNT2 activation through proximal germline deletion predisposes to small intestinal neuroendocrine tumors and intestinal adenocarcinomas.

Many hereditary cancer syndromes are associated with an increased risk of small and large intestinal adenocarcinomas. However, conditions bearing a high risk to both adenocarcinomas and neuroendocrine tumors are yet to be described.We studied a family with 16 individuals in four generations affected by a wide spectrum of intestinal tumors, including hyperplastic polyps, adenomas, small intestinal neuroendocrine tumors, and colorectal and small intestinal adenocarcinomas.To assess the genetic susceptibility and understand the novel phenotype, we utilized multiple molecular methods, including whole genome sequencing, RNA sequencing, single cell sequencing, RNA in situ hybridization and organoid culture.We detected a heterozygous deletion at the cystic fibrosis locus (7q31.2) perfectly segregating with the intestinal tumor predisposition in the family. The deletion removes a topologically associating domain border between CFTR and WNT2, aberrantly activating WNT2 in the intestinal epithelium. These consequences suggest that the deletion predisposes to small intestinal neuroendocrine tumors and small and large intestinal adenocarcinomas, and reveals the broad tumorigenic effects of aberrant WNT activation in the human intestine.

Specific survival nomograms based on SEER database for small intestine adenocarcinoma.

Small intestine cancers, as an extremely rare tumor type, account only for 3% of all gastrointestinal tumors. Small intestine adenocarcinoma (SIA), representing approximately one-third of all small bowel cancers, has received relatively little attention, both in research efforts and clinical cognizance. Owing to anatomical proximity and rarity, small bowel adenocarcinomas are frequently grouped with colorectal adenocarcinomas. Therefore, a large SIA patient cohort is needed to develop and validate new nomogram prognostic models specific to SIA patients. Patients diagnosed with SIA between 2004 and 2016 were extracted from the Surveillance, Epidemiology, and Final Results (SEER) database. All patients were randomly assigned to the training cohort and the validation cohort (2:1). The basic clinical information, detailed pathological staging, and treatment information of the patients were included in the analysis. Nomograms were shaped following the evaluations of the Cox regression model and verified using the decision curve analysis (DCA), time-dependent receiver operating characteristic (ROC) curves, concordance index (C-index), and calibration curves. The entire group comprised 6,947 patients with small intestine adenocarcinoma. According to the results of the multivariate Cox regression analysis, ten variables, including marital status, age, pathological grade, tumor location, T (tumor), N (nodes), M (metastasis) stage, surgery, chemotherapy, and regional nodes examined (RNE), were independent predictors of both of overall survival (OS) and cancer-specific survival (CSS). All significant variables were used to create the nomograms for OS and CSS. Various methods verified the reliability of the nomograms. The C-indexes of the OS and CSS nomogram were 0.756 (95% CI, 0.748-0.764) and 0.771 (95% CI, 0.761-0.781) in the training cohort and 0.748 (95% CI, 0.736-0.760) and 0.767 (95% CI, 0.752-0.781) in the validation cohort. The calibration curve showed good agreement between the nomogram prediction and actual survival. DCA indicated a clear net benefit of these new forecasting models. This study built and verified nomograms to predict OS and CSS for rare SIA, which appear to be excellent tools to augment the clinically available evidence to facilitate the discussion between SIA patients and clinicians regarding therapeutic choice.

P-147 Favorable survival for endonasal endoscopic resection in locally advanced sinonasal intestinal type adenocarcinoma: a long-term comparative study

P-147 Favorable survival for endonasal endoscopic resection in locally advanced sinonasal intestinal type adenocarcinoma: a long-term comparative study

#51: Neurotropic Astrovirus-VA1: Identifying the distinctions from classical genotypes

Abstract Background Human astroviruses (HAstV) are a leading cause of acute gastroenteritis in children, particularly those under the age of 2 or with immunosuppressive conditions. Indeed, our studies suggest that children with hematological malignancies are at high risk of infection. However, it has become increasingly clear that HAstV infections can also be associated with respiratory and even central nervous system (CNS) diseases. In the last decade, there have been at least 12 cases of astrovirus-induced CNS disease resulting in encephalitis and meningitis, including 2 St Jude patients. The CNS-associated infections are overwhelmingly fatal and are primarily caused by a novel astrovirus genotype, VA1, that is genetically more similar to animal astroviruses that also induce CNS-associated infections. The recent ability to propagate the VA1 strain in cell lines affords us the opportunity to better understand VA1 infection and how it compares to the better-studied HAstV1 strain. Methods Viral kinetics were determined by infection of human intestinal adenocarcinoma Caco-2 cells with either HAstV1 or VA1 and monitored for 24 hours post-infection (hpi). Infected cells were identified via immunofluorescent microscopy using antibodies against double-stranded RNA and viral capsid. Epithelial permeability of astrovirus-infected Caco-2 cells was measured using transepithelial electrical resistance (TER) and monitored for 24hpi. Nitazoxanide efficacy was identified by immunofluorescent analysis as described previously. Results Our findings demonstrate that HAstV1 and VA1 replicate in intestinal epithelial cells without inducing cell death or a pro-inflammatory cytokine response. However, these two strains have distinct replication kinetics. VA1 appears to have an ~8 hour lag in the expression of dsRNA and capsid protein compared to HAstV1 and does not require exogenous proteases to process the viral outer coat (capsid) protein, Additionally, we demonstrated that the increase in epithelial barrier permeability associated with HAstV1-infection is not found in VA1-infected cells, which is intriguing and may explain why HAstV1 is more likely to cause diarrhea. Of clinical importance, we have revealed a similar susceptibility of VA1 to the antiviral drug, nitazoxanide, which we have recently demonstrated its effectiveness inhibiting classical HAstV strains. Conclusion Overall, our studies highlight that VA1 pathogenesis is distinct from HAstV1, which could explain the differences in vivo. Future studies will be necessary to investigate viral replication and pathogenesis in distinct neuronal cells and in vivo.