The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Francis M Giardiello - One of the best experts on this subject based on the ideXlab platform.
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rapid development of Colorectal neoplasia in patients with lynch syndrome
Clinical Gastroenterology and Hepatology, 2011Co-Authors: Daniel L Edelstein, Linda M Hylind, Katharine E Romans, Jennifer E Axilbund, Marcia Cruzcorrea, Melanie D Baxter, Constance A Griffin, Francis M GiardielloAbstract:Background & Aims Patients with Lynch syndrome have a high risk for Colorectal adenomas and carcinomas. We evaluated the development of Colorectal neoplasia in these patients. Methods We assessed serial colonoscopy findings from 54 persons from 29 pedigrees with pathogenic mutations in MSH2 or MLH1; we evaluated the development of Colorectal neoplasia by age, sex, tumor location, and number (mean follow-up time, 9.3 years; colonoscopy interval, 1.7 ± 1.2 years; 112 adenomas and 31 cancers). Differences in Colorectal phenotype were analyzed by genotype, and dwell time was calculated for advanced neoplasias. Results Among mutation carriers, the cumulative risk of Colorectal neoplasia was 43% by age 40 years and 72% by 80 years. There were no statistically significant associations between time to development of Colorectal neoplasia and sex or mutation type. Most female patients had left-sided neoplasms, whereas most male patients developed right-sided lesions. The mean cumulative numbers of neoplastic lesions in patients were 1.3 ± 0.5 by age 30 years and 7.6 ± 6.8 by age 80 years. Polyp dwell time was 33.0 ± 16.2 months and 35.2 ± 22.3 months for advanced adenoma and Colorectal cancer, respectively. The 5-year survival rate for patients with Colorectal cancer was 96%. Conclusions High percentages of individuals with pathogenic mutations in MSH2 or MLH1 develop Colorectal neoplasia by age 40. Left-sided Colorectal neoplasias are more frequent in female patients. The development of 3 or more Colorectal neoplasms by age 30 years indicates a possible polyposis syndrome rather than Lynch syndrome. Polyp dwell time is short for advanced neoplasias, arguing for annual colonoscopic screening and surveillance.
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risk of Colorectal cancer in juvenile polyposis
Gut, 2007Co-Authors: Lodewijk A A Brosens, Arnout Van Hattem, Linda M Hylind, Christine A Iacobuziodonahue, Katharine E Romans, Jennifer E Axilbund, Marcia Cruzcorrea, Anne C Tersmette, Johan G A Offerhaus, Francis M GiardielloAbstract:Background: Juvenile polyposis is an autosomal dominant syndrome characterized by development of hamartomatous gastrointestinal polyps and associated with Colorectal cancer. However, the relative and absolute risk of Colorectal malignancy in these patients is not known. Methods: The incidence rates of Colorectal cancer in juvenile polyposis patients were compared with the general population through person-year analysis with adjustment for demographics. Results: In juvenile polyposis patients, the relative risk (RR) of Colorectal cancer was 34.0 (95% confidence limits [CL], 14.4, 65.7). Similar risks were noted in both males (30.0, CL, 9.6, 68.6) and females (43.7, CL, 8.8-125). The cumulative life time risk for Colorectal cancer was 38.7%. The mean age of Colorectal cancer was 43.9+10.4 (SD). Other gastrointestinal malignancies were not noted in this cohort. Conclusion: Patients with juvenile polyposis have a markedly elevated relative and absolute risk for Colorectal cancer and require vigilant Colorectal surveillance starting at young age. A low threshold for recommending surgery with consideration for removal of the entire colorectum seems warranted.
Reetesh K Pai - One of the best experts on this subject based on the ideXlab platform.
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braf mutated microsatellite stable Colorectal carcinoma an aggressive adenocarcinoma with reduced cdx2 and increased cytokeratin 7 immunohistochemical expression
Human Pathology, 2014Co-Authors: Michael S Landau, Shihfan Kuan, Simion I Chiosea, Reetesh K PaiAbstract:Reduced CDX2 and cytokeratin 20 (CK20) expression in Colorectal carcinoma with BRAF mutation and high-level microsatellite instability (MSI-H) has been well documented. The immunophenotype of BRAF-mutated microsatellite stable (MSS) Colorectal carcinoma has not been reported. We analyzed 205 Colorectal carcinomas including 28 BRAF-mutated MSS, 53 BRAF-mutated MSI-H, and 124 BRAF wild-type MSS tumors for CDX2, cytokeratin 7 (CK7), and CK20 immunohistochemical expression. CDX2 was scored semiquantitatively for both staining intensity and percent of tumor cells staining and a modified CDX2 H-score was calculated. Patients with BRAF-mutated MSS Colorectal carcinomas were more frequently stage IV at presentation compared to patients with BRAF-mutated MSI-H Colorectal carcinomas and BRAF wild-type MSS Colorectal carcinomas (32% versus 8% versus 15%, P < .001). BRAF-mutated MSS Colorectal carcinoma displayed reduced CDX2 expression compared to BRAF wild-type MSS Colorectal carcinoma (75% versus 94%; mean CDX2 H-score 98 versus 150, P < .001). CK7 expression was more often identified in BRAF-mutated MSS Colorectal carcinoma compared to both BRAF-mutated MSI-H Colorectal carcinoma and BRAF wild-type MSS Colorectal carcinoma (39% versus 6% versus 6%, P = .0001). BRAF-mutated MSI-H Colorectal carcinomas were less often CK20 positive compared to BRAF-mutated MSS and BRAF wild-type MSS tumors (70% versus 93% versus 90%, P = 0.001). In summary, BRAF-mutated MSS Colorectal carcinoma often displays reduced CDX2 and increased CK7 expression. Knowledge of this altered immunophenotype is important as patients with BRAF-mutated MSS Colorectal carcinoma often present with metastatic disease and the altered tumor immunophenotype may lead to the erroneous assumption that origin from the colon/rectum is unlikely.
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lynch syndrome associated Colorectal carcinoma frequent involvement of the left colon and rectum and late onset presentation supports a universal screening approach
Human Pathology, 2013Co-Authors: Douglas J Hartman, Randall E Brand, Nathan Bahary, Beth Dudley, Simon I Chiosea, Marina N Nikiforova, Reetesh K PaiAbstract:The optimal strategy for screening patients with Colorectal carcinoma for Lynch syndrome (LS) is a subject of continued debate in the literature with some advocating universal screening while others arguing for selective screening. We evaluated 1292 Colorectal carcinomas for DNA mismatch repair protein abnormalities and identified 150 (11.6%) tumors demonstrating high-levels of microsatellite instability (MSI-H). MSI-H Colorectal carcinomas were divided into sporadic (112/1292, 8.7%) and LS/probable LS-associated (38/1292, 2.9%) groups based on BRAF V600E mutation, MLH1 promoter hypermethylation, cancer history, and germline mismatch repair gene mutation. All MSI-H Colorectal carcinomas were analyzed for grade, location, and tumor histology. The utility of the revised Bethesda guidelines and published predictive pathology models for MSI-H Colorectal carcinomas (PREDICT and MSPath) were evaluated. Left-sided MSI-H Colorectal carcinomas were more frequently associated with LS compared with right-sided MSI-H Colorectal carcinomas (12/21, 57% versus 26/129, 20%, P = .0008). There was no significant difference in histology between sporadic MSI-H and LS/probable LS-associated Colorectal carcinomas except for a slightly higher proportion of sporadic MSI-H tumors demonstrating tumor-infiltrating lymphocytes (81% versus 61%, P = .015). Neither pathology predictive model identified all LS-associated Colorectal carcinomas (PREDICT: 33/38, 87%; MSPath: 35/38, 92%). 12/117 (10%) MSI-H Colorectal carcinomas identified in patients >60 years were LS/probable LS-associated. Our results demonstrate that models of predicting MSI-H fail to identify LS-associated Colorectal carcinoma given their reliance on right-sided location. A significant proportion (32%) of LS-associated Colorectal carcinoma is identified in patients >60 years. Finally, our results demonstrate similar morphologic features between LS-associated and sporadic MSI-H Colorectal carcinomas.
Shuang Wang - One of the best experts on this subject based on the ideXlab platform.
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satb2 as1 suppresses Colorectal carcinoma aggressiveness by inhibiting satb2 dependent snail transcription and epithelial mesenchymal transition
Cancer Research, 2019Co-Authors: Yiqing Wang, Shasha Hu, Meiling Ai, Minhui Yang, Dongmei Jiang, Huijuan Jiang, Yanqing Ding, Lan Wang, Li Zhao, Shuang WangAbstract:Accumulating evidence suggests that long noncoding RNA (lncRNA) plays important regulatory roles in cancer biology. However, the involvement of lncRNA in Colorectal carcinoma progression remains largely unknown, especially in Colorectal carcinoma metastasis. In this study, we investigated the changes in lncRNA expression in Colorectal carcinoma and identified a new lncRNA, the antisense transcript of SATB2 (SATB2-AS1), as a key regulator of Colorectal carcinoma progression. SATB2-AS1 was frequently downregulated in Colorectal carcinoma cells and tissues, and patients whose tumors expressed SATB2-AS1 at low levels had a shorter overall survival and poorer prognosis. Downregulation of SATB2-AS1 significantly promoted cell proliferation, migration, and invasion in vitro and in vivo, demonstrating that it acts as a tumor suppressor in Colorectal carcinoma. SATB2-AS1 suppressed Colorectal carcinoma progression by serving as a scaffold to recruit p300, whose acetylation of H3K27 and H3K9 at the SATB2 promoter upregulated expression of SATB2, a suppressor of Colorectal carcinoma growth and metastasis. SATB2 subsequently recruited HDAC1 to the Snail promoter, repressing Snail transcription and inhibiting epithelial-to-mesenchymal transition. Taken together, these data reveal SATB2-AS1 as a novel regulator of the SATB2-Snail axis whose loss facilitates progression of Colorectal carcinoma. Significance: These data show that the lncRNA SATB2-AS1 mediates epigenetic regulation of SATB2 and Snail expression to suppress Colorectal cancer progression. See related commentary by Li, p. 3536
Yoshiharu Sakai - One of the best experts on this subject based on the ideXlab platform.
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loss of smad4 promotes Colorectal cancer progression by recruiting tumor associated neutrophils via the cxcl1 8 cxcr2 axis
Clinical Cancer Research, 2019Co-Authors: Ryotaro Ogawa, Hideyo Hirai, Keita Hanada, Yoshiyuki Kiyasu, Gen Nishikawa, Takamasa Yamamoto, Susumu Inamoto, Rei Mizuno, Yoshiro Itatani, Yoshiharu SakaiAbstract:Purpose: SMAD4 is a key transcriptional factor of TGFβ signaling and acts as a tumor suppressor in Colorectal cancer. In the present study, we explored the immunologic effect of SMAD4 on the tumor microenvironment. Experimental Design: Using 99 clinical specimens and human Colorectal cancer cell lines, we investigate the relationship between SMAD4 expression and neutrophil accumulation. We immunohistochemically analyzed expression of SMAD4, CXCL1, CXCL8, CXCR2, and other proteins with clinical specimens. Finally, we determined the serum levels of CXCL1 and CXCL8 in 125 patients with Colorectal cancer. Results: SMAD4 knockdown from human Colorectal cancer cells upregulated the expression of CXCL1 and CXCL8, which recruited neutrophils to Colorectal cancer tumor via CXCR2. In turn, when neutrophils were exposed to the supernatant of SMAD4-negative Colorectal cancer cells, they produced a large amount of CXCL1 and CXCL8 by themselves in vitro. In human clinical specimens, we found that neutrophil infiltration into the peritumoral stroma was more marked in SMAD4-negative Colorectal cancer compared with that in SMAD4-positive Colorectal cancer, and that both CXCL1 and CXCL8 were abundantly expressed in the tumor-infiltrating neutrophils. Neutrophils isolated from primary Colorectal cancer expressed significantly higher levels of CXCL1 and CXCL8 than did those isolated from peripheral blood. Furthermore, tumor-infiltrating neutrophils expressed MMP2 and MMP9 in addition to ARG1 and IDO. Serum CXCL8 level was significantly higher in Colorectal cancer patients, especially those at stage II/III, and statistical analysis indicated a high CXCL8 level was associated with a shorter overall survival and relapse-free survival. Conclusions: Blockade of the CXCL1/8–CXCR2 axis could be a novel therapeutic approach against SMAD4-negative Colorectal cancer.
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loss of smad4 promotes Colorectal cancer progression by recruiting tumor associated neutrophils via the cxcl1 8 cxcr2 axis
Clinical Cancer Research, 2019Co-Authors: Ryotaro Ogawa, Hideyo Hirai, Keita Hanada, Yoshiyuki Kiyasu, Gen Nishikawa, Takamasa Yamamoto, Susumu Inamoto, Rei Mizuno, Yoshiro Itatani, Yoshiharu SakaiAbstract:Purpose: SMAD4 is a key transcriptional factor of TGFβ signaling and acts as a tumor suppressor in Colorectal cancer. In the present study, we explored the immunologic effect of SMAD4 on the tumor microenvironment. Experimental Design: Using 99 clinical specimens and human Colorectal cancer cell lines, we investigate the relationship between SMAD4 expression and neutrophil accumulation. We immunohistochemically analyzed expression of SMAD4, CXCL1, CXCL8, CXCR2, and other proteins with clinical specimens. Finally, we determined the serum levels of CXCL1 and CXCL8 in 125 patients with Colorectal cancer. Results: SMAD4 knockdown from human Colorectal cancer cells upregulated the expression of CXCL1 and CXCL8, which recruited neutrophils to Colorectal cancer tumor via CXCR2. In turn, when neutrophils were exposed to the supernatant of SMAD4-negative Colorectal cancer cells, they produced a large amount of CXCL1 and CXCL8 by themselves in vitro. In human clinical specimens, we found that neutrophil infiltration into the peritumoral stroma was more marked in SMAD4-negative Colorectal cancer compared with that in SMAD4-positive Colorectal cancer, and that both CXCL1 and CXCL8 were abundantly expressed in the tumor-infiltrating neutrophils. Neutrophils isolated from primary Colorectal cancer expressed significantly higher levels of CXCL1 and CXCL8 than did those isolated from peripheral blood. Furthermore, tumor-infiltrating neutrophils expressed MMP2 and MMP9 in addition to ARG1 and IDO. Serum CXCL8 level was significantly higher in Colorectal cancer patients, especially those at stage II/III, and statistical analysis indicated a high CXCL8 level was associated with a shorter overall survival and relapse-free survival. Conclusions: Blockade of the CXCL1/8–CXCR2 axis could be a novel therapeutic approach against SMAD4-negative Colorectal cancer.
Yiqing Wang - One of the best experts on this subject based on the ideXlab platform.
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satb2 as1 suppresses Colorectal carcinoma aggressiveness by inhibiting satb2 dependent snail transcription and epithelial mesenchymal transition
Cancer Research, 2019Co-Authors: Yiqing Wang, Shasha Hu, Meiling Ai, Minhui Yang, Dongmei Jiang, Huijuan Jiang, Yanqing Ding, Lan Wang, Li Zhao, Shuang WangAbstract:Accumulating evidence suggests that long noncoding RNA (lncRNA) plays important regulatory roles in cancer biology. However, the involvement of lncRNA in Colorectal carcinoma progression remains largely unknown, especially in Colorectal carcinoma metastasis. In this study, we investigated the changes in lncRNA expression in Colorectal carcinoma and identified a new lncRNA, the antisense transcript of SATB2 (SATB2-AS1), as a key regulator of Colorectal carcinoma progression. SATB2-AS1 was frequently downregulated in Colorectal carcinoma cells and tissues, and patients whose tumors expressed SATB2-AS1 at low levels had a shorter overall survival and poorer prognosis. Downregulation of SATB2-AS1 significantly promoted cell proliferation, migration, and invasion in vitro and in vivo, demonstrating that it acts as a tumor suppressor in Colorectal carcinoma. SATB2-AS1 suppressed Colorectal carcinoma progression by serving as a scaffold to recruit p300, whose acetylation of H3K27 and H3K9 at the SATB2 promoter upregulated expression of SATB2, a suppressor of Colorectal carcinoma growth and metastasis. SATB2 subsequently recruited HDAC1 to the Snail promoter, repressing Snail transcription and inhibiting epithelial-to-mesenchymal transition. Taken together, these data reveal SATB2-AS1 as a novel regulator of the SATB2-Snail axis whose loss facilitates progression of Colorectal carcinoma. Significance: These data show that the lncRNA SATB2-AS1 mediates epigenetic regulation of SATB2 and Snail expression to suppress Colorectal cancer progression. See related commentary by Li, p. 3536
