Research Spotlight

Posted January 27th 2016

Serum angiopoietin-like protein 2 as a potential biomarker for diagnosis, early recurrence and prognosis in gastric cancer patients.

Ajay Goel Ph.D.

Ajay Goel, Ph.D.

Toiyama, Y., K. Tanaka, T. Kitajima, T. Shimura, H. Imaoka, K. Mori, M. Okigami, H. Yasuda, Y. Okugawa, S. Saigusa, M. Ohi, Y. Inoue, Y. Mohri, A. Goel and M. Kusunoki (2015). “Serum angiopoietin-like protein 2 as a potential biomarker for diagnosis, early recurrence and prognosis in gastric cancer patients.” Carcinogenesis 36(12): 1474-1483.

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Chronic inflammation of gastric mucosa by Helicobacter pylori infection can initiate gastric carcinogenesis. As angiopoietin-like protein 2 (ANGPTL2) mediates inflammation and inflammation-associated carcinogenesis, we investigated the functional and clinical significance of ANGPTL2 in human gastric cancer (GC). SiRNA knockdown studies were performed for the functional assessment of ANGPTL2 in GC cell lines. ANGPTL2 expression was evaluated immunohistochemically in 192 tissue specimens from GC patients. In addition, we screened serum ANGPTL2 levels from 32 GC patients and 23 healthy controls; and validated these results in 194 serum samples from GC patients and 45 healthy controls by ELISA. ANGPTL2 knockdown caused anoikis and inhibited proliferation, invasion and migration in GC cells. ANGPTL2 expression was upregulated in GC tissues compared to normal gastric mucosa; and high ANGPTL2 expression was significantly associated with tumor progression, early recurrence (P = 0.003) and poor prognosis (P = 0.007). Serum ANGPTL2 in GC patients was significantly higher than for healthy controls (P < 0.05), and accurately distinguished GC patients from healthy control (AUC = 0.865). The validation step confirmed significantly higher serum ANGPTL2 levels in GC patients than healthy controls (P < 0.0001). Receiver operating characteristic curves yielded robust AUC value (0.831) accompanied by high sensitivity (73.0%) and specificity (82.2%) in distinguishing GC patients from healthy controls. High serum ANGPTL2, rather than its expression in matched tissues, was significantly associated with tumor progression, and emerged as an independent marker for recurrence (HR: 5.05, P = 0.0004) and prognosis (HR: 3.6, P = 0.01). Serum ANGPTL2 expression is a potential noninvasive biomarker for diagnosis, early recurrence and prognosis of GC patients.


Posted January 27th 2016

Serum miR-21, miR-29a, and miR-125b Are Promising Biomarkers for the Early Detection of Colorectal Neoplasia.

Ajay Goel Ph.D.

Ajay Goel, Ph.D.

Yamada, A., T. Horimatsu, Y. Okugawa, N. Nishida, H. Honjo, H. Ida, T. Kou, T. Kusaka, Y. Sasaki, M. Yagi, T. Higurashi, N. Yukawa, Y. Amanuma, O. Kikuchi, M. Muto, Y. Ueno, A. Nakajima, T. Chiba, C. R. Boland and A. Goel (2015). “Serum miR-21, miR-29a, and miR-125b Are Promising Biomarkers for the Early Detection of Colorectal Neoplasia.” Clinical Cancer Research 21(18): 4234-4242.

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Purpose: Circulating microRNAs (miRNA) are emerging as promising diagnostic biomarkers for colorectal cancer, but their usefulness for detecting early colorectal neoplasms remains unclear. This study aimed to identify serum miRNA biomarkers for the identification of patients with early colorectal neoplasms. Experimental Design: A cohort of 237 serum samples from 160 patients with early colorectal neoplasms (148 precancerous lesions and 12 cancers) and 77 healthy subjects was analyzed in a three-step approach that included a comprehensive literature review for published biomarkers, a screening phase, and a validation phase. RNA was extracted from sera, and levels of miRNAs were examined by real-time RT-PCR. Results: Nine miRNAs (miR-18a, miR-19a, miR-19b, miR-20a, miR-21, miR-24,miR-29a, miR-92, and miR-125b) were selected as candidate biomarkers for initial analysis. In the screening phase, serum levels of miR-21, miR-29a, and miR-125b were significantly higher in patients with early colorectal neoplasm than in healthy controls. Elevated levels of miR-21, miR-29a, and miR-125b were confirmed in the validation phase using an independent set of subjects. Area under the curve (AUC) values for serum miR-21, miR-29a, miR-125b, and their combined score in discriminating patients with early colorectal neoplasm from healthy controls were 0.706, 0.741, 0.806, and 0.827, respectively. Serum levels of miR-29a and miR-125b were significantly higher in patients who had only small colorectal neoplasms (<= 5 mm) than in healthy subjects. Conclusions: Because serum levels of miR-21, miR-29a, and miR-125b discriminated patients with early colorectal neoplasm from healthy controls, our data highlight the potential clinical use of these molecular signatures for noninvasive screening of patients with colorectal neoplasia.


Posted January 27th 2016

The effect of multidisciplinary teams for rectal cancer on delivery of care and patient outcome: has the use of multidisciplinary teams for rectal cancer affected the utilization of available resources, proportion of patients meeting the standard of care, and does this translate into changes in patient outcome?

James W. Fleshman M.D.
James W. Fleshman, M.D.

Richardson, B., J. Preskitt, W. Lichliter, S. Peschka, S. Carmack, G. de Prisco and J. Fleshman (2016). “The effect of multidisciplinary teams for rectal cancer on delivery of care and patient outcome: has the use of multidisciplinary teams for rectal cancer affected the utilization of available resources, proportion of patients meeting the standard of care, and does this translate into changes in patient outcome?” American Journal of Surgery 211(1): 46-52.

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OBJECTIVES: To identify predictors of positive circumferential resection margin following rectal cancer resection in the United States. BACKGROUND: Positive circumferential resection margin is associated with a high rate of local recurrence and poor morbidity and mortality for rectal cancer patients. Prior study has shown poor compliance with national rectal cancer guidelines, but whether this finding is reflected in patient outcomes has yet to be shown. METHODS: Patients who underwent resection for stage I-III rectal cancer were identified from the 2010-2011 National Cancer Database. The primary outcome was a positive circumferential resection margin. The relationship between patient, hospital, tumor, and treatment-related characteristics was analyzed using bivariate and multivariate analysis. RESULTS: A positive circumferential resection margin was noted in 2859 (17.2%) of the 16,619 patients included. Facility location, clinical T and N stage, histologic type, tumor size, tumor grade, lymphovascular invasion, perineural invasion, type of operation, and operative approach were significant predictors of positive circumferential resection margin on multivariable analysis. Total proctectomy had nearly a 30% increased risk of positive margin compared with partial proctectomy (OR 1.293, 95%CI 1.185-1.411) and a laparoscopic approach had nearly 22% less risk of a positive circumferential resection margin compared with an open approach (OR 0.882, 95%CI 0.790-0.985). CONCLUSIONS: Despite advances in surgical technique and multimodality therapy, rates of positive circumferential resection margin remain high in the United States. Several tumor and treatment characteristics were identified as independent risk factors, and advances in rectal cancer care are necessary to approach the outcomes seen in other countries.


Posted January 27th 2016

High Rate of Positive Circumferential Resection Margins Following Rectal Cancer Surgery: A Call to Action.

James W. Fleshman M.D.

James W. Fleshman, M.D.

Rickles, A. S., D. W. Dietz, G. J. Chang, S. D. Wexner, M. E. Berho, F. H. Remzi, F. L. Greene, J. W. Fleshman, M. A. Abbas, W. Peters, K. Noyes, J. R. Monson and F. J. Fleming (2015). “High Rate of Positive Circumferential Resection Margins Following Rectal Cancer Surgery: A Call to Action.” Annals of Surgery 262(6): 891-898.

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OBJECTIVES: To identify predictors of positive circumferential resection margin following rectal cancer resection in the United States. BACKGROUND: Positive circumferential resection margin is associated with a high rate of local recurrence and poor morbidity and mortality for rectal cancer patients. Prior study has shown poor compliance with national rectal cancer guidelines, but whether this finding is reflected in patient outcomes has yet to be shown. METHODS: Patients who underwent resection for stage I-III rectal cancer were identified from the 2010-2011 National Cancer Database. The primary outcome was a positive circumferential resection margin. The relationship between patient, hospital, tumor, and treatment-related characteristics was analyzed using bivariate and multivariate analysis. RESULTS: A positive circumferential resection margin was noted in 2859 (17.2%) of the 16,619 patients included. Facility location, clinical T and N stage, histologic type, tumor size, tumor grade, lymphovascular invasion, perineural invasion, type of operation, and operative approach were significant predictors of positive circumferential resection margin on multivariable analysis. Total proctectomy had nearly a 30% increased risk of positive margin compared with partial proctectomy (OR 1.293, 95%CI 1.185-1.411) and a laparoscopic approach had nearly 22% less risk of a positive circumferential resection margin compared with an open approach (OR 0.882, 95%CI 0.790-0.985). CONCLUSIONS: Despite advances in surgical technique and multimodality therapy, rates of positive circumferential resection margin remain high in the United States. Several tumor and treatment characteristics were identified as independent risk factors, and advances in rectal cancer care are necessary to approach the outcomes seen in other countries.


Posted January 27th 2016

The Influence of Immunosuppressive Agents on the Risk of De Novo Donor-Specific HLA Antibody Production in Solid Organ Transplant Recipients.

Jacqueline O'Leary M.D.

Jacqueline O’Leary, M.D.

O’Leary, J. G., M. Samaniego, M. C. Barrio, L. Potena, A. Zeevi, A. Djamali and E. Cozzi (2016). “The Influence of Immunosuppressive Agents on the Risk of De Novo Donor-Specific HLA Antibody Production in Solid Organ Transplant Recipients.” Transplantation 100(1): 39-53.

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Production of de novo donor-specific antibodies (dnDSA) is a major risk factor for acute and chronic antibody-mediated rejection and graft loss after all solid organ transplantation. In this article, we review the data available on the risk of individual immunosuppressive agents and their ability to prevent dnDSA production. Induction therapy with rabbit antithymocyte globulin may achieve a short-term decrease in dnDSA production in moderately sensitized patients. Rituximab induction may be beneficial in sensitized patients, and in abrogating rebound antibody response in patients undergoing desensitization or treatment for antibody-mediated rejection. Use of bortezomib for induction therapy in at-risk patients is of interest, but the benefits are unproven. In maintenance regimens, nonadherent and previously sensitized patients are not suitable for aggressive weaning protocols, particularly early calcineurin inhibitor withdrawal without lymphocyte-depleting induction. Early conversion to mammalian target of rapamycin inhibitor monotherapy has been reported to increase the risk of dnDSA formation, but a combination of mammalian target of rapamycin inhibitor and reduced-exposure calcineurin inhibitor does not appear to alter the risk. Early steroid therapy withdrawal in standard-risk patients after induction has no known dnDSA penalty. The available data do not demonstrate a consistent effect of mycophenolic acid on dnDSA production. Risk minimization for dnDSA requires monitoring of adherence, appropriate risk stratification, risk-based immunosuppression intensity, and prospective DSA surveillance.