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Chung, Daniel

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Chung

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Daniel

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Chung, Daniel
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    ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED): a study protocol for a randomized controlled trial
    (BioMed Central, 2017) Drew, David; Chin, Samantha M.; Gilpin, Katherine K.; Parziale, Melanie; Pond, Emily; Schuck, Madeline M.; Stewart, Kathleen; Flagg, Meaghan; Rawlings, Crystal; Backman, Vadim; Carolan, Peter; Chung, Daniel; Colizzo, Francis; Freedman, Matthew; Gala, Manish; Garber, John; Huttenhower, Curtis; Kedrin, Dmitriy; Khalili, Hamed; Kwon, Douglas S.; Markowitz, Sanford D.; Milne, Ginger L.; Nishioka, Norman; Richter, James; Roy, Hemant K.; Staller, Kyle; Wang, Molin; Chan, Andrew
    Background: Although aspirin is recommended for the prevention of colorectal cancer, the specific individuals for whom the benefits outweigh the risks are not clearly defined. Moreover, the precise mechanisms by which aspirin reduces the risk of cancer are unclear. We recently launched the ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED) trial to address these uncertainties. Methods/design ASPIRED is a prospective, double-blind, multidose, placebo-controlled, biomarker clinical trial of aspirin use in individuals previously diagnosed with colorectal adenoma. Individuals (n = 180) will be randomized in a 1:1:1 ratio to low-dose (81 mg/day) or standard-dose (325 mg/day) aspirin or placebo. At two study visits, participants will provide lifestyle, dietary and biometric data in addition to urine, saliva and blood specimens. Stool, grossly normal colorectal mucosal biopsies and cytology brushings will be collected during a flexible sigmoidoscopy without bowel preparation. The study will examine the effect of aspirin on urinary prostaglandin metabolites (PGE-M; primary endpoint), plasma inflammatory markers (macrophage inhibitory cytokine-1 (MIC-1)), colonic expression of transcription factor binding (transcription factor 7-like 2 (TCF7L2)), colonocyte gene expression, including hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD) and those that encode Wnt signaling proteins, colonic cellular nanocytology and oral and gut microbial composition and function. Discussion Aspirin may prevent colorectal cancer through multiple, interrelated mechanisms. The ASPIRED trial will scrutinize these pathways and investigate putative mechanistically based risk-stratification biomarkers. Trial registration This protocol is registered with the U.S. National Institutes of Health trial registry, ClinicalTrials.gov, under the identifier NCT02394769. Registered on 16 March 2015. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1744-z) contains supplementary material, which is available to authorized users.
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    Efficacy, Safety, and Biomarkers of Neoadjuvant Bevacizumab, Radiation Therapy, and Fluorouracil in Rectal Cancer: A Multidisciplinary Phase II Study
    (American Society of Clinical Oncology (ASCO), 2009) Willett, C. G.; Duda, Dan; di Tomaso, E.; Boucher, Yves; Ancukiewicz, M.; Sahani, Dushyant; Lahdenranta, J.; Chung, Daniel; Fischman, A. J.; Lauwers, Gregory Y.; Shellito, Paul; Czito, B. G.; Wong, T. Z.; Paulson, E.; Poleski, M.; Vujaskovic, Z.; Bentley, R.; Chen, H. X.; Clark, J. W.; Jain, Rakesh
    PURPOSE: To assess the safety and efficacy of neoadjuvant bevacizumab with standard chemoradiotherapy in locally advanced rectal cancer and explore biomarkers for response. PATIENTS AND METHODS: In a phase I/II study, 32 patients received four cycles of therapy consisting of: bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; fluorouracil infusion (225 mg/m(2)/24 hours) during cycles 2 to 4; external-beam irradiation (50.4 Gy in 28 fractions over 5.5 weeks); and surgery 7 to 10 weeks after completion of all therapies. We measured molecular, cellular, and physiologic biomarkers before treatment, during bevacizumab monotherapy, and during and after combination therapy. RESULTS: Tumors regressed from a mass with mean size of 5 cm (range, 3 to 12 cm) to an ulcer/scar with mean size of 2.4 cm (range, 0.7 to 6.0 cm) in all 32 patients. Histologic examination revealed either no cancer or varying numbers of scattered cancer cells in a bed of fibrosis at the primary site. This treatment resulted in an actuarial 5-year local control and overall survival of 100%. Actuarial 5-year disease-free survival was 75% and five patients developed metastases postsurgery. Bevacizumab with chemoradiotherapy showed acceptable toxicity. Bevacizumab decreased tumor interstitial fluid pressure and blood flow. Baseline plasma soluble vascular endothelial growth factor receptor 1 (sVEGFR1), plasma vascular endothelial growth factor (VEGF), placental-derived growth factor (PlGF), and interleukin 6 (IL-6) during treatment, and circulating endothelial cells (CECs) after treatment showed significant correlations with outcome. CONCLUSION: Bevacizumab with chemoradiotherapy appears safe and active and yields promising survival results in locally advanced rectal cancer. Plasma VEGF, PlGF, sVEGFR1, and IL-6 and CECs should be further evaluated as candidate biomarkers of response for this regimen.
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    Prophylactic total gastrectomy for individuals with germline CDH1 mutation
    (Elsevier BV, 2011) Pandalai, Prakash K.; Lauwers, Gregory Y.; Chung, Daniel; Patel, Devanshi; Yoon, Sam
    BACKGROUND: Germline mutation of the CDH1 gene, which encodes for the E-cadherin adhesion protein, is rare but confers an estimated lifetime risk of hereditary diffuse gastric cancer of 87%. Fewer than 100 prophylactic total gastrectomies have been reported for this condition. METHODS: Patients with germline CDH1 mutation who underwent multidisciplinary counseling followed by prophylactic total gastrectomy were reviewed. RESULTS: Ten patients (6 male, 4 female) with a median age of 42 years (range, 26-51) underwent prophylactic total gastrectomy between 2006 and 2009. Of the 6 families represented, there were 4 missense, 1 frameshift, and 1 splice site mutation. Median time from genetic testing to surgery was 3 months (range, 1-7). All patients had an upper endoscopy before surgery, identifying only 1 patient with a focus of diffuse gastric cancer. After prophylactic total gastrectomy, extensive pathologic analysis demonstrated that 9 patients had up to 77 foci of noninvasive cancer, and 2 of these patients had 4-12 foci of T1 invasive cancer. Median operative time was 213 minutes; there were no anastomotic leaks, and the length of stay was 7-8 days. One patient had a complication within 30 days (pulmonary embolism), and 3 patients had late complications (2 small bowel obstructions and 1 anastomotic stricture). Median weight loss at 6 months was 19%. CONCLUSION: The majority of patients with germline CDH1 mutation have foci of noninvasive or invasive gastric cancer by middle age. Serial upper endoscopies provide inadequate screening. Prophylactic total gastrectomy is the procedure of choice for definitive treatment.
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    Endoscopic Surveillance of Patients With Hereditary Diffuse Gastric Cancer: Biopsy Recommendations After Topographic Distribution of Cancer Foci in a Series of 10 CDH1-mutated Gastrectomies
    (Ovid Technologies (Wolters Kluwer Health), 2012) Fujita, Hiroshi; Lennerz, Jochen K.M.; Chung, Daniel; Patel, Devanshi; Deshpande, Vikram; Yoon, Sam; Lauwers, Gregory Y.
    The management of hereditary diffuse-type gastric cancer revolves around surveillance biopsies and the timing of prophylactic gastrectomy. In the absence of a validated surveillance biopsy protocol, we modeled bioptic diagnostic yield on the basis of the topographic distribution of cancer foci in a series of 10 gastrectomies in CDH1-mutation carriers. Complete histologic examination was performed in all cases, and 1817 slides were evaluated for the presence of in situ, intramucosal, or submucosal diffuse-type carcinoma. Detailed maps determined the density of cancer foci. On the basis of the number of sampled glands per biopsy in routine surveillance preoperative endoscopy, we estimated the theoretical number of biopsies necessary for a 90% rate of detection of neoplastic foci, and we evaluated this number, taking into account the regional distribution of these foci. A total of 96 m of gastric mucosa with ∼1,193,453 gastric glands yielded 302 cancer foci [in situ (n=89), intramucosal (n=209), and submucosal (n=4)] spanning the width of a total of 1820 glands (8 to 1205 per case; average 182±115). On the basis of the number of glands per stomach and the average number of glands sampled during surveillance biopsy (28.7±1.7; range, 0 to 79; n=112), the theoretical number of biopsies necessary to capture at least 1 cancer focus was estimated to be 1768 (range, 50 to 5832) to assure a 90% detection rate. Mapping of cancer foci showed the highest density in the anterior proximal fundus (37%) and cardia/proximal fundus (27%). Our results argue for the incorporation of cancer focus distribution into any biopsy protocol, although detection is likely to remain extremely low, and they call into question the validity of endoscopic surveillance.
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    Microsatellite Instability is Frequently Observed in Rectal Cancer and Influenced by Neoadjuvant Chemoradiation
    (Elsevier BV, 2007) Choi, Michael; Lauwers, Gregory Y.; Hur, Chin; Willett, Christopher G.; Chung, Daniel
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    A Safety and Survival Analysis of Neoadjuvant Bevacizumab with Standard Chemoradiation in a Phase I/II Study Compared with Standard Chemoradiation in Locally Advanced Rectal Cancer
    (Alphamed Press, 2010) Willett, C. G.; Duda, Dan; Ancukiewicz, Marek; Shah, M.; Czito, B. G.; Bentley, R.; Poleski, M.; Fujita, H.; Lauwers, Gregory Y.; Carroll, M.; Tyler, D.; Mantyh, C.; Shellito, Paul; Chung, Daniel; Clark, Jeffrey; Jain, Rakesh
    Introduction. Bevacizumab is increasingly being tested with neoadjuvant regimens in patients with localized cancer, but its effects on metastasis and survival remain unknown. This study examines the long-term outcome of clinical stage II/III rectal cancer patients treated in a prospective phase II study of bevacizumab with chemoradiation and surgery. As a benchmark, we used data from an analysis of 42 patients with locally advanced rectal cancer treated with a contemporary approach of preoperative fluoropyrimidine-based radiation therapy. Materials and Methods. Outcome analyses were performed on 32 patients treated prospectively with neoadjuvant bevacizumab, 5-fluorouracil, radiation therapy, and surgery as well as 42 patients treated with standard fluoropyrimidine-based chemoradiation. Results. Overall survival, disease-free survival, and local control showed favorable trends in patients treated with bevacizumab with chemoradiation followed by surgery. Acute and postoperative toxicity appeared acceptable. Conclusions. Neoadjuvant bevacizumab with standard chemoradiation and surgery shows promising long-term efficacy and safety profiles in locally advanced rectal cancer patients.
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    Survival outcomes and surgical intervention of small intestinal neuroendocrine tumors: a population based retrospective study
    (Impact Journals LLC, 2017) Wu, Lunpo; Fu, Jianfei; Wan, Li; Pan, Jie; Lai, Sanchuan; Zhong, Jing; Chung, Daniel; Wang, Liangjing
    Background: Small intestinal neuroendocrine tumors (SiNETs) without distant metastasis typically behave in an indolent manner, but there can be heterogeneity. We aimed to define the survival outcomes and impacts of surgical intervention. Methods: A retrospective cohort study was conducted by using data from the Surveillance, Epidemiology, and End Results (SEER) database. Clinicopathologic features were analyzed in 4407 patients between 2000 and 2012. The cancer specific survival (CSS) was calculated by the Kaplan-Meier method. Multivariable Cox regression models with hazard ratios (HRs) were constructed to analyze survival outcomes and risk factors. Results: The adjusted incidence of early SiNETs is 1.3/100,000. Tumors are most commonly located in the ileum and are small (≤ 2 cm). The 5-year and 10-year CSS rates were 95.0% and 88.5%, respectively. Age > 50 years, large tumor size (> 2cm), poor differentiation, advanced T classification, and absence of surgical treatment were independent predictors of poor survival. Stratified analysis indicated that surgery significantly improved survival in patients that were white (HR, 0.45), > 50 years old (HR, 0.61), had duodenal tumors (HR, 0.43), large tumors (> 2cm) (HR, 0.32), advanced T classification (T3: HR, 0.29; T4: HR, 0.18) or well differentiation (HR, 0.55). There was no significant survival difference between local resection and radical resection (P =0.884). Conclusions: Early SiNETs have a favorable prognosis. Surgical resection may improve outcomes, particularly in older patients and those with large tumors. More aggressive resections couldn't improve outcomes.
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    Screening for Pancreatic Adenocarcinoma in BRCA2 Mutation Carriers: Results of a Disease Simulation Model
    (Elsevier, 2015) Pandharipande, Pari; Jeon, Alvin; Heberle, Curtis R.; Dowling, Emily C.; Chung, Daniel; Kong, Chung Yin; Brugge, William; Hur, Chin
    Background: BRCA2 mutation carriers are at increased risk for multiple cancers including pancreatic adenocarcinoma (PAC). Our goal was to compare the effectiveness of different PAC screening strategies in BRCA2 mutation carriers, from the standpoint of life expectancy. Methods: A previously published Markov model of PAC was updated and extended to incorporate key aspects of BRCA2 mutation carrier status, including competing risks of breast- and ovarian-cancer specific mortality. BRCA2 mutation carriers were modeled and analyzed as the primary cohort for the analysis. Additional higher risk BRCA2 cohorts that were stratified according to the number of first-degree relatives (FDRs) with PAC were also analyzed. For each cohort, one-time screening and annual screening were evaluated, with screening starting at age 50 in both strategies. The primary outcome was net gain in life expectancy (LE) compared to no screening. Sensitivity analysis was performed on key model parameters, including surgical mortality and MRI test performance. Findings: One-time screening at age 50 resulted in a LE gain of 3.9 days for the primary BRCA2 cohort, and a gain of 5.8 days for those with BRCA2 and one FDR. Annual screening resulted in LE loss of 12.9 days for the primary cohort and 1.3 days for BRCA2 carriers with 1 FDR, but resulted in 20.6 days gained for carriers with 2 FDRs and 260 days gained for those with 3 FDRs. For patients with ≥ 3 FDRs, annual screening starting at an earlier age (i.e. 35–40) was optimal. Interpretation Among BRCA2 mutation carriers, aggressive screening regimens may be ineffective unless additional indicators of elevated risk (e.g., 2 or more FDRs) are present. More clinical studies are needed to confirm these findings. Funding American Cancer Society – New England Division – Ellison Foundation Research Scholar Grant (RSG-15-129-01-CPHPS).
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    Clinical Genetic Testing in Gastroenterology
    (Nature Publishing Group, 2016) Goodman, Russell; Chung, Daniel
    Rapid advances in genetics have led to an increased understanding of the genetic determinants of human disease, including many gastrointestinal (GI) disorders. Coupled with a proliferation of genetic testing services, this has resulted in a clinical landscape where commercially available genetic tests for GI disorders are now widely available. In this review, we discuss the current status of clinical genetic testing for GI illnesses, review the available testing options, and briefly discuss indications for and practical aspects of such testing. Our goal is to familiarize the practicing gastroenterologist with this rapidly changing and important aspect of clinical care.
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    c-Myc is regulated by HIF-2α in chronic hypoxia and influences sensitivity to 5-FU in colon cancer
    (Impact Journals LLC, 2016) Wang, Liangjing; Xue, Meng; Chung, Daniel
    Colorectal cancers (CRCs) invariably become hypoxic as they enlarge, and this places unique metabolic demands upon the tumor cells. Hypoxic stress can enhance the invasiveness of cancer cells and induce chemoresistance. c-Myc, an oncogene regulated by hypoxia inducible factors (HIFs), plays a critical role in cell proliferation and metabolism. However, the interplay between c-Myc and HIFs and its clinical significance in hypoxic adaptation in CRCs are unknown. We demonstrate that c-Myc mRNA and protein levels in colon cancer cells are induced within 2 h of hypoxic stress (1% O2) but are then significantly downregulated when exposed to prolonged hypoxia. In chronic hypoxia (over 8 h at 1% O2), HIF-2α but not HIF-1α gradually accumulated in colon cancer cells. Knockdown of HIF-2α increased levels of c-Myc and its downstream target cyclinD1 in chronic hypoxia, indicating that HIF-2α may function to downregulate c-Myc. Chronic hypoxia suppressed the expression of cyclinD1, CDK4, and CDK6, inducing G1 phase block and 5-flurouracil (5-FU) chemoresistance. Overexpression of c-Myc reversed the inhibition of cyclinD1, CDK4, and CDK6, which accelerated the G1/S phase transition under hypoxia and enhanced sensitivity to 5-FU. In contrast, knockdown of c-Myc impaired 5-FU chemosensitivity in colon cancer cells. In summary, HIF-2α plays an important role in regulating the expression of c-Myc in chronic hypoxia, and consequently controls the sensitivity of colon cancer cells to 5-FU treatment in this environment.