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Metformin use and incidence cancer risk: evidence for a selective protective effect against liver cancer.
Murff HJ, Roumie CL, Greevy RA, Hackstadt AJ, McGowan LED, Hung AM, Grijalva CG, Griffin MR
(2018) Cancer Causes Control 29: 823-832
MeSH Terms: Aged, Carcinoma, Hepatocellular, Female, Humans, Hypoglycemic Agents, Incidence, Liver Neoplasms, Male, Metformin, Middle Aged, Proportional Hazards Models, Retrospective Studies, Risk, Sulfonylurea Compounds, United States, Veterans
Show Abstract · Added July 27, 2018
PURPOSE - Several observational studies suggest that metformin reduces incidence cancer risk; however, many of these studies suffer from time-related biases and several cancer outcomes have not been investigated due to small sample sizes.
METHODS - We constructed a propensity score-matched retrospective cohort of 84,434 veterans newly prescribed metformin or a sulfonylurea as monotherapy. We used Cox proportional hazard regression to assess the association between metformin use compared to sulfonylurea use and incidence cancer risk for 10 solid tumors. We adjusted for clinical covariates including hemoglobin A1C, antihypertensive and lipid-lowering medications, and body mass index. Incidence cancers were defined by ICD-9-CM codes.
RESULTS - Among 42,217 new metformin users and 42,217 matched-new sulfonylurea users, we identified 2,575 incidence cancers. Metformin was inversely associated with liver cancer (adjusted hazard ratio [aHR] = 0.44, 95% CI 0.31, 0.64) compared to sulfonylurea. We found no association between metformin use and risk of incidence bladder, breast, colorectal, esophageal, gastric, lung, pancreatic, prostate, or renal cancer when compared to sulfonylurea use.
CONCLUSIONS - In this large cohort study that accounted for time-related biases, we observed no association between the use of metformin and most cancers; however, we found a strong inverse association between metformin and liver cancer. Randomized trials of metformin for prevention of liver cancer would be useful to verify these observations.
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16 MeSH Terms
Hepatic micrometastases are associated with poor prognosis in patients with liver metastases from neuroendocrine tumors of the digestive tract.
Gibson WE, Gonzalez RS, Cates JMM, Liu E, Shi C
(2018) Hum Pathol 79: 109-115
MeSH Terms: Adult, Aged, Aged, 80 and over, Female, Hepatectomy, Humans, Intestinal Neoplasms, Intestine, Small, Liver Neoplasms, Male, Metastasectomy, Middle Aged, Neoplasm Micrometastasis, Neuroendocrine Tumors, Pancreatic Neoplasms, Retrospective Studies, Risk Factors, Time Factors, Treatment Outcome, Young Adult
Show Abstract · Added November 1, 2018
Pathologic examination of hepatic metastasectomies from patients with metastatic small intestinal or pancreatic neuroendocrine tumor frequently reveals micrometastases undetectable by radiologic or macroscopic gross examination. This finding raises the possibility that undetectable micrometastases remain in these patients after metastasectomy. Here we examined liver resections for micrometastases and assessed their impact on prognosis. Hepatic metastasectomies from 65 patients with neuroendocrine tumor of the small intestine (N = 43) or pancreas (N = 22) were reviewed for the presence of micrometastases, which were defined as microscopic tumor foci ≤1 mm in greatest dimension. Medical records were also reviewed for patient demographics, clinical history, and follow-up data. Micrometastasis was identified in 36 (55%) of 65 hepatic resection specimens. More hepatic micrometastases were seen in small intestinal cases than in pancreatic cases (29/43, 67%, versus 7/22, 32%; P < .01). They were typically present within portal tracts, sometimes with extension into the periportal region or sinusoidal spaces away from the portal tracts. Patients without hepatic micrometastases had fewer macrometastases or more R0 hepatic resections than those with micrometastases. The presence of hepatic micrometastases was associated with poor overall survival both before (hazard ratio [HR] 3.43; 95% CI 1.14-10.30; P = .03) and after accounting for confounding variables in stratified Cox regression (HR 4.82; 95% CI 1.0621.79; P = .04). In conclusion, hepatic micrometastases are common in patients with metastatic small intestinal or pancreatic neuroendocrine tumor and are independently associated with poor prognosis. These data suggest that surgical resection of hepatic metastases is likely not curative in these patients.
Copyright © 2018 Elsevier Inc. All rights reserved.
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20 MeSH Terms
Shanghai Score: A Prognostic and Adjuvant Treatment-evaluating System Constructed for Chinese Patients with Hepatocellular Carcinoma after Curative Resection.
Sun HC, Xie L, Yang XR, Li W, Yu J, Zhu XD, Xia Y, Zhang T, Xu Y, Hu B, Du LP, Zeng LY, Ouyang J, Zhang W, Song TQ, Li Q, Shi YH, Zhou J, Qiu SJ, Liu Q, Li YX, Tang ZY, Shyr Y, Shen F, Fan J
(2017) Chin Med J (Engl) 130: 2650-2660
MeSH Terms: Adult, Carcinoma, Hepatocellular, China, Female, Hepatitis B Surface Antigens, Humans, Liver Neoplasms, Male, Middle Aged, Prognosis, Proportional Hazards Models
Show Abstract · Added April 3, 2018
BACKGROUND - For Chinese patients with hepatocellular carcinoma (HCC), surgical resection is the most important treatment to achieve long-term survival for patients with an early-stage tumor, and yet the prognosis after surgery is diverse. We aimed to construct a scoring system (Shanghai Score) for individualized prognosis estimation and adjuvant treatment evaluation.
METHODS - A multivariate Cox proportional hazards model was constructed based on 4166 HCC patients undergoing resection during 2001-2008 at Zhongshan Hospital. Age, hepatitis B surface antigen, hepatitis B e antigen, partial thromboplastin time, total bilirubin, alkaline phosphatase, γ-glutamyltransferase, α-fetoprotein, tumor size, cirrhosis, vascular invasion, differentiation, encapsulation, and tumor number were finally retained by a backward step-down selection process with the Akaike information criterion. The Harrell's concordance index (C-index) was used to measure model performance. Shanghai Score is calculated by summing the products of the 14 variable values times each variable's corresponding regression coefficient. Totally 1978 patients from Zhongshan Hospital undergoing resection during 2009-2012, 808 patients from Eastern Hepatobiliary Surgery Hospital during 2008-2010, and 244 patients from Tianjin Medical University Cancer Hospital during 2010-2011 were enrolled as external validation cohorts. Shanghai Score was also implied in evaluating adjuvant treatment choices based on propensity score matching analysis.
RESULTS - Shanghai Score showed good calibration and discrimination in postsurgical HCC patients. The bootstrap-corrected C-index (confidence interval [CI]) was 0.74 for overall survival (OS) and 0.68 for recurrence-free survival (RFS) in derivation cohort (4166 patients), and in the three independent validation cohorts, the CI s for OS ranged 0.70-0.72 and that for RFS ranged 0.63-0.68. Furthermore, Shanghai Score provided evaluation for adjuvant treatment choices (transcatheter arterial chemoembolization or interferon-α). The identified subset of patients at low risk could be ideal candidates for curative surgery, and subsets of patients at moderate or high risk could be recommended with possible adjuvant therapies after surgery. Finally, a web server with individualized outcome prediction and treatment recommendation was constructed.
CONCLUSIONS - Based on the largest cohort up to date, we established Shanghai Score - an individualized outcome prediction system specifically designed for Chinese HCC patients after surgery. The Shanghai Score web server provides an easily accessible tool to stratify the prognosis of patients undergoing liver resection for HCC.
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Prevention of breast cancer skeletal metastases with parathyroid hormone.
Swami S, Johnson J, Bettinson LA, Kimura T, Zhu H, Albertelli MA, Johnson RW, Wu JY
(2017) JCI Insight 2:
MeSH Terms: Animals, Bone Neoplasms, Breast Neoplasms, Cell Line, Tumor, Cellular Microenvironment, Female, Gene Expression Profiling, Heterografts, Liver Neoplasms, Lung Neoplasms, Mice, Parathyroid Hormone, Splenic Neoplasms, Survival Analysis, X-Ray Microtomography
Show Abstract · Added March 26, 2019
Advanced breast cancer is frequently associated with skeletal metastases and accelerated bone loss. Recombinant parathyroid hormone [teriparatide, PTH(1-34)] is the first anabolic agent approved in the US for treatment of osteoporosis. While signaling through the PTH receptor in the osteoblast lineage regulates bone marrow hematopoietic niches, the effects of anabolic PTH on the skeletal metastatic niche are unknown. Here, we demonstrate, using orthotopic and intratibial models of 4T1 murine and MDA-MB-231 human breast cancer tumors, that anabolic PTH decreases both tumor engraftment and the incidence of spontaneous skeletal metastasis in mice. Microcomputed tomography and histomorphometric analyses revealed that PTH increases bone volume and reduces tumor engraftment and volume. Transwell migration assays with murine and human breast cancer cells revealed that PTH alters the gene expression profile of the metastatic niche, in particular VCAM-1, to inhibit recruitment of cancer cells. While PTH did not affect growth or migration of the primary tumor, it elicited several changes in the tumor gene expression profile resulting in a less metastatic phenotype. In conclusion, PTH treatment in mice alters the bone microenvironment, resulting in decreased cancer cell engraftment, reduced incidence of metastases, preservation of bone microarchitecture and prolonged survival.
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15 MeSH Terms
Deformation correction for image guided liver surgery: An intraoperative fidelity assessment.
Clements LW, Collins JA, Weis JA, Simpson AL, Kingham TP, Jarnagin WR, Miga MI
(2017) Surgery 162: 537-547
MeSH Terms: Adult, Aged, Female, Follow-Up Studies, Hepatectomy, Humans, Imaging, Three-Dimensional, Liver, Liver Neoplasms, Male, Middle Aged, Monitoring, Intraoperative, Outcome Assessment (Health Care), Single-Blind Method, Statistics, Nonparametric, Surgery, Computer-Assisted, Treatment Outcome
Show Abstract · Added July 23, 2018
BACKGROUND - Although systems of 3-dimensional image-guided surgery are a valuable adjunct across numerous procedures, differences in organ shape between that reflected in the preoperative image data and the intraoperative state can compromise the fidelity of such guidance based on the image. In this work, we assessed in real time a novel, 3-dimensional image-guided operation platform that incorporates soft tissue deformation.
METHODS - A series of 125 alignment evaluations were performed across 20 patients. During the operation, the surgeon assessed the liver by swabbing an optically tracked stylus over the liver surface and viewing the image-guided operation display. Each patient had approximately 6 intraoperative comparative evaluations. For each assessment, 1 of only 2 types of alignments were considered: conventional rigid and novel deformable. The series of alignment types used was randomized and blinded to the surgeon. The surgeon provided a rating, R, from -3 to +3 for each display compared with the previous display, whereby a negative rating indicated degradation in fidelity and a positive rating an improvement.
RESULTS - A statistical analysis of the series of rating data by the clinician indicated that the surgeons were able to perceive an improvement (defined as a R > 1) of the model-based registration over the rigid registration (P = .01) as well as a degradation (defined as R < -1) when the rigid registration was compared with the novel deformable guidance information (P = .03).
CONCLUSION - This study provides evidence of the benefit of deformation correction in providing an accurate location for the liver for use in image-guided surgery systems.
Copyright © 2017 Elsevier Inc. All rights reserved.
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Non-Invasive Glutamine PET Reflects Pharmacological Inhibition of BRAF In Vivo.
Schulte ML, Hight MR, Ayers GD, Liu Q, Shyr Y, Washington MK, Manning HC
(2017) Mol Imaging Biol 19: 421-428
MeSH Terms: Amino Acid Transport System ASC, Animals, Cell Line, Tumor, Colonic Neoplasms, Female, Glutamine, Humans, Liver Neoplasms, Mice, Nude, Minor Histocompatibility Antigens, Mutation, Positron-Emission Tomography, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Xenograft Model Antitumor Assays
Show Abstract · Added April 6, 2017
PURPOSE - This study aimed to study whether cancer cells possess distinguishing metabolic features compared with surrounding normal cells, such as increased glutamine uptake. Given this, quantitative measures of glutamine uptake may reflect critical processes in oncology. Approximately, 10 % of patients with colorectal cancer (CRC) express BRAF , which may be actionable with selective BRAF inhibitors or in combination with inhibitors of complementary signaling axes. Non-invasive and quantitative predictive measures of response to these targeted therapies remain poorly developed in this setting. The primary objective of this study was to explore 4-[F]fluoroglutamine (4-[F]F-GLN) positron emission tomography (PET) to predict response to BRAF-targeted therapy in preclinical models of colon cancer.
PROCEDURES - Tumor microarrays from patients with primary human colon cancers (n = 115) and CRC liver metastases (n = 111) were used to evaluate the prevalence of ASCT2, the primary glutamine transporter in oncology, by immunohistochemistry. Subsequently, 4-[F]F-GLN PET was evaluated in mouse models of human BRAF -expressing and BRAF wild-type CRC.
RESULTS - Approximately 70 % of primary colon cancers and 53 % of metastases exhibited positive ASCT2 immunoreactivity, suggesting that [F]4-F-GLN PET could be applicable to a majority of patients with colon cancer. ASCT2 expression was not associated selectively with the expression of mutant BRAF. Decreased 4-[F]F-GLN predicted pharmacological response to single-agent BRAF and combination BRAF and PI3K/mTOR inhibition in BRAF -mutant Colo-205 tumors. In contrast, a similar decrease was not observed in BRAF wild-type HCT-116 tumors, a setting where BRAF-targeted therapies are ineffective.
CONCLUSIONS - 4-[F]F-GLN PET selectively reflected pharmacodynamic response to BRAF inhibition when compared with 2-deoxy-2[F]fluoro-D-glucose PET, which was decreased non-specifically for all treated cohorts, regardless of downstream pathway inhibition. These findings illustrate the utility of non-invasive PET imaging measures of glutamine uptake to selectively predict response to BRAF-targeted therapy in colon cancer and may suggest further opportunities to inform colon cancer clinical trials using targeted therapies against MAPK activation.
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15 MeSH Terms
Mesenteric Tumor Deposits in Midgut Small Intestinal Neuroendocrine Tumors Are a Stronger Indicator Than Lymph Node Metastasis for Liver Metastasis and Poor Prognosis.
Fata CR, Gonzalez RS, Liu E, Cates JM, Shi C
(2017) Am J Surg Pathol 41: 128-133
MeSH Terms: Adult, Aged, Aged, 80 and over, Disease-Free Survival, Female, Humans, Intestinal Neoplasms, Intestine, Small, Kaplan-Meier Estimate, Liver Neoplasms, Lymphatic Metastasis, Male, Mesentery, Middle Aged, Neuroendocrine Tumors, Prognosis, Proportional Hazards Models, Young Adult
Show Abstract · Added November 1, 2018
Mesenteric tumor deposits (MTDs) are not included in the American Joint Committee on Cancer (AJCC) staging system for midgut small intestinal neuroendocrine tumors (NETs). We examined the prognostic significance of MTDs associated with midgut NETs. Hematoxylin and eosin slides from 132 resected jejunal/ileal NETs were reviewed for AJCC tumor stage, lymph node (LN) metastasis, MTDs, and hepatic metastases. MTDs were defined as discrete irregular mesenteric tumor nodules discontinuous from the primary tumor. Clinical or pathologic evidence of metastases and survival data were abstracted from electronic medical records. The cohort included 72 male and 60 female patients with a median age of 60 years. LN metastasis, MTDs, and liver metastasis were present in 80%, 68%, and 58% of patients, respectively. Female sex and presence of MTDs were independent predictors of liver metastasis. The odds ratio for hepatic metastasis in the presence of MTDs was 16.68 (95% confidence interval [CI], 4.66-59.73) and 0.81 (95% CI, 0.20-3.26) for LN metastasis. Age, MTDs, and hepatic metastasis were associated with disease-specific survival (DSS) in univariate analysis. Primary tumor histologic grade, pT3/T4 stage, and LN metastasis were not associated with DSS. Multivariate analysis of liver metastasis-free survival stratified by tumor grade showed that MTDs were associated with adverse outcomes. The hazard ratio for MTDs was 4.58 (95% CI, 1.89-11.11), compared with 0.98 (95% CI, 0.47-2.05) for LN metastasis. MTDs, but not LN metastasis, in midgut NETs are a strong predictor for hepatic metastasis and are associated with poor DSS.
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Utility of [F]FSPG PET to Image Hepatocellular Carcinoma: First Clinical Evaluation in a US Population.
Kavanaugh G, Williams J, Morris AS, Nickels ML, Walker R, Koglin N, Stephens AW, Washington MK, Geevarghese SK, Liu Q, Ayers D, Shyr Y, Manning HC
(2016) Mol Imaging Biol 18: 924-934
MeSH Terms: Acetates, Adult, Aged, Amino Acid Transport System y+, Carbon Radioisotopes, Carcinoma, Hepatocellular, Female, Glutamates, Glutamic Acid, Humans, Liver Neoplasms, Male, Middle Aged, Positron-Emission Tomography, Radiopharmaceuticals, Sequence Analysis, RNA, Tissue Array Analysis
Show Abstract · Added April 6, 2017
PURPOSE - Non-invasive imaging is central to hepatocellular carcinoma (HCC) diagnosis; however, conventional modalities are limited by smaller tumors and other chronic diseases that are often present in patients with HCC, such as cirrhosis. This pilot study evaluated the feasibility of (4S)-4-(3-[F]fluoropropyl)-L-glutamic acid ([F]FSPG) positron emission tomography (PET)/X-ray computed tomography (CT) to image HCC. [F]FSPG PET/CT was compared to standard-of-care (SOC) magnetic resonance imaging (MRI) and CT, and [C]acetate PET/CT, commonly used in this setting. We report the largest cohort of HCC patients imaged to date with [F]FSPG PET/CT and present the first comparison to [C]acetate PET/CT and SOC imaging. This study represents the first in a US HCC population, which is distinguished by different underlying comorbidities than non-US populations.
PROCEDURES - x transporter RNA and protein levels were evaluated in HCC and matched liver samples from The Cancer Genome Atlas (n = 16) and a tissue microarray (n = 83). Eleven HCC patients who underwent prior MRI or CT scans were imaged by [F]FSPG PET/CT, with seven patients also imaged with [C]acetate PET/CT.
RESULTS - x transporter RNA and protein levels were elevated in HCC samples compared to background liver. Over 50 % of low-grade HCCs and ~70 % of high-grade tumors exceeded background liver protein expression. [F]FSPG PET/CT demonstrated a detection rate of 75 %. [F]FSPG PET/CT also identified an HCC devoid of typical MRI enhancement pattern. Patients scanned with [F]FSPG and [C]acetate PET/CT exhibited a 90 and 70 % detection rate, respectively. In dually positive tumors, [F]FSPG accumulation consistently resulted in significantly greater tumor-to-liver background ratios compared with [C]acetate PET/CT.
CONCLUSIONS - [F]FSPG PET/CT is a promising modality for HCC imaging, and larger studies are warranted to examine [F]FSPG PET/CT impact on diagnosis and management of HCC. [F]FSPG PET/CT may also be useful for phenotyping HCC tumor metabolism as part of precision cancer medicine.
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17 MeSH Terms
A nonrandomized cohort and a randomized study of local control of large hepatocarcinoma by targeting intratumoral lactic acidosis.
Chao M, Wu H, Jin K, Li B, Wu J, Zhang G, Yang G, Hu X
(2016) Elife 5:
MeSH Terms: Acidosis, Lactic, Adult, Aged, Aged, 80 and over, Bicarbonates, Carcinoma, Chemoembolization, Therapeutic, Combined Modality Therapy, Female, Humans, Liver Neoplasms, Male, Middle Aged, Survival Analysis, Treatment Outcome
Show Abstract · Added May 4, 2017
STUDY DESIGN - Previous works suggested that neutralizing intratumoral lactic acidosis combined with glucose deprivation may deliver an effective approach to control tumor. We did a pilot clinical investigation, including a nonrandomized (57 patients with large HCC) and a randomized controlled (20 patients with large HCC) studies.
METHODS - The patients were treated with transarterial chemoembolization (TACE) with or without bicarbonate local infusion into tumor.
RESULTS - In the nonrandomized controlled study, geometric mean of viable tumor residues (VTR) in TACE with bicarbonate was 6.4-fold lower than that in TACE without bicarbonate (7.1% [95% CI: 4.6%-10.9%] vs 45.6% [28.9%-72.0%]; p<0.0001). This difference was recapitulated by a subsequent randomized controlled study. TACE combined with bicarbonate yielded a 100% objective response rate (ORR), whereas the ORR treated with TACE alone was 44.4% (nonrandomized) and 63.6% (randomized). The survival data suggested that bicarbonate may bring survival benefit.
CONCLUSION - Bicarbonate markedly enhances the anticancer activity of TACE.Clinical trail registration: ChiCTR-IOR-14005319.
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The Attenuation Distribution Across the Long Axis (ADLA): Preliminary Findings for Assessing Response to Cancer Treatment.
Lakomkin N, Kang H, Landman B, Hutson MS, Abramson RG
(2016) Acad Radiol 23: 718-23
MeSH Terms: Colorectal Neoplasms, Contrast Media, Humans, Image Processing, Computer-Assisted, Kaplan-Meier Estimate, Liver Neoplasms, Portal Vein, Response Evaluation Criteria in Solid Tumors, Retrospective Studies, Tomography, X-Ray Computed, Treatment Outcome
Show Abstract · Added November 2, 2016
RATIONALE AND OBJECTIVES - Novel image analysis methods may be useful adjuncts to standard cancer treatment response assessment techniques. The attenuation distribution across the long axis (ADLA) is a simple measure of lesion heterogeneity that can be obtained while measuring the long axis diameter of a target lesion. The purpose of this study was to obtain preliminary validation of the ADLA method for predicting treatment response in a small clinical trial.
MATERIALS AND METHODS - Under an Institutional Review Board waiver, we obtained de-identified imaging and clinical data from a phase 2 trial of an investigational anticancer therapy at our institution. We retrospectively analyzed all patients with at least one liver metastasis measuring ≥15 mm on baseline contrast-enhanced computed tomography. For each patient at every imaging time point, up to two target liver lesions were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and ADLA measurements. The ADLA was obtained as the standard deviation of the post-contrast computed tomography attenuation values in the portal venous phase across a linear function spanning the long-axis diameter. Using Kaplan-Meier survival analysis, the log-rank test was used to evaluate the ability of RECIST 1.1 and ADLA measurements to discriminate patients with longer overall survival (OS).
RESULTS - Fifteen patients met inclusion criteria. Median survival was 149 days (range 57-487). Best overall response by the ADLA method successfully separated patients with longer OS (p = .04). Best overall response by RECIST 1.1 did not discriminate patients with longer survival (P > .05).
CONCLUSION - In retrospective data analysis from a phase 2 clinical trial, the ADLA method was more predictive of OS than RECIST 1.1. Further studies are needed to explore the utility of this measurement in predicting response to cancer treatment.
Copyright © 2016 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.
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11 MeSH Terms