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Enrichment and detection of bone disseminated tumor cells in models of low tumor burden.
Sowder ME, Johnson RW
(2018) Sci Rep 8: 14299
MeSH Terms: Animals, Antigens, CD, Bone Marrow, Bone and Bones, Estradiol, Humans, MCF-7 Cells, Mice, Inbred BALB C, Mice, Nude, Models, Biological, Neoplasms, Osteolysis, Time Factors, Tumor Burden
Show Abstract · Added March 26, 2019
Breast cancer cells frequently home to the bone, but the mechanisms controlling tumor colonization of the bone marrow remain unclear. We report significant enrichment of bone-disseminated estrogen receptor positive human MCF7 cells by 17 β-estradiol (E2) following intracardiac inoculation. Using flow cytometric and quantitative PCR approaches, tumor cells were detected in >80% of MCF7 tumor-inoculated mice, regardless of E2, suggesting that E2 is not required for MCF7 dissemination to the bone marrow. Furthermore, we propose two additional models in which to study prolonged latency periods by bone-disseminated tumor cells: murine D2.0R and human SUM159 breast carcinoma cells. Tumor cells were detected in bone marrow of up to 100% of D2.0R and SUM159-inoculated mice depending on the detection method. These findings establish novel models of bone colonization in which to study mechanisms underlying tumor cell seeding to the marrow and prolonged latency, and provide highly sensitive methods to detect these rare events.
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14 MeSH Terms
p52 expression enhances lung cancer progression.
Saxon JA, Yu H, Polosukhin VV, Stathopoulos GT, Gleaves LA, McLoed AG, Massion PP, Yull FE, Zhao Z, Blackwell TS
(2018) Sci Rep 8: 6078
MeSH Terms: Adenocarcinoma of Lung, Animals, Cell Proliferation, Disease Progression, Gene Expression, Gene Expression Regulation, Neoplastic, Humans, Lung, Lung Neoplasms, Mice, Transgenic, Middle Aged, NF-kappa B p52 Subunit, Prognosis, Tumor Burden
Show Abstract · Added May 29, 2018
While many studies have demonstrated that canonical NF-κB signaling is a central pathway in lung tumorigenesis, the role of non-canonical NF-κB signaling in lung cancer remains undefined. We observed frequent nuclear accumulation of the non-canonical NF-κB component p100/p52 in human lung adenocarcinoma. To investigate the impact of non-canonical NF-κB signaling on lung carcinogenesis, we employed transgenic mice with doxycycline-inducible expression of p52 in airway epithelial cells. p52 over-expression led to increased tumor number and progression after injection of the carcinogen urethane. Gene expression analysis of lungs from transgenic mice combined with in vitro studies suggested that p52 promotes proliferation of lung epithelial cells through regulation of cell cycle-associated genes. Using gene expression and patient information from The Cancer Genome Atlas (TCGA) database, we found that expression of p52-associated genes was increased in lung adenocarcinomas and correlated with reduced survival, even in early stage disease. Analysis of p52-associated gene expression in additional human lung adenocarcinoma datasets corroborated these findings. Together, these studies implicate the non-canonical NF-κB component p52 in lung carcinogenesis and suggest modulation of p52 activity and/or downstream mediators as new therapeutic targets.
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14 MeSH Terms
The AJCC 8th Edition Staging System for Soft Tissue Sarcoma of the Extremities or Trunk: A Cohort Study of the SEER Database.
Cates JMM
(2018) J Natl Compr Canc Netw 16: 144-152
MeSH Terms: Aged, Cohort Studies, Extremities, Female, Humans, Incidence, Kaplan-Meier Estimate, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Staging, Practice Guidelines as Topic, Prognosis, ROC Curve, SEER Program, Sarcoma, Tumor Burden
Show Abstract · Added November 1, 2018
The AJCC recently published the 8th edition of its cancer staging system. Significant changes were made to the staging algorithm for soft tissue sarcoma (STS) of the extremities or trunk, including the addition of 2 additional T (size) classifications in lieu of tumor depth and grouping lymph node metastasis (LNM) with distant metastasis as stage IV disease. Whether these changes improve staging system performance is questionable. This retrospective cohort analysis of 21,396 adult patients with STS of the extremity or trunk in the SEER database compares the AJCC 8th edition staging system with the 7th edition and a newly proposed staging algorithm using a variety of statistical techniques. The effect of tumor size on disease-specific survival was assessed by flexible, nonlinear Cox proportional hazard regression using restricted cubic splines and fractional polynomials. The slope of covariate-adjusted log hazards for sarcoma-specific survival decreases for tumors >8 cm in greatest dimension, limiting prognostic information contributed by the new T4 classification in the AJCC 8th edition. Anatomic depth independently provides significant prognostic information. LNM is not equivalent to distant, non-nodal metastasis. Based on these findings, an alternative staging system is proposed and demonstrated to outperform both AJCC staging schemes. The analyses presented also disclose no evidence of improved clinical performance of the 8th edition compared with the previous edition. The AJCC 8th edition staging system for STS is no better than the previous 7th edition. Instead, a proposed staging system based on histologic grade, tumor size, and anatomic depth shows significantly higher predictive accuracy, with higher model concordance than either AJCC staging system. Changes to existing staging systems should improve the performance of prognostic models. Until such improvements are documented, AJCC committees should refrain from modifying established staging schemes.
Copyright © 2018 by the National Comprehensive Cancer Network.
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17 MeSH Terms
Biophysical Modeling of In Vivo Glioma Response After Whole-Brain Radiation Therapy in a Murine Model of Brain Cancer.
Hormuth DA, Weis JA, Barnes SL, Miga MI, Quaranta V, Yankeelov TE
(2018) Int J Radiat Oncol Biol Phys 100: 1270-1279
MeSH Terms: Animals, Brain Neoplasms, Cell Death, Cell Proliferation, Contrast Media, Cranial Irradiation, Diffusion Magnetic Resonance Imaging, Disease Models, Animal, Female, Glioma, Magnetic Resonance Imaging, Models, Biological, Radiation Dosage, Rats, Rats, Wistar, Treatment Outcome, Tumor Burden
Show Abstract · Added July 23, 2018
PURPOSE - To develop and investigate a set of biophysical models based on a mechanically coupled reaction-diffusion model of the spatiotemporal evolution of tumor growth after radiation therapy.
METHODS AND MATERIALS - Post-radiation therapy response is modeled using a cell death model (M), a reduced proliferation rate model (M), and cell death and reduced proliferation model (M). To evaluate each model, rats (n = 12) with C6 gliomas were imaged with diffusion-weighted magnetic resonance imaging (MRI) and contrast-enhanced MRI at 7 time points over 2 weeks. Rats received either 20 or 40 Gy between the third and fourth imaging time point. Diffusion-weighted MRI was used to estimate tumor cell number within enhancing regions in contrast-enhanced MRI data. Each model was fit to the spatiotemporal evolution of tumor cell number from time point 1 to time point 5 to estimate model parameters. The estimated model parameters were then used to predict tumor growth at the final 2 imaging time points. The model prediction was evaluated by calculating the error in tumor volume estimates, average surface distance, and voxel-based cell number.
RESULTS - For both the rats treated with either 20 or 40 Gy, significantly lower error in tumor volume, average surface distance, and voxel-based cell number was observed for the M and M models compared with the M model. The M model fit, however, had significantly lower sum squared error compared with the M and M models.
CONCLUSIONS - The results of this study indicate that for both doses, the M and M models result in accurate predictions of tumor growth, whereas the M model poorly describes response to radiation therapy.
Copyright © 2017 Elsevier Inc. All rights reserved.
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17 MeSH Terms
Admixture mapping of uterine fibroid size and number in African American women.
Bray MJ, Edwards TL, Wellons MF, Jones SH, Hartmann KE, Velez Edwards DR
(2017) Fertil Steril 108: 1034-1042.e26
MeSH Terms: Adult, African Americans, Biological Specimen Banks, Biomarkers, Tumor, Cross-Sectional Studies, Databases, Factual, Electronic Health Records, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Heredity, Humans, Leiomyoma, Leiomyomatosis, Linear Models, Logistic Models, Middle Aged, Odds Ratio, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Tumor Burden, United States, Uterine Neoplasms
Show Abstract · Added February 21, 2019
OBJECTIVE - To evaluate the relationship between genetic ancestry and uterine fibroid characteristics.
DESIGN - Cross-sectional study.
SETTING - Not applicable.
PATIENT(S) - A total of 609 African American participants with image- or surgery-confirmed fibroids in a biorepository at Vanderbilt University electronic health record biorepository and the Coronary Artery Risk Development in Young Adults studies were included.
INTERVENTION(S) - None.
MAIN OUTCOME MEASURE(S) - Outcome measures include fibroid number (single vs. multiple), volume of largest fibroid, and largest fibroid dimension of all fibroid measurements.
RESULT(S) - Global ancestry meta-analyses revealed a significant inverse association between percentage of European ancestry and risk of multiple fibroids (odds ratio: 0.78; 95% confidence interval 0.66, 0.93; P=6.05 × 10). Local ancestry meta-analyses revealed five suggestive (P<4.80 × 10) admixture mapping peaks in 2q14.3-2q21.1, 3p14.2-3p14.1, 7q32.2-7q33, 10q21.1, 14q24.2-14q24.3, for number of fibroids and one suggestive admixture mapping peak (P<1.97 × 10) in 10q24.1-10q24.32 for volume of largest fibroid. Single variant association meta-analyses of the strongest associated region from admixture mapping of fibroid number (10q21.1) revealed a strong association at single nucleotide polymorphism variant rs12219990 (odds ratio: 0.41; 95% confidence interval 0.28, 0.60; P=3.82 × 10) that was significant after correction for multiple testing.
CONCLUSION(S) - Increasing African ancestry is associated with multiple fibroids but not with fibroid size. Local ancestry analyses identified several novel genomic regions not previously associated with fibroid number and increasing volume. Future studies are needed to explore the genetic impact that ancestry plays into the development of fibroid characteristics.
Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
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Modeling Continuous Prognostic Factors in Survival Analysis: Implications for Tumor Staging and Assessing Chemotherapy Effect in Osteosarcoma.
Cates JMM
(2018) Am J Surg Pathol 42: 485-491
MeSH Terms: Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Bone Neoplasms, Chemotherapy, Adjuvant, Child, Databases, Factual, Decision Support Techniques, Female, Humans, Male, Middle Aged, Models, Statistical, Necrosis, Neoadjuvant Therapy, Neoplasm Staging, Orthopedic Procedures, Osteosarcoma, Predictive Value of Tests, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, Tumor Burden, United States, Young Adult
Show Abstract · Added November 1, 2018
Extent of response to neoadjuvant chemotherapy, tumor size, and patient age are important prognostic variables for patients with osteosarcoma, but applying information from these continuous variables in survival models is difficult. Dichotomization is usually inappropriate and alternative statistical techniques should be considered instead. Nonlinear multivariable regression methods (restricted cubic splines and fractional polynomials) were applied to data from the National Cancer Database to model continuous prognostic factors for overall survival from localized, high-grade osteosarcoma of the appendicular and nonspinal skeleton following neoadjuvant chemotherapy and surgical resection (N=2493). The assumption that log hazard ratios were linear in relation to these continuous prognostic factors was tested using likelihood ratio tests of model deviance and Wald tests of spline coefficients. Log hazard ratios for increasing patient age were linear over the range of 4 to 80 years, but showed evidence for variation in the coefficient over elapsed follow-up time. Tumor size also showed a linear relationship with log hazard over the range of 1 to 30 cm. Hazard ratios for chemotherapy effect profoundly deviated from log-linear (P<0.004), with significantly decreased hazard for death from baseline for patients with ≥90% tumor necrosis (hazard ratio, 0.32; 95% confidence interval, 0.20-0.52; P<0.0001). Important implications of these results include: (1) ≥90% tumor necrosis defines good chemotherapy response in a clinically useful manner; (2) staging osteosarcoma by dichotomizing tumor size is inappropriate; and (3) patient age can be modeled as a linear effect on the log hazard ratio in prognostic models with the caveat that risk may change over duration of the analysis.
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28 MeSH Terms
Genetic variation in SLC7A2 interacts with calcium and magnesium intakes in modulating the risk of colorectal polyps.
Sun P, Zhu X, Shrubsole MJ, Ness RM, Hibler EA, Cai Q, Long J, Chen Z, Li G, Hou L, Smalley WE, Edwards TL, Giovannucci E, Zheng W, Dai Q
(2017) J Nutr Biochem 47: 35-40
MeSH Terms: Adenoma, Amino Acid Transport Systems, Basic, Calcium, Dietary, Case-Control Studies, Colonic Polyps, Colonoscopy, Colorectal Neoplasms, Diet, Healthy, Dietary Supplements, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Magnesium, Male, Middle Aged, Neoplasm Grading, Patient Compliance, Polymorphism, Single Nucleotide, Self Report, Tennessee, Tumor Burden
Show Abstract · Added April 3, 2018
Solute carrier family 7, member 2 (SLC7A2) gene encodes a protein called cationic amino acid transporter 2, which mediates the transport of arginine, lysine and ornithine. l-Arginine is necessary for cancer development and progression, including an important role in colorectal cancer pathogenesis. Furthermore, previous studies found that both calcium and magnesium inhibit the transport of arginine. Thus, calcium, magnesium or calcium:magnesium intake ratio may interact with polymorphisms in the SLC7A2 gene in association with colorectal cancer. We conducted a two-phase case-control study within the Tennessee Colorectal Polyps Study. In the first phase, 23 tagging single-nucleotide polymorphisms in the SLC7A2 gene were included for 725 colorectal adenoma cases and 755 controls. In the second phase conducted in an independent set of 607 cases and 2113 controls, we replicated the significant findings in the first phase. We observed that rs2720574 significantly interacted with calcium:magnesium intake ratio in association with odds of adenoma, particularly multiple/advanced adenoma. In the combined analysis, among those with a calcium:magnesium intake ratio below 2.78, individuals who carried GC/CC genotypes demonstrated higher odds of adenoma [OR (95% CI):1.36 (1.11-1.68)] and multiple/advanced adenoma [OR (95% CI): 1.68 (1.28, 2.20)] than those who carried the GG genotype. The P values for interactions between calcium:magnesium intake ratio and rs2720574 were .002 for all adenomas and <.001 for multiple/advanced adenoma. Among those with the GG genotype, a high calcium:magnesium ratio was associated with increased odds of colorectal adenoma [OR (95% CI): 1.73 (1.27-2.36)] and advanced/multiple adenomas [1.62 (1.05-2.50)], whereas among those with the GC/CC genotypes, high calcium:magnesium ratio was related to reduced odds of colorectal adenoma [0.64 (0.42-0.99)] and advanced/multiple adenomas [0.55 (0.31-1.00)].
Copyright © 2017 Elsevier Inc. All rights reserved.
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Associations between Tumor Vascularity, Vascular Endothelial Growth Factor Expression and PET/MRI Radiomic Signatures in Primary Clear-Cell-Renal-Cell-Carcinoma: Proof-of-Concept Study.
Yin Q, Hung SC, Wang L, Lin W, Fielding JR, Rathmell WK, Khandani AH, Woods ME, Milowsky MI, Brooks SA, Wallen EM, Shen D
(2017) Sci Rep 7: 43356
MeSH Terms: Adult, Aged, Carcinoma, Renal Cell, Female, Gene Expression, Humans, Image Interpretation, Computer-Assisted, Kidney Neoplasms, Magnetic Resonance Imaging, Male, Middle Aged, Neovascularization, Pathologic, Positron-Emission Tomography, Proof of Concept Study, Retrospective Studies, Tumor Burden, Vascular Endothelial Growth Factor A
Show Abstract · Added October 30, 2019
Studies have shown that tumor angiogenesis is an essential process for tumor growth, proliferation and metastasis. Also, tumor angiogenesis is an important prognostic factor of clear cell renal cell carcinoma (ccRCC), as well as a factor in guiding treatment with antiangiogenic agents. Here, we attempted to find the associations between tumor angiogenesis and radiomic imaging features from PET/MRI. Specifically, sparse canonical correlation analysis was conducted on 3 feature datasets (i.e., radiomic imaging features, tumor microvascular density (MVD), and vascular endothelial growth factor (VEGF) expression) from 9 patients with primary ccRCC. In order to overcome the potential bias of intratumoral heterogeneity of angiogenesis, this study investigated the relationship between regional expressions of angiogenesis and VEGF, and localized radiomic features from different parts within the tumors. Our study highlighted the significant strong correlations between radiomic features and MVD, and also demonstrated that the spatiotemporal features extracted from DCE-MRI provided stronger radiomic correlation to MVD than the textural features extracted from Dixon sequences and FDG PET. Furthermore, PET/MRI, which takes advantage of the combined functional and structural information, had higher radiomics correlation to MVD than solely utilizing PET or MRI alone.
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Preoperative Chemotherapy and Survival for Large Anorectal Gastrointestinal Stromal Tumors: A National Analysis of 333 Cases.
Hawkins AT, Wells KO, Krishnamurty DM, Hunt SR, Mutch MG, Glasgow SC, Wise PE, Silviera ML
(2017) Ann Surg Oncol 24: 1195-1201
MeSH Terms: Adult, Age Factors, Aged, Aged, 80 and over, Antineoplastic Agents, Anus Neoplasms, Chemotherapy, Adjuvant, Female, Gastrointestinal Stromal Tumors, Humans, Imatinib Mesylate, Male, Middle Aged, Neoadjuvant Therapy, Rectal Neoplasms, Survival Rate, Tumor Burden, United States, Young Adult
Show Abstract · Added March 21, 2017
PURPOSE - Anorectal gastrointestinal stromal tumors (GISTs) are exceedingly rare, and management remains controversial in regard to local resection (LR) and preoperative chemotherapy.
METHODS - The National Cancer Data Base was queried from 1998 to 2012 for cases of GIST resection in the rectum or anus. Patient demographics, type of surgery (LR vs. radical excision [RE]), short-term outcomes, and overall survival (OS) were analyzed. Preoperative chemotherapy was recorded following the US FDA approval of imatinib in 2002.
RESULTS - Overall, 333 patients with resection of anorectal GISTs were included. Mean age at presentation was 62.3 years (range 22-90), and median tumor size was 4.0 cm (interquartile range 2.2-7.0). Five-year OS for all patients was 77.6%. In a multivariable survival analysis, only age and tumor size >5 cm (hazard ratio 2.48, 95% confidence interval 1.50-4.01; p = 0.004) were associated with increased mortality. One hundred and sixty-three (49.0%) patients underwent LR, compared with 158 (47.4%) who underwent RE. For tumors smaller than 5 cm, no difference in 5-year survival by surgical approach was observed (LR 82.3% vs. RE 82.6%; p = 0.71). Fifty-nine patients (17.7%) received preoperative chemotherapy; for patients undergoing RE with tumors >5 cm, there was decreased mortality in the group who received preoperative chemotherapy (5-year OS with chemotherapy 79.2% vs. no chemotherapy 51.2%; p = 0.03).
CONCLUSIONS - Size is the most important determinant in survival following resection. Local excision is common, with resection split between LR and RE. For smaller tumors, LR may be adequate therapy. Preoperative chemotherapy may result in improved survival for large tumors treated with radical resection, but the data are imperfect.
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Development of a RSK Inhibitor as a Novel Therapy for Triple-Negative Breast Cancer.
Ludwik KA, Campbell JP, Li M, Li Y, Sandusky ZM, Pasic L, Sowder ME, Brenin DR, Pietenpol JA, O'Doherty GA, Lannigan DA
(2016) Mol Cancer Ther 15: 2598-2608
MeSH Terms: Animals, Antineoplastic Agents, Benzopyrans, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cell Survival, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Activation, Female, Gene Silencing, Humans, Mice, Monosaccharides, Neoplasm Metastasis, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Ribosomal Protein S6 Kinases, 90-kDa, Triple Negative Breast Neoplasms, Tumor Burden, Xenograft Model Antitumor Assays
Show Abstract · Added September 14, 2016
Metastatic breast cancer is an incurable disease and identification of novel therapeutic opportunities is vital. Triple-negative breast cancer (TNBC) frequently metastasizes and high levels of activated p90RSK (RSK), a downstream MEK-ERK1/2 effector, are found in TNBC. We demonstrate, using direct pharmacologic and genetic inhibition of RSK1/2, that these kinases contribute to the TNBC metastatic process in vivo Kinase profiling showed that RSK1 and RSK2 are the predominant kinases targeted by the new inhibitor, which is based on the natural product SL0101. Further evidence for selectivity was provided by the observations that silencing RSK1 and RSK2 eliminated the ability of the analogue to further inhibit survival or proliferation of a TNBC cell line. In vivo, the new derivative was as effective as the FDA-approved MEK inhibitor trametinib in reducing the establishment of metastatic foci. Importantly, inhibition of RSK1/2 did not result in activation of AKT, which is known to limit the efficacy of MEK inhibitors in the clinic. Our results demonstrate that RSK is a major contributor to the TNBC metastatic program and provide preclinical proof-of-concept for the efficacy of the novel SL0101 analogue in vivo Mol Cancer Ther; 15(11); 2598-608. ©2016 AACR.
©2016 American Association for Cancer Research.
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